Science.gov

Sample records for activate multiple signaling

  1. Imaging the coordination of multiple signaling activities in living cells

    PubMed Central

    Welch, Christopher M.; Elliott, Hunter; Danuser, Gaudenz; Hahn, Klaus M.

    2013-01-01

    Preface Cellular signal transduction occurs in complex and redundant interaction networks that are best examined at the level of single cells by simultaneously monitoring the activation dynamics of multiple components. Recent advances in biosensor technology have made it possible to visualize and quantify the activation of multiple network nodes in the same living cell. The precision and scope of this approach has been greatly extended by novel computational approaches to determine the relationships between different networks, studied in separate cells. PMID:22016058

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

    SciTech Connect

    Chung, Byung-Hee; Lee, Jung Joon; Kim, Jong-Dai; Jeoung, Dooil; Lee, Hansoo; Choe, Jongseon; Ha, Kwon-Soo; Kwon, Young-Geun; Kim, Young-Myeong

    2010-01-01

    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-, p125{sup FAK}-, and p38 MAPK-dependent pathways, without increasing vascular inflammation, and may be used for treating ischemic diseases and tissue regeneration.

  3. Multiple signals modulate the activity of the complex sensor kinase TodS

    PubMed Central

    Silva-Jiménez, Hortencia; Ortega, Álvaro; García-Fontana, Cristina; Ramos, Juan Luis; Krell, Tino

    2015-01-01

    The reason for the existence of complex sensor kinases is little understood but thought to lie in the capacity to respond to multiple signals. The complex, seven-domain sensor kinase TodS controls in concert with the TodT response regulator the expression of the toluene dioxygenase pathway in Pseudomonas putida F1 and DOT-T1E. We have previously shown that some aromatic hydrocarbons stimulate TodS activity whereas others behave as antagonists. We show here that TodS responds in addition to the oxidative agent menadione. Menadione but no other oxidative agent tested inhibited TodS activity in vitro and reduced PtodX expression in vivo. The menadione signal is incorporated by a cysteine-dependent mechanism. The mutation of the sole conserved cysteine of TodS (C320) rendered the protein insensitive to menadione. We evaluated the mutual opposing effects of toluene and menadione on TodS autophosphorylation. In the presence of toluene, menadione reduced TodS activity whereas toluene did not stimulate activity in the presence of menadione. It was shown by others that menadione increases expression of glucose metabolism genes. The opposing effects of menadione on glucose and toluene metabolism may be partially responsible for the interwoven regulation of both catabolic pathways. This work provides mechanistic detail on how complex sensor kinases integrate different types of signal molecules. PMID:24986263

  4. Activation of multiple signaling modules is critical in angiotensin IV-induced lung endothelial cell proliferation.

    PubMed

    Li, Yong D; Block, Edward R; Patel, Jawaharlal M

    2002-10-01

    Signaling events involving angiotensin IV (ANG IV)-mediated pulmonary artery endothelial cell (PAEC) proliferation were examined. ANG IV significantly increased upstream phosphatidylinositide (PI) 3-kinase (PI3K), PI-dependent kinase-1 (PDK-1), extracellular signal-related kinases (ERK1/2), and protein kinase B-alpha/Akt (PKB-alpha) activities, as well as downstream p70 ribosomal S6 kinase (p70S6K) activities and/or phosphorylation of these proteins. ANG IV also significantly increased 5-bromo-2'-deoxy-uridine incorporation into newly synthesized DNA in a concentration- and time-dependent manner. Pretreatment of cells with wortmannin and LY-294002, inhibitors of PI3K, or rapamycin, an inhibitor of the mammalian target of rapamycin kinase and p70S6K, diminished the ANG IV-mediated activation of PDK-1 and PKB-alpha as well as phosphorylation of p70S6K. Although an inhibitor of mitogen-activated protein kinase kinase, PD-98059, but not rapamycin, blocked ANG IV-induced phosphorylation of ERK1/2, both PD-98059 and rapamycin independently caused partial reduction in ANG IV-mediated cell proliferation. However, simultaneous treatment with PD-98059 and rapamycin resulted in total inhibition of ANG IV-induced cell proliferation. These results demonstrate that ANG IV-induced DNA synthesis is regulated in a coordinated fashion involving multiple signaling modules in PAEC. PMID:12225947

  5. Multiple signal amplification electrogenerated chemiluminescence biosensors for sensitive protein kinase activity analysis and inhibition.

    PubMed

    Wang, Zonghua; Yan, Zhiyong; Sun, Na; Liu, Yang

    2015-06-15

    A novel electrogenerated chemiluminescence (ECL) biosensor was built for the detection of kinase activity based on multiple signal amplification nanoprobes. In this strategy, the Xanthine oxidase (XOD) and 5'-phosphate group end DNA conjugated AuNPs was integrated with the phosphorylated peptide by Zr(4+). The XOD on gold nanoparticles can catalyze dissolved oxygen to produce H2O2 in the presence of hypoxanthine (HA) which acts as a coreactor for luminol ECL reaction. In addition, due to the excellent catalytic activity of gold nanoparticle toward luminol ECL reaction and its large surface area that can accommodate large number of XOD and DNA on the surface, the ECL signal of luminol was significantly amplified, affording a highly sensitive ECL analysis of kinase activity. The as-proposed biosensor presents a low detection limit of 0.09 U mL(-1) for protein kinase A (PKA) activity, wide linear range (from 0.1 to 10 U mL(-1)) and excellent stability even in serum samples. This biosensor can also be applied for quantitative kinase inhibitor evaluation. The robust ECL biosensor provides a valuable tool for the high throughput assay in the applications of clinic diagnostic and therapeutic. PMID:25682506

  6. Pituitary Adenylate Cyclase-activating Polypeptide (PACAP)/PAC1HOP1 Receptor Activation Coordinates Multiple Neurotrophic Signaling Pathways

    PubMed Central

    May, Victor; Lutz, Eve; MacKenzie, Christopher; Schutz, Kristin C.; Dozark, Kate; Braas, Karen M.

    2010-01-01

    MAPK and Akt pathways are predominant mediators of trophic signaling for many neuronal systems. Among the vasoactive intestinal peptide/secretin/glucagon family of related peptides, pituitary adenylate cyclase-activating polypeptide (PACAP) binding to specific PAC1 receptor isoforms can engage multiple signaling pathways and promote neuroprotection through mechanisms that are not well understood. Using a primary sympathetic neuronal system, the current studies demonstrate that PACAP activation of PAC1HOP1 receptors engages both MAPK and Akt neurotrophic pathways in an integrated program to facilitate neuronal survival after growth factor withdrawal. PACAP not only stimulated prosurvival ERK1/2 and ERK5 activation but also abrogated SAPK/JNK and p38 MAPK signaling in parallel. In contrast to the potent and rapid effects of PACAP in ERK1/2 phosphorylation, PACAP stimulated Akt phosphorylation in a late phase of PAC1HOP1 receptor signaling. From inhibitor and immunoprecipitation analyses, the PACAP/PAC1HOP1 receptor-mediated Akt responses did not represent transactivation mechanisms but appeared to depend on Gαq/phosphatidylinositol 3-kinase γ activity and vesicular internalization pathways. Phosphatidylinositol 3-kinase γ-selective inhibitors blocked PACAP-stimulated Akt phosphorylation in primary neuronal cultures and in PAC1HOP1-overexpressing cell lines; RNA interference-mediated knockdown of the receptor effectors attenuated PACAP-mediated Akt activation. Similarly, perturbation of endocytic pathways also blocked Akt phosphorylation. Between ERK and Akt pathways, PACAP-stimulated Akt signaling was the primary cascade that attenuated cultured neuron apoptosis after growth factor withdrawal. The partitioning of PACAP-mediated Akt signaling in endosomes may be a key mechanism contributing to the high spatial and temporal specificity in signal transduction necessary for survival pathways. PMID:20093365

  7. Adenomatous polyposis coli (APC) regulates multiple signaling pathways by enhancing glycogen synthase kinase-3 (GSK-3) activity.

    PubMed

    Valvezan, Alexander J; Zhang, Fang; Diehl, J Alan; Klein, Peter S

    2012-02-01

    Glycogen synthase kinase-3 (GSK-3) is essential for many signaling pathways and cellular processes. As Adenomatous Polyposis Coli (APC) functions in many of the same processes, we investigated a role for APC in the regulation of GSK-3-dependent signaling. We find that APC directly enhances GSK-3 activity. Furthermore, knockdown of APC mimics inhibition of GSK-3 by reducing phosphorylation of glycogen synthase and by activating mTOR, revealing novel roles for APC in the regulation of these enzymes. Wnt signaling inhibits GSK-3 through an unknown mechanism, and this results in both stabilization of β-catenin and activation of mTOR. We therefore hypothesized that Wnts may regulate GSK-3 by disrupting the interaction between APC and the Axin-GSK-3 complex. We find that Wnts rapidly induce APC dissociation from Axin, correlating with β-catenin stabilization. Furthermore, Axin interaction with the Wnt co-receptor LRP6 causes APC dissociation from Axin. We propose that APC regulates multiple signaling pathways by enhancing GSK-3 activity, and that Wnts induce APC dissociation from Axin to reduce GSK-3 activity and activate downstream signaling. APC regulation of GSK-3 also provides a novel mechanism for Wnt regulation of multiple downstream effectors, including β-catenin and mTOR. PMID:22184111

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

    PubMed

    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

  9. Inhibition of host extracellular signal-regulated kinase (ERK) activation decreases new world alphavirus multiplication in infected cells

    SciTech Connect

    Voss, Kelsey; Amaya, Moushimi; Mueller, Claudius; Roberts, Brian; Kehn-Hall, Kylene; Bailey, Charles; Petricoin, Emanuel; Narayanan, Aarthi

    2014-11-15

    New World alphaviruses belonging to the family Togaviridae are classified as emerging infectious agents and Category B select agents. Our study is focused on the role of the host extracellular signal-regulated kinase (ERK) in the infectious process of New World alphaviruses. Infection of human cells by Venezuelan equine encephalitis virus (VEEV) results in the activation of the ERK-signaling cascade. Inhibition of ERK1/2 by the small molecule inhibitor Ag-126 results in inhibition of viral multiplication. Ag-126-mediated inhibition of VEEV was due to potential effects on early and late stages of the infectious process. While expression of viral proteins was down-regulated in Ag-126 treated cells, we did not observe any influence of Ag-126 on the nuclear distribution of capsid. Finally, Ag-126 exerted a broad-spectrum inhibitory effect on New World alphavirus multiplication, thus indicating that the host kinase, ERK, is a broad-spectrum candidate for development of novel therapeutics against New World alphaviruses. - Highlights: • VEEV infection activated multiple components of the ERK signaling cascade. • Inhibition of ERK activation using Ag-126 inhibited VEEV multiplication. • Activation of ERK by Ceramide C6 increased infectious titers of TC-83. • Ag-126 inhibited virulent strains of all New World alphaviruses. • Ag-126 treatment increased percent survival of infected cells.

  10. Cadmium Activates Multiple Signaling Pathways That Coordinately Stimulate Akt Activity to Enhance c-Myc mRNA Stability

    PubMed Central

    Tsai, Jia-Shiuan; Chao, Cheng-Han; Lin, Lih-Yuan

    2016-01-01

    Cadmium is a known environmental carcinogen. Exposure of Cd leads to the activation of several proto-oncogenes in cells. We investigated here the mechanism of c-Myc expression in hepatic cells under Cd treatment. The c-Myc protein and mRNA levels increased in dose- and time-dependent manners in HepG2 cells with Cd treatment. This increase was due to an increase in c-Myc mRNA stability. To explore the mechanism involved in enhancing the mRNA stability, several cellular signaling factors that evoked by Cd treatment were analyzed. PI3K, p38, ERK and JNK were activated by Cd. However, ERK did not participate in the Cd-induced c-Myc expression. Further analysis revealed that mTORC2 was a downstream factor of p38. PI3K, JNK and mTORC2 coordinately activated Akt. Akt was phosphorylated at Thr450 in the untreated cells. Cd treatment led to additional phosphorylation at Thr308 and Ser473. Blocking any of the three signaling factors resulted in the reduction of phosphorylation level at all three Akt sites. The activated Akt phosphorylated Foxo1 and allowed the modified protein to translocate into the cytoplasm. We conclude that Cd-induced accumulation of c-Myc requires the activation of several signaling pathways. The signals act coordinately for Akt activation and drive the Foxo1 from the nucleus to the cytoplasm. Reduction of Foxo1 in the nucleus reduces the transcription of its target genes that may affect c-Myc mRNA stability, resulting in a higher accumulation of the c-Myc proteins. PMID:26751215

  11. Inhibition of host extracellular signal-regulated kinase (ERK) activation decreases new world alphavirus multiplication in infected cells.

    PubMed

    Voss, Kelsey; Amaya, Moushimi; Mueller, Claudius; Roberts, Brian; Kehn-Hall, Kylene; Bailey, Charles; Petricoin, Emanuel; Narayanan, Aarthi

    2014-11-01

    New World alphaviruses belonging to the family Togaviridae are classified as emerging infectious agents and Category B select agents. Our study is focused on the role of the host extracellular signal-regulated kinase (ERK) in the infectious process of New World alphaviruses. Infection of human cells by Venezuelan equine encephalitis virus (VEEV) results in the activation of the ERK-signaling cascade. Inhibition of ERK1/2 by the small molecule inhibitor Ag-126 results in inhibition of viral multiplication. Ag-126-mediated inhibition of VEEV was due to potential effects on early and late stages of the infectious process. While expression of viral proteins was down-regulated in Ag-126 treated cells, we did not observe any influence of Ag-126 on the nuclear distribution of capsid. Finally, Ag-126 exerted a broad-spectrum inhibitory effect on New World alphavirus multiplication, thus indicating that the host kinase, ERK, is a broad-spectrum candidate for development of novel therapeutics against New World alphaviruses. PMID:25261871

  12. Concurrent activation of multiple vasoactive signaling pathways in vasoconstriction caused by tubuloglomerular feedback: a quantitative assessment.

    PubMed

    Schnermann, Jurgen

    2015-01-01

    Tubuloglomerular feedback (TGF) describes the negative relationship between (a) NaCl concentration at the macula densa and (b) glomerular filtration rate or glomerular capillary pressure. TGF-induced vasoconstriction of the afferent arteriole results from the enhanced effect of several vasoconstrictors with an effect size sequence of adenosine = 20-HETE > angiotensin II > thromboxane = superoxide > renal nerves > ATP. TGF-mediated vasoconstriction is limited by the simultaneous release of several vasodilators with an effect size sequence of nitric oxide > carbon monoxide = kinins > adenosine. The sum of the constrictor effects exceeds that of the dilator effects by the magnitude of the TGF response. The validity of the additive model used in this analysis can be tested by determining the effect of combined inhibition of some or all agents contributing to TGF. Multiple independent contributors to TGF are consistent with the variability of TGF and of the factors contributing to TGF resetting. PMID:25668021

  13. Organized emergence of multiple-generations of teeth in snakes is dysregulated by activation of Wnt/beta-catenin signalling.

    PubMed

    Gaete, Marcia; Tucker, Abigail S

    2013-01-01

    In contrast to mammals, most reptiles constantly regenerate their teeth. In the snake, the epithelial dental lamina ends in a successional lamina, which proliferates and elongates forming multiple tooth generations, all linked by a permanent dental lamina. To investigate the mechanisms used to control the initiation of new tooth germs in an ordered sequential pattern we utilized the polyphodont (multiple-generation) corn snake (Pantherophis guttatus). We observed that the dental lamina expressed the transcription factor Sox2, a multipotent stem cell marker, whereas the successional lamina cells expressed the transcription factor Lef1, a Wnt/β-catenin pathway target gene. Activation of the Wnt/β-catenin pathway in culture increased the number of developing tooth germs, in comparison to control untreated cultures. These additional tooth germs budded off from ectopic positions along the dental lamina, rather than in an ordered sequence from the successional lamina. Wnt/β-catenin activation enhanced cell proliferation, particularly in normally non-odontogenic regions of the dental lamina, which widely expressed Lef1, restricting the Sox2 domain. This suggests an expansion of the successional lamina at the expense of the dental lamina. Activation of the Wnt/β-catenin pathway in cultured snake dental organs, therefore, led to changes in proliferation and to the molecular pattern of the dental lamina, resulting in loss of the organised emergence of tooth germs. These results suggest that epithelial compartments are critical for the arrangement of organs that develop in sequence, and highlight the role of Wnt/β-catenin signalling in such processes. PMID:24019968

  14. Organized Emergence of Multiple-Generations of Teeth in Snakes Is Dysregulated by Activation of Wnt/Beta-Catenin Signalling

    PubMed Central

    Gaete, Marcia; Tucker, Abigail S.

    2013-01-01

    In contrast to mammals, most reptiles constantly regenerate their teeth. In the snake, the epithelial dental lamina ends in a successional lamina, which proliferates and elongates forming multiple tooth generations, all linked by a permanent dental lamina. To investigate the mechanisms used to control the initiation of new tooth germs in an ordered sequential pattern we utilized the polyphodont (multiple-generation) corn snake (Pantherophis guttatus). We observed that the dental lamina expressed the transcription factor Sox2, a multipotent stem cell marker, whereas the successional lamina cells expressed the transcription factor Lef1, a Wnt/β-catenin pathway target gene. Activation of the Wnt/β-catenin pathway in culture increased the number of developing tooth germs, in comparison to control untreated cultures. These additional tooth germs budded off from ectopic positions along the dental lamina, rather than in an ordered sequence from the successional lamina. Wnt/β-catenin activation enhanced cell proliferation, particularly in normally non-odontogenic regions of the dental lamina, which widely expressed Lef1, restricting the Sox2 domain. This suggests an expansion of the successional lamina at the expense of the dental lamina. Activation of the Wnt/β-catenin pathway in cultured snake dental organs, therefore, led to changes in proliferation and to the molecular pattern of the dental lamina, resulting in loss of the organised emergence of tooth germs. These results suggest that epithelial compartments are critical for the arrangement of organs that develop in sequence, and highlight the role of Wnt/β-catenin signalling in such processes. PMID:24019968

  15. Epigenetic identification of ZNF545 as a functional tumor suppressor in multiple myeloma via activation of p53 signaling pathway.

    PubMed

    Fan, Yu; Zhan, Qian; Xu, Hongying; Li, Lili; Li, Chen; Xiao, Qian; Xiang, Shili; Hui, Tianli; Xiang, Tingxiu; Ren, Guosheng

    2016-06-10

    The KRAB-zinc-finger protein ZNF545 was recently identified as a potential suppressor gene in several tumors. However, the regulatory mechanisms of ZNF545 in tumorigenesis remain unclear. In this study, we investigated the expression and roles of ZNF545 in multiple myeloma (MM). ZNF545 was frequently downregulated in MM tissues compared with non-tumor bone marrow tissues. ZNF545 expression was silenced by promoter methylation in MM cell lines, and could be restored by demethylation treatment. ZNF545 methylation was detected in 28.3% of MM tissues, compared with 4.3% of normal bone marrow tissues. ZNF545 transcriptionally activated the p53 signaling pathway but had no effect on Akt in MM, whereas ectopic expression of ZNF545 in silenced cells suppressed their proliferation and induced apoptosis. We therefore identified ZNF545 as a novel tumor suppressor inhibiting tumor growth through activation of the p53 pathway in MM. Moreover, tumor-specific methylation of ZNF545 may represent an epigenetic biomarker for MM diagnosis, and a potential target for specific therapy. PMID:27150632

  16. PSMB4 promotes multiple myeloma cell growth by activating NF-κB-miR-21 signaling

    SciTech Connect

    Zheng, Peihao; Guo, Honggang; Li, Guangchao; Han, Siqi; Luo, Fei; Liu, Yi

    2015-03-06

    Proteasomal subunit PSMB4, was recently identified as potential cancer driver genes in several tumors. However, the regulatory mechanism of PSMB4 on carcinogenesis process remains unclear. In this study, we investigated the expression and roles of PSMB4 in multiple myeloma (MM). We found a significant up-regulation of PSMB4 in MM plasma and cell lines. Ectopic overexpression of PSMB4 promoted cell growth and colony forming ability of MM cells, whereas inhibition of PSMB4 led to a decrease of such events. Furthermore, our results demonstrated the up-regulation of miR-21 and a positive correlation between the levels of miR-21 and PSMB4 in MM. Re-expression of miR-21 markedly rescued PSMB4 knockdown-mediated suppression of cell proliferation and clone-formation. Additionally, while enforced expression of PSMB4 profoundly increased NF-κB activity and the level of miR-21, PSMB4 knockdown or NF-κB inhibition suppressed miR-21 expression in MM cells. Taken together, our results demonstrated that PSMB4 regulated MM cell growth in part by activating NF-κB-miR-21 signaling, which may represent promising targets for novel specific therapies. - Highlights: • First reported upregulation of PSMB4 in MM plasma and cell lines. • PSMB4 promoted MM cell growth and colony forming ability. • Further found miR-21 was up-regulated by PSMB4 in MM plasma and cell lines. • PSMB4-induced miR-21 expression was modulated by NF-κB. • PSMB4-NF-κB-miR-21 axis may be potential therapeutic targets of MM.

  17. Thymoquinone inhibits proliferation, induces apoptosis and chemosensitizes human multiple myeloma cells through suppression of signal transducer and activator of transcription 3 activation pathway

    PubMed Central

    Li, Feng; Rajendran, Peramaiyan; Sethi, Gautam

    2010-01-01

    BACKGROUND AND PURPOSE Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) pathway is frequently encountered in several human cancers including multiple myeloma (MM). Thus, agents that suppress STAT3 phosphorylation have a potential for treatment of MM. In the present report, we investigated whether thymoquinone (TQ), the main component isolated from the medicinal plant Nigella sativa, modulated the STAT3 signalling pathway in MM cells. EXPERIMENTAL APPROACH The effect of TQ on both constitutive and IL-6-induced STAT3 activation, associated protein kinases, STAT3-regulated gene products involved in proliferation, survival and angiogenesis, cellular proliferation and apoptosis in MM cells, was investigated. KEY RESULTS We found that TQ inhibited both constitutive and IL-6-inducible STAT3 phosphorylation which correlated with the inhibition of c-Src and JAK2 activation. Vanadate reversed the TQ-induced down-regulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that TQ can induce the expression of Src homology-2 phosphatase 2 that correlated with suppression of STAT3 activation. TQ also down-regulated the expression of STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1 and vascular endothelial growth factor. Finally, TQ induced the accumulation of cells in sub-G1 phase, inhibited proliferation and induced apoptosis, as indicated by poly ADP ribose polymerase cleavage. TQ also significantly potentiated the apoptotic effects of thalidomide and bortezomib in MM cells. CONCLUSIONS AND IMPLICATIONS Our study has identified STAT3 signalling as a target of TQ and has thus raised its potential application in the prevention and treatment of MM and other cancers. PMID:20880395

  18. Pituitary adenylate cyclase-activating polypeptide (PACAP) inhibits the slow afterhyperpolarizing current sIAHP in CA1 pyramidal neurons by activating multiple signaling pathways

    PubMed Central

    Taylor, Ruth DT; Madsen, Marita Grønning; Krause, Michael; Sampedro-Castañeda, Marisol; Stocker, Martin; Pedarzani, Paola

    2014-01-01

    The slow afterhyperpolarizing current (sIAHP) is a calcium-dependent potassium current that underlies the late phase of spike frequency adaptation in hippocampal and neocortical neurons. sIAHP is a well-known target of modulation by several neurotransmitters acting via the cyclic AMP (cAMP) and protein kinase A (PKA)-dependent pathway. The neuropeptide pituitary adenylate cyclase activating peptide (PACAP) and its receptors are present in the hippocampal formation. In this study we have investigated the effect of PACAP on the sIAHP and the signal transduction pathway used to modulate intrinsic excitability of hippocampal pyramidal neurons. We show that PACAP inhibits the sIAHP, resulting in a decrease of spike frequency adaptation, in rat CA1 pyramidal cells. The suppression of sIAHP by PACAP is mediated by PAC1 and VPAC1 receptors. Inhibition of PKA reduced the effect of PACAP on sIAHP, suggesting that PACAP exerts part of its inhibitory effect on sIAHP by increasing cAMP and activating PKA. The suppression of sIAHP by PACAP was also strongly hindered by the inhibition of p38 MAP kinase (p38 MAPK). Concomitant inhibition of PKA and p38 MAPK indicates that these two kinases act in a sequential manner in the same pathway leading to the suppression of sIAHP. Conversely, protein kinase C is not part of the signal transduction pathway used by PACAP to inhibit sIAHP in CA1 neurons. Our results show that PACAP enhances the excitability of CA1 pyramidal neurons by inhibiting the sIAHP through the activation of multiple signaling pathways, most prominently cAMP/PKA and p38 MAPK. Our findings disclose a novel modulatory action of p38 MAPK on intrinsic excitability and the sIAHP, underscoring the role of this current as a neuromodulatory hub regulated by multiple protein kinases in cortical neurons. © 2013 The Authors. Hippocampus Published by Wiley Periodicals, Inc. PMID:23996525

  19. Multiple source navigation signal generator

    NASA Astrophysics Data System (ADS)

    Bojda, Petr

    2010-09-01

    The paper presents a FPGA based digital VOR/LOC signal generator. It provides the composite signal, which consists of the particular signals of several predefined navigation sources - VOR beacons. Design of the generator is implemented into the two different FPGA DSP platforms.

  20. Multiple signals in anterior cingulate cortex

    PubMed Central

    Kolling, N; Behrens, TEJ; Wittmann, MK; Rushworth, MFS

    2016-01-01

    Activity in anterior cingulate cortex (ACC) has been linked both to commitment to a course of action, even when it is associated with costs, and to exploring or searching for alternative courses of action. Here we review evidence that this is due to the presence of multiple signals in ACC reflecting the updating of beliefs and internal models of the environment and encoding aspects of choice value, including the average value of choices afforded by the environment (‘search value’). We contrast this evidence with the influential view that ACC activity is better described as reflecting task difficulty. A consideration of cortical neural network properties explains why ACC may carry such signals and also exhibit sensitivity to task difficulty. PMID:26774693

  1. Inhibition of STAT3 signaling and induction of SHP1 mediate antiangiogenic and antitumor activities of ergosterol peroxide in U266 multiple myeloma cells

    PubMed Central

    2012-01-01

    Background Ergosterol peroxide (EP) derived from edible mushroom has been shown to exert anti-tumor activity in several cancer cells. In the present study, anti-angiogenic activity of EP was investigated with the underlying molecular mechanisms in human multiple myeloma U266 cells. Results Despite weak cytotoxicity against U266 cells, EP suppressed phosphorylation, DNA binding activity and nuclear translocalization of signal transducer and activator of transcription 3 (STAT3) in U266 cells at nontoxic concentrations. Also, EP inhibited phosphorylation of the upstream kinases Janus kinase 2 (JAK2) and Src in a time-dependent manner. Furthermore, EP increased the expression of protein tyrosine phosphatase SHP-1 at protein and mRNA levels, and conversely silencing of the SHP-1 gene clearly blocked EP-mediated STAT3 inactivation. In addition, EP significantly decreased vascular endothelial growth factor (VEGF), one of STAT3 target genes at cellular and protein levels as well as disrupted in vitro tube formation assay. Moreover, EP significantly suppressed the growth of U266 cells inoculated in female BALB/c athymic nude mice and immunohistochemistry revealed that EP effectively reduced the expression of STAT3 and CD34 in tumor sections compared to untreated control. Conclusion These findings suggest that EP can exert antitumor activity in multiple myeloma U266 cells partly with antiangiogenic activity targeting JAK2/STAT3 signaling pathway as a potent cancer preventive agent for treatment of multiple myeloma cells. PMID:22260501

  2. Coupling of a signal response domain in I kappa B alpha to multiple pathways for NF-kappa B activation.

    PubMed Central

    Brockman, J A; Scherer, D C; McKinsey, T A; Hall, S M; Qi, X; Lee, W Y; Ballard, D W

    1995-01-01

    The eukaryotic transcription factor NF-kappa B plays a central role in the induced expression of human immunodeficiency virus type 1 and in many aspects of the genetic program mediating normal T-cell activation and growth. The nuclear activity of NF-kappa B is tightly regulated from the cytoplasmic compartment by an inhibitory subunit called I kappa B alpha. This cytoplasmic inhibitor is rapidly phosphorylated and degraded in response to a diverse set of NF-kappa B-inducing agents, including T-cell mitogens, proinflammatory cytokines, and viral transactivators such as the Tax protein of human T-cell leukemia virus type 1. To explore these I kappa B alpha-dependent mechanisms for NF-kappa B induction, we identified novel mutants of I kappa B alpha that uncouple its inhibitory and signal-transducing functions in human T lymphocytes. Specifically, removal of the N-terminal 36 amino acids of I kappa B alpha failed to disrupt its ability to form latent complexes with NF-kappa B in the cytoplasm. However, this deletion mutation prevented the induced phosphorylation, degradative loss, and functional release of I kappa B alpha from NF-kappa B in Tax-expressing cells. Alanine substitutions introduced at two serine residues positioned within this N-terminal regulatory region of I kappa B alpha also yielded constitutive repressors that escaped from Tax-induced turnover and that potently inhibited immune activation pathways for NF-kappa B induction, including those initiated from antigen and cytokine receptors. In contrast, introduction of a phosphoserine mimetic at these sites rectified this functional defect, a finding consistent with a causal linkage between the phosphorylation status and proteolytic stability of this cytoplasmic inhibitor. Together, these in vivo studies define a critical signal response domain in I kappa B alpha that coordinately controls the biologic activities of I kappa B alpha and NF-kappa B in response to viral and immune stimuli. PMID:7739562

  3. Approach for LIDAR signals with multiple returns.

    PubMed

    Yin, Wenye; He, Weiji; Gu, Guohua; Chen, Qian

    2014-10-20

    Time-correlated single photon counting (TCSPC) and burst illumination laser (BIL) data can be used for depth reconstruction of a target surface; the problem is how to analyze the response for the reconstruction. We propose a fast-approach STMCMC (Simulated Tempering Markov Chain Monte Carlo) for LIDAR signals with multiple return, in order to obtain a complete characterization of a 3D surface by the laser range system. STMCMC is used to explore the spaces by the preset distributions instead of the prior distributions. Added active intervention tempering makes the Markov chain mix better through the temporary expansion of the solutions. The added step keeps the operation under control and yet retains the Markov characteristic of the operation. The theoretical analysis and the demonstrations on the practical data show flexible operation, and the parameters can be estimated to a high degree of accuracy. PMID:25402782

  4. Retinol induces morphological alterations and proliferative focus formation through free radical-mediated activation of multiple signaling pathways

    PubMed Central

    Gelain, Daniel Pens; Pasquali, Matheus Augusto de Bittencourt; Caregnato, Fernanda Freitas; Castro, Mauro Antonio Alves; Moreira, José Claudio Fonseca

    2012-01-01

    Aim: Toxicity of retinol (vitamin A) has been previously associated with apoptosis and/or cell malignant transformation. Thus, we investigated the pathways involved in the induction of proliferation, deformation and proliferative focus formation by retinol in cultured Sertoli cells of rats. Methods: Sertoli cells were isolated from immature rats and cultured. The cells were subjected to a 24-h treatment with different concentrations of retinol. Parameters of oxidative stress and cytotoxicity were analyzed. The effects of the p38 inhibitor SB203580 (10 μmol/L), the JNK inhibitor SP600125 (10 μmol/L), the Akt inhibitor LY294002 (10 μmol/L), the ERK inhibitor U0126 (10 μmol/L) the pan-PKC inhibitor Gö6983 (10 μmol/L) and the PKA inhibitor H89 (1 μmol/L) on morphological and proliferative/transformation-associated modifications were studied. Results: Retinol (7 and 14 μmol/L) significantly increases the reactive species production in Sertoli cells. Inhibition of p38, JNK, ERK1/2, Akt, and PKA suppressed retinol-induced [3H]dT incorporation into the cells, while PKC inhibition had no effect. ERK1/2 and p38 inhibition also blocked retinol-induced proliferative focus formation in the cells, while Akt and JNK inhibition partially decreased focus formation. ERK1/2 and p38 inhibition hindered transformation-associated deformation in retinol-treated cells, while other treatments had no effect. Conclusion: Our results suggest that activation of multiple kinases is responsible for morphological and proliferative changes associated to malignancy development in Sertoli cells by retinol at the concentrations higher than physiological level. PMID:22426700

  5. SC06, a novel small molecule compound, displays preclinical activity against multiple myeloma by disrupting the mTOR signaling pathway

    PubMed Central

    Han, Kunkun; Xu, Xin; Xu, Zhuan; Chen, Guodong; Zeng, Yuanying; Zhang, Zubin; Cao, Biyin; Kong, Yan; Tang, Xiaowen; Mao, Xinliang

    2015-01-01

    The mammalian target of rapamycin (mTOR) is extensively involved in multiple myeloma (MM) pathophysiology. In the present study, we reported a novel small molecule SC06 that induced MM cell apoptosis and delayed MM xenograft growth in vivo. Oral administration of SC06 to mice bearing human MM xenografts resulted in significant inhibition of tumor growth at doses that were well tolerated. Mechanistic studies revealed that SC06 selectively inhibited the mTOR signaling pathway but had no effects on other associated kinases, such as AKT, ERK, p38, c-Src and JNK. Further studies showed that SC06-decreased mTOR activation was associated with the downregulation of Raptor, a key component of the mTORC1 complex. SC06 also suppressed the phosphorylation of 4E-BP1 and P70S6K, two typical substrates in the mTORC1 signaling pathway. Notably, expression of Raptor, phosphorylation of mTOR and phosphorylated 4E-BP1 was also decreased in the tumor tissues from SC06-treated mice, which was consistent with the cellular studies. Therefore, given the potency and low toxicity, SC06 could be developed as a potential anti-MM drug candidate by disrupting the mTOR signaling. PMID:26329846

  6. Global phosphotyrosine survey in triple-negative breast cancer reveals activation of multiple tyrosine kinase signaling pathways

    PubMed Central

    Ma, Binyun; Liu, Ren; Renuse, Santosh; Sahasrabuddhe, Nandini A.; Chen, Lily; Chaerkady, Raghothama; Kim, Min-Sik; Zhong, Jun; Jelinek, Christine; Barbhuiya, Mustafa A.; Leal-Rojas, Pamela; Yang, Yi; Kashyap, Manoj Kumar; Marimuthu, Arivusudar; Ling, Min; Fackler, Mary Jo; Merino, Vanessa; Zhang, Zhen; Zahnow, Cynthia A.; Gabrielson, Edward; Stearns, Vered; Roa, Juan Carlos; Sukumar, Saraswati; Gill, Parkash S.; Pandey, Akhilesh

    2015-01-01

    Breast cancer is the most prevalent cancer in women worldwide. About 15–20% of all breast cancers are triple negative breast cancer (TNBC) and are often highly aggressive when compared to other subtypes of breast cancers. To better characterize the biology that underlies the TNBC phenotype, we profiled the phosphotyrosine proteome of a panel of twenty-six TNBC cell lines using quantitative high resolution Fourier transform mass spectrometry. A heterogeneous pattern of tyrosine kinase activation was observed based on 1,789 tyrosine-phosphorylated peptides identified from 969 proteins. One of the tyrosine kinases, AXL, was found to be activated in a majority of aggressive TNBC cell lines and was accompanied by a higher level of AXL expression. High levels of AXL expression are correlated with a significant decrease in patient survival. Treatment of cells bearing activated AXL with a humanized AXL antibody inhibited cell proliferation and migration in vitro, and tumor growth in mice. Overall, our global phosphoproteomic analysis provided new insights into the heterogeneity in the activation status of tyrosine kinase pathways in TNBCs. Our approach presents an effective means of identifying important novel biomarkers and targets for therapy such as AXL in TNBC. PMID:26356563

  7. UL16-binding proteins, novel MHC class I-related proteins, bind to NKG2D and activate multiple signaling pathways in primary NK cells.

    PubMed

    Sutherland, Claire L; Chalupny, N Jan; Schooley, Kenneth; VandenBos, Tim; Kubin, Marek; Cosman, David

    2002-01-15

    The UL16-binding proteins (ULBPs) are a novel family of MHC class I-related molecules that were identified as targets of the human CMV glycoprotein, UL16. We have previously shown that ULBP expression renders a relatively resistant target cell sensitive to NK cytotoxicity, presumably by engaging NKG2D, an activating receptor expressed by NK and other immune effector cells. In this study we show that NKG2D is the ULBP counterstructure on primary NK cells and that its expression is up-regulated by IL-15 stimulation. Soluble forms of ULBPs induce marked protein tyrosine phosphorylation, and activation of the Janus kinase 2, STAT5, extracellular signal-regulated kinase, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase (PI 3-kinase)/Akt signal transduction pathways. ULBP-induced activation of Akt and extracellular signal-regulated kinase and ULBP-induced IFN-gamma production are blocked by inhibitors of PI 3-kinase, consistent with the known binding of PI 3-kinase to DAP10, the membrane-bound signal-transducing subunit of the NKG2D receptor. While all three ULBPs activate the same signaling pathways, ULBP3 was found to bind weakly and to induce the weakest signal. In summary, we have shown that NKG2D is the ULBP counterstructure on primary NK cells and for the first time have identified signaling pathways that are activated by NKG2D ligands. These results increase our understanding of the mechanisms by which NKG2D activates immune effector cells and may have implications for immune surveillance against pathogens and tumors. PMID:11777960

  8. Notch signaling deregulation in multiple myeloma: A rational molecular target

    PubMed Central

    Garavelli, Silvia; Platonova, Natalia; Paoli, Alessandro; Basile, Andrea; Taiana, Elisa; Neri, Antonino; Chiaramonte, Raffaella

    2015-01-01

    Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple myeloma onset and progression. Unlike other Notch-related malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, in MM cell Notch signaling is aberrantly activated due to an increased expression of Notch receptors and ligands; notably, this also results in the activation of Notch signaling in surrounding stromal cells which contributes to myeloma cell proliferation, survival and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance. Here we review the last findings on the mechanisms and the effects of Notch signaling dysregulation in MM and provide a rationale for a therapeutic strategy aiming at inhibiting Notch signaling, along with a complete overview on the currently available Notch-directed approaches. PMID:26308486

  9. Pentagone internalises glypicans to fine-tune multiple signalling pathways

    PubMed Central

    Norman, Mark; Vuilleumier, Robin; Springhorn, Alexander; Gawlik, Jennifer; Pyrowolakis, George

    2016-01-01

    Tight regulation of signalling activity is crucial for proper tissue patterning and growth. Here we investigate the function of Pentagone (Pent), a secreted protein that acts in a regulatory feedback during establishment and maintenance of BMP/Dpp morphogen signalling during Drosophila wing development. We show that Pent internalises the Dpp co-receptors, the glypicans Dally and Dally-like protein (Dlp), and propose that this internalisation is important in the establishment of a long range Dpp gradient. Pent-induced endocytosis and degradation of glypicans requires dynamin- and Rab5, but not clathrin or active BMP signalling. Thus, Pent modifies the ability of cells to trap and transduce BMP by fine-tuning the levels of the BMP reception system at the plasma membrane. In addition, and in accordance with the role of glypicans in multiple signalling pathways, we establish a requirement of Pent for Wg signalling. Our data propose a novel mechanism by which morphogen signalling is regulated. DOI: http://dx.doi.org/10.7554/eLife.13301.001 PMID:27269283

  10. Multiplicity and plasticity of natural killer cell signaling pathways

    PubMed Central

    Chiesa, Sabrina; Mingueneau, Michael; Fuseri, Nicolas; Malissen, Bernard; Raulet, David H.; Malissen, Marie; Vivier, Eric; Tomasello, Elena

    2006-01-01

    Natural killer (NK) cells express an array of activating receptors that associate with DAP12 (KARAP), CD3ζ, and/or FcRγ ITAM (immunoreceptor tyrosine-based activation motif)–bearing signaling subunits. In T and mast cells, ITAM-dependent signals are integrated by critical scaffolding elements such as LAT (linker for activation of T cells) and NTAL (non–T-cell activation linker). Using mice that are deficient for ITAM-bearing molecules, LAT or NTAL, we show that NK cell cytotoxicity and interferon-γ secretion are initiated by ITAM-dependent and -independent as well as LAT/NTAL-dependent and -independent pathways. The role of these various signaling circuits depends on the target cell as well as on the activation status of the NK cell. The multiplicity and the plasticity of the pathways that initiate NK cell effector functions contrast with the situation in T cells and B cells and provide an explanation for the resiliency of NK cell effector functions to various pharmacologic inhibitors and genetic mutations in signaling molecules. PMID:16291591

  11. Signal focusing through active transport

    NASA Astrophysics Data System (ADS)

    Godec, Aljaž; Metzler, Ralf

    2015-07-01

    The accuracy of molecular signaling in biological cells and novel diagnostic devices is ultimately limited by the counting noise floor imposed by the thermal diffusion. Motivated by the fact that messenger RNA and vesicle-engulfed signaling molecules transiently bind to molecular motors and are actively transported in biological cells, we show here that the random active delivery of signaling particles to within a typical diffusion distance to the receptor generically reduces the correlation time of the counting noise. Considering a variety of signaling particle sizes from mRNA to vesicles and cell sizes from prokaryotic to eukaryotic cells, we show that the conditions for active focusing—faster and more precise signaling—are indeed compatible with observations in living cells. Our results improve the understanding of molecular cellular signaling and novel diagnostic devices.

  12. Performance of Multiple Pulse Multiple Delay Modulated UWB Signals in a Multiple Access Indoor Wireless Channel

    SciTech Connect

    Nekoogar, F

    2003-06-12

    In this paper, the performance of a two user UWB multiple access (UWB-MA) system based on multiple-pulse multiple-delay (MPMD) modulation scheme in an indoor wireless channel is evaluated by computer simulations. The indoor multipath propagation channel model used in this study is based on the modified statistical Saleh-Valenzuela model proposed by Foerester and Li from Intel. The simulation results indicate that the multipath performance of MPMD modulated signals in a multiple access system outperforms the nonmultipath case as the number of autocorrelation function (ACF) sampling points increases for each user. This is an unusual but important result, since MPMD receiver exploits multipath phenomenon in indoor wireless channels to increase the BER performance, hence the transmission rate in a UWB-MA system.

  13. Human T-cell leukemia virus type 1 Tax activates transcription of the human fra-1 gene through multiple cis elements responsive to transmembrane signals.

    PubMed Central

    Tsuchiya, H; Fujii, M; Niki, T; Tokuhara, M; Matsui, M; Seiki, M

    1993-01-01

    We have shown that Tax1 of human T-cell leukemia virus type 1 stimulates the expression of several cellular immediate-early genes (M. Fujii, T. Niki, T. Mori, T. Matsuda, M. Matsui, N. Nomura, and M. Seiki, Oncogene 6:1023-1029, 1991). In this study, the 5'-flanking region of the human fra-1 gene, which is a Tax1-inducible fos-related gene, was isolated and Tax1 or serum-responsive cis elements were analyzed to obtain further insight into the mechanism of Tax1 action. The 62-bp sequence starting 46 nucleotides upstream from the translation initiation site showed 71% homology with the sequence surrounding the TATA box of the c-fos promoter. Regulatory motifs identified in the c-fos promoter, such as an Ets-binding site, E boxes, a CArG box, c-fos AP-1 sites, and two retinoblastoma control elements, were also found upstream of the c-fos homology region. A 502-bp fragment containing these motifs mediated transcriptional activation by Tax1 or by serum in a transient transfection assay. Three independent Tax1-responsive regions (TRRs) were identified, and mutations in each revealed that one of the retinoblastoma control elements in TRR1 and the c-fos AP-1 sites in TRR2 and TRR3 were essential for the activation. Although TRR2 contains a CArG box-like sequence, it was a weak binding site for p67SRF, if it bound at all, and was not required for activation. All three TRRs could also mediate the signals stimulated by serum. Thus, Tax1 appears to activate fra-1 gene expression by means of a part of the cellular machinery similar to that which mediates growth signals. Images PMID:8230424

  14. Platelet 12-lipoxygenase activation via glycoprotein VI: involvement of multiple signaling pathways in agonist control of H(P)ETE synthesis.

    PubMed

    Coffey, Marcus J; Jarvis, Gavin E; Gibbins, Jonathan M; Coles, Barbara; Barrett, Natasha E; Wylie, Oliver R E; O'Donnell, Valerie B

    2004-06-25

    Lipoxygenases (LOX) contribute to vascular disease and inflammation through generation of bioactive lipids, including 12-hydro(pero)xyeicosatetraenoic acid (12-H(P)ETE). The physiological mechanisms that acutely control LOX product generation in mammalian cells are uncharacterized. Human platelets that contain a 12-LOX isoform (p12-LOX) were used to define pathways that activate H(P)ETE synthesis in the vasculature. Collagen and collagen-related peptide (CRP) (1 to 10 microg/mL) acutely induced platelet 12-H(P)ETE synthesis. This implicated the collagen receptor glycoprotein VI (GPVI), which signals via the immunoreceptor-based activatory motif (ITAM)-containing FcRgamma chain. Conversely, thrombin only activated at high concentrations (> 0.2 U/mL), whereas U46619 and ADP alone were ineffective. Collagen or CRP-stimulated 12-H(P)ETE generation was inhibited by staurosporine, PP2, wortmannin, BAPTA/AM, EGTA, and L-655238, implicating src-tyrosine kinases, PI3-kinase, Ca2+ mobilization, and p12-LOX translocation. In contrast, protein kinase C (PKC) inhibition potentiated 12-H(P)ETE generation. Finally, activation of the immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing platelet endothelial cell adhesion molecule (PECAM-1) inhibited p12-LOX product generation. This study characterizes a receptor-dependent pathway for 12-H(P)ETE synthesis via the collagen receptor GPVI, which is negatively regulated by PECAM-1 and PKC, and demonstrates a novel link between immune receptor signaling and lipid mediator generation in the vasculature. PMID:15142951

  15. A Pivotal Role of DELLAs in Regulating Multiple Hormone Signals.

    PubMed

    Davière, Jean-Michel; Achard, Patrick

    2016-01-01

    Plant phenotypic plasticity is controlled by diverse hormone pathways, which integrate and convey information from multiple developmental and environmental signals. Moreover, in plants many processes such as growth, development, and defense are regulated in similar ways by multiple hormones. Among them, gibberellins (GAs) are phytohormones with pleiotropic actions, regulating various growth processes throughout the plant life cycle. Previous work has revealed extensive interplay between GAs and other hormones, but the molecular mechanism became apparent only recently. Molecular and physiological studies have demonstrated that DELLA proteins, considered as master negative regulators of GA signaling, integrate multiple hormone signaling pathways through physical interactions with transcription factors or regulatory proteins from different families. In this review, we summarize the latest progress in GA signaling and its direct crosstalk with the main phytohormone signaling, emphasizing the multifaceted role of DELLA proteins with key components of major hormone signaling pathways. PMID:26415696

  16. Estrogen Signaling Multiple Pathways to Impact Gene Transcription

    PubMed Central

    Marino, Maria; Galluzzo, Paola; Ascenzi, Paolo

    2006-01-01

    Steroid hormones exert profound effects on cell growth, development, differentiation, and homeostasis. Their effects are mediated through specific intracellular steroid receptors that act via multiple mechanisms. Among others, the action mechanism starting upon 17β-estradiol (E2) binds to its receptors (ER) is considered a paradigmatic example of how steroid hormones function. Ligand-activated ER dimerizes and translocates in the nucleus where it recognizes specific hormone response elements located in or near promoter DNA regions of target genes. Behind the classical genomic mechanism shared with other steroid hormones, E2 also modulates gene expression by a second indirect mechanism that involves the interaction of ER with other transcription factors which, in turn, bind their cognate DNA elements. In this case, ER modulates the activities of transcription factors such as the activator protein (AP)-1, nuclear factor-κB (NF-κB) and stimulating protein-1 (Sp-1), by stabilizing DNA-protein complexes and/or recruiting co-activators. In addition, E2 binding to ER may also exert rapid actions that start with the activation of a variety of signal transduction pathways (e.g. ERK/MAPK, p38/MAPK, PI3K/AKT, PLC/PKC). The debate about the contribution of different ER-mediated signaling pathways to coordinate the expression of specific sets of genes is still open. This review will focus on the recent knowledge about the mechanism by which ERs regulate the expression of target genes and the emerging field of integration of membrane and nuclear receptor signaling, giving examples of the ways by which the genomic and non-genomic actions of ERs on target genes converge. PMID:18369406

  17. Orexin-stimulated MAP kinase cascades are activated through multiple G-protein signalling pathways in human H295R adrenocortical cells: diverse roles for orexins A and B.

    PubMed

    Ramanjaneya, Manjunath; Conner, Alex C; Chen, Jing; Kumar, Prashanth; Brown, James E P; Jöhren, Olaf; Lehnert, Hendrik; Stanfield, Peter R; Randeva, Harpal S

    2009-08-01

    Orexins A and B (ORA and ORB) are neuropeptide hormones found throughout the central nervous system and periphery. They are required for a host of physiological processes including mitogen-activated protein kinase (MAPK) regulation, steroidogenesis, appetite control and energy regulation. While some signalling mechanisms have been proposed for individual recombinant orexin receptors in generic mammalian cell types, it is clear that the peripheral effects of orexin are spatially and temporally complex. This study dissects the different G-protein signalling and MAPK pathways activated in a pluripotent human adrenal H295R cell line capable of all the physiological steps involved in steroidogenesis. Both extracellular receptor kinase 1/2 (ERK1/2) and p38 were phosphorylated rapidly with a subsequent decline, in a time- and dose-dependent manner, in response to both ORA and ORB. Conversely, there was little or no direct activation of the ERK5 or JNK pathway. Analysis using signalling and MAPK inhibitors as well as receptor-specific antagonists determined the precise mediators of the orexin response in these cells. Both ERK1/2 and p38 activation were predominantly G(q)- and to a lesser extent G(s)-mediated; p38 activation even had a small G(i)-component. Effects were broadly comparable for both orexin sub-types ORA and ORB and although most of the effects were transmitted through the orexin receptor-1 subtype, we did observe a role for orexin receptor-2-mediated activation of both ERK1/2 and p38. Cortisol secretion also differed in response to ORA and ORB. These data suggest multiple roles for orexin-mediated MAPK activation in an adrenal cell-line, this complexity may help to explain the diverse biological actions of orexins with wide-ranging consequences for our understanding of the mechanisms initiated by these steroidogenic molecules. PMID:19460850

  18. Photonic generation and independent steering of multiple RF signals for software defined radars.

    PubMed

    Ghelfi, Paolo; Laghezza, Francesco; Scotti, Filippo; Serafino, Giovanni; Pinna, Sergio; Bogoni, Antonella

    2013-09-23

    As the improvement of radar systems claims for digital approaches, photonics is becoming a solution for software defined high frequency and high stability signal generation. We report on our recent activities on the photonic generation of flexible wideband RF signals, extending the proposed architecture to the independent optical beamforming of multiple signals. The scheme has been tested generating two wideband signals at 10 GHz and 40 GHz, and controlling their independent delays at two antenna elements. Thanks to the multiple functionalities, the proposed scheme allows to improve the effectiveness of the photonic approach, reducing its cost and allowing flexibility, extremely wide bandwidth, and high stability. PMID:24104176

  19. Serotonergic neurons signal reward and punishment on multiple timescales

    PubMed Central

    Cohen, Jeremiah Y; Amoroso, Mackenzie W; Uchida, Naoshige

    2015-01-01

    Serotonin's function in the brain is unclear. One challenge in testing the numerous hypotheses about serotonin's function has been observing the activity of identified serotonergic neurons in animals engaged in behavioral tasks. We recorded the activity of dorsal raphe neurons while mice experienced a task in which rewards and punishments varied across blocks of trials. We ‘tagged’ serotonergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to light. We found three main features of serotonergic neuron activity: (1) a large fraction of serotonergic neurons modulated their tonic firing rates over the course of minutes during reward vs punishment blocks; (2) most were phasically excited by punishments; and (3) a subset was phasically excited by reward-predicting cues. By contrast, dopaminergic neurons did not show firing rate changes across blocks of trials. These results suggest that serotonergic neurons signal information about reward and punishment on multiple timescales. DOI: http://dx.doi.org/10.7554/eLife.06346.001 PMID:25714923

  20. Hexagonal multiple phase-and-amplitude-shift-keyed signal sets

    NASA Technical Reports Server (NTRS)

    Simon, M. K.; Smith, J. G.

    1973-01-01

    Selection of a particular signal set array for a bandwidth-constrained multiple phase-and-amplitude-shift-keyed (MPASK) communication system for a linear additive Gaussian noise channel requires consideration of factors such as average and/or peak power vs symbol error probability, signal amplitude dynamic range, simplicity of generation and detection, and number of bit errors per symbol error (Gray code properties). A simple technique is presented for generating and optimally detecting the honeycomb (hexagonal) signal set, i.e., the signal set that has the tightest sphere-packing properties. The symbol and bit error probability performance of this set is compared to other two-dimensional signal sets that have been investigated in the literature, and is shown to be slightly superior from an average power standpoint. The paper concludes with a comparison of all of these signal sets from the standpoint of the factors listed above.

  1. BK channels: multiple sensors, one activation gate.

    PubMed

    Yang, Huanghe; Zhang, Guohui; Cui, Jianmin

    2015-01-01

    Ion transport across cell membranes is essential to cell communication and signaling. Passive ion transport is mediated by ion channels, membrane proteins that create ion conducting pores across cell membrane to allow ion flux down electrochemical gradient. Under physiological conditions, majority of ion channel pores are not constitutively open. Instead, structural region(s) within these pores breaks the continuity of the aqueous ion pathway, thereby serves as activation gate(s) to control ions flow in and out. To achieve spatially and temporally regulated ion flux in cells, many ion channels have evolved sensors to detect various environmental stimuli or the metabolic states of the cell and trigger global conformational changes, thereby dynamically operate the opening and closing of their activation gate. The sensors of ion channels can be broadly categorized as chemical sensors and physical sensors to respond to chemical (such as neural transmitters, nucleotides and ions) and physical (such as voltage, mechanical force and temperature) signals, respectively. With the rapidly growing structural and functional information of different types of ion channels, it is now critical to understand how ion channel sensors dynamically control their gates at molecular and atomic level. The voltage and Ca(2+) activated BK channels, a K(+) channel with an electrical sensor and multiple chemical sensors, provide a unique model system for us to understand how physical and chemical energy synergistically operate its activation gate. PMID:25705194

  2. BK channels: multiple sensors, one activation gate

    PubMed Central

    Yang, Huanghe; Zhang, Guohui; Cui, Jianmin

    2015-01-01

    Ion transport across cell membranes is essential to cell communication and signaling. Passive ion transport is mediated by ion channels, membrane proteins that create ion conducting pores across cell membrane to allow ion flux down electrochemical gradient. Under physiological conditions, majority of ion channel pores are not constitutively open. Instead, structural region(s) within these pores breaks the continuity of the aqueous ion pathway, thereby serves as activation gate(s) to control ions flow in and out. To achieve spatially and temporally regulated ion flux in cells, many ion channels have evolved sensors to detect various environmental stimuli or the metabolic states of the cell and trigger global conformational changes, thereby dynamically operate the opening and closing of their activation gate. The sensors of ion channels can be broadly categorized as chemical sensors and physical sensors to respond to chemical (such as neural transmitters, nucleotides and ions) and physical (such as voltage, mechanical force and temperature) signals, respectively. With the rapidly growing structural and functional information of different types of ion channels, it is now critical to understand how ion channel sensors dynamically control their gates at molecular and atomic level. The voltage and Ca2+ activated BK channels, a K+ channel with an electrical sensor and multiple chemical sensors, provide a unique model system for us to understand how physical and chemical energy synergistically operate its activation gate. PMID:25705194

  3. The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism

    PubMed Central

    Kopan, Raphael; Ilagan, Ma. Xenia G.

    2009-01-01

    Notch signaling regulates many aspects of metazoan development and tissue renewal. Accordingly, misregulation or loss of Notch signaling underlies multiple human disorders, from developmental syndromes to adult onset diseases and cancer. Notch receptor activation is irreversible as it involves proteolysis-mediated release of the Notch intracellular domain, translocation to the nucleus, and association with a DNA-bound protein. Even though each Notch molecule signals only once without amplification by secondary messenger cascades, Notch signaling is remarkably robust in most tissues. In this review, we highlight the recent studies that reveal new molecular details involved in regulating ligand-mediated activation, receptor proteolysis and target selection. PMID:19379690

  4. Signal simulation and signal processing for multiple reference optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Neuhaus, Kai; Subhash, Hrebesh; Dsouza, Roshan; Hogan, Josh; Wilson, Carol; Leahy, Martin

    2015-03-01

    The generation of a synthetic MR-OCT signal is presented and compared to a real acquired signal. Multiple reference optical coherence tomography (MR-OCT) is a novel time-domain interferometric system. The MR-OCT principle is adding a partial mirror to extend the axial scan range, which effectively extends the scan depth for imaging. The actuation of the scan mirror required for time-domain OCT, was demonstrated to operate with a low cost miniature voice coil, such as a speaker extracted from a smartphone or CD/DVD pick-up system. Building a compact and cost-effective optical imaging system will enable affordable medical diagnosis at low-resource setting applications. The partial mirror recirculates multiple reflections (orders) into the interferometric system and the increase of optical path delay does increase the beat frequency of the interference signal. The synthesis of such an interference signal using a numerical method is described in this manuscript.

  5. Multiple signal classification for self-mixing flowmetry.

    PubMed

    Nikolić, Milan; Lim, Yah Leng; Bertling, Karl; Taimre, Thomas; Rakić, Aleksandar D

    2015-03-20

    For the first time to our knowledge, we apply the multiple signal classification (MUSIC) algorithm to signals obtained from a self-mixing flow sensor. We find that MUSIC accurately extracts the fluid velocity and exhibits a markedly better signal-to-noise ratio (SNR) than the commonly used fast Fourier transform (FFT) method. We compare the performance of the MUSIC and FFT methods for three decades of scatterer concentration and fluid velocities from 0.5 to 50 mm/s. MUSIC provided better linearity than the FFT and was able to accurately function over a wider range of algorithm parameters. MUSIC exhibited excellent linearity and SNR even at low scatterer concentration, at which the FFT's SNR decreased to impractical levels. This makes MUSIC a particularly attractive method for flow measurement systems with a low density of scatterers such as microfluidic and nanofluidic systems and blood flow in capillaries. PMID:25968500

  6. High integrity carrier phase navigation using multiple civil GPS signals

    NASA Astrophysics Data System (ADS)

    Jung, Jaewoo

    2000-11-01

    A navigation system should guide users to their destinations accurately and reliably. Among the many available navigation aids, the Global Positioning System stands out due to its unique capabilities. It is a satellite-based navigation system which covers the entire Earth with horizontal accuracy of 20 meters for stand alone civil users. Today, the GPS provides only one civil signal, but two more signals will be available in the near future. GPS will provide a second signal at 1227.60 MHz (L2) and a third signal at 1176.45 MHz (Lc), in addition to the current signal at 1575.42 MHz (L1). The focus of this thesis is exploring the possibility of using beat frequencies of these signals to provide navigation aid to users with high accuracy and integrity. To achieve high accuracy, the carrier phase differential GPS is used. The integer ambiguity is resolved using the Cascade Integer Resolution (CIR), which is defined in this thesis. The CIR is an instantaneous, geometry-free integer resolution method utilizing beat frequencies of GPS signals. To insure high integrity, the probability of incorrect integer ambiguity resolution using the CIR is analyzed. The CIR can immediately resolve the Lc integer ambiguity up to 2.4 km from the reference receiver, the Widelane (L1-L2) integer ambiguity up to 22 km, and the Extra Widelane (L2-Lc) integer ambiguity from there on, with probability of incorrect integer resolution of 10-4 . The optimal use of algebraic combinations of multiple GPS signals are also investigated in this thesis. Finally, the gradient of residual differential ionospheric error is estimated to stimated to increase performance of the CIR.

  7. Multiple Stress Signals Induce p73β Accumulation1

    PubMed Central

    Lin, Kai Wei; Nam, Shin Yuen; Toh, Wen Hong; Dulloo, Iqbal; Sabapathy, Kanaga

    2004-01-01

    Abstract Although p73 is a structural and functional homologue of the tumor-suppressor gene p53, it is not mutated in many human cancers as p53. Besides, p73 was shown to be activated by only a subset of signals that activate p53, such as γ-irradiation and cisplatin, but not by other common genotoxic stress-inducing agents such as ultraviolet (UV) irradiation, although many of these signals are also capable of inducing p53-independent cell death. Using a p73-specific antibody, we confirmed that c-Abl is required for cisplatin-induced p73 upregulation, and further demonstrate that the p73 protein is upregulated by UV irradiation and other stress stimuli including sorbitol, hydrogen peroxide, nocodazol, and taxol. These stress signals upregulate both p73 mRNA and increases the stability of p73, indicating that p73 is regulated transcriptionally and posttranslationally. Cells stably expressing the dominant-negative p73 inhibitor protein (p73DD) and p73-/- fibroblasts are more resistant than control cells to apoptosis induced by these stress signals, suggesting that p73 contributes to apoptosis induction. Together, the data demonstrate that several stress signals can signal to p73 in vivo, which raises the possibility of eradicating cancers with an unmutated p73 gene by activating them with stress-inducing agents or their mimetics. PMID:15548364

  8. Multiple-channel optical signal processing with wavelength-waveform conversions, pulsewidth tunability, and signal regeneration.

    PubMed

    Nguyen Tan, Hung; Matsuura, Motoharu; Katafuchi, Tomoya; Kishi, Naoto

    2009-12-01

    A multiple-channel multiple-function optical signal processor (MCMF-OSP) including wavelength-waveform conversions, pulsewidth tunability, and signal regeneration is realized through AND logic gate based on optical parametric processing with a pulsewidth-tunable RZ clock pump. The proposed scheme simultaneously offers four signal processing functions which are useful in wavelength-division multiplexing (WDM) transmission systems, and at network nodes with the necessity for multiple-channel data processing. After the discussions on the concept of MCMF-OSP, a proof-of concept experiment is demonstrated on four 10 Gb/s nonreturn-to-zero (NRZ) data format channels using nonlinearities in semiconductor optical amplifier (SOA) and highly nonlinear fiber (HNLF). A wavelength and waveform conversions to return-to-zero (RZ) modulation format are obtained together with pulsewidth-tunable range from 20% to 80% duty cycles for all input signals. The converted signals inherit the timing and waveform of the RZ clock pump, thus resulting in a time regeneration and large tolerance to narrow-band optical filtering (NAOF) and fiber accumulated chromatic dispersion (CD). PMID:20052222

  9. PIF4 Integrates Multiple Environmental and Hormonal Signals for Plant Growth Regulation in Arabidopsis

    PubMed Central

    Choi, Hyunmo; Oh, Eunkyoo

    2016-01-01

    As sessile organisms, plants must be able to adapt to the environment. Plants respond to the environment by adjusting their growth and development, which is mediated by sophisticated signaling networks that integrate multiple environmental and endogenous signals. Recently, increasing evidence has shown that a bHLH transcription factor PIF4 plays a major role in the multiple signal integration for plant growth regulation. PIF4 is a positive regulator in cell elongation and its activity is regulated by various environmental signals, including light and temperature, and hormonal signals, including auxin, gibberellic acid and brassinosteroid, both transcriptionally and post-translationally. Moreover, recent studies have shown that the circadian clock and metabolic status regulate endogenous PIF4 level. The PIF4 transcription factor cooperatively regulates the target genes involved in cell elongation with hormone-regulated transcription factors. Therefore, PIF4 is a key integrator of multiple signaling pathways, which optimizes growth in the environment. This review will discuss our current understanding of the PIF4-mediated signaling networks that control plant growth. PMID:27432188

  10. PIF4 Integrates Multiple Environmental and Hormonal Signals for Plant Growth Regulation in Arabidopsis.

    PubMed

    Choi, Hyunmo; Oh, Eunkyoo

    2016-08-31

    As sessile organisms, plants must be able to adapt to the environment. Plants respond to the environment by adjusting their growth and development, which is mediated by sophisticated signaling networks that integrate multiple environmental and endogenous signals. Recently, increasing evidence has shown that a bHLH transcription factor PIF4 plays a major role in the multiple signal integration for plant growth regulation. PIF4 is a positive regulator in cell elongation and its activity is regulated by various environmental signals, including light and temperature, and hormonal signals, including auxin, gibberellic acid and brassinosteroid, both transcriptionally and post-translationally. Moreover, recent studies have shown that the circadian clock and metabolic status regulate endogenous PIF4 level. The PIF4 transcription factor cooperatively regulates the target genes involved in cell elongation with hormone-regulated transcription factors. Therefore, PIF4 is a key integrator of multiple signaling pathways, which optimizes growth in the environment. This review will discuss our current understanding of the PIF4-mediated signaling networks that control plant growth. PMID:27432188

  11. Estimation and detection of signals in multiplicative noise

    NASA Technical Reports Server (NTRS)

    Willsky, A. S.

    1974-01-01

    We define a class of detection-estimation problems on matrix Lie groups in which the observation noise is multiplicative in nature. By examining the differential versions of the hypotheses, which are bilinear, we are able to derive the relevant likelihood ratio formula and the associated optimal estimation equations for the signal given the observations and the assumption that the signal is present. These estimation equations are of interest in their own right, in that they represent a finite-dimensional optimal solution to a nonlinear estimation problem and consist of a Kalman-Bucy filter along with the on-line computation of the solution of the associated Riccati equation, which is driven by the observations. The usefulness of these results is illustrated via an example concerning the detection of an actuator failure in a rigid-body rotational control system.

  12. Extraction of quadrature phase information from multiple pulse NMR signals

    NASA Technical Reports Server (NTRS)

    Rhim, W.-K.; Burum, D. P.; Vaughan, R. W.

    1976-01-01

    A multiple pulse sequence (8-pulse sequence) used for high-resolution solid state NMR is analyzed with regard to the information available from each of the four wide sampling windows. It is demonstrated that full quadrature phase information can be obtained using only a single phase detector and that, for the commonly encountered situation where the spectral width is much less than the folding frequency, the signals from the various windows can be combined easily using standard complex Fourier transform software. An improvement in the signal-to-noise ratio equal to the square root of 3 is obtained over either standard single or quadrature phase detection schemes. Procedures for correcting spectral distortions are presented.

  13. Estimation and detection of signals in multiplicative noise

    NASA Technical Reports Server (NTRS)

    Willsky, A. S.

    1973-01-01

    A class of detection-estimation problems on matrix Lie groups is defined in which the observation noise is multiplicative in nature. By examining the differential versions of the hypotheses, which are bilinear in nature, it is possible to derive the relevant likelihood ratio formula and the associated optimal estimation equations for the signal given the observations and the assumption that the signal is present. These estimation equations are of interest in their own right, in that they represent a finite dimensional optimal solution to a nonlinear estimation problem and can be viewed as consisting of a Kalman-Bucy filter along with the on-line computation of the solution of the associated Riccati equation, which is driven by the observations. The usefulness of these results is illustrated via an example concerning the detection of an actuator failure in a rigid body rotational control system.

  14. Analysis and Design of Multiple-Antenna Cognitive Radios With Multiple Primary User Signals

    NASA Astrophysics Data System (ADS)

    Morales-Jimenez, David; Louie, Raymond H. Y.; McKay, Matthew R.; Chen, Yang

    2015-09-01

    We consider multiple-antenna signal detection of primary user transmission signals by a secondary user receiver in cognitive radio networks. The optimal detector is analyzed for the scenario where the number of primary user signals is no less than the number of receive antennas at the secondary user. We first derive exact expressions for the moments of the generalized likelihood ratio test (GLRT) statistic, yielding approximations for the false alarm and detection probabilities. We then show that the normalized GLRT statistic converges in distribution to a Gaussian random variable when the number of antennas and observations grow large at the same rate. Further, using results from large random matrix theory, we derive expressions to compute the detection probability without explicit knowledge of the channel, and then particularize these expressions for two scenarios of practical interest: 1) a single primary user sending spatially multiplexed signals, and 2) multiple spatially distributed primary users. Our analytical results are finally used to obtain simple design rules for the signal detection threshold.

  15. Signaling during platelet adhesion and activation

    PubMed Central

    Li, Zhenyu; Delaney, M. Keegan; O’Brien, Kelly A.; Du, Xiaoping

    2011-01-01

    Upon vascular injury, platelets are activated by adhesion to adhesive proteins like von Willebrand factor and collagen, or by soluble platelet agonists like ADP, thrombin, and thromboxane A2. These adhesive proteins and soluble agonists induce signal transduction via their respective receptors. The various receptor-specific platelet activation signaling pathways converge into common signaling events, which stimulate platelet shape change, granule secretion, and ultimately induce the “inside-out” signaling process leading to activation of the ligand binding function of integrin αIIbβ3. Ligand binding to integrin αIIbβ3 mediates platelet adhesion and aggregation and triggers “outside-in” signaling, resulting in platelet spreading, additional granule secretion, stabilization of platelet adhesion and aggregation, and clot retraction. It has become increasingly evident that agonist-induced platelet activation signals also crosstalk with integrin “outside-in” signals to regulate platelet responses. Platelet activation involves a series of rapid positive feedback loops that greatly amplify initial activation signals, and enable robust platelet recruitment and thrombus stabilization. Recent studies have provided novel insight into the molecular mechanisms of these processes. PMID:21071698

  16. Elevated PI3K signaling drives multiple Breast Cancer subtypes

    PubMed Central

    Adams, Jessica R.; Schachter, Nathan F.; Liu, Jeff C.; Zacksenhaus, Eldad; Egan, Sean E.

    2011-01-01

    Most human breast tumors have mutations that elevate signaling through a key metabolic pathway that is induced by insulin and a number of growth factors. This pathway serves to activate an enzyme known as phosphatidylinositol 3' kinase (PI3K) as well as to regulate proteins that signal in response to lipid products of PI3K. The specific mutations that activate this pathway in breast cancer can occur in genes coding for tyrosine kinase receptors, adaptor proteins linked to PI3K, catalytic and regulatory subunits of PI3K, serine/threonine kinases that function downstream of PI3K, and also phosphatidylinositol phosphatase tumor suppressors that function to antagonize this pathway. While each genetic change results in net elevation of PI3K pathway signaling, and all major breast cancer subtypes show pathway activation, the specific mutation(s) involved in any one tumor may play an important role in defining tumor subtype, prognosis and even sensitivity to therapy. Here, we describe mouse models of breast cancer with elevated PI3K signaling, and how they may be used to guide development of novel therapeutics. PMID:21646685

  17. Integration of C/N-nutrient and multiple environmental signals into the ABA signaling cascade

    PubMed Central

    Lu, Yu; Yamaguchi, Junji; Sato, Takeo

    2015-01-01

    Due to their immobility, plants have developed sophisticated mechanisms to robustly monitor and appropriately respond to dynamic changes in nutrient availability. Carbon (C) and nitrogen (N) are especially important in regulating plant metabolism and development, thereby affecting crop productivity. In addition to their independent utilization, the ratio of C to N metabolites in the cell, referred to as the “C/N balance”, is important for the regulation of plant growth, although molecular mechanisms mediating C/N signaling remain unclear. Recently ABI1, a protein phosphatase type 2C (PP2C), was shown to be a regulator of C/N response in Arabidopsis plants. ABI1 functions as a negative regulator of abscisic acid (ABA) signal transduction. ABA is versatile phytohormone that regulates multiple aspects of plant growth and adaptation to environmental stress. This review highlights the regulation of the C/N response mediated by a non-canonical ABA signaling pathway that is independent of ABA biosynthesis, as well as recent findings on the direct crosstalk between multiple cellular signals and the ABA signaling cascade. PMID:26786013

  18. Multiple Identities and Education for Active Citizenship

    ERIC Educational Resources Information Center

    Ross, Alistair

    2007-01-01

    This paper explores concepts of multiple and nested identities and how these relate to citizenship and rights, and the implications of identities and rights for active citizenship education. Various theoretical conceptions of identity are analysed, and in particular ideas concerning multiple identities that are used contingently, and about…

  19. Reception of Multiple Telemetry Signals via One Dish Antenna

    NASA Technical Reports Server (NTRS)

    Mukai, Ryan; Vilnrotter, Victor

    2010-01-01

    A microwave aeronautical-telemetry receiver system includes an antenna comprising a seven-element planar array of receiving feed horns centered at the focal point of a paraboloidal dish reflector that is nominally aimed at a single aircraft or at multiple aircraft flying in formation. Through digital processing of the signals received by the seven feed horns, the system implements a method of enhanced cancellation of interference, such that it becomes possible to receive telemetry signals in the same frequency channel simultaneously from either or both of two aircraft at slightly different angular positions within the field of view of the antenna, even in the presence of multipath propagation. The present system is an advanced version of the system described in Spatio- Temporal Equalizer for a Receiving-Antenna Feed Array NPO-43077, NASA Tech Briefs, Vol. 34, No. 2 (February 2010), page 32. To recapitulate: The radio-frequency telemetry signals received by the seven elements of the array are digitized, converted to complex baseband form, and sent to a spatio-temporal equalizer that consists mostly of a bank of seven adaptive finite-impulse-response (FIR) filters (one for each element in the array) plus a unit that sums the outputs of the filters. The combination of the spatial diversity of the feedhorn array and the temporal diversity of the filter bank affords better multipath suppression performance than is achievable by means of temporal equalization alone. The FIR filter bank adapts itself in real time to enable reception of telemetry at a low bit error rate, even in the presence of frequency-selective multipath propagation like that commonly found at flight-test ranges. The combination of the array and the filter bank makes it possible to constructively add multipath incoming signals to the corresponding directly arriving signals, thereby enabling reductions in telemetry bit-error rates.

  20. Hippo signaling regulates Drosophila intestine stem cell proliferation through multiple pathways

    PubMed Central

    Ren, Fangfang; Wang, Bing; Yue, Tao; Yun, Eun-Young; Ip, Y. Tony; Jiang, Jin

    2010-01-01

    Intestinal stem cells (ISCs) in the Drosophila adult midgut are essential for maintaining tissue homeostasis and replenishing lost cells in response to tissue damage. Here we demonstrate that the Hippo (Hpo) signaling pathway, an evolutionarily conserved pathway implicated in organ size control and tumorigenesis, plays an essential role in regulating ISC proliferation. Loss of Hpo signaling in either midgut precursor cells or epithelial cells stimulates ISC proliferation. We provide evidence that loss of Hpo signaling in epithelial cells increases the production of cytokines of the Upd family and multiple EGFR ligands that activate JAK-STAT and EGFR signaling pathways in ISCs to stimulate their proliferation, thus revealing a unique non–cell-autonomous role of Hpo signaling in blocking ISC proliferation. Finally, we show that the Hpo pathway mediator Yorkie (Yki) is also required in precursor cells for injury-induced ISC proliferation in response to tissue-damaging reagent DSS. PMID:21078993

  1. NMDA Receptors Multiplicatively Scale Visual Signals and Enhance Directional Motion Discrimination in Retinal Ganglion Cells.

    PubMed

    Poleg-Polsky, Alon; Diamond, Jeffrey S

    2016-03-16

    Postsynaptic responses in many CNS neurons are typically small and variable, often making it difficult to distinguish physiologically relevant signals from background noise. To extract salient information, neurons are thought to integrate multiple synaptic inputs and/or selectively amplify specific synaptic activation patterns. Here, we present evidence for a third strategy: directionally selective ganglion cells (DSGCs) in the mouse retina multiplicatively scale visual signals via a mechanism that requires both nonlinear NMDA receptor (NMDAR) conductances in DSGC dendrites and directionally tuned inhibition provided by the upstream retinal circuitry. Postsynaptic multiplication enables DSGCs to discriminate visual motion more accurately in noisy visual conditions without compromising directional tuning. These findings demonstrate a novel role for NMDARs in synaptic processing and provide new insights into how synaptic and network features interact to accomplish physiologically relevant neural computations. PMID:26948896

  2. [Quality of neuronal signal registered in the monkey motor cortex with chronically implanted multiple microwires].

    PubMed

    Bondar', I V; Vasil'eva, L N; Badakva, A M; Miller, N V; Zobova, L N; Roshchin, V Iu

    2014-01-01

    Disconnection of central and peripheral parts of motor system leads to severe forms of disability. However, current research of brain-computer interfaces will solve the problem of rehabilitation of patients with motor disorders in future. Chronic recordings of single-unit activity in specialized areas of cerebral cortex could provide appropriate control signal for effectors with multiple degrees of freedom. In present article we evaluated the quality of chronic single-unit recordings in the primary motor cortex of awake behaving monkeys obtained with bundles of multiple microwires. Action potentials of proper quality were recorded from single units during three months. In some cases up to 7 single units could be extracted on a channel. Recording quality stabilized after 40 days since electrodes were implanted. Ultimately, functionality of multiple electrodes bundle makes it highly usable and reliable instrument for obtaining of control neurophysiologic signal from populations of neurons for brain-computer interfaces. PMID:25710068

  3. The Multiple Signaling Systems Regulating Virulence in Pseudomonas aeruginosa

    PubMed Central

    Nadal Jimenez, Pol; Koch, Gudrun; Thompson, Jessica A.; Xavier, Karina B.; Cool, Robbert H.

    2012-01-01

    Summary: Cell-to-cell communication is a major process that allows bacteria to sense and coordinately react to the fluctuating conditions of the surrounding environment. In several pathogens, this process triggers the production of virulence factors and/or a switch in bacterial lifestyle that is a major determining factor in the outcome and severity of the infection. Understanding how bacteria control these signaling systems is crucial to the development of novel antimicrobial agents capable of reducing virulence while allowing the immune system of the host to clear bacterial infection, an approach likely to reduce the selective pressures for development of resistance. We provide here an up-to-date overview of the molecular basis and physiological implications of cell-to-cell signaling systems in Gram-negative bacteria, focusing on the well-studied bacterium Pseudomonas aeruginosa. All of the known cell-to-cell signaling systems in this bacterium are described, from the most-studied systems, i.e., N-acyl homoserine lactones (AHLs), the 4-quinolones, the global activator of antibiotic and cyanide synthesis (GAC), the cyclic di-GMP (c-di-GMP) and cyclic AMP (cAMP) systems, and the alarmones guanosine tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp), to less-well-studied signaling molecules, including diketopiperazines, fatty acids (diffusible signal factor [DSF]-like factors), pyoverdine, and pyocyanin. This overview clearly illustrates that bacterial communication is far more complex than initially thought and delivers a clear distinction between signals that are quorum sensing dependent and those relying on alternative factors for their production. PMID:22390972

  4. Multiple Signals Regulate PLC beta 3 in Human Myometrial Cells

    PubMed Central

    Zhong, Miao; Murtazina, Dilyara A.; Phillips, Jennifer; Ku, Chun-Ying; Sanborn, Barbara M.

    2008-01-01

    Summary The regulation of PLCB3-Serine1105 phosphorylation by both negative feedback and negative crosstalk facilitates the integration of multiple signaling pathways in myometrial cells. Phospholipase CB3 (PLCB3) Serine1105, a substrate for multiple protein kinases, represents a potential point of convergence of several signaling pathways in the myometrium. To explore this hypothesis, the regulation of PLCB3-Serine1105 phosphorylation (P-S1105) was studied in immortalized and primary human myometrial cells. CPT-cAMP and calcitonin gene-related peptide (CALCA) transiently increased P-S1105. Relaxin also stimulated P-S1105; this effect was partially blocked by the protein kinase A (PRKA) inhibitor Rp-8-CPT-cAMPS. Oxytocin, which stimulates Gαq-mediated pathways, also rapidly increased P-S1105, as did PGF2α and ATP. Oxytocin-stimulated phosphorylation was blocked by the protein kinase C (PRKC) inhibitor Go6976 and by pretreatment overnight with a phorbol ester. Cypermethrin, a PP2B phosphatase inhibitor, but not okadaic acid, a PP1/PP2A inhibitor, prolonged the effect of CALCA on P-S1105, whereas the reverse was the case for the oxytocin-stimulated increase in P-S1105. PLCB3 was the predominant PLC isoform expressed in the myometrial cells and PLCB3 shRNA constructs significantly attenuated oxytocin-stimulated increases in intracellular calcium. Oxytocin-induced phosphatidylinositol (PI) turnover was inhibited by CPT-cAMP and okadaic acid but enhanced by pretreatment with Go6976. CPT-cAMP inhibited oxytocin-stimulated PI turnover in the presence of overexpressed PLCB3, but not overexpressed PLCB3-S1105A. These data demonstrate that both negative crosstalk from the cAMP/PRKA pathway and a negative feedback loop in the oxytocin/G protein/PLCB pathway involving PRKC operate in myometrial cells and suggest that different protein phosphatases predominate in mediating P-S1105 dephosphorylation in these pathways. The integration of multiple signal components at the level

  5. Activation of Notch-Mediated Protective Signaling in the Myocardium

    PubMed Central

    Gude, Natalie A.; Emmanuel, Gregory; Wu, Weitao; Cottage, Christopher T.; Fischer, Kimberlee; Quijada, Pearl; Muraski, John A.; Alvarez, Roberto; Rubio, Marta; Schaefer, Eric; Sussman, Mark A.

    2013-01-01

    The Notch network regulates multiple cellular processes, including cell fate determination, development, differentiation, proliferation, apoptosis, and regeneration. These processes are regulated via Notch-mediated activity that involves hepatocyte growth factor (HGF)/c-Met receptor and phosphatidylinositol 3-kinase/Akt signaling cascades. The impact of HGF on Notch signaling was assessed following myocardial infarction as well as in cultured cardiomyocytes. Notch1 is activated in border zone cardiomyocytes coincident with nuclear c-Met following infarction. Intramyocardial injection of HGF enhances Notch1 and Akt activation in adult mouse myocardium. Corroborating evidence in cultured cardiomyocytes shows treatment with HGF or insulin increases levels of Notch effector Hes1 in immunoblots, whereas overexpression of activated Notch intracellular domain prompts a 3-fold increase in phosphorylated Akt. Infarcted hearts injected with adenoviral vector expressing Notch intracellular domain treatment exhibit improved hemodynamic function in comparison with control mice after 4 weeks, implicating Notch signaling in a cardioprotective role following cardiac injury. These results indicate Notch activation in cardiomyocytes is mediated through c-Met and Akt survival signaling pathways, and Notch1 signaling in turn enhances Akt activity. This mutually supportive crosstalk suggests a positive survival feedback mechanism between Notch and Akt signaling in adult myocardium following injury. PMID:18369158

  6. The Expected Impact of Multiple Scattering on ATLID Signals

    NASA Astrophysics Data System (ADS)

    Donovan, D. P.

    2016-06-01

    ATLID stands for "ATmospheric LIDar" and is the lidar to be flown on the Earth Clouds and Radiation Explorer (EarthCARE) platform in 2018. ATLID is a High-Spectral Resolution (HSRL) system operating at 355nm with a narrower field-of-view and lower orbit than the CALIPSO lidar. In spite of the smaller footprint multiple-scattering (MS) will have an important impact on ATLID cloud signals and, in some aspects, the accurate treatment of MS will be more important for ATLID than CALIPSO. On the other hand, the relationship between integrated backscatter and integrated MS induced depolarization in water clouds will be similar between ATLID and CALIPSO indicating that a CALIPSO-like strategy for cloud-phase identification can be successfully applied to ATLID.

  7. Identifying causal variants at loci with multiple signals of association.

    PubMed

    Hormozdiari, Farhad; Kostem, Emrah; Kang, Eun Yong; Pasaniuc, Bogdan; Eskin, Eleazar

    2014-10-01

    Although genome-wide association studies have successfully identified thousands of risk loci for complex traits, only a handful of the biologically causal variants, responsible for association at these loci, have been successfully identified. Current statistical methods for identifying causal variants at risk loci either use the strength of the association signal in an iterative conditioning framework or estimate probabilities for variants to be causal. A main drawback of existing methods is that they rely on the simplifying assumption of a single causal variant at each risk locus, which is typically invalid at many risk loci. In this work, we propose a new statistical framework that allows for the possibility of an arbitrary number of causal variants when estimating the posterior probability of a variant being causal. A direct benefit of our approach is that we predict a set of variants for each locus that under reasonable assumptions will contain all of the true causal variants with a high confidence level (e.g., 95%) even when the locus contains multiple causal variants. We use simulations to show that our approach provides 20-50% improvement in our ability to identify the causal variants compared to the existing methods at loci harboring multiple causal variants. We validate our approach using empirical data from an expression QTL study of CHI3L2 to identify new causal variants that affect gene expression at this locus. CAVIAR is publicly available online at http://genetics.cs.ucla.edu/caviar/. PMID:25104515

  8. Identifying Causal Variants at Loci with Multiple Signals of Association

    PubMed Central

    Hormozdiari, Farhad; Kostem, Emrah; Kang, Eun Yong; Pasaniuc, Bogdan; Eskin, Eleazar

    2014-01-01

    Although genome-wide association studies have successfully identified thousands of risk loci for complex traits, only a handful of the biologically causal variants, responsible for association at these loci, have been successfully identified. Current statistical methods for identifying causal variants at risk loci either use the strength of the association signal in an iterative conditioning framework or estimate probabilities for variants to be causal. A main drawback of existing methods is that they rely on the simplifying assumption of a single causal variant at each risk locus, which is typically invalid at many risk loci. In this work, we propose a new statistical framework that allows for the possibility of an arbitrary number of causal variants when estimating the posterior probability of a variant being causal. A direct benefit of our approach is that we predict a set of variants for each locus that under reasonable assumptions will contain all of the true causal variants with a high confidence level (e.g., 95%) even when the locus contains multiple causal variants. We use simulations to show that our approach provides 20–50% improvement in our ability to identify the causal variants compared to the existing methods at loci harboring multiple causal variants. We validate our approach using empirical data from an expression QTL study of CHI3L2 to identify new causal variants that affect gene expression at this locus. CAVIAR is publicly available online at http://genetics.cs.ucla.edu/caviar/. PMID:25104515

  9. Recruitment-dance signals draw larger audiences when honey bee colonies have multiple patrilines

    PubMed Central

    Mattila, H. R.; Seeley, T. D.

    2010-01-01

    Honey bee queens (Apis mellifera) who mate with multiple males produce colonies that are filled with numerous genetically distinct patrilines of workers. A genetically diverse colony benefits from an enhanced foraging effort, fuelled in part by an increase in the number of recruitment signals that are produced by foragers. However, the influence of patriline diversity on the attention paid to these signals by audiences of potentially receptive workers remains unexplored. To determine whether recruitment dances performed by foragers in multiple-patriline colonies attract a greater number of dance followers than dances in colonies that lack patriline diversity, we trained workers from multiple- and single-patriline colonies to forage in a greenhouse and monitored their dance-following activity back in the hives. On average, more workers followed a dance if it was performed in a multiple-patriline colony rather than a single-patriline colony (33% increase), and for a greater number of dance circuits per follower. Furthermore, dance-following workers in multiple-patriline colonies were more likely to exit their hive after following a dance, although this did not translate to a difference in colony-level exit rates between treatment types. Recruiting nest mates to profitable food sources through dance communication is critical to a colony’s foraging success and long-term fitness; polyandrous queens produce colonies that benefit not only from increased recruitment signalling, but also from the generation of larger and more attentive audiences of signal receivers. This study highlights the importance of integrating responses of both signal senders and receivers to understand more fully the success of animal-communication systems. PMID:21350596

  10. AMPylation of Rho GTPases Subverts Multiple Host Signaling Processes*

    PubMed Central

    Woolery, Andrew R.; Yu, Xiaobo; LaBaer, Joshua; Orth, Kim

    2014-01-01

    Rho GTPases are frequent targets of virulence factors as they are keystone signaling molecules. Herein, we demonstrate that AMPylation of Rho GTPases by VopS is a multifaceted virulence mechanism that counters several host immunity strategies. Activation of NFκB, Erk, and JNK kinase signaling pathways were inhibited in a VopS-dependent manner during infection with Vibrio parahaemolyticus. Phosphorylation and degradation of IKBα were inhibited in the presence of VopS as was nuclear translocation of the NFκB subunit p65. AMPylation also prevented the generation of superoxide by the phagocytic NADPH oxidase complex, potentially by inhibiting the interaction of Rac and p67. Furthermore, the interaction of GTPases with the E3 ubiquitin ligases cIAP1 and XIAP was hindered, leading to decreased degradation of Rac and RhoA during infection. Finally, we screened for novel Rac1 interactions using a nucleic acid programmable protein array and discovered that Rac1 binds to the protein C1QA, a protein known to promote immune signaling in the cytosol. Interestingly, this interaction was disrupted by AMPylation. We conclude that AMPylation of Rho Family GTPases by VopS results in diverse inhibitory consequences during infection beyond the most obvious phenotype, the collapse of the actin cytoskeleton. PMID:25301945

  11. Structure of the EGF receptor transactivation circuit integrates multiple signals with cell context

    SciTech Connect

    Joslin, Elizabeth J.; Shankaran, Harish; Opresko, Lee K.; Bollinger, Nikki; Lauffenburger, Douglas A.; Wiley, H. S.

    2010-05-10

    Transactivation of the epidermal growth factor receptor (EGFR) has been proposed to be a mechanism by which a variety of cellular inputs can be integrated into a single signaling pathway, but the regulatory topology of this important system is unclear. To understand the transactivation circuit, we first created a “non-binding” reporter for ligand shedding. We then quantitatively defined how signals from multiple agonists were integrated both upstream and downstream of the EGFR into the extracellular signal regulated kinase (ERK) cascade in human mammary epithelial cells. We found that transactivation is mediated by a recursive autocrine circuit where ligand shedding drives EGFR-stimulated ERK that in turn drives further ligand shedding. The time from shedding to ERK activation is fast (<5 min) whereas the recursive feedback is slow (>15 min). Simulations showed that this delay in positive feedback greatly enhanced system stability and robustness. Our results indicate that the transactivation circuit is constructed so that the magnitude of ERK signaling is governed by the sum of multiple direct inputs, while recursive, autocrine ligand shedding controls signal duration.

  12. Romidepsin targets multiple survival signaling pathways in malignant T cells.

    PubMed

    Valdez, B C; Brammer, J E; Li, Y; Murray, D; Liu, Y; Hosing, C; Nieto, Y; Champlin, R E; Andersson, B S

    2015-01-01

    Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC50 values of 10.8, 7.9 and 7.0 nm in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and β-catenin pro-survival pathways were inhibited. The decreased level of β-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies. PMID:26473529

  13. Romidepsin targets multiple survival signaling pathways in malignant T cells

    PubMed Central

    Valdez, B C; Brammer, J E; Li, Y; Murray, D; Liu, Y; Hosing, C; Nieto, Y; Champlin, R E; Andersson, B S

    2015-01-01

    Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC50 values of 10.8, 7.9 and 7.0 nm in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and β-catenin pro-survival pathways were inhibited. The decreased level of β-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies. PMID:26473529

  14. Following the trail of lipids: Signals initiated by PI3K function at multiple cellular membranes.

    PubMed

    Naguib, Adam

    2016-01-01

    Phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] is the signaling currency of the phosphoinositide 3-kinase (PI3K)/AKT pathway; transduction through this axis depends on this signaling lipid. Formation of PtdIns(3,4,5)P3 is dictated not only by PI3K activation but also by the localization and access of PI3K to its substrate PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate). PI3K/AKT-mediated signaling is antagonized by PtdIns(3,4,5)P3 dephosphorylation. Although previously typically considered an event associated with the plasma membrane, it is now appreciated that the formation and metabolism of PtdIns(3,4,5)P3 occur on multiple membranes with distinct kinetics. Modulated activity of phosphatidylinositol lipid kinases and phosphatases contributes to intricately orchestrated lipid gradients that define the signaling status of the pathway at multiple sites within the cell. PMID:27188443

  15. Paired inhibitory and activating receptor signals.

    PubMed

    Taylor, L S; Paul, S P; McVicar, D W

    2000-01-01

    The immunological literature has become inundated with reports regarding paired inhibitory receptors. Paired inhibitory receptor systems are highly conserved families that contain receptors involved in either cellular inhibition or activation. In most cases the paired putative biochemical antagonists are co-expressed on a given cell and thought to bind similar, if not identical, ligands making their biological role difficult to understand. Examples of these systems include immunoglobulin (Ig)-like receptors (Killer Ig Receptors, Immunoglobulin-like Transcripts/Leukocyte Ig-like Receptors/Monocyte Macrophage Ig Receptors, and Paired Ig-like Receptors), and type II lectin-like receptor systems (NKG2 and Ly49). General characteristics of these inhibitory receptors include a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM). The ITIM is phosphorylated upon engagement and recruits protein tyrosine phosphatases that dephosphorylate cellular substrates that would otherwise mediate activation. In contrast, the activating receptors of these pairs use charged residues within their transmembrane domains to associate with various signal transduction chains including the gamma chain of the receptor for the Fc portion of IgE, DAP12 or DAP10. Once phosphorylated, these chains direct the signal transduction cascade resulting in cellular activation. Here we review the signaling of several paired systems and present the current models for their signal transduction cascades. PMID:11258418

  16. Cellular phosphatases facilitate combinatorial processing of receptor-activated signals

    PubMed Central

    Kumar, Dhiraj; Dua, Raina; Srikanth, Ravichandran; Jayaswal, Shilpi; Siddiqui, Zaved; Rao, Kanury VS

    2008-01-01

    Background Although reciprocal regulation of protein phosphorylation represents a key aspect of signal transduction, a larger perspective on how these various interactions integrate to contribute towards signal processing is presently unclear. For example, a key unanswered question is that of how phosphatase-mediated regulation of phosphorylation at the individual nodes of the signaling network translates into modulation of the net signal output and, thereby, the cellular phenotypic response. Results To address the above question we, in the present study, examined the dynamics of signaling from the B cell antigen receptor (BCR) under conditions where individual cellular phosphatases were selectively depleted by siRNA. Results from such experiments revealed a highly enmeshed structure for the signaling network where each signaling node was linked to multiple phosphatases on the one hand, and each phosphatase to several nodes on the other. This resulted in a configuration where individual signaling intermediates could be influenced by a spectrum of regulatory phosphatases, but with the composition of the spectrum differing from one intermediate to another. Consequently, each node differentially experienced perturbations in phosphatase activity, yielding a unique fingerprint of nodal signals characteristic to that perturbation. This heterogeneity in nodal experiences, to a given perturbation, led to combinatorial manipulation of the corresponding signaling axes for the downstream transcription factors. Conclusion Our cumulative results reveal that it is the tight integration of phosphatases into the signaling network that provides the plasticity by which perturbation-specific information can be transmitted in the form of a multivariate output to the downstream transcription factor network. This output in turn specifies a context-defined response, when translated into the resulting gene expression profile. PMID:18798986

  17. Targeting Apoptosis and Multiple Signaling Pathways with Icariside II in Cancer Cells

    PubMed Central

    Khan, Muhammad; Maryam, Amara; Qazi, Javed Iqbal; Ma, Tonghui

    2015-01-01

    Cancer is the second leading cause of deaths worldwide. Despite concerted efforts to improve the current therapies, the prognosis of cancer remains dismal. Highly selective or specific blocking of only one of the signaling pathways has been associated with limited or sporadic responses. Using targeted agents to inhibit multiple signaling pathways has emerged as a new paradigm for anticancer treatment. Icariside II, a flavonol glycoside, is one of the major components of Traditional Chinese Medicine Herba epimedii and possesses multiple biological and pharmacological properties including anti-inflammatory, anti-osteoporosis, anti-oxidant, anti-aging, and anticancer activities. Recently, the anticancer activity of Icariside II has been extensively investigated. Here, in this review, our aim is to give our perspective on the current status of Icariside II, and discuss its natural sources, anticancer activity, molecular targets and the mechanisms of action with specific emphasis on apoptosis pathways which may help the further design and conduct of preclinical and clinical trials. Icariside II has been found to induce apoptosis in various human cancer cell lines of different origin by targeting multiple signaling pathways including STAT3, PI3K/AKT, MAPK/ERK, COX-2/PGE2 and β-Catenin which are frequently deregulated in cancers, suggesting that this collective activity rather than just a single effect may play an important role in developing Icariside II into a potential lead compound for anticancer therapy. This review suggests that Icariside II provides a novel opportunity for treatment of cancers, but additional investigations and clinical trials are still required to fully understand the mechanism of therapeutic effects to further validate it in anti-tumor therapy. PMID:26221076

  18. Chemical activation of a food deprivation signal extends lifespan.

    PubMed

    Lucanic, Mark; Garrett, Theo; Yu, Ivan; Calahorro, Fernando; Asadi Shahmirzadi, Azar; Miller, Aaron; Gill, Matthew S; Hughes, Robert E; Holden-Dye, Lindy; Lithgow, Gordon J

    2016-10-01

    Model organisms subject to dietary restriction (DR) generally live longer. Accompanying this lifespan extension are improvements in overall health, based on multiple metrics. This indicates that pharmacological treatments that mimic the effects of DR could improve health in humans. To find new chemical structures that extend lifespan, we screened 30 000 synthetic, diverse drug-like chemicals in Caenorhabditis elegans and identified several structurally related compounds that acted through DR mechanisms. The most potent of these NP1 impinges upon a food perception pathway by promoting glutamate signaling in the pharynx. This results in the overriding of a GPCR pathway involved in the perception of food and which normally acts to decrease glutamate signals. Our results describe the activation of a dietary restriction response through the pharmacological masking of a novel sensory pathway that signals the presence of food. This suggests that primary sensory pathways may represent novel targets for human pharmacology. PMID:27220516

  19. Activity Dependent Signal Transduction in Skeletal Muscle

    NASA Technical Reports Server (NTRS)

    Hamilton, Susan L.

    1999-01-01

    The overall goals of this project are: 1) to define the initial signal transduction events whereby the removal of gravitational load from antigravity muscles, such as the soleus, triggers muscle atrophy, and 2) to develop countermeasures to prevent this from happening. Our rationale for this approach is that, if countermeasures can be developed to regulate these early events, we could avoid having to deal with the multiple cascades of events that occur downstream from the initial event. One of our major findings is that hind limb suspension causes an early and sustained increase in intracellular Ca(2+) concentration ([Ca (2+)](sub i)). In most cells the consequences of changes in ([Ca (2+)](sub i))depend on the amplitude, frequency and duration of the Ca(2+) signal and on other factors in the intracellular environment. We propose that muscle remodeling in microgravity represents a change in the balance among several CA(2+) regulated signal transduction pathways, in particular those involving the transcription factors NFAT and NFkB and the pro-apoptotic protein BAD. Other Ca(2+) sensitive pathways involving PKC, ras, rac, and CaM kinase II may also contribute to muscle remodeling.

  20. Multiple Running Speed Signals in Medial Entorhinal Cortex.

    PubMed

    Hinman, James R; Brandon, Mark P; Climer, Jason R; Chapman, G William; Hasselmo, Michael E

    2016-08-01

    Grid cells in medial entorhinal cortex (MEC) can be modeled using oscillatory interference or attractor dynamic mechanisms that perform path integration, a computation requiring information about running direction and speed. The two classes of computational models often use either an oscillatory frequency or a firing rate that increases as a function of running speed. Yet it is currently not known whether these are two manifestations of the same speed signal or dissociable signals with potentially different anatomical substrates. We examined coding of running speed in MEC and identified these two speed signals to be independent of each other within individual neurons. The medial septum (MS) is strongly linked to locomotor behavior, and removal of MS input resulted in strengthening of the firing rate speed signal, while decreasing the strength of the oscillatory speed signal. Thus, two speed signals are present in MEC that are differentially affected by disrupted MS input. PMID:27427460

  1. Constitutive CD40 Signaling Calibrates Differentiation Outcomes in Responding B Cells via Multiple Molecular Pathways.

    PubMed

    Basu, Srijani; Kaw, Sheetal; D'Souza, Lucas; Vaidya, Tushar; Bal, Vineeta; Rath, Satyajit; George, Anna

    2016-08-01

    CD40 signaling during B cell activation is known to inhibit terminal differentiation and promote memory generation. Blimp-1 is essential for efficient plasma cell (PC) generation, and although CD40 signaling is known to inhibit Blimp-1 induction during B cell activation, the mechanisms involved have been unclear. We report that CD40 signaling induces miR-125b that targets Blimp-1 transcripts, and increases amounts of the ubiquitin ligase Hrd1 that targets BLIMP-1 protein for proteasomal degradation. CD40 signaling also inhibits the early unfolded protein response (UPR) of activated B cells that precedes the induction of terminal differentiation, and Hrd1 feeds into this pathway by targeting the core UPR component IRE-1α. Strikingly, CD40 signaling in the absence of BCR- or TLR-ligation also repressed Blimp-1 transcripts, suggesting that noncognate ligation of CD40 via T-B interactions may repress Blimp-1 in vivo. In support of this, we find that naive B cells purified from CD40-CD154 interaction-deficient mice express higher amounts of Blimp-1 and lower amounts of microRNAs and Hrd1. Higher basal amounts of Blimp-1 in naive CD40(-/-) B cells correlate with an increased tendency of the cells to undergo terminal differentiation upon LPS stimulation. Conversely, a 24-h exposure to CD40 ligation during LPS stimulation of wild-type B cells is sufficient to inhibit PC generation. The data show that CD40-mediated inhibition of PC generation is via engagement of multiple pathways that involve repression of Blimp-1 and inhibition of the UPR that prepares cells to become professional secretors. They also show that constitutive CD40 signaling in vivo involving bystander T-B interactions can calibrate B cell differentiation outcomes. PMID:27342845

  2. FGFR3 Deficiency Causes Multiple Chondroma-like Lesions by Upregulating Hedgehog Signaling

    PubMed Central

    Zhou, Siru; Xie, Yangli; Tang, Junzhou; Huang, Junlan; Huang, Qizhao; Xu, Wei; Wang, Zuqiang; Luo, Fengtao; Wang, Quan; Chen, Hangang; Du, Xiaolan; Shen, Yue; Chen, Di; Chen, Lin

    2015-01-01

    Most cartilaginous tumors are formed during skeletal development in locations adjacent to growth plates, suggesting that they arise from disordered endochondral bone growth. Fibroblast growth factor receptor (FGFR)3 signaling plays essential roles in this process; however, the role of FGFR3 in cartilaginous tumorigenesis is not known. In this study, we found that postnatal chondrocyte-specific Fgfr3 deletion induced multiple chondroma-like lesions, including enchondromas and osteochondromas, adjacent to disordered growth plates. The lesions showed decreased extracellular signal-regulated kinase (ERK) activity and increased Indian hedgehog (IHH) expression. The same was observed in Fgfr3-deficient primary chondrocytes, in which treatment with a mitogen-activated protein kinase (MEK) inhibitor increased Ihh expression. Importantly, treatment with an inhibitor of IHH signaling reduced the occurrence of chondroma-like lesions in Fgfr3-deficient mice. This is the first study reporting that the loss of Fgfr3 function leads to the formation of chondroma-like lesions via downregulation of MEK/ERK signaling and upregulation of IHH, suggesting that FGFR3 has a tumor suppressor-like function in chondrogenesis. PMID:26091072

  3. Andrographolide inhibits multiple myeloma cells by inhibiting the TLR4/NF-κB signaling pathway.

    PubMed

    Gao, Hui; Wang, Jianrong

    2016-02-01

    Andrographolide is an active component from the extract of Andrographis paniculata [(Burm.f) Nees], a medicinal plant from the Acanthaceae family. Pharmacological studies have revealed that andrographolide possesses anti-bacterial, anti-inflammatory, anti-viral, immune regulatory and hepatoprotective properties, and is efficacious in the treatment of cardiovascular diseases, while exhibiting low toxicity and low cost. The present study aimed to determine the inhibitory effects of andrographolide on the growth of multiple myeloma (MM) cells and its possible impact on the Toll-like receptor (TLR)4/nuclear factor (NF)-κB signaling pathway. Cell proliferation was detected using an MTT assay, cellular apoptosis was measured using flow cytometry, and caspase-9/3 activation were assessed using colorimetric assay kits. Furthermore, TLR4 and NF-κB protein expression was determined by western blot analysis. The results revealed that andrographolide reduced the proliferation, while increasing cellular apoptosis and caspase-9/3 activation of MM cells, in addition to downregulating the expression of TLR4 and NF-κB protein. Of note, TLR4- or NF-κB-targeting small-interfering (si)RNA enhanced the andrographolide-induced inhibition of cell proliferation and induction of apoptosis of MM cells. The results of the present study therefore suggested that andrographolide inhibited multiple myeloma cells via the TLR4/NF-κB signaling pathway. PMID:26707811

  4. Multiple Model-Informed Open-Loop Control of Uncertain Intracellular Signaling Dynamics

    PubMed Central

    Perley, Jeffrey P.; Mikolajczak, Judith; Harrison, Marietta L.; Buzzard, Gregery T.; Rundell, Ann E.

    2014-01-01

    Computational approaches to tune the activation of intracellular signal transduction pathways both predictably and selectively will enable researchers to explore and interrogate cell biology with unprecedented precision. Techniques to control complex nonlinear systems typically involve the application of control theory to a descriptive mathematical model. For cellular processes, however, measurement assays tend to be too time consuming for real-time feedback control and models offer rough approximations of the biological reality, thus limiting their utility when considered in isolation. We overcome these problems by combining nonlinear model predictive control with a novel adaptive weighting algorithm that blends predictions from multiple models to derive a compromise open-loop control sequence. The proposed strategy uses weight maps to inform the controller of the tendency for models to differ in their ability to accurately reproduce the system dynamics under different experimental perturbations (i.e. control inputs). These maps, which characterize the changing model likelihoods over the admissible control input space, are constructed using preexisting experimental data and used to produce a model-based open-loop control framework. In effect, the proposed method designs a sequence of control inputs that force the signaling dynamics along a predefined temporal response without measurement feedback while mitigating the effects of model uncertainty. We demonstrate this technique on the well-known Erk/MAPK signaling pathway in T cells. In silico assessment demonstrates that this approach successfully reduces target tracking error by 52% or better when compared with single model-based controllers and non-adaptive multiple model-based controllers. In vitro implementation of the proposed approach in Jurkat cells confirms a 63% reduction in tracking error when compared with the best of the single-model controllers. This study provides an experimentally

  5. Multiple model-informed open-loop control of uncertain intracellular signaling dynamics.

    PubMed

    Perley, Jeffrey P; Mikolajczak, Judith; Harrison, Marietta L; Buzzard, Gregery T; Rundell, Ann E

    2014-04-01

    Computational approaches to tune the activation of intracellular signal transduction pathways both predictably and selectively will enable researchers to explore and interrogate cell biology with unprecedented precision. Techniques to control complex nonlinear systems typically involve the application of control theory to a descriptive mathematical model. For cellular processes, however, measurement assays tend to be too time consuming for real-time feedback control and models offer rough approximations of the biological reality, thus limiting their utility when considered in isolation. We overcome these problems by combining nonlinear model predictive control with a novel adaptive weighting algorithm that blends predictions from multiple models to derive a compromise open-loop control sequence. The proposed strategy uses weight maps to inform the controller of the tendency for models to differ in their ability to accurately reproduce the system dynamics under different experimental perturbations (i.e. control inputs). These maps, which characterize the changing model likelihoods over the admissible control input space, are constructed using preexisting experimental data and used to produce a model-based open-loop control framework. In effect, the proposed method designs a sequence of control inputs that force the signaling dynamics along a predefined temporal response without measurement feedback while mitigating the effects of model uncertainty. We demonstrate this technique on the well-known Erk/MAPK signaling pathway in T cells. In silico assessment demonstrates that this approach successfully reduces target tracking error by 52% or better when compared with single model-based controllers and non-adaptive multiple model-based controllers. In vitro implementation of the proposed approach in Jurkat cells confirms a 63% reduction in tracking error when compared with the best of the single-model controllers. This study provides an experimentally

  6. Activators of G Protein Signaling in the Kidney

    PubMed Central

    2015-01-01

    Heterotrimeric G proteins play a crucial role in regulating signal processing to maintain normal cellular homeostasis, and subtle perturbations in its activity can potentially lead to the pathogenesis of renal disorders or diseases. Cell-surface receptors and accessory proteins, which normally modify and organize the coupling of individual G protein subunits, contribute to the regulation of heterotrimeric G protein activity and their convergence and/or divergence of downstream signaling initiated by effector systems. Activators of G protein signaling (AGS) are a family of accessory proteins that intervene at multiple distinct points during the activation–inactivation cycle of G proteins, even in the absence of receptor stimulation. Perturbations in the expression of individual AGS proteins have been reported to modulate signal transduction pathways in a wide array of diseases and disorders within the brain, heart, immune system, and more recently, the kidney. This review will provide an overview of the expression profile, localization, and putative biologic role of the AGS family in the context of normal and diseased states of the kidney. PMID:25628392

  7. Application of differential analysis of VLF signals for seismic-ionospheric precursor detection from multiple receivers

    NASA Astrophysics Data System (ADS)

    Skeberis, Christos; Zaharis, Zaharias; Xenos, Thomas; Contadakis, Michael; Stratakis, Dimitrios; Tommaso, Maggipinto; Biagi, Pier Francesco

    2015-04-01

    This study investigates the application of differential analysis on VLF signals emitted from a single transmitter and received by multiple stations in order to filter and detect disturbances that can be attributed to seismic-ionospheric precursor phenomena. The cross-correlation analysis applied on multiple VLF signals provides a way of discerning the nature of a given disturbance and accounts for more widespread geomagnetic interferences compared to local precursor phenomena. For the purpose of this paper, data acquired in Thessaloniki (40.59N, 22,78E) and in Heraklion (35.31N, 25.10E) from the VLF station in Tavolara, Italy (ICV station Lat. 40.923, Lon. 9.731) for a period of four months (September 2014 - December 2014) are used. The receivers have been developed by Elettronika Srl and are part of the International Network for Frontier Research on Earthquake Precursors (INFREP). A normalization process and an improved variant of the Hilbert-Huang transform are initially applied to the received VLF signals. The signals derived from the first two Intrinsic Mode Functions (IMF1 and IMF2) undergo a cross-correlation analysis and, in this way, time series from the two receivers can be compared. The efficacy of the processing method and the results produced by the proposed process are then discussed. Finally, results are presented along with an evaluation of the discrimination and detection capabilities of the method on disturbances of the received signals. Based upon the results, the merits of such a processing method are discussed to further improve the current method by using differential analysis to better classify between different disturbances but, more importantly, discriminate between points of interest in the provided spectra. This could provide an improved method of detecting disturbances attributed to seismic-ionospheric precursor phenomena and also contribute to a real-time method for correlating seismic activity with the observed disturbances.

  8. Intracortical Multiplication of Thalamocortical Signals in Mouse Auditory Cortex

    PubMed Central

    Li, Ling-yun; Li, Ya-tang; Zhou, Mu; Tao, Huizhong W.; Zhang, Li I.

    2013-01-01

    Cortical processing of sensory information initiates from the transformation of thalamically-relayed signals. By optogenetically silencing intracortical circuits to isolate thalamic inputs to layer 4 neurons, we show that intracortical excitation linearly amplifies thalamocortical responses underlying frequency and direction selectivity with preserved spectral range and tuning, and prolongs the response duration. This signal pre-amplification and prolongation enhances the salience of thalamocortically-relayed information and ensures its robust, faithful and more persistent representation. PMID:23933752

  9. Notum deacylates Wnts to suppress signalling activity

    PubMed Central

    Howell, Steve; Chang, Tao-Hsin; Liu, Yan; Feizi, Ten; Bineva, Ganka; O’Reilly, Nicola; Snijders, Ambrosius P.; Jones, E. Yvonne; Vincent, Jean-Paul

    2015-01-01

    Signalling by Wnts is finely balanced to ensure normal development and tissue homeostasis while avoiding diseases such as cancer. This is achieved in part by Notum, a highly conserved secreted feedback antagonist. Notum has been thought to act as a phospholipase, shedding glypicans and associated Wnts from the cell surface. However, this view fails to explain specificity since glypicans bind many extracellular ligands. Here we provide genetic evidence in Drosophila that Notum requires glypicans to suppress Wnt signalling, but does not cleave their glycophosphatidylinositol anchor. Structural analyses reveal glycosaminoglycan binding sites on Notum, which likely help Notum colocalise with Wnts. They also identify, at the active site of human and Drosophila Notum, a large hydrophobic pocket that accommodates palmitoleate. Kinetic and mass spectrometric analyses of human proteins show that Notum is a carboxylesterase that removes an essential palmitoleate moiety from Wnts and thus constitutes the first known extracellular protein deacylase. PMID:25731175

  10. Signal Design for Improved Ranging Among Multiple Transceivers

    NASA Technical Reports Server (NTRS)

    Young, Lawrence; Tien, Jeffrey; Srinivasan, Jeffrey

    2004-01-01

    "Ultra-BOC" (where "BOC" signifies "binary offset carrier") is the name of an improved generic design of microwave signals to be used by a group of spacecraft flying in formation to measure ranges and bearings among themselves and to exchange telemetry needed for these measurements. Ultra-BOC could also be applied on Earth for diverse purposes -- for example, measuring relative positions of vehicles on highways for traffic-control purposes and determining the relative alignments of machines operating in mines and of construction machines and structures at construction sites. Ultra-BOC provides for rapid and robust acquisition of signals, even when signal-to-noise ratios are low. The design further provides that each spacecraft or other platform constantly strives to acquire and track the signals from the other platforms while simultaneously transmitting signals that provide full range, bearing, and telemetry service to the other platforms. In Ultra-BOC, unlike in other signal designs that have been considered for the same purposes, it is not necessary to maneuver the spacecraft or other platforms to obtain the data needed for resolving integer-carrier-cycle phase ambiguities.

  11. Regularized Embedded Multiple Kernel Dimensionality Reduction for Mine Signal Processing

    PubMed Central

    Li, Shuang; Liu, Bing; Zhang, Chen

    2016-01-01

    Traditional multiple kernel dimensionality reduction models are generally based on graph embedding and manifold assumption. But such assumption might be invalid for some high-dimensional or sparse data due to the curse of dimensionality, which has a negative influence on the performance of multiple kernel learning. In addition, some models might be ill-posed if the rank of matrices in their objective functions was not high enough. To address these issues, we extend the traditional graph embedding framework and propose a novel regularized embedded multiple kernel dimensionality reduction method. Different from the conventional convex relaxation technique, the proposed algorithm directly takes advantage of a binary search and an alternative optimization scheme to obtain optimal solutions efficiently. The experimental results demonstrate the effectiveness of the proposed method for supervised, unsupervised, and semisupervised scenarios. PMID:27247562

  12. Regularized Embedded Multiple Kernel Dimensionality Reduction for Mine Signal Processing.

    PubMed

    Li, Shuang; Liu, Bing; Zhang, Chen

    2016-01-01

    Traditional multiple kernel dimensionality reduction models are generally based on graph embedding and manifold assumption. But such assumption might be invalid for some high-dimensional or sparse data due to the curse of dimensionality, which has a negative influence on the performance of multiple kernel learning. In addition, some models might be ill-posed if the rank of matrices in their objective functions was not high enough. To address these issues, we extend the traditional graph embedding framework and propose a novel regularized embedded multiple kernel dimensionality reduction method. Different from the conventional convex relaxation technique, the proposed algorithm directly takes advantage of a binary search and an alternative optimization scheme to obtain optimal solutions efficiently. The experimental results demonstrate the effectiveness of the proposed method for supervised, unsupervised, and semisupervised scenarios. PMID:27247562

  13. Implementation of linear sensory signaling via multiple coordinated mechanisms at central vestibular nerve synapses

    PubMed Central

    McElvain, Lauren E.; Faulstich, Michael; Jeanne, James M.; Moore, Jeffrey D.; du Lac, Sascha

    2015-01-01

    Summary Signal transfer in neural circuits is dynamically modified by the recent history of neuronal activity. Short-term plasticity endows synapses with nonlinear transmission properties, yet synapses in sensory and motor circuits are capable of signaling linearly over a wide range of presynaptic firing rates. How do such synapses achieve rate-invariant transmission despite history-dependent nonlinearities? Here, ultrastructural, biophysical, and computational analyses demonstrate that concerted molecular, anatomical, and physiological refinements are required for central vestibular nerve synapses to linearly transmit rate-coded sensory signals. Vestibular synapses operate in a physiological regime of steady-state depression imposed by tonic firing. Rate-invariant transmission relies on brief presynaptic action potentials that delimit calcium influx, large pools of rapidly mobilized vesicles, multiple low-probability release sites, robust postsynaptic receptor sensitivity, and efficient transmitter clearance. Broadband linear synaptic filtering of head motion signals is thus achieved by coordinately tuned synaptic machinery that maintains physiological operation within inherent cell biological limitations. PMID:25704949

  14. Effects of multiple scattering on scintillation of transionospheric radio signals

    NASA Technical Reports Server (NTRS)

    Liu, C. H.; Yeh, K. C.; Youakim, M. Y.; Wernik, A. W.

    1974-01-01

    Recent development in the optical scintillation theory has been adapted to the ionospheric geometry in order to study the ionospheric scintillation phenomenon in the presence of multiple scattering. Under approximations well satisfied in typical ionospheres for a frequency above about 20 MHz, the first through fourth moment equations have been derived and some analytic solutions given. The fourth moment equation has also been solved numerically. The numerical results show clearly the occurrence of focusing and saturation phenomena. The new multiple-scatter effects are emphasized.

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

    PubMed Central

    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

  16. Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma.

    PubMed

    Hunsucker, Sally A; Magarotto, Valeria; Kuhn, Deborah J; Kornblau, Steven M; Wang, Michael; Weber, Donna M; Thomas, Sheeba K; Shah, Jatin J; Voorhees, Peter M; Xie, Hong; Cornfeld, Mark; Nemeth, Jeffrey A; Orlowski, Robert Z

    2011-03-01

    Signalling through the interleukin (IL)-6 pathway induces proliferation and drug resistance of multiple myeloma cells. We therefore sought to determine whether the IL-6-neutralizing monoclonal antibody siltuximab, formerly CNTO 328, could enhance the activity of melphalan, and to examine some of the mechanisms underlying this interaction. Siltuximab increased the cytotoxicity of melphalan in KAS-6/1, INA-6, ANBL-6, and RPMI 8226 human myeloma cell lines (HMCLs) in an additive-to-synergistic manner, and sensitized resistant RPMI 8226.LR5 cells to melphalan. These anti-proliferative effects were accompanied by enhanced activation of drug-specific apoptosis in HMCLs grown in suspension, and in HMCLs co-cultured with a human-derived stromal cell line. Siltuximab with melphalan enhanced activation of caspase-8, caspase-9, and the downstream effector caspase-3 compared with either of the single agents. This increased induction of cell death occurred in association with enhanced Bak activation. Neutralization of IL-6 also suppressed signalling through the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased phosphorylation of Akt, p70 S6 kinase and 4E-BP1. Importantly, the siltuximab/melphalan regimen demonstrated enhanced anti-proliferative effects against primary plasma cells derived from patients with myeloma, monoclonal gammopathy of undetermined significance, and amyloidosis. These studies provide a rationale for translation of siltuximab into the clinic in combination with melphalan-based therapies. PMID:21241278

  17. Stretchable Multichannel Electromyography Sensor Array Covering Large Area for Controlling Home Electronics with Distinguishable Signals from Multiple Muscles.

    PubMed

    Kim, Namyun; Lim, Taehoon; Song, Kwangsun; Yang, Sung; Lee, Jongho

    2016-08-17

    Physiological signals provide important information for biomedical applications and, more recently, in the form of wearable electronics for active interactions between bodies and external environments. Multiple physiological sensors are often required to map distinct signals from multiple points over large areas for more diverse applications. In this paper, we present a reusable, multichannel, surface electromyography (EMG) sensor array that covers multiple muscles over relatively large areas, with compliant designs that provide different levels of stiffness for repetitive uses, without backing layers. Mechanical and electrical characteristics along with distinct measurements from different muscles demonstrate the feasibility of the concept. The results should be useful to actively control devices in the environment with one array of wearable sensors, as demonstrated with home electronics. PMID:27500864

  18. Biomechanical Signals Suppress TAK1 Activation to Inhibit NF-κB Transcriptional Activation in Fibrochondrocytes

    PubMed Central

    Madhavan, Shashi; Anghelina, Mirela; Sjostrom, Danen; Dossumbekova, Anar; Guttridge, Denis C.; Agarwal, Sudha

    2016-01-01

    Exercise/joint mobilization is therapeutic for inflammatory joint diseases like rheumatoid and osteoarthritis, but the mechanisms underlying its actions remain poorly understood. We report that biomechanical signals at low/physiological magnitudes are potent inhibitors of inflammation induced by diverse proinflammatory activators like IL-1β, TNF-α, and lipopolysaccharides, in fibrochondrocytes. These signals exert their anti-inflammatory effects by inhibiting phosphorylation of TAK1, a critical point where signals generated by IL-1β, TNF-α, and LPS converge to initiate NF-κB signaling cascade and proinflammatory gene induction. Additionally, biomechanical signals inhibit multiple steps in the IL-1β-induced proinflammatory cascade downstream of IκB kinase activation to regulate IκBα and IκBβ degradation and synthesis, and promote IκBα shuttling to export nuclear NF-κB and terminate its transcriptional activity. The findings demonstrate that biomechanical forces are but another important signal that uses NF-κB pathway to regulate inflammation by switching the molecular activation of discrete molecules involved in proinflammatory gene transcription. PMID:17947700

  19. Adaptive frequency estimation by MUSIC (Multiple Signal Classification) method

    NASA Astrophysics Data System (ADS)

    Karhunen, Juha; Nieminen, Esko; Joutsensalo, Jyrki

    During the last years, the eigenvector-based method called MUSIC has become very popular in estimating the frequencies of sinusoids in additive white noise. Adaptive realizations of the MUSIC method are studied using simulated data. Several of the adaptive realizations seem to give in practice equally good results as the nonadaptive standard realization. The only exceptions are instantaneous gradient type algorithms that need considerably more samples to achieve a comparable performance. A new method is proposed for constructing initial estimates to the signal subspace. The method improves often dramatically the performance of instantaneous gradient type algorithms. The new signal subspace estimate can also be used to define a frequency estimator directly or to simplify eigenvector computation.

  20. Storage and switching of multiple optical signals among three channels

    SciTech Connect

    Song Xiaoli; Li Aijun; Wang Lei; Kang Zhihui; Kou Jun; Wang Chunliang; Jiang Yun; Gao Jinyue; Zhang Bing

    2009-05-15

    We experimentally and theoretically demonstrate that multioptical signals can be effectively stored and retrieved by fractional stimulated Raman adiabatic passage technique in a tripod-type four-level {sup 87}Rb atomic system. The optical pulses stored can be controllably released into two of the three different channels. The restored pulses have the same frequency, polarization, and propagation direction as the writing pulses. The experimental results fit very well with the numerical simulations.

  1. Code division multiple access signaling for modulated reflector technology

    DOEpatents

    Briles, Scott D.

    2012-05-01

    A method and apparatus for utilizing code division multiple access in modulated reflectance transmissions comprises the steps of generating a phase-modulated reflectance data bit stream; modifying the modulated reflectance data bit stream; providing the modified modulated reflectance data bit stream to a switch that connects an antenna to an infinite impedance in the event a "+1" is to be sent, or connects the antenna to ground in the event a "0" or a "-1" is to be sent.

  2. Multiple Functions of Endocannabinoid Signaling in the Brain

    PubMed Central

    Katona, István; Freund, Tamás F.

    2014-01-01

    Despite being regarded as a hippie science for decades, cannabinoid research has finally found its well-deserved position in mainstream neuroscience. A series of groundbreaking discoveries revealed that endocannabinoid molecules are as widespread and important as conventional neurotransmitters like glutamate or GABA, yet act in profoundly unconventional ways. We aim to illustrate how uncovering the molecular, anatomical and physiological characteristics of endocannabinoid signaling revealed new mechanistic insights into several fundamental phenomena in synaptic physiology. First, we summarize unexpected advances in the molecular complexity of biogenesis and inactivation of the two endocannabinoids, anandamide and 2-arachidonoylglycerol. Then we show how these new metabolic routes are integrated into well-known intracellular signaling pathways. These endocannabinoid-producing signalosomes operate in phasic and tonic modes thereby differentially governing homeostatic, short-term and long-term synaptic plasticity throughout the brain. Finally, we discuss how cell type- and synapse-specific refinement of endocannabinoid signaling may explain the characteristic behavioral effects of cannabinoids. PMID:22524785

  3. MicroRNAs targeting TGFβ signalling underlie the regulatory T cell defect in multiple sclerosis.

    PubMed

    Severin, Mary E; Lee, Priscilla W; Liu, Yue; Selhorst, Amanda J; Gormley, Matthew G; Pei, Wei; Yang, Yuhong; Guerau-de-Arellano, Mireia; Racke, Michael K; Lovett-Racke, Amy E

    2016-06-01

    Transforming growth factor beta (TGFβ) signalling is critical for regulatory T cell development and function, and regulatory T cell dysregulation is a common observation in autoimmune diseases, including multiple sclerosis. In a comprehensive miRNA profiling study of patients with multiple sclerosis naïve CD4 T cells, 19 differentially expressed miRNAs predicted to target the TGFβ signalling pathway were identified, leading to the hypothesis that miRNAs may be responsible for the regulatory T cell defect observed in patients with multiple sclerosis. Patients with multiple sclerosis had reduced levels of TGFβ signalling components in their naïve CD4 T cells. The differentially expressed miRNAs negatively regulated the TGFβ pathway, resulting in a reduced capacity of naïve CD4 T cells to differentiate into regulatory T cells. Interestingly, the limited number of regulatory T cells, that did develop when these TGFβ-targeting miRNAs were overexpressed, were capable of suppressing effector T cells. As it has previously been demonstrated that compromising TGFβ signalling results in a reduced regulatory T cell repertoire insufficient to control autoimmunity, and patients with multiple sclerosis have a reduced regulatory T cell repertoire, these data indicate that the elevated expression of multiple TGFβ-targeting miRNAs in naïve CD4 T cells of patients with multiple sclerosis impairs TGFβ signalling, and dampens regulatory T cell development, thereby enhancing susceptibility to developing multiple sclerosis. PMID:27190026

  4. The application of multiple biophysical cues to engineer functional neocartilage for treatment of osteoarthritis. Part II: signal transduction.

    PubMed

    Brady, Mariea A; Waldman, Stephen D; Ethier, C Ross

    2015-02-01

    The unique mechanoelectrochemical environment of cartilage has motivated researchers to investigate the effect of multiple biophysical cues, including mechanical, magnetic, and electrical stimulation, on chondrocyte biology. It is well established that biophysical stimuli promote chondrocyte proliferation, differentiation, and maturation within "biological windows" of defined dose parameters, including mode, frequency, magnitude, and duration of stimuli (see companion review Part I: Cellular Response). However, the underlying molecular mechanisms and signal transduction pathways activated in response to multiple biophysical stimuli remain to be elucidated. Understanding the mechanisms of biophysical signal transduction will deepen knowledge of tissue organogenesis, remodeling, and regeneration and aiding in the treatment of pathologies such as osteoarthritis. Further, this knowledge will provide the tissue engineer with a potent toolset to manipulate and control cell fate and subsequently develop functional replacement cartilage. The aim of this article is to review chondrocyte signal transduction pathways in response to mechanical, magnetic, and electrical cues. Signal transduction does not occur along a single pathway; rather a number of parallel pathways appear to be activated, with calcium signaling apparently common to all three types of stimuli, though there are different modes of activation. Current tissue engineering strategies, such as the development of "smart" functionalized biomaterials that enable the delivery of growth factors or integration of conjugated nanoparticles, may further benefit from targeting known signal transduction pathways in combination with external biophysical cues. PMID:25065615

  5. Multiple Forms of Endocannabinoid and Endovanilloid Signaling Regulate the Tonic Control of GABA Release

    PubMed Central

    Lee, Sang-Hun; Ledri, Marco; Tóth, Blanka; Marchionni, Ivan; Henstridge, Christopher M.; Dudok, Barna; Kenesei, Kata; Barna, László; Szabó, Szilárd I.; Renkecz, Tibor; Oberoi, Michelle; Watanabe, Masahiko; Limoli, Charles L.; Horvai, George; Soltesz, Ivan

    2015-01-01

    Persistent CB1 cannabinoid receptor activity limits neurotransmitter release at various synapses throughout the brain. However, it is not fully understood how constitutively active CB1 receptors, tonic endocannabinoid signaling, and its regulation by multiple serine hydrolases contribute to the synapse-specific calibration of neurotransmitter release probability. To address this question at perisomatic and dendritic GABAergic synapses in the mouse hippocampus, we used a combination of paired whole-cell patch-clamp recording, liquid chromatography/tandem mass spectrometry, stochastic optical reconstruction microscopy super-resolution imaging, and immunogold electron microscopy. Unexpectedly, application of the CB1 antagonist and inverse agonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide], but not the neutral antagonist NESS0327 [8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-5,6-dihydro-4H-benzo[2,3]cyclohepta[2,4-b]pyrazole-3-carboxamine], significantly increased synaptic transmission between CB1-positive perisomatic interneurons and CA1 pyramidal neurons. JZL184 (4-nitrophenyl 4-[bis(1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate), a selective inhibitor of monoacylglycerol lipase (MGL), the presynaptic degrading enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), elicited a robust increase in 2-AG levels and concomitantly decreased GABAergic transmission. In contrast, inhibition of fatty acid amide hydrolase (FAAH) by PF3845 (N-pyridin-3-yl-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide) elevated endocannabinoid/endovanilloid anandamide levels but did not change GABAergic synaptic activity. However, FAAH inhibitors attenuated tonic 2-AG increase and also decreased its synaptic effects. This antagonistic interaction required the activation of the transient receptor potential vanilloid receptor TRPV1, which was concentrated on postsynaptic

  6. Wireless sensor networks for monitoring physiological signals of multiple patients.

    PubMed

    Dilmaghani, R S; Bobarshad, H; Ghavami, M; Choobkar, S; Wolfe, C

    2011-08-01

    This paper presents the design of a novel wireless sensor network structure to monitor patients with chronic diseases in their own homes through a remote monitoring system of physiological signals. Currently, most of the monitoring systems send patients' data to a hospital with the aid of personal computers (PC) located in the patients' home. Here, we present a new design which eliminates the need for a PC. The proposed remote monitoring system is a wireless sensor network with the nodes of the network installed in the patients' homes. These nodes are then connected to a central node located at a hospital through an Internet connection. The nodes of the proposed wireless sensor network are created by using a combination of ECG sensors, MSP430 microcontrollers, a CC2500 low-power wireless radio, and a network protocol called the SimpliciTI protocol. ECG signals are first sampled by a small portable device which each patient carries. The captured signals are then wirelessly transmitted to an access point located within the patients' home. This connectivity is based on wireless data transmission at 2.4-GHz frequency. The access point is also a small box attached to the Internet through a home asynchronous digital subscriber line router. Afterwards, the data are sent to the hospital via the Internet in real time for analysis and/or storage. The benefits of this remote monitoring are wide ranging: the patients can continue their normal lives, they do not need a PC all of the time, their risk of infection is reduced, costs significantly decrease for the hospital, and clinicians can check data in a short time. PMID:23851949

  7. The PKC-NFκB Signaling Pathway Induces APOBEC3B Expression in Multiple Human Cancers

    PubMed Central

    Leonard, Brandon; McCann, Jennifer L.; Starrett, Gabriel J.; Kosyakovsky, Leah; Luengas, Elizabeth M.; Molan, Amy M.; Burns, Michael B.; McDougle, Rebecca M.; Parker, Peter J.; Brown, William L.; Harris, Reuben S.

    2015-01-01

    Overexpression of the antiviral DNA cytosine deaminase APOBEC3B has been linked to somatic mutagenesis in many cancers. HPV infection accounts for APOBEC3B upregulation in cervical and head/neck cancers, but the mechanisms underlying non-viral malignancies are unclear. In this study, we investigated the signal transduction pathways responsible for APOBEC3B upregulation. Activation of protein kinase C (PKC) by the diacylglycerol (DAG) mimic phorbol-myristic acid (PMA) resulted in specific and dose-responsive increases in APOBEC3B expression and activity, which could then be strongly suppressed by PKC or NFκB inhibition. PKC activation caused the recruitment of RELB, but not RELA, to the APOBEC3B promoter implicating non-canonical NFκB signaling. Notably, PKC was required for APOBEC3B upregulation in cancer cell lines derived from multiple tumor types. By revealing how APOBEC3B is upregulated in many cancers, our findings suggest that PKC and NFκB inhibitors may be repositioned to suppress cancer mutagenesis, dampen tumor evolution, and decrease the probability of adverse outcomes such as drug resistance and metastases. PMID:26420215

  8. γ-Tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways

    PubMed Central

    Yap, W N; Chang, P N; Han, H Y; Lee, D T W; Ling, M T; Wong, Y C; Yap, Y L

    2008-01-01

    Tocotrienol-rich fraction (TRF) has demonstrated antiproliferative effect on prostate cancer (PCa) cells. To elucidate this anticancer property in PCa cells, this study aimed, first, to identify the most potent isomer for eliminating PCa cells; and second, to decipher the molecular pathway responsible for its activity. Results showed that the inhibitory effect of γ-tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of pro-caspases and the presence of sub-G1 cell population. Examination of the pro-survival genes revealed that the γ-tocotrienol-induced cell death was associated with suppression of NF-κB, EGF-R and Id family proteins (Id1 and Id3). Meanwhile, γ-tocotrienol treatment also resulted in the induction of JNK-signalling pathway and inhibition of JNK activity by a specific inhibitor (SP600125) was able to partially block the effect of γ-tocotrienol. Interestingly, γ-tocotrienol treatment led to suppression of mesenchymal markers and the restoration of E-cadherin and γ-catenin expression, which was associated with suppression of cell invasion capability. Furthermore, a synergistic effect was observed when cells were co-treated with γ-tocotrienol and Docetaxel. Our results suggested that the antiproliferative effect of γ-tocotrienol act through multiple-signalling pathways, and demonstrated for the first time the anti-invasion and chemosensitisation effect of γ-tocotrienol against PCa cells. PMID:19002171

  9. Epithelial SCAP/INSIG/SREBP Signaling Regulates Multiple Biological Processes during Perinatal Lung Maturation

    PubMed Central

    Bridges, James P.; Schehr, Angelica; Wang, Yanhua; Huo, Liya; Besnard, Valérie; Ikegami, Machiko; Whitsett, Jeffrey A.; Xu, Yan

    2014-01-01

    Pulmonary surfactant is required for lung function at birth and throughout postnatal life. Defects in the surfactant system are associated with common pulmonary disorders including neonatal respiratory distress syndrome and acute respiratory distress syndrome in children and adults. Lipogenesis is essential for the synthesis of pulmonary surfactant by type II epithelial cells lining the alveoli. This study sought to identify the role of pulmonary epithelial SREBP, a transcriptional regulator of cellular lipid homeostasis, during a critical time period of perinatal lung maturation in the mouse. Genome wide mRNA expression profiling of lung tissue from transgenic mice with epithelial-specific deletions of Scap (ScapΔ/Δ, resulting in inactivation of SREBP signaling) or Insig1 and Insig2 (Insig1/2Δ/Δ, resulting in activation of SREBP signaling) was assessed. Differentially expressed genes responding to SREBP perturbations were identified and subjected to functional enrichment analysis, pathway mapping and literature mining to predict upstream regulators and transcriptional networks regulating surfactant lipid homeostasis. Through comprehensive data analysis and integration, time dependent effects of epithelial SCAP/INSIG/SREBP deletion and defined SCAP/INSIG/SREBP-associated genes, bioprocesses and downstream pathways were identified. SREBP signaling influences epithelial development, cell death and cell proliferation at E17.5, while primarily influencing surfactant physiology, lipid/sterol synthesis, and phospholipid transport after birth. SREBP signaling integrated with the Wnt/β-catenin and glucocorticoid receptor signaling pathways during perinatal lung maturation. SREBP regulates perinatal lung lipogenesis and maturation through multiple mechanisms by interactions with distinct sets of regulatory partners. PMID:24806461

  10. Sleep Loss Activates Cellular Inflammatory Signaling

    PubMed Central

    Irwin, Michael R.; Wang, Minge; Ribeiro, Denise; Cho, Hyong Jin; Olmstead, Richard; Breen, Elizabeth Crabb; Martinez-Maza, Otoniel; Cole, Steve

    2008-01-01

    Background Accumulating evidence suggests that sleep disturbance is associated with inflammation and related disorders including cardiovascular disease, arthritis, and diabetes mellitus. This study was undertaken to test the effects of sleep loss on activation of nuclear factor (NF) -κB, a transcription factor that serves a critical role in the inflammatory signaling cascade. Methods In 14 healthy adults (7 females; 7 males), peripheral blood mononuclear cell NF-κB was repeatedly assessed, along with enumeration of lymphocyte subpopulations, in the morning after baseline sleep, partial sleep deprivation (awake from 23:00 h to 03:00 h), and recovery sleep. Results In the morning after a night of sleep loss, mononuclear cell NF-κB activation was significantly greater compared with morning levels following uninterrupted baseline or recovery sleep, in which the response was found in females but not in males. Conclusions These results identify NF-κB activation as a molecular pathway by which sleep disturbance may influence leukocyte inflammatory gene expression and the risk of inflammation-related disease. PMID:18561896

  11. Heat dissipation guides activation in signaling proteins

    PubMed Central

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

    2015-01-01

    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

  12. Heat dissipation guides activation in signaling proteins.

    PubMed

    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

  13. Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration

    PubMed Central

    Ren, Fangfang; Shi, Qing; Chen, Yongbin; Jiang, Alice; Ip, Y Tony; Jiang, Huaqi; Jiang, Jin

    2013-01-01

    Intestinal stem cells (ISCs) in the Drosophila adult midgut are essential for maintaining tissue homeostasis, and their proliferation and differentiation speed up in order to meet the demand for replenishing the lost cells in response to injury. Several signaling pathways including JAK-STAT, EGFR and Hippo (Hpo) pathways have been implicated in damage-induced ISC proliferation, but the mechanisms that integrate these pathways have remained elusive. Here, we demonstrate that the Drosophila homolog of the oncoprotein Myc (dMyc) functions downstream of these signaling pathways to mediate their effects on ISC proliferation. dMyc expression in precursor cells is stimulated in response to tissue damage, and dMyc is essential for accelerated ISC proliferation and midgut regeneration. We show that tissue damage caused by dextran sulfate sodium feeding stimulates dMyc expression via the Hpo pathway, whereas bleomycin feeding activates dMyc through the JAK-STAT and EGFR pathways. We provide evidence that dMyc expression is transcriptionally upregulated by multiple signaling pathways, which is required for optimal ISC proliferation in response to tissue damage. We have also obtained evidence that tissue damage can upregulate dMyc expression post-transcriptionally. Finally, we show that a basal level of dMyc expression is required for ISC maintenance, proliferation and lineage differentiation during normal tissue homeostasis. PMID:23896988

  14. Multiple myeloma and physical activity: a scoping review

    PubMed Central

    Smith, Lee; McCourt, Orla; Henrich, Malgorzata; Paton, Bruce; Yong, Kwee; Wardle, Jane; Fisher, Abigail

    2015-01-01

    Objectives Multiple myeloma is the second most common haematological cancer. A growing body of literature is emerging that investigates the role physical activity plays in all stages of multiple myeloma (prevention and survivorship) and to date no attempt has been made to collate and understand this literature. Therefore, this scoping review aims to (1) outline what is already known about physical activity in all stages of multiple myeloma (2) map the literature on physical activity and multiple myeloma and (3) identify future directions for research. Design Scoping Review. Data Sources Searches were carried out in May 2015. Searchers were conducted in PubMed, Web of Science, SPORTdiscus and MEDLINE. Eligibility criteria for selecting studies To be included studies had to report original data, investigate physical activity per se or physical activity correlates and multiple myeloma or smouldering multiple myeloma. Results A total of 19 papers received full screening, 5 of these papers were excluded. This review identified three journal articles relating to the role of physical activity in the prevention of multiple myeloma, nine papers were identified in the treatment of multiple myeloma and two on smouldering multiple myeloma. Conclusions The search identified that the literature surrounding multiple myeloma and physical activity is very limited. We encourage those designing new cohort studies to allow for future assessment of associations between physical activity and onset of multiple myeloma and smouldering multiple myeloma, as well as the potential role that physical activity plays in the progression from smouldering multiple myeloma to multiple myeloma. Second, we encourage the design and investigation of gender and treatment-specific physical activity interventions in patients with multiple myeloma. Finally, we highlight the need for more randomised controlled trials to evaluate the impact of different types, frequencies and intensities of physical activity

  15. Active voltammetric microsensors with neural signal processing.

    SciTech Connect

    Vogt, M. C.

    1998-12-11

    Many industrial and environmental processes, including bioremediation, would benefit from the feedback and control information provided by a local multi-analyte chemical sensor. For most processes, such a sensor would need to be rugged enough to be placed in situ for long-term remote monitoring, and inexpensive enough to be fielded in useful numbers. The multi-analyte capability is difficult to obtain from common passive sensors, but can be provided by an active device that produces a spectrum-type response. Such new active gas microsensor technology has been developed at Argonne National Laboratory. The technology couples an electrocatalytic ceramic-metallic (cermet) microsensor with a voltammetric measurement technique and advanced neural signal processing. It has been demonstrated to be flexible, rugged, and very economical to produce and deploy. Both narrow interest detectors and wide spectrum instruments have been developed around this technology. Much of this technology's strength lies in the active measurement technique employed. The technique involves applying voltammetry to a miniature electrocatalytic cell to produce unique chemical ''signatures'' from the analytes. These signatures are processed with neural pattern recognition algorithms to identify and quantify the components in the analyte. The neural signal processing allows for innovative sampling and analysis strategies to be employed with the microsensor. In most situations, the whole response signature from the voltammogram can be used to identify, classify, and quantify an analyte, without dissecting it into component parts. This allows an instrument to be calibrated once for a specific gas or mixture of gases by simple exposure to a multi-component standard rather than by a series of individual gases. The sampled unknown analytes can vary in composition or in concentration, the calibration, sensing, and processing methods of these active voltammetric microsensors can detect, recognize, and

  16. Photonic generation of a millimeter-wave signal based on sextuple-frequency multiplication.

    PubMed

    Zhang, Jian; Chen, Hongwei; Chen, Minghua; Wang, Tianliang; Xie, Shizhong

    2007-05-01

    A millimeter-wave signal with sextuple-frequency multiplication of a microwave source is obtained with two cascaded optical modulators, which are driven by the same microwave source with phase deviation of pi/2 introduced by an electrical phase shifter. Without any optical filter, a wideband continuously tunable millimeter-wave signal is easily generated. PMID:17410221

  17. Photonic generation of a millimeter-wave signal based on sextuple-frequency multiplication

    NASA Astrophysics Data System (ADS)

    Zhang, Jian; Chen, Hongwei; Chen, Minghua; Wang, Tianliang; Xie, Shizhong

    2007-05-01

    A millimeter-wave signal with sextuple-frequency multiplication of a microwave source is obtained with two cascaded optical modulators, which are driven by the same microwave source with phase deviation of π/2 introduced by an electrical phase shifter. Without any optical filter, a wideband continuously tunable millimeter-wave signal is easily generated.

  18. Multiple Signaling Pathways of the Insulin-Like Growth Factor 1 Receptor in Protection from Apoptosis

    PubMed Central

    Peruzzi, Francesca; Prisco, Marco; Dews, Michael; Salomoni, Paolo; Grassilli, Emanuela; Romano, Gaetano; Calabretta, Bruno; Baserga, Renato

    1999-01-01

    The type 1 insulin-like growth factor receptor (IGF-1R), activated by its ligands, protects several cell types from a variety of apoptotic injuries. The main signaling pathway for IGF-1R-mediated protection from apoptosis has been previously elucidated and rests on the activation of phosphatidylinositol 3-kinase, Akt/protein kinase B, and the phosphorylation and inactivation of BAD, a member of the Bcl-2 family of proteins. In 32D cells (a murine hemopoietic cell line devoid of insulin receptor substrate 1 [IRS-1]), the IGF-1R activates alternative pathways for protection from apoptosis induced by withdrawal of interleukin-3. One of these pathways leads to the activation of mitogen-activated protein kinase, while a third pathway results in the mitochondrial translocation of Raf and depends on the integrity of a group of serines in the C terminus of the receptor that are known to interact with 14.3.3 proteins. All three pathways, however, result in BAD phosphorylation. The presence of multiple antiapoptotic pathways may explain the remarkable efficacy of the IGF-1R in protecting cells from apoptosis. PMID:10490655

  19. ASIC3 Channels Integrate Agmatine and Multiple Inflammatory Signals through the Nonproton Ligand Sensing Domain

    PubMed Central

    2010-01-01

    Background Acid-sensing ion channels (ASICs) have long been known to sense extracellular protons and contribute to sensory perception. Peripheral ASIC3 channels represent natural sensors of acidic and inflammatory pain. We recently reported the use of a synthetic compound, 2-guanidine-4-methylquinazoline (GMQ), to identify a novel nonproton sensing domain in the ASIC3 channel, and proposed that, based on its structural similarity with GMQ, the arginine metabolite agmatine (AGM) may be an endogenous nonproton ligand for ASIC3 channels. Results Here, we present further evidence for the physiological correlation between AGM and ASIC3. Among arginine metabolites, only AGM and its analog arcaine (ARC) activated ASIC3 channels at neutral pH in a sustained manner similar to GMQ. In addition to the homomeric ASIC3 channels, AGM also activated heteromeric ASIC3 plus ASIC1b channels, extending its potential physiological relevance. Importantly, the process of activation by AGM was highly sensitive to mild acidosis, hyperosmolarity, arachidonic acid (AA), lactic acid and reduced extracellular Ca2+. AGM-induced ASIC3 channel activation was not through the chelation of extracellular Ca2+ as occurs with increased lactate, but rather through a direct interaction with the newly identified nonproton ligand sensing domain. Finally, AGM cooperated with the multiple inflammatory signals to cause pain-related behaviors in an ASIC3-dependent manner. Conclusions Nonproton ligand sensing domain might represent a novel mechanism for activation or sensitization of ASIC3 channels underlying inflammatory pain-sensing under in vivo conditions. PMID:21143836

  20. Functional mapping of reaction norms to multiple environmental signals.

    PubMed

    Wu, Jiasheng; Zeng, Yanru; Huang, Jianqing; Hou, Wei; Zhu, Jun; Wu, Rongling

    2007-02-01

    Whether there are different genes involved in response to different environmental signals and how these genes interact to determine the final expression of the trait are of fundamental importance in agricultural and biological research. We present a statistical framework for mapping environment-induced genes (or quantitative trait loci, QTLs) of major effects on the expression of a trait that respond to changing environments. This framework is constructed with a maximum-likelihood-based mixture model, in which the mean and covariance structure of environment-induced responses is modelled. The means for responses to continuous environmental states, referred to as reaction norms, are approximated for different QTL genotypes by mathematical equations that were derived from fundamental biological principles or based on statistical goodness-of-fit to observational data. The residual covariance between different environmental states was modelled by autoregressive processes. Such an approach to studying the genetic control of reaction norms can be expected to be advantageous over traditional mapping approaches in which no biological principles and statistical structures are considered. We demonstrate the analytical procedure and power of this approach by modelling the photosynthetic rate process as a function of temperature and light irradiance. Our approach allows for testing how a QTL affects the reaction norm of photosynthetic rate to a specific environment and whether there exist different QTLs to mediate photosynthetic responses to temperature and light irradiance, respectively. PMID:17517157

  1. Concentric core optical fiber with multiple-mode signal transmission

    DOEpatents

    Muhs, Jeffrey D.

    1997-01-01

    A concentric core optical fiber provides for the simultaneous but independent transmission of signals over a single optical fiber. The concentric optical fiber is constructed of a single-mode or multimode inner optical fiber defined by a core and a cladding of a lower index of refraction than the core and an outer optical fiber defined by additional cladding concentrically disposed around the cladding and of an index of refraction lower than the first mentioned cladding whereby the latter functions as the core of the outer optical fiber. By employing such an optical fiber construction with a single-mode inner core or optical fiber, highly sensitive interferometric and stable less sensitive amplitude based sensors can be placed along the same length of a concentric core optical fiber. Also, by employing the concentric core optical fiber secure telecommunications can be achieved via the inner optical fiber since an intrusion of the concentric optical fiber will first cause a variation in the light being transmitted through the outer optical fiber and this variation of light being used to trigger a suitable alarm indicative of the intrusion.

  2. Concentric core optical fiber with multiple-mode signal transmission

    DOEpatents

    Muhs, J.D.

    1997-05-06

    A concentric core optical fiber provides for the simultaneous but independent transmission of signals over a single optical fiber. The concentric optical fiber is constructed of a single-mode or multimode inner optical fiber defined by a core and a cladding of a lower index of refraction than the core and an outer optical fiber defined by additional cladding concentrically disposed around the cladding and of an index of refraction lower than the first mentioned cladding whereby the latter functions as the core of the outer optical fiber. By employing such an optical fiber construction with a single-mode inner core or optical fiber, highly sensitive interferometric and stable less sensitive amplitude based sensors can be placed along the same length of a concentric core optical fiber. Also, by employing the concentric core optical fiber secure telecommunications can be achieved via the inner optical fiber since an intrusion of the concentric optical fiber will first cause a variation in the light being transmitted through the outer optical fiber and this variation of light being used to trigger a suitable alarm indicative of the intrusion. 3 figs.

  3. Male satin bowerbirds (Ptilonorhynchus violaceus) compensate for sexual signal loss by enhancing multiple display features

    NASA Astrophysics Data System (ADS)

    Bravery, Benjamin D.; Goldizen, Anne W.

    2007-06-01

    Numerous studies have focussed on the relationship between female choice and the multiple exaggerated sexual traits of males. However, little is known about the ability of males to actively enhance specific components of their display in response to the loss of one component. We investigated the capacity of male satin bowerbirds (Ptilonorhynchus violaceus) to respond to the loss of one of their sexual signals by performing an experiment in which we removed decorations at their bowers. We found that males compensated for decoration loss by increasing bower construction behaviour and decreasing their latency to bower painting. These results are novel because they suggest that males can assess the quality of their own display and make decisions about how to augment their displays. We discuss these results in the context of previous studies of mate choice in satin bowerbirds, as both of the supplementary behaviours we observed are known correlates of male mating success.

  4. Identification and characterization of multiple conserved nuclear localization signals within adenovirus E1A

    SciTech Connect

    Marshall, Kris S.; Cohen, Michael J.; Fonseca, Greg J.; Todorovic, Biljana; King, Cason R.; Yousef, Ahmed F.; Zhang, Zhiying; Mymryk, Joe S.

    2014-04-15

    The human adenovirus 5 (HAdV-5) E1A protein has a well defined canonical nuclear localization signal (NLS) located at its C-terminus. We used a genetic assay in the yeast Saccharomyces cerevisiae to demonstrate that the canonical NLS is present and functional in the E1A proteins of each of the six HAdV species. This assay also detects a previously described non-canonical NLS within conserved region 3 and a novel active NLS within the N-terminal/conserved region 1 portion of HAdV-5 E1A. These activities were also present in the E1A proteins of each of the other five HAdV species. These results demonstrate that, despite substantial differences in primary sequence, HAdV E1A proteins are remarkably consistent in that they contain one canonical and two non-canonical NLSs. By utilizing independent mechanisms, these multiple NLSs ensure nuclear localization of E1A in the infected cell. - Highlights: • HAdV E1A uses multiple mechanisms for nuclear import. • We identified an additional non-canonical NLS in the N-terminal/CR1 portion of E1A. • The new NLS does not contact importin-alpha directly. • All NLSs are functionally conserved in the E1A proteins of all 6 HAdV species.

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

    PubMed

    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

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

    PubMed

    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: 1) Ang II → Gq → PLC → IP3 → IP3Rs → Ca(2+) 2) Gβγ → PI3Kγ → PKB 3) PKB → eNOS → NO → PKG 4) CD38 → cADPR → RyRs → Ca(2+) 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 2 diabetes. PMID:26850364

  7. Recognition of forearm muscle activity by continuous classification of multi-site mechanomyogram signals.

    PubMed

    Alves, Natasha; Chau, Tom

    2010-01-01

    Recent studies on identifying multiple activation states from mechanomyogram (MMG) signals for the purpose of controlling switching interfaces have employed pattern recognition methods where MMG signal features from multiple muscle sites are extracted and classified. The purpose of this study is to determine if MMG signal features retain enough discriminatory information to allow reliable continuous classification, and to determine if there is a decline in classification accuracy over short time periods. MMG signals were recorded from two accelerometers attached to the flexor carpi radialis and extensor carpi radialis muscles of 12 able-bodied participants as participants performed three classes of forearm muscle activity. The data were collected over five recording sessions, with a ten-minute interval between each session. The data were spliced into 256 ms epochs, and a comprehensive set of signal features was extracted. A pattern classifier, trained with continuously acquired signal features from the first recording session, was tested with signals recorded from the other sessions. The average classification accuracy over the five sessions was 89 ± 2%. There was no obvious declining trend in classification accuracy with time. These results show that MMG signals recorded at the forearm retain enough discriminatory information to allow continuous recognition of hand motion across multiple (>90) repetitions, and the MMG-classifier does not show short-term degradation. These results indicate the potential of MMG as a multifunction control signal for muscle-machine interfaces. PMID:21097038

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

    PubMed

    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. Apparatus and method for measuring relative phase of signals in a multiple-echo system

    NASA Technical Reports Server (NTRS)

    Froggatt, Mark E. (Inventor)

    1998-01-01

    An apparatus and method for measuring the relative phase of echo signals in a multiple-echo system. A signal generator generates an exciting tone burst and subsequent tone bursts delayed in phase from the exciting tone burst. The exciting tone burst is gated into a transducer coupled to the multiple-echo system. Each subsequent tone burst is converted into a series of pulses. Each pulse triggers a sample/hold circuit to sample each echo signal. The samples of the echo signal are averaged and then compared to a reference value. The signal generator is controlled to vary the subsequent tone burst phase delay to determine for each echo signal a subsequent tone burst phase delay that causes the average of the samples of the echo signal to be substantially equal to the reference value wherein the determined subsequent tone burst phase delay is the phase delay of the echo signal with respect to the exciting tone burst. The control circuit then determines the difference in phase delay between echo signals to determine the relative phase delay of the echo signals.

  10. Iterative signal separation based multiple phase estimation in digital holographic interferometry.

    PubMed

    Kulkarni, Rishikesh; Rastogi, Pramod

    2015-10-01

    We propose a new method for signal separation from a multicomponent interference field recorded in a digital holographic interferometry setup. The setup consisting of multiple object illuminating beams results in an interference field containing multiple signal components. The proposed method utilizes an amplitude discrimination criteria established by setting different intensities to the object illuminating beams in order to separate the signal components iteratively. The signal separation is performed in a small block of the interference field at a time. The augmentation of the block matrix with its own rows and columns is performed which has an effect of noise subspace inflation. This operation offers an improved noise robustness to the signal separation capability of the proposed method. The simulation and experimental results are provided to substantiate the applicability of the proposed method in multidimensional deformation measurement. PMID:26480195

  11. Photonic-assisted microwave signal multiplication and modulation using a silicon Mach-Zehnder modulator.

    PubMed

    Long, Yun; Zhou, Linjie; Wang, Jian

    2016-01-01

    Photonic generation of microwave signal is obviously attractive for many prominent advantages, such as large bandwidth, low loss, and immunity to electromagnetic interference. Based on a single integrated silicon Mach-Zehnder modulator (MZM), we propose and experimentally demonstrate a simple and compact photonic scheme to enable frequency-multiplicated microwave signal. Using the fabricated integrated MZM, we also demonstrate the feasibility of microwave amplitude-shift keying (ASK) modulation based on integrated photonic approach. In proof-of-concept experiments, 2-GHz frequency-doubled microwave signal is generated using a 1-GHz driving signal. 750-MHz/1-GHz frequency-tripled/quadrupled microwave signals are obtained with a driving signal of 250 MHz. In addition, a 50-Mb/s binary amplitude coded 1-GHz microwave signal is also successfully generated. PMID:26832305

  12. Photonic-assisted microwave signal multiplication and modulation using a silicon Mach-Zehnder modulator

    NASA Astrophysics Data System (ADS)

    Long, Yun; Zhou, Linjie; Wang, Jian

    2016-02-01

    Photonic generation of microwave signal is obviously attractive for many prominent advantages, such as large bandwidth, low loss, and immunity to electromagnetic interference. Based on a single integrated silicon Mach-Zehnder modulator (MZM), we propose and experimentally demonstrate a simple and compact photonic scheme to enable frequency-multiplicated microwave signal. Using the fabricated integrated MZM, we also demonstrate the feasibility of microwave amplitude-shift keying (ASK) modulation based on integrated photonic approach. In proof-of-concept experiments, 2-GHz frequency-doubled microwave signal is generated using a 1-GHz driving signal. 750-MHz/1-GHz frequency-tripled/quadrupled microwave signals are obtained with a driving signal of 250 MHz. In addition, a 50-Mb/s binary amplitude coded 1-GHz microwave signal is also successfully generated.

  13. Photonic-assisted microwave signal multiplication and modulation using a silicon Mach–Zehnder modulator

    PubMed Central

    Long, Yun; Zhou, Linjie; Wang, Jian

    2016-01-01

    Photonic generation of microwave signal is obviously attractive for many prominent advantages, such as large bandwidth, low loss, and immunity to electromagnetic interference. Based on a single integrated silicon Mach–Zehnder modulator (MZM), we propose and experimentally demonstrate a simple and compact photonic scheme to enable frequency-multiplicated microwave signal. Using the fabricated integrated MZM, we also demonstrate the feasibility of microwave amplitude-shift keying (ASK) modulation based on integrated photonic approach. In proof-of-concept experiments, 2-GHz frequency-doubled microwave signal is generated using a 1-GHz driving signal. 750-MHz/1-GHz frequency-tripled/quadrupled microwave signals are obtained with a driving signal of 250 MHz. In addition, a 50-Mb/s binary amplitude coded 1-GHz microwave signal is also successfully generated. PMID:26832305

  14. Recursive ideal observer detection of known M-ary signals in multiplicative and additive Gaussian noise.

    NASA Technical Reports Server (NTRS)

    Painter, J. H.; Gupta, S. C.

    1973-01-01

    This paper presents the derivation of the recursive algorithms necessary for real-time digital detection of M-ary known signals that are subject to independent multiplicative and additive Gaussian noises. The motivating application is minimum probability of error detection of digital data-link messages aboard civil aircraft in the earth reflection multipath environment. For each known signal, the detector contains one Kalman filter and one probability computer. The filters estimate the multipath disturbance. The estimates and the received signal drive the probability computers. Outputs of all the computers are compared in amplitude to give the signal decision. The practicality and usefulness of the detector are extensively discussed.

  15. Charge-signal multiplication mediated by urea wires inside Y-shaped carbon nanotubes

    NASA Astrophysics Data System (ADS)

    Lv, Mei; He, Bing; Liu, Zengrong; Xiu, Peng; Tu, Yusong

    2014-07-01

    In previous studies, we reported molecular dynamics (MD) simulations showing that single-file water wires confined inside Y-shaped single-walled carbon nanotubes (Y-SWNTs) held strong and robust capability to convert and multiply charge signals [Y. S. Tu, P. Xiu, R. Z. Wan, J. Hu, R. H. Zhou, and H. P. Fang, Proc. Natl. Acad. Sci. U.S.A. 106, 18120 (2009); Y. Tu, H. Lu, Y. Zhang, T. Huynh, and R. Zhou, J. Chem. Phys. 138, 015104 (2013)]. It is fascinating to see whether the signal multiplication can be realized by other kinds of polar molecules with larger dipole moments (which make the experimental realization easier). In this article, we use MD simulations to study the urea-mediated signal conversion and multiplication with Y-SWNTs. We observe that when a Y-SWNT with an external charge of magnitude 1.0 e (the model of a signal at the single-electron level) is solvated in 1 M urea solutions, urea can induce drying of the Y-SWNT and fill its interiors in single-file, forming Y-shaped urea wires. The external charge can effectively control the dipole orientation of the urea wire inside the main channel (i.e., the signal can be readily converted), and this signal can further be multiplied into 2 (or more) output signals by modulating dipole orientations of urea wires in bifurcated branch channels of the Y-SWNT. This remarkable signal transduction capability arises from the strong dipole-induced ordering of urea wires under extreme confinement. We also discuss the advantage of urea as compared with water in the signal multiplication, as well as the robustness and biological implications of our findings. This study provides the possibility for multiplying signals by using urea molecules (or other polar organic molecules) with Y-shaped nanochannels and might also help understand the mechanism behind signal conduction in both physical and biological systems.

  16. Charge-signal multiplication mediated by urea wires inside Y-shaped carbon nanotubes

    SciTech Connect

    Lv, Mei; Liu, Zengrong; He, Bing; Xiu, Peng E-mail: ystu@shu.edu.cn; Tu, Yusong E-mail: ystu@shu.edu.cn

    2014-07-28

    In previous studies, we reported molecular dynamics (MD) simulations showing that single-file water wires confined inside Y-shaped single-walled carbon nanotubes (Y-SWNTs) held strong and robust capability to convert and multiply charge signals [Y. S. Tu, P. Xiu, R. Z. Wan, J. Hu, R. H. Zhou, and H. P. Fang, Proc. Natl. Acad. Sci. U.S.A. 106, 18120 (2009); Y. Tu, H. Lu, Y. Zhang, T. Huynh, and R. Zhou, J. Chem. Phys. 138, 015104 (2013)]. It is fascinating to see whether the signal multiplication can be realized by other kinds of polar molecules with larger dipole moments (which make the experimental realization easier). In this article, we use MD simulations to study the urea-mediated signal conversion and multiplication with Y-SWNTs. We observe that when a Y-SWNT with an external charge of magnitude 1.0 e (the model of a signal at the single-electron level) is solvated in 1 M urea solutions, urea can induce drying of the Y-SWNT and fill its interiors in single-file, forming Y-shaped urea wires. The external charge can effectively control the dipole orientation of the urea wire inside the main channel (i.e., the signal can be readily converted), and this signal can further be multiplied into 2 (or more) output signals by modulating dipole orientations of urea wires in bifurcated branch channels of the Y-SWNT. This remarkable signal transduction capability arises from the strong dipole-induced ordering of urea wires under extreme confinement. We also discuss the advantage of urea as compared with water in the signal multiplication, as well as the robustness and biological implications of our findings. This study provides the possibility for multiplying signals by using urea molecules (or other polar organic molecules) with Y-shaped nanochannels and might also help understand the mechanism behind signal conduction in both physical and biological systems.

  17. Multiple Signaling Pathways Contribute to the Thrombin-induced Secretory Phenotype in Vascular Smooth Muscle Cells

    PubMed Central

    Jeong, Ji Young; Son, Younghae; Kim, Bo-Young; Eo, Seong-Kug; Rhim, Byung-Yong

    2015-01-01

    We attempted to investigate molecular mechanisms underlying phenotypic change of vascular smooth muscle cells (VSMCs) by determining signaling molecules involved in chemokine production. Treatment of human aortic smooth muscle cells (HAoSMCs) with thrombin resulted not only in elevated transcription of the (C-C motif) ligand 11 (CCL11) gene but also in enhanced secretion of CCL11 protein. Co-treatment of HAoSMCs with GF109230X, an inhibitor of protein kinase C, or GW5074, an inhibitor of Raf-1 kinase, caused inhibition of ERK1/2 phosphorylation and significantly attenuated expression of CCL11 at transcriptional and protein levels induced by thrombin. Both Akt phosphorylation and CCL11 expression induced by thrombin were attenuated in the presence of pertussis toxin (PTX), an inhibitor of Gi protein-coupled receptor, or LY294002, a PI3K inhibitor. In addition, thrombin-induced production of CCL11 was significantly attenuated by pharmacological inhibition of Akt or MEK which phosphorylates ERK1/2. These results indicate that thrombin is likely to promote expression of CCL11 via PKC/Raf-1/ERK1/2 and PTX-sensitive protease-activated receptors/PI3K/Akt pathways in HAoSMCs. We propose that multiple signaling pathways are involved in change of VSMCs to a secretory phenotype. PMID:26557022

  18. Multiple Signaling Pathways Contribute to the Thrombin-induced Secretory Phenotype in Vascular Smooth Muscle Cells.

    PubMed

    Jeong, Ji Young; Son, Younghae; Kim, Bo-Young; Eo, Seong-Kug; Rhim, Byung-Yong; Kim, Koanhoi

    2015-11-01

    We attempted to investigate molecular mechanisms underlying phenotypic change of vascular smooth muscle cells (VSMCs) by determining signaling molecules involved in chemokine production. Treatment of human aortic smooth muscle cells (HAoSMCs) with thrombin resulted not only in elevated transcription of the (C-C motif) ligand 11 (CCL11) gene but also in enhanced secretion of CCL11 protein. Co-treatment of HAoSMCs with GF109230X, an inhibitor of protein kinase C, or GW5074, an inhibitor of Raf-1 kinase, caused inhibition of ERK1/2 phosphorylation and significantly attenuated expression of CCL11 at transcriptional and protein levels induced by thrombin. Both Akt phosphorylation and CCL11 expression induced by thrombin were attenuated in the presence of pertussis toxin (PTX), an inhibitor of Gi protein-coupled receptor, or LY294002, a PI3K inhibitor. In addition, thrombin-induced production of CCL11 was significantly attenuated by pharmacological inhibition of Akt or MEK which phosphorylates ERK1/2. These results indicate that thrombin is likely to promote expression of CCL11 via PKC/Raf-1/ERK1/2 and PTX-sensitive protease-activated receptors/PI3K/Akt pathways in HAoSMCs. We propose that multiple signaling pathways are involved in change of VSMCs to a secretory phenotype. PMID:26557022

  19. Distinct Signaling Mechanisms in Multiple Developmental Pathways by the SCRAMBLED Receptor of Arabidopsis1[OPEN

    PubMed Central

    Kwak, Su-Hwan; Woo, Sooah; Lee, Myeong Min; Schiefelbein, John

    2014-01-01

    SCRAMBLED (SCM), a leucine-rich repeat receptor-like kinase in Arabidopsis (Arabidopsis thaliana), is required for positional signaling in the root epidermis and for tissue/organ development in the shoot. To further understand SCM action, we generated a series of kinase domain variants and analyzed their ability to complement scm mutant defects. We found that the SCM kinase domain, but not kinase activity, is required for its role in root epidermal patterning, supporting the view that SCM is an atypical receptor kinase. We also describe a previously uncharacterized role for SCM in fruit dehiscence, because mature siliques from scm mutants fail to open properly. Interestingly, the kinase domain of SCM appears to be dispensable for this developmental process. Furthermore, we found that most of the SCM kinase domain mutations dramatically inhibit inflorescence development. Because this process is not affected in scm null mutants, it is likely that SCM acts redundantly to regulate inflorescence size. The importance of distinct kinase residues for these three developmental processes provides an explanation for the maintenance of the conserved kinase domain in the SCM protein, and it may generally explain its conservation in other atypical kinases. Furthermore, these results indicate that individual leucine-rich repeat receptor-like kinases may participate in multiple pathways using distinct signaling mechanisms to mediate diverse cellular communication events. PMID:25136062

  20. Differential rates of phenotypic introgression are associated with male behavioral responses to multiple signals.

    PubMed

    Greig, Emma I; Baldassarre, Daniel T; Webster, Michael S

    2015-10-01

    Sexual selection on multiple signals may lead to differential rates of signal introgression across hybrid zones if some signals contribute to reproductive isolation but others facilitate gene flow. Competition among males is one powerful form of sexual selection, but male behavioral responses to multiple traits have not been considered in a system where traits have introgressed differentially. Using playbacks, mounts, and a reciprocal experimental design, we tested the hypothesis that male responses to song and plumage in two subspecies of red-backed fairy-wren (Malurus melanocephalus) explain patterns of differential signal introgression (song has not introgressed, whereas plumage color has introgressed asymmetrically). We found that males of both subspecies discriminated symmetrically between subspecies' songs at a long range, but at a close range, we found that aggression was equal for both subspecies' plumage and songs. Taken together, our results suggest that male behavioral responses hinder the introgression of song, but allow for the observed asymmetrical introgression of plumage. Our results highlight how behavioral responses are a key component of signal evolution when recently divergent taxa come together, and how differential responses to multiple signals may lead to differential signal introgression and novel trait combinations. PMID:26292844

  1. Active Debris Removal of Multiple Priority Targets

    NASA Astrophysics Data System (ADS)

    Braun, Vitali; Flegel, Sven Kevin; Vörsmann, Peter; Wiedemann, Carsten; Gelhaus, Johannes; Moeckel, Marek; Kebschull, Christopher

    2012-07-01

    Today's space debris environment shows major concentrations of objects within distinct orbital regions for nearly all size regimes. The most critical region is found at orbital altitudes near 800 kilometers with high declinations. Within this region many satellites are operated in so called sun-synchronous orbits (SSO). Among those, there are Earth observation, communication and weather satellites. Due to the orbital geometry, head-on encounters with relative velocities of about 15 km/s are most probable and would thus result in highly energetic collisions, which are often referred to as catastrophic collisions, leading to the complete fragmentation of the participating objects. So called feedback collisions can then be triggered by the newly generated fragments, thus leading to a further population increase in the affected orbital region. This effect is known as the Kessler syndrome. Current studies show that catastrophic collisions are not a major problem today, but will become the main process for debris generation within the SSO region in the near future, even without any future launches. In order to avoid this effect, objects with a major impact on collisional cascading have to be actively removed from the critical region after their end of life. Not having the capability to perform an end-of-life maneuver in order to transfer to a graveyard orbit or to de-orbit, many satellites and rocket bodies would have to be de-orbited within a dedicated mission. In such a mission, a service satellite would perform a de-orbit maneuver, after having docked to a specific target. In this paper several systems, e.g. chemical and electrical engines are analysed with the main focus on removing multiple targets within one single mission. The service satellite has to undock from the previously de-orbited target in order to start the rendezvous and docking phase for a subsequent target. The targets are chosen from a previously defined priority list in order to enhance the mission

  2. Active debris removal of multiple priority targets

    NASA Astrophysics Data System (ADS)

    Braun, Vitali; Lüpken, A.; Flegel, S.; Gelhaus, J.; Möckel, M.; Kebschull, C.; Wiedemann, C.; Vörsmann, P.

    2013-05-01

    Today's space debris environment shows major concentrations of objects within distinct orbital regions for nearly all size regimes. The most critical region is found at orbital altitudes near 800 km with high declinations. Within this region many satellites are operated in so called sun-synchronous orbits (SSO). Among those, there are Earth observation, communication and weather satellites. Due to the orbital geometry in SSO, head-on encounters with relative velocities of about 15 km/s are most probable and would thus result in highly energetic collisions, which are often referred to as catastrophic collisions, leading to the complete fragmentation of the participating objects. So called feedback collisions can then be triggered by the newly generated fragments, thus leading to a further population increase in the affected orbital region. This effect is known as the Kessler syndrome.Current studies show that catastrophic collisions are not a major problem today, but will become the main process for debris generation within the SSO region in the near future, even without any further launches. In order to avoid this effect, objects with a major impact on collisional cascading have to be actively removed from the critical region after their end of life. Not having the capability to perform an end-of-life maneuver in order to transfer to a graveyard orbit or to de-orbit, many satellites and rocket bodies would have to be de-orbited within a dedicated mission. In such a mission, a service satellite would perform a de-orbit maneuver, after having docked to a specific target.In this paper, chemical and electric propulsion systems were analysed with the main focus on removing multiple targets within one single mission. The targets were chosen from a previously defined priority list in order to enhance the mission efficiency. Total mission time, ΔV and system mass were identified as key parameters to allow for an evaluation of the different concepts. It was shown that it

  3. Parasites and health affect multiple sexual signals in male common wall lizards, Podarcis muralis

    NASA Astrophysics Data System (ADS)

    Martín, José; Amo, Luisa; López, Pilar

    2008-04-01

    Multiple advertising sexual traits may either advertise different characteristics of male condition or be redundant to reinforce reliability of signals. Research has focused on multiple visual traits. However, in animals that use different multiple additional sensory systems, such as chemoreception, different types of traits might have evolved to signal similar characteristics of a male quality using different sensory channels. We examined whether ventral coloration and chemicals in femoral gland secretions of male common wall lizards, Podarcis muralis, are affected by their health state (blood-parasite load and cell-mediated immune response). Our results indicated that less parasitized lizards had brighter and more yellowish ventral colorations and also femoral secretions with higher proportions of two esters of octadecenoic acid. In addition, lizards with a greater immune response had more saturated coloration and secretions with higher proportions of octadecenoic acid methyl ester. We suggest that these signals would be reliable because only healthier males seemed able to allocate more carotenoids to coloration and presumably costly chemicals to secretions. The use of multiple sensory channels may provide more opportunities to signal a male quality under different circumstances, but also may reinforce the reliability of the signal when both types of traits may be perceived simultaneously.

  4. Variables associated with patient activation in persons with multiple sclerosis.

    PubMed

    Goodworth, Marie-Christine R; Stepleman, Lara; Hibbard, Judith; Johns, Lisa; Wright, Dustin; Hughes, Mary D; Williams, Mitzi J

    2016-01-01

    Identifying variables associated with patient activation in the multiple sclerosis population could serve to facilitate better multiple sclerosis self-management behaviors. Using a cross-sectional survey design, 199 participants were recruited from a multiple sclerosis center in the Southeastern United States. Depression, multiple sclerosis quality of life, and multiple Sclerosis self-efficacy were all significantly correlated with patient activation. Results of a hierarchical regression indicated that patient activation was significantly related to educational attainment, depression, and self-efficacy but not to quality of life. The results suggest several possible targets for intervention to increase patient activation, including health literacy, depression symptoms, and self-efficacy for multiple sclerosis disease management. PMID:24591120

  5. Kinase active Misshapen regulates Notch signaling in Drosophila melanogaster.

    PubMed

    Mishra, Abhinava K; Sachan, Nalani; Mutsuddi, Mousumi; Mukherjee, Ashim

    2015-11-15

    Notch signaling pathway represents a principal cellular communication system that plays a pivotal role during development of metazoans. Drosophila misshapen (msn) encodes a protein kinase, which is related to the budding yeast Ste20p (sterile 20 protein) kinase. In a genetic screen, using candidate gene approach to identify novel kinases involved in Notch signaling, we identified msn as a novel regulator of Notch signaling. Data presented here suggest that overexpression of kinase active form of Msn exhibits phenotypes similar to Notch loss-of-function condition and msn genetically interacts with components of Notch signaling pathway. Kinase active form of Msn associates with Notch receptor and regulate its signaling activity. We further show that kinase active Misshapen leads to accumulation of membrane-tethered form of Notch. Moreover, activated Msn also depletes Armadillo and DE-Cadherin from adherens junctions. Thus, this study provides a yet unknown mode of regulation of Notch signaling by Misshapen. PMID:26431585

  6. Biomechanical Signals Inhibit IKK Activity to Attenuate NF-κB Transcription Activity in Inflamed Chondrocytes

    PubMed Central

    Dossumbekova, Anar; Anghelina, Mirela; Madhavan, Shashi; He, Lingli; Quan, Ning; Knobloch, Thomas; Agarwal, Sudha

    2016-01-01

    Objective While the effects of biomechanical signals in the form of joint movement and exercise are known to be beneficial to inflamed joints, limited information is available regarding the intracellular mechanisms of their actions. This study was undertaken to examine the intracellular mechanisms by which biomechanical signals suppress proinflammatory gene induction by the interleukin-1-β (IL-1β)–induced NF-κB signaling cascade in articular chondrocytes. Methods Primary rat articular chondrocytes were exposed to biomechanical signals in the form of cyclic tensile strain, and the effects on the NF-κB signaling cascade were examined by Western blot analysis, real-time polymerase chain reaction, and immunofluorescence. Results Cyclic tensile strain rapidly inhibited the IL-1β–induced nuclear translocation of NF-κB, but not its IL-1β–induced phosphorylation at serine 276 and serine 536, which are necessary for its transactivation and transcriptional efficacy, respectively. Examination of upstream events revealed that cyclic tensile strain also inhibited the cytoplasmic protein degradation of IκBβ and IκBα, as well as repressed their gene transcription. Additionally, cyclic tensile strain induced a rapid nuclear translocation of IκBα to potentially prevent NF-κB binding to DNA. Furthermore, the inhibition of IL-1β–induced degradation of IκB by cyclic tensile strain was mediated by down-regulation of IκB kinase activity. Conclusion These results indicate that the signals generated by cyclic tensile strain act at multiple sites within the NF-κB signaling cascade to inhibit IL-1β–induced proinflammatory gene induction. Taken together, these findings provide insight into how biomechanical signals regulate and reduce inflammation, and underscore their potential in enhancing the ability of chondrocytes to curb inflammation in diseased joints. PMID:17907174

  7. A novel EMD selecting thresholding method based on multiple iteration for denoising LIDAR signal

    NASA Astrophysics Data System (ADS)

    Li, Meng; Jiang, Li-hui; Xiong, Xing-long

    2015-06-01

    Empirical mode decomposition (EMD) approach has been believed to be potentially useful for processing the nonlinear and non-stationary LIDAR signals. To shed further light on its performance, we proposed the EMD selecting thresholding method based on multiple iteration, which essentially acts as a development of EMD interval thresholding (EMD-IT), and randomly alters the samples of noisy parts of all the corrupted intrinsic mode functions to generate a better effect of iteration. Simulations on both synthetic signals and LIDAR signals from real world support this method.

  8. Code extraction from encoded signal in time-spreading optical code division multiple access.

    PubMed

    Si, Zhijian; Yin, Feifei; Xin, Ming; Chen, Hongwei; Chen, Minghua; Xie, Shizhong

    2010-01-15

    A vulnerability that allows eavesdroppers to extract the code from the waveform of the noiselike encoded signal of an isolated user in a standard time-spreading optical code division multiple access communication system using bipolar phase code is experimentally demonstrated. The principle is based on fine structure in the encoded signal. Each dip in the waveform corresponds to a transition of the bipolar code. Eavesdroppers can get the code by analyzing the chip numbers between any two transitions; then a decoder identical to the legal user's can be fabricated, and they can get the properly decoded signal. PMID:20081977

  9. Power-efficient method for IM-DD optical transmission of multiple OFDM signals.

    PubMed

    Effenberger, Frank; Liu, Xiang

    2015-05-18

    We propose a power-efficient method for transmitting multiple frequency-division multiplexed (FDM) orthogonal frequency-division multiplexing (OFDM) signals in intensity-modulation direct-detection (IM-DD) optical systems. This method is based on quadratic soft clipping in combination with odd-only channel mapping. We show, both analytically and experimentally, that the proposed approach is capable of improving the power efficiency by about 3 dB as compared to conventional FDM OFDM signals under practical bias conditions, making it a viable solution in applications such as optical fiber-wireless integrated systems where both IM-DD optical transmission and OFDM signaling are important. PMID:26074605

  10. Signaling mechanisms of bortezomib in TRAF3-deficient mouse B lymphoma and human multiple myeloma cells.

    PubMed

    Edwards, Shanique K E; Han, Yeming; Liu, Yingying; Kreider, Benjamin Z; Liu, Yan; Grewal, Sukhdeep; Desai, Anand; Baron, Jacqueline; Moore, Carissa R; Luo, Chang; Xie, Ping

    2016-02-01

    Bortezomib, a clinical drug for multiple myeloma (MM) and mantle cell lymphoma, exhibits complex mechanisms of action, which vary depending on the cancer type and the critical genetic alterations of each cancer. Here we investigated the signaling mechanisms of bortezomib in mouse B lymphoma and human MM cells deficient in a new tumor suppressor gene, TRAF3. We found that bortezomib consistently induced up-regulation of the cell cycle inhibitor p21(WAF1) and the pro-apoptotic protein Noxa as well as cleavage of the anti-apoptotic protein Mcl-1. Interestingly, bortezomib induced the activation of NF-κB1 and the accumulation of the oncoprotein c-Myc, but inhibited the activation of NF-κB2. Furthermore, we demonstrated that oridonin (an inhibitor of NF-κB1 and NF-κB2) or AD 198 (a drug targeting c-Myc) drastically potentiated the anti-cancer effects of bortezomib in TRAF3-deficient malignant B cells. Taken together, our findings increase the understanding of the mechanisms of action of bortezomib, which would aid the design of novel bortezomib-based combination therapies. Our results also provide a rationale for clinical evaluation of the combinations of bortezomib and oridonin (or other inhibitors of NF-κB1/2) or AD 198 (or other drugs targeting c-Myc) in the treatment of lymphoma and MM, especially in patients containing TRAF3 deletions or relevant mutations. PMID:26740054

  11. High-power optical millimeter-wave signal generation with tunable frequency multiplication factor

    NASA Astrophysics Data System (ADS)

    Han, Yi-shi; Zheng, Zhenyu; Luo, Zhixiao; Min, Zhixuan; Xu, Ou; Liu, Jie

    2015-01-01

    This work demonstrates a simple and novel scheme for millimeter-wave (MMW) signal generation using optical multi-sidebands (OMSB) modulation. In the proposed methods, several pairs of optical sidebands can be generated by employing parallel phase modulators driven by a low frequency radio frequency (RF) signal. The optical sidebands will beat at a photodetector (PD) to generate high frequency MMW signal with tunable frequency multiplication factor, such as frequency octupling, 12-tupling, 16-tupling and 18-tupling. Since no optical filters or DC bias are used, the MMW signal has the evident character of high-power output. A generalized analytic expression and simulation verification for generating the frequency multi-tupling MMW signal are developed. The influences caused by non-ideal factors are discussed in detail, and undesired power ratios versus non-ideal factors are plotted and analyzed.

  12. Error detection and correction for a multiple frequency quaternary phase shift keyed signal

    NASA Astrophysics Data System (ADS)

    Hopkins, Kevin S.

    1989-06-01

    A multiple frequency quaternary phased shift (MFQPSK) signaling system was developed and experimentally tested in a controlled environment. In order to insure that the quality of the received signal is such that information recovery is possible, error detection/correction (EDC) must be used. Various EDC coding schemes available are reviewed and their application to the MFQPSK signal system is analyzed. Hamming, Golay, Bose-Chaudhuri-Hocquenghem (BCH), Reed-Solomon (R-S) block codes as well as convolutional codes are presented and analyzed in the context of specific MFQPSK system parameters. A computer program was developed in order to compute bit error probabilities as a function of signal to noise ratio. Results demonstrate that various EDC schemes are suitable for the MFQPSK signal structure, and that significant performance improvements are possible with the use of certain error correction codes.

  13. Human ECG signal parameters estimation during controlled physical activity

    NASA Astrophysics Data System (ADS)

    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.

  14. Twist1 activity thresholds define multiple functions in limb development

    PubMed Central

    Krawchuk, Dayana; Weiner, Shoshana J.; Chen, You-Tzung; Lu, Benson; Costantini, Frank; Behringer, Richard R.; Laufer, Ed

    2010-01-01

    Summary The basic helix-loop-helix transcription factor Twist1 is essential for normal limb development. Twist1−/− embryos die at midgestation. However, studies on early limb buds found that Twist1−/− mutant limb mesenchyme has an impaired response to FGF signaling from the apical ectodermal ridge, which disrupts the feedback loop between the mesenchyme and AER, and reduces and shifts anteriorly Shh expression in the zone of polarizing activity. We have combined Twist1 null, hypomorph and conditional alleles to generate a Twist1 allelic series that survives to birth. As Twist1 activity is reduced, limb skeletal defects progress from preaxial polydactyly to girdle reduction combined with hypoplasia, aplasia or mirror symmetry of all limb segments. With reduced Twist1 activity there is striking and progressive upregulation of ectopic Shh expression in the anterior of the limb, combined with an anterior shift in the posterior Shh domain, which is expressed at normal intensity, and loss of the posterior AER. Consequently limb outgrowth is initially impaired, before an ectopic anterior Shh domain expands the AER, promoting additional growth and repatterning. Reducing the dosage of FGF targets of the Etv gene family, which are known repressors of Shh expression in the anterior limb mesenchyme, strongly enhances the anterior skeletal phenotype. Conversely this and other phenotypes are suppressed by reducing the dosage of the Twist1 antagonist Hand2. Our data support a model whereby multiple Twist1 activity thresholds contribute to early limb bud patterning, and suggest how particular combinations of skeletal defects result from differing amounts of Twist1 activity. PMID:20732316

  15. Making Sense of Multiple Physical Activity Recommendations.

    ERIC Educational Resources Information Center

    Corbin, Charles B.; LeMasurier, Guy; Franks, B. Don

    2002-01-01

    This digest provides basic information designed to help people determine which of the many physical activity guidelines are most appropriate for use in specific situations. After an introduction, the digest focuses on: "Factors to Consider in Selecting Appropriate Physical Activity Guidelines" (group credibility and purpose, benefits to be…

  16. Queen signals in a stingless bee: suppression of worker ovary activation and spatial distribution of active compounds

    PubMed Central

    Nunes, Túlio M.; Mateus, Sidnei; Favaris, Arodi P.; Amaral, Mônica F. Z. J.; von Zuben, Lucas G.; Clososki, Giuliano C.; Bento, José M. S.; Oldroyd, Benjamin P.; Silva, Ricardo; Zucchi, Ronaldo; Silva, Denise B.; Lopes, Norberto P.

    2014-01-01

    In most species of social insect the queen signals her presence to her workers via pheromones. Worker responses to queen pheromones include retinue formation around the queen, inhibition of queen cell production and suppression of worker ovary activation. Here we show that the queen signal of the Brazilian stingless bee Friesella schrottkyi is a mixture of cuticular hydrocarbons. Stingless bees are therefore similar to ants, wasps and bumble bees, but differ from honey bees in which the queen's signal mostly comprises volatile compounds originating from the mandibular glands. This shows that cuticular hydrocarbons have independently evolved as the queen's signal across multiple taxa, and that the honey bees are exceptional. We also report the distribution of four active queen-signal compounds by Matrix-assisted laser desorption/ionization (MALDI) imaging. The results indicate a relationship between the behavior of workers towards the queen and the likely site of secretion of the queen's pheromones. PMID:25502598

  17. Detection of geodesic acoustic mode oscillations, using multiple signal classification analysis of Doppler backscattering signal on Tore Supra

    NASA Astrophysics Data System (ADS)

    Vermare, L.; Hennequin, P.; Gürcan, Ö. D.; the Tore Supra Team

    2012-06-01

    This paper presents the first observation of geodesic acoustic modes (GAMs) on Tore Supra plasmas. Using the Doppler backscattering system, the oscillations of the plasma flow velocity, localized between r/a = 0.85 and r/a = 0.95, and with a frequency, typically around 10 kHz, have been observed at the plasma edge in numerous discharges. When the additional heating power is varied, the frequency is found to scale with Cs/R. The MUltiple SIgnal Classification (MUSIC) algorithm is employed to access the temporal evolution of the perpendicular velocity of density fluctuations. The method is presented in some detail, and is validated and compared against standard methods, such as the conventional fast Fourier transform method, using a synthetic signal. It stands out as a powerful data analysis method to follow the Doppler frequency with a high temporal resolution, which is important in order to extract the dynamics of GAMs.

  18. Tuning cell migration: contractility as an integrator of intracellular signals from multiple cues

    PubMed Central

    Bordeleau, Francois; Reinhart-King, Cynthia A.

    2016-01-01

    There has been immense progress in our understanding of the factors driving cell migration in both two-dimensional and three-dimensional microenvironments over the years. However, it is becoming increasingly evident that even though most cells share many of the same signaling molecules, they rarely respond in the same way to migration cues. To add to the complexity, cells are generally exposed to multiple cues simultaneously, in the form of growth factors and/or physical cues from the matrix. Understanding the mechanisms that modulate the intracellular signals triggered by multiple cues remains a challenge. Here, we will focus on the molecular mechanism involved in modulating cell migration, with a specific focus on how cell contractility can mediate the crosstalk between signaling initiated at cell-matrix adhesions and growth factor receptors. PMID:27508074

  19. Tuning cell migration: contractility as an integrator of intracellular signals from multiple cues.

    PubMed

    Bordeleau, Francois; Reinhart-King, Cynthia A

    2016-01-01

    There has been immense progress in our understanding of the factors driving cell migration in both two-dimensional and three-dimensional microenvironments over the years. However, it is becoming increasingly evident that even though most cells share many of the same signaling molecules, they rarely respond in the same way to migration cues. To add to the complexity, cells are generally exposed to multiple cues simultaneously, in the form of growth factors and/or physical cues from the matrix. Understanding the mechanisms that modulate the intracellular signals triggered by multiple cues remains a challenge. Here, we will focus on the molecular mechanism involved in modulating cell migration, with a specific focus on how cell contractility can mediate the crosstalk between signaling initiated at cell-matrix adhesions and growth factor receptors. PMID:27508074

  20. Raman signal enhancement by multiple beam excitation and its application for the detection of chemicals

    SciTech Connect

    Gupta, Sakshi; Ahmad, Azeem; Mehta, Dalip S.; Gambhir, Vijayeta; Reddy, Martha N.

    2015-08-31

    In a typical Raman based sensor, a single laser beam is used for exciting the sample and the backscattered or forward scattered light is collected using collection optics and is analyzed by a spectrometer. We have investigated that by means of exciting the sample with multiple beams, i.e., by dividing the same input power of the single beam into two or three or more beams and exciting the sample from different angles, the Raman signal enhances significantly. Due to the presence of multiple beams passing through the same volume of the sample, an interference pattern is formed and the volume of interaction of excitation beams with the sample increases. By means of this geometry, the enhancement in the Raman signal is observed and it was found that the signal strength increases linearly with the increase in number of excitation beams. Experimental results of this scheme for excitation of the samples are reported for explosive detection at a standoff distance.

  1. A calmodulin-binding/CGCG box DNA-binding protein family involved in multiple signaling pathways in plants

    NASA Technical Reports Server (NTRS)

    Yang, Tianbao; Poovaiah, B. W.

    2002-01-01

    We reported earlier that the tobacco early ethylene-responsive gene NtER1 encodes a calmodulin-binding protein (Yang, T., and Poovaiah, B. W. (2000) J. Biol. Chem. 275, 38467-38473). Here we demonstrate that there is one NtER1 homolog as well as five related genes in Arabidopsis. These six genes are rapidly and differentially induced by environmental signals such as temperature extremes, UVB, salt, and wounding; hormones such as ethylene and abscisic acid; and signal molecules such as methyl jasmonate, H(2)O(2), and salicylic acid. Hence, they were designated as AtSR1-6 (Arabidopsis thaliana signal-responsive genes). Ca(2+)/calmodulin binds to all AtSRs, and their calmodulin-binding regions are located on a conserved basic amphiphilic alpha-helical motif in the C terminus. AtSR1 targets the nucleus and specifically recognizes a novel 6-bp CGCG box (A/C/G)CGCG(G/T/C). The multiple CGCG cis-elements are found in promoters of genes such as those involved in ethylene signaling, abscisic acid signaling, and light signal perception. The DNA-binding domain in AtSR1 is located on the N-terminal 146 bp where all AtSR1-related proteins share high similarity but have no similarity to other known DNA-binding proteins. The calmodulin-binding nuclear proteins isolated from wounded leaves exhibit specific CGCG box DNA binding activities. These results suggest that the AtSR gene family encodes a family of calmodulin-binding/DNA-binding proteins involved in multiple signal transduction pathways in plants.

  2. Multiple plasma enzyme activities in liver disease

    PubMed Central

    Hargreaves, T.; Janota, I.; Smith, M. J. H.

    1961-01-01

    The measurement of the plasma activities of glutamic-oxaloacetic and glutamic-pyruvic transaminases, aldolase, cholinesterase, and isocitric, lactic, and phosphogluconic dehydrogenases in random samples of blood was found to be of no value in the differential diagnosis of hepatitis, obstructive jaundice, hepatic cirrhosis, and neoplastic conditions involving the liver. Serial determinations of the enzyme activities provided useful information about the course of certain hepatic disorders, particularly acute viral hepatitis. PMID:13711559

  3. Sensitive SERS detection of DNA methyltransferase by target triggering primer generation-based multiple signal amplification strategy.

    PubMed

    Li, Ying; Yu, Chuanfeng; Han, Huixia; Zhao, Caisheng; Zhang, Xiaoru

    2016-07-15

    A novel and sensitive surface-enhanced Raman scattering (SERS) method is proposed for the assay of DNA methyltransferase (MTase) activity and evaluation of inhibitors by developing a target triggering primer generation-based multiple signal amplification strategy. By using of a duplex substrate for Dam MTase, two hairpin templates and a Raman probe, multiple signal amplification mode is achieved. Once recognized by Dam MTase, the duplex substrate can be cleaved by Dpn I endonuclease and two primers are released for triggering the multiple signal amplification reaction. Consequently, a wide dynamic range and remarkably high sensitivity are obtained under isothermal conditions. The detection limit is 2.57×10(-4)UmL(-1). This assay exhibits an excellent selectivity and is successfully applied in the screening of inhibitors for Dam MTase. In addition, this novel sensing system is potentially universal as the recognition element can be conveniently designed for other target analytes by changing the substrate of DNA MTase. PMID:26926592

  4. Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types.

    PubMed

    Chartier, Cecile; Raval, Janak; Axelrod, Fumiko; Bond, Chris; Cain, Jennifer; Dee-Hoskins, Cristina; Ma, Shirley; Fischer, Marcus M; Shah, Jalpa; Wei, Jie; Ji, May; Lam, Andrew; Stroud, Michelle; Yen, Wan-Ching; Yeung, Pete; Cancilla, Belinda; O'Young, Gilbert; Wang, Min; Kapoun, Ann M; Lewicki, John; Hoey, Timothy; Gurney, Austin

    2016-02-01

    Deregulation of the β-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and β-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate β-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate β-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, gene-expression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited β-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of β-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis. PMID:26719531

  5. Signaling Interplay between Bone Marrow Adipose Tissue and Multiple Myeloma cells

    PubMed Central

    Falank, Carolyne; Fairfield, Heather; Reagan, Michaela R.

    2016-01-01

    In the year 2000, Hanahan and Weinberg (1) defined the six Hallmarks of Cancer as: self-sufficiency in growth signals, evasion of apoptosis, insensitivity to antigrowth mechanisms, tissue invasion and metastasis, limitless replicative potential, and sustained angiogenesis. Eleven years later, two new Hallmarks were added to the list (avoiding immune destruction and reprograming energy metabolism) and two new tumor characteristics (tumor-promoting inflammation and genome instability and mutation) (2). In multiple myeloma (MM), a destructive cancer of the plasma cell that grows predominantly in the bone marrow (BM), it is clear that all these hallmarks and characteristics are in play, contributing to tumor initiation, drug resistance, disease progression, and relapse. Bone marrow adipose tissue (BMAT) is a newly recognized contributor to MM oncogenesis and disease progression, potentially affecting MM cell metabolism, immune action, inflammation, and influences on angiogenesis. In this review, we discuss the confirmed and hypothetical contributions of BMAT to MM development and disease progression. BMAT has been understudied due to technical challenges and a previous lack of appreciation for the endocrine function of this tissue. In this review, we define the dynamic, responsive, metabolically active BM adipocyte. We then describe how BMAT influences MM in terms of: lipids/metabolism, hypoxia/angiogenesis, paracrine or endocrine signaling, and bone disease. We then discuss the connection between BMAT and systemic inflammation and potential treatments to inhibit the feedback loops between BM adipocytes and MM cells that support MM progression. We aim for researchers to use this review to guide and help prioritize their experiments to develop better treatments or a cure for cancers, such as MM, that associate with and may depend on BMAT. PMID:27379019

  6. Signaling Interplay between Bone Marrow Adipose Tissue and Multiple Myeloma cells.

    PubMed

    Falank, Carolyne; Fairfield, Heather; Reagan, Michaela R

    2016-01-01

    In the year 2000, Hanahan and Weinberg (1) defined the six Hallmarks of Cancer as: self-sufficiency in growth signals, evasion of apoptosis, insensitivity to antigrowth mechanisms, tissue invasion and metastasis, limitless replicative potential, and sustained angiogenesis. Eleven years later, two new Hallmarks were added to the list (avoiding immune destruction and reprograming energy metabolism) and two new tumor characteristics (tumor-promoting inflammation and genome instability and mutation) (2). In multiple myeloma (MM), a destructive cancer of the plasma cell that grows predominantly in the bone marrow (BM), it is clear that all these hallmarks and characteristics are in play, contributing to tumor initiation, drug resistance, disease progression, and relapse. Bone marrow adipose tissue (BMAT) is a newly recognized contributor to MM oncogenesis and disease progression, potentially affecting MM cell metabolism, immune action, inflammation, and influences on angiogenesis. In this review, we discuss the confirmed and hypothetical contributions of BMAT to MM development and disease progression. BMAT has been understudied due to technical challenges and a previous lack of appreciation for the endocrine function of this tissue. In this review, we define the dynamic, responsive, metabolically active BM adipocyte. We then describe how BMAT influences MM in terms of: lipids/metabolism, hypoxia/angiogenesis, paracrine or endocrine signaling, and bone disease. We then discuss the connection between BMAT and systemic inflammation and potential treatments to inhibit the feedback loops between BM adipocytes and MM cells that support MM progression. We aim for researchers to use this review to guide and help prioritize their experiments to develop better treatments or a cure for cancers, such as MM, that associate with and may depend on BMAT. PMID:27379019

  7. Altered signaling for mitochondrial and myofibrillar biogenesis in skeletal muscles of patients with multiple sclerosis.

    PubMed

    Hansen, Dominique; Wens, Inez; Vandenabeele, Frank; Verboven, Kenneth; Eijnde, Bert O

    2015-07-01

    Patients with multiple sclerosis (pwMS) experience muscle weakness and lowered muscle oxidative capacity. To explore the etiology for the development of such muscle phenotype we studied skeletal muscle adenosine monophosphate (AMP)-activated protein kinase phosphorylation (phospho-AMPKα, governing mitochondrial biogenesis) and mammalian target of rapamycin phosphorylation (phospho-mTOR, governing myofibrillar biogenesis) in pwMS. After assessment of body composition, muscle strength, exercise tolerance, and muscle fiber type, muscle phospho-AMPKα and phospho-mTOR were assessed in 14 pwMS and 10 healthy controls (part 1). Next, an endurance exercise bout was executed by 9 pwMS and 7 healthy subjects, with assessment of changes in muscle phospho-AMPKα and phospho-mTOR (part 2). Increased basal muscle phospho-AMPKα and phospho-mTOR were present in MS (P < 0.01) and independently related to MS. Correlations between muscle phospho-AMPKα or phospho-mTOR and whole-body fat mass, peak oxygen uptake, and expanded disability status scale (P < 0.05) were found. After endurance exercise muscle phospho-AMPKα and phospho-mTOR remained increased in pwMS (P < 0.01). Muscle signaling cascades for mitochondrial and myofibrillar biogenesis are altered in MS and related to the impairment and disability level. These findings indicate a link between muscle signaling cascades and the level of disability and impairment, and thus may open a new area for the development of novel therapies for peripheral muscle impairment in MS. PMID:25666356

  8. Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma.

    PubMed

    Carapuça, Elisabete F; Gemenetzidis, Emilios; Feig, Christine; Bapiro, Tashinga E; Williams, Michael D; Wilson, Abigail S; Delvecchio, Francesca R; Arumugam, Prabhu; Grose, Richard P; Lemoine, Nicholas R; Richards, Frances M; Kocher, Hemant M

    2016-07-01

    Stromal targeting for pancreatic ductal adenocarcinoma (PDAC) is rapidly becoming an attractive option, due to the lack of efficacy of standard chemotherapy and increased knowledge about PDAC stroma. We postulated that the addition of stromal therapy may enhance the anti-tumour efficacy of chemotherapy. Gemcitabine and all-trans retinoic acid (ATRA) were combined in a clinically applicable regimen, to target cancer cells and pancreatic stellate cells (PSCs) respectively, in 3D organotypic culture models and genetically engineered mice (LSL-Kras(G12D) (/+) ;LSL-Trp53(R172H) (/+) ;Pdx-1-Cre: KPC mice) representing the spectrum of PDAC. In two distinct sets of organotypic models as well as KPC mice, we demonstrate a reduction in cancer cell proliferation and invasion together with enhanced cancer cell apoptosis when ATRA is combined with gemcitabine, compared to vehicle or either agent alone. Simultaneously, PSC activity (as measured by deposition of extracellular matrix proteins such as collagen and fibronectin) and PSC invasive ability were both diminished in response to combination therapy. These effects were mediated through a range of signalling cascades (Wnt, hedgehog, retinoid, and FGF) in cancer as well as stellate cells, affecting epithelial cellular functions such as epithelial-mesenchymal transition, cellular polarity, and lumen formation. At the tissue level, this resulted in enhanced tumour necrosis, increased vascularity, and diminished hypoxia. Consequently, there was an overall reduction in tumour size. The enhanced effect of stromal co-targeting (ATRA) alongside chemotherapy (gemcitabine) appears to be mediated by dampening multiple signalling cascades in the tumour-stroma cross-talk, rather than ablating stroma or targeting a single pathway. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID:27061193

  9. Varicella Viruses Inhibit Interferon-Stimulated JAK-STAT Signaling through Multiple Mechanisms

    PubMed Central

    Verweij, Marieke C.; Wellish, Mary; Whitmer, Travis; Malouli, Daniel; Lapel, Martin; Jonjić, Stipan; Haas, Juergen G.; DeFilippis, Victor R.; Mahalingam, Ravi; Früh, Klaus

    2015-01-01

    Varicella zoster virus (VZV) causes chickenpox in humans and, subsequently, establishes latency in the sensory ganglia from where it reactivates to cause herpes zoster. Infection of rhesus macaques with simian varicella virus (SVV) recapitulates VZV pathogenesis in humans thus representing a suitable animal model for VZV infection. While the type I interferon (IFN) response has been shown to affect VZV replication, the virus employs counter mechanisms to prevent the induction of anti-viral IFN stimulated genes (ISG). Here, we demonstrate that SVV inhibits type I IFN-activated signal transduction via the JAK-STAT pathway. SVV-infected rhesus fibroblasts were refractory to IFN stimulation displaying reduced protein levels of IRF9 and lacking STAT2 phosphorylation. Since previous work implicated involvement of the VZV immediate early gene product ORF63 in preventing ISG-induction we studied the role of SVV ORF63 in generating resistance to IFN treatment. Interestingly, SVV ORF63 did not affect STAT2 phosphorylation but caused IRF9 degradation in a proteasome-dependent manner, suggesting that SVV employs multiple mechanisms to counteract the effect of IFN. Control of SVV ORF63 protein levels via fusion to a dihydrofolate reductase (DHFR)-degradation domain additionally confirmed its requirement for viral replication. Our results also show a prominent reduction of IRF9 and inhibition of STAT2 phosphorylation in VZV-infected cells. In addition, cells expressing VZV ORF63 blocked IFN-stimulation and displayed reduced levels of the IRF9 protein. Taken together, our data suggest that varicella ORF63 prevents ISG-induction both directly via IRF9 degradation and indirectly via transcriptional control of viral proteins that interfere with STAT2 phosphorylation. SVV and VZV thus encode multiple viral gene products that tightly control IFN-induced anti-viral responses. PMID:25973608

  10. Multiple Nuclear Localization Signals Mediate Nuclear Localization of the GATA Transcription Factor AreA

    PubMed Central

    Hunter, Cameron C.; Siebert, Kendra S.; Downes, Damien J.; Wong, Koon Ho; Kreutzberger, Sara D.; Fraser, James A.; Clarke, David F.; Hynes, Michael J.; Davis, Meryl A.

    2014-01-01

    The Aspergillus nidulans GATA transcription factor AreA activates transcription of nitrogen metabolic genes in response to nitrogen limitation and is known to accumulate in the nucleus during nitrogen starvation. Sequence analysis of AreA revealed multiple nuclear localization signals (NLSs), five putative classical NLSs conserved in fungal AreA orthologs but not in the Saccharomyces cerevisiae functional orthologs Gln3p and Gat1p, and one putative noncanonical RRX33RXR bipartite NLS within the DNA-binding domain. In order to identify the functional NLSs in AreA, we constructed areA mutants with mutations in individual putative NLSs or combinations of putative NLSs and strains expressing green fluorescent protein (GFP)-AreA NLS fusion genes. Deletion of all five classical NLSs individually or collectively did not affect utilization of nitrogen sources or AreA-dependent gene expression and did not prevent AreA nuclear localization. Mutation of the bipartite NLS conferred the inability to utilize alternative nitrogen sources and abolished AreA-dependent gene expression likely due to effects on DNA binding but did not prevent AreA nuclear localization. Mutation of all six NLSs simultaneously prevented AreA nuclear accumulation. The bipartite NLS alone strongly directed GFP to the nucleus, whereas the classical NLSs collaborated to direct GFP to the nucleus. Therefore, AreA contains multiple conserved NLSs, which show redundancy and together function to mediate nuclear import. The noncanonical bipartite NLS is conserved in GATA factors from Aspergillus, yeast, and mammals, indicating an ancient origin. PMID:24562911

  11. Therapeutic Impact of Sphingosine 1-phosphate Receptor Signaling in Multiple Sclerosis.

    PubMed

    Candido, Kristina; Soufi, Henry; Bandyopadhyay, Mausumi; Dasgupta, Subhajit

    2016-01-01

    Multiple sclerosis (MS) is a female predominant autoimmune demyelinating disease of central nervous system. The proper etiology is not clear. The existing therapies with interferon beta (Betaseron, Rebif), glatiramer acetate (copolymer 1, copaxone) are found to be promising for MS patients. The alpha-4 integrin antagonist monoclonal antibody Natalizumab has been found to decrease brain inflammation in relapsing-remitting MS via inhibition of alpha-4 beta- 1 integrinmediated mode of action of antigen -primed T cells to enter into central nervous system through blood brain barrier. The advancement of drug development introduced prospects of CD52 monoclonal antibody Alemtuzumab and CD20 monoclonal antibody Rituximab in MS therapy. The benefit versus risk ratios of these therapeutic monoclonal antibodies are currently under clinical trial. The ongoing researches demonstrated the importance of HMG-CoA reductase inhibitor statins, NF-κBp65 inhibitor NBD peptide, and antagonist of poly-ADP-ribose polymerase (PARP) in experimental autoimmune encephalomyelitis (EAE), animal model for MS. Recently, the clinical trials indicated the therapeutic prospect of G-protein coupled sphingosine 1-phosphate receptor (S1PR) in MS patients. Recent studies showed remyelination through selective activation of oligodendrocyte progenitor cells. In the context, role of S1PR-mediated signals following interaction with natural ligand S1P and agonist Fingolimod (FTY720) gain profound therapeutic importance in prevention of demyelination in MS brain. The S1PR agonist Fingolimod (FTY 720) has recently been approved by Food and Drug Administration for MS therapy. In the review, we provided an insight on S1PR mode of action in the aspect of treatment of autoimmune disorder, re-myelination and regeneration of axons in damaged central nervous system in multiple sclerosis. PMID:26156414

  12. Brain source localization: A new method based on MUltiple SIgnal Classification algorithm and spatial sparsity of the field signal for electroencephalogram measurements

    NASA Astrophysics Data System (ADS)

    Vergallo, P.; Lay-Ekuakille, A.

    2013-08-01

    Brain activity can be recorded by means of EEG (Electroencephalogram) electrodes placed on the scalp of the patient. The EEG reflects the activity of groups of neurons located in the head, and the fundamental problem in neurophysiology is the identification of the sources responsible of brain activity, especially if a seizure occurs and in this case it is important to identify it. The studies conducted in order to formalize the relationship between the electromagnetic activity in the head and the recording of the generated external field allow to know pattern of brain activity. The inverse problem, that is given the sampling field at different electrodes the underlying asset must be determined, is more difficult because the problem may not have a unique solution, or the search for the solution is made difficult by a low spatial resolution which may not allow to distinguish between activities involving sources close to each other. Thus, sources of interest may be obscured or not detected and known method in source localization problem as MUSIC (MUltiple SIgnal Classification) could fail. Many advanced source localization techniques achieve a best resolution by exploiting sparsity: if the number of sources is small as a result, the neural power vs. location is sparse. In this work a solution based on the spatial sparsity of the field signal is presented and analyzed to improve MUSIC method. For this purpose, it is necessary to set a priori information of the sparsity in the signal. The problem is formulated and solved using a regularization method as Tikhonov, which calculates a solution that is the better compromise between two cost functions to minimize, one related to the fitting of the data, and another concerning the maintenance of the sparsity of the signal. At the first, the method is tested on simulated EEG signals obtained by the solution of the forward problem. Relatively to the model considered for the head and brain sources, the result obtained allows to

  13. Wogonin inhibits multiple myeloma-stimulated angiogenesis via c-Myc/VHL/HIF-1α signaling axis

    PubMed Central

    Wang, Xiao-Ping; An, Teng; Tao, Lei; Zhou, Yu-Xin; Huang, Yu-Jie; Chen, Bao-An; Li, Zhi-Yu; You, Qi-Dong; Guo, Qing-Long; Wu, Zhao-Qiu

    2016-01-01

    Angiogenesis is associated with the progression of multiple myeloma (MM). Wogonin is an active mono-flavonoid with remarkable antitumor activity. However, its impact on MM-stimulated angiogenesis remains largely unknown. Here, we demonstrated that wogonin decreased expression and secretion of pro-angiogenic factors in MM cells via c-Myc/HIF-1α signaling axis, reducing MM-stimulated angiogenesis and MM cell proliferation in vivo. Overexpression of c-Myc in MM cells disrupted the balance between VHL SUMOylation and ubiquitination, and thus inhibited proteasome-mediated HIF-1α degradation. Impaired function of VHL ubiquitination complex in c-Myc-overexpressing cells was fully reversed by wogonin treatment via increasing HIF-1α-VHL interaction and promoting HIF-1α degradation. Collectively, our in vitro and in vivo studies reveal for the first time that wogonin represses MM-stimulated angiogenesis and tumor progression via c-Myc/VHL/HIF-1α signaling axis. PMID:26735336

  14. Signal processing for the detection of multiple imperfection echoes drowned in the structural noise.

    PubMed

    Drai, R; Benammar, A; Benchaala, A

    2004-04-01

    In this work, we propose to develop algorithms based on the split spectrum processing method associated with the multi-steps method based on "Group delay moving entropy" (GDME) allowing detecting and locating multiple imperfection echoes drowned in the structural noise of materials. In fact, GDME is based on the fact that defect echoes have a constant group delay while the noise has a random group delay. The investigation is performed with 4 known defect echoes with different characteristics (position, center frequency and bandwidth). The defect echo frequency is varied around the frequency of the input signal in order to evaluate, by signal to noise ratio calculation, the robustness of the detection method. The grain noise signal is generated first, by a simple clutter model which consider the noise, in the time domain, as the superimposed of signal coming from backscaterers in the medium and second, experimentally by a material with coarse grains. PMID:15047392

  15. Multiple objective optimization for active sensor management

    NASA Astrophysics Data System (ADS)

    Page, Scott F.; Dolia, Alexander N.; Harris, Chris J.; White, Neil M.

    2005-03-01

    The performance of a multi-sensor data fusion system is inherently constrained by the configuration of the given sensor suite. Intelligent or adaptive control of sensor resources has been shown to offer improved fusion performance in many applications. Common approaches to sensor management select sensor observation tasks that are optimal in terms of a measure of information. However, optimising for information alone is inherently sub-optimal as it does not take account of any other system requirements such as stealth or sensor power conservation. We discuss the issues relating to developing a suite of performance metrics for optimising multi-sensor systems and propose some candidate metrics. In addition it may not always be necessary to maximize information gain, in some cases small increases in information gain may take place at the cost of large sensor resource requirements. Additionally, the problems of sensor tasking and placement are usually treated separately, leading to a lack of coherency between sensor management frameworks. We propose a novel approach based on a high level decentralized information-theoretic sensor management architecture that unifies the processes of sensor tasking and sensor placement into a single framework. Sensors are controlled using a minimax multiple objective optimisation approach in order to address probability of target detection, sensor power consumption, and sensor survivability whilst maintaining a target estimation covariance threshold. We demonstrate the potential of the approach through simulation of a multi-sensor, target tracking scenario and compare the results with a single objective information based approach.

  16. Signaling system for multiple-access laser communications and interference protection.

    PubMed

    Riza, N A; Hershey, J E; Hassan, A A

    1993-04-10

    Signaling by spatial coding is proposed for asynchronous multiple-access free-space optical communications and interference mitigation. The large spatial bandwidth (e.g., 10(6) pixels) of each laser transmitter aperture is utilized for user coding, while the transmitter temporal bandwidth is preserved for information signals. Signal recovery is based on incoherent optical detection, spatial sampling, and electronic or optical matched filtering of the remotely received transmit optical beam Fresnel or Fraunhofer diffraction pattern. The proposed signaling method is appropriate for multiple-access free-space laser links involving multiple transmitters that use a common receiver. With electronic filtering, low-to-medium (e.g., 3 Mbits/s) data-rate users are appropriate. With a lenslet-array-based incoherent optical correlator, higher (e.g., 100 Mbits/s) data rates can be achieved. Improved interference protection is achieved cby spatially distributed bit-duration-based processing. Preliminary simulation results are carried out to demonstrate operating principles. PMID:20820331

  17. Immobilized Metal Affinity Chromatography Coupled to Multiple Reaction Monitoring Enables Reproducible Quantification of Phospho-signaling.

    PubMed

    Kennedy, Jacob J; Yan, Ping; Zhao, Lei; Ivey, Richard G; Voytovich, Uliana J; Moore, Heather D; Lin, Chenwei; Pogosova-Agadjanyan, Era L; Stirewalt, Derek L; Reding, Kerryn W; Whiteaker, Jeffrey R; Paulovich, Amanda G

    2016-02-01

    A major goal in cell signaling research is the quantification of phosphorylation pharmacodynamics following perturbations. Traditional methods of studying cellular phospho-signaling measure one analyte at a time with poor standardization, rendering them inadequate for interrogating network biology and contributing to the irreproducibility of preclinical research. In this study, we test the feasibility of circumventing these issues by coupling immobilized metal affinity chromatography (IMAC)-based enrichment of phosphopeptides with targeted, multiple reaction monitoring (MRM) mass spectrometry to achieve precise, specific, standardized, multiplex quantification of phospho-signaling responses. A multiplex immobilized metal affinity chromatography- multiple reaction monitoring assay targeting phospho-analytes responsive to DNA damage was configured, analytically characterized, and deployed to generate phospho-pharmacodynamic curves from primary and immortalized human cells experiencing genotoxic stress. The multiplexed assays demonstrated linear ranges of ≥3 orders of magnitude, median lower limit of quantification of 0.64 fmol on column, median intra-assay variability of 9.3%, median inter-assay variability of 12.7%, and median total CV of 16.0%. The multiplex immobilized metal affinity chromatography- multiple reaction monitoring assay enabled robust quantification of 107 DNA damage-responsive phosphosites from human cells following DNA damage. The assays have been made publicly available as a resource to the community. The approach is generally applicable, enabling wide interrogation of signaling networks. PMID:26621847

  18. Modulation of the Tumor Metastatic Microenvironment and Multiple Signal Pathways by Prunella vulgaris in Human Hepatocellular Carcinoma.

    PubMed

    Su, Yu-Chieh; Lin, I-Hsin; Siao, Yu-Miao; Liu, Ching-Ju; Yeh, Chia-Chou

    2016-01-01

    Prunella vulgaris (PV) is a traditional Chinese medicine that has been used clinically for centuries in Asian countries to treat herpetic keratitis. In previous studies, PV was shown to suppress TPA-induced activation of MMP-9 and inhibit cell invasion and migration in hepatoma cell lines. However, the detailed molecular mechanism underlying these effects is still unclear. In this study, we investigated the mechanisms underlying PV-mediated inhibition of 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced cell invasion and inhibition of secreted and cytosolic MMP-9 production in human hepatoma cells (Huh-7 and HA22T). PV suppressed VEGF and MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-[Formula: see text]B (NF-[Formula: see text]B) activity. PV suppressed TPA-induced AP-1 activity by inhibiting phosphorylation of the extracellular signal-related kinase (ERK), downregulating p38 signaling pathways, and suppressing TPA-induced inhibition of NF-[Formula: see text]B nuclear translocation through I[Formula: see text]B. PV suppressed TPA-induced activation of ERK/phosphatidylinositol-3-kinase/Akt upstream of NF-[Formula: see text]B and AP-1. These data suggest that PV modifies the metastatic microenvironment of hepatocellular carcinoma (HCC) by inhibiting multiple signal transduction pathways. PV thus may have the therapeutic potential to inhibit the migration and invasion of HCC and act as potential agent for systemic therapies. PMID:27222069

  19. Multiple effects of protein phosphatase 2A on nutrient-induced signalling in the yeast Saccharomyces cerevisiae.

    PubMed

    Sugajska, E; Swiatek, W; Zabrocki, P; Geyskens, I; Thevelein, J M; Zolnierowicz, S; Wera, S

    2001-05-01

    The trehalose-degrading enzyme trehalase is activated upon addition of glucose to derepressed cells or in response to nitrogen source addition to nitrogen-starved glucose-repressed yeast (Saccharomyces cerevisiae) cells. Trehalase activation is mediated by phosphorylation. Inactivation involves dephosphorylation, as trehalase protein levels do not change upon multiple activation/inactivation cycles. Purified trehalase can be inactivated by incubation with protein phosphatase 2A (PP2A) in vitro. To test whether PP2A was involved in trehalase inactivation in vivo, we overexpressed the yeast PP2A isoform Pph22. Unexpectedly, the moderate (approximately threefold) overexpression of Pph22 that we obtained increased basal trehalase activity and rendered this activity unresponsive to the addition of glucose or a nitrogen source. Concomitant with higher basal trehalase activity, cells overexpressing Pph22 did not store trehalose efficiently and were heat sensitive. After the addition of glucose or of a nitrogen source to starved cells, Pph22-overexpressing cells showed a delayed exit from stationary phase, a delayed induction of ribosomal gene expression and constitutive repression of stress-regulated element-controlled genes. Deletion of the SCH9 gene encoding a protein kinase involved in nutrient-induced signal transduction restored glucose-induced trehalase activation in Pph22-overexpressing cells. Taken together, our results indicate that yeast PP2A overexpression leads to the activation of nutrient-induced signal transduction pathways in the absence of nutrients. PMID:11401708

  20. Ammonium Activates Ouabain-Activated Signalling Pathway in Astrocytes: Therapeutic Potential of Ouabain Antagonist

    PubMed Central

    Song, Dan; Du, Ting

    2014-01-01

    The causal role of ammonium in hepatic encephalopathy was identified in 1930s. Astroglial cells are primary cellular elements of hepatic encephalopathy which conceptually, can be considered a toxic astrogliopathology. Previously we have reported that acute exposure to ammonium activated ouabain/Na,K-ATPase signalling pathway, which includes Src, EGF receptor, Raf, Ras, MEK and ERK1/2. Chronic incubation of astrocytes with ammonium increased production of endogenous ouabain-like compound. Ouabain antagonist canrenone abolished effects of ammonium on astrocytic swelling, ROS production, and upregulation of gene expression and function of TRPC1 and Cav1.2. However, ammonium induces multiple pathological modifications in astrocytes, and some of them may be not related to this signalling pathway. In this review, we focus on the effect of ammonium on ouabain/Na,K-ATPase signalling pathway and its involvement in ammonium-induced ROS production, cell swelling and aberration of Ca2+ signals in astrocytes. We also briefly discuss Na,K-ATPase, EGF receptor, endogenous ouabain and ouabain antagonist. PMID:25342941

  1. Active neutron multiplicity analysis and Monte Carlo calculations

    NASA Astrophysics Data System (ADS)

    Krick, M. S.; Ensslin, N.; Langner, D. G.; Miller, M. C.; Siebelist, R.; Stewart, J. E.; Ceo, R. N.; May, P. K.; Collins, L. L., Jr.

    Active neutron multiplicity measurements of high-enrichment uranium metal and oxide samples have been made at Los Alamos and Y-12. The data from the measurements of standards at Los Alamos were analyzed to obtain values for neutron multiplication and source-sample coupling. These results are compared to equivalent results obtained from Monte Carlo calculations. An approximate relationship between coupling and multiplication is derived and used to correct doubles rates for multiplication and coupling. The utility of singles counting for uranium samples is also examined.

  2. Analytical multiple scattering correction to the Mie theory: Application to the analysis of the lidar signal

    NASA Technical Reports Server (NTRS)

    Flesia, C.; Schwendimann, P.

    1992-01-01

    The contribution of the multiple scattering to the lidar signal is dependent on the optical depth tau. Therefore, the radar analysis, based on the assumption that the multiple scattering can be neglected is limited to cases characterized by low values of the optical depth (tau less than or equal to 0.1) and hence it exclude scattering from most clouds. Moreover, all inversion methods relating lidar signal to number densities and particle size must be modified since the multiple scattering affects the direct analysis. The essential requests of a realistic model for lidar measurements which include the multiple scattering and which can be applied to practical situations follow. (1) Requested are not only a correction term or a rough approximation describing results of a certain experiment, but a general theory of multiple scattering tying together the relevant physical parameter we seek to measure. (2) An analytical generalization of the lidar equation which can be applied in the case of a realistic aerosol is requested. A pure analytical formulation is important in order to avoid the convergency and stability problems which, in the case of numerical approach, are due to the large number of events that have to be taken into account in the presence of large depth and/or a strong experimental noise.

  3. Wnt Signaling in Neurogenesis during Aging and Physical Activity

    PubMed Central

    Chen, Michael; Do, Huong

    2012-01-01

    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. PMID:24961268

  4. Active control technology and the use of multiple control surfaces

    NASA Technical Reports Server (NTRS)

    Hart, J. E.

    1976-01-01

    Needed criteria for active control technology applications in commercial transports are lacking. Criteria for redundancy requirements, believed to be consistent with certification philosophy, are postulated to afford a discussion of the relative value of multiple control surfaces. The control power and frequency bandpass requirements of various active control technology applications are shown to be such that multiple control surfaces offer advantages in minimizing the hydraulic or auxiliary power for the control surface actuators.

  5. Fungal proteinaceous compounds with multiple biological activities.

    PubMed

    Ng, Tzi Bun; Cheung, Randy Chi Fai; Wong, Jack Ho; Chan, Yau Sang; Dan, Xiuli; Pan, Wenliang; Wang, Hexiang; Guan, Suzhen; Chan, Ki; Ye, Xiuyun; Liu, Fang; Xia, Lixin; Chan, Wai Yee

    2016-08-01

    Fungi comprise organisms like molds, yeasts and mushrooms. They have been used as food or medicine for a long time. A large number of fungal proteins or peptides with diverse biological activities are considered as antibacterial, antifungal, antiviral and anticancer agents. They encompass proteases, ribosome inactivating proteins, defensins, hemolysins, lectins, laccases, ribonucleases, immunomodulatory proteins, and polysaccharopeptides. The target of the present review is to update the status of the various bioactivities of these fungal proteins and peptides and discuss their therapeutic potential. PMID:27338574

  6. Cellular Cholesterol Directly Activates Smoothened in Hedgehog Signaling.

    PubMed

    Huang, Pengxiang; Nedelcu, Daniel; Watanabe, Miyako; Jao, Cindy; Kim, Youngchang; Liu, Jing; Salic, Adrian

    2016-08-25

    In vertebrates, sterols are necessary for Hedgehog signaling, a pathway critical in embryogenesis and cancer. Sterols activate the membrane protein Smoothened by binding its extracellular, cysteine-rich domain (CRD). Major unanswered questions concern the nature of the endogenous, activating sterol and the mechanism by which it regulates Smoothened. We report crystal structures of CRD complexed with sterols and alone, revealing that sterols induce a dramatic conformational change of the binding site, which is sufficient for Smoothened activation and is unique among CRD-containing receptors. We demonstrate that Hedgehog signaling requires sterol binding to Smoothened and define key residues for sterol recognition and activity. We also show that cholesterol itself binds and activates Smoothened. Furthermore, the effect of oxysterols is abolished in Smoothened mutants that retain activation by cholesterol and Hedgehog. We propose that the endogenous Smoothened activator is cholesterol, not oxysterols, and that vertebrate Hedgehog signaling controls Smoothened by regulating its access to cholesterol. PMID:27545348

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

    PubMed Central

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

    PubMed

    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

  9. Naringenin suppresses TPA-induced tumor invasion by suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells.

    PubMed

    Yen, Hung-Rong; Liu, Ching-Ju; Yeh, Chia-Chou

    2015-06-25

    Naringenin, a common dietary flavonoid abundantly present in fruits and vegetables, is believed to possess strong anti-proliferative properties and the ability to induce apoptosis in hepatoma cell lines. However, there are no reports describing its effects on the invasion and metastasis of hepatoma cell lines, and the detailed molecular mechanisms of its effects are still unclear. In this study, we investigated the mechanisms underlying naringenin-mediated inhibition of 12-O-Tetradecanoylphorbol-13-acetate (TPA)-induced cell invasion and inhibition of secreted and cytosolic MMP-9 production in human hepatoma cells (HepG2, Huh-7, and HA22T) and murine embryonic liver cells (BNL CL2). Naringenin suppressed MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-κB (NF-κB) activity. It suppressed TPA-induced AP-1 activity through inhibiting the phosphorylation of the extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways, and it suppressed TPA-induced inhibition of NF-κB nuclear translocation through IκB. Additionally, it suppressed TPA-induced activation of ERK/phosphatidylinositol 3-kinase/Akt upstream of NF-κB and AP-1. These data suggest that naringenin suppresses the invasiveness and metastatic potential of hepatocellular carcinoma (HCC) by inhibiting multiple signal transduction pathways. PMID:25866363

  10. Damped oscillations in a multiple delayed feedback NF-[Formula: see text]B signaling module.

    PubMed

    Yu, Wen-Ting; Tang, Jun; Ma, Jun; Luo, Jin-Ming; Yang, Xian-Qing

    2015-12-01

    The NF-[Formula: see text]B signaling system regulates a number of cellular processes. Recent studies with simplified models found a damped function of the dual delayed feedback NF-[Formula: see text]B signaling module. We use a computational model to investigate how multiple delayed feedback aids achieving damping oscillation in the system and how internal noise can influence the damping function. A curve-fitting method (CFM) is introduced to quantify the damped oscillation. Our results show that (1) the structure of multiple delayed feedback, containing double or triple significantly delayed feedback, determines achieving damped oscillation. (2) Internal noise could aid the system to achieve damped oscillation under almost all circumstances. PMID:26290058

  11. Multiple GPCR conformations and signalling pathways: implications for antagonist affinity estimates

    PubMed Central

    Baker, Jillian G.; Hill, Stephen J.

    2007-01-01

    Antagonist affinity measurements have traditionally been considered important in characterizing the cell-surface receptors present in a particular cell or tissue. A central assumption has been that antagonist affinity is constant for a given receptor–antagonist interaction, regardless of the agonist used to stimulate that receptor or the downstream response that is measured. As a consequence, changes in antagonist affinity values have been taken as initial evidence for the presence of novel receptor subtypes. Emerging evidence suggests, however, that receptors can possess multiple binding sites and the same receptor can show different antagonist affinity measurements under distinct experimental conditions. Here, we discuss several mechanisms by which antagonists have different affinities for the same receptor as a consequence of allosterism, coupling to different G proteins, multiple (but non-interacting) receptor sites, and signal-pathway-dependent pharmacology (where the pharmacology observed varies depending on the signalling pathway measured). PMID:17629959

  12. O-GlcNAcylation of master growth repressor DELLA by SECRET AGENT modulates multiple signaling pathways in Arabidopsis.

    PubMed

    Zentella, Rodolfo; Hu, Jianhong; Hsieh, Wen-Ping; Matsumoto, Peter A; Dawdy, Andrew; Barnhill, Benjamin; Oldenhof, Harriëtte; Hartweck, Lynn M; Maitra, Sushmit; Thomas, Stephen G; Cockrell, Shelley; Boyce, Michael; Shabanowitz, Jeffrey; Hunt, Donald F; Olszewski, Neil E; Sun, Tai-Ping

    2016-01-15

    The DELLA family of transcription regulators functions as master growth repressors in plants by inhibiting phytohormone gibberellin (GA) signaling in response to developmental and environmental cues. DELLAs also play a central role in mediating cross-talk between GA and other signaling pathways via antagonistic direct interactions with key transcription factors. However, how these crucial protein-protein interactions can be dynamically regulated during plant development remains unclear. Here, we show that DELLAs are modified by the O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) SECRET AGENT (SEC) in Arabidopsis. O-GlcNAcylation of the DELLA protein REPRESSOR OF ga1-3 (RGA) inhibits RGA binding to four of its interactors-PHYTOCHROME-INTERACTING FACTOR3 (PIF3), PIF4, JASMONATE-ZIM DOMAIN1, and BRASSINAZOLE-RESISTANT1 (BZR1)-that are key regulators in light, jasmonate, and brassinosteroid signaling pathways, respectively. Consistent with this, the sec-null mutant displayed reduced responses to GA and brassinosteroid and showed decreased expression of several common target genes of DELLAs, BZR1, and PIFs. Our results reveal a direct role of OGT in repressing DELLA activity and indicate that O-GlcNAcylation of DELLAs provides a fine-tuning mechanism in coordinating multiple signaling activities during plant development. PMID:26773002

  13. O-GlcNAcylation of master growth repressor DELLA by SECRET AGENT modulates multiple signaling pathways in Arabidopsis

    PubMed Central

    Zentella, Rodolfo; Hu, Jianhong; Hsieh, Wen-Ping; Matsumoto, Peter A.; Dawdy, Andrew; Barnhill, Benjamin; Oldenhof, Harriëtte; Hartweck, Lynn M.; Maitra, Sushmit; Thomas, Stephen G.; Cockrell, Shelley; Boyce, Michael; Shabanowitz, Jeffrey; Hunt, Donald F.; Olszewski, Neil E.; Sun, Tai-ping

    2016-01-01

    The DELLA family of transcription regulators functions as master growth repressors in plants by inhibiting phytohormone gibberellin (GA) signaling in response to developmental and environmental cues. DELLAs also play a central role in mediating cross-talk between GA and other signaling pathways via antagonistic direct interactions with key transcription factors. However, how these crucial protein–protein interactions can be dynamically regulated during plant development remains unclear. Here, we show that DELLAs are modified by the O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) SECRET AGENT (SEC) in Arabidopsis. O-GlcNAcylation of the DELLA protein REPRESSOR OF ga1-3 (RGA) inhibits RGA binding to four of its interactors—PHYTOCHROME-INTERACTING FACTOR3 (PIF3), PIF4, JASMONATE-ZIM DOMAIN1, and BRASSINAZOLE-RESISTANT1 (BZR1)—that are key regulators in light, jasmonate, and brassinosteroid signaling pathways, respectively. Consistent with this, the sec-null mutant displayed reduced responses to GA and brassinosteroid and showed decreased expression of several common target genes of DELLAs, BZR1, and PIFs. Our results reveal a direct role of OGT in repressing DELLA activity and indicate that O-GlcNAcylation of DELLAs provides a fine-tuning mechanism in coordinating multiple signaling activities during plant development. PMID:26773002

  14. Quantifying bursting neuron activity from calcium signals using blind deconvolution.

    PubMed

    Park, In Jun; Bobkov, Yuriy V; Ache, Barry W; Principe, Jose C

    2013-09-15

    Advances in calcium imaging have enabled studies of the dynamic activity of both individual neurons and neuronal assemblies. However, challenges, such as unknown nonlinearities in the spike-calcium relationship, noise, and the often relatively low temporal resolution of the calcium signal compared to the time-scale of spike generation, restrict the accurate estimation of action potentials from the calcium signal. Complex neuronal discharge, such as the activity demonstrated by bursting and rhythmically active neurons, represents an even greater challenge for reconstructing spike trains based on calcium signals. We propose a method using blind calcium signal deconvolution based on an information-theoretic approach. This model is meant to maximise the output entropy of a nonlinear filter where the nonlinearity is defined by the cumulative distribution function of the spike signal. We tested our maximum entropy (ME) algorithm using bursting olfactory receptor neurons (bORNs) of the lobster olfactory organ. The advantage of the ME algorithm is that the filter can be trained online based only on the statistics of the spike signal, without any assumptions regarding the unknown transfer function characterizing the relation between the spike and calcium signal. We show that the ME method is able to more accurately reconstruct the timing of the first and last spikes of a burst compared to other methods and that it improves the temporal precision fivefold compared to direct timing resolution of calcium signal. PMID:23711821

  15. Observed multivariable signals of late 20th and early 21st century volcanic activity

    NASA Astrophysics Data System (ADS)

    Santer, Benjamin D.; Solomon, Susan; Bonfils, Céline; Zelinka, Mark D.; Painter, Jeffrey F.; Beltran, Francisco; Fyfe, John C.; Johannesson, Gardar; Mears, Carl; Ridley, David A.; Vernier, Jean-Paul; Wentz, Frank J.

    2015-01-01

    The relatively muted warming of the surface and lower troposphere since 1998 has attracted considerable attention. One contributory factor to this "warming hiatus" is an increase in volcanically induced cooling over the early 21st century. Here we identify the signals of late 20th and early 21st century volcanic activity in multiple observed climate variables. Volcanic signals are statistically discernible in spatial averages of tropical and near-global SST, tropospheric temperature, net clear-sky short-wave radiation, and atmospheric water vapor. Signals of late 20th and early 21st century volcanic eruptions are also detectable in near-global averages of rainfall. In tropical average rainfall, however, only a Pinatubo-caused drying signal is identifiable. Successful volcanic signal detection is critically dependent on removal of variability induced by the El Niño-Southern Oscillation.

  16. Packet communications in satellites with multiple-beam antennas and signal processing

    NASA Technical Reports Server (NTRS)

    Davies, R.; Chethik, F.; Penick, M.

    1980-01-01

    A communication satellite with a multiple-beam antenna and onboard signal processing is considered for use in a 'message-switched' data relay system. The signal processor may incorporate demodulation, routing, storage, and remodulation of the data. A system user model is established and key functional elements for the signal processing are identified. With the throughput and delay requirements as the controlled variables, the hardware complexity, operational discipline, occupied bandwidth, and overall user end-to-end cost are estimated for (1) random-access packet switching; and (2) reservation-access packet switching. Other aspects of this network (eg, the adaptability to channel switched traffic requirements) are examined. For the given requirements and constraints, the reservation system appears to be the most attractive protocol.

  17. Spectral and temporal properties of optical signals with multiple sinusoidal phase modulations.

    PubMed

    Dorrer, C

    2014-02-10

    Optical signals generated by multiple sinusoidal temporal phase modulations (multi-FMs) applied to a monochromatic field are studied from the viewpoint of their optical spectrum and temporal modulations arising from spectral impairments. Statistical analysis based on the central limit theorem shows that the signals' optical spectrum converges to a normal distribution as the number of modulations increases, allowing one to predict the frequency range containing a given fraction of the total energy with the associated cumulative density function. The conversion of frequency modulation to amplitude modulation is analyzed and simulated for arbitrary multi-FM signals. These developments are of theoretical and practical importance for high-energy laser systems, where optical pulses are phase modulated in the front end to smooth out the on-target beam profile and prevent potentially catastrophic damage to optical components. PMID:24663283

  18. Signal peptides are allosteric activators of the protein translocase.

    PubMed

    Gouridis, Giorgos; Karamanou, Spyridoula; Gelis, Ioannis; Kalodimos, Charalampos G; Economou, Anastassios

    2009-11-19

    Extra-cytoplasmic polypeptides are usually synthesized as 'preproteins' carrying amino-terminal, cleavable signal peptides and secreted across membranes by translocases. The main bacterial translocase comprises the SecYEG protein-conducting channel and the peripheral ATPase motor SecA. Most proteins destined for the periplasm and beyond are exported post-translationally by SecA. Preprotein targeting to SecA is thought to involve signal peptides and chaperones like SecB. Here we show that signal peptides have a new role beyond targeting: they are essential allosteric activators of the translocase. On docking on their binding groove on SecA, signal peptides act in trans to drive three successive states: first, 'triggering' that drives the translocase to a lower activation energy state; second, 'trapping' that engages non-native preprotein mature domains docked with high affinity on the secretion apparatus; and third, 'secretion' during which trapped mature domains undergo several turnovers of translocation in segments. A significant contribution by mature domains renders signal peptides less critical in bacterial secretory protein targeting than currently assumed. Rather, it is their function as allosteric activators of the translocase that renders signal peptides essential for protein secretion. A role for signal peptides and targeting sequences as allosteric activators may be universal in protein translocases. PMID:19924216

  19. p38 and Extracellular Signal-Regulated Kinases Regulate the Myogenic Program at Multiple Steps

    PubMed Central

    Wu, Zhenguo; Woodring, Pamela J.; Bhakta, Kunjan S.; Tamura, Kumiko; Wen, Fang; Feramisco, James R.; Karin, Michael; Wang, Jean Y. J.; Puri, Pier Lorenzo

    2000-01-01

    The extracellular signals which regulate the myogenic program are transduced to the nucleus by mitogen-activated protein kinases (MAPKs). We have investigated the role of two MAPKs, p38 and extracellular signal-regulated kinase (ERK), whose activities undergo significant changes during muscle differentiation. p38 is rapidly activated in myocytes induced to differentiate. This activation differs from those triggered by stress and cytokines, because it is not linked to Jun–N-terminal kinase stimulation and is maintained during the whole process of myotube formation. Moreover, p38 activation is independent of a parallel promyogenic pathway stimulated by insulin-like growth factor 1. Inhibition of p38 prevents the differentiation program in myogenic cell lines and human primary myocytes. Conversely, deliberate activation of endogenous p38 stimulates muscle differentiation even in the presence of antimyogenic cues. Much evidence indicates that p38 is an activator of MyoD: (i) p38 kinase activity is required for the expression of MyoD-responsive genes, (ii) enforced induction of p38 stimulates the transcriptional activity of a Gal4-MyoD fusion protein and allows efficient activation of chromatin-integrated reporters by MyoD, and (iii) MyoD-dependent myogenic conversion is reduced in mouse embryonic fibroblasts derived from p38α−/− embryos. Activation of p38 also enhances the transcriptional activities of myocyte enhancer binding factor 2A (MEF2A) and MEF2C by direct phosphorylation. With MEF2C, selective phosphorylation of one residue (Thr293) is a tissue-specific activating signal in differentiating myocytes. Finally, ERK shows a biphasic activation profile, with peaks of activity in undifferentiated myoblasts and postmitotic myotubes. Importantly, activation of ERK is inhibitory toward myogenic transcription in myoblasts but contributes to the activation of myogenic transcription and regulates postmitotic responses (i.e., hypertrophic growth) in myotubes. PMID

  20. Genotype to Phenotype Maps: Multiple Input Abiotic Signals Combine to Produce Growth Effects via Attenuating Signaling Interactions in Maize

    PubMed Central

    Makumburage, G. Buddhika; Richbourg, H. Lee; LaTorre, Kalindi D.; Capps, Andrew; Chen, Cuixen; Stapleton, Ann E.

    2013-01-01

    The complexity of allele interactions constrains crop improvement and the prediction of disease susceptibility. Additive allele effects are the foundation for selection in animal and plant breeding, and complex genetic and environmental interactions contribute to inefficient detection of desirable loci. Manipulation and modeling of other sources of variation, such as environmental variables, have the potential to improve our prediction of phenotype from genotype. As an example of our approach to analysis of the network linking environmental input to alleles, we mapped the genetic architecture of single and combined abiotic stress responses in two maize mapping populations and compared the observed genetic architecture patterns to simple theoretical predictions. Comparisons of single and combined stress effects on growth and biomass traits exhibit patterns of allele effects that suggest attenuating interactions among physiological signaling steps in drought and ultraviolet radiation stress responses. The presence of attenuating interactions implies that shared QTL found in sets of environments could be used to group environment types and identify underlying environmental similarities, and that patterns of stress-dependent genetic architecture should be studied as a way to prioritize prebreeding populations. A better understanding of whole-plant interactor pathways and genetic architecture of multiple-input environmental signaling has the potential to improve the prediction of genomic value in plant breeding and crop modeling. PMID:24142926

  1. Control of IL-17 receptor signaling and tissue inflammation by the p38α–MKP-1 signaling axis in a mouse model of multiple sclerosis

    PubMed Central

    Vogel, Peter; Chi, Hongbo

    2015-01-01

    T helper 17 (TH17) cells are CD4+ T cells that secrete the proinflammatory cytokine interleukin-17 (IL-17) and that play a key pathogenic role in autoimmune diseases. Through inducible and tissue-specific deletion systems, we described the temporal and cell type–specific roles of the mitogen-activated protein kinase (MAPK) p38α in mediating TH17 cell–induced tissue inflammation. Inducible deletion of Mapk14 (which encodes p38α) after the onset of experimental autoimmune encephalomyelitis (EAE), a murine model for human multiple sclerosis, protected mice from inflammation. Furthermore, the severity of EAE was markedly reduced in mice with specific loss of p38α in neuroectoderm-derived cells, including astrocytes, an effect that was associated with defective production of chemokines and decreased infiltration of the target tissue by immune cells. p38α linked IL-17 receptor (IL-17R) signaling to the expression of genes encoding proinflammatory chemokines and cytokines. Mice that lacked MAPK phosphatase 1 (MKP-1), an inhibitor of p38α, had exacerbated EAE and enhanced expression of IL-17R–dependent genes. Our results suggest that the p38α–MKP-1 signaling axis links IL-17R signaling in tissue-resident cells to autoimmune inflammation dependent on infiltrating TH17 cells. PMID:25737586

  2. Sprouty genes prevent excessive FGF signalling in multiple cell types throughout development of the cerebellum

    PubMed Central

    Yu, Tian; Yaguchi, Yuichiro; Echevarria, Diego; Martinez, Salvador; Basson, M. Albert

    2011-01-01

    Fibroblast growth factors (FGFs) and regulators of the FGF signalling pathway are expressed in several cell types within the cerebellum throughout its development. Although much is known about the function of this pathway during the establishment of the cerebellar territory during early embryogenesis, the role of this pathway during later developmental stages is still poorly understood. Here, we investigated the function of sprouty genes (Spry1, Spry2 and Spry4), which encode feedback antagonists of FGF signalling, during cerebellar development in the mouse. Simultaneous deletion of more than one of these genes resulted in a number of defects, including mediolateral expansion of the cerebellar vermis, reduced thickness of the granule cell layer and abnormal foliation. Analysis of cerebellar development revealed that the anterior cerebellar neuroepithelium in the early embryonic cerebellum was expanded and that granule cell proliferation during late embryogenesis and early postnatal development was reduced. We show that the granule cell proliferation deficit correlated with reduced sonic hedgehog (SHH) expression and signalling. A reduction in Fgfr1 dosage during development rescued these defects, confirming that the abnormalities are due to excess FGF signalling. Our data indicate that sprouty acts both cell autonomously in granule cell precursors and non-cell autonomously to regulate granule cell number. Taken together, our data demonstrate that FGF signalling levels have to be tightly controlled throughout cerebellar development in order to maintain the normal development of multiple cell types. PMID:21693512

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

    PubMed

    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

  4. A novel reporter of notch signalling indicates regulated and random notch activation during vertebrate neurogenesis

    PubMed Central

    2011-01-01

    Background Building the complex vertebrate nervous system involves the regulated production of neurons and glia while maintaining a progenitor cell population. Neurogenesis starts asynchronously in different regions of the embryo and occurs over a long period of time, allowing progenitor cells to be exposed to multiple extrinsic signals that regulate the production of different cell types. Notch-mediated cell-cell signalling is one of the mechanisms that maintain the progenitor pool, however, little is known about how the timing of Notch activation is related to the cell cycle and the distinct modes of cell division that generate neurons. An essential tool with which to investigate the role of Notch signalling on cell by cell basis is the development a faithful reporter of Notch activity. Results Here we present a novel reporter for Notch activity based on the promoter of the well characterised Notch target chick Hes5-1, coupled with multiple elements that confer instability, including a destabilized nuclear Venus fluorescent protein and the 3' untranslated region (UTR) of Hes5-1. We demonstrate that this reporter faithfully recapitulates the endogenous expression of Hes5-1 and that it robustly responds to Notch activation in the chick neural tube. Analysis of the patterns of Notch activity revealed by this reporter indicates that although Notch is most frequently activated prior to mitosis it can be activated at any time within the cell cycle. Notch active progenitors undergoing mitosis generate two daughters that both continue to experience Notch signalling. However, cells lacking Notch activity before and during mitosis generate daughters with dissimilar Notch activity profiles. Conclusions A novel Notch reporter with multiple destabilisation elements provides a faithful read-out of endogenous Notch activity on a cell-by-cell basis, as neural progenitors progress through the cell cycle in the chick neural tube. Notch activity patterns in this cell population

  5. Robust algorithm to locate heart beats from multiple physiological waveforms by individual signal detector voting.

    PubMed

    Galeotti, Loriano; Scully, Christopher G; Vicente, Jose; Johannesen, Lars; Strauss, David G

    2015-08-01

    Alarm fatigue is a top medical device hazard in patient monitoring that could be reduced by merging physiological information from multiple sensors, minimizing the impact of a single sensor failing. We developed a heart beat detection algorithm that utilizes multi-modal physiological signals (e.g. electrocardiogram, blood pressure, stroke volume, photoplethysmogram and electro-encephalogram) by merging the heart beats obtained from signal-specific detectors. We used the PhysioNet/Computing in Cardiology Challenge 2014 training set to develop the algorithm, and we refined it with a mix of signals from the multiparameter intelligent monitoring in intensive care (MIMIC II) database and artificially disrupted waveforms. The algorithm had an average sensitivity of 95.67% and positive predictive value (PPV) of 92.28% when applied to the PhysioNet/Computing in Cardiology Challenge 2014 200 record training set. On a refined dataset obtained by removing 5 records with arrhythmias and inconsistent reference annotations we obtained an average sensitivity of 97.43% and PPV of 94.17%. Algorithm performance was assessed with the Physionet Challenge 2014 test set that consisted of 200 records (each up to 10 min length) containing multiple physiological signals and reference annotations verified by the PhysioNet/Computing in Cardiology Challenge 2014 organizers. Our algorithm had a sensitivity of 92.74% and PPV of 87.37% computed over all annotated beats, and a record average sensitivity of 91.08%, PPV of 86.96% and an overall score (average of all 4 measures) of 89.53%. Our algorithm is an example of a data fusion approach that can improve patient monitoring and reduce false alarms by reducing the effect of individual signal failures. PMID:26218439

  6. Crosstalk and Signaling Switches in Mitogen-Activated Protein Kinase Cascades

    PubMed Central

    Fey, Dirk; Croucher, David R.; Kolch, Walter; Kholodenko, Boris N.

    2012-01-01

    Mitogen-activated protein kinase (MAPK) cascades control cell fate decisions, such as proliferation, differentiation, and apoptosis by integrating and processing intra- and extracellular cues. However, similar MAPK kinetic profiles can be associated with opposing cellular decisions depending on cell type, signal strength, and dynamics. This implies that signaling by each individual MAPK cascade has to be considered in the context of the entire MAPK network. Here, we develop a dynamic model of feedback and crosstalk for the three major MAPK cascades; extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38), c-Jun N-terminal kinase (JNK), and also include input from protein kinase B (AKT) signaling. Focusing on the bistable activation characteristics of the JNK pathway, this model explains how pathway crosstalk harmonizes different MAPK responses resulting in pivotal cell fate decisions. We show that JNK can switch from a transient to sustained activity due to multiple positive feedback loops. Once activated, positive feedback locks JNK in a highly active state and promotes cell death. The switch is modulated by the ERK, p38, and AKT pathways. ERK activation enhances the dual specificity phosphatase (DUSP) mediated dephosphorylation of JNK and shifts the threshold of the apoptotic switch to higher inputs. Activation of p38 restores the threshold by inhibiting ERK activity via the PP1 or PP2A phosphatases. Finally, AKT activation inhibits the JNK positive feedback, thus abrogating the apoptotic switch and allowing only proliferative signaling. Our model facilitates understanding of how cancerous deregulations disturb MAPK signal processing and provides explanations for certain drug resistances. We highlight a critical role of DUSP1 and DUSP2 expression patterns in facilitating the switching of JNK activity and show how oncogene induced ERK hyperactivity prevents the normal apoptotic switch explaining the failure of certain drugs to

  7. Regulator of G Protein Signaling 17 as a Negative Modulator of GPCR Signaling in Multiple Human Cancers.

    PubMed

    Hayes, Michael P; Roman, David L

    2016-05-01

    Regulators of G protein signaling (RGS) proteins modulate G protein-coupled receptor (GPCR) signaling networks by terminating signals produced by active Gα subunits. RGS17, a member of the RZ subfamily of RGS proteins, is typically only expressed in appreciable amounts in the human central nervous system, but previous works have shown that RGS17 expression is selectively upregulated in a number of malignancies, including lung, breast, prostate, and hepatocellular carcinoma. In addition, this upregulation of RGS17 is associated with a more aggressive cancer phenotype, as increased proliferation, migration, and invasion are observed. Conversely, decreased RGS17 expression diminishes the response of ovarian cancer cells to agents commonly used during chemotherapy. These somewhat contradictory roles of RGS17 in cancer highlight the need for selective, high-affinity inhibitors of RGS17 to use as chemical probes to further the understanding of RGS17 biology. Based on current evidence, these compounds could potentially have clinical utility as novel chemotherapeutics in the treatment of lung, prostate, breast, and liver cancers. Recent advances in screening technologies to identify potential inhibitors coupled with increasing knowledge of the structural requirements of RGS-Gα protein-protein interaction inhibitors make the future of drug discovery efforts targeting RGS17 promising. This review highlights recent findings related to RGS17 as both a canonical and atypical RGS protein, its role in various human disease states, and offers insights on small molecule inhibition of RGS17. PMID:26928451

  8. Analytical expressions for the gate utilization factors of passive multiplicity counters including signal build-up

    SciTech Connect

    Croft, Stephen; Evans, Louise G; Schear, Melissa A

    2010-01-01

    In the realm of nuclear safeguards, passive neutron multiplicity counting using shift register pulse train analysis to nondestructively quantify Pu in product materials is a familiar and widely applied technique. The approach most commonly taken is to construct a neutron detector consisting of {sup 3}He filled cylindrical proportional counters embedded in a high density polyethylene moderator. Fast neutrons from the item enter the moderator and are quickly slowed down, on timescales of the order of 1-2 {micro}s, creating a thermal population which then persists typically for several 10's {micro}s and is sampled by the {sup 3}He detectors. Because the initial transient is of comparatively short duration it has been traditional to treat it as instantaneous and furthermore to approximate the subsequent capture time distribution as exponential in shape. With these approximations simple expressions for the various Gate Utilization Factors (GUFs) can be obtained. These factors represent the proportion of time correlated events i.e. Doubles and Triples signal present in the pulse train that is detected by the coincidence gate structure chosen (predelay and gate width settings of the multiplicity shift register). More complicated expressions can be derived by generalizing the capture time distribution to multiple time components or harmonics typically present in real systems. When it comes to applying passive neutron multiplicity methods to extremely intense (i.e. high emission rate and highly multiplying) neutron sources there is a drive to use detector types with very fast response characteristics in order to cope with the high rates. In addition to short pulse width, detectors with a short capture time profile are also desirable so that a short coincidence gate width can be set in order to reduce the chance or Accidental coincidence signal. In extreme cases, such as might be realized using boron loaded scintillators, the dieaway time may be so short that the build

  9. Nitric Oxide-cGMP Signaling Stimulates Erythropoiesis through Multiple Lineage-Specific Transcription Factors: Clinical Implications and a Novel Target for Erythropoiesis

    PubMed Central

    Ikuta, Tohru; Sellak, Hassan; Odo, Nadine; Adekile, Adekunle D.; Gaensler, Karin M. L.

    2016-01-01

    Much attention has been directed to the physiological effects of nitric oxide (NO)-cGMP signaling, but virtually nothing is known about its hematologic effects. We reported for the first time that cGMP signaling induces human γ-globin gene expression. Aiming at developing novel therapeutics for anemia, we examined here the hematologic effects of NO-cGMP signaling in vivo and in vitro. We treated wild-type mice with NO to activate soluble guanylate cyclase (sGC), a key enzyme of cGMP signaling. Compared to untreated mice, NO-treated mice had higher red blood cell counts and total hemoglobin but reduced leukocyte counts, demonstrating that when activated, NO-cGMP signaling exerts hematopoietic effects on multiple types of blood cells in vivo. We next generated mice which overexpressed rat sGC in erythroid and myeloid cells. The forced expression of sGCs activated cGMP signaling in both lineage cells. Compared with non-transgenic littermates, sGC mice exhibited hematologic changes similar to those of NO-treated mice. Consistently, a membrane-permeable cGMP enhanced the differentiation of hematopoietic progenitors toward erythroid-lineage cells but inhibited them toward myeloid-lineage cells by controlling multiple lineage-specific transcription factors. Human γ-globin gene expression was induced at low but appreciable levels in sGC mice carrying the human β-globin locus. Together, these results demonstrate that NO-cGMP signaling is capable of stimulating erythropoiesis in both in vitro and vivo settings by controlling the expression of multiple lineage-specific transcription factors, suggesting that cGMP signaling upregulates erythropoiesis at the level of gene transcription. The NO-cGMP signaling axis may constitute a novel target to stimulate erythropoiesis in vivo. PMID:26727002

  10. Coco is a dual activity modulator of TGFβ signaling

    PubMed Central

    Deglincerti, Alessia; Haremaki, Tomomi; Warmflash, Aryeh; Sorre, Benoit; Brivanlou, Ali H.

    2015-01-01

    The TGFβ signaling pathway is a crucial regulator of developmental processes and disease. The activity of TGFβ ligands is modulated by various families of soluble inhibitors that interfere with the interactions between ligands and receptors. In an unbiased, genome-wide RNAi screen to identify genes involved in ligand-dependent signaling, we unexpectedly identified the BMP/Activin/Nodal inhibitor Coco as an enhancer of TGFβ1 signaling. Coco synergizes with TGFβ1 in both cell culture and Xenopus explants. Molecularly, Coco binds to TGFβ1 and enhances TGFβ1 binding to its receptor Alk5. Thus, Coco acts as both an inhibitor and an enhancer of signaling depending on the ligand it binds. This finding raises the need for a global reconsideration of the molecular mechanisms regulating TGFβ signaling. PMID:26116664

  11. Membrane-anchored Plakoglobins Have Multiple Mechanisms of Action in Wnt Signaling

    PubMed Central

    Klymkowsky, Michael W.; Williams, Bart O.; Barish, Grant D.; Varmus, Harold E.; Vourgourakis, Yanni E.

    1999-01-01

    In Wnt signaling, β-catenin and plakoglobin transduce signals to the nucleus through interactions with TCF-type transcription factors. However, when plakoglobin is artificially engineered to restrict it to the cytoplasm by fusion with the transmembrane domain of connexin (cnxPg), it efficiently induces a Wnt-like axis duplication phenotype in Xenopus. In Xenopus embryos, maternal XTCF3 normally represses ventral expression of the dorsalizing gene Siamois. Two models have been proposed to explain the Wnt-like activity of cnxPg: 1) that cnxPg inhibits the machinery involved in the turnover of cytosolic β-catenin, which then accumulates and inhibits maternal XTCF3, and 2) that cnxPg directly acts to inhibit XTCF3 activity. To distinguish between these models, we created a series of N-terminal deletion mutations of cnxPg and examined their ability to induce an ectopic axis in Xenopus, activate a TCF-responsive reporter (OT), stabilize β-catenin, and colocalize with components of the Wnt signaling pathway. cnxPg does not colocalize with the Wnt pathway component Dishevelled, but it does lead to the redistribution of APC and Axin, two proteins involved in the regulation of β-catenin turnover. Expression of cnxPg increases levels of cytosolic β-catenin; however, this effect does not completely explain its signaling activity. Although cnxPg and Wnt-1 stabilize β-catenin to similar extents, cnxPg activates OT to 10- to 20-fold higher levels than Wnt-1. Moreover, although LEF1 and TCF4 synergize with β-catenin and plakoglobin to activate OT, both suppress the signaling activity of cnxPg. In contrast, XTCF3 suppresses the signaling activity of both β-catenin and cnxPg. Both exogenous XLEF1 and XTCF3 are sequestered in the cytoplasm of Xenopus cells by cnxPg. Based on these data, we conclude that, in addition to its effects on β-catenin, cnxPg interacts with other components of the Wnt pathway, perhaps TCFs, and that these interactions contribute to its signaling

  12. Which is the best intrinsic motivation signal for learning multiple skills?

    PubMed

    Santucci, Vieri G; Baldassarre, Gianluca; Mirolli, Marco

    2013-01-01

    Humans and other biological agents are able to autonomously learn and cache different skills in the absence of any biological pressure or any assigned task. In this respect, Intrinsic Motivations (i.e., motivations not connected to reward-related stimuli) play a cardinal role in animal learning, and can be considered as a fundamental tool for developing more autonomous and more adaptive artificial agents. In this work, we provide an exhaustive analysis of a scarcely investigated problem: which kind of IM reinforcement signal is the most suitable for driving the acquisition of multiple skills in the shortest time? To this purpose we implemented an artificial agent with a hierarchical architecture that allows to learn and cache different skills. We tested the system in a setup with continuous states and actions, in particular, with a kinematic robotic arm that has to learn different reaching tasks. We compare the results of different versions of the system driven by several different intrinsic motivation signals. The results show (a) that intrinsic reinforcements purely based on the knowledge of the system are not appropriate to guide the acquisition of multiple skills, and (b) that the stronger the link between the IM signal and the competence of the system, the better the performance. PMID:24273511

  13. Active microdisk resonators in an optical code division multiple access system

    NASA Astrophysics Data System (ADS)

    Akhavan, Hooman

    2013-02-01

    An optical code division multiple access design consisting of a set of active microdisks coupled to a waveguide bus for both encoder and decoder is presented. This integrated design is beneficial for secure transmission of data through an optical fiber channel. Device optimization and performance analysis shows dependence of the output signal quality on number of users and necessity of proper adjustment of quality factor of the resonators considering intended transmitted data rate.

  14. Body mass index, physical activity, and risk of multiple myeloma

    PubMed Central

    Birmann, Brenda M.; Giovannucci, Edward; Rosner, Bernard; Anderson, Kenneth C.; Colditz, Graham A.

    2013-01-01

    Several studies have reported a positive relation of baseline body mass index (BMI) with multiple myeloma, but data on other correlates of energy balance are limited. We undertook the present analyses to further examine the role of energy balance in multiple myeloma etiology in two large prospective cohorts with biennially updated exposure data. We followed members of the Nurses’ Health Study and Health Professionals Follow-up Study cohorts from baseline until multiple myeloma diagnosis, death, or 2002. Adult height and current weight were reported at enrollment, and weight every 2 years thereafter. Physical activity was queried at baseline and updated every 2-4 years. We computed age-adjusted relative risks (RR) of multiple myeloma for categories of BMI and physical activity using Cox proportional hazards regression. We conducted analyses on each cohort separately and on both cohorts combined. We confirmed 215 incident cases of multiple myeloma in the combined cohort of 136,623 individuals (>2.1 million person-years at risk). BMI was positively associated with multiple myeloma in all analyses. The association was strongest in men with BMI ≥30 kg/m2 (v. BMI <22.0 kg/m2; RR=2.4, 95% confidence interval (CI)=1.0-6.0) and modest in overweight (BMI 25-29.9 kg/m2) and obese (BMI ≥30 kg/m2) women (v. BMI <22.0 kg/m2; RR (95% CI)=1.6 (1.0-2.7) and 1.2 (0.7-2.2), respectively). Physical activity was not significantly related to multiple myeloma risk, although an inverse association was suggested in women. In conclusion, obesity appears to have an etiologic role in multiple myeloma, but the role of other correlates of energy balance remains uncertain. PMID:17627013

  15. Multiple active forms of thrombin. IV. Relative activities of meizothrombins

    SciTech Connect

    Doyle, M.F.; Mann, K.G. )

    1990-06-25

    The prothrombin activation intermediates meizothrombin and meizothrombin(desF1) (meizothrombin that has been autoproteolyzed to remove fragment 1) have been obtained in a relatively pure, active form with minimal autolysis, making them suitable for enzymatic characterization. When compared at equimolar concentrations, alpha-thrombin, fragment 1.2+ alpha-thrombin, meizothrombin(desF1), and meizothrombin have approximately 100, 100, 10, and 1% activity, respectively, toward the macromolecular substrates factor V, fibrinogen, and platelets. The difference in activity of these four enzymes cannot be attributed to alterations in the catalytic triad, as all four enzymes have nearly identical catalytic efficiency toward the chromogenic substrate S2238. Further, the ability of meizothrombin and meizothrombin(desF1) to activate protein C was 75% of the activity exhibited by alpha-thrombin or fragment 1.2+ alpha-thrombin. All four enzymes bind to thrombomodulin, as judged by the enhanced rate of protein C activation upon preincubation of the enzymes with thrombomodulin. The extent of rate enhancement varied, with meizothrombin/thrombomodulin exhibiting only 50% of the alpha-thrombin/thrombomodulin rate. This difference in rate is not due to a decreased affinity of the meizothrombin for thrombomodulin since the apparent dissociation constants for the alpha-thrombin-thrombomodulin complex and the meizothrombin-thrombomodulin complex are virtually identical. The difference in the observed rate is due in part to the higher Km for protein C exhibited by the meizothrombin-thrombomodulin complex. Incubation of the thrombomodulin-enzyme complex with phospholipid vesicles caused an increase in the protein C activation rates. The kinetic constants for protein C activation in the presence of phospholipid are virtually identical for these enzyme-thrombomodulin complexes.

  16. Intracellular calcium signals display an avalanche-like behavior over multiple lengthscales

    PubMed Central

    Lopez, Lucía; Piegari, Estefanía; Sigaut, Lorena; Ponce Dawson, Silvina

    2012-01-01

    Many natural phenomena display “self-organized criticality” (SOC), (Bak et al., 1987). This refers to spatially extended systems for which patterns of activity characterized by different lengthscales can occur with a probability density that follows a power law with pattern size. Differently from power laws at phase transitions, systems displaying SOC do not need the tuning of an external parameter. Here we analyze intracellular calcium (Ca2+) signals, a key component of the signaling toolkit of almost any cell type. Ca2+ signals can either be spatially restricted (local) or propagate throughout the cell (global). Different models have suggested that the transition from local to global signals is similar to that of directed percolation. Directed percolation has been associated, in turn, to the appearance of SOC. In this paper we discuss these issues within the framework of simple models of Ca2+ signal propagation. We also analyze the size distribution of local signals (“puffs”) observed in immature Xenopus Laevis oocytes. The puff amplitude distribution obtained from observed local signals is not Gaussian with a noticeable fraction of large size events. The experimental distribution of puff areas in the spatio-temporal record of the image has a long tail that is approximately log-normal. The distribution can also be fitted with a power law relationship albeit with a smaller goodness of fit. The power law behavior is encountered within a simple model that includes some coupling among individual signals for a wide range of parameter values. An analysis of the model shows that a global elevation of the Ca2+ concentration plays a major role in determining whether the puff size distribution is long-tailed or not. This suggests that Ca2+-clearing from the cytosol is key to determine whether IP3-mediated Ca2+ signals can display a SOC-like behavior or not. PMID:22969730

  17. Intracellular calcium signals display an avalanche-like behavior over multiple lengthscales.

    PubMed

    Lopez, Lucía; Piegari, Estefanía; Sigaut, Lorena; Ponce Dawson, Silvina

    2012-01-01

    Many natural phenomena display "self-organized criticality" (SOC), (Bak et al., 1987). This refers to spatially extended systems for which patterns of activity characterized by different lengthscales can occur with a probability density that follows a power law with pattern size. Differently from power laws at phase transitions, systems displaying SOC do not need the tuning of an external parameter. Here we analyze intracellular calcium (Ca(2+)) signals, a key component of the signaling toolkit of almost any cell type. Ca(2+) signals can either be spatially restricted (local) or propagate throughout the cell (global). Different models have suggested that the transition from local to global signals is similar to that of directed percolation. Directed percolation has been associated, in turn, to the appearance of SOC. In this paper we discuss these issues within the framework of simple models of Ca(2+) signal propagation. We also analyze the size distribution of local signals ("puffs") observed in immature Xenopus Laevis oocytes. The puff amplitude distribution obtained from observed local signals is not Gaussian with a noticeable fraction of large size events. The experimental distribution of puff areas in the spatio-temporal record of the image has a long tail that is approximately log-normal. The distribution can also be fitted with a power law relationship albeit with a smaller goodness of fit. The power law behavior is encountered within a simple model that includes some coupling among individual signals for a wide range of parameter values. An analysis of the model shows that a global elevation of the Ca(2+) concentration plays a major role in determining whether the puff size distribution is long-tailed or not. This suggests that Ca(2+)-clearing from the cytosol is key to determine whether IP(3)-mediated Ca(2+) signals can display a SOC-like behavior or not. PMID:22969730

  18. Activity Monitoring and Motion Classification of the Lizard Chamaeleo jacksonii Using Multiple Doppler Radars

    PubMed Central

    Singh, Aditya; Lee, Scott SK; Butler, Marguerite; Lubecke, Victor

    2016-01-01

    We describe a simple, non-contact and efficient tool for monitoring the natural activity of a small lizard (Chamaeleo jacksonii) to yield valuable information about their metabolic activity and energy expenditure. It allows monitoring in a non-confined laboratory environment and uses multiple Doppler radars operating at 10.525 GHz. We developed a classification algorithm that can differentiate between fidgeting and locomotion by processing the quadrature baseband signals from the radars. The results have been verified by visual inspection and indicate that the tool could also be used for automated monitoring of the activities of reptiles and other small animals. PMID:23366934

  19. Activation of cell signaling via optical manipulation of gold-coated liposomes encapsulating signaling molecules

    NASA Astrophysics Data System (ADS)

    Orsinger, Gabriel V.; Leung, Sarah J.; Romanowski, Marek

    2013-02-01

    Many diseases involve changes in cell signaling cascades, as seen commonly in drug resistant cancers. To better understand these intricate signaling events in diseased cells and tissues, experimental methods of probing cellular communication at a single to multi-cell level are required. We recently introduced a general platform for activation of selected signaling pathways by optically controlled delivery and release of water soluble factors using gold-coated liposomes. In the example presented here, we encapsulated inositol trisphosphate (IP3), a ubiquitous intracellular secondary messenger involved in GPCR and Akt signaling cascades, within 100 nm gold-coated liposomes. The high polarizability of the liposome's unique gold pseudo-shell allows stable optical trapping for subcellular manipulation in the presence of cells. We take this optical manipulation further by optically injecting IP3-containing liposomes into the cytosol of a single cell to initiate localized cell signaling. Upon optical injection of liposomal IP3 into a single ovarian carcinoma cell, we observed localized activation as reported by changes in Indo-1 fluorescence intensity. With established gap junctions between the injected cell and neighboring cells, we monitored propagation of this signaling to and through nearby cells.

  20. Brain activity mapping at multiple scales with silicon microprobes containing 1,024 electrodes

    PubMed Central

    Shobe, Justin L.; Claar, Leslie D.; Parhami, Sepideh; Bakhurin, Konstantin I.

    2015-01-01

    The coordinated activity of neural ensembles across multiple interconnected regions has been challenging to study in the mammalian brain with cellular resolution using conventional recording tools. For instance, neural systems regulating learned behaviors often encompass multiple distinct structures that span the brain. To address this challenge we developed a three-dimensional (3D) silicon microprobe capable of simultaneously measuring extracellular spike and local field potential activity from 1,024 electrodes. The microprobe geometry can be precisely configured during assembly to target virtually any combination of four spatially distinct neuroanatomical planes. Here we report on the operation of such a device built for high-throughput monitoring of neural signals in the orbitofrontal cortex and several nuclei in the basal ganglia. We perform analysis on systems-level dynamics and correlations during periods of conditioned behavioral responding and rest, demonstrating the technology's ability to reveal functional organization at multiple scales in parallel in the mouse brain. PMID:26133801

  1. TGF-β signaling is altered in the peripheral blood of subjects with multiple sclerosis

    PubMed Central

    Meoli, Elise M.; Oh, Unsong; Grant, Christian W.; Jacobson, Steven

    2016-01-01

    Multiple sclerosis (MS) is a central nervous system inflammatory disorder with evidence of peripheral immune dysregulation. Abnormalities of the immune suppressive cytokine TGF-β have been reported, but not fully defined, in MS. Through a pathway-focused expression profiling of the peripheral blood, we found abnormalities of TGF-βRII, SMAD4 and SMAD7 expression in subjects with MS, and reduction in the levels of TGF-β regulated genes, indicating an overall reduction in TGF-β signaling in MS. The response to exogenous TGF-β was intact, however, indicating an extrinsic defect of TGF-β signaling in MS. These results indicate that TGF-β control is diminished in MS. PMID:21093933

  2. Gigabit Ethernet signal transmission using asynchronous optical code division multiple access.

    PubMed

    Ma, Philip Y; Fok, Mable P; Shastri, Bhavin J; Wu, Ben; Prucnal, Paul R

    2015-12-15

    We propose and experimentally demonstrate a novel architecture for interfacing and transmitting a Gigabit Ethernet (GbE) signal using asynchronous incoherent optical code division multiple access (OCDMA). This is the first such asynchronous incoherent OCDMA system carrying GbE data being demonstrated to be working among multi-users where each user is operating with an independent clock/data rate and is granted random access to the network. Three major components, the GbE interface, the OCDMA transmitter, and the OCDMA receiver are discussed in detail. The performance of the system is studied and characterized through measuring eye diagrams, bit-error rate and packet loss rate in real-time file transfer. Our Letter also addresses the near-far problem and realizes asynchronous transmission and detection of signal. PMID:26670529

  3. A different approach to use narrowband super-resolution multiple signal classification algorithm on wideband sources.

    PubMed

    Asgari, Mohammad; Soltani, Nasim Yahya; Riahi, Ali

    2010-01-01

    There are varieties of wideband direction-of-arrival (DOA) estimation algorithms. Their structure comprises a number of narrowband ones, each performs in one frequency in a given bandwidth, and then different responses should be combined in a proper way to yield true DOAs. Hence, wideband algorithms are always complex and so non-real-time. This paper investigates a method to derive a flat response of narrowband multiple signal classification (MUSIC) [R. O. Schmidt, IEEE Trans. Antennas Propag., 34, 276-280 (1986)] algorithm in the whole frequencies of given band. Therefore, required conditions of applying narrowband algorithm on wideband impinging signals will be given through a concrete analysis. It could be found out that array sensor locations are able to compensate the frequency variations to reach a flat response of DOAs in a specified wideband frequency. PMID:20058975

  4. Sunitinib activates Axl signaling in renal cell cancer.

    PubMed

    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

  5. Multidimensional signal exploration using multiple correspondence analysis. An example of a load lifting study.

    PubMed

    Loslever, Pierre; Bouilland, Stéphane

    2003-09-01

    Most empirical studies concerning rehabilitation yield numerous multidimensional signals (dozens of time variables are obtained for dozens of empirical situations). The purpose of this paper is to suggest a statistical analysis procedure based on: 1) space-time fuzzy windowing; 2) signal behavior characterization within the windows using membership value averages (MVA); and 3) MVA analysis using the multiple correspondence analysis (MCA). A load lifting study provided an example of 78 multidimensional signals including 89 time variables (forces, energy indicators, linear and angular positions, speeds, and accelerations). The main goal of MCA was to compare and contrast biomechanical signals from two lifting modes: "free" and "isokinetic." In the first mode, three loads were tested--light, medium, and heavy. In the second, three speeds were tested--slow, medium, and fast. Thirteen male individuals without disabilities participated in this study. The MCA showed that most of the free load-lifting strategies cannot be used in isokinetic lifting because the constraints of the subject and the environment are different. In addition, as the level of difficulty increases, free lifting became more economical while isokinetic lifting became less economical. These results would appear to indicate that movement strategies used for free lifting cannot be learned using an isokinetic machine during rehabilitation sessions for chronic low back pain. MCA was also suggested as a tool for comparing patients with control individuals. To achieve this aim, the notion of "supplementary data" was introduced. PMID:14518795

  6. Environmental signals elicit multiple responses in dorsal telencephalic progenitors by threshold-dependent mechanisms.

    PubMed

    Lillien, Laura; Gulacsi, Alexandra

    2006-07-01

    Environmental signals including epidermal growth factor family members, Shh, fibroblast growth factor, and bone morphogenetic protein (BMP) can affect multiple processes during the development of the central nervous system, raising questions about the mechanisms that determine how these pleiotropic signals are interpreted to elicit appropriate responses at specific times and locations. Here we address the idea that different thresholds of stimulation determine how progenitors in the dorsal telencephalon interpret these signals. One mechanism for achieving different thresholds of signaling is illustrated by the developmental increase in the level of epidermal growth factor receptor (EGFR) expression among a subset of progenitors in the late embryonic telencephalon. Another mechanism is illustrated by the antagonistic interaction of BMP with Shh, which can influence EGFR expression and neuron subtype choice. We focus on the similarities and differences in the control of these responses and address the possibility that the gamma-aminobutyric acidergic neuron specification might be linked to progenitor expression of a higher level of EGFRs. PMID:16766711

  7. Correlation of nighttime MF signal strength with solar activity

    NASA Astrophysics Data System (ADS)

    Kohata, Hiroki; Kimura, Iwane; Wakai, Noboru; Ogawa, Tadahiko

    Observations of the signal strength of MF broadcasting signals (774/770 kHz) transmitted from Akita, Japan, on board the Japanese Antarctic ice breaker Fuji, bound from Japan to Syowa station, Antarctica, have revealed an interesting positive correlation between strengths of long distance signals propagating at night and solar activity. It is already known that MF propagation characteristics in North America show a negative correlation with solar activity. The present paper, interprets the results by using the multihop method with full-wave analysis. The difference in correlation with solar activity between the results of Fuji and those in North America can be elucidated if it is assumed that there is a ledge in the electron-density profile around an altitude range of 85 to 90 km and that the density of the ledge is smaller in the North American region than in the equatorial region.

  8. Opposing activities of Notch and Wnt signaling regulate intestinal stem cells and gut homeostasis.

    PubMed

    Tian, Hua; Biehs, Brian; Chiu, Cecilia; Siebel, Christian W; Wu, Yan; Costa, Mike; de Sauvage, Frederic J; Klein, Ophir D

    2015-04-01

    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. PMID:25818302

  9. Multiple functionally redundant signals mediate targeting to the apicoplast in the apicomplexan parasite Toxoplasma gondii.

    PubMed

    Harb, Omar S; Chatterjee, Bithi; Fraunholz, Martin J; Crawford, Michael J; Nishi, Manami; Roos, David S

    2004-06-01

    Most species of the protozoan phylum Apicomplexa harbor an endosymbiotic organelle--the apicoplast--acquired when an ancestral parasite engulfed a eukaryotic plastid-containing alga. Several hundred proteins are encoded in the parasite nucleus and are posttranslationally targeted to the apicoplast by a distinctive bipartite signal. The N-terminal 20 to 30 amino acids of nucleus-encoded apicoplast targeted proteins function as a classical signal sequence, mediating entry into the secretory pathway. Cleavage of the signal sequence exposes a transit peptide of variable length (50 to 200 amino acids) that is required for directing proteins to the apicoplast. Although these peptides are enriched in basic amino acids, their structural and functional characteristics are not well understood, which hampers the identification of apicoplast proteins that may constitute novel chemotherapeutic targets. To identify functional domains for a model apicoplast transit peptide, we generated more than 80 deletions and mutations throughout the transit peptide of Toxoplasma gondii ferredoxin NADP+ reductase (TgFNR) and examined the ability of these altered transit peptides to mediate proper targeting and processing of a fluorescent protein reporter. These studies revealed the presence of numerous functional domains. Processing can take place at multiple sites in the protein sequence and may occur outside of the apicoplast lumen. The TgFNR transit peptide contains at least two independent and functionally redundant targeting signals, each of which contains a subdomain that is required for release from or proper sorting within the endoplasmic reticulum. Certain deletion constructs traffic to multiple locations, including the apicoplast periphery, the rhoptries, and the parasitophorous vacuole, suggesting a common thread for targeting to these specialized compartments. PMID:15189987

  10. Multiple Active Volcanoes in the Northeast Lau Basin

    NASA Astrophysics Data System (ADS)

    Baker, E. T.; Resing, J. A.; Lupton, J. E.; Walker, S. L.; Embley, R. W.; Rubin, K. H.; Buck, N.; de Ronde, C. E.; Arculus, R. J.

    2010-12-01

    The northeast Lau Basin occupies a complex geological area between the Tafua arc front, the E-W trending Tonga Trench, and the Northeast Lau Spreading Center. These boundaries create multiple zones of extension and thus provide abundant opportunities for magma to invade the crust. The 25-km-long chain of “Mata” volcanoes lies near the center of this area, separated from both the arc front and the spreading ridge. In 2008 we discovered hydrothermal venting on the largest and most southerly of these volcanoes, W and E Mata. In 2010 we visited the 7 smaller volcanoes that form a 15-km-long arcuate sweep to the north from W and E Mata (the “North Matas”). We also revisited W and E Mata. Over each volcano we conducted CTD tows to map plumes and collect water samples. Based on the CTD results, camera tows searched for seafloor sources on three volcanoes. The N Mata volcanoes, extending from Mata Taha (1) in the south to Mata Fitu (7) in the north, lie within a prominent gap in the shallow bathymetry along the southern border of the Tonga trench. Northward from E Mata the Mata volcanoes degrade from large symmetrical cones to smaller and blocky volcanic edifices. Summit depths range from 1165 m (W Mata) to 2670 m (Mata Nima (5)). The most active volcano in the chain is the erupting W Mata, with an intense plume that extended 250 m above the summit. Hydrothermal temperature anomalies (Δθ, corrected for hydrographic masking effects) reached ˜1.7°C, with light-scattering values as high as 2-5 ΔNTU. The 2010 surveys now show that 6 of the 7 N Mata volcanoes are also hydrothermally active. Along the N Matas, Δθ and ΔNTU signals ranged from robust to weak, but distinct oxidation-reduction potential (aka Eh) anomalies confirmed active venting in each case. The most concentrated plumes were found near Mata Ua (2) and Mata Fitu (7), with Δθ and ΔNTU maxima of 0.1-0.17°C and 0.3, respectively. Despite the variability in plume strength, however, ΔNTU/Δθ ratios

  11. Receptor tyrosine kinases: mechanisms of activation and signaling

    PubMed Central

    Hubbard, Stevan R.; Miller, W. Todd

    2008-01-01

    Receptor tyrosine kinases (RTKs) are essential components of signal transduction pathways that mediate cell-to-cell communication. These single-pass transmembrane receptors, which bind polypeptide ligands — mainly growth factors — play key roles in processes such as cellular growth, differentiation, metabolism and motility. Recent progress has been achieved towards an understanding of the precise (and varied) mechanisms by which RTKs are activated by ligand binding and by which signals are propagated from the activated receptors to downstream targets in the cell. PMID:17306972

  12. Multiple Shh signaling centers participate in fungiform papilla and taste bud formation and maintenance

    PubMed Central

    Liu, H-X; Ermilov, A; Grachtchouk, M; Li, L; Gumucio, DL; Dlugosz, AA; Mistretta, CM

    2014-01-01

    The adult fungiform taste papilla is a complex of specialized cell types residing in the stratified squamous tongue epithelium. This unique sensory organ includes taste buds, papilla epithelium and lateral walls that extend into underlying connective tissue to surround a core of lamina propria cells. Fungiform papillae must contain long-lived, sustaining or stem cells and short-lived, maintaining or transit amplifying cells that support the papilla and specialized taste buds. Shh signaling has established roles in supporting fungiform induction, development and patterning. However, for a full understanding of how Shh transduced signals act in tongue, papilla and taste bud formation and maintenance, it is necessary to know where and when the Shh ligand and pathway components are positioned. We used immunostaining, in situ hybridization and mouse reporter strains for Shh, Ptch1, Gli1 and Gli2-expression and proliferation markers to identify cells that participate in hedgehog signaling. Whereas there is a progressive restriction in location of Shh ligand-expressing cells, from placode and apical papilla cells to taste bud cells only, a surrounding population of Ptch1 and Gli1 responding cells is maintained in signaling centers throughout papilla and taste bud development and differentiation. The Shh signaling targets are in regions of active cell proliferation. Using genetic-inducible lineage tracing for Gli1-expression, we found that Shh-responding cells contribute not only to maintenance of filiform and fungiform papillae, but also to taste buds. A requirement for normal Shh signaling in fungiform papilla, taste bud and filiform papilla maintenance was shown by Gli2 constitutive activation. We identified proliferation niches where Shh signaling is active and suggest that epithelial and mesenchymal compartments harbor potential stem and/or progenitor cell zones. In all, we report a set of hedgehog signaling centers that regulate development and maintenance of taste

  13. Multiple strategies to activate gold nanoparticles as antibiotics

    NASA Astrophysics Data System (ADS)

    Zhao, Yuyun; Jiang, Xingyu

    2013-08-01

    Widespread antibiotic resistance calls for new strategies. Nanotechnology provides a chance to overcome antibiotic resistance by multiple antibiotic mechanisms. This paper reviews the progress in activating gold nanoparticles with nonantibiotic or antibiotic molecules to combat bacterial resistance, analyzes the gap between experimental achievements and real clinical application, and suggests some potential directions in developing antibacterial nanodrugs.

  14. Multiple strategies to activate gold nanoparticles as antibiotics.

    PubMed

    Zhao, Yuyun; Jiang, Xingyu

    2013-09-21

    Widespread antibiotic resistance calls for new strategies. Nanotechnology provides a chance to overcome antibiotic resistance by multiple antibiotic mechanisms. This paper reviews the progress in activating gold nanoparticles with nonantibiotic or antibiotic molecules to combat bacterial resistance, analyzes the gap between experimental achievements and real clinical application, and suggests some potential directions in developing antibacterial nanodrugs. PMID:23893008

  15. Physical Activities for Children with Severe Multiple Impairments.

    ERIC Educational Resources Information Center

    Grosse, Susan J.

    1981-01-01

    Intended for teachers of students with severe multiple impairments, the booklet examines the role of physical activities in the education of this population and suggests approaches to exhancing their motor development. Suggestions are offered for stimulating movement in preschool, elementary, and secondary immobile children, including tactile…

  16. Notch signaling promotes osteoclast maturation and resorptive activity.

    PubMed

    Ashley, Jason W; Ahn, Jaimo; Hankenson, Kurt D

    2015-11-01

    The role of Notch signaling in osteoclast differentiation is controversial with conflicting experimental evidence indicating both stimulatory and inhibitory roles. Differences in experimental protocols and in vivo versus in vitro models may explain the discrepancies between studies. In this study, we investigated cell autonomous roles of Notch signaling in osteoclast differentiation and function by altering Notch signaling during osteoclast differentiation using stimulation with immobilized ligands Jagged1 or Delta-like1 or by suppression with γ-secretase inhibitor DAPT or transcriptional inhibitor SAHM1. Stimulation of Notch signaling in committed osteoclast precursors resulted in larger osteoclasts with a greater number of nuclei and resorptive activity whereas suppression resulted in smaller osteoclasts with fewer nuclei and suppressed resorptive activity. Conversely, stimulation of Notch signaling in osteoclast precursors prior to induction of osteoclastogenesis resulted in fewer osteoclasts. Our data support a mechanism of context-specific Notch signaling effects wherein Notch stimulation inhibits commitment to osteoclast differentiation, but enhances the maturation and function of committed precursors. PMID:25914241

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

    PubMed

    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

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

    PubMed Central

    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 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

  19. Reelin promotes the adhesion and drug resistance of multiple myeloma cells via integrin β1 signaling and STAT3

    PubMed Central

    Lv, Meng; Liang, Xiaodong; Dai, Hui; Qin, Xiaodan; Zhang, Yan; Hao, Jie; Sun, Xiuyuan; Yin, Yanhui; Huang, Xiaojun; Zhang, Jun; Lu, Jin; Ge, Qing

    2016-01-01

    Reelin is an extracellular matrix (ECM) protein that is essential for neuron migration and positioning. The expression of reelin in multiple myeloma (MM) cells and its association with cell adhesion and survival were investigated. Overexpression, siRNA knockdown, and the addition of recombinant protein of reelin were used to examine the function of reelin in MM cells. Clinically, high expression of reelin was negatively associated with progression-free survival and overall survival. Functionally, reelin promoted the adhesion of MM cells to fibronectin via activation of α5β1 integrin. The resulting phosphorylation of Focal Adhesion Kinase (FAK) led to the activation of Src/Syk/STAT3 and Akt, crucial signaling molecules involved in enhancing cell adhesion and protecting cells from drug-induced cell apoptosis. These findings indicate reelin's important role in the activation of integrin-β1 and STAT3/Akt pathways in multiple myeloma and highlight the therapeutic potential of targeting reelin/integrin/FAK axis. PMID:26848618

  20. Signaling pathways activated by a protease allergen in basophils

    PubMed Central

    Rosenstein, Rachel K.; Bezbradica, Jelena S.; Yu, Shuang; Medzhitov, Ruslan

    2014-01-01

    Allergic diseases represent a significant burden in industrialized countries, but why and how the immune system responds to allergens remain largely unknown. Because many clinically significant allergens have proteolytic activity, and many helminths express proteases that are necessary for their life cycles, host mechanisms likely have evolved to detect the proteolytic activity of helminth proteases, which may be incidentally activated by protease allergens. A cysteine protease, papain, is a prototypic protease allergen that can directly activate basophils and mast cells, leading to the production of cytokines, including IL-4, characteristic of the type 2 immune response. The mechanism of papain’s immunogenic activity remains unknown. Here we have characterized the cellular response activated by papain in basophils. We find that papain-induced IL-4 production requires calcium flux and activation of PI3K and nuclear factor of activated T cells. Interestingly, papain-induced IL-4 production was dependent on the immunoreceptor tyrosine-based activation motif (ITAM) adaptor protein Fc receptor γ-chain, even though the canonical ITAM signaling was not activated by papain. Collectively, these data characterize the downstream signaling pathway activated by a protease allergen in basophils. PMID:25369937

  1. Multiple target tracking and classification improvement using data fusion at node level using acoustic signals

    NASA Astrophysics Data System (ADS)

    Damarla, T. R.; Whipps, Gene

    2005-05-01

    Target tracking and classification using passive acoustic signals is difficult at best as the signals are contaminated by wind noise, multi-path effects, road conditions, and are generally not deterministic. In addition, microphone characteristics, such as sensitivity, vary with the weather conditions. The problem is further compounded if there are multiple targets, especially if some are measured with higher signal-to-noise ratios (SNRs) than the others and they share spectral information. At the U. S. Army Research Laboratory we have conducted several field experiments with a convoy of two, three, four and five vehicles traveling on different road surfaces, namely gravel, asphalt, and dirt roads. The largest convoy is comprised of two tracked vehicles and three wheeled vehicles. Two of the wheeled vehicles are heavy trucks and one is a light vehicle. We used a super-resolution direction-of-arrival estimator, specifically the minimum variance distortionless response, to compute the bearings of the targets. In order to classify the targets, we modeled the acoustic signals emanated from the targets as a set of coupled harmonics, which are related to the engine-firing rate, and subsequently used a multivariate Gaussian classifier. Independent of the classifier, we find tracking of wheeled vehicles to be intermittent as the signals from vehicles with high SNR dominate the much quieter wheeled vehicles. We used several fusion techniques to combine tracking and classification results to improve final tracking and classification estimates. We will present the improvements (or losses) made in tracking and classification of all targets. Although improvements in the estimates for tracked vehicles are not noteworthy, significant improvements are seen in the case of wheeled vehicles. We will present the fusion algorithm used.

  2. A Temporal Window for Signal Activation Dictates the Dimensions of a Nodal Signaling Domain

    PubMed Central

    van Boxtel, Antonius L.; Chesebro, John E.; Heliot, Claire; Ramel, Marie-Christine; Stone, Richard K.; Hill, Caroline S.

    2015-01-01

    Summary Morphogen signaling is critical for the growth and patterning of tissues in embryos and adults, but how morphogen signaling gradients are generated in tissues remains controversial. The morphogen Nodal was proposed to form a long-range signaling gradient via a reaction-diffusion system, on the basis of differential diffusion rates of Nodal and its antagonist Lefty. Here we use a specific zebrafish Nodal biosensor combined with immunofluorescence for phosphorylated Smad2 to demonstrate that endogenous Nodal is unlikely to diffuse over a long range. Instead, short-range Nodal signaling activation in a temporal window is sufficient to determine the dimensions of the Nodal signaling domain. The size of this temporal window is set by the differentially timed production of Nodal and Lefty, which arises mainly from repression of Lefty translation by the microRNA miR-430. Thus, temporal information is transformed into spatial information to define the dimensions of the Nodal signaling domain and, consequently, to specify mesendoderm. PMID:26506307

  3. A Temporal Window for Signal Activation Dictates the Dimensions of a Nodal Signaling Domain.

    PubMed

    van Boxtel, Antonius L; Chesebro, John E; Heliot, Claire; Ramel, Marie-Christine; Stone, Richard K; Hill, Caroline S

    2015-10-26

    Morphogen signaling is critical for the growth and patterning of tissues in embryos and adults, but how morphogen signaling gradients are generated in tissues remains controversial. The morphogen Nodal was proposed to form a long-range signaling gradient via a reaction-diffusion system, on the basis of differential diffusion rates of Nodal and its antagonist Lefty. Here we use a specific zebrafish Nodal biosensor combined with immunofluorescence for phosphorylated Smad2 to demonstrate that endogenous Nodal is unlikely to diffuse over a long range. Instead, short-range Nodal signaling activation in a temporal window is sufficient to determine the dimensions of the Nodal signaling domain. The size of this temporal window is set by the differentially timed production of Nodal and Lefty, which arises mainly from repression of Lefty translation by the microRNA miR-430. Thus, temporal information is transformed into spatial information to define the dimensions of the Nodal signaling domain and, consequently, to specify mesendoderm. PMID:26506307

  4. Carotenoid-based bill colour is an integrative signal of multiple parasite infection in blackbird

    NASA Astrophysics Data System (ADS)

    Biard, Clotilde; Saulnier, Nicolas; Gaillard, Maria; Moreau, Jérôme

    2010-11-01

    In the study of parasite-mediated sexual selection, there has been controversial evidence for the prediction that brighter males should have fewer parasites. Most of these studies have focused on one parasite species. Our aim was to investigate the expression of carotenoid-based coloured signals in relation to patterns of multiple parasite infections, to determine whether colour reflects parasite load of all parasite species, or whether different relationships might be found when looking at each parasite species independently. We investigated the relationship between bill colour, body mass and plasma carotenoids and parasite load (feather chewing lice, blood parasite Plasmodium sp., intestinal parasites cestodes and coccidia) in the blackbird ( Turdus merula). Bill colour on its own appeared to be a poor predictor of parasite load when investigating its relationships with individual parasite species. Variation in parasite intensities at the community level was summarised using principal component analysis to derive synthetic indexes of relative parasite species abundance and absolute parasite load. The relative abundance of parasite species was strongly related to bill colour, plasma carotenoid levels and body mass: birds with relatively more cestodes and chewing lice and relatively less Plasmodium and coccidia had a more colourful bill, circulated more carotenoids and were heavier. These results suggest that bill colour more accurately reflects the relative intensities of parasite infection, rather than one-by-one relationships with parasites or absolute parasite burden. Investigating patterns of multiple parasite infection would thus improve our understanding of the information conveyed by coloured signals on parasite load.

  5. Asymmetric signal amplification for simultaneous SERS detection of multiple cancer markers with significantly different levels.

    PubMed

    Ye, Sujuan; Wu, Yanying; Zhai, Xiaomo; Tang, Bo

    2015-08-18

    Simultaneous detection of cancer biomarkers holds great promise for the early diagnosis of different cancers. However, in the presence of high-concentration biomarkers, the signals of lower-expression biomarkers are overlapped. Existing techniques are not suitable for simultaneously detecting multiple biomarkers at concentrations with significantly different orders of magnitude. Here, we propose an asymmetric signal amplification method for simultaneously detecting multiple biomarkers with significantly different levels. Using the bifunctional probe, a linear amplification mode responds to high-concentration markers, and quadratic amplification mode responds to low-concentration markers. With the combined biobarcode probe and hybridization chain reaction (HCR) amplification method, the detection limits of microRNA (miRNA) and ATP via surface-enhanced Raman scattering (SERS) detection are 0.15 fM and 20 nM, respectively, with a breakthrough of detection concentration difference over 11 orders of magnitude. Furthermore, successful determination of miRNA and ATP in cancer cells supports the practicability of the assay. This methodology promises to open an exciting new avenue for the detection of various types of biomolecules. PMID:26218034

  6. Incident signal power comparison for localization of concurrent multiple acoustic sources.

    PubMed

    Salvati, Daniele; Canazza, Sergio

    2014-01-01

    In this paper, a method to solve the localization of concurrent multiple acoustic sources in large open spaces is presented. The problem of the multisource localization in far-field conditions is to correctly associate the direction of arrival (DOA) estimated by a network array system to the same source. The use of systems implementing a Bayesian filter is a traditional approach to address the problem of localization in multisource acoustic scenario. However, in a real noisy open space the acoustic sources are often discontinuous with numerous short-duration events and thus the filtering methods may have difficulty to track the multiple sources. Incident signal power comparison (ISPC) is proposed to compute DOAs association. ISPC is based on identifying the incident signal power (ISP) of the sources on a microphone array using beamforming methods and comparing the ISP between different arrays using spectral distance (SD) measurement techniques. This method solves the ambiguities, due to the presence of simultaneous sources, by identifying sounds through a minimization of an error criterion on SD measures of DOA combinations. The experimental results were conducted in an outdoor real noisy environment and the ISPC performance is reported using different beamforming techniques and SD functions. PMID:24701179

  7. Incident Signal Power Comparison for Localization of Concurrent Multiple Acoustic Sources

    PubMed Central

    2014-01-01

    In this paper, a method to solve the localization of concurrent multiple acoustic sources in large open spaces is presented. The problem of the multisource localization in far-field conditions is to correctly associate the direction of arrival (DOA) estimated by a network array system to the same source. The use of systems implementing a Bayesian filter is a traditional approach to address the problem of localization in multisource acoustic scenario. However, in a real noisy open space the acoustic sources are often discontinuous with numerous short-duration events and thus the filtering methods may have difficulty to track the multiple sources. Incident signal power comparison (ISPC) is proposed to compute DOAs association. ISPC is based on identifying the incident signal power (ISP) of the sources on a microphone array using beamforming methods and comparing the ISP between different arrays using spectral distance (SD) measurement techniques. This method solves the ambiguities, due to the presence of simultaneous sources, by identifying sounds through a minimization of an error criterion on SD measures of DOA combinations. The experimental results were conducted in an outdoor real noisy environment and the ISPC performance is reported using different beamforming techniques and SD functions. PMID:24701179

  8. PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling

    PubMed Central

    Shrestha, Yashaswi; Schafer, Eric J.; Boehm, Jesse S.; Thomas, Sapana R.; He, Frank; Du, Jinyan; Wang, Shumei; Barretina, Jordi; Weir, Barbara A.; Zhao, Jean J.; Polyak, Kornelia; Golub, Todd R.; Beroukhim, Rameen; Hahn, William C.

    2011-01-01

    Activating mutations in the RAS family or BRAF frequently occur in many types of human cancers but are rarely detected in breast tumors. However, activation of the RAS-RAF-MEK-ERK Mitogen-Activated Protein Kinase (MAPK) pathway is commonly observed in human breast cancers, suggesting that other genetic alterations lead to activation of this signaling pathway. To identify breast cancer oncogenes that activate the MAPK pathway, we screened a library of human kinases for their ability to induce anchorage-independent growth in a derivative of immortalized human mammary epithelial cells (HMLE). We identified PAK1 as a kinase that permitted HMLE cells to form anchorage-independent colonies. PAK1 is amplified in several human cancer types, including 33% of breast tumor samples and cancer cell lines. The kinase activity of PAK1 is necessary for PAK1-induced transformation. Moreover, we show that PAK1 simultaneously activates MAPK and MET signaling; the latter via inhibition of Merlin. Disruption of these activities inhibits PAK1-driven anchorage-independent growth. These observations establish PAK1 amplification as an alternative mechanism for MAPK activation in human breast cancer and credential PAK1 as a breast cancer oncogene that coordinately regulates multiple signaling pathways, the cooperation of which leads to malignant transformation. PMID:22105362

  9. Metabolic signals and innate immune activation in obesity and exercise.

    PubMed

    Ringseis, Robert; Eder, Klaus; Mooren, Frank C; Krüger, Karsten

    2015-01-01

    The combination of a sedentary lifestyle and excess energy intake has led to an increased prevalence of obesity which constitutes a major risk factor for several co-morbidities including type 2 diabetes and cardiovascular diseases. Intensive research during the last two decades has revealed that a characteristic feature of obesity linking it to insulin resistance is the presence of chronic low-grade inflammation being indicative of activation of the innate immune system. Recent evidence suggests that activation of the innate immune system in the course of obesity is mediated by metabolic signals, such as free fatty acids (FFAs), being elevated in many obese subjects, through activation of pattern recognition receptors thereby leading to stimulation of critical inflammatory signaling cascades, like IκBα kinase/nuclear factor-κB (IKK/NF- κB), endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and NOD-like receptor P3 (NLRP3) inflammasome pathway, that interfere with insulin signaling. Exercise is one of the main prescribed interventions in obesity management improving insulin sensitivity and reducing obesity- induced chronic inflammation. This review summarizes current knowledge of the cellular recognition mechanisms for FFAs, the inflammatory signaling pathways triggered by excess FFAs in obesity and the counteractive effects of both acute and chronic exercise on obesity-induced activation of inflammatory signaling pathways. A deeper understanding of the effects of exercise on inflammatory signaling pathways in obesity is useful to optimize preventive and therapeutic strategies to combat the increasing incidence of obesity and its comorbidities. PMID:25825956

  10. Activation of signalling by the activin receptor complex.

    PubMed Central

    Attisano, L; Wrana, J L; Montalvo, E; Massagué, J

    1996-01-01

    Activin exerts its effects by simultaneously binding to two types of p rotein serine/threonine kinase receptors, each type existing in various isoforms. Using the ActR-IB and ActR-IIB receptor isoforms, we have investigated the mechanism of activin receptor activation. ActR-IIB are phosphoproteins with demonstrable affinity for each other. However, activin addition strongly promotes an interaction between these two proteins. Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires the kinase activity of ActR-IIB. Mutation of conserved serines and threonines in the GS domain, a region just upstream of the kinase domain in ActR-IB, abrogates both phosphorylation and signal propagation, suggesting that this domain contains phosphorylation sites required for signalling. ActR-IB activation can be mimicked by mutation of Thr-206 to aspartic acid, which yields a construct, ActR-IB(T206D), that signals in the absence of ligand. Furthermore, the signalling activity of this mutant construct is undisturbed by overexpression of a dominant negative kinase-defective ActR-IIB construct, indicating that ActR-IB(T206D) can signal independently of ActR-IIB. The evidence suggests that ActR-IIB acts as a primary activin receptor and ActR-IB acts as a downstream transducer of activin signals. PMID:8622651

  11. Simultaneous Reconstruction of Multiple Signaling Pathways via the Prize-Collecting Steiner Forest Problem

    PubMed Central

    Tuncbag, Nurcan; Braunstein, Alfredo; Pagnani, Andrea; Huang, Shao-Shan Carol; Chayes, Jennifer; Borgs, Christian; Zecchina, Riccardo

    2013-01-01

    Abstract Signaling and regulatory networks are essential for cells to control processes such as growth, differentiation, and response to stimuli. Although many “omic” data sources are available to probe signaling pathways, these data are typically sparse and noisy. Thus, it has been difficult to use these data to discover the cause of the diseases and to propose new therapeutic strategies. We overcome these problems and use “omic” data to reconstruct simultaneously multiple pathways that are altered in a particular condition by solving the prize-collecting Steiner forest problem. To evaluate this approach, we use the well-characterized yeast pheromone response. We then apply the method to human glioblastoma data, searching for a forest of trees, each of which is rooted in a different cell-surface receptor. This approach discovers both overlapping and independent signaling pathways that are enriched in functionally and clinically relevant proteins, which could provide the basis for new therapeutic strategies. Although the algorithm was not provided with any information about the phosphorylation status of receptors, it identifies a small set of clinically relevant receptors among hundreds present in the interactome. PMID:23383998

  12. Inhibition of CXCR2 signaling promotes recovery in models of Multiple Sclerosis

    PubMed Central

    Kerstetter, AE; Padovani-Claudio, DA; Bai, L; Miller, RH

    2009-01-01

    Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination/remyelination episodes that ultimately fail. Chemokines and their receptors have been implicated in both myelination and remyelination failure. Chemokines regulate migration, proliferation and differentiation of immune and neural cells during development and pathology. Previous studies have demonstrated that the absence of the chemokine receptor CXCR2 results in both disruption of early oligodendrocyte development and long term structural alterations in myelination. Histological studies suggest CXCL1, the primary ligand for CXCR2, is upregulated around the peripheral areas of demyelination suggesting this receptor/ligand combination modulates responses to injury. Here we show that in focal LPC induced demyelinating lesions, localized inhibition of CXCR2 signaling reduced lesion size and enhanced remyelination while systemic treatments were relatively less effective. Treatment of spinal cord cultures with CXCR2 antagonists reduced CXCL1 induced A2B5+ cell proliferation and increased differentiation of myelin producing cells. More critically, treatment of myelin oligodendrocyte glycoprotein peptide 35-55-induced EAE mice, an animal model of multiple sclerosis, with small molecule antagonists against CXCR2 results in increased functionality, decreased lesion load, and enhanced remyelination. Our findings demonstrate the importance of antagonizing CXCR2 in enhancing myelin repair by reducing lesion load and functionality in models of multiple sclerosis and thus provide a therapeutic target for demyelinating diseases. PMID:19616545

  13. Sensitive detection of multiple mycotoxins by SPRi with gold nanoparticles as signal amplification tags.

    PubMed

    Hu, Weihua; Chen, Hongming; Zhang, Huanhuan; He, Guangli; Li, Xin; Zhang, Xiaoxing; Liu, Yang; Li, Chang Ming

    2014-10-01

    Detection of multiple toxic mycotoxins is of importance in food quality control. Surface plasmon resonance imaging (SPRi) is an advanced tool for simultaneously multiple detections with accuracy; however, it suffers from limited sensitivity due to the instrumental constraint and small sizes of mycotoxins with only one epitope for an insensitive competitive immunoassay. In this work a gold nanoparticle (AuNP)-enhanced SPRi chip is designed to sensitively detect multiple mycotoxins using a competitive immunoassay format. The sensing surface is constructed by uniformly attaching dense mycotoxin antigens on poly[oligo(ethylene glycol) methacrylate-co-glycidyl methacrylate] (POEGMA-co-GMA) brush modified SPRi gold chip. After competitive binding in a sample solution containing respective monoclonal antibodies, secondary antibody-conjugated AuNPs are employed to bind with the captured monoclonal antibodies for further amplification of the SPRi signal. Highly specific and sensitive simultaneous detection is achieved for three typical mycotoxins including Aflatoxin B1 (AFB1), Ochratoxin A (OTA) and Zearalenone (ZEN) with low detection limits of 8, 30 and 15 pg mL(-1) and dynamic ranges covering three orders of magnitude. PMID:24992296

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

    NASA Astrophysics Data System (ADS)

    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. Protein kinase A activity and Hedgehog signaling pathway.

    PubMed

    Kotani, Tomoya

    2012-01-01

    Protein kinase A (PKA) is a well-known kinase that plays fundamental roles in a variety of biological processes. In Hedgehog-responsive cells, PKA plays key roles in proliferation and fate specification by modulating the transduction of Hedgehog signaling. In the absence of Hedgehog, a basal level of PKA activity represses the transcription of Hedgehog target genes. The main substrates of PKA in this process are the Ci/Gli family of bipotential transcription factors, which activate and repress Hedgehog target gene expression. PKA phosphorylates Ci/Gli, promoting the production of the repressor forms of Ci/Gli and thus repressing Hedgehog target gene expression. In contrast, the activation of Hedgehog signaling in response to Hedgehog increases the active forms of Ci/Gli, resulting in Hedgehog target gene expression. Because both decreased and increased levels of PKA activity cause abnormal cell proliferation and alter cell fate specification, the basal level of PKA activity in Hedgehog-responsive cells should be precisely regulated. However, the mechanism by which PKA activity is regulated remains obscure and appears to vary between cell types, tissues, and organisms. To date, two mechanisms have been proposed. One is a classical mechanism in which PKA activity is regulated by a small second messenger, cAMP; the other is a novel mechanism in which PKA activity is regulated by a protein, Misty somites. PMID:22391308

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

    NASA Astrophysics Data System (ADS)

    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.

  17. G-protein Signaling Components GCR1 and GPA1 Mediate Responses to Multiple Abiotic Stresses in Arabidopsis

    PubMed Central

    Chakraborty, Navjyoti; Singh, Navneet; Kaur, Kanwaljeet; Raghuram, Nandula

    2015-01-01

    G-protein signaling components have been implicated in some individual stress responses in Arabidopsis, but have not been comprehensively evaluated at the genetic and biochemical level. Stress emerged as the largest functional category in our whole transcriptome analyses of knock-out mutants of GCR1 and/or GPA1 in Arabidopsis (Chakraborty et al., 2015a,b). This led us to ask whether G-protein signaling components offer converging points in the plant's response to multiple abiotic stresses. In order to test this hypothesis, we carried out detailed analysis of the abiotic stress category in the present study, which revealed 144 differentially expressed genes (DEGs), spanning a wide range of abiotic stresses, including heat, cold, salt, light stress etc. Only 10 of these DEGs are shared by all the three mutants, while the single mutants (GCR1/GPA1) shared more DEGs between themselves than with the double mutant (GCR1-GPA1). RT-qPCR validation of 28 of these genes spanning different stresses revealed identical regulation of the DEGs shared between the mutants. We also validated the effects of cold, heat and salt stresses in all the 3 mutants and WT on % germination, root and shoot length, relative water content, proline content, lipid peroxidation and activities of catalase, ascorbate peroxidase and superoxide dismutase. All the 3 mutants showed evidence of stress tolerance, especially to cold, followed by heat and salt, in terms of all the above parameters. This clearly shows the role of GCR1 and GPA1 in mediating the plant's response to multiple abiotic stresses for the first time, especially cold, heat and salt stresses. This also implies a role for classical G-protein signaling pathways in stress sensitivity in the normal plants of Arabidopsis. This is also the first genetic and biochemical evidence of abiotic stress tolerance rendered by knock-out mutation of GCR1 and/or GPA1. This suggests that G-protein signaling pathway could offer novel common targets for the

  18. Falls and Physical Activity in Persons with Multiple Sclerosis

    PubMed Central

    Sosnoff, J. J.; Sandroff, B. M.; Pula, J. H.; Morrison, S. M.; Motl, R. W.

    2012-01-01

    Objectives. To examine the association between fall history and physical activity using an objective measure of physical activity (i.e., accelerometry) in persons with multiple sclerosis. Design. A community-based sample of 75 ambulatory persons with multiple sclerosis volunteered for the investigation. Participants self-reported fall history in the last year, underwent a neurological exam to determine Expanded Disability Status Scale (EDSS) score, and wore an accelerometer around the waist for 7 consecutive days to determine physical activity. Results. Overall, 37 persons (49.3% of the sample) reported falling in the last year with 28 of the 37 falling more than once. Persons who fell in the last year had a significantly lower number of steps/day than nonfallers (3510 versus 4940 steps/day; P < .05). However, when controlling for disability status there was no statistically significant difference between fallers and nonfallers (4092 versus 4373 steps/day; P > .05). Conclusions. Collectively, the findings suggest that fall history may have little impact on current physical activity levels in persons with multiple sclerosis. PMID:22966459

  19. Hedgehog signaling is required at multiple stages of zebrafish tooth development

    PubMed Central

    2010-01-01

    Background The accessibility of the developing zebrafish pharyngeal dentition makes it an advantageous system in which to study many aspects of tooth development from early initiation to late morphogenesis. In mammals, hedgehog signaling is known to be essential for multiple stages of odontogenesis; however, potential roles for the pathway during initiation of tooth development or in later morphogenesis are incompletely understood. Results We have identified mRNA expression of the hedgehog ligands shha and the receptors ptc1 and ptc2 during zebrafish pharyngeal tooth development. We looked for, but did not detect, tooth germ expression of the other known zebrafish hedgehog ligands shhb, dhh, ihha, or ihhb, suggesting that as in mammals, only Shh participates in zebrafish tooth development. Supporting this idea, we found that morphological and gene expression evidence of tooth initiation is eliminated in shha mutant embryos, and that morpholino antisense oligonucleotide knockdown of shha, but not shhb, function prevents mature tooth formation. Hedgehog pathway inhibition with the antagonist compound cyclopamine affected tooth formation at each stage in which we applied it: arresting development at early stages and disrupting mature tooth morphology when applied later. These results suggest that hedgehog signaling is required continuously during odontogenesis. In contrast, over-expression of shha had no effect on the developing dentition, possibly because shha is normally extensively expressed in the zebrafish pharyngeal region. Conclusion We have identified previously unknown requirements for hedgehog signaling for early tooth initiation and later morphogenesis. The similarity of our results with data from mouse and other vertebrates suggests that despite gene duplication and changes in the location of where teeth form, the roles of hedgehog signaling in tooth development have been largely conserved during evolution. PMID:21118524

  20. Activation of B cells by non-canonical helper signals

    PubMed Central

    Cerutti, Andrea; Cols, Montserrat; Puga, Irene

    2012-01-01

    Cognate interaction between T and B lymphocytes of the adaptive immune system is essential for the production of high-affinity antibodies against microbes, and for the establishment of long-term immunological memory. Growing evidence shows that—in addition to presenting antigens to T and B cells—macrophages, dendritic cells and other cells of the innate immune system provide activating signals to B cells, as well as survival signals to antibody-secreting plasma cells. Here, we discuss how these innate immune cells contribute to the induction of highly diversified and temporally sustained antibody responses, both systemically and at mucosal sites of antigen entry. PMID:22868664

  1. Molecular hydrogen suppresses activated Wnt/β-catenin signaling.

    PubMed

    Lin, Yingni; Ohkawara, Bisei; Ito, Mikako; Misawa, Nobuaki; Miyamoto, Kentaro; Takegami, Yasuhiko; Masuda, Akio; Toyokuni, Shinya; Ohno, Kinji

    2016-01-01

    Molecular hydrogen (H2) is effective for many diseases. However, molecular bases of H2 have not been fully elucidated. Cumulative evidence indicates that H2 acts as a gaseous signal modulator. We found that H2 suppresses activated Wnt/β-catenin signaling by promoting phosphorylation and degradation οf β-catenin. Either complete inhibition of GSK3 or mutations at CK1- and GSK3-phosphorylation sites of β-catenin abolished the suppressive effect of H2. H2 did not increase GSK3-mediated phosphorylation of glycogen synthase, indicating that H2 has no direct effect on GSK3 itself. Knock-down of adenomatous polyposis coli (APC) or Axin1, which form the β-catenin degradation complex, minimized the suppressive effect of H2 on β-catenin accumulation. Accordingly, the effect of H2 requires CK1/GSK3-phosphorylation sites of β-catenin, as well as the β-catenin degradation complex comprised of CK1, GSK3, APC, and Axin1. We additionally found that H2 reduces the activation of Wnt/β-catenin signaling in human osteoarthritis chondrocytes. Oral intake of H2 water tended to ameliorate cartilage degradation in a surgery-induced rat osteoarthritis model through attenuating β-catenin accumulation. We first demonstrate that H2 suppresses abnormally activated Wnt/β-catenin signaling, which accounts for the protective roles of H2 in a fraction of diseases. PMID:27558955

  2. Spatial Regulation and the Rate of Signal Transduction Activation

    PubMed Central

    Batada, Nizar N; Shepp, Larry A; Siegmund, David O; Levitt, Michael

    2006-01-01

    Of the many important signaling events that take place on the surface of a mammalian cell, activation of signal transduction pathways via interactions of cell surface receptors is one of the most important. Evidence suggests that cell surface proteins are not as freely diffusible as implied by the classic fluid mosaic model and that their confinement to membrane domains is regulated. It is unknown whether these dynamic localization mechanisms function to enhance signal transduction activation rate or to minimize cross talk among pathways that share common intermediates. To determine which of these two possibilities is more likely, we derive an explicit equation for the rate at which cell surface membrane proteins interact based on a Brownian motion model in the presence of endocytosis and exocytosis. We find that in the absence of any diffusion constraints, cell surface protein interaction rate is extremely high relative to cytoplasmic protein interaction rate even in a large mammalian cell with a receptor abundance of a mere two hundred molecules. Since a larger number of downstream signaling events needs to take place, each occurring at a much slower rate than the initial activation via association of cell surface proteins, we conclude that the role of co-localization is most likely that of cross-talk reduction rather than coupling efficiency enhancement. PMID:16699596

  3. Molecular hydrogen suppresses activated Wnt/β-catenin signaling

    PubMed Central

    Lin, Yingni; Ohkawara, Bisei; Ito, Mikako; Misawa, Nobuaki; Miyamoto, Kentaro; Takegami, Yasuhiko; Masuda, Akio; Toyokuni, Shinya; Ohno, Kinji

    2016-01-01

    Molecular hydrogen (H2) is effective for many diseases. However, molecular bases of H2 have not been fully elucidated. Cumulative evidence indicates that H2 acts as a gaseous signal modulator. We found that H2 suppresses activated Wnt/β-catenin signaling by promoting phosphorylation and degradation οf β-catenin. Either complete inhibition of GSK3 or mutations at CK1- and GSK3-phosphorylation sites of β-catenin abolished the suppressive effect of H2. H2 did not increase GSK3-mediated phosphorylation of glycogen synthase, indicating that H2 has no direct effect on GSK3 itself. Knock-down of adenomatous polyposis coli (APC) or Axin1, which form the β-catenin degradation complex, minimized the suppressive effect of H2 on β-catenin accumulation. Accordingly, the effect of H2 requires CK1/GSK3-phosphorylation sites of β-catenin, as well as the β-catenin degradation complex comprised of CK1, GSK3, APC, and Axin1. We additionally found that H2 reduces the activation of Wnt/β-catenin signaling in human osteoarthritis chondrocytes. Oral intake of H2 water tended to ameliorate cartilage degradation in a surgery-induced rat osteoarthritis model through attenuating β-catenin accumulation. We first demonstrate that H2 suppresses abnormally activated Wnt/β-catenin signaling, which accounts for the protective roles of H2 in a fraction of diseases. PMID:27558955

  4. Growth inhibition and apoptosis in cancer cells induced by polyphenolic compounds of Acacia hydaspica: Involvement of multiple signal transduction pathways

    PubMed Central

    Afsar, Tayyaba; Trembley, Janeen H.; Salomon, Christine E.; Razak, Suhail; Khan, Muhammad Rashid; Ahmed, Khalil

    2016-01-01

    Acacia hydaspica R. Parker is known for its medicinal uses in multiple ailments. In this study, we performed bioassay-guided fractionation of cytotoxic compounds from A. hydaspica and investigated their effects on growth and signaling activity in prostate and breast cancer cell lines. Four active polyphenolic compounds were identified as 7-O-galloyl catechin (GC), catechin (C), methyl gallate (MG), and catechin-3-O-gallate (CG). The four compounds inhibited prostate cancer PC-3 cell growth in a dose-dependent manner, whereas CG and MG inhibited breast cancer MDA-MB-231 cell growth. All tested compounds inhibited cell survival and colony growth in both cell lines, and there was evidence of chromatin condensation, cell shrinkage and apoptotic bodies. Further, acridine orange, ethidium bromide, propidium iodide and DAPI staining demonstrated that cell death occurred partly via apoptosis in both PC-3 and MDA-MB-231 cells. In PC-3 cells treatment repressed the expression of anti-apoptotic molecules Bcl-2, Bcl-xL and survivin, coupled with down-regulation of signaling pathways AKT, NFκB, ERK1/2 and JAK/STAT. In MDA-MB-231 cells, treatment induced reduction of CK2α, Bcl-xL, survivin and xIAP protein expression along with suppression of NFκB, JAK/STAT and PI3K pathways. Our findings suggest that certain polyphenolic compounds derived from A. hydaspica may be promising chemopreventive/therapeutic candidates against cancer. PMID:26975752

  5. Growth inhibition and apoptosis in cancer cells induced by polyphenolic compounds of Acacia hydaspica: Involvement of multiple signal transduction pathways.

    PubMed

    Afsar, Tayyaba; Trembley, Janeen H; Salomon, Christine E; Razak, Suhail; Khan, Muhammad Rashid; Ahmed, Khalil

    2016-01-01

    Acacia hydaspica R. Parker is known for its medicinal uses in multiple ailments. In this study, we performed bioassay-guided fractionation of cytotoxic compounds from A. hydaspica and investigated their effects on growth and signaling activity in prostate and breast cancer cell lines. Four active polyphenolic compounds were identified as 7-O-galloyl catechin (GC), catechin (C), methyl gallate (MG), and catechin-3-O-gallate (CG). The four compounds inhibited prostate cancer PC-3 cell growth in a dose-dependent manner, whereas CG and MG inhibited breast cancer MDA-MB-231 cell growth. All tested compounds inhibited cell survival and colony growth in both cell lines, and there was evidence of chromatin condensation, cell shrinkage and apoptotic bodies. Further, acridine orange, ethidium bromide, propidium iodide and DAPI staining demonstrated that cell death occurred partly via apoptosis in both PC-3 and MDA-MB-231 cells. In PC-3 cells treatment repressed the expression of anti-apoptotic molecules Bcl-2, Bcl-xL and survivin, coupled with down-regulation of signaling pathways AKT, NFκB, ERK1/2 and JAK/STAT. In MDA-MB-231 cells, treatment induced reduction of CK2α, Bcl-xL, survivin and xIAP protein expression along with suppression of NFκB, JAK/STAT and PI3K pathways. Our findings suggest that certain polyphenolic compounds derived from A. hydaspica may be promising chemopreventive/therapeutic candidates against cancer. PMID:26975752

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

    PubMed

    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

  7. The HAMP Signal Relay Domain Adopts Multiple Conformational States through Collective Piston and Tilt Motions

    PubMed Central

    Zhu, Lizhe; Bolhuis, Peter G.; Vreede, Jocelyne

    2013-01-01

    The HAMP domain is a linker region in prokaryotic sensor proteins and relays input signals to the transmitter domain and vice versa. Functional as a dimer, the structure of HAMP shows a parallel coiled-coil motif comprising four helices. To date, it is unclear how HAMP can relay signals from one domain to another, although several models exist. In this work, we use molecular simulation to test the hypothesis that HAMP adopts different conformations, one of which represents an active, signal-relaying configuration, and another an inactive, resting state. We first performed molecular dynamics simulation on the prototype HAMP domain Af1503 from Archaeoglobus fulgidus. We explored its conformational space by taking the structure of the A291F mutant disabling HAMP activity as a starting point. These simulations revealed additional conformational states that differ in the tilt angles between the helices as well as the relative piston shifts of the helices relative to each other. By enhancing the sampling in a metadynamics set up, we investigated three mechanistic models for HAMP signal transduction. Our results indicate that HAMP can access additional conformational states characterized by piston motion. Furthermore, the piston motion of the N-terminal helix of one monomer is directly correlated with the opposite piston motion of the C-terminal helix of the other monomer. The change in piston motion is accompanied by a change in tilt angle between the monomers, thus revealing that HAMP exhibits a collective motion, i.e. a combination of changes in tilt angles and a piston-like displacement. Our results provide insights into the conformational changes that underlie the signaling mechanism involving HAMP. PMID:23468603

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

    PubMed

    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

  9. Free energy landscape of activation in a signalling protein at atomic resolution

    NASA Astrophysics Data System (ADS)

    Pontiggia, F.; Pachov, D. V.; Clarkson, M. W.; Villali, J.; Hagan, M. F.; Pande, V. S.; Kern, D.

    2015-06-01

    The interconversion between inactive and active protein states, traditionally described by two static structures, is at the heart of signalling. However, how folded states interconvert is largely unknown due to the inability to experimentally observe transition pathways. Here we explore the free energy landscape of the bacterial response regulator NtrC by combining computation and nuclear magnetic resonance, and discover unexpected features underlying efficient signalling. We find that functional states are defined purely in kinetic and not structural terms. The need of a well-defined conformer, crucial to the active state, is absent in the inactive state, which comprises a heterogeneous collection of conformers. The transition between active and inactive states occurs through multiple pathways, facilitated by a number of nonnative transient hydrogen bonds, thus lowering the transition barrier through both entropic and enthalpic contributions. These findings may represent general features for functional conformational transitions within the folded state.

  10. A Phosphatase Activity of Sts-1 Contributes to the Suppression of TCR Signaling

    SciTech Connect

    Mikhailik,A.; Ford, B.; Keller, J.; Chen, Y.; Nassar, N.; Carpino, N.

    2007-01-01

    Precise signaling by the T cell receptor (TCR) is crucial for a proper immune response. To ensure that T cells respond appropriately to antigenic stimuli, TCR signaling pathways are subject to multiple levels of regulation. Sts-1 negatively regulates signaling pathways downstream of the TCR by an unknown mechanism(s). Here, we demonstrate that Sts-1 is a phosphatase that can target the tyrosine kinase Zap-70 among other proteins. The X-ray structure of the Sts-1 C terminus reveals that it has homology to members of the phosphoglycerate mutase/acid phosphatase (PGM/AcP) family of enzymes, with residues known to be important for PGM/AcP catalytic activity conserved in nature and position in Sts-1. Point mutations that impair Sts-1 phosphatase activity in vitro also impair the ability of Sts-1 to regulate TCR signaling in T cells. These observations reveal a PGM/AcP-like enzyme activity involved in the control of antigen receptor signaling.

  11. G Protein Activation Stimulates Phospholipase D Signaling in Plants.

    PubMed Central

    Munnik, T.; Arisz, S. A.; De Vrije, 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 water as a transphosphatidylation substrate. The product was a phosphatidyl alcohol, which, in contrast to the normal product phosphatidic acid, is a specific measure of PLD activity. When 32P-labeled cells were treated with 0.1% n-butanol, 32P-phosphatidyl butanol (32P-PtdBut) was formed in a time-dependent manner. In cells treated with any of the three G protein activators, the production of 32P-PtdBut was increased in a dose-dependent manner. The G protein involved was pertussis toxin insensitive. Ethanol could activate PLD but was itself consumed by PLD as transphosphatidylation substrate. In contrast, secondary alcohols (e.g., sec-butyl alcohol) activated PLD but did not function as substrate, whereas tertiary alcohols did neither. Although most of the experiments were performed with the green alga Chlamydomonas eugametos, the relevance for higher plants was demonstrated by showing that PLD in carnation petals could also be activated by mastoparan. The results indicate that PLD activation must be considered as a potential signal transduction mechanism in plants, just as in animals. PMID:12242371

  12. Purmorphamine induces osteogenesis by activation of the hedgehog signaling pathway.

    PubMed

    Wu, Xu; Walker, John; Zhang, Jie; Ding, Sheng; Schultz, Peter G

    2004-09-01

    Previously, a small molecule, purmorphamine, was identified that selectively induces osteogenesis in multipotent mesenchymal progenitor cells. In order to gain insights into the mechanism of action of purmorphamine, high-density oligonucleotide microarrays were used to profile gene expression in multipotent mesenchymal progenitor cells treated with either purmorphamine or bone morphogenetic protein-4 (BMP-4). In contrast to BMP-4 treatment, purmorphamine activates the Hedgehog (Hh) signaling pathway, resulting in the up- and downregulation of its downstream target genes, including Gli1 and Patched. Moreover, the known Hh signaling antagonists, cyclopamine and forskolin, completely block the osteogenesis and Glimediated transcription induced by purmorphamine. These results demonstrate that purmorphamine is a small molecule agonist of Hedgehog signaling, and it may ultimately be useful in the treatment of bone-related disease and neurodegenerative disease. PMID:15380183

  13. Multiple LREK active contours for knee meniscus ultrasound image segmentation.

    PubMed

    Faisal, Amir; Ng, Siew-Cheok; Goh, Siew-Li; George, John; Supriyanto, Eko; Lai, Khin W

    2015-10-01

    Quantification of knee meniscus degeneration and displacement in an ultrasound image requires simultaneous segmentation of femoral condyle, meniscus, and tibial plateau in order to determine the area and the position of the meniscus. In this paper, we present an active contour for image segmentation that uses scalable local regional information on expandable kernel (LREK). It includes using a strategy to adapt the size of a local window in order to avoid being confined locally in a homogeneous region during the segmentation process. We also provide a multiple active contours framework called multiple LREK (MLREK) to deal with multiple object segmentation without merging and overlapping between the neighboring contours in the shared boundaries of separate regions. We compare its performance to other existing active contour models and show an improvement offered by our model. We then investigate the choice of various parameters in the proposed framework in response to the segmentation outcome. Dice coefficient and Hausdorff distance measures over a set of real knee meniscus ultrasound images indicate a potential application of MLREK for assessment of knee meniscus degeneration and displacement. PMID:25910057

  14. Efficient methods for joint estimation of multiple fundamental frequencies in music signals

    NASA Astrophysics Data System (ADS)

    Pertusa, Antonio; Iñesta, José M.

    2012-12-01

    This study presents efficient techniques for multiple fundamental frequency estimation in music signals. The proposed methodology can infer harmonic patterns from a mixture considering interactions with other sources and evaluate them in a joint estimation scheme. For this purpose, a set of fundamental frequency candidates are first selected at each frame, and several hypothetical combinations of them are generated. Combinations are independently evaluated, and the most likely is selected taking into account the intensity and spectral smoothness of its inferred patterns. The method is extended considering adjacent frames in order to smooth the detection in time, and a pitch tracking stage is finally performed to increase the temporal coherence. The proposed algorithms were evaluated in MIREX contests yielding state of the art results with a very low computational burden.

  15. A signal processing framework for simultaneous detection of multiple environmental contaminants

    NASA Astrophysics Data System (ADS)

    Chakraborty, Subhadeep; Manahan, Michael P.; Mench, Matthew M.

    2013-11-01

    The possibility of large-scale attacks using chemical warfare agents (CWAs) has exposed the critical need for fundamental research enabling the reliable, unambiguous and early detection of trace CWAs and toxic industrial chemicals. This paper presents a unique approach for the identification and classification of simultaneously present multiple environmental contaminants by perturbing an electrochemical (EC) sensor with an oscillating potential for the extraction of statistically rich information from the current response. The dynamic response, being a function of the degree and mechanism of contamination, is then processed with a symbolic dynamic filter for the extraction of representative patterns, which are then classified using a trained neural network. The approach presented in this paper promises to extend the sensing power and sensitivity of these EC sensors by augmenting and complementing sensor technology with state-of-the-art embedded real-time signal processing capabilities.

  16. Gli Activity Is Critical at Multiple Stages of Embryonic Mammary and Nipple Development

    PubMed Central

    Pinderhughes, Alicia; Koetz, Lisa; Cowin, Pamela

    2013-01-01

    Gli3 is a transcriptional regulator of Hedgehog (Hh) signaling that functions as a repressor (Gli3R) or activator (Gli3A) depending upon cellular context. Previously, we have shown that Gli3R is required for the formation of mammary placodes #3 and #5. Here, we report that this early loss of Gli3 results in abnormal patterning of two critical regulators: Bmp4 and Tbx3, within the presumptive mammary rudiment (MR) #3 zone. We also show that Gli3 loss leads to failure to maintain mammary mesenchyme specification and loss of epithelial Wnt signaling, which impairs the later development of remaining MRs: MR#2 showed profound evagination and ectopic hairs formed within the presumptive areola; MR#4 showed mild invagination defects and males showed inappropriate retention of mammary buds in Gli3xt/xt mice. Importantly, mice genetically manipulated to misactivate Hh signaling displayed the same phenotypic spectrum demonstrating that the repressor function of Gli3R is essential during multiple stages of mammary development. In contrast, positive Hh signaling occurs during nipple development in a mesenchymal cuff around the lactiferous duct and in muscle cells of the nipple sphincter. Collectively, these data show that repression of Hh signaling by Gli3R is critical for early placodal patterning and later mammary mesenchyme specification whereas positive Hh signaling occurs during nipple development. PMID:24260306

  17. An inside job: hacking into Janus kinase/signal transducer and activator of transcription signaling cascades by the intracellular protozoan Toxoplasma gondii.

    PubMed

    Denkers, Eric Y; Bzik, David J; Fox, Barbara A; Butcher, Barbara A

    2012-02-01

    The intracellular protozoan Toxoplasma gondii is well known for its skill at invading and living within host cells. New discoveries are now also revealing the astounding ability of the parasite to inject effector proteins into the cytoplasm to seize control of the host cell. This review summarizes recent advances in our understanding of one such secretory protein called ROP16. This molecule is released from rhoptries into the host cell during invasion. The ROP16 molecule acts as a kinase, directly activating both signal transducer and activator of transcription 3 (STAT3) and STAT6 signaling pathways. In macrophages, an important and preferential target cell of parasite infection, the injection of ROP16 has multiple consequences, including downregulation of proinflammatory cytokine signaling and macrophage deviation to an alternatively activated phenotype. PMID:22104110

  18. An Inside Job: Hacking into Janus Kinase/Signal Transducer and Activator of Transcription Signaling Cascades by the Intracellular Protozoan Toxoplasma gondii

    PubMed Central

    Bzik, David J.; Fox, Barbara A.; Butcher, Barbara A.

    2012-01-01

    The intracellular protozoan Toxoplasma gondii is well known for its skill at invading and living within host cells. New discoveries are now also revealing the astounding ability of the parasite to inject effector proteins into the cytoplasm to seize control of the host cell. This review summarizes recent advances in our understanding of one such secretory protein called ROP16. This molecule is released from rhoptries into the host cell during invasion. The ROP16 molecule acts as a kinase, directly activating both signal transducer and activator of transcription 3 (STAT3) and STAT6 signaling pathways. In macrophages, an important and preferential target cell of parasite infection, the injection of ROP16 has multiple consequences, including downregulation of proinflammatory cytokine signaling and macrophage deviation to an alternatively activated phenotype. PMID:22104110

  19. Robust Indoor Human Activity Recognition Using Wireless Signals.

    PubMed

    Wang, Yi; Jiang, Xinli; Cao, Rongyu; Wang, Xiyang

    2015-01-01

    Wireless signals-based activity detection and recognition technology may be complementary to the existing vision-based methods, especially under the circumstance of occlusions, viewpoint change, complex background, lighting condition change, and so on. This paper explores the properties of the channel state information (CSI) of Wi-Fi signals, and presents a robust indoor daily human activity recognition framework with only one pair of transmission points (TP) and access points (AP). First of all, some indoor human actions are selected as primitive actions forming a training set. Then, an online filtering method is designed to make actions' CSI curves smooth and allow them to contain enough pattern information. Each primitive action pattern can be segmented from the outliers of its multi-input multi-output (MIMO) signals by a proposed segmentation method. Lastly, in online activities recognition, by selecting proper features and Support Vector Machine (SVM) based multi-classification, activities constituted by primitive actions can be recognized insensitive to the locations, orientations, and speeds. PMID:26184231

  20. Small molecule activation of NOTCH signaling inhibits acute myeloid leukemia

    PubMed Central

    Ye, Qi; Jiang, Jue; Zhan, Guanqun; Yan, Wanyao; Huang, Liang; Hu, Yufeng; Su, Hexiu; Tong, Qingyi; Yue, Ming; Li, Hua; Yao, Guangmin; Zhang, Yonghui; Liu, Hudan

    2016-01-01

    Aberrant activation of the NOTCH signaling pathway is crucial for the onset and progression of T cell leukemia. Yet recent studies also suggest a tumor suppressive role of NOTCH signaling in acute myeloid leukemia (AML) and reactivation of this pathway offers an attractive opportunity for anti-AML therapies. N-methylhemeanthidine chloride (NMHC) is a novel Amaryllidaceae alkaloid that we previously isolated from Zephyranthes candida, exhibiting inhibitory activities in a variety of cancer cells, particularly those from AML. Here, we report NMHC not only selectively inhibits AML cell proliferation in vitro but also hampers tumor development in a human AML xenograft model. Genome-wide gene expression profiling reveals that NMHC activates the NOTCH signaling. Combination of NMHC and recombinant human NOTCH ligand DLL4 achieves a remarkable synergistic effect on NOTCH activation. Moreover, pre-inhibition of NOTCH by overexpression of dominant negative MAML alleviates NMHC-mediated cytotoxicity in AML. Further mechanistic analysis using structure-based molecular modeling as well as biochemical assays demonstrates that NMHC docks in the hydrophobic cavity within the NOTCH1 negative regulatory region (NRR), thus promoting NOTCH1 proteolytic cleavage. Our findings thus establish NMHC as a potential NOTCH agonist that holds great promises for future development as a novel agent beneficial to patients with AML. PMID:27211848

  1. Activation of a signaling cascade by cytoskeleton stretch.

    PubMed

    Tamada, Masako; Sheetz, Michael P; Sawada, Yasuhiro

    2004-11-01

    Cells sense and respond to mechanical force. However, the mechanisms of transduction of extracellular matrix (ECM) forces to biochemical signals are not known. After removing the cell membrane and soluble proteins by Triton X-100 extraction, we found that the remaining complex (Triton cytoskeletons) activated Rap1 upon stretch. Rap1 guanine nucleotide exchange factor, C3G, was required for this activation; C3G as well as the adaptor protein, CrkII, in cell extract bound to Triton cytoskeletons in a stretch-dependent manner. CrkII binding, which was Cas dependent, correlated with stretch-dependent tyrosine phosphorylation of proteins in Triton cytoskeletons including Cas at the contacts with ECM. These in vitro findings were compatible with in vivo observations of stretch-enhanced phosphotyrosine signals, accumulation of CrkII at cell-ECM contacts, and CrkII-Cas colocalization. We suggest that mechanical force on Triton cytoskeletons activates local tyrosine phosphorylation, which provides docking sites for cytosolic proteins, and initiates signaling to activate Rap1. PMID:15525532

  2. Small molecule activation of NOTCH signaling inhibits acute myeloid leukemia.

    PubMed

    Ye, Qi; Jiang, Jue; Zhan, Guanqun; Yan, Wanyao; Huang, Liang; Hu, Yufeng; Su, Hexiu; Tong, Qingyi; Yue, Ming; Li, Hua; Yao, Guangmin; Zhang, Yonghui; Liu, Hudan

    2016-01-01

    Aberrant activation of the NOTCH signaling pathway is crucial for the onset and progression of T cell leukemia. Yet recent studies also suggest a tumor suppressive role of NOTCH signaling in acute myeloid leukemia (AML) and reactivation of this pathway offers an attractive opportunity for anti-AML therapies. N-methylhemeanthidine chloride (NMHC) is a novel Amaryllidaceae alkaloid that we previously isolated from Zephyranthes candida, exhibiting inhibitory activities in a variety of cancer cells, particularly those from AML. Here, we report NMHC not only selectively inhibits AML cell proliferation in vitro but also hampers tumor development in a human AML xenograft model. Genome-wide gene expression profiling reveals that NMHC activates the NOTCH signaling. Combination of NMHC and recombinant human NOTCH ligand DLL4 achieves a remarkable synergistic effect on NOTCH activation. Moreover, pre-inhibition of NOTCH by overexpression of dominant negative MAML alleviates NMHC-mediated cytotoxicity in AML. Further mechanistic analysis using structure-based molecular modeling as well as biochemical assays demonstrates that NMHC docks in the hydrophobic cavity within the NOTCH1 negative regulatory region (NRR), thus promoting NOTCH1 proteolytic cleavage. Our findings thus establish NMHC as a potential NOTCH agonist that holds great promises for future development as a novel agent beneficial to patients with AML. PMID:27211848

  3. Androgen activates β-catenin signaling in bladder cancer cells.

    PubMed

    Li, Yi; Zheng, Yichun; Izumi, Koji; Ishiguro, Hitoshi; Ye, Bo; Li, Faqian; Miyamoto, Hiroshi

    2013-06-01

    Androgen receptor (AR) signals have been implicated in bladder carcinogenesis and tumor progression. Activation of Wnt/β-catenin signaling has also been reported to correlate with bladder cancer progression and poor patients' outcomes. However, cross talk between AR and β-catenin pathways in bladder cancer remains uncharacterized. In radical cystectomy specimens, we immunohistochemically confirmed aberrant expression of β-catenin especially in aggressive tumors. There was a strong association between nuclear expressions of AR and β-catenin in bladder tumors (P=0.0215). Kaplan-Meier and log-rank tests further revealed that reduced membranous β-catenin expression (P=0.0276), nuclear β-catenin expression (P=0.0802), and co-expression of nuclear AR and β-catenin (P=0.0043) correlated with tumor progression after cystectomy. We then assessed the effects of androgen on β-catenin in AR-positive and AR-negative bladder cancer cell lines. A synthetic androgen R1881 increased the expression of an active form of β-catenin and its downstream target c-myc only in AR-positive lines. R1881 also enhanced the activity of β-catenin-mediated transcription, which was abolished by an AR antagonist hydroxyflutamide. Using western blotting and immunofluorescence, R1881 was found to induce nuclear translocation of β-catenin when co-localized with AR. Finally, co-immunoprecipitation revealed androgen-induced associations of AR with β-catenin or T-cell factor (TCF) in bladder cancer cells. Thus, it was likely that androgen was able to activate β-catenin signaling through the AR pathway in bladder cancer cells. Our results also suggest that activation of β-catenin signaling possibly via formation of AR/β-catenin/TCF complex contributes to the progression of bladder cancer, which may enhance the feasibility of androgen deprivation as a potential therapeutic approach. PMID:23447569

  4. A modular cell-based biosensor using engineered genetic logic circuits to detect and integrate multiple environmental signals.

    PubMed

    Wang, Baojun; Barahona, Mauricio; Buck, Martin

    2013-02-15

    Cells perceive a wide variety of cellular and environmental signals, which are often processed combinatorially to generate particular phenotypic responses. Here, we employ both single and mixed cell type populations, pre-programmed with engineered modular cell signalling and sensing circuits, as processing units to detect and integrate multiple environmental signals. Based on an engineered modular genetic AND logic gate, we report the construction of a set of scalable synthetic microbe-based biosensors comprising exchangeable sensory, signal processing and actuation modules. These cellular biosensors were engineered using distinct signalling sensory modules to precisely identify various chemical signals, and combinations thereof, with a quantitative fluorescent output. The genetic logic gate used can function as a biological filter and an amplifier to enhance the sensing selectivity and sensitivity of cell-based biosensors. In particular, an Escherichia coli consortium-based biosensor has been constructed that can detect and integrate three environmental signals (arsenic, mercury and copper ion levels) via either its native two-component signal transduction pathways or synthetic signalling sensors derived from other bacteria in combination with a cell-cell communication module. We demonstrate how a modular cell-based biosensor can be engineered predictably using exchangeable synthetic gene circuit modules to sense and integrate multiple-input signals. This study illustrates some of the key practical design principles required for the future application of these biosensors in broad environmental and healthcare areas. PMID:22981411

  5. Expression of multiple sexual signals by fathers and sons in the East-Mediterranean barn swallow: are advertising strategies heritable?

    PubMed

    Vortman, Yoni; Safran, Rebecca J; Reiner Brodetzki, Tali; Dor, Roi; Lotem, Arnon

    2015-01-01

    The level of expression of sexually selected traits is generally determined by genes, environment and their interaction. In species that use multiple sexual signals which may be costly to produce, investing in the expression of one sexual signal may limit the expression of the other, favoring the evolution of a strategy for resource allocation among signals. As a result, even when the expression of sexual signals is condition dependent, the relative level of expression of each signal may be heritable. We tested this hypothesis in the East-Mediterranean barn swallow (Hirundo rustica transitiva), in which males have been shown to express two uncorrelated sexual signals: red-brown ventral coloration, and long tail streamers. We show that variation in both signals may partially be explained by age, as well as by paternal origin (genetic father-son regressions), but that the strongest similarity between fathers and sons is the relative allocation towards one trait or the other (relative expression index), rather than the expression of the traits themselves. These results suggest that the expression of one signal is not independent of the other, and that genetic strategies for resource allocation among sexual signals may be selected for during the evolution of multiple sexual signals. PMID:25679206

  6. Expression of Multiple Sexual Signals by Fathers and Sons in the East-Mediterranean Barn Swallow: Are Advertising Strategies Heritable?

    PubMed Central

    Vortman, Yoni; Safran, Rebecca J.; Reiner Brodetzki, Tali; Dor, Roi; Lotem, Arnon

    2015-01-01

    The level of expression of sexually selected traits is generally determined by genes, environment and their interaction. In species that use multiple sexual signals which may be costly to produce, investing in the expression of one sexual signal may limit the expression of the other, favoring the evolution of a strategy for resource allocation among signals. As a result, even when the expression of sexual signals is condition dependent, the relative level of expression of each signal may be heritable. We tested this hypothesis in the East-Mediterranean barn swallow (Hirundo rustica transitiva), in which males have been shown to express two uncorrelated sexual signals: red-brown ventral coloration, and long tail streamers. We show that variation in both signals may partially be explained by age, as well as by paternal origin (genetic father-son regressions), but that the strongest similarity between fathers and sons is the relative allocation towards one trait or the other (relative expression index), rather than the expression of the traits themselves. These results suggest that the expression of one signal is not independent of the other, and that genetic strategies for resource allocation among sexual signals may be selected for during the evolution of multiple sexual signals. PMID:25679206

  7. Analysis of signal degradation in an integrated active crossbar switch

    NASA Astrophysics Data System (ADS)

    Probst, David K.; Sodergren, Clifford C.; Krainak, Michael A.

    1996-01-01

    One of the most desirable features for a modern systems architecture is reconfigurability. It facilitates the sharing of various processing and memory resources among many different subsystems, thereby reducing the need for each subsystem to duplicate these resources. Reducing duplication also reduces size, weight, power consumption, and cost; all important considerations, especially in modern military systems. Sensor data requires very-wide- bandwidth, point-to-point connections, which are easily provided by fiber optics with good noise immunity, but the switching of such wide-bandwidth signals is problematic because electrical switches have both limited bandwidth and limited switching times. A wide- bandwidth, reconfigurable optical switch is required that overcomes coupling and splitting losses experienced by the optical signal passing through the switch so that sufficient signal- fidelity is maintained. In this paper, we investigate an integrated, active (i.e. amplifying) photonic crossbar switch to determine the signal degradation incurred for intensity modulation and direct detection using an NRZ data format and an ideal, matched-filter receiver. Various device configurations are analyzed in order to determine which produces the smallest degradation of the signal-to-noise ratio.

  8. Methoxychlor affects multiple hormone signaling pathways in the largemouth bass (Micropterus salmoides) liver

    PubMed Central

    Martyniuk, Christopher J.; Spade, Daniel J.; Blum, Jason L.; Kroll, Kevin J.; Denslow, Nancy D.

    2011-01-01

    Methoxychlor (MXC) is an organochlorine pesticide that has been shown to have estrogenic activity by activating estrogen receptors and inducing vitellogenin production in male fish. Previous studies report that exposure to MXC induces changes in mRNA abundance of reproductive genes in the liver and testes of largemouth bass (Micropterus salmoides). The objective of the present study was to better characterize the mode of action of MXC by measuring the global transcriptomic response in the male largemouth liver using an oligonucleotide microarray. Microarray analysis identified highly significant changes in the expression of 37 transcripts (p<0.001) (20 induced and 17 decreased) in the liver after MXC injection and a total of 900 expression changes (p<0.05) in transcripts with high homology to known genes. Largemouth bass estrogen receptor alpha (esr1) and androgen receptor (ar) were among the transcripts that were increased in the liver after MXC treatment. Functional enrichment analysis identified the molecular functions of steroid binding and androgen receptor activity as well as steroid hormone receptor activity as being significantly over-represented gene ontology terms. Pathway analysis identified c-fos signaling as being putatively affected through both estrogen and androgen signaling. This study provides evidence that MXC elicits transcriptional effects through the estrogen receptor as well as androgen receptor-mediated pathways in the liver. PMID:21276474

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

    PubMed Central

    Tarayrah, Lama; Li, Yuping; Gan, Qiang; Chen, Xin

    2015-01-01

    ABSTRACT 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. PMID:26490676

  10. Recommendations for physical activity in patients with multiple sclerosis.

    PubMed

    Petajan, J H; White, A T

    1999-03-01

    For many years, patients with multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system, have been advised to avoid exercise. MS is believed to be autoimmune in origin, mediated by activated T cells which penetrate the blood-brain barrier and attack myelin. The pathophysiology, with respect to function is an impairment of saltatory conduction, specifically, slowing of conduction speed and/or conduction block. Symptoms can temporarily worsen on exposure to heat or during physical exercise. Exercise programmes must be designed to activate working muscles but avoid overload that results in conduction block. Fatigue, often severe, affects about 85% of MS patients and, along with motor and sensory symptoms, results in decreased mobility and reduced quality of life. Physical activity and recreation are reduced in patients with MS. Before developing recommendations, physical activity patterns and the physical effects of MS should be assessed in individual patients. Patients may then be functionally classified. Physical activity can also be classified in a pyramid structure, with the most basic functions forming the base and the most integrated functions on top. The muscular fitness pyramid progresses through passive range of motion, active resistive, specific strengthening and integrated strength exercises Overall physical activity may be increased according to functional level by performing activities of daily living, incorporating inefficiencies into daily living, pursuing more active recreation and eventually developing a structured exercise programme. The importance of the proper exercise environment, balance and coordination issues and factors related to adherence are discussed. PMID:10222541

  11. Performance of a novel multiple-signal luminescence sediment tracing method

    NASA Astrophysics Data System (ADS)

    Reimann, Tony

    2014-05-01

    Optically Stimulated Luminescence (OSL) is commonly used for dating sediments. Luminescence signals build up due to exposure of mineral grains to natural ionizing radiation, and are reset when these grains are exposed to (sun)light during sediment transport and deposition. Generally, luminescence signals can be read in two ways, potentially providing information on the burial history (dating) or the transport history (sediment tracing) of mineral grains. In this study we use a novel luminescence measurement procedure (Reimann et al., submitted) that simultaneously monitors six different luminescence signals from the same sub-sample (aliquot) to infer the transport history of sand grains. Daylight exposure experiments reveal that each of these six signals resets (bleaches) at a different rate, thus allowing to trace the bleaching history of the sediment in six different observation windows. To test the feasibility of luminescence sediment tracing in shallow-marine coastal settings we took eight sediment samples from the pilot mega-nourishment Zandmotor in Kijkduin (South-Holland). This site provides relatively controlled conditions as the morphological evolution of this nourishment is densely monitored (Stive et al., 2013). After sampling the original nourishment source we took samples along the seaward facing contour of the spit that was formed from August 2011 (start of nourishment) to June 2012 (sampling). It is presumed that these samples originate from the source and were transported and deposited within the first year after construction. The measured luminescence of a sediment sample was interpolated onto the daylight bleaching curve of each signal to assign the Equivalent Exposure Time (EET) to a sample. The EET is a quantitative measure of the full daylight equivalent a sample was exposed to during sediment transport, i.e. the higher the EET the longer the sample has been transported or the more efficient it has been exposed to day-light during sediment

  12. Physical basis for signal separation for remote sensing of multiple high energy radiation sources

    NASA Astrophysics Data System (ADS)

    Richards, J.; Jain, V. K.

    2015-08-01

    In `radiation remote sensing' multiple unknown high energy sources are generally involved. The detectors, upon sensing the corresponding mixed signals, must separate their contributions blindly for further analysis. A practical way to perform this separation could be through the Independent Component Analysis algorithm. However, the challenge faced is that theoretically there is no correlation among events, even those arising from the same source - thereby disabling meaningful ICA analysis. We overcome this hurdle by use of a thin barrier and by providing wide detector pulses. The radiation events that interact with the barrier take a longer time to reach the detector due to their increased path length. They also lose some energy, which makes them increasingly prone to capture in the barrier once they have scattered. These observations are confirmed through Monte-Carlo simulations upon Gamma-ray sources. Normalized crosscovariance up to 0.22 was found, but is actually controllable through appropriate selection of the detector shaping-pulse width. Experiments on a physical setup confirm these findings. Finally, the application of the ICA approach is demonstrated to demix, or separate, the individual contributions of the sources to the observed detector signals.

  13. The impact of relative intensity noise on the signal in multiple reference optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Neuhaus, Kai; Subhash, Hrebesh; Alexandrov, Sergey; Dsouza, Roshan; Hogan, Josh; Wilson, Carol; Leahy, Martin; Slepneva, Svetlana; Huyet, Guillaume

    2016-03-01

    Multiple reference optical coherence tomography (MR-OCT) applies a unique low-cost solution to enhance the scanning depth of standard time domain OCT by inserting an partial mirror into the reference arm of the interferometric system. This novel approach achieves multiple reflections for different layers and depths of an sample with minimal effort of engineering and provides an excellent platform for low-cost OCT systems based on well understood production methods for micro-mechanical systems such as CD/DVD pick-up systems. The direct integration of a superluminescent light-emitting diode (SLED) is a preferable solution to reduce the form- factor of an MR-OCT system. Such direct integration exposes the light source to environmental conditions that can increase fluctuations in heat dissipation and vibrations and affect the noise characteristics of the output spectrum. This work describes the impact of relative intensity noise (RIN) on the quality of the interference signal of MR-OCT related to a variety of environmental conditions, such as temperature.

  14. Systematic identification of signal-activated stochastic gene regulation.

    PubMed

    Neuert, Gregor; Munsky, Brian; Tan, Rui Zhen; Teytelman, Leonid; Khammash, Mustafa; van Oudenaarden, Alexander

    2013-02-01

    Although much has been done to elucidate the biochemistry of signal transduction and gene regulatory pathways, it remains difficult to understand or predict quantitative responses. We integrate single-cell experiments with stochastic analyses, to identify predictive models of transcriptional dynamics for the osmotic stress response pathway in Saccharomyces cerevisiae. We generate models with varying complexity and use parameter estimation and cross-validation analyses to select the most predictive model. This model yields insight into several dynamical features, including multistep regulation and switchlike activation for several osmosensitive genes. Furthermore, the model correctly predicts the transcriptional dynamics of cells in response to different environmental and genetic perturbations. Because our approach is general, it should facilitate a predictive understanding for signal-activated transcription of other genes in other pathways or organisms. PMID:23372015

  15. Gq signaling causes glomerular injury by activating TRPC6

    PubMed Central

    Wang, Liming; Jirka, Grant; Rosenberg, Paul B.; Buckley, Anne F.; Gomez, Jose A.; Fields, Timothy A.; Winn, Michelle P.; Spurney, Robert F.

    2015-01-01

    Familial forms of focal segmental glomerulosclerosis (FSGS) have been linked to gain-of-function mutations in the gene encoding the transient receptor potential channel C6 (TRPC6). GPCRs coupled to Gq signaling activate TRPC6, suggesting that Gq-dependent TRPC6 activation underlies glomerular diseases. Here, we developed a murine model in which a constitutively active Gq α subunit (GqQ209L, referred to herein as GqQ>L) is specifically expressed in podocytes and examined the effects of this mutation in response to puromycin aminonucleoside (PAN) nephrosis. We found that compared with control animals, animals expressing GqQ>L exhibited robust albuminuria, structural features of FSGS, and reduced numbers of glomerular podocytes. Gq activation stimulated calcineurin (CN) activity, resulting in CN-dependent upregulation of TRPC6 in murine kidneys. Deletion of TRPC6 in GqQ>L-expressing mice prevented FSGS development and inhibited both tubular damage and podocyte loss induced by PAN nephrosis. Similarly, administration of the CN inhibitor FK506 reduced proteinuria and tubular injury but had more modest effects on glomerular pathology and podocyte numbers in animals with constitutive Gq activation. Moreover, these Gq-dependent effects on podocyte injury were generalizable to diabetic kidney disease, as expression of GqQ>L promoted albuminuria, mesangial expansion, and increased glomerular basement membrane width in diabetic mice. Together, these results suggest that targeting Gq/TRPC6 signaling may have therapeutic benefits for the treatment of glomerular diseases. PMID:25844902

  16. Gambogic acid inhibits multiple myeloma mediated osteoclastogenesis through suppression of chemokine receptor CXCR4 signaling pathways.

    PubMed

    Pandey, Manoj K; Kale, Vijay P; Song, Chunhua; Sung, Shen-shu; Sharma, Arun K; Talamo, Giampaolo; Dovat, Sinisa; Amin, Shantu G

    2014-10-01

    Bone disease, characterized by the presence of lytic lesions and osteoporosis is the hallmark of multiple myeloma (MM). Stromal cell-derived factor 1α (SDF-1α) and its receptor, CXC chemokine receptor 4 (CXCR4), has been implicated as a regulator of bone resorption, suggesting that agents that can suppress SDF1α/CXCR4 signaling might inhibit osteoclastogenesis, a process closely linked to bone resorption. We, therefore, investigated whether gambogic acid (GA), a xanthone, could inhibit CXCR4 signaling and suppress osteoclastogenesis induced by MM cells. Through docking studies we predicted that GA directly interacts with CXCR4. This xanthone down-regulates the expression of CXCR4 on MM cells in a dose- and time-dependent manner. The down-regulation of CXCR4 was not due to proteolytic degradation, but rather GA suppresses CXCR4 mRNA expression by inhibiting nuclear factor-kappa B (NF-κB) DNA binding. This was further confirmed by quantitative chromatin immunoprecipitation assay, as GA inhibits p65 binding at the CXCR4 promoter. GA suppressed SDF-1α-induced chemotaxis of MM cells and downstream signaling of CXCR4 by inhibiting phosphorylation of Akt, p38, and Erk1/2 in MM cells. GA abrogated the RANKL-induced differentiation of macrophages to osteoclasts in a dose- and time-dependent manner. In addition, we found that MM cells induced differentiation of macrophages to osteoclasts, and that GA suppressed this process. Importantly, suppression of osteoclastogenesis by GA was mediated through IL-6 inhibition. Overall, our results show that GA is a novel inhibitor of CXCR4 expression and has a strong potential to suppress osteoclastogenesis mediated by MM cells. PMID:25034231

  17. Optical telecommunications system and signal analysis using data-entropy and multiple-centroid data-scatter

    NASA Astrophysics Data System (ADS)

    Egan, J.; McMillan, N. D.; Denieffe, D.; Riedel, S.; Doyle, G.; Farrell, G.

    2005-09-01

    The data-entropy quality-budget developed by the authors is used as an alternative to the conventional power budget. The traditional power budget approach is not capable of providing a full analysis of a system with different noise types and specifically providing a measure of signal quality. The quality-budget addressed this issue by applying its dimensionless 'bit measure' to integrate the analysis of all types of losses. A data-entropy visualisation is produced for each set of points in a reference and test signal. This data-entropy signal is a measure of signal disorder and reflects the power loss and types of signal degradation experienced by the test signal. To analyse the differences between two signals an algorithm known as phase-coherent data-scatter (PCDS) is used to assess levels of attenuation, dispersion, jitter, etc. Practical analysis of telecommunications signals using the new multiple-centroid (MC) PCDS is presented here for the first time. MC-PCDS is then used to analyse differences between sets of data-entropy signals and digital signals. The theory behind MC data-scatter is discussed and its advantages for the quantification of signal degradations are assessed. Finally, a brief consideration is given to the use of pattern recognition algorithms to measure optical signal degrading factors.

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

    NASA Astrophysics Data System (ADS)

    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.

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

    PubMed Central

    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 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. PMID:27346979

  20. Contributions to gene activation by multiple functions of Bicoid.

    PubMed Central

    Ma, X; Yuan, D; Scarborough, T; Ma, J

    1999-01-01

    Bicoid is a Drosophila morphogenetic protein required for the development of anterior structures in the embryo. To gain a better understanding of how Bicoid works as a transcriptional activator, we systematically analysed various functions of Bicoid required for gene activation. We provide evidence suggesting that Bicoid is an intrinsically weak activator. First, our biochemical experiments demonstrate that the Bicoid-DNA complexes are very unstable, suggesting a weak DNA-binding function of Bicoid. This idea is further supported by our experiments demonstrating that the same number of LexA-Bicoid fusion molecules can activate transcription more effectively from LexA sites than from Bicoid sites. Secondly, we demonstrate that transcriptional activation by the weak activator Bicoid is readily influenced by the local enhancer environment. These influences are decreased when the Bicoid function is enforced by attaching to it either a known dimerization domain or the strong activation domain VP16. VP16 can also compensate for the loss of some Bicoid sites in an enhancer element. Our experiments demonstrate that the outcome of transcriptional activation by Bicoid is determined by multiple weak functions that are interconnected, a finding that can further help us to understand how this morphogenetic protein achieves its molecular functions. PMID:10024522

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

    PubMed

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

    2016-04-13

    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. Wnt Signaling Activates Shh Signaling in Early Postnatal Intervertebral Discs, and Re-Activates Shh Signaling in Old Discs in the Mouse

    PubMed Central

    Sinner, Debora; Wylie, Christopher C.; Dahia, Chitra Lekha

    2014-01-01

    Intervertebral discs (IVDs) are strong fibrocartilaginous joints that connect adjacent vertebrae of the spine. As discs age they become prone to failure, with neurological consequences that are often severe. Surgical repair of discs treats the result of the disease, which affects as many as one in seven people, rather than its cause. An ideal solution would be to repair degenerating discs using the mechanisms of their normal differentiation. However, these mechanisms are poorly understood. Using the mouse as a model, we previously showed that Shh signaling produced by nucleus pulposus cells activates the expression of differentiation markers, and cell proliferation, in the postnatal IVD. In the present study, we show that canonical Wnt signaling is required for the expression of Shh signaling targets in the IVD. We also show that Shh and canonical Wnt signaling pathways are down-regulated in adult IVDs. Furthermore, this down-regulation is reversible, since re-activation of the Wnt or Shh pathways in older discs can re-activate molecular markers of the IVD that are lost with age. These data suggest that biological treatments targeting Wnt and Shh signaling pathways may be feasible as a therapeutic for degenerative disc disease. PMID:24892825

  3. Exploiting the yeast stress-activated signaling network to inform on stress biology and disease signaling

    PubMed Central

    Ho, Yi-Hsuan

    2016-01-01

    Healthy cells utilize intricate systems to monitor their environment and mount robust responses in the event of cellular stress. Whether stress arises from external insults or defects due to mutation and disease, cells must be able to respond precisely to mount the appropriate defenses. Multi-faceted stress responses are generally coupled with arrest of growth and cell-cycle progression, which both limits the transmission of damaged materials and serves to reallocate limited cellular resources toward defense. Therefore, stress defense versus rapid growth represent competing interests in the cell. How eukaryotic cells set the balance between defense versus proliferation, and in particular knowledge of the regulatory networks that control this decision, are poorly understood. In this perspective, we expand upon our recent work inferring the stress-activated signaling network in budding yeast, which captures pathways controlling stress defense and regulators of growth and cell-cycle progression. We highlight similarities between the yeast and mammalian stress responses and explore how stress-activated signaling networks in yeast can inform on signaling defects in human cancers. PMID:25957506

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

    PubMed

    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

  5. Crosstalk between signaling pathways provided by single and multiple protein phosphorylation sites

    PubMed Central

    Nishi, Hafumi; Demir, Emek; Panchenko, Anna R.

    2014-01-01

    Cellular fate depends on the spatio-temporal separation and integration of signaling processes which can be provided by phosphorylation events. In this study we identify the crucial points in signaling crosstalk which can be triggered by discrete phosphorylation events on a single target protein. We integrated the data on individual human phosphosites with the evidence on their corresponding kinases, the functional consequences on phosphorylation on activity of the target protein and corresponding pathways. Our results show that there is a substantial fraction of phosphosites that can play critical roles in crosstalk between alternative or redundant pathways and regulatory outcome of phosphorylation can be linked to a type of phosphorylated residue. These regulatory phosphosites can serve as hubs in the signal flow and their functional roles are directly connected to their specific properties. Namely, phosphosites with similar regulatory functions are phosphorylated by the same kinases and participate in regulation of similar biochemical pathways. Such sites are more likely to cluster in sequence and space unlike sites with antagonistic outcomes of their phosphorylation on a target protein. In addition we found that in silico phosphorylation of sites with similar functional consequences have comparable outcomes on a target protein stability. An important role of phosphorylation sites in biological crosstalk is evident from the analysis of their evolutionary conservation. PMID:25451034

  6. Ginseng saponin metabolite 20(S)-protopanaxadiol inhibits tumor growth by targeting multiple cancer signaling pathways

    PubMed Central

    GAO, JIAN-LI; LV, GUI-YUAN; HE, BAI-CHENG; ZHANG, BING-QIANG; ZHANG, HONGYU; WANG, NING; WANG, CHONG-ZHI; DU, WEI; YUAN, CHUN-SU; HE, TONG-CHUAN

    2013-01-01

    Plant-derived active constituents and their semi-synthetic or synthetic analogs have served as major sources of anticancer drugs. 20(S)-protopanaxadiol (PPD) is a metabolite of ginseng saponin of both American ginseng (Panax quinquefolius L.) and Asian ginseng (Panax ginseng C.A. Meyer). We previously demonstrated that ginsenoside Rg3, a glucoside precursor of PPD, exhibits anti-proliferative effects on HCT116 cells and reduces tumor size in a xenograft model. Our subsequent study indicated that PPD has more potent antitumor activity than that of Rg3 in vitro although the mechanism underlying the anticancer activity of PPD remains to be defined. Here, we investigated the mechanism underlying the anticancer activity of PPD in human cancer cells in vitro and in vivo. PPD was shown to inhibit growth and induce cell cycle arrest in HCT116 cells. The in vivo studies indicate that PPD inhibits xenograft tumor growth in athymic nude mice bearing HCT116 cells. The xenograft tumor size was significantly reduced when the animals were treated with PPD (30 mg/kg body weight) for 3 weeks. When the expression of previously identified Rg3 targets, A kinase (PRKA) anchor protein 8 (AKAP8L) and phosphatidylinositol transfer protein α (PITPNA), was analyzed, PPD was shown to inhibit the expression of PITPNA while upregulating AKAP8L expression in HCT116 cells. Pathway-specific reporter assays indicated that PPD effectively suppressed the NF-κB, JNK and MAPK/ERK signaling pathways. Taken together, our results suggest that the anticancer activity of PPD in colon cancer cells may be mediated through targeting NF-κB, JNK and MAPK/ERK signaling pathways, although the detailed mechanisms underlying the anticancer mode of PPD action need to be fully elucidated. PMID:23633038

  7. Canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling.

    PubMed

    Bush, Erik W; Hood, David B; Papst, Philip J; Chapo, Joseph A; Minobe, Wayne; Bristow, Michael R; Olson, Eric N; McKinsey, Timothy A

    2006-11-01

    The calcium/calmodulin-dependent phosphatase calcineurin plays a central role in the control of cardiomyocyte hypertrophy in response to pathological stimuli. Although calcineurin is present at high levels in normal heart, its activity appears to be unaffected by calcium during the course of a cardiac cycle. The mechanism(s) whereby calcineurin is selectively activated by calcium under pathological conditions has remained unclear. Here, we demonstrate that diverse signals for cardiac hypertrophy stimulate expression of canonical transient receptor potential (TRPC) channels. TRPC consists of a family of seven membrane-spanning nonselective cation channels that have been implicated in the nonvoltage-gated influx of calcium in response to G protein-coupled receptor signaling, receptor tyrosine kinase signaling, and depletion of internal calcium stores. TRPC3 expression is up-regulated in multiple rodent models of pathological cardiac hypertrophy, whereas TRPC5 expression is induced in failing human heart. We demonstrate that TRPC promotes cardiomyocyte hypertrophy through activation of calcineurin and its downstream effector, the nuclear factor of activated T cells transcription factor. These results define a novel role for TRPC channels in the control of cardiac growth, and suggest that a TRPC-derived pool of calcium contributes to selective activation of calcineurin in diseased heart. PMID:16950785

  8. Pathologic Heterogeneity Persists in Early Active Multiple Sclerosis Lesions

    PubMed Central

    Metz, Imke; Weigand, Stephen D; Popescu, Bogdan F G; Frischer, Josa M; Parisi, Joseph E; Guo, Yong; Lassmann, Hans; Brück, Wolfgang; Lucchinetti, Claudia F.

    2014-01-01

    Objective Multiple sclerosis (MS) lesions demonstrate immunopathological heterogeneity in patterns of demyelination. Previous cross-sectional studies reported immunopatterns of demyelination were identical among multiple active demyelinating lesions from the same individual, but differed between individuals, leading to the hypothesis of intraindividual pathological homogeneity and interindividual heterogeneity. Other groups suggested a time-dependent heterogeneity of lesions. The objective of our present study was to analyze tissue samples collected longitudinally to determine whether patterns of demyelination persist over time within a given patient. Methods Archival tissue samples derived from patients with pathologically confirmed CNS inflammatory demyelinating disease who had undergone either diagnostic serial biopsy or biopsy followed by autopsy, were analyzed immunohistochemically. Inclusion criteria was the presence of early active demyelinating lesions - required for immunopattern classification - obtained from the same patient at two or more time points. Results Among 1321 surgical biopsies consistent with MS, 22 cases met study inclusion criteria. Twenty-one patients (95%) showed a persistence of immunopathological patterns in tissue sampled from different time points. This persistence was demonstrated for all major patterns of demyelination. A single patient showed features suggestive of both pattern II and pattern III on biopsy, but only pattern II among all active lesions examined at autopsy. Interpretation These findings continue to support the concept of patient-dependent immunopathological heterogeneity in early MS and suggest that the mechanisms and targets of tissue injury may differ among patient subgroups. These observations have potentially significant implications for individualized therapeutic approaches. PMID:24771535

  9. New orally active proteasome inhibitors in multiple myeloma.

    PubMed

    Allegra, Alessandro; Alonci, Andrea; Gerace, Demetrio; Russo, Sabina; Innao, Vanessa; Calabrò, Laura; Musolino, Caterina

    2014-01-01

    Bortezomib is the first proteasome inhibitor approved for the therapy of multiple myeloma (MM). Although Bortezomib has renovated the treatment of MM, a considerable proportion of subjects fail to respond to Bortezomib treatment and almost all patients relapse from this drug either alone or when used in combination therapies. However, the good clinical outcome of Bortezomib treatment in MM patients gave impulsion for the development of second generation proteasome inhibitors with the ambition of improving efficacy of proteasome inhibition, enhancing antitumor activity, and decreasing toxicity, as well as providing flexible dosing schedules and patient convenience. This review provides an overview of the role of oral proteasome inhibitors including Marizomib, Oprozomib, Delanzomib, chemical proteasome inhibitors, and cinnabaramides, in the therapy of MM, focusing on developments over the past five years. These emerging drugs with different mechanisms of action have exhibited promising antitumor activity in patients with relapsed/refractory MM, and they are creating chances to target multiple pathways, overcome resistance, and improve clinical outcomes, mainly for those subjects who are refractory to approved agents. Future steps in the clinical development of oral inhibitors include the optimization of the schedule and the definition of their antitumor activity in MM. PMID:24239172

  10. Knee-clicks and visual traits indicate fighting ability in eland antelopes: multiple messages and back-up signals

    PubMed Central

    Bro-Jørgensen, Jakob; Dabelsteen, Torben

    2008-01-01

    Background Given the costs of signalling, why do males often advertise their fighting ability to rivals using several signals rather than just one? Multiple signalling theories have developed largely in studies of sexual signals, and less is known about their applicability to intra-sexual communication. We here investigate the evolutionary basis for the intricate agonistic signalling system in eland antelopes, paying particular attention to the evolutionary phenomenon of loud knee-clicking. Results A principal components analysis separated seven male traits into three groups. The dominant frequency of the knee-clicking sound honestly indicated body size, a main determinant of fighting ability. In contrast, the dewlap size increased with estimated age rather than body size, suggesting that, by magnifying the silhouette of older bulls disproportionately, the dewlap acts as an indicator of age-related traits such as fighting experience. Facemask darkness, frontal hairbrush size and body greyness aligned with a third underlying variable, presumed to be androgen-related aggression. A longitudinal study provided independent support of these findings. Conclusion The results show that the multiple agonistic signals in eland reflect three separate components of fighting ability: (1) body size, (2) age and (3) presumably androgen-related aggression, which is reflected in three backup signals. The study highlights how complex agonistic signalling systems can evolve through the simultaneous action of several selective forces, each of which favours multiple signals. Specifically, loud knee-clicking is discovered to be an honest signal of body size, providing an exceptional example of the potential for non-vocal acoustic communication in mammals. PMID:18986518

  11. Brazilian Red Propolis Attenuates Inflammatory Signaling Cascade in LPS-Activated Macrophages

    PubMed Central

    Bueno-Silva, Bruno; Kawamoto, Dione; Ando-Suguimoto, Ellen S.; Alencar, Severino M.; Rosalen, Pedro L.; Mayer, Marcia P. A.

    2015-01-01

    Although previous studies suggested an anti-inflammatory property of Brazilian red propolis (BRP), the mechanisms involved in the anti-inflammatory effects of BRP and its activity on macrophages were still not elucidated. This study aimed to evaluate whether BRP attenuates the inflammatory effect of LPS on macrophages and to investigate its underlying mechanisms. BRP was added to RAW 264.7 murine macrophages after activation with LPS. NO production, cell viability, cytokines profile were evaluated. Activation of inflammatory signaling pathways and macrophage polarization were determined by RT-qPCR and Western blot. BRP at 50 μg/ml inhibited NO production by 78% without affecting cell viability. Cd80 and Cd86 were upregulated whereas mrc1 was down regulated by BRP indicating macrophage polarization at M1. BRP attenuated the production of pro-inflammatory mediators IL-12, GM-CSF, IFN-Ɣ, IL-1β in cell supernatants although levels of TNF- α and IL-6 were slightly increased after BRP treatment. Levels of IL-4, IL-10 and TGF-β were also reduced by BRP. BRP significantly reduced the up-regulation promoted by LPS of transcription of genes in inflammatory signaling (Pdk1, Pak1, Nfkb1, Mtcp1, Gsk3b, Fos and Elk1) and of Il1β and Il1f9 (fold-change rate > 5), which were further confirmed by the inhibition of NF-κB and MAPK signaling pathways. Furthermore, the upstream adaptor MyD88 adaptor-like (Mal), also known as TIRAP, involved in TLR2 and TLR4 signaling, was down- regulated in BRP treated LPS-activated macrophages. Given that BRP inhibited multiple signaling pathways in macrophages involved in the inflammatory process activated by LPS, our data indicated that BRP is a noteworthy food-source for the discovery of new bioactive compounds and a potential candidate to attenuate exhacerbated inflammatory diseases. PMID:26660901

  12. Signal integration by Ca2+ regulates intestinal stem cell activity

    PubMed Central

    Deng, Hansong; Gerencser, Akos A.; Jasper, Heinrich

    2015-01-01

    Summary Somatic stem cells (SCs) maintain tissue homeostasis by dynamically adjusting proliferation and differentiation in response to stress and metabolic cues. Here, we identify Ca2+ signaling as a central regulator of intestinal SC (ISC) activity in Drosophila. We find that dietary L-glutamate stimulates ISC division and gut growth. The metabotropic glutamate receptor (mGluR) is required in ISCs for this response and for an associated modulation of cytosolic Ca2+ oscillations that results in sustained high cytosolic Ca2+ concentrations. High cytosolic Ca2+ induces ISC proliferation by regulating Calcineurin and CREB - regulated transcriptional co-activator (CRTC). In response to a wide range of dietary and stress stimuli, ISCs reversibly transition between Ca2+ oscillation states that represent poised or activated modes of proliferation, respectively. We propose that the dynamic regulation of intracellular Ca2+ levels allows effective integration of diverse mitogenic signals in ISCs to tailor their proliferative activity to the needs of the tissue. PMID:26633624

  13. Robust Indoor Human Activity Recognition Using Wireless Signals

    PubMed Central

    Wang, Yi; Jiang, Xinli; Cao, Rongyu; Wang, Xiyang

    2015-01-01

    Wireless signals–based activity detection and recognition technology may be complementary to the existing vision-based methods, especially under the circumstance of occlusions, viewpoint change, complex background, lighting condition change, and so on. This paper explores the properties of the channel state information (CSI) of Wi-Fi signals, and presents a robust indoor daily human activity recognition framework with only one pair of transmission points (TP) and access points (AP). First of all, some indoor human actions are selected as primitive actions forming a training set. Then, an online filtering method is designed to make actions’ CSI curves smooth and allow them to contain enough pattern information. Each primitive action pattern can be segmented from the outliers of its multi-input multi-output (MIMO) signals by a proposed segmentation method. Lastly, in online activities recognition, by selecting proper features and Support Vector Machine (SVM) based multi-classification, activities constituted by primitive actions can be recognized insensitive to the locations, orientations, and speeds. PMID:26184231

  14. Robust myoelectric signal detection based on stochastic resonance using multiple-surface-electrode array made of carbon nanotube composite paper

    NASA Astrophysics Data System (ADS)

    Shirata, Kento; Inden, Yuki; Kasai, Seiya; Oya, Takahide; Hagiwara, Yosuke; Kaeriyama, Shunichi; Nakamura, Hideyuki

    2016-04-01

    We investigated the robust detection of surface electromyogram (EMG) signals based on the stochastic resonance (SR) phenomenon, in which the response to weak signals is optimized by adding noise, combined with multiple surface electrodes. Flexible carbon nanotube composite paper (CNT-cp) was applied to the surface electrode, which showed good performance that is comparable to that of conventional Ag/AgCl electrodes. The SR-based EMG signal system integrating an 8-Schmitt-trigger network and the multiple-CNT-cp-electrode array successfully detected weak EMG signals even when the subject’s body is in the motion, which was difficult to achieve using the conventional technique. The feasibility of the SR-based EMG detection technique was confirmed by demonstrating its applicability to robot hand control.

  15. Multiple Transduction Pathways Mediate Thyrotropin Receptor Signaling in Preosteoblast-Like Cells.

    PubMed

    Boutin, Alisa; Neumann, Susanne; Gershengorn, Marvin C

    2016-05-01

    It has been shown that the TSH receptor (TSHR) couples to a number of different signaling pathways, although the Gs-cAMP pathway has been considered primary. Here, we measured the effects of TSH on bone marker mRNA and protein expression in preosteoblast-like U2OS cells stably expressing TSHRs. We determined which signaling cascades are involved in the regulation of IL-11, osteopontin (OPN), and alkaline phosphatase (ALPL). We demonstrated that TSH-induced up-regulation of IL-11 is primarily mediated via the Gs pathway as IL-11 was up-regulated by forskolin (FSK), an adenylyl cyclase activator, and inhibited by protein kinase A inhibitor H-89 and by silencing of Gαs by small interfering RNA. OPN levels were not affected by FSK, but its up-regulation was inhibited by TSHR/Gi-uncoupling by pertussis toxin. Pertussis toxin decreased p38 MAPK kinase phosphorylation, and a p38 inhibitor and small interfering RNA knockdown of p38α inhibited OPN induction by TSH. Up-regulation of ALPL expression required high doses of TSH (EC50 = 395nM), whereas low doses (EC50 = 19nM) were inhibitory. FSK-stimulated cAMP production decreased basal ALPL expression, whereas protein kinase A inhibition by H-89 and silencing of Gαs increased basal levels of ALPL. Knockdown of Gαq/11 and a protein kinase C inhibitor decreased TSH-stimulated up-regulation of ALPL, whereas a protein kinase C activator increased ALPL levels. A MAPK inhibitor and silencing of ERK1/2 inhibited TSH-stimulated ALPL expression. We conclude that TSH regulates expression of different bone markers via distinct signaling pathways. PMID:26950201

  16. Multiple Transduction Pathways Mediate Thyrotropin Receptor Signaling in Preosteoblast-Like Cells

    PubMed Central

    Boutin, Alisa; Neumann, Susanne

    2016-01-01

    It has been shown that the TSH receptor (TSHR) couples to a number of different signaling pathways, although the Gs-cAMP pathway has been considered primary. Here, we measured the effects of TSH on bone marker mRNA and protein expression in preosteoblast-like U2OS cells stably expressing TSHRs. We determined which signaling cascades are involved in the regulation of IL-11, osteopontin (OPN), and alkaline phosphatase (ALPL). We demonstrated that TSH-induced up-regulation of IL-11 is primarily mediated via the Gs pathway as IL-11 was up-regulated by forskolin (FSK), an adenylyl cyclase activator, and inhibited by protein kinase A inhibitor H-89 and by silencing of Gαs by small interfering RNA. OPN levels were not affected by FSK, but its up-regulation was inhibited by TSHR/Gi-uncoupling by pertussis toxin. Pertussis toxin decreased p38 MAPK kinase phosphorylation, and a p38 inhibitor and small interfering RNA knockdown of p38α inhibited OPN induction by TSH. Up-regulation of ALPL expression required high doses of TSH (EC50 = 395nM), whereas low doses (EC50 = 19nM) were inhibitory. FSK-stimulated cAMP production decreased basal ALPL expression, whereas protein kinase A inhibition by H-89 and silencing of Gαs increased basal levels of ALPL. Knockdown of Gαq/11 and a protein kinase C inhibitor decreased TSH-stimulated up-regulation of ALPL, whereas a protein kinase C activator increased ALPL levels. A MAPK inhibitor and silencing of ERK1/2 inhibited TSH-stimulated ALPL expression. We conclude that TSH regulates expression of different bone markers via distinct signaling pathways. PMID:26950201

  17. Physical activity and pediatric multiple sclerosis: Developing a research agenda.

    PubMed

    Yeh, E Ann; Kinnett-Hopkins, Dominique; Grover, Stephanie A; Motl, Robert W

    2015-11-01

    Three-quarters of children with multiple sclerosis (MS) experience fatigue or depression, and progressive neurocognitive decline may be seen as early as two years after MS diagnosis. Furthermore, a higher magnetic resonance imaging disease burden is seen in pediatric-onset MS compared with adult-onset MS. To date, limited knowledge exists regarding behavioral methods for managing symptoms and disease progression in pediatric MS. To that end, this paper builds an evidence-based argument for the possible symptomatic and disease-modifying effects of exercise and physical activity in pediatric MS. This will be accomplished through: (a) a review of pediatric MS and its consequences; (b) a brief overview of physical activity and its consequences in children and adults with MS; and (c) a selective review of research on the neurological benefits of physical activity in pediatric populations. This topical review concludes with a list of 10 questions to guide future research on physical activity and pediatric MS. The objective of this paper is the provision of a research interest, focus and agenda involving pediatric MS and its lifelong management though exercise and physical activity behavior. Such an agenda is critical as the effects and maintenance of physical activity and exercise track across the lifespan, particularly when developed in the early stages of life. PMID:26447061

  18. Notum deacylates Wnt proteins to suppress signalling activity.

    PubMed

    Kakugawa, Satoshi; Langton, Paul F; Zebisch, Matthias; Howell, Steven A; Chang, Tao-Hsin; Liu, Yan; Feizi, Ten; Bineva, Ganka; O'Reilly, Nicola; Snijders, Ambrosius P; Jones, E Yvonne; Vincent, Jean-Paul

    2015-03-12

    Signalling by Wnt proteins is finely balanced to ensure normal development and tissue homeostasis while avoiding diseases such as cancer. This is achieved in part by Notum, a highly conserved secreted feedback antagonist. Notum has been thought to act as a phospholipase, shedding glypicans and associated Wnt proteins from the cell surface. However, this view fails to explain specificity, as glypicans bind many extracellular ligands. Here we provide genetic evidence in Drosophila that Notum requires glypicans to suppress Wnt signalling, but does not cleave their glycophosphatidylinositol anchor. Structural analyses reveal glycosaminoglycan binding sites on Notum, which probably help Notum to co-localize with Wnt proteins. They also identify, at the active site of human and Drosophila Notum, a large hydrophobic pocket that accommodates palmitoleate. Kinetic and mass spectrometric analyses of human proteins show that Notum is a carboxylesterase that removes an essential palmitoleate moiety from Wnt proteins and thus constitutes the first known extracellular protein deacylase. PMID:25731175

  19. Pathway connectivity and signaling coordination in the yeast stress-activated signaling network

    PubMed Central

    Chasman, Deborah; Ho, Yi-Hsuan; Berry, David B; Nemec, Corey M; MacGilvray, Matthew E; Hose, James; Merrill, Anna E; Lee, M Violet; Will, Jessica L; Coon, Joshua J; Ansari, Aseem Z; Craven, Mark; Gasch, Audrey P

    2014-01-01

    Stressed cells coordinate a multi-faceted response spanning many levels of physiology. Yet knowledge of the complete stress-activated regulatory network as well as design principles for signal integration remains incomplete. We developed an experimental and computational approach to integrate available protein interaction data with gene fitness contributions, mutant transcriptome profiles, and phospho-proteome changes in cells responding to salt stress, to infer the salt-responsive signaling network in yeast. The inferred subnetwork presented many novel predictions by implicating new regulators, uncovering unrecognized crosstalk between known pathways, and pointing to previously unknown ‘hubs’ of signal integration. We exploited these predictions to show that Cdc14 phosphatase is a central hub in the network and that modification of RNA polymerase II coordinates induction of stress-defense genes with reduction of growth-related transcripts. We find that the orthologous human network is enriched for cancer-causing genes, underscoring the importance of the subnetwork's predictions in understanding stress biology. PMID:25411400

  20. Clonal B cells in Waldenström's macroglobulinemia exhibit functional features of chronic active B-cell receptor signaling

    PubMed Central

    Argyropoulos, K V; Vogel, R; Ziegler, C; Altan-Bonnet, G; Velardi, E; Calafiore, M; Dogan, A; Arcila, M; Patel, M; Knapp, K; Mallek, C; Hunter, Z R; Treon, S P; van den Brink, M R M; Palomba, M L

    2016-01-01

    Waldenström's macroglobulinemia (WM) is a B-cell non-Hodgkin's lymphoma (B-NHL) characterized by immunoglobulin M (IgM) monoclonal gammopathy and the medullary expansion of clonal lymphoplasmacytic cells. Neoplastic transformation has been partially attributed to hyperactive MYD88 signaling, secondary to the MYD88 L265P mutation, occurring in the majority of WM patients. Nevertheless, the presence of chronic active B-cell receptor (BCR) signaling, a feature of multiple IgM+ B-NHL, remains a subject of speculation in WM. Here, we interrogated the BCR signaling capacity of primary WM cells by utilizing multiparametric phosphoflow cytometry and found heightened basal phosphorylation of BCR-related signaling proteins, and augmented phosphoresponses on surface IgM (sIgM) crosslinking, compared with normal B cells. In support of those findings we observed high sIgM expression and loss of phosphatase activity in WM cells, which could both lead to signaling potentiation in clonal cells. Finally, led by the high-signaling heterogeneity among WM samples, we generated patient-specific phosphosignatures, which subclassified patients into a ‘high' and a ‘healthy-like' signaling group, with the second corresponding to patients with a more indolent clinical phenotype. These findings support the presence of chronic active BCR signaling in WM while providing a link between differential BCR signaling utilization and distinct clinical WM subgroups. PMID:26867669

  1. Mitogen Activated Protein kinase signal transduction pathways in the prostate

    PubMed Central

    Maroni, Paul D; Koul, Sweaty; Meacham, Randall B; Koul, Hari K

    2004-01-01

    The biochemistry of the mitogen activated protein kinases ERK, JNK, and p38 have been studied in prostate physiology in an attempt to elucidate novel mechanisms and pathways for the treatment of prostatic disease. We reviewed articles examining mitogen-activated protein kinases using prostate tissue or cell lines. As with other tissue types, these signaling modules are links/transmitters for important pathways in prostate cells that can result in cellular survival or apoptosis. While the activation of the ERK pathway appears to primarily result in survival, the roles of JNK and p38 are less clear. Manipulation of these pathways could have important implications for the treatment of prostate cancer and benign prostatic hypertrophy. PMID:15219238

  2. Learning Activity Models for Multiple Agents in a Smart Space

    NASA Astrophysics Data System (ADS)

    Crandall, Aaron; Cook, Diane J.

    With the introduction of more complex intelligent environment systems, the possibilities for customizing system behavior have increased dramatically. Significant headway has been made in tracking individuals through spaces using wireless devices [1, 18, 26] and in recognizing activities within the space based on video data (see chapter by Brubaker et al. and [6, 8, 23]), motion sensor data [9, 25], wearable sensors [13] or other sources of information [14, 15, 22]. However, much of the theory and most of the algorithms are designed to handle one individual in the space at a time. Resident tracking, activity recognition, event prediction, and behavior automation becomes significantly more difficult for multi-agent situations, when there are multiple residents in the environment.

  3. Resource Constrained Planning of Multiple Projects with Separable Activities

    NASA Astrophysics Data System (ADS)

    Fujii, Susumu; Morita, Hiroshi; Kanawa, Takuya

    In this study we consider a resource constrained planning problem of multiple projects with separable activities. This problem provides a plan to process the activities considering a resource availability with time window. We propose a solution algorithm based on the branch and bound method to obtain the optimal solution minimizing the completion time of all projects. We develop three methods for improvement of computational efficiency, that is, to obtain initial solution with minimum slack time rule, to estimate lower bound considering both time and resource constraints and to introduce an equivalence relation for bounding operation. The effectiveness of the proposed methods is demonstrated by numerical examples. Especially as the number of planning projects increases, the average computational time and the number of searched nodes are reduced.

  4. Bone morphogenetic protein signalling activity distinguishes histological subsets of paediatric germ cell tumours.

    PubMed

    Fustino, N; Rakheja, D; Ateek, C S; Neumann, J C; Amatruda, J F

    2011-08-01

    Germ cell tumours (GCTs) are cancers of the testis, ovary or extragonadal sites that occur in infants, children and adults. Testicular GCT is the most common cancer in young men aged 15-40 years. Abnormalities in developmental signalling pathways such as wnt/β-catenin, TGF-β/BMP and Hedgehog have been described in many childhood tumours. To date, however, the status of BMP signalling in GCTs has not been described. Herein, we examine BMP-SMAD signalling in a set of clinically-annotated paediatric GCTs. We find that BMP signalling activity is absent in undifferentiated tumours such as seminomas and dysgerminomas, but robustly present in most yolk sac tumours, a differentiated tumour type. Gene expression profiling of TGF-β/BMP pathway genes in germinomas and yolk sac tumours reveals a set of genes that distinguish the two tumour types. There is significant intertumoural heterogeneity between tumours of the same histological subclass, implying that the BMP pathway can be differentially regulated in individual tumours. Finally, through miRNA expression profiling, we identify differential regulation of a set of miRNAs predicted to target the TGF-β/BMP pathway at multiple sites. Taken together, these results suggest that the BMP signalling pathway may represent a new therapeutical target for childhood GCTs. PMID:21696393

  5. Interaction proteome of human Hippo signaling: modular control of the co-activator YAP1.

    PubMed

    Hauri, Simon; Wepf, Alexander; van Drogen, Audrey; Varjosalo, Markku; Tapon, Nic; Aebersold, Ruedi; Gstaiger, Matthias

    2013-01-01

    Tissue homeostasis is controlled by signaling systems that coordinate cell proliferation, cell growth and cell shape upon changes in the cellular environment. Deregulation of these processes is associated with human cancer and can occur at multiple levels of the underlying signaling systems. To gain an integrated view on signaling modules controlling tissue growth, we analyzed the interaction proteome of the human Hippo pathway, an established growth regulatory signaling system. The resulting high-resolution network model of 480 protein-protein interactions among 270 network components suggests participation of Hippo pathway components in three distinct modules that all converge on the transcriptional co-activator YAP1. One of the modules corresponds to the canonical Hippo kinase cassette whereas the other two both contain Hippo components in complexes with cell polarity proteins. Quantitative proteomic data suggests that complex formation with cell polarity proteins is dynamic and depends on the integrity of cell-cell contacts. Collectively, our systematic analysis greatly enhances our insights into the biochemical landscape underlying human Hippo signaling and emphasizes multifaceted roles of cell polarity complexes in Hippo-mediated tissue growth control. PMID:24366813

  6. Active immunization therapies for Parkinson's disease and multiple system atrophy.

    PubMed

    Schneeberger, Achim; Tierney, Lanay; Mandler, Markus

    2016-02-01

    Vaccination is increasingly being investigated as a potential treatment for synucleinopathies, a group of neurodegenerative diseases including Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies associated with α-synuclein pathology. All lack a causal therapy. Development of novel, disease-altering treatment strategies is urgently needed. Vaccination has positioned itself as a prime strategy for addressing these diseases because it is broadly applicable, requires infrequent administration, and maintains low production costs for treating a large population or as a preventive measure. Current evidence points to a causal role of misfolded α-synuclein in the development and progression of synucleinopathies. In the past decade, significant progress in active immunization against α-synuclein has been shown both in preclinical animal models and in early clinical development. In this review, we describe the state-of-the-art in active immunization approaches to synucleinopathies, with a focus on advances in Parkinson's disease (PD) and multiple-system atrophy (MSA). We first review preclinical animal models, highlighting their progress in translation to the clinical setting. We then discuss current clinical applications, stressing different approaches taken to address α-synuclein pathology. Finally, we address challenges, trends, and future perspectives of current vaccination programs. PMID:26260853

  7. Activities-Specific Balance Confidence in People with Multiple Sclerosis

    PubMed Central

    Nilsagård, Ylva; Carling, Anna; Forsberg, Anette

    2012-01-01

    Objective. To evaluate the validity of the Activities-specific Balance Confidence scale (ABC) in people with multiple sclerosis (PwMS). Design. A multicentre, cross-sectional study. Setting. Six rural and urban Swedish sites, including specialized units at hospitals and primary care centers. Participants. A sample of 84 PwMS with subjective gait and balance impairment but still able to walk 100 m (comparable with EDSS 1–6). Outcome Measures. Timed Up and Go, Timed Up and Gocog, 25-foot Timed Walk Test, Four Square Step Test, Dynamic Gait Index, Chair Stand Test, 12-item MS Walking Scale, self-reported falls, and use of assistive walking device were used for validation. Results. The concurrent convergent validity was moderate to good (0.50 to −0.75) with the highest correlation found for the 12-item MS Walking Scale. The ABC discriminated between multiple fallers and nonfallers but not between men and women. Ecological validity is suggested since ABC discriminated between users of assistive walking device and nonusers. The internal consistency was high at α = 0.95, and interitem correlations were between 0.30 and 0.83. Conclusion. This study supports the validity of the ABC for persons with mild-to-moderate MS. The participants lacked balance confidence in many everyday activities, likely restricting their participation in society. PMID:22919491

  8. Digital signaling decouples activation probability and population heterogeneity

    PubMed Central

    Kellogg, Ryan A; Tian, Chengzhe; Lipniacki, Tomasz; Quake, Stephen R; Tay, Savaş

    2015-01-01

    Digital signaling enhances robustness of cellular decisions in noisy environments, but it is unclear how digital systems transmit temporal information about a stimulus. To understand how temporal input information is encoded and decoded by the NF-κB system, we studied transcription factor dynamics and gene regulation under dose- and duration-modulated inflammatory inputs. Mathematical modeling predicted and microfluidic single-cell experiments confirmed that integral of the stimulus (or area, concentration × duration) controls the fraction of cells that activate NF-κB in the population. However, stimulus temporal profile determined NF-κB dynamics, cell-to-cell variability, and gene expression phenotype. A sustained, weak stimulation lead to heterogeneous activation and delayed timing that is transmitted to gene expression. In contrast, a transient, strong stimulus with the same area caused rapid and uniform dynamics. These results show that digital NF-κB signaling enables multidimensional control of cellular phenotype via input profile, allowing parallel and independent control of single-cell activation probability and population heterogeneity. DOI: http://dx.doi.org/10.7554/eLife.08931.001 PMID:26488364

  9. Digital signaling decouples activation probability and population heterogeneity.

    PubMed

    Kellogg, Ryan A; Tian, Chengzhe; Lipniacki, Tomasz; Quake, Stephen R; Tay, Savaş

    2015-01-01

    Digital signaling enhances robustness of cellular decisions in noisy environments, but it is unclear how digital systems transmit temporal information about a stimulus. To understand how temporal input information is encoded and decoded by the NF-κB system, we studied transcription factor dynamics and gene regulation under dose- and duration-modulated inflammatory inputs. Mathematical modeling predicted and microfluidic single-cell experiments confirmed that integral of the stimulus (or area, concentration × duration) controls the fraction of cells that activate NF-κB in the population. However, stimulus temporal profile determined NF-κB dynamics, cell-to-cell variability, and gene expression phenotype. A sustained, weak stimulation lead to heterogeneous activation and delayed timing that is transmitted to gene expression. In contrast, a transient, strong stimulus with the same area caused rapid and uniform dynamics. These results show that digital NF-κB signaling enables multidimensional control of cellular phenotype via input profile, allowing parallel and independent control of single-cell activation probability and population heterogeneity. PMID:26488364

  10. Activity-Based Probe for Histidine Kinase Signaling

    PubMed Central

    Wilke, Kaelyn E.; Francis, Samson; Carlson, Erin E.

    2012-01-01

    Bacterial two-component systems (TCSs) are signaling pathways composed of two proteins, a histidine kinase (HK) and a response regulator (RR). Upon stimulation, the HK autophosphorylates at a conserved histidine. The phosphoryl group is subsequently transferred to an aspartate on a RR, eliciting an adaptive response, often up- or downregulation of gene expression. TCS signaling controls many functions in bacteria including development, virulence and antibiotic resistance, making the proteins involved in these systems potential therapeutic targets. Efficient methods for the profiling of HKs are currently lacking. For direct readout of HK activity, we sought to design a probe that enables detection of the phosphotransfer event; however, analysis of the phosphohistidine species is made difficult by the instability of the P-N bond. We anticipated that use of a γ-thiophosphorylated ATP analog, which would yield a thiophosphorylated histidine intermediate, could overcome this challenge. We determined that the fluorophore-conjugated probe, ATPγS-BODIPY, labels active HK proteins and is competitive for the ATP-binding site. This activity-based probe provides a new strategy for analysis of TCSs and other HK-mediated processes and will facilitate both functional studies and inhibitor identification. PMID:22606938

  11. Female preference for multiple condition-dependent components of a sexually selected signal.

    PubMed

    Scheuber, Hannes; Jacot, Alain; Brinkhof, Martin W G

    2004-12-01

    Theoretical models explain the evolution of multi-cue mate-choice decisions from a trade-off between benefits owing to improved assessment of potential mates and costs linked to the use of multiple signals. However, empirical support for these basic assumptions is lacking. In field crickets (Gryllus campestris) we experimentally investigated the female preference to variation in two key components of the male calling song: carrier frequency and chirp rate. Previous studies have revealed carrier frequency and chirp rate as reliable indicators of male quality that reflect past condition and current condition, respectively. In a two-way choice experiment, females significantly preferred test songs of lower carrier frequency and higher chirp rate, but prioritized the carrier frequency over the chirp rate. Hence, the static long-term indicator of mate quality was weighted more than the dynamic short-term one. Our results thus indicate that females integrate information from independent condition-dependent cues to discriminate between available males in mate-choice decisions. PMID:15590595

  12. Female preference for multiple condition-dependent components of a sexually selected signal.

    PubMed Central

    Scheuber, Hannes; Jacot, Alain; Brinkhof, Martin W. G.

    2004-01-01

    Theoretical models explain the evolution of multi-cue mate-choice decisions from a trade-off between benefits owing to improved assessment of potential mates and costs linked to the use of multiple signals. However, empirical support for these basic assumptions is lacking. In field crickets (Gryllus campestris) we experimentally investigated the female preference to variation in two key components of the male calling song: carrier frequency and chirp rate. Previous studies have revealed carrier frequency and chirp rate as reliable indicators of male quality that reflect past condition and current condition, respectively. In a two-way choice experiment, females significantly preferred test songs of lower carrier frequency and higher chirp rate, but prioritized the carrier frequency over the chirp rate. Hence, the static long-term indicator of mate quality was weighted more than the dynamic short-term one. Our results thus indicate that females integrate information from independent condition-dependent cues to discriminate between available males in mate-choice decisions. PMID:15590595

  13. Saccharomyces cerevisiae vacuolar H+-ATPase regulation by disassembly and reassembly: one structure and multiple signals.

    PubMed

    Parra, Karlett J; Chan, Chun-Yuan; Chen, Jun

    2014-06-01

    Vacuolar H(+)-ATPases (V-ATPases) are highly conserved ATP-driven proton pumps responsible for acidification of intracellular compartments. V-ATPase proton transport energizes secondary transport systems and is essential for lysosomal/vacuolar and endosomal functions. These dynamic molecular motors are composed of multiple subunits regulated in part by reversible disassembly, which reversibly inactivates them. Reversible disassembly is intertwined with glycolysis, the RAS/cyclic AMP (cAMP)/protein kinase A (PKA) pathway, and phosphoinositides, but the mechanisms involved are elusive. The atomic- and pseudo-atomic-resolution structures of the V-ATPases are shedding light on the molecular dynamics that regulate V-ATPase assembly. Although all eukaryotic V-ATPases may be built with an inherent capacity to reversibly disassemble, not all do so. V-ATPase subunit isoforms and their interactions with membrane lipids and a V-ATPase-exclusive chaperone influence V-ATPase assembly. This minireview reports on the mechanisms governing reversible disassembly in the yeast Saccharomyces cerevisiae, keeping in perspective our present understanding of the V-ATPase architecture and its alignment with the cellular processes and signals involved. PMID:24706019

  14. Digital Signal Processing System for Active Noise Reduction

    NASA Astrophysics Data System (ADS)

    Edmonson, William W.; Tucker, Jerry

    2002-12-01

    Over the years there has been a need to improve the comfort of passengers in flight. One avenue for increasing comfort is to reduce cabin noise that is attributed to the engine and the vibration of fuselage panels that radiate sound. High frequency noise can be abated using sound absorbing material. Though, for low frequency noise the sound absorption material would have to very thick, thereby reducing the cabin size. To reduce these low frequency disturbances, active noise control systems (ANC) is being developed that utilizes feedback for cancellation of the disturbance. The active noise control system must be small in size, be a low power device, and operate in real-time. It must also be numerically stable i.e. insensitive to temperature and pressure variations. The ANC system will be a module that consists of digital signal processor (DSP), analog-digital and digital-analog converters, power converters, an actuator and sensors. The DSP will implement the feedback control algorithm that controls the actuators. This module will be attached to panels on the inside of the fuselage for actively eliminating resonant modes of the structure caused by turbulent flow across the fuselage Skin. A hardware prototype of the ANC system must be able to eliminate broadband noise consisting of a bandwidth between 100 Hz and 1500 Hz, which requires a sample rate of 5000 Hz. The analog/digital converters output accuracy is 16 bits with a 2's-compliment format and a very short acquisition time. This will also yield the appropriate dynamic range. Similar specifications are required of the digital/analog converter. The processor section of the system integrates a digital signal processor (TI TMS320C33) with analog/digital (Burr-Brown ADS8320) and digital/analog signal (DAC853 1) converters. The converters with associated power conditioning circuitry and test points reside on a daughter board that sits on top of a Spectrum Digital evaluation module. This will have the ability to test

  15. The role of the Janus kinase family/signal transducer and activator of transcription signaling pathway in fibrotic renal disease

    PubMed Central

    Matsui, Futoshi; Meldrum, Kirstan K.

    2012-01-01

    Over the past several years, a number of cytokines and growth factors including transforming growth factor β1, tumor necrosis factor α, and angiotensin II have been shown to play a crucial role in renal fibrosis. The Janus kinase family (JAK) and signal transducers and activators of transcription (STATs) constitute one of the primary signaling pathways that regulate cytokine expression, and the JAK/STAT signaling pathway has increasingly been implicated in the pathophysiology of renal disease. This review examines the role of the JAK/STAT signaling pathway in fibrotic renal disease. The JAK/STAT signaling pathway is activated in a variety of renal diseases and has been implicated in the pathophysiology of renal fibrosis. Experimental evidence suggests that inhibition of the JAK/STAT signaling pathway, in particular JAK2 and STAT3, may suppress renal fibrosis and protect renal function. However, it is incompletely understood which cells activate the JAK/STAT signaling pathway and which JAK/STAT signaling pathway is activated in each renal disease. Research regarding JAK/STAT signaling and its contribution to renal disease is still ongoing in humans. Future studies are required to elucidate the potential role of JAK/STAT signaling inhibition as a therapeutic strategy in the attenuation of renal fibrosis. PMID:22883438

  16. Vector Time-Series from Multiple Aperture Interferometry in Regions with Small Deformation Signals

    NASA Astrophysics Data System (ADS)

    Wortham, C.; Zebker, H. A.

    2012-12-01

    We estimate 3-D deformation from the June 2007 eruption along the East Rift Zone (ERZ) of Kilauea Volcano, Hawaii, using new extensions to InSAR small baseline subset (SBAS) analysis. Given the east-west orientation of the ERZ, a large component of the deformation is in the north-south direction with velocities on the order of 19 cm/yr for dates spanning the event and 4 cm/yr following the eruption. Similarly, we see deflation at the Kilauea caldera on the order of 7 cm/yr, with deformation in the east, north, and up directions. We use multiple geometries from ALOS/PALSAR and a modified SBAS algorithm to estimate all three components of the time-series. Ascending and descending geometries give measurements in the east and up directions, and we use multiple aperture InSAR (MAI) to estimate the along-track deformation. The azimuthal MAI method adds the missing component from the InSAR observations. However, due to aperture splitting, these MAI measurements are highly sensitive to phase errors and are only useful in areas with large signals. Given the pre and post-eruption velocities of the Hawaii data set, most MAI interferograms have very low SNR. Furthermore, the acquisition times of ascending and descending geometries differ by weeks or months. With at most two observations at each time step, the resulting system of equations is highly underdetermined. Both the low MAI SNR and rank deficiency of the inversion complicate the time-series estimation. We present our extension of SBAS time-series to vector deformation in which multiple radar geometries are combined in the geodetic domain. We show that by using ascending and descending acquisitions, along with their corresponding MAI measurements, accurate, three-dimensional time-series are possible, despite the time offset between each radar geometry. In combining these data sets, the temporal resolution of the time-series is increased, however, as a consequence of the lower MAI SNR, the spatial coverage from viable

  17. Computer modeling of multiple-channel input signals and intermodulation losses caused by nonlinear traveling wave tube amplifiers

    NASA Technical Reports Server (NTRS)

    Stankiewicz, N.

    1982-01-01

    The multiple channel input signal to a soft limiter amplifier as a traveling wave tube is represented as a finite, linear sum of Gaussian functions in the frequency domain. Linear regression is used to fit the channel shapes to a least squares residual error. Distortions in output signal, namely intermodulation products, are produced by the nonlinear gain characteristic of the amplifier and constitute the principal noise analyzed in this study. The signal to noise ratios are calculated for various input powers from saturation to 10 dB below saturation for two specific distributions of channels. A criterion for the truncation of the series expansion of the nonlinear transfer characteristic is given. It is found that he signal to noise ratios are very sensitive to the coefficients used in this expansion. Improper or incorrect truncation of the series leads to ambiguous results in the signal to noise ratios.

  18. Asynchronous detection of optical code division multiple access signals using a bandwidth-efficient and wavelength-aware receiver.

    PubMed

    Fok, Mable P; Deng, Yanhua; Prucnal, Paul R

    2010-04-01

    We experimentally demonstrate what we believe to be a novel detection scheme for interfacing asynchronous optical code division multiple access (CDMA) signals with an electronic clock and data recovery system that operates only at the baseband bandwidth. This allows using a large optical bandwidth expansion factor in which the optical chip rate is much larger than the bandwidth of the optoelectronic receiver. The received optical CDMA signal is launched into a four-wave-mixing-based wavelength-aware all-optical front end that rejects multiaccess interference, followed by an amplitude-noise suppression stage comprised of a semiconductor optical amplifier. The clean signal is then converted into a non-return-to-zero-like signal by a baseband receiver. Using the proposed detection scheme, asynchronous transmission and detection of optical CDMA signals is implemented. With the novel detection scheme, the classic CDMA near-far problem is mitigated, and error-free detection is easily obtained. PMID:20364229

  19. Calcium-Oxidant Signaling Network Regulates AMP-activated Protein Kinase (AMPK) Activation upon Matrix Deprivation*

    PubMed Central

    Sundararaman, Ananthalakshmy; Amirtham, Usha; Rangarajan, Annapoorni

    2016-01-01

    The AMP-activated protein kinase (AMPK) has recently been implicated in anoikis resistance. However, the molecular mechanisms that activate AMPK upon matrix detachment remain unexplored. In this study, we show that AMPK activation is a rapid and sustained phenomenon upon matrix deprivation, whereas re-attachment to the matrix leads to its dephosphorylation and inactivation. Because matrix detachment leads to loss of integrin signaling, we investigated whether integrin signaling negatively regulates AMPK activation. However, modulation of focal adhesion kinase or Src, the major downstream components of integrin signaling, failed to cause a corresponding change in AMPK signaling. Further investigations revealed that the upstream AMPK kinases liver kinase B1 (LKB1) and Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) contribute to AMPK activation upon detachment. In LKB1-deficient cells, we found AMPK activation to be predominantly dependent on CaMKKβ. We observed no change in ATP levels under detached conditions at early time points suggesting that rapid AMPK activation upon detachment was not triggered by energy stress. We demonstrate that matrix deprivation leads to a spike in intracellular calcium as well as oxidant signaling, and both these intracellular messengers contribute to rapid AMPK activation upon detachment. We further show that endoplasmic reticulum calcium release-induced store-operated calcium entry contributes to intracellular calcium increase, leading to reactive oxygen species production, and AMPK activation. We additionally show that the LKB1/CaMKK-AMPK axis and intracellular calcium levels play a critical role in anchorage-independent cancer sphere formation. Thus, the Ca2+/reactive oxygen species-triggered LKB1/CaMKK-AMPK signaling cascade may provide a quick, adaptable switch to promote survival of metastasizing cancer cells. PMID:27226623

  20. Brain Activation of Identity Switching in Multiple Identity Tracking Task

    PubMed Central

    Lyu, Chuang; Hu, Siyuan; Wei, Liuqing; Zhang, Xuemin; Talhelm, Thomas

    2015-01-01

    When different objects switch identities in the multiple identity tracking (MIT) task, viewers need to rebind objects’ identity and location, which requires attention. This rebinding helps people identify the regions targets are in (where they need to focus their attention) and inhibit unimportant regions (where distractors are). This study investigated the processing of attentional tracking after identity switching in an adapted MIT task. This experiment used three identity-switching conditions: a target-switching condition (where the target objects switched identities), a distractor-switching condition (where the distractor objects switched identities), and a no-switching condition. Compared to the distractor-switching condition, the target-switching condition elicited greater activation in the frontal eye fields (FEF), intraparietal sulcus (IPS), and visual cortex. Compared to the no-switching condition, the target-switching condition elicited greater activation in the FEF, inferior frontal gyrus (pars orbitalis) (IFG-Orb), IPS, visual cortex, middle temporal lobule, and anterior cingulate cortex. Finally, the distractor-switching condition showed greater activation in the IFG-Orb compared to the no-switching condition. These results suggest that, in the target-switching condition, the FEF and IPS (the dorsal attention network) might be involved in goal-driven attention to targets during attentional tracking. In addition, in the distractor-switching condition, the activation of the IFG-Orb may indicate salient change that pulls attention away automatically. PMID:26699865

  1. Cucurbitacin-E inhibits multiple cancer cells proliferation through attenuation of Wnt/β-catenin signaling.

    PubMed

    Feng, Hui; Zang, Li; Zhao, Zhen-Xia; Kan, Quan-Cheng

    2014-06-01

    Recent studies suggest that the use of cucurbitacins could inhibit cancer cell progression. In the current study, the authors analyzed the effect of cucurbitacin-E (CuE) in cancer cells using A549, Hep3B, and SW480 cells. The authors found that CuE inhibited cell proliferation and modulated the expression of cell cycle regulators in these cells. Moreover, the authors found that CuE inhibited Wnt/β-catenin signaling activation through upregulation of tumor suppressor Menin. Indeed, ablation of Menin using small interfering RNA (siRNA) oligos attenuated the antiproliferative roles of CuE. Taken together, the results of this study provide a novel mechanism that may contribute to the antineoplastic effects of CuE in cancer cells. PMID:24885795

  2. The proinflammatory cytokine interleukin-18 alters multiple signaling pathways to inhibit natural killer cell death

    USGS Publications Warehouse

    Hodge, D.L.; Subleski, J.J.; Reynolds, D.A.; Buschman, M.D.; Schill, W.B.; Burkett, M.W.; Malyguine, A.M.; Young, H.A.

    2006-01-01

    The proinflammatory cytokine, interleukin-18 (IL-18), is a natural killer (NK) cell activator that induces NK cell cytotoxicity and interferon-?? (IFN-??) expression. In this report, we define a novel role for IL-18 as an NK cell protective agent. Specifically, IL-18 prevents NK cell death initiated by different and distinct stress mechanisms. IL-18 reduces NK cell self-destruction during NK-targeted cell killing, and in the presence of staurosporin, a potent apoptotic inducer, IL-18 reduces caspase-3 activity. The critical regulatory step in this process is downstream of the mitochondrion and involves reduced cleavage and activation of caspase-9 and caspase-3. The ability of IL-18 to regulate cell survival is not limited to a caspase death pathway in that IL-18 augments tumor necrosis factor (TNF) signaling, resulting in increased and prolonged mRNA expression of c-apoptosis inhibitor 2 (cIAP2), a prosurvival factor and caspase-3 inhibitor, and TNF receptor-associated factor 1 (TRAF1), a prosurvival protein. The cumulative effects of IL-18 define a novel role for this cytokine as a molecular survival switch that functions to both decrease cell death through inhibition of the mitochondrial apoptotic pathway and enhance TNF induction of prosurvival factors. ?? Mary Ann Liebert, Inc.

  3. Genistein alleviates lead-induced neurotoxicity in vitro and in vivo: Involvement of multiple signaling pathways.

    PubMed

    Su, Peng; Zhang, Jianbin; Wang, Siwang; Aschner, Michael; Cao, Zipeng; Zhao, Fang; Wang, Diya; Chen, Jiangyuan; Luo, Wenjing

    2016-03-01

    Lead (Pb) is a ubiquitous environmental and industrial pollutant. It induces neurotoxicity and cell death by disrupting the pro- and anti-oxidative balance; however, the mechanisms of its toxicity have yet to be fully understood. The soy-derived isoflavonoid, genistein (GEN), was reported to possess neuroprotective and antioxidative properties. The present study investigated the molecular mechanisms of Pb-induced neurotoxicity in vivo and in vitro, addressing the efficacy of GEN in protecting against Pb-induced toxicity. Pb exposure was associated with reduction of cell viability and cell apoptosis, concomitant with reactive oxygen species (ROS) generation in vitro, and pre-treatment with GEN markedly ameliorated the Pb-induced oxidative injury by increasing the expression of key antioxidant enzymes and the antioxidant transcription factor, nuclear factor erythroid 2 p45-related factor 2 (Nrf2). Next, PKC-α activation was found after Pb exposure in vitro and pretreatment with GEN attenuated Pb-induced ROS generation by PKC-α inhibition. MAPK-NF-κB activation triggered by Pb was also inhibited by GEN. In summary, our study establishes that GEN alleviates Pb-induced impairment in spatial memory, and reduces cell apoptosis caused by Pb exposure and GEN protects neurons from Pb-induced neurotoxicity by downstream activation of antioxidant and anti-apoptotic pathways via regulation of Nrf2 and MAPK-NF-κB signaling. PMID:26797587

  4. Relation of intracellular signal levels and promoter activities in the gal regulon of Escherichia coli.

    PubMed

    Krishna, Sandeep; Orosz, László; Sneppen, Kim; Adhya, Sankar; Semsey, Szabolcs

    2009-08-28

    Transcription of many genes is regulated by combinations of multiple signals. In Escherichia coli, combinatorial control is typical in the case of operons related to utilization of different sugars in the absence of glucose. To understand regulation of the transport and metabolic pathways in the galactose system, we measured activities of the six gal regulon promoters simultaneously, using an in vitro transcription system containing purified components. Input functions were computed on the basis of the experimental measurements. We observed four different shapes of input functions. From the results, we can conclude that the structure of the regulatory network is insufficient for the determination of signal integration. It is the actual structure of the promoter and regulatory region, the mechanism of transcription regulation, and the interplay between transcription factors that shape the input function to be suitable for adaptation. PMID:19559028

  5. Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus

    PubMed Central

    Wu, Tianfu; Qin, Xiangmei; Kurepa, Zoran; Kumar, Kirthi Raman; Liu, Kui; Kanta, Hasna; Zhou, Xin J.; Satterthwaite, Anne B.; Davis, Laurie S.; Mohan, Chandra

    2007-01-01

    Though B cells play key roles in lupus pathogenesis, the molecular circuitry and its dysregulation in these cells as disease evolves remain poorly understood. To address this, a comprehensive scan of multiple signaling axes using multiplexed Western blotting was undertaken in several different murine lupus strains. PI3K/AKT/mTOR (mTOR, mammalian target of rapamycin), MEK1/Erk1/2, p38, NF-κB, multiple Bcl-2 family members, and cell-cycle molecules were observed to be hyperexpressed in lupus B cells in an age-dependent and lupus susceptibility gene–dose–dependent manner. Therapeutic targeting of the AKT/mTOR axis using a rapamycin (sirolimus) derivative ameliorated the serological, cellular, and pathological phenotypes associated with lupus. Surprisingly, the targeting of this axis was associated with the crippling of several other signaling axes. These studies reveal that lupus pathogenesis is contingent upon the activation of an elaborate network of signaling cascades that is shared among genetically distinct mouse models and raise hope that targeting pivotal nodes in these networks may offer therapeutic benefit. PMID:17641780

  6. Transsynaptic signaling by activity-dependent cleavage of neuroligin-1.

    PubMed

    Peixoto, Rui T; Kunz, Portia A; Kwon, Hyungbae; Mabb, Angela M; Sabatini, Bernardo L; Philpot, Benjamin D; Ehlers, Michael D

    2012-10-18

    Adhesive contact between pre- and postsynaptic neurons initiates synapse formation during brain development and provides a natural means of transsynaptic signaling. Numerous adhesion molecules and their role during synapse development have been described in detail. However, once established, the mechanisms of adhesive disassembly and its function in regulating synaptic transmission have been unclear. Here, we report that synaptic activity induces acute proteolytic cleavage of neuroligin-1 (NLG1), a postsynaptic adhesion molecule at glutamatergic synapses. NLG1 cleavage is triggered by NMDA receptor activation, requires Ca2+ /calmodulin-dependent protein kinase, and is mediated by proteolytic activity of matrix metalloprotease 9 (MMP9). Cleavage of NLG1 occurs at single activated spines, is regulated by neural activity in vivo, and causes rapid destabilization of its presynaptic partner neurexin-1β (NRX1β). In turn, NLG1 cleavage depresses synaptic transmission by abruptly reducing presynaptic release probability. Thus, local proteolytic control of synaptic adhesion tunes synaptic transmission during brain development and plasticity. PMID:23083741

  7. Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors

    PubMed Central

    Gautier, Hélène O. B.; Evans, Kimberley A.; Volbracht, Katrin; James, Rachel; Sitnikov, Sergey; Lundgaard, Iben; James, Fiona; Lao-Peregrin, Cristina; Reynolds, Richard; Franklin, Robin J. M.; Káradóttir, Ragnhildur T

    2015-01-01

    Myelin regeneration can occur spontaneously in demyelinating diseases such as multiple sclerosis (MS). However, the underlying mechanisms and causes of its frequent failure remain incompletely understood. Here we show, using an in-vivo remyelination model, that demyelinated axons are electrically active and generate de novo synapses with recruited oligodendrocyte progenitor cells (OPCs), which, early after lesion induction, sense neuronal activity by expressing AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate receptors. Blocking neuronal activity, axonal vesicular release or AMPA receptors in demyelinated lesions results in reduced remyelination. In the absence of neuronal activity there is a ∼6-fold increase in OPC number within the lesions and a reduced proportion of differentiated oligodendrocytes. These findings reveal that neuronal activity and release of glutamate instruct OPCs to differentiate into new myelinating oligodendrocytes that recover lost function. Co-localization of OPCs with the presynaptic protein VGluT2 in MS lesions implies that this mechanism may provide novel targets to therapeutically enhance remyelination. PMID:26439639

  8. Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors.

    PubMed

    Gautier, Hélène O B; Evans, Kimberley A; Volbracht, Katrin; James, Rachel; Sitnikov, Sergey; Lundgaard, Iben; James, Fiona; Lao-Peregrin, Cristina; Reynolds, Richard; Franklin, Robin J M; Káradóttir, Ragnhildur T

    2015-01-01

    Myelin regeneration can occur spontaneously in demyelinating diseases such as multiple sclerosis (MS). However, the underlying mechanisms and causes of its frequent failure remain incompletely understood. Here we show, using an in-vivo remyelination model, that demyelinated axons are electrically active and generate de novo synapses with recruited oligodendrocyte progenitor cells (OPCs), which, early after lesion induction, sense neuronal activity by expressing AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate receptors. Blocking neuronal activity, axonal vesicular release or AMPA receptors in demyelinated lesions results in reduced remyelination. In the absence of neuronal activity there is a ∼6-fold increase in OPC number within the lesions and a reduced proportion of differentiated oligodendrocytes. These findings reveal that neuronal activity and release of glutamate instruct OPCs to differentiate into new myelinating oligodendrocytes that recover lost function. Co-localization of OPCs with the presynaptic protein VGluT2 in MS lesions implies that this mechanism may provide novel targets to therapeutically enhance remyelination. PMID:26439639

  9. Heparin suppresses lipid raft-mediated signaling and ligand-independent EGF receptor activation.

    PubMed

    Liu, Yuan-Tao; Song, Lifang; Templeton, Douglas M

    2007-04-01

    Heparin is well known to suppress vascular smooth muscle cell (VSMC) proliferation, and attempts to exploit this therapeutically have led to recognition of multiple pathways for heparin's anti-mitogenic actions. At low concentrations (ca. 1 microg.ml(-1)), these suppressive effects may reflect physiological activities of endogenous heparan sulfates, and appear to be rapid responses to extracellular or cell surface-associated heparin. Because heparin has been shown to influence expression of caveolin proteins, and caveolae/lipid rafts are critical structures modulating cell signaling, we examined the effect of heparin on signaling involving cholesterol-rich membrane microdomains. The VSMC line PAC-1 activates the MAP kinase Erk in response to the cholesterol-sequestering agents methyl-beta-cyclodextrin and nystatin. This follows a temporal sequence that involves Ras-GTP activation of MEK, and is independent of PKC, Src, and PI3 kinase. However, ligand-independent phosphorylation of the EGF receptor (EGFR) by removal of cholesterol precedes Ras activation, and the EGFR kinase inhibitor AG1478 blocks Erk phosphorylation, supporting occurrence of the signaling sequence EGFR-Ras-MEK-Erk. Phosphorylation of EGFR occurs predominantly in caveolin-rich microdomains as identified by Western blotting of fractions from density gradient centrifugation of membranes prepared under detergent-free conditions. In these situations, heparin inhibits phosphorylation of EGFR on the Src-dependent site Tyr(845), but not the autophosphorylation of Tyr(1173), and decreases Ras activation and Erk phosphorylation. We conclude that heparin can suppress Erk signaling in VSMC with effects on site-specific phosphorylation of EGFR localized in caveolin-enriched lipid rafts. PMID:17226785

  10. Simultaneous multiple-depths en-face optical coherence tomography using multiple signal excitation of acousto-optic deflectors.

    PubMed

    Zurauskas, Mantas; Rogers, John; Podoleanu, Adrian Gh

    2013-01-28

    We present a novel low-coherence interferometer configuration, equipped with acousto-optic deflectors that can be used to simultaneously acquire up to eight time domain optical coherence tomography en-face images. The capabilities of the configuration are evaluated in terms of depth resolution, signal to noise ratio and crosstalk. Then the configuration is employed to demonstrate simultaneous en-face optical coherence tomography imaging at five different depths in a specimen of armadillidium vulgare. PMID:23389175

  11. Activation of the chicken gonadotropin-inhibitory hormone receptor reduces gonadotropin releasing hormone receptor signaling.

    PubMed

    Shimizu, Mamiko; Bédécarrats, Grégoy Y

    2010-06-01

    Gonadotropin-inhibitory hormone (GnIH) is a hypothalamic peptide from the RFamide peptide family that has been identified in multiple avian species. Although GnIH has clearly been shown to reduce LH release from the anterior pituitary gland, its mechanism of action remains to be determined. The overall objectives of this study were (1) to characterize the GnIH receptor (GnIH-R) signaling pathway, (2) to evaluate potential interactions with gonadotropin releasing hormone type III receptor (GnRH-R-III) signaling, and (3) to determine the molecular mechanisms by which GnIH and GnRH regulate pituitary gonadotrope function during a reproductive cycle in the chicken. Using real-time PCR, we showed that in the chicken pituitary gland, GnIH-R mRNA levels fluctuate in an opposite manner to GnRH-R-III, with higher and lower levels observed during inactive and active reproductive stages, respectively. We demonstrated that the chicken GnIH-R signals by inhibiting adenylyl cyclase cAMP production, most likely by coupling to G(alphai). We also showed that this inhibition is sufficient to significantly reduce GnRH-induced cAMP responsive element (CRE) activation in a dose-dependent manner, and that the ratio of GnRH/GnIH receptors is a significant factor. We propose that in avian species, sexual maturation is characterized by a change in GnIH/GnRH receptor ratio, resulting in a switch in pituitary sensitivity from inhibitory (involving GnIH) to stimulatory (involving GnRH). In turn, decreasing GnIH-R signaling, combined with increasing GnRH-R-III signaling, results in significant increases in CRE activation, possibly initiating gonadotropin synthesis. PMID:20350548

  12. A novel nuclear export signal in Smad1 is essential for its signaling activity.

    PubMed

    Xiao, Zhan; Brownawell, Amy M; Macara, Ian G; Lodish, Harvey F

    2003-09-01

    To investigate the subcellular distributions of Smad proteins, the intracellular mediators of transforming growth factor-beta family cytokines, we examined their sequences for nuclear export signals (NES). We found a leucine-rich NES-like motif (termed NES2) in the central linker region of the receptor-regulated Smads that is absent from the other two classes of Smads (Co-Smads and I-Smads). In microinjection assays, NES2 peptide caused nuclear export of a fused glutathione S-transferase protein. Mutations in NES2 converted Smad1 from an even distribution throughout the cells into an exclusive nuclear localization in both transiently and stably expressing cell lines, and this nuclear enrichment was more pronounced than that induced by mutations in NES1. Furthermore, overexpression of CRM1, the cellular export receptor, transforms Smad1 into a mostly cytoplasmic profile by enhancing its nuclear export. The Smad1 NES2 mutant but not the Smad1 NES1 mutant is mostly resistant to this cytoplasmic targeting, indicating that NES2, not NES1, is the major target for CRM1 in Smad1. We further confirmed the functionality of NES2 by a heterokaryon assay. The Smad1 NES1 mutant displays good ligand responsiveness and moderately lowered transcriptional activity compared with wild type Smad1. In contrast, the Smad1 NES2 mutant shows a severe disruption in reporter gene activation, minimal response to bone morphogenetic protein stimulation, and significantly lowered bone morphogenetic protein-induced phosphorylation, which may be the reason for its deficient transcription activity. Thus, we have defined a major NES in Smad1 that is essential for its ligand-induced coupling with cell surface receptors and hence, transcriptional activity. Our study, along with recent studies of the nucleocytoplasmic shuttling of Smad2 and Smad3 proteins, demonstrate that continued nucleocytoplasmic shuttling is a common requisite for the active signaling of R-Smads. Although conserved in other R

  13. Signal Transducer and Activator of Transcription-3, Inflammation, and Cancer

    PubMed Central

    Aggarwal, Bharat B.; Kunnumakkara, Ajaikumar B.; Harikumar, Kuzhuvelil B.; Gupta, Shan R.; Tharakan, Sheeja T.; Koca, Cemile; Dey, Sanjit; Sung, Bokyung

    2011-01-01

    Signal transducer and activator of transcription-3 (STAT-3) is one of six members of a family of transcription factors. It was discovered almost 15 years ago as an acute-phase response factor. This factor has now been associated with inflammation, cellular transformation, survival, proliferation, invasion, angiogenesis, and metastasis of cancer. Various types of carcinogens, radiation, viruses, growth factors, oncogenes, and inflammatory cytokines have been found to activate STAT-3. STAT-3 is constitutively active in most tumor cells but not in normal cells. Phosphorylation of STAT-3 at tyrosine 705 leads to its dimerization, nuclear translocation, DNA binding, and gene transcription. The phosphorylation of STAT-3 at serine 727 may regulate its activity negatively or positively. STAT-3 regulates the expression of genes that mediate survival (survivin, bcl-xl, mcl-1, cellular FLICE-like inhibitory protein), proliferation (c-fos, c-myc, cyclin D1), invasion (matrix metalloproteinase-2), and angiogenesis (vascular endothelial growth factor). STAT-3 activation has also been associated with both chemoresistance and radioresistance. STAT-3 mediates these effects through its collaboration with various other transcription factors, including nuclear factor-κB, hypoxia-inducible factor-1, and peroxisome proliferator activated receptor-γ. Because of its critical role in tumorigenesis, inhibitors of this factor’s activation are being sought for both prevention and therapy of cancer. This has led to identification of small peptides, oligonucleotides, and small molecules as potential STAT-3 inhibitors. Several of these small molecules are chemo-preventive agents derived from plants. This review discusses the intimate relationship between STAT-3, inflammation, and cancer in more detail. PMID:19723038

  14. Dynamic neural activity during stress signals resilient coping.

    PubMed

    Sinha, Rajita; Lacadie, Cheryl M; Constable, R Todd; Seo, Dongju

    2016-08-01

    Active coping underlies a healthy stress response, but neural processes supporting such resilient coping are not well-known. Using a brief, sustained exposure paradigm contrasting highly stressful, threatening, and violent stimuli versus nonaversive neutral visual stimuli in a functional magnetic resonance imaging (fMRI) study, we show significant subjective, physiologic, and endocrine increases and temporally related dynamically distinct patterns of neural activation in brain circuits underlying the stress response. First, stress-specific sustained increases in the amygdala, striatum, hypothalamus, midbrain, right insula, and right dorsolateral prefrontal cortex (DLPFC) regions supported the stress processing and reactivity circuit. Second, dynamic neural activation during stress versus neutral runs, showing early increases followed by later reduced activation in the ventrolateral prefrontal cortex (VLPFC), dorsal anterior cingulate cortex (dACC), left DLPFC, hippocampus, and left insula, suggested a stress adaptation response network. Finally, dynamic stress-specific mobilization of the ventromedial prefrontal cortex (VmPFC), marked by initial hypoactivity followed by increased VmPFC activation, pointed to the VmPFC as a key locus of the emotional and behavioral control network. Consistent with this finding, greater neural flexibility signals in the VmPFC during stress correlated with active coping ratings whereas lower dynamic activity in the VmPFC also predicted a higher level of maladaptive coping behaviors in real life, including binge alcohol intake, emotional eating, and frequency of arguments and fights. These findings demonstrate acute functional neuroplasticity during stress, with distinct and separable brain networks that underlie critical components of the stress response, and a specific role for VmPFC neuroflexibility in stress-resilient coping. PMID:27432990

  15. Myeloid cell distribution and activity in multiple sclerosis.

    PubMed

    Moliné-Velázquez, Verónica; Vila-Del Sol, Virginia; de Castro, Fernando; Clemente, Diego

    2016-04-01

    Multiple sclerosis (MS) is a demyelinating disease in which an exacerbated immune response provokes oligodendrocyte loss and demyelination, the hallmarks of this neurological disease. The destruction of myelin due to the uncontrolled activity of the invading immune cells leads to the formation of MS plaques. Among the different leukocytes that participate in the immune response associated with MS, the role of myeloid cells has been analyzed extensively (i.e. macrophages, dendritic cells -DCs- and neutrophils). Hence, in this review we will summarize what is known about the distribution, expression and markers available to study myeloid cells, and their histopathology, not only in a standard animal model of MS (autoimmune experimental encephalomyelitis -EAE) but also in MS tissue. In this review, we will not only refer to mature myeloid cells but also to the undifferentiated and almost unexplored myeloid-derived suppressor cells (MDSCs). The active role of MDSCs in the prompt resolution of an immune episode is gaining importance, yet is still the subject of some debate. Finally, the similarities and differences between MS and EAE are discussed, particularly in terms of myeloid cell phenotype, activity and the markers used. PMID:26592711

  16. Activation of endogenous neural stem cells for multiple sclerosis therapy.

    PubMed

    Michailidou, Iliana; de Vries, Helga E; Hol, Elly M; van Strien, Miriam E

    2014-01-01

    Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, leading to severe neurological deficits. Current MS treatment regimens, consist of immunomodulatory agents aiming to reduce the rate of relapses. However, these agents are usually insufficient to treat chronic neurological disability. A promising perspective for future therapy of MS is the regeneration of lesions with replacement of the damaged oligodendrocytes or neurons. Therapies targeting to the enhancement of endogenous remyelination, aim to promote the activation of either the parenchymal oligodendrocyte progenitor cells or the subventricular zone-derived neural stem cells (NSCs). Less studied but highly potent, is the strategy of neuronal regeneration with endogenous NSCs that although being linked to numerous limitations, is anticipated to ameliorate cognitive disability in MS. Focusing on the forebrain, this review highlights the role of NSCs in the regeneration of MS lesions. PMID:25653584

  17. Activation of endogenous neural stem cells for multiple sclerosis therapy

    PubMed Central

    Michailidou, Iliana; de Vries, Helga E.; Hol, Elly M.; van Strien, Miriam E.

    2015-01-01

    Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, leading to severe neurological deficits. Current MS treatment regimens, consist of immunomodulatory agents aiming to reduce the rate of relapses. However, these agents are usually insufficient to treat chronic neurological disability. A promising perspective for future therapy of MS is the regeneration of lesions with replacement of the damaged oligodendrocytes or neurons. Therapies targeting to the enhancement of endogenous remyelination, aim to promote the activation of either the parenchymal oligodendrocyte progenitor cells or the subventricular zone-derived neural stem cells (NSCs). Less studied but highly potent, is the strategy of neuronal regeneration with endogenous NSCs that although being linked to numerous limitations, is anticipated to ameliorate cognitive disability in MS. Focusing on the forebrain, this review highlights the role of NSCs in the regeneration of MS lesions. PMID:25653584

  18. The root hair assay facilitates the use of genetic and pharmacological tools in order to dissect multiple signalling pathways that lead to programmed cell death.

    PubMed

    Kacprzyk, Joanna; Devine, Aoife; McCabe, Paul F

    2014-01-01

    The activation of programmed cell death (PCD) is often a result of complex signalling pathways whose relationship and intersection are not well understood. We recently described a PCD root hair assay and proposed that it could be used to rapidly screen genetic or pharmacological modulators of PCD. To further assess the applicability of the root hair assay for studying multiple signalling pathways leading to PCD activation we have investigated the crosstalk between salicylic acid, autophagy and apoptosis-like PCD (AL-PCD) in Arabidopsis thaliana. The root hair assay was used to determine rates of AL-PCD induced by a panel of cell death inducing treatments in wild type plants treated with chemical modulators of salicylic acid synthesis or autophagy, and in genetic lines defective in autophagy or salicylic acid signalling. The assay demonstrated that PCD induced by exogenous salicylic acid or fumonisin B1 displayed a requirement for salicylic acid signalling and was partially dependent on the salicylic acid signal transducer NPR1. Autophagy deficiency resulted in an increase in the rates of AL-PCD induced by salicylic acid and fumonisin B1, but not by gibberellic acid or abiotic stress. The phenylalanine ammonia lyase-dependent salicylic acid synthesis pathway contributed only to death induced by salicylic acid and fumonisin B1. 3-Methyladenine, which is commonly used as an inhibitor of autophagy, appeared to influence PCD induction in all treatments suggesting a possible secondary, non-autophagic, effect on a core component of the plant PCD pathway. The results suggest that salicylic acid signalling is negatively regulated by autophagy during salicylic acid and mycotoxin-induced AL-PCD. However, this crosstalk does not appear to be directly involved in PCD induced by gibberellic acid or abiotic stress. This study demonstrates that the root hair assay is an effective tool for relatively rapid investigation of complex signalling pathways leading to the activation of

  19. The Root Hair Assay Facilitates the Use of Genetic and Pharmacological Tools in Order to Dissect Multiple Signalling Pathways That Lead to Programmed Cell Death

    PubMed Central

    Kacprzyk, Joanna; Devine, Aoife; McCabe, Paul F.

    2014-01-01

    The activation of programmed cell death (PCD) is often a result of complex signalling pathways whose relationship and intersection are not well understood. We recently described a PCD root hair assay and proposed that it could be used to rapidly screen genetic or pharmacological modulators of PCD. To further assess the applicability of the root hair assay for studying multiple signalling pathways leading to PCD activation we have investigated the crosstalk between salicylic acid, autophagy and apoptosis-like PCD (AL-PCD) in Arabidopsis thaliana. The root hair assay was used to determine rates of AL-PCD induced by a panel of cell death inducing treatments in wild type plants treated with chemical modulators of salicylic acid synthesis or autophagy, and in genetic lines defective in autophagy or salicylic acid signalling. The assay demonstrated that PCD induced by exogenous salicylic acid or fumonisin B1 displayed a requirement for salicylic acid signalling and was partially dependent on the salicylic acid signal transducer NPR1. Autophagy deficiency resulted in an increase in the rates of AL-PCD induced by salicylic acid and fumonisin B1, but not by gibberellic acid or abiotic stress. The phenylalanine ammonia lyase-dependent salicylic acid synthesis pathway contributed only to death induced by salicylic acid and fumonisin B1. 3-Methyladenine, which is commonly used as an inhibitor of autophagy, appeared to influence PCD induction in all treatments suggesting a possible secondary, non-autophagic, effect on a core component of the plant PCD pathway. The results suggest that salicylic acid signalling is negatively regulated by autophagy during salicylic acid and mycotoxin-induced AL-PCD. However, this crosstalk does not appear to be directly involved in PCD induced by gibberellic acid or abiotic stress. This study demonstrates that the root hair assay is an effective tool for relatively rapid investigation of complex signalling pathways leading to the activation of

  20. Quantitative solid-state 13C NMR with signal enhancement by multiple cross polarization

    NASA Astrophysics Data System (ADS)

    Johnson, Robert L.; Schmidt-Rohr, Klaus

    2014-02-01

    A simple new method is presented that yields quantitative solid-state magic-angle spinning (MAS) 13C NMR spectra of organic materials with good signal-to-noise ratios. It achieves long (>10 ms) cross polarization (CP) from 1H without significant magnetization losses due to relaxation and with a moderate duty cycle of the radio-frequency irradiation, by multiple 1-ms CP periods alternating with 1H spin-lattice relaxation periods that repolarize the protons. The new method incorporates previous techniques that yield less distorted CP/MAS spectra, such as a linear variation (“ramp”) of the radio-frequency field strength, and it overcomes their main limitation, which is T1ρ relaxation of the spin-locked 1H magnetization. The ramp of the radio-frequency field strength and the asymptotic limit of cross polarization makes the spectral intensity quite insensitive to the exact field strengths used. The new multiCP pulse sequence is a “drop-in” replacement for previous CP methods and produces no additional data-processing burden. Compared to the only reliable quantitative 13C NMR method for unlabeled solids previously available, namely direct-polarization NMR, the measuring time is reduced by more than a factor of 50, enabling higher-throughput quantitative NMR studies. The new multiCP technique is validated with 14-kHz MAS on amino-acid derivatives, plant matter, a highly aromatic humic acid, and carbon materials made by low-temperature pyrolysis.

  1. Accelerated Lactate Dehydrogenase Activity Potentiates Osteoclastogenesis via NFATc1 Signaling

    PubMed Central

    Kim, Jin Man; Kwon, So Hyun; Lee, Seoung Hoon; Lee, Soo Young; Jeong, Daewon

    2016-01-01

    Osteoclasts seem to be metabolic active during their differentiation and bone-resorptive activation. However, the functional role of lactate dehydrogenase (LDH), a tetrameric enzyme consisting of an A and/or B subunit that catalyzes interconversion of pyruvate to lactate, in RANKL-induced osteoclast differentiation is not known. In this study, RANKL treatment induced gradual gene expression and activation of the LDH A2B2 isotype during osteoclast differentiation as well as the LDH A1B3 and B4 isotypes during osteoclast maturation after pre-osteoclast formation. Glucose consumption and lactate production in growth media were accelerated during osteoclast differentiation, together with enhanced expression of H+-lactate co-transporter and increased extracellular acidification, demonstrating that glycolytic metabolism was stimulated during differentiation. Further, oxygen consumption via mitochondria was stimulated during osteoclast differentiation. On the contrary, depletion of LDH-A or LDH-B subunit suppressed both glycolytic and mitochondrial metabolism, resulting in reduced mature osteoclast formation via decreased osteoclast precursor fusion and down-regulation of the osteoclastogenic critical transcription factor NFATc1 and its target genes. Collectively, our findings suggest that RANKL-induced LDH activation stimulates glycolytic and mitochondrial respiratory metabolism, facilitating mature osteoclast formation via osteoclast precursor fusion and NFATc1 signaling. PMID:27077737

  2. Aurora A kinase activity influences calcium signaling in kidney cells.

    PubMed

    Plotnikova, Olga V; Pugacheva, Elena N; Golemis, Erica A

    2011-06-13

    Most studies of Aurora A (AurA) describe it as a mitotic centrosomal kinase. However, we and others have recently identified AurA functions as diverse as control of ciliary resorption, cell differentiation, and cell polarity control in interphase cells. In these activities, AurA is transiently activated by noncanonical signals, including Ca(2+)-dependent calmodulin binding. These and other observations suggested that AurA might be involved in pathological conditions, such as polycystic kidney disease (PKD). In this paper, we show that AurA is abundant in normal kidney tissue but is also abnormally expressed and activated in cells lining PKD-associated renal cysts. PKD arises from mutations in the PKD1 or PKD2 genes, encoding polycystins 1 and 2 (PC1 and PC2). AurA binds, phosphorylates, and reduces the activity of PC2, a Ca(2+)-permeable nonselective cation channel and, thus, limits the amplitude of Ca(2+) release from the endoplasmic reticulum. These and other findings suggest AurA may be a relevant new biomarker or target in the therapy of PKD. PMID:21670214

  3. Signal-to-noise ratio in neuro activation PET studies

    SciTech Connect

    Votaw, J.R.

    1996-04-01

    It has become commonplace to compare scanner sensitivity characteristics by comparing noise equivalent count rate curves. However, because a 20-cm diameter uniform phantom is drastically difference from a human brain, these curves give misleading information when planning a neuro activation PET experiment. Signal-to-noise ratio (SNR) calculations have been performed using measured data (Siemens 921 scanner) from the three-dimensional (3-D) Hoffman brain phantom for the purpose of determining the optimal injection and scanning protocol for [{sup 15}O] labeled activation experiments. Region of interest (ROI) values along with the variance due to prompt (trues plus randoms) and random events were determined for various regions and radioactivity concentrations. Calculated attenuation correction was used throughout. Scatter correction was not used when calculating the SNR in activation studies because the number of scattered events is almost identical in each data acquisition and hence cancels. The results indicate that randoms correction should not be performed and that rather than being limited by the scanner capabilities, neuro activation experiments are limited by the amount of radioactivity that can be injected and the length of time the patient can stay in the scanner.

  4. Investigation of Pseudomonas aeruginosa quorum-sensing signaling system for identifying multiple inhibitors using molecular docking and structural analysis methodology.

    PubMed

    Soheili, Vahid; Bazzaz, Bibi Sedigheh Fazly; Abdollahpour, Nooshin; Hadizadeh, Farzin

    2015-12-01

    Pseudomonas aeruginosa is an opportunistic human pathogen and a common Gram-negative bacterium in hospital-acquired infections. It causes death in many burn victims, cystic-fibrosis and neutropenic-cancer patients. It is known that P. aeruginosa biofilm maturation and production of cell-associated and extracellular virulence factors such as pyocyanin, elastase and rhamnolipids are under the control of a quorum-sensing (QS) system. Among several proteins involved in the Pseudomonas QS mechanism, LasR and PqsE play an important role in its cascade signaling system. They can cause increases in QS factors, biofilm maturation, and the production of virulence factors. Therefore, inhibition of these proteins can reduce the pathogenicity of P. aeruginosa. According to the structure of corresponding auto-inducers bound to these proteins, in silico calculations were performed with some non-steroidal anti-inflammatory drugs (NSAIDs) to estimate possible interactions and find the co-inhibitors of LasR and PqsE. The results showed that oxicams (Piroxicam and Meloxicam) can interact well with active sites of both proteins with the Ki of 119.43 nM and 4.0 μM for Meloxicam and 201.39 nM and 4.88 μM against LasR and PqsE, respectively. These findings suggested that Piroxicam and Meloxicam can be used as potential inhibitors for control of the P. aeruginosa QS signaling system and biofilm formation, and may be used in the design of multiple inhibitors. PMID:26358567

  5. Ubiquitination in Signaling to and Activation of IKK

    PubMed Central

    Chen, Zhijian J.

    2013-01-01

    A role of polyubiquitination in the activation of IκB kinase (IKK) through a proteasome-independent mechanism was first reported in 1996, but the physiological significance of this finding was not clear until 2000 when TRAF6 was found to be a ubiquitin E3 ligase that catalyzes lysine-63 (K63) polyubiquitination. Since then, several proteins known to regulate IKK have been linked to the ubiquitin pathway. These include the deubiquitination enzymes CYLD and A20 that inhibit IKK, and the ubiquitin binding proteins NEMO and TAB2 which are the regulatory subunits of IKK and TAK1 kinase complexes, respectively. Now accumulating evidence strongly supports a central role of K63 polyubiquitination in IKK activation by multiple immune and inflammatory pathways. Interestingly, recent research suggests that some alternative ubiquitin chains such as linear or K11 ubiquitin chains may also play a role in certain pathways such as the TNF pathway. Here I present a historical narrative of the discovery of the role of ubiquitin in IKK activation, review recent advances in understanding the role and mechanism of ubiquitin-mediated IKK activation, and raise some questions to be resolved in future research. PMID:22435549

  6. Klf5 Deletion Promotes Pten Deletion–Initiated Luminal-Type Mouse Prostate Tumors through Multiple Oncogenic Signaling Pathways12

    PubMed Central

    Xing, Changsheng; Ci, Xinpei; Sun, Xiaodong; Fu, Xiaoying; Zhang, Zhiqian; Dong, Eric N.; Hao, Zhao-Zhe; Dong, Jin-Tang

    2014-01-01

    Krüppel-like factor 5 (KLF5) regulates multiple biologic processes. Its function in tumorigenesis appears contradictory though, showing both tumor suppressor and tumor promoting activities. In this study, we examined whether and how Klf5 functions in prostatic tumorigenesis using mice with prostate-specific deletion of Klf5 and phosphatase and tensin homolog (Pten), both of which are frequently inactivated in human prostate cancer. Histologic analysis demonstrated that when one Pten allele was deleted, which causes mouse prostatic intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth, increased cell proliferation, and caused more severe morphologic and molecular alterations. Homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Pten deletion alone expanded basal cell population in a tumor as reported, Klf5 deletion in the Pten-null background clearly reduced basal cell population while expanding luminal cell population. Global gene expression profiling, pathway analysis, and experimental validation indicate that multiple mechanisms could mediate the tumor-promoting effect of Klf5 deletion, including the up-regulation of epidermal growth factor and its downstream signaling molecules AKT and ERK and the inactivation of the p15 cell cycle inhibitor. KLF5 also appears to cooperate with several transcription factors, including CREB1, Sp1, Myc, ER and AR, to regulate gene expression. These findings validate the tumor suppressor function of KLF5. They also yield a mouse model that shares two common genetic alterations with human prostate cancer—mutation/deletion of Pten and deletion of Klf5. PMID:25425963

  7. Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression.

    PubMed

    Frank, Valeska; Habbig, Sandra; Bartram, Malte P; Eisenberger, Tobias; Veenstra-Knol, Hermine E; Decker, Christian; Boorsma, Reinder A C; Göbel, Heike; Nürnberg, Gudrun; Griessmann, Anabel; Franke, Mareike; Borgal, Lori; Kohli, Priyanka; Völker, Linus A; Dötsch, Jörg; Nürnberg, Peter; Benzing, Thomas; Bolz, Hanno J; Johnson, Colin; Gerkes, Erica H; Schermer, Bernhard; Bergmann, Carsten

    2013-06-01

    Mutations affecting the integrity and function of cilia have been identified in various genes over the last decade accounting for a group of diseases called ciliopathies. Ciliopathies display a broad spectrum of phenotypes ranging from mild manifestations to lethal combinations of multiple severe symptoms and most of them share cystic kidneys as a common feature. Our starting point was a consanguineous pedigree with three affected fetuses showing an early embryonic phenotype with enlarged cystic kidneys, liver and pancreas and developmental heart disease. By genome-wide linkage analysis, we mapped the disease locus to chromosome 17q11 and identified a homozygous nonsense mutation in NEK8/NPHP9 that encodes a kinase involved in ciliary dynamics and cell cycle progression. Missense mutations in NEK8/NPHP9 have been identified in juvenile cystic kidney jck mice and in patients suffering from nephronophthisis (NPH), an autosomal-recessive cystic kidney disease. This work confirmed a complete loss of NEK8 expression in the affected fetuses due to nonsense-mediated decay. In cultured fibroblasts derived from these fetuses, the expression of prominent polycystic kidney disease genes (PKD1 and PKD2) was decreased, whereas the oncogene c-MYC was upregulated, providing potential explanations for the observed renal phenotype. We furthermore linked NEK8 with NPHP3, another NPH protein known to cause a very similar phenotype in case of null mutations. Both proteins interact and activate the Hippo effector TAZ. Taken together, our study demonstrates that NEK8 is essential for organ development and that the complete loss of NEK8 perturbs multiple signalling pathways resulting in a severe early embryonic phenotype. PMID:23418306

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

    PubMed

    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

  9. The β-catenin Axis Integrates Multiple Signals Downstream From RET/PTC and Leads to Cell Proliferation

    PubMed Central

    Castellone, Maria Domenica; De Falco, Valentina; Rao, Deva Magendra; Bellelli, Roberto; Muthu, Magesh; Basolo, Fulvio; Fusco, Alfredo; Gutkind, J. Silvio; Santoro, Massimo

    2009-01-01

    RET/PTC (RET/papillary thyroid carcinoma) oncoproteins result from the in-frame fusion of the RET receptor tyrosine kinase domain with protein dimerization motifs encoded by heterologous genes. Here we show that RET/PTC stimulates the β-catenin pathway. By stimulating PI3K/AKT and Ras/ERK, RET/PTC promotes GSK3β phosphorylation, thereby reducing GSK3β-mediated N-terminal β-catenin (Ser33/Ser37/Thr41) phosphorylation. In addition, RET/PTC physically interacts with β-catenin, and increases its phosphotyrosine content. The increased free pool of S/T(nonphospho)/Y(phospho)β-catenin is stabilized as a result of the reduced binding affinity for the Axin/GSK3β complex and activates the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factor. Moreover, through the ERK pathway, RET/PTC stimulates cAMP-responsive element binding protein (CREB) phosphorylation and promotes the formation of a β-catenin-CREB-CBP/p300 transcriptional complex. Transcriptional complexes containing β-catenin are recruited to the cyclin D1 promoter and a cyclin D1 gene promoter reporter is active in RET/PTC expressing cells. Silencing of β-catenin by siRNA inhibits proliferation of RET/PTC transformed PC thyrocytes, whereas a constitutively active form of β-catenin stimulates autonomous proliferation of thyroid cells. Thus, multiple signaling events downstream from RET/PTC converge on β-catenin to stimulate cell proliferation. PMID:19223551

  10. Bisphenol A (BPA) stimulates the interferon signaling and activates the inflammasome activity in myeloid cells.

    PubMed

    Panchanathan, Ravichandran; Liu, Hongzhu; Leung, Yuet-Kin; Ho, Shuk-mei; Choubey, Divaker

    2015-11-01

    Environmental factors contribute to the development of autoimmune diseases, including systemic lupus erythematosus (SLE), which exhibits a strong female bias (female-to-male ratio 9:1). However, the molecular mechanisms remain largely unknown. Because a feedforward loop between the female sex hormone estrogen (E2) and type I interferon (IFN-α/β)-signaling induces the expression of certain p200-family proteins (such as murine p202 and human IFI16) that regulate innate immune responses and modify lupus susceptibility, we investigated whether treatment of myeloid cells with bisphenol A (BPA), an environmental estrogen, could regulate the p200-family proteins and activate innate immune responses. We found that treatment of murine bone marrow-derived cells (BMCs) and human peripheral blood mononuclear cells with BPA induced the expression of ERα and IFN-β, activated the IFN-signaling, and stimulated the expression of the p202 and IFI16 proteins. Further, the treatment increased levels of the NLRP3 inflammasome and stimulated its activity. Accordingly, BPA-treatment of BMCs from non lupus-prone C57BL/6 and the lupus-prone (NZB×NZW)F1 mice activated the type I IFN-signaling, induced the expression of p202, and activated an inflammasome activity. Our study demonstrates that BPA-induced signaling in the murine and human myeloid cells stimulates the type I IFN-signaling that results in an induction of the p202 and IFI16 innate immune sensors for the cytosolic DNA and activates an inflammasome activity. These observations provide novel molecular insights into the role of environmental BPA exposures in potentiating the development of certain autoimmune diseases such as SLE. PMID:26277401

  11. NK Cell-extrinsic IL-18 Signaling Is Required for Efficient NK Cell Activation to Vaccinia Virus

    PubMed Central

    Brandstadter, Joshua D.; Huang, Xiaopei; Yang, Yiping

    2014-01-01

    Summary NK cells are important for the control of vaccinia virus (VV) in vivo. Recent studies have shown that multiple pathways are required for effective activation of NK cells. These include both TLR-dependent and -independent pathways, as well as the NKG2D activating receptor that recognizes host stress-induced NKG2D ligands. However, it remains largely unknown what controls the upregulation of NKG2D ligands in response to VV infection. In this study, we first showed that IL-18 is critical for NK cell activation and viral clearance. We then demonstrated that IL-18 signaling on both NK cells and DCs is required for efficient NK cell activation upon VV infection in vitro. We further showed in vivo that efficient NK cell activation to VV is dependent on DCs and IL-18 signaling in non-NK cells, suggesting an essential role for NK cell-extrinsic IL-18 signaling in NK cell activation. Mechanistically, IL-18 signaling in DCs promotes expression of Rae-1, an NKG2D ligand. Collectively, our data reveal a previously unrecognized role for NK cell-extrinsic IL-18 signaling in NK cell activation through upregulation of NKG2D ligands. These observations may provide insights into the design of effective NK cell-based therapies for viral infections and cancer. PMID:24846540

  12. Lipoicmethylenedioxyphenol Reduces Experimental Atherosclerosis through Activation of Nrf2 Signaling

    PubMed Central

    Ying, Zhekang; Chen, Minjie; Xie, Xiaoyun; Wang, Xiaoke; Kherada, Nisharahmed; Desikan, Rajagopal; Mihai, Georgeta; Burns, Patrick; Sun, Qinghua; Rajagopalan, Sanjay

    2016-01-01

    Objective Oxidative stress is implicated in the pathogenesis of atherosclerosis, and Nrf2 is the transcriptional factor central in cellular antioxidant responses. In the present study, we investigate the effect of a dihydrolipoic acid derivative lipoicmethylenedioxyphenol (LMDP) on the progression of atherosclerosis and test whether its effect on atherosclerosis is mediated by Nrf2. Methods and Results Both magnetic resonance imaging (MRI) scanning and en face analysis reveal that 14 weeks of treatment with LMDP markedly reduced atherosclerotic burden in a rabbit balloon vascular injury model. Myograph analyses show decreased aortic contractile response to phenylephrine and increased aortic response to acetylcholine and insulin in LMDP-treated animals, suggesting that LMDP inhibits atherosclerosis through improving vascular function. A role of Nrf2 signaling in mediating the amelioration of vascular function by LMDP was supported by increased Nrf2 translocation into nuclear and increased expression of Nrf2 target genes. Furthermore, chemotaxis analysis with Boydem chamber shows that leukocytes isolated from LMDP-treated rabbits had reduced chemotaxis, and knock-down of Nrf2 significantly reduced the effect of LMDP on the chemotaxis of mouse macrophages. Conclusion Our results support that LMDP has an anti-atherosclerotic effect likely through activation of Nrf2 signaling and subsequent inhibition of macrophage chemotaxis. PMID:26859892

  13. Multiple phosphorylation events control chicken ovalbumin upstream promoter transcription factor I orphan nuclear receptor activity.

    PubMed

    Gay, Frédérique; Baráth, Peter; Desbois-Le Péron, Christine; Métivier, Raphaël; Le Guével, Rémy; Birse, Darcy; Salbert, Gilles

    2002-06-01

    Chicken ovalbumin upstream promoter transcription factor I (COUP-TFI) is an orphan member of the nuclear hormone receptor superfamily that comprises key regulators of many biological functions, such as embryonic development, metabolism, homeostasis, and reproduction. Although COUP-TFI can both actively silence gene transcription and antagonize the functions of various other nuclear receptors, the COUP-TFI orphan receptor also acts as a transcriptional activator in certain contexts. Moreover, COUP-TFI has recently been shown to serve as an accessory factor for some ligand-bound nuclear receptors, suggesting that it may modulate, both negatively and positively, a wide range of hormonal responses. In the absence of any identified cognate ligand, the mechanisms involved in the regulation of COUP-TFI activity remain unclear. The elucidation of several putative phosphorylation sites for MAPKs, PKC, and casein kinase II within the sequence of this orphan receptor led us to investigate phosphorylation events regulating the various COUP-TFI functions. After showing that COUP-TFI is phosphorylated in vivo, we provide evidence that in vivo inhibition of either MAPK or PKC signaling pathway leads to a specific and pronounced decrease in COUP-TFI-dependent transcriptional activation of the vitronectin gene promoter. Focusing on the molecular mechanisms underlying the MAPK- and PKC-mediated regulation of COUP-TFI activity, we show that COUP-TFI can be directly targeted by PKC and MAPK. These phosphorylation events differentially modulate COUP-TFI functions: PKC-mediated phosphorylation enhances COUP-TFI affinity for DNA and MAPK-mediated phosphorylation positively regulates the transactivation function of COUP-TFI, possibly through enhancing specific coactivator recruitment. These data provide evidence that COUP-TFI is likely to integrate distinct signaling pathways and raise the possibility that multiple extracellular signals influence biological processes controlled by COUP

  14. Multiple Beneficial Roles of Repressor of Estrogen Receptor Activity (REA) in Suppressing the Progression of Endometriosis.

    PubMed

    Zhao, Yuechao; Chen, Yiru; Kuang, Ye; Bagchi, Milan K; Taylor, Robert N; Katzenellenbogen, John A; Katzenellenbogen, Benita S

    2016-02-01

    Endometriosis is an estrogen-dependent, inflammation-driven gynecologic disorder in which endometrial tissue creates inflammatory lesions at extrauterine sites, leading to pelvic pain and impaired fertility. Although dysregulated estrogen receptor (ER) signaling has been implicated, understanding of this disease is incomplete and current therapies are of limited benefit. Using an immunocompetent syngeneic murine model, we used combinations of donor uterine tissue and/or recipient host mice with partial genetic deletion of the ER coregulator, repressor of ER activity (REA) (also known as prohibitin 2), to investigate roles of REA in the contributions of donor uterine tissue and host cell influences on endometriosis establishment and progression. Ectopic lesions derived from donor tissue with half the wild-type gene dosage of REA (REA(+/-)) grown in REA(+/-) hosts displayed enhanced proliferation, vascularization, and markedly increased neuron innervation and inflammatory responses, including elevated cytokine production, nuclear factor kappa B activation, cyclooxygenase-2 expression, and immune cell infiltration. Although lesion progression was greatest when REA was reduced in both donor tissue and host animals, other donor/host combinations indicated that distinct stimulatory inputs were derived from ectopic tissue (proliferative signals) and host cells (inflammatory signals). Importantly, depletion of REA in primary human endometriotic stromal cells led to elevated proliferation and expression of cell cycle regulators. Notably, REA was significantly lower in human endometriotic tissue versus normal human endometrium. Thus, REA modulates cross talk among multiple cell types in the uterine tissue and host background, serving as a brake on the estradiol-ER axis and restraining multiple aspects that contribute to the pathologic progression of endometriosis. PMID:26653759

  15. Inferring Human Activity in Mobile Devices by Computing Multiple Contexts

    PubMed Central

    Chen, Ruizhi; Chu, Tianxing; Liu, Keqiang; Liu, Jingbin; Chen, Yuwei

    2015-01-01

    This paper introduces a framework for inferring human activities in mobile devices by computing spatial contexts, temporal contexts, spatiotemporal contexts, and user contexts. A spatial context is a significant location that is defined as a geofence, which can be a node associated with a circle, or a polygon; a temporal context contains time-related information that can be e.g., a local time tag, a time difference between geographical locations, or a timespan; a spatiotemporal context is defined as a dwelling length at a particular spatial context; and a user context includes user-related information that can be the user’s mobility contexts, environmental contexts, psychological contexts or social contexts. Using the measurements of the built-in sensors and radio signals in mobile devices, we can snapshot a contextual tuple for every second including aforementioned contexts. Giving a contextual tuple, the framework evaluates the posteriori probability of each candidate activity in real-time using a Naïve Bayes classifier. A large dataset containing 710,436 contextual tuples has been recorded for one week from an experiment carried out at Texas A&M University Corpus Christi with three participants. The test results demonstrate that the multi-context solution significantly outperforms the spatial-context-only solution. A classification accuracy of 61.7% is achieved for the spatial-context-only solution, while 88.8% is achieved for the multi-context solution. PMID:26343665

  16. Pollutants in particulate and gaseous fractions of ambient air interfere with multiple signaling pathways in vitro.

    PubMed

    Novák, Jirí; Jálová, Veronika; Giesy, John P; Hilscherová, Klára

    2009-01-01

    Traditionally, contamination of air has been evaluated primarily by chemical analyses of indicator contaminants and these studies have focused mainly on compounds associated with particulates. Some reports have shown that air contaminants can produce specific biological effects such as toxicity mediated by the aryl hydrocarbon receptor (AhR) or modulation of the endocrine system. This study assessed the dioxin-like toxicity, anti-/estrogenicity, anti-/androgenicity and anti-/retinoic activity of both the particulate and gas phase fractions of air in two regions with different types of pollution sources and a background locality situated in an agricultural area of Central Europe. The first region (A) is known to be significantly contaminated by organochlorine pesticides and chemical industry. The other region (B) has been polluted by historical releases of PCBs, but the major current sources of contamination are probably combustion sources from local traffic and heating. Samples of both particle and gas fractions produced dioxin-like (AhR-mediated) activity, anti-estrogenic and antiandrogenic effects, but none had any effect on retinoid signaling. AhR-mediated activities were observed in all samples and the TEQ values were comparable in both fractions in region A, but significantly greater in the particulate fraction in region B. The greater AhR-mediated activity corresponded to a greater coincident antiestrogenicity of both phases in region B. Our study is the first report of antiestrogenicity and antiandrogenicity in ambient air. Anti-androgenicity was observed in the gas phase of all regions, while in the particulate phase only in one region due to the specific type of pollution in that area. Even though based on concentrations of individual compounds, except for the OCPs, the level of contamination of the two regions was similar, there were strong differences in responses in the bioassays between the two regions. Moreover, AhR-mediated activity and

  17. Mouse Visual Neocortex Supports Multiple Stereotyped Patterns of Microcircuit Activity

    PubMed Central

    Sadovsky, Alexander J.

    2014-01-01

    Spiking correlations between neocortical neurons provide insight into the underlying synaptic connectivity that defines cortical microcircuitry. Here, using two-photon calcium fluorescence imaging, we observed the simultaneous dynamics of hundreds of neurons in slices of mouse primary visual cortex (V1). Consistent with a balance of excitation and inhibition, V1 dynamics were characterized by a linear scaling between firing rate and circuit size. Using lagged firing correlations between neurons, we generated functional wiring diagrams to evaluate the topological features of V1 microcircuitry. We found that circuit connectivity exhibited both cyclic graph motifs, indicating recurrent wiring, and acyclic graph motifs, indicating feedforward wiring. After overlaying the functional wiring diagrams onto the imaged field of view, we found properties consistent with Rentian scaling: wiring diagrams were topologically efficient because they minimized wiring with a modular architecture. Within single imaged fields of view, V1 contained multiple discrete circuits that were overlapping and highly interdigitated but were still distinct from one another. The majority of neurons that were shared between circuits displayed peri-event spiking activity whose timing was specific to the active circuit, whereas spike times for a smaller percentage of neurons were invariant to circuit identity. These data provide evidence that V1 microcircuitry exhibits balanced dynamics, is efficiently arranged in anatomical space, and is capable of supporting a diversity of multineuron spike firing patterns from overlapping sets of neurons. PMID:24899701

  18. Dynamics of biomembranes with active multiple-state inclusions.

    PubMed

    Chen, Hsuan-Yi; Mikhailov, Alexander S

    2010-03-01

    Nonequilibrium dynamics of biomembranes with active multiple-state inclusions is considered. The inclusions represent protein molecules which perform cyclic internal conformational motions driven by the energy brought with adenosine triphosphate (ATP) ligands. As protein conformations cyclically change, this induces hydrodynamical flows and also directly affects the local curvature of a membrane. On the other hand, variations in the local curvature of the membrane modify the transition rates between conformational states in a protein, leading to a feedback in the considered system. Moreover, active inclusions can move diffusively through the membrane so that their surface concentration varies. The kinetic description of this system is constructed and the stability of the uniform stationary state is analytically investigated. We show that, as the rate of supply of chemical energy is increased above a certain threshold, this uniform state becomes unstable and stationary or traveling waves spontaneously develop in the system. Such waves are accompanied by periodic spatial variations of the membrane curvature and the inclusion density. For typical parameter values, their characteristic wavelengths are of the order of hundreds of nanometers. For traveling waves, the characteristic frequency is of the order of a thousand Hz or less. The predicted instabilities are possible only if at least three internal inclusion states are present. PMID:20365764

  19. Pharmacology of Signaling Induced by Dopamine D1-Like Receptor Activation

    PubMed Central

    Undieh, Ashiwel S.

    2010-01-01

    Dopamine D1-like receptors consisting of D1 and D5 subtypes are intimately implicated in dopaminergic regulation of fundamental neurophysiologic processes such as mood, motivation, cognitive function, and motor activity. Upon stimulation, D1-like receptors initiate signal transduction cascades that are mediated through adenylyl cyclase or phosphoinositide metabolism, with subsequent enhancement of multiple downstream kinase cascades. The latter actions propagate and further amplify the receptor signals, thus predisposing D1-like receptors to multifaceted interactions with various other mediators and receptor systems. The adenylyl cyclase response to dopamine or selective D1-like receptor agonists is reliably associated with the D1 subtype, while emerging evidence indicates that the phosphoinositide responses in native brain tissues may be preferentially mediated through stimulation of the D5 receptor. Besides classic coupling of each receptor subtype to specific G proteins, additional biophysical models are advanced in attempts to account for differential subcellular distribution, heteromolecular oligomerization, and activity-dependent selectivity of the receptors. It is expected that significant advances in understanding of dopamine neurobiology will emerge from current and anticipated studies directed at uncovering the molecular mechanisms of D5 coupling to phosphoinositide signaling, the structural features that might enhance pharmacological selectivity for D5 versus D1 subtypes, the mechanism by which dopamine may modulate phosphoinositide synthesis, the contributions of the various responsive signal mediators to D1 or D5 interactions with D2-like receptors, and the spectrum of dopaminergic functions that may be attributed to each receptor subtype and signaling pathway. PMID:20547182

  20. Activation of the Extracellular Signal-Regulated Kinase Signaling Is Critical for Human Umbilical Cord Mesenchymal Stem Cell Osteogenic Differentiation

    PubMed Central

    Li, Chen-Shuang; Zheng, Zhong; Su, Xiao-Xia; Wang, Fei; Ling, Michelle; Zou, Min; Zhou, Hong

    2016-01-01

    Human umbilical cord mesenchymal stem cells (hUCMSCs) are recognized as candidate progenitor cells for bone regeneration. However, the mechanism of hUCMSC osteogenesis remains unclear. In this study, we revealed that mitogen-activated protein kinases (MAPKs) signaling is involved in hUCMSC osteogenic differentiation in vitro. Particularly, the activation of c-Jun N-terminal kinases (JNK) and p38 signaling pathways maintained a consistent level in hUCMSCs through the entire 21-day osteogenic differentiation period. At the same time, the activation of extracellular signal-regulated kinases (ERK) signaling significantly increased from day 5, peaked at day 9, and declined thereafter. Moreover, gene profiling of osteogenic markers, alkaline phosphatase (ALP) activity measurement, and alizarin red staining demonstrated that the application of U0126, a specific inhibitor for ERK activation, completely prohibited hUCMSC osteogenic differentiation. However, when U0126 was removed from the culture at day 9, ERK activation and osteogenic differentiation of hUCMSCs were partially recovered. Together, these findings demonstrate that the activation of ERK signaling is essential for hUCMSC osteogenic differentiation, which points out the significance of ERK signaling pathway to regulate the osteogenic differentiation of hUCMSCs as an alternative cell source for bone tissue engineering. PMID:26989682

  1. Novel robust biomarkers for human bladder cancer based on activation of intracellular signaling pathways

    PubMed Central

    Lezhnina, Ksenia; Kovalchuk, Olga; Zhavoronkov, Alexander A.; Korzinkin, Mikhail B.; Zabolotneva, Anastasia A.; Shegay, Peter V.; Sokov, Dmitry G.; Gaifullin, Nurshat M.; Rusakov, Igor G.; Aliper, Alexander M.; Roumiantsev, Sergey A.; Alekseev, Boris Y.; Borisov, Nikolay M.; Buzdin, Anton A.

    2014-01-01

    We recently proposed a new bioinformatic algorithm called OncoFinder for quantifying the activation of intracellular signaling pathways. It was proved advantageous for minimizing errors of high-throughput gene expression analyses and showed strong potential for identifying new biomarkers. Here, for the first time, we applied OncoFinder for normal and cancerous tissues of the human bladder to identify biomarkers of bladder cancer. Using Illumina HT12v4 microarrays, we profiled gene expression in 17 cancer and seven non-cancerous bladder tissue samples. These experiments were done in two independent laboratories located in Russia and Canada. We calculated pathway activation strength values for the investigated transcriptomes and identified signaling pathways that were regulated differently in bladder cancer (BC) tissues compared with normal controls. We found, for both experimental datasets, 44 signaling pathways that serve as excellent new biomarkers of BC, supported by high area under the curve (AUC) values. We conclude that the OncoFinder approach is highly efficient in finding new biomarkers for cancer. These markers are mathematical functions involving multiple gene products, which distinguishes them from “traditional” expression biomarkers that only assess concentrations of single genes. PMID:25296972

  2. Activated WNT signaling in postnatal SOX2-positive dental stem cells can drive odontoma formation

    PubMed Central

    Xavier, Guilherme M.; Patist, Amanda L.; Healy, Chris; Pagrut, Ankita; Carreno, Gabriela; Sharpe, Paul T.; Pedro Martinez-Barbera, Juan; Thavaraj, Selvam; Cobourne, Martyn T.; Andoniadou, Cynthia L.

    2015-01-01

    In common with most mammals, humans form only two dentitions during their lifetime. Occasionally, supernumerary teeth develop in addition to the normal complement. Odontoma represent a small group of malformations containing calcified dental tissues of both epithelial and mesenchymal origin, with varying levels of organization, including tooth-like structures. The specific cell type responsible for the induction of odontoma, which retains the capacity to re-initiate de novo tooth development in postnatal tissues, is not known. Here we demonstrate that aberrant activation of WNT signaling by expression of a non-degradable form of β-catenin specifically in SOX2-positive postnatal dental epithelial stem cells is sufficient to generate odontoma containing multiple tooth-like structures complete with all dental tissue layers. Genetic lineage-tracing confirms that odontoma form in a similar manner to normal teeth, derived from both the mutation-sustaining epithelial stem cells and adjacent mesenchymal tissues. Activation of the WNT pathway in embryonic SOX2-positive progenitors results in ectopic expression of secreted signals that promote odontogenesis throughout the oral cavity. Significantly, the inductive potential of epithelial dental stem cells is retained in postnatal tissues, and up-regulation of WNT signaling specifically in these cells is sufficient to promote generation and growth of ectopic malformations faithfully resembling human odontoma. PMID:26411543

  3. Activated WNT signaling in postnatal SOX2-positive dental stem cells can drive odontoma formation.

    PubMed

    Xavier, Guilherme M; Patist, Amanda L; Healy, Chris; Pagrut, Ankita; Carreno, Gabriela; Sharpe, Paul T; Martinez-Barbera, Juan Pedro; Thavaraj, Selvam; Cobourne, Martyn T; Andoniadou, Cynthia L

    2015-01-01

    In common with most mammals, humans form only two dentitions during their lifetime. Occasionally, supernumerary teeth develop in addition to the normal complement. Odontoma represent a small group of malformations containing calcified dental tissues of both epithelial and mesenchymal origin, with varying levels of organization, including tooth-like structures. The specific cell type responsible for the induction of odontoma, which retains the capacity to re-initiate de novo tooth development in postnatal tissues, is not known. Here we demonstrate that aberrant activation of WNT signaling by expression of a non-degradable form of β-catenin specifically in SOX2-positive postnatal dental epithelial stem cells is sufficient to generate odontoma containing multiple tooth-like structures complete with all dental tissue layers. Genetic lineage-tracing confirms that odontoma form in a similar manner to normal teeth, derived from both the mutation-sustaining epithelial stem cells and adjacent mesenchymal tissues. Activation of the WNT pathway in embryonic SOX2-positive progenitors results in ectopic expression of secreted signals that promote odontogenesis throughout the oral cavity. Significantly, the inductive potential of epithelial dental stem cells is retained in postnatal tissues, and up-regulation of WNT signaling specifically in these cells is sufficient to promote generation and growth of ectopic malformations faithfully resembling human odontoma. PMID:26411543

  4. Mechanisms for multiple activity modes of VTA dopamine neurons

    PubMed Central

    Oster, Andrew; Faure, Philippe; Gutkin, Boris S.

    2015-01-01

    Midbrain ventral segmental area (VTA) dopaminergic neurons send numerous projections to cortical and sub-cortical areas, and diffusely release dopamine (DA) to their targets. DA neurons display a range of activity modes that vary in frequency and degree of burst firing. Importantly, DA neuronal bursting is associated with a significantly greater degree of DA release than an equivalent tonic activity pattern. Here, we introduce a single compartmental, conductance-based computational model for DA cell activity that captures the behavior of DA neuronal dynamics and examine the multiple factors that underlie DA firing modes: the strength of the SK conductance, the amount of drive, and GABA inhibition. Our results suggest that neurons with low SK conductance fire in a fast firing mode, are correlated with burst firing, and require higher levels of applied current before undergoing depolarization block. We go on to consider the role of GABAergic inhibition on an ensemble of dynamical classes of DA neurons and find that strong GABA inhibition suppresses burst firing. Our studies suggest differences in the distribution of the SK conductance and GABA inhibition levels may indicate subclasses of DA neurons within the VTA. We further identify, that by considering alternate potassium dynamics, the dynamics display burst patterns that terminate via depolarization block, akin to those observed in vivo in VTA DA neurons and in substantia nigra pars compacta (SNc) DA cell preparations under apamin application. In addition, we consider the generation of transient burst firing events that are NMDA-initiated or elicited by a sudden decrease of GABA inhibition, that is, disinhibition. PMID:26283955

  5. Statistics of cellular signal transduction as a race to the nucleus by multiple random walkers in compartment/phosphorylation space

    PubMed Central

    Lu, Ting; Shen, Tongye; Zong, Chenghang; Hasty, Jeff; Wolynes, Peter G.

    2006-01-01

    Cellular signal transduction often involves a reaction network of phosphorylation and transport events arranged with a ladder topology. If we keep track of the location of the phosphate groups describing an abstract state space, a simple model of signal transduction involving enzymes can be mapped on to a problem of how multiple biased random walkers compete to reach their target in the nucleus yielding a signal. Here, the first passage time probability and the survival probability for multiple walkers can be used to characterize the response of the network. The statistics of the first passage through the network has an asymmetric distribution with a long tail arising from the hierarchical structure of the network. This distribution implies a significant difference between the mean and the most probable signal transduction time. The response patterns for various external inputs generated by our model agree with recent experiments. In addition, the model predicts that there is an optimal phosphorylation enzyme concentration for rapid signal transduction. PMID:17071742

  6. Multiple feature extraction and classification of electroencephalograph signal for Alzheimers' with spectrum and bispectrum

    NASA Astrophysics Data System (ADS)

    Wang, Ruofan; Wang, Jiang; Li, Shunan; Yu, Haitao; Deng, Bin; Wei, Xile

    2015-01-01

    In this paper, we have combined experimental neurophysiologic recording and statistical analysis to investigate the nonlinear characteristic and the cognitive function of the brain. Spectrum and bispectrum analyses are proposed to extract multiple effective features of electroencephalograph (EEG) signals from Alzheimer's disease (AD) patients and further applied to distinguish AD patients from the normal controls. Spectral analysis based on autoregressive Burg method is first used to quantify the power distribution of EEG series in the frequency domain. Compared to the control group, the relative power spectral density of AD group is significantly higher in the theta frequency band, while lower in the alpha frequency bands. In addition, median frequency of spectrum is decreased, and spectral entropy ratio of these two frequency bands undergoes drastic changes at the P3 electrode in the central-parietal brain region, implying that the electrophysiological behavior in AD brain is much slower and less irregular. In order to explore the nonlinear high order information, bispectral analysis which measures the complexity of phase-coupling is further applied to P3 electrode in the whole frequency band. It is demonstrated that less bispectral peaks appear and the amplitudes of peaks fall, suggesting a decrease of non-Gaussianity and nonlinearity of EEG in ADs. Notably, the application of this method to five brain regions shows higher concentration of the weighted center of bispectrum and lower complexity reflecting phase-coupling by bispectral entropy. Based on spectrum and bispectrum analyses, six efficient features are extracted and then applied to discriminate AD from the normal in the five brain regions. The classification results indicate that all these features could differentiate AD patients from the normal controls with a maximum accuracy of 90.2%. Particularly, different brain regions are sensitive to different features. Moreover, the optimal combination of

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

    PubMed

    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

  8. BAY 11-7082 Is a Broad-Spectrum Inhibitor with Anti-Inflammatory Activity against Multiple Targets

    PubMed Central

    Lee, Jaehwi; Rhee, Man Hee; Kim, Eunji; Cho, Jae Youl

    2012-01-01

    BAY 11-7082 (BAY) is an inhibitor of κB kinase (IKK) that has pharmacological activities that include anticancer, neuroprotective, and anti-inflammatory effects. In this study, BAY-pharmacological target pathways were further characterized to determine how this compound simultaneously suppresses various responses. Primary and cancerous (RAW264.7 cells) macrophages were activated by lipopolysaccharide, a ligand of toll-like receptor 4. As reported previously, BAY strongly suppressed the production of nitric oxide, prostaglandin E2, and tumor necrosis factor-α and reduced the translocation of p65, major subunit of nuclear factor-κB, and its upstream signaling events such as phosphorylation of IκBα, IKK, and Akt. In addition, BAY also suppressed the translocation and activation of activator protein-1, interferon regulatory factor-3, and signal transducer and activator of transcription-1 by inhibiting the phosphorylation or activation of extracellular signal-related kinase, p38, TANK-binding protein, and Janus kinase-2. These data strongly suggest that BAY is an inhibitor with multiple targets and could serve as a lead compound in developing strong anti-inflammatory drugs with multiple targets in inflammatory responses. PMID:22745523

  9. Regulators of G-protein signaling accelerate GPCR signaling kinetics and govern sensitivity solely by accelerating GTPase activity.

    PubMed

    Lambert, Nevin A; Johnston, Christopher A; Cappell, Steven D; Kuravi, Sudhakiranmayi; Kimple, Adam J; Willard, Francis S; Siderovski, David P

    2010-04-13

    G-protein heterotrimers, composed of a guanine nucleotide-binding G alpha subunit and an obligate G betagamma dimer, regulate signal transduction pathways by cycling between GDP- and GTP-bound states. Signal deactivation is achieved by G alpha-mediated GTP hydrolysis (GTPase activity) which is enhanced by the GTPase-accelerating protein (GAP) activity of "regulator of G-protein signaling" (RGS) proteins. In a cellular context, RGS proteins have also been shown to speed up the onset of signaling, and to accelerate deactivation without changing amplitude or sensitivity of the signal. This latter paradoxical activity has been variably attributed to GAP/enzymatic or non-GAP/scaffolding functions of these proteins. Here, we validated and exploited a G alpha switch-region point mutation, known to engender increased GTPase activity, to mimic in cis the GAP function of RGS proteins. While the transition-state, GDP x AlF(4)(-)-bound conformation of the G202A mutant was found to be nearly identical to wild-type, G alpha(i1)(G202A) x GDP assumed a divergent conformation more closely resembling the GDP x AlF(4)(-)-bound state. When placed within Saccharomyces cerevisiae G alpha subunit Gpa1, the fast-hydrolysis mutation restored appropriate dose-response behaviors to pheromone signaling in the absence of RGS-mediated GAP activity. A bioluminescence resonance energy transfer (BRET) readout of heterotrimer activation with high temporal resolution revealed that fast intrinsic GTPase activity could recapitulate in cis the kinetic sharpening (increased onset and deactivation rates) and blunting of sensitivity also engendered by RGS protein action in trans. Thus G alpha-directed GAP activity, the first biochemical function ascribed to RGS proteins, is sufficient to explain the activation kinetics and agonist sensitivity observed from G-protein-coupled receptor (GPCR) signaling in a cellular context. PMID:20351284

  10. Wnt5a can both activate and repress Wnt/β-catenin signaling during mouse embryonic development

    PubMed Central

    van Amerongen, Renée; Fuerer, Christophe; Mizutani, Makiko; Nusse, Roel

    2012-01-01

    Embryonic development is controlled by a small set of signal transduction pathways, with vastly different phenotypic outcomes depending on the time and place of their recruitment. How the same molecular machinery can elicit such specific and distinct responses, remains one of the outstanding questions in developmental biology. Part of the answer may lie in the high inherent genetic complexity of these signaling cascades, as observed for the Wnt-pathway. The mammalian genome encodes multiple Wnt proteins and receptors, each of which show dynamic and tightly controlled expression patterns in the embryo. Yet how these components interact in the context of the whole organism remains unknown. Here we report the generation of a novel, inducible transgenic mouse model that allows spatiotemporal control over the expression of Wnt5a, a protein implicated in many developmental processes and multiple Wnt-signaling responses. We show that ectopic Wnt5a expression from E10.5 onwards results in a variety of developmental defects, including loss of hair follicles and reduced bone formation in the skull. Moreover, we find that Wnt5a can have dual signaling activities during mouse embryonic development. Specifically, Wnt5a is capable of both inducing and repressing β-catenin/TCF signaling in vivo, depending on the time and site of expression and the receptors expressed by receiving cells. These experiments show for the first time that a single mammalian Wnt protein can have multiple signaling activities in vivo, thereby furthering our understanding of how signaling specificity is achieved in a complex developmental context. PMID:22771246

  11. Key gravity-sensitive signaling pathways drive T cell activation.

    PubMed

    Boonyaratanakornkit, J B; Cogoli, A; Li, C-F; Schopper, T; Pippia, P; Galleri, G; Meloni, M A; Hughes-Fulford, M

    2005-12-01

    Returning astronauts have experienced altered immune function and increased vulnerability to infection during spaceflights dating back to Apollo and Skylab. Lack of immune response in microgravity occurs at the cellular level. We analyzed differential gene expression to find gravity-dependent genes and pathways. We found inhibited induction of 91 genes in the simulated freefall environment of the random positioning machine. Altered induction of 10 genes regulated by key signaling pathways was verified using real-time RT-PCR. We discovered that impaired induction of early genes regulated primarily by transcription factors NF-kappaB, CREB, ELK, AP-1, and STAT after crosslinking the T-cell receptor contributes to T-cell dysfunction in altered gravity environments. We have previously shown that PKA and PKC are key early regulators in T-cell activation. Since the majority of the genes were regulated by NF-kappaB, CREB, and AP-1, we studied the pathways that regulated these transcription factors. We found that the PKA pathway was down-regulated in vg. In contrast, PI3-K, PKC, and its upstream regulator pLAT were not significantly down-regulated by vectorless gravity. Since NF-kappaB, AP-1, and CREB are all regulated by PKA and are transcription factors predicted by microarray analysis to be involved in the altered gene expression in vectorless gravity, the data suggest that PKA is a key player in the loss of T-cell activation in altered gravity. PMID:16210397

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

    PubMed

    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

  13. The Satiety Signaling Neuropeptide Perisulfakinin Inhibits the Activity of Central Neurons Promoting General Activity

    PubMed Central

    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 (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. PMID:18946521

  14. Deriving stellar inclination of slow rotators using stellar activity signal

    NASA Astrophysics Data System (ADS)

    Dumusque, Xavier

    2015-01-01

    Stellar inclination is an important parameter for many astrophysical studies. In the context of exoplanets, this allows us to derive the true obliquity of a system if the projected stellar spin-planetary orbit angle can measured via the Rossiter-Mclaughlin effect. Although different techniques allow us to estimate stellar inclination for fast rotators, it becomes much more difficult when stars are rotating slower than 2-2.5 km.s-1. By using the new activity simulation SOAP 2.0 that can reproduce the photometric and spectroscopic variations induced by stellar activity, we are able to fit the activity variation of solar-type stars and derive their inclination. The case of the equator-on star HD189733 will be presented, as well as the case of Alpha Centauri B, which present an inclination of 45+9-19 degrees, implying that the earth-mass orbiting planet is not transiting if aligned with its host star. Other exemples will also demonstrate the power of the technique, that can infer a stellar inclination, even for slow rotators like Alpha Centauri B, that present a projected rotational velocity smaller than 1.15 km.s-1. In addition, the SOAP 2.0 simulation can be used to correct for the effect of activity when one major active region is dominating the RV signal. This could enhance the detection of small mass exoplanets orbiting slightly active stars.This project is funded by ETAEARTH (European Union Seventh Framework Programme (FP7/2007-2013) under Grant Agreement n. 313014), a transnational collaboration between European countries and the US (the Swiss Space Office, the Harvard Origin of Life Initiative, the Scottish Universities Physics Alliance, the University of Geneva, the Smithsonian Astrophysical Observatory, the Italian National Astrophysical Institute, the University of St. Andrews, Queens University Belfast, and the University of Edinburgh) setup to optimize the synergy between space-and ground-based data whose scientific potential for the characterization of

  15. 3D Actin Network Centerline Extraction with Multiple Active Contours

    PubMed Central

    Xu, Ting; Vavylonis, Dimitrios; Huang, Xiaolei

    2013-01-01

    Fluorescence microscopy is frequently used to study two and three dimensional network structures formed by cytoskeletal polymer fibers such as actin filaments and actin cables. While these cytoskeletal structures are often dilute enough to allow imaging of individual filaments or bundles of them, quantitative analysis of these images is challenging. To facilitate quantitative, reproducible and objective analysis of the image data, we propose a semi-automated method to extract actin networks and retrieve their topology in 3D. Our method uses multiple Stretching Open Active Contours (SOACs) that are automatically initialized at image intensity ridges and then evolve along the centerlines of filaments in the network. SOACs can merge, stop at junctions, and reconfigure with others to allow smooth crossing at junctions of filaments. The proposed approach is generally applicable to images of curvilinear networks with low SNR. We demonstrate its potential by extracting the centerlines of synthetic meshwork images, actin networks in 2D Total Internal Reflection Fluorescence Microscopy images, and 3D actin cable meshworks of live fission yeast cells imaged by spinning disk confocal microscopy. Quantitative evaluation of the method using synthetic images shows that for images with SNR above 5.0, the average vertex error measured by the distance between our result and ground truth is 1 voxel, and the average Hausdorff distance is below 10 voxels. PMID:24316442

  16. Circulating polymerase chain reaction chips utilizing multiple-membrane activation

    NASA Astrophysics Data System (ADS)

    Wang, Chih-Hao; Chen, Yi-Yu; Liao, Chia-Sheng; Hsieh, Tsung-Min; Luo, Ching-Hsing; Wu, Jiunn-Jong; Lee, Huei-Huang; Lee, Gwo-Bin

    2007-02-01

    This paper reports a new micromachined, circulating, polymerase chain reaction (PCR) chip for nucleic acid amplification. The PCR chip is comprised of a microthermal control module and a polydimethylsiloxane (PDMS)-based microfluidic control module. The microthermal control modules are formed with three individual heating and temperature-sensing sections, each modulating a specific set temperature for denaturation, annealing and extension processes, respectively. Micro-pneumatic valves and multiple-membrane activations are used to form the microfluidic control module to transport sample fluids through three reaction regions. Compared with other PCR chips, the new chip is more compact in size, requires less time for heating and cooling processes, and has the capability to randomly adjust time ratios and cycle numbers depending on the PCR process. Experimental results showed that detection genes for two pathogens, Streptococcus pyogenes (S. pyogenes, 777 bps) and Streptococcus pneumoniae (S. pneumoniae, 273 bps), can be successfully amplified using the new circulating PCR chip. The minimum number of thermal cycles to amplify the DNA-based S. pyogenes for slab gel electrophoresis is 20 cycles with an initial concentration of 42.5 pg µl-1. Experimental data also revealed that a high reproducibility up to 98% could be achieved if the initial template concentration of the S. pyogenes was higher than 4 pg µl-1. The preliminary results of the current paper were presented at the 19th IEEE International Conference on Micro Electro Mechanical Systems (IEEE MEMS 2006), Istanbul, Turkey, 22-26 January, 2006.

  17. 3D Filament Network Segmentation with Multiple Active Contours

    NASA Astrophysics Data System (ADS)

    Xu, Ting; Vavylonis, Dimitrios; Huang, Xiaolei

    2014-03-01

    Fluorescence microscopy is frequently used to study two and three dimensional network structures formed by cytoskeletal polymer fibers such as actin filaments and microtubules. While these cytoskeletal structures are often dilute enough to allow imaging of individual filaments or bundles of them, quantitative analysis of these images is challenging. To facilitate quantitative, reproducible and objective analysis of the image data, we developed a semi-automated method to extract actin networks and retrieve their topology in 3D. Our method uses multiple Stretching Open Active Contours (SOACs) that are automatically initialized at image intensity ridges and then evolve along the centerlines of filaments in the network. SOACs can merge, stop at junctions, and reconfigure with others to allow smooth crossing at junctions of filaments. The proposed approach is generally applicable to images of curvilinear networks with low SNR. We demonstrate its potential by extracting the centerlines of synthetic meshwork images, actin networks in 2D TIRF Microscopy images, and 3D actin cable meshworks of live fission yeast cells imaged by spinning disk confocal microscopy.

  18. Hypoxia promotes drug resistance in osteosarcoma cells via activating AMP-activated protein kinase (AMPK) signaling

    PubMed Central

    Zhao, Changfu; Zhang, Qiao; Yu, Tao; Sun, Shudong; Wang, Wenjun; Liu, Guangyao

    2016-01-01

    Purpose Drug resistance has been recognized to be a major obstacle to the chemotherapy for osteosarcoma. And the potential importance of hypoxia as a target to reverse drug resistance in osteosarcoma has been indicated, though the mechanism underlining such role is not clarified. The present study aims to investigate the role of hypoxia in the drug resistance in osteosarcoma cells via activating AMP-activated protein kinase (AMPK) signaling. Experimental design We investigated the promotion of the resistance to doxorubicin of osteosarcoma MG-63 and U2-os cells in vitro, and then determined the role of hypoxia-inducible factor-1 (HIF-1)α and HIF-1β, the activation and regulatory role of AMPK in the osteosarcoma U2-os cells which were treated with doxorubicin under hypoxia. Results It was demonstrated that hypoxia significantly reduced the sensitivity of MG-63 and U2-os cells to doxorubicin, indicating an inhibited viability reduction and a reduced apoptosis promotion. And such reduced sensitivity was not associated with HIF-1α, though it was promoted by hypoxia in U2-os cells. Interestingly, the AMPK signaling was significantly promoted by hypoxia in the doxorubicin-treated U2-os cells, with a marked upregulation of phosphorylated AMPK (Thr 172) and phosphorylated acetyl-CoA carboxylase (ACC) (Ser 79), which were sensitive to the AMPK activator, AICAR and the AMPK inhibitor, Compound C. Moreover, the promoted AMPK activity by AICAR or the downregulated AMPK activity by Compound C significantly reduced or promoted the sensitivity of U2-os cells to doxorubicin. Conclusion The present study confirmed the AMPK signaling activation in the doxorubicin-treated osteosarcoma cells, in response to hypoxia, and the chemical upregulation or downregulation of AMPK signaling reduced or increased the chemo-sensitivity of osteosarcoma U2-os cells in vitro. Our study implies that AMPK inhibition might be a effective strategy to sensitize osteocarcoma cells to chemotherapy. PMID

  19. GABA signalling modulates plant growth by directly regulating the activity of plant-specific anion transporters

    PubMed Central

    Ramesh, Sunita A.; Tyerman, Stephen D.; Xu, Bo; Bose, Jayakumar; Kaur, Satwinder; Conn, Vanessa; Domingos, Patricia; Ullah, Sana; Wege, Stefanie; Shabala, Sergey; Feijó, José A.; Ryan, Peter R.; Gillham, Matthew

    2015-01-01

    The non-protein amino acid, gamma-aminobutyric acid (GABA) rapidly accumulates in plant tissues in response to biotic and abiotic stress, and regulates plant growth. Until now it was not known whether GABA exerts its effects in plants through the regulation of carbon metabolism or via an unidentified signalling pathway. Here, we demonstrate that anion flux through plant aluminium-activated malate transporter (ALMT) proteins is activated by anions and negatively regulated by GABA. Site-directed mutagenesis of selected amino acids within ALMT proteins abolishes GABA efficacy but does not alter other transport properties. GABA modulation of ALMT activity results in altered root growth and altered root tolerance to alkaline pH, acid pH and aluminium ions. We propose that GABA exerts its multiple physiological effects in plants via ALMT, including the regulation of pollen tube and root growth, and that GABA can finally be considered a legitimate signalling molecule in both the plant and animal kingdoms. PMID:26219411

  20. Allosteric modulation of metabotropic glutamate receptor 4 activates IDO1-dependent, immunoregulatory signaling in dendritic cells

    PubMed Central

    Volpi, Claudia; Mondanelli, Giada; Pallotta, Maria T.; Vacca, Carmine; Iacono, Alberta; Gargaro, Marco; Albini, Elisa; Bianchi, Roberta; Belladonna, Maria L.; Celanire, Sylvain; Mordant, Céline; Heroux, Madeleine; Royer-Urios, Isabelle; Schneider, Manfred; Vitte, Pierre-Alain; Cacquevel, Mathias; Galibert, Laurent; Poli, Sonia-Maria; Solari, Aldo; Bicciato, Silvio; Calvitti, Mario; Antognelli, Cinzia; Puccetti, Paolo; Orabona, Ciriana; Fallarino, Francesca; Grohmann, Ursula

    2016-01-01

    Metabotropic glutamate receptor 4 (mGluR4) possesses immune modulatory properties in vivo, such that a positive allosteric modulator (PAM) of the receptor confers protection on mice with relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE). ADX88178 is a newly-developed, one such mGluR4 modulator with high selectivity, potency, and optimized pharmacokinetics. Here we found that application of ADX88178 in the RR-EAE model system converted disease into a form of mild—yet chronic—neuroinflammation that remained stable for over two months after discontinuing drug treatment. In vitro, ADX88178 modulated the cytokine secretion profile of dendritic cells (DCs), increasing production of tolerogenic IL-10 and TGF-β. The in vitro effects required activation of a Gi-independent, alternative signaling pathway that involved phosphatidylinositol-3-kinase (PI3K), Src kinase, and the signaling activity of indoleamine 2,3-dioxygenase 1 (IDO1). A PI3K inhibitor as well as small interfering RNA targeting Ido1—but not pertussis toxin, which affects Gi protein-dependent responses—abrogated the tolerogenic effects of ADX88178-conditioned DCs in vivo. Thus our data indicate that, in DCs, highly selective and potent mGluR4 PAMs such as ADX88178 may activate a Gi-independent, long-lived regulatory pathway that could be therapeutically exploited in chronic autoimmune diseases such as multiple sclerosis. PMID:26522434

  1. Global Transcription Profiling Reveals Multiple Sugar Signal Transduction Mechanisms in ArabidopsisW⃞

    PubMed Central

    Price, John; Laxmi, Ashverya; St. Martin, Steven K.; Jang, Jyan-Chyun

    2004-01-01

    Complex and interconnected signaling networks allow organisms to control cell division, growth, differentiation, or programmed cell death in response to metabolic and environmental cues. In plants, it is known that sugar and nitrogen are critical nutrient signals; however, our understanding of the molecular mechanisms underlying nutrient signal transduction is very limited. To begin unraveling complex sugar signaling networks in plants, DNA microarray analysis was used to determine the effects of glucose and inorganic nitrogen source on gene expression on a global scale in Arabidopsis thaliana. In whole seedling tissue, glucose is a more potent signal in regulating transcription than inorganic nitrogen. In fact, other than genes associated with nitrate assimilation, glucose had a greater effect in regulating nitrogen metabolic genes than nitrogen itself. Glucose also regulated a broader range of genes, including genes associated with carbohydrate metabolism, signal transduction, and metabolite transport. In addition, a large number of stress responsive genes were also induced by glucose, indicating a role of sugar in environmental responses. Cluster analysis revealed significant interaction between glucose and nitrogen in regulating gene expression because glucose can modulate the effects of nitrogen and vise versa. Intriguingly, cycloheximide treatment appeared to disrupt glucose induction more than glucose repression, suggesting that de novo protein synthesis is an intermediary event required before most glucose induction can occur. Cross talk between sugar and ethylene signaling may take place on the transcriptional level because several ethylene biosynthetic and signal transduction genes are repressed by glucose, and the repression is largely unaffected by cycloheximide. Collectively, our global expression data strongly support the idea that glucose and inorganic nitrogen act as both metabolites and signaling molecules. PMID:15273295

  2. Structural Insights into the Inhibition of Wnt Signaling by Cancer Antigen 5T4/Wnt-Activated Inhibitory Factor 1

    PubMed Central

    Zhao, Yuguang; Malinauskas, Tomas; Harlos, Karl; Jones, E. Yvonne

    2014-01-01

    Summary The tumor antigen 5T4/WAIF1 (Wnt-activated inhibitory factor 1; also known as Trophoblast glycoprotein TPBG) is a cell surface protein targeted in multiple cancer immunotherapy clinical trials. Recently, it has been shown that 5T4/WAIF1 inhibits Wnt/β-catenin signaling, a signaling system central to many developmental and pathological processes. Wnt/β-catenin signaling is controlled by multiple inhibitors and activators. Here, we report crystal structures for the extracellular domain of 5T4/WAIF1 at 1.8 Å resolution. They reveal a highly glycosylated, rigid core, comprising eight leucine-rich repeats (LRRs), which serves as a platform to present evolutionarily conserved surface residues in the N-terminal LRR1. Structural and cell-based analyses, coupled with previously reported in vivo data, suggest that Tyr325 plus the LRR1 surface centered on a second exposed aromatic residue, Phe97, are essential for inhibition of Wnt/β-catenin signaling. These results provide a structural basis for the development of 5T4/WAIF1-targeted therapies that preserve or block 5T4/WAIF1-mediated inhibition of Wnt/β-catenin signaling. PMID:24582434

  3. Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells.

    PubMed

    Hideshima, Teru; Ikeda, Hiroshi; Chauhan, Dharminder; Okawa, Yutaka; Raje, Noopur; Podar, Klaus; Mitsiades, Constantine; Munshi, Nikhil C; Richardson, Paul G; Carrasco, Ruben D; Anderson, Kenneth C

    2009-07-30

    Bortezomib is a proteasome inhibitor with remarkable preclinical and clinical antitumor activity in multiple myeloma (MM) patients. The initial rationale for its use in MM was inhibition of nuclear factor (NF)-kappaB activity by blocking proteasomal degradation of inhibitor of kappaBalpha (IkappaBalpha). Bortezomib inhibits inducible NF-kappaB activity; however, its impact on constitutive NF-kappaB activity in MM cells has not yet been defined. In this study, we demonstrate that bortezomib significantly down-regulated IkappaBalpha expression and triggered NF-kappaB activation in MM cell lines and primary tumor cells from MM patients. Importantly, no inhibition of p65 (RelA) nuclear translocation was recognized after bortezomib treatment in a murine xenograft model bearing human MM cells. Bortezomib-induced NF-kappaB activation was mediated via the canonical pathway. Moreover, other classes of proteasome inhibitors also induced IkappaBalpha down-regulation associated with NF-kappaB activation. Molecular mechanisms whereby bortezomib induced IkappaBalpha down-regulation were further examined. Bortezomib triggered phosphorylation of IkappaB kinase (IKKbeta) and its upstream receptor-interacting protein 2, whereas IKKbeta inhibitor MLN120B blocked bortezomib-induced IkappaBalpha down-regulation and NF-kappaB activation, indicating receptor-interacting protein 2/IKKbeta signaling plays crucial role in bortezomib-induced NF-kappaB activation. Moreover, IKKbeta inhibitors enhanced bortezomib-induced cytotoxicity. Our studies therefore suggest that bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-kappaB activity in MM cells. PMID:19436050

  4. Active beam shaping in multiple laser guide stars

    NASA Astrophysics Data System (ADS)

    Jones, Katharine J.

    2012-10-01

    Adaptive beam shaping is a critical part of multiple Laser Guide Stars (LGS) for Multiple Conjugate Adaptive Optics (MCAO) for ground-based astronomical telescopes. There are two kinds of Laser Guide Stars: Na Laser Guide Stars (at 589 nm and 92 km altitude) and Rayleigh Laser Guide Stars (at 532 nm and 20 km altitude). Multiple Conjugate Adaptive Optics (MCAO) corrects for each "layer" of atmosphere independently. Multiple Laser Guide Stars are being developed to achieve a measure of tilt and increase the isoplanatic patch. Multiple Laser Guide Stars are being combined with Multiple Conjugate Optics in the Large Binocular Telescope (LBT): more than one Laser Guide Star (4-5) and two different wavelengths: 589 nm and 532 nm. Other observatories have multiple Laser Guide Stars but only one wavelength: 589 nm or 532 nm. Because Laser Guide Stars are launched into the atmosphere, adaptive beam shaping will be carried out before the laser is launched and will be different depending on which laser is being used, presumably to effect the tightest beam which can be achieved at the power level which is required to provide the requisite return to gound-based wavefront sensors. A complete range of devices are used. Beam attenuation and divergnece will take place. Multiple Laser Guide Stars of major observatories (SOR, LBT, MMT, ESO VLT and Gemini South) will be evaluated for effective adaptive beam shaping and impact on performance

  5. 14-3-3ζ Interacts with Stat3 and Regulates Its Constitutive Activation in Multiple Myeloma Cells

    PubMed Central

    Li, Wenliang; Xiong, Qian; Yang, Mingkun; Zheng, Peng; Li, Chongyang; Pei, Jianfeng; Ge, Feng

    2012-01-01

    The 14-3-3 proteins are a family of regulatory signaling molecules that interact with other proteins in a phosphorylation-dependent manner and function as adapter or scaffold proteins in signal transduction pathways. One family member, 14-3-3ζ, is believed to function in cell signaling, cycle control, and apoptotic death. A systematic proteomic analysis done in our laboratory has identified signal transducers and activators of transcription 3 (Stat3) as a novel 14-3-3ζ interacting protein. Following our initial finding, in this study, we provide evidence that 14-3-3ζ interacts physically with Stat3. We further demonstrate that phosphorylation of Stat3 at Ser727 is vital for 14-3-3ζ interaction and mutation of Ser727 to Alanine abolished 14-3-3ζ/Stat3 association. Inhibition of 14-3-3ζ protein expression in U266 cells inhibited Stat3 Ser727 phosphorylation and nuclear translocation, and decreased both Stat3 DNA binding and transcriptional activity. Moreover, 14-3-3ζ is involved in the regulation of protein kinase C (PKC) activity and 14-3-3ζ binding to Stat3 protects Ser727 dephosphorylation from protein phosphatase 2A (PP2A). Taken together, our findings support the model that multiple signaling events impinge on Stat3 and that 14-3-3ζ serves as an essential coordinator for different pathways to regulate Stat3 activation and function in MM cells. PMID:22279540

  6. A coherent digital demodulator for multiple signal formats and widely varying data rates

    NASA Technical Reports Server (NTRS)

    Mcguffin, Bruce F.

    1989-01-01

    The Tracking and Data Relay Satellite System (TDRSS) uses four ground station demodulators for K-band signals with data rates from 1 kb/s to 300 Mb/s. The author discusses the feasibility of replacing these demodulators with a single digital demodulator that may be reconfigured by altering stored parameters to accommodate all signal formats and data rates. This implementation will reduce total ground station cost and facilitate automation of ground station operation. Analysis of system performance concentrates on the carrier tracking loop. Analytic and simulation results relate system performance to parameter values and signal format as data rate and power vary independently on the In-phase and quadrature channels. It is demonstrated that a single digital demodulator can support TDRSS-compatible signals at data rates conservatively extending from 1K symbols/s to 10M symbols/s, using off-the-shelf hardware with 6 or more bits of accuracy.

  7. Unmasking local activity within local field potentials (LFPs) by removing distal electrical signals using independent component analysis

    PubMed Central

    Whitmore, Nathan W.; Lin, Shih-Chieh

    2016-01-01

    Local field potentials (LFPs) are commonly thought to reflect the aggregate dynamics in local neural circuits around recording electrodes. However, we show that when LFPs are recorded in awake behaving animals against a distal reference on the skull as commonly practiced, LFPs are significantly contaminated by non-local and non-neural sources arising from the reference electrode and from movement-related noise. In a data set with simultaneously recorded LFPs and electroencephalograms (EEGs) across multiple brain regions while rats perform an auditory oddball task, we used independent component analysis (ICA) to identify signals arising from electrical reference and from volume-conducted noise based on their distributed spatial pattern across multiple electrodes and distinct power spectral features. These sources of distal electrical signals collectively accounted for 23–77% of total variance in unprocessed LFPs, as well as most of the gamma oscillation responses to the target stimulus in EEGs. Gamma oscillation power was concentrated in volume-conducted noise and was tightly coupled with the onset of licking behavior, suggesting a likely origin of muscle activity associated with body movement or orofacial movement. The removal of distal signal contamination also selectively reduced correlations of LFP/EEG signals between distant brain regions but not within the same region. Finally, the removal of contamination from distal electrical signals preserved an event-related potential (ERP) response to auditory stimuli in the frontal cortex and also increased the coupling between the frontal ERP amplitude and neuronal activity in the basal forebrain, supporting the conclusion that removing distal electrical signals unmasked local activity within LFPs. Together, these results highlight the significant contamination of LFPs by distal electrical signals and caution against the straightforward interpretation of unprocessed LFPs. Our results provide a principled approach to

  8. Unmasking local activity within local field potentials (LFPs) by removing distal electrical signals using independent component analysis.

    PubMed

    Whitmore, Nathan W; Lin, Shih-Chieh

    2016-05-15

    Local field potentials (LFPs) are commonly thought to reflect the aggregate dynamics in local neural circuits around recording electrodes. However, we show that when LFPs are recorded in awake behaving animals against a distal reference on the skull as commonly practiced, LFPs are significantly contaminated by non-local and non-neural sources arising from the reference electrode and from movement-related noise. In a data set with simultaneously recorded LFPs and electroencephalograms (EEGs) across multiple brain regions while rats perform an auditory oddball task, we used independent component analysis (ICA) to identify signals arising from electrical reference and from volume-conducted noise based on their distributed spatial pattern across multiple electrodes and distinct power spectral features. These sources of distal electrical signals collectively accounted for 23-77% of total variance in unprocessed LFPs, as well as most of the gamma oscillation responses to the target stimulus in EEGs. Gamma oscillation power was concentrated in volume-conducted noise and was tightly coupled with the onset of licking behavior, suggesting a likely origin of muscle activity associated with body movement or orofacial movement. The removal of distal signal contamination also selectively reduced correlations of LFP/EEG signals between distant brain regions but not within the same region. Finally, the removal of contamination from distal electrical signals preserved an event-related potential (ERP) response to auditory stimuli in the frontal cortex and also increased the coupling between the frontal ERP amplitude and neuronal activity in the basal forebrain, supporting the conclusion that removing distal electrical signals unmasked local activity within LFPs. Together, these results highlight the significant contamination of LFPs by distal electrical signals and caution against the straightforward interpretation of unprocessed LFPs. Our results provide a principled approach to

  9. Multiple logistic regression model of signalling practices of drivers on urban highways

    NASA Astrophysics Data System (ADS)

    Puan, Othman Che; Ibrahim, Muttaka Na'iya; Zakaria, Rozana

    2015-05-01

    Giving signal is a way of informing other road users, especially to the conflicting drivers, the intention of a driver to change his/her movement course. Other users are exposed to hazard situation and risks of accident if the driver who changes his/her course failed to give signal as required. This paper describes the application of logistic regression model for the analysis of driver's signalling practices on multilane highways based on possible factors affecting driver's decision such as driver's gender, vehicle's type, vehicle's speed and traffic flow intensity. Data pertaining to the analysis of such factors were collected manually. More than 2000 drivers who have performed a lane changing manoeuvre while driving on two sections of multilane highways were observed. Finding from the study shows that relatively a large proportion of drivers failed to give any signals when changing lane. The result of the analysis indicates that although the proportion of the drivers who failed to provide signal prior to lane changing manoeuvre is high, the degree of compliances of the female drivers is better than the male drivers. A binary logistic model was developed to represent the probability of a driver to provide signal indication prior to lane changing manoeuvre. The model indicates that driver's gender, type of vehicle's driven, speed of vehicle and traffic volume influence the driver's decision to provide a signal indication prior to a lane changing manoeuvre on a multilane urban highway. In terms of types of vehicles driven, about 97% of motorcyclists failed to comply with the signal indication requirement. The proportion of non-compliance drivers under stable traffic flow conditions is much higher than when the flow is relatively heavy. This is consistent with the data which indicates a high degree of non-compliances when the average speed of the traffic stream is relatively high.

  10. Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells.

    PubMed

    Choi, Dongwon; Ramu, Swapnika; Park, Eunkyung; Jung, Eunson; Yang, Sara; Jung, Wonhyeuk; Choi, Inho; Lee, Sunju; Kim, Kyu Eui; Seong, Young Jin; Hong, Mingu; Daghlian, George; Kim, Daniel; Shin, Eugene; Seo, Jung In; Khatchadourian, Vicken; Zou, Mengchen; Li, Wei; De Filippo, Roger; Kokorowski, Paul; Chang, Andy; Kim, Steve; Bertoni, Ana; Furlanetto, Tania Weber; Shin, Sung; Li, Meng; Chen, Yibu; Wong, Alex; Koh, Chester; Geliebter, Jan; Hong, Young-Kwon

    2016-02-01

    Papillary thyroid cancer (PTC) is one of the most common endocrine malignancies associated with significant morbidity and mortality. Although multiple studies have contributed to a better understanding of the genetic alterations underlying this frequently arising disease, the downstream molecular effectors that impact PTC pathogenesis remain to be further defined. Here, we report that the regulator of cell fate specification, PROX1, becomes inactivated in PTC through mRNA downregulation and cytoplasmic mislocalization. Expression studies in clinical specimens revealed that aberrantly activated NOTCH signaling promoted PROX1 downregulation and that cytoplasmic mislocalization significantly altered PROX1 protein stability. Importantly, restoration of PROX1 activity in thyroid carcinoma cells revealed that PROX1 not only enhanced Wnt/β-catenin signaling but also regulated several genes known to be associated with PTC, including thyroid cancer protein (TC)-1, SERPINA1, and FABP4. Furthermore, PROX1 reexpression suppressed the malignant phenotypes of thyroid carcinoma cells, such as proliferation, motility, adhesion, invasion, anchorage-independent growth, and polyploidy. Moreover, animal xenograft studies demonstrated that restoration of PROX1 severely impeded tumor formation and suppressed the invasiveness and the nuclear/cytoplasmic ratio of PTC cells. Taken together, our findings demonstrate that NOTCH-induced PROX1 inactivation significantly promotes the malignant behavior of thyroid carcinoma and suggest that PROX1 reactivation may represent a potential therapeutic strategy to attenuate disease progression. PMID:26609053

  11. Perivascular innervation: A multiplicity of roles in vasomotor control and myoendothelial signaling

    PubMed Central

    Westcott, Erika B.; Segal, Steven S.

    2013-01-01

    The control of vascular resistance and tissue perfusion reflect coordinated changes in the diameter of feed arteries and the arteriolar networks they supply. Against a background of myogenic tone and metabolic demand, vasoactive signals originating from perivascular sympathetic and sensory nerves are integrated with endothelium-derived signals to produce vasodilation or vasoconstriction. PVNs release adrenergic, cholinergic, peptidergic, purinergic, and nitrergic neurotransmitters that lead to SMC contraction or relaxation via their actions on SMCs, ECs, or other PVNs. ECs release autacoids that can have opposing actions on SMCs. Respective cell layers are connected directly to each other through GJs at discrete sites via MEJs projecting through holes in the IEL. Whereas studies of intercellular communication in the vascular wall have centered on endothelium-derived signals that govern SMC relaxation, attention has increasingly focused on signaling from SMCs to ECs. Thus, via MEJs, neurotransmission from PVNs can evoke distinct responses from ECs subsequent to acting on SMCs. To integrate this emerging area of investigation in light of vasomotor control, the present review synthesizes current understanding of signaling events that originate within SMCs in response to perivascular neurotransmission in light of EC feedback. Though often ignored in studies of the resistance vasculature, PVNs are integral to blood flow control and can provide a physiological stimulus for myoendothelial communication. Greater understanding of these underlying signaling events and how they may be affected by aging and disease will provide new approaches for selective therapeutic interventions. PMID:23289720

  12. IFNAR signaling directly modulates T lymphocyte activity, resulting in milder experimental autoimmune encephalomyelitis development.

    PubMed

    Kavrochorianou, Nadia; Evangelidou, Maria; Markogiannaki, Melina; Tovey, Michael; Thyphronitis, George; Haralambous, Sylva

    2016-01-01

    Although interferon-β is used as first-line therapy for multiple sclerosis, the cell type-specific activity of type I interferons in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis, remains obscure. In this study, we have elucidated the in vivo immunomodulatory role of type I interferon signaling in T cells during experimental autoimmune encephalomyelitis by use of a novel transgenic mouse, carrying a cd2-ifnar1 transgene on a interferon-α/β receptor 1 null genetic background, thus allowing expression of the interferon-α/β receptor 1 and hence, a functional type I interferon receptor exclusively on T cells. These transgenic mice exhibited milder experimental autoimmune encephalomyelitis with reduced T cell infiltration, demyelination, and axonal damage in the central nervous system. It is noteworthy that interferon-β administration in transgenic mice generated a more pronounced, protective effect against experimental autoimmune encephalomyelitis compared with untreated littermates. In vivo studies demonstrated that before experimental autoimmune encephalomyelitis onset, endogenous type I interferon receptor signaling in T cells led to impaired T-helper 17 responses, with a reduced fraction of CCR6(+) CD4(+) T cells in the periphery. At the acute phase, an increased proportion of interleukin-10- and interferon-γ-producing CD4(+) T cells was detected in the periphery of the transgenic mice, accompanied by up-regulation of the interferon-γ-induced gene Irgm1 in peripheral T cells. Together, these results reveal a hitherto unknown T cell-associated protective role of type I interferon in experimental autoimmune encephalomyelitis that may provide valuable clues for designing novel therapeutic strategies for multiple sclerosis. PMID:26232452

  13. Cucurbitacin IIb exhibits anti-inflammatory activity through modulating multiple cellular behaviors of mouse lymphocytes.

    PubMed

    Wang, Yao; Zhao, Gao-Xiang; Xu, Li-Hui; Liu, Kun-Peng; Pan, Hao; He, Jian; Cai, Ji-Ye; Ouyang, Dong-Yun; He, Xian-Hui

    2014-01-01

    Cucurbitacin IIb (CuIIb) is one of the major active compounds in Hemsleyadine tablets which have been used for clinical treatment of bacillary dysentery, enteritis and acute tonsilitis. However, its action mechanism has not been completely understood. This study aimed to explore the anti-inflammatory activity of CuIIb and its underlying mechanism in mitogen-activated lymphocytes isolated from mouse mesenteric lymph nodes. The results showed that CuIIb inhibited the proliferation of concanavalin A (Con A)-activated lymphocytes in a time- and dose-dependent manner. CuIIb treatment arrested their cell cycle in S and G2/M phases probably due to the disruption of the actin cytoskeleton and the modulation of p27(Kip1) and cyclin levels. Moreover, the surface expression of activation markers CD69 and CD25 on Con A-activated CD3(+) T lymphocytes was suppressed by CuIIb treatment. Both Con A- and phorbol ester plus ionomycin-induced expression of TNF-α, IFN-γ and IL-6 proteins was attenuated upon exposure to CuIIb. Mechanistically, CuIIb treatment suppressed the phosphorylation of JNK and Erk1/2 but not p38 in Con A-activated lymphocytes. Although CuIIb unexpectedly enhanced the phosphorylation of IκB and NF-κB (p65), it blocked the nuclear translocation of NF-κB (p65). In support of this, CuIIb significantly decreased the mRNA levels of IκBα and TNF-α, two target genes of NF-κB, in Con A-activated lymphocytes. In addition, CuIIb downregulated Con A-induced STAT3 phosphorylation and increased cell apoptosis. Collectively, these results suggest that CuIIb exhibits its anti-inflammatory activity through modulating multiple cellular behaviors and signaling pathways, leading to the suppression of the adaptive immune response. PMID:24587010

  14. Cucurbitacin IIb Exhibits Anti-Inflammatory Activity through Modulating Multiple Cellular Behaviors of Mouse Lymphocytes

    PubMed Central

    Liu, Kun-Peng; Pan, Hao; He, Jian; Cai, Ji-Ye; Ouyang, Dong-Yun; He, Xian-Hui

    2014-01-01

    Cucurbitacin IIb (CuIIb) is one of the major active compounds in Hemsleyadine tablets which have been used for clinical treatment of bacillary dysentery, enteritis and acute tonsilitis. However, its action mechanism has not been completely understood. This study aimed to explore the anti-inflammatory activity of CuIIb and its underlying mechanism in mitogen-activated lymphocytes isolated from mouse mesenteric lymph nodes. The results showed that CuIIb inhibited the proliferation of concanavalin A (Con A)-activated lymphocytes in a time- and dose-dependent manner. CuIIb treatment arrested their cell cycle in S and G2/M phases probably due to the disruption of the actin cytoskeleton and the modulation of p27Kip1 and cyclin levels. Moreover, the surface expression of activation markers CD69 and CD25 on Con A-activated CD3+ T lymphocytes was suppressed by CuIIb treatment. Both Con A- and phorbol ester plus ionomycin-induced expression of TNF-α, IFN-γ and IL-6 proteins was attenuated upon exposure to CuIIb. Mechanistically, CuIIb treatment suppressed the phosphorylation of JNK and Erk1/2 but not p38 in Con A-activated lymphocytes. Although CuIIb unexpectedly enhanced the phosphorylation of IκB and NF-κB (p65), it blocked the nuclear translocation of NF-κB (p65). In support of this, CuIIb significantly decreased the mRNA levels of IκBα and TNF-α, two target genes of NF-κB, in Con A-activated lymphocytes. In addition, CuIIb downregulated Con A-induced STAT3 phosphorylation and increased cell apoptosis. Collectively, these results suggest that CuIIb exhibits its anti-inflammatory activity through modulating multiple cellular behaviors and signaling pathways, leading to the suppression of the adaptive immune response. PMID:24587010

  15. Signal Activation and Inactivation by the Gα Helical Domain: A Long-Neglected Partner in G Protein Signaling

    PubMed Central

    Dohlman, Henrik G.; Jones, Janice C.

    2013-01-01

    Heterotrimeric guanine nucleotide–binding proteins (G proteins) are positioned at the top of many signal transduction pathways. The G protein α subunit is composed of two domains, one that resembles Ras and another that is composed entirely of α helices. Historically, most attention has focused on the Ras-like domain, but emerging evidence reveals that the helical domain is an active participant in G protein signaling. PMID:22649098

  16. CD28 costimulatory signals in T lymphocyte activation: Emerging functions beyond a qualitative and quantitative support to TCR signalling.

    PubMed

    Porciello, Nicla; Tuosto, Loretta

    2016-04-01

    CD28 is one of the most important co-stimulatory receptors necessary for full T lymphocyte activation. By binding its cognate ligands, B7.1/CD80 or B7.2/CD86, expressed on the surface of professional antigen presenting cells (APC), CD28 initiates several signalling cascades, which qualitatively and quantitatively support T cell receptor (TCR) signalling. More recent data evidenced that human CD28 can also act as a TCR-independent signalling unit, by delivering specific signals, which regulate the expression of pro-inflammatory cytokine/chemokines. Despite the enormous progresses made in identifying the mechanisms and molecules involved in CD28 signalling properties, much remains to be elucidated, especially in the light of the functional differences observed between human and mouse CD28. In this review we provide an overview of the current mechanisms and molecules through which CD28 support TCR signalling and highlight recent findings on the specific signalling motifs that regulate the unique pro-inflammatory activity of human CD28. PMID:26970725

  17. Small Molecule APY606 Displays Extensive Antitumor Activity in Pancreatic Cancer via Impairing Ras-MAPK Signaling.

    PubMed

    Guo, Na; Liu, Zuojia; Zhao, Wenjing; Wang, Erkang; Wang, Jin

    2016-01-01

    Pancreatic cancer has been found with abnormal expression or mutation in Ras proteins. Oncogenic Ras activation exploits their extensive signaling reach to affect multiple cellular processes, in which the mitogen-activated protein kinase (MAPK) signaling exerts important roles in tumorigenesis. Therapies targeted Ras are thus of major benefit for pancreatic cancer. Although small molecule APY606 has been successfully picked out by virtual drug screening based on Ras target receptor, its in-depth mechanism remains to be elucidated. We herein assessed the antitumor activity of APY606 against human pancreatic cancer Capan-1 and SW1990 cell lines and explored the effect of Ras-MAPK and apoptosis-related signaling pathway on the activity of APY606. APY606 treatment resulted in a dose- and time-dependent inhibition of cancer cell viability. Additionally, APY606 exhibited strong antitumor activity, as evidenced not only by reduction in tumor cell invasion, migration and mitochondrial membrane potential but also by alteration in several apoptotic indexes. Furthermore, APY606 treatment directly inhibited Ras-GTP and the downstream activation of MAPK, which resulted in the down-regulation of anti-apoptotic protein Bcl-2, leading to the up-regulation of mitochondrial apoptosis pathway-related proteins (Bax, cytosolic Cytochrome c and Caspase 3) and of cyclin-dependent kinase 2 and Cyclin A, E. These data suggest that impairing Ras-MAPK signaling is a novel mechanism of action for APY606 during therapeutic intervention in pancreatic cancer. PMID:27223122

  18. Small Molecule APY606 Displays Extensive Antitumor Activity in Pancreatic Cancer via Impairing Ras-MAPK Signaling

    PubMed Central

    Guo, Na; Liu, Zuojia; Zhao, Wenjing; Wang, Erkang; Wang, Jin

    2016-01-01

    Pancreatic cancer has been found with abnormal expression or mutation in Ras proteins. Oncogenic Ras activation exploits their extensive signaling reach to affect multiple cellular processes, in which the mitogen-activated protein kinase (MAPK) signaling exerts important roles in tumorigenesis. Therapies targeted Ras are thus of major benefit for pancreatic cancer. Although small molecule APY606 has been successfully picked out by virtual drug screening based on Ras target receptor, its in-depth mechanism remains to be elucidated. We herein assessed the antitumor activity of APY606 against human pancreatic cancer Capan-1 and SW1990 cell lines and explored the effect of Ras-MAPK and apoptosis-related signaling pathway on the activity of APY606. APY606 treatment resulted in a dose- and time-dependent inhibition of cancer cell viability. Additionally, APY606 exhibited strong antitumor activity, as evidenced not only by reduction in tumor cell invasion, migration and mitochondrial membrane potential but also by alteration in several apoptotic indexes. Furthermore, APY606 treatment directly inhibited Ras-GTP and the downstream activation of MAPK, which resulted in the down-regulation of anti-apoptotic protein Bcl-2, leading to the up-regulation of mitochondrial apoptosis pathway-related proteins (Bax, cytosolic Cytochrome c and Caspase 3) and of cyclin-dependent kinase 2 and Cyclin A, E. These data suggest that impairing Ras-MAPK signaling is a novel mechanism of action for APY606 during therapeutic intervention in pancreatic cancer. PMID:27223122

  19. Application of the multiple signal classification (MUSIC) method for one-pulse burst-echo Doppler sonar data

    NASA Astrophysics Data System (ADS)

    Iwata, Tetsuo; Goto, Yoji; Susaki, Hironori

    2001-12-01

    In order to estimate ship velocity, we have applied the multiple signal classification (MUSIC) method to one-pulse burst-echo Doppler sonar data. The MUSIC method enabled us to estimate the Doppler frequency shift precisely under a low-signal-to-noise ratio (SNR) situation even from a one-pulse burst-echo signal with small data points. In simulation experiments, a signal frequency component of f = 16 Hz could be extracted from N = 128 data-point data under a 40% Gaussian-distributed additive noise with a sampling frequency fs = 2048 Hz. From actual one-pulse burst-echo signal data of N = 128 points, a Doppler frequency shift of Δf = 1.45 kHz, corresponding to a ship velocity 1.76 knots, was clearly detected, the frequency resolution of which was almost impossible to attain by the conventional Fourier transform (FFT) method. We found that the MUSIC method was useful especially for estimating the ship velocity at a very low speed.

  20. A parallel unbalanced digitization architecture to reduce the dynamic range of multiple signals

    NASA Astrophysics Data System (ADS)

    Vallérian, Mathieu; HuÅ£u, Florin; Villemaud, Guillaume; Miscopein, Benoît; Risset, Tanguy

    2016-05-01

    Technologies employed in urban sensor networks are permanently evolving, and thus the gateways employed to collect data in such kind of networks have to be very flexible in order to be compliant with the new communication standards. A convenient way to do that is to digitize all the received signals in one shot and then to digitally perform the signal processing, as it is done in software-defined radio (SDR). All signals can be emitted with very different features (bandwidth, modulation type, and power level) in order to respond to the various propagation conditions. Their difference in terms of power levels is a problem when digitizing them together, as no current commercial analog-to-digital converter (ADC) can provide a fine enough resolution to digitize this high dynamic range between the weakest possible signal in the presence of a stronger signal. This paper presents an RF front end receiver architecture capable of handling this problem by using two ADCs of lower resolutions. The architecture is validated through a set of simulations using Keysight's ADS software. The main validation criterion is the bit error rate comparison with a classical receiver.

  1. Akt1 signaling coordinates BMP signaling and β-catenin activity to regulate second heart field progenitor development.

    PubMed

    Luo, Wen; Zhao, Xia; Jin, Hengwei; Tao, Lichan; Zhu, Jingai; Wang, Huijuan; Hemmings, Brian A; Yang, Zhongzhou

    2015-02-15

    Second heart field (SHF) progenitors exhibit continued proliferation and delayed differentiation, which are modulated by FGF4/8/10, BMP and canonical Wnt/β-catenin signaling. PTEN-Akt signaling regulates the stem cell/progenitor cell homeostasis in several systems, such as hematopoietic stem cells, intestinal stem cells and neural progenitor cells. To address whether PTEN-Akt signaling is involved in regulating cardiac progenitors, we deleted Pten in SHF progenitors. Deletion of Pten caused SHF expansion and increased the size of the SHF derivatives, the right ventricle and the outflow tract. Cell proliferation of cardiac progenitors was enhanced, whereas cardiac differentiation was unaffected by Pten deletion. Removal of Akt1 rescued the phenotype and early lethality of Pten deletion mice, suggesting that Akt1 was the key downstream target that was negatively regulated by PTEN in cardiac progenitors. Furthermore, we found that inhibition of FOXO by Akt1 suppressed the expression of the gene encoding the BMP ligand (BMP7), leading to dampened BMP signaling in the hearts of Pten deletion mice. Cardiac activation of Akt also increased the Ser552 phosphorylation of β-catenin, thus enhancing its activity. Reducing β-catenin levels could partially rescue heart defects of Pten deletion mice. We conclude that Akt signaling regulates the cell proliferation of SHF progenitors through coordination of BMP signaling and β-catenin activity. PMID:25670795

  2. Activation of TLR3/interferon signaling pathway by bluetongue virus results in HIV inhibition in macrophages.

    PubMed

    Dai, Ming; Wang, Xu; Li, Jie-Liang; Zhou, Yu; Sang, Ming; Liu, Jin-Biao; Wu, Jian-Guo; Ho, Wen-Zhe

    2015-12-01

    Bluetongue virus (BTV), a nonenveloped double-stranded RNA virus, is a potent inducer of type Ι interferons in multiple cell systems. In this study, we report that BTV16 treatment of primary human macrophages induced both type I and III IFN expression, resulting in the production of multiple antiviral factors, including myxovirus resistance protein A, 2',5'-oligoadenylate synthetase, and the IFN-stimulated gene 56. Additionally, BTV-treated macrophages expressed increased HIV restriction factors (apolipoprotein B mRNA-editing enzyme catalytic polypeptide 3 G/F/H) and CC chemokines (macrophage inflammatory protein 1-α, macrophage inflammatory protein 1-β, regulated on activation of normal T cell expressed and secreted), the ligands for HIV entry coreceptor CC chemokine receptor type 5. BTV16 also induced the expression of tetherin, which restricts HIV release from infected cells. Furthermore, TLR3 signaling of macrophages by BTV16 resulted in the induction of several anti-HIV microRNAs (miRNA-28, -29a, -125b, -150, -223, and -382). More importantly, the induction of antiviral responses by BTV resulted in significant suppression of HIV in macrophages. These findings demonstrate the potential of BTV-mediated TLR3 activation in macrophage innate immunity against HIV. PMID:26296370

  3. Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

    PubMed Central

    Amin Al Olama, Ali; Dadaev, Tokhir; Hazelett, Dennis J.; Li, Qiuyan; Leongamornlert, Daniel; Saunders, Edward J.; Stephens, Sarah; Cieza-Borrella, Clara; Whitmore, Ian; Benlloch Garcia, Sara; Giles, Graham G.; Southey, Melissa C.; Fitzgerald, Liesel; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E.; Schumacher, Fredrick; Haiman, Christopher A.; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L.; Nordestgaard, Børge G.; Key, Tim J.; Travis, Ruth C.; Neal, David E.; Donovan, Jenny L.; Hamdy, Freddie C.; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L.; Thibodeau, Stephen N.; Mcdonnell, Shannon K.; Schaid, Daniel J.; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S.; Cybulski, Cezary; Wokołorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Brenner, Hermann; Butterbach, Katja; Arndt, Volker; Park, Jong Y.; Sellers, Thomas; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Clements, Judith A.; Spurdle, Amanda; Teixeira, Manuel R.; Paulo, Paula; Maia, Sofia; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej; Govindasami, Koveela; Guy, Michelle; Lophatonanon, Artitaya; Muir, Kenneth; Viñuela, Ana; Brown, Andrew A.; Freedman, Mathew; Conti, David V.; Easton, Douglas; Coetzee, Gerhard A.; Eeles, Rosalind A.; Kote-Jarai, Zsofia

    2015-01-01

    Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region. PMID:26025378

  4. Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans.

    PubMed

    Amin Al Olama, Ali; Dadaev, Tokhir; Hazelett, Dennis J; Li, Qiuyan; Leongamornlert, Daniel; Saunders, Edward J; Stephens, Sarah; Cieza-Borrella, Clara; Whitmore, Ian; Benlloch Garcia, Sara; Giles, Graham G; Southey, Melissa C; Fitzgerald, Liesel; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E; Schumacher, Fredrick; Haiman, Christopher A; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L; Nordestgaard, Børge G; Key, Tim J; Travis, Ruth C; Neal, David E; Donovan, Jenny L; Hamdy, Freddie C; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L; Thibodeau, Stephen N; Mcdonnell, Shannon K; Schaid, Daniel J; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S; Cybulski, Cezary; Wokołorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Brenner, Hermann; Butterbach, Katja; Arndt, Volker; Park, Jong Y; Sellers, Thomas; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Clements, Judith A; Spurdle, Amanda; Teixeira, Manuel R; Paulo, Paula; Maia, Sofia; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej; Govindasami, Koveela; Guy, Michelle; Lophatonanon, Artitaya; Muir, Kenneth; Viñuela, Ana; Brown, Andrew A; Freedman, Mathew; Conti, David V; Easton, Douglas; Coetzee, Gerhard A; Eeles, Rosalind A; Kote-Jarai, Zsofia

    2015-10-01

    Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same region. PMID:26025378

  5. Objective evaluation of speech signal quality by the prediction of multiple foreground diagnostic acceptability measure attributes.

    PubMed

    Sen, Deep; Lu, W

    2012-05-01

    A methodology is described to objectively diagnose the quality of speech signals by predicting the perceptual detectability of a selected set of distortions. The distortions are a statistically selected subset of the broad number of distortions used in diagnostic acceptability measure (DAM) testing. The justification for such a methodology is established from the analysis of a set of speech signals representing a broad set of distortions and their respective DAM scores. At the heart of the ability to isolate and diagnose the perceptibility of the individual distortions is a physiologically motivated cochlear model. The philosophy and methodology is thus distinct from traditional objective measures that are typically designed to predict mean opinion scores (MOS) using well versed functional psychoacoustic models. Even so, a weighted sum of these objectively predicted set of distortions is able to predict accurate and robust MOS scores, even when the reference speech signals have been subject to the Lombard effect. PMID:22559381

  6. Regulation of cellular signals from nutritional molecules: a specific role for phytochemicals, beyond antioxidant activity.

    PubMed

    Virgili, Fabio; Marino, Maria

    2008-11-01

    Phytochemicals (PhC) are a ubiquitous class of plant secondary metabolites. A "recommended" human diet should warrant a high proportion of energy from fruits and vegetables, therefore providing, among other factors, a huge intake of PhC, in general considered "health promoting" by virtue of their antioxidant activity and positive modulation, either directly or indirectly, of the cellular and tissue redox balance. Diet acts through multiple pathways and the association between the consumption of specific food items and the risk of degenerative diseases is extremely complex. Recent literature suggests that molecules having a chemical structure compatible with a putative antioxidant capacity can actually "perform" activities and roles independent of such capacity, interacting with cellular functions at different levels, such as affecting enzyme activities, binding to membrane or nuclear receptors as either an elective ligand or a ligand mimic. Inductive or signaling effects may occur at concentrations much lower than that required for effective antioxidant activity. Therefore, the "antioxidant hypothesis" is to be considered in some cases an intellectual "shortcut" possibly biasing the real understanding of the molecular mechanisms underlying the beneficial effects of various classes of food items. In the past few years, many exciting new indications elucidating the mechanisms of polyphenols have been published. Here, we summarize the current knowledge of the mechanisms by which specific molecules of nutritional interest, and in particular polyphenols, play a role in cellular response and in preventing pathologies. In particular, their direct interaction with nuclear receptors and their ability to modulate the activity of key enzymes involved in cell signaling and antioxidant responses are presented and discussed. PMID:18762244

  7. A sequential method for passive detection, characterization, and localization of multiple low probability of intercept LFMCW signals

    NASA Astrophysics Data System (ADS)

    Hamschin, Brandon M.

    A method for passive Detection, Characterization, and Localization (DCL) of multiple low power, Linear Frequency Modulated Continuous Wave (LFMCW) (i.e., Low Probability of Intercept (LPI)) signals is proposed. We demonstrate, via simulation, laboratory, and outdoor experiments, that the method is able to detect and correctly characterize the parameters that define two simultaneous LFMCW signals with probability greater than 90% when the signal to noise ratio is -10 dB or greater. While this performance is compelling, it is far from the Cramer-Rao Lower Bound (CRLB), which we derive, and the performance of the Maximum Likelihood Estimator (MLE), whose performance we simulate. The loss in performance relative to the CRLB and the MLE is the price paid for computational tractability. The LFMCW signal is the focus of this work because of its common use in modern, low-cost radar systems. In contrast to other detection and characterization approaches, such as the MLE and those based on the Wigner-Ville Transform (WVT) or the Wigner-Ville Hough Transform (WVHT), our approach does not begin with a parametric model of the received signal that is specified directly in terms of its LFMCW constituents. Rather, we analyze the signal over time intervals that are short, non-overlapping, and contiguous by modeling it within these intervals as a sum of a small number sinusoidal (i.e., harmonic) components with unknown frequencies, deterministic but unknown amplitudes, unknown order (i.e., number of harmonic components), and unknown noise autocorrelation function. It is this model of the data that makes the solution computationally feasible, but also what leads to a degradation in performance since estimates are not based on the full time series. By modeling the signal in this way, we reliably detect the presence of multiple LFMCW signals in colored noise without the need for prewhitening, efficiently estimate (i.e. , characterize) their parameters, provide estimation error

  8. Nuclear factor of activated T-cells 5 increases intestinal goblet cell differentiation through an mTOR/Notch signaling pathway

    PubMed Central

    Zhou, Yuning; Wang, Qingding; Weiss, Heidi L.; Evers, B. Mark

    2014-01-01

    The intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis that is regulated by multiple signaling pathways. Previously, we have shown that the nuclear factor of activated T-cells 5 (NFAT5) is involved in the regulation of intestinal enterocyte differentiation. Here we show that treatment with sodium chloride (NaCl), which activates NFAT5 signaling, increased mTORC1 repressor regulated in development and DNA damage response 1 (REDD1) protein expression and inhibited mTOR signaling; these alterations were attenuated by knockdown of NFAT5. Knockdown of NFAT5 activated mammalian target of rapamycin (mTOR) signaling and significantly inhibited REDD1 mRNA expression and protein expression. Consistently, overexpression of NFAT5 increased REDD1 expression. In addition, knockdown of REDD1 activated mTOR and Notch signaling, whereas treatment with mTOR inhibitor rapamycin repressed Notch signaling and increased the expression of the goblet cell differentiation marker mucin 2 (MUC2). Moreover, knockdown of NFAT5 activated Notch signaling and decreased MUC2 expression, while overexpression of NFAT5 inhibited Notch signaling and increased MUC2 expression. Our results demonstrate a role for NFAT5 in the regulation of mTOR signaling in intestinal cells. Importantly, these data suggest that NFAT5 participates in the regulation of intestinal homeostasis via the suppression of mTORC1/Notch signaling pathway. PMID:25057011

  9. Integrating Multiple Types of Data for Signaling Research: Challenges and Opportunities

    SciTech Connect

    Wiley, H. S.

    2011-02-15

    New technologies promise to provide unprecedented amounts of information that can provide a foundation for creating predictive models of cell signaling pathways. To be useful, however, this information must be integrated into a coherent framework. In addition, the sheer volume of data gathered from the new technologies requires computational approaches for its analysis. Unfortunately, there are many barriers to data integration and analysis, mostly because of a lack of adequate data standards and their inconsistent use by scientists. However, solving the fundamental issues of data sharing will enable the investigation of entirely new areas of cell signaling research.

  10. Dermatophytes Activate Skin Keratinocytes via Mitogen-Activated Protein Kinase Signaling and Induce Immune Responses

    PubMed Central

    Achterman, Rebecca R.; Moyes, David L.; Thavaraj, Selvam; Smith, Adam R.; Blair, Kris M.

    2015-01-01

    Dermatophytes cause superficial and cutaneous fungal infections in immunocompetent hosts and invasive disease in immunocompromised hosts. However, the host mechanisms that regulate innate immune responses against these fungi are largely unknown. Here, we utilized commercially available epidermal tissues and primary keratinocytes to assess (i) damage induction by anthropophilic, geophilic, and zoophilic dermatophyte strains and (ii) the keratinocyte signaling pathways, transcription factors, and proinflammatory responses induced by a representative dermatophyte, Trichophyton equinum. Initially, five dermatophyte species were tested for their ability to invade, cause tissue damage, and induce cytokines, with Microsporum gypseum inducing the greatest level of damage and cytokine release. Using T. equinum as a representative dermatophyte, we found that the mitogen-activated protein kinase (MAPK) pathways were predominantly affected, with increased levels of phospho-p38 and phospho-Jun N-terminal protein kinase (JNK) but decreased levels of phospho-extracellular signal-regulated kinases 1 and 2 (ERK1/2). Notably, the NF-κB and PI3K pathways were largely unaffected. T. equinum also significantly increased expression of the AP-1-associated transcription factor, c-Fos, and the MAPK regulatory phosphatase, MKP1. Importantly, the ability of T. equinum to invade, cause tissue damage, activate signaling and transcription factors, and induce proinflammatory responses correlated with germination, indicating that germination may be important for dermatophyte virulence and host immune activation. PMID:25667269

  11. Signal-on electrochemical detection of antibiotics at zeptomole level based on target-aptamer binding triggered multiple recycling amplification.

    PubMed

    Wang, Hongzhi; Wang, Yu; Liu, Su; Yu, Jinghua; Guo, Yuna; Xu, Ying; Huang, Jiadong

    2016-06-15

    In the work, a signal-on electrochemical DNA sensor based on multiple amplification for ultrasensitive detection of antibiotics has been reported. In the presence of target, the ingeniously designed hairpin probe (HP1) is opened and the polymerase-assisted target recycling amplification is triggered, resulting in autonomous generation of secondary target. It is worth noting that the produced secondary target could not only hybridize with other HP1, but also displace the Helper from the electrode. Consequently, methylene blue labeled HP2 forms a "close" probe structure, and the increase of signal is monitored. The increasing current provides an ultrasensitive electrochemical detection for antibiotics down to 1.3 fM. To our best knowledge, such work is the first report about multiple recycling amplification combing with signal-on sensing strategy, which has been utilized for quantitative determination of antibiotics. It would be further used as a general strategy associated with more analytical techniques toward the detection of a wide spectrum of analytes. Thus, it holds great potential for the development of ultrasensitive biosensing platform for the applications in bioanalysis, disease diagnostics, and clinical biomedicine. PMID:26878484

  12. Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9.

    PubMed

    Lindner, Maren; Thümmler, Katja; Arthur, Ariel; Brunner, Sarah; Elliott, Christina; McElroy, Daniel; Mohan, Hema; Williams, Anna; Edgar, Julia M; Schuh, Cornelia; Stadelmann, Christine; Barnett, Susan C; Lassmann, Hans; Mücklisch, Steve; Mudaliar, Manikhandan; Schaeren-Wiemers, Nicole; Meinl, Edgar; Linington, Christopher

    2015-07-01

    Remyelination failure plays an important role in the pathophysiology of multiple sclerosis, but the underlying cellular and molecular mechanisms remain poorly understood. We now report actively demyelinating lesions in patients with multiple sclerosis are associated with increased glial expression of fibroblast growth factor 9 (FGF9), which we demonstrate inhibits myelination and remyelination in vitro. This inhibitory activity is associated with the appearance of multi-branched 'pre-myelinating' MBP+ / PLP+ oligodendrocytes that interact with axons but fail to assemble myelin sheaths; an oligodendrocyte phenotype described previously in chronically demyelinated multiple sclerosis lesions. This inhibitory activity is not due to a direct effect of FGF9 on cells of the oligodendrocyte lineage but is mediated by factors secreted by astrocytes. Transcriptional profiling and functional validation studies demonstrate that these include effects dependent on increased expression of tissue inhibitor of metalloproteinase-sensitive proteases, enzymes more commonly associated with extracellular matrix remodelling. Further, we found that FGF9 induces expression of Ccl2 and Ccl7, two pro-inflammatory chemokines that contribute to recruitment of microglia and macrophages into multiple sclerosis lesions. These data indicate glial expression of FGF9 can initiate a complex astrocyte-dependent response that contributes to two distinct pathogenic pathways involved in the development of multiple sclerosis lesions. Namely, induction of a pro-inflammatory environment and failure of remyelination; a combination of effects predicted to exacerbate axonal injury and loss in patients. PMID:25907862

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

    PubMed

    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

  14. Multiple inductive signals are involved in the development of the ctenophore Mnemiopsis leidyi

    NASA Technical Reports Server (NTRS)

    Henry, J. Q.; Martindale, M. Q.

    2001-01-01

    Ctenophores possess eight longitudinally arrayed rows of comb plate cilia. Previous intracellular cell lineage analysis has shown that these comb rows are derived from two embryonic lineages, both daughters of the four e(1) micromeres (e(11) and e(12)) and a single daughter of the four m(1) micromeres (the m(12) micromeres). Although isolated e(1) micromeres will spontaneously generate comb plates, cell deletion experiments have shown that no comb plates appear during embryogenesis following the removal of e(1) descendents. Thus, the m(1) lineage requires the inductive interaction of the e(1) lineage to contribute to comb plate formation. Here we show that, although m(12) cells are normally the only m(1) derivatives to contribute to comb plate formation, m(11) cells are capable of generating comb plates in the absence m(12) cells. The reason that m(11) cells do not normally make comb rows may be attributable either to their more remote location relative to critical signaling centers (e.g., e(1) descendants) or to inhibitory signals that may be provided by other nearby cells such as sister cells m(12). In addition, we show that the signals provided by the e(1) lineage are not sufficient for m(1)-derived comb plate formation. Signals provided by endomesodermal progeny of either the E or the M lineages (the 3E or 2M macromeres) are also required. Copyright 2001 Academic Press.

  15. Comprehending Multiple Documents on Scientific Controversies: Effects of Reading Goals and Signaling Rhetorical Relationships

    ERIC Educational Resources Information Center

    Stadtler, Marc; Scharrer, Lisa; Skodzik, Timo; Bromme, Rainer

    2014-01-01

    Understanding conflicts between sources is an inherent part of science text comprehension. We examined whether readers' memories for conflicts and their situational interpretation of conflicts would be affected by reading goals and lexical cue phrases that signal rhetorical relationships. To this end, 198 undergraduates read multiple…

  16. MULTIPLE TRANSCRIPTION-FACTOR GENES ARE EARLY TARGETS OF PHYTOCHROME A SIGNALING

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The phytochrome family of sensory photoreceptors directs adaptational changes in gene expression in response to environmental light signals. Using oligonucleotide microarrays to measure expression profiles in wild-type and phytochrome A (phyA) null-mutant Arabidopsis seedlings, we have shown that 10...

  17. An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo

    PubMed Central

    De, Pradip; Dey, Nandini; Terakedis, Breanne; Bersagel, Leif; Li, Zhi Hua; Mahadevan, Daruka; Garlich, Joseph R.; Trudel, Suzanne; Makale, Milan T.; Durden, Donald L.

    2013-01-01

    Purpose Multiple reports point to an important role for the phosphoinositide-3 kinase (PI3K) and AKT signaling pathways in tumor survival and chemoresistance in multiple myeloma (MM). The goals of our study were: (1) to generate the preclinical results necessary to justify a Phase I clinical trial of SF1126 in hematopoietic malignancies including multiple myeloma, and (2) to begin combining pan PI-3 kinase inhibitors with other agents to augment antitumor activity of this class of agent in preparation for combination therapy in Phase I/II trials. Methods We determined the in vitro activity of SF1126 with16 human MM cell lines. In vivo tumor growth suppression was determined with human myeloma (MM.1R) xenografts in athymic mice. In addition, we provide evidence that SF1126 has pharmacodynamic activity in the treatment of patients with MM. Results SF1126 was cytotoxic to all tested MM lines and potency was augmented by the addition of bortezomib. SF1126 affected MM.1R cell line signaling in vitro, inhibiting phospho-AKT, phospho-ERK, and the hypoxic stabilization of HIF1α. Tumor growth was 94% inhibited, with a marked decrease in both cellular proliferation (PCNA immunostaining) and angiogenesis (tumor microvessel density via CD31 immunostaining). Our clinical results demonstrate pharmacodynamic knockdown of p-AKT in primary patient derived MM tumor cells in vivo. Conclusions Our results establish three important points: (1) SF1126, a pan PI-3 kinase inhibitor has potent antitumor activity against multiple myeloma in vitro and in vivo, (2) SF1126 displays augmented antimyeloma activity when combined with proteasome inhibitor, bortezomib/Velcade®, and (3) SF1126 blocks the IGF-1 induced activation of AKT in primary MM tumor cells isolated from SF1126 treated patients The results support the ongoing early Phase I clinical trial in MM and suggest a future Phase I trial in combination with bortezomib in hematopoietic malignancies. PMID:23355037

  18. 3-Formylchromone inhibits proliferation and induces apoptosis of multiple myeloma cells by abrogating STAT3 signaling through the induction of PIAS3.

    PubMed

    Ko, Jeong-Hyeon; Ho Baek, Seung; Nam, Dongwoo; Chung, Won-Seok; Lee, Seok-Geun; Lee, Junhee; Mo Yang, Woong; Um, Jae-Young; Seok Ahn, Kwang

    2016-10-01

    Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently observed and closely linked with proliferation, survival, metastasis and angiogenesis of various cancer cells, and thus its inhibition can be considered a potential therapeutic strategy. We found that 3-formylchromone (3FC) inhibited both constitutive and inducible STAT3 activation in multiple myeloma (MM) cells. Besides the inhibition of STAT3 phosphorylation, 3FC also abrogated constitutive activity and nuclear translocation of STAT3. This suppression was mediated through the inhibition of phosphorylation of Janus-activated kinase (JAK) 1/2 and Src. Furthermore, 3FC induced the expression of the protein inhibitors of activated STAT3 (PIAS3), and gene silencing of the PIAS3 by small interfering RNA abolished the ability of 3FC to inhibit STAT3 activation, suggesting a critical role for PIAS3 in the action of 3FC. 3FC also downregulated the expression of STAT3-regulated gene products such as Bcl-2, Bcl-xl, Mcl-1, Survivin, inhibitor of apoptosis protein-1 (IAP-1), Cyclin D1, cyclooxygenase-2 (COX-2), and matrix metalloproteinases-9 (MMP-9) in MM cells. This correlated with induction of substantial apoptosis as indicated by an increase in the sub-G1 cell population and caspase-3 induced poly ADP ribose polymerase (PARP) cleavage. Overall, these results suggest that 3FC is a novel blocker of STAT3 activation pathway thus may have a potential in therapy of MM and other cancers. PMID:27324722

  19. Calcium signaling and the secretory activity of bile duct epithelia.

    PubMed

    Amaya, Maria Jimena; Nathanson, Michael H

    2014-06-01

    Cytosolic calcium (Cai(2+)) is a second messenger that is important for the regulation of secretion in many types of tissues. Bile duct epithelial cells, or cholangiocytes, are polarized epithelia that line the biliary tree in liver and are responsible for secretion of bicarbonate and other solutes into bile. Cai(2+) signaling plays an important role in the regulation of secretion by cholangiocytes, and this review discusses the machinery involved in the formation of Ca(2+) signals in cholangiocytes, along with the evidence that these signals regulate ductular secretion. Finally, this review discusses the evidence that impairments in cholangiocyte Ca(2+) signaling play a primary role in the pathogenesis of cholestatic disorders, in which hepatic bile secretion is impaired. PMID:24612866

  20. Analysis of active neutron multiplicity data for Y-12 skull oxide samples

    SciTech Connect

    Krick, M.S.; Ensslin, N.; Ceo, R.N.; May, P.K.

    1996-09-01

    Previous work on active neutron multiplicity measurements and analyses is summarized. New active multiplicity measurements are described for samples of Y-12 skull oxide using an Active Well Coincidence Counter and MSR4 multiplicity electronics. Neutron multiplication values for the samples were determined from triples/doubles ratios. Neutron multiplication values were also obtained from Monte Carlo calculations using the MCNP code and the results compared with the experimental values. A calibration curve of AmLi source-sample coupling vs neutron multiplication was determined and used for active multiplicity assay of the skull oxides. The results are compared with those obtained from assay with the conventional calibration-curve technique, where the doubles rate is calibrated vs the {sup 235}U mass. The coupling-multiplication relationship determined for the skull oxides is compared with that determined earlier for pure high-enrichment uranium metal and pure uranium oxide. Conclusions are drawn about the application of active multiplicity techniques to uranium assay. Additional active multiplicity measurements and calculations are recommended.

  1. Context-dependent transcriptional interpretation of mitogen activated protein kinase signaling in the Drosophila embryo

    NASA Astrophysics Data System (ADS)

    Kim, Yoosik; Iagovitina, Antonina; Ishihara, Keisuke; Fitzgerald, Kate M.; Deplancke, Bart; Papatsenko, Dmitri; Shvartsman, Stanislav Y.

    2013-06-01

    Terminal regions of the Drosophila embryo are patterned by the localized activation of Mitogen Activated Protein Kinase (MAPK), which induces zygotic genes through relief of their repression by transcriptional repressor Capicua. The levels of MAPK activation at the anterior and posterior termini are close to each other, but the expression patterns of MAPK-target genes, such as zerknüllt (zen) and tailless (tll), display strong anterior-posterior (AP) asymmetry. This region-specific response to MAPK activation provides a clear example of context-dependent interpretation of inductive signaling, a common developmental effect that remains poorly understood. In the past, the AP asymmetry of zen expression was attributed to a mechanism that depends on MAPK substrate competition. We present data suggesting that the asymmetric expression of tll is generated by a different mechanism, based on feedforward control and multiple enhancers of the tll gene. A simple mathematical model of this mechanism correctly predicts how the wild-type expression pattern of tll changes in mutants affecting the anterior, dorsoventral, and terminal patterning systems and some of their direct targets.

  2. Pharmacological inhibition of KIT activates MET signaling in gastrointestinal stromal tumors

    PubMed Central

    Cohen, Noah A.; Zeng, Shan; Seifert, Adrian M.; Kim, Teresa S.; Sorenson, Eric C.; Greer, Jonathan B.; Beckman, Michael J.; Santamaria-Barria, Juan A.; Crawley, Megan H.; Green, Benjamin L.; Rossi, Ferdinand; Besmer, Peter; Antonescu, Cristina R.; DeMatteo, Ronald P.

    2015-01-01

    Gastrointestinal stromal tumors (GIST) are the most common adult sarcomas and the oncogenic driver is usually a KIT or PDGFRA mutation. While GIST are often initially sensitive to imatinib or other tyrosine kinase inhibitors, resistance generally develops necessitating backup strategies for therapy. In this study, we determined that a subset of human GIST specimens that acquired imatinib resistance acquired expression of activated forms of the MET oncogene. MET activation also developed after imatinib therapy in a mouse model of GIST (KitV558del/+ mice), where it was associated with increased tumor hypoxia. MET activation also occurred in imatinib-sensitive human GIST cell lines after imatinib treatment in vitro. MET inhibition by crizotinib or RNA interference was cytotoxic to an imatinib-resistant human GIST cell population. Moreover, combining crizotinib and imatinib was more effective than imatinib alone in imatinib-sensitive GIST models. Lastly, cabozantinib, a dual MET and KIT small molecule inhibitor, was markedly more effective than imatinib in multiple preclinical models of imatinib-sensitive and imatinib-resistant GIST. Collectively, our findings showed that activation of compensatory MET signaling by KIT inhibition may contribute to tumor resistance. Furthermore, our work offered a preclinical proof of concept for MET inhibition by cabozantinib as an effective strategy for GIST treatment. PMID:25836719

  3. Context-dependent transcriptional interpretation of mitogen activated protein kinase signaling in the Drosophila embryo

    PubMed Central

    Kim, Yoosik; Iagovitina, Antonina; Ishihara, Keisuke; Fitzgerald, Kate M.; Deplancke, Bart; Papatsenko, Dmitri; Shvartsman, Stanislav Y.

    2013-01-01

    Terminal regions of the Drosophila embryo are patterned by the localized activation of Mitogen Activated Protein Kinase (MAPK), which induces zygotic genes through relief of their repression by transcriptional repressor Capicua. The levels of MAPK activation at the anterior and posterior termini are close to each other, but the expression patterns of MAPK-target genes, such as zerknüllt (zen) and tailless (tll), display strong anterior-posterior (AP) asymmetry. This region-specific response to MAPK activation provides a clear example of context-dependent interpretation of inductive signaling, a common developmental effect that remains poorly understood. In the past, the AP asymmetry of zen expression was attributed to a mechanism that depends on MAPK substrate competition. We present data suggesting that the asymmetric expression of tll is generated by a different mechanism, based on feedforward control and multiple enhancers of the tll gene. A simple mathematical model of this mechanism correctly predicts how the wild-type expression pattern of tll changes in mutants affecting the anterior, dorsoventral, and terminal patterning systems and some of their direct targets. PMID:23822503

  4. Stimulation of Fas signaling down-regulates activity of neutrophils from major trauma patients with SIRS.

    PubMed

    Paunel-Görgülü, Adnana; Lögters, Tim; Flohé, Sascha; Cinatl, Jindrich; Altrichter, Jens; Windolf, Joachim; Scholz, Martin

    2011-03-01

    Posttrauma apoptosis resistance of neutrophils (PMN) is related to overshooting immune responses, systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF). Recently, we have shown that the apoptosis resistance in circulating PMN from severely injured patients which is known to be mediated by high serum levels of pro-inflammatory cytokines can be overcome by the activation of Fas death receptor. Here, we aimed to study whether stimulation of surface Fas leads to the inactivation of hyperactivated PMN from critically ill patients with SIRS. PMN from 23 multiple trauma patients (mean injury severity score (ISS) 34±1.9) were isolated at day 1 after admission to the trauma center. PMN from 17 volunteer blood donors served as controls. Neutrophil activity has been determined after ex vivo short (1 h) and long-term (4 h) stimulation of freshly isolated PMN with immobilized agonistic anti-Fas antibodies. We found neutrophil chemotactic migration in response to IL-8, phagocytosis and oxidative burst to be significantly inhibited in control cells already after short-term (1 h) Fas stimulation. In contrast, inactivation of trauma PMN by agonistic anti-Fas antibodies was found to be efficient only after long-term (4 h) incubation of cells with agonistic antibodies. Thus, in trauma PMN down-regulation of neutrophil activity seems to be delayed when compared to cells isolated from healthy controls, suggesting impaired susceptibility for Fas stimulation in these cells. Interestingly, whereas Fas-mediated inhibition of phagocytosis and oxidative burst could be prevented by the broad range caspase inhibitor t-butoxycarbonyl-aspartyl(O-methyl)-fluoromethyl ketone (BocD-fmk), the chemotactic activity in response to IL-8 was unaffected. In conclusion, we demonstrate that stimulation of neutrophil Fas does not only initiate apoptosis but also induces inhibition of neutrophil functions, partially by non-apoptotic signaling. PMID:20832139

  5. Molecular mechanism of anticancer effect of Sclerotium rolfsii lectin in HT29 cells involves differential expression of genes associated with multiple signaling pathways: A microarray analysis.

    PubMed

    Barkeer, Srikanth; Guha, Nilanjan; Hothpet, Vishwanathreddy; Saligrama Adavigowda, Deepak; Hegde, Prajna; Padmanaban, Arunkumar; Yu, Lu-Gang; Swamy, Bale M; Inamdar, Shashikala R

    2015-12-01

    Sclerotium rolfsii lectin (SRL) is a lectin isolated from fungus S. rolfsii and has high binding specificity toward the oncofetal Thomsen-Friedenreich carbohydrate antigen (Galβ1-3GalNAc-α-O-Ser/Thr, T or TF), which is expressed in more than 90% of human cancers. Our previous studies have shown that binding of SRL to human colon, breast and ovarian cancer cells induces cell apoptosis in vitro and suppresses tumor growth in vivo. This study investigated the SRL-mediated cell signaling in human colon cancer HT29 cells by mRNA and miRNA microarrays. It was found that SRL treatment results in altered expression of several hundred molecules including mitogen-activated protein kinase (MAPK) and c-JUN-associated, apoptosis-associated and cell cycle and DNA replication-associated signaling molecules. Pathway analysis using GeneSpring 12.6.1 revealed that SRL treatment induces changes of MAPK and c-JUN-associated signaling pathways as early as 2 h while changes of cell cycle, DNA replication and apoptosis pathways were significantly affected only after 24 h. A significant change of cell miRNA expression was also observed after 12 h treatment of the cells with SRL. These changes were further validated by quantitative real time polymerase chain reaction and immunoblotting. This study thus suggests that the presence of SRL affects multiple signaling pathways in cancer cells with early effects on cell proliferation pathways associated with MAPK and c-JUN, followed by miRNA-associated cell activity and apoptosis. This provides insight information into the molecular mechanism of the anticancer activity of this fungal lectin. PMID:26347523

  6. The high risk HPV16 L2 minor capsid protein has multiple transport signals that mediate its nucleocytoplasmic traffic

    SciTech Connect

    Mamoor, Shahan; Onder, Zeynep; Karanam, Balasubramanyam; Kwak, Kihyuck; Bordeaux, Jennifer; Crosby, Lauren; Roden, Richard B.S.; Moroianu, Junona

    2012-01-20

    In this study we examined the transport signals contributing to HPV16 L2 nucleocytoplasmic traffic using confocal microscopy analysis of enhanced green fluorescent protein-L2 (EGFP-L2) fusions expressed in HeLa cells. We confirmed that both nuclear localization signals (NLSs), the nNLS (1MRHKRSAKRTKR12) and cNLS (456RKRRKR461), previously characterized in vitro (Darshan et al., 2004), function independently in vivo. We discovered that a middle region rich in arginine residues (296SRRTGIRYSRIGNKQTLRTRS316) functions as a nuclear retention sequence (NRS), as mutagenesis of critical arginine residues within this NRS reduced the fraction of L2 in the nucleus despite the presence of both NLSs. Significantly, the infectivity of HPV16 pseudoviruses containing either RR297AA or RR297EE within the L2 NRS was strongly reduced both in HaCaT cells and in a murine challenge model. Experiments using Ratjadone A nuclear export inhibitor and mutation-localization analysis lead to the discovery of a leucine-rich nuclear export signal ({sub 462}LPYFFSDVSL) mediating 16L2 nuclear export. These data indicate that HPV16 L2 nucleocytoplasmic traffic is dependent on multiple functional transport signals.

  7. Simultaneous decomposition of multiple hyperspectral data sets: signal recovery of unknown fluorophores in the retinal pigment epithelium.

    PubMed

    Smith, R Theodore; Post, Robert; Johri, Ansh; Lee, Michele D; Ablonczy, Zsolt; Curcio, Christine A; Ach, Thomas; Sajda, Paul

    2014-12-01

    Upon excitation with different wavelengths of light, biological tissues emit distinct but related autofluorescence signals. We used non-negative matrix factorization (NMF) to simultaneously decompose co-registered hyperspectral emission data from human retinal pigment epithelium/Bruch's membrane specimens illuminated with 436 and 480 nm light. NMF analysis was initialized with Gaussian mixture model fits and constrained to provide identical abundance images for the two excitation wavelengths. Spectra recovered this way were smoother than those obtained separately; fluorophore abundances more clearly localized within tissue compartments. These studies provide evidence that leveraging multiple co-registered hyperspectral emission data sets is preferential for identifying biologically relevant fluorophore information. PMID:25574430

  8. Experimental demonstration of multiple pulse nonlinear optoacoustic signal generation and control.

    PubMed

    Blackmon, Fletcher; Antonelli, Lynn

    2005-01-01

    Generating underwater acoustic signals from a remote, aerial location by use of a high-energy pulsed infrared laser has been demonstrated. The laser beam is directed from the air and focused onto the water surface, where the optical energy was converted into a propagating acoustic wave. Sound pressure levels of 185 dB re microPa (decibel re microPa) were consistently recorded under freshwater laboratory conditions at laser-pulse repetition rates of up to 1000 pulses/s. The nonlinear optoacoustic transmission concept is outlined, and the experimental results from investigation of the time-domain and frequency-domain characteristics of the generated underwater sound are provided. A high repetition rate, high-energy per pulse laser was used in this test under freshwater laboratory conditions. A means of deterministically controlling the spectrum of the underwater acoustic signal was investigated and demonstrated by varying the laser-pulse repetition rate. PMID:15662891

  9. Tyrosine kinase BMX phosphorylates phosphotyrosine-primed motif mediating the activation of multiple receptor tyrosine kinases.

    PubMed

    Chen, Sen; Jiang, Xinnong; Gewinner, Christina A; Asara, John M; Simon, Nicholas I; Cai, Changmeng; Cantley, Lewis C; Balk, Steven P

    2013-05-28

    The nonreceptor tyrosine kinase BMX (bone marrow tyrosine kinase gene on chromosome X) is abundant in various cell types and activated downstream of phosphatidylinositol-3 kinase (PI3K) and the kinase Src, but its substrates are unknown. Positional scanning peptide library screening revealed a marked preference for a priming phosphorylated tyrosine (pY) in the -1 position, indicating that BMX substrates may include multiple tyrosine kinases that are fully activated by pYpY sites in the kinase domain. BMX phosphorylated focal adhesion kinase (FAK) at Tyr⁵⁷⁷ subsequent to its Src-mediated phosphorylation at Tyr⁵⁷⁶. Loss of BMX by RNA interference or by genetic deletion in mouse embryonic fibroblasts (MEFs) markedly impaired FAK activity. Phosphorylation of the insulin receptor in the kinase domain at Tyr¹¹⁸⁹ and Tyr¹¹⁹⁰, as well as Tyr¹¹⁸⁵, and downstream phosphorylation of the kinase AKT at Thr³⁰⁸ were similarly impaired by BMX deficiency. However, insulin-induced phosphorylation of AKT at Ser⁴⁷³ was not impaired in Bmx knockout MEFs or liver tissue from Bmx knockout mice, which also showed increased insulin-stimulated glucose uptake, possibly because of decreased abundance of the phosphatase PHLPP (PH domain leucine-rich repeat protein phosphatase). Thus, by identifying the pYpY motif as a substrate for BMX, our findings suggest that BMX functions as a central regulator among multiple signaling pathways mediated by tyrosine kinases. PMID:23716717

  10. Multiple signaling pathways control nitrogen-mediated root elongation in maize

    PubMed Central

    Chen, Fanjun; Zhang, Fusuo

    2008-01-01

    Response of root system architecture to nutrient availability is an essential way for plants to adapt to soil environments. Nitrogen can affect root development either as a result of changes in the external concentration, or through changes in the internal nutrient status of the plant. Low soil N stimulates root elongation in maize. Recent evidence suggests that plant hormones auxin and cytokinin, as well as NO signaling pathway, are involved in the regulation of root elongation by low nitrogen nutrition. PMID:19704443

  11. Histamine H4 Receptor mediates interleukin-8 and TNF-α release in human mast cells via multiple signaling pathways.

    PubMed

    Chen, X-F; Zhang, Z; Dou, X; Li, J-J; Zhang, W; Yu, Y-Y; Yu, B; Yu, B

    2016-01-01

    Histamine, mainly produced by mast cells, is an important inflammatory mediator in immune response. Recently Histamine H4 Receptor (H4R) was also identified in mast cells, from which pro-inflammatory cytokines and chemokines are released. However, the mechanism of how H4R mediates these cytokines and chemokines release in mast cells was still unclear. To further explore the role of H4R in the immune inflammatory response in mast cells, we tested the release of inflammatory cytokine tumor necrosis factor-α (TNF-α), chemokine interleukin-8 (IL-8) and the relevant signaling pathways activated by H4R on LAD2 cells (a human mast cell line). We found that the release of IL-8 and TNF-α were blocked by inhibitors of PI3K, ERK and Ca2+-Calcineurin-NFAT signaling pathways, while the release of these cytokines and chemokines were enhanced by the inhibitor of P38 signaling pathway. However, inhibitors of the JNK and NF-κB signaling pathways had little effect on the expression of the pro-inflammatory mediators. Moreover, activation of the H4R could induce phosphorylation of ERK, p38 and AKT in mast cells. In conclusion, we found that H4R mediates the release of inflammatory cytokine TNF-α and chemokine IL-8 in human mast cells via PI3K, Ca2+-Calcineurin-NFAT and MAPKs signaling pathways. PMID:26828993

  12. New Constitutively Active Phytochromes Exhibit Light-Independent Signaling Activity1[OPEN

    PubMed Central

    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

    2016-01-01

    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

  13. Notch Signaling Activation in Pediatric Low-Grade Astrocytoma

    PubMed Central

    Brandt, William D.; Schreck, Karisa C.; Bar, Eli E.; Taylor, Isabella; Marchionni, Luigi; Raabe, Eric; Eberhart, Charles G.; Rodriguez, Fausto J.

    2014-01-01

    Pilocytic astrocytoma (PA) is the most common primary brain tumor in children; various signaling pathways have been implicated in its biology. The Notch signaling pathway has been found to play a role in development, stem cell biology, and the pathogenesis of several cancers but its role in PA has not been investigated. We studied alterations in Notch signaling components in tumor tissue from 18 patients with PA and 4 with other low-grade astrocytomas to identify much needed therapeutic targets. We found that Notch pathway members were overexpressed at the mRNA (NOTCH1, NOTCH2, HEY1, HEY2) and protein (HES1) levels in PAs at various anatomical sites compared to non-neoplastic brain samples. These changes were not associated with specific BRAF alterations. Inhibiting the Notch pathway in the pediatric low-grade astrocytoma cell lines Res 186 and Res 259 using either RNA interference or a γ-secretase inhibitor resulted in variable but significant reduction in cell growth and migration. This study suggests a potential role for Notch signaling in pediatric low-grade astrocytoma tumorigenesis and that Notch signaling may be a viable pathway therapeutic target. PMID:25575134

  14. Notch signaling activation in pediatric low-grade astrocytoma.

    PubMed

    Brandt, William D; Schreck, Karisa C; Bar, Eli E; Taylor, Isabella; Marchionni, Luigi; Raabe, Eric; Eberhart, Charles G; Rodriguez, Fausto J

    2015-02-01

    Pilocytic astrocytoma (PA) is the most common primary brain tumor in children; various signaling pathways have been implicated in its biology. The Notch signaling pathway has been found to play a role in the development, stem cell biology, and pathogenesis of several cancers, but its role in PA has not been investigated. We studied alterations in Notch signaling components in tumor tissue from 18 patients with PA and 4 with other low-grade astrocytomas to identify much needed therapeutic targets. We found that Notch pathway members were overexpressed at the mRNA (NOTCH1, NOTCH2, HEY1, HEY2) and protein (HES1) levels in PAs at various anatomic sites compared with non-neoplastic brain samples. These changes were not associated with specific BRAF alterations. Inhibiting the Notch pathway in the pediatric low-grade astrocytoma cell lines Res186 and Res259 using either RNA interference or a γ-secretase inhibitor resulted in variable, but significant, reduction in cell growth and migration. This study suggests a potential role for Notch signaling in pediatric low-grade astrocytoma tumorigenesis and that Notch signaling may be a viable pathway therapeutic target. PMID:25575134

  15. Assigning Quantitative Function to Post-Translational Modifications Reveals Multiple Sites of Phosphorylation That Tune Yeast Pheromone Signaling Output

    SciTech Connect

    Pincus, David; Ryan, Christopher J.; Smith, Richard D.; Brent, Roger; Resnekov, Orna; Hakimi, Mohamed Ali

    2013-03-12

    Cell signaling systems transmit information by post-­translationally modifying signaling proteins, often via phosphorylation. While thousands of sites of phosphorylation have been identified in proteomic studies, the vast majority of sites have no known function. Assigning functional roles to the catalog of uncharacterized phosphorylation sites is a key research challenge. Here we present a general approach to address this challenge and apply it to a prototypical signaling pathway, the pheromone response pathway in Saccharomyces cerevisiae. The pheromone pathway includes a mitogen activated protein kinase (MAPK) cascade activated by a G-­protein coupled receptor (GPCR). We used mass spectrometry-based proteomics to identify sites whose phosphorylation changed when the system was active, and evolutionary conservation to assign priority to a list of candidate MAPK regulatory sites. We made targeted alterations in those sites, and measured the effects of the mutations on pheromone pathway output in single cells. Our work identified six new sites that quantitatively tuned system output. We developed simple computational models to find system architectures that recapitulated the quantitative phenotypes of the mutants. Our results identify a number of regulated phosphorylation events that contribute to adjust the input-­output relationship of this model eukaryotic signaling system. We believe this combined approach constitutes a general means not only to reveal modification sites required to turn a pathway on and off, but also those required for more subtle quantitative effects that tune pathway output. Our results further suggest that relatively small quantitative influences from individual regulatory phosphorylation events endow signaling systems with plasticity that evolution may exploit to quantitatively tailor signaling outcomes.

  16. Multi-Parameter Observation and Detection of Pre-Earthquake Signals in Seismically Active Areas

    NASA Technical Reports Server (NTRS)

    Ouzounov, D.; Pulinets, S.; Parrot, M.; Liu, J. Y.; Hattori, K.; Kafatos, M.; Taylor, P.

    2012-01-01

    The recent large earthquakes (M9.0 Tohoku, 03/2011; M7.0 Haiti, 01/2010; M6.7 L Aquila, 04/2008; and M7.9 Wenchuan 05/2008) have renewed interest in pre-anomalous seismic signals associated with them. Recent workshops (DEMETER 2006, 2011 and VESTO 2009 ) have shown that there were precursory atmospheric /ionospheric signals observed in space prior to these events. Our initial results indicate that no single pre-earthquake observation (seismic, magnetic field, electric field, thermal infrared [TIR], or GPS/TEC) can provide a consistent and successful global scale early warning. This is most likely due to complexity and chaotic nature of earthquakes and the limitation in existing ground (temporal/spatial) and global satellite observations. In this study we analyze preseismic temporal and spatial variations (gas/radon counting rate, atmospheric temperature and humidity change, long-wave radiation transitions and ionospheric electron density/plasma variations) which we propose occur before the onset of major earthquakes:. We propose an Integrated Space -- Terrestrial Framework (ISTF), as a different approach for revealing pre-earthquake phenomena in seismically active areas. ISTF is a sensor web of a coordinated observation infrastructure employing multiple sensors that are distributed on one or more platforms; data from satellite sensors (Terra, Aqua, POES, DEMETER and others) and ground observations, e.g., Global Positioning System, Total Electron Content (GPS/TEC). As a theoretical guide we use the Lithosphere-Atmosphere-Ionosphere Coupling (LAIC) model to explain the generation of multiple earthquake precursors. Using our methodology, we evaluated retrospectively the signals preceding the most devastated earthquakes during 2005-2011. We observed a correlation between both atmospheric and ionospheric anomalies preceding most of these earthquakes. The second phase of our validation include systematic retrospective analysis for more than 100 major earthquakes (M>5

  17. Effects of Project Activities Based on Multiple Intelligences to Elementary School Children's Science Achievement.

    ERIC Educational Resources Information Center

    Lim, Chaeseong; Wang, Kyungsoon

    2001-01-01

    Examines the influence of project activities based on multiple intelligences on the science achievement of elementary school children. Explains the proportions of variance of science achievement by General Intelligence (GI), analyzes Multiple Intelligences (MI), and investigates the influence of project activities that used various aspects of MI.…

  18. GSK621 Targets Glioma Cells via Activating AMP-Activated Protein Kinase Signalings

    PubMed Central

    Jiang, Hong; Liu, Wei; Zhan, Shi-Kun; Pan, Yi-Xin; Bian, Liu-Guan; Sun, Bomin; Sun, Qing-Fang; Pan, Si-Jian

    2016-01-01

    Here, we studied the anti-glioma cell activity by a novel AMP-activated protein kinase (AMPK) activator GSK621. We showed that GSK621 was cytotoxic to human glioma cells (U87MG and U251MG lines), possibly via provoking caspase-dependent apoptotic cell death. Its cytotoxicity was alleviated by caspase inhibitors. GSK621 activated AMPK to inhibit mammalian target of rapamycin (mTOR) and downregulate Tetraspanin 8 (Tspan8) in glioma cells. AMPK inhibition, through shRNA knockdown of AMPKα or introduction of a dominant negative (T172A) AMPKα, almost reversed GSK621-induced AMPK activation, mTOR inhibition and Tspan8 degradation. Consequently, GSK621’s cytotoxicity in glioma cells was also significantly attenuated by AMPKα knockdown or mutation. Further studies showed that GSK621, at a relatively low concentration, significantly potentiated temozolomide (TMZ)’s sensitivity and lethality against glioma cells. We summarized that GSK621 inhibits human glioma cells possibly via activating AMPK signaling. This novel AMPK activator could be a novel and promising anti-glioma cell agent. PMID:27532105

  19. Rap1 promotes multiple pancreatic islet cell functions and signals through mammalian target of rapamycin complex 1 to enhance proliferation.

    PubMed

    Kelly, Patrick; Bailey, Candice L; Fueger, Patrick T; Newgard, Christopher B; Casey, Patrick J; Kimple, Michelle E

    2010-05-21

    Recent studies have implicated Epac2, a guanine-nucleotide exchange factor for the Rap subfamily of monomeric G proteins, as an important regulator of insulin secretion from pancreatic beta-cells. Although the Epac proteins were originally identified as cAMP-responsive activators of Rap1 GTPases, the role of Rap1 in beta-cell biology has