Science.gov

Sample records for activated signal transducer

  1. Signal Transducers and Activators of Transcription (STAT) Family Members in Helminth Infections

    PubMed Central

    Becerra-Díaz, Mireya; Valderrama-Carvajal, Héctor; Terrazas, Luis I.

    2011-01-01

    Helminth parasites are a diverse group of multicellular organisms. Despite their heterogeneity, helminths share many common characteristics, such as the modulation of the immune system of their hosts towards a permissive state that favors their development. They induce strong Th2-like responses with high levels of IL-4, IL-5 and IL-13 cytokines, and decreased production of proinflammatory cytokines such as IFN-γ. IL-4, IFN-γ and other cytokines bind with their specific cytokine receptors to trigger an immediate signaling pathway in which different tyrosine kinases (e.g. Janus kinases) are involved. Furthermore, a seven-member family of transcription factors named Signal Transducers and Activators of Transcription (STAT) that initiate the transcriptional activation of different genes are also involved and regulate downstream the JAK/STAT signaling pathway. However, how helminths avoid and modulate immune responses remains unclear; moreover, information concerning STAT-mediated immune regulation during helminth infections is scarce. Here, we review the research on mice deficient in STAT molecules, highlighting the importance of the JAK/STAT signaling pathway in regulating susceptibility and/or resistance in these infections. PMID:22110388

  2. Inhibition of constitutive signal transducer and activator of transcription 3 activation by novel platinum complexes with potent antitumor activity.

    PubMed

    Turkson, James; Zhang, Shumin; Palmer, Jay; Kay, Heidi; Stanko, Joseph; Mora, Linda B; Sebti, Said; Yu, Hua; Jove, Richard

    2004-12-01

    DNA-alkylating agents that are platinum complexes induce apoptotic responses and have wide application in cancer therapy. The potential for platinum compounds to modulate signal transduction events that contribute to their therapeutic outcome has not been extensively examined. Among the signal transducer and activator of transcription (STAT) proteins, Stat3 activity is frequently up-regulated in many human tumors. Various lines of evidence have established a causal role for aberrant Stat3 activity in malignant transformation and provided validation for its targeting in the development of small-molecule inhibitors as novel cancer therapeutics. We report here that platinum-containing compounds disrupt Stat3 signaling and suppress its biological functions. The novel platinum (IV) compounds, CPA-1, CPA-7, and platinum (IV) tetrachloride block Stat3 activity in vitro at low micromolar concentrations. In malignant cells that harbor constitutively activated Stat3, CPA-1, CPA-7, and platinum (IV) tetrachloride inhibit cell growth and induce apoptosis in a manner that reflects the attenuation of persistent Stat3 activity. By contrast, cells that do not contain persistent Stat3 activity are marginally affected or are not affected by these compounds. Moreover, CPA-7 induces the regression of mouse CT26 colon tumor, which correlates with the abrogation of persistent Stat3 activity in tumors. Thus, the modulation of oncogenic signal transduction pathways, such as Stat3, may be one of the key molecular mechanisms for the antitumor effects of platinum (IV)-containing complexes.

  3. Feedback regulation of PRL secretion is mediated by the transcription factor, signal transducer, and activator of transcription 5b.

    PubMed

    Grattan, D R; Xu, J; McLachlan, M J; Kokay, I C; Bunn, S J; Hovey, R C; Davey, H W

    2001-09-01

    PRL secretion from the anterior pituitary gland is inhibited by dopamine produced in the tuberoinfundibular dopamine neurons of the hypothalamus. The activity of tuberoinfundibular dopamine neurons is stimulated by PRL; thus, PRL regulates its own secretion by a negative feedback mechanism. PRL receptors are expressed on tuberoinfundibular dopamine neurons, but the intracellular signaling pathway is not known. We have observed that mice with a disrupted signal transducer and activator of transcription 5b gene have grossly elevated serum PRL concentrations. Despite this hyperprolactinemia, mRNA levels and immunoreactivity of tyrosine hydroxylase, the key enzyme in dopamine synthesis, were significantly lower in the tuberoinfundibular dopamine neurons of these signal transducer and activator of transcription 5b-deficient mice. Concentrations of the dopamine metabolite dihydroxyphenylacetic acid in the median eminence were also significantly lower in signal transducer and activator of transcription 5b-deficient mice than in wild-type mice. No changes were observed in nonhypothalamic dopaminergic neuronal populations, indicating that the effects were selective to tuberoinfundibular dopamine neurons. These data indicate that in the absence of signal transducer and activator of transcription 5b, PRL signal transduction in tuberoinfundibular dopamine neurons is impaired, and they demonstrate that this transcription factor plays an obligatory and nonredundant role in mediating the negative feedback action of PRL on tuberoinfundibular dopamine neurons.

  4. Signal transducer and activator of transcription 5B (STAT5B) modulates adipocyte differentiation via MOF.

    PubMed

    Gao, Peng; Zhang, Yuchao; Liu, Yuantao; Chen, Jicui; Zong, Chen; Yu, Cong; Cui, Shang; Gao, Weina; Qin, Dandan; Sun, Wenchuan; Li, Xia; Wang, Xiangdong

    2015-12-01

    The role and mechanism of signal transducer and activator of transcription 5B (STAT5B) in adipogenesis remain unclear. In this study, our data showed that Males absent on the first (MOF) protein expression was increased during 3 T3-L1 preadipocytes differentiation accompanied with STAT5B expression increasing. Over-expression STAT5B enhanced MOF promoter trans-activation in HeLa cells. Mutagenesis assay and ChIP analysis exhibited that STAT5B was able to bind MOF promoter. Knocking-down STAT5B in 3 T3-L1 preadipocytes led to decreased expression of MOF, but resulted in increased expression of peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα) and fatty acid-binding protein 4 (Fabp4), which were important factors or enzymes for adipogenesis. We also found that knocking-down MOF in 3 T3-L1 preadipocytes resulted in increased expression of PPARγ, C/EBPα and Fabp4, which was in the same trend as STAT5B knocking-down. Over-expression MOF resulted in reduced promoter trans-activation activity of C/EBPα. These results suggest that STAT5B and MOF work as negative regulators in adipogenesis, and STAT5B modulates preadipocytes differentiation partially by regulating MOF expression.

  5. Characteristics of receptor- and transducer-coupled activation of the intracellular signalling in sensory neuron revealed by atomic force microscopy

    NASA Astrophysics Data System (ADS)

    Khalisov, M. M.; Penniyaynen, V. A.; Esikova, N. A.; Ankudinov, A. V.; Krylov, B. V.

    2017-01-01

    The mechanical properties of sensory neurons upon activation of intracellular cascade processes by comenic acid binding to a membrane opioid-like receptor (receptor-coupled), as well as a very low (endogenous) concentration of ouabain (transducer-coupled), have been investigated. Using atomic force microscopy, it is established that exposure to ouabain, in contrast to the impact of comenic acid, leads to a hardening of the neuron soma. This suggests that the receptor-coupled signal transmission to the cell genome is carried out through mechanisms that are different from the transducer-coupled signal pathways.

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

    SciTech Connect

    Shu, Guangwen; Yang, Jing; Zhao, Wenhao; Xu, Chan; Hong, Zongguo; Mei, Zhinan; Yang, Xinzhou

    2014-12-01

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

  7. Sorafenib inhibits signal transducer and activator of transcription 3 signaling associated with growth arrest and apoptosis of medulloblastomas.

    PubMed

    Yang, Fan; Van Meter, Timothy E; Buettner, Ralf; Hedvat, Michael; Liang, Wei; Kowolik, Claudia M; Mepani, Nilesh; Mirosevich, Janni; Nam, Sangkil; Chen, Mike Y; Tye, Gary; Kirschbaum, Mark; Jove, Richard

    2008-11-01

    Medulloblastomas are the most frequent malignant brain tumors in children. Sorafenib (Nexavar, BAY43-9006), a multikinase inhibitor, blocks cell proliferation and induces apoptosis in a variety of tumor cells. Sorafenib inhibited proliferation and induced apoptosis in two established cell lines (Daoy and D283) and a primary culture (VC312) of human medulloblastomas. In addition, sorafenib inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) in both cell lines and primary tumor cells. The inhibition of phosphorylated STAT3 (Tyr(705)) occurs in a dose- and time-dependent manner. In contrast, AKT (protein kinase B) was only decreased in D283 and VC312 medulloblastoma cells and mitogen-activated protein kinases (extracellular signal-regulated kinase 1/2) were not inhibited by sorafenib in these cells. Both D-type cyclins (D1, D2, and D3) and E-type cyclin were down-regulated by sorafenib. Also, expression of the antiapoptotic protein Mcl-1, a member of the Bcl-2 family, was decreased and correlated with apoptosis induced by sorafenib. Finally, sorafenib suppressed the growth of human medulloblastoma cells in a mouse xenograft model. Together, our data show that sorafenib blocks STAT3 signaling as well as expression of cell cycle and apoptosis regulatory proteins, associated with inhibition of cell proliferation and induction of apoptosis in medulloblastomas. These findings provide a rationale for treatment of pediatric medulloblastomas with sorafenib.

  8. Mammary ductal growth is impaired in mice lacking leptin-dependent signal transducer and activator of transcription 3 signaling.

    PubMed

    Thorn, Stephanie R; Giesy, Sarah L; Myers, Martin G; Boisclair, Yves R

    2010-08-01

    Mice lacking leptin (ob/ob) or its full-length receptor (db/db) are obese and reproductively incompetent. Fertility, pregnancy, and lactation are restored, respectively, in ob/ob mice treated with leptin through mating, d 6.5 post coitum, and pregnancy. Therefore, leptin signaling is needed for lactation, but the timing of its action and the affected mammary process remain unknown. To address this issue, we used s/s mice lacking only leptin-dependent signal transducer and activator of transcription (STAT)3 signaling. These mice share many features with db/db mice, including obesity, but differ by retaining sufficient activity of the hypothalamic-pituitary-ovarian axis to support reproduction. The s/s mammary epithelium was normal at 3 wk of age but failed to expand through the mammary fat pad (MFP) during the subsequent pubertal period. Ductal growth failure was not corrected by estrogen therapy and did not relate to inadequate IGF-I production by the MFP or to the need for epithelial or stromal leptin-STAT3 signaling. Ductal growth failure coincided with adipocyte hypertrophy and increased MFP production of leptin, TNFalpha, and IL6. These cytokines, however, were unable to inhibit the proliferation of a collection of mouse mammary epithelial cell lines. In conclusion, the very first step of postnatal mammary development fails in s/s mice despite sufficient estrogen IGF-I and an hypothalamic-pituitary-ovarian axis capable of supporting reproduction. This failure is not caused by mammary loss of leptin-dependent STAT3 signaling or by the development of inflammation. These data imply the existence of an unknown mechanism whereby leptin-dependent STAT3 signaling and obesity alter mammary ductal development.

  9. The role of signal transducer and activator of transcription 3 in Rift Valley fever virus infection.

    PubMed

    Pinkham, Chelsea; An, Soyeon; Lundberg, Lindsay; Bansal, Neha; Benedict, Ashwini; Narayanan, Aarthi; Kehn-Hall, Kylene

    2016-09-01

    Rift Valley fever (RVF) is a zoonotic disease that can cause severe illness in humans and livestock, triggering spontaneous abortion in almost 100% of pregnant ruminants. In this study, we demonstrate that signal transducer and activator of transcription 3 (STAT3) is phosphorylated on its conserved tyrosine residue (Y705) following RVFV infection. This phosphorylation was dependent on a major virulence factor, the viral nonstructural protein NSs. Loss of STAT3 had little effect on viral replication, but rather resulted in cells being more susceptible to RVFV-induced cell death. Phosphorylated STAT3 translocated to the nucleus, coinciding with inhibition of fos, jun, and nr4a2 gene expression, and the presence of STAT3 and NSs at the nr4a2 promoter. NSs was found predominantly in the cytoplasm of STAT3 null cells, indicating that STAT3 influences NSs nuclear localization. Collectively, these data demonstrate that STAT3 functions in a pro-survival capacity through modulation of NSs localization.

  10. The role of signal transducer and activator of transcription 3 in Rift Valley fever virus infection

    SciTech Connect

    Pinkham, Chelsea; An, Soyeon; Lundberg, Lindsay; Bansal, Neha; Benedict, Ashwini; Narayanan, Aarthi; Kehn-Hall, Kylene

    2016-09-15

    Rift Valley fever (RVF) is a zoonotic disease that can cause severe illness in humans and livestock, triggering spontaneous abortion in almost 100% of pregnant ruminants. In this study, we demonstrate that signal transducer and activator of transcription 3 (STAT3) is phosphorylated on its conserved tyrosine residue (Y705) following RVFV infection. This phosphorylation was dependent on a major virulence factor, the viral nonstructural protein NSs. Loss of STAT3 had little effect on viral replication, but rather resulted in cells being more susceptible to RVFV-induced cell death. Phosphorylated STAT3 translocated to the nucleus, coinciding with inhibition of fos, jun, and nr4a2 gene expression, and the presence of STAT3 and NSs at the nr4a2 promoter. NSs was found predominantly in the cytoplasm of STAT3 null cells, indicating that STAT3 influences NSs nuclear localization. Collectively, these data demonstrate that STAT3 functions in a pro-survival capacity through modulation of NSs localization. - Highlights: • STAT3 is phosphorylated on tyrosine residue 705 following RVFV infection. • Phosphorylation of STAT3 was dependent on the viral protein NSs. • STAT3 -/- MEFs were more susceptible to RVFV-induced cell death. • Loss of STAT3 led to an increase in pro-apoptotic gene expression. • STAT3 functions in a pro-survival capacity by modulation of NSs localization.

  11. Signal transducer and activator of transcription 3 promotes angiogenesis and drives malignant progression in glioma.

    PubMed

    Doucette, Tiffany A; Kong, Ling-Yuan; Yang, Yuhui; Ferguson, Sherise D; Yang, Jinbo; Wei, Jun; Qiao, Wei; Fuller, Gregory N; Bhat, Krishna P; Aldape, Kenneth; Priebe, Waldemar; Bögler, Oliver; Heimberger, Amy B; Rao, Ganesh

    2012-09-01

    Signal transducer and activator of transcription (STAT) 3 has been described as a "master regulator" of signaling pathways involved in the transition from low-grade glioma (LGG) to high-grade glioma (HGG). Although STAT3 is overexpressed in HGGs, it remains unclear whether its overexpression is sufficient to induce or promote the malignant progression of glioma. To characterize the effect of STAT3 expression on tumor progression in vivo, we expressed the STAT3 gene in glioneuronal progenitor cells in mice. STAT3 was expressed alone or concurrently with platelet-derived growth factor B (PDGFB), a well-described initiator of LGG. STAT3 alone was insufficient to induce tumor formation; however, coexpression of STAT3 with PDGFB in mice resulted in a significantly higher incidence of HGGs than PDGFB alone. The median symptomatic tumor latency in mice coexpressing STAT3 and PDGFB was significantly shorter, and mice that developed symptomatic tumors demonstrated significantly higher expression of phosphorylated STAT3 intratumorally. In HGGs, expression of STAT3 was associated with suppression of apoptosis and an increase in tumor cell proliferation. HGGs induced by STAT3 and PDGFB also displayed frequent foci of necrosis and microvascular proliferation. The expression of CD31 (a marker of endothelial proliferation) was significantly higher in tumors induced by coexpression of STAT3 and PDGFB. When mice injected with PDGFB and STAT3 were treated with a STAT3 inhibitor, median survival increased and the incidence of HGG and CD31 expression decreased significantly. These results demonstrate that STAT3 promotes the malignant progression of glioma. Inhibiting STAT3 expression mitigates tumor progression and improves survival, validating it as a therapeutic target.

  12. Signal transducer and activator of transcription 3 mutation with invasive eosinophilic disease

    PubMed Central

    Swender, David; Chernin, Leah; Hafez-Khayyata, Said; Ochs, Hans; Tcheurekdjian, Haig; Hostoffer, Robert

    2012-01-01

    Hyper-IgE syndrome (HIES), or Jobs disease, is a rare immunologic disorder characterized by the triad of staphylococcal abscesses, pneumonia with pneumatocele formation, and elevated IgE. It has been shown to have multiple modes of inheritance, autosomal dominant being more common than autosomal recessive, with sporadic cases as well. A mutation in signal transducer and activator of transcription 3 (STAT3) gene has been linked to the development of the sporadic and dominant forms of HIES. Peripheral eosinophilia, typically greater than two standard deviations from the normal population, is often seen in association with HIES. Despite these elevated levels of blood eosinophils, there have been no reported cases of invasive eosinophilic disease, such as eosonophilic esophagitic. Here we report the first description, to our knowledge, of a patient with HIES with a STAT3 mutation involving exon 12, Thr389Ile, and invasive eosinophilic disease of the esophagus. STAT3 modulates the expression of several genes that control central cell processes such as growth and death in response to external soluble stimuli. A mutation in the STAT3 molecule may affect the eosinophil's response to IL-5 and thus reduce the chemotaxic ability of those cells to migrate into tissues. This may then explain the paucity of eosinophilic infiltrative disease in patients with STAT3 mutations. The level of eosinophilic involvement may be related to the site or type of mutation within the STAT3 molecule. As more data are collected, we may be able to assess whether certain mutations dictate different clinical outcomes, which could prove helpful in directing therapy. PMID:23342295

  13. Signal Transducer and Activator of Transcription 3 Limits Epstein-Barr Virus Lytic Activation in B Lymphocytes

    PubMed Central

    Hill, Erik R.; Koganti, Siva; Zhi, Jizu; Megyola, Cynthia; Freeman, Alexandra F.; Palendira, Umaimainthan; Tangye, Stuart G.; Farrell, Paul J.

    2013-01-01

    Lytic activation of Epstein-Barr virus (EBV) is central to its life cycle and to most EBV-related diseases. However, not every EBV-infected B cell is susceptible to lytic activation. This lack of uniform susceptibility to lytic activation also directly impacts the success of viral oncolytic therapy for EBV cancers, yet determinants of susceptibility to lytic induction signals are not well understood. To determine if host factors influence susceptibility to EBV lytic activation, we developed a technique to separate lytic from refractory cells and reported that EBV lytic activation occurs preferentially in cells with lower levels of signal transducer and activator of transcription 3 (STAT3). Using this tool to detect single cells, we now extend the correlation between STAT3 and lytic versus refractory states to EBV-infected circulating B cells in patients with primary EBV infection, leading us to investigate whether STAT3 controls susceptibility to EBV lytic activation. In loss-of-function and gain-of-function studies in EBV-positive B lymphoma and lymphoblastoid cells, we found that the levels of functional STAT3 regulate susceptibility to EBV lytic activation. This prompted us to identify a pool of candidate cellular genes that might be regulated by STAT3 to limit EBV lytic activation. From this pool, we confirmed increases in transcript levels in refractory cells of a set of genes known to participate in transcription repression. Taken together, our findings place STAT3 at a critical crossroads between EBV latency and lytic activation, processes fundamental to EBV lymphomagenesis. PMID:23966384

  14. Signal transducer and activator of transcription 3 (Stat3) expression and activation in rat uterus during early pregnancy.

    PubMed

    Teng, Chun-Bo; Diao, Hong-Lu; Ma, Hong; Cong, Jing; Yu, Hao; Ma, Xing-Hong; Xu, Li-Bin; Yang, Zeng-Ming

    2004-08-01

    Signal transducer and activator of transcription 3 (Stat3), a member of the Stat family, is specifically activated during mouse embryo implantation. The aim of this study was to investigate the expression, activation and regulation of Stat3 in rat uterus during early pregnancy, pseudopregnancy, delayed implantation and artificial decidualization. Stat3 mRNA was highly expressed in the luminal epithelium on day 5 and in the luminal epithelium and underlying stromal cells at implantation sites on day 6 of pregnancy. There was a strong level of Stat3 protein expression and phosphorylation in the stromal cells near the lumen and in the luminal epithelium on day 5 of pregnancy, which was similar to day 5 of pseudopregnancy. In the afternoon of day 6, the strong level of Stat3 phosphorylation was detected only in the luminal epithelium. Stat3 was highly expressed and activated in the decidual cells from days 7 to 9 of pregnancy and under artificial decidualization in the present study. Our results suggest that the strong level of Stat3 activation in the luminal epithelium and underlying stromal cells during the pre-implantation period may be important for establishing uterine receptivity as in mice, and the high level of Stat3 expression and activation in decidual cells may play a role during decidualization.

  15. Hypoxia induces chemoresistance in ovarian cancer cells by activation of signal transducer and activator of transcription 3

    PubMed Central

    Selvendiran, Karuppaiyah; Bratasz, Anna; Kuppusamy, M. Lakshmi; Tazi, Mia F.; Rivera, Brian K.; Kuppusamy, Periannan

    2010-01-01

    Signal transducer and activator of transcription 3 (STAT3) is activated in a variety of human cancers, including ovarian cancer. The molecular mechanism by which the STAT3 is activated in cancer cells is poorly understood. We observed that human ovarian xenograft tumors (A2780) in mice were severely hypoxic (pO2 ∼ 2 mmHg). We further observed that hypoxic exposure significantly increased the phosphorylation of STAT3 (pSTAT3) at the Tyr705 residue in A2780 cell line. The pSTAT3 (Tyr705) level was highly dependent on cellular oxygenation levels, with a significant increase at <2% O2, and without any change in the pSTAT3 (Ser727) or total STAT3 levels. The pSTAT3 (Tyr705) elevation following hypoxic exposure could be reversed within 12 hr after returning the cells to normoxia. The increased level of pSTAT3 was partly mediated by increased levels of reactive oxygen species generation in the hypoxic cancer cells. Conventional chemotherapeutic drugs cisplatin and taxol were far less effective in eliminating the hypoxic ovarian cancer cells suggesting a role for pSTAT3 in cellular resistance to chemotherapy. Inhibition of STAT3 by AG490 followed by treatment with cisplatin or taxol resulted in a significant increase in apoptosis suggesting that hypoxia-induced STAT3 activation is responsible for chemoresistance. The results have important clinical implications for the treatment of hypoxic ovarian tumors using STAT3-specific inhibitors. PMID:19623660

  16. Sleep Loss Activates Cellular Inflammation and Signal Transducer and Activator of Transcription (STAT) Family Proteins in Humans

    PubMed Central

    Irwin, Michael R.; Witarama, Tuff; Caudill, Marissa; Olmstead, Richard; Breen, Elizabeth Crabb

    2014-01-01

    Sleep disturbance and short sleep duration are associated with inflammation and related disorders including cardiovascular disease, arthritis, diabetes mellitus, and certain cancers. This study was undertaken to test the effects of experimental sleep loss on spontaneous cellular inflammation and activation of signal transducer and activator of transcription (STAT) family proteins, which together promote an inflammatory microenvironment. In 24 healthy adults (16 females; 8 males), spontaneous production of IL-6 and TNF in monocytes and spontaneous intranuclear expression of activated STAT1, STAT3, and STAT5 in peripheral blood mononuclear cells (PBMC), monocyte-, and lymphocyte populations were measured in the morning after uninterrupted baseline sleep, partial sleep deprivation (PSD, sleep period from 3 a.m. to 7 a.m.), and recovery sleep. Relative to baseline, spontaneous monocytic expression of IL-6 and TNF-α was significantly greater after PSD (P<0.02) and after recovery sleep (P<0.01). Relative to baseline, spontaneous monocytic expression of activated STAT 1 and STAT 5 was significantly greater after recovery sleep (P<0.007P<0.02, respectively) but not STAT 3 (P=0.09). No changes in STAT1, STAT3, or STAT5 were found in lymphocyte populations. Sleep loss induces activation of spontaneous cellular innate immunity and of STAT family proteins, which together map the dynamics of sleep loss on the molecular signaling pathways that regulate inflammatory and other immune responses. Treatments that target short sleep duration have the potential to constrain inflammation and reduce the risk for inflammatory disorders and some cancers in humans. PMID:25451613

  17. Peroxisome proliferator-activated receptor gamma regulates expression of signal transducer and activator of transcription 5A

    SciTech Connect

    Olsen, Hanne; Haldosen, Lars-Arne . E-mail: Lars-Arne.Haldosen@mednut.ki.se

    2006-05-01

    Signal transducer and activator of transcription 5A (STAT5A) has been shown to be important for terminal differentiation of mammary epithelial cells. In order to understand regulation of expression of STAT5A, the 5' end of the mouse Stat5a gene was isolated. Putative regulatory elements was searched for and several peroxisome proliferator response elements (PPREs) were found, one with high (12/13 nucleotides) and three with less (8-10/13) similarity to the reported consensus sequence. Mouse mammary epithelial HC11 cells were treated with peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) ligand, the thiazolidinedione (TZD) troglitazone, and an increase in STAT5A protein expression was seen. The 5' flank of Stat5a gene was cloned in a luciferase reporter vector. A concentration dependent activation of the STAT5A-luciferase reporter was detected, when transiently transfected HC11 cells were treated with TZD. The activation could be inhibited by treatment with a PPAR{gamma} antagonist. It has earlier been shown that epidermal growth factor (EGF) induces MAPK phosphorylation of PPAR{gamma} resulting in a less transcriptionally active receptor. In HC11 cells, EGF inhibited TZD induced STAT5A-reporter activity suggesting that our previously reported EGF-mediated suppression of STAT5A expression is mediated in all or partly through inhibition of PPAR{gamma} activity. Furthermore, the MEK inhibitor PD98059 inhibited the EGF effect. All together, data presented suggest that PPAR{gamma} participates in regulation of STAT5A expression.

  18. Leukemia inhibitory factor and NGF regulate signal transducers and activators of transcription activation in sympathetic ganglia: convergence of cytokine- and neurotrophin-signaling pathways.

    PubMed

    Rajan, P; Gearan, T; Fink, J S

    1998-08-17

    We have used the response of the superior cervical ganglia (SCG) to axotomy to investigate interactions between neuropoietic cytokines and neurotrophins. Postganglionic sympathetic axotomy leads to a prolonged leukemia inhibitory factor (LIF)-dependent activation of signal transducers and activators of transcription (STAT) factors. To study regulation of LIF-dependent activation of STAT proteins and to mimic the loss of target-derived NGF resulting from postganglionic axotomy in vivo, SCG were explanted into media lacking NGF and activation of STAT proteins was assessed by electrophoretic mobility shift assay. Like postganglionic axotomy in vivo. STAT proteins were activated for up to 8 days after explantation of SCG in vitro. SCG cultured in the presence of NGF showed decreased STAT binding when compared to ganglia cultured in NGF-free media. This inhibition of STAT activation by NGF was only present in ganglia cultured for more than 5 days and was mimicked by brain-derived neurotrophic factor (BDNF). The serine kinase inhibitor H7 augmented the increase of STAT binding produced by explantation, suggesting the presence of a labile repressor of STAT activation in the SCG. These data indicated that the neuropoietic cytokine-signaling pathway interacts with neurotrophin and H7-sensitive-signaling pathways to regulate activation of STAT proteins in sympathetic neurons. Moreover, these data suggest that one of the mechanisms leading to prolonged activation of STAT proteins after postganglionic axotomy in vivo is loss of target-derived neurotrophins.

  19. Signal Transducer and Activator of Transcription (STAT)-3 Activates Nuclear Factor (NF)-κB in Chronic Lymphocytic Leukemia Cells

    PubMed Central

    Liu, Zhiming; Hazan-Halevy, Inbal; Harris, David M.; Li, Ping; Ferrajoli, Alessandra; Faderl, Stefan; Keating, Michael J.; Estrov, Zeev

    2014-01-01

    Nuclear factor (NF)-κB plays a major role in the pathogenesis of B-cell neoplasms. A broad array of mostly extracellular stimuli has been reported to activate NF-κB, to various degrees, in chronic lymphocytic leukemia (CLL) cells. Because CLL cells harbor high levels of unphosphorylated (U) signal transducer and activator of transcription (STAT)-3 protein and U-STAT3 was reported to activate NF-κB, we sought to determine whether U-STAT3 activates NF-κB in CLL. Using the electrophoretic mobility shift assay (EMSA) we studied peripheral blood low-density cells from 15 patients with CLL and found that CLL cell nuclear extracts from all the samples bound to an NF-κB DNA probe, suggesting that NF-κB is constitutively activated in CLL. Immunoprecipitation studies showed that STAT3 bound NF-κB p65, and confocal microscopy studies detected U-STAT3/NF-κB complexes in the nuclei of CLL cells, thereby confirming these findings. Furthermore, infection of CLL cells with retroviral STAT3-shRNA attenuated the binding of NF-κB to DNA, as assessed by EMSA, and downregulated mRNA levels of NF-κB-regulated genes, as assessed by quantitative polymerase chain reaction. Taken together, our data suggest that U-STAT3 binds to the NF-κB p50/p65 dimers and that the U-STAT3/NF-κB complexes bind to DNA and activate NF-κB-regulated genes in CLL cells. PMID:21364020

  20. Emerging therapeutic paradigms to target the dysregulated Janus kinase/signal transducer and activator of transcription pathway in hematological malignancies.

    PubMed

    Mughal, Tariq I; Girnius, Saulius; Rosen, Steven T; Kumar, Shaji; Wiestner, Adrian; Abdel-Wahab, Omar; Kiladjian, Jean-Jacques; Wilson, Wyndham H; Van Etten, Richard A

    2014-09-01

    Over the past decade, there has been increasing biochemical evidence that the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is aberrantly activated in malignant cells from patients with a wide spectrum of cancers of the blood and immune systems. The emerging availability of small molecule inhibitors of JAK and other signaling molecules in the JAK/STAT pathway has allowed preclinical studies validating an important role of this pathway in the pathogenesis of many hematologic malignancies, and provided motivation for new strategies for treatment of these diseases. Here, a round-table panel of experts review the current preclinical and clinical landscape of the JAK/STAT pathway in acute lymphoid and myeloid leukemias, lymphomas and myeloma, and chronic myeloid neoplasms.

  1. Mechanisms of disease: Insights into the emerging role of signal transducers and activators of transcription in cancer.

    PubMed

    Haura, Eric B; Turkson, James; Jove, Richard

    2005-06-01

    Members of the signal transducers and activators of transcription (STAT) pathway, which were originally identified as key components linking cytokine signals to transcriptional events in cells, have recently been demonstrated to have a major role in cancer. They are cytoplasmic proteins that form functional dimers with each other when activated by tyrosine phosphorylation. Activated STAT proteins translocate to the nucleus to regulate expression of genes by binding to specific elements within gene promoters. Constitutive activation of the STAT family members Stat3 and Stat5, and/or loss of Stat1 signaling, is found in a large group of diverse tumors. Increasing evidence demonstrates that STAT proteins can regulate many pathways important in oncogenesis including cell-cycle progression, apoptosis, tumor angiogenesis, tumor-cell invasion and metastasis, and tumor-cell evasion of the immune system. Based on these findings, a growing effort is underway to target STAT proteins directly and indirectly for cancer therapy. This review will highlight STAT signaling pathways, STAT target genes involved in cancer, evidence for STAT activation in human cancers, and therapeutic strategies to target STAT molecules for anticancer therapy.

  2. Activated signal transducers and activators of transcription 3 signaling induces CD46 expression and protects human cancer cells from complement-dependent cytotoxicity.

    PubMed

    Buettner, Ralf; Huang, Mei; Gritsko, Tanya; Karras, Jim; Enkemann, Steve; Mesa, Tania; Nam, Sangkil; Yu, Hua; Jove, Richard

    2007-08-01

    CD46 is one of the complement-regulatory proteins expressed on the surface of normal and tumor cells for protection against complement-dependent cytotoxicity. Cancer cells need to access the blood circulation for continued growth and metastasis, thus exposing themselves to destruction by complement system components. Previous studies have established that the signal transducers and activators of transcription 3 (STAT3) transcription factor is persistently activated in a wide variety of human cancer cells and primary tumor tissues compared with their normal counterparts. Using microarray gene expression profiling, we identified the CD46 gene as a target for activated STAT3 signaling in human breast and prostate cancer cells. The CD46 promoter contains two binding sites for activated STAT3 and mutations introduced into the major site abolished STAT3 binding. Chromatin immunoprecipitation confirms binding of STAT3 to the CD46 promoter. CD46 promoter activity is induced by activation of STAT3 and blocked by a dominant-negative form of STAT3 in luciferase reporter assays. CD46 mRNA expression is induced by interleukin-6 and by transient transfection of normal human epithelial cells with a persistently active mutant construct of STAT3, STAT3C. Furthermore, we show that inhibition of STAT3-mediated CD46 cell surface expression sensitizes DU145 prostate cancer cells to cytotoxicity in an in vitro complement lysis assay using rabbit anti-DU145 antiserum and rabbit complement. These results show that activated STAT3 signaling induces the CD46 promoter and protects human cancer cells from complement-dependent cytotoxicity, suggesting a potential mechanism whereby oncogenic signaling contributes to tumor cell evasion of antibody-mediated immunity.

  3. Signal transducer and activator of transcription 3 in myeloid-derived suppressor cells: an opportunity for cancer therapy

    PubMed Central

    Dufait, Inès; Van Valckenborgh, Els; Menu, Eline; Escors, David; De Ridder, Mark; Breckpot, Karine

    2016-01-01

    Cancer progression is in part determined by interactions between cancer cells and stromal cells in the tumor microenvironment (TME). The identification of cytotoxic tumor-infiltrating lymphocytes has instigated research into immune stimulating cancer therapies. Although a promising direction, immunosuppressive mechanisms exerted at the TME hamper its success. Myeloid-derived suppressor cells (MDSCs) have come to the forefront as stromal cells that orchestrate the immunosuppressive TME. Consequently, this heterogeneous cell population has been the object of investigation. Studies revealed that the transcription factor signal transducer and activator of transcription 3 (STAT3) largely dictates the recruitment, activation and function of MDSCs in the TME. Therefore, this review will focus on the role of this key transcription factor during the MDSC's life cycle and on the therapeutic opportunities it offers. PMID:27029037

  4. 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.

  5. lschemic preconditioning in pigs: a causal role for signal transducer and activator of transcription 3.

    PubMed

    Gent, Sabine; Skyschally, Andreas; Kleinbongard, Petra; Heusch, Gerd

    2017-03-01

    Ischemic preconditioning (IPC), i.e., brief episodes of nonlethal myocardial ischemia-reperfusion (I/R) before sustained ischemia with subsequent reperfusion, reduces infarct size in all species tested so far, including humans. In rodents, the cardioprotective signal transduction causally involves an activation of Akt, ERK1/2, and STAT3. However, there are apparent species differences in the signal transduction between rodents and larger mammals such as pigs, where data on IPC's signal transduction are inconsistent for Akt and ERK1/2. The role of STAT3 has not yet been analyzed. Pigs were subjected to 60 min of left anterior descending coronary artery occlusion and 180 min of reperfusion without or with IPC (2 cycles of 3-min occlusion separated by 2 min of reperfusion 15 min before sustained I/R). Infarct size was analyzed by triphenyl tetrazolium chloride staining, and Akt, ERK1/2, and STAT3 phosphorylation was quantified in myocardial biopsies taken at baseline and early reperfusion. AG490 was used to block the STAT3 signaling pathway. IPC reduced infarct size (%area at risk; mean ± SE, I/R, 45 ± 3 vs. IPC, 18 ± 3, P < 0.05). Akt and ERK1/2 phosphorylation was increased at early reperfusion without and with IPC. In contrast, STAT3 phosphorylation at early reperfusion was only increased with IPC (%baseline; mean ± SE, I/R, 126 ± 29 vs. IPC, 408 ± 147, P < 0.05). AG490 prevented the IPC-related increase of STAT3 phosphorylation at reperfusion (%baseline; mean ± SE, 82 ± 12) and abolished IPC's cardioprotection (%area at risk; mean ± SE, 35 ± 4). In pigs, increased phosphorylation of STAT3 is causally involved, whereas Akt and ERK1/2 seem to play no role in IPC's cardioprotection.NEW & NOTEWORTHY In pig hearts in situ, ischemic preconditioning (IPC) causally involves increased phosphorylation of STAT3, whereas Akt and ERK1/2 play no role for cardioprotection. The cardioprotective signal transduction of IPC is similar to that of ischemic postconditioning

  6. Effects of activated ACM on expression of signal transducers in cerebral cortical neurons of rats.

    PubMed

    Wang, Xiaojing; Li, Zhengli; Zhu, Changgeng; Li, Zhongyu

    2007-06-01

    To explore the roles of astrocytes in the epileptogenesis, astrocytes and neurons were isolated, purified and cultured in vitro from cerebral cortex of rats. The astrocytes were activated by ciliary neurotrophic factor (CNTF) and astrocytic conditioned medium (ACM) was collected to treat neurons for 4, 8 and 12 h. By using Western blot, the expression of calmodulin dependent protein kinase II (CaMK II), inducible nitric oxide synthase (iNOS) and adenylate cyclase (AC) was detected in neurons. The results showed that the expression of CaMK II, iNOS and AC was increased significantly in the neurons treated with ACM from 4 h to 12 h (P<0.05), and that of iNOS and AC peaked at 8 h and 12 h respectively. It was suggested that there might be some epileptogenic factors in the ACM and such signal pathways as NOS-NO-cGMP, Ca2+/CaM-CaMK II and AC-cAMP-PKA might take part in the signal transduction of epileptogenesis.

  7. How Intrinsic Molecular Dynamics Control Intramolecular Communication in Signal Transducers and Activators of Transcription Factor STAT5

    PubMed Central

    Langenfeld, Florent; Guarracino, Yann; Arock, Michel; Trouvé, Alain; Tchertanov, Luba

    2015-01-01

    Signal Transducer and Activator of Transcription STAT5 is a key mediator of cell proliferation, differentiation and survival. While STAT5 activity is tightly regulated in normal cells, its constitutive activation directly contributes to oncogenesis and is associated with a broad range of hematological and solid tumor cancers. Therefore the development of compounds able to modulate pathogenic activation of this protein is a very challenging endeavor. A crucial step of drug design is the understanding of the protein conformational features and the definition of putative binding site(s) for such modulators. Currently, there is no structural data available for human STAT5 and our study is the first footprint towards the description of structure and dynamics of this protein. We investigated structural and dynamical features of the two STAT5 isoforms, STAT5a and STAT5b, taken into account their phosphorylation status. The study was based on the exploration of molecular dynamics simulations by different analytical methods. Despite the overall folding similarity of STAT5 proteins, the MD conformations display specific structural and dynamical features for each protein, indicating first, sequence-encoded structural properties and second, phosphorylation-induced effects which contribute to local and long-distance structural rearrangements interpreted as allosteric event. Further examination of the dynamical coupling between distant sites provides evidence for alternative profiles of the communication pathways inside and between the STAT5 domains. These results add a new insight to the understanding of the crucial role of intrinsic molecular dynamics in mediating intramolecular signaling in STAT5. Two pockets, localized in close proximity to the phosphotyrosine-binding site and adjacent to the channel for communication pathways across STAT5, may constitute valid targets to develop inhibitors able to modulate the function-related communication properties of this signaling

  8. Phosphorylation of signal transducer and activator of transcription 1 reduces bortezomib-mediated apoptosis in cancer cells

    PubMed Central

    Kao, C; Chao, A; Tsai, C L; Lin, C Y; Chuang, W C; Chen, H W; Yen, T C; Wang, T H; Lai, C H; Wang, H S

    2013-01-01

    The potent and selective proteasome inhibitor bortezomib has shown remarkable antitumor activity and is now entering clinical trials for several cancers. However, the molecular mechanisms by which bortezomib induces cytotoxicity in ovarian cancer cells still remain unclear. In this study, we show that bortezomib induced apoptosis, which was demonstrated by the downregulation of antiapoptotic molecules (Bcl-2, Bcl-XL, p-Bad, and p-AKT) and the upregulation of proapoptotic proteins (p21, p27, and cleaved-Bid) in ovarian cancer cell lines. Moreover, bortezomib stimulates Janus kinase (JAK) phosphorylation and activates heat-shock transcription factor-1 (HSF-1) and heat-shock protein 70 (HSP70), ultimately leading to signal transducer and activator of transcription 1 (STAT1) phosphorylation. Phosphorylated STAT1 partially counteracted apoptosis induced by bortezomib in cancer cells. These findings suggest that the antitumor activity of bortezomib in ovarian cancer can be improved by inhibiting bortezomib-induced STAT1 phosphorylation. This effect can be achieved by STAT1 knockdown, HSP70 knockdown, JAK inhibition, or the addition of cisplatin, one of the most commonly used anticancer drugs. These results provide the first evidence that STAT1 phosphorylation can play a role in bortezomib resistance by exerting antiapoptotic effects. They also suggest the possibility to abolish or reduce bortezomib chemoresistance in ovarian cancer by the addition of cisplatin or JAK inhibitors. PMID:23449448

  9. Signal transducer and activator of transcription 2 deficiency is a novel disorder of mitochondrial fission.

    PubMed

    Shahni, Rojeen; Cale, Catherine M; Anderson, Glenn; Osellame, Laura D; Hambleton, Sophie; Jacques, Thomas S; Wedatilake, Yehani; Taanman, Jan-Willem; Chan, Emma; Qasim, Waseem; Plagnol, Vincent; Chalasani, Annapurna; Duchen, Michael R; Gilmour, Kimberly C; Rahman, Shamima

    2015-10-01

    Defects of mitochondrial dynamics are emerging causes of neurological disease. In two children presenting with severe neurological deterioration following viral infection we identified a novel homozygous STAT2 mutation, c.1836 C>A (p.Cys612Ter), using whole exome sequencing. In muscle and fibroblasts from these patients, and a third unrelated STAT2-deficient patient, we observed extremely elongated mitochondria. Western blot analysis revealed absence of the STAT2 protein and that the mitochondrial fission protein DRP1 (encoded by DNM1L) is inactive, as shown by its phosphorylation state. All three patients harboured decreased levels of DRP1 phosphorylated at serine residue 616 (P-DRP1(S616)), a post-translational modification known to activate DRP1, and increased levels of DRP1 phosphorylated at serine 637 (P-DRP1(S637)), associated with the inactive state of the DRP1 GTPase. Knockdown of STAT2 in SHSY5Y cells recapitulated the fission defect, with elongated mitochondria and decreased P-DRP1(S616) levels. Furthermore the mitochondrial fission defect in patient fibroblasts was rescued following lentiviral transduction with wild-type STAT2 in all three patients, with normalization of mitochondrial length and increased P-DRP1(S616) levels. Taken together, these findings implicate STAT2 as a novel regulator of DRP1 phosphorylation at serine 616, and thus of mitochondrial fission, and suggest that there are interactions between immunity and mitochondria. This is the first study to link the innate immune system to mitochondrial dynamics and morphology. We hypothesize that variability in JAK-STAT signalling may contribute to the phenotypic heterogeneity of mitochondrial disease, and may explain why some patients with underlying mitochondrial disease decompensate after seemingly trivial viral infections. Modulating JAK-STAT activity may represent a novel therapeutic avenue for mitochondrial diseases, which remain largely untreatable. This may also be relevant for more

  10. Molecular cloning and expression analysis of signal transducer and activator of transcription (STAT) from the Chinese white shrimp Fenneropenaeus chinensis.

    PubMed

    Sun, Chen; Shao, Hong-Lian; Zhang, Xiao-Wen; Zhao, Xiao-Fan; Wang, Jin-Xing

    2011-11-01

    Innate immunity is the first line of defense by a host against invading pathogens. Several signaling pathways participate in the immune response, one of which is the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Various evidences have been provided to suggest that the JAK/STAT pathway is involved in both antibacterial and antiviral immunities. In this study, the full-length cDNA and gene sequence of STAT (designated as FcSTAT) was cloned from the Chinese white shrimp, Fenneropenaeus chinensis. Phylogenetic analysis reveals that the FcSTAT is clustered with STAT5s and STAT6s from vertebrates and STATs from invertebrates. Quantitative real-time PCR exhibited that the FcSTAT had a wide distribution in all detected tissues and developmental stages. Time course analysis of the transcription level after WSSV challenge showed a noticeably early up-regulation of FcSTAT in hemocytes, hepatopancreas, and intestines. The expression levels of FcSTAT increased corresponding to Vibrio anguillarum stimulation in both hemocytes and hepatopancreas as well. All these imply that the JAK/STAT pathway participates in the immune response against bacteria and virus in F. chinensis.

  11. Cross-Talk between CLL Cells and Bone Marrow Endothelial Cells: Role of Signal Transducer and Activator of Transcription-3

    PubMed Central

    Badoux, Xavier; Bueso-Ramos, Carlos; Harris, David; Li, Ping; Liu, Zhiming; Burger, Jan; O’Brien, Susan; Ferrajoli, Alessandra; Keating, Michael J.; Estrov, Zeev

    2014-01-01

    Summary Chronic lymphocytic leukemia (CLL) bone marrow is characterized by increased angiogenesis. However, the molecular mediators of neovascularization and the biological significance of increased endothelial cell proliferation in CLL require further investigation. Because signal transducer and activator of transcription (STAT)-3 is constitutively activated in CLL we studied the role of STAT3 in modulating vascular endothelial growth factor (VEGF) expression and the effect of vascular endothelial cells on CLL cells. Using chromatin immunoprecipitation (ChIP) we found that anti-STAT3 antibodies immunoprecipitated DNA of STAT3, VEGF and other STAT3-regulated genes. In addition, STAT3-short interfering RNA significantly reduced mRNA levels of VEGF in CLL cells suggesting that STAT3 induces VEGF expression in CLL. Remarkably, bone marrow CLL cells expressed high levels of VEGF and high VEGF levels were detected in the plasma of patients with untreated CLL and correlated with white blood cell count. CLL bone marrow biopsies revealed increased microvascular density and attachment of CLL cells to endothelial cells. Co-culture of CLL and human umbilical vein endothelial cells (HUVEC) cells showed a similar attachment. Furthermore, co-culture studies with HUVEC showed that HUVEC protected CLL cells from spontaneous apoptosis by direct cell-to-cell contact as assessed by flow cytometry using Annexin V. Our data suggest that constitutively activated STAT3 induces VEGF production by CLL cells and CLL cells derive a survival advantage from endothelial cells via cell-to cell contact. PMID:21733558

  12. Signal transducer and activator of transcription (STAT)-3 regulates microRNA gene expression in chronic lymphocytic leukemia cells

    PubMed Central

    2013-01-01

    Backgrounds Approximately 1,000 microRNAs (miRs) are present in the human genome; however, little is known about the regulation of miR transcription. Because miR levels are deregulated in chronic lymphocytic leukemia (CLL) and signal transducer and activator of transcription (STAT)-3 is constitutively activated in CLL, we sought to determine whether STAT3 affects the transcription of miR genes in CLL cells. Methods We used publically available data from the ENCODE project to identify putative STAT3 binding sites in the promoters of miR genes. Then we transfected CLL cells with STAT3-shRNA or with an empty vector, and to determine which miRs are differentially expressed, we used a miR microarray approach followed by validation of the microarray results for 6 miRs using quantitative real-time polymerase chain reaction (qRT-PCR). Results We identified putative STAT3 binding sites in 160 promoter regions of 200 miRs, including miR-21, miR-29, and miR-155, whose levels have been reported to be upregulated in CLL. Levels of 72 miRs were downregulated (n = 63) or upregulated (n = 9). qRT-PCR confirmed the array data in 5 of 6 miRs. Conclusions The presence of activated STAT3 has a profound effect on miR expression in CLL cells. PMID:23725032

  13. RADIO-ACTIVE TRANSDUCER

    DOEpatents

    Wanetick, S.

    1962-03-01

    ABS>ure the change in velocity of a moving object. The transducer includes a radioactive source having a collimated beam of radioactive particles, a shield which can block the passage of the radioactive beam, and a scintillation detector to measure the number of radioactive particles in the beam which are not blocked by the shield. The shield is operatively placed across the radioactive beam so that any motion normal to the beam will cause the shield to move in the opposite direction thereby allowing more radioactive particles to reach the detector. The number of particles detected indicates the acceleration. (AEC)

  14. A hardware model of the auditory periphery to transduce acoustic signals into neural activity

    PubMed Central

    Tateno, Takashi; Nishikawa, Jun; Tsuchioka, Nobuyoshi; Shintaku, Hirofumi; Kawano, Satoyuki

    2013-01-01

    To improve the performance of cochlear implants, we have integrated a microdevice into a model of the auditory periphery with the goal of creating a microprocessor. We constructed an artificial peripheral auditory system using a hybrid model in which polyvinylidene difluoride was used as a piezoelectric sensor to convert mechanical stimuli into electric signals. To produce frequency selectivity, the slit on a stainless steel base plate was designed such that the local resonance frequency of the membrane over the slit reflected the transfer function. In the acoustic sensor, electric signals were generated based on the piezoelectric effect from local stress in the membrane. The electrodes on the resonating plate produced relatively large electric output signals. The signals were fed into a computer model that mimicked some functions of inner hair cells, inner hair cell–auditory nerve synapses, and auditory nerve fibers. In general, the responses of the model to pure-tone burst and complex stimuli accurately represented the discharge rates of high-spontaneous-rate auditory nerve fibers across a range of frequencies greater than 1 kHz and middle to high sound pressure levels. Thus, the model provides a tool to understand information processing in the peripheral auditory system and a basic design for connecting artificial acoustic sensors to the peripheral auditory nervous system. Finally, we discuss the need for stimulus control with an appropriate model of the auditory periphery based on auditory brainstem responses that were electrically evoked by different temporal pulse patterns with the same pulse number. PMID:24324432

  15. Protein tyrosine phosphatase Meg2 dephosphorylates signal transducer and activator of transcription 3 and suppresses tumor growth in breast cancer

    PubMed Central

    2012-01-01

    Introduction Signal transducer and activator of transcription 3 (STAT3) is over-activated or phosphorylated in breast cancers. The hyper-phosphorylation of STAT3 was attributed to either up-regulated phosphorylation by several tyrosine-kinases or down-regulated activity of phosphatases. Although several factors have been identified to phosphorylate STAT3, it remains unclear how STAT3 is dephosphorylated by PTPMeg2. The aim of this study was to determine the role of PTPMeg2 as a phosphatase in regulation of the activity of STAT3 in breast cancers. Methods Immunoprecipitation assays were used to study the interaction of STAT3 with PTPMeg2. A series of biochemistry experiments were performed to evaluate the role of PTPMeg2 in the dephosphorylation of STAT3. Two breast cancer cell lines MCF7 (PTPMeg2 was depleted as it was endogenously high) and MDA-MB-231 (PTPMeg2 was overexpressed as it was endogenously low) were used to compare the level of phosphorylated STAT3 and the tumor growth ability in vitro and in vivo. Samples from breast carcinoma (n = 73) were subjected to a pair-wise Pearson correlation analysis for the correlation of levels of PTPMeg2 and phosphorylated STAT3. Results PTPMeg2 directly interacts with STAT3 and mediates its dephosphorylation in the cytoplasm. Over-expression of PTPMeg2 decreased tyrosine phosphorylation of STAT3 while depletion of PTPMeg2 increased its phosphorylation. The decreased tyrosine phosphorylation of STAT3 is coupled with suppression of STAT3 transcriptional activity and reduced tumor growth in vitro and in vivo. Levels of PTPMeg2 and phosphorylated STAT3 were inversely correlated in breast cancer tissues (P = 0.004). Conclusions PTPMeg2 is an important phosphatase for the dephosphorylation of STAT3 and plays a critical role in breast cancer development. PMID:22394684

  16. Signal transducer and activator of transcription 3 (STAT3) homologue in turbot (Scophthalmus maximus): molecular characterization and expression analysis.

    PubMed

    Wang, Na; Yang, Chang-Geng; Sun, Zhong-Zhi; Wang, Xian-Li; Chen, Song-Lin

    2011-01-01

    Signal transducer and activator of transcription 3 (STAT3) acts as an important mediator in multiple biological processes induced by different cytokines. So far, little information is available in fish STAT3. In this study, turbot (Scophthalmus maximus) STAT3 gene was cloned and characterized for the first time. The turbot STAT3 full-length cDNA consists of 2355 nucleotides encoding a polypeptide of 784 amino acids with four conserved domains including STAT_int, STAT_alpha, STAT_bind and SH2 domain. The phylogenetic tree showed that turbot STAT3 shared the closest relationship with mandarin fish (Siniperca chuatsi) STAT3. The autoactivation experiment in yeast proved that turbot STAT3 was a strong transcription factor. The quantitative RT-PCR experiment indicated that Stat3 mRNA was expressed in widespread tissues with the highest expression levels in the liver. And the further expression patterns analysis revealed that turbot Stat3 expression levels were increased in liver, spleen, kidney of fish infected with Vibrio anguillarum and liver of fish infected with LCDV. Meantime, hepcidin, one of STAT3 target gene, was also up-regulated in liver of fish infected with two pathogens. These results suggested that turbot Stat3 may involved in the immune defense process as a transcription factor.

  17. Involvement of the Janus Kinase/Signal Transducer and Activator of Transcription Signaling Pathway in Multiple Sclerosis and the Animal Model of Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Liu, Yudong; McFarland, Braden C.; Qin, Hongwei

    2014-01-01

    Multiple sclerosis (MS) and its animal model of experimental autoimmune encephalomyelitis (EAE) are characterized by focal inflammatory infiltrates into the central nervous system, demyelinating lesions, axonal damage, and abundant production of cytokines that activate immune cells and damage neurons and oligodendrocytes, including interleukin-12 (IL-12), IL-6, IL-17, IL-21, IL-23, granulocyte macrophage-colony stimulating factor, and interferon-gamma. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway mediates the biological activities of these cytokines and is essential for the development and regulation of immune responses. Dysregulation of the JAK/STAT pathway contributes to numerous autoimmune diseases, including MS/EAE. The JAK/STAT pathway is aberrantly activated in MS/EAE because of excessive production of cytokines, loss of expression of negative regulators such as suppressors of cytokine signaling proteins, and significant enrichment of genes encoding components of the JAK/STAT pathway, including STAT3. Specific JAK/STAT inhibitors have been used in numerous preclinical models of MS and demonstrate beneficial effects on the clinical course of disease and attenuation of innate and adaptive immune responses. In addition, other drugs such as statins, glatiramer acetate, laquinimod, and fumarates have beneficial effects that involve inhibition of the JAK/STAT pathway. We conclude by discussing the feasibility of the JAK/STAT pathway as a target for neuroinflammatory diseases. PMID:25084174

  18. Preclinical Characterization of Signal Transducer and Activator of Transcription 3 Small Molecule Inhibitors for Primary and Metastatic Brain Cancer Therapy

    PubMed Central

    Assi, Hikmat H.; Paran, Chris; VanderVeen, Nathan; Savakus, Jonathan; Doherty, Robert; Petruzzella, Emanuele; Hoeschele, James D.; Appelman, Henry; Raptis, Leda; Mikkelsen, Tom; Lowenstein, Pedro R.

    2014-01-01

    Signal transducer and activator of transcription 3 (STAT3) has been implicated as a hub for multiple oncogenic pathways. The constitutive activation of STAT3 is present in several cancers, including gliomas (GBMs), and is associated with poor therapeutic responses. Phosphorylation of STAT3 triggers its dimerization and nuclear transport, where it promotes the transcription of genes that stimulate tumor growth. In light of this role, inhibitors of the STAT3 pathway are attractive therapeutic targets for cancer. To this end, we evaluated the STAT3-inhibitory activities of three compounds (CPA-7 [trichloronitritodiammineplatinum(IV)], WP1066 [(S,E)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-phenylethyl)acrylamide, C17H14BrN3O], and ML116 [4-benzyl-1-{thieno[2,3-d]pyrimidin-4-yl}piperidine, C18H19N3S]) in cultured rodent and human glioma cells, including GBM cancer stem cells. Our results demonstrate a potent induction of growth arrest in GBM cells after drug treatment with a concomitant induction of cell death. Although these compounds were effective at inhibiting STAT3 phosphorylation, they also displayed variable dose-dependent inhibition of STAT1, STAT5, and nuclear factor κ light-chain enhancer of activated B cells. The therapeutic efficacy of these compounds was further evaluated in peripheral and intracranial mouse tumor models. Whereas CPA-7 elicited regression of peripheral tumors, both melanoma and GBM, its efficacy was not evident when the tumors were implanted within the brain. Our data suggest poor permeability of this compound to tumors located within the central nervous system. WP1066 and ML116 exhibited poor in vivo efficacy. In summary, CPA-7 constitutes a powerful anticancer agent in models of peripheral solid cancers. Our data strongly support further development of CPA-7–derived compounds with increased permeability to enhance their efficacy in primary and metastatic brain tumors. PMID:24696041

  19. Preclinical characterization of signal transducer and activator of transcription 3 small molecule inhibitors for primary and metastatic brain cancer therapy.

    PubMed

    Assi, Hikmat H; Paran, Chris; VanderVeen, Nathan; Savakus, Jonathan; Doherty, Robert; Petruzzella, Emanuele; Hoeschele, James D; Appelman, Henry; Raptis, Leda; Mikkelsen, Tom; Lowenstein, Pedro R; Castro, Maria G

    2014-06-01

    Signal transducer and activator of transcription 3 (STAT3) has been implicated as a hub for multiple oncogenic pathways. The constitutive activation of STAT3 is present in several cancers, including gliomas (GBMs), and is associated with poor therapeutic responses. Phosphorylation of STAT3 triggers its dimerization and nuclear transport, where it promotes the transcription of genes that stimulate tumor growth. In light of this role, inhibitors of the STAT3 pathway are attractive therapeutic targets for cancer. To this end, we evaluated the STAT3-inhibitory activities of three compounds (CPA-7 [trichloronitritodiammineplatinum(IV)], WP1066 [(S,E)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-phenylethyl)acrylamide, C17H14BrN3O], and ML116 [4-benzyl-1-{thieno[2,3-d]pyrimidin-4-yl}piperidine, C18H19N3S]) in cultured rodent and human glioma cells, including GBM cancer stem cells. Our results demonstrate a potent induction of growth arrest in GBM cells after drug treatment with a concomitant induction of cell death. Although these compounds were effective at inhibiting STAT3 phosphorylation, they also displayed variable dose-dependent inhibition of STAT1, STAT5, and nuclear factor κ light-chain enhancer of activated B cells. The therapeutic efficacy of these compounds was further evaluated in peripheral and intracranial mouse tumor models. Whereas CPA-7 elicited regression of peripheral tumors, both melanoma and GBM, its efficacy was not evident when the tumors were implanted within the brain. Our data suggest poor permeability of this compound to tumors located within the central nervous system. WP1066 and ML116 exhibited poor in vivo efficacy. In summary, CPA-7 constitutes a powerful anticancer agent in models of peripheral solid cancers. Our data strongly support further development of CPA-7-derived compounds with increased permeability to enhance their efficacy in primary and metastatic brain tumors.

  20. Evaluation of quantitative assays for the identification of direct signal transducer and activator of transcription 3 (STAT3) inhibitors.

    PubMed

    Furtek, Steffanie L; Matheson, Christopher J; Backos, Donald S; Reigan, Philip

    2016-11-22

    In many forms of cancer the signal transducer and activator of transcription 3 (STAT3) transcription factor remains constitutively active, driving cancer survival and progression. The critical role of STAT3 in tumorigenesis has prompted a campaign of drug discovery programs to identify small molecules that disrupt the function of STAT3, with more recent efforts focusing on direct STAT3 inhibition. There are two target binding sites for direct STAT3 inhibitors: the SH2 dimerization domain and the DNA-binding domain. An in vitro fluorescence polarization assay, using recombinant STAT3 protein, has successfully identified compounds that target the SH2 domain; however, no assay has been reported to identify inhibitors that bind the DNA-binding domain. The lack of such a quantitative assay has limited the identification and development of STAT3 DNA-binding domain inhibitors. Here, we report a modified DNA-binding ELISA to incorporate recombinant STAT3 protein to evaluate small molecules that prevent STAT3-DNA binding. The concomitant use of the ELISA and fluorescence polarization assay enables the classification of direct STAT3 inhibitors by their site of action. Our data provide further support that niclosamide inhibits STAT3 through interaction with the DNA-binding domain. Furthermore, the ELISA can support medicinal chemistry efforts by identifying DNA-binding domain inhibitors and allowing the determination of an IC50 value, supporting the ranking of inhibitors and development of structure-activity relationships. Therefore, we propose a tandem evaluation approach to identify small molecules that target the SH2 domain or the DNA-binding domain of STAT3, which allows for quantitative evaluation of candidate STAT3 inhibitors.

  1. Evaluation of quantitative assays for the identification of direct signal transducer and activator of transcription 3 (STAT3) inhibitors

    PubMed Central

    Furtek, Steffanie L.; Matheson, Christopher J.; Backos, Donald S.; Reigan, Philip

    2016-01-01

    In many forms of cancer the signal transducer and activator of transcription 3 (STAT3) transcription factor remains constitutively active, driving cancer survival and progression. The critical role of STAT3 in tumorigenesis has prompted a campaign of drug discovery programs to identify small molecules that disrupt the function of STAT3, with more recent efforts focusing on direct STAT3 inhibition. There are two target binding sites for direct STAT3 inhibitors: the SH2 dimerization domain and the DNA-binding domain. An in vitro fluorescence polarization assay, using recombinant STAT3 protein, has successfully identified compounds that target the SH2 domain; however, no assay has been reported to identify inhibitors that bind the DNA-binding domain. The lack of such a quantitative assay has limited the identification and development of STAT3 DNA-binding domain inhibitors. Here, we report a modified DNA-binding ELISA to incorporate recombinant STAT3 protein to evaluate small molecules that prevent STAT3-DNA binding. The concomitant use of the ELISA and fluorescence polarization assay enables the classification of direct STAT3 inhibitors by their site of action. Our data provide further support that niclosamide inhibits STAT3 through interaction with the DNA-binding domain. Furthermore, the ELISA can support medicinal chemistry efforts by identifying DNA-binding domain inhibitors and allowing the determination of an IC50 value, supporting the ranking of inhibitors and development of structure-activity relationships. Therefore, we propose a tandem evaluation approach to identify small molecules that target the SH2 domain or the DNA-binding domain of STAT3, which allows for quantitative evaluation of candidate STAT3 inhibitors. PMID:27793003

  2. Investigation and analysis of single nucleotide polymorphisms in Janus kinase/signal transducer and activator of transcription genes with leukemia.

    PubMed

    Zhong, Yuejiao; Wu, Jianzhong; Chen, Baoan; Ma, Rong; Cao, Haixia; Wang, Zhuo; Cheng, Lu; Ding, Jiahua; Feng, Jifeng

    2012-06-01

    Aberrant activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway may predispose to leukemia due to deregulation of proliferation, differentiation or apoptosis. This study was conducted to investigate whether any association exists between genetic polymorphisms in the JAK2, STAT3 and STAT5 genes and individual susceptibility to leukemia. A case-control study was carried out using a Chinese sample set with 344 cases of leukemia and 346 controls matched by age and ethnicity. Genomic DNA was assayed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) on 13 single nucleotide polymorphisms (SNPs). Genotype analyses showed that two SNPs, namely rs17886724 and rs2293157 located in STAT3 and STAT5, respectively, were significantly associated with leukemia (p < 0.05 for all). Interaction analyses of SNPs (rs17886724|rs2293157; rs11079041| rs2293157) showed that there were inferior associations in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) compared to the control group (0.1 > p > 0.05). Linkage disequilibrium existed between rs11079041 and rs2293157 in both leukemia and control groups (r(2) = 0.7). The haplotypes displayed significant association between rs11079041 and rs2293157 in both leukemia and control groups (p < 0.05). The accuracy rate of the support vector machine (SVM) classification model in making a prediction of leukemia was 97%. The results indicated that STAT3 and STAT5 gene SNPs may be prognostic of leukemia.

  3. Manassantin A and B from Saururus chinensis inhibit interleukin-6-induced signal transducer and activator of transcription 3 activation in Hep3B cells.

    PubMed

    Chang, Jong Sun; Lee, Seung Woong; Kim, Myo Sun; Yun, Bo Ra; Park, Mi Hye; Lee, Seok-Geun; Park, Su-Jin; Lee, Woo Song; Rho, Mun-Chual

    2011-01-01

    Inhibition of interleukin-6 (IL-6) has been postulated to be an effective therapy in the pathogenesis of several inflammatory diseases. The current study was performed to examine potential effects of manassantin A and B isolated from Saururus chinensis on the IL-6-induced response to human hepatoma cells. We found that manassantin A and B inhibit signal transducer and activator of transcription 3 (Stat3) activity stimulated by IL-6. We also found that both compounds decreased IL-6-induced Stat3 phosphorylation and nuclear translocation. Both compounds blocked suppressor of cytokine signaling 3 (SOCS-3)-mRNA expression induced by IL-6. In addition, we found that Stat3 inhibitory effects of these compounds could be related to protein tyrosine phosphatase. These findings suggest that manassantin A and B could be useful remedies for treatment of inflammatory diseases by inhibiting IL-6 action.

  4. Photochemical "triode" molecular signal transducer.

    PubMed

    Keirstead, Amy E; Bridgewater, James W; Terazono, Yuichi; Kodis, Gerdenis; Straight, Stephen; Liddell, Paul A; Moore, Ana L; Moore, Thomas A; Gust, Devens

    2010-05-12

    A molecular "hexad" in which five bis(phenylethynyl)anthracene (BPEA) fluorophores and a dithienylethene photochrome are organized by a central hexaphenylbenzene unit has been prepared. Singlet-singlet energy transfer among the BPEA units occurs on the 0.4 and 60 ps time scales, and when the dithienylethene is in the open form, the BPEA units fluoresce in the 515 nm region with a quantum yield near unity. When the dithienylethene is photoisomerized by UV light to the closed form, which absorbs in the 500-700 nm region, the closed isomer strongly quenches all of the excited singlet states of BPEA via energy transfer, causing the fluorescence quantum yield to drop to near zero. This photochemical behavior permits the hexad to function in a manner analogous to a triode vacuum tube or transistor. When a solution of the hexad is irradiated with steady-state light at 350 nm and with red light (>610 nm) of modulated intensity, the BPEA fluorescence excited by the 350 nm light is modulated accordingly. The fluorescence corresponds to the output of a triode tube or transistor and the modulated red light to the grid signal of the tube or gate voltage of the transistor. Frequency modulation, amplitude modulation, and phase modulation are all observed. The unusual ability to modulate intense, shorter-wavelength fluorescence with longer-wavelength light could be useful for the detection of fluorescence from probe molecules without interference from other emitters in biomolecular or nanotechnological applications.

  5. Involvement of fish signal transducer and activator of transcription 3 (STAT3) in SGIV replication and virus induced paraptosis.

    PubMed

    Huang, Xiaohong; Huang, Youhua; Yang, Ying; Wei, Shina; Qin, Qiwei

    2014-12-01

    Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor which plays crucial roles in immune regulation, inflammation, cell proliferation, transformation, and other physiological processes of the organism. In this study, a novel STAT3 gene from orange spotted grouper (Ec-STAT3) was cloned and characterized. Bioinformatic analysis revealed that full-length of Ec-STAT3 was 3105-bp long and contained a 280-bp 5'UTR, a 470-bp 3'UTR, and a 2355-bp open reading frame (ORF) that encoded a 784-amino acid peptide. The deduced protein of Ec-STAT3 showed 98% identity to that of turbot (Scophthalmus maximus). Amino acid alignment showed that Ec-STAT3 contained four conserved domains, including a protein interaction domain, a coiled coil domain, a DNA binding domain, and an SH2 domain. Quantitative real-time PCR analysis showed that the highest expression level was detected in the liver, followed by skin and spleen. After injection with Singapore grouper iridovirus (SGIV), the transcript of Ec-STAT3 in spleen was increased significantly. To further explore the function of Ec-STAT3, we investigated the roles of Ec-STAT3 in SGIV infection in vitro. Immune fluorescence analysis indicated that SGIV infection altered the distribution of phosphorylated Ec-STAT3 in nucleus, and a small part of phosphorylated Ec-STAT3 was associated with virus assembly sites, suggesting that Ec-STAT3 might be important for SGIV infection. Using STAT3 specific inhibitor, S3I-201, we found that inhibition of Ec-STAT3 activation decreased the SGIV replication significantly. Moreover, inhibition of Ec-STAT3 activation obviously altered SGIV infection induced cell cycle arrest and the expression of pro-survival genes, including Bcl-2, Bcl-xL and Bax inhibitor. Together, our results firstly demonstrated the critical roles of fish STAT3 in DNA virus replication and virus induced paraptosis, but also provided new insights into the mechanism of iridovirus pathogenesis.

  6. Cellular prion protein transduces neuroprotective signals

    PubMed Central

    Chiarini, Luciana B.; Freitas, Adriana R.O.; Zanata, Silvio M.; Brentani, Ricardo R.; Martins, Vilma R.; Linden, Rafael

    2002-01-01

    To test for a role for the cellular prion protein (PrPc) in cell death, we used a PrPc-binding peptide. Retinal explants from neonatal rats or mice were kept in vitro for 24 h, and anisomycin (ANI) was used to induce apoptosis. The peptide activated both cAMP/protein kinase A (PKA) and Erk pathways, and partially prevented cell death induced by ANI in explants from wild-type rodents, but not from PrPc-null mice. Neuroprotection was abolished by treatment with phosphatidylinositol-specific phospholipase C, with human peptide 106–126, with certain antibodies to PrPc or with a PKA inhibitor, but not with a MEK/Erk inhibitor. In contrast, antibodies to PrPc that increased cAMP also induced neuroprotection. Thus, engagement of PrPc transduces neuroprotective signals through a cAMP/PKA-dependent pathway. PrPc may function as a trophic receptor, the activation of which leads to a neuroprotective state. PMID:12093733

  7. 21 CFR 870.2060 - Transducer signal amplifier and conditioner.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Transducer signal amplifier and conditioner. 870.2060 Section 870.2060 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Transducer signal amplifier and conditioner. (a) Identification. A transducer signal amplifier...

  8. 21 CFR 870.2060 - Transducer signal amplifier and conditioner.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Transducer signal amplifier and conditioner. 870.2060 Section 870.2060 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Transducer signal amplifier and conditioner. (a) Identification. A transducer signal amplifier...

  9. 21 CFR 870.2060 - Transducer signal amplifier and conditioner.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Transducer signal amplifier and conditioner. 870.2060 Section 870.2060 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Transducer signal amplifier and conditioner. (a) Identification. A transducer signal amplifier...

  10. 21 CFR 870.2060 - Transducer signal amplifier and conditioner.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Transducer signal amplifier and conditioner. 870.2060 Section 870.2060 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Transducer signal amplifier and conditioner. (a) Identification. A transducer signal amplifier...

  11. 21 CFR 870.2060 - Transducer signal amplifier and conditioner.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Transducer signal amplifier and conditioner. 870.2060 Section 870.2060 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Transducer signal amplifier and conditioner. (a) Identification. A transducer signal amplifier...

  12. Signal processing schemes for optical voltage transducer

    NASA Astrophysics Data System (ADS)

    Chen, Jinling; Xie, Delin; Chen, Hongbin; Xie, Latang; Song, Jianhe; Luo, Xiaoni

    2006-02-01

    This paper describes an optical voltage transducer(OVT) for a 35kV system based on Pockels effect in a BGO(Bi 4Ge 3O 12) crystal. OVT used to measure the voltage of power are superior to conventional electromagnet-induced voltage transducer in many aspects, thus it has great potential to applications. It has some advantages. These advantages are: 1)Optics provides total galvanic separation between the measuring point at high voltage (HV) potential and the measuring equipment at ground potential. 2)Transmission of measuring signals in optical fibers is immune to induced electromagnetic noise even in EMI-environment of switchyards and other high voltage installations. 3)Optics and especially optical fibers make the insulation costs independent of voltage levels thus giving an economical advantage at voltage levels above 100kV. 4)The use of optics is expected to reduce the weight of the transducers. 5)Optical transducers are expected to have a large bandwidth than conventional transducers. 6)The output-signals from an optical transducer are easily interfaced with computers and electronically operated equipment such as digital relays. New techniques developed in electronics and optical field including fiber optic technology bring new contributions to the measurement of voltage and electric field. A Pockels voltage sensor has been widely introduced to electrical power transmission and distribution systems and some advantage of the optical voltage measuring techniques are reported. In this paper, a brief summary of electro-optic effects and the principle of OVT is proposed. The signal processing schemes of different optical path and features are analyzed. The basic principle of OVT is to modulate the irradiance of the light-directed to OVT by an optical fiber-according to the potential difference between the HV-line and the ground potential. The modulation of the light is accomplished by placing a material-that has an optical property (the birefringence), which is

  13. Viral protein R of HIV type-1 induces retrotransposition and upregulates glutamate synthesis by the signal transducer and activator of transcription 1 signaling pathway.

    PubMed

    Doi, Akihiro; Iijima, Kenta; Kano, Shigeyuki; Ishizaka, Yukihito

    2015-07-01

    Viral protein R (Vpr) of HIV-1 plays an important role in viral replication in macrophages. Various lines of evidence suggest that expression of Vpr in macrophages causes immunopathogenesis; however, the underlying mechanism is not yet fully understood. In this study, it was shown that recombinant Vpr (rVpr) induces retrotransposition of long interspersed element-1 in RAW264.7, a macrophage-like cell line, and activates reverse transcriptase-dependent immunotoxic cascades including production of IFN-β and phosphorylation of signal transducer and activator of transcription 1 (STAT1). Knockout experiments based on the CRISPR/Cas9 nickase system further demonstrated that cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and stimulator of interferon gene (STING) are responsible for IFN-β production and STAT1 phosphorylation, respectively. Moreover, rVpr was found to increase production of glutaminase C, a regulator of glutamate synthesis, which is also dependent on the cGAS-STING pathway. Taken together with reports that glutaminase C is involved in the pathogenesis of HIV-associated neurocognitive disorder (HAND) and that Vpr is detectable in the cerebrospinal fluid of HIV-1-positive patients, a possible role of Vpr-induced L1-RTP and immunotoxic cascades in the development of HAND is discussed.

  14. Apigenin induces caspase-dependent apoptosis by inhibiting signal transducer and activator of transcription 3 signaling in HER2-overexpressing SKBR3 breast cancer cells.

    PubMed

    Seo, Hye-Sook; Ku, Jin Mo; Choi, Han-Seok; Woo, Jong-Kyu; Jang, Bo-Hyoung; Go, Hoyeon; Shin, Yong Cheol; Ko, Seong-Gyu

    2015-08-01

    Phytoestrogens have been demonstrated to inhibit tumor induction; however, their molecular mechanisms of action have remained elusive. The present study aimed to investigate the effects of a phytoestrogen, apigenin, on proliferation and apoptosis of the human epidermal growth factor receptor 2 (HER2)-expressing breast cancer cell line SKBR3. Proliferation assay, MTT assay, fluorescence-activated cell sorting analysis, western blot analysis, immunocytochemistry, reverse transcription-polymerase chain reaction and ELISA assay were used in the present study. The results of the present study indicated that apigenin inhibited the proliferation of SKBR3 cells in a dose-and time-dependent manner. This inhibition of growth was accompanied by an increase in the sub-G0/G1 apoptotic population. Furthermore, apigenin enhanced the expression levels of cleaved caspase-8 and -3, and induced the cleavage of poly(adenosine diphosphate ribose) polymerase in SKBR3 cells, confirming that apigenin promotes apoptosis via a caspase-dependent pathway. Apigenin additionally reduced the expression of phosphorylated (p)-janus kinase 2 and p-signal transducer and activator of transcription 3 (STAT3), inhibited CoCl2-induced vascular endothelial growth factor (VEGF) secretion and decreased the nuclear localization of STAT3. The STAT3 inhibitor S31-201 decreased the cellular proliferation rate and reduced the expression of p-STAT3 and VEGF. Therefore, these results suggested that apigenin induced apoptosis via the inhibition of STAT3 signaling in SKBR3 cells. In conclusion, the results of the present study indicated that apigenin may be a potentially useful compound for the prevention or treatment of HER2-overexpressing breast cancer.

  15. The guanylyl cyclase-A receptor transduces an atrial natriuretic peptide/ATP activation signal in the absence of other proteins.

    PubMed

    Wong, S K; Ma, C P; Foster, D C; Chen, A Y; Garbers, D L

    1995-12-22

    Attempts to activate partially purified preparations of the guanylyl cyclase-A (GC-A) receptor with atrial natriuretic peptide (ANP) have previously failed, leading to speculation that essential cofactors are lost during purification procedures. The receptor was modified to contain the FLAG epitope (DYKDDDDK), expressed in Sf9 cells, and purified to apparent homogeneity (4.3 mumol cyclic GMP formed/min/mg protein; 5.8 mmol 125I-ANP binding site/mg protein) by a combination of immunoaffinity, Q-Sepharose FF, and wheat germ agglutinin batch chromatography. High initial protein/detergent ratios, the presence of glycerol (40%), and the inclusion of protein phosphatase inhibitors in all buffers resulted in the purification of a receptor that continued to transduce the ANP/ATP activation signal. Both native and purified GC-A contained a single class of high affinity ANP binding sites (Kd = 60 pM) and an equivalent EC50 for ATP (0.3 mM). Positive cooperativity as a function of MnGTP was retained during purification. Thus, GC-A is capable of transducing a ligand binding signal in the absence of other proteins.

  16. MicroR-146 blocks the activation of M1 macrophage by targeting signal transducer and activator of transcription 1 in hepatic schistosomiasis.

    PubMed

    He, Xing; Tang, Rui; Sun, Yue; Wang, Yan-Ge; Zhen, Kui-Yang; Zhang, Dong-Mei; Pan, Wei-Qing

    2016-11-01

    Schistosomiasis is a chronic disease caused by the parasite of the Schistosoma genus and is characterized by egg-induced hepatic granulomas and fibrosis. Macrophages play a central role in schistosomiasis with several studies highlighting their differentiation into M2 cells involved in the survival of infected mice through limitation of immunopathology. However, little is known regarding the mechanisms of regulating macrophage differentiation. Here, we showed that the early stage of infection by Schistosoma japonicum induced expression of type 1T-helper-cell (Th1) cytokine, interferon-γ (IFN-γ), leading to increase in M1 cells. However, the presence of liver-trapped eggs induced the expression of Th2 cytokines including interleukin-4 (IL-4), IL-10, and IL-13 that upregulated the transcription of miR-146b by activating signal transducer and activator of transcription 3/6 (STAT3/6) that bind to the promoter of the pre-miR-146b gene. We found that the miR-146a/b was significantly upregulated in macrophages during the progression of hepatic schistosomiasis. The elevated miR-146a/b inhibited the IFN-γ-induced differentiation of macrophages to M1 cells through targeting STAT1. Our data indicate the protective roles of miR-146a/b in hepatic schistosomiasis through regulating the differentiation of macrophages into M2 cells.

  17. Isolation and expression profile of a gene encoding for the Signal Transducer and Activator of Transcription STAT2 in Atlantic salmon (Salmo salar).

    PubMed

    Collet, Bertrand; Ganne, Géraldine; Bird, Steve; Collins, Catherine M

    2009-07-01

    Signal Transducer and Activator of Transcription (STAT)-2 is a molecule involved in the type I interferon (IFN) signalling pathway. The full length cDNA sequence of Atlantic salmon (Salmo salar) ssSTAT2 was determined and phylogenetic analysis of the amino acid sequence grouped this novel salmon gene to the STAT2 clade. This represents the first fish STAT2 report. The gene encodes for a 802 aa polypeptide that has 38% identity to the human or murine STAT2. The expression was monitored by qPCR in the kidney of animals over the time of infection with the Infectious Salmon Anaemia Virus (ISAV) and in TO cells infected with Infectious Pancreatic Necrosis Virus (IPNV) or with the Salmon Alphavirus (SAV). SAV and ISAV induced an approximate 10-fold increase in the level of expression of ssSTAT2 gene whilst IPNV only induced a 1.5-fold increase.

  18. Constitutive activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor κB signaling in glioblastoma cancer stem cells regulates the Notch pathway.

    PubMed

    Garner, Jo Meagan; Fan, Meiyun; Yang, Chuan He; Du, Ziyun; Sims, Michelle; Davidoff, Andrew M; Pfeffer, Lawrence M

    2013-09-06

    Malignant gliomas are locally aggressive, highly vascular tumors that have a dismal prognosis, and present therapies provide little improvement in the disease course and outcome. Many types of malignancies, including glioblastoma, originate from a population of cancer stem cells (CSCs) that are able to initiate and maintain tumors. Although CSCs only represent a small fraction of cells within a tumor, their high tumor-initiating capacity and therapeutic resistance drives tumorigenesis. Therefore, it is imperative to identify pathways associated with CSCs to devise strategies to selectively target them. In this study, we describe a novel relationship between glioblastoma CSCs and the Notch pathway, which involves the constitutive activation of STAT3 and NF-κB signaling. Glioma CSCs were isolated and maintained in vitro using an adherent culture system, and the biological properties were compared with the traditional cultures of CSCs grown as multicellular spheres under nonadherent culture conditions. Interestingly, both adherent and spheroid glioma CSCs show constitutive activation of the STAT3/NF-κB signaling pathway and up-regulation of STAT3- and NF-κB-dependent genes. Gene expression profiling also identified components of the Notch pathway as being deregulated in glioma CSCs, and the deregulated expression of these genes was sensitive to treatment with STAT3 and NF-κB inhibitors. This finding is particularly important because Notch signaling appears to play a key role in CSCs in a variety of cancers and controls cell fate determination, survival, proliferation, and the maintenance of stem cells. The constitutive activation of STAT3 and NF-κB signaling pathways that leads to the regulation of Notch pathway genes in glioma CSCs identifies novel therapeutic targets for the treatment of glioma.

  19. TRAF6 is a signal transducer for interleukin-1.

    PubMed

    Cao, Z; Xiong, J; Takeuchi, M; Kurama, T; Goeddel, D V

    1996-10-03

    Many cytokines signal through different cell-surface receptors to activate the transcription factor NF-kappaB. Members of the TRAF protein family have been implicated in the activation of NF-kappaB by the tumour-necrosis factor (TNF)-receptor superfamily. Here we report the identification of a new TRAF family member, designated TRAF6. When overexpressed in human 293 cells, TRAF6 activates NF-kappaB. A dominant-negative mutant of TRAF6 inhibits NF-kappaB activation signalled by interleukin-1 (IL-1) but not by TNF. IL-1 treatment of 293 cells induces the association of TRAF6 with IRAK, a serine/threonine kinase that is rapidly recruited to the IL-1 receptor after IL-1 induction. These findings indicate that TRAF proteins may function as signal transducers for distinct receptor families and that TRAF6 participates in IL-1 signalling.

  20. Acoustic Emission Transducers: Calibration Activities and Transducer Development.

    DTIC Science & Technology

    2014-09-26

    transducer calibration and development activities -j at NBS is summiarized. DO Fo"� roiion or olv as is OBSOLETE DOS/N 0 102. LP.60 4. 6601...developed. This development was partially supported by the Electric Power Research Institute and the Office of Naval Research. The calibration subjects the...and tangential components of motion must be measured tb describe the dynamic displacement at a point on a surface. We previously have developed the NBS

  1. Vav1 transduces T cell receptor signals to the activation of phospholipase C-gamma1 via phosphoinositide 3-kinase-dependent and -independent pathways.

    PubMed

    Reynolds, Lucinda F; Smyth, Lesley A; Norton, Trisha; Freshney, Norman; Downward, Julian; Kioussis, Dimitris; Tybulewicz, Victor L J

    2002-05-06

    Vav1 is a signal transducing protein required for T cell receptor (TCR) signals that drive positive and negative selection in the thymus. Furthermore, Vav1-deficient thymocytes show greatly reduced TCR-induced intracellular calcium flux. Using a novel genetic system which allows the study of signaling in highly enriched populations of CD4(+)CD8(+) double positive thymocytes, we have studied the mechanism by which Vav1 regulates TCR-induced calcium flux. We show that in Vav1-deficient double positive thymocytes, phosphorylation, and activation of phospholipase C-gamma1 (PLCgamma1) is defective. Furthermore, we demonstrate that Vav1 regulates PLCgamma1 phosphorylation by at least two distinct pathways. First, in the absence of Vav1 the Tec-family kinases Itk and Tec are no longer activated, most likely as a result of a defect in phosphoinositide 3-kinase (PI3K) activation. Second, Vav1-deficient thymocytes show defective assembly of a signaling complex containing PLCgamma1 and the adaptor molecule Src homology 2 domain-containing leukocyte phosphoprotein 76. We show that this latter function is independent of PI3K.

  2. Vav1 Transduces T Cell Receptor Signals to the Activation of Phospholipase C-γ1 via Phosphoinositide 3-Kinase-dependent and -independent Pathways

    PubMed Central

    Reynolds, Lucinda F.; Smyth, Lesley A.; Norton, Trisha; Freshney, Norman; Downward, Julian; Kioussis, Dimitris; Tybulewicz, Victor L.J.

    2002-01-01

    Vav1 is a signal transducing protein required for T cell receptor (TCR) signals that drive positive and negative selection in the thymus. Furthermore, Vav1-deficient thymocytes show greatly reduced TCR-induced intracellular calcium flux. Using a novel genetic system which allows the study of signaling in highly enriched populations of CD4+CD8+ double positive thymocytes, we have studied the mechanism by which Vav1 regulates TCR-induced calcium flux. We show that in Vav1-deficient double positive thymocytes, phosphorylation, and activation of phospholipase C-γ1 (PLCγ1) is defective. Furthermore, we demonstrate that Vav1 regulates PLCγ1 phosphorylation by at least two distinct pathways. First, in the absence of Vav1 the Tec-family kinases Itk and Tec are no longer activated, most likely as a result of a defect in phosphoinositide 3-kinase (PI3K) activation. Second, Vav1-deficient thymocytes show defective assembly of a signaling complex containing PLCγ1 and the adaptor molecule Src homology 2 domain–containing leukocyte phosphoprotein 76. We show that this latter function is independent of PI3K. PMID:11994416

  3. Proline-rich tyrosine kinase 2 via enhancing signal transducer and activator of transcription 3-dependent cJun expression mediates retinal neovascularization

    PubMed Central

    Kumar, Raj; Singh, Nikhlesh K.; Rao, Gadiparthi N.

    2016-01-01

    Despite the involvement of proline-rich tyrosine kinase 2 (Pyk2) in endothelial cell angiogenic responses, its role in pathological retinal angiogenesis is not known. In the present study, we show that vascular endothelial growth factor A (VEGFA) induces Pyk2 activation in mediating human retinal microvascular endothelial cell (HRMVEC) migration, sprouting and tube formation. Downstream to Pyk2, VEGFA induced signal transducer and activator of transcription 3 (STAT3) activation and cJun expression in the modulation of HRMVEC migration, sprouting and tube formation. Consistent with these observations, hypoxia induced activation of Pyk2-STAT3-cJun signaling axis and siRNA-mediated downregulation of Pyk2, STAT3 or cJun levels substantially inhibited hypoxia-induced retinal endothelial cell proliferation, tip cell formation and neovascularization. Together, these observations suggest that activation of Pyk2-mediated STAT3-cJun signaling is required for VEGFA-induced HRMVEC migration, sprouting and tube formation in vitro and hypoxia-induced retinal endothelial cell proliferation, tip cell formation and neovascularization in vivo. PMID:27210483

  4. NOX3 NADPH Oxidase Couples Transient Receptor Potential Vanilloid 1 to Signal Transducer and Activator of Transcription 1-Mediated Inflammation and Hearing Loss

    PubMed Central

    Mukherjea, Debashree; Jajoo, Sarvesh; Sheehan, Kelly; Kaur, Tejbeer; Sheth, Sandeep; Bunch, Jennifer; Perro, Christopher; Rybak, Leonard P.

    2011-01-01

    Abstract Transient receptor potential vanilloid 1 (TRPV1) is implicated in cisplatin ototoxicity. Activation of this channel by cisplatin increases reactive oxygen species generation, which contribute to loss of outer hair cells in the cochlea. Knockdown of TRPV1 by short interfering RNA protected against cisplatin ototoxicity. In this study, we examined the mechanism underlying TRPV1-mediated ototoxicity using cultured organ of Corti transformed cells (UB/OC-1) and rats. Trans-tympanic injections of capsaicin produced transient hearing loss within 24 h, which recovered by 72 h. In UB/OC-1 cells, capsaicin increased NOX3 NADPH oxidase activity and activation of signal transducer and activator of transcription 1 (STAT1). Intratympanic administration of capsaicin transiently increased STAT1 activity and expression of downstream proinflammatory molecules. Capsaicin produced a transient increase in CD14-positive inflammatory cells into the cochlea, which mimicked the temporal course of STAT1 activation but did not alter the expression of apoptotic genes or damage to outer hair cells. In addition, trans-tympanic administration of STAT1 short interfering RNA protected against capsaicin-induced hearing loss. These data suggest that activation of TRPV1 mediates temporary hearing loss by initiating an inflammatory process in the cochlea via activation of NOX3 and STAT1. Thus, these proteins represent reasonable targets for ameliorating hearing loss. Antioxid. Redox Signal. 14, 999–1010. PMID:20712533

  5. Activation of Janus kinase/signal transducers and activators of transcription pathway involved in megakaryocyte proliferation induced by vanadium resembles some aspects of essential thrombocythemia.

    PubMed

    Gonzalez-Villalva, Adriana; Piñon-Zarate, Gabriela; Falcon-Rodriguez, Carlos; Lopez-Valdez, Nelly; Bizarro-Nevares, Patricia; Rojas-Lemus, Marcela; Rendon-Huerta, Erika; Colin-Barenque, Laura; Fortoul, Teresa I

    2016-05-01

    Vanadium (V) is an air pollutant released into the atmosphere by burning fossil fuels. Also, it has been recently evaluated for their carcinogenic potential to establish permissible limits of exposure at workplaces. We previously reported an increase in the number and size of platelets and their precursor cells and megakaryocytes in bone marrow and spleen. The aim of this study was to identify the involvement of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and thrombopoietin (TPO) receptor, and myeloproliferative leukemia virus oncogene (Mpl), in megakaryocyte proliferation induced by this compound. Mice were exposed twice a week to vanadium pentoxide inhalation (0.02 M) and were killed at 4th, 6th, and 8th week of exposure. Phosphorylated JAK2 (JAK2 ph), STAT3 (STAT3 ph), STAT5, and Mpl were identified in mice spleen megakaryocytes by cytofluorometry and immunohistochemistry. An increase in JAK2 ph and STAT3 ph, but a decrease in Mpl at 8-week exposure was identified in our findings. Taking together, we propose that the morphological findings, JAK/STAT activation, and decreased Mpl receptor induced by V leads to a condition comparable to essential thrombocythemia, so the effect on megakaryocytes caused by different mechanisms is similar. We also suggest that the decrease in Mpl is a negative feedback mechanism after the JAK/STAT activation. Since megakaryocytes are platelet precursors, their alteration affects platelet morphology and function, which might have implications in hemostasis as demonstrated previously, so it is important to continue evaluating the effects of toxics and pollutants on megakaryocytes and platelets.

  6. Signal Transducers and Activators of Transcription (STAT) Regulatory Networks in Marine Organisms: From Physiological Observations towards Marine Drug Discovery

    PubMed Central

    Lee, Jin-Young; Orlikova, Barbora; Diederich, Marc

    2015-01-01

    Part of our ocean’s richness comes from its extensive history of supporting life, resulting in a highly diverse ecological system. To date, over 250,000 species of marine organisms have been identified, but it is speculated that the actual number of marine species exceeds one million, including several hundreds of millions of species of marine microorganisms. Past studies suggest that approximately 70% of all deep-sea microorganisms, gorgonians, and sea sponges produce secondary metabolites with anti-cancer activities. Recently, novel FDA-approved drugs derived from marine sponges have been shown to reduce metastatic breast cancer, malignant lymphoma, and Hodgkin’s disease. Despite the fact that many marine natural products have been shown to possess a good inhibition potential against most of the cancer-related cell signaling pathways, only a few marine natural products have been shown to target JAK/STAT signaling. In the present paper, we describe the JAK/STAT signaling pathways found in marine organisms, before elaborating on the recent advances in the field of STAT inhibition by marine natural products and the potential application in anti-cancer drug discovery. PMID:26262624

  7. Novel synthetic (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol inhibits arthritis by targeting signal transducer and activator of transcription 3

    PubMed Central

    Son, Dong Ju; Kim, Dae Hwan; Nah, Seong-Su; Park, Mi Hee; Lee, Hee Pom; Han, Sang Bae; Venkatareddy, Udumula; Gann, Benjamin; Rodriguez, Kevin; Burt, Scott R.; Ham, Young Wan; Jung, Yu Yeon; Hong, Jin Tae

    2016-01-01

    Rheumatoid arthritis (RA) is a severely debilitating chronic autoimmune disease that leads to long-term joint damage. Signal transducer and activator of transcription 3 (STAT3)-targeted small molecules have shown promise as therapeutic drugs for treating RA. We previously identified (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (BHPB), a tyrosine-fructose Maillard reaction product, as a small molecule with potent anti-inflammatory and anti-arthritic properties, mediated through the inhibition of STAT3 activation. The aim of this study was to develop a novel BHPH derivative with improved anti-arthritic properties and drug-likeness. We designed and synthesised (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a novel synthetic BHPB analogue, and investigated its anti-inflammatory and anti-arthritic activities in experimentally-induced RA. We showed that MMPP strongly inhibited pro-inflammatory responses by inhibiting in vitro STAT3 activation and its downstream signalling in murine macrophages and human synoviocytes from patients with RA. Furthermore, we demonstrated that MMPP exhibited potent anti-arthritic activity in a collagen antibody-induced arthritis (CAIA) mouse model in vivo. Collectively, our results suggest that MMPP has great potential for use in the treatment of RA. PMID:27845373

  8. Molecular cloning, subcelluar location and expression profile of signal transducer and activator of transcription 2 (STAT2) from turbot, Scophthalmus maximus.

    PubMed

    Wang, Na; Wang, Xian-Li; Yang, Chang-Geng; Chen, Song-Lin

    2013-10-01

    Signal transducer and activator of transcription 2 (STAT2) is an important molecule involved in the type I interferon signalling pathway. To date, little STAT2 homologue is available in fish except Atlantic salmon and goldfish. In this paper, STAT2 was firstly cloned and characterized from turbot, a marine flatfish with high economic value. Briefly, turbot STAT2 cDNA is 3206 bp in length encoding a predicted protein of 793 amino acids. The phylogenetic tree shows that turbot STAT2 protein shared the closest relationship with Atlantic salmon. Analysis of subcellular distribution indicates that STAT2 is mainly present in the cytoplasm of TK cells. Stat2 mRNA is constitutively expressed in widespread tissues and induced by several folds in turbot tissues and TK cells after stimulation with Vibrio anguillarum and lymphocystis disease virus (LCDV). Unlike the higher vertebrate STAT2, turbot STAT2 nuclear export signal (NES) exists not in the C-terminal 79 amino acids but in N-terminal 137-312 amino acids (STAT_alpha domain). The nuclear translocation of turbot STAT2 after Poly(I:C) treatment proved its transcription activity in TK cells. All these results suggested that STAT2 may be involved in the immune response in turbot as a transcription factor.

  9. NOX3 NADPH oxidase couples transient receptor potential vanilloid 1 to signal transducer and activator of transcription 1-mediated inflammation and hearing loss.

    PubMed

    Mukherjea, Debashree; Jajoo, Sarvesh; Sheehan, Kelly; Kaur, Tejbeer; Sheth, Sandeep; Bunch, Jennifer; Perro, Christopher; Rybak, Leonard P; Ramkumar, Vickram

    2011-03-15

    Transient receptor potential vanilloid 1 (TRPV1) is implicated in cisplatin ototoxicity. Activation of this channel by cisplatin increases reactive oxygen species generation, which contribute to loss of outer hair cells in the cochlea. Knockdown of TRPV1 by short interfering RNA protected against cisplatin ototoxicity. In this study, we examined the mechanism underlying TRPV1-mediated ototoxicity using cultured organ of Corti transformed cells (UB/OC-1) and rats. Trans-tympanic injections of capsaicin produced transient hearing loss within 24 h, which recovered by 72 h. In UB/OC-1 cells, capsaicin increased NOX3 NADPH oxidase activity and activation of signal transducer and activator of transcription 1 (STAT1). Intratympanic administration of capsaicin transiently increased STAT1 activity and expression of downstream proinflammatory molecules. Capsaicin produced a transient increase in CD14-positive inflammatory cells into the cochlea, which mimicked the temporal course of STAT1 activation but did not alter the expression of apoptotic genes or damage to outer hair cells. In addition, trans-tympanic administration of STAT1 short interfering RNA protected against capsaicin-induced hearing loss. These data suggest that activation of TRPV1 mediates temporary hearing loss by initiating an inflammatory process in the cochlea via activation of NOX3 and STAT1. Thus, these proteins represent reasonable targets for ameliorating hearing loss.

  10. Signal transducer and activator of transcription 2 (STAT2) metabolism coupling postmitotic outgrowth to visual and sound perception network in human left cerebrum by biocomputation.

    PubMed

    Wang, Lin; Huang, Juxiang; Jiang, Minghu; Lin, Hong

    2012-07-01

    We constructed the high-expression signal transducer and activator of transcription 2 (STAT2) metabolism coupling postmitotic outgrowth to visual and sound perception network in human left cerebrum compared with low-expression (fold change ≥2) chimpanzee left cerebrum in GEO data set by using integration of gene regulatory network inference method with gene ontology (GO) analysis of STAT2-activated up- and downstream network. Our result showed that upstream RECQL, PDIA2, ENOSF1, THBS4, RASGRP1, PER2, PDE8A, ORC2L, DCI, OGG1_2, SMA4, GPD1, etc. activated STAT2, and downstream STAT2-activated GSTM3_1, GOSR1, SH3BGR, OSBPL8, PHYH, SAPS2, C21orf33, PDIA2, TRAPPC6A, ENOSF1, CAMTA1, GTF2I_2, etc. in human left cerebrum. STAT2-activated network enhanced regulation of small GTPase-mediated signal transduction, regulation of transcription, regulation of mitosis, regulation of cell growth, positive regulation of phosphoinositide 3-kinase cascade, positive regulation of fat cell differentiation, negative regulation of DNA replication, negative regulation of progression through cell cycle, cyclic nucleotide metabolism, lipid metabolism, carbohydrate metabolism, vitamin A metabolism, N-acetylglucosamine metabolism, UDP-N-acetylgalactosamine metabolism, fatty acid transport, intracellular protein transport, vesicle-mediated transport, lipid transport, retrograde transport, Ras protein signal transduction, Wnt receptor signaling pathway, nervous system development, cell extension, cell adhesion, cell differentiation, circadian rhythm, generation of precursor metabolites and energy, establishment of blood-nerve barrier, visual perception, sensory perception of sound, and poly-N-acetyllactosamine biosynthesis, as a result of inducing metabolism coupling postmitotic outgrowth to visual and sound perception in human left cerebrum.

  11. Caveolin-1 Mediates Low-Intensity Ultrasound-Induced Apoptosis via Downregulation of Signal Transducer and Activator of Transcription 3 Phosphorylation in Laryngeal Carcinoma Cells.

    PubMed

    Ye, Qingsheng; Meng, Cuida; Shen, Yannan; Ji, Jianjun; Wang, Xiaochun; Zhou, Sheng; Jia, Lili; Wang, Yanqun

    2016-09-01

    Low-intensity ultrasound therapy has been found to be a potential tool in the management of malignant tumors in recent years. However, the molecular mechanism underlying low-intensity ultrasound-induced apoptosis is still not clear. In this study, we investigated the effects of low-intensity ultrasound-induced apoptosis in HEp-2 cells. We found that low-intensity ultrasound significantly induced apoptosis, and the expression level of caveolin-1 (Cav-1) was dramatically increased after ultrasound treatment of HEp-2 cells. After inhibiting the expression level of Cav-1 using siRNA transfection, we found that the cellular apoptosis induced by low-intensity ultrasound was significantly suppressed. In addition, inhibition of Cav-1 expression promoted phosphorylation of signal transducer and activator of transcription 3 (STAT3), suggesting that the STAT3 signaling pathway was involved in low-intensity ultrasound-induced apoptosis via Cav-1 regulation. Our results indicate that Cav-1/STAT3 signaling pathway may mediate low-intensity ultrasound-induced apoptosis, and this technology could potentially be used clinically for the treatment of cancers.

  12. Dysregulation of sterol regulatory element binding protein-1c in livers of morbidly obese women is associated with altered suppressor of cytokine signaling-3 and signal transducer and activator of transcription-1 signaling.

    PubMed

    Elam, Marshall B; Yellaturu, Chandrahasa; Howell, George E; Deng, Xiong; Cowan, George S; Kumar, Poonam; Park, Edwards A; Hiler, M Lloyd; Wilcox, Henry G; Hughes, Thomas A; Cook, George A; Raghow, Rajendra

    2010-04-01

    We compared hepatic expression of genes that regulate lipid biosynthesis and metabolic signaling in liver biopsy specimens from women who were undergoing gastric bypass surgery (GBP) for morbid obesity with that in women undergoing ventral hernia repair who had experienced massive weight loss (MWL) after prior GBP. Comprehensive metabolic profiles of morbidly obese (MO) (22 subjects) and MWL (9 subjects) were also compared. Analyses of gene expression in liver biopsies from MO and MWL were accomplished by Affymetrix microarray, real-time polymerase chain reaction, and Western blotting techniques. After GBP, MWL subjects had lost on average 102 lb as compared with MO subjects. This was accompanied by effective reversal of the dyslipidemia and insulin resistance that were present in MO. As compared with MWL, livers of MO subjects exhibited increased expression of sterol regulatory element binding protein (SREBP)-1c and its downstream lipogenic targets, fatty acid synthase and acetyl-coenzyme A-carboxylase-1. Livers of MO subjects also exhibited enhanced expression of suppressor of cytokine signaling-3 protein and attenuated Janus kinase signal transducer and activator of transcription (JAK/STAT) signaling. Consistent with these findings, we found that the human SREBP-1c promoter was positively regulated by insulin and negatively regulated by STAT3. These data support the hypothesis that suppressor of cytokine signaling-3-mediated attenuation of the STAT signaling pathway and resulting enhanced expression of SREBP-1c, a key regulator of de novo lipid biosynthesis, are mechanistically related to the development of hepatic insulin resistance and dyslipidemia in MO women.

  13. Sorafenib induces growth arrest and apoptosis of human glioblastoma cells through the dephosphorylation of signal transducers and activators of transcription 3.

    PubMed

    Yang, Fan; Brown, Christine; Buettner, Ralf; Hedvat, Michael; Starr, Renate; Scuto, Anna; Schroeder, Anne; Jensen, Michael; Jove, Richard

    2010-04-01

    Glioblastoma is the most common type of primary brain tumor and is rapidly progressive with few treatment options. Here, we report that sorafenib (< or =10 micromol/L) inhibited cell proliferation and induced apoptosis in two established cell lines (U87 and U251) and two primary cultures (PBT015 and PBT022) from human glioblastomas. The effects of sorafenib on these tumor cells were associated with inhibiting phosphorylated signal transducers and activators of transcription 3 (STAT3; Tyr705). Expression of a constitutively activated STAT3 mutant partially blocked the effects of sorafenib, consistent with a role for STAT3 inhibition in the response to sorafenib. Phosphorylated Janus-activated kinase (JAK)1 was inhibited in U87 and U251 cells, whereas phosphorylated JAK2 was inhibited in primary cultures. Sodium vanadate, a general inhibitor of protein tyrosine phosphatases, blocked the inhibition of phosphorylation of STAT3 (Tyr705) induced by sorafenib. These data indicate that the inhibition of STAT3 activity by sorafenib involves both the inhibition of upstream kinases (JAK1 and JAK2) of STAT3 and increased phosphatase activity. Phosphorylation of AKT was also reduced by sorafenib. In contrast, mitogen-activated protein kinases were not consistently inhibited by sorafenib in these cells. Two key cyclins (D and E) and the antiapoptotic protein Mcl-1 were downregulated by sorafenib in both cell lines and primary cultures. Our data suggest that inhibition of STAT3 signaling by sorafenib contributes to growth arrest and induction of apoptosis in glioblastoma cells. These findings provide a rationale for potential treatment of malignant gliomas with sorafenib. Mol Cancer Ther; 9(4); 953-62. (c)2010 AACR.

  14. Role of an expansin-like molecule in Dictyostelium morphogenesis and regulation of its gene expression by the signal transducer and activator of transcription protein Dd-STATa.

    PubMed

    Ogasawara, Shun; Shimada, Nao; Kawata, Takefumi

    2009-02-01

    Expansins are proteins involved in plant morphogenesis, exerting their effects on cellulose to extend cell walls. Dictyostelium is an organism that possesses expansin-like molecules, but their functions are not known. In this study, we analyzed the expL7 (expansin-like 7) gene, which has been identified as a putative target of Dd-STATa, a Dictyostelium homolog of the metazoan signal transducer and activator of transcription (STAT) proteins. Promoter fragments of the expL7 were fused to a lacZ reporter and the expression patterns determined. As expected from the behavior of the endogenous expL7 gene, the expL7/lacZ fusion gene was downregulated in Dd-STATa null slugs. In the parental strain, the expL7 promoter was activated in the anterior tip region. Mutational analysis of the promoter identified a sequence that was necessary for expression in tip cells. In addition, an activator sequence for pstAB cells was identified. These sequences act in combination with the repressor region to prevent ectopic expL7 expression in the prespore and prestalk regions of the slug and culminant. Although the expL7 null mutant showed no phenotypic change, the expL7 overexpressor showed aberrant stalk formation. These results indicate that the expansin-like molecule is important for morphogenesis in Dictyostelium.

  15. Triggering of human monocyte activation through CD69, a member of the natural killer cell gene complex family of signal transducing receptors

    PubMed Central

    1994-01-01

    The expression and function of CD69, a member of the natural killer cell gene complex family of signal transducing receptors, was investigated on human monocytes. CD69 was found expressed on all peripheral blood monocytes, as a 28- and 32-kD disulfide-linked dimer. Molecular cross-linking of CD69 receptors induced extracellular Ca2+ influx, as revealed by flow cytometry. CD69 cross-linking resulted also in phospholipase A2 activation, as detected by in vivo arachidonic acid release measurement from intact cells and by direct in vitro measurement of enzymatic activity using radiolabeled phosphatidylcholine vesicles. Prostaglandin E 2 alpha, 6-keto- prostaglandin F 1 alpha, and leukotriene B4 were detected by radioimmunoassay in supernatants from CD69-stimulated monocytes, suggesting the activation of both cyclooxygenase and lipoxygenase pathways after CD69 stimulation. CD69 cross-linking, moreover, was able to induce strong nitric oxide (NO) production from monocytes, as detected by accumulation of NO oxydixed derivatives, and cyclic GMP. It is important to note that NO generation was responsible for CD69- mediated increase in spontaneous cytotoxicity against L929 murine transformed fibroblast cell line and induction of redirected cytotoxicity towards P815 FcRII+ murine mastocytoma cell line. These data indicate that CD69 can act as a potent stimulatory molecule on the surface of human peripheral blood monocytes. PMID:7964477

  16. Pulse transducer with artifact signal attenuator. [heart rate sensors

    NASA Technical Reports Server (NTRS)

    Cash, W. H., Jr.; Polhemus, J. T. (Inventor)

    1980-01-01

    An artifact signal attenuator for a pulse rate sensor is described. The circuit for attenuating background noise signals is connected with a pulse rate transducer which has a light source and a detector for light reflected from blood vessels of a living body. The heart signal provided consists of a modulated dc signal voltage indicative of pulse rate. The artifact signal resulting from light reflected from the skin of the body comprises both a constant dc signal voltage and a modulated dc signal voltage. The amplitude of the artifact signal is greater and the frequency less than that of the heart signal. The signal attenuator circuit includes an operational amplifier for canceling the artifact signal from the output signal of the transducer and has the capability of meeting packaging requirements for wrist-watch-size packages.

  17. Emerging EPO and EPO receptor regulators and signal transducers.

    PubMed

    Kuhrt, David; Wojchowski, Don M

    2015-06-04

    As essential mediators of red cell production, erythropoietin (EPO) and its cell surface receptor (EPO receptor [EPOR]) have been intensely studied. Early investigations defined basic mechanisms for hypoxia-inducible factor induction of EPO expression, and within erythroid progenitors EPOR engagement of canonical Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5), rat sarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (RAS/MEK/ERK), and phosphatidylinositol 3-kinase (PI3K) pathways. Contemporary genetic, bioinformatic, and proteomic approaches continue to uncover new clinically relevant modulators of EPO and EPOR expression, and EPO's biological effects. This Spotlight review highlights such factors and their emerging roles during erythropoiesis and anemia.

  18. Sequential Phosphorylation of Smoothened Transduces Graded Hedgehog Signaling

    PubMed Central

    Su, Ying; Ospina, Jason K.; Zhang, Junzheng; Michelson, Andrew P.; Schoen, Adam M.; Zhu, Alan Jian

    2012-01-01

    The correct interpretation of a gradient of the morphogen Hedgehog (Hh) during development requires phosphorylation of the Hh signaling activator Smoothened (Smo); however, the molecular mechanism by which Smo transduces graded Hh signaling is not well understood. We show that regulation of the phosphorylation status of Smo by distinct phosphatases at specific phosphorylated residues creates differential thresholds of Hh signaling. Phosphorylation of Smo was initiated by adenosine 3′,5′-monophosphate (cAMP)–dependent protein kinase (PKA) and further enhanced by casein kinase I (CKI). We found that protein phosphatase 1 (PP1) directly dephosphorylated PKA-phosphorylated Smo to reduce signaling mediated by intermediate concentrations of Hh, whereas PP2A specifically dephosphorylated PKA-primed, CKI-phosphorylated Smo to restrict signaling by high concentrations of Hh. We also established a functional link between sequentially phosphorylated Smo species and graded Hh activity. Thus, we propose a sequential phosphorylation model in which precise interpretation of morphogen concentration can be achieved upon versatile phosphatase-mediated regulation of the phosphorylation status of an essential activator in developmental signaling. PMID:21730325

  19. Signal-transducing mechanisms involved in activation of the platelet collagen receptor integrin alpha(2)beta(1).

    PubMed

    Jung, S M; Moroi, M

    2000-03-17

    Evidence was obtained about the mechanism responsible for platelet integrin alpha(2)beta activation by determining effects of various inhibitors on soluble collagen binding, a parameter to assess integrin alpha(2)beta(1) activation, in stimulated platelets. Agonists that can also activate platelet glycoprotein IIb/IIIa are able to activate integrin alpha(2)beta(1), but those operating via glycoprotein Ib cannot. Activation of alpha(2)beta(1) induced by low thrombin or collagen-related peptide concentrations was almost completely inhibited by apyrase, and the inhibitors wortmannin, 4-amino-5-(chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, bisindolylmaleimide I, and SQ29548 significantly inhibited it. Activation induced by high thrombin or collagen-related peptide concentrations was far less sensitive to these inhibitors. However, only wortmannin markedly inhibited ADP-induced integrin alpha(2)beta(1) activation, and this was not ADP concentration-dependent. These results suggest that at the low agonist concentrations, the released ADP would be a primary inducer of integrin alpha(2)beta(1) activation, while at the high agonist concentrations, there would be several pathways through which integrin alpha(2)beta(1) activation can be induced. Kinetic analyses revealed that ADP-induced platelets had about the same number of binding sites (B(max)) as thrombin-induced platelets, but their affinity (K(d)) for soluble collagen was 3.7-12.7-fold lower, suggesting that activated integrin alpha(2)beta(1) induced by ADP is different from that induced by thrombin. The data are consistent with an activation mechanism involving released ADP and in which there exists two different states of activated integrin alpha(2)beta(1); these activated forms of integrin alpha(2)beta(1) would have different conformations that determine their ligand affinity.

  20. Ubiquitin-specific peptidase 22 inhibits colon cancer cell invasion by suppressing the signal transducer and activator of transcription 3/matrix metalloproteinase 9 pathway.

    PubMed

    Ao, Ning; Liu, Yanyan; Bian, Xiaocui; Feng, Hailiang; Liu, Yuqin

    2015-08-01

    Colon cancer is associated with increased cell migration and invasion. In the present study, the role of ubiquitin-specific peptidase 22 (USP22) in signal transducer and activator of transcription 3 (STAT3)-mediated colon cancer cell invasion was investigated. The messenger RNA levels of STAT3 target genes were measured by reverse transcription-quantitative polymerase chain reaction, following USP22 knockdown by RNA interference in SW480 colon cancer cells. The matrix metalloproteinase 9 (MMP9) proteolytic activity and invasion potential of SW480 cells were measured by zymography and Transwell assay, respectively, following combined USP22 and STAT3 short interfering (si)RNA treatment or STAT3 siRNA treatment alone. Similarly, a cell counting kit-8 assay was used to detect the proliferation potential of SW480 cells. The protein expression levels of USP22, STAT3 and MMP9 were detected by immunohistochemistry in colon cancer tissue microarrays (TMAs) and the correlation between USP22, STAT3 and MMP9 was analyzed. USP22/STAT3 co-depletion partly rescued the MMP9 proteolytic activity and invasion of SW480 cells, compared with that of STAT3 depletion alone. However, the proliferation of USP22/STAT3si-SW480 cells was decreased compared with that of STAT3si-SW480 cells. USP22 expression was positively correlated with STAT3 and MMP9 expression in colon cancer TMAs. In conclusion, USP22 attenuated the invasion capacity of colon cancer cells by inhibiting the STAT3/MMP9 signaling pathway.

  1. The NAMPT Promoter Is Regulated by Mechanical Stress, Signal Transducer and Activator of Transcription 5, and Acute Respiratory Distress Syndrome–Associated Genetic Variants

    PubMed Central

    Sun, Xiaoguang; Elangovan, Venkateswaran Ramamoorthi; Mapes, Brandon; Camp, Sara M.; Sammani, Saad; Saadat, Laleh; Ceco, Ermelinda; Ma, Shwu-Fan; Flores, Carlos; MacDougall, Matthew S.; Quijada, Hector; Liu, Bin; Kempf, Carrie L.; Wang, Ting; Chiang, Eddie T.

    2014-01-01

    Increased nicotinamide phosphoribosyltransferase (NAMPT) transcription is mechanistically linked to ventilator-induced inflammatory lung injury (VILI), with VILI severity attenuated by reduced NAMPT bioavailability. The molecular mechanisms of NAMPT promoter regulation in response to excessive mechanical stress remain poorly understood. The objective of this study was to define the contribution of specific transcription factors, acute respiratory distress syndrome (ARDS)-associated single nucleotide polymorphisms (SNPs), and promoter demethylation to NAMPT transcriptional regulation in response to mechanical stress. In vivo NAMPT protein expression levels were examined in mice exposed to high tidal volume mechanical ventilation. In vitro NAMPT expression levels were examined in human pulmonary artery endothelial cells exposed to 5 or 18% cyclic stretch (CS), with NAMPT promoter activity assessed using NAMPT promoter luciferase reporter constructs with a series of nested deletions. In vitro NAMPT transcriptional regulation was further characterized by measuring luciferase activity, DNA demethylation, and chromatin immunoprecipitation. VILI-challenged mice exhibited significantly increased NAMPT expression in bronchoalveolar lavage leukocytes and in lung endothelium. A mechanical stress–inducible region (MSIR) was identified in the NAMPT promoter from −2,428 to −2,128 bp. This MSIR regulates NAMPT promoter activity, mRNA expression, and signal transducer and activator of transcription 5 (STAT5) binding, which is significantly increased by 18% CS. In addition, NAMPT promoter activity was increased by pharmacologic promoter demethylation and inhibited by STAT5 silencing. ARDS-associated NAMPT promoter SNPs rs59744560 (−948G/T) and rs7789066 (−2,422A/G) each significantly elevated NAMPT promoter activity in response to 18% CS in a STAT5-dependent manner. Our results show that NAMPT is a key novel ARDS therapeutic target and candidate gene with genetic

  2. Signal transducer and activator of transcription 3‐mediated CD133 up‐regulation contributes to promotion of hepatocellular carcinoma

    PubMed Central

    Won, Cheolhee; Kim, Byung‐Hak; Yi, Eun Hee; Choi, Kyung‐Ju; Kim, Eun‐Kyung; Jeong, Jong‐Min; Lee, Jae‐Ho; Jang, Ja‐June; Yoon, Jung‐Hwan; Jeong, Won‐Il; Park, In‐Chul; Kim, Tae Woo; Bae, Sun Sik; Factor, Valentina M.; Ma, Stephanie; Thorgeirsson, Snorri S.

    2015-01-01

    Enhanced expression of the cancer stem cell (CSC) marker, CD133, is closely associated with a higher rate of tumor formation and poor prognosis in hepatocellular carcinoma (HCC) patients. Despite its clinical significance, the molecular mechanism underlying the deregulation of CD133 during tumor progression remains to be clarified. Here, we report on a novel mechanism by which interleukin‐6/signal transducer and activator of transcription 3 (IL‐6/STAT3) signaling up‐regulates expression of CD133 and promotes HCC progression. STAT3 activated by IL‐6 rapidly bound to CD133 promoter and increased protein levels of CD133 in HCC cells. Reversely, in hypoxic conditions, RNA interference silencing of STAT3 resulted in decrease of CD133 levels, even in the presence of IL‐6, with a concomitant decrease of hypoxia‐inducible factor 1 alpha (HIF‐1α) expression. Active STAT3 interacted with nuclear factor kappa B (NF‐κB) p65 subunit to positively regulate the transcription of HIF‐1α providing a mechanistic explanation on how those three oncogenes work together to increase the activity of CD133 in a hypoxic liver microenvironment. Activation of STAT3 and its consequent induction of HIF‐1α and CD133 expression were not observed in Toll‐like receptor 4/IL‐6 double‐knockout mice. Long‐term silencing of CD133 by a lentiviral‐based approach inhibited cancer cell‐cycle progression and suppressed in vivo tumorigenicity by down‐regulating expression of cytokinesis‐related genes, such as TACC1, ACF7, and CKAP5. We also found that sorafenib and STAT3 inhibitor nifuroxazide inhibit HCC xenograft formation by blocking activation of STAT3 and expression of CD133 and HIF‐1α proteins. Conclusion: IL‐6/STAT3 signaling induces expression of CD133 through functional cooperation with NF‐κB and HIF‐1α during liver carcinogenesis. Targeting STAT3‐mediated CD133 up‐regulation may represent a novel, effective treatment by eradicating the liver

  3. Regulation of signal transducer and activator of transcription 3 and apoptotic pathways by betaine attenuates isoproterenol-induced acute myocardial injury in rats.

    PubMed

    Zheng, P; Liu, J; Mai, S; Yuan, Y; Wang, Y; Dai, G

    2015-05-01

    The present study was designed to investigate the cardioprotective effects of betaine on acute myocardial ischemia induced experimentally in rats focusing on regulation of signal transducer and activator of transcription 3 (STAT3) and apoptotic pathways as the potential mechanism underlying the drug effect. Male Sprague Dawley rats were treated with betaine (100, 200, and 400 mg/kg) orally for 40 days. Acute myocardial ischemic injury was induced in rats by subcutaneous injection of isoproterenol (85 mg/kg), for two consecutive days. Serum cardiac marker enzyme, histopathological variables and expression of protein levels were analyzed. Oral administration of betaine (200 and 400 mg/kg) significantly reduced the level of cardiac marker enzyme in the serum and prevented left ventricular remodeling. Western blot analysis showed that isoproterenol-induced phosphorylation of STAT3 was maintained or further enhanced by betaine treatment in myocardium. Furthermore, betaine (200 and 400 mg/kg) treatment increased the ventricular expression of Bcl-2 and reduced the level of Bax, therefore causing a significant increase in the ratio of Bcl-2/Bax. The protective role of betaine on myocardial damage was further confirmed by histopathological examination. In summary, our results showed that betaine pretreatment attenuated isoproterenol-induced acute myocardial ischemia via the regulation of STAT3 and apoptotic pathways.

  4. Inhibition of ErbB-2 Mitogenic and Transforming Activity by RALT, a Mitogen-Induced Signal Transducer Which Binds to the ErbB-2 Kinase Domain†

    PubMed Central

    Fiorentino, Loredana; Pertica, Chiara; Fiorini, Monia; Talora, Claudio; Crescenzi, Marco; Castellani, Loriana; Alemà, Stefano; Benedetti, Piero; Segatto, Oreste

    2000-01-01

    The product of rat gene 33 was identified as an ErbB-2-interacting protein in a two-hybrid screen employing the ErbB-2 juxtamembrane and kinase domains as bait. This interaction was reproduced in vitro with a glutathione S-transferase fusion protein spanning positions 282 to 395 of the 459-residue gene 33 protein. Activation of ErbB-2 catalytic function was required for ErbB-2–gene 33 physical interaction in living cells, whereas ErbB-2 autophosphorylation was dispensable. Expression of gene 33 protein was absent in growth-arrested NIH 3T3 fibroblasts but was induced within 60 to 90 min of serum stimulation or activation of the ErbB-2 kinase and decreased sharply upon entry into S phase. New differentiation factor stimulation of mitogen-deprived mammary epithelial cells also caused accumulation of gene 33 protein, which could be found in a complex with ErbB-2. Overexpression of gene 33 protein in mouse fibroblasts inhibited (i) cell proliferation driven by ErbB-2 but not by serum, (ii) cell transformation induced by ErbB-2 but not by Ras or Src, and (iii) sustained activation of ERK 1 and 2 by ErbB-2 but not by serum. The gene 33 protein may convey inhibitory signals downstream to ErbB-2 by virtue of its association with SH3-containing proteins, including GRB-2, which was found to associate with gene 33 protein in living cells. These data indicate that the gene 33 protein is a feedback inhibitor of ErbB-2 mitogenic function and a suppressor of ErbB-2 oncogenic activity. We propose that the gene 33 protein be renamed with the acronym RALT (receptor-associated late transducer). PMID:11003669

  5. Inhibition of ErbB-2 mitogenic and transforming activity by RALT, a mitogen-induced signal transducer which binds to the ErbB-2 kinase domain.

    PubMed

    Fiorentino, L; Pertica, C; Fiorini, M; Talora, C; Crescenzi, M; Castellani, L; Alemà, S; Benedetti, P; Segatto, O

    2000-10-01

    The product of rat gene 33 was identified as an ErbB-2-interacting protein in a two-hybrid screen employing the ErbB-2 juxtamembrane and kinase domains as bait. This interaction was reproduced in vitro with a glutathione S-transferase fusion protein spanning positions 282 to 395 of the 459-residue gene 33 protein. Activation of ErbB-2 catalytic function was required for ErbB-2-gene 33 physical interaction in living cells, whereas ErbB-2 autophosphorylation was dispensable. Expression of gene 33 protein was absent in growth-arrested NIH 3T3 fibroblasts but was induced within 60 to 90 min of serum stimulation or activation of the ErbB-2 kinase and decreased sharply upon entry into S phase. New differentiation factor stimulation of mitogen-deprived mammary epithelial cells also caused accumulation of gene 33 protein, which could be found in a complex with ErbB-2. Overexpression of gene 33 protein in mouse fibroblasts inhibited (i) cell proliferation driven by ErbB-2 but not by serum, (ii) cell transformation induced by ErbB-2 but not by Ras or Src, and (iii) sustained activation of ERK 1 and 2 by ErbB-2 but not by serum. The gene 33 protein may convey inhibitory signals downstream to ErbB-2 by virtue of its association with SH3-containing proteins, including GRB-2, which was found to associate with gene 33 protein in living cells. These data indicate that the gene 33 protein is a feedback inhibitor of ErbB-2 mitogenic function and a suppressor of ErbB-2 oncogenic activity. We propose that the gene 33 protein be renamed with the acronym RALT (receptor-associated late transducer).

  6. Signal Transducer and Activator of Transcription 3/MicroRNA-21 Feedback Loop Contributes to Atrial Fibrillation by Promoting Atrial Fibrosis in a Rat Sterile Pericarditis Model

    PubMed Central

    Huang, Zhengrong; Chen, Xiao-jun; Qian, Cheng; Dong, Qian; Ding, Dan; Wu, Qiong-feng; Li, Jing; Wang, Hong-fei; Li, Wei-hua; Xie, Qiang; Cheng, Xiang; Liao, Yu-hua

    2016-01-01

    Background— Postoperative atrial fibrillation is a frequent complication in cardiac surgery. The aberrant activation of signal transducer and activator of transcription 3 (STAT3) contributes to the pathogenesis of atrial fibrillation. MicroRNA-21 (miR-21) promotes atrial fibrosis. Recent studies support the existence of reciprocal regulation between STAT3 and miR-21. Here, we test the hypothesis that these 2 molecules might form a feedback loop that contributes to postoperative atrial fibrillation by promoting atrial fibrosis. Methods and Results— A sterile pericarditis model was created using atrial surfaces dusted with sterile talcum powder in rats. The inflammatory cytokines interleukin (IL)-1β, IL-6, transforming growth factor-β, and tumor necrosis factor-α, along with STAT3 and miR-21, were highly upregulated in sterile pericarditis rats. The inhibition of STAT3 by S3I-201 resulted in miR-21 downregulation, which ameliorated atrial fibrosis and decreased the expression of the fibrosis-related genes, α-smooth muscle actin, collagen-1, and collagen-3; reduced the inhomogeneity of atrial conduction; and attenuated atrial fibrillation vulnerability. Meanwhile, treatment with antagomir-21 decreased STAT3 phosphorylation, alleviated atrial remodeling, abrogated sterile pericarditis–induced inhomogeneous conduction, and prevented atrial fibrillation promotion. The culturing of cardiac fibroblasts with IL-6 resulted in progressively augmented STAT3 phosphorylation and miR-21 levels. S3I-201 blocked IL-6 induced the expression of miR-21 and fibrosis-related genes in addition to cardiac fibroblast proliferation. Transfected antagomir-21 decreased the IL-6–induced cardiac fibroblast activation and STAT3 phosphorylation. The overexpression of miR-21 in cardiac fibroblasts caused the upregulation of STAT3 phosphorylation, enhanced fibrosis-related genes, and increased cell numbers. Conclusions— Our results have uncovered a novel reciprocal loop between STAT3

  7. Signal transducer and activator of transcription 3 (Stat3) regulates host defense and protects mice against herpes simplex virus-1 (HSV-1) infection.

    PubMed

    Hsia, Hung-Ching; Stopford, Charles M; Zhang, Zhigang; Damania, Blossom; Baldwin, Albert S

    2016-12-13

    Signal transducer and activator of transcription 3 (STAT3) mediates cellular responses to multiple cytokines, governs gene expression, and regulates the development and activation of immune cells. STAT3 also modulates reactivation of latent herpes simplex virus-1 (HSV-1) in ganglia. However, it is unclear how STAT3 regulates the innate immune response during the early phase of HSV-1 lytic infection. Many cell types critical for the innate immunity are derived from the myeloid lineage. Therefore, in this study, we used myeloid-specific Stat3 knockout mice to investigate the role of STAT3 in the innate immune response against HSV-1. Our results demonstrate that Stat3 knockout bone marrow-derived macrophages (BMMs) expressed decreased levels of interferon-α (IFN-α) and interferon-stimulated genes (ISGs) upon HSV-1 infection. In vivo, knockout mice were more susceptible to HSV-1, as marked by higher viral loads and more significant weight loss. Splenic expression of IFN-α and ISGs was reduced in the absence of STAT3, indicating that STAT3 is required for optimal type I interferon response to HSV-1. Expression of TNF-α and IL-12, cytokines that have been shown to limit HSV-1 replication and pathogenesis, was also significantly lower in knockout mice. Interestingly, Stat3 knockout mice failed to expand the CD8(+) conventional DC (cDC) population upon HSV-1 infection, and this was accompanied by impaired NK and CD8 T cell activation. Collectively, our data demonstrate that myeloid-specific Stat3 deletion causes defects in multiple aspects of the immune system and that STAT3 has a protective role at the early stage of systemic HSV-1 infection.

  8. Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions

    PubMed Central

    Villarino, Alejandro; Laurence, Arian; Robinson, Gertraud W; Bonelli, Michael; Dema, Barbara; Afzali, Behdad; Shih, Han-Yu; Sun, Hong-Wei; Brooks, Stephen R; Hennighausen, Lothar; Kanno, Yuka; O'Shea, John J

    2016-01-01

    The transcription factor STAT5 is fundamental to the mammalian immune system. However, the relationship between its two paralogs, STAT5A and STAT5B, and the extent to which they are functionally distinct, remain uncertain. Using mouse models of paralog deficiency, we demonstrate that they are not equivalent for CD4+ 'helper' T cells, the principal orchestrators of adaptive immunity. Instead, we find that STAT5B is dominant for both effector and regulatory (Treg) responses and, therefore, uniquely necessary for immunological tolerance. Comparative analysis of genomic distribution and transcriptomic output confirm that STAT5B has fargreater impact but, surprisingly, the data point towards asymmetric expression (i.e. paralog dose), rather than distinct functional properties, as the key distinguishing feature. Thus, we propose a quantitative model of STAT5 paralog activity whereby relative abundance imposes functional specificity (or dominance) in the face of widespread structural homology. DOI: http://dx.doi.org/10.7554/eLife.08384.001 PMID:26999798

  9. Effect of growth hormone on the differentiation of bovine preadipocytes into adipocytes and the role of the signal transducer and activator of transcription 5b.

    PubMed

    Zhao, L; Wang, A; Corl, B A; Jiang, H

    2014-05-01

    We evaluated the effect of GH on the differentiation of primary bovine preadipocytes into adipocytes. Bovine preadipocytes, derived from adipose tissue explants, were induced to differentiate into adipocytes in the presence or absence of recombinant bovine GH. The differentiation status of adipocytes was assessed by Oil Red O staining and by measuring the activity of glycerol-3-phosphate dehydrogenase (G3PDH) and the rate of acetate incorporation. Fewer preadipocytes became adipocytes in the presence of GH than in the absence of GH; adipocytes formed in the presence of GH had lower G3PDH activity and lower rate of acetate incorporation than those formed without GH treatment (P < 0.05). These data suggest an inhibitory effect of GH on the differentiation of bovine preadipocytes into adipocytes. Growth hormone decreased the expression of C/EBPα and PPARγ mRNA in bovine adipocytes (P < 0.05). Because C/EBPα and PPARγ are the master regulators of adipocyte differentiation, this data suggests that GH might inhibit the differentiation of bovine preadipocytes into adipocytes by inhibiting the expression of C/EBPα and/or PPARγ. Because the signal transducer and activator of transcription 5 (STAT5) is a major component of signaling from the GH receptor, we next determined the potential role of STAT5 in GH inhibition of bovine adipocyte differentiation. Overexpression of a constitutively active form of STAT5b (STAT5bCA) in bovine preadipocytes through adenoviral transduction mimicked the effects of GH on the formation of lipid-containing adipocytes, G3PDH activity, and acetate incorporation rate. Overexpression of STAT5bCA was associated with decreased expression of C/EBPα mRNA (P < 0.05) but not that of PPARγ mRNA in bovine adipocytes. These results support a role of STAT5b in mediating GH inhibition of C/EBPα expression but not that of PPARγ expression in bovine preadipocytes. Overall, the present study suggests that GH may inhibit adipose growth in cattle in

  10. Conjugated bilirubin affects cytokine profiles in hepatitis A virus infection by modulating function of signal transducer and activator of transcription factors.

    PubMed

    Castro-García, Flor P; Corral-Jara, Karla F; Escobedo-Melendez, Griselda; Sandoval-Hernandez, Monserrat A; Rosenstein, Yvonne; Roman, Sonia; Panduro, Arturo; Fierro, Nora A

    2014-12-01

    Hepatitis A virus (HAV) infection is the major cause of acute liver failure in paediatric patients. The clinical spectrum of infection is variable, and liver injury is determined by altered hepatic enzyme function and bilirubin concentration. We recently reported differences in cytokine profiles between distinct HAV-induced clinical courses, and bilirubin has been recognized as a potential immune-modulator. However, how bilirubin may affect cytokine profiles underlying the variability in the course of infection has not been determined. Herein, we used a transcription factor (TF) binding site identification approach to retrospectively analyse cytokine expression in HAV-infected children and to predict the entire set of TFs associated with the expression of specific cytokine profiles. The results suggested that modulation of the activity of signal transducers and activators of transcription proteins (STATs) may play a central role during HAV infection. This led us to compare the degree of STAT phosphorylation in peripheral blood lymphoid cells (PBLCs) from paediatric patients with distinct levels of conjugated bilirubin (CB). Low CB levels in sera were associated with increased STAT-1 and STAT-5 phosphorylation. A positive correlation was observed between the serum interleukin-6 (IL-6) content and CB values, whereas higher levels of CB correlated with reduced serum IL-8 values and with a reduction in the proportion of PBLCs positive for STAT-5 phosphorylation. When CB was used to stimulate patients' PBLCs in vitro, the levels of IL-6 and tumour necrosis factor-α were increased. The data showed that bilirubin plays a role in STAT function and affects cytokine profile expression during HAV infection.

  11. Conjugated bilirubin affects cytokine profiles in hepatitis A virus infection by modulating function of signal transducer and activator of transcription factors

    PubMed Central

    Castro-García, Flor P; Corral-Jara, Karla F; Escobedo-Melendez, Griselda; Sandoval-Hernandez, Monserrat A; Rosenstein, Yvonne; Roman, Sonia; Panduro, Arturo; Fierro, Nora A

    2014-01-01

    Hepatitis A virus (HAV) infection is the major cause of acute liver failure in paediatric patients. The clinical spectrum of infection is variable, and liver injury is determined by altered hepatic enzyme function and bilirubin concentration. We recently reported differences in cytokine profiles between distinct HAV-induced clinical courses, and bilirubin has been recognized as a potential immune-modulator. However, how bilirubin may affect cytokine profiles underlying the variability in the course of infection has not been determined. Herein, we used a transcription factor (TF) binding site identification approach to retrospectively analyse cytokine expression in HAV-infected children and to predict the entire set of TFs associated with the expression of specific cytokine profiles. The results suggested that modulation of the activity of signal transducers and activators of transcription proteins (STATs) may play a central role during HAV infection. This led us to compare the degree of STAT phosphorylation in peripheral blood lymphoid cells (PBLCs) from paediatric patients with distinct levels of conjugated bilirubin (CB). Low CB levels in sera were associated with increased STAT-1 and STAT-5 phosphorylation. A positive correlation was observed between the serum interleukin-6 (IL-6) content and CB values, whereas higher levels of CB correlated with reduced serum IL-8 values and with a reduction in the proportion of PBLCs positive for STAT-5 phosphorylation. When CB was used to stimulate patients’ PBLCs in vitro, the levels of IL-6 and tumour necrosis factor-α were increased. The data showed that bilirubin plays a role in STAT function and affects cytokine profile expression during HAV infection. PMID:24943111

  12. Mitochondrial translocation of signal transducer and activator of transcription 5 (STAT5) in leukemic T cells and cytokine-stimulated cells

    SciTech Connect

    Chueh, Fu-Yu; Leong, King-Fu; Yu, Chao-Lan

    2010-11-26

    Research highlights: {yields} STAT5 interacts with a mitochondrial protein PDC-E2 in a leukemic T cell line LSTRA. {yields} Tyrosine-phosphorylated STAT5, but not STAT3, is present in LSTRA mitochondria. {yields} Cytokines induce mitochondrial translocation of STAT5, but not STAT1 or STAT3. {yields} Cytokine-induced mitochondrial translocation of tyrosine-phosphorylated STAT5 is transient. {yields} Mitochondrial STAT5 binds to a putative STAT5 site in the mitochondrial DNA in vitro. -- Abstract: Signal transducers and activators of transcription (STATs) were first identified as key signaling molecules in response to cytokines. Constitutive STAT activation also has been widely implicated in oncogenesis. We analyzed STAT5-associated proteins in a leukemic T cell line LSTRA, which exhibits constitutive tyrosine phosphorylation and activation of STAT5. A cellular protein was found to specifically interact with STAT5 in LSTRA cells by co-immunoprecipitation. Sequencing analysis and subsequent immunoblotting confirmed the identity of this STAT5-associated protein as the E2 component of mitochondrial pyruvate dehydrogenase complex (PDC-E2). Consistent with this interaction, both subcellular fractionation and immunofluorescence microscopy revealed mitochondrial localization of STAT5 in LSTRA cells. Mitochondrial localization of tyrosine-phosphorylated STAT5 also occurred in cytokine-stimulated cells. A time course experiment further demonstrated the transient kinetics of STAT5 mitochondrial translocation after cytokine stimulation. In contrast, cytokine-induced STAT1 and STAT3 activation did not result in their translocation into mitochondria. Furthermore, we showed that mitochondrial STAT5 bound to the D-loop regulatory region of mitochondrial DNA in vitro. It suggests a potential role of STAT5 in regulating the mitochondrial genome. Proliferative metabolism toward aerobic glycolysis is well known in cancer cells as the Warburg effect and is also observed in cytokine

  13. On involvement of transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells, activator protein-1 and signal transducer and activator of transcription-3 in photodynamic therapy-induced death of crayfish neurons and satellite glial cells

    NASA Astrophysics Data System (ADS)

    Berezhnaya, Elena; Neginskaya, Marya; Kovaleva, Vera; Sharifulina, Svetlana; Ischenko, Irina; Komandirov, Maxim; Rudkovskii, Mikhail; Uzdensky, Anatoly B.

    2015-07-01

    Photodynamic therapy (PDT) is currently used in the treatment of brain tumors. However, not only malignant cells but also neighboring normal neurons and glial cells are damaged during PDT. In order to study the potential role of transcription factors-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein (AP-1), and signal transducer and activator of transcription-3 (STAT-3)-in photodynamic injury of normal neurons and glia, we photosensitized the isolated crayfish mechanoreceptor consisting of a single sensory neuron enveloped by glial cells. Application of different inhibitors and activators showed that transcription factors NF-κB (inhibitors caffeic acid phenethyl ester and parthenolide, activator betulinic acid), AP-1 (inhibitor SR11302), and STAT-3 (inhibitors stattic and cucurbitacine) influenced PDT-induced death and survival of neurons and glial cells in different ways. These experiments indicated involvement of NF-κB in PDT-induced necrosis of neurons and apoptosis of glial cells. However, in glial cells, it played the antinecrotic role. AP-1 was not involved in PDT-induced necrosis of neurons and glia, but mediated glial apoptosis. STAT-3 was involved in PDT-induced apoptosis of glial cells and necrosis of neurons and glia. Therefore, signaling pathways that regulate cell death and survival in neurons and glial cells are different. Using various inhibitors or activators of transcription factors, one can differently influence the sensitivity and resistance of neurons and glial cells to PDT.

  14. Cloning, molecular characterization, and expression analysis of the signal transducer and activator of transcription 3 (STAT₃) gene from grass carp (Ctenopharyngodon idellus).

    PubMed

    Guo, Ting; Leng, Xiang-Jun; Wu, Xiao-Feng; Li, Jia-Le; Gao, Jian-Zhong; Li, Xiao-Qin; Gan, Tian; Wei, Jing

    2013-11-01

    Signal transducer and activator of transcription 3 (STAT₃) binds to Janus kinase 2 (JAK₂) to initiate the JAK₂/STAT₃ signal transduction pathway, which plays an important role in cancer cell proliferation, immune regulation, reproduction, lipid metabolism, and other physiological processes of the organism. In this study, the cDNA sequence of the STAT₃ gene from grass carp was cloned using RACE (rapid-amplification of cDNA ends). Twelve characteristics of the STAT₃ gene and its encoded protein sequence were predicted and analyzed using bioinformatics methods; these features included the general physical and chemical properties, the hydrophobicity, the secondary structure and the three-dimensional structure of the protein. Quantitative real-time PCR was employed to detect grass carp STAT₃ expression pattern in different tissues. The results showed that the full-length STAT₃ gene from grass carp is 2739-bp long and contains a 216-bp 5'UTR, a 300-bp 3'UTR, and a 2223-bp open reading frame (ORF) that encodes a 740-amino acid peptide. The deduced protein exhibited 99%∼94% homology to the STAT₃ protein of zebrafish (Danio rerio), medaka (Oryzias latipes), turbot (Scophthalmus maximus), white-spotted char (Salvelinus leucomaenis), mandarin fish (Siniperca chuatsi), rainbow trout (Oncorhynchus mykiss), and green pufferfish (Tetraodon fluviatilis). The deduced grass carp STAT₃ protein contains a protein interaction domain, an alpha domain, a DNA binding domain, and an SH2 domain. The STAT₃ protein of grass carp is a hydrophilic and non-secretory protein, and its molecular mass and isoeletronic point were found to be 98,5412.1 Da and 6.39, respectively. The structural elements of STAT₃ included α-helixes, β-sheets, and loops. The grass carp STAT₃ is expressed in all of the six tissues tested, which were the liver, spleen, gill, muscle, heart, and brain. The highest expression level was found in the liver (P < 0.05), whereas a significantly

  15. Signal transducer and activator of transcription 5a inhibited by pimozide may regulate survival of goat mammary gland epithelial cells by regulating parathyroid hormone-related protein.

    PubMed

    Li, Hui; Zheng, Huiling; Sun, Yongsen; Yu, Qian; Li, Lihui

    2014-11-10

    The signal transducer and activator of transcription 5a (Stat5a) modulates genes involved in proliferation and survival and plays pivotal roles in regulating the function of the mammary gland during pregnancy, lactation, and involution. However, there is little information about the effects of Stat5a on apoptosis of goat mammary gland epithelial cells (GMECs). In addition, parathyroid hormone-related protein (PTHrP) is a key regulator in cellular calcium transport, mammary gland development and breast tumor biology. This study aimed to explore the interaction of Stat5a and PTHrP in GMEC apoptosis. Quantitative real time PCR (qRT-PCR) suggested that Stat5a was predominantly expressed in the mammary gland, lung, liver and spleen of goats. Treating the GMECs with pimozide, an inhibitor of Stat5a that decreases Stat5a tyrosine phosphorylation, increased PTHrP levels in GMECs in a dose-dependent manner and simultaneously promoted apoptosis of the GMECs. We also demonstrated that PTHrP inhibition induced GMEC apoptosis and restrained cell proliferation. In contrast, PTHrP overexpression protected GMECs from pimozide- and calcium-induced apoptosis, and promoted cell proliferation. Furthermore, pimozide and CaCl2 downregulated the antiapoptotic protein Bcl-2 mRNA expression, respectively, and these effects were protected by PTHrP overexpression. Interestingly, we also found that Stat5a suppressed the expression of matrix metalloproteinase 9 (MMP-9) which can induce goat mammary epithelial cell migration, but PTHrP increased MMP-9 mRNA level. Thus, Stat5a may regulate GMEC survival by regulating the expression of PTHrP.

  16. MiR-361-5p acts as a tumor suppressor in prostate cancer by targeting signal transducer and activator of transcription-6(STAT6)

    SciTech Connect

    Liu, Dachuang; Tao, Tao; Xu, Bin; Chen, Shuqiu; Liu, Chunhui; Zhang, Lei; Lu, Kai; Huang, Yeqing; Jiang, Liang; Zhang, Xiaowen; Huang, Xiaoming; Zhang, Lihua; Han, Conghui; Chen, Ming

    2014-02-28

    Highlights: • The role of miR-361-5p in prostate cancer (PCa) has not been evaluated until date. • We found that the expression of miR-361-5p in CRPC was lower than in ADPC. • MiR-361-5p suppressed DU145 cell proliferation and triggered apoptosis. • STAT6 is a direct target of miR-361-5p. • STAT6 enhances the expression of Bcl-xL at the transcriptional level. - Abstract: Castration-resistant prostate cancer (CRPC), whose pathogenesis is known to be regulated by microRNAs (miRNAs), has a poor prognosis. In our present study, we found that the expression of miR-361-5p in CRPC was lower than in androgen-dependent prostate cancer (ADPC), indicating that miR-361-5p may play an important role in the progression of ADPC to CRPC. The role of miR-361-5p in prostate cancer (PCa) has not been evaluated until date. Our findings suggest that miR-361-5p is a suppressor in CRPC. Signal transducer and activator of transcription-6 (STAT6), a direct target of miR-361-5p, enhances the expression of B-cell lymphoma-extra large (Bcl-xL), while miR-361-5p inhibits its expression through STAT6. Therefore, miR-361-5p has great clinical significance in preventing the malignant progression of PCa.

  17. MicroRNA-361-5p suppresses cancer progression by targeting signal transducer and activator of transcription 6 in non-small cell lung cancer

    PubMed Central

    MA, YUEFENG; BAO, CHUANEN; KONG, RANRAN; XING, XIN; ZHANG, YAYA; LI, SHAOMIN; ZHANG, WEI; JIANG, JIANTAO; ZHANG, JIN; QIAO, ZHE; ZHANG, DANJIE; MA, ZHENCHUAN; SUN, LIANGZHANG; ZHOU, BIN

    2015-01-01

    The incidence of non-small cell lung cancer (NSCLC) has significantly increased in China, while the prognosis of affected patients is poor. The pathogenesis of NSCLC is thought to be regulated by microRNAs (miRs). The present study used a miR array in order to determine the expression of miR-361-5p, which was significantly lower in NSCLC tissues compared with that in adjacent tissues, indicating a crucial role of miR-361-5p during the progression of NSCLC. Furthermore, the effects of transfection-induced upregulation of miR-361-5p on the NSCLC cell line H23 were assessed. Overexpression of miR-361-5p inhibited the proliferation and colony formation ability of H23 cells. In addition, apoptosis of H23 cells was induced by upregulation of miR-361-5p. Furthermore, signal transducer and activator of transcription 6 (STAT6) was confirmed as a direct target of miR-361-5p by a dual-luciferase reporter assay. Moreover, inhibition of STAT6 by small interfering RNA or miR-361-5p also decreased the expression of B-cell lymphoma extra large (Bcl-xL). In vivo, miR-361-5p significantly reduced tumor growth in a nude mouse xenograft model, and suppressed STAT6 and Bcl-xL expression. In conclusion, the present study indicated that miR-361-5p may represent a novel molecular tool for therapeutic and diagnostic strategies in NSCLC. PMID:26461141

  18. Simulation of transducer-couplant effects on broadband ultrasonic signals

    NASA Technical Reports Server (NTRS)

    Vary, A.

    1980-01-01

    The increasing use of broadband, pulse-echo ultrasonics in nondestructive evaluation of flaws and material properties has generated a need for improved understanding of the way signals are modified by coupled and bonded thin-layer interfaces associated with transducers. This understanding is most important when using frequency spectrum analyses for characterizing material properties. In this type of application, signals emanating from material specimens can be strongly influenced by couplant and bond-layers in the acoustic path. Computer synthesized waveforms were used to simulate a range of interface conditions encountered in ultrasonic transducer systems operating in the 20 to 80 MHz regime. The adverse effects of thin-layer multiple reflections associated with various acoustic impedance conditions are demonstrated. The information presented is relevant to ultrasonic transducer design, specimen preparation, and couplant selection.

  19. Serine kinase activity of a Bacillus subtilis switch protein is required to transduce environmental stress signals but not to activate its target PP2C phosphatase.

    PubMed

    Kang, C M; Vijay, K; Price, C W

    1998-10-01

    The RsbT serine kinase has two known functions in the signal transduction pathway that activates the general stress factor sigmaB of Bacillus subtilis. First, RsbT can phosphorylate and inactivate its specific antagonist protein, RsbS. Second, upon phosphorylation of RsbS, RsbT is released to stimulate RsbU, a PP2C phosphatase, thereby initiating a signalling cascade that ultimately activates sigmaB. Here we describe a mutation that separates these two functions of RsbT. Although the mutant RsbT protein had essentially no kinase activity, it still retained the capacity to stimulate the RsbU phosphatase in vitro and to activate sigmaB when overexpressed in vivo. These results support the hypothesis that phosphatase activation is accomplished via a long-lived interaction between RsbT and RsbU. In contrast, RsbT kinase activity was found to be integral for the transmission of external stimuli to sigmaB. Thus, one route by which environmental stress signals could enter the sigmaB network is by modulation of the RsbT kinase activity, thereby controlling the magnitude of the partner switch between the RsbS-RsbT complex and the RsbT-RsbU complex.

  20. BPTF transduces MITF-driven prosurvival signals in melanoma cells.

    PubMed

    Dar, Altaf A; Majid, Shahana; Bezrookove, Vladimir; Phan, Binh; Ursu, Sarah; Nosrati, Mehdi; De Semir, David; Sagebiel, Richard W; Miller, James R; Debs, Robert; Cleaver, James E; Kashani-Sabet, Mohammed

    2016-05-31

    Microphthalmia-associated transcription factor (MITF) plays a critical and complex role in melanocyte transformation. Although several downstream targets of MITF action have been identified, the precise mechanisms by which MITF promotes melanocytic tumor progression are incompletely understood. Recent studies identified an oncogenic role for the bromodomain plant homeodomain finger transcription factor (BPTF) gene in melanoma progression, in part through activation of BCL2, a canonical target of MITF signaling. Analysis of the BPTF promoter identified a putative MITF-binding site, suggesting that MITF may regulate BPTF expression. Overexpression of MITF resulted in up-regulation of BPTF in a panel of melanoma and melanocyte cell lines. shRNA-mediated down-regulation of MITF in melanoma cells was accompanied by down-regulation of BPTF and BPTF-regulated genes (including BCL2) and resulted in reduced proliferative capacity of melanoma cells. The suppression of cell growth mediated by MITF silencing was rescued by overexpression of BPTF cDNA. Binding of MITF to the BPTF promoter was demonstrated using ChIP analysis. MITF overexpression resulted in direct transcriptional activation of BPTF, as evidenced by increased luciferase activity driven by the BPTF promoter. These results indicate that BPTF transduces key prosurvival signals driven by MITF, further supporting its important role in promoting melanoma cell survival and progression.

  1. BPTF transduces MITF-driven prosurvival signals in melanoma cells

    PubMed Central

    Dar, Altaf A.; Majid, Shahana; Bezrookove, Vladimir; Phan, Binh; Ursu, Sarah; Nosrati, Mehdi; De Semir, David; Sagebiel, Richard W.; Miller, James R.; Debs, Robert; Cleaver, James E.; Kashani-Sabet, Mohammed

    2016-01-01

    Microphthalmia-associated transcription factor (MITF) plays a critical and complex role in melanocyte transformation. Although several downstream targets of MITF action have been identified, the precise mechanisms by which MITF promotes melanocytic tumor progression are incompletely understood. Recent studies identified an oncogenic role for the bromodomain plant homeodomain finger transcription factor (BPTF) gene in melanoma progression, in part through activation of BCL2, a canonical target of MITF signaling. Analysis of the BPTF promoter identified a putative MITF-binding site, suggesting that MITF may regulate BPTF expression. Overexpression of MITF resulted in up-regulation of BPTF in a panel of melanoma and melanocyte cell lines. shRNA-mediated down-regulation of MITF in melanoma cells was accompanied by down-regulation of BPTF and BPTF-regulated genes (including BCL2) and resulted in reduced proliferative capacity of melanoma cells. The suppression of cell growth mediated by MITF silencing was rescued by overexpression of BPTF cDNA. Binding of MITF to the BPTF promoter was demonstrated using ChIP analysis. MITF overexpression resulted in direct transcriptional activation of BPTF, as evidenced by increased luciferase activity driven by the BPTF promoter. These results indicate that BPTF transduces key prosurvival signals driven by MITF, further supporting its important role in promoting melanoma cell survival and progression. PMID:27185926

  2. Transducer Signal Noise Analysis for Sensor Authentication

    SciTech Connect

    John M. Svoboda; Mark J. Schanfein

    2012-07-01

    The abstract is being passed through STIMS for submision to the conference. International safeguards organizations charged with promoting the peaceful use of nuclear energy employ unattended and remote monitoring systems supplemented with onsite inspections to ensure nuclear materials are not diverted for weaponization purposes. These systems are left unattended for periods of several months between inspections. During these periods physical security means are the main deterrent used to detect intentional monitoring system tampering. The information gathering components are locked in secure and sealed rooms. The sensor components (i.e. neutron and gamma detectors) are located throughout the plant in unsecure areas where sensor tampering could take place during the periods between inspections. Sensor tampering could allow the diversion of nuclear materials from the accepted and intended use to uses not consistent with the peaceful use of nuclear energy. A method and an apparatus is presented that address the detection of sensor tampering during the periods between inspections. It was developed at the Idaho National Laboratory (INL) for the Department of Energy (DOE) in support of the IAEA. The method is based on the detailed analysis of the sensor noise floor after the sensor signal is removed. The apparatus consists of a 2.1” x 2.6” electronic circuit board containing all signal conditioning and processing components and a laptop computer running an application that acquires and stores the analysis results between inspection periods. The sensors do not require any modification and are remotely located in their normal high radiation zones. The apparatus interfaces with the sensor signal conductors using a simple pass through connector at the normal sensor electronics interface package located in the already secure and sealed rooms. The apparatus does not require hardening against the effects of radiation due to its location. Presented is the apparatus design

  3. Polished Downhole Transducer Having Improved Signal Coupling

    DOEpatents

    Hall, David R.; Fox, Joe

    2006-03-28

    Apparatus and methods to improve signal coupling in downhole inductive transmission elements to reduce the dispersion of magnetic energy at the tool joints and to provide consistent impedance and contact between transmission elements located along the drill string. A transmission element for transmitting information between downhole tools is disclosed in one embodiment of the invention as including an annular core constructed of a magnetically conductive material. The annular core forms an open channel around its circumference and is configured to form a closed channel by mating with a corresponding annular core along an annular mating surface. The mating surface is polished to provide improved magnetic coupling with the corresponding annular core. An annular conductor is disposed within the open channel.

  4. Sesamin induces cell cycle arrest and apoptosis through the inhibition of signal transducer and activator of transcription 3 signalling in human hepatocellular carcinoma cell line HepG2.

    PubMed

    Deng, Pengyi; Wang, Chen; Chen, Liulin; Wang, Cheng; Du, Yuhan; Yan, Xu; Chen, Mingjie; Yang, Guangxiao; He, Guangyuan

    2013-01-01

    Sesamin, one of the most abundant lignans in sesame seeds, has been shown to exhibit various pharmacological effects. The aim of this study was to elucidate whether sesamin promotes cell cycle arrest and induces apoptosis in HepG2 cells and further to explore the underlying molecular mechanisms. Here, we found that sesamin inhibited HepG2 cell growth by inducing G2/M phase arrest and apoptosis. Furthermore, sesamin suppressed the constitutive and interleukin (IL)-6-induced signal transducer and activator of transcription 3 (STAT3) signalling pathway in HepG2 cells, leading to regulate the downstream genes, including p53, p21, cyclin proteins and the Bcl-2 protein family. Our studies showed that STAT3 signalling played a key role in sesamin-induced G2/M phase arrest and apoptosis in HepG2 cells. These findings provided a molecular basis for understanding of the effects of sesamin in hepatocellular carcinoma tumour cell proliferation. Therefore, sesamin may thus be a potential chemotherapy drug for liver cancer.

  5. Induction of caspase-dependent extrinsic apoptosis by apigenin through inhibition of signal transducer and activator of transcription 3 (STAT3) signalling in HER2-overexpressing BT-474 breast cancer cells.

    PubMed

    Seo, Hye-Sook; Jo, Jae Kyung; Ku, Jin Mo; Choi, Han-Seok; Choi, Youn Kyung; Woo, Jong-Kyu; Kim, Hyo In; Kang, Soo-Yeon; Lee, Kang Min; Nam, Koong Won; Park, Namkyu; Jang, Bo-Hyoung; Shin, Yong Cheol; Ko, Seong-Gyu

    2015-10-23

    Phytoestrogen intake is known to be beneficial to decrease breast cancer incidence and progression. But its molecular mechanisms of action are still unknown. The present study aimed to examine the effect of apigenin on proliferation and apoptosis in HER2-expressing breast cancer cells. In our experiments, apigenin inhibited the proliferation of BT-474 cells in a dose- and time-dependent manner. Apigenin also inhibited clonogenic survival (anchorage-dependent and -independent) of BT-474 cells in a dose-dependent manner. These growth inhibitions were accompanied with an increase in sub-G0/G1 apoptotic populations. Apigenin-induced extrinsic a caspase-dependent apoptosis up-regulating the levels of cleaved caspase-8 and cleaved caspase-3, and inducing the cleavage of poly (ADP-ribose) polymerase (PARP). Whereas, apigenin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease mitochondrial membrane potential without affecting the levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX). Apigenin reduced the expression of phospho-JAK1, phospho-JAK2 and phospho-STAT3 and decreased signal transducer and activator of transcription 3 (STAT3) dependent luciferase reporter gene activity in BT-474 cells. Apigenin inhibited CoCl2-induced VEGF secretion and decreased the nuclear translocation of STAT3. Our study indicates that apigenin induces apoptosis through inhibition of STAT3 signalling and could serve as a useful compound to prevent or treat HER2-overexpressing breast cancer.

  6. Angiogenesis Induced by Signal Transducer and Activator of Transcription 5A (STAT5A) Is Dependent on Autocrine Activity of Proliferin*

    PubMed Central

    Yang, Xinhai; Qiao, Dianhua; Meyer, Kristy; Pier, Thomas; Keles, Sunduz; Friedl, Andreas

    2012-01-01

    Multiple secreted factors induce the formation of new blood vessels (angiogenesis). The signal transduction events that orchestrate the numerous cellular activities required for angiogenesis remain incompletely understood. We have shown previously that STAT5 plays a pivotal role in angiogenesis induced by FGF2 and FGF8b. To delineate the signaling pathway downstream of STAT5, we expressed constitutively active (CA) or dominant-negative (DN) mutant STAT5A in mouse brain endothelial cells (EC). We found that the conditioned medium from CA-STAT5A but not from dominant-negative STAT5A overexpressing EC is sufficient to induce EC invasion and tube formation, indicating that STAT5A regulates the secretion of autocrine proangiogenic factors. Conversely, CA-STAT5A-induced conditioned medium had no effect on EC proliferation. Using a comparative genome-wide transcription array screen, we identified the prolactin family member proliferin (PLF1 and PLF4) as a candidate autocrine factor. The CA-STAT5A-dependent transcription and secretion of PLF by EC was confirmed by quantitative RT-PCR and Western blotting, respectively. CA-STAT5A binds to the PLF1 promoter region, suggesting a direct transcriptional regulation. Knockdown of PLF expression by shRNA or by blocking of PLF activity with neutralizing antibodies removed the CA-STAT5A-dependent proangiogenic activity from the conditioned medium of EC. Similarly, the ability of concentrated conditioned medium from CA-STAT5A transfected EC to induce angiogenesis in Matrigel plugs in vivo was abolished when PLF was depleted from the medium. These observations demonstrate a FGF/STAT5/PLF signaling cascade in EC and implicate PLF as autocrine regulator of EC invasion and tube formation. PMID:22199350

  7. Tautomeric states of the active-site histidines of phosphorylated and unphosphorylated IIIGlc, a signal-transducing protein from Escherichia coli, using two-dimensional heteronuclear NMR techniques.

    PubMed Central

    Pelton, J. G.; Torchia, D. A.; Meadow, N. D.; Roseman, S.

    1993-01-01

    IIIGlc is an 18.1-kDa signal-transducing phosphocarrier protein of the phosphoenolpyruvate:glycose phosphotransferase system from Escherichia coli. The 1H, 15N, and 13C histidine ring NMR signals of both the phosphorylated and unphosphorylated forms of IIIGlc have been assigned using two-dimensional 1H-15N and 1H-13C heteronuclear multiple-quantum coherence (HMQC) experiments and a two-dimensional 13C-13C-1H correlation spectroscopy via JCC coupling experiment. The data were acquired on uniformly 15N-labeled and uniformly 15N/13C-labeled protein samples. The experiments rely on one-bond and two-bond J couplings that allowed for assignment of the signals without the need for the analysis of through-space (nuclear Overhauser effect spectroscopy) correlations. The 15N and 13C chemical shifts were used to determine that His-75 exists predominantly in the N epsilon 2-H tautomeric state in both the phosphorylated and unphosphorylated forms of IIIGlc, and that His-90 exists primarily in the N delta 1-H state in the unphosphorylated protein. Upon phosphorylation of the N epsilon 2 nitrogen of His-90, the N delta 1 nitrogen remains protonated, resulting in the formation of a charged phospho-His-90 moiety. The 1H, 15N, and 13C signals of the phosphorylated and unphosphorylated proteins showed only minor shifts in the pH range from 6.0 to 9.0. These data indicate that the pK alpha values for both His-75 and His-90 in IIIGlc and His-75 in phospho-IIIGlc are less than 5.0, and that the pK alpha value for phospho-His-90 is greater than 10. The results are presented in relation to previously obtained structural data on IIIGlc, and implications for proposed mechanisms of phosphoryl transfer are discussed. PMID:8518729

  8. Sensing feeble microwave signals via an optomechanical transducer

    NASA Astrophysics Data System (ADS)

    Zhang, Keye; Bariani, Francesco; Dong, Ying; Zhang, Weiping; Meystre, Pierre

    2015-05-01

    Due to their low energy content microwave signals at the single-photon level are extremely challenging to measure. Guided by recent progress in single-photon optomechanics and hybrid optomechanical systems, we propose a multimode optomechanical transducer that can detect intensities significantly below the single-photon level via off-resonant adiabatic transfer of the microwave signal to the optical frequency domain where the measurement is then performed. The influence of intrinsic quantum and thermal fluctuations on the performance of this detector are considered in detail. We acknowledge financial support from National Basic Research Program of China, NSF, ARO and the DARPA QuaSAR and ORCHID programs.

  9. YC-1 enhances the anti-tumor activity of sorafenib through inhibition of signal transducer and activator of transcription 3 (STAT3) in hepatocellular carcinoma

    PubMed Central

    2014-01-01

    Background Traditional systemic chemotherapy does not provide survival benefits in patients with hepatocellular carcinoma (HCC). Molecular targeted therapy shows promise for HCC treatment, however, the duration of effectiveness for targeted therapies is finite and combination therapies offer the potential for improved effectiveness. Methods Sorafenib, a multikinase inhibitor, and YC-1, a soluble guanylyl cyclase (sGC) activator, were tested in HCC by proliferation assay, cell cycle analysis and western blot in vitro and orthotopic and ectopic HCC models in vivo. Results In vitro, combination of sorafenib and YC-1 synergistically inhibited proliferation and colony formation of HepG2, BEL-7402 and HCCLM3 cells. The combination also induced S cell cycle arrest and apoptosis, as observed by activated PARP and caspase 8. Sorafenib and YC-1 respectively suppressed the expression of phosphorylated STAT3 (p-STAT3) (Y705) in a dose- and time-dependent manner. Combination of sorafenib and YC-1 significantly inhibited the expression of p-STAT3 (Y705) (S727), p-ERK1/2, cyclin D1 and survivin and SHP-1 activity compared with sorafenib or YC-1 used alone in all tested HCC cell lines. In vivo, sorafenib-YC-1 combination significantly suppressed the growth of HepG2 tumor xenografts with decreased cell proliferation and increased apoptosis observed by PCNA and PARP. Similar results were also confirmed in a HCCLM3 orthotopic model. There was a reduction in CD31-positive blood vessels and reduced VEGF expression, which suggested a combinational effect of sorafenib and YC-1 on angiogenesis. The reduced expression of p-STAT3, cyclin D1 and survivin was also observed with the combination of sorafenib and YC-1. Conclusions Our data show that sorafenib-YC-1 combination is a novel potent therapeutic agent that can target the STAT3 signaling pathway to inhibit HCC tumor growth. PMID:24418169

  10. Cooperative unfolding of distinctive mechanoreceptor domains transduces force into signals

    PubMed Central

    Ju, Lining; Chen, Yunfeng; Xue, Lingzhou; Du, Xiaoping; Zhu, Cheng

    2016-01-01

    How cells sense their mechanical environment and transduce forces into biochemical signals is a crucial yet unresolved question in mechanobiology. Platelets use receptor glycoprotein Ib (GPIb), specifically its α subunit (GPIbα), to signal as they tether and translocate on von Willebrand factor (VWF) of injured arterial surfaces against blood flow. Force elicits catch bonds to slow VWF–GPIbα dissociation and unfolds the GPIbα leucine-rich repeat domain (LRRD) and juxtamembrane mechanosensitive domain (MSD). How these mechanical processes trigger biochemical signals remains unknown. Here we analyze these extracellular events and the resulting intracellular Ca2+ on a single platelet in real time, revealing that LRRD unfolding intensifies Ca2+ signal whereas MSD unfolding affects the type of Ca2+ signal. Therefore, LRRD and MSD are analog and digital force transducers, respectively. The >30 nm macroglycopeptide separating the two domains transmits force on the VWF–GPIbα bond (whose lifetime is prolonged by LRRD unfolding) to the MSD to enhance its unfolding, resulting in unfolding cooperativity at an optimal force. These elements may provide design principles for a generic mechanosensory protein machine. DOI: http://dx.doi.org/10.7554/eLife.15447.001 PMID:27434669

  11. Calyculin A Reveals Serine/Threonine Phosphatase Protein Phosphatase 1 as a Regulatory Nodal Point in Canonical Signal Transducer and Activator of Transcription 3 Signaling of Human Microvascular Endothelial Cells

    PubMed Central

    Zgheib, Carlos; Zouein, Fouad A.; Chidiac, Rony; Kurdi, Mazen

    2012-01-01

    Vascular inflammation is initiated by stimuli acting on endothelial cells. A clinical feature of vascular inflammation is increased circulating interleukin 6 (IL-6) type cytokines such as leukemia inhibitory factor (LIF), but their role in vascular inflammation is not fully defined. IL-6 type cytokines activate transcription factor signal transducer and activator of transcription 3 (STAT3), which has a key role in inflammation and the innate immune response. Canonical STAT3 gene induction is due to phosphorylation of (1) Y705, leading to STAT3 dimerization and DNA binding and (2) S727, enhancing homodimerization and DNA binding by recruiting p300/CBP. We asked whether enhancing S727 STAT3 phosphorylation using the protein phosphatase 1 (PP1) inhibitor, calyculin A, would enhance LIF-induced gene expression in human microvascular endothelial cells (HMEC-1). Cotreatment with calyculin A and LIF markedly increased STAT3 S727 phosphorylation, without affecting the increase in the nuclear fraction of STAT3 phosphorylated on Y705. PP2A inhibitors, okadaic acid and fostriecin, did not enhance STAT3 S727 phosphorylation. Surprisingly, calyculin A eliminated LIF-induced gene expression: (1) calyculin A reduced binding of nuclear extracts to a STAT3 consensus site, thereby reducing the overall level of binding observed with LIF; and (2) calyculin A caused p300/CBP phosphorylation, thus resulting in reduced acetylation activity and degradation. Together, these findings reveal a pivotal role of a protein serine/threonine phosphatases that is likely PP1 in HMEC in controlling STAT3 transcriptional activity. PMID:22142222

  12. Platelet-derived growth factor (PDGF)-induced activation of signal transducer and activator of transcription (Stat) 5 is mediated by PDGF beta-receptor and is not dependent on c-src, fyn, jak1 or jak2 kinases.

    PubMed Central

    Paukku, K; Valgeirsdóttir, S; Saharinen, P; Bergman, M; Heldin, C H; Silvennoinen, O

    2000-01-01

    Several growth factors activate signal transducers and activators of transcription (Stats) but the mechanism of Stat activation in receptor tyrosine kinase signalling has remained elusive. In the present study we have analysed the roles of different platelet-derived growth factor (PDGF)-induced tyrosine kinases in the activation of Stat5. Co-expression experiments in insect and mammalian cells demonstrated that both PDGF beta-receptor (PDGF beta-R) and Jak1, but not c-Src, induced the activation of Stat5. Furthermore, immune-complex-purified PDGF beta-R was able to phosphorylate Stat5 directly. The role of the cytoplasmic tyrosine kinases in the PDGF-induced activation of Stat5 was further investigated by overexpressing kinase-negative (KN) and wild-type Jak and c-Src kinases. Jak1-KN or Jak2-KN had no effect but both Src-KN and wild-type c-Src similarly decreased the PDGF-beta-R-induced activation of Stat5. The activation of both Src and Stat5 is dependent on the same tyrosine residues Tyr(579) and Tyr(581) in PDGF beta-R; thus the observed inhibition by Src might result from competition for binding of Stat5 to the receptor. Finally, fibroblasts derived from Src(-/-) and Fyn(-/-) mice showed normal pattern of PDGF-induced tyrosine phosphorylation of Stat5. Taken together, these results indicate that Stat5 is a direct substrate for PDGF beta-R and that the activation does not require Jak1, Jak2, c-Src or Fyn tyrosine kinases. PMID:10642538

  13. Signal processing for damage detection using two different array transducers.

    PubMed

    El Youbi, F; Grondel, S; Assaad, J

    2004-04-01

    This work describes an investigation into the development of a new health monitoring system for aeronautical applications. The health monitoring system is based on the emission and reception of Lamb waves by multi-element piezoelectric transducers (i.e., arrays) bonded to the structure. The emitter array consists of three different elementary bar transducers. These transducers have the same thickness and length but different widths. The receiver array has 32 same elements. This system offers the possibility to understand the nature of the generated waves and to determine the sensitivity of each mode to possible damage. It presents two principal advantages: Firstly, by exciting all elements in phase, it is possible to generate several Lamb modes in the same time. Secondly, the two-dimensional fourier transform (2D-FT) of the received signal can be easily computed. Experimental results concerning an aluminum plate with different hole sizes will be shown. The A0-, S0-, A1-, S1- and S2-modes are generated at the same time. This study shows that the A0 mode seems particularly interesting to detect flaws of this geometrical type.

  14. Activation of interleukin-6/signal transducer and activator of transcription 3 by human papillomavirus early proteins 6 induces fibroblast senescence to promote cervical tumourigenesis through autocrine and paracrine pathways in tumour microenvironment.

    PubMed

    Ren, Chunxia; Cheng, Xi; Lu, Bei; Yang, Gong

    2013-12-01

    Although it is reported that interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) is activated by human papillomavirus (HPV) infection in cervical cancer cells, little is known about the role of IL-6/STAT3 in tumour microenvironment during development of the disease. In this study, we found that cancer-associated fibroblasts (CAF) but not normal fibroblasts (NF) secrete high level of IL-6 with activated STAT3 and appear senescent at early passages in culture or in cervical cancer tissues infected with high-risk HPV, and that treatment of NF with recombinant IL-6 or CAF conditioned medium (CM) induces activation of STAT3 and cellular senescence. IL-6 and STAT3 are either upregulated or activated in Siha and Hela cells infected with HPV 16 or 18, but not in C33A and ME180 cells without HPV 16 or 18 infection. Overexpression of HPV early proteins 6 (E6) activates STAT3, increases IL-6 expression and tumour burden in C33A and ME180 cells, while silencing of HPV E6 by specific shRNA reduces STAT3 activation, IL-6 expression, and tumour formation in Siha and HeLa cells, so does silencing of STAT3 by specific shRNA in HeLa and C33A/E6 cells. The tumour growth of cervical cancer cells reconstituted with CAF or NF is largely affected by inhibition of fibroblast senescence with STAT3 inhibitor or with IL-6 antibody treatment. Thus, we have uncovered a mechanism that fibroblast senescence promotes cervical cancer development through high-risk HPV E6-activated IL-6/STAT3 signalling in tumour microenvironment.

  15. ETV6/ARG oncoprotein confers autonomous cell growth by enhancing c-Myc expression via signal transducer and activator of transcription 5 activation in the acute promyelocytic leukemia cell line HT93A.

    PubMed

    Iriyama, Noriyoshi; Hatta, Yoshihiro; Takei, Masami

    2015-01-01

    We investigated the role of ETV6/ARG fusion gene by exposing the HT93A cell line to nilotinib. HT93A cells were cultured with or without nilotinib±50 ng/mL of granulocyte colony-stimulating factor (G-CSF). Nilotinib treatment inhibited cell growth by increasing the percentage of cells in G0/G1 phase through the decrease of phosphorylated signal transducer and activator of transcription 3 (STAT3) (Y705), STAT5 (Y694) and c-Myc expression. After stimulation with G-CSF, STAT5 but not STAT3 was significantly phosphorylated in both nilotinib-treated and untreated cells. Moreover, combination therapy with nilotinib and G-CSF returned the expression level of c-Myc, cell growth and cell cycle distribution to the control level. These findings suggest that the ETV6/ARG oncoprotein contributes to autonomous cell growth by compensating for the requirement of growth factor through activating STAT5 signaling, which leads to the up-regulation of c-Myc. Our data suggest that ETV6/ARG oncoprotein is a potential target in the treatment of leukemia.

  16. Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2.

    PubMed

    Yang, Cuiping; Chen, Wenlin; Chen, Yongbin; Jiang, Jin

    2012-11-01

    Hedgehog (Hh) signaling plays pivotal roles in embryonic development and adult tissue homeostasis in species ranging from Drosophila to mammals. The Hh signal is transduced by Smoothened (Smo), a seven-transmembrane protein related to G protein coupled receptors. Despite a conserved mechanism by which Hh activates Smo in Drosophila and mammals, how mammalian Hh signal is transduced from Smo to the Gli transcription factors is poorly understood. Here, we provide evidence that two ciliary proteins, Evc and Evc2, the products of human disease genes responsible for the Ellis-van Creveld syndrome, act downstream of Smo to transduce the Hh signal. We found that loss of Evc/Evc2 does not affect Sonic Hedgehog-induced Smo phosphorylation and ciliary localization but impedes Hh pathway activation mediated by constitutively active forms of Smo. Evc/Evc2 are dispensable for the constitutive Gli activity in Sufu(-/-) cells, suggesting that Evc/Evc2 act upstream of Sufu to promote Gli activation. Furthermore, we demonstrated that Hh stimulates binding of Evc/Evc2 to Smo depending on phosphorylation of the Smo C-terminal intracellular tail and that the binding is abolished in Kif3a(-/-) cilium-deficient cells. We propose that Hh activates Smo by inducing its phosphorylation, which recruits Evc/Evc2 to activate Gli proteins by antagonizing Sufu in the primary cilia.

  17. Signal transducer and activator of transcription 5b (Stat5b) serine 193 is a novel cytokine-induced phospho-regulatory site that is constitutively activated in primary hematopoietic malignancies.

    PubMed

    Mitra, Abhisek; Ross, Jeremy A; Rodriguez, Georgialina; Nagy, Zsuzsanna S; Wilson, Harry L; Kirken, Robert A

    2012-05-11

    Signal transducer and activator of transcription 5b (Stat5b) is a critical node in the signaling network downstream of external (cytokines or growth factors) or internal (oncogenic tyrosine kinases) stimuli. Maximum transcriptional activation of Stat5b requires both tyrosine and serine phosphorylation. Although the mechanisms governing tyrosine phosphorylation and activation of Stat5b have been extensively studied, the role of serine phosphorylation remains to be fully elucidated. Using mass spectrometry and phospho-specific antibodies, we identified Ser-193 as a novel site of cytokine-induced phosphorylation within human Stat5b. Stat5b Ser(P)-193 was detected in activated primary human peripheral blood mononuclear cells or lymphoid cell lines in response to several γ common (γc) cytokines, including interleukin (IL)-2, IL-7, IL-9, and IL-15. Kinetic and spatial analysis indicated that Stat5b Ser-193 phosphorylation was rapid and transient and occurred in the cytoplasmic compartment of the cell prior to Stat5b translocation to the nucleus. Moreover, inducible Stat5b Ser-193 phosphorylation was sensitive to inhibitors of mammalian target of rapamycin (mTOR), whereas inhibition of protein phosphatase 2A (PP2A) induced phosphorylation of Ser-193. Reconstitution assays in HEK293 cells in conjunction with site-directed mutagenesis, EMSA, and reporter assays indicated that Ser(P)-193 is required for maximal Stat5b transcriptional activity. Indeed, Stat5b Ser-193 was found constitutively phosphorylated in several lymphoid tumor cell lines as well as primary leukemia and lymphoma patient tumor cells. Taken together, IL-2 family cytokines tightly control Stat5b Ser-193 phosphorylation through a rapamycin-sensitive mechanism. Furthermore, constitutive Ser-193 phosphorylation is associated with Stat5b proto-oncogenic activity and therefore may serve as a novel therapeutic target for treating hematopoietic malignancies.

  18. Angiotensin II activates signal transducers and activators of transcription 3 via Rac1 in the atrial tissue in permanent atrial fibrillation patients with rheumatic heart disease.

    PubMed

    Xue, Xiao-Dong; Huang, Jian-Hua; Wang, Hui-Shan

    2015-01-01

    Patients with rheumatic heart disease (RHD) often experience persistent atrial fibrillation (AF) associated with adverse atrial structural remodeling (ASR) manifested by atrial fibrosis and left atrial enlargement. The aim of this study was to explore the potential molecular signaling mechanisms for atrial fibrosis and ASR. Twenty RHD patients with persistent AF and 10 RHD patients with sinus rhythm (Group A) were recruited in our study, which all underwent transthoracic echocardiography. Right atrial appendage (RAA) tissue samples were obtained from these patients during mitral/aortic valve replacement operation. The AF patients were further divided into two groups according to left atrial diameter (LAD): Group B with LAD ranging 50-65 mm and Group C with LAD >65 mm. Histological examinations were performed with hematoxylin-eosin staining and Masson's trichrome staining. Atrial angiotensin II (AngII) content was measured by ELISA. Rac1 and STAT3 protein levels were determined by Western blot analysis. Hematoxylin-eosin staining demonstrated highly organized arrangement of atrial muscles in control Group A and significant derangement in both Group B and C AF patients with reduced cell density and increased cell size. Moreover, Masson's trichrome staining showed that atrial myocytes were surrounded by large trunks of collagen fibers in both Group B and C, but not in Group A. There was a positive correlation between atrial tissue fibrosis and LAD. AngII content was markedly higher in Group C than in Group B than in Group A, which was positively correlated with LAD. Similarly, Rac1 and STAT3 protein levels were found considerably higher in Group C and B than in Group A with excellent correlation to LAD. Our study unraveled for the first time the AngII/Rac1/STAT3 signaling as a mechanism for ASR thereby AF in a particular clinical setting-RHD patients with persistent AF and indicated inhibition of this pathway may help ameliorating adverse ASR.

  19. Signal Transducer and Activator of  Transcription (STAT)5 Activation by BCR/ABL Is Dependent on Intact Src Homology (SH)3 and SH2 Domains of BCR/ABL and Is Required for Leukemogenesis

    PubMed Central

    Nieborowska-Skorska, Malgorzata; Wasik, Mariusz A.; Slupianek, Artur; Salomoni, Paolo; Kitamura, Toshio; Calabretta, Bruno; Skorski, Tomasz

    1999-01-01

    Signal transducer and activator of transcription (STAT)5 is constitutively activated in BCR/ ABL-expressing cells, but the mechanisms and functional consequences of such activation are unknown. We show here that BCR/ABL induces phosphorylation and activation of STAT5 by a mechanism that requires the BCR/ABL Src homology (SH)2 domain and the proline-rich binding site of the SH3 domain. Upon expression in 32Dcl3 growth factor–dependent myeloid precursor cells, STAT5 activation–deficient BCR/ABL SH3+SH2 domain mutants functioned as tyrosine kinase and activated Ras, but failed to protect from apoptosis induced by withdrawal of interleukin 3 and/or serum and did not induce leukemia in severe combined immunodeficiency mice. In complementation assays, expression of a dominant-active STAT5B mutant (STAT5B-DAM), but not wild-type STAT5B (STAT5B-WT), in 32Dcl3 cells transfected with STAT5 activation–deficient BCR/ABL SH3+SH2 mutants restored protection from apoptosis, stimulated growth factor–independent cell cycle progression, and rescued the leukemogenic potential in mice. Moreover, expression of a dominant-negative STAT5B mutant (STAT5B-DNM) in 32Dcl3 cells transfected with wild-type BCR/ABL inhibited apoptosis resistance, growth factor–independent proliferation, and the leukemogenic potential of these cells. In retrovirally infected mouse bone marrow cells, expression of STAT5B-DNM inhibited BCR/ABL-dependent transformation. Moreover, STAT5B-DAM, but not STAT5B-WT, markedly enhanced the ability of STAT5 activation–defective BCR/ABL SH3+SH2 mutants to induce growth factor–independent colony formation of primary mouse bone marrow progenitor cells. However, STAT5B-DAM did not rescue the growth factor–independent colony formation of kinase-deficient K1172R BCR/ABL or the triple mutant Y177F+R522L+ Y793F BCR/ABL, both of which also fail to activate STAT5. Together, these data demonstrate that STAT5 activation by BCR/ABL is dependent on signaling from more

  20. Electromechanically active polymer transducers: research in Europe

    NASA Astrophysics Data System (ADS)

    Carpi, Federico; Graz, Ingrid; Jager, Edwin; Ladegaard Skov, Anne; Vidal, Frédéric

    2013-10-01

    Smart materials and structures based on electromechanically active polymers (EAPs) represent a fast growing and stimulating field of research and development. EAPs are materials capable of changing dimensions and/or shape in response to suitable electrical stimuli. They are commonly classified in two major families: ionic EAPs (activated by an electrically induced transport of ions and/or solvent) and electronic EAPs (activated by electrostatic forces). These polymers show interesting properties, such as sizable active strains and/or stresses in response to electrical driving, high mechanical flexibility, low density, structural simplicity, ease of processing and scalability, no acoustic noise and, in most cases, low costs. Since many of these characteristics can also describe natural muscle tissues from an engineering standpoint, it is not surprising that EAP transducers are sometimes also referred to as 'muscle-like smart materials' or 'artificial muscles'. They are used not only to generate motion, but also to sense or harvest energy from it. In particular, EAP electromechanical transducers are studied for applications that can benefit from their 'biomimetic' characteristics, with possible usages from the micro- to the macro-scale, spanning several disciplines, such as mechatronics, robotics, automation, biotechnology and biomedical engineering, haptics, fluidics, optics and acoustics. Currently, the EAP field is just undergoing its initial transition from academic research into commercialization, with companies starting to invest in this technology and the first products appearing on the market. This focus issue is intentionally aimed at gathering contributions from the most influential European groups working in the EAP field. In fact, today Europe hosts the broadest EAP community worldwide. The rapid expansion of the EAP field in Europe, where it historically has strong roots, has stimulated the creation of the 'European Scientific Network for Artificial

  1. G-quadruplex as signal transducer for biorecognition events.

    PubMed

    Lv, Lei; Guo, Zhijun; Wang, Jiahai; Wang, Erkang

    2012-01-01

    G-rich nucleic acid oligomers can form G-quadruplexes built by G-tetrads stacked upon each other. The basic building block of the G-quadruplexes is similar, but the formation of different quadruplex structures is highly responsive to the strand stoichiometry, strand orientation, guanine glycosidic torsion angle, connecting loops, and the metal coordination. Because of its structural variations and different functions, G-quadruplex applied in biorecognition events can function as a versatile signaling component. A variety of strategies that incorporate G-quadruplex have also been reported. In this review, we mainly discuss G-quadruplex as signal transducer from the following aspects for biorecognition events: analyte-induced G-quadruplex reconfiguration and fluorescence enhancement of small ligand; analyte-induced G-quadruplex reconstruction and formation of DNAzyme; Stimulus-responsive G-quadruplex refolding and manipulation of electron transfer; Stimulus-responsive G-quadruplex and its combination with nanopore systems; Small ligand-responsive G-quadruplex stabilization for drug screening; Nanomaterial-reponsive G-quadruplex reformation; Target-triggered continuous formation of G-quadruplex by DNA nanomachine. We have comprehensively described the recent progress in our labs and others. Undoubtedly, bioanalytical technology and nanotechnology based on G-quadruplex will continue to grow, leading to develop new diagnostics, therapeutics and drug development.

  2. Caerulomycin A Enhances Transforming Growth Factor-β (TGF-β)-Smad3 Protein Signaling by Suppressing Interferon-γ (IFN-γ)-Signal Transducer and Activator of Transcription 1 (STAT1) Protein Signaling to Expand Regulatory T Cells (Tregs)*

    PubMed Central

    Gurram, Rama Krishna; Kujur, Weshely; Maurya, Sudeep K.; Agrewala, Javed N.

    2014-01-01

    Cytokines play a very important role in the regulation of immune homeostasis. Regulatory T cells (Tregs) responsible for the generation of peripheral tolerance are under the tight regulation of the cytokine milieu. In this study, we report a novel role of a bipyridyl compound, Caerulomycin A (CaeA), in inducing the generation of Tregs. It was observed that CaeA substantially up-regulated the pool of Tregs, as evidenced by an increased frequency of CD4+ Foxp3+ cells. In addition, CaeA significantly suppressed the number of Th1 and Th17 cells, as supported by a decreased percentage of CD4+/IFN-γ+ and CD4+/IL-17+ cells, respectively. Furthermore, we established the mechanism and observed that CaeA interfered with IFN-γ-induced STAT1 signaling by augmenting SOCS1 expression. An increase in the TGF-β-mediated Smad3 activity was also noted. Furthermore, CaeA rescued Tregs from IFN-γ-induced inhibition. These results were corroborated by blocking Smad3 activity, which abolished the CaeA-facilitated generation of Tregs. In essence, our results indicate a novel role of CaeA in inducing the generation of Tregs. This finding suggests that CaeA has enough potential to be considered as a potent future drug for the treatment of autoimmunity. PMID:24811173

  3. Signal transducer and activator of transcription-3 licenses Toll-like receptor 4-dependent interleukin (IL)-6 and IL-8 production via IL-6 receptor-positive feedback in endometrial cells

    PubMed Central

    Cronin, J G; Kanamarlapudi, V; Thornton, C A; Sheldon, I M

    2016-01-01

    Interleukin 6 (IL-6), acting via the IL-6 receptor (IL6R) and signal transducer and activator of transcription-3 (STAT3), limits neutrophil recruitment once bacterial infections are resolved. Bovine endometritis is an exemplar mucosal disease, characterized by sustained neutrophil infiltration and elevated IL-6 and IL-8, a neutrophil chemoattractant, following postpartum Gram-negative bacterial infection. The present study examined the impact of the IL6R/STAT3 signaling pathway on IL-8 production by primary endometrial cells in response to short- or long-term exposure to lipopolysaccharide (LPS) from Gram-negative bacteria. Tyrosine phosphorylation of STAT3 is required for DNA binding and expression of specific targets genes. Immunoblotting indicated constitutive tyrosine phosphorylation of STAT3 in endometrial cells was impeded by acute exposure to LPS. After 24 h exposure to LPS, STAT3 returned to a tyrosine phosphorylated state, indicating cross-talk between the Toll-like receptor 4 (TLR4) and the IL6R/STAT3 signaling pathways. This was confirmed by short interfering RNA targeting the IL6R, which abrogated the accumulation of IL-6 and IL-8, induced by LPS. Furthermore, there was a differential endometrial cell response, as the accumulation of IL-6 and IL-8 was dependent on STAT3, suppressor of cytokine signaling 3, and Src kinase signaling in stromal cells, but not epithelial cells. In conclusion, positive feedback through the IL6R amplifies LPS-induced IL-6 and IL-8 production in the endometrium. These findings provide a mechanistic insight into how elevated IL-6 concentrations in the postpartum endometrium during bacterial infection leads to marked and sustained neutrophil infiltration. PMID:26813342

  4. Modeling of Ultrasonic Signals from a Side-Drilled Hole Captured By a Rectangular Transducer

    NASA Astrophysics Data System (ADS)

    Kim, Hak-Joon; Song, Sung-Jin; Schmerr, Lester W.

    2006-03-01

    In ultrasonic nondestructive testing an angle beam transducer with a rectangular piezoelectric element is often adopted in practice to detect flaws. Also, a side-drilled hole (SDH) is very widely used as a standard reflector in ultrasonic testing. For proper interpretation of the measurement results from a SDH using a rectangular transducer, it is very helpful to have a complete ultrasonic measurement model including an ultrasonic beam model of the rectangular transducer, a scattering model of the SDH, and an ultrasonic system model. Recently, a highly efficient ultrasonic beam model of the rectangular transducer and an accurate scattering model of the SDH have been proposed. Thus, in this study, by combining those components with a system efficiency factor for a rectangular transducer, we develop a complete ultrasonic measurement model to predict ultrasonic signals from a SDH. Based on this model, we have calculated the ultrasonic signals from a SDH at different transducer orientations. The predicted results are compared with the experiments.

  5. An invertebrate signal transducer and activator of transcription 5 (STAT5) ortholog from the disk abalone, Haliotis discus discus: Genomic structure, early developmental expression, and immune responses to bacterial and viral stresses.

    PubMed

    Bathige, S D N K; Umasuthan, Navaneethaiyer; Park, Hae-Chul; Lee, Jehee

    2016-03-01

    Signal transducer and activator of transcription (STAT) family members are key signaling molecules that transduce cellular responses from the cell membrane to the nucleus upon Janus kinase (JAK) activation. Although seven STAT members have been reported in mammals, very limited information on STAT genes in molluscans is available. In this study, we identified and characterized a STAT paralog that is homologous to STAT5 from the disk abalone, Haliotis discus discus, and designated as AbSTAT5. Comparison of the deduced amino acid sequence for AbSTAT5 (790 amino acids) with other counterparts revealed conserved residues important for functions and typical domain regions, including the N-terminal domain, coiled-coil domain, DNA-binding domain, linker domain, and Src homology 2 (SH2) domains as mammalian counterparts. Analysis of STAT phylogeny revealed that AbSTAT5 was clustered with the molluscan subgroup in STAT5 clade with distinct evolution. According to the genomic structure of AbSTAT5, the coding sequence was distributed into 20 exons with 19 introns. Immunologically essential transcription factor-binding sites, such as GATA-1, HNF, SP1, C/EBP, Oct-1, AP1, c-Jun, and Sox-2, were predicted at the 5'-proximal region of AbSTAT5. Expression of AbSTAT5 mRNA was detected in different stages of embryonic development and observed at considerably higher levels in the morula and late veliger stages. Tissue-specific expressional studies revealed that the highest level of AbSTAT5 transcripts was detected in hemocytes, followed by gill tissues. Temporal expressions of AbSTAT5 were analyzed upon live bacterial (Vibrio parahemolyticus and Listeria monocytogenes), viral (viral hemorrhagic septicemia virus), and pathogen-associated molecular pattern (lipopolysaccharides and Poly I:C) stimulations, and significant elevations indicated immune modulation. These results suggest that AbSTAT5 may be involved in maintaining innate immune responses from developmental to adult stages in

  6. New Insights on Signal Propagation by Sensory Rhodopsin II/Transducer Complex

    PubMed Central

    Ishchenko, A.; Round, E.; Borshchevskiy, V.; Grudinin, S.; Gushchin, I.; Klare, J. P.; Remeeva, A.; Polovinkin, V.; Utrobin, P.; Balandin, T.; Engelhard, M.; Büldt, G.; Gordeliy, V.

    2017-01-01

    The complex of two membrane proteins, sensory rhodopsin II (NpSRII) with its cognate transducer (NpHtrII), mediates negative phototaxis in halobacteria N. pharaonis. Upon light activation NpSRII triggers a signal transduction chain homologous to the two-component system in eubacterial chemotaxis. Here we report on crystal structures of the ground and active M-state of the complex in the space group I212121. We demonstrate that the relative orientation of symmetrical parts of the dimer is parallel (“U”-shaped) contrary to the gusset-like (“V”-shaped) form of the previously reported structures of the NpSRII/NpHtrII complex in the space group P21212, although the structures of the monomers taken individually are nearly the same. Computer modeling of the HAMP domain in the obtained “V”- and “U”-shaped structures revealed that only the “U”-shaped conformation allows for tight interactions of the receptor with the HAMP domain. This is in line with existing data and supports biological relevance of the “U” shape in the ground state. We suggest that the “V”-shaped structure may correspond to the active state of the complex and transition from the “U” to the “V”-shape of the receptor-transducer complex can be involved in signal transduction from the receptor to the signaling domain of NpHtrII. PMID:28165484

  7. Attractant and repellent signaling conformers of sensory rhodopsin-transducer complexes.

    PubMed

    Sineshchekov, Oleg A; Sasaki, Jun; Wang, Jihong; Spudich, John L

    2010-08-10

    Attractant and repellent signaling conformers of the dual-signaling phototaxis receptor sensory rhodopsin I and its transducer subunit (SRI-HtrI) have recently been distinguished experimentally by the opposite connection of their retinylidene protonated Schiff bases to the outwardly located periplasmic side and inwardly located cytoplasmic side. Here we show that the pK(a) of the outwardly located Asp76 counterion in the outwardly connected conformer is lowered by approximately 1.5 units from that of the inwardly connected conformer. The pK(a) difference enables quantitative determination of the relative amounts of the two conformers in wild-type cells and behavioral mutants prior to photoexcitation, comparison of their absorption spectra, and determination of their relative signaling efficiency. We have shown that the one-photon excitation of the SRI-HtrI attractant conformer causes a Schiff base connectivity switch from inwardly connected to outwardly connected states in the attractant signaling photoreaction. Conversely, a second near-UV photon drives the complex back to the inwardly connected conformer in the repellent signaling photoreaction. The results suggest a model of the color-discriminating dual-signaling mechanism in which phototaxis responses (his-kinase modulation) result from the photointerconversion of the two oppositely connected SRI-HtrI conformers by one-photon and two-photon activation. Furthermore, we find that the related repellent phototaxis SRII-HtrII receptor complex has an outwardly connected retinylidene Schiff base like the repellent signaling forms of the SRI-HtrI complex, indicating the general applicability of macro conformational changes, which can be detected by the connectivity switch, to phototaxis signaling by sensory rhodopsin-transducer complexes.

  8. Attractant and Repellent Signaling Conformers of Sensory Rhodopsin−Transducer Complexes†

    PubMed Central

    2010-01-01

    Attractant and repellent signaling conformers of the dual-signaling phototaxis receptor sensory rhodopsin I and its transducer subunit (SRI−HtrI) have recently been distinguished experimentally by the opposite connection of their retinylidene protonated Schiff bases to the outwardly located periplasmic side and inwardly located cytoplasmic side. Here we show that the pKa of the outwardly located Asp76 counterion in the outwardly connected conformer is lowered by ∼1.5 units from that of the inwardly connected conformer. The pKa difference enables quantitative determination of the relative amounts of the two conformers in wild-type cells and behavioral mutants prior to photoexcitation, comparison of their absorption spectra, and determination of their relative signaling efficiency. We have shown that the one-photon excitation of the SRI−HtrI attractant conformer causes a Schiff base connectivity switch from inwardly connected to outwardly connected states in the attractant signaling photoreaction. Conversely, a second near-UV photon drives the complex back to the inwardly connected conformer in the repellent signaling photoreaction. The results suggest a model of the color-discriminating dual-signaling mechanism in which phototaxis responses (his-kinase modulation) result from the photointerconversion of the two oppositely connected SRI−HtrI conformers by one-photon and two-photon activation. Furthermore, we find that the related repellent phototaxis SRII−HtrII receptor complex has an outwardly connected retinylidene Schiff base like the repellent signaling forms of the SRI−HtrI complex, indicating the general applicability of macro conformational changes, which can be detected by the connectivity switch, to phototaxis signaling by sensory rhodopsin−transducer complexes. PMID:20590098

  9. Targeting Signal Transducers and Activators of Transcription-3 (Stat3) As a Novel Strategy In Sensitizing Breast Cancer To Egfr-Targeted Therapy

    DTIC Science & Technology

    2008-06-01

    transition of the epithelial to the mesenchymal -like phenotype in cultured breast cancer cells . Cancer cells of epithelial origin undergo EMT as...induce epithelial mesenchymal transition by activating expression of TWIST, an E-cadherin repressor. In breast cancer cells with high levels of EGFR...expressing cancer cells to undergo a transition from the epithelial to the spindle-like

  10. High mobility group box 1 induces the activation of the Janus kinase 2 and signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway in pancreatic acinar cells in rats, while AG490 and rapamycin inhibit their activation

    PubMed Central

    Wang, Guoliang; Zhang, Jingchao; Dui, Danhua; Ren, Haoyuan; Liu, Jin

    2016-01-01

    The pathogenesis of severe acute pancreatitis (SAP) remains unclear. The Janus kinase and signal transducer and activator of transcription (JAK/STAT) pathway is important for various cytokines and growth factors. This study investigated the effect of the late inflammatory factor high mobility group box 1 (HMGB1) on the activation of JAK2/STAT3 in pancreatic acinar cells and the inhibitory effects of AG490 (a JAK2 inhibitor) and rapamycin (a STAT3 inhibitor) on this pathway. Rat pancreatic acinar cells were randomly divided into the control, HMGB1, AG490, and rapamycin groups. The mRNA levels of JAK2 and STAT3 at 10, 30, 60, and 120 minutes were detected using reverse transcription polymerase chain reaction (RT-PCR). The protein levels of JAK2 and STAT3 at 60 and 120 minutes were observed using Western blotting. Compared with the control group, the HMGB1 group exhibited significantly increased levels of JAK2 mRNA at each time point; STAT3 mRNA at 30, 60, and 120 minutes; and JAK2 and STAT3 proteins at 60 and 120 minutes (p < 0.01). Compared with the HMGB1 group, the AG490 and rapamycin groups both exhibited significantly decreased levels of JAK2 mRNA at each time point (p < 0.05); STAT3 mRNA at 30, 60, and 120 minutes (p < 0.01); and JAK2 and STAT3 proteins at 60 and 120 minutes (p < 0.01). HMGB1 induces the activation of the JAK2/STAT3 signaling pathway in rat pancreatic acinar cells, and this activation can be inhibited by AG490 and rapamycin. The results of this study may provide new insights for the treatment of SAP. PMID:27754827

  11. Convection-enhanced delivery of sorafenib and suppression of tumor progression in a murine model of brain melanoma through the inhibition of signal transducer and activator of transcription 3.

    PubMed

    Zou, Zhaoxia; Yin, Yufang; Lin, Jenny; Hsu, Li-Chen J; Brandon, Vanessa L; Yang, Fan; Jove, Richard; Jandial, Rahul; Li, Gang; Chen, Mike Y

    2016-05-01

    OBJECT Despite recent advances, metastatic melanoma remains a terminal disease, in which life-threatening brain metastasis occurs in approximately half of patients. Sorafenib is a multikinase inhibitor that induces apoptosis of melanoma cells in vitro. However, systemic administration has been ineffective because adequate tissue concentrations cannot be achieved. This study investigated if convection-enhanced delivery (CED) of sorafenib would enhance tumor control and survival via inhibition of the signal transducer and activator of transcription 3 (Stat3) pathway in a murine model of metastatic brain melanoma. METHODS Melanoma cells treated with sorafenib in vitro were examined for signaling and survival changes. The effect of sorafenib given by CED was assessed by bioluminescent imaging and animal survival. RESULTS The results showed that sorafenib induced cell death in the 4 established melanoma cell lines and in 1 primary cultured melanoma cell line. Sorafenib inhibited Stat3 phosphorylation in HTB65, WYC1, and B16 cells. Accordingly, sorafenib treatment also decreased expression of Mcl-1 mRNA in melanoma cell lines. Because sorafenib targets multiple pathways, the present study demonstrated the contribution of the Stat3 pathway by showing that mouse embryonic fibroblast (MEF) Stat3 +/+ cells were significantly more sensitive to sorafenib than MEF Stat3 -/- cells. In the murine model of melanoma brain metastasis used in this study, CED of sorafenib increased survival by 150% in the treatment group compared with animals receiving the vehicle control (p < 0.01). CED of sorafenib also significantly abrogated tumor growth. CONCLUSIONS The data from this study indicate that local delivery of sorafenib effectively controls brain melanoma. These findings validate further investigation of the use of CED to distribute molecularly targeted agents.

  12. Serotonin suppresses β-casein expression via inhibition of the signal transducer and activator of transcription 5 (STAT5) protein phosphorylation in human mammary epithelial cells MCF-12A.

    PubMed

    Chiba, Takeshi; Kimura, Soichiro; Takahashi, Katsuo; Morimoto, Yasunori; Sanbe, Atsushi; Ueda, Hideo; Kudo, Kenzo

    2014-01-01

    Serotonin (5-hydroxytryptamine; 5-HT) has an important physiological role in controlling lactation, namely, milk volume homeostasis, within mammary glands. The objectives of this study were to evaluate whether exogenous 5-HT can suppress β-casein expression, a differentiation marker, produced in human mammary epithelial cells, and to determine whether 5-HT can attenuate β-casein signaling via the prolactin (PRL) receptor (PRLr) and Janus kinase 2/signal transducer and activator of transcription 5 (STAT5) pathway. PRL treatment increased the mRNA level of β-casein in the MCF-12A human mammary epithelial cell line, and the highest level occurred at days 7 and 14 of culture. In contrast, PRLr expression was not affected significantly by PRL treatment. PRL treatment in MCF-12A cells increased levels of β-casein and phosphorylated STAT5 (pSTAT5) proteins in a concentration-dependent manner, with a slight increase of STAT5 protein. β-Casein expression was inhibited by 0.1 mM 5-HT in a time-dependent manner. Additionally, treatment with 0.1 mM 5-HT for 72 h decreased protein levels of β-casein and pSTAT5, with a slight decrease in STAT5 levels. These results suggest that exogenous 5-HT can inhibit STAT5 phosphorylation, resulting in a decrease in β-Casein expression. In conclusion, we showed that exogenous 5-HT decreased β-casein expression in MCF-12A human mammary epithelial cells, and that 5-HT was responsible for inhibiting phosphorylation of STAT5, resulting in a decline in lactational function.

  13. Discovery of Potent Anticancer Agent HJC0416, an Orally Bioavailable Small Molecule Inhibitor of Signal Transducer and Activator of Transcription 3 (STAT3)

    PubMed Central

    Chen, Haijun; Yang, Zhengduo; Ding, Chunyong; Xiong, Ailian; Wild, Christopher; Wang, Lili; Ye, Na; Cai, Guoshuai; Flores, Rudolfo M.; Ding, Ye; Shen, Qiang; Zhou, Jia

    2014-01-01

    In a continuing effort to develop orally bioavailable small-molecule STAT3 inhibitors as potential therapeutic agents for human cancer, a series of novel diversified analogues based on our identified lead compound HJC0149 (1) (5-chloro-N-(1,1-dioxo-1H-1λ6-benzo[b]thiophen-6-yl)-2-hydroxybenzamide, Eur. J. Med. Chem. 2013, 62, 498–507) have been rationally designed, synthesized, and pharmacologically evaluated. Molecular docking studies and biological characterization supported our earlier findings that the O-alkylamino-tethered side chain on the hydroxyl group is an effective and essential structural determinant for improving biological activities and druglike properties of these molecules. Compounds with such modifications exhibited potent antiproliferative effects against breast and pancreatic cancer cell lines with IC50 values from low micromolar to nanomolar range. Among them, the newly discovered STAT3 inhibitor 12 (HJC0416) displayed an intriguing anticancer profile both in vitro and in vivo (i.p. & p.o.). More importantly, HJC0416 is an orally bioavailable anticancer agent as a promising candidate for further development. PMID:24904966

  14. A bioinformatics approach identifies signal transducer and activator of transcription-3 and checkpoint kinase 1 as upstream regulators of kidney injury molecule-1 after kidney injury.

    PubMed

    Ajay, Amrendra Kumar; Kim, Tae-Min; Ramirez-Gonzalez, Victoria; Park, Peter J; Frank, David A; Vaidya, Vishal S

    2014-01-01

    Kidney injury molecule-1 (KIM-1)/T cell Ig and mucin domain-containing protein-1 (TIM-1) is upregulated more than other proteins after AKI, and it is highly expressed in renal damage of various etiologies. In this capacity, KIM-1/TIM-1 acts as a phosphatidylserine receptor on the surface of injured proximal tubular epithelial cells, mediating phagocytosis of apoptotic cells, and it may also act as a costimulatory molecule for immune cells. Despite recognition of KIM-1 as an important therapeutic target for kidney disease, the regulators of KIM-1 transcription in the kidney remain unknown. Using a bioinformatics approach, we identified upstream regulators of KIM-1 after AKI. In response to tubular injury in rat and human kidneys or oxidant stress in human proximal tubular epithelial cells (HPTECs), KIM-1 expression increased significantly in a manner that corresponded temporally and regionally with increased phosphorylation of checkpoint kinase 1 (Chk1) and STAT3. Both ischemic and oxidant stress resulted in a dramatic increase in reactive oxygen species that phosphorylated and activated Chk1, which subsequently bound to STAT3, phosphorylating it at S727. Furthermore, STAT3 bound to the KIM-1 promoter after ischemic and oxidant stress, and pharmacological or genetic induction of STAT3 in HPTECs increased KIM-1 mRNA and protein levels. Conversely, inhibition of STAT3 using siRNAs or dominant negative mutants reduced KIM-1 expression in a kidney cancer cell line (769-P) that expresses high basal levels of KIM-1. These observations highlight Chk1 and STAT3 as critical upstream regulators of KIM-1 expression after AKI and may suggest novel approaches for therapeutic intervention.

  15. Fas transduces dual apoptotic and trophic signals in hematopoietic progenitors.

    PubMed

    Pearl-Yafe, Michal; Stein, Jerry; Yolcu, Esma S; Farkas, Daniel L; Shirwan, Haval; Yaniv, Isaac; Askenasy, Nadir

    2007-12-01

    Stem cells and progenitors are often required to realize their differentiation potential in hostile microenvironments. The Fas/Fas ligand (FasL) interaction is a major effector pathway of apoptosis, which negatively regulates the expansion of differentiated hematopoietic cells. The involvement of this molecular interaction in the function of hematopoietic stem and progenitor cells is not well understood. In the murine syngeneic transplant setting, both Fas and FasL are acutely upregulated in bone marrow-homed donor cells; however, the Fas(+) cells are largely insensitive to FasL-induced apoptosis. In heterogeneous populations of lineage-negative (lin(-)) bone marrow cells and progenitors isolated by counterflow centrifugal elutriation, trimerization of the Fas receptor enhanced the clonogenic activity. Inhibition of caspases 3 and 8 did not affect the trophic signals mediated by Fas, yet it efficiently blocked the apoptotic pathways. Fas-mediated tropism appears to be of physiological significance, as pre-exposure of donor cells to FasL improved the radioprotective qualities of hematopoietic progenitors, resulting in superior survival of myeloablated hosts. Under these conditions, the activity of long-term reconstituting cells was not affected, as determined in sequential secondary and tertiary transplants. Dual caspase-independent tropic and caspase-dependent apoptotic signaling place the Fas receptor at an important junction of activation and death. This regulatory mechanism of hematopoietic homeostasis activates progenitors to promote the recovery from aplasia and converts into a negative regulator in distal stages of cell differentiation. Disclosure of potential conflicts of interest is found at the end of this article.

  16. Fluidic Active Transducer for Electricity Generation

    PubMed Central

    Yang, YoungJun; Park, Junwoo; Kwon, Soon-Hyung; Kim, Youn Sang

    2015-01-01

    Flows in small size channels have been studied for a long time over multidisciplinary field such as chemistry, biology and medical through the various topics. Recently, the attempts of electricity generation from the small flows as a new area for energy harvesting in microfluidics have been reported. Here, we propose for the first time a new fluidic electricity generator (FEG) by modulating the electric double layer (EDL) with two phase flows of water and air without external power sources. We find that an electric current flowed by the forming/deforming of the EDL with a simple separated phase flow of water and air at the surface of the FEG. Electric signals between two electrodes of the FEG are checked from various water/air passing conditions. Moreover, we verify the possibility of a self-powered air slug sensor by applying the FEG in the detection of an air slug. PMID:26511626

  17. Fluidic Active Transducer for Electricity Generation.

    PubMed

    Yang, YoungJun; Park, Junwoo; Kwon, Soon-Hyung; Kim, Youn Sang

    2015-10-29

    Flows in small size channels have been studied for a long time over multidisciplinary field such as chemistry, biology and medical through the various topics. Recently, the attempts of electricity generation from the small flows as a new area for energy harvesting in microfluidics have been reported. Here, we propose for the first time a new fluidic electricity generator (FEG) by modulating the electric double layer (EDL) with two phase flows of water and air without external power sources. We find that an electric current flowed by the forming/deforming of the EDL with a simple separated phase flow of water and air at the surface of the FEG. Electric signals between two electrodes of the FEG are checked from various water/air passing conditions. Moreover, we verify the possibility of a self-powered air slug sensor by applying the FEG in the detection of an air slug.

  18. Mechanosensitive Molecular Networks Involved in Transducing Resistance Exercise-Signals into Muscle Protein Accretion

    PubMed Central

    Rindom, Emil; Vissing, Kristian

    2016-01-01

    Loss of skeletal muscle myofibrillar protein with disease and/or inactivity can severely deteriorate muscle strength and function. Strategies to counteract wasting of muscle myofibrillar protein are therefore desirable and invite for considerations on the potential superiority of specific modes of resistance exercise and/or the adequacy of low load resistance exercise regimens as well as underlying mechanisms. In this regard, delineation of the potentially mechanosensitive molecular mechanisms underlying muscle protein synthesis (MPS), may contribute to an understanding on how differentiated resistance exercise can transduce a mechanical signal into stimulation of muscle accretion. Recent findings suggest specific upstream exercise-induced mechano-sensitive myocellular signaling pathways to converge on mammalian target of rapamycin complex 1 (mTORC1), to influence MPS. This may e.g. implicate mechanical activation of signaling through a diacylglycerol kinase (DGKζ)-phosphatidic acid (PA) axis or implicate integrin deformation to signal through a Focal adhesion kinase (FAK)-Tuberous Sclerosis Complex 2 (TSC2)-Ras homolog enriched in brain (Rheb) axis. Moreover, since initiation of translation is reliant on mRNA, it is also relevant to consider potentially mechanosensitive signaling pathways involved in muscle myofibrillar gene transcription and whether some of these pathways converge with those affecting mTORC1 activation for MPS. In this regard, recent findings suggest how mechanical stress may implicate integrin deformation and/or actin dynamics to signal through a Ras homolog gene family member A protein (RhoA)-striated muscle activator of Rho signaling (STARS) axis or implicate deformation of Notch to affect Bone Morphogenetic Protein (BMP) signaling through a small mother of decapentaplegic (Smad) axis. PMID:27909410

  19. Mechanosensitive Molecular Networks Involved in Transducing Resistance Exercise-Signals into Muscle Protein Accretion.

    PubMed

    Rindom, Emil; Vissing, Kristian

    2016-01-01

    Loss of skeletal muscle myofibrillar protein with disease and/or inactivity can severely deteriorate muscle strength and function. Strategies to counteract wasting of muscle myofibrillar protein are therefore desirable and invite for considerations on the potential superiority of specific modes of resistance exercise and/or the adequacy of low load resistance exercise regimens as well as underlying mechanisms. In this regard, delineation of the potentially mechanosensitive molecular mechanisms underlying muscle protein synthesis (MPS), may contribute to an understanding on how differentiated resistance exercise can transduce a mechanical signal into stimulation of muscle accretion. Recent findings suggest specific upstream exercise-induced mechano-sensitive myocellular signaling pathways to converge on mammalian target of rapamycin complex 1 (mTORC1), to influence MPS. This may e.g. implicate mechanical activation of signaling through a diacylglycerol kinase (DGKζ)-phosphatidic acid (PA) axis or implicate integrin deformation to signal through a Focal adhesion kinase (FAK)-Tuberous Sclerosis Complex 2 (TSC2)-Ras homolog enriched in brain (Rheb) axis. Moreover, since initiation of translation is reliant on mRNA, it is also relevant to consider potentially mechanosensitive signaling pathways involved in muscle myofibrillar gene transcription and whether some of these pathways converge with those affecting mTORC1 activation for MPS. In this regard, recent findings suggest how mechanical stress may implicate integrin deformation and/or actin dynamics to signal through a Ras homolog gene family member A protein (RhoA)-striated muscle activator of Rho signaling (STARS) axis or implicate deformation of Notch to affect Bone Morphogenetic Protein (BMP) signaling through a small mother of decapentaplegic (Smad) axis.

  20. Evidence that Armadillo transduces wingless by mediating nuclear export or cytosolic activation of Pangolin.

    PubMed

    Chan, Siu-Kwong; Struhl, Gary

    2002-10-18

    Secreted proteins of the Wnt family have profound organizing roles during animal development and are transduced via the activities of the Frizzled (Fz) class of transmembrane receptors and the TCF/LEF/Pangolin class of transcription factors. beta-catenins, including Drosophila Armadillo (Arm), link activation of Fz at the cell surface to transcriptional regulation by TCF in the nucleus. The consensus view is that Wnt signaling induces beta-catenin to enter the nucleus and combine with TCF to form a transcription factor complex in which TCF binds DNA and the C-terminal domain of beta-catenin activates transcription. Here, we present findings, which challenge this view and suggest instead that beta-catenin may transduce Wnt signals by exporting TCF from the nucleus or activating it in the cytoplasm.

  1. Highly sensitive devices for primary signal processing of the micromechanical capacitive transducers

    NASA Astrophysics Data System (ADS)

    Konoplev, B.; Ryndin, E.; Lysenko, I.; Denisenko, M.; Isaeva, A.

    2016-12-01

    A method of signal processing devices design for micromechanical accelerometers with capacitive transducers is proposed. This method provides the complex solution of the sensibility increasing and noise immunity problems by finding of the difference frequency of signals, which are formed by two identical generators with micromechanical capacitive transducers in frequency control circuits. In this study the analog and digital versions of the highly sensitive signal processing devices circuits with frequency output were developed. The breadboards of these devices are fabricated and studied and the project of their integral realization is designed.

  2. Model based separation of transmitted and received signal for single transducer distance measurement applications

    NASA Astrophysics Data System (ADS)

    Schröder, A.; Henning, B.

    2012-05-01

    Single transducer distance measurement systems have a blind zone which is increased if the transmitted signals are coded to reduce errors due to crosstalk. A method to reduce this blind zone is a model based separation of the transmitted and received signal. This contribution compares two systems, one working with the measured band pass signals, and another one which is based on I/Q-demodulated base band signals.

  3. A nuclear protein tyrosine phosphatase TC-PTP is a potential negative regulator of the PRL-mediated signaling pathway: dephosphorylation and deactivation of signal transducer and activator of transcription 5a and 5b by TC-PTP in nucleus.

    PubMed

    Aoki, Naohito; Matsuda, Tsukasa

    2002-01-01

    In the present study we examined involvement of nuclear protein tyrosine phosphatase TC-PTP in PRL-mediated signaling. TC-PTP could dephosphorylate signal transducer and activator of transcription 5a (STAT5a) and STAT5b, but the apparent dephosphorylation activity of TC-PTP was weaker than that of cytosolic PTP1B 30 min after PRL stimulation in transfected COS-7 cells, whereas both STAT5a and STAT5b were dephosphorylated to the same extent by recombinant TC-PTP and PTP1B in vitro. Tyrosine-phosphorylated STAT5 was coimmunoprecipitated with substrate trapping mutants of TC-PTP, suggesting that STAT5 is a specific substrate of TC-PTP. These observations were further extended in mammary epithelial COMMA-1D cells stably expressing TC-PTP. A time-course study revealed that dephosphorylation of STAT5 by TC-PTP was delayed compared with that by cytosolic PTP1B due to nuclear localization of TC-PTP throughout PRL stimulation in mammary epithelial cells. Endogenous beta-casein gene expression and beta-casein gene promoter activation in COS-7 cells were largely suppressed by TC-PTP wild type as well as catalytically inactive mutants, suggesting that stable complexes formed between STAT5 and TC-PTP in the nucleus. Taken together, we conclude that TC-PTP is catalytically competent with respect to dephosphorylation and deactivation of PRL-activated STAT5 in the nucleus.

  4. Signals, Transducers, and Modulation: A Wireless Design Challenge

    ERIC Educational Resources Information Center

    Rose, Mary Annette

    2006-01-01

    In this age of cell phones, digital television, and satellite radio, individuals easily forget that information and energy must undergo complex transformations to enable real-time wireless communication. This article describes a practical and proven design activity that enables secondary and post-secondary students to design and test a modulator…

  5. Ultrasonic Detection of Cracks in a Complex Aircraft Structure Using a Local Correlation Method for Signals from a Moving Transducer

    NASA Astrophysics Data System (ADS)

    Aldrin, John C.; Mandeville, John R.; Kropas-Hughes, Claudia V.

    2004-02-01

    A challenge in nondestructive evaluation is the ability to discern signals that are closely spaced or superimposed in time. A feature extraction methodology is proposed where signals from a moving transducer are accurately aligned to a primary part feature and analyzed within multiple time gates for shifting signals from a defect. The local correlation method functions to detect the relative shift of signals in time for adjacent transducer locations due to differing echo dynamics from cracks and part geometries.

  6. Gadd45 Proteins as Critical Signal Transducers Linking NF-κB to MAPK Cascades

    PubMed Central

    Yang, Z.; Song, L.; Huang, C.

    2013-01-01

    The growth arrest and DNA damage-inducible 45 (Gadd45) proteins are a group of critical signal transducers that are involved in regulations of many cellular functions. Accumulated data indicate that all three Gadd45 proteins (i.e., Gadd45α, Gadd45β, and Gadd45γ) play essential roles in connecting an upstream sensor module, the transcription Nuclear Factor-κB (NF-κB), to a transcriptional regulating module, mitogen-activated protein kinase (MAPK). This NF-κB-Gadd45(s)-MAPK pathway responds to various kinds of extracellular stimuli and regulates such cell activities as growth arrest, differentiation, cell survival, and apoptosis. Defects in this pathway can also be related to oncogenesis. In the first part of this review, the functions of Gadd45 proteins, and briefly NF-κB and MAPK, are summarized. In the second part, the mechanisms by which Gadd45 proteins are regulated by NF-κB, and how they affect MAPK activation, are reviewed. PMID:20025601

  7. The measurement of tremor using a velocity transducer: comparison to simultaneous recordings using transducers of displacement, acceleration and muscle activity.

    PubMed

    Norman, K E; Edwards, R; Beuter, A

    1999-10-15

    Precise kinematic measurements of tremor have historically been obtained using accelerometers. However, current technology permits precise measurements in velocity and displacement. The primary advantage of velocity recording is that only one step of integration or differentiation is required for either displacement or acceleration. A method is presented of measuring finger tremor using a laser system that transduces velocity precisely. Measurements of postural finger tremor thus obtained were compared to those simultaneously obtained from a laser system that transduces displacement, from an accelerometer and from surface electromyography (EMG) of the extensor digitorum communis. A range of amplitude and frequency content was obtained by testing control subjects and subjects with Parkinson's disease. The velocity transducer showed excellent correspondence of amplitude and frequency measurement with the displacement transducer. Measures of absolute and relative amplitude correlated well (r > or = 0.96 in amplitude measures in displacement, velocity and acceleration), and high coherence was found throughout the frequency range of interest. Measurements by the accelerometer generally showed poorer correspondence with those of the other instruments. EMG measurements showed good correspondence in some trials but poorer correspondence in others, attributed to the low level of muscle activity required in the task. Precise kinematic measurements appear to be highly sensitive to neuromotor impairment.

  8. Embedded Ultrasonic Transducers for Active and Passive Concrete Monitoring

    PubMed Central

    Niederleithinger, Ernst; Wolf, Julia; Mielentz, Frank; Wiggenhauser, Herbert; Pirskawetz, Stephan

    2015-01-01

    Recently developed new transducers for ultrasonic transmission, which can be embedded right into concrete, are now used for non-destructive permanent monitoring of concrete. They can be installed during construction or thereafter. Large volumes of concrete can be monitored for changes of material properties by a limited number of transducers. The transducer design, the main properties as well as installation procedures are presented. It is shown that compressional waves with a central frequency of 62 kHz are mainly generated around the transducer’s axis. The transducer can be used as a transmitter or receiver. Application examples demonstrate that the transducers can be used to monitor concrete conditions parameters (stress, temperature, …) as well as damages in an early state or the detection of acoustic events (e.g., crack opening). Besides application in civil engineering our setups can also be used for model studies in geosciences. PMID:25923928

  9. Piezoelectric transducer

    NASA Technical Reports Server (NTRS)

    Conragan, J.; Muller, R. S.

    1970-01-01

    Transducer consists of a hybrid thin film and a piezoelectric transistor that acts as a stress-sensitive device with built-in gain. It provides a stress/strain transducer that incorporates a signal amplification stage and sensor in a single package.

  10. Pipe wall damage detection by electromagnetic acoustic transducer generated guided waves in absence of defect signals.

    PubMed

    Vasiljevic, Milos; Kundu, Tribikram; Grill, Wolfgang; Twerdowski, Evgeny

    2008-05-01

    Most investigators emphasize the importance of detecting the reflected signal from the defect to determine if the pipe wall has any damage and to predict the damage location. However, often the small signal from the defect is hidden behind the other arriving wave modes and signal noise. To overcome the difficulties associated with the identification of the small defect signal in the time history plots, in this paper the time history is analyzed well after the arrival of the first defect signal, and after different wave modes have propagated multiple times through the pipe. It is shown that the defective pipe can be clearly identified by analyzing these late arriving diffuse ultrasonic signals. Multiple reflections and scattering of the propagating wave modes by the defect and pipe ends do not hamper the defect detection capability; on the contrary, it apparently stabilizes the signal and makes it easier to distinguish the defective pipe from the defect-free pipe. This paper also highlights difficulties associated with the interpretation of the recorded time histories due to mode conversion by the defect. The design of electro-magnetic acoustic transducers used to generate and receive the guided waves in the pipe is briefly described in the paper.

  11. The Aer protein and the serine chemoreceptor Tsr independently sense intracellular energy levels and transduce oxygen, redox, and energy signals for Escherichia coli behavior

    PubMed Central

    Rebbapragada, Anuradha; Johnson, Mark S.; Harding, Gordon P.; Zuccarelli, Anthony J.; Fletcher, Hansel M.; Zhulin, Igor B.; Taylor, Barry L.

    1997-01-01

    We identified a protein, Aer, as a signal transducer that senses intracellular energy levels rather than the external environment and that transduces signals for aerotaxis (taxis to oxygen) and other energy-dependent behavioral responses in Escherichia coli. Domains in Aer are similar to the signaling domain in chemotaxis receptors and the putative oxygen-sensing domain of some transcriptional activators. A putative FAD-binding site in the N-terminal domain of Aer shares a consensus sequence with the NifL, Bat, and Wc-1 signal-transducing proteins that regulate gene expression in response to redox changes, oxygen, and blue light, respectively. A double mutant deficient in aer and tsr, which codes for the serine chemoreceptor, was negative for aerotaxis, redox taxis, and glycerol taxis, each of which requires the proton motive force and/or electron transport system for signaling. We propose that Aer and Tsr sense the proton motive force or cellular redox state and thereby integrate diverse signals that guide E. coli to environments where maximal energy is available for growth. PMID:9380671

  12. Metallic Nanoislands on Graphene as Highly Sensitive Transducers of Mechanical, Biological, and Optical Signals

    PubMed Central

    2016-01-01

    This article describes an effect based on the wetting transparency of graphene; the morphology of a metallic film (≤20 nm) when deposited on graphene by evaporation depends strongly on the identity of the substrate supporting the graphene. This control permits the formation of a range of geometries, such as tightly packed nanospheres, nanocrystals, and island-like formations with controllable gaps down to 3 nm. These graphene-supported structures can be transferred to any surface and function as ultrasensitive mechanical signal transducers with high sensitivity and range (at least 4 orders of magnitude of strain) for applications in structural health monitoring, electronic skin, measurement of the contractions of cardiomyocytes, and substrates for surface-enhanced Raman scattering (SERS, including on the tips of optical fibers). These composite films can thus be treated as a platform technology for multimodal sensing. Moreover, they are low profile, mechanically robust, semitransparent and have the potential for reproducible manufacturing over large areas. PMID:26765039

  13. Metallic Nanoislands on Graphene as Highly Sensitive Transducers of Mechanical, Biological, and Optical Signals.

    PubMed

    Zaretski, Aliaksandr V; Root, Samuel E; Savchenko, Alex; Molokanova, Elena; Printz, Adam D; Jibril, Liban; Arya, Gaurav; Mercola, Mark; Lipomi, Darren J

    2016-02-10

    This article describes an effect based on the wetting transparency of graphene; the morphology of a metallic film (≤20 nm) when deposited on graphene by evaporation depends strongly on the identity of the substrate supporting the graphene. This control permits the formation of a range of geometries, such as tightly packed nanospheres, nanocrystals, and island-like formations with controllable gaps down to 3 nm. These graphene-supported structures can be transferred to any surface and function as ultrasensitive mechanical signal transducers with high sensitivity and range (at least 4 orders of magnitude of strain) for applications in structural health monitoring, electronic skin, measurement of the contractions of cardiomyocytes, and substrates for surface-enhanced Raman scattering (SERS, including on the tips of optical fibers). These composite films can thus be treated as a platform technology for multimodal sensing. Moreover, they are low profile, mechanically robust, semitransparent and have the potential for reproducible manufacturing over large areas.

  14. Characterization of dielectric electroactive polymer transducers

    NASA Astrophysics Data System (ADS)

    Nielsen, Dennis; Møller, Martin B.; Sarban, Rahimullah; Lassen, Benny; Knott, Arnold; Andersen, Michael A. E.

    2014-03-01

    Throughout this paper, a small-signal model of the Dielectric Electro Active Polymer (DEAP) transducer is analyzed. The DEAP transducer have been proposed as an alternative to the electrodynamic transducer in sound reproduction systems. In order to understand how the DEAP transducer works, and provide guidelines for design optimization, accurate characterization of the transducer must be established. A small signal model of the DEAP transducer is derived and its validity is investigated using impedance measurements. Impedance measurements are shown for a push-pull DEAP based loudspeaker, and the dependency of the biasing voltage is explained. A measuring setup is proposed, which allows the impedance to be measured, while the DEAP transducer is connected to its biasing source.

  15. Electro-Active Transducer Using Radial Electric Field To Produce/Motion Sense Out-Of-Plane Transducer

    NASA Technical Reports Server (NTRS)

    Bryant, Robert G. (Inventor); Fox, Robert L. (Inventor)

    2006-01-01

    An electro-active transducer includes a ferroelectric material sandwiched by first and second electrode patterns. When the device is used as an actuator, the first and second electrode patterns are configured to introduce an electric field into the ferroelectric material when voltage is applied to the electrode patterns. When the device is used as a sensor. the first and second electrode patterns are configured to introduce an electric field into the ferroelectric material when the ferroelectric material experiences deflection in a direction substantially perpendicular thereto. In each case, the electrode patterns are designed to cause the electric field to: i) originate at a region of the ferroelectric material between the first and second electrode patterns. and ii) extend radially outward from the region of the ferroelectric material (at which the electric field originates) and substantially parallel to the ferroelectric material s plane.

  16. Investigation of signal transduction routes within the sensor/transducer protein BlaR1 of Staphylococcus aureus.

    PubMed

    Staude, Michael W; Frederick, Thomas E; Natarajan, Sivanandam V; Wilson, Brian D; Tanner, Carol E; Ruggiero, Steven T; Mobashery, Shahriar; Peng, Jeffrey W

    2015-03-03

    The transmembrane antibiotic sensor/signal transducer protein BlaR1 is part of a cohort of proteins that confer β-lactam antibiotic resistance in methicillin-resistant Staphylococcus aureus (MRSA) [Fisher, J. F., Meroueh, S. O., and Mobashery, S. (2005) Chem. Rev. 105, 395-424; Llarrull, L. I., Fisher, J. F., and Mobashery, S. (2009) Antimicrob. Agents Chemother. 53, 4051-4063; Llarrull, L. I., Toth, M., Champion, M. M., and Mobashery, S. (2011) J. Biol. Chem. 286, 38148-38158]. Specifically, BlaR1 regulates the inducible expression of β-lactamases that hydrolytically destroy β-lactam antibiotics. The resistance phenotype starts with β-lactam antibiotic acylation of the BlaR1 extracellular domain (BlaRS). The acylation activates the cytoplasmic protease domain through an obscure signal transduction mechanism. Here, we compare protein dynamics of apo versus antibiotic-acylated BlaRS using nuclear magnetic resonance. Our analyses reveal inter-residue interactions that relay acylation-induced perturbations within the antibiotic-binding site to the transmembrane helix regions near the membrane surface. These are the first insights into the process of signal transduction by BlaR1.

  17. A genome-wide RNAi screen reveals a Trio-regulated Rho GTPase circuitry transducing mitogenic signals initiated by G protein-coupled receptors.

    PubMed

    Vaqué, Jose P; Dorsam, Robert T; Feng, Xiaodong; Iglesias-Bartolome, Ramiro; Forsthoefel, David J; Chen, Qianming; Debant, Anne; Seeger, Mark A; Ksander, Bruce R; Teramoto, Hidemi; Gutkind, J Silvio

    2013-01-10

    Activating mutations in GNAQ and GNA11, encoding members of the Gα(q) family of G protein α subunits, are the driver oncogenes in uveal melanoma, and mutations in Gq-linked G protein-coupled receptors have been identified recently in numerous human malignancies. How Gα(q) and its coupled receptors transduce mitogenic signals is still unclear because of the complexity of signaling events perturbed upon Gq activation. Using a synthetic-biology approach and a genome-wide RNAi screen, we found that a highly conserved guanine nucleotide exchange factor, Trio, is essential for activating Rho- and Rac-regulated signaling pathways acting on JNK and p38, and thereby transducing proliferative signals from Gα(q) to the nucleus independently of phospholipase C-β. Indeed, whereas many biological responses elicited by Gq depend on the transient activation of second-messenger systems, Gq utilizes a hard-wired protein-protein-interaction-based signaling circuitry to achieve the sustained stimulation of proliferative pathways, thereby controlling normal and aberrant cell growth.

  18. Hepatitis C virus core protein inhibits interferon production by a human plasmacytoid dendritic cell line and dysregulates interferon regulatory factor-7 and signal transducer and activator of transcription (STAT) 1 protein expression.

    PubMed

    Stone, Amy E L; Mitchell, Angela; Brownell, Jessica; Miklin, Daniel J; Golden-Mason, Lucy; Polyak, Stephen J; Gale, Michael J; Rosen, Hugo R

    2014-01-01

    Plasmacytoid Dendritic Cells (pDCs) represent a key immune cell population in the defense against viruses. pDCs detect viral pathogen associated molecular patterns (PAMPs) through pattern recognition receptors (PRR). PRR/PAMP interactions trigger signaling events that induce interferon (IFN) production to initiate local and systemic responses. pDCs produce Type I and Type III (IFNL) IFNs in response to HCV RNA. Extracellular HCV core protein (Core) is found in the circulation in chronic infection. This study defined how Core modulates PRR signaling in pDCs. Type I and III IFN expression and production following exposure to recombinant Core or β-galactosiade was assessed in human GEN2.2 cells, a pDC cell line. Core suppressed type I and III IFN production in response to TLR agonists and the HCV PAMP agonist of RIG-I. Core suppression of IFN induction was linked with decreased IRF-7 protein levels and increased non-phosphorylated STAT1 protein. Circulating Core protein interferes with PRR signaling by pDCs to suppress IFN production. Strategies to define and target Core effects on pDCs may serve to enhance IFN production and antiviral actions against HCV.

  19. CDIP1-BAP31 complex transduces apoptotic signals from endoplasmic reticulum to mitochondria under endoplasmic reticulum stress.

    PubMed

    Namba, Takushi; Tian, Fang; Chu, Kiki; Hwang, So-Young; Yoon, Kyoung Wan; Byun, Sanguine; Hiraki, Masatsugu; Mandinova, Anna; Lee, Sam W

    2013-10-31

    Resolved endoplasmic reticulum (ER) stress response is essential for intracellular homeostatic balance, but unsettled ER stress can lead to apoptosis. Here, we show that a proapoptotic p53 target, CDIP1, acts as a key signal transducer of ER-stress-mediated apoptosis. We identify B-cell-receptor-associated protein 31 (BAP31) as an interacting partner of CDIP1. Upon ER stress, CDIP1 is induced and enhances an association with BAP31 at the ER membrane. We also show that CDIP1 binding to BAP31 is required for BAP31 cleavage upon ER stress and for BAP31-Bcl-2 association. The recruitment of Bcl-2 to the BAP31-CDIP1 complex, as well as CDIP1-dependent truncated Bid (tBid) and caspase-8 activation, contributes to BAX oligomerization. Genetic knockout of CDIP1 in mice leads to impaired response to ER-stress-mediated apoptosis. Altogether, our data demonstrate that the CDIP1/BAP31-mediated regulation of mitochondrial apoptosis pathway represents a mechanism for establishing an ER-mitochondrial crosstalk for ER-stress-mediated apoptosis signaling.

  20. Nitric-oxide synthase is a mechanical signal transducer that modulates talin and vinculin expression

    NASA Technical Reports Server (NTRS)

    Tidball, J. G.; Spencer, M. J.; Wehling, M.; Lavergne, E.

    1999-01-01

    Mechanical stimuli can cause changes in muscle mass and structure which indicate that mechanisms exist for transducing mechanical stimuli into signals that influence gene expression. Myotendinous junctions show adaptations to modified muscle loading which suggest that these are transcriptionally distinct domains in muscle fibers that may experience local regulation of expression of structural proteins that are concentrated at these sites. Vinculin and talin are cytoskeletal proteins that are highly enriched at myotendinous junctions that we hypothesize to be subject to local transcriptional regulation. Our findings show that mechanical stimulation of muscle cells in vivo and in vitro causes an increase in the expression of vinculin and talin that is mediated by nitric oxide. Furthermore, nitric oxide-stimulated increases in vinculin and talin expression occur through a protein kinase G-dependent pathway and therefore differ from other mechanisms through which nitric oxide has been shown previously to modulate transcription. Analysis of vinculin mRNA distribution in mechanically stimulated muscle fibers shows that the mRNA is highly concentrated at myotendinous junctions, which supports the hypothesis that myotendinous junctions are distinct domains in which the expression of cytoskeletal proteins is modulated by mechanical stimuli through a nitric oxide and protein kinase G-dependent pathway.

  1. Acoustic transducer

    DOEpatents

    Drumheller, Douglas S.

    2000-01-01

    An active acoustic transducer tool for use down-hole applications. The tool includes a single cylindrical mandrel including a shoulder defining the boundary of a narrowed portion over which is placed a sandwich-style piezoelectric tranducer assembly. The piezoelectric transducer assembly is prestressed by being placed in a thermal interference fit between the shoulder of the mandrel and the base of an anvil which is likewise positioned over the narrower portion of the mandrel. In the preferred embodiment, assembly of the tool is accomplished using a hydraulic jack to stretch the mandrel prior to emplacement of the cylindrical sandwich-style piezoelectric transducer assembly and anvil. After those elements are positioned and secured, the stretched mandrel is allowed to return substantially to its original (pre-stretch) dimensions with the result that the piezoelectric transducer elements are compressed between the anvil and the shoulder of the mandrel.

  2. A Smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia.

    PubMed

    Dorn, Karolin V; Hughes, Casey E; Rohatgi, Rajat

    2012-10-16

    Vertebrate Hedgehog (Hh) signaling is initiated at primary cilia by the ligand-triggered accumulation of Smoothened (Smo) in the ciliary membrane. The underlying biochemical mechanisms remain unknown. We find that Hh agonists promote the association between Smo and Evc2, a ciliary protein that is defective in two human ciliopathies. The formation of the Smo-Evc2 complex is under strict spatial control, being restricted to a distinct ciliary compartment, the EvC zone. Mutant Evc2 proteins that localize in cilia but are displaced from the EvC zone are dominant inhibitors of Hh signaling. Disabling Evc2 function blocks Hh signaling at a specific step between Smo and the downstream regulators protein kinase A and Suppressor of Fused, preventing activation of the Gli transcription factors. Our data suggest that the Smo-Evc2 signaling complex at the EvC zone is required for Hh signal transmission and elucidate the molecular basis of two human ciliopathies.

  3. pangolin encodes a Lef-1 homologue that acts downstream of Armadillo to transduce the Wingless signal in Drosophila.

    PubMed

    Brunner, E; Peter, O; Schweizer, L; Basler, K

    1997-02-27

    Members of the Wnt/Wingless (Wg) family of signalling proteins organize many aspects of animal development by regulating the expression of particular target genes in responding cells. Recent biochemical studies indicate that the vertebrate HMG-domain proteins Lef-1 and XTcf-3 can physically interact with beta-catenin, a homologue of Drosophila Armadillo (Arm), the most downstream component known in the Wnt signal transduction pathway. However, these studies do not address whether the endogenous Lef/Tcf family members are required in vivo to transduce Wnt signals. Using genetic methods in Drosophila, we define a new segment polarity gene, pangolin (pan), and show that its product is required in vivo for Wg signal transduction in embryos and in developing adult tissues. In addition, we show that pan encodes a Lef/Tcf homologue and provide evidence that its protein product binds to the beta-catenin homologue Armadillo in vivo. Finally, we demonstrate that Pan functions downstream of Arm to transduce the Wg signal. Thus, our results indicate that Pan is an essential component of the Wg transduction pathway and suggest that it acts directly to regulate gene transcription in response to Wg signalling.

  4. Prediction of flat-bottom hole signals received by a spherically focused transducer for an ultrasonic pulse echo immersion testing

    NASA Astrophysics Data System (ADS)

    Xiao, Huifang; Sun, Yunyun; Chen, Dan; Xu, Jinwu

    2016-11-01

    The spherically focused transducer has been widely used for nondestructive evaluation of micrometer-scale inner defects in material and microelectronic devices due to its outstanding transverse resolution and high beam intensity. In this paper, by combining the beam model, the flaw scattering model and the system efficiency factor, an ultrasonic measurement model is developed for the spherically focused transducer in an ultrasonic pulse-echo immersion testing and is used to predict the ultrasonic flaw signal for flat bottom hole (FBH). The multi-Gaussian beam (MGB) model and the Gaussian beam equivalent point source (GBEPS) model are extended to evaluate the beam fields radiated by the spherically focused transducer in water and transmitted into solid through a planar interface. Results show that the MGB model is more excellent considering both the accuracy and efficiency. Experiments are performed to determine the system efficiency factor and the experimental measured flaw signal is compared with the model predictions to validate the accuracy of the proposed model. Effects of the depth and size of the FBH are further studied using the established model.

  5. An Active Damping at Blade Resonances Using Piezoelectric Transducers

    NASA Technical Reports Server (NTRS)

    Choi, Benjamin; Morrison, Carlos; Duffy, Kirsten

    2008-01-01

    The NASA Glenn Research Center (GRC) is developing an active damping at blade resonances using piezoelectric structure to reduce excessive vibratory stresses that lead to high cycle fatigue (HCF) failures in aircraft engine turbomachinery. Conventional passive damping work was shown first on a nonrotating beam made by Ti-6A1-4V with a pair of identical piezoelectric patches, and then active feedback control law was derived in terms of inductor, resister, and capacitor to control resonant frequency only. Passive electronic circuit components and adaptive feature could be easily programmable into control algorithm. Experimental active damping was demonstrated on two test specimens achieving significant damping on tip displacement and patch location. Also a multimode control technique was shown to control several modes.

  6. Digital ultrasonic signal processing: Primary ultrasonics task and transducer characterization use and detailed description

    NASA Technical Reports Server (NTRS)

    Hammond, P. L.

    1979-01-01

    This manual describes the use of the primary ultrasonics task (PUT) and the transducer characterization system (XC) for the collection, processing, and recording of data received from a pulse-echo ultrasonic system. Both PUT and XC include five primary functions common to many real-time data acquisition systems. Some of these functions are implemented using the same code in both systems. The solicitation and acceptance of operator control input is emphasized. Those operations not under user control are explained.

  7. Effects of adhesive thickness on the Lamb wave pitch-catch signal using bonded piezoelectric wafer transducers

    NASA Astrophysics Data System (ADS)

    Islam, M. M.; Huang, H.

    2016-08-01

    This paper investigates the effects of adhesive layer on Lamb wave ultrasound pitch-catch signals that are excited and sensed by piezoelectric wafer transducers bonded on a slender structure. Analytical models were established to simulate the longitudinal and flexural vibrations of the structures separately and parametric studies of the bonding layer properties, i.e. the shear transfer parameter, adhesive thickness, and shear modulus, were performed. The parametric studies indicate that there exists an optimal adhesive layer thickness that generates maximum ultrasound pitch-catch signal for both wave modes. This prediction was subsequently validated by measurements. In addition, an improved match between the measured and simulated pitch-catch signals was achieved by adjusting the adhesive layer parameters.

  8. An isoform of Taiman that contains a PRD-repeat motif is indispensable for transducing the vitellogenic juvenile hormone signal in Locusta migratoria.

    PubMed

    Wang, Zhiming; Yang, Libin; Song, Jiasheng; Kang, Le; Zhou, Shutang

    2017-03-01

    Taiman (Tai) has been recently identified as the dimerizing partner of juvenile hormone (JH) receptor, Methoprene-tolerant (Met). However, the role of Tai isoforms in transducing vitellogenic signal of JH has not been determined. In this study, we show that the migratory locust Locusta migratoria has two Tai isoforms, which differ in an INDEL-1 domain with the PRD-repeat motif rich in histidine and proline at the C-terminus. Tai-A with the INDEL-1 is expressed at levels about 50-fold higher than Tai-B without the INDEL-1 in the fat body of vitellogenic adult females. Knockdown of Tai-A but not Tai-B results in a substantial reduction of vitellogenin expression in the fat body accompanied by the arrest of ovarian development and oocyte maturation, similar to that caused by depletion of both Tai isoforms. Either Tai-A or Tai-B combined with Met can induce target gene transcription in response to JH, but Tai-A appears to mediate a significantly higher transactivation. Our data suggest that the INDEL-1 domain plays a critical role in Tai function during reproduction as Tai-A appears be more active than Tai-B in transducing the vitellogenic JH signal in L. migratoria.

  9. A state feedback electro-acoustic transducer for active control of acoustic impedance.

    PubMed

    Samejima, Toshiya

    2003-03-01

    In this paper, a new control system in which the acoustic impedance of an electro-acoustic transducer diaphragm can be actively varied by modifying design parameters is presented and its effectiveness is theoretically investigated. The proposed control system is based on a state-space description of the control system derived from an electrical equivalent circuit of an electro-acoustic transducer to which a differentiating circuit is connected, and is designed using modem control theory. The optimal quadratic regulator is used in the control system design, with its quadratic performance index formulated for producing desired acoustic impedance. Computer simulations indicate that the acoustic impedance of the diaphragm can be significantly varied over a wide frequency range that includes the range below the resonance frequency of the electro-acoustic transducer. A computer model of the proposed control system is used to illustrate its application to semi-active noise control in a duct. It is demonstrated that the proposed control system provides substantial reductions in the noise radiating from the outlet of the duct, both in the stiffness control range and in the mass control range.

  10. Modulation of signal-transducing function of neuronal membrane Na+,K+-ATPase by endogenous ouabain and low-power infrared radiation leads to pain relief.

    PubMed

    Lopatina, Ekaterina V; Yachnev, Igor L; Penniyaynen, Valentina A; Plakhova, Vera B; Podzorova, Svetlana A; Shelykh, Tatiana N; Rogachevsky, Ilya V; Butkevich, Irina P; Mikhailenko, Viktor A; Kipenko, Anna V; Krylov, Boris V

    2012-01-01

    Effects of infrared (IR) radiation generated by a low-power Co2-laser on sensory neurons of chick embryos were investigated by organotypic culture method. Low-power IR radiation firstly results in marked neurite suppressing action, probably induced by activation of Na+,K+-ATPase signal-transducing function. A further increase in energy of radiation leads to stimulation of neurite growth. We suggest that this effect is triggered by activation of Na+,K+-ATPase pumping function. Involvement of Na+,K+-ATPase in the control of the transduction process was proved by results obtained after application of ouabain at very low concentrations. Physiological significance of low-power IR radiation and effects of ouabain at nanomolar level was investigated in behavioral experiments (formalin test). It is shown that inflammatory pain induced by injection of formalin is relieved both due to ouabain action and after IR irradiation.

  11. Neem Leaf Glycoprotein Prophylaxis Transduces Immune Dependent Stop Signal for Tumor Angiogenic Switch within Tumor Microenvironment

    PubMed Central

    Banerjee, Saptak; Ghosh, Tithi; Barik, Subhasis; Das, Arnab; Ghosh, Sarbari; Bhuniya, Avishek

    2014-01-01

    We have reported that prophylactic as well as therapeutic administration of neem leaf glycoprotein (NLGP) induces significant restriction of solid tumor growth in mice. Here, we investigate whether the effect of such pretreatment (25µg/mice; weekly, 4 times) benefits regulation of tumor angiogenesis, an obligate factor for tumor progression. We show that NLGP pretreatment results in vascular normalization in melanoma and carcinoma bearing mice along with downregulation of CD31, VEGF and VEGFR2. NLGP pretreatment facilitates profound infiltration of CD8+ T cells within tumor parenchyma, which subsequently regulates VEGF-VEGFR2 signaling in CD31+ vascular endothelial cells to prevent aberrant neovascularization. Pericyte stabilization, VEGF dependent inhibition of VEC proliferation and subsequent vascular normalization are also experienced. Studies in immune compromised mice confirmed that these vascular and intratumoral changes in angiogenic profile are dependent upon active adoptive immunity particularly those mediated by CD8+ T cells. Accumulated evidences suggest that NLGP regulated immunomodulation is active in tumor growth restriction and normalization of tumor angiogenesis as well, thereby, signifying its clinical translation. PMID:25391149

  12. A Multi-Mode Blade Damping Control using Shunted Piezoelectric Transducers with Active Feedback Structure

    NASA Technical Reports Server (NTRS)

    Choi, Benjamin; Morrison, Carlos; Min, James

    2009-01-01

    The Structural Dynamics and. Mechanics branch (RXS) is developing smart adaptive structures to improve fan blade damping at resonances using piezoelectric (PE) transducers. In this presentation, only one shunted PE transducer was used to demonstrate active control of multi-mode blade resonance damping on a titanium alloy (Ti-6A1-4V) flat plate model, regardless of bending, torsion, and 2-stripe modes. This work would have a significant impact on the conventional passive shunt damping world because the standard feedback control design tools can now be used to design and implement electric shunt for vibration control. In other words, the passive shunt circuit components using massive inductors and. resistors for multi-mode resonance control can be replaced with digital codes. Furthermore, this active approach with multi patches can simultaneously control several modes in the engine operating range. Dr. Benjamin Choi presented the analytical and experimental results from this work at the Propulsion-Safety and. Affordable Readiness (P-SAR) Conference in March, 2009.

  13. Diamond Radio Receiver: Nitrogen-Vacancy Centers as Fluorescent Transducers of Microwave Signals

    NASA Astrophysics Data System (ADS)

    Shao, Linbo; Zhang, Mian; Markham, Matthew; Edmonds, Andrew M.; Lončar, Marko

    2016-12-01

    We demonstrate a robust frequency-modulated radio receiver using electron-spin-dependent photoluminescence of nitrogen-vacancy centers in diamond. The carrier frequency of the frequency-modulated signal is in the 2.8-GHz range, determined by the zero-field splitting in the nitrogen-vacancy electronic ground state. The radio can be tuned over 300 MHz by applying an external dc magnetic field. We show the transmission of high-fidelity audio signals over a bandwidth of 91 kHz using the diamond radio. We demonstrate operating temperature of the radio as high as 350 ° C .

  14. Large-signal model of a resonating cantilever-based transducer for system level electrical simulation

    NASA Astrophysics Data System (ADS)

    Verd, Jaume; Teva, Jordi; Abadal, Gabriel; Perez-Murano, Francesc; Esteve, Jaume; Barniol, Nuria

    2005-07-01

    In this work, we present a non-linear electromechanical model of an electrostatically excited cantilever that can be used to perform system level electrical simulations. This model is implemented by using an analog hardware description language (VHDL-AMS) that allows its use in a common IC CAD environment like CADENCE. Small-signal and large-signal simulations are performed and the results are compared with a simple linear model (RLC//C) showing the benefits of this model. This model is validated by its fit with the experimental results obtained from a monolithic sub-micrometer cantilever based sensor

  15. Lung carcinogenesis from chronic obstructive pulmonary disease: characteristics of lung cancer from COPD and contribution of signal transducers and lung stem cells in the inflammatory microenvironment.

    PubMed

    Sekine, Yasuo; Hata, Atsushi; Koh, Eitetsu; Hiroshima, Kenzo

    2014-07-01

    Chronic obstructive pulmonary disease (COPD) and lung cancer are closely related. The annual incidence of lung cancer arising from COPD has been reported to be 0.8-1.7 %. Treatment of lung cancer from COPD is very difficult due to low cardiopulmonary function, rapid tumor growth, and resistance to molecularly targeted therapies. Chronic inflammation caused by toxic gases can induce COPD and lung cancer. Carcinogenesis in the inflammatory microenvironment occurs during cycles of tissue injury and repair. Cellular damage can induce induction of necrotic cell death and loss of tissue integrity. Quiescent normal stem cells or differentiated progenitor cells are introduced to repair injured tissues. However, inflammatory mediators may promote the growth of bronchioalveolar stem cells, and activation of NF-κB and signal transducer and activator of transcription 3 (STAT3) play crucial roles in the development of lung cancer from COPD. Many of the protumorgenic effects of NF-κB and STAT3 activation in immune cells are mediated through paracrine signaling. NF-κB and STAT3 also contribute to epithelial-mesenchymal transition. To improve lung cancer treatment outcomes, lung cancer from COPD must be overcome. In this article, we review the characteristics of lung cancer from COPD and the mechanisms of carcinogenesis in the inflammatory microenvironment. We also propose the necessity of identifying the mechanisms underlying progression of COPD to lung cancer, and comment on the clinical implications with respect to lung cancer prevention, screening, and therapy.

  16. Transducer characterization

    SciTech Connect

    Cross, B. T.; Eoff, J. M.; Schuetz, L. J.; Cunningham, K. R.

    1980-07-02

    This report has been prepared specifically for ultrasonic transducer users within the Nondestructive Testing Evaluation (NDE) community of the weapons complex. The purpose of the report is to establish an initial set of uniform procedures for measuring and recording transducer performance data, and to establish a common foundation on which more comprehensive transducer performance evaluations may be added as future transducer performance criteria expands. Transducer parameters and the problems with measuring them are discussed and procedures for measuring transducer performance are recommended with special precautionary notes regarding critical aspects of each measurement. An important consideration regarding the recommended procedures is the cost of implementation. There are two distinct needs for transducer performance characterization in the complex. Production oriented users need a quick, reliable means to check a transducer to ascertain its suitability for continued service. Development groups and the Transducer Center need a comprehensive characterization means to collect adequate data to evaluate theoretical concepts or to build exact replacement transducers. The instrumentation, equipment, and procedures recommended for monitoring production transducers are utilitarian and provide only that information needed to determine transducer condition.

  17. Jasmonic acid is a crucial signal transducer in heat shock induced sesquiterpene formation in Aquilaria sinensis.

    PubMed

    Xu, Yan-Hong; Liao, Yong-Cui; Zhang, Zheng; Liu, Juan; Sun, Pei-Wen; Gao, Zhi-Hui; Sui, Chun; Wei, Jian-He

    2016-02-23

    Agarwood, a highly valuable resinous and fragrant heartwood of Aquilaria plants, is widely used in traditional medicines, incense and perfume. Only when Aquilaria trees are wounded by external stimuli do they form agarwood sesquiterpene defensive compounds. Therefore, understanding the signaling pathway of wound-induced agarwood formation is important. Jasmonic acid (JA) is a well-characterized molecule that mediates a plant's defense response and secondary metabolism. However, little is known about the function of endogenous JA in agarwood sesquiterpene biosynthesis. Here, we report that heat shock can up-regulate the expression of genes in JA signaling pathway, induce JA production and the accumulation of agarwood sesquiterpene in A. sinensis cell suspension cultures. A specific inhibitor of JA, nordihydroguaiaretic acid (NDGA), could block the JA signaling pathway and reduce the accumulation of sesquiterpene compounds. Additionally, compared to SA and H2O2, exogenously supplied methyl jasmonate has the strongest stimulation effect on the production of sesquiterpene compounds. These results clearly demonstrate the central induction role of JA in heat-shock-induced sesquiterpene production in A. sinensis.

  18. Jasmonic acid is a crucial signal transducer in heat shock induced sesquiterpene formation in Aquilaria sinensis

    PubMed Central

    Xu, Yan-Hong; Liao, Yong-Cui; Zhang, Zheng; Liu, Juan; Sun, Pei-Wen; Gao, Zhi-Hui; Sui, Chun; Wei, Jian-He

    2016-01-01

    Agarwood, a highly valuable resinous and fragrant heartwood of Aquilaria plants, is widely used in traditional medicines, incense and perfume. Only when Aquilaria trees are wounded by external stimuli do they form agarwood sesquiterpene defensive compounds. Therefore, understanding the signaling pathway of wound-induced agarwood formation is important. Jasmonic acid (JA) is a well-characterized molecule that mediates a plant’s defense response and secondary metabolism. However, little is known about the function of endogenous JA in agarwood sesquiterpene biosynthesis. Here, we report that heat shock can up-regulate the expression of genes in JA signaling pathway, induce JA production and the accumulation of agarwood sesquiterpene in A. sinensis cell suspension cultures. A specific inhibitor of JA, nordihydroguaiaretic acid (NDGA), could block the JA signaling pathway and reduce the accumulation of sesquiterpene compounds. Additionally, compared to SA and H2O2, exogenously supplied methyl jasmonate has the strongest stimulation effect on the production of sesquiterpene compounds. These results clearly demonstrate the central induction role of JA in heat-shock-induced sesquiterpene production in A. sinensis. PMID:26902148

  19. Influences of Surface and Ionic Properties on Electricity Generation of an Active Transducer Driven by Water Motion.

    PubMed

    Park, Junwoo; Yang, YoungJun; Kwon, Soon-Hyung; Kim, Youn Sang

    2015-02-19

    In this Letter, we discuss the surface, ionic properties, and scale-up potential of an active transducer that generated electricity from natural water motion. When a liquid contacts a solid surface, an electrical double layer (EDL) is always formed at the solid/liquid interface. By modulating the EDL, the active transducer could generate a peak voltage of ∼3 V and a peak power of ∼5 μW. Interestingly, there were specific salinities of solution droplets that showed maximum performance and different characteristics according to the ions' nature. Analyzing the results macroscopically, we tried to figure out the origins of the active transducing precipitated by ions dynamics. Also, we demonstrated the scale-up potential for practical usage by multiple electrode design.

  20. Possibility of cellulose-based electro-active paper energy scavenging transducer.

    PubMed

    Abas, Zafar; Kim, Heung Soo; Zhai, Lindong; Kim, Jaehwan; Kim, Joo Hyung

    2014-10-01

    In this paper, a cellulose-based Electro-Active Paper (EAPap) energy scavenging transducer is presented. Cellulose is proven as a smart material, and exhibits piezoelectric effect. Specimens were prepared by coating gold electrodes on both sides of cellulose film. The fabricated specimens were tested by a base excited aluminum cantilever beam at resonant frequency. Different tests were performed with single and multiple parallel connected electrodes coated on the cellulose film. A maximum of 131 mV output voltage was measured, when three electrodes were connected in parallel. It was observed that voltage output increases significantly with the area of electrodes. From these results, it can be concluded that the piezoelectricity of cellulose-based EAPap can be used in energy transduction application.

  1. Brachial artery vasomotion and transducer pressure effect on measurements by active contour segmentation on ultrasound

    SciTech Connect

    Cary, Theodore W.; Sultan, Laith R.; Sehgal, Chandra M.; Reamer, Courtney B.; Mohler, Emile R.

    2014-02-15

    Purpose: To use feed-forward active contours (snakes) to track and measure brachial artery vasomotion on ultrasound images recorded in both transverse and longitudinal views; and to compare the algorithm's performance in each view. Methods: Longitudinal and transverse view ultrasound image sequences of 45 brachial arteries were segmented by feed-forward active contour (FFAC). The segmented regions were used to measure vasomotion artery diameter, cross-sectional area, and distention both as peak-to-peak diameter and as area. ECG waveforms were also simultaneously extracted frame-by-frame by thresholding a running finite-difference image between consecutive images. The arterial and ECG waveforms were compared as they traced each phase of the cardiac cycle. Results: FFAC successfully segmented arteries in longitudinal and transverse views in all 45 cases. The automated analysis took significantly less time than manual tracing, but produced superior, well-behaved arterial waveforms. Automated arterial measurements also had lower interobserver variability as measured by correlation, difference in mean values, and coefficient of variation. Although FFAC successfully segmented both the longitudinal and transverse images, transverse measurements were less variable. The cross-sectional area computed from the longitudinal images was 27% lower than the area measured from transverse images, possibly due to the compression of the artery along the image depth by transducer pressure. Conclusions: FFAC is a robust and sensitive vasomotion segmentation algorithm in both transverse and longitudinal views. Transverse imaging may offer advantages over longitudinal imaging: transverse measurements are more consistent, possibly because the method is less sensitive to variations in transducer pressure during imaging.

  2. Trimeric G protein-CARMA1 axis links smoothened, the hedgehog receptor transducer, to NF-κB activation in diffuse large B-cell lymphoma.

    PubMed

    Qu, Changju; Liu, Yadong; Kunkalla, Kranthi; Singh, Rajesh R; Blonska, Marzenna; Lin, Xin; Agarwal, Nitin Kumar; Vega, Francisco

    2013-06-06

    Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. Aberrant activation of Hedgehog (Hh) and nuclear factor (NF)-κB pathways is ubiquitously observed and known to mediate tumor growth, survival, and chemoresistance in DLBCL. Here, we find that activation of Hh signaling is positively correlated with NF-κB pathway in DLBCL tumors, and that smoothened (SMO), the signal transducer subunit of Hh pathway, contributes to NF-κB activation through recruiting G protein subunits Gαi and Gα12 to activate PKCβ/CARMA1/TRAF6/NEMO signaling axis followed by assembling of the CARMA1/BCL10/MALT1/TRAF6 complex to SMO. Moreover, functional inhibition of SMO enhances the cytotoxic effects of NF-κB inhibitor. Altogether, our study reveals a noncanonical Hh signaling pathway in which SMO activates trimeric G proteins and CARMA1-associated signaling complex, leading to NF-κB activation. This signaling cascade contributes to the survival of DLBCL and may serve as a potential target for combination therapies in DLBCL.

  3. The Molecular Interaction of CAR and JAML Recruits the Central Cell Signal Transducer PI3K

    SciTech Connect

    Verdino, Petra; Witherden, Deborah A.; Havran, Wendy L.; Wilson, Ian A.

    2010-11-15

    Coxsackie and adenovirus receptor (CAR) is the primary cellular receptor for group B coxsackieviruses and most adenovirus serotypes and plays a crucial role in adenoviral gene therapy. Recent discovery of the interaction between junctional adhesion molecule-like protein (JAML) and CAR uncovered important functional roles in immunity, inflammation, and tissue homeostasis. Crystal structures of JAML ectodomain (2.2 angstroms) and its complex with CAR (2.8 angstroms) reveal an unusual immunoglobulin-domain assembly for JAML and a charged interface that confers high specificity. Biochemical and mutagenesis studies illustrate how CAR-mediated clustering of JAML recruits phosphoinositide 3-kinase (P13K) to a JAML intracellular sequence motif as delineated for the {alpha}{beta} T cell costimulatory receptor CD28. Thus, CAR and JAML are cell signaling receptors of the immune system with implications for asthma, cancer, and chronic nonhealing wounds.

  4. The application of 1-3 cement-based piezoelectric transducers in active and passive health monitoring for concrete structures

    NASA Astrophysics Data System (ADS)

    Qin, Lei; Huang, Shifeng; Cheng, Xin; Lu, Youyuan; Li, Zongjin

    2009-09-01

    1-3 cement-based piezoelectric composite has been developed for health monitoring of concrete structures. Transducers made of this type of composite have broadband frequency response. Plain concrete and engineered cement composite (ECC) beams with embedded 1-3 cement-based piezoelectric transducers were prepared and tested. During experiments, the transducers were used to perform active and passive detection of the damage evolution of the beams. In active detection, a damage index based on the average energy of the received waves was proposed and used. In passive detection, acoustic emission (AE) events were recorded and the accumulated AE event number was analyzed with the loading history. Crack localization was also accomplished in the passive monitoring. The results of the two methods demonstrated similar trends in interpreting the damage evolution of the concrete beam. The results were also consistent with each material's characteristics.

  5. Signal-transducing mechanisms of ketamine-caused inhibition of interleukin-1{beta} gene expression in lipopolysaccharide-stimulated murine macrophage-like Raw 264.7 cells

    SciTech Connect

    Chen, T.-L.; Chang, C.-C.; Lin, Y.-L.; Ueng, Y.-F.; Chen, R.-M.

    2009-10-01

    Ketamine may affect the host immunity. Interleukin-1{beta} (IL-1{beta}), IL-6, and tumor necrosis factor-{alpha} (TNF-{alpha}) are pivotal cytokines produced by macrophages. This study aimed to evaluate the effects of ketamine on the regulation of inflammatory cytokine gene expression, especially IL-1{beta}, in lipopolysaccharide (LPS)-activated murine macrophage-like Raw 264.7 cells and its possible signal-transducing mechanisms. Administration of Raw 264.7 cells with a therapeutic concentration of ketamine (100 {mu}M), LPS, or a combination of ketamine and LPS for 1, 6, and 24 h was not cytotoxic to macrophages. Exposure to 100 {mu}M ketamine decreased the binding affinity of LPS and LPS-binding protein but did not affect LPS-induced RNA and protein synthesis of TLR4. Treatment with LPS significantly increased IL-1{beta}, IL-6, and TNF-{alpha} gene expressions in Raw 264.7 cells. Ketamine at a clinically relevant concentration did not affect the synthesis of these inflammatory cytokines, but significantly decreased LPS-caused increases in these cytokines. Immunoblot analyses, an electrophoretic mobility shift assay, and a reporter luciferase activity assay revealed that ketamine significantly decreased LPS-induced translocation and DNA binding activity of nuclear factor-kappa B (NF{kappa}B). Administration of LPS sequentially increased the phosphorylations of Ras, Raf, MEK1/2, ERK1/2, and IKK. However, a therapeutic concentration of ketamine alleviated such augmentations. Application of toll-like receptor 4 (TLR4) small interfering (si)RNA reduced cellular TLR4 amounts and ameliorated LPS-induced RAS activation and IL-1{beta} synthesis. Co-treatment with ketamine and TLR4 siRNA synergistically ameliorated LPS-caused enhancement of IL-1{beta} production. Results of this study show that a therapeutic concentration of ketamine can inhibit gene expression of IL-1{beta} possibly through suppressing TLR4-mediated signal-transducing phosphorylations of Ras, Raf, MEK1

  6. Ciliary neurotropic factor, interleukin 11, leukemia inhibitory factor, and oncostatin M are growth factors for human myeloma cell lines using the interleukin 6 signal transducer gp130

    PubMed Central

    1994-01-01

    Interleukin 6 (IL-6) is a major growth factor for tumor plasma cells involved in human multiple myeloma (MM). In particular, human myeloma cell lines (HMCL), whose growth is completely dependent on addition of exogenous IL-6, can be obtained reproducibly from every patient with terminal disease. Four cytokines, ciliary neurotropic factor (CNTF), IL- 11, leukemia inhibitory factor (LIF), and oncostatin M (OM), use the same transducer chain (signal transducer gp130) as IL-6 and share numerous biological activities with this IL. We found that these four cytokines stimulated proliferation and supported the long-term growth of two out of four IL-6-dependent HMCL obtained in our laboratory. Half- maximal proliferation was obtained with cytokine concentrations ranging from 0.4 to 1.2 ng/ml for IL-11, LIF, and OM. CNTF worked at high concentrations only (90 ng/ml), but addition of soluble CNTF receptor increased sensitivity to CNTF 30-fold. The growth-promoting effect of these four cytokines was abrogated by anti-gp130 antibodies, contrary to results for anti-IL-6 receptor or anti-IL-6 antibodies. No detectable changes in the morphology and phenotype were found when myeloma cells were cultured with one of these four cytokines instead of IL-6. Concordant with their IL-6-dependent growth, the four HMCL expressed membrane IL-6R and gp130 detected by FACS analysis. LIF- binding chain gene (LIFR) was expressed only in the two HMCL responsive to LIF and OM. PMID:8145045

  7. Chemotaxis of Escherichia coli to pyrimidines: a new role for the signal transducer tap.

    PubMed

    Liu, Xianxian; Parales, Rebecca E

    2008-02-01

    Escherichia coli exhibits chemotactic responses to sugars, amino acids, and dipeptides, and the responses are mediated by methyl-accepting chemotaxis proteins (MCPs). Using capillary assays, we demonstrated that Escherichia coli RP437 is attracted to the pyrimidines thymine and uracil and the response was constitutively expressed under all tested growth conditions. All MCP mutants lacking the MCP Tap protein showed no response to pyrimidines, suggesting that Tap, which is known to mediate dipeptide chemotaxis, is required for pyrimidine chemotaxis. In order to confirm the role of Tap in pyrimidine chemotaxis, we constructed chimeric chemoreceptors (Tapsr and Tsrap), in which the periplasmic and cytoplasmic domains of Tap and Tsr were switched. When Tapsr and Tsrap were individually expressed in an E. coli strain lacking all four native MCPs, Tapsr mediated chemotaxis toward pyrimidines and dipeptides, but Tsrap did not complement the chemotaxis defect. The addition of the C-terminal 19 amino acids from Tsr to the C terminus of Tsrap resulted in a functional chemoreceptor that mediated chemotaxis to serine but not pyrimidines or dipeptides. These results indicate that the periplasmic domain of Tap is responsible for detecting pyrimidines and the Tsr signaling domain confers on Tapsr the ability to mediate efficient chemotaxis. A mutant lacking dipeptide binding protein (DBP) was wild type for pyrimidine taxis, indicating that DBP, which is the primary chemoreceptor for dipeptides, is not responsible for detecting pyrimidines. It is not yet known whether Tap detects pyrimidines directly or via an additional chemoreceptor protein.

  8. Experiments with Ultrasonic Transducers.

    ERIC Educational Resources Information Center

    Greenslade, Thomas R., Jr.

    1994-01-01

    Discusses the use of 40 kHz ultrasonic transducers to study wave phenomena. Determines that the resulting wavelength of 9 mm allows acoustic experiments to be performed on a tabletop. Includes transducer characteristics and activities on speed of sound, reflection, double- and single-slit diffraction, standing waves, acoustical zone plate, and…

  9. Intracellular calcium overloading and oxidative stress in cardiomyocyte necrosis via a mitochondriocentric signal-transducer-effector pathway

    PubMed Central

    Shaheen, Mazen; Cheema, Yaser; Shahbaz, Atta U; Bhattacharya, Syamal K; Weber, Karl T

    2011-01-01

    Congestive heart failure (CHF), a common clinical syndrome, has reached epidemic proportions. Its disabling symptoms account for frequent hospitalizations and readmissions. Pathophysiological mechanisms that lead to CHF and account for its progressive nature are of considerable interest. Important scientific observations obtained from Dr Pawan K Singal’s laboratory in Winnipeg, Manitoba, have provided crucial insights to our understanding of the pathophysiological factors that contribute to cardiomyocyte necrosis (the heart is a postmitotic organ incapable of tolerating an ongoing loss of these cells without adverse functional consequences). This increment in knowledge and the mechanistic insights afforded by Dr Singal and his colleagues have highlighted the role of excessive intracellular calcium accumulation and the appearance of oxidative stress in CHF, in which the rate of reactive oxygen species generation overwhelms their rate of detoxification by antioxidant defenses. They have shown that this common pathophysiological scenario applies to diverse entities such as ischemia/reperfusion and hypoxia/reoxygenation forms of injury, myocardial infarction and the cardiomyopathies that accompany diabetes and excess levels of catecholamines and adriamycin. The authors are honoured to be invited to contribute to the present focus issue of Experimental & Clinical Cardiology in recognizing Dr Singal’s numerous scholarly accomplishments. The present article reviews the authors’ recent work on a mitochondriocentric signal-transducer-effector pathway to cardiomyocyte necrosis found in rats with either an acute stressor state that accompanies isoproterenol administration or a chronic stressor state manifested after four weeks of aldosterone/salt treatment. PMID:22131852

  10. Active control of microbubbles stream in multi-bifurcated flow by using 2D phased array ultrasound transducer.

    PubMed

    Koda, Ren; Koido, Jun; Hosaka, Naoto; Ito, Takumi; Onogi, Shinya; Mochizuki, Takashi; Masuda, Kohji; Ikeda, Seiichi; Arai, Fumihito

    2013-01-01

    We have previously reported our attempt to propel microbbles in flow by a primary Bjerknes force, which is a physical phenomenon where an acoustic wave pushes an obstacle along its direction of propagation. However, when ultrasound was emitted from surface of the body, controlling bubbles in against flow was needed. It is unpractical to use multiple transducers to produce the same number of focal points because single element transducer cannot produce more than two focal points. In this study, we introduced a complex artificial blood vessel according to a capillary model and a 2D array transducer to produce multiple focal points for active control of microbubbles in against flow. Furthermore, we investigated bubble control in viscous fluid. As the results, we confirmed clearly path selection of MBs in viscous fluid as well as in water.

  11. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis

    PubMed Central

    Bataller, Ramón; Schwabe, Robert F.; Choi, Youkyung H.; Yang, Liu; Paik, Yong Han; Lindquist, Jeffrey; Qian, Ting; Schoonhoven, Robert; Hagedorn, Curt H.; Lemasters, John J.; Brenner, David A.

    2003-01-01

    Angiotensin II (Ang II) is a pro-oxidant and fibrogenic cytokine. We investigated the role of NADPH oxidase in Ang II–induced effects in hepatic stellate cells (HSCs), a fibrogenic cell type. Human HSCs express mRNAs of key components of nonphagocytic NADPH oxidase. Ang II phosphorylated p47phox, a regulatory subunit of NADPH oxidase, and induced reactive oxygen species formation via NADPH oxidase activity. Ang II phosphorylated AKT and MAPKs and increased AP-1 DNA binding in a redox-sensitive manner. Ang II stimulated DNA synthesis, cell migration, procollagen α1(I) mRNA expression, and secretion of TGF-β1 and inflammatory cytokines. These effects were attenuated by N-acetylcysteine and diphenylene iodonium, an NADPH oxidase inhibitor. Moreover, Ang II induced upregulation of genes potentially involved in hepatic wound-healing response in a redox-sensitive manner, as assessed by microarray analysis. HSCs isolated from p47phox–/– mice displayed a blunted response to Ang II compared with WT cells. We also assessed the role of NADPH oxidase in experimental liver fibrosis. After bile duct ligation, p47phox–/– mice showed attenuated liver injury and fibrosis compared with WT counterparts. Moreover, expression of smooth muscle α-actin and expression of TGF-β1 were reduced in p47phox–/– mice. Thus, NADPH oxidase mediates the actions of Ang II on HSCs and plays a critical role in liver fibrogenesis. PMID:14597764

  12. Measurement of Contractile Activity in Small Animal's Digestive Organ by Carbon Nanotube-Based Force Transducer

    NASA Astrophysics Data System (ADS)

    Hirata, Takamichi; Takeda, Naoki; Tsutsui, Chihiro; Koike, Kanako; Shimatani, Yuichi; Sakai, Takafumi; Akiya, Masahiro; Taguchi, Akira

    2011-03-01

    A carbon nanotube (CNT)-based force transducer designed to be embedded in the body of a live animal was fabricated and implanted into the stomach of a rat omit to measure contractile movement. The transducer comprised dispersed poly(ethylene glycol)-grafted multiwalled CNTs applied to a comb-like Au-electrode formed on a poly(dimethylsiloxane) sheet. The implanted rat was injected with acetylcholine to induce muscular contractions and changes in the resistance of the transducer were measured. Such changes arise owing to strain in the CNT network upon distortion. The measured resistance change was found to be proportional to the concentration of injected acetylcholine.

  13. Auto-positioning ultrasonic transducer system

    NASA Technical Reports Server (NTRS)

    Buchanan, Randy K. (Inventor)

    2010-01-01

    An ultrasonic transducer apparatus and process for determining the optimal transducer position for flow measurement along a conduit outer surface. The apparatus includes a transmitting transducer for transmitting an ultrasonic signal, said transducer affixed to a conduit outer surface; a guide rail attached to a receiving transducer for guiding movement of a receiving transducer along the conduit outer surface, wherein the receiving transducer receives an ultrasonic signal from the transmitting transducer and sends a signal to a data acquisition system; and a motor for moving the receiving transducer along the guide rail, wherein the motor is controlled by a controller. The method includes affixing a transmitting transducer to an outer surface of a conduit; moving a receiving transducer on the conduit outer surface, wherein the receiving transducer is moved along a guide rail by a motor; transmitting an ultrasonic signal from the transmitting transducer that is received by the receiving transducer; communicating the signal received by the receiving transducer to a data acquisition and control system; and repeating the moving, transmitting, and communicating along a length of the conduit.

  14. Manipulation of acoustic focusing with an active and configurable planar metasurface transducer

    PubMed Central

    Zhao, Jiajun; Ye, Huapeng; Huang, Kun; Chen, Zhi Ning; Li, Baowen; Qiu, Cheng-Wei

    2014-01-01

    It has a pivotal role in medical science and in industry to concentrate the acoustic energy created with piezoelectric transducers (PTs) into a specific area. However, previous researches seldom consider the focal resolution, whose focal size is much larger than one wavelength. Furthermore, there is to date no such design method of PTs that allows a large degree of freedom to achieve designed focal patterns. Here, an active and configurable planar metasurface PT prototype is proposed to manipulate the acoustic focal pattern and the focal resolution freely. By suitably optimized ring configurations of the active metasurface PT, we demonstrate the manipulation of focal patterns in acoustic far fields, such as the designed focal needle and multi foci. Our method is also able to manipulate and improve the cross-sectional focal resolution from subwavelength to the extreme case: the deep sub-diffraction-limit resolution. Via the acoustic Rayleigh-Sommerfeld diffraction integral (RSI) cum the binary particle swarm optimization (BPSO), the free manipulation of focusing properties is achieved in acoustics for the first time. Our approach may offer more initiatives where the strict control of acoustic high-energy areas is demanding. PMID:25174409

  15. Manipulation of acoustic focusing with an active and configurable planar metasurface transducer

    NASA Astrophysics Data System (ADS)

    Zhao, Jiajun; Ye, Huapeng; Huang, Kun; Chen, Zhi Ning; Li, Baowen; Qiu, Cheng-Wei

    2014-09-01

    It has a pivotal role in medical science and in industry to concentrate the acoustic energy created with piezoelectric transducers (PTs) into a specific area. However, previous researches seldom consider the focal resolution, whose focal size is much larger than one wavelength. Furthermore, there is to date no such design method of PTs that allows a large degree of freedom to achieve designed focal patterns. Here, an active and configurable planar metasurface PT prototype is proposed to manipulate the acoustic focal pattern and the focal resolution freely. By suitably optimized ring configurations of the active metasurface PT, we demonstrate the manipulation of focal patterns in acoustic far fields, such as the designed focal needle and multi foci. Our method is also able to manipulate and improve the cross-sectional focal resolution from subwavelength to the extreme case: the deep sub-diffraction-limit resolution. Via the acoustic Rayleigh-Sommerfeld diffraction integral (RSI) cum the binary particle swarm optimization (BPSO), the free manipulation of focusing properties is achieved in acoustics for the first time. Our approach may offer more initiatives where the strict control of acoustic high-energy areas is demanding.

  16. Microinterferometer transducer

    DOEpatents

    Corey, III, Harry S.

    1979-01-01

    An air-bearing microinterferometer transducer is provided for increased accuracy, range and linearity over conventional displacement transducers. A microinterferometer system is housed within a small compartment of an air-bearing displacement transducer housing. A movable cube corner reflector of the interferometer is mounted to move with the displacement gauging probe of the transducer. The probe is disposed for axial displacement by means of an air-bearing. Light from a single frequency laser is directed into an interferometer system within the transducer housing by means of a self-focusing fiber optic cable to maintain light coherency. Separate fringe patterns are monitored by a pair of fiber optic cables which transmit the patterns to a detecting system. The detecting system includes a bidirectional counter which counts the light pattern fringes according to the direction of movement of the probe during a displacement gauging operation.

  17. Modeling of phased array transducers.

    PubMed

    Ahmad, Rais; Kundu, Tribikram; Placko, Dominique

    2005-04-01

    Phased array transducers are multi-element transducers, where different elements are activated with different time delays. The advantage of these transducers is that no mechanical movement of the transducer is needed to scan an object. Focusing and beam steering is obtained simply by adjusting the time delay. In this paper the DPSM (distributed point source method) is used to model the ultrasonic field generated by a phased array transducer and to study the interaction effect when two phased array transducers are placed in a homogeneous fluid. Earlier investigations modeled the acoustic field for conventional transducers where all transducer points are excited simultaneously. In this research, combining the concepts of delayed firing and the DPSM, the phased array transducers are modeled semi-analytically. In addition to the single transducer modeling the ultrasonic fields from two phased array transducers placed face to face in a fluid medium is also modeled to study the interaction effect. The importance of considering the interaction effect in multiple transducer modeling is discussed, pointing out that neighboring transducers not only act as ultrasonic wave generators but also as scatterers.

  18. Acoustic transducer for nuclear reactor monitoring

    DOEpatents

    Ahlgren, Frederic F.; Scott, Paul F.

    1977-01-01

    A transducer to monitor a parameter and produce an acoustic signal from which the monitored parameter can be recovered. The transducer comprises a modified Galton whistle which emits a narrow band acoustic signal having a frequency dependent upon the parameter being monitored, such as the temperature of the cooling media of a nuclear reactor. Multiple locations within a reactor are monitored simultaneously by a remote acoustic receiver by providing a plurality of transducers each designed so that the acoustic signal it emits has a frequency distinct from the frequencies of signals emitted by the other transducers, whereby each signal can be unambiguously related to a particular transducer.

  19. Test rig with active damping control for the simultaneous evaluation of vibration control and energy harvesting via piezoelectric transducers

    NASA Astrophysics Data System (ADS)

    Perfetto, S.; Rohlfing, J.; Infante, F.; Mayer, D.; Herold, S.

    2016-09-01

    Piezoelectric transducers can be used to harvest electrical energy from structural vibrations in order to power continuously operating condition monitoring systems local to where they operate. However, excessive vibrations can compromise the safe operation of mechanical systems. Therefore, absorbers are commonly used to control vibrations. With an integrated device, the mechanical energy that otherwise would be dissipated can be converted via piezoelectric transducers. Vibration absorbers are designed to have high damping factors. Hence, the integration of transducers would lead to a low energy conversion. Efficient energy harvesters usually have low damping capabilities; therefore, they are not effective for vibration suppression. Thus, the design of an integrated device needs to consider the two conflicting requirements on the damping. This study focuses on the development of a laboratory test rig with a host structure and a vibration absorber with tunable damping via an active relative velocity feedback. A voice coil actuator is used for this purpose. To overcome the passive damping effects of the back electromagnetic force a novel voltage feedback control is proposed, which has been validated both in simulation and experimentally. The aim of this study is to have a test rig ready for the introduction of piezo-transducers and available for future experimental evaluations of the damping effect on the effectiveness of vibration reduction and energy harvesting efficiency.

  20. High energy, low frequency, ultrasonic transducer

    DOEpatents

    Brown, Albert E.

    2000-01-01

    A wide bandwidth, ultrasonic transducer to generate nondispersive, extensional, pulsed acoustic pressure waves into concrete reinforced rods and tendons. The wave propagation distance is limited to double the length of the rod. The transducer acoustic impedance is matched to the rod impedance for maximum transfer of acoustic energy. The efficiency of the transducer is approximately 60 percent, depending upon the type of active elements used in the transducer. The transducer input energy is, for example, approximately 1 mJ. Ultrasonic reflections will occur at points along the rod where there are changes of one percent of a wavelength in the rod diameter. A reduction in the rod diameter will reflect a phase reversed echo, as compared with the reflection from an incremental increase in diameter. Echo signal processing of the stored waveform permits a reconstruction of those echoes into an image of the rod. The ultrasonic transducer has use in the acoustic inspection of long (40+foot) architectural reinforcements and structural supporting members, such as in bridges and dams.

  1. Wideband Single Crystal Transducer for Bone Characterization

    NASA Technical Reports Server (NTRS)

    Sahul, Raffi

    2015-01-01

    Phase II objectives: Optimize the Phase I transducer for sensitivity; Test different transmit signals for optimum performance; Demonstrate compatibility with electronics; Confirm additional transducer capabilities over conventional systems by calibrating with other methods.

  2. Multi sensor transducer and weight factor

    NASA Technical Reports Server (NTRS)

    Immer, Christopher D. (Inventor); Lane, John (Inventor); Eckhoff, Anthony J. (Inventor); Perotti, Jose M. (Inventor)

    2004-01-01

    A multi-sensor transducer and processing method allow insitu monitoring of the senor accuracy and transducer `health`. In one embodiment, the transducer has multiple sensors to provide corresponding output signals in response to a stimulus, such as pressure. A processor applies individual weight factors to reach of the output signals and provide a single transducer output that reduces the contribution from inaccurate sensors. The weight factors can be updated and stored. The processor can use the weight factors to provide a `health` of the transducer based upon the number of accurate versus in-accurate sensors in the transducer.

  3. Identification of a novel actin-dependent signal transducing module allows for the targeted degradation of GLI1.

    PubMed

    Schneider, Philipp; Bayo-Fina, Juan Miguel; Singh, Rajeev; Kumar Dhanyamraju, Pavan; Holz, Philipp; Baier, Aninja; Fendrich, Volker; Ramaswamy, Annette; Baumeister, Stefan; Martinez, Elisabeth D; Lauth, Matthias

    2015-08-27

    The Down syndrome-associated DYRK1A kinase has been reported as a stimulator of the developmentally important Hedgehog (Hh) pathway, but cells from Down syndrome patients paradoxically display reduced Hh signalling activity. Here we find that DYRK1A stimulates GLI transcription factor activity through phosphorylation of general nuclear localization clusters. In contrast, in vivo and in vitro experiments reveal that DYRK1A kinase can also function as an inhibitor of endogenous Hh signalling by negatively regulating ABLIM proteins, the actin cytoskeleton and the transcriptional co-activator MKL1 (MAL). As a final effector of the DYRK1A-ABLIM-actin-MKL1 sequence, we identify the MKL1 interactor Jumonji domain demethylase 1A (JMJD1A) as a novel Hh pathway component stabilizing the GLI1 protein in a demethylase-independent manner. Furthermore, a Jumonji-specific small-molecule antagonist represents a novel and powerful inhibitor of Hh signal transduction by inducing GLI1 protein degradation in vitro and in vivo.

  4. Acylcarnitines activate proinflammatory signaling pathways.

    PubMed

    Rutkowsky, Jennifer M; Knotts, Trina A; Ono-Moore, Kikumi D; McCoin, Colin S; Huang, Shurong; Schneider, Dina; Singh, Shamsher; Adams, Sean H; Hwang, Daniel H

    2014-06-15

    Incomplete β-oxidation of fatty acids in mitochondria is a feature of insulin resistance and type 2 diabetes mellitus (T2DM). Previous studies revealed that plasma concentrations of medium- and long-chain acylcarnitines (by-products of incomplete β-oxidation) are elevated in T2DM and insulin resistance. In a previous study, we reported that mixed D,L isomers of C12- or C14-carnitine induced an NF-κB-luciferase reporter gene in RAW 264.7 cells, suggesting potential activation of proinflammatory pathways. Here, we determined whether the physiologically relevant L-acylcarnitines activate classical proinflammatory signaling pathways and if these outcomes involve pattern recognition receptor (PRR)-associated pathways. Acylcarnitines induced the expression of cyclooxygenase-2 in a chain length-dependent manner in RAW 264.7 cells. L-C14 carnitine (5-25 μM), used as a representative acylcarnitine, stimulated the expression and secretion of proinflammatory cytokines in a dose-dependent manner. Furthermore, L-C14 carnitine induced phosphorylation of JNK and ERK, common downstream components of many proinflammatory signaling pathways including PRRs. Knockdown of MyD88, a key cofactor in PRR signaling and inflammation, blunted the proinflammatory effects of acylcarnitine. While these results point to potential involvement of PRRs, L-C14 carnitine promoted IL-8 secretion from human epithelial cells (HCT-116) lacking Toll-like receptors (TLR)2 and -4, and did not activate reporter constructs in TLR overexpression cell models. Thus, acylcarnitines have the potential to activate inflammation, but the specific molecular and tissue target(s) involved remain to be identified.

  5. Acylcarnitines activate proinflammatory signaling pathways

    PubMed Central

    Rutkowsky, Jennifer M.; Knotts, Trina A.; Ono-Moore, Kikumi D.; McCoin, Colin S.; Huang, Shurong; Schneider, Dina; Singh, Shamsher; Hwang, Daniel H.

    2014-01-01

    Incomplete β-oxidation of fatty acids in mitochondria is a feature of insulin resistance and type 2 diabetes mellitus (T2DM). Previous studies revealed that plasma concentrations of medium- and long-chain acylcarnitines (by-products of incomplete β-oxidation) are elevated in T2DM and insulin resistance. In a previous study, we reported that mixed d,l isomers of C12- or C14-carnitine induced an NF-κB-luciferase reporter gene in RAW 264.7 cells, suggesting potential activation of proinflammatory pathways. Here, we determined whether the physiologically relevant l-acylcarnitines activate classical proinflammatory signaling pathways and if these outcomes involve pattern recognition receptor (PRR)-associated pathways. Acylcarnitines induced the expression of cyclooxygenase-2 in a chain length-dependent manner in RAW 264.7 cells. l-C14 carnitine (5–25 μM), used as a representative acylcarnitine, stimulated the expression and secretion of proinflammatory cytokines in a dose-dependent manner. Furthermore, l-C14 carnitine induced phosphorylation of JNK and ERK, common downstream components of many proinflammatory signaling pathways including PRRs. Knockdown of MyD88, a key cofactor in PRR signaling and inflammation, blunted the proinflammatory effects of acylcarnitine. While these results point to potential involvement of PRRs, l-C14 carnitine promoted IL-8 secretion from human epithelial cells (HCT-116) lacking Toll-like receptors (TLR)2 and -4, and did not activate reporter constructs in TLR overexpression cell models. Thus, acylcarnitines have the potential to activate inflammation, but the specific molecular and tissue target(s) involved remain to be identified. PMID:24760988

  6. Acoustic transducer

    DOEpatents

    Drumheller, D.S.

    1997-12-30

    An acoustic transducer is described comprising a one-piece hollow mandrel into the outer surface of which is formed a recess with sides perpendicular to the central axis of the mandrel and separated by a first distance and with a bottom parallel to the central axis and within which recess are a plurality of washer-shaped discs of a piezoelectric material and at least one disc of a temperature-compensating material with the discs being captured between the sides of the recess in a pre-stressed interference fit, typically at 2,000 psi of compressive stress. The transducer also includes a power supply and means to connect to a measurement device. The transducer is intended to be used for telemetry between a measurement device located downhole in an oil or gas well and the surface. The transducer is of an construction that is stronger with fewer joints that could leak fluids into the recess holding the piezoelectric elements than is found in previous acoustic transducers. 4 figs.

  7. Acoustic transducer

    DOEpatents

    Drumheller, Douglas S.

    1997-01-01

    An acoustic transducer comprising a one-piece hollow mandrel into the outer surface of which is formed a recess with sides perpendicular to the central axis of the mandrel and separated by a first distance and with a bottom parallel to the central axis and within which recess are a plurality of washer-shaped discs of a piezoelectric material and at least one disc of a temperature-compensating material with the discs being captured between the sides of the recess in a pre-stressed interference fit, typically at 2000 psi of compressive stress. The transducer also includes a power supply and means to connect to a measurement device. The transducer is intended to be used for telemetry between a measurement device located downhole in an oil or gas well and the surface. The transducer is of an construction that is stronger with fewer joints that could leak fluids into the recess holding the piezoelectric elements than is found in previous acoustic transducers.

  8. Ultrasonic transducer

    DOEpatents

    Taylor, Steven C.; Kraft, Nancy C.

    2007-03-13

    An ultrasonic transducer having an effective center frequency of about 42 MHz; a bandwidth of greater than 85% at 6 dB; a spherical focus of at least 0.5 inches in water; an F4 lens; a resolution sufficient to be able to detect and separate a 0.005 inch flat-bottomed hole at 0.005 inches below surface; and a beam size of approximately 0.006–0.008 inches measured off a 11/2 mm ball in water at the transducer's focal point.

  9. The haematopoietic specific signal transducer Vav1 is aberrantly expressed in lung cancer and plays a role in tumourigenesis.

    PubMed

    Lazer, Galit; Idelchuk, Yulia; Schapira, Vered; Pikarsky, Eli; Katzav, Shulamit

    2009-09-01

    Lung cancer is the leading cause of cancer death worldwide. The spectrum of aberrations affecting signalling pathways in lung cancer pathogenesis has not been fully elucidated. Physiological expression of Vav1 is restricted to the haematopoietic system, where its best-known function is as a GDP/GTP nucleotide exchange factor for Rho/RacGTPases, an activity strictly controlled by tyrosine phosphorylation downstream of cell surface receptors. Here we find Vav1 expression in 42% of 78 lung cancer cell lines analysed. Moreover, immunohistochemical analysis of primary human lung cancer tissue samples revealed Vav1 expression in 26/59 malignant samples, including adenocarcinoma, squamous cell carcinoma and bronchioloalveolar carcinoma. Stronger Vav1 staining was associated with larger tumour size. siRNA-mediated knockdown of Vav1 in lung cancer cells reduced proliferation in agar and tumour growth in nude mice, while control siRNA had no effect, suggesting that Vav1 plays a critical role in the tumorigenicity of lung cancer cells. Vav1 is tyrosine-phosphorylated in lung cancer cells following activation by the growth factors EGF and TGFalpha, suggesting its participation in signalling events in these cells. Depletion of Vav1 reduced Rac-GTP activation and decreased expression of TGFalpha, an autocrine growth factor. These data suggest that Vav1 plays a role in the neoplastic process in lung cancer, identifying it as a potential therapeutic target for lung cancer therapy.

  10. A signal transducer and activator of transcription 3·Nuclear Factor κB (Stat3·NFκB) complex is necessary for the expression of fascin in metastatic breast cancer cells in response to interleukin (IL)-6 and tumor necrosis factor (TNF)-α.

    PubMed

    Snyder, Marylynn; Huang, Jianyun; Huang, Xin-Yun; Zhang, J Jillian

    2014-10-24

    IL-6 mediated activation of Stat3 is a major signaling pathway in the process of breast cancer metastasis. One important mechanism by which the IL-6/Stat3 pathway promotes metastasis is through transcriptional regulation of the actin-bundling protein fascin. In this study, we further analyzed the transcriptional regulation of the fascin gene promoter. We show that in addition to IL-6, TNF-α increases Stat3 and NFκB binding to the fascin promoter to induce its expression. We also show that NFκB is required for Stat3 recruitment to the fascin promoter in response to IL-6. Furthermore, Stat3 and NFκB form a protein complex in response to cytokine stimulation. Finally, we demonstrate that an overlapping STAT/NFκB site in a highly conserved 160-bp region of the fascin promoter is sufficient and necessary to induce transcription in response to IL-6 and TNF-α.

  11. Amorphous force transducers in ac applications

    NASA Astrophysics Data System (ADS)

    Meydan, T.; Overshott, K. J.

    1982-11-01

    The high stress sensitivity and high yield stress properties of amorphous ribbon materials make them suitable for magnetic sensors and tranducer applications. Recently the authors have shown that ac systems eliminate the offset voltage and drift problems of the previously published dc systems. Further investigations proved that these transducers could be operated with a linear characteristic up to 1000 g in multiwrap toroidal configurations. The cause of the transducing behavior of the materials was proved to be variation of permeability with stress. It was previously suggested that the optimum operating frequency of the ac transducers is dependent on the physical configuration of the core. Further investigations have shown that the optimum operating frequency is linearly dependent on the amplitude of the input signal to the transducer. Double-core systems have been previously described in the literature where one core acts as a dummy core and the force is applied to the active core. The disadvantage of the double-core system is that aging of the active core changes the performance of the transducer by as much as 10%. A new system will be presented which uses an accurate analog memory to reduce the ageing effect to a fraction of one percent.

  12. Tpl2 and ERK transduce antiproliferative T cell receptor signals and inhibit transformation of chronically stimulated T cells.

    PubMed

    Tsatsanis, Christos; Vaporidi, Katerina; Zacharioudaki, Vassiliki; Androulidaki, Ariadne; Sykulev, Yuri; Margioris, Andrew N; Tsichlis, Philip N

    2008-02-26

    The protein kinase encoded by the Tpl2 protooncogene plays an obligatory role in the transduction of Toll-like receptor and death receptor signals in macrophages, B cells, mouse embryo fibroblasts, and epithelial cells in culture and promotes inflammatory responses in animals. To address its role in T cell activation, we crossed the T cell receptor (TCR) transgene 2C, which recognizes class I MHC presented peptides, into the Tpl2(-/-) genetic background. Surprisingly, the TCR2C(tg/tg)/Tpl2(-/-) mice developed T cell lymphomas with a latency of 4-6 months. The tumor cells were consistently TCR2C(+)CD8(+)CD4(-), suggesting that they were derived either from chronically stimulated mature T cells or from immature single positive (ISP) cells. Further studies showed that the population of CD8(+) ISP cells was not expanded in the thymus of TCR2C(tg/tg)/Tpl2(-/-) mice, making the latter hypothesis unlikely. Mature peripheral T cells of Tpl2(-/-) mice were defective in ERK activation and exhibited enhanced proliferation after TCR stimulation. The same cells were defective in the induction of CTLA4, a negative regulator of the T cell response, which is induced by TCR signals via ERK. These findings suggest that Tpl2 functions normally in a feedback loop that switches off the T cell response to TCR stimulation. As a result, Tpl2, a potent oncogene, functions as a tumor suppressor gene in chronically stimulated T cells.

  13. Signal transducing molecules and glycosyl-phosphatidylinositol-linked proteins form a caveolin-rich insoluble complex in MDCK cells

    PubMed Central

    1993-01-01

    GPI-linked protein molecules become Triton-insoluble during polarized sorting to the apical cell surface of epithelial cells. These insoluble complexes, enriched in cholesterol, glycolipids, and GPI-linked proteins, have been isolated by flotation on sucrose density gradients and are thought to contain the putative GPI-sorting machinery. As the cellular origin and molecular protein components of this complex remain unknown, we have begun to characterize these low-density insoluble complexes isolated from MDCK cells. We find that these complexes, which represent 0.4-0.8% of the plasma membrane, ultrastructurally resemble caveolae and are over 150-fold enriched in a model GPI-anchored protein and caveolin, a caveolar marker protein. However, they exclude many other plasma membrane associated molecules and organelle-specific marker enzymes, suggesting that they represent microdomains of the plasma membrane. In addition to caveolin, these insoluble complexes contain a subset of hydrophobic plasma membrane proteins and cytoplasmically-oriented signaling molecules, including: (a) GTP- binding proteins--both small and heterotrimeric; (b) annex II--an apical calcium-regulated phospholipid binding protein with a demonstrated role in exocytic fusion events; (c) c-Yes--an apically localized member of the Src family of non-receptor type protein- tyrosine kinases; and (d) an unidentified serine-kinase activity. As we demonstrate that caveolin is both a transmembrane molecule and a major phospho-acceptor component of these complexes, we propose that caveolin could function as a transmembrane adaptor molecule that couples luminal GPI-linked proteins with cytoplasmically oriented signaling molecules during GPI-membrane trafficking or GPI-mediated signal transduction events. In addition, our results have implications for understanding v- Src transformation and the actions of cholera and pertussis toxins on hetero-trimeric G proteins. PMID:8349730

  14. Improved Piezoelectric Loudspeakers And Transducers

    NASA Technical Reports Server (NTRS)

    Regan, Curtis Randall; Jalink, Antony; Hellbaum, Richard F.; Rohrbach, Wayne W.

    1995-01-01

    Loudspeakers and related acoustic transducers of improved type feature both light weight and energy efficiency of piezoelectric transducers and mechanical coupling efficiency. Active component of transducer made from wafer of "rainbow" piezoelectric material, ceramic piezoelectric material chemically reduced on one face. Chemical treatment forms wafer into dishlike shallow section of sphere. Both faces then coated with electrically conductive surface layers serving as electrodes. Applications include high-fidelity loudspeakers, and underwater echo ranging devices.

  15. 21 CFR 870.2900 - Patient transducer and electrode cable (including connector).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... transducer and electrode cable (including connector) is an electrical conductor used to transmit signals from, or power or excitation signals to, patient-connected electrodes or transducers. (b)...

  16. PRESSURE TRANSDUCER

    DOEpatents

    Sander, H.H.

    1959-10-01

    A pressure or mechanical force transducer particularly adaptable to miniature telemetering systems is described. Basically the device consists of a transistor located within a magnetic field adapted to change in response to mechanical force. The conduction characteristics of the transistor in turn vary proportionally with changes in the magnetic flux across the transistor such that the output (either frequency of amplitude) of the transistor circuit is proportional to mechanical force or pressure.

  17. Pressure transducer

    DOEpatents

    Anderson, Thomas T.; Roop, Conard J.; Schmidt, Kenneth J.; Gunchin, Elmer R.

    1989-01-01

    A pressure transducer suitable for use in high temperature environments includes two pairs of induction coils, each pair being bifilarly wound together, and each pair of coils connected as opposite arms of a four arm circuit; an electrically conductive target moveably positioned between the coil pairs and connected to a diaphragm such that deflection of the diaphragm causes axial movement of the target and an unbalance in the bridge output.

  18. Pressure transducer

    DOEpatents

    Anderson, T.T.; Roop, C.J.; Schmidt, K.J.; Gunchin, E.R.

    1987-02-13

    A pressure transducer suitable for use in high temperature environments includes two pairs of induction coils, each pair being bifilarly wound together, and each pair of coils connected as opposite arms of a four arm circuit; an electrically conductive target moveably positioned between the coil pairs and connected to a diaphragm such that deflection of the diaphragm causes axial movement of the target and an unbalance in the bridge output. 7 figs.

  19. Ferrofluid Transducer.

    DTIC Science & Technology

    The patent discloses magnetic fluid transducer for producing a low-frequency sound field in a fluid medium. The device comprises a non-magnetic...cylindrical housing with end windows. The housing is surrounded by a magnetic-field-generator means and contains a magnetic fluid within the housing. The...magnetic field penetrates the housing and interacts with the magnetic fluid . A body force is developed within the fluid which produces an internal

  20. Pressure compensated transducer system with constrained diaphragm

    NASA Astrophysics Data System (ADS)

    Percy, Joseph L.

    1992-08-01

    An acoustic source apparatus has an acoustic transducer that is enclosed in a substantially rigid and watertight enclosure to resist the pressure of water on the transducer and to seal the transducer from the water. The enclosure has an opening through which acoustic signals pass and over which is placed a resilient, expandable and substantially water-impermeable diaphragm. A net stiffens and strengthens the diaphragm as well as constrains the diaphragm from overexpansion or from migrating due to buoyancy forces. Pressurized gas, regulated at slightly above ambient pressure, is supplied to the enclosure and the diaphragm to compensate for underwater ambient pressures. Gas pressure regulated at above ambient pressure is used to selectively tune the pressure levels within the enclosure and diaphragm so that diaphragm resonance can be achieved. Controls are used to selectively fill, as well as vent the enclosure and diaphragm during system descent and ascent, respectively. A signal link is used to activate these controls and to provide the driving force for the acoustic transducer.

  1. Nano-optomechanical transducer

    DOEpatents

    Rakich, Peter T; El-Kady, Ihab F; Olsson, Roy H; Su, Mehmet Fatih; Reinke, Charles; Camacho, Ryan; Wang, Zheng; Davids, Paul

    2013-12-03

    A nano-optomechanical transducer provides ultrabroadband coherent optomechanical transduction based on Mach-wave emission that uses enhanced photon-phonon coupling efficiencies by low impedance effective phononic medium, both electrostriction and radiation pressure to boost and tailor optomechanical forces, and highly dispersive electromagnetic modes that amplify both electrostriction and radiation pressure. The optomechanical transducer provides a large operating bandwidth and high efficiency while simultaneously having a small size and minimal power consumption, enabling a host of transformative phonon and signal processing capabilities. These capabilities include optomechanical transduction via pulsed phonon emission and up-conversion, broadband stimulated phonon emission and amplification, picosecond pulsed phonon lasers, broadband phononic modulators, and ultrahigh bandwidth true time delay and signal processing technologies.

  2. Integration of light and metabolic signals for stem cell activation at the shoot apical meristem

    PubMed Central

    Pfeiffer, Anne; Janocha, Denis; Dong, Yihan; Medzihradszky, Anna; Schöne, Stefanie; Daum, Gabor; Suzaki, Takuya; Forner, Joachim; Langenecker, Tobias; Rempel, Eugen; Schmid, Markus; Wirtz, Markus; Hell, Rüdiger; Lohmann, Jan U

    2016-01-01

    A major feature of embryogenesis is the specification of stem cell systems, but in contrast to the situation in most animals, plant stem cells remain quiescent until the postembryonic phase of development. Here, we dissect how light and metabolic signals are integrated to overcome stem cell dormancy at the shoot apical meristem. We show on the one hand that light is able to activate expression of the stem cell inducer WUSCHEL independently of photosynthesis and that this likely involves inter-regional cytokinin signaling. Metabolic signals, on the other hand, are transduced to the meristem through activation of the TARGET OF RAPAMYCIN (TOR) kinase. Surprisingly, TOR is also required for light signal dependent stem cell activation. Thus, the TOR kinase acts as a central integrator of light and metabolic signals and a key regulator of stem cell activation at the shoot apex. DOI: http://dx.doi.org/10.7554/eLife.17023.001 PMID:27400267

  3. Fluid force transducer

    DOEpatents

    Jendrzejczyk, Joseph A.

    1982-01-01

    An electrical fluid force transducer for measuring the magnitude and direction of fluid forces caused by lateral fluid flow, includes a movable sleeve which is deflectable in response to the movement of fluid, and a rod fixed to the sleeve to translate forces applied to the sleeve to strain gauges attached to the rod, the strain gauges being connected in a bridge circuit arrangement enabling generation of a signal output indicative of the magnitude and direction of the force applied to the sleeve.

  4. Inter-costal Liver Ablation Under Real Time MR-Thermometry With Partial Activation Of A HIFU Phased Array Transducer

    NASA Astrophysics Data System (ADS)

    Quesson, Bruno; Merle, Mathilde; Köhler, Max; Mougenot, Charles; Roujol, Sebastien; de Senneville, Baudouin Denis; Moonen, Chrit

    2010-03-01

    HIFU ablation of tumours located inside the liver is hampered by the rib cage, which partially obstructs the beam path and may create adverse effects such as skin burns. This study presents a method for selectively deactivating the transducer elements causing undesired temperature increases near the bones. A manual segmentation of the bones visualized on 3D anatomical MR images acquired prior to sonication was performed to identify the beam obstruction. The resulting mask was projected (ray tracing starting from the focal point) on the transducer and elements with more than 50% obstruction of their active surface were deactivated. The effectiveness of the method for HIFU ablations is demonstrated ex vivo and in vivo in the liver of pigs with real-time MR thermometry, using the proton resonant frequency (PRF) method. For both ex vivo and in vivo experiments, the temperature increase near the bones was significantly reduced when the elements located in front of the ribs were deactivated. The temperature evolution at the focal point were similar, indicative of the absence of loss of heating efficacy when the elements were deactivated. This method is simple, rapid and reliable and allows to perform intercostal MRgHIFU ablation of the liver while sparing the ribs.

  5. Active incremental Support Vector Machine for oil and gas pipeline defects prediction system using long range ultrasonic transducers.

    PubMed

    Akram, Nik Ahmad; Isa, Dino; Rajkumar, Rajprasad; Lee, Lam Hong

    2014-08-01

    This work proposes a long range ultrasonic transducers technique in conjunction with an active incremental Support Vector Machine (SVM) classification approach that is used for real-time pipeline defects prediction and condition monitoring. Oil and gas pipeline defects are detected using various techniques. One of the most prevalent techniques is the use of "smart pigs" to travel along the pipeline and detect defects using various types of sensors such as magnetic sensors and eddy-current sensors. A critical short coming of "smart pigs" is the inability to monitor continuously and predict the onset of defects. The emergence of permanently installed long range ultrasonics transducers systems enable continuous monitoring to be achieved. The needs for and the challenges of the proposed technique are presented. The experimental results show that the proposed technique achieves comparable classification accuracy as when batch training is used, while the computational time is decreased, using 56 feature data points acquired from a lab-scale pipeline defect generating experimental rig.

  6. Cost-effective broad-band electrical impedance spectroscopy measurement circuit and signal analysis for piezo-materials and ultrasound transducers

    PubMed Central

    Lewis, George K; Lewis, George K; Olbricht, William

    2008-01-01

    This paper explains the circuitry and signal processing to perform electrical impedance spectroscopy on piezoelectric materials and ultrasound transducers. Here, we measure and compare the impedance spectra of 2−5 MHz piezoelectrics, but the methodology applies for 700 kHz–20 MHz ultrasonic devices as well. Using a 12 ns wide 5 volt pulsing circuit as an impulse, we determine the electrical impedance curves experimentally using Ohm's law and fast Fourier transform (FFT), and compare results with mathematical models. The method allows for rapid impedance measurement for a range of frequencies using a narrow input pulse, digital oscilloscope and FFT techniques. The technique compares well to current methodologies such as network and impedance analyzers while providing additional versatility in the electrical impedance measurement. The technique is theoretically simple, easy to implement and completed with ordinary laboratory instrumentation for minimal cost. PMID:19081773

  7. Cost-effective broad-band electrical impedance spectroscopy measurement circuit and signal analysis for piezo-materials and ultrasound transducers.

    PubMed

    Lewis, George K; Lewis, George K; Olbricht, William

    2008-10-01

    This paper explains the circuitry and signal processing to perform electrical impedance spectroscopy on piezoelectric materials and ultrasound transducers. Here, we measure and compare the impedance spectra of 2-5 MHz piezoelectrics, but the methodology applies for 700 kHz-20 MHz ultrasonic devices as well. Using a 12 ns wide 5 volt pulsing circuit as an impulse, we determine the electrical impedance curves experimentally using Ohm's law and fast Fourier transform (FFT), and compare results with mathematical models. The method allows for rapid impedance measurement for a range of frequencies using a narrow input pulse, digital oscilloscope and FFT techniques. The technique compares well to current methodologies such as network and impedance analyzers while providing additional versatility in the electrical impedance measurement. The technique is theoretically simple, easy to implement and completed with ordinary laboratory instrumentation for minimal cost.

  8. Multifunctional transducer

    NASA Technical Reports Server (NTRS)

    Feldstein, C.; Lewis, G. W.; Culler, V. H.; Merrbaum, S. (Inventor)

    1981-01-01

    Several parameters of a small region of a muscle tissue or other object, can be simultaneously measured using with minimal traumatizing or damage of the object, a trifunctional transducer which can determine the force applied by a muscle fiber, the displacement of the fiber, and the change in thickness of the fiber. The transducer has three legs with inner ends joined together and outer ends formed to piece the tissue and remain within it. Two of the legs are relatively stiff, to measure force applied by the tissue, and a third leg is relatively flexible to measure displacement of the tissue relative to one or both stiff legs, and with the three legs lying in a common plane so that the force and displacement measurements all relate to the same direction of muscle movements. A flexible loop is attached to one of the stiff legs to measure changes in muscle thickness, with the upper end of the loop fixed to the leg and the lower end of the loop bearing against the surface of the tissue and being free to slide on the leg.

  9. An enzyme logic bioprotonic transducer

    SciTech Connect

    Miyake, Takeo; Keene, Scott; Deng, Yingxin; Rolandi, Marco; Josberger, Erik E.

    2015-01-01

    Translating ionic currents into measureable electronic signals is essential for the integration of bioelectronic devices with biological systems. We demonstrate the use of a Pd/PdH{sub x} electrode as a bioprotonic transducer that connects H{sup +} currents in solution into an electronic signal. This transducer exploits the reversible formation of PdH{sub x} in solution according to PdH↔Pd + H{sup +} + e{sup −}, and the dependence of this formation on solution pH and applied potential. We integrate the protonic transducer with glucose dehydrogenase as an enzymatic AND gate for glucose and NAD{sup +}. PdH{sub x} formation and associated electronic current monitors the output drop in pH, thus transducing a biological function into a measurable electronic output.

  10. An enzyme logic bioprotonic transducer

    NASA Astrophysics Data System (ADS)

    Miyake, Takeo; Josberger, Erik E.; Keene, Scott; Deng, Yingxin; Rolandi, Marco

    2015-01-01

    Translating ionic currents into measureable electronic signals is essential for the integration of bioelectronic devices with biological systems. We demonstrate the use of a Pd/PdHx electrode as a bioprotonic transducer that connects H+ currents in solution into an electronic signal. This transducer exploits the reversible formation of PdHx in solution according to PdH↔Pd + H+ + e-, and the dependence of this formation on solution pH and applied potential. We integrate the protonic transducer with glucose dehydrogenase as an enzymatic and gate for glucose and NAD+. PdHx formation and associated electronic current monitors the output drop in pH, thus transducing a biological function into a measurable electronic output.

  11. Wellbore pressure transducer

    DOEpatents

    Shuck, Lowell Z.

    1979-01-01

    Subterranean earth formations containing energy values are subjected to hydraulic fracturing procedures to enhance the recovery of the energy values. These fractures are induced in the earth formation by pumping liquid into the wellbore penetrating the earth formation until the pressure of the liquid is sufficient to fracture the earth formation adjacent to the wellbore. The present invention is directed to a transducer which is positionable within the wellbore to generate a signal indicative of the fracture initiation useful for providing a timing signal to equipment for seismic mapping of the fracture as it occurs and for providing a measurement of the pressure at which the fracture is initiated.

  12. Molecular Characterization of Striated Muscle-Specific Gab1 Isoform as a Critical Signal Transducer for Neuregulin-1/ErbB Signaling in Cardiomyocytes

    PubMed Central

    Yasui, Taku; Masaki, Takeshi; Arita, Yoh; Ishibashi, Tomohiko; Inagaki, Tadakatsu; Okazawa, Makoto; Oka, Toru; Shioyama, Wataru; Yamauchi-Takihara, Keiko; Komuro, Issei; Sakata, Yasushi; Nakaoka, Yoshikazu

    2016-01-01

    Grb2-associated binder (Gab) docking proteins regulate signals downstream of a variety of growth factors and receptor tyrosine kinases. Neuregulin-1 (NRG-1), a member of epidermal growth factor family, plays a critical role for cardiomyocyte proliferation and prevention of heart failure via ErbB receptors. We previously reported that Gab1 and Gab2 in the myocardium are essential for maintenance of myocardial function in the postnatal heart via transmission of NRG-1/ErbB-signaling through analysis of Gab1/Gab2 cardiomyocyte-specific double knockout mice. In that study, we also found that there is an unknown high-molecular weight (high-MW) Gab1 isoform (120 kDa) expressed exclusively in the heart, in addition to the ubiquitously expressed low-MW (100 kDa) Gab1. However, the high-MW Gab1 has been molecularly ill-defined to date. Here, we identified the high-MW Gab1 as a striated muscle-specific isoform. The high-MW Gab1 has an extra exon encoding 27 amino acid residues between the already-known 3rd and 4th exons of the ubiquitously expressed low-MW Gab1. Expression analysis by RT-PCR and immunostaining with the antibody specific for the high-MW Gab1 demonstrate that the high-MW Gab1 isoform is exclusively expressed in striated muscle including heart and skeletal muscle. The ratio of high-MW Gab1/ total Gab1 mRNAs increased along with heart development. The high-MW Gab1 isoform in heart underwent tyrosine-phosphorylation exclusively after intravenous administration of NRG-1, among several growth factors. Adenovirus-mediated overexpression of the high-MW Gab1 induces more sustained activation of AKT after stimulation with NRG-1 in cardiomyocytes compared with that of β-galactosidase. On the contrary, siRNA-mediated knockdown of the high-MW Gab1 significantly attenuated AKT activation after stimulation with NRG-1 in cardiomyocytes. Taken together, these findings suggest that the striated muscle-specific high-MW isoform of Gab1 has a crucial role for NRG-1/ErbB signaling

  13. Cooling Acoustic Transducer with Heat Pipes

    DTIC Science & Technology

    2009-07-29

    0013] Most transducer packages involve a stack of active ceramic. A Tonpilz transducer 10 in the prior art, as depicted in FIG. 1, consists...or corresponding parts throughout the several views and wherein: [0023] FIG. 1 is a prior art depiction of a Tonpilz transducer design; [0024...Distribution is unlimited Attorney Docket No. 97001 COOLING ACOUSTIC TRANSDUCER WITH HEAT PIPES STATEMENT OF GOVERNMENT INTEREST [0001] The

  14. 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

  15. CDPK Activation in PRR Signaling.

    PubMed

    Seybold, Heike; Boudsocq, Marie; Romeis, Tina

    2017-01-01

    Calcium-dependent protein kinases undergo a rapid biochemical activation in response to an intracellular Ca increase induced by the PRR-dependent perception of a pathogen-related stimulus. Based on SDS gel resolution, the in-gel kinase assay allows the analysis of multiple in vivo protein samples in parallel, combining the advantage of protein separation according to molecular mass with the activity read-out of a protein kinase assay. It thus enables to follow the transient CDPK activation and inactivation in response to in vivo elicitation with a time-wise resolution. In addition, changes of CDPK phosphorylation activity often correlate with slight shifts in the enzyme's apparent molecular mass, indicating posttranslational modifications and a conformational change of the active enzyme compared to its inactive resting form. These band shifts can be detected by a simple immunoblotting to monitor CDPK activation.

  16. The signal transducer NPH3 integrates the phototropin1 photosensor with PIN2-based polar auxin transport in Arabidopsis root phototropism.

    PubMed

    Wan, Yinglang; Jasik, Jan; Wang, Li; Hao, Huaiqing; Volkmann, Dieter; Menzel, Diedrik; Mancuso, Stefano; Baluška, František; Lin, Jinxing

    2012-02-01

    Under blue light (BL) illumination, Arabidopsis thaliana roots grow away from the light source, showing a negative phototropic response. However, the mechanism of root phototropism is still unclear. Using a noninvasive microelectrode system, we showed that the BL sensor phototropin1 (phot1), the signal transducer NONPHOTOTROPIC HYPOCOTYL3 (NPH3), and the auxin efflux transporter PIN2 were essential for BL-induced auxin flux in the root apex transition zone. We also found that PIN2-green fluorescent protein (GFP) localized to vacuole-like compartments (VLCs) in dark-grown root epidermal and cortical cells, and phot1/NPH3 mediated a BL-initiated pathway that caused PIN2 redistribution to the plasma membrane. When dark-grown roots were exposed to brefeldin A (BFA), PIN2-GFP remained in VLCs in darkness, and BL caused PIN2-GFP disappearance from VLCs and induced PIN2-GFP-FM4-64 colocalization within enlarged compartments. In the nph3 mutant, both dark and BL BFA treatments caused the disappearance of PIN2-GFP from VLCs. However, in the phot1 mutant, PIN2-GFP remained within VLCs under both dark and BL BFA treatments, suggesting that phot1 and NPH3 play different roles in PIN2 localization. In conclusion, BL-induced root phototropism is based on the phot1/NPH3 signaling pathway, which stimulates the shootward auxin flux by modifying the subcellular targeting of PIN2 in the root apex transition zone.

  17. Crystal structure of Gib2, a signal-transducing protein scaffold associated with ribosomes in Cryptococcus neoformans.

    PubMed

    Ero, Rya; Dimitrova, Valya Tenusheva; Chen, Yun; Bu, Wenting; Feng, Shu; Liu, Tongbao; Wang, Ping; Xue, Chaoyang; Tan, Suet Mien; Gao, Yong-Gui

    2015-03-03

    The atypical Gβ-like/RACK1 Gib2 protein promotes cAMP signalling that plays a central role in regulating the virulence of Cryptococcus neoformans. Gib2 contains a seven-bladed β transducin structure and is emerging as a scaffold protein interconnecting signalling pathways through interactions with various protein partners. Here, we present the crystal structure of Gib2 at a 2.2-Å resolution. The structure allows us to analyse the association between Gib2 and the ribosome, as well as to identify the Gib2 amino acid residues involved in ribosome binding. Our studies not only suggest that Gib2 has a role in protein translation but also present Gib2 as a physical link at the crossroads of various regulatory pathways important for the growth and virulence of C. neoformans.

  18. Crystal structure of Gib2, a signal-transducing protein scaffold associated with ribosomes in Cryptococcus neoformans

    NASA Astrophysics Data System (ADS)

    Ero, Rya; Dimitrova, Valya Tenusheva; Chen, Yun; Bu, Wenting; Feng, Shu; Liu, Tongbao; Wang, Ping; Xue, Chaoyang; Tan, Suet Mien; Gao, Yong-Gui

    2015-03-01

    The atypical Gβ-like/RACK1 Gib2 protein promotes cAMP signalling that plays a central role in regulating the virulence of Cryptococcus neoformans. Gib2 contains a seven-bladed β transducin structure and is emerging as a scaffold protein interconnecting signalling pathways through interactions with various protein partners. Here, we present the crystal structure of Gib2 at a 2.2-Å resolution. The structure allows us to analyse the association between Gib2 and the ribosome, as well as to identify the Gib2 amino acid residues involved in ribosome binding. Our studies not only suggest that Gib2 has a role in protein translation but also present Gib2 as a physical link at the crossroads of various regulatory pathways important for the growth and virulence of C. neoformans.

  19. Acoustic transducer with damping means

    DOEpatents

    Smith, Richard W.; Adamson, Gerald E.

    1976-11-02

    An ultrasonic transducer specifically suited to high temperature sodium applications is described. A piezoelectric active element is joined to the transducer faceplate by coating the faceplate and juxtaposed active element face with wetting agents specifically compatible with the bonding procedure employed to achieve the joint. The opposite face of the active element is fitted with a backing member designed to assure continued electrical continuity during adverse operating conditions which can result in the fracturing of the active element. The fit is achieved employing a spring-loaded electrode operably arranged to electrically couple the internal transducer components, enclosed in a hermetically sealed housing, to accessory components normally employed in transducer applications. Two alternative backing members are taught for assuring electrical continuity. The first employs a resilient, discrete multipoint contact electrode in electrical communication with the active element face. The second employs a resilient, elastomeric, electrically conductive, damped member in electrical communication with the active element face in a manner to effect ring-down of the transducer. Each embodiment provides continued electrical continuity within the transducer in the event the active element fractures, while the second provides the added benefit of damping.

  20. Involvement of Transducer of Regulated cAMP Response Element-Binding Protein Activity on Corticotropin Releasing Hormone Transcription

    PubMed Central

    Liu, Ying; Coello, Ana G.; Grinevich, Valery; Aguilera, Greti

    2010-01-01

    We have recently shown that phospho-cAMP response element-binding protein (CREB) is essential but not sufficient for activation of CRH transcription, suggesting the requirement of a coactivator. Here, we test the hypothesis that the CREB coactivator, transducer of regulated CREB activity (TORC), is required for activation of CRH transcription, using the cell line 4B and primary cultures of hypothalamic neurons. Immunohistochemistry and Western blot experiments in 4B cells revealed time-dependent nuclear translocation of TORC1,TORC 2, and TORC3 by forskolin [but not by the phorbol ester, phorbol 12-myristate 13-acetate (PMA)] in a concentration-dependent manner. In reporter gene assays, cotransfection of TORC1 or TORC2 potentiated the stimulatory effect of forskolin on CRH promoter activity but had no effect in cells treated with PMA. Knockout of endogenous TORC using silencing RNA markedly inhibited forskolin-activated CRH promoter activity in 4B cells, as well as the induction of endogenous CRH primary transcript by forskolin in primary neuronal cultures. Coimmunoprecipitation and chromatin immunoprecipitation experiments in 4B cells revealed association of CREB and TORC in the nucleus, and recruitment of TORC2 by the CRH promoter, after 20-min incubation with forskolin. These studies demonstrate a correlation between nuclear translocation of TORC with association to the CRH promoter and activation of CRH transcription. The data suggest that TORC is required for transcriptional activation of the CRH promoter by acting as a CREB coactivator. In addition, cytoplasmic retention of TORC during PMA treatment is likely to explain the failure of phorbolesters to activate CRH transcription in spite of efficiently phosphorylating CREB. PMID:20080871

  1. Curved PVDF airborne transducer.

    PubMed

    Wang, H; Toda, M

    1999-01-01

    In the application of airborne ultrasonic ranging measurement, a partially cylindrical (curved) PVDF transducer can effectively couple ultrasound into the air and generate strong sound pressure. Because of its geometrical features, the ultrasound beam angles of a curved PVDF transducer can be unsymmetrical (i.e., broad horizontally and narrow vertically). This feature is desired in some applications. In this work, a curved PVDF air transducer is investigated both theoretically and experimentally. Two resonances were observed in this transducer. They are length extensional mode and flexural bending mode. Surface vibration profiles of these two modes were measured by a laser vibrometer. It was found from the experiment that the surface vibration was not uniform along the curvature direction for both vibration modes. Theoretical calculations based on a model developed in this work confirmed the experimental results. Two displacement peaks were found in the piezoelectric active direction of PVDF film for the length extensional mode; three peaks were found for the flexural bending mode. The observed peak positions were in good agreement with the calculation results. Transient surface displacement measurements revealed that vibration peaks were in phase for the length extensional mode and out of phase for the flexural bending mode. Therefore, the length extensional mode can generate a stronger ultrasound wave than the flexural bending mode. The resonance frequencies and vibration amplitudes of the two modes strongly depend on the structure parameters as well as the material properties. For the transducer design, the theoretical model developed in this work can be used to optimize the ultrasound performance.

  2. ERROR COMPENSATOR FOR A POSITION TRANSDUCER

    DOEpatents

    Fowler, A.H.

    1962-06-12

    A device is designed for eliminating the effect of leadscrew errors in positioning machines in which linear motion of a slide is effected from rotary motion of a leadscrew. This is accomplished by providing a corrector cam mounted on the slide, a cam follower, and a transducer housing rotatable by the follower to compensate for all the reproducible errors in the transducer signal which can be related to the slide position. The transducer has an inner part which is movable with respect to the transducer housing. The transducer inner part is coupled to the means for rotating the leadscrew such that relative movement between this part and its housing will provide an output signal proportional to the position of the slide. The corrector cam and its follower perform the compensation by changing the angular position of the transducer housing by an amount that is a function of the slide position and the error at that position. (AEC)

  3. Supramolecular organizing centers (SMOCs) as signaling machines in innate immune activation.

    PubMed

    Qiao, Qi; Wu, Hao

    2015-11-01

    Innate immunity offers the first line of defense against infections and other types of danger such as tumorigenesis. Its discovery provides tremendous therapeutic opportunities for numerous human diseases. Delving into the structural basis of signal transduction by innate immune receptors, our lab has recently helped to establish the new paradigm in which innate immune receptors transduce ligand-binding signals through formation of higher-order assemblies containing intracellular adapters, signaling enzymes and their substrates. These large signalosome assemblies may be visible under light microscopy as punctate structures in the µm scale, connecting to the underlying molecular structures in the nm scale. They drive proximity-induced enzyme activation, and provide a mechanism for signaling amplification by nucleated polymerization. These supramolecular signaling complexes also open new questions on their cellular organization and mode of regulation, pose challenges to our methodology, and afford valuable implications in drug discovery against these medically important pathways.

  4. Thin film strain transducer

    NASA Technical Reports Server (NTRS)

    Rand, J. L. (Inventor)

    1984-01-01

    A strain transducer system and process for making the same is disclosed. A beryllium copper ring having four strain gages is electrically connected in Wheatstone bridge fashion to the output instrumentation. Tabs are bonded to a balloon or like surface with strain on the surface causing bending of a ring which provides an electrical signal through the gages proportional to the surface strain. A photographic pattern of a one half ring segment as placed on a sheet of beryllium copper for chem-mill etch formation is illustrated.

  5. Lithium tetraborate transducer cuts

    NASA Astrophysics Data System (ADS)

    Kosinski, John; Ballato, Arthur; Lukaszek, Theodore

    1990-03-01

    Lithium tetraborate is a tetragonal material of considerable promise for frequency control and signal processing applications. It exhibits piezoelectric coupling values that fall between those of lithium niobate and quartz, but possesses orientations for which the temperature coefficient of frequency and delay time is zero for bulk and surface acoustic waves. In this report, we discuss the properties of two doubly rotated bulk wave resonator orientations having both first- and second-order temperature coefficients equal to zero. These are suitable for shear and compressional wave transducers in applications where very low temperature sensitivity is required simultaneously with moderately strong piezocoupling coefficients.

  6. Lithium tetraborate transducers

    NASA Astrophysics Data System (ADS)

    Ballato, Arthur; Kosinski, John A.; Lukaszek, Ted J.

    1991-01-01

    Lithium tetraborate is a tetragonal material of considerable promise for frequency control and signal processing applications. It exhibits piezoelectric coupling values that fall between those of lithium niobate and quartz, but possesses orientations for which the temperature coefficient of frequency and delay time is zero for bulk and surface acoustic waves. The properties of two doubly rotated bulk wave resonator orientations having first- and second-order temperature coefficients equal to zero are discussed. These are suitable for shear and compressional wave transducers in applications where very low temperature sensitivity is required simultaneously with moderately strong piezocoupling coefficients.

  7. 25 MHz ultrasonic transducers with lead-free piezoceramic, 1-3 PZT fiber-epoxy composite, and PVDF polymer active elements.

    PubMed

    Jadidian, Bahram; Hagh, Nader Marandian; Winder, Alan A; Safari, Ahmad

    2009-02-01

    This paper presents the fabrication and characterization of single-element ultrasonic transducers whose active elements are made of lead-free piezoceramic, 1-3 PZT/polymer composite and PVDF film. The lead free piezoelectric KNNLT- LS(K(0.44)Na(0.52)Li(0.04))(Nb(0.84)Ta(0.10)S(0.06)b)O(3) powders and ceramics were prepared under controlled humidity and oxygen flow rate during sintering. Due to its moderate longitudinal piezoelectric charge coefficient (175 pC/N) and k(t) of 0.50, the KNN-LT-LS composition may be a good candidate for high frequency transducer applications. PZT fibers with 25 microm diameter formed by the viscose suspension spinning process were incorporated into epoxy to fabricate 1-3 composites with the averaged k(t) = 0.64 and d(33) = 400 pC/N. Using KNN-LS-LT ceramic, 1-3 PZT fiber composite, and PVDF film, 3 different unfocused single element transducers with center frequencies of 25 MHz were fabricated. The acoustic characterization of the transducers demonstrated that wideband and low insertion loss could be obtained employing KNN-LS-LT ceramic. The -6 dB bandwidth and insertion loss were 70% and -21 dB, respectively. In comparison, the insertion loss of the ceramic transducer was much smaller than those made with 1-3 composite and PVDF film. This was attributed to closer electrical impedance match to 50 ohm and higher thickness coupling coefficient of the ceramic transducer.

  8. alpha-latrotoxin action probed with recombinant toxin: receptors recruit alpha-latrotoxin but do not transduce an exocytotic signal.

    PubMed Central

    Ichtchenko, K; Khvotchev, M; Kiyatkin, N; Simpson, L; Sugita, S; Südhof, T C

    1998-01-01

    alpha-Latrotoxin stimulates neurotransmitter release probably by binding to two receptors, CIRL/latrophilin 1 (CL1) and neurexin Ialpha. We have now produced recombinant alpha-latrotoxin (LtxWT) that is as active as native alpha-latrotoxin in triggering synaptic release of glutamate, GABA and norepinephrine. We have also generated three alpha-latrotoxin mutants with substitutions in conserved cysteine residues, and a fourth mutant with a four-residue insertion. All four alpha-latrotoxin mutants were found to be unable to trigger release. Interestingly, the insertion mutant LtxN4C exhibited receptor-binding affinities identical to wild-type LtxWT, bound to CL1 and neurexin Ialpha as well as LtxWT, and similarly stimulated synaptic hydrolysis of phosphatidylinositolphosphates. Therefore, receptor binding by alpha-latrotoxin and stimulation of phospholipase C are insufficient to trigger exocytosis. This conclusion was confirmed in experiments with La3+ and Cd2+. La3+ blocked release triggered by LtxWT, whereas Cd2+ enhanced it. Both cations, however, had no effect on the stimulation by LtxWT of phosphatidylinositolphosphate hydrolysis. Our data show that receptor binding by alpha-latrotoxin and activation of phospholipase C do not by themselves trigger exocytosis. Thus receptors recruit alpha-latrotoxin to its point of action without activating exocytosis. Exocytosis probably requires an additional receptor-independent activity of alpha-latrotoxin that is selectively inhibited by the LtxN4C mutation and by La3+. PMID:9799228

  9. Phosphorylation and activation of a transducible recombinant form of human HSP20 in E. coli

    PubMed Central

    Flynn, Charles R.; Smoke, Christopher C.; Furnish, Elizabeth; Komalavilas, Padmini; Thresher, Jeffrey; Yi, Zhengping; Mandarino, Lawrence J.; Brophy, Colleen M.

    2007-01-01

    Protein based cellular therapeutics have been limited by getting the molecules into cells and the fact that many proteins require post-translational modifications for activation. Protein transduction domains (PTDs), including that from the HIV TAT protein (TAT), are small arginine rich peptides that carry molecules across the cell membrane. We have shown that the heat shock-related protein, HSP20 is a downstream mediator of cyclic nucleotide-dependent relaxation of vascular smooth muscle and is activated by phosphorylation. In this study, we co-expressed in E. coli the cDNAs encoding the catalytic subunit of protein kinase G and a TAT-HSP20 fusion protein composed of the TAT PTD (-YGRKKRRQRRR-) fused to the N-terminus of human HSP20. Immunoblot and HPLC-ESI-MS/MS analysis of the purified TAT-HSP20 demonstrated that it was phosphorylated at serine 40 (equivalent to serine 16 in wild-type human HSP20). This phosphorylated TAT-HSP20 was physiologically active in intact smooth muscles in that it inhibited 5-hydroxytryptamine-induced contractions by 57% ± 4.5. The recombinant phosphorylated protein also led to changes in actin cytoskeletal morphology in 3T3 cells. These results delineate strategies for the expression and activation of therapeutic molecules for intracellular protein based therapeutics. PMID:17084643

  10. Active-passive vibration absorber of beam-cart-seesaw system with piezoelectric transducers

    NASA Astrophysics Data System (ADS)

    Lin, J.; Huang, C. J.; Chang, Julian; Wang, S.-W.

    2010-09-01

    In contrast with fully controllable systems, a super articulated mechanical system (SAMS) is a controlled underactuated mechanical system in which the dimensions of the configuration space exceed the dimensions of the control input space. The objectives of the research are to develop a novel SAMS model which is called beam-cart-seesaw system, and renovate a novel approach for achieving a high performance active-passive piezoelectric vibration absorber for such system. The system consists of two mobile carts, which are coupled via rack and pinion mechanics to two parallel tracks mounted on pneumatic rodless cylinders. One cart carries an elastic beam, and the other cart acts as a counterbalance. One adjustable counterweight mass is also installed underneath the seesaw to serve as a passive damping mechanism to absorb impact and shock energy. The motion and control of a Bernoulli-Euler beam subjected to the modified cart/seesaw system are analyzed first. Moreover, gray relational grade is utilized to investigate the sensitivity of tuning the active proportional-integral-derivative (PID) controller to achieve desired vibration suppression performance. Consequently, it is shown that the active-passive vibration absorber can not only provide passive damping, but can also enhance the active action authority. The proposed software/hardware platform can also be profitable for the standardization of laboratory equipment, as well as for the development of entertainment tools.

  11. Ethanol activates midkine and anaplastic lymphoma kinase signaling in neuroblastoma cells and in the brain.

    PubMed

    He, Donghong; Chen, Hu; Muramatsu, Hisako; Lasek, Amy W

    2015-11-01

    Alcohol engages signaling pathways in the brain. Midkine (MDK) is a neurotrophic factor that is over-expressed in the prefrontal cortex of alcoholics. MDK and one of its receptors, anaplastic lymphoma kinase (ALK), also regulate behavioral responses to ethanol in mice. The goal of this study was to determine whether MDK and ALK expression and signaling are activated by ethanol. We found that ethanol treatment of neuroblastoma cells increased MDK and ALK expression. We also assessed activation of ALK by ethanol in cells and found that ALK and ALK-dependent extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) phosphorylation increased rapidly with ethanol exposure. Similarly, treatment of cells with recombinant MDK protein increased ALK, ERK and STAT3 phosphorylation, suggesting that ethanol may utilize MDK to activate ALK signaling. In support of this, transfection of cells with MDK siRNAs attenuated ALK signaling in response to ethanol. Ethanol also activates ERK signaling in the brain. We found that inhibition of ALK or knockout of MDK attenuated ethanol-induced ERK phosphorylation in mouse amygdala. These results demonstrate that ethanol engages MDK and ALK signaling, which has important consequences for alcohol-induced neurotoxicity and the regulation of behaviors related to alcohol abuse.

  12. CD28 is an Inducible T Cell Surface Antigen that Transduces a Proliferative Signal in CD3(+) Mature Thymocytes

    DTIC Science & Technology

    1990-03-01

    CD3-C28"" l . Despite the 99% of T cells die within the thymus and thus never ability of PMA to induce high density CD28 expres- achieve functional...density of the CD3 surface Ag. In this thymus . few cells stained with anti-CD28 alone, and the intensity of staining In the CD3- cells was less than that...activation alone is sufficient to Induce thymus . We and others (28: present report) have now expression of the CD28 gene. CD28" T cells were cultured with

  13. Structural and Functional Analysis of the Signal-Transducing Linker in the pH-Responsive One-Component System CadC of Escherichia coli.

    PubMed

    Buchner, Sophie; Schlundt, Andreas; Lassak, Jürgen; Sattler, Michael; Jung, Kirsten

    2015-07-31

    The pH-responsive one-component signaling system CadC in Escherichia coli belongs to the family of ToxR-like proteins, whose members share a conserved modular structure, with an N-terminal cytoplasmic winged helix-turn-helix DNA-binding domain being followed by a single transmembrane helix and a C-terminal periplasmic pH-sensing domain. In E. coli CadC, a cytoplasmic linker comprising approximately 50 amino acids is essential for transmission of the signal from the sensor to the DNA-binding domain. However, the mechanism of transduction is poorly understood. Using NMR spectroscopy, we demonstrate here that the linker region is intrinsically disordered in solution. Furthermore, mutational analyses showed that it tolerates a range of amino acid substitutions (altering polarity, rigidity and α-helix-forming propensity), is robust to extension but is sensitive to truncation. Indeed, truncations either reversed the expression profile of the target operon cadBA or decoupled expression from external pH altogether. CadC dimerizes via its periplasmic domain, but light-scattering analysis provided no evidence for dimerization of the isolated DNA-binding domain, with or without the linker region. However, bacterial two-hybrid analysis revealed that CadC forms stable dimers in a stimulus- and linker-dependent manner, interacting only at pH<6.8. Strikingly, a variant with inversed cadBA expression profile, which lacks most of the linker, dimerizes preferentially at higher pH. Thus, we propose that the disordered CadC linker is required for transducing the pH-dependent response of the periplasmic sensor into a structural rearrangement that facilitates dimerization of the cytoplasmic CadC DNA-binding domain.

  14. A Gβγ effector, ElmoE, transduces GPCR signaling to the actin network during chemotaxis.

    PubMed

    Yan, Jianshe; Mihaylov, Vassil; Xu, Xuehua; Brzostowski, Joseph A; Li, Hongyan; Liu, Lunhua; Veenstra, Timothy D; Parent, Carole A; Jin, Tian

    2012-01-17

    Activation of G protein-coupled receptors (GPCRs) leads to the dissociation of heterotrimeric G-proteins into Gα and Gβγ subunits, which go on to regulate various effectors involved in a panoply of cellular responses. During chemotaxis, Gβγ subunits regulate actin assembly and migration, but the protein(s) linking Gβγ to the actin cytoskeleton remains unknown. Here, we identified a Gβγ effector, ElmoE in Dictyostelium, and demonstrated that it is required for GPCR-mediated chemotaxis. Remarkably, ElmoE associates with Gβγ and Dock-like proteins to activate the small GTPase Rac, in a GPCR-dependent manner, and also associates with Arp2/3 complex and F-actin. Thus, ElmoE serves as a link between chemoattractant GPCRs, G-proteins and the actin cytoskeleton. The pathway, consisting of GPCR, Gβγ, Elmo/Dock, Rac, and Arp2/3, spatially guides the growth of dendritic actin networks in pseudopods of eukaryotic cells during chemotaxis.

  15. Scaffolds are 'active' regulators of signaling modules.

    PubMed

    Alexa, Anita; Varga, János; Reményi, Attila

    2010-11-01

    Signaling cascades, in addition to proteins with obvious signaling-relevant activities (e.g. protein kinases or receptors), also employ dedicated 'inactive' proteins whose functions appear to be the organization of the former components into higher order complexes through protein-protein interactions. The core function of signaling adaptors, anchors and scaffolds is the recruitment of proteins into one macromolecular complex. Several recent studies have demonstrated that the recruiter and the recruited molecules mutually influence each other in a scaffolded complex. This yields fundamentally novel properties for the signaling complex as a whole. Because these are not merely additive to the properties of the individual components, scaffolded signaling complexes may behave as functionally distinct modules.

  16. Adaptation of PWAS transducers to acoustic emission sensors

    NASA Astrophysics Data System (ADS)

    Yu, Lingyu; Momeni, Sepandarmaz; Godinez, Valery; Giurgiutiu, Victor

    2011-04-01

    Piezoelectric wafer active sensors (PWAS) are non-intrusive transducers that can convert mechanical energy into electrical energy, and vice versa. They are well known for their dual use as either actuators or sensors. Though PWAS has shown great potential for active sensing, its capability for acoustic emission (AE) detection has not yet been exploited. In the reported work, we have explored the implementation of PWAS transducers for both passive (AE sensors) and active (in-situ ultrasonic transducers) sensing using a single PWAS network. The objective of the work presented in this paper is to adapt PWAS as AE sensors and compare it to the commercially available AE transducers such as PAC R15. An experiment has been designed to show how PWAS can be used for AE detection and the results were compared to a standard AE sensor, PAC R15I. Tests on compact tension specimens have also been conducted to show PWAS capability to pick up AE events during fatigue loading. PWAS field installation technology has been tested with packaging similar to that used for traditional strain gauges. The performance of packaged PWAS has been compared with that of conventional AE transducers R15I. We have found that PWAS not only can detect the presence of AE events but also can provide a wide frequency bandwidth. At this stage, PWAS underperforms the commercial AE sensors. To make PWAS ready for field test, signal to noise ratio needs to be significantly improved.

  17. The Distribution of messenger RNAs Encoding the Three Isoforms of the Transducer Of Regulated CREB Activity (TORC) in The Rat Forebrain

    PubMed Central

    Watts, Alan G.; Sanchez-Watts, Graciela; Liu, Ying; Aguilera, Greti

    2012-01-01

    Increasing evidence indicates that the CREB-dependent transcriptional activation of a number of genes requires the CREB co-activator, transducer of regulated CREB activity (TORC). Because of the central importance of CREB in many brain functions we examined the topographic distribution of TORC1, 2, and 3 mRNAs in specific regions of the rat forebrain. In situ hybridisation (ISH) analysis revealed that TORC1 is the most abundant isoform in most forebrain structures, followed by TORC2 and TORC3. All three TORC isoforms were found in a number of brain nuclei, the ventricular ependyma, and pia mater. While high levels of TORC1 were widely distributed in the forebrain, TORC2 was found in discrete nuclei and TORC3 mostly in the ependyma, and pia mater. The relative expression of TORC isoforms was confirmed by qRT-PCR analysis in the hippocampus and hypothalamus. In the paraventricular nucleus of the hypothalamus, TORC1 and 2 mRNAs were abundant in the parvicellular and magnocellular neuroendocrine compartments, while TORC3 expression was low. All three isoform mRNAs were found elsewhere in the hypothalamus, with the most prominent expression of TORC1 in the ventromedial nucleus, TORC2 in the dorsomedial and arcuate nuclei, TORCs 1 and 2 in the supraoptic, and TORC2 in the suprachiasmatic nuclei. These differential distribution patterns are consistent with complex roles for all three TORC isoforms in diverse brain structures, and provide a foundation for further studies on the mechanisms of CREB/TORC signalling on brain function. PMID:21679259

  18. An alternative mode of CD43 signal transduction activates pro-survival pathways of T lymphocytes.

    PubMed

    Bravo-Adame, Maria Elena; Vera-Estrella, Rosario; Barkla, Bronwyn J; Martínez-Campos, Cecilia; Flores-Alcantar, Angel; Ocelotl-Oviedo, Jose Pablo; Pedraza-Alva, Gustavo; Rosenstein, Yvonne

    2017-01-01

    CD43 is one of the most abundant co-stimulatory molecules on a T-cell surface; it transduces activation signals through its cytoplasmic domain, contributing to modulation of the outcome of T-cell responses. The aim of this study was to uncover new signalling pathways regulated by this sialomucin. Analysis of changes in protein abundance allowed us to identify pyruvate kinase isozyme M2 (PKM2), an enzyme of the glycolytic pathway, as an element potentially participating in the signalling cascade resulting from the engagement of CD43 and the T-cell receptor (TCR). We found that the glycolytic activity of this enzyme was not significantly increased in response to TCR+CD43 co-stimulation, but that PKM2 was tyrosine phosphorylated, suggesting that it was performing moonlight functions. We report that phosphorylation of both Y(105) of PKM2 and of Y(705) of signal transducer and activator of transcription 3 was induced in response to TCR+CD43 co-stimulation, resulting in activation of the mitogen-activated protein kinase kinase 5/extracellular signal-regulated kinase 5 (MEK5/ERK5) pathway. ERK5 and the cAMP response element binding protein (CREB) were activated, and c-Myc and nuclear factor-κB (p65) nuclear localization, as well as Bad phosphorylation, were augmented. Consistent with this, expression of human CD43 in a murine T-cell hybridoma favoured cell survival. Altogether, our data highlight novel signalling pathways for the CD43 molecule in T lymphocytes, and underscore a role for CD43 in promoting cell survival through non-glycolytic functions of metabolic enzymes.

  19. Stabilization of activity and repeated usage of biomaterial during integration with transducers and analysis of irreversible inhibitors

    NASA Astrophysics Data System (ADS)

    Starodub, Nickolaj F.; Torbicz, Wladislaw; Starodub, Valentyna M.; Kanjuk, Mykola I.; Ternovoj, Konstantin S.

    1997-09-01

    At the creation and application of biosensors appeared a number of problems which are: 1) optimization of process connected with stabilization of the structure of biomolecules at the integration with the transducers to preserve their maximum activity and 2) search of approaches to accomplish repeated analysis of substances which are irreversible inhibitors of activity of above mentioned molecules. In this article the results obtained in time of solving of these problems at the usage of enzymes as sensitive bilayer of biosensors are analyzed. For stabilization of the structure of such enzymes as:(beta) - glucose oxydase, urease, cholinesterases during their immobilization the following approaches were examined: 1) usage of one or combination of chemical substances: protein, saccharose, ethylendiamine tetraacetic acid (EDTA), glycerol, ditiotrie-tole (DTT) and specific substrates or their homologues; 2) variation of covalent crosslinking methods including usage of bifunctional reagents in aqueous and vaporous phases; 3) change of time of the influence of this reagent. Optimization of these parameters can allow to preserve about 70-80 percent of initial enzyme activity at the usage of such bifunctional reagent as glutaraldehyde. For repeated analysis of phosphoroganic pesticides and heavy metal ions which are irreversible inhibitors of enzymes the following approaches were applied: 1) treatment of enzyme membrane by special reactivating substances ; 2) usage of easily replaceable enzymatic membrane. It was shown that the last way is more preferable, particularly if alginate gel or nitrocellulose is used for direct enzyme immobilization or preparation of separated biomembrane respectively. Standard deviation of sensor responses for different membrane castings did not exceed 10 percent. At the same time this parameter changed more strongly after even one use of reactivating reagents.

  20. Activation of transgenic estrogen receptor-beta by selected phytoestrogens in a stably transduced rat serotonergic cell line.

    PubMed

    Amer, Dena A M; Kretzschmar, Georg; Müller, Nicole; Stanke, Nicole; Lindemann, Dirk; Vollmer, Günter

    2010-06-01

    Many flavonoids, a major group of phenolic plant-derived secondary metabolites, are known to possess estrogen-like bioactivities. However, little is known about their estrogenic properties in the central nervous system due to the lack of suitable cellular models expressing sufficient amounts of functional estrogen receptor beta (ERbeta). To overcome this deficit, we have created a cellular model, which is serotonergic in origin, to study properties of estrogenic substances by stably transducing RN46A-B14 cells derived from raphe nuclei region of the rat brain with a lentiviral vector encoding a human ERbeta. We clearly showed that the transgenic human ERbeta is a spontaneously expressed and a functional receptor. We have further assessed the estrogenicity of three different isoflavones and four different naringenin-type flavanones in this cell line utilizing a luciferase reporter gene assay. Genistein (GEN), Daidzein (DAI), Equol (EQ), Naringenin (NAR) and 8-prenylnaringenin (8-PN) showed strong estrogenic activity in a concentration-dependent manner as compared to 7-(O-prenyl)naringenin-4'-acetate (7-O-PN) which was only slightly estrogenic and 6-(1,1-dimethylallyl)naringenin (6-DMAN) that neither showed estrogenic nor anti-estrogenic activity in our model. All observed effects could be antagonized by the anti-estrogen fulvestrant. Moreover, co-treatment of cells with 17beta-estradiol (E2) and either GEN or DAI showed a slight additive effect as compared to EQ. On the other hand, 8-PN in addition to 7-O-PN, but not NAR and 6-DMAN, were able to slightly antagonize the responses triggered by E2. Our newly established cellular model may prove to be a useful tool in explicating basic physiological properties of ERbeta in the brain and may help unravel molecular and cellular mechanisms involved in serotonergic mood regulation by estrogen or potential plant-derived secondary metabolites.

  1. Global calcium transducer P-type Ca²⁺-ATPases open new avenues for agriculture by regulating stress signalling.

    PubMed

    Huda, Kazi Md Kamrul; Banu, Mst Sufara Akhter; Tuteja, Renu; Tuteja, Narendra

    2013-08-01

    Food security is in danger under the continuous growing threat of various stresses including climate change and global warming, which ultimately leads to a reduction in crop yields. Calcium plays a very important role in many signal transduction pathways including stress signalling. Different extracellular stimuli trigger increases in cytosolic calcium, which is detrimental to plants. To cope with such stresses, plants need to develop efficient efflux mechanisms to maintain ionic homeostasis. The Ca(2+)-ATPases are members of the P-type ATPase superfamily, which perform many fundamental processes in organisms by actively transporting ions across cellular membranes. In recent years, many studies have revealed that, as well as efflux mechanisms, Ca(2+)-ATPases also play critical roles in sensing calcium fluctuations and relaying downstream signals by activating definitive targets, thus modulating corresponding metabolic pathways. As calcium-activated calmodulin (CaM) is reported to play vital roles in stress tolerance, the presence of a unique CaM-binding site in type IIB Ca(2+)-ATPases indicates their potential role in biotic as well as abiotic stress tolerance. The key roles of Ca(2+)-ATPases in transport systems and stress signalling in cellular homeostasis are addressed in this review. A complete understanding of plant defence mechanisms under stress will allow bioengineering of improved crop plants, which will be crucial for food security currently observed worldwide in the context of global climate changes. Overall, this article covers classification, evolution, structural aspects of Ca(2+)-ATPases, and their emerging roles in plant stress signalling.

  2. Transducer characterization for Vibrothermography

    NASA Astrophysics Data System (ADS)

    Vaddi, Jyani Somayajulu

    Vibrothermography, also known as Sonic IR and Thermosonics, is an NDE technique for finding cracks and flaws based on vibration-induced frictional rubbing of unbonded surfaces. The vibration is usually generated by a piezoelectric stack transducer which transduces electrical energy into large amplitude mechanical vibrations. The purpose of this study is to develop an understanding of the excitation process for vibrothermography so that optimal parameters and transducers for the testing can be selected. The amplitude and impedance transfer characteristics of the transducer system control the vibration of the sample. Within a linear contact (no tip chatter) model, the interaction between the transducer system and the specimen can be characterized using the theory of linear time-invariant (LTI) systems and electro-mechanical Norton equivalence. This work presents quantitative measurements of the performance of piezoelectric stack transducers in a vibrothermography excitation system and the effect of transducer performance and specimen characteristics on the induced vibration in the specimen. We show that with compliant coupling, the specimen vibration is directly proportional to the transducer open circuit velocity and that the system resonances generated because of metal-metal contact of specimen and transducer are disconnected by adding a couplant between specimen and transducer. We then give suggestions for transducer and couplant selection for vibrothermography and suggest methods to flatten the velocity spectrum of the transducer. We extend our analysis to high amplitude transducer behavior and elaborate on the effect of power amplifier saturation on the transducer behavior. The saturation effect negates the effect of adding an external inductance to flatten the transducer velocity spectrum. Finally, preliminary results are reported on the effect of transducer degradation phenomenon.

  3. PRESSURE TRANSDUCER RESEARCH.

    DTIC Science & Technology

    PIEZOELECTRIC TRANSDUCERS, PRESSURE), UNDERGROUND EXPLOSIONS, ELECTRICAL RESISTANCE, SEEBECK EFFECT , PRESSURE GAGES, SHOCK WAVES, STRESSES, COMPUTER PROGRAMMING, NUCLEAR EXPLOSIONS, NUCLEAR RADIATION.

  4. Measurement methods of ultrasonic transducer sensitivity.

    PubMed

    Xiao, Dingguo; Fan, Qiong; Xu, Chunguang; Zhang, Xiuhua

    2016-05-01

    Sensitivity is an important parameter to describe the electro-acoustic energy conversion efficiency of ultrasonic transducer. In this paper, the definition of sensitivity and reciprocity of ultrasonic transducer is studied. The frequency response function of a transducer is the spectrum of its sensitivity, which reflects the response sensitivity of the transducer for input signals at different frequencies. Four common methods which are used to measure the disc-vibrator transducer sensitivity are discussed in current investigation. The reciprocity method and the pulse-echo method are based on the reciprocity of the transducer. In the laser vibrometer method measurement, the normal velocity on the transducer radiating surface is directly measured by a laser vibrometer. In the measurement process of the hydrophone method, a calibrated hydrophone is used to measure the transmitted field. The validity of these methods is checked by experimental test. All of the four methods described are sufficiently accurate for transducer sensitivity measurement, while each method has its advantages and limitations. In practical applications, the appropriate method to measure transducer sensitivity should be selected based on actual conditions.

  5. Transducer applications, a compilation

    NASA Technical Reports Server (NTRS)

    1972-01-01

    The characteristics and applications of transducers are discussed. Subjects presented are: (1) thermal measurements, (2) liquid level and fluid flow measurements, (3) pressure transducers, (4) stress-strain measurements, (5) acceleration and velocity measurements, (6) displacement and angular rotation, and (7) transducer test and calibration methods.

  6. Megahertz tonpilz transducer

    NASA Astrophysics Data System (ADS)

    Van Tol, Dave; Hughes, W. Jack

    1999-06-01

    The tonpilz configuration is applied to a transducer operating in the megahertz frequency range. The KLM model is used to design the transducer using readily available components. The construction techniques used are the same as those applied to standard high frequency transducers. Modeled and measured pulse-echo results display a high level of agreement, but impedance and sensitivity comparisons are less promising.

  7. MECHANISTIC PATHWAYS AND BIOLOGICAL ROLES FOR RECEPTOR-INDEPENDENT ACTIVATORS OF G-PROTEIN SIGNALING

    PubMed Central

    Blumer, Joe B.; Smrcka, Alan V.; Lanier, S.M.

    2007-01-01

    Signal processing via heterotrimeric G-proteins in response to cell surface receptors is a central and much investigated aspect of how cells integrate cellular stimuli to produce coordinated biological responses. The system is a target of numerous therapeutic agents, plays an important role in adaptive processes of organs, and aberrant processing of signals through these transducing systems is a component of various disease states. In addition to GPCR-mediated activation of G-protein signaling, nature has evolved creative ways to manipulate and utilize the Gαβγ heterotrimer or Gα and Gαβγ subunits independent of the cell surface receptor stimuli. In such situations, the G-protein subunits (Gα and Gαβγ) may actually be complexed with alternative binding partners independent of the typical heterotrimeric Gαβγ. Such regulatory accessory proteins include the family of RGS proteins that accelerate the GTPase activity of Gα and various entities that influence nucleotide binding properties and/or subunit interaction. The latter group of proteins includes receptor independent activators of G-protein signaling or AGS proteins that play surprising roles in signal processing. This review provides an overview of our current knowledge regarding AGS proteins. AGS proteins are indicative of a growing number of accessory proteins that influence signal propagation, facilitate cross talk between various types of signaling pathways and provide a platform for diverse functions of both the heterotrimeric Gαβγ and the individual Gα and Gαβγ subunits. PMID:17240454

  8. Electromagnetic acoustic transducer

    DOEpatents

    Alers, George A.; Burns, Jr., Leigh R.; MacLauchlan, Daniel T.

    1988-01-01

    A noncontact ultrasonic transducer for studying the acoustic properties of a metal workpiece includes a generally planar magnetizing coil positioned above the surface of the workpiece, and a generally planar eddy current coil between the magnetizing coil and the workpiece. When a large current is passed through the magnetizing coil, a large magnetic field is applied to the near-surface regions of the workpiece. The eddy current coil can then be operated as a transmitter by passing an alternating current therethrough to excite ultrasonic waves in the surface of the workpiece, or operated as a passive receiver to sense ultrasonic waves in the surface by measuring the output signal. The geometries of the two coils can be varied widely to be effective for different types of ultrasonic waves. The coils are preferably packaged in a housing which does not interfere with their operation, but protects them from a variety of adverse environmental conditions.

  9. The Max b-HLH-LZ can transduce into cells and inhibit c-Myc transcriptional activities.

    PubMed

    Montagne, Martin; Beaudoin, Nicolas; Fortin, David; Lavoie, Christine L; Klinck, Roscoe; Lavigne, Pierre

    2012-01-01

    The inhibition of the functions of c-Myc (endogenous and oncogenic) was recently shown to provide a spectacular therapeutic index in cancer mouse models, with complete tumor regression and minimal side-effects in normal tissues. This was achieved by the systemic and conditional expression of omomyc, the cDNA of a designed mutant of the b-HLH-LZ of c-Myc named Omomyc. The overall mode of action of Omomyc consists in the sequestration of Max and the concomitant competition of the Omomyc/Max complex with the endogenous c-Myc/Max heterodimer. This leads to the inhibition of the transactivation of Myc target genes involved in proliferation and metabolism. While this body of work has provided extraordinary insights to guide the future development of new cancer therapies that target c-Myc, Omomyc itself is not a therapeutic agent. In this context, we sought to exploit the use of a b-HLH-LZ to inhibit c-Myc in a cancer cell line in a more direct fashion. We demonstrate that the b-HLH-LZ domain of Max (Max*) behaves as a bona fide protein transduction domain (PTD) that can efficiently transduce across cellular membrane via through endocytosis and translocate to the nucleus. In addition, we show that the treatment of HeLa cells with Max* leads to a reduction of metabolism and proliferation rate. Accordingly, we observe a decrease of the population of HeLa cells in S phase, an accumulation in G1/G0 and the induction of apoptosis. In agreement with these phenotypic changes, we show by q-RT-PCR that the treatment of HeLa cells with Max* leads to the activation of the transcription c-Myc repressed genes as well as the repression of the expression of c-Myc activated genes. In addition to the novel discovery that the Max b-HLH-LZ is a PTD, our findings open up new avenues and strategies for the direct inhibition of c-Myc with b-HLH-LZ analogs.

  10. Integrated transducer systems

    NASA Astrophysics Data System (ADS)

    Syrzycki, Marek; Parameswaran, M.; Chapman, Glenn H.

    1995-06-01

    In the paper we discuss possible solutions to problems pertaining the implementation of integrated transducer systems, based on examples of WSI image transducers, magnetic field sensors and tactile sensors arrays, as well as arrays of chemical sensors. We also present the issues common to large area transducer arrays, such as building-in redundancy into WSI transducer arrays, and frequency domain circuits for the future communication pathway in integrated transducer systems. Advantages of standard CMOS technology, enhanced with various post-fabrication processes such as silicon micromachining and laser linking, are also stressed.

  11. Trielectrode capacitive pressure transducer

    NASA Technical Reports Server (NTRS)

    Coon, G. W. (Inventor)

    1976-01-01

    A capacitive transducer and circuit especially suited for making measurements in a high-temperature environment are described. The transducer includes two capacitive electrodes and a shield electrode. As the temperature of the transducer rises, the resistance of the insulation between the capacitive electrode decreases and a resistive current attempts to interfere with the capacitive current between the capacitive electrodes. The shield electrode and the circuit coupled there reduce the resistive current in the transducer. A bridge-type circuit coupled to the transducer ignores the resistive current and measures only the capacitive current flowing between the capacitive electrodes.

  12. Instrument For Simulation Of Piezoelectric Transducers

    NASA Technical Reports Server (NTRS)

    Mcnichol, Randal S.

    1996-01-01

    Electronic instrument designed to simulate dynamic output of integrated-circuit piezoelectric acceleration or pressure transducer. Operates in conjunction with external signal-conditioning circuit, generating square-wave signal of known amplitude for use in calibrating signal-conditioning circuit. Instrument also useful as special-purpose square-wave generator in other applications.

  13. Heparin activates Wnt signaling for neuronal morphogenesis.

    PubMed

    Colombres, Marcela; Henríquez, Juan Pablo; Reig, Germán F; Scheu, Jessica; Calderón, Rosario; Alvarez, Alejandra; Brandan, Enrique; Inestrosa, Nibaldo C

    2008-09-01

    Wnt factors are secreted ligands that affect different aspects of the nervous system behavior like neurodevelopment, synaptogenesis and neurodegeneration. In different model systems, Wnt signaling has been demonstrated to be regulated by heparan sulfate proteoglycans (HSPGs). Whether HSPGs modulate Wnt signaling in the context of neuronal behavior is currently unknown. Here we demonstrate that activation of Wnt signaling with the endogenous ligand Wnt-7a results in an increased of neurite outgrowth in the neuroblastoma N2a cell line. Interestingly, heparin induces glycogen synthase kinase-3beta (GSK-3beta) inhibition, beta-catenin stabilization and morphological differentiation in both N2a cells and in rat primary hippocampal neuronal cultures. We also show that heparin modulates Wnt-3a-induced stabilization of beta-catenin. Several extracellular matrix and membrane-attached HSPGs were found to be expressed in both in vitro neuronal models. Changes in the expression of specific HSPGs were observed upon differentiation of N2a cells. Taken together, our findings suggest that HSPGs may modulate canonical Wnt signaling for neuronal morphogenesis.

  14. Mild hyperoxia limits hTR levels, telomerase activity, and telomere length maintenance in hTERT-transduced bone marrow endothelial cells.

    PubMed

    Napier, Christine E; Veas, Laura A; Kan, Chin-Yi; Taylor, Lisa M; Yuan, Jun; Wen, Victoria W; James, Alexander; O'Brien, Tracey A; Lock, Richard B; MacKenzie, Karen L

    2010-10-01

    Reactivation of telomerase in endothelial cells (ECs) may be an effective approach to the treatment of vascular disorders associated with telomere attrition and EC senescence. However, overexpression of human telomerase reverse transcriptase (hTERT) does not prevent net telomere loss in ECs grown in standard culture medium with exposure to atmospheric oxygen (21% O(2)). Since these culture conditions are hyperoxic relative to normal tissue in vivo, where oxygen tension is estimated to be 1%-6%, we examined the effects of reduced exposure to oxidative stress (OS) on telomere length maintenance in hTERT-transduced bone marrow endothelial (BMhTERT) cells. Propagation of BMhTERT cells in the free radical scavenger, tert-butylhydroxylamine (tBN), and/or in 5% O(2) increased telomerase enzyme activity and facilitated telomere length maintenance. The enhancement of telomerase activity correlated with higher levels of the telomerase RNA component (hTR). We also investigated the role of the telomere binding protein, TRF1, in telomere length regulation under alternate OS conditions. Inhibition of TRF1 function had no effect on telomere length in BMhTERT cells grown under standard culture conditions. However, alleviation of OS by growth in tBN plus 5% O(2), elevated hTR levels, enhanced telomerase enzyme activity, and enabled progressive telomere lengthening. The direct impact of hTR levels on telomerase-mediated telomere lengthening was demonstrated by overexpression of hTR. BMhTERT cells transduced with hTR exhibited very high telomerase enzyme activity and underwent dramatic telomere lengthening under standard culture conditions. Overall, these results demonstrate that hTR levels are reduced by mild hyperoxia and limit telomerase-mediated telomere lengthening in hTERT-transduced ECs.

  15. Micromachined silicon seismic transducers

    SciTech Connect

    Barron, C.C.; Fleming, J.G.; Sniegowski, J.J.; Armour, D.L.; Fleming, R.P.

    1995-08-01

    Batch-fabricated silicon seismic transducers could revolutionize the discipline of CTBT monitoring by providing inexpensive, easily depolyable sensor arrays. Although our goal is to fabricate seismic sensors that provide the same performance level as the current state-of-the-art ``macro`` systems, if necessary one could deploy a larger number of these small sensors at closer proximity to the location being monitored in order to compensate for lower performance. We have chosen a modified pendulum design and are manufacturing prototypes in two different silicon micromachining fabrication technologies. The first set of prototypes, fabricated in our advanced surface- micromachining technology, are currently being packaged for testing in servo circuits -- we anticipate that these devices, which have masses in the 1--10 {mu}g range, will resolve sub-mG signals. Concurrently, we are developing a novel ``mold`` micromachining technology that promises to make proof masses in the 1--10 mg range possible -- our calculations indicate that devices made in this new technology will resolve down to at least sub-{mu}G signals, and may even approach to 10{sup {minus}10} G/{radical}Hz acceleration levels found in the low-earth-noise model.

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

    PubMed

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

    2015-06-01

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

  17. A magnetic field measurement technique using a miniature transducer

    NASA Technical Reports Server (NTRS)

    Fales, C. L., Jr.; Breckenridge, R. A.; Debnam, W. J., Jr.

    1974-01-01

    The development, fabrication, and application of a magnetometer are described. The magnetometer has a miniature transducer and is capable of automatic scanning. The magnetometer described here is capable of detecting static magnetic fields as low as 1.6 A/m and its transducer has an active area 0.64 mm by 0.76 mm. Thin and rugged, the transducer uses wire, 0.05 mm in diameter, which is plated with a magnetic film, enabling measurement of transverse magnetic fields as close as 0.08 mm from a surface. The magnetometer, which is simple to operate and has a fast response, uses an inexpensive clip-on milliammeter (commonly found in most laboratories) for driving and processing the electrical signals and readout. A specially designed transducer holding mechanism replaces the XY recorder ink pen; this mechanism provides the basis for an automatic scanning technique. The instrument has been applied to the measurements of magnetic fields arising from remanent magnetization in experimental plated-wire memory planes and regions of magnetic activity in geological rock specimens.

  18. An opening electromagnetic transducer

    NASA Astrophysics Data System (ADS)

    Sun, Yanhua; Kang, Yihua

    2013-12-01

    Tubular solenoids have been widely used without any change since an electrical wire was discovered to create magnetic fields by Hans Christian Oersted in 1820 and thereby the wire was first coiled as a helix into a solenoid coil by William Sturgeon in 1823 and was improved by Joseph Henry in 1829 [see http://www.myetymology.com/encyclopedia/History_of_the_electricity.html; J. M. D. Coey, Magnetism and Magnetic Materials (Cambridge University Press, New York, 2010); and F. Winterberg, Plasma Phys. 8, 541553 (1996)]. A magnetic control method of C-shaped carrying-current wire is proposed, and thereby a new opening electromagnetic transducer evidently differing from the traditional tubular solenoid is created, capable of directly encircling and centering the acted objects in it, bringing about convenient and innovative electromagnetic energy conversion for electromagnetic heating, electromagnetic excitation, physical information capture, and electro-mechanical motion used in science research, industry, and even biomedical activities.

  19. Immunoreceptor tyrosine-based activation motif (ITAM), a unique module linking antigen and Fc receptors to their signaling cascades.

    PubMed

    Isakov, N

    1997-01-01

    Signal transduction by the T cell and B cell antigen receptors and by receptors for a variety of immunoglobulins' Fc region is strictly dependent on a receptor subunit cytoplasmic module termed immunoreceptor tyrosine-based activation motif (ITAM). This module exists in one or more copies in each of the receptor-associated signal-transducing molecules and it possesses two repeats of the consensus sequence Tyr-X-X-Leu/Ile spaced by six to eight amino acids. Receptor engagement is followed by a rapid and transient phosphorylation of tyrosine residues within their ITAMs, thereby creating temporary binding sites for Src homology 2 (SH2)-containing signaling molecules operating downstream of the activated receptor. The purpose of this review is to discuss recent findings on the functional role of ITAMs in antigen and Fc receptor-mediated signal transduction, with a particular emphasis on kinases operating upstream and downstream of the ITAMs.

  20. Crossflow force transducer. [LMFBR

    SciTech Connect

    Mulcahy, T M

    1982-05-01

    A force transducer for measuring lift and drag coefficients for a circular cylinder in turbulent water flow is presented. In addition to describing the actual design and construction of the strain-gauged force- ring based transducer, requirements for obtained valid fluid force test data are discussed, and pertinent flow test experience is related.

  1. Triple-resonant transducers.

    PubMed

    Butler, Stephen C

    2012-06-01

    A detailed analysis is presented of two novel multiple-resonant transducers which produce a wider transmit response than that of a conventional Tonpilz-type transducer. These multi-resonant transducers are Tonpilz-type longitudinal vibrators that produce three coupled resonances and are referred to as triple-resonant transducers (TRTs). One of these designs is a mechanical series arrangement of a tail mass, piezoelectric ceramic stack, central mass, compliant spring, second central mass, second compliant spring, and a piston-radiating head mass. The other TRT design is a mechanical series arrangement of a tail mass, piezoelectric ceramic stack, central mass, compliant spring, and head mass with a quarter-wave matching layer of poly(methyl methacrylate) on the head mass. Several prototype transducer element designs were fabricated that demonstrated proof-of-concept.

  2. 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

  3. Opto-acoustic transducer for medical applications

    DOEpatents

    Benett, William; Celliers, Peter; Da Silva, Luiz; Glinsky, Michael; London, Richard; Maitland, Duncan; Matthews, Dennis; Krulevich, Peter; Lee, Abraham

    2002-01-01

    This invention is an optically activated transducer for generating acoustic vibrations in a biological medium. The transducer is located at the end of a fiber optic which may be located within a catheter. Energy for operating the transducer is provided optically by laser light transmitted through the fiber optic to the transducer. Pulsed laser light is absorbed in the working fluid of the transducer to generate a thermal pressure and consequent adiabatic expansion of the transducer head such that it does work against the ambient medium. The transducer returns to its original state by a process of thermal cooling. The motion of the transducer within the ambient medium couples acoustic energy into the medium. By pulsing the laser at a high repetition rate (which may vary from CW to 100 kHz) an ultrasonic radiation field can be established locally in the medium. This method of producing ultrasonic vibrations can be used in vivo for the treatment of stroke-related conditions in humans, particularly for dissolving thrombus. The catheter may also incorporate anti-thrombolytic drug treatments as an adjunct therapy and it may be operated in conjunction with ultrasonic detection equipment for imaging and feedback control.

  4. Opto-acoustic transducer for medical applications

    DOEpatents

    Benett, W.; Celliers, P.; Da Silva, L.; Glinsky, M.; London, R.; Maitland, D.; Matthews, D.; Krulevich, P.; Lee, A.

    1999-08-31

    This invention is an optically activated transducer for generating acoustic vibrations in a biological medium. The transducer is located at the end of a fiber optic which may be located within a catheter. Energy for operating the transducer is provided optically by laser light transmitted through the fiber optic to the transducer. Pulsed laser light is absorbed in the working fluid of the transducer to generate a thermal pressure and consequent adiabatic expansion of the transducer head such that it does work against the ambient medium. The transducer returns to its original state by a process of thermal cooling. The motion of the transducer within the ambient medium couples acoustic energy into the medium. By pulsing the laser at a high repetition rate (which may vary from CW to 100 kHz) an ultrasonic radiation field can be established locally in the medium. This method of producing ultrasonic vibrations can be used in vivo for the treatment of stroke-related conditions in humans, particularly for dissolving thrombus. The catheter may also incorporate anti-thrombolytic drug treatments as an adjunct therapy and it may be operated in conjunction with ultrasonic detection equipment for imaging and feedback control. 7 figs.

  5. Opto-acoustic transducer for medical applications

    DOEpatents

    Benett, William; Celliers, Peter; Da Silva, Luiz; Glinsky, Michael; London, Richard; Maitland, Duncan; Matthews, Dennis; Krulevich, Peter; Lee, Abraham

    1999-01-01

    This invention is an optically activated transducer for generating acoustic vibrations in a biological medium. The transducer is located at the end of a fiber optic which may be located within a catheter. Energy for operating the transducer is provided optically by laser light transmitted through the fiber optic to the transducer. Pulsed laser light is absorbed in the working fluid of the transducer to generate a thermal pressure and consequent adiabatic expansion of the transducer head such that it does work against the ambient medium. The transducer returns to its original state by a process of thermal cooling. The motion of the transducer within the ambient medium couples acoustic energy into the medium. By pulsing the laser at a high repetition rate (which may vary from CW to 100 kHz) an ultrasonic radiation field can be established locally in the medium. This method of producing ultrasonic vibrations can be used in vivo for the treatment of stroke-related conditions in humans, particularly for dissolving thrombus. The catheter may also incorporate anti-thrombolytic drug treatments as an adjunct therapy and it may be operated in conjunction with ultrasonic detection equipment for imaging and feedback control.

  6. 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

  7. 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

  8. Advanced Geothermal Optical Transducer (AGOT)

    SciTech Connect

    2004-09-01

    -expansion, pressurized tubes machined from a single piece of Ni-spane-C 902 alloy, the instrument is insensitive to temperature- and temperature-gradient-induced errors and, by virtue of its inherent ruggedness, withstands 50G shocks and 100G acceleration. In operation the DPT sensor employs a micro-measurement technology employing the variation of signal amplitude as opposed illuminating and detector fibers deviate from their initial alignment under the influence of pressure forces. Phase I demonstrated that a temperature-sensing column can readily be appended to this device, transforming it into a 250 C-plus pressure-temperature Tool. Phase I testing of an unsophisticated laboratory transducer proved the concept's viability; the test instrument was linear to 5,000 psi (its design limit), exhibited 10 psi sensitivity (0.2 % of full scale), and demonstrated excellent repeatability when cycled from 0 to 5,000 psi and back. The impediments to extrapolating from this device to a working transducer were, therefore, practical engineering problems rather than fundamental limitations imposed by physics. One of these was packaging the sensing unit in a housing sufficiently robust and small enough in diameter for insertion through several kilometers of typical geothermal pipe; another was designing it to carry auxiliary weight great enough to drop the instrument against a large pressure gradient, while at the same time making provision for easy recovery via standard 'fishing' tools should the transducer separate from its cable and fall into the well. An optimal arrangement of optical delivery and signal extraction elements and their configuration was to be selected and suitable signal and data processing hardware and software provided.

  9. Aurora A kinase activates YAP signaling in triple-negative breast cancer.

    PubMed

    Chang, S-S; Yamaguchi, H; Xia, W; Lim, S-O; Khotskaya, Y; Wu, Y; Chang, W-C; Liu, Q; Hung, M-C

    2017-03-02

    The Yes-associated protein (YAP) is an effector that transduces the output of the Hippo pathway to transcriptional modulation. Considering the role of YAP in cancers, this protein has emerged as a key node in malignancy development. In this study, we determined that Aurora A kinase acts as a positive regulator for YAP-mediated transcriptional machinery. Specifically, YAP associates with Aurora A predominantly in the nucleus. Activation of Aurora A can impinge on YAP activity through direct phosphorylation. Moreover, aberrant expression of YAP and Aurora A signaling is highly correlated with triple-negative breast cancer (TNBC). We herein provide evidence to establish the functional relevance of this newly discovered regulatory axis in TNBC.

  10. Signal transducer and oxidative stress mediated modulation of phenylpropanoid pathway to enhance rosmarinic acid biosynthesis in fungi elicited whole plant culture of Solenostemon scutellarioides.

    PubMed

    Dewanjee, Saikat; Gangopadhyay, Moumita; Das, Urmi; Sahu, Ranabir; Samanta, Amalesh; Banerjee, Pamela

    2014-11-01

    This study aimed to improve rosmarinic acid (RA) production in the whole plant culture of Solenostemon scutellarioides through elicitation with phytopathogenic fungi. Amongst selected fungi, Aternaria alternata caused significant elevation (p<0.05-0.01) in RA accumulation (∼1.3-1.6-fold) between 25 and 100 μg l(-1). However, elicitation at the dose of 50 μg l(-1) has been found to be most effective and intracellular RA content reached almost ∼1.6-fold (p<0.01) higher in day 7. Therefore, A. alternata (50 μg l(-1)) was selected for mechanism evaluation. A significant elevation of intercellular jasmonic acid was observed up to day 6 after elicitation with A. alternata (50 μg l(-1)). A significant increase in tissue H2O2 and lipid peroxidation coupled with depletion of antioxidant enzymes superoxide dismutase and catalase indicated augmented oxidative stress associated with biotic interaction. Preceding the elicitor-induced RA accumulation, a notable alteration in the specific activities of biosynthetic enzymes namely PAL and TAT was recorded, while, no significant change in the activities of RAS was observed. HPPR activity was slightly improved in elicited plant. Therefore, it could be concluded that A. alternata elicited the biosynthesis of rosmarinic acid via signal transduction through jasmonic acid coupled with elicitor induced oxidative stress and associated mechanism.

  11. Fundamentals of heat measurement. [heat flux transducers

    NASA Technical Reports Server (NTRS)

    Gerashchenko, O. A.

    1979-01-01

    Various methods and devices for obtaining experimental data on heat flux density over wide ranges of temperature and pressure are examined. Laboratory tests and device fabrication details are supplemented by theoretical analyses of heat-conduction and thermoelectric effects, providing design guidelines and information relevant to further research and development. A theory defining the measure of correspondence between transducer signal and the measured heat flux is established for individual (isolated) heat flux transducers subject to space and time-dependent loading. An analysis of the properties of stacked (series-connected) transducers of various types (sandwich-type, plane, and spiral) is used to derive a similarity theory providing general governing relationships. The transducers examined are used in 36 types of derivative devices involving direct heat loss measurements, heat conduction studies, radiation pyrometry, calorimetry in medicine and industry and nuclear reactor dosimetry.

  12. Micromachined Tunneling Displacement Transducers for Physical Sensors

    NASA Technical Reports Server (NTRS)

    Kenny, T. W.; Kaiser, W. J.; Podosek, J. A.; Rockstad, H. K.; Reynolds, J. K.; Vote, E. C.

    1993-01-01

    We have designed and constructed a series of tunneling sensors which take advantage of the extreme position sensitivity of electron tunneling. In these sensors, a tunneling displacement transducer, based on scanning tunneling microscopy principles, is used to detect the signal-induced motion of a sensor element. Through the use of high-resonant frequency mechanical elements for the transducer, sensors may be constructed which offer wide bandwidth, and are robust and easily operated. Silicon micromachining may be used to fabricate the transducer elements, allowing integration of sensor and control electronics. Examples of tunneling accelerometers and infrared detectors will be discussed. In each case, the use of the tunneling transducer allows miniaturization of the sensor as well as enhancement of the sensor performance.

  13. AUTOMATIC CALIBRATING SYSTEM FOR PRESSURE TRANSDUCERS

    DOEpatents

    Amonette, E.L.; Rodgers, G.W.

    1958-01-01

    An automatic system for calibrating a number of pressure transducers is described. The disclosed embodiment of the invention uses a mercurial manometer to measure the air pressure applied to the transducer. A servo system follows the top of the mercury column as the pressure is changed and operates an analog- to-digital converter This converter furnishes electrical pulses, each representing an increment of pressure change, to a reversible counterThe transducer furnishes a signal at each calibration point, causing an electric typewriter and a card-punch machine to record the pressure at the instant as indicated by the counter. Another counter keeps track of the calibration points so that a number identifying each point is recorded with the corresponding pressure. A special relay control system controls the pressure trend and programs the sequential calibration of several transducers.

  14. Spikelet-specific variation in ethylene production and constitutive expression of ethylene receptors and signal transducers during grain filling of compact- and lax-panicle rice (Oryza sativa) cultivars.

    PubMed

    Sekhar, Sudhanshu; Panda, Binay B; Mohapatra, Trupti; Das, Kaushik; Shaw, Birendra P; Kariali, Ekamber; Mohapatra, Pravat K

    2015-05-01

    Grain yields in modern super rice cultivars do not always meet the expectations because many spikelets are located on secondary branches in closely packed homogeneous distribution in these plants, and they do not fill properly. The factors limiting grain filling of such spikelets, especially in the lower panicle branches, are elusive. Two long-duration rice cultivars differing in panicle density, Mahalaxmi (compact) and Upahar (lax), were cultivated in an open field plot. Grain filling, ethylene production and constitutive expression of ethylene receptors and ethylene signal transducers in apical and basal spikelets of the panicle were compared during the early post-anthesis stage, which is the most critical period for grain development. In another experiment, a similar assessment was made for the medium-duration cultivars compact-panicle OR-1918 and lax-panicle Lalat. Grain weight of the apical spikelets was always higher than that of the basal spikelets. This gradient of grain weight was wide in the compact-panicle cultivars and narrow in the lax-panicle cultivars. Compared to apical spikelets, the basal spikelets produced more ethylene at anthesis and retained the capacity for post-anthesis expression of ethylene receptors and ethylene signal transducers longer. High ethylene production enhanced the expression of the RSR1 gene, but reduced expression of the GBSS1 gene. Ethylene inhibited the partitioning of assimilates of developing grains resulting in low starch biosynthesis and high accumulation of soluble carbohydrates. It is concluded that an increase in grain/spikelet density in rice panicles reduces apical dominance to the detriment of grain filling by production of ethylene and/or enhanced perception of the ethylene signal. Ethylene could be a second messenger for apical dominance in grain filling. The manipulation of the ethylene signal would possibly improve rice grain yield.

  15. Compact Transducers and Arrays

    DTIC Science & Technology

    2005-05-01

    Soc. Am., 104, pp.64-71 44 25.Decarpigny, J.N., J.C. Debus, B. Tocquet & D. Boucher. 1985. "In-Air Analysis Of Piezoelectric Tonpilz Transducers In A... Transducers and Arrays Final Report May 2005 Contacts: Dr. Robert E. Newnham The Pennsylvania State University, 251 MRL, University Park, PA 16802 phone...814) 865-1612 fax: (814) 865-2326 email: ....c xx.....i.i.....ht.. .u a.p.u..c.e.du. Dr. Richard J. Meyer, Jr. Systems Engineering ( Transducers ), ARL

  16. Volumetric photoacoustic endoscopy of upper gastrointestinal tract: ultrasonic transducer technology development

    NASA Astrophysics Data System (ADS)

    Yang, Joon-Mo; Favazza, Christopher; Chen, Ruimin; Maslov, Konstantin; Cai, Xin; Zhou, Qifa; Shung, K. Kirk; Wang, Lihong V.

    2011-03-01

    We have successfully implemented a focused ultrasonic transducer for photoacoustic endoscopy. The photoacoustic endoscopic probe's ultrasound transducer determines the lateral resolution of the system. By using a focused ultrasonic transducer, we significantly improved the endoscope's spatial resolution and signal-to-noise ratio. This paper describes the technical details of the ultrasonic transducer incorporated into the photoacoustic endoscopic probe and the experimental results from which the transducer's resolution is quantified and the image improvement is validated.

  17. Mechano-electric optoisolator transducer with hysteresis

    NASA Astrophysics Data System (ADS)

    Ciuruş, I. M.; Dimian, M.; Graur, A.

    2011-01-01

    This article presents a theoretical and experimental study of designing a mechano-electric optoisolator transducer with hysteresis. Our research is centred upon designing transducers on the basis of optical sensors, as photoelectric conversions eliminate the influence of electromagnetic disturbances. Conversion of the rotation/translation motions into electric signals is performed with the help of a LED-photoresistor Polaroid optocoupler. The driver of the optocoupler's transmitter module is an independent current source. The signal conditioning circuit is a Schmitt trigger circuit. The device is designed to be applied in the field of automation and mechatronics.

  18. The simulation model of planar electrochemical transducer

    NASA Astrophysics Data System (ADS)

    Zhevnenko, D. A.; Vergeles, S. S.; Krishtop, T. V.; Tereshonok, D. V.; Gornev, E. S.; Krishtop, V. G.

    2016-12-01

    Planar electrochemical systems are very perspective to build modern motion and pressure sensors. Planar microelectronic technology is successfully used for electrochemical transducer of motion parameters. These systems are characterized by an exceptionally high sensitivity towards mechanic exposure due to high rate of conversion of the mechanic signal to electric current. In this work, we have developed a mathematical model of this planar electrochemical system, which detects the mechanical signals. We simulate the processes of mass and charge transfer in planar electrochemical transducer and calculated its transfer function with different geometrical parameters of the system.

  19. Digital magnetic temperature transducer.

    NASA Technical Reports Server (NTRS)

    Tchernev, D. I.; Collier, T. E.

    1971-01-01

    A new digital magnetic temperature transducer is reported. The device utilizes the discontinuous behavior of the initial permeability with temperature at the Curie temperature of some magnetic materials. Since the Curie temperature is determined by the chemical and crystallographic composition of the particular material only, the transducer requires no calibration and has extremely high stability and reproducibility with time. The output of the transducer is inherently digital and, therefore, is directly compatible with the digital information processing and control without A/D conversion. The temperature-sensing portion of the transducer consists only of magnetic cores and wire and, therefore, has extremely high reliability, is shock and radiation insensitive, small, and virtually indestructible.

  20. Improved myocardium transducer

    NASA Technical Reports Server (NTRS)

    Culler, V. H.; Feldstein, C.; Lewis, G. W.

    1979-01-01

    Method of implanting myocardium transducer uses special indented pins that are caught and securely held by epicardial fibers. Pins are small enough to cause minimum of trauma to myocardium during implantation or removal.

  1. Multilayer ionic polymer transducer

    NASA Astrophysics Data System (ADS)

    Akle, Barbar J.; Leo, Donald J.

    2003-07-01

    A transducer consisting of multiple layers of ionic polymer material is developed for applications in sensing, actuation, and control. The transducer consists of two to four individual layers each approximately 200 microns thick. The transducers are connected in parallel to minimize the electric field requirements for actuation. The tradeoff in deflection and force can be controlled by controlling the mechanical constraint at the interface. Packaging the transducer in an outer coating produces a hard constraint between layers and reduces the deflection with a force that increases linearly with the number of layers. This configuration also increases the bandwidth of the transducer. Removing the outer packaging produces an actuator that maintains the deflection of a single layer but has an increased force output. This is obtained by allowing the layers to slide relative to one another during bending. Experiments on transducers with one to three layers are performed and the results are compared to Newbury"s equivalent circuit model, which was modified to accommodate the multilayer polymers. The modification was performed on four different boundary conditions, two electrical the series and the parallel connection, and two mechanical the zero interfacial friction and the zero slip on the interface. Results demonstrate that the largest obstacle to obtaining good performance is water transport between the individual layers. Water crossover produces a near short circuit electrical condition and produces feedthrough between actuation layers and sensing layers. Electrical feedthrough due to water crossover eliminates the ability to produce a transducer that has combined sensing and actuation properties. Eliminating water crossover through good insulation enables the development of a small (5 mm x 30 mm) transducer that has sensing and actuation bandwidth on the order of 100 Hz.

  2. Effects of Transducer Installation on Unsteady Pressure Measurements on Oscillating Blades

    NASA Technical Reports Server (NTRS)

    Lepicovsky, Jan

    2006-01-01

    Unsteady pressures were measured above the suction side of a blade that was oscillated to simulate blade stall flutter. Measurements were made at blade oscillation frequencies up to 500 Hz. Two types of miniature pressure transducers were used: surface-mounted flat custom-made, and conventional miniature, body-mounted transducers. The signals of the surface-mounted transducers are significantly affected by blade acceleration, whereas the signals of body-mounted transducers are practically free of this distortion. A procedure was introduced to correct the signals of surface-mounted transducers to rectify the signal distortion due to blade acceleration. The signals from body-mounted transducers, and corrected signals from surface-mounted transducers represent true unsteady pressure signals on the surface of a blade subjected to forced oscillations. However, the use of body-mounted conventional transducers is preferred for the following reasons: no signal corrections are needed for blade acceleration, the conventional transducers are noticeably less expensive than custom-made flat transducers, the survival rate of body-mounted transducers is much higher, and finally installation of body-mounted transducers does not disturb the blade surface of interest.

  3. Ca²⁺ signal-induced cardiomyocyte hypertrophy through activation of myocardin.

    PubMed

    Li, Man; Wang, Nan; Gong, Hui-Qin; Li, Wei-Zong; Liao, Xing-Hua; Yang, Xiao-Long; He, Hong-Peng; Cao, Dong-Sun; Zhang, Tong-Cun

    2015-02-15

    Hypertrophic growth of cardiomyocytes in response to pressure overload is an important stage during the development of many cardiac diseases. Ca(2+) overload as well as subsequent activation of Ca(2+) signaling pathways has been reported to induce cardiac hypertrophy. Myocardin, a transcription cofactor of serum response factor (SRF), is a key transducer of hypertrophic signals. However, the direct role of myocardin in Ca(2+) signal-induced cardiomyocyte hypertrophy has not been explained clearly. In the present study, we discovered that embryonic rat heart-derived H9c2 cells responded to the stimulation of calcium ionophore A23187 with a cell surface area enlargement and an increased expression of cardiac hypertrophy marker genes. Increased Ca(2+) also induces an organization of sarcomeres in neonatal rat cardiomyocytes, as revealed by α-actinin staining. Increased Ca(2+) could upregulate the expression of myocardin. Knockdown of myocardin by shRNA attenuates hypertrophic responses triggered by increased intracellular Ca(2+), suggesting that Ca(2+) signals induce cardiomyocyte hypertrophy partly through activation of myocardin. Furthermore, A23187 treatment directly activates myocardin promoter, chelation of Ca(2+) by EGTA inhibits this activation and knockdown of myocardin expression using shRNA also abrogates A23187-induced ANF and SK-α-actin promoter activity. CSA (calcineurin inhibitor) and KN93 (CaMKII inhibitor) inhibit A23187-induced the increase in myocardin expression. These results suggest that myocardin plays a critical role in Ca(2+) signal-induced cardiomyocyte hypertrophy, which may serve as a novel mechanism that is important for cardiac hypertrophy.

  4. Activation of the cell integrity pathway is channelled through diverse signalling elements in fission yeast.

    PubMed

    Barba, Gregorio; Soto, Teresa; Madrid, Marisa; Núñez, Andrés; Vicente, Jeronima; Gacto, Mariano; Cansado, José

    2008-04-01

    MAPK Pmk1p is the central element of a cascade involved in the maintenance of cell integrity and other functions in Schizosaccharomyces pombe. Pmk1p becomes activated by multiple stressing situations and also during cell separation. GTPase Rho2p acts upstream of the protein kinase C homolog Pck2p to activate the Pmk1 signalling pathway through direct interaction with MAPKKK Mkh1p. In this work we analyzed the functional significance of both Rho2p and Pck2p in the transduction of various stress signals by the cell integrity pathway. The results indicate that basal Pmk1p activity can be positively regulated by alternative mechanisms which are independent on the control by Rho2p and/or Pck2p. Unexpectedly, Pck1p, another protein kinase C homolog, negatively modulates Pmk1p basal activity by an unknown mechanism. Moreover, different elements appear to regulate the stress-induced activation of Pmk1p depending on the nature of the triggering stimuli. Whereas Pmk1p activation induced by hyper- or hypotonic stresses is channeled through Rho2p-Pck2p, other stressors, like glucose deprivation or cell wall disturbance, are transduced via other pathways in addition to that of Rho2p-Pck2p. On the contrary, Pmk1p activation observed during cell separation or after treatment with hydrogen peroxide does not involve Rho2p-Pck2p. Finally, Pck2p function is critical to maintain a Pmk1p basal activity that allows Pmk1p activation induced by heat stress. These data demonstrate the existence of a complex signalling network modulating Pmk1p activation in response to a variety of stresses in fission yeast.

  5. Design considerations for piezoelectric polymer ultrasound transducers.

    PubMed

    Brown, L F

    2000-01-01

    Much work has been published on the design of ultrasound transducers using piezoelectric ceramics, but a great deal of this work does not apply when using the piezoelectric polymers because of their unique electrical and mechanical properties. The purpose of this paper is to review and present new insight into seven important considerations for the design of active piezoelectric polymer ultrasound transducers: piezoelectric polymer materials selection, transducer construction and packaging requirements, materials characterization and modeling, film thickness and active area design, electroding selection, backing material design, and front protection/matching layer design. Besides reviewing these design considerations, this paper also presents new insight into the design of active piezoelectric polymer ultrasonic transducers. The design and fabrication of an immersible ultrasonic transducer, which has no adhesive layer between the active element and backing layer, is included. The transducer features direct deposition of poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE)] copolymer onto an insulated aluminum backing substrate. Pulse-echo tests indicated a minimum insertion loss of 37 dB and -6 dB bandwidth of 9.8 to 22 MHz (71%). The use of polymer wear-protection/quarter-wave matching layers is also discussed. Test results on a P(VDF-TrFE) transducer showed that a Mylar/sup TM/ front layer provided a slight increase in pulse-echo amplitude of 15% (or 1.2 dB) and an increase in -6 dB pulse-echo fractional bandwidth from 86 to 95%. Theoretical derivations are reported for optimizing the active area of the piezoelectric polymer element for maximum power transfer at resonance. These derivations are extended to the special case for a low profile (i.e., thin) shielded transducer. A method for modeling the non-linear loading effects of a commercial pulser-receiver is also included.

  6. Resonant capacitive MEMS acoustic emission transducers

    NASA Astrophysics Data System (ADS)

    Ozevin, D.; Greve, D. W.; Oppenheim, I. J.; Pessiki, S. P.

    2006-12-01

    We describe resonant capacitive MEMS transducers developed for use as acoustic emission (AE) detectors, fabricated in the commercial three-layer polysilicon surface micromachining process (MUMPs). The 1 cm square device contains six independent transducers in the frequency range between 100 and 500 kHz, and a seventh transducer at 1 MHz. Each transducer is a parallel plate capacitor with one plate free to vibrate, thereby causing a capacitance change which creates an output signal in the form of a current under a dc bias voltage. With the geometric proportions we employed, each transducer responds with two distinct resonant frequencies. In our design the etch hole spacing was chosen to limit squeeze film damping and thereby produce an underdamped vibration when operated at atmospheric pressure. Characterization experiments obtained by capacitance and admittance measurements are presented, and transducer responses to physically simulated AE source are discussed. Finally, we report our use of the device to detect acoustic emissions associated with crack initiation and growth in weld metal.

  7. Acoustooptic pulse-echo transducer system

    NASA Technical Reports Server (NTRS)

    Claus, R. O.; Wade, J. C.

    1983-01-01

    A pulse-echo transducer system which uses an ultrasonic generating element and an optical detection technique is described. The transmitting transducer consists of a concentric ring electrode pattern deposited on a circular, X-cut quartz substrate with a circular hole in the center. The rings are independently pulsed with a sequence high voltage signals phased in such a way that the ultrasonic waves generated by the separate rings superimpose to produce a composite field which is focused at a controllable distance below the surface of the specimen. The amplitude of the field reflected from this focus position is determined by the local reflection coefficient of the medium at the effective focal point. By processing the signals received for a range of ultrasonic transducer array focal lengths, the system can be used to locate and size anomalies within solids and liquids. Applications in both nondestructive evaluation and biomedical scanning are suggested.

  8. Signal Destruction Tunes the Zone of Activation in Spatially Distributed Signaling Networks.

    PubMed

    Silva, Kalinga Pavan; Chellamuthu, Prithiviraj; Boedicker, James Q

    2017-03-14

    Diverse microbial communities coordinate group behaviors through signal exchange, such as the exchange of acyl-homoserine lactones (AHLs) by Gram-negative bacteria. Cellular communication is prone to interference by neighboring microbes. One mechanism of interference is signal destruction through the production of an enzyme that cleaves the signaling molecule. Here we examine the ability of one such interference enzyme, AiiA, to modulate signal propagation in a spatially distributed system of bacteria. We have developed an experimental assay to measure signal transduction and implement a theoretical model of signaling dynamics to predict how the system responds to interference. We show that titration of an interfering strain into a signaling network tunes the spatial range of activation over the centimeter length scale, quantifying the robustness of the signaling network to signal destruction and demonstrating the ability to program systems-level responses of spatially heterogeneous cellular networks.

  9. Stat3 signaling is present and active during development of the central nervous system and eye of vertebrates.

    PubMed

    Yan, Ye; Bian, Wei; Xie, Zhiqin; Cao, Xinmin; Le Roux, Isabelle; Guillemot, Francois; Jing, Naihe

    2004-10-01

    Stat3, a member of the signal transducer and activator of transcription (STAT) family, plays a central role in mediating cell growth, differentiation, and survival signals. In this report, we show that Stat3 immunoreactivity was localized to specific regions in the developing mouse brain, neural tube, and eye from embryonic day 10.5 to postnatal day 0. The active form of Stat3 protein, which is phosphorylated on tyrosine 705 (pYStat3), was also found in the developing neural tube with more restricted distribution. An in ovo chick embryo electroporation assay showed that the endogenous chick Stat3 could drive consensus sis-inducible element-directed reporter gene expression. These results demonstrate that the active Stat3 protein is present and might play a role during the development of the central nervous system and eye.

  10. 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.

  11. STAT1 signaling within macrophages is required for antifungal activity against Cryptococcus neoformans.

    PubMed

    Leopold Wager, Chrissy M; Hole, Camaron R; Wozniak, Karen L; Olszewski, Michal A; Mueller, Mathias; Wormley, Floyd L

    2015-12-01

    Cryptococcus neoformans, the predominant etiological agent of cryptococcosis, is an opportunistic fungal pathogen that primarily affects AIDS patients and patients undergoing immunosuppressive therapy. In immunocompromised individuals, C. neoformans can lead to life-threatening meningoencephalitis. Studies using a virulent strain of C. neoformans engineered to produce gamma interferon (IFN-γ), denoted H99γ, demonstrated that protection against pulmonary C. neoformans infection is associated with the generation of a T helper 1 (Th1)-type immune response and signal transducer and activator of transcription 1 (STAT1)-mediated classical (M1) macrophage activation. However, the critical mechanism by which M1 macrophages mediate their anti-C. neoformans activity remains unknown. The current studies demonstrate that infection with C. neoformans strain H99γ in mice with macrophage-specific STAT1 ablation resulted in severely increased inflammation of the pulmonary tissue, a dysregulated Th1/Th2-type immune response, increased fungal burden, deficient M1 macrophage activation, and loss of protection. STAT1-deficient macrophages produced significantly less nitric oxide (NO) than STAT1-sufficient macrophages, correlating with an inability to control intracellular cryptococcal proliferation, even in the presence of reactive oxygen species (ROS). Furthermore, macrophages from inducible nitric oxide synthase knockout mice, which had intact ROS production, were deficient in anticryptococcal activity. These data indicate that STAT1 activation within macrophages is required for M1 macrophage activation and anti-C. neoformans activity via the production of NO.

  12. The Neurospora Transcription Factor ADV-1 Transduces Light Signals and Temporal Information to Control Rhythmic Expression of Genes Involved in Cell Fusion

    PubMed Central

    Dekhang, Rigzin; Wu, Cheng; Smith, Kristina M.; Lamb, Teresa M.; Peterson, Matthew; Bredeweg, Erin L.; Ibarra, Oneida; Emerson, Jillian M.; Karunarathna, Nirmala; Lyubetskaya, Anna; Azizi, Elham; Hurley, Jennifer M.; Dunlap, Jay C.; Galagan, James E.; Freitag, Michael; Sachs, Matthew S.; Bell-Pedersen, Deborah

    2016-01-01

    Light and the circadian clock have a profound effect on the biology of organisms through the regulation of large sets of genes. Toward understanding how light and the circadian clock regulate gene expression, we used genome-wide approaches to identify the direct and indirect targets of the light-responsive and clock-controlled transcription factor ADV-1 in Neurospora crassa. A large proportion of ADV-1 targets were found to be light- and/or clock-controlled, and enriched for genes involved in development, metabolism, cell growth, and cell fusion. We show that ADV-1 is necessary for transducing light and/or temporal information to its immediate downstream targets, including controlling rhythms in genes critical to somatic cell fusion. However, while ADV-1 targets are altered in predictable ways in Δadv-1 cells in response to light, this is not always the case for rhythmic target gene expression. These data suggest that a complex regulatory network downstream of ADV-1 functions to generate distinct temporal dynamics of target gene expression relative to the central clock mechanism. PMID:27856696

  13. Support-vector-machines-based multidimensional signal classification for fetal activity characterization

    NASA Astrophysics Data System (ADS)

    Ribes, S.; Voicu, I.; Girault, J. M.; Fournier, M.; Perrotin, F.; Tranquart, F.; Kouamé, D.

    2011-03-01

    Electronic fetal monitoring may be required during the whole pregnancy to closely monitor specific fetal and maternal disorders. Currently used methods suffer from many limitations and are not sufficient to evaluate fetal asphyxia. Fetal activity parameters such as movements, heart rate and associated parameters are essential indicators of the fetus well being, and no current device gives a simultaneous and sufficient estimation of all these parameters to evaluate the fetus well-being. We built for this purpose, a multi-transducer-multi-gate Doppler system and developed dedicated signal processing techniques for fetal activity parameter extraction in order to investigate fetus's asphyxia or well-being through fetal activity parameters. To reach this goal, this paper shows preliminary feasibility of separating normal and compromised fetuses using our system. To do so, data set consisting of two groups of fetal signals (normal and compromised) has been established and provided by physicians. From estimated parameters an instantaneous Manning-like score, referred to as ultrasonic score was introduced and was used together with movements, heart rate and associated parameters in a classification process using Support Vector Machines (SVM) method. The influence of the fetal activity parameters and the performance of the SVM were evaluated using the computation of sensibility, specificity, percentage of support vectors and total classification accuracy. We showed our ability to separate the data into two sets : normal fetuses and compromised fetuses and obtained an excellent matching with the clinical classification performed by physician.

  14. Functional properties of extracellular domains of transducer receptor gp130.

    PubMed

    Kostjukova, M N; Tupitsyn, N N

    2011-04-01

    Cytokine receptor molecules have been shown to have extracellular domains of complex structure and a multi-step activation system. Glycoprotein gp130 is a typical transducer of cytokine signal; it functions by forming multicomponent receptor complexes and transferring signals of tens of cytokines from the IL-6 family. Structural organization and basic functioning principles of gp130 are well known, as well as related signal pathways, which function during normal differentiation and are involved in pathogenesis of many tumors. The role of gp130 in IL-6-dependent tumors is best studied. In this review, based on extensive accumulated data, we examine the functional significance of certain parts of gp130 extracellular domains. Potentials of a recently developed method for estimation of receptor activation at the level of epitope structure are discussed.

  15. Postsynaptic Signaling and Plasticity Mechanisms

    NASA Astrophysics Data System (ADS)

    Sheng, Morgan; Jong Kim, Myung

    2002-10-01

    In excitatory synapses of the brain, specific receptors in the postsynaptic membrane lie ready to respond to the release of the neurotransmitter glutamate from the presynaptic terminal. Upon stimulation, these glutamate receptors activate multiple biochemical pathways that transduce signals into the postsynaptic neuron. Different kinds of synaptic activity elicit different patterns of postsynaptic signals that lead to short- or long-lasting strengthening or weakening of synaptic transmission. The complex molecular mechanisms that underlie postsynaptic signaling and plasticity are beginning to emerge.

  16. Electropneumatic transducer automatically limits motor current

    NASA Technical Reports Server (NTRS)

    Lovitt, T. F.

    1966-01-01

    Pneumatic controller regulates the load on a centrifugal freon compressor in a water cooling system, thus limiting the current input to an electric motor driving it. An electromechanical transducer monitoring the motor input current sends out air signals which indicate changes in the current to the pneumatic controller.

  17. Gain-of-function Lyn induces anemia: appropriate Lyn activity is essential for normal erythropoiesis and Epo receptor signaling.

    PubMed

    Slavova-Azmanova, Neli S; Kucera, Nicole; Satiaputra, Jiulia; Stone, Leah; Magno, Aaron; Maxwell, Mhairi J; Quilici, Cathy; Erber, Wendy; Klinken, S Peter; Hibbs, Margaret L; Ingley, Evan

    2013-07-11

    Lyn is involved in erythropoietin (Epo)-receptor signaling and erythroid homeostasis. Downstream pathways influenced following Lyn activation and their significance to erythropoiesis remain unclear. To address this, we assessed a gain-of-function Lyn mutation (Lyn(up/up)) on erythropoiesis and Epo receptor signaling. Adult Lyn(up/up) mice were anemic, with dysmorphic red cells (spherocyte-like, acanthocytes) in their circulation, indicative of hemolytic anemia and resembling the human disorder chorea acanthocytosis. Heterozygous Lyn(+/up) mice became increasingly anemic with age, indicating that the mutation was dominant. In an attempt to overcome this anemia, extramedullary erythropoiesis was activated. As the mice aged, the levels of different immature erythroid populations changed, indicating compensatory mechanisms to produce more erythrocytes were dynamic. Changes in Epo signaling were observed in Lyn(+/up) erythroid cell lines and primary CD71(+) Lyn(up/up) erythroblasts, including significant alterations to the phosphorylation of Lyn, the Epo receptor, Janus kinase 2, Signal Transducer and Action of Transcription-5, GRB2-associated-binding protein-2, Akt, and Forkhead box O3. As a consequence of altered Lyn signaling, Lyn(+/up) cells remained viable in the absence of Epo but displayed delayed Epo-induced differentiation. These data demonstrate that Lyn gene dosage and activity are critical for normal erythropoiesis; constitutively active Lyn alters Epo signaling, which in turn produces erythroid defects.

  18. 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.

  19. Activation of DNA damage response signaling by condensed chromatin.

    PubMed

    Burgess, Rebecca C; Burman, Bharat; Kruhlak, Michael J; Misteli, Tom

    2014-12-11

    The DNA damage response (DDR) occurs in the context of chromatin, and architectural features of chromatin have been implicated in DNA damage signaling and repair. Whereas a role of chromatin decondensation in the DDR is well established, we show here that chromatin condensation is integral to DDR signaling. We find that, in response to DNA damage chromatin regions transiently expand before undergoing extensive compaction. Using a protein-chromatin-tethering system to create defined chromatin domains, we show that interference with chromatin condensation results in failure to fully activate DDR. Conversely, forced induction of local chromatin condensation promotes ataxia telangiectasia mutated (ATM)- and ATR-dependent activation of upstream DDR signaling in a break-independent manner. Whereas persistent chromatin compaction enhanced upstream DDR signaling from irradiation-induced breaks, it reduced recovery and survival after damage. Our results demonstrate that chromatin condensation is sufficient for activation of DDR signaling and is an integral part of physiological DDR signaling.

  20. Biological Activities of Reactive Oxygen and Nitrogen Species: Oxidative Stress versus Signal Transduction

    PubMed Central

    Weidinger, Adelheid; Kozlov, Andrey V.

    2015-01-01

    In the past, reactive oxygen and nitrogen species (RONS) were shown to cause oxidative damage to biomolecules, contributing to the development of a variety of diseases. However, recent evidence has suggested that intracellular RONS are an important component of intracellular signaling cascades. The aim of this review was to consolidate old and new ideas on the chemical, physiological and pathological role of RONS for a better understanding of their properties and specific activities. Critical consideration of the literature reveals that deleterious effects do not appear if only one primary species (superoxide radical, nitric oxide) is present in a biological system, even at high concentrations. The prerequisite of deleterious effects is the formation of highly reactive secondary species (hydroxyl radical, peroxynitrite), emerging exclusively upon reaction with another primary species or a transition metal. The secondary species are toxic, not well controlled, causing irreversible damage to all classes of biomolecules. In contrast, primary RONS are well controlled (superoxide dismutase, catalase), and their reactions with biomolecules are reversible, making them ideal for physiological/pathophysiological intracellular signaling. We assume that whether RONS have a signal transducing or damaging effect is primarily defined by their quality, being primary or secondary RONS, and only secondly by their quantity. PMID:25884116

  1. 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.

  2. Catheter transducer and circuit

    NASA Technical Reports Server (NTRS)

    Harrison, D. R.; Kerwin, W. J.

    1971-01-01

    Simple integrated circuit located at transducer, enables use of single coaxial cable for both input and output connections. Circuit is sensitive to changes in RC time constant, has much improved sensitivity characteristics, and is unaffected by changes in cable capacitance effects.

  3. Broadband Ultrasonic Transducers

    NASA Technical Reports Server (NTRS)

    Heyser, R. C.

    1986-01-01

    New geometry spreads out resonance region of piezoelectric crystal. In new transducer, crystal surfaces made nonparallel. One surface planar; other, concave. Geometry designed to produce nearly uniform response over a predetermined band of frequencies and to attenuate strongly frequencies outside band. Greater bandwidth improves accuracy of sonar and ultrasonic imaging equipment.

  4. A Cell-Permeable Phospholipase C[gamma]1-Binding Peptide Transduces Neurons and Impairs Long-Term Spatial Memory

    ERIC Educational Resources Information Center

    Blum, Sonja; Dash, Pramod K.

    2004-01-01

    Growth factor-mediated signaling has emerged as an essential component of memory formation. In this study, we used a phospholipase C gamma 1 (PLC[gamma]1) binding, cell-penetrating peptide to sequester PLC[gamma]1 away from its target, the phosphotyrosine residues within the activated growth factor receptor. Peptides appear to transduce neurons…

  5. Activation of the Notch1/STAT3/Twist signaling axis promotes gastric cancer progression.

    PubMed

    Hsu, Kai-Wen; Hsieh, Rong-Hong; Huang, Kuo-Hung; Fen-Yau Li, Anna; Chi, Chin-Wen; Wang, Tzu-Yin; Tseng, Min-Jen; Wu, Kou-Juey; Yeh, Tien-Shun

    2012-08-01

    Gastric carcinoma is one of the most common malignancies and a lethal cancer in the world. Notch signaling and transcription factors STAT3 (signal transducer and activator of transcription 3) and Twist regulate tumor development and are critical regulators of gastric cancer progression. Herein, the relationship among Notch, STAT3 and Twist pathways in the control of gastric cancer progression was studied. We found that Twist and phosphorylated STAT3 levels were promoted by the activated Notch1 receptor in human stomach adenocarcinoma SC-M1, embryonic kidney HEK293 and erythroleukemia K562 cells. Notch1 signaling dramatically induced Twist promoter activity through a C promoter binding factor-1-independent manner and STAT3 phosphorylation. Overexpression of Notch1 receptor intracellular domain (N1IC) enhanced the interaction between nuclear STAT3 and Twist promoter in cells. Gastric cancer progression of SC-M1 cells was promoted by N1IC through STAT3 phosphorylation and Twist expression including colony formation, migration and invasion. STAT3 regulated gastric cancer progression of SC-M1 cells via Twist. N1IC also elevated the progression of other gastric cancer cells such as AGS and KATO III cells through STAT3 and Twist. The N1IC-promoted tumor growth and lung metastasis of SC-M1 cells in mice were suppressed by the STAT3 inhibitor JSI-124 and Twist knockdown. Furthermore, Notch1 and Notch ligand Jagged1 expressions were significantly associated with phosphorylated STAT3 and Twist levels in gastric cancer tissues of patients. Taken together, these results suggest that Notch1/STAT3/Twist signaling axis is involved in progression of human gastric cancer and modulation of this cascade has potential for the targeted combination therapy.

  6. Development of Flexible Capacitive Ultrasound Transducers and the Use of Ultrasound for Bone Repair

    NASA Astrophysics Data System (ADS)

    Wentzell, Scott A.

    Ultrasound is a widely applicable technique for therapy in the biomedical arena. However, conventional ultrasound transducers are not conducive for non-planar surfaces. Therefore, we developed flexible transducers capable of performing ultrasound and evaluated their use in biomedical applications. Flexible capacitive ultrasound transducers based on micrometer-thick dielectric tapes were developed and fabricated. These transducers were able to be made by hand at low-cost while still demonstrating good tolerances in center operating frequency. Intensities of up to 120 mW/cm2 were recorded and operation was dependent upon the applied AC and DC voltages along with the thickness of the dielectric insulation. These capacitive ultrasound transducers were used to stimulate MC3T3-E1 murine osteoblast cells to investigate the effects of low-frequency ultrasound on osteogenic gene expression and anabolic signaling pathways. After stimulation by 94.5 kHz continuous wave ultrasound for 20 minutes, significant increases in the activation of the Wnt signaling pathway and concentration of intracellular calcium were observed. Daily stimulation by ultrasound showed a trend of increased osteogenic gene expression across the phases of matrix deposition, maturation and calcification by osteoblasts. Finally, the heating of osteoblasts for stimulating osteoclastogenic responses was investigated. The application of increased temperatures of 42 and 47 degrees Celsius for 5 minutes showed significant increases in the RANKL/OPG ratio in media conditioned by osteoblasts. However, the altered RANKL/OPG ratio was not able to generate increases in osteoclastogenesis for RAW 264.7 murine macrophage cells culture in the condition media. This was possibly due to high overall osteoprotegerin expression, or unwanted inducement of M1 and M2 macrophage activation in the cell population. The overall work of this thesis demonstrates the development of novel capacitive transducers. These conformable

  7. MRI-guided Therapeutic Ultrasound : In vitro Validation of a New MR Compatible, Phased Array, Contact Endorectal Ultrasound Transducer with Active Feedback Control of Temperature Evolution

    NASA Astrophysics Data System (ADS)

    Salomir, Rares; Rata, Mihaela; Lafon, Cyril; Melodelima, David; Chapelon, Jean-Yves; Mathias, Adrien; Cotton, François; Bonmartin, Alain; Cathignol, Dominique

    2006-05-01

    Contact application of high intensity ultrasound was demonstrated to be suitable for thermal ablation of sectorial tumours of the digestive duct. Experimental validation of a new MR compatible ultrasonic device is described here, dedicated to the minimal invasive therapy of localized colorectal cancer. This is a cylindrical 1D 64-element phased array transducer of 14 mm diameter and 25 mm height (Imasonic, France) allowing electronic rotation of the acoustic beam. Operating frequency ranges from 3.5 to 4.0 MHz and up to 5 effective electrical watts per element are available. A plane wave is reconstructed by simultaneous excitation of eigth adjacent elements with an appropriate phase law. Driving electronics operates outside the Faraday cage of the scanner and provides fast switching capabilities. Excellent passive and active compatibility with the MRI data acquisition has been demonstrated. In addition, feasibility of active temperature control has been demonstrated based on real-time data export out of the MR scanner and a PID feedback algorithm. Further studies will address the in-vivo validation and the integration of a miniature NMR coil for increased SNR in the near field.

  8. SUMO regulates the activity of Smoothened and Costal-2 in Drosophila Hedgehog signaling

    PubMed Central

    Zhang, Jie; Liu, Yajuan; Jiang, Kai; Jia, Jianhang

    2017-01-01

    In Hedgehog (Hh) signaling, the GPCR-family protein Smoothened (Smo) acts as a signal transducer that is regulated by phosphorylation and ubiquitination, which ultimately change the cell surface accumulation of Smo. However, it is not clear whether Smo is regulated by other post-translational modifications, such as sumoylation. Here, we demonstrate that knockdown of the small ubiquitin-related modifier (SUMO) pathway components Ubc9 (a SUMO-conjugating enzyme E2), PIAS (a SUMO-protein ligase E3), and Smt3 (the SUMO isoform in Drosophila) by RNAi prevents Smo accumulation and alters Smo activity in the wing. We further show that Hh-induced-sumoylation stabilizes Smo, whereas desumoylation by Ulp1 destabilizes Smo in a phosphorylation independent manner. Mechanistically, we discover that excessive Krz, the Drosophila β-arrestin 2, inhibits Smo sumoylation and prevents Smo accumulation through Krz regulatory domain. Krz likely facilitates the interaction between Smo and Ulp1 because knockdown of Krz by RNAi attenuates Smo-Ulp1 interaction. Finally, we provide evidence that Cos2 is also sumoylated, which counteracts its inhibitory role on Smo accumulation in the wing. Taken together, we have uncovered a novel mechanism for Smo activation by sumoylation that is regulated by Hh and Smo interacting proteins. PMID:28195188

  9. Future needs for biomedical transducers

    NASA Technical Reports Server (NTRS)

    Wooten, F. T.

    1971-01-01

    In summary there are three major classes of transducer improvements required: improvements in existing transducers, needs for unexploited physical science phenomena in transducer design, and needs for unutilized physiological phenomena in transducer design. During the next decade, increasing emphasis will be placed on noninvasive measurement in all of these areas. Patient safety, patient comfort, and the need for efficient utilization of the time of both patient and physician requires that noninvasive methods of monitoring be developed.

  10. A preliminary evaluation work on a 3D ultrasound imaging system for 2D array transducer

    NASA Astrophysics Data System (ADS)

    Zhong, Xiaoli; Li, Xu; Yang, Jiali; Li, Chunyu; Song, Junjie; Ding, Mingyue; Yuchi, Ming

    2016-04-01

    This paper presents a preliminary evaluation work on a pre-designed 3-D ultrasound imaging system. The system mainly consists of four parts, a 7.5MHz, 24×24 2-D array transducer, the transmit/receive circuit, power supply, data acquisition and real-time imaging module. The row-column addressing scheme is adopted for the transducer fabrication, which greatly reduces the number of active channels . The element area of the transducer is 4.6mm by 4.6mm. Four kinds of tests were carried out to evaluate the imaging performance, including the penetration depth range, axial and lateral resolution, positioning accuracy and 3-D imaging frame rate. Several strong reflection metal objects , fixed in a water tank, were selected for the purpose of imaging due to a low signal-to-noise ratio of the transducer. The distance between the transducer and the tested objects , the thickness of aluminum, and the seam width of the aluminum sheet were measured by a calibrated micrometer to evaluate the penetration depth, the axial and lateral resolution, respectively. The experiment al results showed that the imaging penetration depth range was from 1.0cm to 6.2cm, the axial and lateral resolution were 0.32mm and 1.37mm respectively, the imaging speed was up to 27 frames per second and the positioning accuracy was 9.2%.

  11. [Growth hormone signaling pathways].

    PubMed

    Zych, Sławomir; Szatkowska, Iwona; Czerniawska-Piatkowska, Ewa

    2006-01-01

    The substantial improvement in the studies on a very complicated mechanism-- growth hormone signaling in a cell, has been noted in last decade. GH-induced signaling is characterized by activation of several pathways, including extracellular signal-regulated kinase (ERK), the signal transducer and activator of transcription and phosphatidylinositol-3 kinase (PI3) pathways. This review shows a current model of the growth hormone receptor dimerization, rotation of subunits and JAK2 kinase activation as the initial steps in the cascade of events. In the next stages of the signaling process, the GH-(GHR)2-(JAK2)2 complex may activate signaling molecules such as Stat, IRS-1 and IRS-2, and particularly all cascade proteins that activate MAP kinase. These pathways regulate basal cellular functions including target gene transcription, enzymatic activity and metabolite transport. Therefore growth hormone is considered as a major regulator of postnatal growth and metabolism, probably for mammary gland growth and development too.

  12. Ionic electroactive hybrid transducers

    NASA Astrophysics Data System (ADS)

    Akle, Barbar J.; Bennett, Matthew D.; Leo, Donald J.

    2005-05-01

    Ionic electroactive actuators have received considerable attention in the past ten years. Ionic electroactive polymers, sometimes referred to as artificial muscles, have the ability to generate large bending strain and moderate stress at low applied voltages. Typical types of ionic electroactive polymer transducers include ionic polymers, conducting polymers, and carbon nanotubes. Preliminary research combining multiple types of materials proved to enhance certain transduction properties such as speed of response, maximum strain, or quasi-static actuation. Recently it was demonstrated that ionomer-ionic liquid transducers can operate in air for long periods of time (>250,000 cycles) and showed potential to reduce or eliminate the back-relaxation issue associated with ionomeric polymers. In addition, ionic liquids have higher electrical stability window than those operated with water as the solvent thereby increasing the maximum strain that the actuator can produce. In this work, a new technique developed for plating metal particulates on the surface of ionomeric materials is applied to the development of hybrid transducers that incorporate carbon nanotubes and conducting polymers as electrode materials. The new plating technique, named the direct assembly process, consists of mixing a conducting powder with an ionomer solution. This technique has demonstrated improved response time and strain output as compared to previous methods. Furthermore, the direct assembly process is less costly to implement than traditional impregnation-reduction methods due to less dependence on reducing agents, it requires less time, and is easier to implement than other processes. Electrodes applied using this new technique of mixing RuO2 (surface area 45~65m2/g) particles and Nafion dispersion provided 5x the displacement and 10x the force compared to a transducer made with conventional methods. Furthermore, the study illustrated that the response speed of the transducer is optimized

  13. Molecular Mechanisms of Chemosensory Receptors, Signal Transducers, and the Activation of Gene Expression Controlling Establishment of a Marine Symbiosis

    DTIC Science & Technology

    1989-07-01

    Our most significant advance in this area this year has been in the molecular cloning and analysis of cDNAs corresponding to the novel serine protease...Biological Chemistry (in preparation). 4. Groppe, J. and D.E. Morse. 1989. Molecular cloning of novel serine protease cDNAs from abalone. For: Proc...phycoerythrin gene. (Poster -- d Abstract) Northwest Algal Symposium, Seattle, WA. 8. Groppe, J.C. and D.E. Morse. 1989. Molecular cloning of novel serine

  14. Molecular Mechanisms of Chemosensory Receptors, Signal Transducers, and the Activation of Gene Expression Controlling Establishment of a Marine Symbiosis

    DTIC Science & Technology

    1990-10-31

    filed.. ........... 0oDt . PUBLICATIONS AND REPORTS: Publications and Manuscripts: I. Groppe, J. and D.E. Morse. 1989. Molecular cloning of novel...Morse. 1989. Molecular cloning of novel serine protease cDNAs from abalone. (Abstract) Proc. First Intl. Symp. Marine Biotechnology, Tokyo. 6. Roell

  15. Cellular Cholesterol Directly Activates Smoothened in Hedgehog Signaling

    SciTech Connect

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

    2016-08-01

    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.

  16. 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

  17. Three dimensional transducer

    DOEpatents

    Warren, Oden Lee; Asif, Syed Amanulla Syed; Oh, Yunje; Feng, Yuxin; Cyrankowski, Edward; Major, Ryan

    2014-09-30

    A testing instrument for mechanical testing at nano or micron scale includes a transducer body, and a coupling shaft coupled with a probe tip. A transducer body houses a capacitor. The capacitor includes first and second counter electrodes and a center electrode assembly interposed therebetween. The center electrode assembly is movable with the coupling shaft relative to the first and second counter electrodes, for instance in one or more of dimensions including laterally and normally. The center electrode assembly includes a center plate coupled with the coupling shaft and one or more springs extending from the center plate. Upper and lower plates are coupled with the center plate and cover the center plate and the one or more springs. A shaft support assembly includes one or more support elements coupled along the coupling shaft. The shaft support assembly provides lateral support to the coupling shaft.

  18. Training Tree Transducers

    DTIC Science & Technology

    2004-01-01

    trees (similar to the role played by the finite- state acceptor FSA for strings). We describe the version (equivalent to TSG ( Schabes , 1990)) where...strictly contained in tree sets of tree adjoining gram- mars (Joshi and Schabes , 1997). 4 Extended-LHS Tree Transducers (xR) Section 1 informally described...changes without modifying the training procedure, as long as we stick to tree automata. 10 Related Work Tree substitution grammars or TSG ( Schabes , 1990

  19. Polymer film composite transducer

    DOEpatents

    Owen, Thomas E.

    2005-09-20

    A composite piezoelectric transducer, whose piezoeletric element is a "ribbon wound" film of piezolectric material. As the film is excited, it expands and contracts, which results in expansion and contraction of the diameter of the entire ribbon winding. This is accompanied by expansion and contraction of the thickness of the ribbon winding, such that the sound radiating plate may be placed on the side of the winding.

  20. Stress wave focusing transducers

    SciTech Connect

    Visuri, S.R., LLNL

    1998-05-15

    Conversion of laser radiation to mechanical energy is the fundamental process behind many medical laser procedures, particularly those involving tissue destruction and removal. Stress waves can be generated with laser radiation in several ways: creation of a plasma and subsequent launch of a shock wave, thermoelastic expansion of the target tissue, vapor bubble collapse, and ablation recoil. Thermoelastic generation of stress waves generally requires short laser pulse durations and high energy density. Thermoelastic stress waves can be formed when the laser pulse duration is shorter than the acoustic transit time of the material: {tau}{sub c} = d/c{sub s} where d = absorption depth or spot diameter, whichever is smaller, and c{sub s} = sound speed in the material. The stress wave due to thermoelastic expansion travels at the sound speed (approximately 1500 m/s in tissue) and leaves the site of irradiation well before subsequent thermal events can be initiated. These stress waves, often evolving into shock waves, can be used to disrupt tissue. Shock waves are used in ophthalmology to perform intraocular microsurgery and photodisruptive procedures as well as in lithotripsy to fragment stones. We have explored a variety of transducers that can efficiently convert optical to mechanical energy. One such class of transducers allows a shock wave to be focused within a material such that the stress magnitude can be greatly increased compared to conventional geometries. Some transducer tips could be made to operate regardless of the absorption properties of the ambient media. The size and nature of the devices enable easy delivery, potentially minimally-invasive procedures, and precise tissue- targeting while limiting thermal loading. The transducer tips may have applications in lithotripsy, ophthalmology, drug delivery, and cardiology.

  1. Thin film strain transducer

    NASA Astrophysics Data System (ADS)

    Rand, J. L.

    1981-01-01

    Previous attempts to develop an appropriate sensor for measuring the stress or strain of high altitude balloons during flight are reviewed as well as the various conditions that must be met by such a device. The design, development and calibration of a transducer which promises to satisfy the necessary design constraints are described. The thin film strain transducer has a low effective modulus so as not to interfere with the strain that would naturally occur in the balloon. In addition, the transducer has a high sensitivity to longitudinal strain (7.216 mV/V/unit strain) which is constant for all temperature from room temperature to -80 C and all strains from 5 percent compression to 10 percent tensile strain. At the same time, the sensor is relatively insensitive (0.27 percent) to transverse forces. The device has a standard 350 ohm impedance which is compatible with available bridge balance, amplification and telemetry instrumentation now available for balloon flight. Recommendations are included for improved coatings to provide passive thermal control as well as model, tethered and full scale flight testing.

  2. Activating Cell Death Ligand Signaling Through Proteasome Inhibition

    DTIC Science & Technology

    2009-05-01

    Activating Cell Death Ligand Signaling Through Proteasome Inhibition PRINCIPAL INVESTIGATOR: Steven R Schwarze...SUBTITLE Activating Cell Death Ligand Signaling Through 5a. CONTRACT NUMBER Proteasome Inhibition 5b. GRANT NUMBER W81XWH-08-1-0392 5c...proteasome inhibition can act as an anti-neoplastic agent in vivo by sensitizing cancer cells to cell death ligands in the tumor microenvironment

  3. Optical nanocluster plasmon sensors as transducers for bioaffinity interactions

    NASA Astrophysics Data System (ADS)

    Schalkhammer, Thomas G. M.; Leitner, Alfred; Aussenegg, Franz R.; Bauer, Georg D.; Pittner, Fritz

    1998-05-01

    Surface enhanced absorption of metal nano-clusters enabled us to transduce bioaffinity interactions highly amplifying the optical effect of changes in sensor surface coverage. The sensors were built depositing multiple nanoscale layers: at first silver or gold were sputtered onto oxygen plasma activated polycarbonate substrates to obtain a semitransparent metal cluster layer. Alternatively the primary metal layer was built of gold colloids covalently coupled to the activated polycarbonate. Next a chemically inert distance layer was applied e.g. by polymer-spinning. Finally a second cluster layer of e.g. gold colloids was coupled via bioaffinity interactions to the surface of the inert distance layer. The optical properties of the senor were found to be dependent on the size, shape and number of the metal-clusters as well as the distance between both metal cluster layers. For biomedical sensing the number and the spatial arrangement of biorecognitive bound metal clusters was transduced into an optical signal with high sensitivity. Since the defined spatial approach of colloids to the sensor surface alone creates the signal we could visually follow molecular binding events in real time. The first setups constructed were based on lectin-hexose or antibody-antigen interaction. The analytes were quantified via a distinct change of the spectral reflectivity of the sensor chip visible to the eye or measured by a miniaturized photometric device.

  4. Hypothalamic mTORC1 signaling controls sympathetic nerve activity and arterial pressure and mediates leptin effects.

    PubMed

    Harlan, Shannon M; Guo, Deng-Fu; Morgan, Donald A; Fernandes-Santos, Caroline; Rahmouni, Kamal

    2013-04-02

    The fundamental importance of the hypothalamus in the regulation of autonomic and cardiovascular functions is well established. However, the molecular processes involved are not well understood. Here, we show that the mammalian (or mechanistic) target of rapamycin (mTOR) signaling in the hypothalamus is tied to the activity of the sympathetic nervous system and to cardiovascular function. Modulation of mTOR complex 1 (mTORC1) signaling caused dramatic changes in sympathetic traffic, blood flow, and arterial pressure. Our data also demonstrate the importance of hypothalamic mTORC1 signaling in transducing the sympathetic and cardiovascular actions of leptin. Moreover, we show that the PI3K pathway links the leptin receptor to mTORC1 signaling and that changes in its activity impact sympathetic traffic and arterial pressure. These findings establish mTORC1 activity in the hypothalamus as a key determinant of sympathetic and cardiovascular regulation and suggest that dysregulated hypothalamic mTORC1 activity may influence the development of cardiovascular diseases.

  5. Hub-activated signal transmission in complex networks

    NASA Astrophysics Data System (ADS)

    Jahnke, Sven; Memmesheimer, Raoul-Martin; Timme, Marc

    2014-03-01

    A wide range of networked systems exhibit highly connected nodes (hubs) as prominent structural elements. The functional roles of hubs in the collective nonlinear dynamics of many such networks, however, are not well understood. Here, we propose that hubs in neural circuits may activate local signal transmission along sequences of specific subnetworks. Intriguingly, in contrast to previous suggestions of the functional roles of hubs, here, not the hubs themselves, but nonhub subnetworks transfer the signals. The core mechanism relies on hubs and nonhubs providing activating feedback to each other. It may, thus, induce the propagation of specific pulse and rate signals in neuronal and other communication networks.

  6. Signal peptides are allosteric activators of the protein translocase

    PubMed Central

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

    2010-01-01

    Extra-cytoplasmic polypeptides are usually synthesized as “preproteins” carrying aminoterminal, cleavable signal peptides1 and secreted across membranes by translocases. The main bacterial translocase comprises the SecYEG protein-conducting channel and the peripheral ATPase motor SecA2,3. Most proteins destined for the periplasm and beyond are exported post-translationally by SecA2,3. Preprotein targeting to SecA is thought to involve signal peptides4 and chaperones like SecB5,6. Here we reveal that signal peptides have a novel role beyond targeting: they are essential allosteric activators of the translocase. Upon 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; then “trapping” that engages non-native preprotein mature domains docked with high affinity on the secretion apparatus and, finally, “secretion” during which trapped mature domains undergo multiple turnovers of translocation in segments7. 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

  7. High Temperature Ultrasonic Transducer for Real-time Inspection

    NASA Astrophysics Data System (ADS)

    Amini, Mohammad Hossein; Sinclair, Anthony N.; Coyle, Thomas W.

    A broadband ultrasonic transducer with a novel porous ceramic backing layer is introduced to operate at 700 °C. 36° Y-cut lithium niobate (LiNbO3) single crystal was selected for the piezoelectric element. By appropriate choice of constituent materials, porosity and pore size, the acoustic impedance and attenuation of a zirconia-based backing layer were optimized. An active brazing alloy with high temperature and chemical stability was selected to bond the transducer layers together. Prototype transducers have been tested at temperatures up to 700 °C. The experiments confirmed that transducer integrity was maintained.

  8. Signaling Components of Redox Active Endosomes: The Redoxosomes

    PubMed Central

    Oakley, Fredrick D.; Abbott, Duane; Li, Qiang

    2009-01-01

    Abstract Subcellular compartmentalization of reactive oxygen species (ROS) plays a critical role in transmitting cell signals in response to environmental stimuli. In this regard, signals at the plasma membrane have been shown to trigger NADPH oxidase-dependent ROS production within the endosomal compartment and this step can be required for redox-dependent signal transduction. Unique features of redox-active signaling endosomes can include NADPH oxidase complex components (Nox1, Noxo1, Noxa1, Nox2, p47phox, p67phox, and/or Rac1), ROS processing enzymes (SOD1 and/or peroxiredoxins), chloride channels capable of mediating superoxide transport and/or membrane gradients required for Nox activity, and novel redox-dependent sensors that control Nox activity. This review will discuss the cytokine and growth factor receptors that likely mediate signaling through redox-active endosomes, and the common mechanisms whereby they act. Additionally, the review will cover ligand-independent environmental injuries, such as hypoxia/reoxygenation injury, that also appear to facilitate cell signaling through NADPH oxidase at the level of the endosome. We suggest that redox-active endosomes encompass a subset of signaling endosomes that we have termed redoxosomes. Redoxosomes are uniquely equipped with redox-processing proteins capable of transmitting ROS signals from the endosome interior to redox-sensitive effectors on the endosomal surface. In this manner, redoxosomes can control redox-dependent effector functions through the spatial and temporal regulation of ROS as second messengers. Antioxid. Redox Signal. 11, 1313–1333. PMID:19072143

  9. Frequency response calibration of recess-mounted pressure transducers

    NASA Astrophysics Data System (ADS)

    Marcolini, M. A.; Lorber, P. F.; Miller, W. T., Jr.; Covino, A. F., Jr.

    1991-03-01

    A technique is described for measuring the frequency response of pressure transducers mounted inside a model, where a narrow pipette leads to an orifice at the surface. An acoustic driver is mounted to a small chamber which has an opening at the opposite end with an O-ring seal to place over the orifice. A 3.18 mm (1/8 inch) reference microphone is mounted to one side of the chamber. The acoustic driver receives an input of white noise, and the transducer and reference microphone outputs are compared to obtain the frequency response of the pressure transducer. Selected results are presented in the form of power spectra for both the transducer and the reference, as well as the amplitude variation and phase shift between the two signals as a function of frequency. The effect of pipette length and the use of this technique for identifying both blocked orifices and faulty transducers are described.

  10. Frequency response calibration of recess-mounted pressure transducers

    NASA Technical Reports Server (NTRS)

    Marcolini, M. A.; Lorber, P. F.; Miller, W. T., Jr.; Covino, A. F., Jr.

    1991-01-01

    A technique is described for measuring the frequency response of pressure transducers mounted inside a model, where a narrow pipette leads to an orifice at the surface. An acoustic driver is mounted to a small chamber which has an opening at the opposite end with an O-ring seal to place over the orifice. A 3.18 mm (1/8 inch) reference microphone is mounted to one side of the chamber. The acoustic driver receives an input of white noise, and the transducer and reference microphone outputs are compared to obtain the frequency response of the pressure transducer. Selected results are presented in the form of power spectra for both the transducer and the reference, as well as the amplitude variation and phase shift between the two signals as a function of frequency. The effect of pipette length and the use of this technique for identifying both blocked orifices and faulty transducers are described.

  11. The Ca(2+) -binding protein PCaP2 located on the plasma membrane is involved in root hair development as a possible signal transducer.

    PubMed

    Kato, Mariko; Aoyama, Takashi; Maeshima, Masayoshi

    2013-05-01

    Plasma membrane-associated Ca(2+) -binding protein-2 (PCaP2) of Arabidopsis thaliana is a novel-type protein that binds to the Ca(2+) /calmodulin complex and phosphatidylinositol phosphates (PtdInsPs) as well as free Ca(2+) . Although the PCaP2 gene is predominantly expressed in root hair cells, it remains unknown how PCaP2 functions in root hair cells via binding to ligands. From biochemical analyses using purified PCaP2 and its variants, we found that the N-terminal basic domain with 23 amino acids (N23) is necessary and sufficient for binding to PtdInsPs and the Ca(2+) /calmodulin complex, and that the residual domain of PCaP2 binds to free Ca(2+) . In mutant analysis, a pcap2 knockdown line displayed longer root hairs than the wild-type. To examine the function of each domain in root hair cells, we over-expressed PCaP2 and its variants using the root hair cell-specific EXPANSIN A7 promoter. Transgenic lines over-expressing PCaP2, PCaP2(G2A) (second glycine substituted by alanine) and ∆23PCaP2 (lacking the N23 domain) exhibited abnormal branched and bulbous root hair cells, while over-expression of the N23 domain suppressed root hair emergence and elongation. The N23 domain was necessary and sufficient for the plasma membrane localization of GFP-tagged PCaP2. These results suggest that the N23 domain of PCaP2 negatively regulates root hair tip growth via processing Ca(2+) and PtdInsP signals on the plasma membrane, while the residual domain is involved in the polarization of cell expansion.

  12. High temperature, high power piezoelectric composite transducers.

    PubMed

    Lee, Hyeong Jae; Zhang, Shujun; Bar-Cohen, Yoseph; Sherrit, Stewart

    2014-08-08

    Piezoelectric composites are a class of functional materials consisting of piezoelectric active materials and non-piezoelectric passive polymers, mechanically attached together to form different connectivities. These composites have several advantages compared to conventional piezoelectric ceramics and polymers, including improved electromechanical properties, mechanical flexibility and the ability to tailor properties by using several different connectivity patterns. These advantages have led to the improvement of overall transducer performance, such as transducer sensitivity and bandwidth, resulting in rapid implementation of piezoelectric composites in medical imaging ultrasounds and other acoustic transducers. Recently, new piezoelectric composite transducers have been developed with optimized composite components that have improved thermal stability and mechanical quality factors, making them promising candidates for high temperature, high power transducer applications, such as therapeutic ultrasound, high power ultrasonic wirebonding, high temperature non-destructive testing, and downhole energy harvesting. This paper will present recent developments of piezoelectric composite technology for high temperature and high power applications. The concerns and limitations of using piezoelectric composites will also be discussed, and the expected future research directions will be outlined.

  13. High Temperature, High Power Piezoelectric Composite Transducers

    PubMed Central

    Lee, Hyeong Jae; Zhang, Shujun; Bar-Cohen, Yoseph; Sherrit, StewarT.

    2014-01-01

    Piezoelectric composites are a class of functional materials consisting of piezoelectric active materials and non-piezoelectric passive polymers, mechanically attached together to form different connectivities. These composites have several advantages compared to conventional piezoelectric ceramics and polymers, including improved electromechanical properties, mechanical flexibility and the ability to tailor properties by using several different connectivity patterns. These advantages have led to the improvement of overall transducer performance, such as transducer sensitivity and bandwidth, resulting in rapid implementation of piezoelectric composites in medical imaging ultrasounds and other acoustic transducers. Recently, new piezoelectric composite transducers have been developed with optimized composite components that have improved thermal stability and mechanical quality factors, making them promising candidates for high temperature, high power transducer applications, such as therapeutic ultrasound, high power ultrasonic wirebonding, high temperature non-destructive testing, and downhole energy harvesting. This paper will present recent developments of piezoelectric composite technology for high temperature and high power applications. The concerns and limitations of using piezoelectric composites will also be discussed, and the expected future research directions will be outlined. PMID:25111242

  14. Biasing of Capacitive Micromachined Ultrasonic Transducers.

    PubMed

    Caliano, Giosue; Matrone, Giulia; Savoia, Alessandro Stuart

    2017-02-01

    Capacitive micromachined ultrasonic transducers (CMUTs) represent an effective alternative to piezoelectric transducers for medical ultrasound imaging applications. They are microelectromechanical devices fabricated using silicon micromachining techniques, developed in the last two decades in many laboratories. The interest for this novel transducer technology relies on its full compatibility with standard integrated circuit technology that makes it possible to integrate on the same chip the transducers and the electronics, thus enabling the realization of extremely low-cost and high-performance devices, including both 1-D or 2-D arrays. Being capacitive transducers, CMUTs require a high bias voltage to be properly operated in pulse-echo imaging applications. The typical bias supply residual ripple of high-quality high-voltage (HV) generators is in the millivolt range, which is comparable with the amplitude of the received echo signals, and it is particularly difficult to minimize. The aim of this paper is to analyze the classical CMUT biasing circuits, highlighting the features of each one, and to propose two novel HV generator architectures optimized for CMUT biasing applications. The first circuit proposed is an ultralow-residual ripple (<5 [Formula: see text]) HV generator that uses an extremely stable sinusoidal power oscillator topology. The second circuit employs a commercially available integrated step-up converter characterized by a particularly efficient switching topology. The circuit is used to bias the CMUT by charging a buffer capacitor synchronously with the pulsing sequence, thus reducing the impact of the switching noise on the received echo signals. The small area of the circuit (about 1.5 cm(2)) makes it possible to generate the bias voltage inside the probe, very close to the CMUT, making the proposed solution attractive for portable applications. Measurements and experiments are shown to demonstrate the effectiveness of the new approaches

  15. Transducers for ultrasonic limb plethysmography

    NASA Technical Reports Server (NTRS)

    Nickell, W. T.; Wu, V. C.; Bhagat, P. K.

    1983-01-01

    The design, construction, and performance characteristics of ultasonic transducers suitable for limb plethysmography are presented. Both 3-mm-diameter flat-plate and 12-mm-diameter hemispheric ceramic transducers operating at 2 MHz were fitted in 1-mm thick epoxy-resin lens/acoustic-coupling structures and mounted in exercie-EKG electrode housings for placement on the calf using adhesive collars. The effects of transducer directional characteristics on performance under off-axis rotation and the electrical impedances of the transducers were measured: The flat transducer was found to be sensitive to rotation and have an impedance of 800 ohms; the hemispheric transducer, to be unaffected by rotation and have an impedance of 80 ohms. The use of hemispheric transducers as both transmitter and receiver, or of a flat transducer as transmitter and a hemispheric transducer as receiver, was found to produce adequate dimensional measurements, with minimum care in transducer placement, in short-term physiological experiments and long-term (up to 7-day) attachment tests.

  16. How to design and construct multielement ultrasonic transducers

    NASA Astrophysics Data System (ADS)

    Burrier, R. A.; Claus, R. O.

    The practical 'how to' design and construction of multielement ultrasonic transducers are described. First, design procedures based on direct calculations of the desired acoustic field are reviewed. Second, techniques for implementing these designs using piezoelectric active elements are discussed. Finally, optical and acoustic test methods for transducer calibration are indicated.

  17. How to design and construct multielement ultrasonic transducers

    NASA Technical Reports Server (NTRS)

    Burrier, R. A.; Claus, R. O.

    1984-01-01

    The practical 'how to' design and construction of multielement ultrasonic transducers are described. First, design procedures based on direct calculations of the desired acoustic field are reviewed. Second, techniques for implementing these designs using piezoelectric active elements are discussed. Finally, optical and acoustic test methods for transducer calibration are indicated.

  18. 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

  19. Coco is a dual activity modulator of TGFβ signaling.

    PubMed

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

    2015-08-01

    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.

  20. An electromechanical displacement transducer

    NASA Astrophysics Data System (ADS)

    Villiers, Marius; Mahboob, Imran; Nishiguchi, Katsuhiko; Hatanaka, Daiki; Fujiwara, Akira; Yamaguchi, Hiroshi

    2016-08-01

    Two modes of an electromechanical resonator are coupled through the strain inside the structure with a cooperativity as high as 107, a state-of-the-art value for purely mechanical systems, which enables the observation of normal-mode splitting. This coupling is exploited to transduce the resonator’s fundamental mode into the bandwidth of the second flexural mode, which is 1.4 MHz higher in frequency. Thus, an all-mechanical heterodyne detection scheme is implemented that can be developed into a high-precision displacement sensor.

  1. Tac-beta1 inhibits FAK activation and Src signaling.

    PubMed

    Berrier, Allison L; Jones, Christopher W; LaFlamme, Susan E

    2008-03-28

    The binding of integrins to extracellular matrix triggers signals that promote cell spreading. We previously demonstrated that expression of the integrin beta1 cytoplasmic domain in the context of a chimeric transmembrane receptor with the Tac subunit of the interleukin-2 receptor (Tac-beta1) inhibits cell spreading. To study the mechanism whereby Tac-beta1 inhibits cell spreading, we examined the effect of Tac-beta1 on early signaling events following integrin engagement namely FAK and Src signaling. We infected primary fibroblasts with adenoviruses expressing Tac or Tac-beta1 and found that Tac-beta1 prevented FAK activation by inhibiting the phosphorylation of FAK at Tyr-397. In contrast, Src activation was maintained, as phosphorylation of Src at Tyr-419 and Tyr-530 were not responsive to expression of Tac-beta1. Importantly, adhesion-induced tyrosine phosphorylation of the Src substrates p130Cas and paxillin was inhibited, indicating that Src signaling was blocked by Tac-beta1. These Src-dependent signaling events were found to require FAK signaling. Our results suggest that Tac-beta1 inhibits cell spreading, at least in part, by preventing the phosphorylation of FAK at Tyr-397 and the assembly of signaling complexes necessary for phosphorylation of p130Cas and other downstream effectors.

  2. Transducer of linear displacements

    NASA Astrophysics Data System (ADS)

    Malamed, Y. R.

    1984-02-01

    The basic PLP transducer is designed for a UIM-29 microscope and a 2-coordinate measuring instrument with electronic digital readout. Its optical system consists of an AL-107B light-emitting diode as light source, two condenser lenses, a special wedge carrying two pairs of joined receiver lenses, a prism-mirror, a photoreceiver, a wedge-shape transparent replica of a twin diffraction grating which prevents light reflected by the air-glass interface from focusing on the receiver photodiodes, and a reflective replica of a diffraction grating on a movable carriage. The already available three models of this transducer are PLP1-0.2, PLP1-0.5, and PLP1-1.0 with respectively 625, 250, 125 lines/mm on the transparent replica and respectively 312.5, 125, 62.5 lines/mm on the reflective replica. The scale of moire-interference fringes characterizing the shift between both diffraction gratings per grating period (9.16 mm in each model) is respectively 0.8, 2.0, 4.0 microns and the angle between the two arrays of grating lines on the transparent replica is respectively 36 + or - 4 deg, 90 + or - 10 deg, 190 + or - 20 deg.

  3. Enhanced Multistatic Active Sonar via Innovative Signal Processing

    DTIC Science & Technology

    2015-09-30

    Grove, CA, November, 2014. [in press, refereed]. C . Gianelli, L. Xu, and J. Li, " Active Sonar Systems in the Presence of Strong Direct Blast", Oceans...3. DATES COVERED (From - To) Oct. 01, 2014-Sept. 30, 2015 4. TITLE AND SUBTITLE Enhanced Multistatic Active Sonar via Innovative Signal... active sonar (CAS) in the presence of strong direct blast is studied for the Doppler-tolerant linear frequency modulation waveform. A receiver design

  4. Enhanced Multistatic Active Sonar via Innovative Signal Processing

    DTIC Science & Technology

    2014-09-30

    DATES COVERED (From - To) Oct. 01. 2013-Sept. 30, 2014 4. TITLE AND SUBTITLE Enhanced Multistatic Active Sonar via Innovative Signal Processing 5a...DISTRIBUTION AVAILABILITY STATEMENT Approved for Public Release; Distribution is Unlimited. 13. SUPPLEMENTARY NOTES 14. ABSTRACT Pulsed active sonar ...PAS) and continuous active sonar (CAS) in the presence of strong direct blast are studied for the Doppler-tolerant linear frequency modulation

  5. Broadband electrical impedance matching for piezoelectric ultrasound transducers.

    PubMed

    Huang, Haiying; Paramo, Daniel

    2011-12-01

    This paper presents a systematic method for designing broadband electrical impedance matching networks for piezoelectric ultrasound transducers. The design process involves three steps: 1) determine the equivalent circuit of the unmatched piezoelectric transducer based on its measured admittance; 2) design a set of impedance matching networks using a computerized Smith chart; and 3) establish the simulation model of the matched transducer to evaluate the gain and bandwidth of the impedance matching networks. The effectiveness of the presented approach is demonstrated through the design, implementation, and characterization of impedance matching networks for a broadband acoustic emission sensor. The impedance matching network improved the power of the acquired signal by 9 times.

  6. Concrete structural health monitoring using embedded piezoceramic transducers

    NASA Astrophysics Data System (ADS)

    Song, G.; Gu, H.; Mo, Y. L.; Hsu, T. T. C.; Dhonde, H.

    2007-08-01

    Health monitoring of reinforced concrete bridges and other large-scale civil infrastructures has received considerable attention in recent years. However, traditional inspection methods (x-ray, C-scan, etc) are expensive and sometimes ineffective for large-scale structures. Piezoceramic transducers have emerged as new tools for the health monitoring of large-scale structures due to their advantages of active sensing, low cost, quick response, availability in different shapes, and simplicity for implementation. In this research, piezoceramic transducers are used for damage detection of a 6.1 m long reinforced concrete bridge bent-cap. Piezoceramic transducers are embedded in the concrete structure at pre-determined spatial locations prior to casting. This research can be considered as a continuation of an earlier work, where four piezoceramic transducers were embedded in planar locations near one end of the bent-cap. This research involves ten piezoceramic patches embedded at spatial locations in four different cross-sections. To induce cracks in the bent-cap, the structure is subjected to loads from four hydraulic actuators with capacities of 80 and 100 ton. In addition to the piezoceramic sensors, strain gages, LVDTs, and microscopes are used in the experiment to provide reference data. During the experiment, one embedded piezoceramic patch is used as an actuator to generate high frequency waves, and the other piezoceramic patches are used as sensors to detect the propagating waves. With the increasing number and severity of cracks, the magnitude of the sensor output decreases. Wavelet packet analysis is used to analyze the recorded sensor signals. A damage index is formed on the basis of the wavelet packet analysis. The experimental results show that the proposed methods of using piezoceramic transducers along with the damage index based on wavelet packet analysis are effective in identifying the existence and severity of cracks inside the concrete structure. The

  7. Monitoring of cracks at an open hole using built-in fibre wave piezoelectric transducers

    NASA Astrophysics Data System (ADS)

    Lee, Jung-Ryul; Tsuda, Hiroshi

    2006-10-01

    This contribution is related to the first application in structural health monitoring network using fibre wave piezoelectric transducers. Fibre wave piezoelectric transducers are applied to ultrasound-based active diagnostics of the crack propagation in the vicinity of an open hole. The usefulness of the fibre wave piezoelectric transducer is demonstrated in the artificial and fatigue crack monitoring experiments. Since the fibre wave piezoelectric transducer possesses jointly many portions of the inherent merits of the fibre optic ultrasonic sensor and the piezoelectric transducer, this paper proposes it as an improved built-in ultrasonic transducer for monitoring the structural integrity of local structural hot spots.

  8. Stra13 regulates satellite cell activation by antagonizing Notch signaling

    PubMed Central

    Sun, Hong; Li, Li; Vercherat, Cécile; Gulbagci, Neriman Tuba; Acharjee, Sujata; Li, Jiali; Chung, Teng-Kai; Thin, Tin Htwe; Taneja, Reshma

    2007-01-01

    Satellite cells play a critical role in skeletal muscle regeneration in response to injury. Notch signaling is vital for satellite cell activation and myogenic precursor cell expansion but inhibits myogenic differentiation. Thus, precise spatial and temporal regulation of Notch activity is necessary for efficient muscle regeneration. We report that the basic helix-loop-helix transcription factor Stra13 modulates Notch signaling in regenerating muscle. Upon injury, Stra13−/− mice exhibit increased cellular proliferation, elevated Notch signaling, a striking regeneration defect characterized by degenerated myotubes, increased mononuclear cells, and fibrosis. Stra13−/− primary myoblasts also exhibit enhanced Notch activity, increased proliferation, and defective differentiation. Inhibition of Notch signaling ex vivo and in vivo ameliorates the phenotype of Stra13−/− mutants. We demonstrate in vitro that Stra13 antagonizes Notch activity and reverses the Notch-imposed inhibition of myogenesis. Thus, Stra13 plays an important role in postnatal myogenesis by attenuating Notch signaling to reduce myoblast proliferation and promote myogenic differentiation. PMID:17502421

  9. Hepatocyte-specific Smad7 deletion accelerates DEN-induced HCC via activation of STAT3 signaling in mice

    PubMed Central

    Feng, T; Dzieran, J; Yuan, X; Dropmann, A; Maass, T; Teufel, A; Marhenke, S; Gaiser, T; Rückert, F; Kleiter, I; Kanzler, S; Ebert, M P; Vogel, A; ten Dijke, P; Dooley, S; Meindl-Beinker, N M

    2017-01-01

    TGF-β signaling in liver cells has variant roles in the dynamics of liver diseases, including hepatocellular carcinoma (HCC). We previously found a correlation of high levels of the important endogenous negative TGF-β signaling regulator SMAD7 with better clinical outcome in HCC patients. However, the underlying tumor-suppressive molecular mechanisms are still unclear. Here, we show that conditional (TTR-Cre) hepatocyte-specific SMAD7 knockout (KO) mice develop more tumors than wild-type and corresponding SMAD7 transgenic mice 9 months after diethylnitrosamine (DEN) challenge, verifying SMAD7 as a tumor suppressor in HCC. In line with our findings in patients, Smad7 levels in both tumor tissue as well as surrounding tissue show a significant inverse correlation with tumor numbers. SMAD7 KO mice presented with increased pSMAD2/3 levels and decreased apoptosis in the tumor tissue. Higher tumor incidence was accompanied by reduced P21 and upregulated c-MYC expression in the tumors. Activation of signal transducer and activator of transcription factor 3 signaling was found in Smad7-deficient mouse tumors and in patients with low tumoral SMAD7 expression as compared with surrounding tissue. Together, our results provide new mechanistic insights into the tumor-suppressive functions of SMAD7 in hepatocarcinogenesis. PMID:28134936

  10. Ultrasonic Transducers for Fourier Analysis.

    ERIC Educational Resources Information Center

    Greenslade, Thomas B., Jr.

    1995-01-01

    Describes an experiment that uses the ultrasonic transducer for demonstrating the Fourier components of waveshapes such as the square and triangular waves produced by laboratory function generators. (JRH)

  11. Platelet-activating factor: receptors and signal transduction.

    PubMed

    Chao, W; Olson, M S

    1993-06-15

    During the past two decades, studies describing the chemistry and biology of PAF have been extensive. This potent phosphoacylglycerol exhibits a wide variety of physiological and pathophysiological effects in various cells and tissues. PAF acts, through specific receptors and a variety of signal transduction systems, to elicit diverse biochemical responses. Several important future directions can be enumerated for the characterization of PAF receptors and their attendant signalling mechanisms. The recent cloning and sequence analysis of the gene for the PAF receptor will allow a number of important experimental approaches for characterizing the structure and analysing the function of the various domains of the receptor. Using molecular genetic and immunological technologies, questions relating to whether there is receptor heterogeneity, the precise mechanism(s) for the regulation of the PAF receptor, and the molecular details of the signalling mechanisms in which the PAF receptor is involved can be explored. Another area of major significance is the examination of the relationship between the signalling response(s) evoked by PAF binding to its receptor and signalling mechanisms activated by a myriad of other mediators, cytokines and growth factors. A very exciting recent development in which PAF receptors undoubtedly play a role is in the regulation of the function of various cellular adhesion molecules. Finally, there remain many incompletely characterized physiological and pathophysiological situations in which PAF and its receptor play a crucial signalling role. Our laboratory has been active in the elucidation of several tissue responses in which PAF exhibits major autocoid signalling responses, e.g. hepatic injury and inflammation, acute and chronic pancreatitis, and cerebral stimulation and/or trauma. As new experimental strategies are developed for characterizing the fine structure of the molecular mechanisms involved in tissue injury and inflammation, the

  12. [Transducer hygiene -- an underrated topic?].

    PubMed

    Merz, E

    2005-02-01

    Transducers are medical products that are categorized as uncritical, semicritical and critical, depending on their applications and perceived risks. Uncritical medical products are transducers that solely come in contact with the intact skin, such as transducers used for sonography of the abdomen or breast. Semicritical medical products are transducers that come in contact with mucosal membranes or diseased skin, comprising transducers used for transesophageal, transvesical, transvaginal, transrectal and perineal sonography. Critical medical products are transducers that come in contact with blood, internal tissues or organs, such as transducers used for intraoperative sonography. Under the most unfavorable circumstances, sonographic transducers can become contaminated with pathogenic agents (e. g., MRSA, HBV, HCV, HIV, Herpes viruses) and turn into a not to be underrated source of infection. For this reason, correct handling as well as cleaning and disinfection of the transducers are indispensable. Depending on the application, the recommended handling of the transducers differs. Transducers counted to the uncritical medical products are adequately cleaned by removal of the applied ultrasound gel with subsequent wipe disinfection (e. g., foam spray). Transducers counted to the semicritical medical products, such as transvaginal or perineal transducers , should be exclusively used after a suitable cover has been applied. A Latex(R) allergy must be excluded before the examination. The cover is to be disposed after completion of the examination and the transducer itself cleaned and disinfected. The disinfecting agent must be antiviral but also compatible with the material (caution: damage to the transducer membrane when using an unsuited alcoholic disinfecting agent). In case of rupture of the protecting cover during the examination, the transducer is considered contaminated with secretion or even blood and must be thoroughly cleaned with subsequent disinfection

  13. DUAL-FOCUS THERAPEUTIC ULTRASOUND TRANSDUCER FOR PRODUCTION OF BROAD TISSUE LESIONS

    PubMed Central

    Jeong, Jong Seob; Cannata, Jonathan M.; Shung, K. Kirk

    2011-01-01

    In noninvasive high-intensity focused ultrasound (HIFU) treatment, formation of a large tissue lesion per sonication is desirable for reducing the overall treatment time. The goal of this study is to show the feasibility of enlarging tissue lesion size with a dual-focus therapeutic ultrasound transducer (DFTUT) by increasing the depth-of-focus (DOF). The proposed transducer consists of a disc- and an annular-type element of different radii of curvatures to produce two focal zones. To increase focal depth and to maintain uniform beamwidth of the elongated DOF, each element transmits ultrasound of a different center frequency: the inner element at a higher frequency for near field focusing and the outer element at a lower frequency for far field focusing. By activating two elements at the same time with a single transmitter capable of generating a dual-frequency mixed signal, the overall DOF of the proposed transducer may be extended considerably. A prototype transducer composed of a 4.1 MHz inner element and a 2.7 MHz outer element was fabricated to obtain preliminary experimental results. The feasibility the proposed technique was demonstrated through sound field, temperature and thermal dose simulations. The performance of the prototype transducer was verified by hydrophone measurements and tissue ablation experiments on a beef liver specimen. When several factors affecting the length and the uniformity of elongated DOF of the DFTUT are optimized, the proposed therapeutic ultrasound transducer design may increase the size of ablated tissues in the axial direction and, thus, decreasing the treatment time for a large volume of malignant tissues especially deep-seated targets. PMID:20870346

  14. A-kinase anchoring protein (AKAP)-Lbc anchors a PKN-based signaling complex involved in α1-adrenergic receptor-induced p38 activation.

    PubMed

    Cariolato, Luca; Cavin, Sabrina; Diviani, Dario

    2011-03-11

    The mitogen-activated protein kinases (MAPKs) pathways are highly organized signaling systems that transduce extracellular signals into a variety of intracellular responses. In this context, it is currently poorly understood how kinases constituting these signaling cascades are assembled and activated in response to receptor stimulation to generate specific cellular responses. Here, we show that AKAP-Lbc, an A-kinase anchoring protein (AKAP) with an intrinsic Rho-specific guanine nucleotide exchange factor activity, is critically involved in the activation of the p38α MAPK downstream of α(1b)-adrenergic receptors (α(1b)-ARs). Our results indicate that AKAP-Lbc can assemble a novel transduction complex containing the RhoA effector PKNα, MLTK, MKK3, and p38α, which integrates signals from α(1b)-ARs to promote RhoA-dependent activation of p38α. In particular, silencing of AKAP-Lbc expression or disrupting the formation of the AKAP-Lbc·p38α signaling complex specifically reduces α(1)-AR-mediated p38α activation without affecting receptor-mediated activation of other MAPK pathways. These findings provide a novel mechanistic hypothesis explaining how assembly of macromolecular complexes can specify MAPK signaling downstream of α(1)-ARs.

  15. Standards for dielectric elastomer transducers

    NASA Astrophysics Data System (ADS)

    Carpi, Federico; Anderson, Iain; Bauer, Siegfried; Frediani, Gabriele; Gallone, Giuseppe; Gei, Massimiliano; Graaf, Christian; Jean-Mistral, Claire; Kaal, William; Kofod, Guggi; Kollosche, Matthias; Kornbluh, Roy; Lassen, Benny; Matysek, Marc; Michel, Silvain; Nowak, Stephan; O'Brien, Benjamin; Pei, Qibing; Pelrine, Ron; Rechenbach, Björn; Rosset, Samuel; Shea, Herbert

    2015-10-01

    Dielectric elastomer transducers consist of thin electrically insulating elastomeric membranes coated on both sides with compliant electrodes. They are a promising electromechanically active polymer technology that may be used for actuators, strain sensors, and electrical generators that harvest mechanical energy. The rapid development of this field calls for the first standards, collecting guidelines on how to assess and compare the performance of materials and devices. This paper addresses this need, presenting standardized methods for material characterisation, device testing and performance measurement. These proposed standards are intended to have a general scope and a broad applicability to different material types and device configurations. Nevertheless, they also intentionally exclude some aspects where knowledge and/or consensus in the literature were deemed to be insufficient. This is a sign of a young and vital field, whose research development is expected to benefit from this effort towards standardisation.

  16. Zinc modulates PPARgamma signaling and activation of porcine endothelial cells.

    PubMed

    Meerarani, Purushothaman; Reiterer, Gudrun; Toborek, Michal; Hennig, Bernhard

    2003-10-01

    Dietary zinc has potent antioxidant and anti-inflammatory properties and is a critical component of peroxisome proliferator-activated receptor (PPAR) gene expression and regulation. To assess the protective mechanisms of PPARgamma in endothelial cell dysfunction and the role of zinc in the modulation of PPARgamma signaling, cultured porcine pulmonary artery endothelial cells were exposed to the membrane-permeable zinc chelator N,N,N'N'-tetrakis (2-pyridylmethyl)-ethylene diamine (TPEN), thiazolidinedione (TZD; PPARgamma agonist) or bisphenol A diglycidyl ether (BADGE; PPARgamma antagonist). Subsequently, endothelial cells were activated by treatment with linoleic acid (90 micro mol/L) for 6 h. Zinc chelation by TPEN increased the DNA binding activity of nuclear factor (NF)-kappaB and activator protein (AP)-1, decreased PPARgamma expression and activation as well as up-regulated interleukin (IL)-6 expression and production. These effects were fully reversed by zinc supplementation. In addition, exposure to TZD down-regulated linoleic acid-induced DNA binding activity of NF-kappaB and AP-1, whereas BADGE further induced activation of these oxidative stress-sensitive transcription factors. Most importantly, the TZD-mediated down-regulation of NF-kappaB and AP-1 and reduced inflammatory response were impaired during zinc chelation. These data suggest that zinc plays a critical role in PPARgamma signaling in linoleic acid-induced endothelial cell activation and indicate that PPARgamma signaling is impaired during zinc deficiency.

  17. Notch signaling promotes osteoclast maturation and resorptive activity

    PubMed Central

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

    2015-01-01

    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

  18. Evolvable Cryogenics (ECRYO) Pressure Transducer Calibration Test

    NASA Technical Reports Server (NTRS)

    Diaz, Carlos E., Jr.

    2015-01-01

    This paper provides a summary of the findings of recent activities conducted by Marshall Space Flight Center's (MSFC) In-Space Propulsion Branch and MSFC's Metrology and Calibration Lab to assess the performance of current "state of the art" pressure transducers for use in long duration storage and transfer of cryogenic propellants. A brief historical narrative in this paper describes the Evolvable Cryogenics program and the relevance of these activities to the program. This paper also provides a review of three separate test activities performed throughout this effort, including: (1) the calibration of several pressure transducer designs in a liquid nitrogen cryogenic environmental chamber, (2) the calibration of a pressure transducer in a liquid helium Dewar, and (3) the calibration of several pressure transducers at temperatures ranging from 20 to 70 degrees Kelvin (K) using a "cryostat" environmental chamber. These three separate test activities allowed for study of the sensors along a temperature range from 4 to 300 K. The combined data shows that both the slope and intercept of the sensor's calibration curve vary as a function of temperature. This homogeneous function is contrary to the linearly decreasing relationship assumed at the start of this investigation. Consequently, the data demonstrates the need for lookup tables to change the slope and intercept used by any data acquisition system. This ultimately would allow for more accurate pressure measurements at the desired temperature range. This paper concludes with a review of a request for information (RFI) survey conducted amongst different suppliers to determine the availability of current "state of the art" flight-qualified pressure transducers. The survey identifies requirements that are most difficult for the suppliers to meet, most notably the capability to validate the sensor's performance at temperatures below 70 K.

  19. Ferroelectret transducers for air-coupled ultrasonic testing of fiber-reinforced polymers

    NASA Astrophysics Data System (ADS)

    Gaal, M.; Döring, J.; Bartusch, J.; Lange, T.; Hillger, W.; Brekow, G.; Kreutzbruck, M.

    2013-01-01

    Ferroelectrets are promising materials for air-coupled ultrasonic transducers. A transducer made of polarized cellular polypropylene, including its electronic interface, was developed and compared with conventional air-coupled probes. Test pieces of fiber-reinforced polymer containing impact flaws and flat-bottom holes were inspected in transmission. The ferroelectret transducers achieved a considerably higher signal-to-noise ratio. The impacts were clearly visible with all transducers, but less noisy with ferroelectret transducers. The flat-bottom holes were better detectable than with a conventional probe with about the same focus size.

  20. Characterization of noncontact piezoelectric transducer with conically shaped piezoelement

    NASA Technical Reports Server (NTRS)

    Williams, James H., Jr.; Ochi, Simeon C. U.

    1988-01-01

    The characterization of a dynamic surface displacement transducer (IQI Model 501) by a noncontact method is presented. The transducer is designed for ultrasonic as well as acoustic emission measurements and, according to the manufacturer, its characteristic features include a flat frequency response range which is from 50 to 1000 kHz and a quality factor Q of less than unity. The characterization is based on the behavior of the transducer as a receiver and involves exciting the transducer directly by transient pulse input stress signals of quasi-electrostatic origin and observing its response in a digital storage oscilloscope. Theoretical models for studying the response of the transducer to pulse input stress signals and for generating pulse stress signals are presented. The characteristic features of the transducer which include the central frequency f sub o, quality factor Q, and flat frequency response range are obtained by this noncontact characterization technique and they compare favorably with those obtained by a tone burst method which are also presented.

  1. Profiling of multiple signal pathway activities by multiplexing antibody and GFP-based translocation assays.

    PubMed

    Henriksen, Ulla; Fog, Jacob; Loechel, Frosty; Praestegaard, Morten

    2008-08-01

    Multiplexing of GFP based and immunofluorescence translocation assays enables easy acquisition of multiple readouts from the same cell in a single assay run. Immunofluorescence assays monitor translocation, phosphorylation, and up/down regulation of endogenous proteins. GFP-based assays monitor translocation of stably expressed GFP-fusion proteins. Such assays may be multiplexed along (vertical), across (horizontal), and between (branch) signal pathways. Examples of these strategies are presented: 1) The MK2-GFP assay monitors translocation of MK2-GFP from the nucleus to the cytoplasm in response to stimulation of the p38 pathway. By applying different immunofluorescent assays to the MK2 assay, a multiplexed HCA system is created for deconvolution of p38 pathway activation including assay readouts for MK2, p38, NFkappaB, and c-Jun. 2) A method for evaluating GPCR activation and internalization in a single assay run has been established by multiplexing GFP-based internalization assays with immunofluorescence assays for downstream transducers of GPCR activity: pCREB (cAMP sensor), NFATc1 (Ca(2+) sensor), and ERK (G-protein activation). Activation of the AT1 receptor is given as an example. 3) Cell toxicity readouts can be linked to primary readouts of interest via acquisition of secondary parameters describing cellular morphology. This approach is used to flag cytotoxic compounds and deselect false positives. The ATF6 Redistribution assay is provided as an example. These multiplex strategies provide a unique opportunity to enhance HCA data quality and save time during drug discovery. From a single assay run, several assay readouts are obtained that help the user to deconvolute the mode of action of test compounds.

  2. Optically transduced MEMS magnetometer

    DOEpatents

    Nielson, Gregory N; Langlois, Eric

    2014-03-18

    MEMS magnetometers with optically transduced resonator displacement are described herein. Improved sensitivity, crosstalk reduction, and extended dynamic range may be achieved with devices including a deflectable resonator suspended from the support, a first grating extending from the support and disposed over the resonator, a pair of drive electrodes to drive an alternating current through the resonator, and a second grating in the resonator overlapping the first grating to form a multi-layer grating having apertures that vary dimensionally in response to deflection occurring as the resonator mechanically resonates in a plane parallel to the first grating in the presence of a magnetic field as a function of the Lorentz force resulting from the alternating current. A plurality of such multi-layer gratings may be disposed across a length of the resonator to provide greater dynamic range and/or accommodate fabrication tolerances.

  3. Simultaneous muscle force and displacement transducer

    NASA Technical Reports Server (NTRS)

    Feldstein, C.; Lewis, G. W.; Culler, V. H. (Inventor)

    1980-01-01

    A myocardial transducer for simultaneously measuring force and displacement within a very small area of myocardium is disclosed. The transducer comprised of an elongated body forked at one end to form an inverted Y shaped beam with each branch of the beam constituting a low compliant tine for penetrating the myocardium to a predetermined depth. Bonded to one of the low compliance tines is a small piezoresistive element for converting a force acting on the beam into an electrical signal. A third high compliant tine of the transducer, which measures displacement of the myocardium in a direction in line with the two low compliant tines, is of a length that just pierces the surface membrane. A small piezoresistive element is bonded to the third tine at its upper end where its bending is greatest. Displacement of the myocardium causes a deformation in curvature of the third tine, and the second small piezoresistive element bonded to the surface of its curved end converts its deformation into an electrical signal.

  4. Overexpression of SMC4 activates TGFβ/Smad signaling and promotes aggressive phenotype in glioma cells.

    PubMed

    Jiang, L; Zhou, J; Zhong, D; Zhou, Y; Zhang, W; Wu, W; Zhao, Z; Wang, W; Xu, W; He, L; Ma, Y; Hu, Y; Zhang, W; Li, J

    2017-03-13

    Overexpression of structural maintenance of chromosomes 4 (SMC4) has been reported to be involved in tumor cell growth, migration and invasion, and to be correlated with poor prognosis of cancer patient. However, its clinical significance and biological role in glioma remain unknown. Herein, we found that SMC4 expression at both mRNA and protein level was markedly increased in glioma cells and clinical tissues and that it correlated with poor prognosis. SMC4 overexpression markedly promoted the glioma cell proliferation rate and migration and invasive capability in vitro and in vivo, whereas SMC4 downregulation reduced it. Moreover, the transforming growth factor β (TGFβ)/Smad signaling pathway, which was activated in SMC4-transduced glioma cells and inhibited in SMC4-silenced glioma cells, contributed to SMC4-mediated glioma cell aggressiveness. Our results provide new insight into the oncofunction of SMC4 and the mechanism by which the TGFβ/Smad pathway is hyperactivated in gliomas, indicating that SMC4 is a valuable prognostic factor and a potential therapeutic target in gliomas.

  5. 5'-AMP-activated protein kinase signaling in Caenorhabditis elegans.

    PubMed

    Beale, Elmus G

    2008-01-01

    5'-AMP-activated protein kinase (AMPK) has been called "the metabolic master switch" because of its central role in regulating fuel homeostasis. AMPK, a heterotrimeric serine/threonine protein kinase composed of alpha, beta, and gamma subunits, is activated by upstream kinases and by 5'-AMP in response to various nutritional and stress signals. Downstream effects include regulation of metabolism, protein synthesis, cell growth, and mediation of the actions of a number of hormones, including leptin. However, AMPK research represents a young and growing field; hence, there are many unanswered questions regarding the control and action of AMPK. This review presents evidence for the existence of AMPK signaling pathways in Caenorhabditis elegans, a genetically tractable model organism that has yet to be fully exploited to elucidate AMPK signaling mechanisms.

  6. Laser-scanning photoacoustic microscopy with ultrasonic phased array transducer.

    PubMed

    Zheng, Fan; Zhang, Xiangyang; Chiu, Chi Tat; Zhou, Bill L; Shung, K Kirk; Zhang, Hao F; Jiao, Shuliang

    2012-11-01

    In this paper, we report our latest progress on proving the concept that ultrasonic phased array can improve the detection sensitivity and field of view (FOV) in laser-scanning photoacoustic microscopy (LS-PAM). A LS-PAM system with a one-dimensional (1D) ultrasonic phased array was built for the experiments. The 1D phased array transducer consists of 64 active elements with an overall active dimension of 3.2 mm × 2 mm. The system was tested on imaging phantom and mouse ear in vivo. Experiments showed a 15 dB increase of the signal-to-noise ratio (SNR) when beamforming was employed compared to the images acquired with each single element. The experimental results demonstrated that ultrasonic phased array can be a better candidate for LS-PAM in high sensitivity applications like ophthalmic imaging.

  7. Laser-scanning photoacoustic microscopy with ultrasonic phased array transducer

    PubMed Central

    Zheng, Fan; Zhang, Xiangyang; Chiu, Chi Tat; Zhou, Bill L.; Shung, K. Kirk; Zhang, Hao F.; Jiao, Shuliang

    2012-01-01

    In this paper, we report our latest progress on proving the concept that ultrasonic phased array can improve the detection sensitivity and field of view (FOV) in laser-scanning photoacoustic microscopy (LS-PAM). A LS-PAM system with a one-dimensional (1D) ultrasonic phased array was built for the experiments. The 1D phased array transducer consists of 64 active elements with an overall active dimension of 3.2 mm × 2 mm. The system was tested on imaging phantom and mouse ear in vivo. Experiments showed a 15 dB increase of the signal-to-noise ratio (SNR) when beamforming was employed compared to the images acquired with each single element. The experimental results demonstrated that ultrasonic phased array can be a better candidate for LS-PAM in high sensitivity applications like ophthalmic imaging. PMID:23162708

  8. BDNF - a key transducer of antidepressant effects.

    PubMed

    Björkholm, Carl; Monteggia, Lisa M

    2016-03-01

    How do antidepressants elicit an antidepressant response? Here, we review accumulating evidence that the neurotrophin brain-derived neurotrophic factor (BDNF) serves as a transducer, acting as the link between the antidepressant drug and the neuroplastic changes that result in the improvement of the depressive symptoms. Over the last decade several studies have consistently highlighted BDNF as a key player in antidepressant action. An increase in hippocampal and cortical expression of BDNF mRNA parallels the antidepressant-like response of conventional antidepressants such as SSRIs. Subsequent studies showed that a single bilateral infusion of BDNF into the ventricles or directly into the hippocampus is sufficient to induce a relatively rapid and sustained antidepressant-like effect. Importantly, the antidepressant-like response to conventional antidepressants is attenuated in mice where the BDNF signaling has been disrupted by genetic manipulations. Low dose ketamine, which has been found to induce a rapid antidepressant effect in patients with treatment-resistant depression, is also dependent on increased BDNF signaling. Ketamine transiently increases BDNF translation in hippocampus, leading to enhanced synaptic plasticity and synaptic strength. Ketamine has been shown to increase BDNF translation by blocking NMDA receptor activity at rest, thereby inhibiting calcium influx and subsequently halting eukaryotic elongation factor 2 (eEF2) kinase leading to a desuppression of protein translation, including BDNF translation. The antidepressant-like response of ketamine is abolished in BDNF and TrkB conditional knockout mice, eEF2 kinase knockout mice, in mice carrying the BDNF met/met allele, and by intra-cortical infusions of BDNF-neutralizing antibodies. In summary, current data suggests that conventional antidepressants and ketamine mediate their antidepressant-like effects by increasing BDNF in forebrain regions, in particular the hippocampus, making BDNF an

  9. Biased signaling by peptide agonists of protease activated receptor 2.

    PubMed

    Jiang, Yuhong; Yau, Mei-Kwan; Kok, W Mei; Lim, Junxian; Wu, Kai-Chen; Liu, Ligong; Hill, Timothy A; Suen, Jacky Y; Fairlie, David P

    2017-02-07

    Protease activated receptor 2 (PAR2) is associated with metabolism, obesity, inflammatory, respiratory and gastrointestinal disorders, pain, cancer and other diseases. The extracellular N-terminus of PAR2 is a common target for multiple proteases, which cleave it at different sites to generate different N-termini that activate different PAR2-mediated intracellular signaling pathways. There are no synthetic PAR2 ligands that reproduce the same signaling profiles and potencies as proteases. Structure-activity relationships here for 26 compounds spanned a signaling bias over 3 log units, culminating in three small ligands as biased agonist tools for interrogating PAR2 functions. DF253 (2f-LAAAAI-NH2) triggered PAR2-mediated calcium release (EC50 2 μM) but not ERK1/2 phosphorylation (EC50 > 100 μM) in CHO cells transfected with hPAR2. AY77 (Isox-Cha-Chg-NH2) was a more potent calcium-biased agonist (EC50 40 nM, Ca2+; EC50 2 μM, ERK1/2), while its analogue AY254 (Isox-Cha-Chg-A-R-NH2) was an ERK-biased agonist (EC50 2 nM, ERK1/2; EC50 80 nM, Ca2+). Signaling bias led to different functional responses in human colorectal carcinoma cells (HT29). AY254, but not AY77 or DF253, attenuated cytokine-induced caspase 3/8 activation, promoted scratch-wound healing and induced IL-8 secretion, all via PAR2-ERK1/2 signaling. Different ligand components were responsible for different PAR2 signaling and functions, clues that can potentially lead to drugs that modulate different pathway-selective cellular and physiological responses.

  10. 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.

  11. Underwater Multimode Directional Transducer Evaluation

    DTIC Science & Technology

    2003-12-01

    The work described in the present thesis is intended to establish a procedure for analyzing directional transducers for future underwater wireless...networks, as well as to carry out the performance evaluation of a multimode transducer prototype with respect to its main operational requirements

  12. Stimulation of the B-cell receptor activates the JAK2/STAT3 signaling pathway in chronic lymphocytic leukemia cells

    PubMed Central

    Rozovski, Uri; Wu, Ji Yuan; Harris, David M.; Liu, Zhiming; Li, Ping; Hazan-Halevy, Inbal; Ferrajoli, Alessandra; Burger, Jan A.; O’Brien, Susan; Jain, Nitin; Verstovsek, Srdan; Wierda, William G.; Keating, Michael J.

    2014-01-01

    In chronic lymphocytic leukemia (CLL), stimulation of the B-cell receptor (BCR) triggers survival signals. Because in various cells activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway provides cells with survival advantage, we wondered whether BCR stimulation activates the JAK/STAT pathway in CLL cells. To stimulate the BCR we incubated CLL cells with anti-IgM antibodies. Anti-IgM antibodies induced transient tyrosine phosphorylation and nuclear localization of phosphorylated (p) STAT3. Immunoprecipitation studies revealed that anti-JAK2 antibodies coimmunoprecipitated pSTAT3 and pJAK2 in IgM-stimulated but not unstimulated CLL cells, suggesting that activation of the BCR induces activation of JAK2, which phosphorylates STAT3. Incubation of CLL cells with the JAK1/2 inhibitor ruxolitinib inhibited IgM-induced STAT3 phosphorylation and induced apoptosis of IgM-stimulated but not unstimulated CLL cells in a dose- and time-dependent manner. Whether ruxolitinib treatment would benefit patients with CLL remains to be determined. PMID:24778152

  13. Stimulation of the B-cell receptor activates the JAK2/STAT3 signaling pathway in chronic lymphocytic leukemia cells.

    PubMed

    Rozovski, Uri; Wu, Ji Yuan; Harris, David M; Liu, Zhiming; Li, Ping; Hazan-Halevy, Inbal; Ferrajoli, Alessandra; Burger, Jan A; O'Brien, Susan; Jain, Nitin; Verstovsek, Srdan; Wierda, William G; Keating, Michael J; Estrov, Zeev

    2014-06-12

    In chronic lymphocytic leukemia (CLL), stimulation of the B-cell receptor (BCR) triggers survival signals. Because in various cells activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway provides cells with survival advantage, we wondered whether BCR stimulation activates the JAK/STAT pathway in CLL cells. To stimulate the BCR we incubated CLL cells with anti-IgM antibodies. Anti-IgM antibodies induced transient tyrosine phosphorylation and nuclear localization of phosphorylated (p) STAT3. Immunoprecipitation studies revealed that anti-JAK2 antibodies coimmunoprecipitated pSTAT3 and pJAK2 in IgM-stimulated but not unstimulated CLL cells, suggesting that activation of the BCR induces activation of JAK2, which phosphorylates STAT3. Incubation of CLL cells with the JAK1/2 inhibitor ruxolitinib inhibited IgM-induced STAT3 phosphorylation and induced apoptosis of IgM-stimulated but not unstimulated CLL cells in a dose- and time-dependent manner. Whether ruxolitinib treatment would benefit patients with CLL remains to be determined.

  14. [Activators, receptors and signal transduction pathways of blood platelets].

    PubMed

    Shaturnyĭ, V I; Shakhidzhanov, S S; Sveshnikova, A N; Panteleev, M A

    2014-01-01

    Platelet participation in hemostatic plug formation requires transition into an activated state (or, rather, variety of states) upon action of agonists like ADP, thromboxane A , collagen, thrombin, and others. The mechanisms of action for different agonists, their receptors and signaling pathways associated with them, as well as the mechanisms of platelet response inhibition are the subject of the present review. Collagen exposed upon vessel wall damage induced initial platelet attachment and start of thrombus formation, which involves numerous processes such as aggregation, activation of integrins, granule secretion and increase of intracellular Ca2+. Thrombin, ADP, thromboxane A , and ATP activated platelets that were not initially in contact with the wall and induce additional secretion of activating substances. Vascular endothelium and secretory organs also affect platelet activation, producing both positive (adrenaline) an d negative (prostacyclin, nitric oxide) regulators, thereby determining the relation of activation and inhibition signals, which plays a significant role in the formation of platelet aggregate under normal and pathological conditions. The pathways of platelet signaling are still incompletely understood, and their exploration presents an important objective both for basic cell biology and for the development of new drugs, the methods of diagnostics and of treatment of hemostasis disorders.

  15. Low Voltage Piezoelectric Composite for Transducer Applications

    DTIC Science & Technology

    2005-02-25

    Pillars 10 are supported in 10 panel 20 by insulating material 18. Insulating material 18 can 11 be a dielectric polymer matrix or an elastomeric ...Additionally, the field. 22 impressed on the surface doesn’t couple completely to the 23 internal volume of the active material . 9 1 In view of the above...The active layer of the transducer is either lead 16 zirconium-titanate or lead magnesium-niobate. This material is 17 incorporated in a polymer

  16. Piezoelectric polymer foams: transducer mechanism and preparation as well as touch-sensor and ultrasonic-transducer properties

    NASA Astrophysics Data System (ADS)

    Wegener, M.

    2010-04-01

    Different materials provide a mechanical-electrical energy conversion and are thus interesting candidates for piezoelectric sensors and actuators. Beside ferroelectric ceramics and polymers, also polymer foams, so-called ferroelectrets, are developed as piezoelectric active materials. Their piezoelectricity originates from optimized structural and elastic-foam properties accompanied with an optimized charge trapping at the polymer layers within the foam structure. The piezoelectric activity arises if mechanical stimuli lead to a thickness variation of the electrically charged voids which results in an electrical signal between the connected electrodes on the film surfaces due to the change of internal electric fields. The concept of such a piezoelectric transducer was developed by investigating cellular polypropylene films with different foam structures and thus different elastic properties. Recently, ferroelectrets were prepared from other polymers following the same concept. Different kind of new foaming procedures are developed in order to broaden the range of usable materials as well as to optimize the adjustment of piezoelectric and ultrasonictransducer properties. The paper provides an overview about ferroelectrets, their underlying working mechanism as well as their preparation possibilities. In detail, piezoelectric properties of polypropylene ferroelectrets are described which are usable for pushbutton or touch-pad applications as well as in ultrasonic-transducer applications.

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

    PubMed

    Cerutti, Andrea; Cols, Montserrat; Puga, Irene

    2012-09-01

    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.

  18. 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

  19. 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.

  20. Regulation of Chemokine Signal Integration by Activator of G-Protein Signaling 4 (AGS4)

    PubMed Central

    Robichaux, William G.; Branham-O’Connor, Melissa; Hwang, Il-Young; Vural, Ali; Kehrl, Johne H.

    2017-01-01

    Activator of G-protein signaling 4 (AGS4)/G-protein signaling modulator 3 (Gpsm3) contains three G-protein regulatory (GPR) motifs, each of which can bind Gαi-GDP free of Gβγ. We previously demonstrated that the AGS4-Gαi interaction is regulated by seven transmembrane-spanning receptors (7-TMR), which may reflect direct coupling of the GPR-Gαi module to the receptor analogous to canonical Gαβγ heterotrimer. We have demonstrated that the AGS4-Gαi complex is regulated by chemokine receptors in an agonist-dependent manner that is receptor-proximal. As an initial approach to investigate the functional role(s) of this regulated interaction in vivo, we analyzed leukocytes, in which AGS4/Gpsm3 is predominantly expressed, from AGS4/Gpsm3-null mice. Loss of AGS4/Gpsm3 resulted in mild but significant neutropenia and leukocytosis. Dendritic cells, T lymphocytes, and neutrophils from AGS4/Gpsm3-null mice also exhibited significant defects in chemoattractant-directed chemotaxis and extracellular signal-regulated kinase activation. An in vivo peritonitis model revealed a dramatic reduction in the ability of AGS4/Gpsm3-null neutrophils to migrate to primary sites of inflammation. Taken together, these data suggest that AGS4/Gpsm3 is required for proper chemokine signal processing in leukocytes and provide further evidence for the importance of the GPR-Gαi module in the regulation of leukocyte function. PMID:28062526

  1. Circuit for Driving Piezoelectric Transducers

    NASA Technical Reports Server (NTRS)

    Randall, David P.; Chapsky, Jacob

    2009-01-01

    The figure schematically depicts an oscillator circuit for driving a piezoelectric transducer to excite vibrations in a mechanical structure. The circuit was designed and built to satisfy application-specific requirements to drive a selected one of 16 such transducers at a regulated amplitude and frequency chosen to optimize the amount of work performed by the transducer and to compensate for both (1) temporal variations of the resonance frequency and damping time of each transducer and (2) initially unknown differences among the resonance frequencies and damping times of different transducers. In other words, the circuit is designed to adjust itself to optimize the performance of whichever transducer is selected at any given time. The basic design concept may be adaptable to other applications that involve the use of piezoelectric transducers in ultrasonic cleaners and other apparatuses in which high-frequency mechanical drives are utilized. This circuit includes three resistor-capacitor networks that, together with the selected piezoelectric transducer, constitute a band-pass filter having a peak response at a frequency of about 2 kHz, which is approximately the resonance frequency of the piezoelectric transducers. Gain for generating oscillations is provided by a power hybrid operational amplifier (U1). A junction field-effect transistor (Q1) in combination with a resistor (R4) is used as a voltage-variable resistor to control the magnitude of the oscillation. The voltage-variable resistor is part of a feedback control loop: Part of the output of the oscillator is rectified and filtered for use as a slow negative feedback to the gate of Q1 to keep the output amplitude constant. The response of this control loop is much slower than 2 kHz and, therefore, does not introduce significant distortion of the oscillator output, which is a fairly clean sine wave. The positive AC feedback needed to sustain oscillations is derived from sampling the current through the

  2. Characterization of Transducers and Resonators under High Drive Levels

    NASA Technical Reports Server (NTRS)

    Sherrit, Stewart; Bao, X.; Sigel, D. A.; Gradziel, M. J.; Askins, S. A.; Dolgin, B. P.; Bar-Cohen, Y.

    2001-01-01

    In many applications, piezoelectric transducers are driven at AC voltage levels well beyond the level for which the material was nominally characterized. In this paper we describe an experimental setup that allows for the determination of the main transducer or resonator properties under large AC drive. A sinusoidal voltage from a waveform generator is amplified and applied across the transducer/resonator in series with a known high power resistor. The amplitude of applied voltage and the amplitude and the relative phase of the current through the resistor are monitored on a digital scope. The frequency of the applied signal is swept through resonance and the voltage/current signals are recorded. After corrections for the series resistance and parasitic elements the technique allows for the determination of the complex impedance spectra of the sample as a function of frequency. In addition, access to the current signal allows for the direct investigation of non-linear effects through the application of Fourier transform techniques on the current signal. Our results indicate that care is required when interpreting impedance data at high drive level due to the frequency dependence of the dissipated power. Although the transducer/resonator at a single frequency and after many cycles may reach thermal equilibrium, the spectra as a whole cannot be considered an isothermal measurement due to the temperature change with frequency. Methods to correct for this effect will be discussed. Results determined from resonators of both soft and hard PZT and a ultrasonic horn transducer are presented.

  3. Sphingosine-1-phosphate enhances satellite cell activation in dystrophic muscles through a S1PR2/STAT3 signaling pathway.

    PubMed

    Loh, Kenneth C; Leong, Weng-In; Carlson, Morgan E; Oskouian, Babak; Kumar, Ashok; Fyrst, Henrik; Zhang, Meng; Proia, Richard L; Hoffman, Eric P; Saba, Julie D

    2012-01-01

    Sphingosine-1-phosphate (S1P) activates a widely expressed family of G protein-coupled receptors, serves as a muscle trophic factor and activates muscle stem cells called satellite cells (SCs) through unknown mechanisms. Here we show that muscle injury induces dynamic changes in S1P signaling and metabolism in vivo. These changes include early and profound induction of the gene encoding the S1P biosynthetic enzyme SphK1, followed by induction of the catabolic enzyme sphingosine phosphate lyase (SPL) 3 days later. These changes correlate with a transient increase in circulating S1P levels after muscle injury. We show a specific requirement for SphK1 to support efficient muscle regeneration and SC proliferation and differentiation. Mdx mice, which serve as a model for muscular dystrophy (MD), were found to be S1P-deficient and exhibited muscle SPL upregulation, suggesting that S1P catabolism is enhanced in dystrophic muscle. Pharmacological SPL inhibition increased muscle S1P levels, improved mdx muscle regeneration and enhanced SC proliferation via S1P receptor 2 (S1PR2)-dependent inhibition of Rac1, thereby activating Signal Transducer and Activator of Transcription 3 (STAT3), a central player in inflammatory signaling. STAT3 activation resulted in p21 and p27 downregulation in a S1PR2-dependent fashion in myoblasts. Our findings suggest that S1P promotes SC progression through the cell cycle by repression of cell cycle inhibitors via S1PR2/STAT3-dependent signaling and that SPL inhibition may provide a therapeutic strategy for MD.

  4. Energetics of neuronal signaling and fMRI activity.

    PubMed

    Maandag, Natasja J G; Coman, Daniel; Sanganahalli, Basavaraju G; Herman, Peter; Smith, Arien J; Blumenfeld, Hal; Shulman, Robert G; Hyder, Fahmeed

    2007-12-18

    Energetics of resting and evoked fMRI signals were related to localized ensemble firing rates (nu) measured by electrophysiology in rats. Two different unstimulated, or baseline, states were established by anesthesia. Halothane and alpha-chloralose established baseline states of high and low energy, respectively, in which forepaw stimulation excited the contralateral primary somatosensory cortex (S1). With alpha-chloralose, forepaw stimulation induced strong and reproducible fMRI activations in the contralateral S1, where the ensemble firing was dominated by slow signaling neurons (SSN; nu range of 1-13 Hz). Under halothane, weaker and less reproducible fMRI activations were observed in the contralateral S1 and elsewhere in the cortex, but ensemble activity in S1 was dominated by rapid signaling neurons (RSN; nu range of 13-40 Hz). For both baseline states, the RSN activity (i.e., higher frequencies, including the gamma band) did not vary upon stimulation, whereas the SSN activity (i.e., alpha band and lower frequencies) did change. In the high energy baseline state, a large majority of total oxidative energy [cerebral metabolic rate of oxygen consumption (CMR(O2))] was devoted to RSN activity, whereas in the low energy baseline state, it was roughly divided between SSN and RSN activities. We hypothesize that in the high energy baseline state, the evoked changes in fMRI activation in areas beyond S1 are supported by rich intracortical interactions represented by RSN. We discuss implications for interpreting fMRI data where stimulus-specific DeltaCMR(O2) is generally small compared with baseline CMR(O2).

  5. Surface acoustic wave unidirectional transducers for quantum applications

    NASA Astrophysics Data System (ADS)

    Ekström, Maria K.; Aref, Thomas; Runeson, Johan; Björck, Johan; Boström, Isac; Delsing, Per

    2017-02-01

    The conversion efficiency of electric microwave signals into surface acoustic waves in different types of superconducting transducers is studied with the aim of quantum applications. We compare delay lines containing either conventional symmetric transducers (IDTs) or unidirectional transducers (UDTs) at 2.3 GHz and 10 mK. The UDT delay lines improve the insertion loss with 4.7 dB and a directivity of 22 dB is found for each UDT, indicating that 99.4% of the acoustic power goes in the desired direction. The power lost in the undesired direction accounts for more than 90% of the total loss in IDT delay lines, but only ˜3% of the total loss in the floating electrode unidirectional transducer delay lines.

  6. Photoacoustic tomography of monkey brain using virtual point ultrasonic transducers.

    PubMed

    Nie, Liming; Guo, Zijian; Wang, Lihong V

    2011-07-01

    A photoacoustic tomography system (PAT) using virtual point ultrasonic transducers was developed and applied to image a monkey brain. The custom-built transducers provide a 10-fold greater field-of-view (FOV) than finite-aperture unfocused transducers as well as an improved signal-to-noise ratio (SNR) and reduced artifacts rather than negative-lens transducers. Their tangential resolution, radial resolution, and (SNR) improvements were quantified using tissue phantoms. Our PAT system can achieve high uniformity in both resolution (<1 mm) and SNR (>8) within a large FOV of 6 cm in diameter, even when the imaging objects are enclosed by a monkey skull. The cerebral cortex of a monkey brain was accurately mapped transcranially, through a skull ranging from 2 to 4 mm in thickness. This study demonstrates that PAT can overcome the optical and ultrasound attenuation of a relatively thick skull and can potentially be applied to human neonatal brain imaging.

  7. Dynamic Hedgehog signalling pathway activity in germline stem cells.

    PubMed

    Sahin, Z; Szczepny, A; McLaughlin, E A; Meistrich, M L; Zhou, W; Ustunel, I; Loveland, K L

    2014-03-01

    Although the contribution of Hedgehog (Hh) signalling to stem cell development and oncogenesis is well recognised, its importance for spermatogonial stem cells (SSCs) has not been established. Here we interrogate adult rat SSCs using an established model in which only undifferentiated spermatogonial cells remain in the testis at 15 weeks following irradiation, and spermatogonial differentiation is induced within 4 weeks by gonadotrophin-releasing hormone antagonist (GnRH-ant) administration. Synthesis of Hh pathway components in untreated adult rat testes was compared with that in irradiated testes prior to and after GnRH-ant exposure using in situ hybridization. In adult testes with complete spermatogenesis, the Desert Hedgehog ligand transcript, Dhh, was detected in Sertoli cells, some spermatogonia and in spermatocytes by in situ hybridization. Spermatogenic cells were identified as sites of Hh signalling through detection of transcripts encoding the Hh receptor, Ptc2 transcripts and proteins for the key downstream target of Hh signalling, Gli1 and the Hh transcriptional activator, Gli2. Remarkably, the undifferentiated spermatogonia present in irradiated adult rat testes contained Dhh in addition to Ptc2, Gli1 and Gli2, revealing the potential for an autocrine Hh signalling loop to sustain undifferentiated spermatogonial cells. These transcripts became undetectable by in situ hybridization following GnRH-ant induction of spermatogonial differentiation, however, detection of Gli1 protein in spermatogonia in all groups indicates that Hh signalling is sustained. This is the first evidence of active Hh signalling in mammalian male germline stem cells, as has been documented for some cancer stem cells.

  8. Folding and Function of Proteorhodopsins in Photoenergy Transducing Membranes

    SciTech Connect

    Spudich, John L

    2012-08-10

    The overall research objectives are to develop proteorhodopsin (PR) proteins as a model system for {alpha}-helical membrane protein insertion and folding, and to advance understanding of the diversity and mechanisms of PRs, a large family of photoenergy transducers (~4000 identified) abundant in the world’s oceans. Specific aims are: (1) To develop a highefficiency genetic selection procedure for light-driven proton-pumping in E. coli cells. Such a procedure would provide a positive selection method for proper folding and function of PRs in the E. coli membrane. (2) Characterize flash-induced absorption changes and photocurrents in PR variants in organisms from various environments, and their expression level and function when expressed in E. coli. Subaims are to: (a) elucidate the relationship of the transport mechanism to mechanisms of other microbial rhodopsins, some of which like PRs function as ion transporters and some of which use light energy to activate signaling pathways (sensory rhodopsins); and (b) identify important residues and chemical events in light-driven proton transport by PRs. In addition to their importance to the energy of the biosphere PRs have attracted interest for their potential for use in making photoenergy-transducing membranes for bioengineering applications.

  9. PMN-PT single crystal focusing transducer fabricated using a mechanical dimpling technique.

    PubMed

    Lam, K H; Chen, Y; Cheung, K F; Dai, J Y

    2012-01-01

    A ∼5MHz focusing PMN-PT single crystal ultrasound transducer has been fabricated utilizing a mechanical dimpling technique, where the dimpled crystal wafer was used as an active element of the focusing transducer. For the dimpled focusing transducer, the effective electromechanical coupling coefficient was enhanced significantly from 0.42 to 0.56. The dimpled transducer also yields a -6dB bandwidth of 63.5% which is almost double the bandwidth of the plane transducer. An insertion loss of the dimpled transducer (-18.1dB) is much lower than that of the plane transducer. Finite element simulation also reveals specific focused beam from concave crystal surface. These promising results show that the dimpling technique can be used to develop high-resolution focusing single crystal transducers.

  10. Different activation signals induce distinct mast cell degranulation strategies

    PubMed Central

    Sibilano, Riccardo; Marichal, Thomas; Reber, Laurent L.; Cenac, Nicolas; McNeil, Benjamin D.; Dong, Xinzhong; Hernandez, Joseph D.; Sagi-Eisenberg, Ronit; Hammel, Ilan; Roers, Axel; Valitutti, Salvatore; Tsai, Mindy

    2016-01-01

    Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules. Conversely, activating MCs with anti-IgE increased the time partition between signaling and secretion, which was associated with a period of sustained elevation of intracellular calcium and formation of larger and more heterogeneously shaped granule structures that underwent prolonged exteriorization. Pharmacological inhibition of IKK-β during IgE-dependent stimulation strongly reduced the time partition between signaling and secretion, inhibited SNAP23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulation induced by substance P. IgE-dependent and substance P–dependent activation in vivo also induced different patterns of mouse MC degranulation that were associated with distinct local and systemic pathophysiological responses. These findings show that cytoplasmic granule secretion from MCs that occurs in response to different activating stimuli can exhibit distinct dynamics and features that are associated with distinct patterns of MC-dependent inflammation. PMID:27643442

  11. 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

  12. Kinetic energy transducing system

    SciTech Connect

    Danihel, M.

    1986-07-08

    A device is described for converting wave energy to mechanical motion comprising: a frame, at least one wave energy transducer each of which has a float to ride upon the undulating surface of a body of water, a rocker shaft rotatably mounted in the frame and connected to the float by a rocker arm to turn in response to movement of the float upon the undulating water surface, a pair of unidirectional clutch mechanisms coupled to the rocker shaft, a drive shaft rotatably mounted on the frame and connected to the clutch mechanisms to turn in a single direction of rotation responsive to alternative engagement of the clutch mechanisms therewith and turning movement of the rocker shaft in both directions of rotation, and a hydrofoil system for each float including a vertical shaft extending downwardly from the bottom of each float, a transverse rod which is rotatably coupled to the vertical shaft, a pair of hydrofoil wings secured to the transverse rod on opposite sides of the vertical shaft, and means for centering the hydrofoil wings acting between the vertical shaft and the transverse rod to urge the hydrofoil wings toward horizontal orientation.

  13. Cherry Valley Ducks Mitochondrial Antiviral-Signaling Protein-Mediated Signaling Pathway and Antiviral Activity Research

    PubMed Central

    Li, Ning; Hong, Tianqi; Li, Rong; Wang, Yao; Guo, Mengjiao; Cao, Zongxi; Cai, Yumei; Liu, Sidang; Chai, Tongjie; Wei, Liangmeng

    2016-01-01

    Mitochondrial antiviral-signaling protein (MAVS), an adaptor protein of retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs)-mediated signal pathway, is involved in innate immunity. In this study, Cherry Valley duck MAVS (duMAVS) was cloned from the spleen and analyzed. duMAVS was determined to have a caspase activation and recruitment domain at N-terminal, followed by a proline-rich domain and a transmembrane domain at C-terminal. Quantitative real-time PCR indicated that duMAVS was expressed in all tissues tested across a broad expression spectrum. The expression of duMAVS was significantly upregulated after infection with duck Tembusu virus (DTMUV). Overexpression of duMAVS could drive the activation of interferon (IFN)-β, nuclear factor-κB, interferon regulatory factor 7, and many downstream factors (such as Mx, PKR, OAS, and IL-8) in duck embryo fibroblast cells. What is more, RNA interference further confirmed that duMAVS was an important adaptor for IFN-β activation. The antiviral assay showed that duMAVS could suppress the various viral replications (DTMUV, novel reovirus, and duck plague virus) at early stages of infection. Overall, these results showed that the main signal pathway mediated by duMAVS and it had a broad-spectrum antiviral ability. This research will be helpful to better understanding the innate immune system of ducks. PMID:27708647

  14. Dynorphin Activates Quorum Sensing Quinolone Signaling in Pseudomonas aeruginosa

    PubMed Central

    Zaborina, Olga; Lepine, Francois; Xiao, Gaoping; Valuckaite, Vesta; Chen, Yimei; Li, Terry; Ciancio, Mae; Zaborin, Alex; Petroff, Elaine; Turner, Jerrold R; Rahme, Laurence G; Chang, Eugene; Alverdy, John C

    2007-01-01

    There is now substantial evidence that compounds released during host stress directly activate the virulence of certain opportunistic pathogens. Here, we considered that endogenous opioids might function as such compounds, given that they are among the first signals to be released at multiple tissue sites during host stress. We tested the ability of various opioid compounds to enhance the virulence of Pseudomonas aeruginosa using pyocyanin production as a biological readout, and demonstrated enhanced virulence when P. aeruginosa was exposed to synthetic (U-50,488) and endogenous (dynorphin) κ-agonists. Using various mutants and reporter strains of P. aeruginosa, we identified involvement of key elements of the quorum sensing circuitry such as the global transcriptional regulator MvfR and the quorum sensing-related quinolone signaling molecules PQS, HHQ, and HQNO that respond to κ-opioids. The in vivo significance of κ-opioid signaling of P. aeruginosa was demonstrated in mice by showing that dynorphin is released from the intestinal mucosa following ischemia/reperfusion injury, activates quinolone signaling in P. aeruginosa, and enhances the virulence of P. aeruginosa against Lactobacillus spp. and Caenorhabditis elegans. Taken together, these data demonstrate that P. aeruginosa can intercept opioid compounds released during host stress and integrate them into core elements of quorum sensing circuitry leading to enhanced virulence. PMID:17367209

  15. Passive wireless ultrasonic transducer systems

    NASA Astrophysics Data System (ADS)

    Zhong, C. H.; Croxford, A. J.; Wilcox, P. D.

    2014-02-01

    Inductive coupling and capacitive coupling both offer simple solutions to wirelessly probe ultrasonic transducers. This paper investigates the theory and feasibility of such system in the context of non-destructive evaluation (NDE) applications. Firstly, the physical principles and construction of an inductively coupled transducer system (ICTS) and a capacitively coupled transducer system (CCTS) are introduced. Then the development of a transmission line model with the measured impedance of a bonded piezoelectric ceramic disc representing a sensor attached to an arbitrary solid substrate for both systems is described. The models are validated experimentally. Several applications of CCTS are presented, such CCTS for the underwater and through-composite testing.

  16. Capacitive Ultrasonic Transducer Development for Acoustic Anemometry on Mars

    NASA Astrophysics Data System (ADS)

    Leonard-Pugh, Eurion; Wilson, C.; Calcutt, S.; Davis, L.

    2012-10-01

    Previous Mars missions have used either mechanical or thermal anemometry techniques. The moving parts of mechanical anemometers are prone to damage during launch and landing and their inertia makes them unsuited for turbulence studies. Thermal anemometers have been used successfully on Mars but are difficult to calibrate and susceptible to varying ambient temperatures. In ultrasonic anemometry, wind speed and sound speed are calculated from two-way time-of-flight measurements between pairs of transducers; three pairs of transducers are used to return a 3-D wind vector. These high-frequency measurements are highly reliable and immune from drift. Piezo-electric ultrasonic anemometers are widely used on Earth due to their full-range accuracy and high measurement frequency. However these transducers have high acoustic impedances and would not work on Mars. We are developing low-mass capacitive ultrasonic transducers for Mars missions which have significantly lower acoustic impedances and would therefore have a much stronger coupling to the Martian atmosphere. These transducers consist of a metallised polymer film pulled taught against a machined metal backplane. The film is drawn towards the backplane by a DC bias voltage. A varying signal is used on top of the DC bias to oscillate the film; generating acoustic waves. This poster will look at the operation of such sensors and the developments necessary to operate the devices under Martian conditions. Transducer performance is determined primarily by two elements; the front film and the backplane. The sensitivity of the transducer is affected by the thickness of the front film; as well as the diameter, curvature and roughness of the metal backplane. We present data on the performance of the sensors and instrument design considerations including signal shapes and transducer arrangements.

  17. Plant PRRs and the activation of innate immune signaling.

    PubMed

    Macho, Alberto P; Zipfel, Cyril

    2014-04-24

    Despite being sessile organisms constantly exposed to potential pathogens and pests, plants are surprisingly resilient to infections. Plants can detect invaders via the recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). Plant PRRs are surface-localized receptor-like kinases, which comprise a ligand-binding ectodomain and an intracellular kinase domain, or receptor-like proteins, which do not exhibit any known intracellular signaling domain. In this review, we summarize recent discoveries that shed light on the molecular mechanisms underlying ligand perception and subsequent activation of plant PRRs. Notably, plant PRRs appear as central components of multiprotein complexes at the plasma membrane that contain additional transmembrane and cytosolic kinases required for the initiation and specificity of immune signaling. PRR complexes are under tight control by protein phosphatases, E3 ligases, and other regulatory proteins, illustrating the exquisite and complex regulation of these molecular machines whose proper activation underlines a crucial layer of plant immunity.

  18. Structure-activity analysis of the Pseudomonas quinolone signal molecule.

    PubMed

    Hodgkinson, James; Bowden, Steven D; Galloway, Warren R J D; Spring, David R; Welch, Martin

    2010-07-01

    We synthesized a range of PQS (Pseudomonas quinolone signal; 2-heptyl-3-hydroxy-4(1H)-quinolone) analogues and tested them for their ability to stimulate MvfR-dependent pqsA transcription, MvfR-independent pyoverdine production, and membrane vesicle production. The structure-activity profile of the PQS analogues was different for each of these phenotypes. Certain inactive PQS analogues were also found to strongly synergize PQS-dependent pyoverdine production.

  19. The primary cilia, a 'Rab-id' transit system for hedgehog signaling.

    PubMed

    Oro, Anthony E

    2007-12-01

    Intense focus has been centered around how the primary cilia transduces the hedgehog (Hh) signal from smoothened (Smo) to the Gli transcription factors. New data indicate that ligand and signaling lipids help regulate small GTPase-dependent accumulation and activity of signaling components.

  20. 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.

  1. Implications of mitogen-activated protein kinase signaling in glioma.

    PubMed

    Pandey, Vimal; Bhaskara, Vasantha Kumar; Babu, Phanithi Prakash

    2016-02-01

    Gliomas are the most common primary central nervous system tumors. Gliomas originate from astrocytes, oligodendrocytes, and neural stem cells or their precursors. According to WHO classification, gliomas are classified into four different malignant grades ranging from grade I to grade IV based on histopathological features and related molecular aberrations. The induction and maintenance of these tumors can be attributed largely to aberrant signaling networks. In this regard, the mitogen-activated protein kinase (MAPK) network has been widely studied and is reported to be severely altered in glial tumors. Mutations in MAPK pathways most frequently affect RAS and B-RAF in the ERK, c-Jun N-terminal kinase (JNK), and p38 pathways leading to malignant transformation. Also, it is linked to both inherited and sequential accumulations of mutations that control receptor tyrosine kinase (RTK)-activated signal transduction pathways, cell cycle growth arrest pathways, and nonresponsive cell death pathways. Genetic alterations that modulate RTK signaling can also alter several downstream pathways, including RAS-mediated MAP kinases along with JNK pathways, which ultimately regulate cell proliferation and cell death. The present review focuses on recent literature regarding important deregulations in the RTK-activated MAPK pathway during gliomagenesis and progression.

  2. Divergent transducer-specific molecular efficacies generate biased agonism at a G protein-coupled receptor (GPCR).

    PubMed

    Strachan, Ryan T; Sun, Jin-peng; Rominger, David H; Violin, Jonathan D; Ahn, Seungkirl; Rojas Bie Thomsen, Alex; Zhu, Xiao; Kleist, Andrew; Costa, Tommaso; Lefkowitz, Robert J

    2014-05-16

    The concept of "biased agonism" arises from the recognition that the ability of an agonist to induce a receptor-mediated response (i.e. "efficacy") can differ across the multiple signal transduction pathways (e.g. G protein and β-arrestin (βarr)) emanating from a single GPCR. Despite the therapeutic promise of biased agonism, the molecular mechanism(s) whereby biased agonists selectively engage signaling pathways remain elusive. This is due in large part to the challenges associated with quantifying ligand efficacy in cells. To address this, we developed a cell-free approach to directly quantify the transducer-specific molecular efficacies of balanced and biased ligands for the angiotensin II type 1 receptor (AT1R), a prototypic GPCR. Specifically, we defined efficacy in allosteric terms, equating shifts in ligand affinity (i.e. KLo/KHi) at AT1R-Gq and AT1R-βarr2 fusion proteins with their respective molecular efficacies for activating Gq and βarr2. Consistent with ternary complex model predictions, transducer-specific molecular efficacies were strongly correlated with cellular efficacies for activating Gq and βarr2. Subsequent comparisons across transducers revealed that biased AT1R agonists possess biased molecular efficacies that were in strong agreement with the signaling bias observed in cellular assays. These findings not only represent the first measurements of the thermodynamic driving forces underlying differences in ligand efficacy between transducers but also support a molecular mechanism whereby divergent transducer-specific molecular efficacies generate biased agonism at a GPCR.

  3. Electromagnetic acoustic transducers (EMATs) for erosion monitoring

    SciTech Connect

    Reimann, K.J.

    1984-05-01

    Early detection, measurement, and monitoring of erosive wear rates can alleviate problems of unpredictable shutdowns, costly downtimes, and improper process operation. The first generation of a nondestructive, noninvasive acoustic-based system was tested on pressure boundaries of fossil energy conversion plants, yielding the desired information. Multiple transducers and wave guides are needed for such a system in order to determine wear profiles in large components. The same information could, however, be obtained with a single, scanning electromagnetic transducer (EMAT). Advantages of such EMAT-based systems motivated this investigation in order to establish criteria and requirements needed for erosion monitoring at elevated (operating) temperatures. The effort concentrated on three areas: (a) development of EMAT design parameters, (b) material-EMAT interaction, and (c) signal processing. Prototype horizontal shearwave EMATs, based on design parameters selected from computer calculations of the static field, were evaluated, and their performance was compared to the performance of piezoelectric transducers. Input power requirements for a larger than 10-dB signal-to-noise (S/N) ratio were established for various structural and hardfacing materials. Effects of surface roughness and temperature were determined for different test conditions. The results indicate that accurate wall thickness measurement can be performed at elevated temperature on rough surfaces as encountered, for instance, in a cyclone. Modern data processing such as signal averaging on correlation improves the S/N ratio from 12 dB to 26 dB and enables wall thickness measurements with an accuracy of +-0.25% of total wall thickness. Additional efforts are needed to determine requirements of EMATs in scanning mode and pulsed static field operation.

  4. Fixture for holding testing transducer

    DOEpatents

    Wagner, T.A.; Engel, H.P.

    A fixture for mounting an ultrasonic transducer against the end of a threaded bolt or stud to test the same for flaws. A base means threadedly secured to the side of the bolt has a rotating ring thereon. A post rising up from the ring (parallel to the axis of the workpiece) pivotally mounts a variable length cross arm, on the inner end of which is mounted the transducer. A spring means acts between the cross arm and the base to apply the testing transducer against the workpiece at a constant pressure. The device maintains constant for successive tests the radial and circumferential positions of the testing transducer and its contact pressure against the end of the workpiece.

  5. Fixture for holding testing transducer

    DOEpatents

    Wagner, Thomas A.; Engel, Herbert P.

    1984-01-01

    A fixture for mounting an ultrasonic transducer against the end of a threaded bolt or stud to test the same for flaws. A base means threadedly secured to the side of the bolt has a rotating ring thereon. A post rising up from the ring (parallel to the axis of the workpiece) pivotally mounts a variable length cross arm, on the inner end of which is mounted the transducer. A spring means acts between the cross arm and the base to apply the testing transducer against the workpiece at a constant pressure. The device maintains constant for successive tests the radial and circumferential positions of the testing transducer and its contact pressure against the end of the workpiece.

  6. TRANSDUCER FIELD IMAGING USING ACOUSTOGRAPHY

    PubMed Central

    Sandhu, Jaswinder S.; Schoonover, Robert W.; Weber, Joshua I.; Tawiah, J.; Kunin, Vitaliy; Anastasio, Mark A.

    2013-01-01

    A common current practice for transducer field mapping is to scan, point-by-point, a hydrophone element in a 2D raster at various distances from the transducer radiating surface. This approach is tedious, requiring hours of scanning time to generate full cross-sectional and/or axial field distributions. Moreover, the lateral resolution of the field distribution image is dependent on the indexing steps between data points. Acoustography is an imaging process in which an acousto-optical (AO) area sensor is employed to record the intensity of an ultrasound wavefield on a two-dimensional plane. This paper reports on the application of acoustography as a simple but practical method for assessing transducer field characteristics. A case study performed on a commercial transducer is reported, where the radiated fields are imaged using acoustography and compared to the corresponding quantities that are predicted numerically. PMID:23967016

  7. ISG12a inhibits HCV replication and potentiates the anti-HCV activity of IFN-α through activation of the Jak/STAT signaling pathway independent of autophagy and apoptosis.

    PubMed

    Chen, Yanzhao; Jiao, Baihai; Yao, Min; Shi, Xuezhen; Zheng, Zhebin; Li, Shilin; Chen, Limin

    2017-01-02

    Interferon stimulated (sensitive) genes (ISGs) are the effector molecules downstream of type I/III interferon (IFN) signaling pathways in host innate immunity. ISG12a can be induced by IFN-α. Although ISG12a has been reported to inhibit the replication of HCV, the exact mechanism remains to be determined. In this study, we investigated the possible mechanisms of ISG12a anti- HCV property by exploring the production of type I IFN and the activation of Janus kinase/signal transducer and activator of transcription (Jak/STAT) signaling pathway, apoptosis and autophagy in Huh7.5.1 cells transiently transfected with ISG12a over-expression plasmid. Interestingly, we found that ISG12a inhibited HCV replication in both Con1b replicon and the HCV JFH1-based cell culture system and potentiated the anti-HCV activity of IFN-α. ISG12a promoted the production of IFN α/β and activated the type I IFN signaling pathway as shown by increased p-STAT1 level, higher Interferon sensitive response element (ISRE) activity and up-regulated ISG levels. However, ISG12a over-expression did not affect cell autophagy and apoptosis. Data from our current study collectively indicated that ISG12a inhibited HCV replication and potentiated the anti-HCV activity of IFN-α possibly through induced production of type I IFNs and activation of Jak/STAT signaling pathway independent of autophagy and cell apoptosis.

  8. Transducer selection and application in magnetoacoustic tomography with magnetic induction

    NASA Astrophysics Data System (ADS)

    Zhou, Yuqi; Wang, Jiawei; Sun, Xiaodong; Ma, Qingyu; Zhang, Dong

    2016-03-01

    As an acoustic receiver, transducer plays a vital role in signal acquisition and image reconstruction for magnetoacoustic tomography with magnetic induction (MAT-MI). In order to optimize signal acquisition, the expressions of acoustic pressure detection and waveform collection are theoretically studied based on the radiation theory of acoustic dipole and the reception pattern of transducer. Pressure distributions are simulated for a cylindrical phantom model using a planar piston transducer with different radii and bandwidths. The proposed theory is also verified by the experimental measurements of acoustic waveform detection for an aluminum foil cylinder. It is proved that acoustic pressure with sharp and clear boundary peaks can be detected by the large-radius transducer with wide bandwidth, reflecting the differential of the induced Lorentz force accurately, which is helpful for precise conductivity reconstruction. To detect acoustic pressure with acceptable pressure amplitude, peak pressure ratio, amplitude ratio, and improved signal to noise ratio, the scanning radius of 5-10 times the radius of the object should be selected to improve the accuracy of image reconstruction. This study provides a theoretical and experimental basis for transducer selection and application in MAT-MI to obtain reconstructed images with improved resolution and definition.

  9. Delimitation of the lung region with distributed ultrasound transducers

    NASA Astrophysics Data System (ADS)

    Cardona Cárdenas, Diego Armando; Furuie, Sérgio Shiguemi

    2016-04-01

    One technique used to infer and monitor patient's respiratory conditions is the electrical impedance tomography (EIT). This provides images with information about lung function. The EIT image contrast is dependent on the variation of electrical impedance, therefore, this image does not provide anatomical details in border regions of several organs. To contribute to a clinical solution, we propose a new method to delimit regions of interest such as the pulmonary region and to improve the reconstruction quality of the EIT. Using a Matlab Toolbox k-wave, the ultrasound propagation phenomenon in homogeneous medium without patient (Reference) and with thoracic models were simulated, separately via a set of several ultrasound transducers distributed around the chest. After pulse emission by a transducer (TR), all received signals were compared considering the two sets of signals. If the energy relation between parts of the signals does not exceed an empirical threshold (30% in this study), a partial mask is generated between the transmitter and the receptor. This process was repeated until all 128 transducers are considered as TR-emitters. The 128 transducers (150kHz) are uniformly distributed. The evaluation was made by visually comparing the resulting images with the respective simulated object. A simple approach was presented to delimit high contrast organs with ultrasound transducers distributed around the patient. This approach allows other lower contrast objects to become invisible by varying the threshold limit. The investigation, based on numerical simulations of ultrasonic propagation, has shown promising results in the delimitation of the pulmonary region.

  10. Ultrasonic flowmeters: temperature gradients and transducer geometry effects.

    PubMed

    Willatzen, M

    2003-03-01

    Ultrasonic flowmeter performance is addressed for the case of cylindrically shaped flowmeters employing two reciprocal ultrasonic transducers A and B so as to measure time-of-flight differences between signals transmitted from transducer A towards B followed by an equivalent signal transmitted from transducer B towards A. In the case where a liquid flows through the flowmeter's measuring section ("spoolpiece"), the arrival times of the two signals differ by an amount related to the flow passing between the two transducers. Firstly, a detailed study of flow measurement errors with mean flow in the laminar flow regime is carried out as a function of the mode index and the transducer diameter/cylinder diameter ratio in the case where no temperature gradients are present in the flowmeter sensor. It is shown that all modes except the fundamental mode overestimate the mean flow by a factor of 33.33% while excitation of the fundamental mode solely give error-free measurements. The immediate consequences are that the flowmeter error decreases as the transducer diameter/cylinder diameter ratio approaches 1 from 0 reflecting the fact that the excitation level of the fundamental mode increases from almost 0 to 1 as this ratio approaches 1 from 0. Secondly, the effect on flowmeter performance due to flow-induced temperature gradients is examined. It is shown that the presence of temperature gradients leads to flowmeter errors at the higher-flow values even in the case where the fundamental mode is the only mode excited. It is also deduced that flowmeter errors in general depend on the distance between transducers A and B whether temperature gradients exist or not. This conclusion is not reflected in the usual definition of flowmeter errors given by the so-called mode-dependent deviation of measurement introduced in earlier works.

  11. Resveratrol inhibits Src and Stat3 signaling and induces the apoptosis of malignant cells containing activated Stat3 protein.

    PubMed

    Kotha, Anupama; Sekharam, Madhavi; Cilenti, Lucia; Siddiquee, Khandaker; Khaled, Annette; Zervos, Antonis S; Carter, Bradford; Turkson, James; Jove, Richard

    2006-03-01

    Resveratrol is a naturally occurring phytoalexin with antioxidant and antiinflammatory properties. Recent studies suggest that resveratrol possesses anticancer effects, although its mechanism of action is not well understood. We now show that resveratrol inhibits Src tyrosine kinase activity and thereby blocks constitutive signal transducer and activator of transcription 3 (Stat3) protein activation in malignant cells. Analyses of resveratrol-treated malignant cells harboring constitutively-active Stat3 reveal irreversible cell cycle arrest of v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), human breast (MDA-MB-231), pancreatic (Panc-1), and prostate carcinoma (DU145) cell lines at the G0-G1 phase or at the S phase of human breast cancer (MDA-MB-468) and pancreatic cancer (Colo-357) cells, and loss of viability due to apoptosis. By contrast, cells treated with resveratrol, but lacking aberrant Stat3 activity, show reversible growth arrest and minimal loss of viability. Moreover, in malignant cells harboring constitutively-active Stat3, including human prostate cancer DU145 cells and v-Src-transformed mouse fibroblasts (NIH3T3/v-Src), resveratrol treatment represses Stat3-regulated cyclin D1 as well as Bcl-xL and Mcl-1 genes, suggesting that the antitumor cell activity of resveratrol is in part due to the blockade of Stat3-mediated dysregulation of growth and survival pathways. Our study is among the first to identify Src-Stat3 signaling as a target of resveratrol, further defining the mechanism of antitumor cell activity of resveratrol and raising its potential application in tumors with an activated Stat3 profile.

  12. Miltefosine Suppresses Hepatic Steatosis by Activating AMPK Signal Pathway

    PubMed Central

    Zhu, Yaqin; Tong, Xing; Li, Kexue; Bai, Hui; Li, Xiaoyu; Ben, Jingjing; Zhang, Hanwen; Yang, Qing; Chen, Qi

    2016-01-01

    Background and Purpose It has been accepted that AMPK (Adenosine monophosphate–activated protein kinase) activation exhibits many beneficial effects on glucolipid metabolism. Lysophosphatidylcholine (LPC) is an important lysophospholipid which can improve blood glucose levels in diabetic mice and attenuate inflammation by activating AMPK signal pathway in macrophages. Synthetic alkylphospholipids (ALPs), such as miltefosine, is used as an alternate of LPC for the clinical application. Here, we investigated whether miltefosine could have an impact on hepatic steatosis and related metabolic disorders. Experimental Approach Mice were fed with high fat diet (HFD) for 16 weeks to generate an obese model. Next, the obese mice were randomly divided into three groups: saline-treated and miltefosine-treated (2.5 or 5 mg/kg/d) groups. Miltefosine was intraperitoneally administrated into mice for additional 4 weeks plus HFD treatment. Key Results It was shown that miltefosine treatment could substantially improve glucose metabolism, prevented hepatic lipid accumulation, and inhibited liver inflammation in HFD-fed mice by activating AMPK signal pathway. In vitro, miltefosine stimulated AMPKα phosphorylation both in time and dose dependent manner and decreased lipid accumulation in liver cells. When a specific AMPK inhibitor compound C was used to treat mice, the antagonistic effects of miltefosine on HFD-induced mouse hyperlipidaemia and liver steatosis were abolished. Treatment with miltefosine also dramatically inhibited the HFD-induced liver inflammation in mice. Conclusions and Implications Here we demonstrated that miltefosine might be a new activator of AMPK signal pathway in vivo and in vitro and be useful for treatment of hepatic steatosis and related metabolic disorders. PMID:27681040

  13. Dual-Use Transducer for Use with a Boundary-Stiffened Panel and Method of Using the Same

    NASA Technical Reports Server (NTRS)

    Schiller, Noah H. (Inventor); Cabell, Randolph H. (Inventor)

    2011-01-01

    A transducer for use with a boundary-stiffened panel has an inter-digitated electrode (IDE) and a piezoelectric wafer portion positioned therebetween. The IDE and/or the wafer portion are triangular, with one edge or side aligned with a boundary edge of the panel. The transducer generates and transmits an output force to the panel in response to an input voltage signal from a sensor, which can be another transducer as described above or an accelerometer. A controller can generate an output force signal in response to the input voltage signal to help cancel the input voltage signal. A method of using the transducer minimizes vibration in the panel by connecting multiple transducers around a perimeter thereof. Motion is measured at different portions of the panel, and a voltage signal determined from the motion is transmitted to the transducers to generate an output force at least partially cancelling or damping the motion.

  14. High-overtone Self-Focusing Acoustic Transducers for High Frequency Ultrasonic Doppler

    PubMed Central

    Zhu, Jie; Lee, Chuangyuan; Kim, Eun Sok; Wu, Dawei; Hu, Changhong; Zhou, Qifa; Shung, K. Kirk.; Wang, Gaofeng; Yu, Hongyu

    2010-01-01

    This work reports the potential use of high-overtone self-focusing acoustic transducers for high frequency ultrasonic Doppler. By using harmonic frequencies of a thick bulk Lead Zirconate Titanate (PZT) transducer with a novel air-reflector Fresnel lens, we obtained strong ultrasound signals at 60 MHz (3rd harmonic) and 100 MHz (5th harmonic). Both experimental and theoretical analysis has demonstrated that the transducers can be applied to Doppler systems with high frequencies up to 100 MHz. PMID:20206371

  15. Wideband Single-Crystal Transducer for Bone Characterization

    NASA Technical Reports Server (NTRS)

    Liang, Yu; Snook, Kevin

    2012-01-01

    The microgravity conditions of space travel result in unique physiological demands on the human body. In particular, the absence of the continual mechanical stresses on the skeletal system that are present on Earth cause the bones to decalcify. Trabecular structure decreases in thickness and increases in spacing, resulting in decreased bone strength and increased risk of injury. Thus, monitoring bone health is a high priority for long-term space travel. A single probe covering all frequency bands of interest would be ideal for such measurements, and this would also minimize storage space and eliminate the complexity of integrating multiple probes. This invention is an ultrasound transducer for the structural characterization of bone. Such characterization measures features of reflected and transmitted ultrasound signals, and correlates these signals with bone structure metrics such as bone mineral density, trabecular spacing, and thickness, etc. The techniques used to determine these various metrics require measurements over a broad range of ultrasound frequencies, and therefore, complete characterization requires the use of several narrowband transducers. This is a single transducer capable of making these measurements in all the required frequency bands. The device achieves this capability through a unique combination of a broadband piezoelectric material; a design incorporating multiple resonator sizes with distinct, overlapping frequency spectra; and a micromachining process for producing the multiple-resonator pattern with common electrode surfaces between the resonators. This device consists of a pattern of resonator bars with common electrodes that is wrapped around a central mandrel such that the radiating faces of the resonators are coplanar and can be simultaneously applied to the sample to be measured. The device operates as both a source and receiver of acoustic energy. It is operated by connection to an electronic system capable of both providing an

  16. Glucocorticoid receptor signalling activates YAP in breast cancer

    PubMed Central

    Sorrentino, Giovanni; Ruggeri, Naomi; Zannini, Alessandro; Ingallina, Eleonora; Bertolio, Rebecca; Marotta, Carolina; Neri, Carmelo; Cappuzzello, Elisa; Forcato, Mattia; Rosato, Antonio; Mano, Miguel; Bicciato, Silvio; Del Sal, Giannino

    2017-01-01

    The Hippo pathway is an oncosuppressor signalling cascade that plays a major role in the control of cell growth, tissue homoeostasis and organ size. Dysregulation of the Hippo pathway leads to aberrant activation of the transcription co-activator YAP (Yes-associated protein) that contributes to tumorigenesis in several tissues. Here we identify glucocorticoids (GCs) as hormonal activators of YAP. Stimulation of glucocorticoid receptor (GR) leads to increase of YAP protein levels, nuclear accumulation and transcriptional activity in vitro and in vivo. Mechanistically, we find that GCs increase expression and deposition of fibronectin leading to the focal adhesion-Src pathway stimulation, cytoskeleton-dependent YAP activation and expansion of chemoresistant cancer stem cells. GR activation correlates with YAP activity in human breast cancer and predicts bad prognosis in the basal-like subtype. Our results unveil a novel mechanism of YAP activation in cancer and open the possibility to target GR to prevent cancer stem cells self-renewal and chemoresistance. PMID:28102225

  17. Gemcitabine enhances cell invasion via activating HAb18G/CD147-EGFR-pSTAT3 signaling

    PubMed Central

    Wu, Xiao-Qing; Wu, Bo; Xu, Liang; Jiang, Jian-Li; Li, Ling; Chen, Zhi-Nan

    2016-01-01

    Pancreatic cancer, one of the most lethal cancers, has very poor 5-year survival partly due to gemcitabine resistance. Recently, it was reported that chemotherapeutic agents may act as stressors to induce adaptive responses and to promote chemoresistance in cancer cells. During long-term drug treatment, the minority of cancer cells survive and acquire an epithelial-mesenchymal transition phenotype with increased chemo-resistance and metastasis. However, the short-term response of most cancer cells remains unclear. This study aimed to investigate the short-term response of pancreatic cancer cells to gemcitabine stress and to explore the corresponding mechanism. Our results showed that gemcitabine treatment for 24 hours enhanced pancreatic cancer cell invasion. In gemcitabine-treated cells, HAb18G/CD147 was up-regulated; and HAb18G/CD147 down-regulation or inhibition attenuated gemcitabine-enhanced invasion. Mechanistically, HAb18G/CD147 promoted gemcitabine-enhanced invasion by activating the EGFR (epidermal growth factor receptor)-STAT3 (signal transducer and activator of transcription 3) signaling pathway. Inhibition of EGFR-STAT3 signaling counteracted gemcitabine-enhanced invasion, and which relied on HAb18G/CD147 levels. In pancreatic cancer tissues, EGFR was highly expressed and positively correlated with HAb18G/CD147. These data indicate that pancreatic cancer cells enhance cell invasion via activating HAb18G/CD147-EGFR-pSTAT3 signaling. Our findings suggest that inhibiting HAb18G/CD147 is a potential strategy for overcoming drug stress-associated resistance in pancreatic cancer. PMID:27556697

  18. 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

  19. 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

  20. Long term performance of wearable transducer for motion energy harvesting

    NASA Astrophysics Data System (ADS)

    McGarry, Scott A.; Behrens, Sam

    2010-04-01

    Personal electronic devices such as cell phones, GPS and MP3 players have traditionally depended on battery energy storage technologies for operation. By harvesting energy from a person's motion, these devices may achieve greater run times without increasing the mass or volume of the electronic device. Through the use of a flexible piezoelectric transducer such as poly-vinylidene fluoride (PVDF), and integrating it into a person's clothing, it becomes a 'wearable transducer'. As the PVDF transducer is strained during the person's routine activities, it produces an electrical charge which can then be harvested to power personal electronic devices. Existing wearable transducers have shown great promise for personal motion energy harvesting applications. However, they are presently physically bulky and not ergonomic for the wearer. In addition, there is limited information on the energy harvesting performance for wearable transducers, especially under realistic conditions and for extended cyclic force operations - as would be experienced when worn. In this paper, we present experimental results for a wearable PVDF transducer using a person's measured walking force profile, which is then cycled for a prolonged period of time using an experimental apparatus. Experimental results indicate that after an initial drop in performance, the transducer energy harvesting performance does not substantially deteriorate over time, as less than 10% degradation was observed. Longevity testing is still continuing at CSIRO.

  1. Focusing of ferroelectret air-coupled ultrasound transducers

    NASA Astrophysics Data System (ADS)

    Gaal, Mate; Bartusch, Jürgen; Dohse, Elmar; Schadow, Florian; Köppe, Enrico

    2016-02-01

    Air-coupled ultrasound has been applied increasingly as a non-destructive testing method for lightweight construction in recent years. It is particularly appropriate for composite materials being used in automotive and aviation industry. Air-coupled ultrasound transducers mostly consist of piezoelectric materials and matching layers. However, their fabrication is challenging and their signal-to-noise ratio often not sufficient for many testing requirements. To enhance the efficiency, air-coupled ultrasound transducers made of cellular polypropylene have been developed. Because of its small density and sound velocity, this piezoelectric ferroelectret matches the small acoustic impedance of air much better than matching layers applied in conventional transducers. In our contribution, we present two different methods of spherical focusing of ferroelectret transducers for the further enhancement of their performance in NDT applications. Measurements on carbon-fiber-reinforced polymer (CFRP) samples and on metal adhesive joints performed with commercially available focused air-coupled ultrasound transducers are compared to measurements executed with self-developed focused ferroelectret transducers.

  2. Piezoelectric transducer design for a miniaturized injectable acoustic transmitter

    NASA Astrophysics Data System (ADS)

    Li, H.; Jung, K. W.; Deng, Z. D.

    2015-11-01

    Implantable acoustic transmitters have been used in the last 20 years to track fish movement for fish survival and migration behavior studies. However, the relatively large weights and sizes of commercial transmitters limit the populations of studied fish. The surgical implantation procedures may also affect fish adversely and incur a significant amount of labor. Therefore, a smaller, lighter, and injectable transmitter was needed, and similar or better acoustic performance and service life over those provided by existing commercial transmitters was desired. To develop such a small transmitter, a number of technical challenges, including design optimization of the piezoelectric transducer, needed to be overcome. Our efforts to optimize the transducer focused on improving the average source level in the 180° range in which the signal was not blocked by the transmitter body. We found that a novel off-center tube transducer improved the average source level by 1.5 dB. An acoustic reflector attached to the back of the transducer also improved the source level by 1.3 dB. We found that too small a gap between the transducer and the component placed behind it resulted in distortion of the beam pattern. Lastly, a tuning inductor in series with the transducer was used to help optimize the source level. The findings and techniques developed in this work contributed to the successful development and implementation of a new injectable transmitter.

  3. Experimental Evaluation of Three Designs of Electrodynamic Flexural Transducers

    PubMed Central

    Eriksson, Tobias J. R.; Laws, Michael; Kang, Lei; Fan, Yichao; Ramadas, Sivaram N.; Dixon, Steve

    2016-01-01

    Three designs for electrodynamic flexural transducers (EDFT) for air-coupled ultrasonics are presented and compared. An all-metal housing was used for robustness, which makes the designs more suitable for industrial applications. The housing is designed such that there is a thin metal plate at the front, with a fundamental flexural vibration mode at ∼50 kHz. By using a flexural resonance mode, good coupling to the load medium was achieved without the use of matching layers. The front radiating plate is actuated electrodynamically by a spiral coil inside the transducer, which produces an induced magnetic field when an AC current is applied to it. The transducers operate without the use of piezoelectric materials, which can simplify manufacturing and prolong the lifetime of the transducers, as well as open up possibilities for high-temperature applications. The results show that different designs perform best for the generation and reception of ultrasound. All three designs produced large acoustic pressure outputs, with a recorded sound pressure level (SPL) above 120 dB at a 40 cm distance from the highest output transducer. The sensitivity of the transducers was low, however, with single shot signal-to-noise ratio (SNR)≃15 dB in transmit–receive mode, with transmitter and receiver 40 cm apart. PMID:27571075

  4. Thermal Wick Cooling for Vibroacoustic Transducers

    DTIC Science & Technology

    2009-09-25

    affecting vibrational characteristics of the transducer . (2) Description of the Prior Art [0004] Vibroacoustic transducers , such as piezoceramic tonpilz ...Distribution is unlimited 20091013084 Attorney Docket No. 84708 THERMAL WICK COOLING FOR VIBROACOUSTIC TRANSDUCERS STATEMENT OF GOVERNMENT INTEREST...INVENTION (1) Field of the Invention [0003] The present invention provides a device for cooling a vibroacoustic transducer without adversely

  5. OsBRI1 Activates BR Signaling by Preventing Binding between the TPR and Kinase Domains of OsBSK3 via Phosphorylation1

    PubMed Central

    Wang, Xiaolong; Zhao, Zhiying; Wang, Ruiju; Huang, Xiahe; Zhu, Yali; Yuan, Li; Wang, Yingchun; Burlingame, Alma L.; Gao, Yingjie

    2016-01-01

    Many plant receptor kinases transduce signals through receptor-like cytoplasmic kinases (RLCKs); however, the molecular mechanisms that create an effective on-off switch are unknown. The receptor kinase BR INSENSITIVE1 (BRI1) transduces brassinosteroid (BR) signal by phosphorylating members of the BR-signaling kinase (BSK) family of RLCKs, which contain a kinase domain and a C-terminal tetratricopeptide repeat (TPR) domain. Here, we show that the BR signaling function of BSKs is conserved in Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) and that the TPR domain of BSKs functions as a “phospho-switchable” autoregulatory domain to control BSKs’ activity. Genetic studies revealed that OsBSK3 is a positive regulator of BR signaling in rice, while in vivo and in vitro assays demonstrated that OsBRI1 interacts directly with and phosphorylates OsBSK3. The TPR domain of OsBSK3, which interacts directly with the protein’s kinase domain, serves as an autoinhibitory domain to prevent OsBSK3 from interacting with bri1-SUPPRESSOR1 (BSU1). Phosphorylation of OsBSK3 by OsBRI1 disrupts the interaction between its TPR and kinase domains, thereby increasing the binding between OsBSK3’s kinase domain and BSU1. Our results not only demonstrate that OsBSK3 plays a conserved role in regulating BR signaling in rice, but also provide insight into the molecular mechanism by which BSK family proteins are inhibited under basal conditions but switched on by the upstream receptor kinase BRI1. PMID:26697897

  6. 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

  7. 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

  8. Visualizing how T cells collect activation signals in vivo.

    PubMed

    Moreau, Hélène D; Bousso, Philippe

    2014-02-01

    A decade ago the first movies depicting T cell behavior in vivo with the help of two-photon microscopy were generated. These initial experiments revealed that T cells migrate rapidly and randomly in secondary lymphoid organs at steady state and profoundly alter their behavior during antigen recognition, establishing both transient and stable contacts with antigen-presenting cells (APCs). Since then, in vivo imaging has continuously improved our understanding of T cell activation. In particular, recent studies uncovered how T cells may be guided in their search for the best APCs. Additionally, the development of more sophisticated fluorescent tools has permitted not only to visualize T cell-APC contacts but also to probe their functional impact on T cell activation. These recent progresses are providing new insights into how T cells sense antigen, collect activation signals during distinct types of interaction and integrate information over successive encounters.

  9. Nucleophosmin leukemogenic mutant activates Wnt signaling during zebrafish development

    PubMed Central

    Barbieri, Elisa; Deflorian, Gianluca; Pezzimenti, Federica; Valli, Debora; Saia, Marco; Meani, Natalia

    2016-01-01

    Nucleophosmin (NPM1) is a ubiquitous multifunctional phosphoprotein with both oncogenic and tumor suppressor functions. Mutations of the NPM1 gene are the most frequent genetic alterations in acute myeloid leukemia (AML) and result in the expression of a mutant protein with aberrant cytoplasmic localization, NPMc+. Although NPMc+ causes myeloproliferation and AML in animal models, its mechanism of action remains largely unknown. Here we report that NPMc+ activates canonical Wnt signaling during the early phases of zebrafish development and determines a Wnt-dependent increase in the number of progenitor cells during primitive hematopoiesis. Coherently, the canonical Wnt pathway is active in AML blasts bearing NPMc+ and depletion of the mutant protein in the patient derived OCI-AML3 cell line leads to a decrease in the levels of active β-catenin and of Wnt target genes. Our results reveal a novel function of NPMc+ and provide insight into the molecular pathogenesis of AML bearing NPM1 mutations. PMID:27486814

  10. p21-activated kinase signaling in breast cancer

    PubMed Central

    Gururaj, Anupama E; Rayala, Suresh K; Kumar, Rakesh

    2005-01-01

    The p21-activated kinases signal through a number of cellular pathways fundamental to growth, differentiation and apoptosis. A wealth of information has accumulated at an impressive pace in the recent past, both with regard to previously identified targets for p21-activated kinases that regulate the actin cytoskeleton and cellular stress pathways and with regard to newly identified targets and their role in cancer. Emerging data also provide new clues towards a previously unappreciated link between these various cellular processes. The present review attempts to provide a quick tutorial to the reader about the evolving significance of p21-activated kinases and small GTPases in breast cancer, using information from mouse models, tissue culture studies, and human materials. PMID:15642175

  11. Designing of Phased Array Transducers for Industrial Applications

    NASA Astrophysics Data System (ADS)

    Dumas, Ph.; Poguet, J.; Fleury, G.

    2004-02-01

    By increasing inspection speed, and deflection capabilities of the transducers, Phased-array technology has proved its interest to face new ∂ NDT challenges, and is becoming more and more popular in the main industrial fields of activities. This paper describes the main effects of specifications on transducer performances, and explains how to defined them. The second part speaks about the manufacturing step, showing the influence of component choice on performances. Several Phased-array applications examples illustrating these considerations will be presented.

  12. Digital signaling and hysteresis characterize Ras activation in lymphoid cells

    PubMed Central

    Das, Jayajit; Ho, Mary; Zikherman, Julie; Govern, Christopher; Yang, Ming; Weiss, Arthur; Chakraborty, Arup K.; Roose, Jeroen P.

    2009-01-01

    Activation of Ras proteins underlies functional decisions in diverse cell types. Two molecules, RasGRP and SOS, catalyze Ras activation in lymphocytes. Binding of active Ras to SOS′ allosteric pocket markedly increases SOS′ activity establishing a positive feedback loop for SOS-mediated Ras activation. Integrating in silico and in vitro studies, we demonstrate that digital signaling in lymphocytes (cells are “on” or “off”) is predicated upon feedback regulation of SOS. SOS′ feedback loop leads to hysteresis in the dose-response curve, which can enable a capacity to sustain Ras activation as stimuli are withdrawn and exhibit “memory” of past encounters with antigen. Ras activation via RasGRP alone is analog (graded increase in amplitude with stimulus). We describe how complementary analog (RasGRP) and digital (SOS) pathways act on Ras to efficiently convert analog input to digital output. Numerous predictions regarding the impact of our findings on lymphocyte function and development are noted. PMID:19167334

  13. Ultrasonic Transducer Irradiation Test Results

    SciTech Connect

    Daw, Joshua; Palmer, Joe; Ramuhalli, Pradeep; Keller, Paul; Montgomery, Robert; Chien, Hual-Te; Kohse, Gordon; Tittmann, Bernhard; Reinhardt, Brian; Rempe, Joy

    2015-02-01

    Ultrasonic technologies offer the potential for high-accuracy and -resolution in-pile measurement of a range of parameters, including geometry changes, temperature, crack initiation and growth, gas pressure and composition, and microstructural changes. Many Department of Energy-Office of Nuclear Energy (DOE-NE) programs are exploring the use of ultrasonic technologies to provide enhanced sensors for in-pile instrumentation during irradiation testing. For example, the ability of small diameter ultrasonic thermometers (UTs) to provide a temperature profile in candidate metallic and oxide fuel would provide much needed data for validating new fuel performance models. Other ongoing efforts include an ultrasonic technique to detect morphology changes (such as crack initiation and growth) and acoustic techniques to evaluate fission gas composition and pressure. These efforts are limited by the lack of identified ultrasonic transducer materials capable of long term performance under irradiation test conditions. For this reason, the Pennsylvania State University (PSU) was awarded an ATR NSUF project to evaluate the performance of promising magnetostrictive and piezoelectric transducers in the Massachusetts Institute of Technology Research Reactor (MITR) up to a fast fluence of at least 1021 n/cm2. The goal of this research is to characterize and demonstrate magnetostrictive and piezoelectric transducer operation during irradiation, enabling the development of novel radiation-tolerant ultrasonic sensors for use in Material Testing Reactors (MTRs). As such, this test is an instrumented lead test and real-time transducer performance data is collected along with temperature and neutron and gamma flux data. The current work bridges the gap between proven out-of-pile ultrasonic techniques and in-pile deployment of ultrasonic sensors by acquiring the data necessary to demonstrate the performance of ultrasonic transducers. To date, one piezoelectric

  14. Tribotronic Tuning Diode for Active Analog Signal Modulation.

    PubMed

    Zhou, Tao; Yang, Zhi Wei; Pang, Yaokun; Xu, Liang; Zhang, Chi; Wang, Zhong Lin

    2017-01-24

    Realizing active interaction with external environment/stimuli is a great challenge for current electronics. In this paper, a tribotronic tuning diode (TTD) is proposed by coupling a variable capacitance diode and a triboelectric nanogenerator in free-standing sliding mode. When the friction layer is sliding on the device surface for electrification, a reverse bias voltage is created and applied to the diode for tuning the junction capacitance. When the sliding distance increases from 0 to 25 mm, the capacitance of the TTD decreases from about 39 to 8 pF. The proposed TTD has been integrated into analog circuits and exhibited excellent performances in frequency modulation, phase shift, and filtering by sliding a finger. This work has demonstrated tunable diode and active analog signal modulation by tribotronics, which has great potential to replace ordinary variable capacitance diodes in various practical applications such as signal processing, electronic tuning circuits, precise tuning circuits, active sensor networks, electronic communications, remote controls, flexible electronics, etc.

  15. Obox4-silencing-activated STAT3 and MPF/MAPK signaling accelerate nuclear membrane breakdown in mouse oocytes.

    PubMed

    Lee, Hyun-Seo; Kim, Kyeoung-Hwa; Kim, Eun-Young; Lee, Su-Yeon; Ko, Jung-Jae; Lee, Kyung-Ah

    2016-04-01

    Mouse oocytes begin to mature in vitro once liberated from ovarian follicles. Previously, we showed that oocyte-specific homeobox 4 (Obox4) is critical for maintaining the intact nuclear membrane of the germinal vesicle (GV) in oocytes and for completing meiosis at the metaphase I-II (MI-MII) transition. This study further examines the molecular mechanisms of OBOX4 in regulating GV nuclear membrane breakdown. Maturation-promoting factor (MPF) and MAPK are normally inactive in GV stage oocytes but were activated prematurely in arrested GV stage oocytes by 3-isobutyl-1-metyl-xanthine (IBMX) in vitro after Obox4 RNA interference (RNAi). Furthermore, signal transducer and activator of transcription 3 (STAT3) was significantly activated by Obox4 RNAi. We confirmed that this Obox4 RNAi-induced premature STAT3 and MPF/MAPK activation at the GV stage provoked subsequent GV breakdown (GVBD) despite the opposing force of high cAMP in the IBMX-supplemented medium to maintain intact GV. When cumulus-oocyte complexes were exposed to interferon α (IFNA), a STAT3 activator, oocytes matured and cumulus cells expanded to resume nuclear maturation in IBMX-supplemented medium, suggesting that STAT3 activation is sufficient for stimulating the continuation of meiosis. Using Stattic, a specific STAT3 inhibitor, we confirmed that GVBD involves STAT3 activation in Obox4-silenced oocytes. Based on these findings, we concluded that i) Obox4 is an important upstream regulator of MPF/MAPK and STAT3 signaling, and ii) Obox4 is a key regulator of the GV arrest mechanism in oocytes.

  16. Multiplexing Transducers Based on Tunnel-Diode Oscillators

    NASA Technical Reports Server (NTRS)

    Chui, Talso; Penanen, Konstantin; Young, Joseph

    2006-01-01

    Multiplexing and differential transducers based on tunnel-diode oscillators (TDOs) would be developed, according to a proposal, for operation at very low and/or widely varying temperatures in applications that involve requirements to minimize the power and mass of transducer electronic circuitry. It has been known since 1975 that TDOs are useful for making high-resolution (of the order of 10(exp -9)) measurements at low temperatures. Since that time, TDO transducers have been found to offer the following additional advantages, which the present proposal is intended to exploit: TDO transducers can operate at temperatures ranging from 1 K to about 400 K. Most electronic components other than tunnel diodes do not operate over such a wide temperature range. TDO transducers can be made to operate at very low power - typically, <1 mW. Inasmuch as the response of a TDO transducer is a small change in an arbitrarily set oscillation frequency, the outputs of many TDOs operating at sufficiently different set frequencies can be multiplexed through a single wire. Inasmuch as frequencies can be easily subtracted by means of mixing circuitry, one can easily use two TDOs to make differential measurements. Differential measurements are generally more precise and less susceptible to environmental variations than are absolute measurements. TDO transducers are tolerant to ionizing radiation. Ultimately, the response of a TDO transducer is measured by use of a frequency counter. Because frequency counting can be easily implemented by use of clock signals available from most microprocessors, it is not necessary to incorporate additional readout circuitry that would, if included, add to the mass and power consumption of the transducer circuitry. In one example of many potential variations on the basic theme of the proposal, the figure schematically depicts a conceptual differential-pressure transducer containing a symmetrical pair of TDOs. The differential pressure would be exerted on

  17. Radially sandwiched cylindrical piezoelectric transducer

    NASA Astrophysics Data System (ADS)

    Lin, Shuyu; Fu, Zhiqiang; Zhang, Xiaoli; Wang, Yong; Hu, Jing

    2013-01-01

    A new type of radially sandwiched piezoelectric short cylindrical transducer is developed and its radial vibration is studied. The transducer is composed of a solid metal disk, a radially polarized piezoelectric ceramic short tube and a metal tube. The radial vibrations of the solid metal disk, the radially polarized piezoelectric tube and the metal tube are analyzed and their electromechanical equivalent circuits are introduced. Based on the mechanical boundary conditions among the metal disk, the piezoelectric tube and the metal tube, a three-port electromechanical equivalent circuit for the radially sandwiched transducer is obtained and the frequency equation is given. The theoretical relationship of the resonance and anti-resonance frequencies and the effective electromechanical coupling coefficient with the geometrical dimensions is analyzed. The radial vibration of the sandwiched transducer is simulated by using two different numerical methods. It is shown that the analytical resonance and anti-resonance frequencies are in good agreement with the numerically simulated results. The transducer is expected to be used in piezoelectric resonators, actuators and ultrasonic radiators in ultrasonic and underwater sound applications.

  18. IGF-1R modulation of acute GH-induced STAT5 signaling: role of protein tyrosine phosphatase activity.

    PubMed

    Gan, Yujun; Zhang, Yue; Buckels, Ashiya; Paterson, Andrew J; Jiang, Jing; Clemens, Thomas L; Zhang, Zhong-Yin; Du, Keyong; Chang, Yingzi; Frank, Stuart J

    2013-11-01

    GH is a potent anabolic and metabolic factor that binds its cell surface receptor (GHR), activating the GHR-associated tyrosine kinase, Janus kinase 2, which phosphorylates and activates the latent transcription factor, signal transducer and activator of transcription 5 (STAT5). Some GH actions are mediated by the elaboration of IGF-1, which exerts effects by binding and activating the heterotetrameric tyrosine kinase growth factor receptor, IGF-1R. In addition to this GH-GHR-IGF-1-IGF-1R scheme, we have demonstrated in primary osteoblasts and in islet β-cells that then deletion or silencing of IGF-1R results in diminished GH-induced STAT5 phosphorylation, suggesting that the presence of IGF-1R may facilitate GH signaling. In this study, we explore potential roles for protein tyrosine phosphatase activity in modulating GH-induced signaling, comparing conditions in which IGF-1R is present or diminished. We confirm that in mouse primary osteoblasts harboring loxP sites flanking the IGF-1R gene, infection with an adenovirus that expresses the Cre recombinase results in IGF-1R deletion and diminished acute GH-induced STAT5 phosphorylation. Furthermore, we present a new model of IGF-1R silencing, in which expression of short hairpin RNA directed at IGF-1R greatly reduces IGF-1R abundance in LNCaP human prostate cancer cells. In both models, treatment with a chemical inhibitor of protein tyrosine phosphatase-1B (PTP-1B), but not one of src homology region 2 domain-containing phosphotase-1 (SHP-1) and SHP-2, reverses the loss of GH-induced STAT5 phosphorylation in cells lacking IGF-1R but has no effect in cells with intact IGF-1R. Furthermore, expression of either a dominant-negative PTP-1B or the PTP-1B-interacting inhibitory protein, constitutive photomorphogenesis 1, also rescues acute GH-induced STAT5 signaling in IGF-1R-deficient cells but has no effect in IGF-1R replete cells. By expressing a substrate-trapping mutant PTP-1B, we demonstrate that tyrosine

  19. "Zero-Mass" Noninvasive Pressure Transducers

    NASA Technical Reports Server (NTRS)

    Hartley, Frank T.

    2009-01-01

    Extremely lightweight, compact, noninvasive, rugged, relatively inexpensive strain-gauge transducers have been developed for use in measuring pressures of fluids in tubes. These gauges were originally intended for measuring pressures of spacecraft-propulsion fluids, but they are also attractive for use in numerous terrestrial applications especially those involving fluids that are extremely chemically reactive, fluids that must be isolated for hygienic purposes, fluids that must be allowed to flow without obstruction, and fluid-containing tubes exposed to severe environments. A basic pressure transducer of this type comprises one or more pair(s) of thin-film strain gauges integral with a tube that contains the fluid of interest. Following established strain-gauge practice, the gauges in each pair are connected into opposite arms of a Wheatstone bridge (see figure). Typically, each pressure transducer includes one pair (the active pair) of strain gauges for measuring the hoop stress proportional to the pressure of the fluid in the tube and another pair (the dummy pair) of strain gauges that are nominally unstrained: The dummy gauges are mounted on a substrate that is made of the same material as that of the tube. The substrate is welded to the tube at only one spot so that stresses and strains are not coupled from the tube into the substrate. The dummy strain gauges measure neutral strains (basically, strains associated with thermal expansion), so that the neutral-strain contribution can be subtracted out of the final gauge reading.

  20. Analytical model of a giant magnetostrictive resonance transducer

    NASA Astrophysics Data System (ADS)

    Sheykholeslami, M.; Hojjat, Y.; Ansari, S.; Cinquemani, S.; Ghodsi, M.

    2016-04-01

    Resonance transducers have been widely developed and studied, as they can be profitably used in many application such as liquid atomizing and sonar technology. The active element of these devices can be a giant magnetostrictive material (GMM) that is known to have significant energy density and good performance at high frequencies. The paper introduces an analytical model of GMM transducers to describe their dynamics in different working conditions and to predict any change in their performance. The knowledge of the transducer behavior, especially in operating conditions different from the ideal ones, is helpful in the design and fabrication of highly efficient devices. This transducer is design to properly work in its second mode of vibration and its working frequency is around 8000 Hz. Most interesting parameters of the device, such as quality factor, bandwidth and output strain are obtained from theoretical analysis.

  1. Tissue deformation induced by radiation force from Gaussian transducers.

    PubMed

    Myers, Matthew R

    2006-05-01

    Imaging techniques based upon the tissue mechanical response to an acoustic radiation force are being actively researched. In this paper a model for predicting steady-state tissue displacement induced by a radiation force arising from the absorption of Gaussian ultrasound beams is presented. A simple analytic expression is derived that agrees closely with the numerical quadrature of the displacement convolution integrals. The analytic result reveals the dependence of the steady-state axial displacement upon the operational parameters, e.g., an inverse proportional relationship to the tissue shear modulus. The derivation requires that the transducer radius be small compared to the focal length, but accurate results were obtained for transducer radii comparable to the focal length. Favorable comparisons with displacement predictions for non-Gaussian transducers indicate that the theory is also useful for a broader range of transducer intensity profiles.

  2. Ultrasonic transducers for cure monitoring: design, modelling and validation

    NASA Astrophysics Data System (ADS)

    Lionetto, Francesca; Montagna, Francesco; Maffezzoli, Alfonso

    2011-12-01

    The finite element method (FEM) has been applied to simulate the ultrasonic wave propagation in a multilayered transducer, expressly designed for high-frequency dynamic mechanical analysis of polymers. The FEM model includes an electro-acoustic (active element) and some acoustic (passive elements) transmission lines. The simulation of the acoustic propagation accounts for the interaction between the piezoceramic and the materials in the buffer rod and backing, and the coupling between the electric and mechanical properties of the piezoelectric material. As a result of the simulations, the geometry and size of the modelled ultrasonic transducer has been optimized and used for the realization of a prototype transducer for cure monitoring. The transducer performance has been validated by measuring the velocity changes during the polymerization of a thermosetting matrix of composite materials.

  3. High Temperature Ultrasonic Transducers : Material Selection and Testing

    NASA Technical Reports Server (NTRS)

    Bar-Cohen, Yoseph; Bruno, Alessandro

    2012-01-01

    The task of my two-months internship was to test different materials to be used to build an high temperature transducer, to develop some prototypes and to test their performance, to assess the reliability of commercial product rated for such a temperature, as well as to collaborate in developing the signal processing code to measure the condensed water levels.

  4. 21 CFR 884.2960 - Obstetric ultrasonic transducer and accessories.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... obstetric ultrasonic transducer is a device used to apply ultrasonic energy to, and to receive ultrasonic energy from, the body in conjunction with an obstetric monitor or imager. The device converts electrical signals into ultrasonic energy, and vice versa, by means of an assembly distinct from an...

  5. Pathway illuminated: visualizing protein kinase C signaling.

    PubMed

    Violin, Jonathan D; Newton, Alexandra C

    2003-12-01

    Protein kinase C has been at the center of cell signaling since the discovery 25 years ago that it transduces signals that promote phospholipid hydrolysis. In recent years, the use of genetically encoded fluorescent reporters has enabled studies of the regulation of protein kinase C signaling in living cells. Advances in imaging techniques have unveiled unprecedented detail of the signal processing mechanics of protein kinase C, from the second messengers calcium and diacylglycerol that regulate protein kinase C activity, to the locations and kinetics of different protein kinase C isozymes, to the spatial and temporal dynamics of substrate phosphorylation by this key enzyme. This review discusses how fluorescence imaging studies have illuminated the fidelity with which protein kinase C transduces rapidly changing extracellular information into intracellular phosphorylation signals.

  6. Activated platelets signal chemokine synthesis by human monocytes.

    PubMed Central

    Weyrich, A S; Elstad, M R; McEver, R P; McIntyre, T M; Moore, K L; Morrissey, J H; Prescott, S M; Zimmerman, G A

    1996-01-01

    Human blood monocytes adhere rapidly and for prolonged periods to activated platelets that display P-selectin, an adhesion protein that recognizes a specific ligand on leukocytes, P-selectin glycoprotein-1. We previously demonstrated that P-selectin regulates expression and secretion of cytokines by stimulated monocytes when it is presented in a purified, immobilized form or by transfected cells. Here we show that thrombin-activated platelets induce the expression and secretion of monocyte chemotactic protein-1 and IL-8 by monocytes. Enhanced monokine synthesis requires engagement of P-selectin glycoprotein-1 on the leukocyte by P-selectin on the platelet. Secretion of the chemokines is not, however, directly signaled by P-selectin; instead, tethering of the monocytes by P-selectin is required for their activation by RANTES (regulated upon activation normal T cell expressed presumed secreted), a platelet chemokine not previously known to induce immediate-early gene products in monocytes. Adhesion of monocytes to activated platelets results in nuclear translocation of p65 (RelA), a component of the NF-kappaB family of transcription factors that binds kappaB sequences in the regulatory regions of monocyte chemotactic protein-1, IL-8, and other immediate-early genes. However, expression of tissue factor, a coagulation protein that also has a kappaB sequence in the 5' regulatory region of its gene, is not induced in monocytes adherent to activated platelets. Thus, contact of monocytes with activated platelets differentially affects the expression of monocyte products. These experiments suggest that activated platelets regulate chemokine secretion by monocytes in inflammatory lesions in vivo and provide a model for the study of gene regulation in cell-cell interactions. PMID:8617886

  7. Psoralen stimulates osteoblast differentiation through activation of BMP signaling.

    PubMed

    Tang, De-Zhi; Yang, Feng; Yang, Zhou; Huang, Jian; Shi, Qi; Chen, Di; Wang, Yong-Jun

    2011-02-11

    Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. In order to improve the treatment of osteoporosis, identification of anabolic and orally available agents with minimal side effects is highly desirable. Psoralen is a coumarin-like derivative extracted from Chinese herbs, which have been used to treat bone diseases for thousands of years. However, the role of Psoralen in osteoblast function and the underlying molecular mechanisms remain poorly understood. In this study, we found that Psoralen promoted osteoblast differentiation in primary mouse calvarial osteoblasts in a dose-dependent manner, demonstrated by up-regulation of expressions of osteoblast-specific marker genes including type I collagen, osteocalcin and bone sialoprotein and enhancement of alkaline phosphatase activity. We further demonstrated that Psoralen up-regulated the expression of Bmp2 and Bmp4 genes, increased the protein level of phospho-Smad1/5/8, and activated BMP reporter (12xSBE-OC-Luc) activity in a dose-dependent manner, as well as enhanced the expression of Osx, the direct target gene of BMP signaling. Deletion of the Bmp2 and Bmp4 genes abolished the stimulatory effect of Psoralen on the expression of osteoblast marker genes, such as Col1, Alp, Oc and Bsp. Our results suggest that Psoralen acts through the activation of BMP signaling to promote osteoblast differentiation and demonstrate that Psoralen could be a potential anabolic agent to treat patients with bone loss-associated diseases such as osteoporosis.

  8. Nitric oxide signaling in Pseudomonas aeruginosa biofilms mediates phosphodiesterase activity, decreased cyclic di-GMP levels, and enhanced dispersal.

    PubMed

    Barraud, Nicolas; Schleheck, David; Klebensberger, Janosch; Webb, Jeremy S; Hassett, Daniel J; Rice, Scott A; Kjelleberg, Staffan

    2009-12-01

    Bacteria in biofilms often undergo active dispersal events and revert to a free-swimming, planktonic state to complete the biofilm life cycle. The signaling molecule nitric oxide (NO) was previously found to trigger biofilm dispersal in the opportunistic pathogen Pseudomonas aeruginosa at low, nontoxic concentrations (N. Barraud, D. J. Hassett, S. H. Hwang, S. A. Rice, S. Kjelleberg, and J. S. Webb, J. Bacteriol. 188:7344-7353, 2006). NO was further shown to increase cell motility and susceptibility to antimicrobials. Recently, numerous studies revealed that increased degradation of the secondary messenger cyclic di-GMP (c-di-GMP) by specific phosphodiesterases (PDEs) triggers a planktonic mode of growth in eubacteria. In this study, the potential link between NO and c-di-GMP signaling was investigated by performing (i) PDE inhibitor studies, (ii) enzymatic assays to measure PDE activity, and (iii) direct quantification of intracellular c-di-GMP levels. The results suggest a role for c-di-GMP signaling in triggering the biofilm dispersal event induced by NO, as dispersal requires PDE activity and addition of NO stimulates PDE and induces the concomitant decrease in intracellular c-di-GMP levels in P. aeruginosa. Furthermore, gene expression studies indicated global responses to low, nontoxic levels of NO in P. aeruginosa biofilms, including upregulation of genes involved in motility and energy metabolism and downregulation of adhesins and virulence factors. Finally, site-directed mutagenesis of candidate genes and physiological characterization of the corresponding mutant strains uncovered that the chemotaxis transducer BdlA is involved in the biofilm dispersal response induced by NO.

  9. DIESEL EXHAUST PARTICULATE (DEP)-INDUCED ACTIV ATION OF STAT3 REQUIRES ACTIVITIES OF EGFR AND SRC IN AIRWAY EPITHELIAL CELLS

    EPA Science Inventory

    In vivo exposure to diesel exhaust particles (DEP) elicits acute inflammatory responses in the lung characterized by inflammatory cell influx and elevated expression of mediators such as cytokines, and chemokines. Signal transducers and activators of transcription (STAT) protein...

  10. Dynamic neural activity during stress signals resilient coping

    PubMed Central

    Sinha, Rajita; Lacadie, Cheryl M.; Constable, R. Todd; Seo, Dongju

    2016-01-01

    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

  11. Model of a Piezoelectric Transducer

    NASA Technical Reports Server (NTRS)

    Goodenow, Debra

    2004-01-01

    It's difficult to control liquid and gas in propellant tanks in zero gravity. A possible a design would utilize acoustic liquid manipulation (ALM) technology which uses ultrasonic beams conducted through a liquid and solid media, to push gas bubbles in the liquid to desirable locations. We can propel and control the bubble with acoustic radiation pressure by aiming the acoustic waves on the bubble s surface. This allows us to design a so called smart tank in which the ALM devices transfer the gas to the outer wall of the tank and isolating the liquid in the center. Because the heat transfer rate of a gas is lower of that of the liquid it would substantially decrease boil off and provide of for a longer storage life. The ALM beam is composed of little wavelets which are individual waves that constructively interfere with each other to produce a single, combined acoustic wave front. This is accomplished by using a set of synchronized ultrasound transducers arranged in an array. A slight phase offset of these elements allows us to focus and steer the beam. The device that we are using to produce the acoustic beam is called the piezoelectric transducer. This device converts electrical energy to mechanical energy, which appears in the form of acoustic energy. Therefore the behavior of the device is dependent on both the mechanical characteristics, such as its density, cross-sectional area, and its electrical characteristics, such as, electric flux permittivity and coupling factor. These devices can also be set up in a number of modes which are determined by the way the piezoelectric device is arranged, and the shape of the transducer. For this application we are using the longitudinal or thickness mode for our operation. The transducer also vibrates in the lateral mode, and one of the goals of my project is to decrease the amount of energy lost to the lateral mode. To model the behavior of the transducers I will be using Pspice, electric circuit modeling tool, to

  12. Environmental control system transducer development study

    NASA Technical Reports Server (NTRS)

    Brudnicki, M. J.

    1973-01-01

    A failure evaluation of the transducers used in the environmental control systems of the Apollo command service module, lunar module, and portable life support system is presented in matrix form for several generic categories of transducers to enable identification of chronic failure modes. Transducer vendors were contacted and asked to supply detailed information. The evaluation data generated for each category of transducer were compiled and published in failure design evaluation reports. The evaluation reports also present a review of the failure and design data for the transducers and suggest both design criteria to improve reliability of the transducers and, where necessary, design concepts for required redesign of the transducers. Remedial designs were implemented on a family of pressure transducers and on the oxygen flow transducer. The design concepts were subjected to analysis, breadboard fabrication, and verification testing.

  13. Cytosolic domain of the type I interleukin-1 receptor spontaneously recruits signaling molecules to activate a proinflammatory gene.

    PubMed Central

    Singh, R; Huang, S; Guth, T; Konieczkowski, M; Sedor, J R

    1997-01-01

    Immediate postreceptor events activated by IL-1-IL-1R interaction remain undefined. We have initiated studies to identify candidate signal transducers that associate with the cytosolic domain (cd) of the IL-1R. Immunocomplex kinase assays demonstrated an IL-1-activated myelin basic protein kinase activity that coprecipitated with the IL-1R from rat mesangial, mouse EL-4, and HeLa cells. Using glutathione-S-transferase (GST) fusion proteins, HeLa cell lysates next were assayed for kinases that associated with IL-1R cytoplasmic sequences. A GST-IL-1R fusion protein containing the entire cd (amino acids 369-569; GST-IL-1Rcd) recruited a kinase activity in the absence and presence of IL-1 stimulation. In contrast, a GST-IL-1R membrane-proximal region mutant (amino acids 369-501; GST-IL-1RcdDelta), which lacks COOH-terminal amino acid residues required for nuclear factor-kappaB activation, poorly phosphorylated MBP. In gel, kinase assays demonstrated 63-, 83-, and 100-kD kinases that specifically coprecipitated with the HeLa IL-1R and the GST-IL-1Rcd, but not GST-IL-1RcdDelta. 35S-labeled proteins, with Mrs identical to the kinase activities, stably associated with GST-IL-1Rcd. Transient transfection assays of 293 cells were used to evaluate the functional significance of these findings. Simply increasing IL-1cd expression in 293 cells stimulated 5'-IL-6 flanking region-regulated CAT activity threefold above control, an effect blocked by the kinase inhibitors staurosporine and calphostin C. In summary, we have identified two previously unrecognized 63- and 83-kD kinases as well as a protein with an Mr similar to the recently cloned IL-1R-associated kinase, all of which associate spontaneously with the IL-1Rcd. Ectopic IL-1Rcd expression was sufficient to trigger cellular activation, suggesting that the extracellular domain of the intact receptor represses signal transduction until IL-1 is bound. Given that the IL-1Rcd signaling domain has been conserved in a

  14. 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.

  15. 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

  16. Simulation study of a chaotic cavity transducer based virtual phased array used for focusing in the bulk of a solid material.

    PubMed

    Delrue, Steven; Van Den Abeele, Koen; Matar, Olivier Bou

    2016-04-01

    In acoustic