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Sample records for activated signal transducer

  1. Signal Transducer and Activator of Transcription-3, Inflammation, and Cancer

    PubMed Central

    Aggarwal, Bharat B.; Kunnumakkara, Ajaikumar B.; Harikumar, Kuzhuvelil B.; Gupta, Shan R.; Tharakan, Sheeja T.; Koca, Cemile; Dey, Sanjit; Sung, Bokyung

    2011-01-01

    Signal transducer and activator of transcription-3 (STAT-3) is one of six members of a family of transcription factors. It was discovered almost 15 years ago as an acute-phase response factor. This factor has now been associated with inflammation, cellular transformation, survival, proliferation, invasion, angiogenesis, and metastasis of cancer. Various types of carcinogens, radiation, viruses, growth factors, oncogenes, and inflammatory cytokines have been found to activate STAT-3. STAT-3 is constitutively active in most tumor cells but not in normal cells. Phosphorylation of STAT-3 at tyrosine 705 leads to its dimerization, nuclear translocation, DNA binding, and gene transcription. The phosphorylation of STAT-3 at serine 727 may regulate its activity negatively or positively. STAT-3 regulates the expression of genes that mediate survival (survivin, bcl-xl, mcl-1, cellular FLICE-like inhibitory protein), proliferation (c-fos, c-myc, cyclin D1), invasion (matrix metalloproteinase-2), and angiogenesis (vascular endothelial growth factor). STAT-3 activation has also been associated with both chemoresistance and radioresistance. STAT-3 mediates these effects through its collaboration with various other transcription factors, including nuclear factor-κB, hypoxia-inducible factor-1, and peroxisome proliferator activated receptor-γ. Because of its critical role in tumorigenesis, inhibitors of this factor’s activation are being sought for both prevention and therapy of cancer. This has led to identification of small peptides, oligonucleotides, and small molecules as potential STAT-3 inhibitors. Several of these small molecules are chemo-preventive agents derived from plants. This review discusses the intimate relationship between STAT-3, inflammation, and cancer in more detail. PMID:19723038

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

    PubMed

    Xie, J X; Gao, Q J

    2016-05-01

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

  3. The role of the Janus kinase family/signal transducer and activator of transcription signaling pathway in fibrotic renal disease

    PubMed Central

    Matsui, Futoshi; Meldrum, Kirstan K.

    2012-01-01

    Over the past several years, a number of cytokines and growth factors including transforming growth factor β1, tumor necrosis factor α, and angiotensin II have been shown to play a crucial role in renal fibrosis. The Janus kinase family (JAK) and signal transducers and activators of transcription (STATs) constitute one of the primary signaling pathways that regulate cytokine expression, and the JAK/STAT signaling pathway has increasingly been implicated in the pathophysiology of renal disease. This review examines the role of the JAK/STAT signaling pathway in fibrotic renal disease. The JAK/STAT signaling pathway is activated in a variety of renal diseases and has been implicated in the pathophysiology of renal fibrosis. Experimental evidence suggests that inhibition of the JAK/STAT signaling pathway, in particular JAK2 and STAT3, may suppress renal fibrosis and protect renal function. However, it is incompletely understood which cells activate the JAK/STAT signaling pathway and which JAK/STAT signaling pathway is activated in each renal disease. Research regarding JAK/STAT signaling and its contribution to renal disease is still ongoing in humans. Future studies are required to elucidate the potential role of JAK/STAT signaling inhibition as a therapeutic strategy in the attenuation of renal fibrosis. PMID:22883438

  4. Suppression of Epithelial Signal Transducer and Activator of Transcription 1 Activation by Extracts of Aspergillus fumigatus

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-07-01

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

  6. Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gp130.

    PubMed Central

    Narazaki, M; Witthuhn, B A; Yoshida, K; Silvennoinen, O; Yasukawa, K; Ihle, J N; Kishimoto, T; Taga, T

    1994-01-01

    The interleukin 6 receptor-associated signal transducer, gp130, is shared by receptor complexes for leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and interleukin 11. We show here that JAK2 kinase is rapidly tyrosine phosphorylated in mouse embryonic stem cells whose pluripotentiality is maintained only by gp130-sharing cytokines after stimulation that is known to induce gp130 homodimerization. JAK1 is also tyrosine phosphorylated, but to a lesser extent, under the same conditions. Comparable results are obtained with hemopoietic lineage cells such as myeloid leukemic M1 cells and pro-B-cell line-derived transfectants expressing gp130, the former of which differentiate into macrophages after stimulation of gp130 and the latter of which initiate DNA synthesis. gp130-dimerizing stimulus upregulates kinase activity of JAK2 as revealed by immunocomplex kinase assay. Deletion or point mutation in the membrane-proximal cytoplasmic motifs in gp130 that are conserved in the hemopoietic cytokine receptor family results in the loss of tyrosine phosphorylation of JAK2, which coincides with the lack of signal transducing capability of gp130 mutants. Images PMID:8134389

  7. TRPC channels as signal transducers.

    PubMed

    Glazebrook, Patricia A; Schilling, William P; Kunze, Diana L

    2005-10-01

    The study of the TRPC cation channels as signal transducers in sensory neurons is in its infancy. Mechanoreceptors that monitor arterial pressure are prime candidates for the involvement of TRPC channels as either primary mechanical transducers or as modulators of the transduction process. Their activity patterns can be regulated by growth factors such as BDNF and by a variety of ligands that activate Gq-coupled receptors, mechanisms that have been shown in heterologous expression systems to activate TRPC channels. We investigated the distribution of TRPC1 and TRPC3-7 in nodose sensory neurons and in their peripheral axons that terminate as mechanosensitive receptors in the aortic arch of the rat. Using immunocytochemical techniques we identified these six TRPC proteins in the soma of the nodose neurons but only TRPC1 and TRPC3-5 were found to distribute to the peripheral axons and the mechanosensory terminals. TRPC1 and TRPC3 extended into the low threshold complex sensory endings with very strong labeling. In contrast, TRPC4 and TRPC5 were found primarily in major branches of the receptor but immunoreactivity was weak in the region where mechanotransduction is presumed to occur. Terminals arising from unmyelinated fibers also expressed TRPC1 and TRPC3-5 but not all fibers expressed all of the channels suggesting that specific TRPC protein may be aligned with previously described subclasses of the unmyelinated C-fibers. PMID:15971079

  8. Conformationally Constrained Peptidomimetic Inhibitors of Signal Transducer and Activator of Transcription 3: Evaluation and Molecular Modeling

    PubMed Central

    Mandal, Pijus K.; Limbrick, Donald; Coleman, David R.; Dyer, Garrett A.; Ren, Zhiyong; Birtwistle, J. Sanderson; Xiong, Chiyi; Chen, Xiaomin; Briggs, James M.; McMurray, John S.

    2009-01-01

    Signal transducer and activator of transcription 3 (Stat3) is involved in aberrant growth and survival signals in malignant tumor cells and is a validated target for anti-cancer drug design. We are targeting its SH2 domain to prevent docking to cytokine and growth factor receptors and subsequent signaling. The amino acids of our lead phosphopeptide, Ac-pTyr-Leu-Pro-Gln-Thr-Val-NH2, were replaced with conformationally constrained mimics. Structure-affinity studies led to the peptidomimetic, pCinn-Haic-Gln-NHBn (21) which had an IC50 of 162 nM (fluorescence polarization), as compared to 290 nM for the lead phosphopeptide (pCinn = 4-phosphoryloxycinnamate, Haic = (2S,5S)-5-amino-1,2,4,5,6,7-hexahydro-4-oxo-azepino[3,2,1-hi]indole-2-carboxylic acid). pCinn-Haic-Gln-OH was docked to the SH2 domain (AUTODOCK) and the two highest populated clusters were subjected to molecular dynamics simulations. Both converged to a common peptide conformation. The complex exhibits unique hydrogen bonding between Haic and Gln and Stat3 as well as hydrophobic interactions between the protein and pCinn and Haic. PMID:19334714

  9. 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.

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

    PubMed

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

    2016-06-01

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

  11. 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. PMID:27318793

  12. 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. PMID:22753228

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

    PubMed Central

    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

    2012-01-01

    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. PMID:22753228

  14. IL-17A induces signal transducers and activators of transcription-6-independent airway mucous cell metaplasia.

    PubMed

    Newcomb, Dawn C; Boswell, Madison G; Sherrill, Taylor P; Polosukhin, Vasiliy V; Boyd, Kelli L; Goleniewska, Kasia; Brody, Steven L; Kolls, Jay K; Adler, Kenneth B; Peebles, R Stokes

    2013-06-01

    Mucous cell metaplasia is a hallmark of asthma, and may be mediated by signal transducers and activators of transcription (STAT)-6 signaling. IL-17A is increased in the bronchoalveolar lavage fluid of patients with severe asthma, and IL-17A also increases mucus production in airway epithelial cells. Asthma therapeutics are being developed that inhibit STAT6 signaling, but the role of IL-17A in inducing mucus production in the absence of STAT6 remains unknown. We hypothesized that IL-17A induces mucous cell metaplasia independent of STAT6, and we tested this hypothesis in two murine models in which increased IL-17A protein expression is evident. In the first model, ovalbumin (OVA)-specific D011.10 Th17 cells were adoptively transferred into wild-type (WT) or STAT6 knockout (KO) mice, and the mice were challenged with OVA or PBS. WT-OVA and STAT6 KO-OVA mice demonstrated increased airway IL-17A and IL-13 protein expression and mucous cell metaplasia, compared with WT-PBS or STAT6 KO-PBS mice. In the second model, WT, STAT1 KO, STAT1/STAT6 double KO (DKO), or STAT1/STAT6/IL-17 receptor A (RA) triple KO (TKO) mice were challenged with respiratory syncytial virus (RSV) or mock viral preparation, and the mucous cells were assessed. STAT1 KO-RSV mice demonstrated increased airway mucous cell metaplasia compared with WT-RSV mice. STAT1 KO-RSV and STAT1/STAT6 DKO-RSV mice also demonstrated increased mucous cell metaplasia, compared with STAT1/STAT6/IL17RA TKO-RSV mice. We also treated primary murine tracheal epithelial cells (mTECs) from WT and STAT6 KO mice. STAT6 KO mTECs showed increased periodic acid-Schiff staining with IL-17A but not with IL-13. Thus, asthma therapies targeting STAT6 may increase IL-17A protein expression, without preventing IL-17A-induced mucus production. PMID:23392574

  15. Signal transducer and activator of transcription 3 limits Epstein-Barr virus lytic activation in B lymphocytes.

    PubMed

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

    2013-11-01

    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

  16. Activation of the signal transducer gp130 by interleukin-11 and interleukin-6 is mediated by similar molecular interactions.

    PubMed Central

    Dahmen, H; Horsten, U; Küster, A; Jacques, Y; Minvielle, S; Kerr, I M; Ciliberto, G; Paonessa, G; Heinrich, P C; Müller-Newen, G

    1998-01-01

    The transmembrane glycoprotein gp130 is involved in many cytokine-mediated cellular responses and acts therein as the signal transducing receptor subunit. Interleukin-6 (IL-6) and interleukin-11 (IL-11), in complex with their specific alpha-receptors, homodimerize gp130 and, as a consequence, activate the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) signalling pathway in their target cells. So far, it is not clear whether gp130 is bound to these cytokines and their specific alpha-receptor subunits through identical or different epitopes. In order to study the interaction of IL-11 and IL-11R with human gp130 the soluble form of the recently cloned human IL-11R was expressed in baculovirus-infected insect cells. By a coprecipitation binding-assay it is demonstrated that IL-11 and IL-6 compete for binding to gp130. Using deletion and point mutants of gp130 it is shown that IL-11-IL-11R and IL-6-IL-6R recognize overlapping binding motifs on gp130. Moreover, using well-established Jak-deficient cell lines we demonstrate that STAT activation by IL-11 requires Jak1. Taken together, our data support the concept that IL-6 and IL-11 activate gp130 by very similar molecular mechanisms. PMID:9560294

  17. Ubiquitously expressed transcript is a novel interacting protein of protein inhibitor of activated signal transducer and activator of transcription 2

    PubMed Central

    KONG, XIANG; MA, SHIKUN; GUO, JIAQIAN; MA, YAN; HU, YANQIU; WANG, JIANJUN; ZHENG, YING

    2015-01-01

    Protein inhibitor of activated signal transducer and activator of transcription 2 (PIAS2) is a member of the PIAS protein family. This protein family modulates the activity of several transcription factors and acts as an E3 ubiquitin ligase in the sumoylation pathway. To improve understanding of the physiological roles of PIAS2, the current study used a yeast two-hybrid system to screen mouse stem cell cDNA libraries for proteins that interact with PIAS2. The screening identified an interaction between PIAS2 and ubiquitously expressed transcript (UXT). UXT, also termed androgen receptor trapped clone-27, is an α-class prefoldin-type chaperone that acts as a coregulator for various transcription factors, including nuclear factor-κB and androgen receptor (AR). A direct interaction between PIAS2 and UXT was confirmed by direct yeast two-hybrid analysis. In vitro evidence of the association of UXT with PIAS2 was obtained by co-immunoprecipitation. Colocalization between PIAS2 and UXT was identified in the nucleus and cytoplasm of HEK 293T and human cervical carcinoma HeLa cells. The results of the current study suggested that UXT is a binding protein of PIAS2, and interaction between PIAS2 and UXT may be important for the transcriptional activation of AR. PMID:25434787

  18. 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

  19. Phosphoproteomic analysis of anaplastic lymphoma kinase (ALK) downstream signaling pathways identifies signal transducer and activator of transcription 3 as a functional target of activated ALK in neuroblastoma cells

    PubMed Central

    Sattu, Kamaraj; Hochgräfe, Falko; Wu, Jianmin; Umapathy, Ganesh; Schönherr, Christina; Ruuth, Kristina; Chand, Damini; Witek, Barbara; Fuchs, James; Li, Pui-Kai; Hugosson, Fredrik; Daly, Roger J; Palmer, Ruth H; Hallberg, Bengt

    2013-01-01

    Activation of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is a key oncogenic mechanism in a growing number of tumor types. In the majority of cases, ALK is activated by fusion with a dimerizing partner protein as a result of chromosomal translocation events, most studied in the case of the nucleophosmin–ALK and echinoderm microtubule-associated protein-like 4–ALK oncoproteins. It is now also appreciated that the full-length ALK receptor can be activated by point mutations and by deletions within the extracellular domain, such as those observed in neuroblastoma. Several studies have employed phosphoproteomics approaches to find substrates of ALK fusion proteins. In this study, we used MS-based phosphotyrosine profiling to characterize phosphotyrosine signaling events associated with the full-length ALK receptor. A number of previously identified and novel targets were identified. One of these, signal transducer and activator of transcription 3 (STAT3), has previously been observed to be activated in response to oncogenic ALK signaling, but the significance of this in signaling from the full-length ALK receptor has not been explored further. We show here that activated ALK robustly activates STAT3 on Tyr705 in a number of independent neuroblastoma cell lines. Furthermore, knockdown of STAT3 by RNA interference resulted in a reduction in myelocytomatosis neuroblastom (MYCN) protein levels downstream of ALK signaling. These observations, together with a decreased level of MYCN and inhibition of neuroblastoma cell growth in the presence of STAT3 inhibitors, suggest that activation of STAT3 is important for ALK signaling activity in neuroblastoma. PMID:23889739

  20. The emerging role of signal transducer and activator of transcription 3 in cerebral ischemic and hemorrhagic stroke.

    PubMed

    Liang, Zhenxing; Wu, Guiling; Fan, Chongxi; Xu, Jing; Jiang, Shuai; Yan, Xiaolong; Di, Shouyin; Ma, Zhiqiang; Hu, Wei; Yang, Yang

    2016-02-01

    Signal transducers and activators of transcription (STATs) comprise a family of cytoplasmic transcription factors that mediate intracellular signaling. This signaling is typically generated at cell surface receptors, the activation of which results in the translocation of STATs to the nucleus. STATs are involved in biological events as diverse as embryonic development, programmed cell death, organogenesis, innate immunity, adaptive immunity and cell growth regulation in organisms ranging from slime molds to insects to humans. Numerous studies have demonstrated the activation of STAT3 in neurological diseases, particularly in cerebral ischemic and hemorrhagic stroke. Additionally, STAT3 has also been reported to play a critical role in neuroprotective therapies. In light of the pleiotropic effects of STAT3 on the nervous system, we present the elaborate network of roles that STAT3 plays in cerebral ischemia and hemorrhage in this review. First, we introduce basic knowledge regarding STAT3 and briefly summarize the activation, inactivation, and regulation of the STAT3 pathway. Next, we describe the activation of STAT3 following cerebral ischemia and hemorrhage. Subsequently, we discuss the physiopathological roles of STAT3 in cerebral ischemia and hemorrhage. Moreover, we summarize several significant cerebral ischemic and hemorrhagic stroke treatments that target the STAT3 signaling pathway, including pharmacological and physical therapies. Finally, we highlight research progress on STAT3 in stroke. This review presents the important roles of STAT3 in the nervous system and may contribute to the promotion of STAT3 as a new therapeutic target. PMID:26738445

  1. Signal Transducer and Activator of Transcription-5 Mediates Neuronal Apoptosis Induced by Inhibition of Rac GTPase Activity*

    PubMed Central

    Stankiewicz, Trisha R.; Loucks, F. Alexandra; Schroeder, Emily K.; Nevalainen, Marja T.; Tyler, Kenneth L.; Aktories, Klaus; Bouchard, Ron J.; Linseman, Daniel A.

    2012-01-01

    In several neuronal cell types, the small GTPase Rac is essential for survival. We have shown previously that the Rho family GTPase inhibitor Clostridium difficile toxin B (ToxB) induces apoptosis in primary rat cerebellar granule neurons (CGNs) principally via inhibition of Rac GTPase function. In the present study, incubation with ToxB activated a proapoptotic Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and a pan-JAK inhibitor protected CGNs from Rac inhibition. STAT1 expression was induced by ToxB; however, CGNs from STAT1 knock-out mice succumbed to ToxB-induced apoptosis as readily as wild-type CGNs. STAT3 displayed enhanced tyrosine phosphorylation following treatment with ToxB, and a reputed inhibitor of STAT3, cucurbitacin (JSI-124), reduced CGN apoptosis. Unexpectedly, JSI-124 failed to block STAT3 phosphorylation, and CGNs were not protected from ToxB by other known STAT3 inhibitors. In contrast, STAT5A tyrosine phosphorylation induced by ToxB was suppressed by JSI-124. In addition, roscovitine similarly inhibited STAT5A phosphorylation and protected CGNs from ToxB-induced apoptosis. Consistent with these results, adenoviral infection with a dominant negative STAT5 mutant, but not wild-type STAT5, significantly decreased ToxB-induced apoptosis of CGNs. Finally, chromatin immunoprecipitation with a STAT5 antibody revealed increased STAT5 binding to the promoter region of prosurvival Bcl-xL. STAT5 was recruited to the Bcl-xL promoter region in a ToxB-dependent manner, and this DNA binding preceded Bcl-xL down-regulation, suggesting transcriptional repression. These data indicate that a novel JAK/STAT5 proapoptotic pathway significantly contributes to neuronal apoptosis induced by the inhibition of Rac GTPase. PMID:22378792

  2. Signal transducer and activator of transcription-5 mediates neuronal apoptosis induced by inhibition of Rac GTPase activity.

    PubMed

    Stankiewicz, Trisha R; Loucks, F Alexandra; Schroeder, Emily K; Nevalainen, Marja T; Tyler, Kenneth L; Aktories, Klaus; Bouchard, Ron J; Linseman, Daniel A

    2012-05-11

    In several neuronal cell types, the small GTPase Rac is essential for survival. We have shown previously that the Rho family GTPase inhibitor Clostridium difficile toxin B (ToxB) induces apoptosis in primary rat cerebellar granule neurons (CGNs) principally via inhibition of Rac GTPase function. In the present study, incubation with ToxB activated a proapoptotic Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and a pan-JAK inhibitor protected CGNs from Rac inhibition. STAT1 expression was induced by ToxB; however, CGNs from STAT1 knock-out mice succumbed to ToxB-induced apoptosis as readily as wild-type CGNs. STAT3 displayed enhanced tyrosine phosphorylation following treatment with ToxB, and a reputed inhibitor of STAT3, cucurbitacin (JSI-124), reduced CGN apoptosis. Unexpectedly, JSI-124 failed to block STAT3 phosphorylation, and CGNs were not protected from ToxB by other known STAT3 inhibitors. In contrast, STAT5A tyrosine phosphorylation induced by ToxB was suppressed by JSI-124. In addition, roscovitine similarly inhibited STAT5A phosphorylation and protected CGNs from ToxB-induced apoptosis. Consistent with these results, adenoviral infection with a dominant negative STAT5 mutant, but not wild-type STAT5, significantly decreased ToxB-induced apoptosis of CGNs. Finally, chromatin immunoprecipitation with a STAT5 antibody revealed increased STAT5 binding to the promoter region of prosurvival Bcl-xL. STAT5 was recruited to the Bcl-xL promoter region in a ToxB-dependent manner, and this DNA binding preceded Bcl-xL down-regulation, suggesting transcriptional repression. These data indicate that a novel JAK/STAT5 proapoptotic pathway significantly contributes to neuronal apoptosis induced by the inhibition of Rac GTPase. PMID:22378792

  3. 17β-Oestradiol enhances the expansion and activation of myeloid-derived suppressor cells via signal transducer and activator of transcription (STAT)-3 signalling in human pregnancy.

    PubMed

    Pan, T; Zhong, L; Wu, S; Cao, Y; Yang, Q; Cai, Z; Cai, X; Zhao, W; Ma, N; Zhang, W; Zhang, H; Zhou, J

    2016-07-01

    During a successful pregnancy, the maternal immune system plays a critical role in maintaining immunotolerance towards semi-allogeneic fetal antigens. Recent studies have indicated that myeloid-derived suppressor cells (MDSCs) are active players in establishing fetal-maternal tolerance; however, the underlying mechanism remains poorly understood. In this study, we observed a significant expansion of monocytic MDSCs (M-MDSCs) in the peripheral blood of pregnant women, which suppressed T cell responses in a reactive oxygen species-dependent manner and required cell-cell contact. The number of M-MDSCs correlated positively with serum oestrogen and progesterone levels. Administration of 17β-oestradiol, but not progesterone, enhanced both the expansion and suppressive activity of M-MDSCs through signal transducer and activator of transcription (STAT)-3. Pretreatment with STAT-3 inhibitor JSI-124 almost completely abrogated the effects of 17β-oestradiol on MDSCs. Collectively, these results demonstrate that 17β-oestradiol-induced STAT-3 signalling plays an important role in both the expansion and activation of MDSCs during human pregnancy, which may benefit the development of novel therapeutic strategies for prevention of immune-related miscarriage. PMID:26969967

  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. PMID:22104110

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

    PubMed Central

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

    2012-01-01

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

  6. Angiotensin II Type-2 Receptors Modulate Inflammation Through Signal Transducer and Activator of Transcription Proteins 3 Phosphorylation and TNFα Production

    PubMed Central

    Abadir, Peter M.; Walston, Jeremy D.; Carey, Robert M.

    2011-01-01

    Angiotensin subtype-1 receptor (AT1R) influences inflammatory processes through enhancing signal transducer and activator of transcription proteins 3 (STAT3) signal transduction, resulting in increased tumor necrosis factor-α (TNF-α) production. Although angiotensin subtype-2 receptor (AT2R), in general, antagonizes AT1R-stimulated activity, it is not known if AT2R has any anti-inflammatory effects. In this study, we tested the hypothesis that AT2R activation plays an anti-inflammatory role by reducing STAT3 phosphorylation and TNF-α production. Changes in AT2R expression, TNF-α production, and STAT3 phosphorylation were quantified by Western blotting, Bio-Plex cytokine, and phosphoprotein cellular signaling assays in PC12W cells that express AT2R but not AT1R, in response to the AT2R agonist, CGP-42112 (CGP, 100 nm), or AT2R antagonist PD-123319 (PD, 1 μm). A 100% increase in AT2R expression in response to stimulation with its agonist CGP was observed. Further, AT2R activation reduced TNF-α production by 39% and STAT3 phosphorylation by 83%. In contrast, PD decreased AT2R expression by 76%, increased TNF-α production by 84%, and increased STAT3 phosphorylation by 67%. These findings suggest that increased AT2R expression may play a role in the observed decrease in inflammatory pathway activation through decreased TNF-α production and STAT3 signaling. Restoration of AT2R expression and/or its activation constitute a potentially novel therapeutic target for the management of inflammatory processes. PMID:21288138

  7. 2-Methoxystypandrone inhibits signal transducer and activator of transcription 3 and nuclear factor-κB signaling by inhibiting Janus kinase 2 and IκB kinase.

    PubMed

    Kuang, Shan; Qi, Chunting; Liu, Jiawei; Sun, Xiaoxiao; Zhang, Qing; Sima, Zhenhua; Liu, Jingli; Li, Wuguo; Yu, Qiang

    2014-04-01

    Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) or the nuclear factor-κB (NF-κB) pathway occurs frequently in cancer cells and contributes to oncogenesis. The activation of Janus kinase 2 (JAK2) and IκB kinase (IKK) are key events in STAT3 and NF-κB signaling, respectively. We have identified 2-methoxystypandrone (2-MS) from a traditional Chinese medicinal herb Polygonum cuspidatum as a novel dual inhibitor of JAK2 and IKK. 2-MS inhibits both interleukin-6-induced and constitutively-activated STAT3, as well as tumor necrosis factor-α-induced NF-κB activation. 2-MS specifically inhibits JAK and IKKβ kinase activities but has little effect on activities of other kinases tested. The inhibitory effects of 2-MS on STAT3 and NF-κB signaling can be eliminated by DTT or glutathione and can last for 4 h after a pulse treatment. Furthermore, 2-MS inhibits growth and induces death of tumor cells, particularly those with constitutively-activated STAT3 or NF-κB signaling. We propose that the natural compound 2-MS, as a potent dual inhibitor of STAT3 and NF-κB pathways, is a promising anticancer drug candidate. PMID:24450414

  8. Dehydrocostuslactone disrupts signal transducers and activators of transcription 3 through up-regulation of suppressor of cytokine signaling in breast cancer cells.

    PubMed

    Kuo, Po-Lin; Ni, Wen-Chiu; Tsai, Eing-Mei; Hsu, Ya-Ling

    2009-05-01

    This study investigates the anticancer effect of dehydrocostuslactone (DHE), a plant-derived sesquiterpene lactone, on human breast cancer cells. DHE inhibits cell proliferation by inducing cells to undergo cell cycle arrest and apoptosis. DHE suppresses the expression of cyclin D, cyclin A, cyclin-dependent kinase 2, and cdc25A and increases the amount of p53 and p21, resulting in G(0)/G(1)-S phase arrest in MCF-7 cells. In contrast, DHE caused S-G(2)/M arrest by increasing p21 expression and chk1 activation and inhibiting cyclin A, cyclin B, cdc25A, and cdc25C expression in MDA-MB-231 cells. DHE induces up-regulation of Bax and Bad, down-regulation of Bcl-2 and Bcl-XL, and nuclear relocation of the mitochondrial factors apoptosis-inducing factor and endonuclease G. We also found that DHE inhibits survival signaling through the Janus tyrosine kinase-signal transducer and activator of transcription-3 signaling by increasing the expression of suppressors of cytokine signaling (SOCS)-1 and SOCS-3. Reduction of SOCS-1 and SOCS-3 expression by small interfering RNA inhibits DHE-mediated signal transducer and activator of transcription-3 inhibition, p21 up-regulation, and cyclin-dependent kinase 2 blockade, supporting the hypothesis that DHE inhibits cell cycle progression and cell death through SOCS-1 and SOCS-3. Significantly, animal studies have revealed a 50% reduction in tumor volume after a 45-day treatment period. Taken together, this study provides new insights into the molecular mechanism of the DHE action that may contribute to the chemoprevention of breast cancer. PMID:19383849

  9. 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

  10. Involvement of fish signal transducer and activator of transcription 3 (STAT3) in nodavirus infection induced cell death.

    PubMed

    Huang, Youhua; Huang, Xiaohong; Yang, Ying; Wang, Wei; Yu, Yepin; Qin, Qiwei

    2015-03-01

    The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway is an important signaling pathway activated by interferons in response to virus infection. Fish STAT3 has been demonstrated to be involved in Singapore grouper iridovirus (SGIV) infection and virus induced paraptosis, but its effects on the replication of other fish viruses still remained uncertain. Here, the roles of grouper STAT3 (Ec-STAT3) in red spotted grouper nervous necrosis virus (RGNNV) infection were investigated. The present data showed that the distribution of phosphorylated Ec-STAT3 was altered in RGNNV infected fish cells, and the promoter activity of STAT3 was significantly increased during virus infection, suggesting that STAT3 activation was involved in RGNNV infection. Using STAT3 specific inhibitor, we found that inhibition of Ec-STAT3 in vitro did not affect the transcription and protein synthesis of RGNNV coat protein (CP), however, the severity of RGNNV induced vacuolation and autophagy was significantly increased. Meanwhile, at the late stage of virus infection, RGNNV induced necrotic cell death was significantly decreased after inhibition of Ec-STAT3. Further studies indicated that Ec-STAT3 inhibition significantly increased the transcript level of autophagy related genes, including UNC-51-like kinase 2 (ULK2) and microtubule-associated protein 1 light chain 3-II (LC3-II) induced by RGNNV infection. Moreover, the expression of several pro-inflammatory factors, including TNFα, IL-1β and IL-8 were mediated by Ec-STAT3 during RGNNV infection. Together, our results not only firstly revealed that STAT3 exerted novel roles in response to fish virus infection, but also provided new insights into understanding the roles of STAT3 in different forms of programmed cell death. PMID:25555814

  11. Prognostic features of signal transducer and activator of transcription 3 in an ER(+) breast cancer model system

    PubMed Central

    Liu, Li-Yu D; Chang, Li-Yun; Kuo, Wen-Hung; Hwa, Hsiao-Lin; Lin, Yi-Shing; Jeng, Meei-Huey; Roth, Don A; Chang, King-Jen; Hsieh, Fon-Jou

    2014-01-01

    The aberrantly expressed signal transducer and activator of transcription 3 (STAT3) predicts poor prognosis, primarily in estrogen receptor positive (ER(+)) breast cancers. Activated STAT3 is overexpressed in luminal A subtype cells. The mechanisms contributing to the prognosis and/or subtype relevant features of STAT3 in ER(+) breast cancers are through multiple interacting regulatory pathways, including STAT3-MYC, STAT3-ERα, and STAT3-MYC-ERα interactions, as well as the direct action of activated STAT3. These data predict malignant events, treatment responses and a novel enhancer of tamoxifen resistance. The inferred crosstalk between ERα and STAT3 in regulating their shared target gene-METAP2 is partially validated in the luminal B breast cancer cell line-MCF7. Taken together, we identify a poor prognosis relevant gene set within the STAT3 network and a robust one in a subset of patients. VEGFA, ABL1, LYN, IGF2R and STAT3 are suggested therapeutic targets for further study based upon the degree of differential expression in our model. PMID:24526833

  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. 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

  14. Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition

    PubMed Central

    Su, Tung-Hung; Shiau, Chung-Wai; Jao, Ping; Liu, Chen-Hua; Liu, Chun-Jen; Tai, Wei-Tien; Jeng, Yung-Ming; Yang, Hung-Chih; Tseng, Tai-Chung; Huang, Hsiang-Po; Cheng, Huei-Ru; Chen, Pei-Jer; Chen, Kuen-Feng; Kao, Jia-Horng; Chen, Ding-Shinn

    2015-01-01

    Signal transducer and activator of transcription 3 (STAT3) had been involved in liver fibrogenesis. We aimed to explore the antifibrotic activities of sorafenib and its derivative SC-1 (devoid of Raf kinase inhibition activity) both in vivo and in vitro with special focus on the STAT3 pathway in hepatic stellate cells (HSCs). The clinical role of STAT3 in chronic hepatitis B (CHB) was also investigated. Experimental fibrosis mouse models were established by thioacetamide injection and bile duct ligation in Balb/C mice and treated with sorafenib and SC-1. Rat and human HSCs were used for mechanistic investigations. Forty CHB patients were enrolled to quantify the hepatic phospho-STAT3 (p-STAT3) levels and correlated with liver fibrosis. Both sorafenib and SC-1 ameliorated liver fibrosis in vivo and promoted HSC apoptosis in vitro. p-STAT3 and downstream signals were down-regulated after sorafenib and SC-1 treatment in HSC. STAT3 overexpression in HSC enhanced cell proliferation and undermined the apoptotic effects of sorafenib and SC-1, whereas STAT3-specific inhibition promoted HSC apoptosis. Sorafenib and SC-1 activated Src-homology protein tyrosine phosphatase-1 (SHP-1) and STAT3 inhibition followed. Of particular interest, in CHB patients with advanced liver fibrosis, p-STAT3 in HSC was significantly overexpressed and positively correlated with the severity of liver fibrosis and plasma IL-6 levels. In conclusion, sorafenib and SC-1 ameliorate liver fibrosis through STAT3 inhibition in HSC and STAT3 may potentially serve as a promising fibrotic biomarker and target in liver fibrosis. SHP-1 phosphatase-directed STAT3 inhibition may represent a previously unidentified strategy for antifibrotic drug discovery. PMID:26039995

  15. Bone marrow mesenchymal stromal cells with CD47 high expression via the signal transducer and activators of transcription signaling pathway preventing myocardial fibrosis

    PubMed Central

    Deng, Wei; Chen, Qing-Wei; Li, Xing-Sheng; Yuan, Zhong-Ming; Li, Gui-Qiong; Ke, Da-Zhi; Wang, Li; Wu, Zhi-Qing; Luo, Shi-Lan

    2015-01-01

    This study was initiated to investigate the efficacy of myocardial fibrosis intervention via signal transducer and activators of transcription (STAT) signaling using bone marrow (BM) mesenchymal stromal cells (MSC) in which being over-expressed with the aid of bispecific antibody (BiAb) and ultrasound-mediated microbubbles (MB). BiAb was prepared and combined with isolated MSC with CD47 overexpression from male mice and trans-fused into female mice with isoproterenol-induced myocardial fibrosis via the tail vein, followed by MB. This study included five groups. Five weeks after treatment, expression levels of the sex-determining region of Y-chromosome (SRY), matrix metalloproteinases (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1 and vascular endothelial growth factor (VEGF) in myocardium were detected by fluorescent quantitative real-time polymerase chain reaction (qRT-PCR). The protein expression of signal transducer and activators of transcription (STAT) 1 and STAT 3 was detected by Western blot. Results: The highest homing number of MSC was in the CD47 + MSC + BiAb + MB group, second highest in the CD47 + MSC + BiAb group, and lowest in MSC alone. Compared with the Control group, CD47 + MSC + BiAb + MB, CD47 + MSC + BiAb, CD47 + MSC and MSC groups had decreased levels of MMP-9, TIMP-1, STAT 1 and collagen deposition, and increased levels of STAT 3. Up regulated STAT 3 and down regulated TIMP-1 were significantly different in CD47 + MSC + BiAb + MB compared with CD47 + MSC or CD47 + MSC + BiAb. Conclusion: CD47 can enhance the homing rate and repairing efficacy of MSC. MSC can improve MMP-TIMP expression in injured myocardium and interfere with myocardial fibrosis after homing, a mechanism that may be related to the STAT-mediated signaling pathway. PMID:26617765

  16. Guggulsterone enhances head and neck cancer therapies via inhibition of signal transducer and activator of transcription-3

    PubMed Central

    Leeman-Neill, Rebecca J.; Wheeler, Sarah E.; Singh, Shivendra V.; Thomas, Sufi M.; Seethala, Raja R.; Neill, Daniel B.; Panahandeh, Mary C.; Hahm, Eun-Ryeong; Joyce, Sonali C.; Sen, Malabika; Cai, Quan; Freilino, Maria L.; Li, Changyou; Johnson, Daniel E.; Grandis, Jennifer R.

    2009-01-01

    Treatment of human head and neck squamous cell carcinoma (HNSCC) cell lines with guggulsterone, a widely available, well-tolerated nutraceutical, demonstrated dose-dependent decreases in cell viability with EC50s ranging from 5 to 8 μM. Guggulsterone induced apoptosis and cell cycle arrest, inhibited invasion and enhanced the efficacy of erlotinib, cetuximab and cisplatin in HNSCC cell lines. Guggulsterone induced decreased expression of both phosphotyrosine and total signal transducer and activator of transcription (STAT)-3, which contributed to guggulsterone's growth inhibitory effect. Hypoxia-inducible factor (HIF)-1α was also decreased in response to guggulsterone treatment. In a xenograft model of HNSCC, guggulsterone treatment resulted in increased apoptosis and decreased expression of STAT3. In vivo treatment with a guggulsterone-containing natural product, Guggulipid, resulted in decreased rates of tumor growth and enhancement of cetuximab's activity. Our results suggest that guggulsterone-mediated inhibition of STAT3 and HIF-1α provide a biologic rationale for further clinical investigation of this compound in the treatment of HNSCC. PMID:19762335

  17. 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)

  18. Modulating antiangiogenic resistance by inhibiting the signal transducer and activator of transcription 3 pathway in glioblastoma.

    PubMed

    de Groot, John; Liang, Ji; Kong, Ling-Yuan; Wei, Jun; Piao, Yuji; Fuller, Gregory; Qiao, Wei; Heimberger, Amy B

    2012-09-01

    Determining the mechanism of treatment failure of VEGF signaling inhibitors for malignant glioma patients would provide insight into approaches to overcome therapeutic resistance. In this study, we demonstrate that human glioblastoma tumors failing bevacizumab have an increase in the mean percentage of p-STAT3-expressing cells compared to samples taken from patients failing non-antiangiogenic therapy containing regimens. Likewise, in murine xenograft models of glioblastoma, the mean percentage of p-STAT3-expressing cells in the gliomas resistant to antiangiogenic therapy was markedly elevated relative to controls. Administration of the JAK/STAT3 inhibitor AZD1480 alone and in combination with cediranib reduced tumor hypoxia and the infiltration of VEGF inhibitor-induced p-STAT3 macrophages. Thus, the combination of AZD1480 with cediranib markedly reduced tumor volume, and microvascular density, indicating that up regulation of the STAT3 pathway can mediate resistance to antiangiogenic therapy and combinational approaches may delay or overcome resistance. PMID:23013619

  19. Immunohistochemical evaluation of stem cell markers and signal transducer and activator of transcription 6 (STAT6) in solitary fibrous tumors.

    PubMed

    Wang, Chengyan; Qi, Yan; Liu, Ruixue; Lan, Jiaojiao; Zhou, Yang; Ju, Xinxin; Chen, Dongdong; Zou, Hong; Li, Shugang; Hu, Jianming; Zhao, Jin; Shen, Yaoyuan; Sun, Zhenzhu; Pang, Lijuan; Li, Feng

    2015-01-01

    Solitary fibrous tumors (SFT) are fibroblastic, ubiquitous mesenchymal tumors. Although several SFT studies have been conducted, the cell of origin of SFT remains controversial and reliable diagnostic markers are needed for SFT identification for proper prognosis and therapeutics. To analyze the immunophenotype of SFT for the identification of specific diagnostic markers and the cell of origin of this tumor, we performed an immunohistochemical study of stem cell markers [aldehyde dehydrogenase 1 (ALDH1), CD29, CD44, CD133, and nestin] and signal transducer and activator of transcription 6 (STAT6) in 18 cases of SFT. The results demonstrated that ALDH1 was present in 16 cases (16/18), STAT6 in 13 cases (13/18), CD44 in 8 cases (8/18), and CD29 in 1 case (1/18), whereas CD133 and nestin were absent in all cases (0/18). Our results indicate that combination with ALDH1 and STAT6 can improve the diagnostic value of CD34 for SFT. The immunohistochemical findings for stem cell surface markers indicate that SFT may originate from stem cells and that ALDH1 plays an important role in the development of SFT. PMID:26617768

  20. 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

  1. 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

  2. Antiproliferative effects of Dangyuja (Citrus grandis Osbeck) leaves through suppression of constitutive signal transducer and activator of transcription 3 activation in human prostate carcinoma DU145 cells.

    PubMed

    Chiang, Shu Yuan; Kim, Sung-Moo; Kim, Chulwon; Um, Jae-Young; Park, Kyung-Ran; Kim, Seong Won; Lee, Seok-Geun; Jang, Hyeung-Jin; Nam, Dongwoo; Ahn, Kyoo Seok; Kim, Sung-Hoon; Choi, Seung-Hoon; Shim, Bum Sang; Na, Yun-Cheol; Jeong, Eun-Kyung; Cho, Somi K; Ahn, Kwang Seok

    2012-02-01

    Although Dangyuja (Citrus grandis Osbeck) exhibits anti-inflammatory and anticancer activities, its molecular targets and pathways, especially in human prostate cancer cells, are not fully understood. In this study, the antiproliferative effect of Dangyuja leaves through the signal transducer and activator of transcription (STAT) 3 signaling pathway was investigated in human prostate carcinoma DU145 cells. The solvent fractions (n-hexane, chloroform, ethyl acetate, and n-butanol) were obtained from a crude extract (80% methanol extract) of Dangyuja leaves. We first found that the chloroform fraction of Dangyuja leaves (DCF) was the most cytotoxic against DU145 cells. DCF inhibited constitutive STAT3 activation through blocking upstream Janus-like kinase 2 and c-Src. Consistent with STAT3 inactivation, DCF down-regulated the expression of STAT3 target genes, including bcl-2, bcl-xl, and cyclin D1; this correlated with the suppression of proliferation, the accumulation of cell cycle at the sub-G(1) phase, and the induction of apoptosis. Furthermore, DCF exerted a relatively minor effect on the growth of human prostate noncancerous RWPE-1 cells. Nobiletin, a major active constituent of DCF, could induce apoptosis via the suppression of constitutive STAT3 activation. Overall, our results indicate that the anti-inflammatory and anticancer activities previously assigned to DCF may be mediated partially through the suppression of the STAT3 signaling. PMID:22273151

  3. N-Sulfonyl-aminobiaryls as Antitubulin Agents and Inhibitors of Signal Transducers and Activators of Transcription 3 (STAT3) Signaling.

    PubMed

    Lai, Mei-Jung; Lee, Hsueh-Yun; Chuang, Hsun-Yueh; Chang, Li-Hsun; Tsai, An-Chi; Chen, Mei-Chuan; Huang, Han-Lin; Wu, Yi-Wen; Teng, Che-Ming; Pan, Shiow-Lin; Liu, Yi-Min; Mehndiratta, Samir; Liou, Jing-Ping

    2015-08-27

    A series of N-sulfonyl-aminobiaryl derivatives have been examined as novel antitubulin agents. Compound 21 [N-(4'-cyano-3'-fluoro-biphenyl-2-yl)-4-methoxy-benzenesulfonamide] exhibits remarkable antiproliferative activity against four cancer cell lines (pancreatic AsPC-1, lung A549, liver Hep3B, and prostate PC-3) with a mean GI50 value of 57.5 nM. Additional assays reveal that 21 inhibits not only tubulin polymerization but also the phosphorylation of STAT3 inhibition with an IC50 value of 0.2 μM. Four additional compounds (8, 10, 19, and 35) are also able to inhibit this phosphorylation. This study describes novel N-sulfonyl-aminobiaryl (biaryl-benzenesulfonamides) as potent anticancer agents targeting both STAT3 and tubulin. PMID:26241032

  4. 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...

  5. 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...

  6. 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...

  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, 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...

  9. Quercetin induces caspase-dependent extrinsic apoptosis through inhibition of signal transducer and activator of transcription 3 signaling in HER2-overexpressing BT-474 breast cancer cells

    PubMed Central

    SEO, HYE-SOOK; KU, JIN MO; CHOI, HAN-SEOK; CHOI, YOUN KYUNG; WOO, JONG-KYU; KIM, MINSOO; KIM, ILHWAN; NA, CHANG HYEOK; HUR, HANSOL; JANG, BO-HYOUNG; SHIN, YONG CHEOL; KO, SEONG-GYU

    2016-01-01

    Flavonoids are assumed to exert beneficial effects in different types of cancers at high concentrations. Yet, their molecular mechanisms of action remain unknown. The present study aimed to examine the effect of quercetin on proliferation and apoptosis in HER2-expressing breast cancer cells. The anti-proliferative effects of quercetin were examined by proliferation, MTT and clonogenic survival assays. The effect of quercetin on expression of apoptotic molecules was determined by western blotting. Luciferase reporter assay was performed to measure signal transducer and activator of transcription 3 (STAT3) transcriptional activity. ELISA assay was performed to measure intracellular MMP-9 levels. Immunocytochemistry was performed to evaluate the nuclear STAT3 level. The results revealed that quercetin inhibited the proliferation of BT-474 cells in a dose- and time-dependent manner. Quercetin 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. Quercetin induced caspase-dependent extrinsic apoptosis upregulating the levels of cleaved caspase-8 and cleaved caspase-3, and inducing the cleavage of poly(ADP-ribose) polymerase (PARP). In contrast, quercetin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease the mitochondrial membrane potential and did not affect the levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX). Quercetin reduced the expression of phospho-JAK1 and phospho-STAT3 and decreased STAT3-dependent luciferase reporter gene activity in the BT-474 cells. Quercetin inhibited MMP-9 secretion and decreased the nuclear translocation of STAT3. Our study indicates that quercetin induces apoptosis at concentrations >20 µM through inhibition of STAT3 signaling and could serve as a useful compound to prevent or treat HER2

  10. Quercetin induces caspase-dependent extrinsic apoptosis through inhibition of signal transducer and activator of transcription 3 signaling in HER2-overexpressing BT-474 breast cancer cells.

    PubMed

    Seo, Hye-Sook; Ku, Jin Mo; Choi, Han-Seok; Choi, Youn Kyung; Woo, Jong-Kyu; Kim, Minsoo; Kim, Ilhwan; Na, Chang Hyeok; Hur, Hansol; Jang, Bo-Hyoung; Shin, Yong Cheol; Ko, Seong-Gyu

    2016-07-01

    Flavonoids are assumed to exert beneficial effects in different types of cancers at high concentrations. Yet, their molecular mechanisms of action remain unknown. The present study aimed to examine the effect of quercetin on proliferation and apoptosis in HER2-expressing breast cancer cells. The anti-proliferative effects of quercetin were examined by proliferation, MTT and clonogenic survival assays. The effect of quercetin on expression of apoptotic molecules was determined by western blotting. Luciferase reporter assay was performed to measure signal transducer and activator of transcription 3 (STAT3) transcriptional activity. ELISA assay was performed to measure intracellular MMP-9 levels. Immunocytochemistry was performed to evaluate the nuclear STAT3 level. The results revealed that quercetin inhibited the proliferation of BT-474 cells in a dose- and time-dependent manner. Quercetin 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. Quercetin induced caspase-dependent extrinsic apoptosis upregulating the levels of cleaved caspase-8 and cleaved caspase-3, and inducing the cleavage of poly(ADP‑ribose) polymerase (PARP). In contrast, quercetin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease the mitochondrial membrane potential and did not affect the levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (BAX). Quercetin reduced the expression of phospho-JAK1 and phospho-STAT3 and decreased STAT3-dependent luciferase reporter gene activity in the BT-474 cells. Quercetin inhibited MMP-9 secretion and decreased the nuclear translocation of STAT3. Our study indicates that quercetin induces apoptosis at concentrations >20 µM through inhibition of STAT3 signaling and could serve as a useful compound to prevent or treat HER2

  11. 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

  12. Membrane Transfer from Mononuclear Cells to Polymorphonuclear Neutrophils Transduces Cell Survival and Activation Signals in the Recipient Cells via Anti-Extrinsic Apoptotic and MAP Kinase Signaling Pathways

    PubMed Central

    Li, Ko-Jen; Wu, Cheng-Han; Shen, Chieh-Yu; Kuo, Yu-Min; Yu, Chia-Li; Hsieh, Song-Chou

    2016-01-01

    The biological significance of membrane transfer (trogocytosis) between polymorphonuclear neutrophils (PMNs) and mononuclear cells (MNCs) remains unclear. We investigated the biological/immunological effects and molecular basis of trogocytosis among various immune cells in healthy individuals and patients with active systemic lupus erythematosus (SLE). By flow cytometry, we determined that molecules in the immunological synapse, including HLA class-I and-II, CD11b and LFA-1, along with CXCR1, are exchanged among autologous PMNs, CD4+ T cells, and U937 cells (monocytes) after cell-cell contact. Small interfering RNA knockdown of the integrin adhesion molecule CD11a in U937 unexpectedly enhanced the level of total membrane transfer from U937 to PMN cells. Functionally, phagocytosis and IL-8 production by PMNs were enhanced after co-culture with T cells. Total membrane transfer from CD4+ T to PMNs delayed PMN apoptosis by suppressing the extrinsic apoptotic molecules, BAX, MYC and caspase 8. This enhancement of activities of PMNs by T cells was found to be mediated via p38- and P44/42-Akt-MAP kinase pathways and inhibited by the actin-polymerization inhibitor, latrunculin B, the clathrin inhibitor, Pitstop-2, and human immunoglobulin G, but not by the caveolin inhibitor, methyl-β-cyclodextrin. In addition, membrane transfer from PMNs enhanced IL-2 production by recipient anti-CD3/anti-CD28 activated MNCs, and this was suppressed by inhibitors of mitogen-activated protein kinase (PD98059) and protein kinase C (Rottlerin). Of clinical significance, decreased total membrane transfer from PMNs to MNCs in patients with active SLE suppressed mononuclear IL-2 production. In conclusion, membrane transfer from MNCs to PMNs, mainly at the immunological synapse, transduces survival and activation signals to enhance PMN functions and is dependent on actin polymerization, clathrin activation, and Fcγ receptors, while membrane transfer from PMNs to MNCs depends on MAP kinase and

  13. Frizzled2 mediates the migration and invasion of human oral squamous cell carcinoma cells through the regulation of the signal transducer and activator of transcription-3 signaling pathway.

    PubMed

    Zhang, Enjiao; Li, Zhenning; Xu, Zhongfei; Duan, Weiyi; Sun, Changfu; Lu, Li

    2015-12-01

    Frizzled2 (Fzd2) is a receptor for wingless-type MMTV integration site family members (Wnts), the aberrant overexpression of which has been noted to contribute to cancer metastasis. The present study was performed to characterize the role of Fzd2 in the migration and invasion of oral squamous cell carcinomas (OSCC) in vitro. Using TSCCa cells (a tongue SCC cell line) for loss- or gain-of-function of Fzd2, we found that a forced overexpression of Fzd2 promoted TSCCa cell migration and invasion, decreased the expression of epithelial‑cadherin (E-cadherin, an epithelial marker) and increased that of vimentin, Snail Slug, matrix metalloproteinases (MMPs)-2/-9/-13 and a-disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS5). By contrast, RNA interference (RNAi)-mediated knockdown of Fzd2 had opposite effects on OSCC cells. In addition, we found that the phosphorylation of signal transducer and activator of transcription-3 (STAT3) was enhanced by Fzd2 overexpression, but suppressed by Fzd2 depletion, and that STAT3‑specific shRNA attenuated Fzd2 overexpression‑induced cell invasion. In summary, the present study demonstrated that Fzd2 contributes to the migration and invasion of OSCC cells, at least partly through regulation of the STAT3 pathway. These results suggest Fzd2 as a novel therapeutic target for OSCC. PMID:26398330

  14. Ginkgetin inhibits the growth of DU−145 prostate cancer cells through inhibition of signal transducer and activator of transcription 3 activity

    PubMed Central

    Jeon, Yoon Jung; Jung, Seung-Nam; Yun, Jieun; Lee, Chang Woo; Choi, Jiyeon; Lee, Yu-Jin; Han, Dong Cho; Kwon, Byoung-Mog

    2015-01-01

    Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in human cancers. Therefore, STAT3 is a therapeutic target of cancer drug discovery. We previously reported that natural products inhibited constitutively activated STAT3 in human prostate tumor cells. We used a dual-luciferase assay to screen 200 natural products isolated from herbal medicines and we identified ginkgetin obtained from the leaves of Ginkgo biloba L. as a STAT3 inhibitor. Ginkgetin inhibited both inducible and constitutively activated STAT3 and blocked the nuclear translocation of p-STAT3 in DU-145 prostate cancer cells. Furthermore, ginkgetin selectively inhibited the growth of prostate tumor cells stimulated with activated STAT3. Ginkgetin induced STAT3 dephosphorylation at Try705 and inhibited its localization to the nucleus, leading to the inhibition of expression of STAT3 target genes such as cell survival-related genes (cyclin D1 and survivin) and anti-apoptotic proteins (Bcl-2 and Bcl-xL). Therefore, ginkgetin inhibited the growth of STAT3-activated tumor cells. We also found that ginkgetin inhibited tumor growth in xenografted nude mice and downregulated p-STAT3Tyr705 and survivin in tumor tissues. This is the first report that ginkgetin exerts antitumor activity by inhibiting STAT3. Therefore, ginkgetin is a good STAT3 inhibitor and may be a useful lead molecule for development of a therapeutic STAT3 inhibitor. PMID:25611086

  15. Angiotensin II and canonical transient receptor potential-6 activation stimulate release of a signal transducer and activator of transcription 3-activating factor from mouse podocytes.

    PubMed

    Abkhezr, Mousa; Dryer, Stuart E

    2014-08-01

    Previous studies have shown that the transcription factor signal transducer and activator of transcription-3 (STAT3) in podocytes plays an important role in progression of HIV nephropathy and in collapsing forms of glomerulonephritis. Here, we have observed that application of 100 nM angiotensin II (Ang II) to cultured podocytes for 6-24 hours causes a marked increase in the phosphorylation of STAT3 on tyrosine Y705 but has no effect on phosphorylation at serine S727. By contrast, Ang II treatment of short periods (20-60 minutes) caused a small but consistent suppression of tyrosine phosphylation of STAT3. A similar biphasic effect was seen after treatment with the diacylglycerol analog 1-oleoyl-2-acetyl-sn-glycerol (OAG), an agent that causes activation of Ca(2+)-permeable canonical transient receptor potential-6 (TRPC6) channels in podocytes. The stimulatory effects of Ang II on STAT3 phosphorylation were abolished by small-interfering RNA knockdown of TRPC6 and also by inhibitors of the Ca(2+)-dependent downstream enzymes calcineurin and Ca(2+)-calmodulin-dependent protein kinase II. The stimulatory effects of Ang II appear to be mediated by secretion and accumulation of an unknown factor into the surrounding medium, as they are no longer detected when medium is replaced every 2 hours even if Ang II is continuously present. By contrast, the inhibitory effect of Ang II on STAT3 phosphorylation persists with frequent medium changes. Experiments with neutralizing and inhibitory antibodies suggest that the STAT3 stimulatory factor secreted from podocytes is not interleukin-6, but also suggest that this factor exerts its actions through a receptor system that requires glycoprotein 130. PMID:24850910

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

    PubMed Central

    Li, Feng; Rajendran, Peramaiyan; Sethi, Gautam

    2010-01-01

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

  17. Helicobacter pylori inhibits dendritic cell maturation via interleukin-10-mediated activation of the signal transducer and activator of transcription 3 pathway.

    PubMed

    Rizzuti, David; Ang, Michelle; Sokollik, Christiane; Wu, Ted; Abdullah, Majd; Greenfield, Laura; Fattouh, Ramzi; Reardon, Colin; Tang, Michael; Diao, Jun; Schindler, Christian; Cattral, Mark; Jones, Nicola L

    2015-01-01

    Helicobacter pylori infects the human gastric mucosa causing a chronic infection that is the primary risk factor for gastric cancer development. Recent studies demonstrate that H. pylori promotes tolerogenic dendritic cell (DC) development indicating that this bacterium evades the host immune response. However, the signaling pathways involved in modulating DC activation during infection remain unclear. Here, we report that H. pylori infection activated the signal transducer and activator of transcription 3 (STAT3) pathway in murine bone marrow-derived DCs (BMDCs) and splenic DCs isolated ex vivo. Isogenic cagA-, cagE-, vacA- and urease-mutants exhibited levels of phosphoSTAT3 that were comparable to in the wild-type (WT) parent strain. H. pylori-infected BMDCs produced increased immunosuppressive IL-10, which activated STAT3 in an autocrine/paracrine fashion. Neutralization of IL-10 prevented H. pylori-mediated STAT3 activation in both BMDCs and splenic DCs. In addition, anti-IL-10 treatment of infected H. pylori-BMDCs was associated with increased CD86 and MHC II expression and enhanced proinflammatory IL-1β cytokine secretion. Finally, increased CD86 and MHC II expression was detected in H. pylori-infected STAT3 knockout DCs when compared to WT controls. Together, these results demonstrate that H. pylori infection induces IL-10 secretion in DCs, which activates STAT3, thereby modulating DC maturation and reducing IL-1β secretion. These findings identify a host molecular mechanism by which H. pylori can manipulate the innate immune response to potentially favor chronic infection and promote carcinogenesis. PMID:25412627

  18. Insulin-like growth factor 1 receptor and p38 mitogen-activated protein kinase signals inversely regulate signal transducer and activator of transcription 3 activity to control human dental pulp stem cell quiescence, propagation, and differentiation.

    PubMed

    Vandomme, Jerome; Touil, Yasmine; Ostyn, Pauline; Olejnik, Cecile; Flamenco, Pilar; El Machhour, Raja; Segard, Pascaline; Masselot, Bernadette; Bailliez, Yves; Formstecher, Pierre; Polakowska, Renata

    2014-04-15

    Dental pulp stem cells (DPSCs) remain quiescent until activated in response to severe dental pulp damage. Once activated, they exit quiescence and enter regenerative odontogenesis, producing reparative dentin. The factors and signaling molecules that control the quiescence/activation and commitment to differentiation of human DPSCs are not known. In this study, we determined that the inhibition of insulin-like growth factor 1 receptor (IGF-1R) and p38 mitogen-activated protein kinase (p38 MAPK) signaling commonly activates DPSCs and promotes their exit from the G0 phase of the cell cycle as well as from the pyronin Y(low) stem cell compartment. The inhibition of these two pathways, however, inversely determines DPSC fate. In contrast to p38 MAPK inhibitors, IGF-1R inhibitors enhance dental pulp cell sphere-forming capacity and reduce the cells' colony-forming capacity without inducing cell death. The inverse cellular changes initiated by IGF-1R and p38 MAPK inhibitors were accompanied by inverse changes in the levels of active signal transducer and activator of transcription 3 (STAT3) factor, inactive glycogen synthase kinase 3, and matrix extracellular phosphoglycoprotein, a marker of early odontoblast differentiation. Our data suggest that there is cross talk between the IGF-1R and p38 MAPK signaling pathways in DPSCs and that the signals provided by these pathways converge at STAT3 and inversely regulate its activity to maintain quiescence or to promote self-renewal and differentiation of the cells. We propose a working model that explains the possible interactions between IGF-1R and p38 MAPK at the molecular level and describes the cellular consequences of these interactions. This model may inspire further fundamental study and stimulate research on the clinical applications of DPSC in cellular therapy and tissue regeneration. PMID:24266654

  19. Insulin-Like Growth Factor 1 Receptor and p38 Mitogen-Activated Protein Kinase Signals Inversely Regulate Signal Transducer and Activator of Transcription 3 Activity to Control Human Dental Pulp Stem Cell Quiescence, Propagation, and Differentiation

    PubMed Central

    Vandomme, Jerome; Touil, Yasmine; Ostyn, Pauline; Olejnik, Cecile; Flamenco, Pilar; El Machhour, Raja; Segard, Pascaline; Masselot, Bernadette; Bailliez, Yves; Formstecher, Pierre

    2014-01-01

    Dental pulp stem cells (DPSCs) remain quiescent until activated in response to severe dental pulp damage. Once activated, they exit quiescence and enter regenerative odontogenesis, producing reparative dentin. The factors and signaling molecules that control the quiescence/activation and commitment to differentiation of human DPSCs are not known. In this study, we determined that the inhibition of insulin-like growth factor 1 receptor (IGF-1R) and p38 mitogen-activated protein kinase (p38 MAPK) signaling commonly activates DPSCs and promotes their exit from the G0 phase of the cell cycle as well as from the pyronin Ylow stem cell compartment. The inhibition of these two pathways, however, inversely determines DPSC fate. In contrast to p38 MAPK inhibitors, IGF-1R inhibitors enhance dental pulp cell sphere-forming capacity and reduce the cells' colony-forming capacity without inducing cell death. The inverse cellular changes initiated by IGF-1R and p38 MAPK inhibitors were accompanied by inverse changes in the levels of active signal transducer and activator of transcription 3 (STAT3) factor, inactive glycogen synthase kinase 3, and matrix extracellular phosphoglycoprotein, a marker of early odontoblast differentiation. Our data suggest that there is cross talk between the IGF-1R and p38 MAPK signaling pathways in DPSCs and that the signals provided by these pathways converge at STAT3 and inversely regulate its activity to maintain quiescence or to promote self-renewal and differentiation of the cells. We propose a working model that explains the possible interactions between IGF-1R and p38 MAPK at the molecular level and describes the cellular consequences of these interactions. This model may inspire further fundamental study and stimulate research on the clinical applications of DPSC in cellular therapy and tissue regeneration. PMID:24266654

  20. WRM-1 activates the LIT-1 protein kinase to transduce anterior/posterior polarity signals in C. elegans.

    PubMed

    Rocheleau, C E; Yasuda, J; Shin, T H; Lin, R; Sawa, H; Okano, H; Priess, J R; Davis, R J; Mello, C C

    1999-06-11

    During C. elegans development, Wnt/WG signaling is required for differences in cell fate between sister cells born from anterior/posterior divisions. A beta-catenin-related gene, wrm-1, and the lit-1 gene are effectors of this signaling pathway and appear to downregulate the activity of POP-1, a TCF/LEF-related protein, in posterior daughter cells. We show here that lit-1 encodes a serine/threonine protein kinase homolog related to the Drosophila tissue polarity protein Nemo. We demonstrate that the WRM-1 protein binds to LIT-1 in vivo and that WRM-1 can activate the LIT-1 protein kinase when coexpressed in vertebrate tissue culture cells. This activation leads to phosphorylation of POP-1 and to apparent changes in its subcellular localization. Our findings provide evidence for novel regulatory avenues for an evolutionarily conserved Wnt/WG signaling pathway. PMID:10380924

  1. Interleukin-10 Contributes to Therapeutic Effect of Mesenchymal Stem Cells for Acute Liver Failure via Signal Transducer and Activator of Transcription 3 Signaling Pathway

    PubMed Central

    Ma, Hu-Cheng; Wang, Xin; Wu, Min-Na; Zhao, Xin; Yuan, Xian-Wen; Shi, Xiao-Lei

    2016-01-01

    Background: Mesenchymal stem cells (MSCs) transplantation has been proven to have therapeutic potential for acute liver failure (ALF). However, the mechanism remains controversial. Recently, modulation of inflammation by MSCs has been regarded as a crucial mechanism. The aim of the present study was to explore the soluble cytokines secreted by MSCs and their therapeutic effects in ALF. Methods: MSCs isolated from Sprague-Dawley rats were identified by fluorescence-activated cell sorting analysis. Conditioned medium derived from MSCs (MSCs-CM) was collected and analyzed by a cytokine microarray. MSCs and MSCs-CM were transplanted into rats with D-galactosamine-induced ALF. Liver function, survival rate, histology, and inflammatory factors were determined. Exogenous recombinant rat interleukin (IL)-10, anti-rat IL-10 antibody, and AG490 (signal transducer and activator of transcription 3 [STAT3] signaling pathway inhibitor) were administered to explore the therapeutic mechanism of MSCs-CM. Statistical analysis was performed with SPSS version 19.0, and all data were analyzed by the independent-sample t-test. Results: There are statistical differences of the survival curve between ALF+MSCs group and ALF+Dulbecco's modified Eagle's medium (DMEM) group, as well as ALF+MSCs-CM group and ALF+DMEM group (all P < 0.05). Serum alanine aminotransferase (ALT) level in the ALF+MSCs and ALF+MSCs-CM groups was lower than that in the ALF+DMEM group (865.53±52.80 vs. 1709.75±372.12 U/L and 964.72±414.59 vs. 1709.75±372.12 U/L, respectively, all P < 0.05); meanwhile, serum aspartate aminotransferase (AST) level in the ALF+MSCs and ALF+MSCs-CM groups was lower than that in the ALF+DMEM group (2440.83±511.94 vs. 4234.35±807.30 U/L and 2739.83±587.33 vs. 4234.35±807.30 U/L, respectively, all P < 0.05). Furthermore, MSCs or MSCs-CM treatment significantly reduced serum interferon-γ (IFN-γ), IL-1β, IL-6 levels and increased serum IL-10 level compared with DMEM (all P < 0

  2. Structure–Activity Studies of Phosphopeptidomimetic Prodrugs Targeting the Src Homology 2 (SH2) Domain of Signal Transducer and Activator of Transcription 3 (Stat3)

    PubMed Central

    Mandal, Pijus K.; Ren, Zhiyong; Chen, Xiaomin; Kaluarachchi, Kumar; Liao, Warren S.-L.; McMurray, John S.

    2013-01-01

    Signal transducer and activator of transcription 3 (Stat3) transmits signals from growth factors and interleukin-6 family cytokines by binding to their receptors via its Src homology 2 (SH2) domain. This results in phosphorylation of Tyr705, dimerization, translocation to the nucleus, and regulation of transcription of downstream genes. Stat3 is constitutively activated in several human cancers and is a target for anti-cancer drug design. We have shown previously phosphorylation of Tyr705 in intact cancer cells can be inhibited with prodrugs of phosphopeptide mimics targeting the SH2 domain. In a series of prodrugs consisting of bis-pivaloyloxymethyl esters of 4′-phosphonodifluoromethyl cinnamoyl-Haic-Gln-NHBn, appending methyl group to the β-position of the cinnamate increased potency ca. twofold, which paralleled the increase in affinity of the corresponding phosphopeptide models. However, dramatic increases in potency were observed when the C-terminal C(O)NHBn of Gln-NHBn was replaced with a simple methyl group. In this communication we continue to explore the effects of structural modifications of prodrugs on their ability to inhibit Tyr705 phosphorylation. A set of 4-substituted prolines incorporated into β-methyl-4-phosphocinnamoyl-leucinyl-Xaa-4-aminopentamide model peptides exhibited affinities of 88–317 nM by fluorescence polarization (Pro IC50 = 156 nM). In corresponding prodrugs, Pro inhibited constitutive Stat3 phosphorylation at 10 μM in MDA-MB-468 breast tumor cells. However, 4,4-difluoroproline and 4,4-dimethylproline resulted in complete inhibition at 0.5 μM. These results suggest that the prodrug with native proline undergoes metabolism that those with substituted prolines do not. In conclusion, changes in structure with minimal impact on intrinsic affinity can nevertheless have profound effects on the cellular potency of prodrug inhibitors of Stat3. PMID:24707243

  3. DOWN-REGULATION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 IMPROVES HUMAN ACUTE MYELOID LEUKEMIA-DERIVED DENDRITIC CELL FUNCTION

    PubMed Central

    Brady, Michael T.; Miller, Austin; Sait, Sheila N.; Ford, Laurie A.; Minderman, Hans; Wang, Eunice S.; Lee, Kelvin P.; Baumann, Heinz; Wetzler, Meir

    2013-01-01

    Signal transducer and activator of transcription (STAT) 3 inhibits dendritic cell (DC) differentiation and is constitutively activated in blasts of approximately half of AML patients. We investigated the correlation between STAT3 activity, DC maturation and the ability to stimulate T-cells in primary acute myeloid leukemia (AML)-derived DCs. STAT3 knock-down by shRNAmir increased the ability of AML-DCs to stimulate T-cells. Treatment of AML-DC with arsenic trioxide, but not AG490, JSI-124 or NSC-74859, led to a more mature phenotype and enhanced T-cell stimulation, while having minimal effect on normal DC. We conclude that AML-DCs have improved immunogenicity after reducing STAT3. PMID:23628554

  4. Novel thiosemicarbazones regulate the signal transducer and activator of transcription 3 (STAT3) pathway: inhibition of constitutive and interleukin 6-induced activation by iron depletion.

    PubMed

    Lui, Goldie Y L; Kovacevic, Zaklina; V Menezes, Sharleen; Kalinowski, Danuta S; Merlot, Angelica M; Sahni, Sumit; Richardson, Des R

    2015-01-01

    Pharmacologic manipulation of metal pools in tumor cells is a promising strategy for cancer treatment. Here, we reveal how the iron-binding ligands desferrioxamine (DFO), di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), and di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) inhibit constitutive and interleukin 6-induced activation of signal transducer and activator of transcription 3 (STAT3) signaling, which promotes proliferation, survival, and metastasis of cancer cells. We demonstrate that DFO, Dp44mT, and DpC significantly decrease constitutive phosphorylation of the STAT3 transcription factor at Tyr705 in the pancreatic cancer cell lines PANC-1 and MIAPaCa-2 as well as the prostate cancer cell line DU145. These compounds also significantly decrease the dimerized STAT3 levels, the binding of nuclear STAT3 to its target DNA, and the expression of downstream targets of STAT3, including cyclin D1, c-myc, and Bcl-2. Examination of upstream mediators of STAT3 in response to these ligands has revealed that Dp44mT and DpC could significantly decrease activation of the nonreceptor tyrosine kinase Src and activation of cAbl in DU145 and MIAPaCa-2 cells. In contrast to the effects of Dp44mT, DpC, or DFO on inhibiting STAT3 activation, the negative control compound di-2-pyridylketone 2-methyl-3-thiosemicarbazone, or the DFO:Fe complex, which cannot bind cellular iron, had no effect. This demonstrates the role of iron-binding in the activity observed. Immunohistochemical staining of PANC-1 tumor xenografts showed a marked decrease in STAT3 in the tumors of mice treated with Dp44mT or DpC compared with the vehicle. Collectively, these studies demonstrate suppression of STAT3 activity by iron depletion in vitro and in vivo, and reveal insights into regulation of the critical oncogenic STAT3 pathway. PMID:25561562

  5. 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

  6. 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

  7. A novel device of bacterial signal transducers.

    PubMed Central

    Ishige, K; Nagasawa, S; Tokishita, S; Mizuno, T

    1994-01-01

    The osmoregulatory expression of ompC and ompF in Escherichia coli is mediated by a pair of bacterial signal transduction proteins, EnvZ (sensory kinase) and OmpR (response regulator). We isolated previously multicopy suppressors which can complement a defect in the phosphotransfer signal transduction caused by an envZ deletion mutation. Among such suppressors, arcB and barA are of particular interest because these gene products are unique in the sense that they contain both an autophosphorylated histidine site (or transmitter module) and a phospho-accepting aspartate site (or receiver module) in their primary amino acid sequences. Here we report that ArcB and BarA possess in the C-terminal region a phosphorylated histidine site which has never been noticed, in addition to the authentic one identified previously. This newly identified histidine in ArcB and BarA was demonstrated to play a crucial role in the observed multicopy suppression. Furthermore, it was demonstrated in vivo and in vitro for ArcB that the C-terminal domain containing the histidine can function as an alternative phosphodonor (or transmitter). This novel type of sensory kinase was therefore revealed to contain two independent phosphodonor sites, together with a phospho-accepting site. These findings suggest that this unique feature of ArcB and BarA, in terms of the signaling modules, make it possible for these sensory kinases to function as dual-signaling transducers. Images PMID:7957084

  8. 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. PMID:24442345

  9. 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

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

    PubMed

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

    2015-08-01

    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

  11. 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. PMID:20712533

  12. Signal Transducer and Activator of Transcription 1 (STAT1) is Essential for Chromium Silencing of Gene Induction in Human Airway Epithelial Cells

    PubMed Central

    Nemec, Antonia A.; Barchowsky, Aaron

    2009-01-01

    Hexavalent chromium (Cr(VI)) promotes lung injury and pulmonary diseases through poorly defined mechanisms that may involve the silencing of inducible protective genes. The current study investigated the hypothesis that Cr(VI) actively signals through a signal transducer and activator of transcription 1 (STAT1)–dependent pathway to silence nickel (Ni)–induced expression of vascular endothelial cell growth factor A (VEGFA), an important mediator of lung injury and repair. In human bronchial airway epithelial (BEAS-2B) cells, Ni-induced VEGFA transcription by stimulating an extracellular regulated kinase (ERK) signaling cascade that involved Src kinase–activated Sp1 transactivation, as well as increased hypoxia-inducible factor-1α (HIF-1α) stabilization and DNA binding. Ni-stimulated ERK, Src, and HIF-1α activities, as well as Ni-induced VEGFA transcript levels were inhibited in Cr(VI)-exposed cells. We previously demonstrated that Cr(VI) stimulates STAT1 to suppress VEGFA expression. In BEAS-2B cells stably expressing STAT1 short hairpin RNA, Cr(VI) increased VEGFA transcript levels and Sp1 transactivation. Moreover, in the absence of STAT1, Cr(VI), and Ni coexposures positively interacted to further increase VEGFA transcripts. This study demonstrates that metal-stimulated signaling cascades interact to regulate transcription and induction of adaptive or repair responses in airway cells. In addition, the data implicate STAT1 as a rate limiting mediator of Cr(VI)-stimulated gene regulation and suggest that cells lacking STAT1, such as many tumor cell lines, have opposite responses to Cr(VI) relative to normal cells. PMID:19403854

  13. Signal transducer and activator of transcription 3 regulates CCAAT-enhancer-binding homologous protein expression in osteoblasts through upregulation of microRNA-205

    PubMed Central

    ZHUANG, JIAN; GAO, RUFENG; WU, HAIHUI; WU, XIAO; PAN, FUGEN

    2015-01-01

    The transcription factor, CCAAT-enhancer-binding protein homologous protein (CHOP), is induced by endoplasmic reticulum-stress and mediates programmed cell death. In osteoblasts, CHOP overexpression increases the rate of apoptosis, leading to osteoblastic dysfunction. However, the regulatory mechanisms underlying CHOP expression remain unclear. In the present study, western blot analysis was used to demonstrate that the activation of signal transducer and activator of transcription 3 (STAT3) inhibited the levels of the CHOP protein, whereas small interfering RNA-mediated the knockdown of STAT3 upregulated CHOP expression. Furthermore, STAT3 was shown to increase the expression level of microRNA (miR)-205. A luciferase reporter assay revealed that miR-205 was able to directly target the 3′-untranslated region of the CHOP gene to inhibit its protein expression. The miR-205 antisense largely abolished the inhibitory effect of STAT3 activation on the levels of CHOP protein. Therefore, the results demonstrated a previously unknown STAT3/miR-205/CHOP signaling pathway in osteoblasts, which may aid the understanding of the pathogenic mechanisms of associated diseases, including osteoporosis. PMID:26170952

  14. Dihydroxypentamethoxyflavone Down-Regulates Constitutive and Inducible Signal Transducers and Activators of Transcription-3 through the Induction of Tyrosine Phosphatase SHP-1

    PubMed Central

    Phromnoi, Kanokkarn; Prasad, Sahdeo; Gupta, Subash C.; Kannappan, Ramaswamy; Reuter, Simone; Limtrakul, Pornngarm

    2011-01-01

    Because constitutive activation of signal transducers and activators of transcription-3 (STAT3) has been linked with cellular transformation, survival, proliferation, chemoresistance, and angiogenesis of various tumor cells, agents that can suppress STAT3 activation have potential as cancer therapeutics. In the present report, we identified a flavone from the leaves of a Thai plant, Gardenia obtusifolia, 5,3′-dihydroxy-3,6,7,8,4′-pentamethoxyflavone (PMF), that has the ability to inhibit STAT3 activation. PMF inhibited both constitutive and interleukin-6-inducible STAT3 activation in multiple myeloma (MM) cells, as indicated by suppression of STAT3 phosphorylation, nuclear translocation, DNA binding, and STAT3-regulated gene expression. The inhibition of STAT3 by PMF was reversible. We found that the activation of various kinases including Janus-like kinase (JAK)-1, JAK-2, c-Src, extracellular signal-regulated kinases 1 and 2, AKT, and epidermal growth factor receptor, implicated in STAT3 activation, were inhibited by the flavone. It is noteworthy that pervanadate suppressed the ability of PMF to inhibit the phosphorylation of STAT3, suggesting that protein tyrosine phosphatase was involved. PMF induced the expression of SHP-1 and was linked to the dephosphorylation of STAT3, because its deletion by small interfering RNA abolished the PMF-induced constitutive and inducible STAT3 inhibition. STAT3 inhibition led to the suppression of proteins involved in proliferation (cyclin D1 and c-myc), survival (survivin, Mcl-1, Bcl-xL, Bcl-2, and cIAP-2), and angiogenesis (vascular endothelial growth factor). Finally, PMF inhibited proliferation and induced apoptosis of MM cells. PMF also significantly potentiated the apoptotic effects of Velcade and thalidomide in MM cells. Overall, these results suggest that PMF is a novel blocker of STAT3 activation and thus may have potential in suppression of tumor cell proliferation and reversal of chemoresistance in MM cells. PMID

  15. STIM proteins: dynamic calcium signal transducers

    PubMed Central

    Soboloff, Jonathan; Rothberg, Brad S.; Madesh, Muniswamy; Gill, Donald L.

    2012-01-01

    Stromal interaction molecule (STIM) proteins function in cells as dynamic coordinators of cellular calcium (Ca2+) signals. Spanning the endoplasmic reticulum (ER) membrane, they sense tiny changes in the levels of Ca2+ stored within the ER lumen. As ER Ca2+ is released to generate primary Ca2+ signals, STIM proteins undergo an intricate activation reaction and rapidly translocate into junctions formed between the ER and the plasma membrane. There, STIM proteins tether and activate the highly Ca2+-selective Orai channels to mediate finely controlled Ca2+ signals and to homeostatically balance cellular Ca2+. Details are emerging on the remarkable organization within these STIM-induced junctional microdomains and the identification of new regulators and alternative target proteins for STIM. PMID:22914293

  16. Deactivation of Signal Transducer and Activator of Transcription 3 Reverses Chemotherapeutics Resistance of Leukemia Cells via Down-Regulating P-gp

    PubMed Central

    Zhang, Xulong; Xiao, Weihua; Wang, Lihua; Tian, Zhigang; Zhang, Jian

    2011-01-01

    Multidrug resistance (MDR) caused by overexpression of p-glycoprotein is a major obstacle in chemotherapy of malignant cancer, which usually is characterized by constitutive activation of signal transducer and activator of transcription 3 (STAT3), but their relation between MDR and STAT3 remains unclear. Here, we showed that STAT3 was overexpressed and highly activated in adriamycin-resistant K562/A02 cells compared with its parental K562 cells. Blockade of activation of STAT3 by STAT3 decoy oligodeoxynucleotide (ODN) promoted the accumulation and increased their sensitivity to adriamycin by down-regulating transcription of mdr1 and expression of P-gp, which were further confirmed by using STAT3-specific inhibitor JSI-124. Inhibition of STAT3 could also decrease mdr1 promoter mediated luciferase expression by using mdr1 promoter luciferase reporter construct. Otherwise, activation of STAT3 by STAT3C improved mdr1 transcription and P-gp expression. The ChIP results demonstrated that STAT3 could bind to the potential promoter region of mdr1, and STAT3 decoy depressed the binding. Further mutation assay show +64∼+72 region could be the STAT3 binding site. Our data demonstrate a role of STAT3 in regulation of mdr1 gene expression in myeloid leukemia and suggest that STAT3 may be a promising therapeutic target for overcoming MDR resistance in myeloid leukemia. PMID:21677772

  17. Regulation of nitrogen fixation in Klebsiella pneumoniae and Azotobacter vinelandii: NifL, transducing two environmental signals to the nif transcriptional activator NifA.

    PubMed

    Schmitz, Ruth A; Klopprogge, Kai; Grabbe, Roman

    2002-05-01

    The enzymatic reduction of molecular nitrogen to ammonia requires high amounts of energy, and the presence of oxygen causes the catalyzing nitrogenase complex to be irreversible inactivated. Thus nitrogen-fixing microorganisms tightly control both the synthesis and activity of nitrogenase to avoid the unnecessary consumption of energy. In the free-living diazotrophs Klebsiella pneumoniae and Azotobacter vinelandii, products of the nitrogen fixation nifLA operon regulate transcription of the other nifoperons. NifA activates transcription of nif genes by the alternative form of RNA-polymerase, sigma54-holoenzyme; NifL modulates the activity of the transcriptional activator NifA in response to the presence of combined nitrogen and molecular oxygen. The translationally-coupled synthesis of the two regulatory proteins, in addition to evidence from studies of NifL/NifA complex formation, imply that the inhibition of NifA activity by NifL occurs via direct protein-protein interaction in vivo. The inhibitory function of the negative regulator NifL appears to lie in the C-terminal domain, whereas the N-terminal domain binds FAD as a redox-sensitive cofactor, which is required for signal transduction of the internal oxygen status. Recently it was shown, that NifL acts as a redox-sensitive regulatory protein, which modulates NifA activity in response to the redox-state of its FAD cofactor, and allows NifA activity only in the absence of oxygen. In K. pneumoniae, the primary oxygen sensor appears to be Fnr (fumarate nitrate reduction regulator), which is presumed to transduce the signal of anaerobiosis towards NifL by activating the transcription of gene(s) whose product(s) function to relieve NifL inhibition through reduction of the FAD cofactor. In contrast, the reduction of A. vinelandii-NifL appears to occur unspecifically in response to the availability of reducing equivalents in the cell. Nitrogen status of the cells is transduced towards the NifL/NifA regulatory system

  18. Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis.

    PubMed

    Sen, Nandini; Che, Xibing; Rajamani, Jaya; Zerboni, Leigh; Sung, Phillip; Ptacek, Jason; Arvin, Ann M

    2012-01-10

    Varicella-zoster virus (VZV) is a human α-herpesvirus that causes varicella (chickenpox) during primary infection and zoster (shingles) upon reactivation. Like other viruses, VZV must subvert the intrinsic antiviral defenses of differentiated human cells to produce progeny virions. Accordingly, VZV inhibits the activation of the cellular transcription factors IFN regulatory factor 3 (IRF3) and signal transducers and activators of transcription 1 (STAT1), thereby downregulating antiviral factors, including IFNs. Conversely, in this study, we found that VZV triggers STAT3 phosphorylation in cells infected in vitro and in human skin xenografts in SCID mice in vivo and that STAT3 activation induces the anti-apoptotic protein survivin. Small-molecule inhibitors of STAT3 phosphorylation and survivin restrict VZV replication in vitro, and VZV infection of skin xenografts in vivo is markedly impaired by the administration of the phospho-STAT3 inhibitor S3I-201. STAT3 and survivin are required for malignant transformation caused by γ-herpesviruses, such as Kaposi's sarcoma virus. We show that STAT3 activation is also critical for VZV, a nononcogenic herpesvirus, via a survivin-dependent mechanism. Furthermore, STAT3 activation is critical for the life cycle of the virus because VZV skin infection is necessary for viral transmission and persistence in the human population. Therefore, we conclude that takeover of this major cell-signaling pathway is necessary, independent of cell transformation, for herpesvirus pathogenesis and that STAT3 activation and up-regulation of survivin is a common mechanism important for the pathogenesis of lytic as well as tumorigenic herpesviruses. PMID:22190485

  19. Hepatitis C virus-induced myeloid-derived suppressor cells regulate T-cell differentiation and function via the signal transducer and activator of transcription 3 pathway.

    PubMed

    Ren, Jun P; Zhao, Juan; Dai, Jun; Griffin, Jeddidiah W D; Wang, Ling; Wu, Xiao Y; Morrison, Zheng D; Li, Guang Y; El Gazzar, Mohamed; Ning, Shun B; Moorman, Jonathan P; Yao, Zhi Q

    2016-08-01

    T cells play a pivotal role in controlling viral infection; however, the precise mechanisms responsible for regulating T-cell differentiation and function during infections are incompletely understood. In this study, we demonstrated an expansion of myeloid-derived suppressor cells (MDSCs), in particular the monocytic MDSCs (M-MDSCs; CD14(+) CD33(+) CD11b(+) HLA-DR(-/low) ), in patients with chronic hepatitis C virus (HCV) infection. Notably, HCV-induced M-MDSCs express high levels of phosphorylated signal transducer and activator of transcription 3 (pSTAT3) and interleukin-10 (IL-10) compared with healthy subjects. Blocking STAT3 signalling reduced HCV-mediated M-MDSC expansion and decreased IL-10 expression. Importantly, we observed a significant increase in the numbers of CD4(+) CD25(+) Foxp3(+) regulatory T (Treg) cells following incubation of healthy peripheral blood mononuclear cells (PBMCs) with MDSCs derived from HCV-infected patients or treated with HCV core protein. In addition, depletion of MDSCs from PBMCs led to a significant reduction of Foxp3(+) Treg cells developed during chronic HCV infection. Moreover, depletion of MDSCs from PBMCs significantly increased interferon-γ production by CD4(+) T effector (Teff) cells derived from HCV patients. These results suggest that HCV-induced MDSCs promote Treg cell development and inhibit Teff cell function, suggesting a novel mechanism for T-cell regulation and a new strategy for immunotherapy against human viral diseases. PMID:27149428

  20. 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.

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

    PubMed

    Kuhrt, David; Wojchowski, Don M

    2015-06-01

    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. PMID:25887776

  2. 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

  3. Endothelial Cell Proteomic Response to Rickettsia conorii Infection Reveals Activation of the Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT)-Inferferon Stimulated Gene (ISG)15 Pathway and Reprogramming Plasma Membrane Integrin/Cadherin Signaling.

    PubMed

    Zhao, Yingxin; Valbuena, Gustavo; Walker, David H; Gazi, Michal; Hidalgo, Marylin; DeSousa, Rita; Oteo, Jose Antonio; Goez, Yenny; Brasier, Allan R

    2016-01-01

    Rickettsia conorii is the etiologic agent of Mediterranean spotted fever, a re-emerging infectious disease with significant mortality. This Gram-negative, obligately intracellular pathogen is transmitted via tick bites, resulting in disseminated vascular endothelial cell infection with vascular leakage. In the infected human, Rickettsia conorii infects endothelial cells, stimulating expression of cytokines and pro-coagulant factors. However, the integrated proteomic response of human endothelial cells to R. conorii infection is not known. In this study, we performed quantitative proteomic profiling of primary human umbilical vein endothelial cells (HUVECs) with established R conorii infection versus those stimulated with endotoxin (LPS) alone. We observed differential expression of 55 proteins in HUVEC whole cell lysates. Of these, we observed induction of signal transducer and activator of transcription (STAT)1, MX dynamin-like GTPase (MX1), and ISG15 ubiquitin-like modifier, indicating activation of the JAK-STAT signaling pathway occurs in R. conorii-infected HUVECs. The down-regulated proteins included those involved in the pyrimidine and arginine biosynthetic pathways. A highly specific biotinylated cross-linking enrichment protocol was performed to identify dysregulation of 11 integral plasma membrane proteins that included up-regulated expression of a sodium/potassium transporter and down-regulation of α-actin 1. Analysis of Golgi and soluble Golgi fractions identified up-regulated proteins involved in platelet-endothelial adhesion, phospholipase activity, and IFN activity. Thirty four rickettsial proteins were identified with high confidence in the Golgi, plasma membrane, or secreted protein fractions. The host proteins associated with rickettsial infections indicate activation of interferon-STAT signaling pathways; the disruption of cellular adhesion and alteration of antigen presentation pathways in response to rickettsial infections are distinct from

  4. B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues.

    PubMed

    Frank, D A; Mahajan, S; Ritz, J

    1997-12-15

    To explore the pathogenesis of chronic lymphocytic leukemia (CLL), we examined whether phosphorylation of one or more signal transducer and activator of transcription (STAT) factors was abnormal in cells from CLL patients. No constitutive tyrosine phosphorylation was detected on any STAT in CLL cells. To assess the phosphorylation of serine residues of STAT1 and STAT3 in CLL cells, we raised antibodies that specifically recognize the form of STAT1 phosphorylated on ser-727 and the form of STAT3 phosphorylated on ser-727. We found that in 100% of patients with CLL (n = 32), STAT1 and STAT3 were constitutively phosphorylated on serine. This was in contrast to normal peripheral blood B lymphocytes or CD5+) B cells isolated from tonsils, in which this phosphorylation was absent. Serine phosphorylation of STAT1 and STAT3 was seen occasionally in other leukemias, but it was a universal finding only in CLL. The serine phosphorylation of these STATs was a continuous process, as incubation of CLL cells with the kinase inhibitor H7 led to the dephosphorylation of these serine residues. The STAT serine kinase in CLL cells has not been identified, and appears to be neither mitogen-activated protein kinase nor pp70(s6k). In summary, the constitutive serine phosphorylation of STAT1 and STAT3 is present in all CLL samples tested to date, although the physiologic significance of this modification remains to be determined. PMID:9399961

  5. Signal transducers and activators of transcription 3 (STAT3) inhibits transcription of the inducible nitric oxide synthase gene by interacting with nuclear factor kappaB.

    PubMed Central

    Yu, Zhiyuan; Zhang, Wenzheng; Kone, Bruce C

    2002-01-01

    Prolific generation of NO by inducible nitric oxide synthase (iNOS) can cause unintended injury to host cells during glomerulonephritis and other inflammatory diseases. While much is known about the mechanisms of iNOS induction, few transcriptional repressors have been found. We explored the role of signal transducers and activators of transcription 3 (STAT3) proteins in interleukin (IL)-1beta- and lipopolysaccharide (LPS)+interferon (IFN)-gamma-mediated iNOS induction in murine mesangial cells. Both stimuli induced rapid phosphorylation of STAT3 and sequence-specific STAT3 DNA-binding activity. Supershift assays with a STAT3 element probe demonstrated that nuclear factor kappaB (NF-kappaB) p65 and p50 complexed with STAT3 in the DNA-protein complex. The direct interaction of STAT3 and NF-kappaB p65 was verified in vivo by co-immunoprecipitation and in vitro by pull-down assays with glutathione S-transferase-NF-kappaB p65 fusion protein and in vitro -translated STAT3alpha. Overexpression of STAT3 dramatically inhibited IL-1beta- or LPS+IFN-gamma-mediated induction of iNOS promoter-luciferase constructs that contained the wild-type iNOS promoter or ones harbouring mutated STAT-binding elements. In tests of indirect inhibitory effects of STAT3, overexpression of STAT3 dramatically inhibited the activity of an NF-kappaB-dependent promoter devoid of STAT-binding elements without affecting NF-kappaB DNA-binding activity. Thus STAT3, via direct interactions with NF-kappaB p65, serves as a dominant-negative inhibitor of NF-kappaB activity to suppress indirectly cytokine induction of the iNOS promoter in mesangial cells. These results provide a new model for the termination of NO production by activated iNOS following exposure to pro-inflammatory stimuli. PMID:12057007

  6. ELMO1 Directly Interacts with Gβγ Subunit to Transduce GPCR Signaling to Rac1 Activation in Chemotaxis

    PubMed Central

    Wang, Youhong; Xu, Xuehua; Pan, Miao; Jin, Tian

    2016-01-01

    Diverse chemokines bind to G protein-coupled receptors (GPCRs) to activate the small GTPase Rac to regulate F-actin dynamics during chemotaxis. ELMO and Dock proteins form complexes that function as guanine nucleotide exchange factors (GEFs) for Rac activation. However, the linkage between GPCR activation and the ELMO/Dock-mediated Rac activation is not fully understood. In the present study, we show that chemoattractants induce dynamic membrane translocation of ELMO1 in mammalian cells. ELMO1 plays an important role in GPCR-mediated chemotaxis. We also reveal that ELMO1 and Dock1 form a stable complex. Importantly, activation of chemokine GPCR promotes the interaction between ELMO1 and Gβγ. The ELMO1-Gβγ interaction is through the N-terminus of ELMO1 protein and is important for the membrane translocation of ELMO1. ELMO1 is required for Rac1 activation upon chemoattractant stimulation. Our results suggest that chemokine GPCR-mediated interaction between Gβγ and ELMO1/Dock1 complex might serve as an evolutionarily conserved mechanism for Rac activation to regulate actin cytoskeleton for chemotaxis of human cells. PMID:27313788

  7. Identification of beta-escin as a novel inhibitor of signal transducer and activator of transcription 3/Janus-activated kinase 2 signaling pathway that suppresses proliferation and induces apoptosis in human hepatocellular carcinoma cells.

    PubMed

    Tan, Sandra Min-Li; Li, Feng; Rajendran, Peramaiyan; Kumar, Alan Prem; Hui, Kam M; Sethi, Gautam

    2010-07-01

    The activation of signal transducer and activator of transcription 3 (STAT3) has been linked with the proliferation, survival, invasion, and angiogenesis of a variety of human cancer cells, including hepatocellular carcinoma (HCC). Agents that can suppress STAT3 activation have potential for the prevention and treatment of HCC. In this study, we tested an agent, beta-escin, for its ability to suppress STAT3 activation. We found that beta-escin, a pentacyclic triterpenoid, inhibited both constitutive and interleukin-6-inducible STAT3 activation in a dose- and time-dependent manner in HCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, and Janus-activated kinase 2. Vanadate treatment reversed the beta-escin-induced down-regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that beta-escin induced the expression of tyrosine phosphatase Src homology phosphatase 1 that correlated with the down-regulation of constitutive STAT3 activation. beta-Escin also down-regulated the expression of STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1, and vascular endothelial growth factor. Finally, beta-escin inhibited proliferation and also substantially potentiated the apoptotic effects of paclitaxel and doxorubicin in HCC cells. Overall, these results suggest that beta-escin is a novel blocker of STAT3 activation that may have potential in the suppression of proliferation and chemosensitization in HCC. PMID:20378717

  8. Hyaluronan-Mediated Leukocyte Adhesion and Dextran Sulfate Sodium-Induced Colitis Are Attenuated in the Absence of Signal Transducer and Activator of Transcription 1

    PubMed Central

    Bandyopadhyay, Sudip K.; de la Motte, Carol A.; Kessler, Sean P.; Hascall, Vincent C.; Hill, David R.; Strong, Scott A.

    2008-01-01

    Inflammatory bowel disease is a chronic inflammatory condition of the intestinal mucosa whose etiology is unclear but is likely to be multifactorial. We have shown previously that an increased amount of hyaluronan (HA) is present both in the inflamed mucosa of inflammatory bowel disease patients and in isolated human cells after polyI:C treatment. The signal transducer and activator of transcription (STAT)1 protein plays an important role in many signaling pathways that are associated with inflammation. We therefore investigated the role of STAT1 in adhesive interactions that occur between leukocytes and polyI:C-induced mucosal smooth muscle cells (M-SMCs). Activation of STAT1 was observed after the polyI:C treatment of M-SMCs. Specific phosphorylation of tyrosine and serine residues of STAT1 was observed in polyI:C-treated, but not untreated, M-SMC cultures. To evaluate further the role of STAT1, a corresponding STAT-1-null mouse was used. PolyI:C-induced, HA-mediated leukocyte adhesion to colon SMCs from STAT1-null mice was significantly decreased compared with that from wild-type control mice. In vivo, using the dextran sulfate sodium-induced model of colon inflammation, both tissue damage and HA deposition were attenuated in STAT1-null mice compared with that in wild-type control mice. Additionally, the inter-α-trypsin inhibitor (IαI), a proteoglycan essential for facilitating leukocyte binding to the HA matrix, was reduced in STAT1-null mice. Together, these results demonstrate that STAT1 plays an important role in HA-mediated inflammatory processes. PMID:18818378

  9. Opposing Actions of Extracellular Signal-regulated Kinase (ERK) and Signal Transducer and Activator of Transcription 3 (STAT3) in Regulating Microtubule Stabilization during Cardiac Hypertrophy*

    PubMed Central

    Ng, Dominic C. H.; Ng, Ivan H. W.; Yeap, Yvonne Y. C.; Badrian, Bahareh; Tsoutsman, Tatiana; McMullen, Julie R.; Semsarian, Christopher; Bogoyevitch, Marie A.

    2011-01-01

    Excessive proliferation and stabilization of the microtubule (MT) array in cardiac myocytes can accompany pathological cardiac hypertrophy, but the molecular control of these changes remains poorly characterized. In this study, we examined MT stabilization in two independent murine models of heart failure and revealed increases in the levels of post-translationally modified stable MTs, which were closely associated with STAT3 activation. To explore the molecular signaling events contributing to control of the cardiac MT network, we stimulated cardiac myocytes with an α-adrenergic agonist phenylephrine (PE), and observed increased tubulin content without changes in detyrosinated (glu-tubulin) stable MTs. In contrast, the hypertrophic interleukin-6 (IL6) family cytokines increased both the glu-tubulin content and glu-MT density. When we examined a role for ERK in regulating cardiac MTs, we showed that the MEK/ERK-inhibitor U0126 increased glu-MT density in either control cardiac myocytes or following exposure to hypertrophic agents. Conversely, expression of an activated MEK1 mutant reduced glu-tubulin levels. Thus, ERK signaling antagonizes stabilization of the cardiac MT array. In contrast, inhibiting either JAK2 with AG490, or STAT3 signaling with Stattic or siRNA knockdown, blocked cytokine-stimulated increases in glu-MT density. Furthermore, the expression of a constitutively active STAT3 mutant triggered increased glu-MT density in the absence of hypertrophic stimulation. Thus, STAT3 activation contributes substantially to cytokine-stimulated glu-MT changes. Taken together, our results highlight the opposing actions of STAT3 and ERK pathways in the regulation of MT changes associated with cardiac myocyte hypertrophy. PMID:21056972

  10. Metformin attenuates graft-versus-host disease via restricting mammalian target of rapamycin/signal transducer and activator of transcription 3 and promoting adenosine monophosphate-activated protein kinase-autophagy for the balance between T helper 17 and Tregs.

    PubMed

    Park, Min-Jung; Lee, Seon-Yeong; Moon, Su-Jin; Son, Hye-Jin; Lee, Sung-Hee; Kim, Eun-Kyung; Byun, Jae-Kyeong; Shin, Dong Yun; Park, Sung-Hwan; Yang, Chul-Woo; Cho, Mi-La

    2016-07-01

    Acute graft-versus-host disease (aGVHD), caused by donor T cell-mediated injury to host tissues, is a problem in allogeneic bone marrow transplantation. The transition from naïve to effector T cells is accompanied by shift in metabolism main pathway; from glucose oxidative phosphorylation to aerobic glycolysis. Adenosine monophosphate-activated protein kinase (AMPK) is a serine/threonine kinase that is a metabolic sensor that helps maintain cellular energy homeostasis. Although AMPK activation can exert anti-inflammatory properties by negatively regulating pro-inflammatory mediators, its role as a therapeutic potential of graft-versus-host disease development remains unclear. In this study, we found that the intraperitoneal administration of metformin, which activates AMPK signaling significantly, ameliorated the clinical severity of aGHVD and lethality. This was associated with reductions in type I T helper (Th1) and Th17 and rises in Th2 and regulatory T (Treg) cell. The enhanced signal transducer and activator of transcription 3 activation noted during the development of aGVHD was reduced by metformin treatment. Furthermore, metformin-treated Th17 cells became converted into Treg cells via enhanced autophagy. The reduction in mortality associated with metformin treatment was associated with inhibition of the mammalian target of rapamycin/signal transducer and activator of transcription 3 pathway. These results suggest that metformin might be of significant use in the treatment of patients with aGVHD. PMID:27126953

  11. DNA transducer-triggered signal switch for visual colorimetric bioanalysis.

    PubMed

    Chen, Wenhong; Yan, Yurong; Zhang, Ye; Zhang, Xuemei; Yin, Yibing; Ding, Shijia

    2015-01-01

    A simple and versatile colorimetric biosensor has been developed for sensitive and specific detection of a wide range of biomolecules, such as oligonucleotides and aptamer-recognized targets. Combining the signal transducer and catalyzed hairpin assembly (CHA)-based signal amplification, the target DNA binds with the hairpin DNA to form a new nucleic acid sequence and creates a toehold in the transducer for initiating the recycle amplification reaction of CHA. The catalyzed assembly process produces a large amount of G-rich DNA. In the presence of hemin, the G-rich DNA forms G-quadruplex/hemin complex and mimic horseradish peroxidase activity, which catalyzes a colorimetric reaction. Under optimal conditions, the calibration curve of synthetic target DNA has good linearity from 50 pM to 200 nM with a detection limit of 32 pM. This strategy has been successfully applied to detect S. pneumoniae as low as 156 CFU mL(-1), and shows a good specificity against closely related streptococci and major pathogenic bacteria. In addition, the developed method enables successful visual analysis of S. pneumoniae in clinical samples by the naked eye. Importantly, this method demonstrates excellent assay versatility for sensitively detecting oligonucleotides or aptamer-recognized targets. PMID:26060886

  12. Expression of signal transducer and activator of transcription 3 and its phosphorylated form is significantly upregulated in patients with papillary thyroid cancer

    PubMed Central

    YAN, LI; LI, LI; LI, QINGHUAI; DI, WANG; SHEN, WEI; ZHANG, LINLEI; GUO, HAO

    2015-01-01

    The aim of the present study was to investigate the expression of signal transducer and activator of transcription 3 (STAT3) and phosphorylated STAT3 (pSTAT3) in tissues of papillary thyroid cancer (PTC) in comparison with the expression in adjacent normal tissues. The expression of STAT3, pSTAT3, fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor-C (VEGF-C) was examined in tissues of 42 cases of PTC and the adjacent normal tissues of 20 of the 42 PTC cases using immunohistochemistry and western blotting. The association between the expression levels and the clinicopathological features was analyzed. The expression of STAT3, pSTAT3, FGF2 and VEGF-C in the PTC tissues (76.2, 42.9, 81.0 and 73.8%, respectively) was significantly higher than that in the normal tissues (P<0.05). In the PTC tissues, the expression of STAT3 was linearly correlated with the levels of pSTAT3 and VEGF-C (P<0.05). In conclusion, STAT3 and pSTAT3 are significantly upregulated in PTC tissues, and may potentially be used as markers to screen for PTC with lymph node metastasis. PMID:26136959

  13. Signal transducer and activator of transcription 3 (STAT3) inhibitor, S3I-201, acts as a potent and non-selective alkylating agent

    PubMed Central

    Williams, Declan; Resetca, Diana; Wilson, Derek J.; Gunning, Patrick T.

    2016-01-01

    The Signal Transducer and Activator of Transcription 3 (STAT3) oncogene is a master regulator of many human cancers, and a well-recognized target for therapeutic intervention. A well known STAT3 inhibitor, S3I-201 (NSC 74859), is hypothesized to block STAT3 function in cancer cells by binding the STAT3 SH2 domain and disrupt STAT3 protein complexation events. In this study, liquid chromatography tandem mass spectrometry analysis revealed that STAT3, in the presence of S3I-201, showed a minimum of five specific sites of modification, cysteine's 108, 259, 367, 542, and 687. Moreover, a prepared fluorescently labeled chemical probe of S3I-201 (DB-6-055) revealed that S3I-201 non-specifically and globally alkylated intracellular proteins at concentrations consistent with S3I-201's reported IC50. These data are consistent with the hypothesis that S3I-201 is a sub-optimal probe for interrogating STAT3-related cell biology. PMID:26942696

  14. 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

  15. Applying Small Molecule Signal Transducer and Activator of Transcription-3 (STAT3) Protein Inhibitors as Pancreatic Cancer Therapeutics.

    PubMed

    Arpin, Carolyn C; Mac, Stephen; Jiang, Yanlin; Cheng, Huiwen; Grimard, Michelle; Page, Brent D G; Kamocka, Malgorzata M; Haftchenary, Sina; Su, Han; Ball, Daniel P; Rosa, David A; Lai, Ping-Shan; Gómez-Biagi, Rodolfo F; Ali, Ahmed M; Rana, Rahul; Hanenberg, Helmut; Kerman, Kagan; McElyea, Kyle C; Sandusky, George E; Gunning, Patrick T; Fishel, Melissa L

    2016-05-01

    Constitutively activated STAT3 protein has been found to be a key regulator of pancreatic cancer and a target for molecular therapeutic intervention. In this study, PG-S3-001, a small molecule derived from the SH-4-54 class of STAT3 inhibitors, was found to inhibit patient-derived pancreatic cancer cell proliferation in vitro and in vivo in the low micromolar range. PG-S3-001 binds the STAT3 protein potently, Kd = 324 nmol/L by surface plasmon resonance, and showed no effect in a kinome screen (>100 cancer-relevant kinases). In vitro studies demonstrated potent cell killing as well as inhibition of STAT3 activation in pancreatic cancer cells. To better model the tumor and its microenvironment, we utilized three-dimensional (3D) cultures of patient-derived pancreatic cancer cells in the absence and presence of cancer-associated fibroblasts (CAF). In this coculture model, inhibition of tumor growth is maintained following STAT3 inhibition in the presence of CAFs. Confocal microscopy was used to verify tumor cell death following treatment of 3D cocultures with PG-S3-001. The 3D model was predictive of in vivo efficacy as significant tumor growth inhibition was observed upon administration of PG-S3-001. These studies showed that the inhibition of STAT3 was able to impact the survival of tumor cells in a relevant 3D model, as well as in a xenograft model using patient-derived cells. Mol Cancer Ther; 15(5); 794-805. ©2016 AACR. PMID:26873728

  16. 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

  17. 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

  18. 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.

    PubMed

    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. PMID:26160345

  19. 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.

  20. 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.

  1. 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

  2. Development of a novel azaspirane that targets the Janus kinase-signal transducer and activator of transcription (STAT) pathway in hepatocellular carcinoma in vitro and in vivo.

    PubMed

    Mohan, Chakrabhavi Dhananjaya; Bharathkumar, Hanumantharayappa; Bulusu, Krishna C; Pandey, Vijay; Rangappa, Shobith; Fuchs, Julian E; Shanmugam, Muthu K; Dai, Xiaoyun; Li, Feng; Deivasigamani, Amudha; Hui, Kam M; Kumar, Alan Prem; Lobie, Peter E; Bender, Andreas; Basappa; Sethi, Gautam; Rangappa, Kanchugarakoppal S

    2014-12-01

    Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates genes involved in cell growth, proliferation, and survival, and given its association with many types of cancers, it has recently emerged as a promising target for therapy. In this work, we present the synthesis of N-substituted azaspirane derivatives and their biological evaluation against hepatocellular carcinoma (HCC) cells (IC50 = 7.3 μm), thereby identifying 2-(1-(4-(2-cyanophenyl)1-benzyl-1H-indol-3-yl)-5-(4-methoxy-phenyl)-1-oxa-3-azaspiro(5,5) undecane (CIMO) as a potent inhibitor of the JAK-STAT pathway with selectivity over normal LO2 cells (IC50 > 100 μm). The lead compound, CIMO, suppresses proliferation of HCC cells and achieves this effect by reducing both constitutive and inducible phosphorylation of JAK1, JAK2, and STAT3. Interestingly, CIMO displayed inhibition of Tyr-705 phosphorylation, which is required for nuclear translocation of STAT3, but it has no effect on Ser-727 phosphorylation. CIMO accumulates cancer cells in the sub-G1 phase and decreases STAT3 in the nucleus and thereby causes down-regulation of genes regulated via STAT3. Suppression of STAT3 phosphorylation by CIMO and knockdown of STAT3 mRNA using siRNA transfection displayed a similar effect on the viability of HCC cells. Furthermore, CIMO significantly decreased the tumor development in an orthotopic HCC mouse model through the modulation of phospho-STAT3, Ki-67, and cleaved caspase-3 in tumor tissues. Thus, CIMO represents a chemically novel and biologically in vitro and in vivo validated compound, which targets the JAK-STAT pathway as a potential cancer treatment. PMID:25320076

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

    PubMed

    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

    2015-11-01

    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

  4. Role of signal transducer and activator of transcription 1 in murine allergen-induced airway remodeling and exacerbation by carbon nanotubes.

    PubMed

    Thompson, Elizabeth A; Sayers, Brian C; Glista-Baker, Ellen E; Shipkowski, Kelly A; Ihrie, Mark D; Duke, Katherine S; Taylor, Alexia J; Bonner, James C

    2015-11-01

    Asthma is characterized by a T helper type 2 phenotype and by chronic allergen-induced airway inflammation (AAI). Environmental exposure to air pollution ultrafine particles (i.e., nanoparticles) exacerbates AAI, and a concern is possible exacerbation posed by engineered nanoparticles generated by emerging nanotechnologies. Signal transducer and activator of transcription (STAT) 1 is a transcription factor that maintains T helper type 1 cell development. However, the role of STAT1 in regulating AAI or exacerbation by nanoparticles has not been explored. In this study, mice with whole-body knockout of the Stat1 gene (Stat1(-/-)) or wild-type (WT) mice were sensitized to ovalbumin (OVA) allergen and then exposed to multiwalled carbon nanotubes (MWCNTs) by oropharygneal aspiration. In Stat1(-/-) and WT mice, OVA increased eosinophils in bronchoalveolar lavage fluid, whereas MWCNTs increased neutrophils. Interestingly, OVA sensitization prevented MWCNT-induced neutrophilia and caused only eosinophilic inflammation. Stat1(-/-) mice displayed increased IL-13 in bronchoalveolar lavage fluid at 1 day compared with WT mice after treatment with OVA or OVA and MWCNTs. At 21 days, the lungs of OVA-sensitized Stat1(-/-) mice displayed increased eosinophilia, goblet cell hyperplasia, airway fibrosis, and subepithelial apoptosis. MWCNTs further increased OVA-induced goblet cell hyperplasia, airway fibrosis, and apoptosis in Stat1(-/-) mice at 21 days. These changes corresponded to increased levels of profibrogenic mediators (transforming growth factor-β1, TNF-α, osteopontin) but decreased IL-10 in Stat1(-/-) mice. Finally, fibroblasts isolated from the lungs of Stat1(-/-) mice produced significantly more collagen mRNA and protein in response to transforming growth factor-β1 compared with WT lung fibroblasts. Our results support a protective role for STAT1 in chronic AAI and exacerbation of remodeling caused by MWCNTs. PMID:25807359

  5. Off-Target Vascular Effects of Cholesteryl Ester Transfer Protein Inhibitors Involve Redox-Sensitive and Signal Transducer and Activator of Transcription 3-Dependent Pathways.

    PubMed

    Rios, Francisco J; Lopes, Rheure A; Neves, Karla B; Camargo, Livia L; Montezano, Augusto C; Touyz, Rhian M

    2016-05-01

    Elevated blood pressure was an unexpected outcome in some cholesteryl ester transfer protein (CETP) inhibitor trials, possibly due to vascular effects of these drugs. We investigated whether CETP inhibitors (torcetrapib, dalcetrapib, anacetrapib) influence vascular function and explored the putative underlying molecular mechanisms. Resistance arteries and vascular smooth muscle cells (VSMC) from rats, which lack the CETP gene, were studied. CETP inhibitors increased phenylephrine-stimulated vascular contraction (logEC50 (:) 6.6 ± 0.1; 6.4 ± 0.06, and 6.2 ± 0.09 for torcetrapib, dalcetrapib, and anacetrapib, respectively, versus control 5.9 ± 0.05). Only torcetrapib reduced endothelium-dependent vasorelaxation. The CETP inhibitor effects were ameliorated by N-acetylcysteine (NAC), a reactive oxygen species (ROS) scavenger, and by S3I-201 [2-hydroxy-4-[[2-(4-methylphenyl)sulfonyloxyacetyl]amino]benzoic acid], a signal transducer and activator of transcription 3 (STAT3) inhibitor. CETP inhibitors increased the phosphorylation (2- to 3-fold) of vascular myosin light chain (MLC) and myosin phosphatase target subunit 1 (MYPT1) (procontractile proteins) and stimulated ROS production. CETP inhibitors increased the phosphorylation of STAT3 (by 3- to 4-fold), a transcription factor important in cell activation. Activation of MLC was reduced by NAC, GKT137831 [2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6-dione] (Nox1/4 inhibitor), and S3I-201. The phosphorylation of STAT3 was unaffected by NAC and GKT137831. CETP inhibitors did not influence activation of mitogen-activated proteins kinases (MAPK) or c-Src. Our data demonstrate that CETP inhibitors influence vascular function and contraction through redox-sensitive, STAT3-dependent, and MAPK-independent processes. These phenomena do not involve CETP because the CETP gene is absent in rodents. Findings from our study indicate that CETP inhibitors have vasoactive properties, which

  6. 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.

  7. 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

  8. TRP channels: sensors and transducers of gasotransmitter signals

    PubMed Central

    Takahashi, Nobuaki; Kozai, Daisuke; Mori, Yasuo

    2012-01-01

    The transient receptor potential (trp) gene superfamily encodes cation channels that act as multimodal sensors for a wide variety of stimuli from outside and inside the cell. Upon sensing, they transduce electrical and Ca2+ signals via their cation channel activities. These functional features of TRP channels allow the body to react and adapt to different forms of environmental changes. Indeed, members of one class of TRP channels have emerged as sensors of gaseous messenger molecules that control various cellular processes. Nitric oxide (NO), a vasoactive gaseous molecule, regulates TRP channels directly via cysteine (Cys) S-nitrosylation or indirectly via cyclic GMP (cGMP)/protein kinase G (PKG)-dependent phosphorylation. Recent studies have revealed that changes in the availability of molecular oxygen (O2) also control the activation of TRP channels. Anoxia induced by O2-glucose deprivation and severe hypoxia (1% O2) activates TRPM7 and TRPC6, respectively, whereas TRPA1 has recently been identified as a novel sensor of hyperoxia and mild hypoxia (15% O2) in vagal and sensory neurons. TRPA1 also detects other gaseous molecules such as hydrogen sulfide (H2S) and carbon dioxide (CO2). In this review, we focus on how signaling by gaseous molecules is sensed and integrated by TRP channels. PMID:22934072

  9. 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

  10. 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.

  11. Regulation of Signal Transducer and Activator of Transcription and Suppressor of Cytokine-Signaling Gene Expression in the Brain of Mice with Astrocyte-Targeted Production of Interleukin-12 or Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Maier, Joachim; Kincaid, Carrie; Pagenstecher, Axel; Campbell, Iain L.

    2002-01-01

    Interleukin (IL)-12 and interferon (IFN)-γ are implicated in the pathogenesis of immune disorders of the central nervous system (CNS). To define the basis for the actions of these cytokines in the CNS, we examined the temporal and spatial regulation of key signal transducers and activators of transcription (STATs) and suppressors of cytokine signaling (SOCS) in the brain of transgenic mice with astrocyte production of IL-12 or in mice with experimental autoimmune encephalomyelitis (EAE). In healthy mice, with the exception of STAT4 and STAT6, the expression of a number of STAT and SOCS genes was detectable. However, in symptomatic transgenic mice and in EAE significant up-regulation of STAT1, STAT2, STAT3, STAT4, IRF9, and SOCS1 and SOCS3 RNA transcripts was observed. Although the increased expression of STAT1 RNA was widely distributed and included neurons, astrocytes, and microglia, STAT4 and STAT3 and SOCS1 and SOCS3 RNA was primarily restricted to the infiltrating mononuclear cell population. The level and location of the STAT1, STAT3, and STAT4 proteins overlapped with their corresponding RNA and additionally showed nuclear localization indicative of activation of these molecules. Thus, in both the glial fibrillary acidic protein-IL-12 mice and in EAE the CNS expression of key STAT and SOCS genes that regulate IL-12 (STAT4) and IFN-γ (STAT1, SOCS1, and SOCS3) receptor signaling is highly regulated and compartmentalized. We conclude the interaction between these positive and negative signaling circuits and their distinct cellular locations likely play a defining role in coordinating the actions of IL-12 and IFN-γ during the pathogenesis of type 1 immune responses in the CNS. PMID:11786421

  12. Granulocyte colony-stimulating factor receptor signalling via Janus kinase 2/signal transducer and activator of transcription 3 in ovarian cancer

    PubMed Central

    Kumar, J; Fraser, F W; Riley, C; Ahmed, N; McCulloch, D R; Ward, A C

    2014-01-01

    Background: Ovarian cancer remains a major cause of cancer mortality in women, with only limited understanding of disease aetiology at the molecular level. Granulocyte colony-stimulating factor (G-CSF) is a key regulator of both normal and emergency haematopoiesis, and is used clinically to aid haematopoietic recovery following ablative therapies for a variety of solid tumours including ovarian cancer. Methods: The expression of G-CSF and its receptor, G-CSFR, was examined in primary ovarian cancer samples and a panel of ovarian cancer cell lines, and the effects of G-CSF treatment on proliferation, migration and survival were determined. Results: G-CSFR was predominantly expressed in high-grade serous ovarian epithelial tumour samples and a subset of ovarian cancer cell lines. Stimulation of G-CSFR-expressing ovarian epithelial cancer cells with G-CSF led to increased migration and survival, including against chemotherapy-induced apoptosis. The effects of G-CSF were mediated by signalling via the downstream JAK2/STAT3 pathway. Conclusion: This study suggests that G-CSF has the potential to impact on ovarian cancer pathogenesis, and that G-CSFR expression status should be considered in determining appropriate therapy. PMID:24220695

  13. 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

  14. Early exposure of interferon-γ inhibits signal transducer and activator of transcription-6 signalling and nuclear factor κB activation in a short-term monocyte-derived dendritic cell culture promoting ‘FAST’ regulatory dendritic cells

    PubMed Central

    Rojas-Canales, D; Krishnan, R; Jessup, C F; Coates, P T

    2012-01-01

    Interferon (IFN)-γ is a cytokine with immunomodulatory properties, which has been shown previously to enhance the generation of tolerogenic dendritic cells (DC) when administered early ex vivo in 7-day monocyte-derived DC culture. To generate tolerogenic DC rapidly within 48 h, human monocytes were cultured for 24 h with interleukin (IL)-4 and granulocyte–macrophage colony-stimulating factor (GM-CSF) in the presence (IFN-γ-DC) or absence of IFN-γ (500 U/ml) (UT-DC). DC were matured for 24 h with TNF-α and prostaglandin E2 (PGE2). DC phenotype, signal transducer and activator of transcription-6 (STAT-6) phosphorylation and promotion of CD4+CD25+CD127neg/lowforkhead box P3 (FoxP3)hi T cells were analysed by flow cytometry. DC nuclear factor (NF)-κB transcription factor reticuloendotheliosis viral oncogene homologue B (RELB) and IL-12p70 protein expression were also determined. Phenotypically, IFN-γ-DC displayed reduced DC maturation marker CD83 by 62% and co-stimulation molecules CD80 (26%) and CD86 (8%). IFN-γ treatment of monocytes inhibited intracellular STAT6, RELB nuclear translocation and IL-12p70 production. IFN-γ-DC increased the proportion of CD4+CD25+CD127neg/lowfoxp3hi T cells compared to UT-DC from 12 to 23%. IFN-γ-DC primed T cells inhibited antigen-specific, autologous naive T cell proliferation by 70% at a 1:1 naive T cells to IFN-γ-DC primed T cell ratio in suppression assays. In addition, we examined the reported paradoxical proinflammatory effects of IFN-γ and confirmed in this system that late IFN-γ exposure does not inhibit DC maturation marker expression. Early IFN-γ exposure is critical in promoting the generation of regulatory DC. Early IFN-γ modulated DC generated in 48 h are maturation arrested and promote the generation of antigen-specific regulatory T cells, which may be clinically applicable as a novel cellular therapy for allograft rejection. PMID:22288588

  15. 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.

  16. 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 Central

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

    2015-01-01

    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. PMID:26500281

  17. 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

  18. 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. PMID:25373509

  19. 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 Central

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

    2012-01-01

    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. PMID:22442148

  20. Identifying Mechanisms by Which Escherichia coli O157:H7 Subverts Interferon-γ Mediated Signal Transducer and Activator of Transcription-1 Activation

    PubMed Central

    Ho, Nathan K.; Crandall, Ian; Sherman, Philip M.

    2012-01-01

    Enterohemorrhagic Escherichia coli serotype O157:H7 is a food borne enteric bacterial pathogen that causes significant morbidity and mortality in both developing and industrialized nations. E. coli O157:H7 infection of host epithelial cells inhibits the interferon gamma pro-inflammatory signaling pathway, which is important for host defense against microbial pathogens, through the inhibition of Stat-1 tyrosine phosphorylation. The aim of this study was to determine which bacterial factors are involved in the inhibition of Stat-1 tyrosine phosphorylation. Human epithelial cells were challenged with either live bacteria or bacterial-derived culture supernatants, stimulated with interferon-gamma, and epithelial cell protein extracts were then analyzed by immunoblotting. The results show that Stat-1 tyrosine phosphorylation was inhibited by E. coli O157:H7 secreted proteins. Using sequential anion exchange and size exclusion chromatography, YodA was identified, but not confirmed to mediate subversion of the Stat-1 signaling pathway using isogenic mutants. We conclude that E. coli O157:H7 subverts Stat-1 tyrosine phosphorylation in response to interferon-gamma through a still as yet unidentified secreted bacterial protein. PMID:22253910

  1. Identifying mechanisms by which Escherichia coli O157:H7 subverts interferon-γ mediated signal transducer and activator of transcription-1 activation.

    PubMed

    Ho, Nathan K; Crandall, Ian; Sherman, Philip M

    2012-01-01

    Enterohemorrhagic Escherichia coli serotype O157:H7 is a food borne enteric bacterial pathogen that causes significant morbidity and mortality in both developing and industrialized nations. E. coli O157:H7 infection of host epithelial cells inhibits the interferon gamma pro-inflammatory signaling pathway, which is important for host defense against microbial pathogens, through the inhibition of Stat-1 tyrosine phosphorylation. The aim of this study was to determine which bacterial factors are involved in the inhibition of Stat-1 tyrosine phosphorylation. Human epithelial cells were challenged with either live bacteria or bacterial-derived culture supernatants, stimulated with interferon-gamma, and epithelial cell protein extracts were then analyzed by immunoblotting. The results show that Stat-1 tyrosine phosphorylation was inhibited by E. coli O157:H7 secreted proteins. Using sequential anion exchange and size exclusion chromatography, YodA was identified, but not confirmed to mediate subversion of the Stat-1 signaling pathway using isogenic mutants. We conclude that E. coli O157:H7 subverts Stat-1 tyrosine phosphorylation in response to interferon-gamma through a still as yet unidentified secreted bacterial protein. PMID:22253910

  2. Active acoustical impedance using distributed electrodynamic transducers

    NASA Astrophysics Data System (ADS)

    Collet, M.; Berthillier, M.; David, P.

    2006-03-01

    New miniaturization and integration capabilities available from the emerging MEMS technology will allow silicon-based artificial skins involving thousands of elementary actuators to be developed in the near future. SMART structures combining large arrays of elementary motion pixels coated with macroscopic components are thus being studied so that fundamental properties such as shape, stiffness, color, and even reflectivity of light and sound could be dynamically adjusted. This paper investigates acoustic impedance capabilities of a set of distributed transducers connected with suitable controlling laws. Basically, we search to design an integrated electro-mechanical system which presents a global behavior with appropriate acoustical characteristics. This problem is intrinsically connected with the control of multi physical system based on PDE and with the notion of multi-scaled physics when we dispose MEMS devices. By using specific techniques based on partial differential equation control theory, we have first build a simple boundary control equation able to annihilate wave reflection. The obtained control strategies can also be discretized to be implemented like a zero or first order spatial operator. Thus, we can use quasi-collocated transducers and their well-known poles-zeros interlacing property to guarantee robust stability. This paper aims at showing in a first part how a well controlled semi-distributed active skin can substantially modify transmissibility or reflectivity of the corresponding homogeneous wall. In a second part numerical and experimental results underline the capabilities of the method. Finally efficiency of such a device is compared theoretically with those obtained by classical x-filtered LMS strategy.

  3. Signaling pathways transduced through the elastin receptor facilitate proliferation of arterial smooth muscle cells.

    PubMed

    Mochizuki, Satsuki; Brassart, Bertrand; Hinek, Aleksander

    2002-11-22

    In this report we demonstrate that soluble peptides, elastin degradation products stimulate proliferation of arterial smooth muscle cells. We show that these effects are due to generation of intracellular signals transduced through the cell surface elastin receptor, which consists of peripheral 67-kDa elastin-binding protein (EBP) (spliced variant of beta-galactosidase), immobilized to the transmembrane sialidase and the protective protein. We found that elastin receptor-transduced signaling triggers activation of G proteins, opening of l-type calcium channels, and a sequential activation of tyrosine kinases: FAK, c-Src, platelet-derived growth factor-receptor kinase and then Ras-Raf-MEK1/2-ERK1/2 phosphorylation cascade. This, in turn, causes an increase in expression of cyclins and cyclin-dependent kinases, and a consequent increase in cellular proliferation. The EBP-transduced signals also induce tyrosine kinase-dependent phosphorylation of beta-tubulin, LC3, microtubule-associated protein 1, and alpha-actin and troponin-T, which could be linked to reorganization of cytoskeleton. We have also disclosed that induction of these signals can be abolished by anti-EBP antibody or by galactosugars, which cause shedding of EBP from the cell surface. Moreover, elastin-derived peptides did not induce proliferation of EBP-deficient cells derived from patients bearing a nonsense mutation of the beta-galactosidase gene or sialidase-deficient cells from patients with congenital sialidosis. PMID:12244048

  4. 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

  5. Active acoustical impedance using distributed electrodynamical transducers.

    PubMed

    Collet, M; David, P; Berthillier, M

    2009-02-01

    New miniaturization and integration capabilities available from emerging microelectromechanical system (MEMS) technology will allow silicon-based artificial skins involving thousands of elementary actuators to be developed in the near future. SMART structures combining large arrays of elementary motion pixels coated with macroscopic components are thus being studied so that fundamental properties such as shape, stiffness, and even reflectivity of light and sound could be dynamically adjusted. This paper investigates the acoustic impedance capabilities of a set of distributed transducers connected with a suitable controlling strategy. Research in this domain aims at designing integrated active interfaces with a desired acoustical impedance for reaching an appropriate global acoustical behavior. This generic problem is intrinsically connected with the control of multiphysical systems based on partial differential equations (PDEs) and with the notion of multiscaled physics when a dense array of electromechanical systems (or MEMS) is considered. By using specific techniques based on PDE control theory, a simple boundary control equation capable of annihilating the wave reflections has been built. The obtained strategy is also discretized as a low order time-space operator for experimental implementation by using a dense network of interlaced microphones and loudspeakers. The resulting quasicollocated architecture guarantees robustness and stability margins. This paper aims at showing how a well controlled semidistributed active skin can substantially modify the sound transmissibility or reflectivity of the corresponding homogeneous passive interface. In Sec. IV, numerical and experimental results demonstrate the capabilities of such a method for controlling sound propagation in ducts. Finally, in Sec. V, an energy-based comparison with a classical open-loop strategy underlines the system's efficiency. PMID:19206865

  6. Leptin modulates the expression of catabolic genes in rat nucleus pulposus cells through the mitogen-activated protein kinase and Janus kinase 2/signal transducer and activator of transcription 3 pathways

    PubMed Central

    MIAO, DAOYI; ZHANG, LINGZHOU

    2015-01-01

    Obesity has been demonstrated to be involved in the progress of intervertebral disc degeneration (IDD). However, the associated mechanisms remain to be elucidated. The purpose the present study was to examine the effect of leptin on the expression of degeneration-associated genes in rat nucleus pulposus (NP) cells, and determine the possible mechanism. Normal NP cells, obtained from Sprague Dawley rats, were identified using immunocytochemistry for the expression of collagen II and CA125, and treated with leptin and/or interleukin (IL)-β. Subsequently, the mRNA expression levels of matrix metalloproteinase (MMP)-1, MMP-3, MMP-9, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, ADAMTS-5, aggrecan and COL2A1 were detected by reverse transcription-quantitative polymerase chain reaction (RT-q-PCR). Alcian staining and immunocytochemistry were used to examine the expression levels of proteoglycan and collagen II. The pathway activation was investigated using western blotting, and inhibitors of the pathways were used to reveal the effect of these pathways on the NP cells. The results of the RT-qPCR demonstrated that leptin alone upregulated the mRNA expression levels of MMP-1, MMP-13, ADAMTS-4, ADAMTS-5 and COL2A1. Synergy of leptin and IL-β was found in the increased expression levels of MMP-1, MMP-3 and ADAMTS-5. The leptin-treated NP cells exhibited decreased expression of collagen II. The mitrogen-activated protein kinase (MAPK) pathway (c-Jun-N-terminal kinase, phosphorylated extracellular signal-regulated kinase and p38), phosphatidylinositol 3-kinase (PI3K)/Akt pathway and Janus kinase (JAK)2/signal transducer and activator of transcription 3 pathway were all activated by leptin, however, inhibitors of all the pathways, with the exception of the PI3K/Akt pathway, reversed the expression levels of MMP-1 and MMP-13. These results suggested that leptin promoted catabolic metabolism in the rat NP cells via the MAPK and JAK2/STAT3

  7. Leptin modulates the expression of catabolic genes in rat nucleus pulposus cells through the mitogen-activated protein kinase and Janus kinase 2/signal transducer and activator of transcription 3 pathways.

    PubMed

    Miao, Daoyi; Zhang, Lingzhou

    2015-08-01

    Obesity has been demonstrated to be involved in the progress of intervertebral disc degeneration (IDD). However, the associated mechanisms remain to be elucidated. The purpose the present study was to examine the effect of leptin on the expression of degeneration-associated genes in rat nucleus pulposus (NP) cells, and determine the possible mechanism. Normal NP cells, obtained from Sprague Dawley rats, were identified using immunocytochemistry for the expression of collagen II and CA125, and treated with leptin and/or interleukin (IL)-β. Subsequently, the mRNA expression levels of matrix metalloproteinase (MMP)-1, MMP-3, MMP-9, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, ADAMTS-5, aggrecan and COL2A1 were detected by reverse transcription-quantitative polymerase chain reaction (RT-q-PCR). Alcian staining and immunocytochemistry were used to examine the expression levels of proteoglycan and collagen II. The pathway activation was investigated using western blotting, and inhibitors of the pathways were used to reveal the effect of these pathways on the NP cells. The results of the RT-qPCR demonstrated that leptin alone upregulated the mRNA expression levels of MMP-1, MMP-13, ADAMTS-4, ADAMTS-5 and COL2A1. Synergy of leptin and IL-β was found in the increased expression levels of MMP-1, MMP-3 and ADAMTS-5. The leptin-treated NP cells exhibited decreased expression of collagen II. The mitrogen-activated protein kinase (MAPK) pathway (c-Jun-N-terminal kinase, phosphorylated extracellular signal-regulated kinase and p38), phosphatidylinositol 3-kinase (PI3K)/Akt pathway and Janus kinase (JAK)2/signal transducer and activator of transcription 3 pathway were all activated by leptin, however, inhibitors of all the pathways, with the exception of the PI3K/Akt pathway, reversed the expression levels of MMP-1 and MMP-13. These results suggested that leptin promoted catabolic metabolism in the rat NP cells via the MAPK and JAK2/STAT3

  8. TRANSDUCING BIOELECTRIC SIGNALS INTO EPIGENETIC PATHWAYS DURING TADPOLE TAIL REGENERATION

    PubMed Central

    Tseng, Ai-Sun; Levin, Michael

    2012-01-01

    One important component of the cell-cell communication that occurs during regenerative patterning is bioelectrical signaling. In particular, the regeneration of the tail in Xenopus laevis tadpoles both requires, and can be initiated at non-regenerative stages by, specific regulation of bioelectrical signaling (alteration in resting membrane potential and a subsequent change in sodium content of blastemal cells). While standing gradients of transmembrane voltage and ion concentration can provide positional guidance and other morphogenetic cues, these biophysical parameters must be transduced into transcriptional responses within cells. A number of mechanisms have been described for linking slow voltage changes to gene expression, but recent data on the importance of epigenetic marks for regeneration suggest a novel hypothesis: that sodium/butyrate transporters link ion flows to influx of small molecules needed to modify chromatin state. Here, we briefly review the data on bioelectricity in tadpole tail regeneration, present a technique for convenient alteration of transmembrane potential in vivo that does not require transgenes, show augmentation of regeneration in vivo by manipulation of voltage, and present new data in the Xenopus tail consistent with the hypothesis that the monocarboxlyate transporter SLC5A8 may link regeneration-relevant epigenetic modification with upstream changes in ion content. PMID:22933452

  9. 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

  10. 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

  11. Toll-like receptors: cellular signal transducers for exogenous molecular patterns causing immune responses.

    PubMed

    Kirschning, C J; Bauer, S

    2001-09-01

    Innate immunity initiates protection of the host organism against invasion and subsequent multiplication of microbes by specific recognition. Germ line-encoded receptors have been identified for microbial products such as mannan, lipopeptide, peptidoglycan (PGN), lipoteichoic acid (LTA), lipopolysaccharide (LPS), and CpG-DNA. The Drosophila Toll protein has been shown to be involved in innate immune response of the adult fruitfly. Members of the family of Toll-like receptors (TLRs) in vertebrates have been implicated as pattern recognition receptors (PRRs). Ten TLRs are known and six of these have been demonstrated to mediate cellular activation by distinct microbial products. TLR4 has been implicated as activator of adaptive immunity, and analysis of systemic LPS responses in mice led to the identification of LPS-resistant strains instrumental in its identification as a transmembrane LPS signal transducer. Structural similarities between TLRs and receptor molecules involved in immune responses such as CD14 and the IL-1 receptors (IL-1Rs), as well as functional analysis qualified TLR2 as candidate receptor for LPS and other microbial products. Targeted disruption of the TLR9 gene in mice led to identification of TLR9 as CpG-DNA signal transducer. Involvement of TLR5 in cell activation by bacterial flagellin has been demonstrated. Further understanding of recognition and cellular signaling activated through the ancient host defense system represented by Toll will eventually lead to means for its therapeutic modulation. PMID:11680785

  12. FSH-induced p38-MAPK-mediated dephosphorylation at serine 727 of the signal transducer and activator of transcription 1 decreases Cyp1b1 expression in mouse granulosa cells.

    PubMed

    Du, Xue-Hai; Zhou, Xiao-Long; Cao, Rui; Xiao, Peng; Teng, Yun; Ning, Cai-Bo; Liu, Hong-Lin

    2015-01-01

    Most mammalian follicles undergo atresia at various stages before ovulation, and granulosa cell apoptosis is a major cause of antral follicular atresia. Estradiol is an essential mitogen for granulosa cell proliferation in vivo and inhibition of apoptosis. The estradiol-producing capacity and metabolism levels are important for follicle health, and sufficient estradiol is necessary for follicle development and ovulation. Cyp1b1, a member of the cytochrome P450 1 subfamily, is responsible for the metabolism of a wide variety of halogenated and polycyclic aromatic hydrocarbons in diverse tissues. In mouse follicles, Cyp1b1 converts estradiol to 4-hydroxyestradiol. We investigated mouse granulosa cells (MGCs) in vivo and in vitro and found that Cyp1b1 played a crucial role in estradiol metabolism in dominant follicles. Follicle-stimulating hormone (FSH) decreased estrogen metabolism by reducing Cyp1b1 mRNA and protein levels in MGCs. Furthermore, FSH regulated signal transducer and activator of transcription 1 (STAT1), a significant transcription factor of Cyp1b1, by mediating the dephosphorylation of STAT1 on serine 727 (Ser(727)) in MGCs. p38 mitogen-activated protein kinase (MAPK) may be involved in the FSH-induced dephosphorylation of STAT1 on Ser(727) in MGCs. These results suggested that FSH functions via p38 MAPK-induced dephosphorylation at Ser(727) of STAT1 to downregulate Cyp1b1 expression and maintain the estradiol levels in mouse dominant follicles. PMID:25315223

  13. Fos-Zippered GH Receptor Cytosolic Tails Act as Jak2 Substrates and Signal Transducers.

    PubMed

    Nespital, Tobias; van der Velden, Lieke M; Mensinga, Anneloes; van der Vaart, Elisabeth D; Strous, Ger J

    2016-03-01

    Members of the Janus kinase (Jak) family initiate the majority of downstream signaling events of the cytokine receptor family. The prevailing principle is that the receptors act in dimers: 2 Jak2 molecules bind to the cytosolic tails of a cytokine receptor family member and initiate Jak-signal transducer and activator of transcription signaling upon a conformational change in the receptor complex, induced by the cognate cytokine. Due to the complexity of signaling complexes, there is a strong need for in vitro model systems. To investigate the molecular details of the Jak2 interaction with the GH receptor (GHR), we used cytosolic tails provided with leucine zippers derived from c-Fos to mimic the dimerized state of GHR. Expressed together with Jak2, fos-zippered tails, but not unzippered tails, were stabilized. In addition, the Jak-signal transducer and activator of transcription signaling pathway was activated by the fos-zippered tails. The stabilization depended also on α-helix rotation of the zippers. Fos-zippered GHR tails and Jak2, both purified from baculovirus-infected insect cells, interacted via box1 with a binding affinity of approximately 40nM. As expected, the Jak kinase inhibitor Ruxolitinib inhibited the stabilization but did not affect the c-Fos-zippered GHR tail-Jak2 interaction. Analysis by blue-native gel electrophoresis revealed high molecular-weight complexes containing both Jak2 and nonphosphorylated GHR tails, whereas Jak2-dissociated tails were highly phosphorylated and monomeric, implying that Jak2 detaches from its substrate upon phosphorylation. PMID:26859362

  14. The Complex of Ciliary Neurotrophic Factor-Ciliary Neurotrophic Factor Receptor α Up-Regulates Connexin43 and Intercellular Coupling in Astrocytes via the Janus Tyrosine Kinase/Signal Transducer and Activator of Transcription PathwayD⃞

    PubMed Central

    Ozog, Mark A.; Bernier, Suzanne M.; Bates, Dave C.; Chatterjee, Bishwanath; Lo, Cecilia W.; Naus, Christian C.G.

    2004-01-01

    Cytokines regulate numerous cell processes, including connexin expression and gap junctional coupling. In this study, we examined the effect of ciliary neurotrophic factor (CNTF) on connexin43 (Cx43) expression and intercellular coupling in astrocytes. Murine cortical astrocytes matured in vitro were treated with CNTF (20 ng/ml), soluble ciliary neurotrophic factor receptor α (CNTFRα) (200 ng/ml), or CNTF-CNTFRα. Although CNTF and CNTFRα alone had no effect on Cx43 expression, the heterodimer CNTF-CNTFRα significantly increased both Cx43 mRNA and protein levels. Cx43 immunostaining correlated with increased intercellular coupling as determined by dye transfer analysis. By using the pharmacological inhibitor α-cyano-(3,4-dihydroxy)-N-benzylcinnamide (AG490), the increase in Cx43 was found to be dependent on the Janus tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Immunocytochemical analysis revealed that CNTF-CNTFRα treatment produced nuclear localization of phosphorylated STAT3, whereas CNTF treatment alone did not. Transient transfection of constructs containing various sequences of the Cx43 promoter tagged to a LacZ reporter into ROS 17/2.8 cells confirmed that the promoter region between -838 to -1693 was deemed necessary for CNTF-CNTFRα to induce heightened expression. CNTF-CNTFRα did not alter Cx30 mRNA levels, suggesting selectivity of CNTF-CNTFRα for connexin signaling. Together in the presence of soluble receptor, CNTF activates the JAK/STAT pathway leading to enhanced Cx43 expression and intercellular coupling. PMID:15342787

  15. The C-terminal tail of polycystin-1 regulates complement factor B expression by signal transducer and activator of transcription 1.

    PubMed

    Wu, Ming; Chen, Meihan; Jing, Ying; Gu, Junhui; Mei, Shuqin; Yao, Qing; Zhou, Jie; Yang, Ming; Sun, Lijun; Wang, Wutao; Hu, Huimin; Wüthrich, Rudolf P; Mei, Changlin

    2016-06-01

    Inhibition of the overactivated alternative complement pathway in autosomal dominant polycystic kidney disease (ADPKD) retards disease progression in animal models; however, it remains unknown how complement factor B (CFB) is upregulated in ADPKD. Here, we showed that the overexpression of CFB in cystic kidneys is associated with increased JAK2/STAT1 activity and enhanced expression of the polycystin-1 C-terminal tail (PC1-CTT). Overexpression or blockage of STAT1 increased or decreased CFB expression and CFB promoter activity. Moreover, overexpression of PC1-CTT induced JAK2/STAT1 activation and CFB upregulation in renal tubular epithelial cells. Furthermore, PC1-CTT overexpression increased human CFB promoter activity, whereas dominant negative STAT1 plasmids or mutation of putative STAT1 responsive elements decreased PC1-CTT-induced CFB promoter activity. The effect of CFB on macrophage differentiation was tested on a mouse macrophage cell line. Bioactive CFB dose dependently promoted macrophage M2 phenotype conversion. In addition, conditioned media from renal epithelial cells promoted macrophage M2 phenotype conversion which was blocked by STAT1 inhibition in a dose-dependent manner. Conditioned media from PC1-CTT-transfected renal epithelial cells further promoted macrophage M2 phenotype conversion, which was suppressed by fludarabine or a CFB antibody. In addition, we show that NF-κB acts downstream of PC1-CTT and may partly mediate PC1-CTT-induced CFB expression. In conclusion, our study reveals possible mechanisms of CFB upregulation in ADPKD and a novel role of PC1-CTT in ADPKD-associated inflammation. Furthermore, our study suggests that targeting STAT1 may be a new strategy to prevent inflammation in the kidney of patients with ADPKD. PMID:26984954

  16. 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. PMID:26544779

  17. DNA G-quadruplex formation in response to remote downstream transcription activity: long-range sensing and signal transducing in DNA double helix.

    PubMed

    Zhang, Chao; Liu, Hong-He; Zheng, Ke-Wei; Hao, Yu-Hua; Tan, Zheng

    2013-08-01

    G-quadruplexes, four-stranded structures formed by Guanine-rich nucleic acids, are implicated in many physiological and pathological processes. G-quadruplex-forming sequences are abundant in genomic DNA, and G-quadruplexes have recently been shown to exist in the genome of mammalian cells. However, how G-quadruplexes are formed in the genomes remains largely unclear. Here, we show that G-quadruplex formation can be remotely induced by downstream transcription events that are thousands of base pairs away. The induced G-quadruplexes alter protein recognition and cause transcription termination at the local region. These results suggest that a G-quadruplex-forming sequence can serve as a sensor or receiver to sense remote DNA tracking activity in response to the propagation of mechanical torsion in a DNA double helix. We propose that the G-quadruplex formation may provide a mean for long-range sensing and communication between distal genomic locations to coordinate regulatory transactions in genomic DNA. PMID:23716646

  18. 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

  19. Fluidic Active Transducer for Electricity Generation

    NASA Astrophysics Data System (ADS)

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

    2015-10-01

    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.

  20. Fluidic Active Transducer for Electricity Generation.

    PubMed

    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

  1. 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

  2. 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. PMID:12408870

  3. Leptomeningeal Cells Transduce Peripheral Macrophages Inflammatory Signal to Microglia in Reponse to Porphyromonas gingivalis LPS

    PubMed Central

    Zhang, Xinwen; Ni, Junjun; Yu, Weixian; Nakanishi, Hiroshi

    2013-01-01

    We report here that the leptomeningeal cells transduce inflammatory signals from peripheral macrophages to brain-resident microglia in response to Porphyromonas gingivalis (P.g.) LPS. The expression of Toll-like receptor 2 (TLR2), TLR4, TNF-α, and inducible NO synthase was mainly detected in the gingival macrophages of chronic periodontitis patients. In in vitro studies, P.g. LPS induced the secretion of TNF-α and IL-1β from THP-1 human monocyte-like cell line and RAW264.7 mouse macrophages. Surprisingly, the mean mRNA levels of TNF-α and IL-1β in leptomeningeal cells after treatment with the conditioned medium from P.g. LPS-stimulated RAW264.7 macrophages were significantly higher than those after treatment with P.g. LPS alone. Furthermore, the mean mRNA levels of TNF-α and IL-1β in microglia after treatment with the conditioned medium from P.g. LPS-stimulated leptomeningeal cells were significantly higher than those after P.g. LPS alone. These observations suggest that leptomeninges serve as an important route for transducing inflammatory signals from macrophages to microglia by secretion of proinflammatory mediators during chronic periodontitis. Moreover, propolis significantly reduced the P.g. LPS-induced TNF-α and IL-1 β production by leptomeningeal cells through inhibiting the nuclear factor-κB signaling pathway. Together with the inhibitory effect on microglial activation, propolis may be beneficial in preventing neuroinflammation during chronic periodontitis. PMID:24363500

  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. Active and structural strain model for magnetostrictive transducers

    NASA Astrophysics Data System (ADS)

    Dapino, Marcelo J.; Smith, Ralph C.; Flatau, Alison B.

    1998-07-01

    We consider the modeling of strains generated by magnetostrictive materials in response to applied magnetic fields. The active or external component of the strain is due to the rotation of magnetic moments within the material to align with the applied field. This is characterized through consideration of the Jiles-Atherton mean field theory for ferromagnetic hysteresis in combination with a quadratic moment rotation model for magnetostriction. The second component of the strain reflects the passive or internal dynamics of the rod as it vibrates. This is modeled through force balancing which yields a wave equation with magnetostrictive inputs. The validity of a combined transducer model is illustrated through comparison with experimental data.

  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. Extracellular UDP-Glucose Activates P2Y14 Receptor and Induces Signal Transducer and Activator of Transcription 3 (STAT3) Tyr705 Phosphorylation and Binding to Hyaluronan Synthase 2 (HAS2) Promoter, Stimulating Hyaluronan Synthesis of Keratinocytes*

    PubMed Central

    Jokela, Tiina A.; Kärnä, Riikka; Makkonen, Katri M.; Laitinen, Jarmo T.; Tammi, Raija H.; Tammi, Markku I.

    2014-01-01

    Hyaluronan, a major matrix molecule in epidermis, is often increased by stimuli that enhance keratinocyte proliferation and migration. We found that small amounts of UDP-sugars were released from keratinocytes and that UDP-glucose (UDP-Glc) added into keratinocyte cultures induced a specific, rapid induction of hyaluronan synthase 2 (HAS2), and an increase of hyaluronan synthesis. The up-regulation of HAS2 was associated with JAK2 and ERK1/2 activation, and specific Tyr705 phosphorylation of transcription factor STAT3. Inhibition of JAK2, STAT3, or Gi-coupled receptors blocked the induction of HAS2 expression by UDP-Glc, the latter inhibitor suggesting that the signaling was triggered by the UDP-sugar receptor P2Y14. Chromatin immunoprecipitations demonstrated increased promoter binding of Tyr(P)705-STAT3 at the time of HAS2 induction. Interestingly, at the same time Ser(P)727-STAT3 binding to its response element regions in the HAS2 promoter was unchanged or decreased. UDP-Glc also stimulated keratinocyte migration, proliferation, and IL-8 expression, supporting a notion that UDP-Glc signals for epidermal inflammation, enhanced hyaluronan synthesis as an integral part of it. PMID:24847057

  8. Investigation of Pulser-transducer Matching Networks for Power Delivery Efficiency of Spread Spectrum Signals

    NASA Astrophysics Data System (ADS)

    Kybartas, Darius; Rodriguez, Alberto; Svilainis, Linas; Chaziachmetovas, Andrius

    Replacement of a single ultrasonic pulse to the spread spectrum signals allows higher energy without losing the bandwidth and it also means higher requirements for energy delivery to test object. Pulser efficiency for single pulse is not essential comparing to high energy signals. Pulser stress is large if power delivery efficiency to transducer is low. In narrowband case the solution is to use the matching network, but matching circuit effect will be different in case of wideband excitation. Aim of the investigation was to evaluate the matching techniques for spread spectrum signals.

  9. Biochemical characterization of the tandem HAMP domain from Natronomonas pharaonis as an intraprotein signal transducer.

    PubMed

    Natarajan, Janani; Schultz, Anita; Kurz, Ursula; Schultz, Joachim E

    2014-07-01

    Available structures of HAMP domains suggest rotation as one potential mechanism in intraprotein signal transduction. It has been proposed that in poly-HAMP modules the signal sign is inverted with each additional HAMP. We examined signal transduction through the HAMP tandem domain from the phototaxis transducer of the halophilic archaeon Natronomonas pharaonis in membrane-bound chimeras consisting of the Escherichia coli chemotaxis receptor for serine, Tsr, as an input and the mycobacterial adenylyl cyclase Rv3645 as an output domain, i.e. the basic chimera was 'Tsr-NpHAMP tandem-Rv3645 cyclase'. Neither of the NpHAMP units alone nor the NpHAMP tandem transduced a serine signal. After five targeted point mutations in the first α-helix of NpHAMP1 , the non-functional NpHAMP modules combined into a functional HAMP tandem. 1 mm serine significantly inhibited cyclase activity (-35%; IC50  = 30 μm) in disagreement with the structure-based predictions. Surprisingly, replacement of NpAS11 in the tandem by the respective AS1 from HAMPT sr resulted in signal inversion, i.e. serine activated cyclase (+129%; EC50  = 10 μm). Examination of 48 mutants of AS11 in the HAMP tandem including two residues of a putative N-terminal control cable identified five residues in NpAS11 which probably define different ground states of the output domain and thus affect the sign of signal output. The data question the predicted HAMP rotation as the predominant mechanism of intraprotein signal transduction and point to as yet unrecognized conformational motions of HAMP domains in intraprotein signaling. PMID:24863503

  10. Embedded ultrasonic transducers for active and passive concrete monitoring.

    PubMed

    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

  11. Dependence of photoacoustic signal generation on the transducer and source type

    NASA Astrophysics Data System (ADS)

    Bravo-Miranda, C. A.; González-Vega, A.; Gutiérrez-Juárez, G.

    2014-03-01

    The influence of size, geometry, temporal response of finite sensors and source geometry on the detected photoacoustic pressure is explored. We started considering the transducer simulated by a mesh of point-like sensors connected in parallel, which implies that appropriate modeling of pressure depends on the discretization size of the sensing surface. On the other hand, in analogy with the approach for the finite sensor, a finite source can be considered as a set of point like sources. We simulated the pressure produced by the linear, cylindrical and spherical source geometries, located at certain position over an axis perpendicular to the sensing surface. In order to simulate the photoacoustic signal, the computed pressure was convolved with the impulse response of two kind of commercial sensors: a low frequency transducer (3.5 MHz) and a high frequency transducer (125 MHz). Taking a fixed coordinate system we investigated the signal variations when the translational degree of freedom was modified. We found that simulated pressure generated by the different geometries using the proposed approach clearly differs from the point-like detection model.

  12. Wideband acoustic activation and detection of droplet vaporization events using a capacitive micromachined ultrasonic transducer.

    PubMed

    Novell, Anthony; Arena, Christopher B; Oralkan, Omer; Dayton, Paul A

    2016-06-01

    An ongoing challenge exists in understanding and optimizing the acoustic droplet vaporization (ADV) process to enhance contrast agent effectiveness for biomedical applications. Acoustic signatures from vaporization events can be identified and differentiated from microbubble or tissue signals based on their frequency content. The present study exploited the wide bandwidth of a 128-element capacitive micromachined ultrasonic transducer (CMUT) array for activation (8 MHz) and real-time imaging (1 MHz) of ADV events from droplets circulating in a tube. Compared to a commercial piezoelectric probe, the CMUT array provides a substantial increase of the contrast-to-noise ratio. PMID:27369143

  13. 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

  14. Complexes between nuclear factor-κB p65 and signal transducer and activator of transcription 3 are key actors in inducing activation-induced cytidine deaminase expression and immunoglobulin A production in CD40L plus interleukin-10-treated human blood B cells.

    PubMed

    Lafarge, S; Hamzeh-Cognasse, H; Richard, Y; Pozzetto, B; Cogné, M; Cognasse, F; Garraud, O

    2011-11-01

    The signal transducer and activator of transcription 3 (STAT3) transcription factor pathway plays an important role in many biological phenomena. STAT3 transcription is triggered by cytokine-associated signals. Here, we use isolated human B cells to analyse the role of STAT3 in interleukin (IL)-10 induced terminal B cell differentiation and in immunoglobulin (Ig)A production as a characteristic readout of IL-10 signalling. We identified optimal conditions for inducing in-vitro IgA production by purified blood naive B cells using IL-10 and soluble CD40L. We show that soluble CD40L consistently induces the phosphorylation of nuclear factor (NF)-κB p65 but not of STAT3, while IL-10 induces the phosphorylation of STAT3 but not of NF-κB p65. Interestingly, while soluble CD40L and IL-10 were synergistic in driving the terminal maturation of B cells into IgA-producing plasma cells, they did not co-operate earlier in the pathway with regard to the transcription factors NF-κB p65 or STAT3. Blocking either NF-κB p65 or STAT3 profoundly altered the production of IgA and mRNA for activation-induced cytidine deaminase (AID), an enzyme strictly necessary for Ig heavy chain recombination. Finally, the STAT3 pathway was directly activated by IL-10, while IL-6, the main cytokine otherwise known for activating the STAT3 pathway, did not appear to be involved in IL-10-induced-STAT3 activation. Our results suggest that STAT3 and NF-κB pathways co-operate in IgA production, with soluble CD40L rapidly activating the NF-κB pathway, probably rendering STAT3 probably more reactive to IL-10 signalling. This novel role for STAT3 in B cell development reveals a potential therapeutic or vaccine target for eliciting IgA humoral responses at mucosal interfaces. PMID:21985363

  15. Complexes between nuclear factor-κB p65 and signal transducer and activator of transcription 3 are key actors in inducing activation-induced cytidine deaminase expression and immunoglobulin A production in CD40L plus interleukin-10-treated human blood B cells

    PubMed Central

    Lafarge, S; Hamzeh-Cognasse, H; Richard, Y; Pozzetto, B; Cogné, M; Cognasse, F; Garraud, O

    2011-01-01

    The signal transducer and activator of transcription 3 (STAT3) transcription factor pathway plays an important role in many biological phenomena. STAT3 transcription is triggered by cytokine-associated signals. Here, we use isolated human B cells to analyse the role of STAT3 in interleukin (IL)-10 induced terminal B cell differentiation and in immunoglobulin (Ig)A production as a characteristic readout of IL-10 signalling. We identified optimal conditions for inducing in-vitro IgA production by purified blood naive B cells using IL-10 and soluble CD40L. We show that soluble CD40L consistently induces the phosphorylation of nuclear factor (NF)-κB p65 but not of STAT3, while IL-10 induces the phosphorylation of STAT3 but not of NF-κB p65. Interestingly, while soluble CD40L and IL-10 were synergistic in driving the terminal maturation of B cells into IgA-producing plasma cells, they did not co-operate earlier in the pathway with regard to the transcription factors NF-κB p65 or STAT3. Blocking either NF-κB p65 or STAT3 profoundly altered the production of IgA and mRNA for activation-induced cytidine deaminase (AID), an enzyme strictly necessary for Ig heavy chain recombination. Finally, the STAT3 pathway was directly activated by IL-10, while IL-6, the main cytokine otherwise known for activating the STAT3 pathway, did not appear to be involved in IL-10-induced-STAT3 activation. Our results suggest that STAT3 and NF-κB pathways co-operate in IgA production, with soluble CD40L rapidly activating the NF-κB pathway, probably rendering STAT3 probably more reactive to IL-10 signalling. This novel role for STAT3 in B cell development reveals a potential therapeutic or vaccine target for eliciting IgA humoral responses at mucosal interfaces. PMID:21985363

  16. Long-chain bases, phosphatidic acid, MAPKs, and reactive oxygen species as nodal signal transducers in stress responses in Arabidopsis

    PubMed Central

    Saucedo-García, Mariana; Gavilanes-Ruíz, Marina; Arce-Cervantes, Oscar

    2015-01-01

    Due to their sessile condition, plants have developed sensitive, fast, and effective ways to contend with environmental changes. These mechanisms operate as informational wires conforming extensive and intricate networks that are connected in several points. The responses are designed as pathways orchestrated by molecules that are transducers of protein and non-protein nature. Their chemical nature imposes selective features such as specificity, formation rate, and generation site to the informational routes. Enzymes such as mitogen-activated protein kinases and non-protein, smaller molecules, such as long-chain bases, phosphatidic acid, and reactive oxygen species are recurrent transducers in the pleiotropic responses to biotic and abiotic stresses in plants. In this review, we considered these four components as nodal points of converging signaling pathways that start from very diverse stimuli and evoke very different responses. These pleiotropic effects may be explained by the potentiality that every one of these four mediators can be expressed from different sources, cellular location, temporality, or magnitude. Here, we review recent advances in our understanding of the interplay of these four specific signaling components in Arabidopsis cells, with an emphasis on drought, cold and pathogen stresses. PMID:25763001

  17. Ultrasound (US) transducer of higher operating frequency detects photoacoustic (PA) signals due to the contrast in elastic property

    NASA Astrophysics Data System (ADS)

    Singh, Mayanglambam Suheshkumar; Jiang, Huabei

    2016-02-01

    We report our study that shows selection in operating frequency of US-transducer used for boundary detection of PA-signals, which result due to the contrast in elastic property distribution ( E ( r → ) ) in sample material other than that of optical absorption coefficient (μa). Studies were carried out, experimentally, in tissue-mimicking Agar phantoms employing acoustic resolution photoacoustic microscopy (AR-PAM) system as an imaging unit. In the experiments, various transducers having different operating frequencies, ranging from 1MHz to 50MHz, were employed for studying frequency response of the photoacoustic signals. The study shows that, for detecting photoacoustic signals due to the contrast in elastic property, ultrasound transducer with higher operating frequency (˜50MHz) is demanded.

  18. 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. PMID:26765039

  19. 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

  20. Activation and adaptation of transducer currents in turtle hair cells.

    PubMed

    Crawford, A C; Evans, M G; Fettiplace, R

    1989-12-01

    1. Transducer currents were recorded in turtle cochlear hair cells during mechanical stimulation of the hair bundle. The currents were measured under whole-cell voltage clamp in isolated cells that were firmly stuck to the floor of the recording chamber. 2. Stimuli were calibrated by projecting the image of the hair bundle onto a rapidly scanned 128 photodiode array. This technique showed that, while the cell body was immobilized, the tip of the bundle would follow faithfully the motion of an attached glass probe up to frequencies of more than 1 kHz. 3. The relationship between inward transducer current and bundle displacement was sigmoidal. Maximum currents of 200-400 pA were observed for deflections of the tip of the bundle of 0.5 microns, equivalent to rotating the bundle by about 5 deg. 4. In response to a step deflection of the bundle, the current developed with a time constant (about 0.4 ms for small stimuli) that decreased with the size of displacement. This suggests that the onset of the current was limited by the gating kinetics of the transduction channel. The onset time course was slowed about fourfold for a 20 degrees C drop in temperature. 5. For small maintained displacements, the current relaxed to about a quarter of the peak level with a time constant of 3-5 ms. This adaptation was associated with a shift of the current-displacement relationship in the direction of the stimulus. The rate and extent of adaptation were decreased by lowering external Ca2+. 6. Adaptation was strongly voltage sensitive, and was abolished at holding potentials positive to the reversal potential of the transducer current of about 0 mV. It was also diminished by loading cells with 10 mM of the Ca2+ chelator BAPTA. These observations suggest that adaptation may be partly controlled by influx of Ca2+ through the transducer channels. 7. Removal of adaptation produced asymmetric responses, with fast onsets but slow decays following return of the bundle to its resting position

  1. Simulation of transducer-couplant effects on broadband ultrasonic signals. [in nondestructive flaw evaluation and materials tests

    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 20to 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.

  2. Kit transduced signals counteract erythroid maturation by MAPK-dependent modulation of erythropoietin signaling and apoptosis induction in mouse fetal liver.

    PubMed

    Haas, N; Riedt, T; Labbaf, Z; Baßler, K; Gergis, D; Fröhlich, H; Gütgemann, I; Janzen, V; Schorle, H

    2015-05-01

    Signaling by the stem cell factor receptor Kit in hematopoietic stem and progenitor cells is functionally associated with the regulation of cellular proliferation, differentiation and survival. Expression of the receptor is downregulated upon terminal differentiation in most lineages, including red blood cell terminal maturation, suggesting that omission of Kit transduced signals is a prerequisite for the differentiation process to occur. However, the molecular mechanisms by which Kit signaling preserves the undifferentiated state of progenitor cells are not yet characterized in detail. In this study, we generated a mouse model for inducible expression of a Kit receptor carrying an activating mutation and studied its effects on fetal liver hematopoiesis. We found that sustained Kit signaling leads to expansion of erythroid precursors and interferes with terminal maturation beyond the erythroblast stage. Primary KIT(D816V) erythroblasts stimulated to differentiate fail to exit cell cycle and show elevated rates of apoptosis because of insufficient induction of survival factors. They further retain expression of progenitor cell associated factors c-Myc, c-Myb and GATA-2 and inefficiently upregulate erythroid transcription factors GATA-1, Klf1 and Tal1. In KIT(D816V) erythroblasts we found constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, elevated expression of the src kinase family member Lyn and impaired Akt activation in response to erythropoietin. We demonstrate that the block in differentiation is partially rescued by MAPK inhibition, and completely rescued by the multikinase inhibitor Dasatinib. These results show that a crosstalk between Kit and erythropoietin receptor signaling cascades exists and that continuous Kit signaling, partly mediated by the MAPK pathway, interferes with this crosstalk. PMID:25323585

  3. Kit transduced signals counteract erythroid maturation by MAPK-dependent modulation of erythropoietin signaling and apoptosis induction in mouse fetal liver

    PubMed Central

    Haas, N; Riedt, T; Labbaf, Z; Baßler, K; Gergis, D; Fröhlich, H; Gütgemann, I; Janzen, V; Schorle, H

    2015-01-01

    Signaling by the stem cell factor receptor Kit in hematopoietic stem and progenitor cells is functionally associated with the regulation of cellular proliferation, differentiation and survival. Expression of the receptor is downregulated upon terminal differentiation in most lineages, including red blood cell terminal maturation, suggesting that omission of Kit transduced signals is a prerequisite for the differentiation process to occur. However, the molecular mechanisms by which Kit signaling preserves the undifferentiated state of progenitor cells are not yet characterized in detail. In this study, we generated a mouse model for inducible expression of a Kit receptor carrying an activating mutation and studied its effects on fetal liver hematopoiesis. We found that sustained Kit signaling leads to expansion of erythroid precursors and interferes with terminal maturation beyond the erythroblast stage. Primary KITD816V erythroblasts stimulated to differentiate fail to exit cell cycle and show elevated rates of apoptosis because of insufficient induction of survival factors. They further retain expression of progenitor cell associated factors c-Myc, c-Myb and GATA-2 and inefficiently upregulate erythroid transcription factors GATA-1, Klf1 and Tal1. In KITD816V erythroblasts we found constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, elevated expression of the src kinase family member Lyn and impaired Akt activation in response to erythropoietin. We demonstrate that the block in differentiation is partially rescued by MAPK inhibition, and completely rescued by the multikinase inhibitor Dasatinib. These results show that a crosstalk between Kit and erythropoietin receptor signaling cascades exists and that continuous Kit signaling, partly mediated by the MAPK pathway, interferes with this crosstalk. PMID:25323585

  4. 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.

  5. Tolerance analysis of the pulse signal of a novel lateral deformable optical NEMS grating transducer

    NASA Astrophysics Data System (ADS)

    Wang, Chen; Bai, Jian; Wang, Kaiwei

    2015-08-01

    This paper discusses the pulse signal of a novel opto-mechanical zeroth-order grating transducer based on an anomalous diffraction phenomenon, Wood's type anomaly and its corresponding tolerance analysis. In this device, tiny changes in the displacement of the nanostructured grating elements lead to a dramatic increase or decrease of the optical reflection amplitude. With this special feature, this structure is ideal to measure very small displacement. Unexpectedly, the original sinusoidal signal of the device develops into a new signal form, i.e. pulse signal with the decrease of the air gap between two layers of gratings. Thus the sensitivity of the structure is improved 8 times higher, as the slope of the pulse signal, namely 2.5%/nm, i.e. 0.65dB/nm, is 8 times higher than that of the original signal form, namely 0.3%/nm, i.e. 0.03dB/nm. However, this device is very sensitive to parameters including wavelength, period, duty ratio, air gap as well as thickness of the gratings. Thus, in this paper the performance of the structures with different parameter settings is analyzed and optimized through rigorous coupled wavelength analysis (RCWA) and 3-D finite difference time domain (FDTD) method. All the calculated data enables us to apply the structure into fields required for different sensitivities with different values of grating parameters and thus broadens the further usage of such novel structure. In addition, a synthetic tolerance analysis of the pulse signal is conducted and indicates the possibility of achieving an actual device with the highest slope superior to 0.5%/nm is close to 85% and the possibility that the highest slope of an actual device falls in the interval ranging from 1.0%/nm to 2.0%/nm is 64%. All the simulated data enables us to get a better understanding of the tolerance of the pulse signal and a guidance of successful realization of an actual device.

  6. 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.

  7. A small and lightweight three-channel signal-conditioning unit for strain-gage transducers: a technical note.

    PubMed

    Sanders, J E; Smith, L M; Spelman, F A

    1995-10-01

    A small and lightweight signal conditioning unit for use with strain-gage transducers is described. The unit provides bridge-balancing, amplification, and filtering for three channels of Wheatstone bridge circuits. The electronics are housed with a 4.5 cm x 3.0 cm x 2.5 cm box that allows connection to a transducer and to a cable that extends to power supplies and a data storage facility. Evaluation tests showed the signal conditioning unit had low noise (0.356 microV, peak-to-peak, referenced to input) with crosstalk between channels of less than 0.02% of the peak-to-peak input signal. The signal conditioning unit has application in biomechanics where a small and lightweight unit is needed; for example, skin/support interface stress measurements in prosthetics and orthotics research. PMID:8592292

  8. 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. PMID:24788809

  9. Air-Coupled Piezoelectric Transducers with Active Polypropylene Foam Matching Layers

    PubMed Central

    Gómez Álvarez-Arenas, Tomás E.

    2013-01-01

    This work presents the design, construction and characterization of air-coupled piezoelectric transducers using 1–3 connectivity piezocomposite disks with a stack of matching layers being the outer one an active quarter wavelength layer made of polypropylene foam ferroelectret film. This kind of material has shown a stable piezoelectric response together with a very low acoustic impedance (<0.1 MRayl). These features make them a suitable candidate for the dual use or function proposed here: impedance matching layer and active material for air-coupled transduction. The transducer centre frequency is determined by the λ/4 resonance of the polypropylene foam ferroelectret film (0.35 MHz), then, the rest of the transducer components (piezocomposite disk and passive intermediate matching layers) are all tuned to this frequency. The transducer has been tested in several working modes including pulse-echo and pitch-catch as well as wide and narrow band excitation. The performance of the proposed novel transducer is compared with that of a conventional air-coupled transducers operating in a similar frequency range. PMID:23666129

  10. 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.

  11. Silica Nanoparticles Target a Wnt Signal Transducer for Degradation and Impair Embryonic Development in Zebrafish.

    PubMed

    Yi, Hongyang; Wang, Zhuyao; Li, Xiaojiao; Yin, Min; Wang, Lihua; Aldalbahi, Ali; El-Sayed, Nahed Nasser; Wang, Hui; Chen, Nan; Fan, Chunhai; Song, Haiyun

    2016-01-01

    Many types of biocompatible nanomaterials have proven of low cytotoxicity and hold great promise for various applications in nanomedicine. Whereas they generally do not cause apparent organ toxicity or tissue damage in adult animals, it is yet to determine their biological consequences in more general contexts. In this study, we investigate how silica nanoparticles (NPs) affect cellular activities and functions under several physiological or pathological conditions. Although silica NPs are generally regarded as "inert" nanocarriers and widely employed in biomedical studies, we find that they actively affect Wnt signaling in various types of cell lines, diminishing its anti-adipogenic effect in preadipocytes and pro-invasive effect in breast cancer cells, and more significantly, impair Wnt-regulated embryonic development in Zebrafish. We further demonstrate that intracellular silica NPs block Wnt signal transduction in a way resembling signaling molecules. Specifically, silica NPs target the Dvl protein, a key component of Wnt signaling cascade, for lysosomal degradation. As Wnt signaling play significant roles in embryonic development and adipogenesis, the observed physiological effects beyond toxicity imply potential risk of obesity, or developmental defects in somitogenesis and osteogenesis upon exposure to silica NPs. In addition, given the clinical implications of Wnt signaling in tumorigenesis and cancer metastasis, our work also establishes for the first time a molecular link between nanomaterials and the Wnt signaling pathway, which opens new door for novel applications of unmodified silica NPs in targeted therapy for cancers and other critical illness. PMID:27570552

  12. Silica Nanoparticles Target a Wnt Signal Transducer for Degradation and Impair Embryonic Development in Zebrafish

    PubMed Central

    Yi, Hongyang; Wang, Zhuyao; Li, Xiaojiao; Yin, Min; Wang, Lihua; Aldalbahi, Ali; El-Sayed, Nahed Nasser; Wang, Hui; Chen, Nan; Fan, Chunhai; Song, Haiyun

    2016-01-01

    Many types of biocompatible nanomaterials have proven of low cytotoxicity and hold great promise for various applications in nanomedicine. Whereas they generally do not cause apparent organ toxicity or tissue damage in adult animals, it is yet to determine their biological consequences in more general contexts. In this study, we investigate how silica nanoparticles (NPs) affect cellular activities and functions under several physiological or pathological conditions. Although silica NPs are generally regarded as “inert” nanocarriers and widely employed in biomedical studies, we find that they actively affect Wnt signaling in various types of cell lines, diminishing its anti-adipogenic effect in preadipocytes and pro-invasive effect in breast cancer cells, and more significantly, impair Wnt-regulated embryonic development in Zebrafish. We further demonstrate that intracellular silica NPs block Wnt signal transduction in a way resembling signaling molecules. Specifically, silica NPs target the Dvl protein, a key component of Wnt signaling cascade, for lysosomal degradation. As Wnt signaling play significant roles in embryonic development and adipogenesis, the observed physiological effects beyond toxicity imply potential risk of obesity, or developmental defects in somitogenesis and osteogenesis upon exposure to silica NPs. In addition, given the clinical implications of Wnt signaling in tumorigenesis and cancer metastasis, our work also establishes for the first time a molecular link between nanomaterials and the Wnt signaling pathway, which opens new door for novel applications of unmodified silica NPs in targeted therapy for cancers and other critical illness. PMID:27570552

  13. 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.

  14. The consequences of selective inhibition of signal transducer and activator of transcription 3 (STAT3) tyrosine705 phosphorylation by phosphopeptide mimetic prodrugs targeting the Src homology 2 (SH2) domain.

    PubMed

    McMurray, John S; Mandal, Pijus K; Liao, Warren S; Klostergaard, Jim; Robertson, Fredika M

    2012-10-01

    Herein we review our progress on the development of phosphopeptide-based prodrugs targeting the SH2 domain of STAT3 to prevent recruitment to cytokine and growth factor receptors, activation, nuclear translocation and transcription of genes involved in cancer. We developed high affinity phosphopeptides (K I = 46-200 nM). Corresponding prodrugs inhibited constitutive and IL-6 induced Tyr705 phosphorylation at 0.5-1 μM in a variety of human cancer cell lines. They were not cytotoxic at 5 μM in vitro but they inhibited tumor growth in a human xenograft breast cancer model in mice, accompanied by reduced VEGF expression and angiogenesis. PMID:24058783

  15. Regulation of the Interferon regulatory factor-8 (IRF-8) Tumor Suppressor Gene by the Signal Transducer and Activator of Transcription 5 (STAT5) Transcription Factor in Chronic Myeloid Leukemia*

    PubMed Central

    Waight, Jeremy D.; Banik, Debarati; Griffiths, Elizabeth A.; Nemeth, Michael J.; Abrams, Scott I.

    2014-01-01

    Tyrosine kinase inhibitors such as imatinib can effectively target the BCR-ABL oncoprotein in a majority of patients with chronic myeloid leukemia (CML). Unfortunately, some patients are resistant primarily to imatinib and others develop drug resistance, prompting interest in the discovery of new drug targets. Although much of this resistance can be explained by the presence of mutations within the tyrosine kinase domain of BCR-ABL, such mutations are not universally identified. Interferon regulatory factor-8 (IRF-8) is a transcription factor that is essential for myelopoiesis. Depressed IRF-8 levels are observed in a majority of CML patients and Irf-8−/− mice exhibit a CML-like disease. The underlying mechanisms of IRF-8 loss in CML are unknown. We hypothesized that BCR-ABL suppresses transcription of IRF-8 through STAT5, a proximal BCR-ABL target. Treatment of primary cells from newly diagnosed CML patients in chronic phase as well as BCR-ABL+ cell lines with imatinib increased IRF-8 transcription. Furthermore, IRF-8 expression in cell line models was necessary for imatinib-induced antitumor responses. We have demonstrated that IRF-8 is a direct target of STAT5 and that silencing of STAT5 induced IRF-8 expression. Conversely, activating STAT5 suppressed IRF-8 transcription. Finally, we showed that STAT5 blockade using a recently discovered antagonist increased IRF-8 expression in patient samples. These data reveal a previously unrecognized BCR-ABL-STAT5-IRF-8 network, which widens the repertoire of potentially new anti-CML targets. PMID:24753251

  16. Evidence that phospholipid turnover is the signal transducing system coupled to serotonin-S2 receptor sites

    SciTech Connect

    de Chaffoy de Courcelles, D.; Leysen, J.E.; De Clerck, F.; Van Belle, H.; Janssen, P.A.

    1985-06-25

    Upon stimulation with serotonin of washed human platelets prelabeled with (/sup 32/P)orthophosphate, the authors found an approximately 250% increase in (/sup 32/P)phosphatidic acid (PA) formation, a small decrease in (/sup 32/P)phosphatidylinositol 4,5-bisphosphate, and a concomitant increase in (/sup 32/P)phosphatidylinositol 4-phosphate. Using (/sup 3/H)arachidonate for prelabeling, (/sup 3/H)diacylglycerol accumulated transiently at 10 s after addition of the agonist, (/sup 3/H)PA increased but to a lower extent compared to /sup 32/P-labeled lipid, and the formation of both (/sup 3/H)polyphosphoinositides increased. The serotonin-induced dose-dependent changes in (/sup 32/P)PA correlate with its effect on the changes in slope of aggregation of platelets. The potency of 13 drugs to antagonize the serotonin-induced PA formation closely corresponds to both their potency to inhibit platelet aggregation and their binding affinity for serotonin-S2 receptor sites. It is suggested that at least part of the signal transducing system following activation of the serotonin-S2 receptors involves phospholipase C catalyzed inositol lipid breakdown yielding diacylglycerol which is subsequently phosphorylated to PA.

  17. Spherically shaped active transducer based on proton-irradiated vinylidene fluoride-trifluoroethylene 70/30 mol % copolymer

    SciTech Connect

    Lau, S.T.; Chan, H.L.W.; Choy, C.L.; Cheung, W.Y.; Wong, S.P.

    2006-05-15

    Spherically shaped active transducers using proton-irradiated vinylidene fluoride-trifluoroethylene 70/30 mol % copolymer films as the active elements are described. The copolymer films prepared by hot compression molding were irradiated with a high energy proton over a broad dose range (20-250 Mrad). The electrostrictive and piezoelectric responses of the copolymer have been characterized before subsequent transducer fabrication. The performances of the focused transducers constructed with a 4 mm aperture size and epoxy backing were evaluated under dc bias voltages. The transducers with focal lengths of 17.4-19.0 mm and a center frequency of 19 MHz display a broad bandwidth up to 94%. Besides, the transmitting output of the transducers increases with the dc bias voltage. For the copolymer active element irradiated at a proton dose of 107 Mrad, the transducer shows the highest transmitting voltage response of 1.34 kPa/V.

  18. Coincident signals from GPCRs and receptor tyrosine kinases are uniquely transduced by PI3Kβ in myeloid cells.

    PubMed

    Houslay, Daniel M; Anderson, Karen E; Chessa, Tamara; Kulkarni, Suhasini; Fritsch, Ralph; Downward, Julian; Backer, Jonathan M; Stephens, Len R; Hawkins, Phillip T

    2016-01-01

    Class I phosphoinositide 3-kinases (PI3Ks) catalyze production of the lipid messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3), which plays a central role in a complex signaling network regulating cell growth, survival, and movement. This network is overactivated in cancer and inflammation, and there is interest in determining the PI3K catalytic subunit (p110α, p110β, p110γ, or p110δ) that should be targeted in different therapeutic contexts. Previous studies have defined unique regulatory inputs for p110β, including direct interaction with Gβγ subunits, Rac, and Rab5. We generated mice with knock-in mutations of p110β that selectively blocked the interaction with Gβγ and investigated its contribution to the PI3K isoform dependency of receptor tyrosine kinase (RTK) and G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) responses in primary macrophages and neutrophils. We discovered a unique role for p110β in supporting synergistic PIP3 formation in response to the coactivation of macrophages by macrophage colony-stimulating factor (M-CSF) and the complement protein C5a. In contrast, we found partially redundant roles for p110α, p110β, and p110δ downstream of M-CSF alone and a nonredundant role for p110γ downstream of C5a alone. This role for p110β completely depended on direct interaction with Gβγ, suggesting that p110β transduces GPCR signals in the context of coincident activation by an RTK. The p110β-Gβγ interaction was also required for neutrophils to generate reactive oxygen species in response to the Fcγ receptor-dependent recognition of immune complexes and for their β2 integrin-mediated adhesion to fibrinogen or poly-RGD+, directly implicating heterotrimeric G proteins in these two responses. PMID:27531651

  19. 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.

  20. Blocked force measurement of an electro-active paper actuator using a cantilevered force transducer

    NASA Astrophysics Data System (ADS)

    Yun, Gyu-young; Kim, Heung Soo; Kim, Jaehwan

    2008-04-01

    The blocked force of an electro-active paper (EAPap) actuator was measured by a custom-built force transducer. The tip deflection of the force transducer was measured and converted into force using a simple Euler beam model. Since the blocked force is the maximum force generated at the tip of a bending actuator without displacement, the blocked force was found from the measured force of the transducer by extrapolating it. The force transducer was made from a thin steel cantilever beam and calibrated using a linear stage and a micro-balance. The measured maximum free bending displacement of the EAPap actuator was 4.4 mm and the blocked force was 224 µN under 350 V mm-1 AC electric field and 33 µN under DC electric field with the same field strength. When an AC electric field was applied to the actuator, the generated blocked force of the EAPap was about 700% larger than that caused by DC excitation. The proposed blocked force measurement is accurate down to a micro-Newton resolution under DC as well as AC electric fields.

  1. 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.

  2. 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.

  3. Does a Common Pathway Transduce Symbiotic Signals in Plant-Microbe Interactions?

    PubMed

    Genre, Andrea; Russo, Giulia

    2016-01-01

    Recent years have witnessed major advances in our knowledge of plant mutualistic symbioses such as the rhizobium-legume symbiosis (RLS) and arbuscular mycorrhizas (AM). Some of these findings caused the revision of longstanding hypotheses, but one of the most solid theories is that a conserved set of plant proteins rules the transduction of symbiotic signals from beneficial glomeromycetes and rhizobia in a so-called common symbiotic pathway (CSP). Nevertheless, the picture still misses several elements, and a few crucial points remain unclear. How does one common pathway discriminate between - at least - two symbionts? Can we exclude that microbes other than AM fungi and rhizobia also use this pathway to communicate with their host plants? We here discuss the possibility that our current view is biased by a long-lasting focus on legumes, whose ability to develop both AM and RLS is an exception among plants and a recent innovation in their evolution; investigations in non-legumes are starting to place legume symbiotic signaling in a broader perspective. Furthermore, recent studies suggest that CSP proteins act in a wider scenario of symbiotic and non-symbiotic signaling. Overall, evidence is accumulating in favor of distinct activities for CSP proteins in AM and RLS, depending on the molecular and cellular context where they act. PMID:26909085

  4. Melanopsin-Expressing Amphioxus Photoreceptors Transduce Light via a Phospholipase C Signaling Cascade

    PubMed Central

    Angueyra, Juan Manuel; Pulido, Camila; Malagón, Gerardo; Nasi, Enrico; Gomez, Maria del Pilar

    2012-01-01

    Melanopsin, the receptor molecule that underlies light sensitivity in mammalian ‘circadian’ receptors, is homologous to invertebrate rhodopsins and has been proposed to operate via a similar signaling pathway. Its downstream effectors, however, remain elusive. Melanopsin also expresses in two distinct light-sensitive cell types in the neural tube of amphioxus. This organism is the most basal extant chordate and can help outline the evolutionary history of different photoreceptor lineages and their transduction mechanisms; moreover, isolated amphioxus photoreceptors offer unique advantages, because they are unambiguously identifiable and amenable to single-cell physiological assays. In the present study whole-cell patch clamp recording, pharmacological manipulations, and immunodetection were utilized to investigate light transduction in amphioxus photoreceptors. A Gq was identified and selectively localized to the photosensitive microvillar membrane, while the pivotal role of phospholipase C was established pharmacologically. The photocurrent was profoundly depressed by IP3 receptor antagonists, highlighting the importance of IP3 receptors in light signaling. By contrast, surrogates of diacylglycerol (DAG), as well as poly-unsaturated fatty acids failed to activate a membrane conductance or to alter the light response. The results strengthen the notion that calcium released from the ER via IP3-sensitive channels may fulfill a key role in conveying - directly or indirectly - the melanopsin-initiated light signal to the photoconductance; moreover, they challenge the dogma that microvillar photoreceptors and phoshoinositide-based light transduction are a prerogative of invertebrate eyes. PMID:22235344

  5. Does a Common Pathway Transduce Symbiotic Signals in Plant–Microbe Interactions?

    PubMed Central

    Genre, Andrea; Russo, Giulia

    2016-01-01

    Recent years have witnessed major advances in our knowledge of plant mutualistic symbioses such as the rhizobium-legume symbiosis (RLS) and arbuscular mycorrhizas (AM). Some of these findings caused the revision of longstanding hypotheses, but one of the most solid theories is that a conserved set of plant proteins rules the transduction of symbiotic signals from beneficial glomeromycetes and rhizobia in a so-called common symbiotic pathway (CSP). Nevertheless, the picture still misses several elements, and a few crucial points remain unclear. How does one common pathway discriminate between – at least – two symbionts? Can we exclude that microbes other than AM fungi and rhizobia also use this pathway to communicate with their host plants? We here discuss the possibility that our current view is biased by a long-lasting focus on legumes, whose ability to develop both AM and RLS is an exception among plants and a recent innovation in their evolution; investigations in non-legumes are starting to place legume symbiotic signaling in a broader perspective. Furthermore, recent studies suggest that CSP proteins act in a wider scenario of symbiotic and non-symbiotic signaling. Overall, evidence is accumulating in favor of distinct activities for CSP proteins in AM and RLS, depending on the molecular and cellular context where they act. PMID:26909085

  6. Comparison of bidirectional power electronics with unidirectional topologies using active discharging circuits for feeding DEAP transducer

    NASA Astrophysics Data System (ADS)

    Hoffstadt, Thorben; Maas, Jürgen

    2015-04-01

    To enable a continuous operation of a DEAP transducer, the feeding power electronics must provide the capability to charge and discharge the transducer to enable a continuous voltage adjustment. While in case of energy harvesting applications a bidirectional power electronics is mandatory, for actuator applications also unidirectional power electronics with active discharging circuits can be used. Thus, in this contribution a bidirectional flyback-converter is compared to a unidirectional with different discharging circuits. For this purpose, the design of a resistive and an inductive-resistive discharging circuit is proposed, that are connected in parallel to the DEAP and activated when required. Modulation schemes for both discharging circuits are derived that enable a continuous voltage control. Based on realized prototypes of the investigated topologies the different converters are finally compared to each other.

  7. REPRODUCIBILITY OF INTRA-ABDOMINAL PRESSURE MEASURED DURING PHYSICAL ACTIVITIES VIA A WIRELESS VAGINAL TRANSDUCER

    PubMed Central

    Egger, Marlene J.; Hamad, Nadia M.; Hitchcock, Robert W.; Coleman, Tanner J.; Shaw, Janet M.; Hsu, Yvonne; Nygaard, Ingrid E.

    2014-01-01

    Aims In the urodynamics laboratory setting, a wireless pressure transducer, developed to facilitate research exploring intra-abdominal pressure (IAP) and pelvic floor disorders, was highly accurate. We aimed to study reproducibility of IAP measured using this transducer in women during activities performed in an exercise science laboratory. Methods Fifty seven women (mean ± SD: age 30.4 ±9.3 years; body mass index=22.4 ± 2.68 kg/m2) completed two standardized activity sessions using the same transducer at least three days apart. Pressure data for 31 activities were transmitted wirelessly to a base station and analyzed for mean net maximal IAP, area under the curve (AUC) and first moment of the area (FMA.) Activities included typical exercises, lifting 13.6 to 18.2 kg, and simulated household tasks. Analysis for test-retest reliability included Bland-Altman plots with absolute limits of agreement (ALOA), Wilcoxon signed rank tests to assess significant differences between sessions, intraclass correlations, and kappa statistics to assess inter-session agreement in highest vs. other quintiles of maximal IAP. Results Few activities exhibited significant differences between sessions in maximal IAP, or in AUC and FMA values. For 13 activities, the agreement between repeat measures of maximal IAP was better than ± 10 cm H20; for 20 activities, better than ± 15 cm H20. ALOA increased with mean IAP. The highest quintile of IAP demonstrated fair/substantial agreement between sessions in 25 of 30 activities. Conclusion Reproducibility of IAP depends on the activity undertaken. Interventions geared towards lowering IAP should account for this, and maximize efforts to improve IAP reproducibility. PMID:25730430

  8. Neuron-derived orphan receptor 1 transduces survival signals in neuronal cells in response to hypoxia-induced apoptotic insults.

    PubMed

    Chio, Chung-Ching; Wei, Li; Chen, Tyng Guey; Lin, Chien-Min; Shieh, Ja-Ping; Yeh, Poh-Shiow; Chen, Ruei-Ming

    2016-06-01

    OBJECT Hypoxia can induce cell death or trigger adaptive mechanisms to guarantee cell survival. Neuron-derived orphan receptor 1 (NOR-1) works as an early-response protein in response to a variety of environmental stresses. In this study, the authors evaluated the roles of NOR-1 in hypoxia-induced neuronal insults. METHODS Neuro-2a cells were exposed to oxygen/glucose deprivation (OGD). Cell viability, cell morphology, cas-pase-3 activity, DNA fragmentation, and cell apoptosis were assayed to determine the mechanisms of OGD-induced neuronal insults. RNA and protein analyses were carried out to evaluate the effects of OGD on expressions of NOR-1, cAMP response element-binding (CREB), and cellular inhibitor of apoptosis protein 2 (cIAP2) genes. Translations of these gene expressions were knocked down using RNA interference. Mice subjected to traumatic brain injury (TBI) and NOR-1 was immunodetected. RESULTS Exposure of neuro-2a cells to OGD decreased cell viability in a time-dependent manner. Additionally, OGD led to cell shrinkage, DNA fragmentation, and cell apoptosis. In parallel, treatment of neuro-2a cells with OGD time dependently increased cellular NOR-1 mRNA and protein expressions. Interestingly, administration of TBI also augmented NOR-1 levels in the impacted regions of mice. As to the mechanism, exposure to OGD increased nuclear levels of the transcription factor CREB protein. Downregulating CREB expression using RNA interference simultaneously inhibited OGD-induced NOR-1 mRNA expression. Also, levels of cIAP2 mRNA and protein in neuro-2a cells were augmented by OGD. After reducing cIAP2 translation, OGD-induced cell death was reduced. Sequentially, application of NOR-1 small interfering RNA to neuro-2a cells significantly inhibited OGD-induced cIAP2 mRNA expression and concurrently alleviated hypoxia-induced alterations in cell viability, caspase-3 activation, DNA damage, and cell apoptosis. CONCLUSIONS This study shows that NOR-1 can transduce survival

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

    NASA Astrophysics Data System (ADS)

    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 modern 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. Intra-abdominal pressures during activity in women using an intra-vaginal pressure transducer.

    PubMed

    Shaw, Janet M; Hamad, Nadia M; Coleman, Tanner J; Egger, Marlene J; Hsu, Yvonne; Hitchcock, Robert; Nygaard, Ingrid E

    2014-01-01

    Strenuous physical activity has been linked to pelvic floor disorders in women. Using a novel wireless intra-vaginal pressure transducer, intra-abdominal pressure was measured during diverse activities in a laboratory. Fifty-seven women performed a prescribed protocol using the intra-vaginal pressure transducer. We calculated maximal, area under the curve and first moment of the area intra-abdominal pressure for each activity. Planned comparisons of pressure were made between levels of walking and cycling and between activities with reported high pressure in the literature. Findings indicate variability in intra-abdominal pressure amongst individuals doing the same activity, especially in activities that required regulation of effort. There were statistically significant differences in maximal pressure between levels of walking, cycling and high pressure activities. Results for area under the curve and first moment of the area were not always consistent with maximal pressure. Coughing had the highest maximal pressure, but had lower area under the curve and first moment of the area compared to most activities. Our data reflect novel findings of maximal, area under the curve and first moment of the area measures of intra-abdominal pressure, which may have clinical relevance for how physical activity relates to pelvic floor dysfunction. PMID:24575741

  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. Phase insensitive acoustoelectric transducer

    NASA Technical Reports Server (NTRS)

    Heyman, J. S.

    1978-01-01

    Conventional ultrasonic transducers transform acoustic waves into electrical signals preserving phase and amplitude information. When the acoustic wavelength is significantly smaller than the transducer diameter, severe phase modulation of the electrical signal can occur. This results in anomalous attenuation measurements, background noise in nondestructive evaluation, and in general complicates data interpretation. This article describes and evaluates a phase-insensitive transducer based on the acoustoelectric effect. Theory of operation of the acoustoelectric transducer (AET) is discussed, and some optimization procedures outlined for its use. Directivity data for the AET are contrasted with a conventional piezoelectric transducer. In addition, transmission scanning data of phantom flaws in metal plates are presented for both transducers and demonstrate a significant improvement in resolution with the AET.

  13. Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis.

    PubMed

    Hainzl, Eva; Stockinger, Silvia; Rauch, Isabella; Heider, Susanne; Berry, David; Lassnig, Caroline; Schwab, Clarissa; Rosebrock, Felix; Milinovich, Gabriel; Schlederer, Michaela; Wagner, Michael; Schleper, Christa; Loy, Alexander; Urich, Tim; Kenner, Lukas; Han, Xiaonan; Decker, Thomas; Strobl, Birgit; Müller, Mathias

    2015-11-15

    In the intestinal tract, IL-22 activates STAT3 to promote intestinal epithelial cell (IEC) homeostasis and tissue healing. The mechanism has remained obscure, but we demonstrate that IL-22 acts via tyrosine kinase 2 (Tyk2), a member of the Jak family. Using a mouse model for colitis, we show that Tyk2 deficiency is associated with an altered composition of the gut microbiota and exacerbates inflammatory bowel disease. Colitic Tyk2(-/-) mice have less p-STAT3 in colon tissue and their IECs proliferate less efficiently. Tyk2-deficient primary IECs show reduced p-STAT3 in response to IL-22 stimulation, and expression of IL-22-STAT3 target genes is reduced in IECs from healthy and colitic Tyk2(-/-) mice. Experiments with conditional Tyk2(-/-) mice reveal that IEC-specific depletion of Tyk2 aggravates colitis. Disease symptoms can be alleviated by administering high doses of rIL-22-Fc, indicating that Tyk2 deficiency can be rescued via the IL-22 receptor complex. The pivotal function of Tyk2 in IL-22-dependent colitis was confirmed in Citrobacter rodentium-induced disease. Thus, Tyk2 protects against acute colitis in part by amplifying inflammation-induced epithelial IL-22 signaling to STAT3. PMID:26432894

  14. Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis

    PubMed Central

    Hainzl, Eva; Rauch, Isabella; Heider, Susanne; Berry, David; Lassnig, Caroline; Schwab, Clarissa; Rosebrock, Felix; Milinovich, Gabriel; Schlederer, Michaela; Wagner, Michael; Schleper, Christa; Loy, Alexander; Urich, Tim; Kenner, Lukas; Han, Xiaonan; Decker, Thomas; Strobl, Birgit

    2015-01-01

    In the intestinal tract, IL-22 activates STAT3 to promote intestinal epithelial cell (IEC) homeostasis and tissue healing. The mechanism has remained obscure, but we demonstrate that IL-22 acts via tyrosine kinase 2 (Tyk2), a member of the Jak family. Using a mouse model for colitis, we show that Tyk2 deficiency is associated with an altered composition of the gut microbiota and exacerbates inflammatory bowel disease. Colitic Tyk2−/− mice have less p-STAT3 in colon tissue and their IECs proliferate less efficiently. Tyk2-deficient primary IECs show reduced p-STAT3 in response to IL-22 stimulation, and expression of IL-22–STAT3 target genes is reduced in IECs from healthy and colitic Tyk2−/− mice. Experiments with conditional Tyk2−/− mice reveal that IEC-specific depletion of Tyk2 aggravates colitis. Disease symptoms can be alleviated by administering high doses of rIL-22–Fc, indicating that Tyk2 deficiency can be rescued via the IL-22 receptor complex. The pivotal function of Tyk2 in IL-22–dependent colitis was confirmed in Citrobacter rodentium–induced disease. Thus, Tyk2 protects against acute colitis in part by amplifying inflammation-induced epithelial IL-22 signaling to STAT3. PMID:26432894

  15. Charged solvatochromic dyes as signal transducers in pH independent fluorescent and colorimetric ion selective nanosensors.

    PubMed

    Xie, Xiaojiang; Gutiérrez, Agustín; Trofimov, Valentin; Szilagyi, Istvan; Soldati, Thierry; Bakker, Eric

    2015-10-01

    Ionophore-based ion selective optical nanosensors that operate independently of the sample pH are developed here by the use of electrically charged solvatochromic dyes as signal transducers. A series of dye molecules with a D-π-A structure was synthesized and characterized in various solvents and incorporated into ion selective nanospheres for K(+), Na(+), and H(+). Since dye leakage was greatly suppressed when the solvatochromic dyes were encapsulated in the nanosphere core, ion sensing nanospheres were explored for cellular ion imaging in Dictyostelium discoideum live cells but spontaneous dye loss resulted in undesired staining of cells. The in vitro analysis of potassium in human plasma was successfully demonstrated with this approach. A theoretical model was developed for the response of the ion selective nanosensors containing charged solvatochromic dyes. The nanosensors exhibited a tunable response range, high sensitivity, and good stability. PMID:26352133

  16. Signal focusing through active transport

    NASA Astrophysics Data System (ADS)

    Godec, Aljaž; Metzler, Ralf

    2015-07-01

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

  17. Energy-Recycling Semi-Active Vibration Suppression Experiment of a Truss with Piezoelectric Transducer

    NASA Astrophysics Data System (ADS)

    Makihara, K.

    2002-01-01

    inherent performance in damping is enhanced. Several semi-active vibration suppression approaches have been proposed based on variable-stiffness members, variable-friction devices, or variable-viscosity dampers, and the performance of each of these systems has been studied. The semi-active approach exploits passive energy-dissipation mechanisms, and supplies the system with no additional energy. Semi-active vibration suppression thus ensures that the system is always stable. This is its advantage. However, its performance in vibration suppression is usually inferior to active vibration suppression. have proposed collection of the energy taken from a vibrating system in suppressing its vibration. Using the collected energy to more quickly suppress the vibration is an attractive possibility. Additional energy is still not supplied to the system, and the vibration energy is finally dissipated. Therefore, this is a kind of semi-active approach, and retains the quality of that the system with it is always stable. method of energy-recycling semi-active vibration suppression is described and its performance is demonstrated by an experiment. A five bay truss beam with a piezoelectric transducer was used, and a simple electric circuit with switches was connected to the transducers. Then the switches were controlled by a processor so that the vibration was quickly suppressed by exploiting the collected electric energy. The results of the experiment demonstrated that the performance in vibration suppression of energy-recycling semi-active vibration suppression with actual hardware is much better than that of a traditional semi-active control. The effects of some non-ideal characteristics of real hardware on the performance in vibration suppression are also investigated.

  18. 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.

  19. Deletion of Interleukin-6 Signal Transducer gp130 in Small Sensory Neurons Attenuates Mechanonociception and Down-Regulates TRPA1 Expression

    PubMed Central

    Malsch, Philipp; Andratsch, Manfred; Vogl, Christian; Link, Andrea S.; Alzheimer, Christian; Brierley, Stuart M.; Hughes, Patrick A.

    2014-01-01

    Glycoprotein 130 (gp130) is the signal transducing receptor subunit for cytokines of the interleukin-6 (IL-6) family, and it is expressed in a multitude of cell types of the immune and nervous system. IL-6-like cytokines are not only key regulators of innate immunity and inflammation but are also essential factors for the differentiation and development of the somatosensory system. Mice with a null mutation of gp130 in primary nociceptive afferents (SNS-gp130−/−) are largely protected from hypersensitivity to mechanical stimuli in mouse models of pathological pain. Therefore, we set out to investigate how neuronal gp130 regulates mechanonociception. SNS-gp130−/− mice revealed reduced mechanosensitivity to high mechanical forces in the von Frey assay in vivo, and this was associated with a reduced sensitivity of nociceptive primary afferents in vitro. Together with these findings, transient receptor potential ankyrin 1 (TRPA1) mRNA expression was significantly reduced in DRG from SNS-gp130−/− mice. This was also reflected by a reduced number of neurons responding with calcium transients to TRPA1 agonists in primary DRG cultures. Downregulation of Trpa1 expression was predominantly discovered in nonpeptidergic neurons, with the deficit becoming evident during stages of early postnatal development. Regulation of Trpa1 mRNA expression levels downstream of gp130 involved the classical Janus kinase family-signal transducer and activator of transcription pathway. Our results closely link proinflammatory cytokines to the expression of TRPA1, both of which have been shown to contribute to hypersensitive pain states. We suggest that gp130 has an essential role in mechanonociception and in the regulation of TRPA1 expression. PMID:25057188

  20. An inexpensive pressure transducer for the measurement of low amplitude unsteady pressure signals

    NASA Astrophysics Data System (ADS)

    Johnston, R. T.; Sullivan, J. P.

    1994-04-01

    Electret microphones were evaluated for use in an experiment to investigate the surface pressures of a wing immersed in a propeller slipstream. Calibration of a typical electret microphone over a range of 50 to 6000 hz showed that at each individual frequency there is less than 1.1% error in linearity for low pressures, but some variation of sensitivity occurs over the range of frequencies tested. This variation of sensitivity with frequency can be corrected using standard signal processing techniques.

  1. 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

  2. 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

    2016-01-01

    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

  3. Cytosolic Glyceraldehyde-3-Phosphate Dehydrogenases Interact with Phospholipase Dδ to Transduce Hydrogen Peroxide Signals in the Arabidopsis Response to Stress[C][W

    PubMed Central

    Guo, Liang; Devaiah, Shivakumar P.; Narasimhan, Rama; Pan, Xiangqing; Zhang, Yanyan; Zhang, Wenhua; Wang, Xuemin

    2012-01-01

    Reactive oxygen species (ROS) are produced in plants under various stress conditions and serve as important mediators in plant responses to stresses. Here, we show that the cytosolic glycolytic enzymes glyceraldehyde-3-phosphate dehydrogenases (GAPCs) interact with the plasma membrane–associated phospholipase D (PLDδ) to transduce the ROS hydrogen peroxide (H2O2) signal in Arabidopsis thaliana. Genetic ablation of PLDδ impeded stomatal response to abscisic acid (ABA) and H2O2, placing PLDδ downstream of H2O2 in mediating ABA-induced stomatal closure. To determine the molecular link between H2O2 and PLDδ, GAPC1 and GAPC2 were identified to bind to PLDδ, and the interaction was demonstrated by coprecipitation using proteins expressed in Escherichia coli and yeast, surface plasmon resonance, and bimolecular fluorescence complementation. H2O2 promoted the GAPC–PLDδ interaction and PLDδ activity. Knockout of GAPCs decreased ABA- and H2O2-induced activation of PLD and stomatal sensitivity to ABA. The loss of GAPCs or PLDδ rendered plants less responsive to water deficits than the wild type. The results indicate that the H2O2-promoted interaction of GAPC and PLDδ may provide a direct connection between membrane lipid–based signaling, energy metabolism and growth control in the plant response to ROS and water stress. PMID:22589465

  4. RNF8 Transduces the DNA-Damage Signal Via Histone Ubiquitylation And Checkpoint Protein Assembly

    SciTech Connect

    Huen, M.S.Y.; Grant, R.; Manke, I.; Minn, K.; Yu, X.; Yaffe, M.B.; Chen, J.

    2009-06-01

    DNA-damage signaling utilizes a multitude of posttranslational modifiers as molecular switches to regulate cell-cycle checkpoints, DNA repair, cellular senescence, and apoptosis. Here we show that RNF8, a FHA/RING domain-containing protein, plays a critical role in the early DNA-damage response. We have solved the X-ray crystal structure of the FHA domain structure at 1.35 {angstrom}. We have shown that RNF8 facilitates the accumulation of checkpoint mediator proteins BRCA1 and 53BP1 to the damaged chromatin, on one hand through the phospho-dependent FHA domain-mediated binding of RNF8 to MDC1, on the other hand via its role in ubiquitylating H2AX and possibly other substrates at damage sites. Moreover, RNF8-depleted cells displayed a defective G2/M checkpoint and increased IR sensitivity. Together, our study implicates RNF8 as a novel DNA-damage-responsive protein that integrates protein phosphorylation and ubiquitylation signaling and plays a critical role in the cellular response to genotoxic stress.

  5. PKR Transduces MDA5-Dependent Signals for Type I IFN Induction.

    PubMed

    Pham, Alissa M; Santa Maria, Felicia Gilfoy; Lahiri, Tanaya; Friedman, Eugene; Marié, Isabelle J; Levy, David E

    2016-03-01

    Sensing invading pathogens early in infection is critical for establishing host defense. Two cytosolic RIG-like RNA helicases, RIG-I and MDA5, are key to type I interferon (IFN) induction in response to viral infection. Mounting evidence suggests that another viral RNA sensor, protein kinase R (PKR), may also be critical for IFN induction during infection, although its exact contribution and mechanism of action are not completely understood. Using PKR-deficient cells, we found that PKR was required for type I IFN induction in response to infection by vaccinia virus lacking the PKR antagonist E3L (VVΔE3L), but not by Sendai virus or influenza A virus lacking the IFN-antagonist NS1 (FluΔNS1). IFN induction required the catalytic activity of PKR, but not the phosphorylation of its principal substrate, eIF2α, or the resulting inhibition of host translation. In the absence of PKR, IRF3 nuclear translocation was impaired in response to MDA5 activators, VVΔE3L and encephalomyocarditis virus, but not during infection with a RIG-I-activating virus. Interestingly, PKR interacted with both RIG-I and MDA5; however, PKR was only required for MDA5-mediated, but not RIG-I-mediated, IFN production. Using an artificially activated form of PKR, we showed that PKR activity alone was sufficient for IFN induction. This effect required MAVS and correlated with IRF3 activation, but no longer required MDA5. Nonetheless, PKR activation during viral infection was enhanced by MDA5, as virus-stimulated catalytic activity was impaired in MDA5-null cells. Taken together, our data describe a critical and non-redundant role for PKR following MDA5, but not RIG-I, activation to mediate MAVS-dependent induction of type I IFN through a kinase-dependent mechanism. PMID:26939124

  6. PKR Transduces MDA5-Dependent Signals for Type I IFN Induction

    PubMed Central

    Lahiri, Tanaya; Friedman, Eugene; Marié, Isabelle J.; Levy, David E.

    2016-01-01

    Sensing invading pathogens early in infection is critical for establishing host defense. Two cytosolic RIG-like RNA helicases, RIG-I and MDA5, are key to type I interferon (IFN) induction in response to viral infection. Mounting evidence suggests that another viral RNA sensor, protein kinase R (PKR), may also be critical for IFN induction during infection, although its exact contribution and mechanism of action are not completely understood. Using PKR-deficient cells, we found that PKR was required for type I IFN induction in response to infection by vaccinia virus lacking the PKR antagonist E3L (VVΔE3L), but not by Sendai virus or influenza A virus lacking the IFN-antagonist NS1 (FluΔNS1). IFN induction required the catalytic activity of PKR, but not the phosphorylation of its principal substrate, eIF2α, or the resulting inhibition of host translation. In the absence of PKR, IRF3 nuclear translocation was impaired in response to MDA5 activators, VVΔE3L and encephalomyocarditis virus, but not during infection with a RIG-I-activating virus. Interestingly, PKR interacted with both RIG-I and MDA5; however, PKR was only required for MDA5-mediated, but not RIG-I-mediated, IFN production. Using an artificially activated form of PKR, we showed that PKR activity alone was sufficient for IFN induction. This effect required MAVS and correlated with IRF3 activation, but no longer required MDA5. Nonetheless, PKR activation during viral infection was enhanced by MDA5, as virus-stimulated catalytic activity was impaired in MDA5-null cells. Taken together, our data describe a critical and non-redundant role for PKR following MDA5, but not RIG-I, activation to mediate MAVS-dependent induction of type I IFN through a kinase-dependent mechanism. PMID:26939124

  7. 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.

  8. 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.

  9. NME2 associates with PTPσ to transduce signals from chondroitin sulfate proteoglycans.

    PubMed

    Hamasaki, Hajime; Fujitani, Masashi; Yamashita, Toshihide

    2016-03-18

    Chondroitin sulfate proteoglycans (CSPGs) are a major component of glial scars, inhibiting axonal growth in the central nervous system. Protein tyrosine phosphatase, receptor type S (PTPσ) has been identified as a receptor for CSPGs, whereas its downstream signaling pathway remains to be fully understood. Here, we report that nucleoside diphosphate kinase 2 (NME2) interacts with PTPσ. We screened proteins associated with PTPσ by mass spectrometry, and obtained NME2. Immunoprecipitation analysis revealed that NME2 associated with the PTPσ intracellular domain in HEK-293T cells. NME2 was expressed in the cytoplasm and nucleus of cortical neurons, and knockdown of NME2 in the cortical neurons completely rescued neurite outgrowth inhibition induced by CSPGs. These results demonstrate that NME2 associates with PTPσ to elicit neurite outgrowth inhibition in response to CSPGs. PMID:26896769

  10. 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

  11. 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. PMID:25942809

  12. 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.

  13. A Recurrent Mosaic Mutation in SMO, Encoding the Hedgehog Signal Transducer Smoothened, Is the Major Cause of Curry-Jones Syndrome.

    PubMed

    Twigg, Stephen R F; Hufnagel, Robert B; Miller, Kerry A; Zhou, Yan; McGowan, Simon J; Taylor, John; Craft, Jude; Taylor, Jenny C; Santoro, Stephanie L; Huang, Taosheng; Hopkin, Robert J; Brady, Angela F; Clayton-Smith, Jill; Clericuzio, Carol L; Grange, Dorothy K; Groesser, Leopold; Hafner, Christian; Horn, Denise; Temple, I Karen; Dobyns, William B; Curry, Cynthia J; Jones, Marilyn C; Wilkie, Andrew O M

    2016-06-01

    Curry-Jones syndrome (CJS) is a multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. Cerebellar medulloblastoma has been described in a single affected individual; in another, biopsy of skin lesions showed features of trichoblastoma. The combination of asymmetric clinical features, patchy skin manifestations, and neoplastic association previously led to the suggestion that this could be a mosaic condition, possibly involving hedgehog (Hh) signaling. Here, we show that CJS is caused by recurrent somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]), encoding smoothened (SMO), a G-protein-coupled receptor that transduces Hh signaling. We identified eight mutation-positive individuals (two of whom had not been reported previously) with highly similar phenotypes and demonstrated varying amounts of the mutant allele in different tissues. We present detailed findings from brain MRI in three mutation-positive individuals. Somatic SMO mutations that result in constitutive activation have been described in several tumors, including medulloblastoma, ameloblastoma, and basal cell carcinoma. Strikingly, the most common of these mutations is the identical nonsynonymous variant encoding p.Leu412Phe. Furthermore, this substitution has been shown to activate SMO in the absence of Hh signaling, providing an explanation for tumor development in CJS. This raises therapeutic possibilities for using recently generated Hh-pathway inhibitors. In summary, our work uncovers the major genetic cause of CJS and illustrates strategies for gene discovery in the context of low-level tissue-specific somatic mosaicism. PMID:27236920

  14. 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…

  15. 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.

  16. 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.

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

    PubMed

    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

  18. 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

  19. Dampening the Signals Transduced through Hedgehog via MicroRNA miR-7 Facilitates Notch-Induced Tumourigenesis

    PubMed Central

    Da Ros, Vanina G.; Gutierrez-Perez, Irene; Ferres-Marco, Dolors; Dominguez, Maria

    2013-01-01

    Fine-tuned Notch and Hedgehog signalling pathways via attenuators and dampers have long been recognized as important mechanisms to ensure the proper size and differentiation of many organs and tissues. This notion is further supported by identification of mutations in these pathways in human cancer cells. However, although it is common that the Notch and Hedgehog pathways influence growth and patterning within the same organ through the establishment of organizing regions, the cross-talk between these two pathways and how the distinct organizing activities are integrated during growth is poorly understood. Here, in an unbiased genetic screen in the Drosophila melanogaster eye, we found that tumour-like growth was provoked by cooperation between the microRNA miR-7 and the Notch pathway. Surprisingly, the molecular basis of this cooperation between miR-7 and Notch converged on the silencing of Hedgehog signalling. In mechanistic terms, miR-7 silenced the interference hedgehog (ihog) Hedgehog receptor, while Notch repressed expression of the brother of ihog (boi) Hedgehog receptor. Tumourigenesis was induced co-operatively following Notch activation and reduced Hedgehog signalling, either via overexpression of the microRNA or through specific down-regulation of ihog, hedgehog, smoothened, or cubitus interruptus or via overexpression of the cubitus interruptus repressor form. Conversely, increasing Hedgehog signalling prevented eye overgrowth induced by the microRNA and Notch pathway. Further, we show that blocking Hh signal transduction in clones of cells mutant for smoothened also enhance the organizing activity and growth by Delta-Notch signalling in the wing primordium. Together, these findings uncover a hitherto unsuspected tumour suppressor role for the Hedgehog signalling and reveal an unanticipated cooperative antagonism between two pathways extensively used in growth control and cancer. PMID:23667323

  20. 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.

  1. Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence.

    PubMed

    Shao, A-W; Sun, H; Geng, Y; Peng, Q; Wang, P; Chen, J; Xiong, T; Cao, R; Tang, J

    2016-05-01

    Inducing senescence in cancer cells is an effective approach to suppress cancer growth, and it contributes significantly to the efficacy of therapeutic drugs. Previous studies indicated that transcription factors NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) and C/EBPβ (CCAAT/enhancer-binding protein-β) play a critical role in the establishment of senescence by upregulating proinflammatory cytokines, notably interleukin-6 (IL-6) and interleukin-8 (IL-8). However, it is not clear how these two factors are activated in response to senescence-inducing stimuli and subsequently regulate gene transcription. Here, we reveal Bcl-2-associated transcription factor 1 (Bclaf1) as a novel player in the therapeutic drug doxorubicin-induced senescence (TIS) in multiple cancer cells. Bclaf1 is upregulated through the ATM/Nemo/NF-κB pathway during TIS and is a direct target of p65 and c-Rel. The induction of Bclaf1 by NF-κB is essential for C/EBPβ upregulation and IL-6/IL-8 transcription during TIS. Bclaf1 can interact with the leucine zipper region of C/EBPβ and cooperate with C/EBPβ to upregulate IL-8. Furthermore, we show that Bclaf1 is required for the effectiveness of doxorubicin (Dox) treatment-induced tumor suppression in a xenograft tumor model. These finding suggest that Bclaf1 plays a crucial role in transducing the senescence-inducing signal from NF-κB to C/EBPβ during TIS, thus amplifying the signals for the establishment of senescence. Given the recent revelation that Bclaf1 is involved in tumorigenesis, our data indicate that the responsiveness of Bclaf1 to NF-κB may determine the effectiveness of therapeutic drugs. PMID:26794446

  2. 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.

  3. Metabotropic glutamate receptors transduce signals for neurite outgrowth after binding of the prion protein to laminin γ1 chain.

    PubMed

    Beraldo, Flavio H; Arantes, Camila P; Santos, Tiago G; Machado, Cleiton F; Roffe, Martin; Hajj, Gláucia N; Lee, Kil S; Magalhães, Ana C; Caetano, Fabiana A; Mancini, Gabriel L; Lopes, Marilene H; Américo, Tatiana A; Magdesian, Margaret H; Ferguson, Stephen S G; Linden, Rafael; Prado, Marco A M; Martins, Vilma R

    2011-01-01

    The prion protein (PrP(C)) is highly expressed in the nervous system, and its abnormal conformer is associated with prion diseases. PrP(C) is anchored to cell membranes by glycosylphosphatidylinositol, and transmembrane proteins are likely required for PrP(C)-mediated intracellular signaling. Binding of laminin (Ln) to PrP(C) modulates neuronal plasticity and memory. We addressed signaling pathways triggered by PrP(C)-Ln interaction in order to identify transmembrane proteins involved in the transduction of PrP(C)-Ln signals. The Ln γ1-chain peptide, which contains the Ln binding site for PrP(C), induced neuritogenesis through activation of phospholipase C (PLC), Ca(2+) mobilization from intracellular stores, and protein kinase C and extracellular signal-regulated kinase (ERK1/2) activation in primary cultures of neurons from wild-type, but not PrP(C)-null mice. Phage display, coimmunoprecipitation, and colocalization experiments showed that group I metabotropic glutamate receptors (mGluR1/5) associate with PrP(C). Expression of either mGluR1 or mGluR5 in HEK293 cells reconstituted the signaling pathways mediated by PrP(C)-Ln γ1 peptide interaction. Specific inhibitors of these receptors impaired PrP(C)-Ln γ1 peptide-induced signaling and neuritogenesis. These data show that group I mGluRs are involved in the transduction of cellular signals triggered by PrP(C)-Ln, and they support the notion that PrP(C) participates in the assembly of multiprotein complexes with physiological functions on neurons. PMID:20876210

  4. Transduced PEP-1-PON1 proteins regulate microglial activation and dopaminergic neuronal death in a Parkinson's disease model.

    PubMed

    Kim, Mi Jin; Park, Meeyoung; Kim, Dae Won; Shin, Min Jea; Son, Ora; Jo, Hyo Sang; Yeo, Hyeon Ji; Cho, Su Bin; Park, Jung Hwan; Lee, Chi Hern; Kim, Duk-Soo; Kwon, Oh-Shin; Kim, Joon; Han, Kyu Hyung; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2015-09-01

    Parkinson's disease (PD) is an oxidative stress-mediated neurodegenerative disorder caused by selective dopaminergic neuronal death in the midbrain substantia nigra. Paraoxonase 1 (PON1) is a potent inhibitor of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) against oxidation by destroying biologically active phospholipids with potential protective effects against oxidative stress-induced inflammatory disorders. In a previous study, we constructed protein transduction domain (PTD) fusion PEP-1-PON1 protein to transduce PON1 into cells and tissue. In this study, we examined the role of transduced PEP-1-PON1 protein in repressing oxidative stress-mediated inflammatory response in microglial BV2 cells after exposure to lipopolysaccharide (LPS). Moreover, we identified the functions of transduced PEP-1-PON1 proteins which include, mitigating mitochondrial damage, decreasing reactive oxidative species (ROS) production, matrix metalloproteinase-9 (MMP-9) expression and protecting against 1-methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity in SH-SY5Y cells. Furthermore, transduced PEP-1-PON1 protein reduced MMP-9 expression and protected against dopaminergic neuronal cell death in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice model. Taken together, these results suggest a promising therapeutic application of PEP-1-PON1 proteins against PD and other inflammation and oxidative stress-related neuronal diseases. PMID:26117230

  5. 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.

  6. 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

    2015-01-01

    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. PMID:26310823

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

    PubMed Central

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

    2015-01-01

    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. PMID:26310823

  8. Signal-transducing protein phosphorylation cascades mediated by Ras/Rho proteins in the mammalian cell: the potential for multiplex signalling.

    PubMed Central

    Denhardt, D T

    1996-01-01

    The features of three distinct protein phosphorylation cascades in mammalian cells are becoming clear. These signalling pathways link receptor-mediated events at the cell surface or intracellular perturbations such as DNA damage to changes in cytoskeletal structure, vesicle transport and altered transcription factor activity. The best known pathway, the Ras-->Raf-->MEK-->ERK cascade [where ERK is extracellular-signal-regulated kinase and MEK is mitogen-activated protein (MAP) kinase/ERK kinase], is typically stimulated strongly by mitogens and growth factors. The other two pathways, stimulated primarily by assorted cytokines, hormones and various forms of stress, predominantly utilize p21 proteins of the Rho family (Rho, Rac and CDC42), although Ras can also participate. Diagnostic of each pathway is the MAP kinase component, which is phosphorylated by a unique dual-specificity kinase on both tyrosine and threonine in one of three motifs (Thr-Glu-Tyr, Thr-Phe-Tyr or Thr-Gly-Tyr), depending upon the pathway. In addition to activating one or more protein phosphorylation cascades, the initiating stimulus may also mobilize a variety of other signalling molecules (e.g. protein kinase C isoforms, phospholipid kinases, G-protein alpha and beta gamma subunits, phospholipases, intracellular Ca2+). These various signals impact to a greater or lesser extent on multiple downstream effectors. Important concepts are that signal transmission often entails the targeted relocation of specific proteins in the cell, and the reversible formation of protein complexes by means of regulated protein phosphorylation. The signalling circuits may be completed by the phosphorylation of upstream effectors by downstream kinases, resulting in a modulation of the signal. Signalling is terminated and the components returned to the ground state largely by dephosphorylation. There is an indeterminant amount of cross-talk among the pathways, and many of the proteins in the pathways belong to families

  9. Shc adaptor proteins are key transducers of mitogenic signaling mediated by the G protein-coupled thrombin receptor.

    PubMed Central

    Chen, Y; Grall, D; Salcini, A E; Pelicci, P G; Pouysségur, J; Van Obberghen-Schilling, E

    1996-01-01

    The serine protease thrombin activates G protein signaling systems that lead to Ras activation and, in certain cells, proliferation. Whereas the steps leading to Ras activation by G protein-coupled receptors are not well defined, the mechanisms of Ras activation by receptor tyrosine kinases have recently been elucidated biochemically and genetically. The present study was undertaken to determine whether common signaling components are used by these two distinct classes of receptors. Here we report that the adaptor protein Shc, is phosphorylated on tyrosine residues following stimulation of the thrombin receptor in growth-responsive CCL39 fibroblasts. Shc phosphorylation by thrombin or the thrombin receptor agonist peptide is maximal by 15 min and persists for > or = 2 h. Following thrombin stimulation, phosphorylated Shc is recruited to Grb2 complexes. One or more pertussis toxin-insensitive proteins appear to mediate this effect, since (i) pertussis toxin pre-treatment of cells does not blunt the action of thrombin and (ii) Shc phosphorylation on tyrosine can be stimulated by the muscarinic m1 receptor. Shc phosphorylation does not appear to involve protein kinase C, since the addition of 4-beta-phorbol-12,13-dibutyrate has no effect. Rather, thrombin-induced Shc phosphorylation is enhanced in cells depleted of phorbol ester-sensitive protein kinase C isoforms. Expression of mutant Shc proteins defective in Grb2 binding displays a dominant-negative effect on thrombin-stimulated p44 MAP kinase activation, gene induction and cell growth. From these data, we conclude that Shc represents a crucial point of convergence between signaling pathways activated by receptor tyrosine kinases and G protein-coupled receptors. Images PMID:8605873

  10. 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.

  11. Cell-Surface Nucleolin is a Signal Transducing P-Selectin Binding Protein for Human Colon Carcinoma Cells

    PubMed Central

    Reyes-Reyes, E. Merit; Akiyama, Steven K.

    2008-01-01

    We have previously shown that P-selectin binding to Colo-320 human colon carcinoma cells induces specific activation of the α5β1 integrin with a concomitant increase of cell adhesion and spreading on fibronectin substrates in a phosphatidylinositol 3-kinase (PI 3-K) and p38 MAPK-dependent manner. Here, we identified by affinity chromatography and characterized nucleolin as a P-selectin receptor on Colo-320 cells. Nucleolin mAb D3 significantly decreases the Colo-320 cell adhesion to immobilized P-selectin-IgG-Fc. Moreover, nucleolin becomes clustered at the external side of the plasma membrane of living, intact cells when bound to cross-linked P-selectin-IgG-Fc chimeric protein. We have also found P-selectin binding to Colo-320 cells induces tyrosine phosphorylation specifically of cell-surface nucleolin and formation of a signaling complex containing cell surface nucleolin, PI 3-K, and p38 MAPK. Using siRNA approaches, we have found that both P-selectin binding to Colo-320 cells and formation of the P-selectin-mediated p38 MAPK/ PI 3-K signaling complex require nucleolin expression. These results show that nucleolin (or a nucleolin-like protein) is a signaling receptor for P-selectin on Colo-320 cells and suggest a mechanism for linkage of nucleolin to P-selectin-induced signal transduction pathways that regulate the adhesion and the spreading of Colo-320 on fibronectin substrates. PMID:18504038

  12. 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.

  13. 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.

  14. Microfiber interferometric acoustic transducers.

    PubMed

    Wang, Xiuxin; Jin, Long; Li, Jie; Ran, Yang; Guan, Bai-Ou

    2014-04-01

    Acoustic and ultrasonic transducers are key components in biomedical information technology, which has been applied in medical diagnosis, photoacoustic endoscopy and photoacoustic imaging. In this paper, an acoustic transducer based on Fabry-Perot interferometer (FPI) fabricated in a microscaled optical fiber is demonstrated. The transducer is fabricated by forming two wavelength-matched Bragg gratings into the microfiber by means of side illumination with a 193nm excimer laser. When placing the transducer in water, the applied acoustic signal periodically changes the refractive index (RI) of the surrounding liquid and modulates the transmission of the FPI based on the evanescent-field interaction between the liquid and the transmitting light. As a result, the acoustic signal can be constructed with a tunable laser whose output wavelength is located at the slope of the inteferometric fringes. The transducer presents a sensitivity of 10 times higher than the counterparts fabricated in conventional singlemode fibers and has great potential to achieve higher resolution for photoacoustic imaging due to its reduced diameter. PMID:24718189

  15. 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.

  16. 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.

  17. Ultrasonic transducer

    SciTech Connect

    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.

  18. Activation of signalling by the activin receptor complex.

    PubMed Central

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

    1996-01-01

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

  19. System for calibrating pressure transducer

    NASA Technical Reports Server (NTRS)

    Rollins, G. N. (Inventor)

    1973-01-01

    A system for calibrating a pressure transducer which has a reference portion and an active portion is reported. A miniature selector valve is positioned immediately adjacent the pressure transducer. A reference pressure, known pressure, and unknown pressure can be selectively admitted to the active side of the pressure transducer by the selector valve to enable calibration of the transducer. A valve admits pressure to the selector valve which has a piston and floating piston arrangement which allows proper selection with very small linear movement.

  20. Arterial pulse wave pressure transducer

    NASA Technical Reports Server (NTRS)

    Kim, C.; Gorelick, D.; Chen, W. (Inventor)

    1974-01-01

    An arterial pulse wave pressure transducer is introduced. The transducer is comprised of a fluid filled cavity having a flexible membrane disposed over the cavity and adapted to be placed on the skin over an artery. An arterial pulse wave creates pressure pulses in the fluid which are transduced, by a pressure sensitive transistor in direct contact with the fluid, into an electric signal. The electrical signal is representative of the pulse waves and can be recorded so as to monitor changes in the elasticity of the arterial walls.

  1. 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

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

    PubMed

    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. PMID:27400267

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. Master regulator for chondrogenesis, Sox9, regulates transcriptional activation of the endoplasmic reticulum stress transducer BBF2H7/CREB3L2 in chondrocytes.

    PubMed

    Hino, Kenta; Saito, Atsushi; Kido, Miori; Kanemoto, Soshi; Asada, Rie; Takai, Tomoko; Cui, Min; Cui, Xiang; Imaizumi, Kazunori

    2014-05-16

    The endoplasmic reticulum (ER) stress transducer, box B-binding factor 2 human homolog on chromosome 7 (BBF2H7), is a basic leucine zipper (bZIP) transmembrane transcription factor. This molecule is activated in response to ER stress during chondrogenesis. The activated BBF2H7 accelerates cartilage matrix protein secretion through the up-regulation of Sec23a, which is responsible for protein transport from the ER to the Golgi apparatus and is a target of BBF2H7. In the present study, we elucidated the mechanisms of the transcriptional activation of Bbf2h7 in chondrocytes. The transcription of Bbf2h7 is regulated by Sex determining region Y-related high-mobility group box 9 (Sox9), a critical factor for chondrocyte differentiation that facilitates the expression of one of the major cartilage matrix proteins Type II collagen (Col2), through binding to the Sox DNA-binding motif in the Bbf2h7 promoter. BBF2H7 is activated as a transcription factor in response to physiological ER stress caused by abundant synthesis of cartilage matrix proteins, and consequently regulates the secretion of cartilage matrix proteins. Taken together, our findings demonstrate novel regulatory mechanisms of Sox9 for controlling the secretion of cartilage matrix proteins through the activation of BBF2H7-Sec23a signaling during chondrogenesis. PMID:24711445

  8. 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.

  9. 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. PMID:19081773

  10. 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

  11. 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.

  12. 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.

  13. 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. PMID:24792683

  14. Miniature multimode monolithic flextensional transducers.

    PubMed

    Hladky-Hennion, Anne-Christine; Uzgur, A Erman; Markley, Douglas C; Safari, Ahmad; Cochran, Joe K; Newnham, Robert E

    2007-10-01

    Traditional flextensional transducers classified in seven groups based on their designs have been used extensively in 1-100 kHz range for mine hunting, fish finding, oil explorations, and biomedical applications. In this study, a new family of small, low cost underwater, and biomedical transducers has been developed. After the fabrication of transducers, finite-elements analysis (FEA) was used extensively in order to optimize these miniature versions of high-power, low-frequency flextensional transducer designs to achieve broad bandwidth for both transmitting and receiving, engineered vibration modes, and optimized acoustic directivity patterns. Transducer topologies with various shapes, cross sections, and symmetries can be fabricated through high-volume, low-cost ceramic and metal extrusion processes. Miniaturized transducers posses resonance frequencies in the range of above 1 MHz to below 10 kHz. Symmetry and design of the transducer, polling patterns, driving and receiving electrode geometries, and driving conditions have a strong effect on the vibration modes, resonance frequencies, and radiation patterns. This paper is devoted to small, multimode flextensional transducers with active shells, which combine the advantages of small size and low-cost manufacturing with control of the shape of the acoustic radiation/receive pattern. The performance of the transducers is emphasized. PMID:18019236

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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. PMID:22374399

  1. The Signal Transducer NPH3 Integrates the Phototropin1 Photosensor with PIN2-Based Polar Auxin Transport in Arabidopsis Root Phototropism[C][W

    PubMed Central

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

    2012-01-01

    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. PMID:22374399

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

    PubMed Central

    Qi, QIAO; Hao, WU

    2016-01-01

    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. PMID:26511517

  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. PMID:26511517

  4. 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.

  5. 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)

  6. Expression and distribution of forkhead activin signal transducer 2 (FAST2) during follicle development in mouse ovaries and pre-implantation embryos.

    PubMed

    Wang, Guiping; Liu, Linlin; Guo, Shujuan; Zhang, Cong

    2016-07-01

    Xenopus forkhead activin signal transducer 1 (xFAST 1) was first characterized in Xenopus as the transcriptional partner for Smad proteins. FAST2, which is the xFAST 1 homologues in mouse, is expressed during early developmental stages of the organism. However, the function of FAST2 in mouse ovaries and pre-implantation embryos is unclear. Therefore, we investigated its expression during these processes. In postnatal mice, FAST2 was expressed in oocytes and thecal cells from postnatal day (PD) 1 to PD 21. In gonadotropin-induced immature mice, FAST2 was expressed in oocytes, thecal cells and newly formed corpora lutea (CLs), but was expressed at a lower level in degenerated CLs. Similar results were observed upon western blot analyses. In meloxicam-treated immature mice, ovulation was inhibited and FAST2 was expressed in thecal cells, luteinized granulosa cells and entrapped oocytes. Immunofluorescence results showed that FAST2 was expressed in the cytoplasm and nucleus but not the nucleolus from the zygote to 8-cell embryo stage, after which it was localized to the cytoplasm of the morulae and inner cell mass of the blastocysts. Taken together, these observations suggest that FAST2 is expressed in a cell-specific manner during ovarian follicle development, ovulation, luteinization and early embryonic development, and that FAST2 might play important roles in these physiological processes. PMID:27432806

  7. Backbone 1H, 13C, and 15N assignments for the tandem ubiquitin binding domains of signal transducing adapter molecule 1.

    PubMed

    Lim, Jongsoo; Hong, Yoon-Hun; Lee, Bong-Jin; Ahn, Hee-Chul

    2011-04-01

    Signal transducing adapter molecule (STAM) forms the endosomal sorting complex required for transport-0 (ESCRT-0) complex with hepatocyte growth factor-regulated substrate (Hrs) to sort the ubiquitinated cargo proteins from the early endosomes to the ESCRT-1 complex. ESCRT-0 complex, STAM and Hrs, contains multiple ubiquitin binding domains, in which STAM has two ubiquitin binding domains, Vps27/Hrs/Stam (VHS) and ubiquitin interacting motif (UIM) at its N-terminus. By the cooperation of the multiple ubiquitin binding domains, the ESCRT-0 complex recognizes poly-ubiquitin, especially Lys63-linked ubiquitin. Here, we report the backbone resonance assignments and the secondary structure of the N-terminal 191 amino acids of the human STAM1 which includes the VHS domain and UIM. The {(1)H}-(15)N heteronuclear NOE experiments revealed that an unstructured and flexible loop region connects the VHS domain and UIM. Our work provides the basic information for the further NMR investigation of the interaction between STAM1 and poly-ubiquitin. PMID:20927613

  8. 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.

  9. Paired inhibitory and activating receptor signals.

    PubMed

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

    2000-01-01

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

  10. Transducer-Mounting Fixture

    NASA Technical Reports Server (NTRS)

    Spiegel, Kirk W.

    1990-01-01

    Transducer-mounting fixture holds transducer securely against stud. Projects only slightly beyond stud after installation. Flanged transducer fits into fixture when hinged halves open. When halves reclosed, fixture tightened onto threaded stud until stud makes contact with transducer. Knurled area on fixture aids in tightening fixture on stud.

  11. A conserved role for Notch signaling in priming the cellular response to Shh through ciliary localisation of the key Shh transducer Smo

    PubMed Central

    Stasiulewicz, Magdalena; Gray, Shona D.; Mastromina, Ioanna; Silva, Joana C.; Björklund, Mia; Seymour, Philip A.; Booth, David; Thompson, Calum; Green, Richard J.; Hall, Emma A.; Serup, Palle; Dale, J. Kim

    2015-01-01

    Notochord-derived Sonic Hedgehog (Shh) is essential for dorsoventral patterning of the overlying neural tube. Increasing concentration and duration of Shh signal induces progenitors to acquire progressively more ventral fates. We show that Notch signalling augments the response of neuroepithelial cells to Shh, leading to the induction of higher expression levels of the Shh target gene Ptch1 and subsequently induction of more ventral cell fates. Furthermore, we demonstrate that activated Notch1 leads to pronounced accumulation of Smoothened (Smo) within primary cilia and elevated levels of full-length Gli3. Finally, we show that Notch activity promotes longer primary cilia both in vitro and in vivo. Strikingly, these Notch-regulated effects are Shh independent. These data identify Notch signalling as a novel modulator of Shh signalling that acts mechanistically via regulation of ciliary localisation of key components of its transduction machinery. PMID:25995356

  12. Dynamic Calibration of Pressure Transducers

    NASA Technical Reports Server (NTRS)

    Hess, R. W.; Davis, W. T.; Davis, P. A.

    1985-01-01

    Sinusoidal calibration signal produced in 4- to 100-Hz range. Portable oscillating-pressure device measures dynamic characteristics of pressure transducers installed in models or aircraft at frequency and oscillating-pressure ranges encountered during unsteady-pressure-measurement tests. Calibration is over range of frequencies and amplitudes not available with commercial acoustic calibration devices.

  13. Phototaxis of Halobacterium salinarium requires a signalling complex of sensory rhodopsin I and its methyl-accepting transducer HtrI.

    PubMed Central

    Krah, M; Marwan, W; Verméglio, A; Oesterhelt, D

    1994-01-01

    Sensory rhodopsin I (SRI) is a photoreceptor that mediates phototaxis in the archaeon Halobacterium salinarium. Receptor excitation is relayed to the motility system of the cell by the methyl-accepting transducer protein HtrI. In membranes prepared from cells that lack HtrI the absorbance difference maximum of SRI was shifted from 587 to 565 nm. The thermal decay of the metastable photocycle intermediate SRI373 was measured as time-dependent recovery of the absorbance at 590 nm. In the absence of HtrI the decay was slowed down by two orders of magnitude. When SRI was overproduced in cells that contained normal levels of HtrI, the decay of SRI373 was biexponential indicating two kinetically distinct species. Spectroscopic measurements on intact cells revealed the same effect of HtrI on SRI photocycling as found in isolated membranes. By transient exposure of membranes from wild-type cells to low ionic strength, the decay of SR373 was slowed to the same value found for untreated membranes in the absence of HtrI. In parallel, the absorbance difference maximum was shifted to 565 nm indicating that a physical interaction of HtrI and SRI had been irreversibly destroyed. Overproduction of SRI in the presence of wild-type amounts of HtrI did not increase the light sensitivity of the cells to orange light step down stimulation. It is concluded that SRI and HtrI form a stable complex in the cell membrane that signals to the flagellar motor and defines absorbance maximum, photocycling rate and photochemical efficiency of SRI. PMID:8187768

  14. Expression of tumor-associated calcium signal transducer 2 in patients with salivary adenoid cystic carcinoma: Correlation with clinicopathological features and prognosis.

    PubMed

    Xia, Yichao; Li, Bo; Gao, Ning; Xia, Hui; Men, Yi; Liu, Ying; Liu, Zhe; Chen, Qianming; Li, Longjiang

    2014-10-01

    Salivary adenoid cystic carcinoma (SACC) is a common salivary malignancy. The current treatment option for SACC is complete surgical excision with postoperative radiotherapy. The prognosis remains unsatisfactory, due to frequent local recurrence and distant metastases that directly reduce the overall survival time. Previous studies have shown that overexpression of tumor-associated calcium signal transducer 2 (TACSTD2) is associated with poor prognosis in various human epithelial cancers. The expression of TACSTD2 in SACC is currently unknown. The present study therefore aimed to retrospectively investigate TACSTD2 protein expression by immunohistochemistry on paraffin-embedded primary tumor tissue samples from a series of consecutive SACC patients (n=81). The correlation of TACSTD2 expression with clinicopathological variables was evaluated using either the Kruskal-Wallis or Mann-Whitney statistical tests. The survival curves were plotted using the Kaplan-Meier method. The parameters of prognostic significance found by univariate analysis were verified in a multivariate Cox regression model. Overexpression of TACSTD2 was detected in 35/81 (44%) SACC patients and was significantly associated with a decreased overall survival (P<0.01). Univariate analysis showed that TACSTD2 overexpression was correlated with TNM stage (P=0.020), local recurrence (P=0.002) and distant metastasis (P=0.001). Multivariate analyses further revealed that TACSTD2 may be an independent prognostic indicator. In conclusion, TACTSD2 could be recognized as an independent prognostic indicator for SACC. Gene therapy targeting TACSTD2 may be a possible treatment approach for patients with SACC overexpressing this cell-surface marker. PMID:25202389

  15. 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. PMID:20433925

  16. 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

  17. Amperometric biosensors based on carbon composite transducers

    NASA Astrophysics Data System (ADS)

    Lu, Fang

    1998-12-01

    Much current work in analytical chemistry is devoted to design of biosensors. One particular area in this field is the development of enzyme-based amperometric biosensors for the quantitative determination of a series of substrates in clinical, environmental, industrial and agricultural significance. This dissertation focuses on the design of improved amperometric biosensors based on carbon composite transducers. The use of metallized carbons as transducer materials results in remarkably selective amperometric biosensors. Such enzyme-based transducers eliminate major electroactive interferences, and hence circumvent the need for mediators or membrane barriers. The remarkable selectivity of metal-dispersed carbons is attributed to their strong, preferential, electrocatalytic capacity towards the reductive detection of biologically-generated hydrogen peroxide. Such electrocatalytic activity allows metal-dispersed biosensors to be operated at the optimal potential region between +0.1 and -0.2 V, where the unwanted reactions are neglected resulting in the lowest noise level. Several new materials (e.g., ruthenium on carbon, rhodium on carbon, etc.) and constructions (e.g., carbon fiber, electrochemical co-deposition transducer, etc.) were applied in the development of novel enzyme-based transducers in order to improve the selectivity and applicability of amperometric biosensors. The susceptibility of first-generation oxidase amperometric biosensing to oxygen fluctuations can be improved by using oxygen-rich fluorocarbons as the pasting binders in carbon paste enzyme transducers. Such binders provide an internal supply of oxygen resulting in efficient detection in oxygen-deficit conditions. In particular, the use of poly-chlorotrifluorethylene (Kel-F) oil as carbon paste binder results in a well-defined response and an identical signal up to 40 mM glucose in both the presence and absence of oxygen. Comparing with mediated or wired enzyme-based transducers, such internal

  18. Magnetometer with a miniature transducer and automatic scanning

    NASA Technical Reports Server (NTRS)

    Debnam, W. J. J.; Fales, C. L., Jr.; Breckenridge, R. A.; Pohm, A. V. (Inventor)

    1978-01-01

    The magnetometer is based on the time variation of the magnetic permeability in the magnetic material of its transducer; however, its operation is substantially different from the ordinary flux-gate magnetometer. The transducer uses 0.05 mm diameter plated magnetic wire and is made flat enabling it to make measurements of transverse magnetic fields as close as 0.08 mm from the surface, and it has very good spatial resolution because of its small active region of approximately 0.64 mm by 0.76 mm. The magnetometer uses an inexpensive clip-on millimeter for driving and processing the electrical signals and readout. It also utilizes an automatic scanning technique which is made possible by a specially designed transducer holding mechanism that replaces the ink pen on an X-Y recorder.

  19. Staphylococcus aureus Enterotoxin B Down-Regulates the Expression of Transforming Growth Factor-Beta (TGF-β) Signaling Transducers in Human Glioblastoma

    PubMed Central

    Akbari, Abolfazl; Farahnejad, Zohreh; Akhtari, Javad; Abastabar, Mahdi; Mobini, Gholam Reza; Mehbod, Amir Seied Ali

    2016-01-01

    Background It has been revealed that Staphylococcus aureus enterotoxin B (SEB) may feature anti-cancer and anti-metastatic advantages due to its ability to modify cell immunity processes and signaling pathways. Glioblastoma is one of the most aggressive human cancers; it has a high mortality nature, which makes it an attractive area for the development of novel therapies. Objectives We examined whether the SEB could exert its growth inhibitory effects on glioblastoma cells partially through the manipulation of a key tumor growth factor termed transforming growth factor-beta (TGF-β). Materials and Methods A human primary glioblastoma cell line, U87, was treated with different concentrations of SEB. The cell quantity was measured by the MTT assay at different exposure times. For molecular assessments, total ribonucleic acid (RNA) was extracted from either non-treated or SEB-treated cells. Subsequently, the gene expression of TGF-β transducers, smad2/3, at the messenger RNA (mRNA) level, was analyzed via a quantitative real-time polymerase chain reaction (qPCR) using the SYBR Green method. Significant differences between cell viability and gene expression levels were determined (Prism 5.0 software) using one-way analyses of variance (ANOVA) test. Results We reported that SEB could effectively down-regulate smad2/3 expression in glioblastoma cells at concentrations as quantity as 1 μg/mL and 2 μg/mL (P < 0.05 and P < 0.01, respectively). The SEB concentrations effective at regulating smad2/3 expression were correlated with those used to inhibit the proliferation of glioblastoma cells. Our results also showed that SEB was able to decrease smad2/3 expression at the mRNA level in a concentration- and time-dependent manner. Conclusions We suggested that SEB could represent an agent that can significantly decrease smad2/3 expression in glioblastoma cells, leading to moderate TGF-β growth signaling and the reduction of tumor cell proliferation. PMID:27540448

  20. The Vps27/Hrs/STAM (VHS) Domain of the Signal-transducing Adaptor Molecule (STAM) Directs Associated Molecule with the SH3 Domain of STAM (AMSH) Specificity to Longer Ubiquitin Chains and Dictates the Position of Cleavage.

    PubMed

    Baiady, Nardeen; Padala, Prasanth; Mashahreh, Bayan; Cohen-Kfir, Einav; Todd, Emily A; Du Pont, Kelly E; Berndsen, Christopher E; Wiener, Reuven

    2016-01-22

    The deubiquitinating enzyme associated molecule with the SH3 domain of STAM (AMSH) is crucial for the removal of ubiquitin molecules during receptor-mediated endocytosis and lysosomal receptor sorting. AMSH interacts with signal transducing adapter molecule (STAM) 1 or 2, which enhances the activity of AMSH through an unknown mechanism. This stimulation is dependent on the ubiquitin-interacting motif of STAM. Here we investigate the specific mechanism of AMSH stimulation by STAM proteins and the role of the STAM Vps27/Hrs/STAM domain. We show that, in the presence of STAM, the length of the ubiquitin chains affects the apparent cleavage rate. Through measurement of the chain cleavage kinetics, we found that, although the kcat of Lys(63)-linked ubiquitin chain cleavage was comparable for di- and tri-ubiquitin, the Km value was lower for tri-ubiquitin. This increased affinity for longer chains was dependent on the Vps27/Hrs/STAM domain of STAM and required that the substrate ubiquitin chain contain homogenous Lys(63)-linkages. In addition, STAM directed AMSH cleavage toward the distal isopeptide bond in tri-ubiquitin chains. Finally, we generated a structural model of AMSH-STAM to show how the complex binds Lys(63)-linked ubiquitin chains and cleaves at the distal end. These data show how a deubiquitinating enzyme-interacting protein dictates the efficiency and specificity of substrate cleavage. PMID:26601948

  1. The Rabies Virus Interferon Antagonist P Protein Interacts with Activated STAT3 and Inhibits Gp130 Receptor Signaling

    PubMed Central

    Lieu, Kim G.; Brice, Aaron; Wiltzer, Linda; Hirst, Bevan; Jans, David A.; Blondel, Danielle

    2013-01-01

    Immune evasion by rabies virus depends on targeting of the signal transducers and activator of transcription 1 (STAT1) and STAT2 proteins by the viral interferon antagonist P protein, but targeting of other STAT proteins has not been investigated. Here, we find that P protein associates with activated STAT3 and inhibits STAT3 nuclear accumulation and Gp130-dependent signaling. This is the first report of STAT3 targeting by the interferon antagonist of a virus other than a paramyxovirus, indicating that STAT3 antagonism is important to a range of human-pathogenic viruses. PMID:23698294

  2. Notum deacylates Wnts to suppress signalling activity

    PubMed Central

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

    2015-01-01

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

  3. Optical measuring displacement transducers

    NASA Astrophysics Data System (ADS)

    Dich, L. Z.

    1994-09-01

    Trends in the development and production of photoelectric displacement transducers are analyzed. The technical characteristics of certain transducers are briefly presented. A table of comparisons is given, based on available information sources.

  4. Noncanonical roles of membranous lysyl-tRNA synthetase in transducing cell-substrate signaling for invasive dissemination of colon cancer spheroids in 3D collagen I gels

    PubMed Central

    Nam, Seo Hee; Kim, Doyeun; Lee, Mi-Sook; Lee, Doohyung; Kwak, Tae Kyoung; Kang, Minkyung; Ryu, Jihye; Kim, Hye-Jin; Song, Haeng Eun; Choi, Jungeun; Lee, Gyu-Ho; Kim, Sang-Yeob; Park, Song Hwa; Kim, Dae Gyu; Kwon, Nam Hoon; Kim, Tai Young; Thiery, Jean Paul; Kim, Sunghoon; Lee, Jung Weon

    2015-01-01

    The adhesion properties of cells are involved in tumor metastasis. Although KRS at the plasma membrane is shown important for cancer metastasis, additionally to canonical roles of cytosolic KRS in protein translation, how KRS and its downstream effectors promote the metastatic migration remains unexplored. Disseminative behaviors (an earlier metastatic process) of colon cancer cell spheroids embedded in 3D collagen gels were studied with regards to cell adhesion properties, and relevance in KRS−/+ knocked-down animal and clinical colon cancer tissues. Time-lapse imaging revealed KRS-dependent cell dissemination from the spheroids, whereas KRS-suppressed spheroids remained static due to the absence of outbound movements supported by cell-extracellular matrix (ECM) adhesion. While keeping E-cadherin at the outward disseminative cells, KRS caused integrin-involved intracellular signaling for ERK/c-Jun, paxillin, and cell-ECM adhesion-mediated signaling to modulate traction force for crawling movement. KRS-suppressed spheroids became disseminative following ERK or paxillin re-expression. The KRS-dependent intracellular signaling activities correlated with the invasiveness in clinical colon tumor tissues and in KRS−/+ knocked-down mice tissues. Collectively, these observations indicate that KRS at the plasma membrane plays new roles in metastatic migration as a signaling inducer, and causes intracellular signaling for cancer dissemination, involving cell-cell and cell-ECM adhesion, during KRS-mediated metastasis. PMID:26091349

  5. 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. PMID:26953638

  6. 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.

  7. 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.

  8. Progesterone and the zona pellucida activate different transducing pathways in the sequence of events leading to diacylglycerol generation during mouse sperm acrosomal exocytosis.

    PubMed Central

    Murase, T; Roldan, E R

    1996-01-01

    We tested the involvement of protein tyrosine kinase and G-protein transducing pathways in the formation of diacylglycerol (DAG) during exocytosis in mouse spermatozoa. In capacitated spermatozoa, stimulation with solubilized zona pellucida (ZP) or progesterone led to the formation of DAG and to exocytosis of the acrosomal granule. Stimulation of DAG formation and exocytosis by ZP were inhibited in a concentration-dependent fashion by pre-exposure to tyrphostin A48, a protein tyrosine kinase inhibitor. These ZP-induced responses were also reduced in a concentration-dependent manner by prior incubation with pertussis toxin, a G-protein (Gi class) inhibitor. On the other hand, generation of DAG and exocytosis triggered by progesterone were inhibited if spermatozoa were preincubated with different concentrations of tyrphostin A48, but were not affected by pre-exposure to pertussis toxin. Progesterone acts on at least two novel surface receptors, one being a gamma-aminobutyric acid (GABA) type A (GABAA)-like receptor. Transducing mechanisms coupled to this receptor were tested directly by stimulating spermatozoa with GABA. Treatment of capacitated spermatozoa with GABA resulted in DAG formation and exocytosis. These responses were not seen when cells were preincubated with tyrphostin A48. Pertussis toxin, however, did not affect the generation of DAG and exocytosis triggered by GABA, in agreement with results obtained using progesterone. Taken together, these results indicate that DAG formation during acrosomal exocytosis is differentially regulated by transducing pathways activated by oocyte-associated agonists. PMID:9003394

  9. Astrocyte Activation via Stat3 Signaling Determines the Balance of Oligodendrocyte versus Schwann Cell Remyelination.

    PubMed

    Monteiro de Castro, Glaucia; Deja, Natalia A; Ma, Dan; Zhao, Chao; Franklin, Robin J M

    2015-09-01

    Remyelination within the central nervous system (CNS) most often is the result of oligodendrocyte progenitor cells differentiating into myelin-forming oligodendrocytes. In some cases, however, Schwann cells, the peripheral nervous system myelinating glia, are found remyelinating demyelinated regions of the CNS. The reason for this peripheral type of remyelination in the CNS and what governs it is unknown. Here, we used a conditional astrocytic phosphorylated signal transducer and activator of transcription 3 knockout mouse model to investigate the effect of abrogating astrocyte activation on remyelination after lysolecithin-induced demyelination of spinal cord white matter. We show that oligodendrocyte-mediated remyelination decreases and Schwann cell remyelination increases in lesioned knockout mice in comparison with lesioned controls. Our study shows that astrocyte activation plays a crucial role in the balance between Schwann cell and oligodendrocyte remyelination in the CNS, and provides further insight into remyelination of CNS axons by Schwann cells. PMID:26193667

  10. Astrocyte Activation via Stat3 Signaling Determines the Balance of Oligodendrocyte versus Schwann Cell Remyelination

    PubMed Central

    Monteiro de Castro, Glaucia; Deja, Natalia A.; Ma, Dan; Zhao, Chao; Franklin, Robin J.M.

    2016-01-01

    Remyelination within the central nervous system (CNS) most often is the result of oligodendrocyte progenitor cells differentiating into myelin-forming oligodendrocytes. In some cases, however, Schwann cells, the peripheral nervous system myelinating glia, are found remyelinating demyelinated regions of the CNS. The reason for this peripheral type of remyelination in the CNS and what governs it is unknown. Here, we used a conditional astrocytic phosphorylated signal transducer and activator of transcription 3 knockout mouse model to investigate the effect of abrogating astrocyte activation on remyelination after lysolecithin-induced demyelination of spinal cord white matter. We show that oligodendrocyte-mediated remyelination decreases and Schwann cell remyelination increases in lesioned knockout mice in comparison with lesioned controls. Our study shows that astrocyte activation plays a crucial role in the balance between Schwann cell and oligodendrocyte remyelination in the CNS, and provides further insight into remyelination of CNS axons by Schwann cells. PMID:26193667

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

    PubMed Central

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

    2015-01-01

    ABSTRACT Signaling pathways and epigenetic mechanisms have both been shown to play essential roles in regulating stem cell activity. While the role of either mechanism in this regulation is well established in multiple stem cell lineages, how the two mechanisms interact to regulate stem cell activity is not as well understood. Here we report that in the Drosophila testis, an H3K4me3-specific histone demethylase encoded by little imaginal discs (lid) maintains germline stem cell (GSC) mitotic index and prevents GSC premature differentiation. Lid is required in germ cells for proper expression of the Stat92E transcription factor, the downstream effector of the Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling pathway. Our findings support a germ cell autonomous role for the JAK-STAT pathway in maintaining GSCs and place Lid as an upstream regulator of this pathway. Our study provides new insights into the biological functions of a histone demethylase in vivo and sheds light on the interaction between epigenetic mechanisms and signaling pathways in regulating stem cell activities. PMID:26490676

  12. 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

  13. 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

  14. Heat dissipation guides activation in signaling proteins.

    PubMed

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

    2015-08-18

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

  15. Zinc Chloride Transiently Maintains Mouse Embryonic Stem Cell Pluripotency by Activating Stat3 Signaling

    PubMed Central

    Hu, Jing; Yang, Zhiyong; Wang, Jinbo; Yu, Jia; Guo, Jing; Liu, Shiying; Qian, Chunmei; Song, Liwen; Wu, Yi; Cheng, Jiajing

    2016-01-01

    An improved understanding of the pluripotency maintenance of embryonic stem (ES) cells is important for investigations of early embryo development and for cell replacement therapy, but the mechanism behind pluripotency is still incompletely understood. Recent findings show that zinc, an essential trace element in humans, is critically involved in regulating various signaling pathways and genes expression. However, its role in ES cell fate determination remains to be further explored. Here we showed that 2μM zinc chloride (ZnCl2) transiently maintained mouse ES cell pluripotency in vitro. The cultured mouse ES cells remained undifferentiated under 2μM ZnCl2 treatment in leukemia inhibitory factor (LIF) withdrawal, retinoic acid (RA) or embryoid bodies (EBs) differentiation assays. In addition, ZnCl2 increased pluripotency genes expression and inhibited differentiation genes expression. Further mechanistic studies revealed that ZnCl2 transiently activated signal transducers and activators of transcription 3 (Stat3) signaling through promoting Stat3 phosphorylation. Inhibition of Stat3 signaling abrogated the effects of ZnCl2 on mouse ES cell pluripotency. Taken together, this study demonstrated a critical role of zinc in the pluripotency maintenance of mouse ES cells, as well as an important regulator of Stat3 signaling. PMID:26910359

  16. 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

  17. Electronic scanning pressure measuring system and transducer package

    NASA Technical Reports Server (NTRS)

    Coe, C. F. (Inventor); Parra, G. T.

    1984-01-01

    An electronic scanning pressure system that includes a plurality of pressure transducers is examined. A means obtains an electrical signal indicative of a pressure measurement from each of the plurality of pressure transducers. A multiplexing means is connected for selectivity supplying inputs from the plurality of pressure transducers to the signal obtaining means. A data bus connects the plurality of pressure transducers to the multiplexing means. A latch circuit is connected to supply control inputs to the multiplexing means. An address bus is connected to supply an address signal of a selected one of the plurality of pressure transducers to the latch circuit. In operation, each of the pressure transducers is successively scanned by the multiplexing means in response to address signals supplied on the address bus to the latch circuit.

  18. Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals.

    PubMed

    Shao, Jian-Su; Cheng, Su-Li; Pingsterhaus, Joyce M; Charlton-Kachigian, Nichole; Loewy, Arleen P; Towler, Dwight A

    2005-05-01

    In diabetic LDLR-/- mice, an ectopic BMP2-Msx2 gene regulatory program is upregulated in association with vascular calcification. We verified the procalcific actions of aortic Msx2 expression in vivo. CMV-Msx2 transgenic (CMV-Msx2Tg(+)) mice expressed 3-fold higher levels of aortic Msx2 than nontransgenic littermates. On high-fat diets, CMV-Msx2Tg(+) mice exhibited marked cardiovascular calcification involving aortic and coronary tunica media. This corresponded to regions of Msx2 immunoreactivity in adjacent adventitial myofibroblasts, suggesting a potential paracrine osteogenic signal. To better understand Msx2-regulated calcification, we studied actions in 10T1/2 cells. We found that conditioned media from Msx2-transduced 10T1/2 cells (Msx2-CM) is both pro-osteogenic and adipostatic; these features are characteristic of Wnt signaling. Msx2-CM stimulated Wnt-dependent TCF/LEF transcription, and Msx2-transduced cells exhibited increased nuclear beta-catenin localization with concomitant alkaline phosphatase induction. Msx2 upregulated Wnt3a and Wnt7a but downregulated expression of the canonical inhibitor Dkk1. Dkk1 treatment reversed osteogenic and adipostatic actions of Msx2. Teriparatide, a PTH1R agonist that inhibits murine vascular calcification, suppressed vascular BMP2-Msx2-Wnt signaling. Analyses of CMV-Msx2Tg(+) mice confirmed that Msx2 suppresses aortic Dkk1 and upregulates vascular Wnts; moreover, TOPGAL(+) (Wnt reporter); CMV-Msx2Tg(+) mice exhibited augmented aortic LacZ expression. Thus, Msx2-expressing cells elaborated an osteogenic milieu that promotes vascular calcification in part via paracrine Wnt signals. PMID:15841209

  19. 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.

  20. 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.

  1. Ultrasensitive ultrasonic transducer studies

    SciTech Connect

    Dixon, R.; Darling, T.; Migliori, A.

    1996-09-01

    This is the final report of a one-year, Laboratory-Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). This project sought to continue development of the ultrasensitive ultrasonic transducers that won a 1994 R&D 100 Award. These transducers have a very smooth response across a broad frequency range and thus are extremely well- suited for resonant ultrasound spectroscopy as well as pulsed-echo and acoustic-emission applications. Current work on these transducers has indicated that bonding the piezoelectric and wear surface to a metal foil and attaching the foil to a body is less expensive and produces a transducer that is as good or better than commercially produced transducers. We have diffusion- bonded piezoelectric crystals and backings to stainless-steel-foil and wear surfaces. These are then attached onto stainless-steel tubes with electrical connectors to form the transducers. The transducers have been characterized using a reciprocity technique, electrical response, and optical interferometry. After characterization, the transducers have been compared to existing transducers by measuring and testing identical properties.

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

    PubMed

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

    2016-08-01

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

  3. 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.

  4. Two Drosophila suppressors of cytokine signaling (SOCS) differentially regulate JAK and EGFR pathway activities

    PubMed Central

    Rawlings, Jason S; Rennebeck, Gabriela; Harrison, Susan MW; Xi, Rongwen; Harrison, Douglas A

    2004-01-01

    Background The Janus kinase (JAK) cascade is an essential and well-conserved pathway required to transduce signals for a variety of ligands in both vertebrates and invertebrates. While activation of the pathway is essential to many processes, mutations from mammals and Drosophila demonstrate that regulation is also critical. The SOCS (Suppressor Of Cytokine Signaling) proteins in mammals are regulators of the JAK pathway that participate in a negative feedback loop, as they are transcriptionally activated by JAK signaling. Examination of one Drosophila SOCS homologue, Socs36E, demonstrated that its expression is responsive to JAK pathway activity and it is capable of downregulating JAK signaling, similar to the well characterized mammalian SOCS. Results Based on sequence analysis of the Drosophila genome, there are three identifiable SOCS homologues in flies. All three are most similar to mammalian SOCS that have not been extensively characterized: Socs36E is most similar to mammalian SOCS5, while Socs44A and Socs16D are most similar to mammalian SOCS6 and 7. Although Socs44A is capable of repressing JAK activity in some tissues, its expression is not regulated by the pathway. Furthermore, Socs44A can enhance the activity of the EGFR/MAPK signaling cascade, in contrast to Socs36E. Conclusions Two Drosophila SOCS proteins have some overlapping and some distinct capabilities. While Socs36E behaves similarly to the canonical vertebrate SOCS, Socs44A is not part of a JAK pathway negative feedback loop. Nonetheless, both SOCS regulate JAK and EGFR signaling pathways, albeit differently. The non-canonical properties of Socs44A may be representative of the class of less characterized vertebrate SOCS with which it shares greatest similarity. PMID:15488148

  5. 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.

  6. 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. PMID:25817414

  7. 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.

  8. 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.

  9. 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.

  10. A novel c-Jun-dependent signal transduction pathway necessary for the transcriptional activation of interferon gamma response genes.

    PubMed

    Gough, Daniel J; Sabapathy, Kanaga; Ko, Enoch Yi-No; Arthur, Helen A; Schreiber, Robert D; Trapani, Joseph A; Clarke, Christopher J P; Johnstone, Ricky W

    2007-01-12

    The biological effects of interferon gamma (IFNgamma) are mediated by interferon-stimulated genes (ISGs), many of which are activated downstream of Janus kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling. Herein we have shown that IFNgamma rapidly activated AP-1 DNA binding that required c-Jun but was independent of JAK1 and STAT1. IFNgamma-induced c-Jun phosphorylation and AP-1 DNA binding required the MEK1/2 and ERK1/2 signaling pathways, whereas the JNK1/2 and p38 mitogen-activated protein kinase pathways were dispensable. The induction of several ISGs, including ifi-205 and iNOS, was impaired in IFNgamma-treated c-Jun-/- cells, but others, such as IP-10 and SOCS3, were unaffected, and chromatin immunoprecipitation demonstrated that c-Jun binds to the iNOS promoter following treatment with IFNgamma. Thus, IFNgamma induced JAK1- and STAT1-independent activation of the ERK mitogen-activated protein kinase pathway, phosphorylation of c-Jun, and activation of AP-1 DNA binding, which are important for the induction of a subset of ISGs. This represents a novel signal transduction pathway induced by IFNgamma that proceeds in parallel with conventional JAK/STAT signaling to activate ISGs. PMID:17105733

  11. 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.

  12. 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.

  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. 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.

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

    PubMed

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

    2015-11-15

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

  16. Magnetometer with miniature transducer and automatic transducer scanning apparatus

    NASA Technical Reports Server (NTRS)

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

    1974-01-01

    Magnetometer is simple to operate and has fast response. Transducer is rugged and flat and can measure magnetic fields as close as 0.08 mm from any relatively flat surface. Magnetometer has active region of approximately 0.64 by 0.76 mm and is capable of good spatial resolution of magnetic fields as low as 0.02 Oe (1.6 A/m).

  17. 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. PMID:26351277

  18. 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.

  19. 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.

  20. 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.

  1. Spark ultrasonic transducer

    NASA Technical Reports Server (NTRS)

    Hoop, J. M.

    1972-01-01

    Nondestructive testing by spark transducer induces ultrasonic pulses in materials without physical contact. High power pulse generator connected to step up transformer produces sparking between two tungsten rods and ultrasonic energy pulses in test samples placed between rods.

  2. 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.

  3. Application of Shaping Deconvolution to the Generation of Arbitrary Acoustic Pulses with Conventional Sonar Transducers

    NASA Astrophysics Data System (ADS)

    Cobo, P.

    1995-11-01

    Conventionally, a transducer driven with an electrical tone burst responds with a pressure wave whose exact waveform is determined by the impulse response of the transducer and the physical properties of the medium to which it is coupled. However, for some active sonar applications it is often desirable to have very specific transmitted acoustic signals rather than simply gated or swept sinusoids. By modelling the underwater transducer as a linear filter and estimating its transfer function it is possible to derive the required time history of the input voltage for a given output spectrum. There is the complication that because the transducer is inevitably band-limited in its frequency reponse, a regularization parameter has to be introduced to avoid division by zero. The feasibility of the method is demonstrated by generating, with the same underwater transducer, zero-phase cosine-magnitude, bionic, Guassian and low transient pulses. The input voltage necessary to generate each pulse is synthesized with a programmable arbitrary waveform generator. The main worth of this method is the versatility it affords in the use of conventional transducers.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Absolute calibration technique for broadband ultrasonic transducers

    NASA Technical Reports Server (NTRS)

    Yost, William T. (Inventor); Cantrell, John H. (Inventor)

    1994-01-01

    Calibrating an ultrasonic transducer can be performed with a reduced number of calculations and testing. A wide-band pulser is connected to an ultrasonic transducer under test to generate ultrasonic waves in a liquid. A single frequency is transmitted to the electrostatic acoustic transducer (ESAT) and the voltage change produced is monitored. Then a broadband ultrasonic pulse is generated by the ultrasonic transducer and received by the ESAT. The output of the ESAT is amplified and input to a digitized oscilloscope for fast Fourier transform. The resulting plot is normalized with the monitored signal from the single frequency pulse. The plot is then corrected for characteristics of the membrane and diffraction effects. The transfer function of the final plot is determined. The transfer function gives the final sensitivity of the ultrasonic transducer as a function of frequency. The advantage of the system is the speed of calibrating the transducer by a reduced number of measurements and removal of the membrane and diffraction effects.

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

    PubMed Central

    Kopan, Raphael; Ilagan, Ma. Xenia G.

    2009-01-01

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

  10. RAGE signaling mediates post-injury arterial neointima formation by suppression of liver kinase B1 and AMPK activity

    PubMed Central

    Yu, Weifang; Liu-Bryan, Ru; Stevens, Stephanie; Damanahalli, Jagadeesha K.; Terkeltaub, Robert

    2012-01-01

    Objective Intima formation involves smooth muscle cell (SMC) proliferation and migration that ultimately drives arterial stenosis, thrombosis, and ischemia in atherosclerosis, hypertension, and arterial revascularization. Receptor for advanced glycation endproducts (RAGE) is a transmembrane signaling receptor implicated in diabetic renal and vascular complications, and post-injury intima formation, partly via Signal transducer and activator of transcription 3 (STAT3) activation. The metabolic super-regulator Adenosine monophosphate kinase (AMPK) inhibits SMC proliferation and intima formation. AMPK activation is promoted by liver kinase B1 (LKB1), and LKB1 inhibits STAT3 activation. Here, we tested the hypothesis that RAGE promotes arterial intima formation by modulating both LKB1 and AMPK. Methods and Results RAGE ligands (the calgranulin S100A11, and glycated albumin) suppressed AMPK activation in conjunction with increased proliferation and migration of cultured SMCs. These effects were inhibited both by RAGE deficiency and by prior AMPK activation. In SMCs, RAGE ligands decreased LKB1 activity. Moreover, knockdown of both LKB1 and AMPK were associated with increased STAT3 phosphorylation levels. In response to murine carotid artery ligation, expression of RAGE and S100A11 increased, whereas AMPK and LKB1 activity decreased in situ. Conversely, LKB1 and AMPK activity increased in situ, and neointima formation was attenuated in Rage−/− mice. Conclusion The linkage of decreased LKB1 and AMPK activity with increased STAT3 in SMCs mediates the capacity of RAGE ligand-induced signaling to promote neointima formation in response to arterial injury. PMID:22552116

  11. UVB Generates Microvesicle Particle Release in Part Due to Platelet-activating Factor Signaling.

    PubMed

    Bihl, Ji C; Rapp, Christine M; Chen, Yanfang; Travers, Jeffrey B

    2016-05-01

    The lipid mediator platelet-activating factor (PAF) and oxidized glycerophosphocholine PAF agonists produced by ultraviolet B (UVB) have been demonstrated to play a pivotal role in UVB-mediated processes, from acute inflammation to delayed systemic immunosuppression. Recent studies have provided evidence that microvesicle particles (MVPs) are released from cells in response to various signals including stressors. Importantly, these small membrane fragments can interact with various cell types by delivering bioactive molecules. The present studies were designed to test if UVB radiation can generate MVP release from epithelial cells, and the potential role of PAF receptor (PAF-R) signaling in this process. We demonstrate that UVB irradiation of the human keratinocyte-derived cell line HaCaT resulted in the release of MVPs. Similarly, treatment of HaCaT cells with the PAF-R agonist carbamoyl PAF also generated equivalent amounts of MVP release. Of note, pretreatment of HaCaT cells with antioxidants blocked MVP release from UVB but not PAF-R agonist N-methyl carbamyl PAF (CPAF). Importantly, UVB irradiation of the PAF-R-negative human epithelial cell line KB and KB transduced with functional PAF-Rs resulted in MVP release only in PAF-R-positive cells. These studies demonstrate that UVB can generate MVPs in vitro and that PAF-R signaling appears important in this process. PMID:26876152

  12. 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

  13. 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.

  14. Improved Ultrasonic Transducer For Measuring Cryogenic Flow

    NASA Technical Reports Server (NTRS)

    Barkhoudarian, Sarkis

    1991-01-01

    Improved ultrasonic transducer used to measure flow of cryogenic fluid. Includes wedge made nonintrusive by machining it out of bulk material of duct carrying fluid. Skewed surfaces of wedge suppress standing waves, thus reducing ringing and increasing signal-to-noise ratio. Increases accuracy of measurements of times of arrival of ultrasonic pulses, from which times flow inferred.

  15. Wnt Signaling in Neurogenesis during Aging and Physical Activity

    PubMed Central

    Chen, Michael; Do, Huong

    2012-01-01

    Over the past decade, much progress has been made regarding our understanding of neurogenesis in both young and old animals and where it occurs throughout the lifespan, although the growth of new neurons declines with increasing age. In addition, physical activity can reverse this age-dependent decline in neurogenesis. Highly correlated with this decline is the degree of inter and intracellular Wnt signaling, the molecular mechanisms of which have only recently started to be elucidated. So far, most of what we know about intracellular signaling during/following exercise centers around the CREB/CRE initiated transcriptional events. Relatively little is known, however, about how aging and physical activity affect the Wnt signaling pathway. Herein, we briefly review the salient features of neurogenesis in young and then in old adult animals. Then, we discuss Wnt signaling and review the very few in vitro and in vivo studies that have examined the Wnt signaling pathways in aging and physical activity. PMID:24961268

  16. Evaluation of several ultrasonic flowmeter transducers in cryogenic environment

    NASA Technical Reports Server (NTRS)

    Moughon, W. C.

    1981-01-01

    Eighteen piezoelectric ultrasonic flowmeter transducers were laboratory tested to determine their suitability and long range reliability for use by the National Transonic Facility (NTF) to measure the flow rate of 450 Kg/sec of liquid nitrogen (LN2). Tests included thermally cycling each transducer 50 to 150 times over a temperature range of 295 K (ambient) to 77 K (LN2). The transducers were submerged in liquid nitrogen for 1 to 4 hours and the signal strength and quality noted. Results disclose that the current state-of-the-art ultrasonic flow transducers are very reliable and will meet the stringent requirements of the NTF.

  17. Evaluation of several ultrasonic flowmeter transducers in cryogenic environment

    NASA Astrophysics Data System (ADS)

    Moughon, W. C.

    1981-04-01

    Eighteen piezoelectric ultrasonic flowmeter transducers were laboratory tested to determine their suitability and long range reliability for use by the National Transonic Facility (NTF) to measure the flow rate of 450 Kg/sec of liquid nitrogen (LN2). Tests included thermally cycling each transducer 50 to 150 times over a temperature range of 295 K (ambient) to 77 K (LN2). The transducers were submerged in liquid nitrogen for 1 to 4 hours and the signal strength and quality noted. Results disclose that the current state-of-the-art ultrasonic flow transducers are very reliable and will meet the stringent requirements of the NTF.

  18. Cellular Cholesterol Directly Activates Smoothened in Hedgehog Signaling.

    PubMed

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

    2016-08-25

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

  19. Three-dimensional ghost imaging using acoustic transducer

    NASA Astrophysics Data System (ADS)

    Zhang, Chi; Guo, Shuxu; Guan, Jian; Cao, Junsheng; Gao, Fengli

    2016-06-01

    We propose a novel three-dimensional (3D) ghost imaging method using unfocused ultrasonic transducer, where the transducer is used as the bucket detector to collect the total photoacoustic signal intensity from spherical surfaces with different radius circling the transducer. This collected signal is a time sequence corresponding to the optic absorption information on the spherical surfaces, and the values at the same moments in all the sequences are used as the bucket signals to restore the corresponding spherical images, which are assembled as the object 3D reconstruction. Numerical experiments show this method can effectively accomplish the 3D reconstruction and by adding up each sequence on time domain as a bucket signal it can also realize two dimensional (2D) ghost imaging. The influence of the measurement times on the 3D and 2D reconstruction is analyzed with Peak Signal to Noise Ratio (PSNR) as the yardstick, and the transducer as a bucket detector is also discussed.

  20. 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

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

    PubMed

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

    2016-01-01

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

  2. Cyclophosphamide and IL-12-transduced DCs enhance the antitumor activity of tumor antigen-stimulated DCs and reduce Tregs and MDSCs number.

    PubMed

    Rossowska, Joanna; Pajtasz-Piasecka, Elżbieta; Anger, Natalia; Wojas-Turek, Justyna; Kicielińska, Jagoda; Piasecki, Egbert; Duś, Danuta

    2014-01-01

    A hostile tumor microenvironment, characterized by an abundance of T regulatory cells and myeloid-derived suppressor cells (MDSCs), considerably limits the efficacy of dendritic cell (DC)-based vaccines. The intention of this study was to enhance the antitumor activity of vaccines consisting of bone marrow-derived DCs stimulated with TAg (BMDC/TAg) via single administration of cyclophosphamide and multiple injections of interleukin (IL)-12-transduced DCs (BMDC/IL-12). The combined chemoimmunotherapy was applied in the treatment of mice with subcutaneously (SC) growing, advanced MC38 colon carcinoma. The highest level of tumor growth inhibition, accompanied by high cytotoxic activity of effector cells, and their increased influx into tumor tissue, was observed after application of cyclophosphamide in combination with BMDC/TAg and BMDC/IL-12. The effect was probably associated with the elimination of T regulatory cells from spleens and tumors, but most of all with changes in the number and differentiation stage of MDSCs. After the therapy, the percentage of granulocytic and monocytic MDSCs in spleens was significantly lower than in the control group. Moreover, MDSCs derived from spleens and tumors showed increased expression of MHC class II, which may indicate the higher maturation stage of the myeloid cells as well as their enhanced capacity toward antigen presentation. The obtained data indicate that the optimal composition of antitumor vaccines able to limit the suppressor activity of MDSCs is essential to enhance the elimination of tumor cells and to achieve an optimal therapeutic effect. PMID:25304726

  3. The transducible TAT-RIZ1-PR protein exerts histone methyltransferase activity and tumor-suppressive functions in human malignant meningiomas.

    PubMed

    Ding, Mao-Hua; Wang, Zhen; Jiang, Lei; Fu, Hua-Lin; Gao, Jie; Lin, Xian-Bin; Zhang, Chun-Lei; Liu, Zhen-Yang; Shi, Yi-Fei; Qiu, Guan-Zhong; Ma, Yue; Cui, Da-Xiang; Hu, Guo-Han; Jin, Wei-Lin

    2015-07-01

    Malignant meningiomas are a rare meningioma subtype and tend to have post-surgical recurrence. Significant endeavors have been taken to identify functional therapeutic targets to halt the growth of this aggressive cancer. We have recently discovered that RIZ1 is downregulated in high-grade meningiomas, and RIZ1 overexpression inhibits proliferation while promoting cell apoptosis of the IOMM-Lee malignant meningioma cell line. In this report, we show that the N-terminal PR domain of RIZ1 alone possessed growth-inhibitory activity and anticancer activity in primary human meningioma cells. Interestingly, the effects seem to be dependent on differential RIZ1 protein levels. Transducible TAT-RIZ1-PR protein could also inhibit meningioma tumor growth in nude mice models. We further demonstrate that PR protein exerts histone methyltransferase activity. A microarray analysis of TAT-RIZ1-PR-treated human malignant meningioma cells reveals 969 differentially expressed genes and 848 alternative splicing exons. Moreover, c-Myc and TXNIP, two putative downstream targets of H3K9 methylation, may be involved in regulating RIZ1 tumor-suppressive effects. The reciprocal relationship between RIZ1 and c-Myc was then validated in primary meningioma cells and human tumor samples. These findings provide insights into RIZ1 tumor suppression mechanisms and suggest that TAT-RIZ1-PR protein is a potential new epigenetic therapeutic agent for advanced meningiomas. PMID:25934289

  4. Miniature biaxial strain transducer

    NASA Technical Reports Server (NTRS)

    Hoffman, I. S. (Inventor)

    1976-01-01

    A reusable miniature strain transducer for use in the measurement of static or quasi-static, high level, biaxial strain on the surface of test specimens or structures was studied. Two cantilever arms, constructed by machining the material to appropriate flexibility, are self-aligning and constitute the transducing elements of the device. Used in conjunction with strain gages, the device enables testing beyond normal gage limits for high strains and number of load cycles. The device does not require conversion computations since the electrical output of the strain gages is directly proportional to the strain measured.

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

    PubMed

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

    2013-09-15

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2009-11-19

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

  8. 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…

  9. 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.

  10. Ultrasonic Transducer Analyzer

    NASA Technical Reports Server (NTRS)

    Grounds, M. K.

    1982-01-01

    Ultrasonic transducer-beam-intensity distributions are determined by analyzing echoes from a spherical ball. Computers control equipment and process data. Important beam characteristics, such as location of best beam focus and beam diameter at focus, can be determined quickly from extensive set of plots generated by apparatus.

  11. Inertia diaphragm pressure transducer

    NASA Technical Reports Server (NTRS)

    Seegmiller, H. L. B.

    1971-01-01

    Transducer measures gas pressure profiles in high temperature, short duration, gas flows usually found in devices where pressure pulses may have durations of few microseconds to several milliseconds. Assembly includes fluid delay line, delay chamber, and flow restrictor for equalizing steady state pressure on diaphragm's sides

  12. Adipose-Specific Disruption of Signal Transducer and Activator of Transcription 3 Increases Body Weight and Adiposity

    PubMed Central

    Cernkovich, Erin R.; Deng, Jianbei; Bond, Michael C.; Combs, Terry P.; Harp, Joyce B.

    2008-01-01

    To determine the role of STAT3 in adipose tissue, we used Cre-loxP DNA recombination to create mice with an adipocyte-specific disruption of the STAT3 gene (ASKO mice). aP2-Cre-driven disappearance of STAT3 expression occurred on d 6 of adipogenesis, a time point when preadipocytes have already undergone conversion to adipocytes. Thus, this knockout model examined the role of STAT3 in mature but not differentiating adipocytes. Beginning at 9 wk of age, ASKO mice weighed more than their littermate controls and had increased adipose tissue mass, associated with adipocyte hypertrophy, but not adipocyte hyperplasia, hyperphagia, or reduced energy expenditure. Leptin-induced, but not isoproterenol-induced, lipolysis was impaired in ASKO adipocytes, which may partially explain the increased cell size. Despite reduced adiponectin and increased liver triacylglycerol, ASKO mice displayed normal glucose tolerance. Overall, these findings demonstrate that adipocyte STAT3 regulates body weight homeostasis in part through direct effects of leptin on adipocytes. PMID:18096662

  13. Design and simulation of an ultrasonic transducer

    NASA Astrophysics Data System (ADS)

    Yu, Zhenxian; Shi, Yanru; Hsu, Hung-Yao; Kong, Lingxue

    2005-12-01

    This paper presents a novel ultrasonic transducer which can be used as a liquid ejector to release drug. The ultrasonic transducer is based on the design of a flextensional transducer, which is composed of interdigital piezoelectric rings and a vibration membrane. The device works at an axisymmetric resonant mode to produce maximum amplitude at the center of the vibration membrane in axial direction. For the usage of multi piezoelectric rings, the flexural plate waves can be generated by applying two out-of-phase signals. The power consumption is of primary importance in the design of this device and the usage of single-ring or multi-ring piezoelectric material instead of bulk piezo material can therefore reduce the power consumption. An optimum working frequency, at which least power is required by the device, can be found by the piezoelectric, coupled field capability of the ANSYS/Multiphysics product.

  14. Development of a wireless intra-vaginal transducer for monitoring intra-abdominal pressure in women

    PubMed Central

    Coleman, Tanner J.; Thomsen, Jens C.; Maass, Sean D.; Hsu, Yvonne; Nygaard, Ingrid E.

    2011-01-01

    Pelvic floor disorders (PFD) affect one of every four women in the United States. Elevated intra-abdominal pressure (IAP) during daily activity or strenuous physical activity has been identified as a risk factor in the prevalence of PFD. However, the relationship between IAP and physical activity is poorly understood and oftentimes activity restrictions are prescribed by physicians without clinical evidence linking various activities to elevated IAP. There are currently no pressure transducers capable of monitoring IAP non-invasively out of a clinical environment. To overcome this shortcoming, a novel intra-vaginal pressure transducer (IVT) was developed to continuously monitor IAP. Improvements were made to the first generation IVT by incorporating wireless capability to enhance the device’s mobility while creating a more robust IAP monitoring system. To ensure the changes maintained the functionality of the original device design, comparison testing with standard clinical pressure transducers in both bench top and clinical settings was conducted. The wireless device was found to have high linearity, robust signal transmission, and dynamic response that outperforms the clinical standard rectal transducer and is similar to the original first generation non-wireless design. The wireless IVT presented here is a mobile wireless device capable of measuring, storing and transmitting IAP data during various physical activities. PMID:22147020

  15. Elucidation of tonic and activated B-cell receptor signaling in Burkitt's lymphoma provides insights into regulation of cell survival.

    PubMed

    Corso, Jasmin; Pan, Kuan-Ting; Walter, Roland; Doebele, Carmen; Mohr, Sebastian; Bohnenberger, Hanibal; Ströbel, Philipp; Lenz, Christof; Slabicki, Mikolaj; Hüllein, Jennifer; Comoglio, Federico; Rieger, Michael A; Zenz, Thorsten; Wienands, Jürgen; Engelke, Michael; Serve, Hubert; Urlaub, Henning; Oellerich, Thomas

    2016-05-17

    Burkitt's lymphoma (BL) is a highly proliferative B-cell neoplasm and is treated with intensive chemotherapy that, because of its toxicity, is often not suitable for the elderly or for patients with endemic BL in developing countries. BL cell survival relies on signals transduced by B-cell antigen receptors (BCRs). However, tonic as well as activated BCR signaling networks and their relevance for targeted therapies in BL remain elusive. We have systematically characterized and compared tonic and activated BCR signaling in BL by quantitative phosphoproteomics to identify novel BCR effectors and potential drug targets. We identified and quantified ∼16,000 phospho-sites in BL cells. Among these sites, 909 were related to tonic BCR signaling, whereas 984 phospho-sites were regulated upon BCR engagement. The majority of the identified BCR signaling effectors have not been described in the context of B cells or lymphomas yet. Most of these newly identified BCR effectors are predicted to be involved in the regulation of kinases, transcription, and cytoskeleton dynamics. Although tonic and activated BCR signaling shared a considerable number of effector proteins, we identified distinct phosphorylation events in tonic BCR signaling. We investigated the functional relevance of some newly identified BCR effectors and show that ACTN4 and ARFGEF2, which have been described as regulators of membrane-trafficking and cytoskeleton-related processes, respectively, are crucial for BL cell survival. Thus, this study provides a comprehensive dataset for tonic and activated BCR signaling and identifies effector proteins that may be relevant for BL cell survival and thus may help to develop new BL treatments. PMID:27155012

  16. 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

  17. Level-dependent auditory tuning: Transducer-based active processes in hearing and best-frequency shifts.

    PubMed

    Nadrowski, Björn; Göpfert, Martin C

    2009-01-01

    Ears boost their sensitivity by means of active, force-generating processes that augment the minute vibrations induced by soft sounds. These processes can alter auditory frequency-tuning in a level-dependent way. In the antennal hearing organ of Drosophila, for example, the active process shifts the best frequency (BF) of the antennal sound receiver when the sound intensity is varied, tuning the receiver to conspecific songs. Here we show that this level-dependent tuning can be reproduced by an active transduction model as proposed for vertebrate hair cells and the Drosophila ear. We further show that the direction of the frequency shift depends on the system to which the molecular modules for auditory transduction connect: If this system is mass-less such as the sensory hair bundles of bullfrog saccular hair cells, the BF of the displacement response will increase as the sound intensity declines. Conversely, BF will decrease with declining intensity if the transduction modules couple to inertial systems such as the fly's antennal sound receiver or cupulae in the fish lateral line. PMID:19704854

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

    PubMed

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

    2015-07-01

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

  19. 21 CFR 870.2900 - Patient transducer and electrode cable (including connector).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Patient transducer and electrode cable (including... § 870.2900 Patient transducer and electrode cable (including connector). (a) Identification. A patient transducer and electrode cable (including connector) is an electrical conductor used to transmit signals...

  20. 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

  1. 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.

  2. 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%.

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

    PubMed Central

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

    2008-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2013-02-01

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

  5. Three dimensional transducer

    SciTech Connect

    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.

  6. 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.

  7. Horizontal geophone transducer assembly

    SciTech Connect

    Hefer, F.W.

    1985-06-25

    The geophone transducer comprises in combination: a geophone capable of detecting horizontal seismic waves, and a rigid casing having a gimbal chamber. A gimbal is provided inside the chamber on which the geophone is mounted for limited free angular movement in one direction only. The gimbal includes in one preferred embodiment a viscous liquid in which the geophone is only partially submerged while it is supported by a U-shaped bracket which is mounted for rotation about a fixed axis.

  8. 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.

  9. Correlation of nighttime MF signal strength with solar activity

    NASA Astrophysics Data System (ADS)

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

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

  10. Receptor tyrosine kinases: mechanisms of activation and signaling

    PubMed Central

    Hubbard, Stevan R.; Miller, W. Todd

    2008-01-01

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

  11. Notch signaling promotes osteoclast maturation and resorptive activity.

    PubMed

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

    2015-11-01

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

  12. 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.

  13. A new transducer system for direct motor unit force measurement.

    PubMed

    Turkawski, S J; van Ruijven, L J; van Kuyen, M; Schreurs, A W; Weijs, W A

    1996-11-01

    A new transducer was developed for in situ measurement of the force vector in a complex muscle. The transducer measures the magnitude, and the line of action of a force in a single plane. The dynamic range of the transducer is 0-5 N. This range includes the small forces developed by an active motor unit and the relatively large passive force of a whole muscle. In this study we present the details of the transducer design and specifications, and describe its application in the measurement of motor unit forces of the rabbit masseter muscle. PMID:8894930

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

    PubMed

    Cossu, G; Borello, U

    1999-12-15

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

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

    PubMed Central

    Cossu, G; Borello, U

    1999-01-01

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

  16. Signaling pathways activated by a protease allergen in basophils

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-10-26

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

  19. Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of scleroderma.

    PubMed

    Takagawa, Shinsuke; Lakos, Gabriella; Mori, Yasuji; Yamamoto, Toshiyuki; Nishioka, Kiyoshi; Varga, John

    2003-07-01

    Transforming growth factor-beta is responsible for triggering a cascade of events leading to fibrosis in scleroderma. The Smads are intracellular signal transducers recently shown to mediate fibroblast activation and other profibrotic responses elicited by transforming growth factor-betain vitro. To understand better the involvement of Smads in the pathogenesis of fibrosis, we examined Smad expression and activation in situ in a murine model of scleroderma. Bleomycin injections induced striking dermal infiltration with macrophages by 3 d, and progressive fibrosis by 2 wk. Infiltrating macrophages and resident fibroblasts expressed Smad3, the positive mediator for transforming growth factor-beta responses. Importantly, in bleomycin-injected skin, fibroblasts showed predominantly nuclear localization of Smad3 and intense staining for phospho-Smad2/3. Furthermore, phosphorylated Smad2/3 in fibroblasts was detected even after the resolution of inflammation. Expression of Smad7, the endogenous inhibitor of transforming growth factor-beta/Smad signaling, was strongly induced in dermal cells by transforming growth factor-beta, but not by bleomycin injections. Collectively, these results indicate that bleomycin-induced murine scleroderma is associated with rapid and sustained induction of transforming growth factor-beta/Smad signaling in resident dermal fibroblasts. Despite apparent activation of the intracellular transforming growth factor-beta signaling pathway in the lesional dermis, the expression of transforming growth factor-beta-inducible Smad7 was not upregulated. In light of the critical function of Smad7 as an endogenous inhibitor of Smad signaling that restricts the duration and magnitude of transforming growth factor-beta responses, and as a mediator of apoptosis, relative Smad7 deficiency observed in the present studies may account for sustained activation of transforming growth factor-beta/Smad signaling in lesional tissues. These findings raise the

  20. 1Application of Fluorescence Resonance Energy Transfer and Magnetic Twisting Cytometry to Quantitate Mechano-Chemical Signaling Activities in a Living Cell

    PubMed Central

    Na, Sungsoo; Wang, Ning

    2009-01-01

    Mechanotransduction is the process by which living cells sense mechanical forces and then convert them into biochemical signaling. Recently we showed that mechanical stress is transduced from the cell surface to remote cytoplasmic sites within 0.3 s, which is at least 40 to 50 times faster than soluble factor-induced signal transduction, and the sites of mechanotransduction colocalize with sites where mechanical stress causes microtubule displacement. These results suggest that mechanotransduction employs mechanisms different from those of soluble factor-induced signal transduction. Here we describe a protocol that utilizes fluorescence resonance energy transfer (FRET) and a magnetic twisting cytometry (MTC) device to capture rapid mechano-chemical signaling activities in living cells. PMID:18728305

  1. NDE of interfaces in the tube geometry with piezofilm transducers

    SciTech Connect

    Hsu, D.K.; Zhang, Zhong.

    1991-01-01

    The flexible polymer piezofilms such as polyvinylidene fluoride (1) (PVDF) posses distinct advantages as ultrasonic transducers for inspecting cylindrically symmetric components, including rods, pipes, cladding, and tube interfaces. The flexibility and contour conforming nature of the film transducer ensure normal incidence and avoid mode conversion. In this work, PVDF transducers are used in the evaluation of interfaces in coaxially extruded Zirconium-Zircaloy tubes and the clamping condition of Nitinol couplers over stainless steel tubing. Detailed description will be given for the evaluation of an interface in a Zirconium-Zircaloy tube, on which the same transducer was used both as the transmitter and the receiver. The multiple echo signals were analyzed and reflection coefficient as small as 0.006 was accurately measured. Comparison will be made with the measurement results of conventional transducers. 5 refs., 6 figs.

  2. NDE of interfaces in the tube geometry with piezofilm transducers

    SciTech Connect

    Hsu, D.K.; Zhang, Zhong

    1991-12-31

    The flexible polymer piezofilms such as polyvinylidene fluoride [1] (PVDF) posses distinct advantages as ultrasonic transducers for inspecting cylindrically symmetric components, including rods, pipes, cladding, and tube interfaces. The flexibility and contour conforming nature of the film transducer ensure normal incidence and avoid mode conversion. In this work, PVDF transducers are used in the evaluation of interfaces in coaxially extruded Zirconium-Zircaloy tubes and the clamping condition of Nitinol couplers over stainless steel tubing. Detailed description will be given for the evaluation of an interface in a Zirconium-Zircaloy tube, on which the same transducer was used both as the transmitter and the receiver. The multiple echo signals were analyzed and reflection coefficient as small as 0.006 was accurately measured. Comparison will be made with the measurement results of conventional transducers. 5 refs., 6 figs.

  3. 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.

  4. Ultrasonic comb transducer for smart materials

    NASA Astrophysics Data System (ADS)

    Rose, J. L.

    1998-04-01

    Installation of a small multi-element comb type ultrasonic transducer is proposed as a component of a smart structure. It can be used in either an active or passive mode in carrying out ultrasonic bulk or guided wave nondestructive evaluation. Theoretical methods are developed and experimental results are presented for guided wave generation and mode control with this very efficient and versatile novel comb type ultrasonic transducer. Excitation and probe design is crucial in mode selection. The comb transducer generates waves that are influenced by such parameters as number of elements, spacing between elements, dimension, pulsing sequence, and pressure distribution. The excited elastic field depends on the excitation frequency, plate thickness, and elastic properties. Techniques are studied to optimize the applied loading and the comb transducer design parameters so that only modes that are most sensitive to particular material characteristics can be generated. Complete understanding of the comb transducer parameters and their impact on the elastic field allows us to efficiently generate higher order modes as well as low phase velocity modes which are valuable in composite material characterization. Sample experiments are presented for various plate and tube like structures.

  5. 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

  6. High temperature, high power piezoelectric composite transducers.

    PubMed

    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

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  9. Characterization of transducer cavities to oscillatory inputs

    SciTech Connect

    Rogers, J.D.; Hollingshead, J.R.

    1993-12-31

    The design and use of measurement systems must ensure that the data are not computed by the measurement system. A wide variety of sources can be responsible for compromising the integrity of test data. Among the sources of error are transducer calibration errors, signal conditioning problems, recording problems, and characteristics of the mechanical system which introduce errors. In this paper, the characteristics of an acoustic cavity are discussed as they apply to a pressure measurement problem.

  10. Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules

    PubMed Central

    Nagata, Takanobu; Yasukawa, Hideo; Kyogoku, Sachiko; Oba, Toyoharu; Takahashi, Jinya; Nohara, Shoichiro; Minami, Tomoko; Mawatari, Kazutoshi; Sugi, Yusuke; Shimozono, Koutatsu; Pradervand, Sylvain; Hoshijima, Masahiko; Aoki, Hiroki; Fukumoto, Yoshihiro; Imaizumi, Tsutomu

    2015-01-01

    Myocardial ischemia reperfusion injury (IRI) adversely affects cardiac performance and the prognosis of patients with acute myocardial infarction. Although myocardial signal transducer and activator of transcription (STAT) 3 is potently cardioprotective during IRI, the inhibitory mechanism responsible for its activation is largely unknown. The present study aimed to investigate the role of the myocardial suppressor of cytokine signaling (SOCS)-3, an intrinsic negative feedback regulator of the Janus kinase (JAK)-STAT signaling pathway, in the development of myocardial IRI. Myocardial IRI was induced in mice by ligating the left anterior descending coronary artery for 1 h, followed by different reperfusion times. One hour after reperfusion, the rapid expression of JAK-STAT–activating cytokines was observed. We precisely evaluated the phosphorylation of cardioprotective signaling molecules and the expression of SOCS3 during IRI and then induced myocardial IRI in wild-type and cardiac-specific SOCS3 knockout mice (SOCS3-CKO). The activation of STAT3, AKT, and ERK1/2 rapidly peaked and promptly decreased during IRI. This decrease correlated with the induction of SOCS3 expression up to 24 h after IRI in wild-type mice. The infarct size 24 h after reperfusion was significantly reduced in SOCS3-CKO compared with wild-type mice. In SOCS3-CKO mice, STAT3, AKT, and ERK1/2 phosphorylation was sustained, myocardial apoptosis was prevented, and the expression of anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) was augmented. Cardiac-specific SOCS3 deletion led to the sustained activation of cardioprotective signaling molecules including and prevented myocardial apoptosis and injury during IRI. Our findings suggest that SOCS3 may represent a key factor that exacerbates the development of myocardial IRI. PMID:26010537

  11. 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.

  12. 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.

  13. Protein kinase A activity and Hedgehog signaling pathway.

    PubMed

    Kotani, Tomoya

    2012-01-01

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

  14. 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.

  15. Improved Micromachined Transducers

    NASA Technical Reports Server (NTRS)

    Hartley, Frank T.; Wise, James H.

    1994-01-01

    Sensor systems of proposed type incorporate micromachined silicon-based structures as electrostatic force and displacement actuators and micromachined quantum-mechanical-tunneling electrodes as one form of displacement transducers, along with electronic circuits providing multiple electrical stimuli to displacement electrodes for measurement, calibration, monitoring of sensor status, and adjustment. Concept applicable to accelerometers, seismometers, geophones, magnetometers, pressure gauges, and other sensors in which phenomena of interest measured in terms of forces on, and/or displacements of, structural components. Provides completely remote measurement, control, health monitoring, treatment, and like, using telemetry commands.

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

    PubMed Central

    Cerutti, Andrea; Cols, Montserrat; Puga, Irene

    2012-01-01

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

  17. Activators of G Protein Signaling in the Kidney

    PubMed Central

    2015-01-01

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

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

    PubMed

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

    2016-01-01

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

  19. Spatial Regulation and the Rate of Signal Transduction Activation

    PubMed Central

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

    2006-01-01

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

  20. 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

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

    PubMed

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

    2016-09-01

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

  2. Reliability of high strain ionomeric polymer transducers fabricated using the direct assembly process

    NASA Astrophysics Data System (ADS)

    Akle, Barbar; Nawshin, Saila; Leo, Donald

    2007-04-01

    actuation signal, while they are only reliable for 3-4 h under a 2 V actuation signal. Solvent evaporation is the main reason for degradation in formamide samples and it is increased at 2 V, indicating some electrochemical activity at such high voltages. Finally the initial drop in performance and the fluctuation in the generated strain are shown to be due to the loss of humidity absorbed from ambient air and the fluctuation in this ambient humidity, respectively.

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

    PubMed Central

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

    1995-01-01

    We provide direct evidence for phospholipase D (PLD) signaling in plants by showing that this enzyme is stimulated by the G protein activators mastoparan, ethanol, and cholera toxin. An in vivo assay for PLD activity in plant cells was developed based on the use of a "reporter alcohol" rather than water as a transphosphatidylation substrate. The product was a phosphatidyl alcohol, which, in contrast to the normal product phosphatidic acid, is a specific measure of PLD activity. When 32P-labeled cells were treated with 0.1% n-butanol, 32P-phosphatidyl butanol (32P-PtdBut) was formed in a time-dependent manner. In cells treated with any of the three G protein activators, the production of 32P-PtdBut was increased in a dose-dependent manner. The G protein involved was pertussis toxin insensitive. Ethanol could activate PLD but was itself consumed by PLD as transphosphatidylation substrate. In contrast, secondary alcohols (e.g., sec-butyl alcohol) activated PLD but did not function as substrate, whereas tertiary alcohols did neither. Although most of the experiments were performed with the green alga Chlamydomonas eugametos, the relevance for higher plants was demonstrated by showing that PLD in carnation petals could also be activated by mastoparan. The results indicate that PLD activation must be considered as a potential signal transduction mechanism in plants, just as in animals. PMID:12242371

  4. 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.

  5. The activation of Wnt signaling by a STAT6-dependent macrophage phenotype promotes mucosal repair in murine IBD.

    PubMed

    Cosín-Roger, J; Ortiz-Masiá, D; Calatayud, S; Hernández, C; Esplugues, J V; Barrachina, M D

    2016-07-01

    The complete repair of the mucosa constitutes a key goal in inflammatory bowel disease (IBD) treatment. The Wnt signaling pathway mediates mucosal repair and M2 macrophages that coordinate efficient healing have been related to Wnt ligand expression. Signal transducer and activator of transcription 6 (STAT6) mediates M2 polarization in vitro and we hypothesize that a STAT6-dependent macrophage phenotype mediates mucosal repair in acute murine colitis by activating the Wnt signaling pathway. Our results reveal an impaired mucosal expression of M2 macrophage-associated genes and delayed wound healing in STAT6(-/-) mice treated with 2,4,6-trinitrobenzenesulfonic acid (TNBS). These mice also exhibited decreased mucosal expression of Wnt2b, Wnt7b, and Wnt10a, diminished protein levels of nuclear β-catenin that is mainly located in crypts adjacent to damage, and reduced mRNA expression of two Wnt/β-catenin target molecules Lgr5 and c-Myc when compared with wild-type (WT) mice. Murine peritoneal macrophages treated with interleukin-4 (IL-4) and polarized toward an M2a phenotype overexpressed Wnt2b, Wnt7b, and Wnt10a in a STAT6-dependent manner. Administration of a Wnt agonist as well as transfer of properly polarized M2a macrophages to STAT6(-/-) mice activated the Wnt signaling pathway in the damaged mucosa and accelerated wound healing. Our results demonstrate that a STAT6-dependent macrophage phenotype promotes mucosal repair in TNBS-treated mice through activation of the Wnt signaling pathway. PMID:26601901

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

    PubMed

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

    2004-09-01

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

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

    PubMed

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

    2016-10-01

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

  8. Dual-focus therapeutic ultrasound transducer for production of broad tissue lesions.

    PubMed

    Jeong, Jong Seob; Cannata, Jonathan M; Shung, K Kirk

    2010-11-01

    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

  9. 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)

  10. Robust Indoor Human Activity Recognition Using Wireless Signals.

    PubMed

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

    2015-01-01

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

  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. Activation of a signaling cascade by cytoskeleton stretch.

    PubMed

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

    2004-11-01

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

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

    PubMed

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

    2016-01-01

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

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

    PubMed

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

    2013-06-01

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

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

    NASA Astrophysics Data System (ADS)

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

    1996-01-01

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

  16. 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.

  17. Mitochondria and cell signalling

    PubMed Central

    Tait, Stephen W. G.; Green, Douglas R.

    2012-01-01

    Mitochondria have long been considered as crucial organelles, primarily for their roles in biosynthetic reactions such as ATP synthesis. However, it is becoming increasingly apparent that mitochondria are intimately involved in cell signalling pathways. Mitochondria perform various signalling functions, serving as platforms to initiate cell signalling, as well as acting as transducers and effectors in multiple processes. Here, we discuss the active roles that mitochondria have in cell death signalling, innate immunity and autophagy. Common themes of mitochondrial regulation emerge from these diverse but interconnected processes. These include: the outer mitochondrial membrane serving as a major signalling platform, and regulation of cell signalling through mitochondrial dynamics and by mitochondrial metabolites, including ATP and reactive oxygen species. Importantly, defects in mitochondrial control of cell signalling and in the regulation of mitochondrial homeostasis might underpin many diseases, in particular age-related pathologies. PMID:22448037

  18. Activation of the IL-6/JAK/STAT3 signaling pathway in human middle ear cholesteatoma epithelium

    PubMed Central

    Liu, Wei; Xie, Shumin; Chen, Xing; Rao, Xingwang; Ren, Hongmiao; Hu, Bing; Yin, Tuanfang; Xiang, Yuyan; Ren, Jihao

    2014-01-01

    Interleukin-6 (IL-6) is one of the most important cytokines which has been shown to play a critical role in the pathogenesis of cholesteatoma. In this study, we aimed to investigate the expression of interleukin-6 (IL-6) and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in middle ear cholesteatoma epithelium in an effort to determine the role of IL-6/JAK/STAT3 signaling pathway in the pathogenesis of cholesteatoma. Immunohistochemistry was used to examine the expression of IL-6 and p-STAT3 in 25 human middle ear cholesteatoma samples and 15 normal external auditory canal (EAC) epithelium specimens. We also analyzed the relation of IL-6 and p-STAT3 expression levels to the degree of bone destruction in cholesteatoma. We found that the expression of IL-6 and p-STAT3 were significantly higher in cholesteatoma epithelium than in normal EAC epithelium (p<0.05). In cholesteatoma epithelium, a significant positive association was observed between IL-6 and p-STAT3 expression (p<0.05). However, no significant relationships were observed between the degree of bone destruction and the levels of IL-6 and p-STAT3 expression (p>0.05). To conclude, our results support the concept that IL-6/JAK/STAT3 signaling pathway is active and may play an important role in the mechanisms of epithelial hyper-proliferation responsible for cholesteatoma. PMID:24551293

  19. Dual Pten/Tp53 Suppression Promotes Sarcoma Progression by Activating Notch Signaling

    PubMed Central

    Guijarro, Maria V.; Dahiya, Sonika; Danielson, Laura S.; Segura, Miguel F.; Vales-Lara, Frances M.; Menendez, Silvia; Popiolek, Dorota; Mittal, Khushbakhat; Wei, Jian Jun; Zavadil, Jiri; Cordon-Cardo, Carlos; Pandolfi, Pier Paolo; Hernando, Eva

    2014-01-01

    Soft tissue sarcomas are a heterogeneous group of tumors associated with poor clinical outcome. Although a subset of soft tissue sarcomas is characterized by simple karyotypes and recurrent chromosomal translocations, the mechanisms driving cytogenetically complex sarcomas are largely unknown. Clinical evidence led us to partially inactivate Pten and Tp53 in the smooth muscle lineage of mice, which developed high-grade undifferentiated pleomorphic sarcomas, leiomyosarcomas, and carcinosarcomas that widely recapitulate the human disease, including the aberrant karyotype and metastatic behavior. Pten was found haploinsufficient, whereas the wild-type allele of Tp53 invariably gained point mutations. Gene expression profiles showed up-regulated Notch signaling in PtenΔ/+Tp53Δ/+ tumors compared with Pten+/+Tp53Δ/+ tumors. Consistently, Pten silencing exacerbated the clonogenic and invasive potential of Tp53-deficient bone marrow–derived mouse mesenchymal stem cells and tumor cells and activated the Notch pathway. Moreover, the increased oncogenic behavior of PtenΔ/+Tp53Δ/+ and shPten-transduced Pten+/+Tp53Δ/+ tumor cells was counteracted by treatment with a γ-secretase inhibitor, suggesting that the aggressiveness of those tumors can be attributed, at least in part, to enhanced Notch signaling. This study demonstrates a cooperative role for Pten and Tp53 suppression in complex karyotype sarcomas while establishing Notch as an important functional player in the cross talk of these pathways during tumor progression. Our results highlight the importance of molecularly subclassifying patients with high-grade sarcoma for targeted treatments. PMID:23708211

  20. HIF-3α1 promotes colorectal tumor cell growth by activation of JAK-STAT3 signaling

    PubMed Central

    Xue, Xiang; Jungles, Kylie; Onder, Gunseli; Samhoun, Jalal; Győrffy, Balázs; Hardiman, Karin M.

    2016-01-01

    Hypoxic environment is critical in colorectal cancer (CRC) development. Most studies have mainly focused on hypoxia-inducible factor (HIF)-1α and HIF-2α as the major hypoxic transcription factors in CRC development and progression. However, the role of HIF-3α in CRC is not clear. Here we found that HIF-3α protein was increased in colorectal tumors from both mouse models and human patients. Moreover, increased HIF-3α expression was correlated with decreased survival. Overexpression of a long isoform of HIF-3α, HIF-3α1, increased cell growth in two CRC cell lines. Surprisingly, overexpressed HIF-3α1 was localized to the cytosol and increased phosphorylated signal transducer and activator of transcription 3 (p-STAT3). STAT3 inhibition effectively reduced p-STAT3 levels and cell growth induced by HIF-3α1. The activation of p-STAT3 was independent of the transcriptional activity of HIF-3α1. However, the inhibition of the upstream regulator Janus kinase (JAK) abolished HIF-3α1-induced p-STAT3 and cell growth. Together, these results demonstrated that HIF-3α1 promotes CRC cell growth by activation of the JAK-STAT3 signaling pathway through non-canonical transcription-independent mechanisms. PMID:26871465

  1. OTUB1 enhances TGFβ signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3

    PubMed Central

    Herhaus, Lina; Al-Salihi, Mazin; Macartney, Thomas; Weidlich, Simone; Sapkota, Gopal P.

    2013-01-01

    SMAD transcription factors are key intracellular transducers of TGFβ cytokines. SMADs are tightly regulated to ensure balanced cellular responses to TGFβ signals. Ubiquitylation has a key role in regulating SMAD stability and activity. Several E3 ubiquitin ligases that regulate the turnover of SMADs are known; however, proteins that prevent the ubiquitylation or cause deubiquitylation of active SMADs remain undefined. Here we demonstrate that OTUB1 is recruited to the active phospho-SMAD2/3 complex only on TGFβ induction. Further, OTUB1 has a crucial role in TGFβ-mediated gene transcription and cellular migration. OTUB1 inhibits the ubiquitylation of phospho-SMAD2/3 by binding to and inhibiting the E2 ubiquitin-conjugating enzymes independent of its catalytic activity. Consequently, depletion of OTUB1 in cells causes a rapid loss in levels of TGFβ-induced phospho-SMAD2/3, which is rescued by the proteasomal inhibitor bortezomib. Our findings uncover a signal-induced phosphorylation-dependent recruitment of OTUB1 to its target in the TGFβ pathway. PMID:24071738

  2. 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.

  3. Sphingosine-1-Phosphate Enhances Satellite Cell Activation in Dystrophic Muscles through a S1PR2/STAT3 Signaling Pathway

    PubMed Central

    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. PMID:22606352

  4. 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. PMID:22606352

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

    PubMed

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

    2013-02-01

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

  6. Gq signaling causes glomerular injury by activating TRPC6

    PubMed Central

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

    2015-01-01

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

  7. 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.

  8. Optically transduced MEMS magnetometer

    SciTech Connect

    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.

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

    PubMed

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

    2016-04-13

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

  10. 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.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

    Ho, Yi-Hsuan

    2016-01-01

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

  13. Adjustable holder for transducer mounting

    NASA Technical Reports Server (NTRS)

    Deotsch, R. C.

    1980-01-01

    Positioning of acoustic sensor, strain gage, or similar transducer is facilitated by adjustable holder. Developed for installation on Space Shuttle, it includes springs for maintaining uniform load on transducer with adjustable threaded cap for precisely controlling position of sensor with respect to surrounding structure.

  14. The Amiloride Derivative Phenamil Attenuates Pulmonary Vascular Remodeling by Activating NFAT and the Bone Morphogenetic Protein Signaling Pathway ▿

    PubMed Central

    Chan, Mun Chun; Weisman, Alexandra S.; Kang, Hara; Nguyen, Peter H.; Hickman, Tyler; Mecker, Samantha V.; Hill, Nicholas S.; Lagna, Giorgio; Hata, Akiko

    2011-01-01

    Pulmonary artery hypertension (PAH) is characterized by elevated pulmonary artery resistance and increased medial thickness due to deregulation of vascular remodeling. Inactivating mutations of the BMPRII gene, which encodes a receptor for bone morphogenetic proteins (BMPs), are identified in ∼60% of familial PAH (FPAH) and ∼30% of idiopathic PAH (IPAH) patients. It has been hypothesized that constitutive reduction in BMP signal by BMPRII mutations may cause abnormal vascular remodeling by promoting dedifferentiation of vascular smooth muscle cells (vSMCs). Here, we demonstrate that infusion of the amiloride analog phenamil during chronic-hypoxia treatment in rat attenuates development of PAH and vascular remodeling. Phenamil induces Tribbles homolog 3 (Trb3), a positive modulator of the BMP pathway that acts by stabilizing the Smad family signal transducers. Through induction of Trb3, phenamil promotes the differentiated, contractile vSMC phenotype characterized by elevated expression of contractile genes and reduced cell growth and migration. Phenamil activates the Trb3 gene transcription via activation of the calcium-calcineurin-nuclear factor of activated T cell (NFAT) pathway. These results indicate that constitutive elevation of Trb3 by phenamil is a potential therapy for IPAH and FPAH. PMID:21135135

  15. 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

  16. 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

  17. Notum deacylates Wnt proteins to suppress signalling activity.

    PubMed

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

    2015-03-12

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

  18. 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

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

    PubMed

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

    2016-03-01

    Angiotensin II (Ang II) is an important mammalian neurohormone involved in reninangiotensin system. Ang II is produced both constitutively and locally by RAS systems, including white fat adipocytes. The influence of Ang II on adipocytes is complex, affecting different systems of signal transduction from early Са(2+) responses to cell proliferation and differentiation, triglyceride accumulation, expression of adipokine-encoding genes and adipokine secretion. It is known that white fat adipocytes express all RAS components and Ang II receptors (АТ1 and АТ2). The current work was carried out with the primary white adipocytes culture, and Са(2+) signaling pathways activated by Ang II were investigated using fluorescent microscopy. Са(2+)-oscillations and transient responses of differentiated adipocytes to Ang II were registered in cells with both small and multiple lipid inclusions. Using inhibitory analysis and selective antagonists, we now show that Ang II initiates periodic Са(2+)-oscillations and transient responses by activating АТ1 and АТ2 receptors and involving branched signaling cascades: 1) Ang II → Gq → PLC → IP3 → IP3Rs → Ca(2+) 2) Gβγ → PI3Kγ → PKB 3) PKB → eNOS → NO → PKG 4) CD38 → cADPR → RyRs → Ca(2+) In these cascades, AT1 receptors play the leading role. The results of the present work open a perspective of using Ang II for correction of signal resistance of adipocytes often observed during obesity and type 2 diabetes. PMID:26850364

  20. 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

  1. 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.

  2. 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

  3. 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.

  4. A Poynting vector transducer for transmission line monitoring and protection

    SciTech Connect

    Fam, W.Z. )

    1994-01-01

    A new type of transducer is described which enables the continuous monitoring of transmission line current voltage, real and reactive power, and which can also be used to operate the relays necessary for the protection of the line. The new transducer is designed as an integrated unit containing both the current and voltage sensors, thus eliminating the need for conventional current transformers and voltage transformers. The signals from the two sensors are processed using a simple electronic circuit which brings them to a level suitable for metering and relaying purposes. An analogue to digital interface enables the transducer to be connected to a computer for continuous data acquisition storage and monitoring. Due to its geometry and its simple structure, the transducer is ideally suitable for integration into a gas-insulated busbar duct system.

  5. Piezoelectric and electrostrictive effects in ferroelectret ultrasonic transducers

    NASA Astrophysics Data System (ADS)

    Döring, Joachim; Bovtun, Viktor; Gaal, Mate; Bartusch, Jürgen; Erhard, Anton; Kreutzbruck, Marc; Yakymenko, Yuriy

    2012-10-01

    Electromechanical response of polypropylene ferroelectret transducers under application of high-voltage pulses was measured by laser Doppler vibrometry and compared with results of ultrasonic through-air transmission between two ferroelectret transducers. The electromechanical response was completely explained by piezoelectric and electrostrictive effects. The electrostrictive effect dominates at high voltages and provides significant enlargement of the transducer constant, up to factor of 2.5. The induced strain of 1.7% was achieved at -2000 V. The nonlinear ultrasonic transmission was shown to be well described by the piezoelectric and electrostrictive response of transmitter, except in the range of high negative exciting voltages where some limitation of the transmitted signal was observed. This limitation seems not to be a fundamental one and does not abolish the advantages of high-voltage excitation of polypropylene ferroelectret transducers.

  6. Photoacoustic tomography of monkey brain using virtual point ultrasonic transducers

    NASA Astrophysics Data System (ADS)

    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. Digital signaling decouples activation probability and population heterogeneity

    PubMed Central

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

    2015-01-01

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

  8. Digital signaling decouples activation probability and population heterogeneity.

    PubMed

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

    2015-01-01

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

  9. Activity-Based Probe for Histidine Kinase Signaling

    PubMed Central

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

    2012-01-01

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

  10. Development of smart piezoelectric transducer self-sensing, self-diagnosis and tuning schemes for structural health monitoring applications

    NASA Astrophysics Data System (ADS)

    Lee, Sang Jun

    Autonomous structural health monitoring (SHM) systems using active sensing devices have been studied extensively to diagnose the current state of aerospace, civil infrastructure and mechanical systems in near real-time and aims to eventually reduce life-cycle costs by replacing current schedule-based maintenance with condition-based maintenance. This research develops four schemes for SHM applications: (1) a simple and reliable PZT transducer self-sensing scheme; (2) a smart PZT self-diagnosis scheme; (3) an instantaneous reciprocity-based PZT diagnosis scheme; and (4) an effective PZT transducer tuning scheme. First, this research develops a PZT transducer self-sensing scheme, which is a necessary condition to accomplish a PZT transducer self-diagnosis. Main advantages of the proposed self-sensing approach are its simplicity and adaptability. The necessary hardware is only an additional self-sensing circuit which includes a minimum of electric components. With this circuit, the self-sensing parameters can be calibrated instantaneously in the presence of changing operational and environmental conditions of the system. In particular, this self-sensing scheme focuses on estimating the mechanical response in the time domain for the subsequent applications of the PZT transducer self-diagnosis and tuning with guided wave propagation. The most significant challenge of this self-sensing comes from the fact that the magnitude of the mechanical response is generally several orders of magnitude smaller than that of the input signal. The proposed self-sensing scheme fully takes advantage of the fact that any user-defined input signals can be applied to a host structure and the input waveform is known. The performance of the proposed self-sensing scheme is demonstrated by theoretical analysis, numerical simulations and various experiments. Second, this research proposes a smart PZT transducer self-diagnosis scheme based on the developed self-sensing scheme. Conventionally, the

  11. Digital Signal Processing System for Active Noise Reduction

    NASA Astrophysics Data System (ADS)

    Edmonson, William W.; Tucker, Jerry

    2002-12-01

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

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

    PubMed

    Baba, Yoshihiro; Kurosaki, Tomohiro

    2016-01-01

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

  13. 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.

  14. 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.

  15. OsBRI1 Activates BR Signaling by Preventing Binding between the TPR and Kinase Domains of OsBSK3 via Phosphorylation.

    PubMed

    Zhang, Baowen; Wang, Xiaolong; Zhao, Zhiying; Wang, Ruiju; Huang, Xiahe; Zhu, Yali; Yuan, Li; Wang, Yingchun; Xu, Xiaodong; Burlingame, Alma L; Gao, Yingjie; Sun, Yu; Tang, Wenqiang

    2016-02-01

    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

  16. Calcium-Oxidant Signaling Network Regulates AMP-activated Protein Kinase (AMPK) Activation upon Matrix Deprivation*

    PubMed Central

    Sundararaman, Ananthalakshmy; Amirtham, Usha; Rangarajan, Annapoorni

    2016-01-01

    The AMP-activated protein kinase (AMPK) has recently been implicated in anoikis resistance. However, the molecular mechanisms that activate AMPK upon matrix detachment remain unexplored. In this study, we show that AMPK activation is a rapid and sustained phenomenon upon matrix deprivation, whereas re-attachment to the matrix leads to its dephosphorylation and inactivation. Because matrix detachment leads to loss of integrin signaling, we investigated whether integrin signaling negatively regulates AMPK activation. However, modulation of focal adhesion kinase or Src, the major downstream components of integrin signaling, failed to cause a corresponding change in AMPK signaling. Further investigations revealed that the upstream AMPK kinases liver kinase B1 (LKB1) and Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) contribute to AMPK activation upon detachment. In LKB1-deficient cells, we found AMPK activation to be predominantly dependent on CaMKKβ. We observed no change in ATP levels under detached conditions at early time points suggesting that rapid AMPK activation upon detachment was not triggered by energy stress. We demonstrate that matrix deprivation leads to a spike in intracellular calcium as well as oxidant signaling, and both these intracellular messengers contribute to rapid AMPK activation upon detachment. We further show that endoplasmic reticulum calcium release-induced store-operated calcium entry contributes to intracellular calcium increase, leading to reactive oxygen species production, and AMPK activation. We additionally show that the LKB1/CaMKK-AMPK axis and intracellular calcium levels play a critical role in anchorage-independent cancer sphere formation. Thus, the Ca2+/reactive oxygen species-triggered LKB1/CaMKK-AMPK signaling cascade may provide a quick, adaptable switch to promote survival of metastasizing cancer cells. PMID:27226623

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

    PubMed Central

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

    2016-01-01

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

  18. 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. PMID:24668815

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

    PubMed

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

    2002-01-15

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

  20. Transsynaptic signaling by activity-dependent cleavage of neuroligin-1.

    PubMed

    Peixoto, Rui T; Kunz, Portia A; Kwon, Hyungbae; Mabb, Angela M; Sabatini, Bernardo L; Philpot, Benjamin D; Ehlers, Michael D

    2012-10-18

    Adhesive contact between pre- and postsynaptic neurons initiates synapse formation during brain development and provides a natural means of transsynaptic signaling. Numerous adhesion molecules and their role during synapse development have been described in detail. However, once established, the mechanisms of adhesive disassembly and its function in regulating synaptic transmission have been unclear. Here, we report that synaptic activity induces acute proteolytic cleavage of neuroligin-1 (NLG1), a postsynaptic adhesion molecule at glutamatergic synapses. NLG1 cleavage is triggered by NMDA receptor activation, requires Ca2+ /calmodulin-dependent protein kinase, and is mediated by proteolytic activity of matrix metalloprotease 9 (MMP9). Cleavage of NLG1 occurs at single activated spines, is regulated by neural activity in vivo, and causes rapid destabilization of its presynaptic partner neurexin-1β (NRX1β). In turn, NLG1 cleavage depresses synaptic transmission by abruptly reducing presynaptic release probability. Thus, local proteolytic control of synaptic adhesion tunes synaptic transmission during brain development and plasticity. PMID:23083741

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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. PMID:12565074

  6. 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.

  7. A novel nuclear export signal in Smad1 is essential for its signaling activity.

    PubMed

    Xiao, Zhan; Brownawell, Amy M; Macara, Ian G; Lodish, Harvey F

    2003-09-01

    To investigate the subcellular distributions of Smad proteins, the intracellular mediators of transforming growth factor-beta family cytokines, we examined their sequences for nuclear export signals (NES). We found a leucine-rich NES-like motif (termed NES2) in the central linker region of the receptor-regulated Smads that is absent from the other two classes of Smads (Co-Smads and I-Smads). In microinjection assays, NES2 peptide caused nuclear export of a fused glutathione S-transferase protein. Mutations in NES2 converted Smad1 from an even distribution throughout the cells into an exclusive nuclear localization in both transiently and stably expressing cell lines, and this nuclear enrichment was more pronounced than that induced by mutations in NES1. Furthermore, overexpression of CRM1, the cellular export receptor, transforms Smad1 into a mostly cytoplasmic profile by enhancing its nuclear export. The Smad1 NES2 mutant but not the Smad1 NES1 mutant is mostly resistant to this cytoplasmic targeting, indicating that NES2, not NES1, is the major target for CRM1 in Smad1. We further confirmed the functionality of NES2 by a heterokaryon assay. The Smad1 NES1 mutant displays good ligand responsiveness and moderately lowered transcriptional activity compared with wild type Smad1. In contrast, the Smad1 NES2 mutant shows a severe disruption in reporter gene activation, minimal response to bone morphogenetic protein stimulation, and significantly lowered bone morphogenetic protein-induced phosphorylation, which may be the reason for its deficient transcription activity. Thus, we have defined a major NES in Smad1 that is essential for its ligand-induced coupling with cell surface receptors and hence, transcriptional activity. Our study, along with recent studies of the nucleocytoplasmic shuttling of Smad2 and Smad3 proteins, demonstrate that continued nucleocytoplasmic shuttling is a common requisite for the active signaling of R-Smads. Although conserved in other R

  8. Dynamic neural activity during stress signals resilient coping.

    PubMed

    Sinha, Rajita; Lacadie, Cheryl M; Constable, R Todd; Seo, Dongju

    2016-08-01

    Active coping underlies a healthy stress response, but neural processes supporting such resilient coping are not well-known. Using a brief, sustained exposure paradigm contrasting highly stressful, threatening, and violent stimuli versus nonaversive neutral visual stimuli in a functional magnetic resonance imaging (fMRI) study, we show significant subjective, physiologic, and endocrine increases and temporally related dynamically distinct patterns of neural activation in brain circuits underlying the stress response. First, stress-specific sustained increases in the amygdala, striatum, hypothalamus, midbrain, right insula, and right dorsolateral prefrontal cortex (DLPFC) regions supported the stress processing and reactivity circuit. Second, dynamic neural activation during stress versus neutral runs, showing early increases followed by later reduced activation in the ventrolateral prefrontal cortex (VLPFC), dorsal anterior cingulate cortex (dACC), left DLPFC, hippocampus, and left insula, suggested a stress adaptation response network. Finally, dynamic stress-specific mobilization of the ventromedial prefrontal cortex (VmPFC), marked by initial hypoactivity followed by increased VmPFC activation, pointed to the VmPFC as a key locus of the emotional and behavioral control network. Consistent with this finding, greater neural flexibility signals in the VmPFC during stress correlated with active coping ratings whereas lower dynamic activity in the VmPFC also predicted a higher level of maladaptive coping behaviors in real life, including binge alcohol intake, emotional eating, and frequency of arguments and fights. These findings demonstrate acute functional neuroplasticity during stress, with distinct and separable brain networks that underlie critical components of the stress response, and a specific role for VmPFC neuroflexibility in stress-resilient coping. PMID:27432990

  9. 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

  10. Integrated transducer for color distinction

    NASA Astrophysics Data System (ADS)

    Kato, Hisao; Kojima, Masahiko; Yoshida, Akira

    1983-06-01

    A method for fabricating the improved version of an integrated transducer for color distinction is proposed. It consists of three SnO2(n)-Si(n) photodiodes on a Si wafer and a trichromatic filter prepared by arranging filters of the three primary colors (Eastman Kodak gelatin filters; Nos. 47B, 58, and 25) on an infrared glass filter (Hoya Glass; B-460). Its photoelectric characteristics and dependence of error of color distinction on the dimension of the transducer are reported. The photodiodes employed in this conversion assembly are produced by the simple spray method and are most suitable for detecting the low illumination. Since this transducer adapts the trichromatic color resolution method, highly accurate color distinction is possible. With this type of transducer, three photodiodes sensitive to the primary colors, red, green, and blue, respectively, are arranged on a plane. An error in color distinction can occur due to the differences in the strength of the light incident upon the respective photodiodes. This problem is reduced by making the transducer more compact. Finally, 11 kinds of colors are discerned in this experiment as an application of the transducer.

  11. 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

  12. Aurora A kinase activity influences calcium signaling in kidney cells.

    PubMed

    Plotnikova, Olga V; Pugacheva, Elena N; Golemis, Erica A

    2011-06-13

    Most studies of Aurora A (AurA) describe it as a mitotic centrosomal kinase. However, we and others have recently identified AurA functions as diverse as control of ciliary resorption, cell differentiation, and cell polarity control in interphase cells. In these activities, AurA is transiently activated by noncanonical signals, including Ca(2+)-dependent calmodulin binding. These and other observations suggested that AurA might be involved in pathological conditions, such as polycystic kidney disease (PKD). In this paper, we show that AurA is abundant in normal kidney tissue but is also abnormally expressed and activated in cells lining PKD-associated renal cysts. PKD arises from mutations in the PKD1 or PKD2 genes, encoding polycystins 1 and 2 (PC1 and PC2). AurA binds, phosphorylates, and reduces the activity of PC2, a Ca(2+)-permeable nonselective cation channel and, thus, limits the amplitude of Ca(2+) release from the endoplasmic reticulum. These and other findings suggest AurA may be a relevant new biomarker or target in the therapy of PKD. PMID:21670214

  13. 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.

  14. Nitric Oxide Signaling in Pseudomonas aeruginosa Biofilms Mediates Phosphodiesterase Activity, Decreased Cyclic Di-GMP Levels, and Enhanced Dispersal▿ †

    PubMed Central

    Barraud, Nicolas; Schleheck, David; Klebensberger, Janosch; Webb, Jeremy S.; Hassett, Daniel J.; Rice, Scott A.; Kjelleberg, Staffan

    2009-01-01

    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. PMID:19801410

  15. 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.

  16. JAK1 Activates STAT3 Activity in Non-Small-Cell Lung Cancer cells and IL-6 Neutralizing Antibodies can Suppress JAK1-STAT3 Signaling

    PubMed Central

    Song, Lanxi; Rawal, Bhupendra; Nemeth, Jeffrey A.; Haura, Eric B.

    2014-01-01

    Members of the signal transducer and activator of transcription (STAT) family of transcription factors are potential targets for the treatment and prevention of cancers including non-small-cell lung cancer. STAT proteins can be phosphorylated and activated by diverse upstream kinases including cytokine receptors and tyrosine kinases. We examined STAT protein activation in lung cancer cell lines including those with activating mutations in the EGFR and examined upstream kinases responsible for STAT3 phosphorylation and activation using small molecules, antibodies, and RNA interference. We found more pronounced STAT3 activation in cells with activating EGFR mutations yet inhibition of EGFR activity had no effect on STAT3 activation. Inhibition of JAK1 with small molecules or RNA interference resulted in loss of STAT3 tyrosine phosphorylation and inhibition of cell growth. An interleukin-6 neutralizing antibody, siltuximab (CNTO 328) could inhibit STAT3 tyrosine phosphorylation in a cell-dependent manner. Siltuximab could completely inhibit STAT3 tyrosine phosphorylation in H1650 cells and this resulted in inhibition of lung cancer cell growth in vivo. Combined EGFR inhibition with erlotinib and siltuximab resulted in dual inhibition of both tyrosine and serine STAT3 phosphorylation, more pronounced inhibition of STAT3 transcriptional activity, and translated into combined effects on lung cancer growth in a mouse model. Our results suggest that JAK1 is responsible for STAT3 activation in lung cancer cells, and that indirect attacks on JAK1-STAT3 using an IL-6 neutralizing antibody with or without EGFR inhibition can inhibit lung cancer growth in lung cancer subsets. PMID:21216930

  17. Bisphenol A (BPA) stimulates the interferon signaling and activates the inflammasome activity in myeloid cells.

    PubMed

    Panchanathan, Ravichandran; Liu, Hongzhu; Leung, Yuet-Kin; Ho, Shuk-mei; Choubey, Divaker

    2015-11-01

    Environmental factors contribute to the development of autoimmune diseases, including systemic lupus erythematosus (SLE), which exhibits a strong female bias (female-to-male ratio 9:1). However, the molecular mechanisms remain largely unknown. Because a feedforward loop between the female sex hormone estrogen (E2) and type I interferon (IFN-α/β)-signaling induces the expression of certain p200-family proteins (such as murine p202 and human IFI16) that regulate innate immune responses and modify lupus susceptibility, we investigated whether treatment of myeloid cells with bisphenol A (BPA), an environmental estrogen, could regulate the p200-family proteins and activate innate immune responses. We found that treatment of murine bone marrow-derived cells (BMCs) and human peripheral blood mononuclear cells with BPA induced the expression of ERα and IFN-β, activated the IFN-signaling, and stimulated the expression of the p202 and IFI16 proteins. Further, the treatment increased levels of the NLRP3 inflammasome and stimulated its activity. Accordingly, BPA-treatment of BMCs from non lupus-prone C57BL/6 and the lupus-prone (NZB×NZW)F1 mice activated the type I IFN-signaling, induced the expression of p202, and activated an inflammasome activity. Our study demonstrates that BPA-induced signaling in the murine and human myeloid cells stimulates the type I IFN-signaling that results in an induction of the p202 and IFI16 innate immune sensors for the cytosolic DNA and activates an inflammasome activity. These observations provide novel molecular insights into the role of environmental BPA exposures in potentiating the development of certain autoimmune diseases such as SLE. PMID:26277401

  18. Software for Correcting the Dynamic Error of Force Transducers

    PubMed Central

    Miyashita, Naoki; Watanabe, Kazuhide; Irisa, Kyouhei; Iwashita, Hiroshi; Araki, Ryosuke; Takita, Akihiro; Yamaguchi, Takao; Fujii, Yusaku

    2014-01-01

    Software which corrects the dynamic error of force transducers in impact force measurements using their own output signal has been developed. The software corrects the output waveform of the transducers using the output waveform itself, estimates its uncertainty and displays the results. In the experiment, the dynamic error of three transducers of the same model are evaluated using the Levitation Mass Method (LMM), in which the impact forces applied to the transducers are accurately determined as the inertial force of the moving part of the aerostatic linear bearing. The parameters for correcting the dynamic error are determined from the results of one set of impact measurements of one transducer. Then, the validity of the obtained parameters is evaluated using the results of the other sets of measurements of all the three transducers. The uncertainties in the uncorrected force and those in the corrected force are also estimated. If manufacturers determine the correction parameters for each model using the proposed method, and provide the software with the parameters corresponding to each model, then users can obtain the waveform corrected against dynamic error and its uncertainty. The present status and the future prospects of the developed software are discussed in this paper. PMID:25004158