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Sample records for multiple downstream signaling

  1. Temporal effects of Notch signaling and potential cooperation with multiple downstream effectors on adenohypophysis cell specification in zebrafish.

    Science.gov (United States)

    Nakahara, Yoshinari; Muto, Akihiko; Hirabayashi, Ryo; Sakuma, Tetsushi; Yamamoto, Takashi; Kume, Shoen; Kikuchi, Yutaka

    2016-05-01

    The adenohypophysis (AH) consists of six distinct types of hormone-secreting cells. In zebrafish, although proper differentiation of all AH cell types has been shown to require Notch signaling within a period of 14-16 h postfertilization (hpf), the mechanisms underlying this process remain to be elucidated. Herein, we observed using the Notch inhibitor dibenzazepine (DBZ) that Notch signaling also contributed to AH cell specification beyond 16 hpf. Specification of distinct cell types was perturbed by DBZ treatment for different time frames, suggesting that AH cells are specified by Notch-dependent and cell-type-specific mechanisms. We also found that two hes-family genes, her4.1 and hey1, were expressed in the developing AH under the influence of Notch signaling. her4.1 knockdown reduced expression of proopiomelanocortin a (pomca), growth hormone (gh), and prolactin, whereas hey1 was responsible only for gh expression. Simultaneous loss of both Her4.1 and Hey1 produced milder phenotypes than that of DBZ-treated embryos. Moreover, DBZ treatment from 18 hpf led to a significant down-regulation of both gh and pomca genes only when combined with injection of a subthreshold level of her4.1-morpholino. These observations suggest that multiple downstream effectors, including Her4.1 and Hey1, mediate Notch signaling during AH cell specification. © 2016 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

  2. HPV18 Persistence Impairs Basal and DNA Ligand-Mediated IFN-β and IFN-λ1 Production through Transcriptional Repression of Multiple Downstream Effectors of Pattern Recognition Receptor Signaling.

    Science.gov (United States)

    Albertini, Silvia; Lo Cigno, Irene; Calati, Federica; De Andrea, Marco; Borgogna, Cinzia; Dell'Oste, Valentina; Landolfo, Santo; Gariglio, Marisa

    2018-03-15

    Although it is clear that high-risk human papillomaviruses (HPVs) can selectively infect keratinocytes and persist in the host, it still remains to be unequivocally determined whether they can escape antiviral innate immunity by interfering with pattern recognition receptor (PRR) signaling. In this study, we have assessed the innate immune response in monolayer and organotypic raft cultures of NIKS cells harboring multiple copies of episomal HPV18 (NIKSmcHPV18), which fully recapitulates the persistent state of infection. We show for the first time, to our knowledge, that NIKSmcHPV18, as well as HeLa cells (a cervical carcinoma-derived cell line harboring integrated HPV18 DNA), display marked downregulation of several PRRs, as well as other PRR downstream effectors, such as the adaptor protein stimulator of IFN genes and the transcription factors IRF1 and 7. Importantly, we provide evidence that downregulation of stimulator of IFN genes, cyclic GMP-AMP synthase, and retinoic acid-inducible gene I mRNA levels occurs at the transcriptional level through a novel epigenetic silencing mechanism, as documented by the accumulation of repressive heterochromatin markers seen at the promoter region of these genes. Furthermore, stimulation of NIKSmcHPV18 cells with salmon sperm DNA or poly(deoxyadenylic-deoxythymidylic) acid, two potent inducers of PRR signaling, only partially restored PRR protein expression. Accordingly, the production of IFN-β and IFN-λ 1 was significantly reduced in comparison with the parental NIKS cells, indicating that HPV18 exerts its immunosuppressive activity through downregulation of PRR signaling. Altogether, our findings indicate that high-risk human papillomaviruses have evolved broad-spectrum mechanisms that allow simultaneous depletion of multiple effectors of the innate immunity network, thereby creating an unreactive cellular milieu suitable for viral persistence. Copyright © 2018 by The American Association of Immunologists, Inc.

  3. Evaluation of Intracellular Signaling Downstream Chimeric Antigen Receptors.

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    Hannah Karlsson

    Full Text Available CD19-targeting CAR T cells have shown potency in clinical trials targeting B cell leukemia. Although mainly second generation (2G CARs carrying CD28 or 4-1BB have been investigated in patients, preclinical studies suggest that third generation (3G CARs with both CD28 and 4-1BB have enhanced capacity. However, little is known about the intracellular signaling pathways downstream of CARs. In the present work, we have analyzed the signaling capacity post antigen stimulation in both 2G and 3G CARs. 3G CAR T cells expanded better than 2G CAR T cells upon repeated stimulation with IL-2 and autologous B cells. An antigen-driven accumulation of CAR+ cells was evident post antigen stimulation. The cytotoxicity of both 2G and 3G CAR T cells was maintained by repeated stimulation. The phosphorylation status of intracellular signaling proteins post antigen stimulation showed that 3G CAR T cells had a higher activation status than 2G. Several proteins involved in signaling downstream the TCR were activated, as were proteins involved in the cell cycle, cell adhesion and exocytosis. In conclusion, 3G CAR T cells had a higher degree of intracellular signaling activity than 2G CARs which may explain the increased proliferative capacity seen in 3G CAR T cells. The study also indicates that there may be other signaling pathways to consider when designing or evaluating new generations of CARs.

  4. Feeding by whiteflies suppresses downstream jasmonic acid signaling by eliciting salicylic acid signaling.

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    Zhang, Peng-Jun; Li, Wei-Di; Huang, Fang; Zhang, Jin-Ming; Xu, Fang-Cheng; Lu, Yao-Bin

    2013-05-01

    Phloem-feeding whiteflies in the species complex Bemisia tabaci cause extensive crop damage worldwide. One of the reasons for their "success" is their ability to suppress the effectual jasmonic acid (JA) defenses of the host plant. However, little is understood about the mechanisms underlying whitefly suppression of JA-regulated defenses. Here, we showed that the expression of salicylic acid (SA)-responsive genes (EDS1 and PR1) in Arabidopsis thaliana was significantly enhanced during feeding by whitefly nymphs. Whereas upstream JA-responsive genes (LOX2 and OPR3) also were induced, the downstream JA-responsive gene (VSP1) was repressed, i.e., whiteflies only suppressed downstream JA signaling. Gene-expression analyses with various Arabidopsis mutants, including NahG, npr-1, ein2-1, and dde2-2, revealed that SA signaling plays a key role in the suppression of downstream JA defenses by whitefly feeding. Assays confirmed that SA activation enhanced whitefly performance by suppressing downstream JA defenses.

  5. Cytoskeletal Reorganization Drives Mesenchymal Condensation and Regulates Downstream Molecular Signaling.

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    Poulomi Ray

    Full Text Available Skeletal condensation occurs when specified mesenchyme cells self-organize over several days to form a distinctive cartilage template. Here, we determine how and when specified mesenchyme cells integrate mechanical and molecular information from their environment, forming cartilage condensations in the pharyngeal arches of chick embryos. By disrupting cytoskeletal reorganization, we demonstrate that dynamic cell shape changes drive condensation and modulate the response of the condensing cells to Fibroblast Growth Factor (FGF, Bone Morphogenetic Protein (BMP and Transforming Growth Factor beta (TGF-β signaling pathways. Rho Kinase (ROCK-driven actomyosin contractions and Myosin II-generated differential cell cortex tension regulate these cell shape changes. Disruption of the condensation process inhibits the differentiation of the mesenchyme cells into chondrocytes, demonstrating that condensation regulates the fate of the mesenchyme cells. We also find that dorsal and ventral condensations undergo distinct cell shape changes. BMP signaling is instructive for dorsal condensation-specific cell shape changes. Moreover, condensations exhibit ventral characteristics in the absence of BMP signaling, suggesting that in the pharyngeal arches ventral morphology is the ground pattern. Overall, this study characterizes the interplay between cytoskeletal dynamics and molecular signaling in a self-organizing system during tissue morphogenesis.

  6. Rapid phospho-turnover by receptor tyrosine kinases impacts downstream signaling and drug binding.

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    Kleiman, Laura B; Maiwald, Thomas; Conzelmann, Holger; Lauffenburger, Douglas A; Sorger, Peter K

    2011-09-02

    Epidermal growth factor receptors (ErbB1-4) are oncogenic receptor tyrosine kinases (RTKs) that regulate diverse cellular processes. In this study, we combine measurement and mathematical modeling to quantify phospho-turnover at ErbB receptors in human cells and to determine the consequences for signaling and drug binding. We find that phosphotyrosine residues on ErbB1 have half-lives of a few seconds and therefore turn over 100-1000 times in the course of a typical immediate-early response to ligand. Rapid phospho-turnover is also observed for EGF-activated ErbB2 and ErbB3, unrelated RTKs, and multiple intracellular adaptor proteins and signaling kinases. Thus, the complexes formed on the cytoplasmic tail of active receptors and the downstream signaling kinases they control are highly dynamic and antagonized by potent phosphatases. We develop a kinetic scheme for binding of anti-ErbB1 drugs to receptors and show that rapid phospho-turnover significantly impacts their mechanisms of action. Copyright © 2011 Elsevier Inc. All rights reserved.

  7. Cetuximab insufficiently inhibits glioma cell growth due to persistent EGFR downstream signaling

    DEFF Research Database (Denmark)

    Hasselbalch, Benedikte; Lassen, Ulrik; Poulsen, Hans S

    2010-01-01

    Overexpression and/or amplification of the epidermal growth factor receptor (EGFR) is present in 35-45% of primary glioblastoma multiforme tumors and has been correlated with a poor prognosis. In this study, we investigated the effect of cetuximab and intracellular signaling pathways downstream...... of EGFR, important for cell survival and proliferation. We show insufficient EGFR downregulation and competition with endogenous EGFR ligands upon cetuximab treatment. Dose-response experiments showed inhibition of EGFR phosphorylation without affecting two of the prominent downstream signaling pathways....... Our results indicate that amplification and/or overexpression of EGFR is an unsatisfactory predictor for response to cetuximab....

  8. Re-modulated technology of WDM-PON employing different DQPSK downstream signals

    Science.gov (United States)

    Gao, Chao; Xin, Xiang-jun; Yu, Chong-xiu

    2012-11-01

    This paper proposes a kind of modulation architecture for wavelength-division-multiplexing passive optical network (WDMPON) employing optical differential quadrature phase shift keying (DQPSK) downstream signals and two different modulation formats of re-modulated upstream signals. At the optical line terminal (OLT), 10 Gbit/s signal is modulated with DQPSK. At the optical network unit (ONU), part of the downstream signal is re-modulated with on-off keying (OOK) or inverse-return-to-zero (IRZ). Simulation results show the impact on the system employing NRZ, RZ and carrier-suppressed return-to-zero (CSRZ). The analyses also reflect that the architecture can restrain chromatic dispersion and channel crosstalk, which makes it the best architecture of access network in the future.

  9. The effect of CD4 receptor downregulation and its downstream signaling molecules on HIV-1 latency

    International Nuclear Information System (INIS)

    Kim, Kyung-Chang; Kim, Hyeon Guk; Roh, Tae-Young; Park, Jihwan; Jung, Kyung-Min; Lee, Joo-Shil; Choi, Sang-Yun; Kim, Sung Soon; Choi, Byeong-Sun

    2011-01-01

    Research highlights: → CD4 receptors were downregulated on the surface of HIV-1 latently infected cells. → CD4 downstream signaling molecules were suppressed in HIV-1 latently infected cells. → HIV-1 progeny can be reactivated by induction of T-cell activation signal molecules. → H3K4me3 and H3K9ac were highly enriched in CD4 downstream signaling molecules. → HIV-1 latency can be maintained by the reduction of downstream signaling molecules. -- Abstract: HIV-1 can establish a latent infection in memory CD4 + T cells to evade the host immune response. CD4 molecules can act not only as the HIV-1 receptor for entry but also as the trigger in an intracellular signaling cascade for T-cell activation and proliferation via protein tyrosine kinases. Novel chronic HIV-1-infected A3.01-derived (NCHA) cells were used to examine the involvement of CD4 downstream signaling in HIV-1 latency. CD4 receptors in NCHA cells were dramatically downregulated on its surface but were slightly decreased in whole-cell lysates. The expression levels of CD4 downstream signaling molecules, including P56 Lck , ZAP-70, LAT, and c-Jun, were sharply decreased in NCHA cells. The lowered histone modifications of H3K4me3 and H3K9ac correlated with the downregulation of P56 Lck , ZAP-70, and LAT in NCHA cells. AP-1 binding activity was also reduced in NCHA cells. LAT and c-Jun suppressed in NCHA cells were highly induced after PMA treatment. In epigenetic analysis, other signal transduction molecules which are associated with active and/or latent HIV-1 infection showed normal states in HIV-1 latently infected cells compared to A3.01 cells. In conclusion, we demonstrated that the HIV-1 latent state is sustained by the reduction of downstream signaling molecules via the downregulation of CD4 and the attenuated activity of transcription factor as AP-1. The HIV-1 latency model via T-cell deactivation may provide some clues for the development of the new antireservoir therapy.

  10. The effect of CD4 receptor downregulation and its downstream signaling molecules on HIV-1 latency

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kyung-Chang [National Institute of Health, Chungbuk (Korea, Republic of); School of Life Science and Biotechnology, Korea University, Seoul (Korea, Republic of); Kim, Hyeon Guk [National Institute of Health, Chungbuk (Korea, Republic of); Roh, Tae-Young [Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Park, Jihwan [Division of Molecular and Life Science, Pohang University of Science and Technology, Pohang, Gyeongbuk (Korea, Republic of); Jung, Kyung-Min; Lee, Joo-Shil [National Institute of Health, Chungbuk (Korea, Republic of); Choi, Sang-Yun [School of Life Science and Biotechnology, Korea University, Seoul (Korea, Republic of); Kim, Sung Soon [National Institute of Health, Chungbuk (Korea, Republic of); Choi, Byeong-Sun, E-mail: byeongsun@korea.kr [National Institute of Health, Chungbuk (Korea, Republic of)

    2011-01-14

    Research highlights: {yields} CD4 receptors were downregulated on the surface of HIV-1 latently infected cells. {yields} CD4 downstream signaling molecules were suppressed in HIV-1 latently infected cells. {yields} HIV-1 progeny can be reactivated by induction of T-cell activation signal molecules. {yields} H3K4me3 and H3K9ac were highly enriched in CD4 downstream signaling molecules. {yields} HIV-1 latency can be maintained by the reduction of downstream signaling molecules. -- Abstract: HIV-1 can establish a latent infection in memory CD4 + T cells to evade the host immune response. CD4 molecules can act not only as the HIV-1 receptor for entry but also as the trigger in an intracellular signaling cascade for T-cell activation and proliferation via protein tyrosine kinases. Novel chronic HIV-1-infected A3.01-derived (NCHA) cells were used to examine the involvement of CD4 downstream signaling in HIV-1 latency. CD4 receptors in NCHA cells were dramatically downregulated on its surface but were slightly decreased in whole-cell lysates. The expression levels of CD4 downstream signaling molecules, including P56{sup Lck}, ZAP-70, LAT, and c-Jun, were sharply decreased in NCHA cells. The lowered histone modifications of H3K4me3 and H3K9ac correlated with the downregulation of P56{sup Lck}, ZAP-70, and LAT in NCHA cells. AP-1 binding activity was also reduced in NCHA cells. LAT and c-Jun suppressed in NCHA cells were highly induced after PMA treatment. In epigenetic analysis, other signal transduction molecules which are associated with active and/or latent HIV-1 infection showed normal states in HIV-1 latently infected cells compared to A3.01 cells. In conclusion, we demonstrated that the HIV-1 latent state is sustained by the reduction of downstream signaling molecules via the downregulation of CD4 and the attenuated activity of transcription factor as AP-1. The HIV-1 latency model via T-cell deactivation may provide some clues for the development of the new

  11. MicroRNA-145 suppresses hepatocellular carcinoma by targeting IRS1 and its downstream Akt signaling

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Yelin [Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Hu, Chen; Cheng, Jun [Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Chen, Binquan [Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Ke, Qinghong; Lv, Zhen; Wu, Jian [Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China); Zhou, Yanfeng, E-mail: zyfhdj@yahoo.com [Department of Anesthesiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou (China)

    2014-04-18

    Highlights: • MiR-145 expression is down-regulated in HCC tissues and inversely related with IRS1 levels. • MiR-145 directly targets IRS1 in HCC cells. • Restored expression of miR-145 suppressed HCC cell proliferation and growth. • MiR-145 induced IRS1 under-expression potentially reduced downstream AKT signaling. - Abstract: Accumulating evidences have proved that dysregulation of microRNAs (miRNAs) is involved in cancer initiation and progression. In this study, we showed that miRNA-145 level was significantly decreased in hepatocellular cancer (HCC) tissues and cell lines, and its low expression was inversely associated with the abundance of insulin receptor substrate 1 (IRS1), a key mediator in oncogenic insulin-like growth factor (IGF) signaling. We verified IRS1 as a direct target of miR-145 using Western blotting and luciferase reporter assay. Further, the restoration of miR-145 in HCC cell lines suppressed cancer cell growth, owing to down-regulated IRS1 expression and its downstream Akt/FOXO1 signaling. Our results demonstrated that miR-145 could inhibit HCC through targeting IRS1 and its downstream signaling, implicating the loss of miR-145 regulation may be a potential molecular mechanism causing aberrant oncogenic signaling in HCC.

  12. A reverse signaling pathway downstream of Sema4A controls cell migration via Scrib.

    Science.gov (United States)

    Sun, Tianliang; Yang, Lida; Kaur, Harmandeep; Pestel, Jenny; Looso, Mario; Nolte, Hendrik; Krasel, Cornelius; Heil, Daniel; Krishnan, Ramesh K; Santoni, Marie-Josée; Borg, Jean-Paul; Bünemann, Moritz; Offermanns, Stefan; Swiercz, Jakub M; Worzfeld, Thomas

    2017-01-02

    Semaphorins comprise a large family of ligands that regulate key cellular functions through their receptors, plexins. In this study, we show that the transmembrane semaphorin 4A (Sema4A) can also function as a receptor, rather than a ligand, and transduce signals triggered by the binding of Plexin-B1 through reverse signaling. Functionally, reverse Sema4A signaling regulates the migration of various cancer cells as well as dendritic cells. By combining mass spectrometry analysis with small interfering RNA screening, we identify the polarity protein Scrib as a downstream effector of Sema4A. We further show that binding of Plexin-B1 to Sema4A promotes the interaction of Sema4A with Scrib, thereby removing Scrib from its complex with the Rac/Cdc42 exchange factor βPIX and decreasing the activity of the small guanosine triphosphatase Rac1 and Cdc42. Our data unravel a role for Plexin-B1 as a ligand and Sema4A as a receptor and characterize a reverse signaling pathway downstream of Sema4A, which controls cell migration. © 2017 Sun et al.

  13. Angiotensin II regulation of neuromodulation: downstream signaling mechanism from activation of mitogen-activated protein kinase.

    Science.gov (United States)

    Lu, D; Yang, H; Raizada, M K

    1996-12-01

    Angiotensin II (Ang II) stimulates expression of tyrosine hydroxylase and norepinephrine transporter genes in brain neurons; however, the signal-transduction mechanism is not clearly defined. This study was conducted to determine the involvement of the mitogen-activated protein (MAP) kinase signaling pathway in Ang II stimulation of these genes. MAP kinase was localized in the perinuclear region of the neuronal soma. Ang II caused activation of MAP kinase and its subsequent translocation from the cytoplasmic to nuclear compartment, both effects being mediated by AT1 receptor subtype. Ang II also stimulated SRE- and AP1-binding activities and fos gene expression and its translocation in a MAP kinase-dependent process. These observations are the first demonstration of a downstream signaling pathway involving MAP kinase in Ang II-mediated neuromodulation in noradrenergic neurons.

  14. Plant GSK3 proteins regulate xylem cell differentiation downstream of TDIF-TDR signalling

    Science.gov (United States)

    Kondo, Yuki; Ito, Tasuku; Nakagami, Hirofumi; Hirakawa, Yuki; Saito, Masato; Tamaki, Takayuki; Shirasu, Ken; Fukuda, Hiroo

    2014-03-01

    During plant radial growth typically seen in trees, procambial and cambial cells act as meristematic cells in the vascular system to self-proliferate and differentiate into xylem cells. These two processes are regulated by a signalling pathway composed of a peptide ligand and its receptor; tracheary element differentiation inhibitory factor (TDIF) and TDIF RECEPTOR (TDR). Here we show that glycogen synthase kinase 3 proteins (GSK3s) are crucial downstream components of the TDIF signalling pathway suppressing xylem differentiation from procambial cells. TDR interacts with GSK3s at the plasma membrane and activates GSK3s in a TDIF-dependent fashion. Consistently, a specific inhibitor of plant GSK3s strongly induces xylem cell differentiation through BRI1-EMS SUPPRESSOR 1 (BES1), a well-known target transcription factor of GSK3s. Our findings provide insight into the regulation of cell fate determination in meristem maintenance.

  15. Downstream reporter gene imaging for signal transduction pathway of dopamine type 2 receptor

    International Nuclear Information System (INIS)

    Le, Uyenchi N.; Min, Jung Joon; Moon, Sung Min; Bom, Hee Seung

    2004-01-01

    The Dopamine 2 receptor (D2R) signal pathway regulates gene expression by phosphorylation of proteins including cAMP reponse element-binding protein (CREB), a transcription factor. In this study, we developed a reporter strategy using the GAL4 fusion CREB to assess the phosphorylation of CREB, one of the targets of the D2R signal transduction pathway. We used three plasmids: GAL4 fusion transactivator (pCMV-CREB), firefly luciferase reporter with GAL4 binding sites (pG5-FLUC), and D2R plasmid (pCMV-D2R). Group 1 293T cells were transiently transfected with pCMV-CREB and pG5-FLUC, and group 2 cells were transfected with all three plasmids. Transfected cells were stimulated with different concentrations of dopamine (0-200 M). For animal studies, group 1 and 2 cells (1x10 6 ) were subcutaneously injected on the left and right thigh of six nude mice, respectively. Dopamine stimiulation was performed with intraperitoneal injection of L-DOPA incombination with carbidopa, a peripheral DOPA decarboxylase inhibitor. Bioluminescence optical imaging studies were performed before and after L-DOPA injection. In cell culture studies, group 1 cells showed strong luciferase activity which implies direct activation of the signaling pathway due to growth factors contained in culture medium. Group 2 cells showed strong luciferase activity and a further increase after administration of dopamine. In animal studies, group 1 and 2 cells showed bioluminescence signal before L-DOPA injection, but signal from group 2 cells significantly increased 12 h after L-DOPA injection. The signal from group 1 cells disappeared thereafter, but group 2 cells continued to show signal until 36 h of L-DOPA injection. This study demonstrates imaging of the D2R signal transduction pathway and should be useful for noninvasive imaging of downstream effects of G-coupled protein pathways

  16. The insulin receptor substrate (IRS)-1 pleckstrin homology domain functions in downstream signaling.

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    Vainshtein, I; Kovacina, K S; Roth, R A

    2001-03-16

    The pleckstrin homology (PH) domain of the insulin receptor substrate-1 (IRS-1) plays a role in directing this molecule to the insulin receptor, thereby regulating its tyrosine phosphorylation. In this work, the role of the PH domain in subsequent signaling was studied by constructing constitutively active forms of IRS-1 in which the inter-SH2 domain of the p85 subunit of phosphatidylinositol 3-kinase was fused to portions of the IRS-1 molecule. Chimeric molecules containing the PH domain were found to activate the downstream response of stimulating the Ser/Thr kinase Akt. A chimera containing point mutations in the PH domain that abolished the ability of this domain to bind phosphatidylinositol 4,5-bisphosphate prevented these molecules from activating Akt. These mutations also decreased by about 70% the amount of the constructs present in a particulate fraction of the cells. These results indicate that the PH domain of IRS-1, in addition to directing this protein to the receptor for tyrosine phosphorylation, functions in the ability of this molecule to stimulate subsequent responses. Thus, compromising the function of the PH domain, e.g. in insulin-resistant states, could decrease both the ability of IRS-1 to be tyrosine phosphorylated by the insulin receptor and to link to subsequent downstream targets.

  17. Rice PLASTOCHRON genes regulate leaf maturation downstream of the gibberellin signal transduction pathway.

    Science.gov (United States)

    Mimura, Manaki; Nagato, Yasuo; Itoh, Jun-Ichi

    2012-05-01

    Rice PLASTOCHRON 1 (PLA1) and PLA2 genes regulate leaf maturation and plastochron, and their loss-of-function mutants exhibit small organs and rapid leaf emergence. They encode a cytochrome P450 protein CYP78A11 and an RNA-binding protein, respectively. Their homologs in Arabidopsis and maize are also associated with plant development/organ size. Despite the importance of PLA genes in plant development, their molecular functions remain unknown. Here, we investigated how PLA1 and PLA2 genes are related to phytohormones. We found that gibberellin (GA) is the major phytohormone that promotes PLA1 and PLA2 expression. GA induced PLA1 and PLA2 expression, and conversely the GA-inhibitor uniconazole suppressed PLA1 and PLA2 expression. In pla1-4 and pla2-1 seedlings, expression levels of GA biosynthesis genes and the signal transduction gene were similar to those in wild-type seedlings. GA treatment slightly down-regulated the GA biosynthesis gene GA20ox2 and up-regulated the GA-catabolizing gene GA2ox4, whereas the GA biosynthesis inhibitor uniconazole up-regulated GA20ox2 and down-regulated GA2ox4 both in wild-type and pla mutants, suggesting that the GA feedback mechanism is not impaired in pla1 and pla2. To reveal how GA signal transduction affects the expression of PLA1 and PLA2, PLA expression in GA-signaling mutants was examined. In GA-insensitive mutant, gid1 and less-sensitive mutant, Slr1-d1, PLA1 and PLA2 expression was down-regulated. On the other hand, the expression levels of PLA1 and PLA2 were highly enhanced in a GA-constitutive-active mutant, slr1-1, causing ectopic overexpression. These results indicate that both PLA1 and PLA2 act downstream of the GA signal transduction pathway to regulate leaf development.

  18. PTHrP promotes malignancy of human oral cancer cell downstream of the EGFR signaling

    International Nuclear Information System (INIS)

    Yamada, Tamaki; Tsuda, Masumi; Ohba, Yusuke; Kawaguchi, Hideaki; Totsuka, Yasunori; Shindoh, Masanobu

    2008-01-01

    Parathyroid hormone-related protein (PTHrP) is detected in many aggressive tumors and involved in malignant conversion; however, the underlying mechanism remains obscure. Here, we identified PTHrP as a mediator of epidermal growth factor receptor (EGFR) signaling to promote the malignancies of oral cancers. PTHrP mRNA was abundantly expressed in most of the quiescent oral cancer cells, and was significantly upregulated by EGF stimulation via ERK and p38 MAPK. PTHrP silencing by RNA interference, as well as EGFR inhibitor AG1478 treatment, significantly suppressed cell proliferation, migration, and invasiveness. Furthermore, combined treatment of AG1478 and PTHrP knockdown achieved synergistic inhibition of malignant phenotypes. Recombinant PTHrP substantially promoted cell motility, and rescued the inhibition by PTHrP knockdown, suggesting the paracrine/autocrine function of PTHrP. These data indicate that PTHrP contributes to the malignancy of oral cancers downstream of EGFR signaling, and may thus provide a therapeutic target for oral cancer

  19. Blocking signaling at the level of GLI regulates downstream gene expression and inhibits proliferation of canine osteosarcoma cells.

    Science.gov (United States)

    Shahi, Mehdi Hayat; Holt, Roseline; Rebhun, Robert B

    2014-01-01

    The Hedgehog-GLI signaling pathway is active in a variety of human malignancies and is known to contribute to the growth and survival of human osteosarcoma cells. In this study, we examined the expression and regulation of GLI transcription factors in multiple canine osteosarcoma cell lines and analyzed the effects of inhibiting GLI with GANT61, a GLI-specific inhibitor. Compared with normal canine osteoblasts, real-time PCR showed that GLI1 and GLI2 were highly expressed in two out of three cell lines and correlated with downstream target gene expression of PTCH1and PAX6. Treatment of canine osteosarcoma cells with GANT61 resulted in decreased expression of GLI1, GLI2, PTCH1, and PAX6. Furthermore, GANT61 inhibited proliferation and colony formation in all three canine osteosarcoma cell lines. The finding that GLI signaling activity is present and active in canine osteosarcoma cells suggests that spontaneously arising osteosarcoma in dogs might serve as a good model for future preclinical testing of GLI inhibitors.

  20. Blocking signaling at the level of GLI regulates downstream gene expression and inhibits proliferation of canine osteosarcoma cells.

    Directory of Open Access Journals (Sweden)

    Mehdi Hayat Shahi

    Full Text Available The Hedgehog-GLI signaling pathway is active in a variety of human malignancies and is known to contribute to the growth and survival of human osteosarcoma cells. In this study, we examined the expression and regulation of GLI transcription factors in multiple canine osteosarcoma cell lines and analyzed the effects of inhibiting GLI with GANT61, a GLI-specific inhibitor. Compared with normal canine osteoblasts, real-time PCR showed that GLI1 and GLI2 were highly expressed in two out of three cell lines and correlated with downstream target gene expression of PTCH1and PAX6. Treatment of canine osteosarcoma cells with GANT61 resulted in decreased expression of GLI1, GLI2, PTCH1, and PAX6. Furthermore, GANT61 inhibited proliferation and colony formation in all three canine osteosarcoma cell lines. The finding that GLI signaling activity is present and active in canine osteosarcoma cells suggests that spontaneously arising osteosarcoma in dogs might serve as a good model for future preclinical testing of GLI inhibitors.

  1. Lamellipodia nucleation by filopodia depends on integrin occupancy and downstream Rac1 signaling

    International Nuclear Information System (INIS)

    Guillou, Herve; Depraz-Depland, Adeline; Planus, Emmanuelle; Vianay, Benoit; Chaussy, Jacques; Grichine, Alexei; Albiges-Rizo, Corinne; Block, Marc R.

    2008-01-01

    Time-lapse video-microscopy unambiguously shows that fibroblast filopodia are the scaffold of lamellipodia nucleation that allows anisotropic cell spreading. This process was dissected into elementary stages by monitoring cell adhesion on micropatterned extracellular matrix arrays of various pitches. Adhesion structures are stabilized by contact with the adhesive plots and subsequently converted into lamellipodia-like extensions starting at the filopodia tips. This mechanism progressively leads to full cell spreading. Stable expression of the dominant-negative Rac1 N17 impairs this change in membrane extension mode and stops cell spreading on matrix arrays. Similar expression of the dominant-negative Cdc42 N17 impairs cell spreading on homogenous and structured substrate, suggesting that filopodia extension is a prerequisite for cell spreading in this model. The differential polarity of the nucleation of lamellipodial structures by filopodia on homogenous and structured surfaces starting from the cell body and of filopodia tip, respectively, suggested that this process is triggered by areas that are in contact with extracellular matrix proteins for longer times. Consistent with this view, wild-type cells cannot spread on microarrays made of function blocking or neutral anti-β 1 integrin antibodies. However, stable expression of a constitutively active Rac1 mutant rescues the cell ability to spread on these integrin microarrays. Thereby, lamellipodia nucleation by filopodia requires integrin occupancy by matrix substrate and downstream Rac1 signaling

  2. Defective Connective Tissue Remodeling in Smad3 Mice Leads to Accelerated Aneurysmal Growth Through Disturbed Downstream TGF-β Signaling

    Directory of Open Access Journals (Sweden)

    I. van der Pluijm, PhD

    2016-10-01

    Smad3 deficiency leads to imbalanced activation of downstream genes, no activation of MMPs in VSMCs, and immune responses resulting in rapid aortic wall dilatation and rupture. Our findings uncover new possibilities for treatment of SMAD3 patients; instead of targeting TGF-β signaling, immune suppression may be more beneficial.

  3. Performance Analysis of Long-Reach Coherent Detection OFDM-PON Downstream Transmission Using m-QAM-Mapped OFDM Signal

    Science.gov (United States)

    Pandey, Gaurav; Goel, Aditya

    2017-12-01

    In this paper, orthogonal frequency division multiplexing (OFDM)-passive optical network (PON) downstream transmission is demonstrated over different lengths of fiber at remote node (RN) for different m-QAM (quadrature amplitude modulation)-mapped OFDM signal (m=4, 16, 32 and 64) transmission from the central office (CO) for different data rates (10, 20 30 and 40 Gbps) using coherent detection at the user end or optical network unit (ONU). Investigation is performed with different number of subcarriers (32, 64, 128, 512 and 1,024), back-to-back optical signal-to-noise ratio (OSNR) along with transmitted and received constellation diagrams for m-QAM-mapped coherent OFDM downstream transmission at different speeds over different transmission distances. Received optical power is calculated for different bit error rates (BERs) at different speeds using m-QAM-mapped coherent detection OFDM downstream transmission. No dispersion compensation is utilized in between the fiber span. Simulation results suggest the different lengths and data rates that can be used for different m-QAM-mapped coherent detection OFDM downstream transmission, and the proposed system may be implemented in next-generation high-speed PONs (NG-PONs).

  4. miR-342-5p Regulates Neural Stem Cell Proliferation and Differentiation Downstream to Notch Signaling in Mice

    Directory of Open Access Journals (Sweden)

    Fang Gao

    2017-04-01

    Full Text Available Summary: Notch signaling is critically involved in neural development, but the downstream effectors remain incompletely understood. In this study, we cultured neurospheres from Nestin-Cre-mediated conditional Rbp-j knockout (Rbp-j cKO and control embryos and compared their miRNA expression profiles using microarray. Among differentially expressed miRNAs, miR-342-5p showed upregulated expression as Notch signaling was genetically or pharmaceutically interrupted. Consistently, the promoter of the miR-342-5p host gene, the Ena-vasodilator stimulated phosphoprotein-like (Evl, was negatively regulated by Notch signaling, probably through HES5. Transfection of miR-342-5p promoted the differentiation of neural stem cells (NSCs into intermediate neural progenitors (INPs in vitro and reduced the stemness of NSCs in vivo. Furthermore, miR-342-5p inhibited the differentiation of neural stem/intermediate progenitor cells into astrocytes, likely mediated by targeting GFAP directly. Our results indicated that miR-342-5p could function as a downstream effector of Notch signaling to regulate the differentiation of NSCs into INPs and astrocytes commitment. : In this article, Han and colleagues show that miR-342-5p acts as a downstream effector of Notch signaling in the mouse CNS. Notch signal inhibits miR-342-5p expression by regulating its host gene Evl. And with attenuated Notch signal in NSCs, miR-342-5p is upregulated to promote NSCs transition into INPs, and to inhibit astrocyte commitment by targeting GFAP. Keywords: neural stem cells, intermediate neural progenitors, Notch, RBP-J, neuron, glia, miR-342-5p

  5. Mixtures of xenoestrogens disrupt estradiol-induced non-genomic signaling and downstream functions in pituitary cells.

    Science.gov (United States)

    Viñas, René; Watson, Cheryl S

    2013-03-26

    Our study examines the effects of xenoestrogen mixtures on estradiol-induced non-genomic signaling and associated functional responses. Bisphenol-A, used to manufacture plastic consumer products, and nonylphenol, a surfactant, are estrogenic by a variety of assays, including altering many intracellular signaling pathways; bisphenol-S is now used as a bisphenol-A substitute. All three compounds contaminate the environment globally. We previously showed that bisphenol-S, bisphenol-A, and nonylphenol alone rapidly activated several kinases at very low concentrations in the GH3/B6/F10 rat pituitary cell line. For each assay we compared the response of individual xenoestrogens at environmentally relevant concentrations (10-15 -10-7 M), to their mixture effects on 10-9 M estradiol-induced responses. We used a medium-throughput plate immunoassay to quantify phosphorylations of extracellular signal-regulated kinases (ERKs) and c-Jun-N-terminal kinases (JNKs). Cell numbers were assessed by crystal violet assay to compare the proliferative effects. Apoptosis was assessed by measuring caspase 8 and 9 activities via the release of the fluorescent product 7-amino-4-trifluoromethylcoumarin. Prolactin release was measured by radio-immunoassay after a 1 min exposure to all individual and combinations of estrogens. Individual xenoestrogens elicited phospho-activation of ERK in a non-monotonic dose- (fM-nM) and mostly oscillating time-dependent (2.5-60 min) manner. When multiple xenoestrogens were combined with nM estradiol, the physiologic estrogen's response was attenuated. Individual bisphenol compounds did not activate JNK, while nonylphenol did; however, the combination of two or three xenoestrogens with estradiol generated an enhanced non-monotonic JNK dose-response. Estradiol and all xenoestrogen compounds induced cell proliferation individually, while the mixtures of these compounds with estradiol suppressed proliferation below that of the vehicle control, suggesting a

  6. Impact of upstream and downstream constraints on a signaling module’s ultrasensitivity

    International Nuclear Information System (INIS)

    Altszyler, Edgar; Chernomoretz, Ariel; Ventura, Alejandra; Colman-Lerner, Alejandro

    2014-01-01

    Much work has been done on the study of the biochemical mechanisms that result in ultrasensitive behavior of simple biochemical modules. However, in a living cell, such modules are embedded in a bigger network that constrains the range of inputs that the module will receive as well as the range of the module’s outputs that network will be able to detect. Here, we studied how the effective ultrasensitivity of a modular system is affected by these restrictions. We use a simple setup to explore to what extent the dynamic range spanned by upstream and downstream components of an ultrasensitive module impact on the effective sensitivity of the system. Interestingly, we found for some ultrasensitive motifs that dynamic range limitations imposed by downstream components can produce effective sensitivities much larger than that of the original module when considered in isolation. (paper)

  7. Focal Adhesion Kinase Is Required for Intestinal Regeneration and Tumorigenesis Downstream of Wnt/c-Myc Signaling

    Science.gov (United States)

    Ashton, Gabrielle H.; Morton, Jennifer P.; Myant, Kevin; Phesse, Toby J.; Ridgway, Rachel A.; Marsh, Victoria; Wilkins, Julie A.; Athineos, Dimitris; Muncan, Vanesa; Kemp, Richard; Neufeld, Kristi; Clevers, Hans; Brunton, Valerie; Winton, Douglas J.; Wang, Xiaoyan; Sears, Rosalie C.; Clarke, Alan R.; Frame, Margaret C.; Sansom, Owen J.

    2012-01-01

    SUMMARY The intestinal epithelium has a remarkable capacity to regenerate after injury and DNA damage. Here, we show that the integrin effector protein Focal Adhesion Kinase (FAK) is dispensable for normal intestinal homeostasis and DNA damage signaling, but is essential for intestinal regeneration following DNA damage. Given Wnt/c-Myc signaling is activated following intestinal regeneration, we investigated the functional importance of FAK following deletion of the Apc tumor suppressor protein within the intestinal epithelium. Following Apc loss, FAK expression increased in a c-Myc-dependent manner. Codeletion of Apc and Fak strongly reduced proliferation normally induced following Apc loss, and this was associated with reduced levels of phospho-Akt and suppression of intestinal tumorigenesis in Apc heterozygous mice. Thus, FAK is required downstream of Wnt Signaling, for Akt/mTOR activation, intestinal regeneration, and tumorigenesis. Importantly, this work suggests that FAK inhibitors may suppress tumorigenesis in patients at high risk of developing colorectal cancer. PMID:20708588

  8. The brassinosteroid receptor BRI1 can generate cGMP enabling cGMP-dependent downstream signaling

    KAUST Repository

    Wheeler, Janet I.

    2017-05-08

    The brassinosteroid receptor BRASSINOSTEROID INSENSITIVE 1 (BRI1) is a member of the leucine rich repeat receptor like kinase family. The intracellular kinase domain of BRI1 is an active kinase and also encapsulates a guanylate cyclase catalytic centre. Using liquid chromatography tandem mass spectrometry, we confirmed that the recombinant cytoplasmic domain of BRI1 generates pmol amounts of cGMP per μg protein with a preference for magnesium over manganese as a co-factor. Importantly, a functional BRI1 kinase is essential for optimal cGMP generation. Therefore, the guanylate cyclase activity of BRI1 is modulated by the kinase while cGMP, the product of the guanylate cyclase, in turn inhibits BRI1 kinase activity. Furthermore, we show using Arabidopsis root cell cultures that cGMP rapidly potentiates phosphorylation of the downstream substrate BRASSINOSTEROID SIGNALING KINASE 1 (BSK1). Taken together, our results suggest that cGMP acts as a modulator that enhances downstream signaling while dampening signal generation from the receptor. This article is protected by copyright. All rights reserved.

  9. The brassinosteroid receptor BRI1 can generate cGMP enabling cGMP-dependent downstream signaling

    KAUST Repository

    Wheeler, Janet I.; Wong, Aloysius Tze; Marondedze, Claudius; Groen, Arnoud J.; Kwezi, Lusisizwe; Freihat, Lubna; Vyas, Jignesh; Raji, Misjudeen; Irving, Helen R.; Gehring, Christoph A

    2017-01-01

    The brassinosteroid receptor BRASSINOSTEROID INSENSITIVE 1 (BRI1) is a member of the leucine rich repeat receptor like kinase family. The intracellular kinase domain of BRI1 is an active kinase and also encapsulates a guanylate cyclase catalytic centre. Using liquid chromatography tandem mass spectrometry, we confirmed that the recombinant cytoplasmic domain of BRI1 generates pmol amounts of cGMP per μg protein with a preference for magnesium over manganese as a co-factor. Importantly, a functional BRI1 kinase is essential for optimal cGMP generation. Therefore, the guanylate cyclase activity of BRI1 is modulated by the kinase while cGMP, the product of the guanylate cyclase, in turn inhibits BRI1 kinase activity. Furthermore, we show using Arabidopsis root cell cultures that cGMP rapidly potentiates phosphorylation of the downstream substrate BRASSINOSTEROID SIGNALING KINASE 1 (BSK1). Taken together, our results suggest that cGMP acts as a modulator that enhances downstream signaling while dampening signal generation from the receptor. This article is protected by copyright. All rights reserved.

  10. Downstream Toll-like receptor signaling mediates adaptor-specific cytokine expression following focal cerebral ischemia

    Directory of Open Access Journals (Sweden)

    Bolanle Famakin

    2012-07-01

    Full Text Available Abstract Background Deletion of some Toll-like receptors (TLRs affords protection against cerebral ischemia, but disruption of their known major downstream adaptors does not. To determine whether compensation in the production of downstream effectors by one pathway when the other is disrupted can explain these findings, we examined cytokine/chemokine expression and inflammatory infiltrates in wild-type (WT, MyD88−/− and TRIF-mutant mice following permanent middle cerebral artery occlusion (pMCAO. Methods Cytokine/chemokine expression was measured with a 25-plex bead array in the serum and brains of all three groups of mice at baseline (no surgery/naïve and at 3 hours and 24 hours following pMCAO. Brain inflammatory and neutrophil infiltrates were examined 24 hours following pMCAO. Results IL-6, keratinocyte chemoattractant (KC, granulocyte colony-stimulating factor (G-CSF and IL-10 were significantly decreased in MyD88−/− mice compared to WT mice following pMCAO. Significantly, decreased levels of the neutrophil chemoattractants KC and G-CSF corresponded with a trend toward fewer neutrophils in the brains of MyD88−/− mice. IP-10 was significantly decreased when either pathway was disrupted. MIP-1α was significantly decreased in TRIF-mutant mice, consistent with TRIF-dependent production. MyD88−/− mice showed elevations of a number of Th2 cytokines, such as IL-13, at baseline, which became significantly decreased following pMCAO. Conclusions Both MyD88 and TRIF mediate pathway-specific cytokine production following focal cerebral ischemia. Our results also suggest a compensatory Th2-type skew at baseline in MyD88−/− mice and a paradoxical switch to a Th1 phenotype following focal cerebral ischemia. The MyD88 pathway directs the expression of neutrophil chemoattractants following cerebral ischemia.

  11. Downstream divergence of the ethylene signaling pathway for harpin-stimulated Arabidopsis growth and insect defense.

    Science.gov (United States)

    Dong, Hong-Ping; Peng, Jianling; Bao, Zhilong; Meng, Xiangdong; Bonasera, Jean M; Chen, Guangyong; Beer, Steven V; Dong, Hansong

    2004-11-01

    Ethylene (ET) signal transduction may regulate plant growth and defense, depending on which components are recruited into the pathway in response to different stimuli. We report here that the ET pathway controls both insect resistance (IR) and plant growth enhancement (PGE) in Arabidopsis (Arabidopsis thaliana) plants responding to harpin, a protein produced by a plant pathogenic bacterium. PGE may result from spraying plant tops with harpin or by soaking seeds in harpin solution; the latter especially enhances root growth. Plants treated similarly develop resistance to the green peach aphid (Myzus persicae). The salicylic acid pathway, although activated by harpin, does not lead to PGE and IR. By contrast, PGE and IR are induced in both wild-type plants and genotypes that have defects in salicylic acid signaling. In response to harpin, levels of jasmonic acid (JA) decrease, and the COI1 gene, which is indispensable for JA signal transduction, is not expressed in wild-type plants. However, PGE and IR are stimulated in the JA-resistant mutant jar1-1. In the wild type, PGE and IR develop coincidently with increases in ET levels and the expression of several genes essential for ET signaling. The ET receptor gene ETR1 is required because both phenotypes are arrested in the etr1-1 mutant. Consistently, inhibition of ET perception nullifies the induction of both PGE and IR. The signal transducer EIN2 is required for IR, and EIN5 is required for PGE because IR and PGE are impaired correspondingly in the ein2-1 and ein5-1 mutants. Therefore, harpin activates ET signaling while conscribing EIN2 and EIN5 to confer IR and PGE, respectively.

  12. Recent Progress on Liver Kinase B1 (LKB1: Expression, Regulation, Downstream Signaling and Cancer Suppressive Function

    Directory of Open Access Journals (Sweden)

    Ren-You Gan

    2014-09-01

    Full Text Available Liver kinase B1 (LKB1, known as a serine/threonine kinase, has been identified as a critical cancer suppressor in many cancer cells. It is a master upstream kinase of 13 AMP-activated protein kinase (AMPK-related protein kinases, and possesses versatile biological functions. LKB1 gene is mutated in many cancers, and its protein can form different protein complexes with different cellular localizations in various cell types. The expression of LKB1 can be regulated through epigenetic modification, transcriptional regulation and post-translational modification. LKB1 dowcnstream pathways mainly include AMPK, microtubule affinity regulating kinase (MARK, salt-inducible kinase (SIK, sucrose non-fermenting protein-related kinase (SNRK and brain selective kinase (BRSK signalings, etc. This review, therefore, mainly discusses recent studies about the expression, regulation, downstream signaling and cancer suppressive function of LKB1, which can be helpful for better understanding of this molecular and its significance in cancers.

  13. Evolutionary divergence of the plant elicitor peptides (Peps) and their receptors: interfamily incompatibility of perception but compatibility of downstream signalling

    KAUST Repository

    Lori, M.

    2015-05-22

    Plant elicitor peptides (Peps) are potent inducers of pattern-triggered immunity and amplify the immune response against diverse pathogens. Peps have been discovered and studied extensively in Arabidopsis and only recently orthologs in maize were also identified and characterized in more detail. Here, the presence of PROPEPs, the Pep precursors, and PEPRs, the Pep receptors, was investigated within the plant kingdom. PROPEPs and PEPRs were identified in most sequenced species of the angiosperms. The conservation and compatibility of the Pep-PEPR-system was analysed by using plants of two distantly related dicot families, Brassicaceae and Solanaceae, and a representative family of monocot plants, the Poaceae. All three plant families contain important crop plants, including maize, rice, tomato, potato, and canola. Peps were not recognized by species outside of their plant family of origin, apparently because of a divergence of the Pep sequences. Three family-specific Pep motifs were defined and the integration of such a motif into the Pep sequence of an unrelated Pep enabled its perception. Transient transformation of Nicotiana benthamiana with the coding sequences of the AtPEPR1 and ZmPEPR1a led to the recognition of Pep peptides of Brassicaceae or Poaceae origin, respectively, and to the proper activation of downstream signalling. It was concluded that signalling machinery downstream of the PEPRs is highly conserved whereas the leucine-rich repeat domains of the PEPRs co-evolved with the Peps, leading to distinct motifs and, with it, interfamily incompatibility.

  14. NANOS2 acts downstream of glial cell line-derived neurotrophic factor signaling to suppress differentiation of spermatogonial stem cells.

    Science.gov (United States)

    Sada, Aiko; Hasegawa, Kazuteru; Pin, Pui Han; Saga, Yumiko

    2012-02-01

    Stem cells are maintained by both stem cell-extrinsic niche signals and stem cell-intrinsic factors. During murine spermatogenesis, glial cell line-derived neurotrophic factor (GDNF) signal emanated from Sertoli cells and germ cell-intrinsic factor NANOS2 represent key regulators for the maintenance of spermatogonial stem cells. However, it remains unclear how these factors intersect in stem cells to control their cellular state. Here, we show that GDNF signaling is essential to maintain NANOS2 expression, and overexpression of Nanos2 can alleviate the stem cell loss phenotype caused by the depletion of Gfra1, a receptor for GDNF. By using an inducible Cre-loxP system, we show that NANOS2 expression is downregulated upon the conditional knockout (cKO) of Gfra1, while ectopic expression of Nanos2 in GFRA1-negative spermatogonia does not induce de novo GFRA1 expression. Furthermore, overexpression of Nanos2 in the Gfra1-cKO testes prevents precocious differentiation of the Gfra1-knockout stem cells and partially rescues the stem cell loss phenotypes of Gfra1-deficient mice, indicating that the stem cell differentiation can be suppressed by NANOS2 even in the absence of GDNF signaling. Taken together, we suggest that NANOS2 acts downstream of GDNF signaling to maintain undifferentiated state of spermatogonial stem cells. Copyright © 2011 AlphaMed Press.

  15. Differential subcellular membrane recruitment of Src may specify its downstream signalling

    International Nuclear Information System (INIS)

    Diesbach, Philippe de; Medts, Thierry; Carpentier, Sarah; D'Auria, Ludovic; Van Der Smissen, Patrick; Platek, Anna; Mettlen, Marcel; Caplanusi, Adrian; Hove, Marie-France van den; Tyteca, Donatienne; Courtoy, Pierre J.

    2008-01-01

    Most Src family members are diacylated and constitutively associate with membrane 'lipid rafts' that coordinate signalling. Whether the monoacylated Src, frequently hyperactive in carcinomas, also localizes at 'rafts' remains controversial. Using polarized MDCK cells expressing the thermosensitive v-Src/tsLA31 variant, we here addressed how Src tyrosine-kinase activation may impact on its (i) membrane recruitment, in particular to 'lipid rafts'; (ii) subcellular localization; and (iii) signalling. The kinetics of Src-kinase thermoactivation correlated with its recruitment from the cytosol to sedimentable membranes where Src largely resisted solubilisation by non-ionic detergents at 4 deg. C and floated into sucrose density gradients like caveolin-1 and flotillin-2, i.e. 'lipid rafts'. By immunofluorescence, activated Src showed a dual localization, at apical endosomes/macropinosomes and at the apical plasma membrane. The plasma membrane Src pool did not colocalize with caveolin-1 and flotillin-2, but extensively overlapped GM1 labelling by cholera toxin. Severe (∼ 70%) cholesterol extraction with methyl-β-cyclodextrin (MβCD) did not abolish 'rafts' floatation, but strongly decreased Src association with floating 'rafts' and abolished its localization at the apical plasma membrane. Src activation independently activated first the MAP-kinase - ERK1/2 pathway, then the PI3-kinase - Akt pathway. MAP-kinase - ERK1/2 activation was insensitive to MβCD, which suppressed Akt phosphorylation and apical endocytosis induced by Src, both depending on the PI3-kinase pathway. We therefore suggest that activated Src is recruited at two membrane compartments, allowing differential signalling, first via ERK1/2 at 'non-raft' domains on endosomes, then via PI3-kinase-Akt on a distinct set of 'rafts' at the apical plasma membrane. Whether this model is applicable to c-Src remains to be examined

  16. Rapid Phospho-Turnover by Receptor Tyrosine Kinases Impacts Downstream Signaling and Drug Binding

    OpenAIRE

    Kleiman, Laura B.; Maiwald, Thomas; Conzelmann, Holger; Lauffenburger, Douglas A.; Sorger, Peter K.

    2011-01-01

    Epidermal growth factor receptors (ErbB1–4) are oncogenic receptor tyrosine kinases (RTKs) that regulate diverse cellular processes. In this study, we combine measurement and mathematical modeling to quantify phospho-turnover at ErbB receptors in human cells and to determine the consequences for signaling and drug binding. We find that phosphotyrosine residues on ErbB1 have half-lives of a few seconds and therefore turn over 100–1000 times in the course of a typical immediate-early response t...

  17. Baicalin inhibits toll-like receptor 2/4 expression and downstream signaling in rat experimental periodontitis.

    Science.gov (United States)

    Sun, Jun-Yi; Li, Dong-Ling; Dong, Yan; Zhu, Chun-Hui; Liu, Jin; Li, Jue-Dan; Zhou, Tao; Gou, Jian-Zhong; Li, Ang; Zang, Wei-Jin

    2016-07-01

    Periodontitis is a severe inflammatory response, leading to characteristic periodontal soft tissue destruction and alveolar bone resorption. Baicalin possesses potent anti-inflammatory activity; however, it is still unclear whether baicalin regulates toll-like receptor (TLR) 2/4 expression and downstream signaling during the process of periodontitis. In this study, the cervical area of the maxillary second molars of rats was ligated and inoculated with Porphyromonas gingivalis (P. gingivalis) for 4weeks to induce periodontitis. Some rats with periodontitis were treated intragastrically with baicalin (50, 100 or 200mg/kg/day) or vehicle for 4weeks. Compared with the sham group, the levels of TLR2, TLR4 and MyD88 expression and the p38 MAPK and NF-κB activation were up-regulated in the experimental periodontitis group (EPG), accompanied by marked alveolar bone loss and severe inflammation. Treatment with 100 or 200mg/kg/day baicalin dramatically reduced the alveolar bone loss, the levels of HMGB1, TNF-α, IL-1β, and MPO expression, and the numbers of inflammatory infiltrates in the gingival tissues. Importantly, treatment with 100 or 200mg/kg/day baicalin mitigated the periodontitis-up-regulated TLR2, TLR4 and MyD88 expression, and the p38 MAPK and NF-κB activation. Hence, the blockage of the TLR2 and TLR4/MyD88/p38 MAPK/NF-κB signaling by baicalin may contribute to its anti-inflammatory effects in rat model of periodontitis. In conclusion, these novel findings indicate that baicalin inhibits the TLR2 and TLR4 expression and the downstream signaling and mitigates inflammatory responses and the alveolar bone loss in rat experimental periodontitis. Therefore, baicalin may be a potential therapeutic agent for treatment of periodontitis. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. KIR2DL4 differentially signals downstream functions in human NK cells through distinct structural modules.

    Science.gov (United States)

    Miah, S M Shahjahan; Hughes, Tracey L; Campbell, Kerry S

    2008-03-01

    KIR2DL4 (2DL4) is a member of the killer cell Ig-like receptor (KIR) family in human NK cells. It can stimulate potent cytokine production and weak cytolytic activity in resting NK cells, but the mechanism for 2DL4-mediated signaling remains unclear. In this study we characterized the signaling pathways stimulated by 2DL4 engagement. In a human NK-like cell line, KHYG-1, cross-linking of 2DL4 activated MAPKs including JNK, ERK, and p38. Furthermore, 2DL4 cross-linking resulted in phosphorylation of IkappaB kinase beta (IKKbeta) and the phosphorylation and degradation of IkappaBalpha, which indicate activation of the classical NF-kappaB pathway. Engagement of 2DL4 was also shown to activate the transcription and translation of a variety of cytokine genes, including TNF-alpha, IFN-gamma, MIP1alpha, MIP1beta, and IL-8. Pharmacological inhibitors of JNK, MEK1/2 and p38, blocked IFN-gamma, IL-8, and MIP1alpha production, suggesting that MAPKs are regulating 2DL4-mediated cytokine production in a nonredundant manner. Activation of both p38 and ERK appear to be upstream of the stimulation of NF-kappaB. Mutation of a transmembrane arginine in 2DL4 to glycine (R/G mutant) abrogated FcepsilonRI-gamma association, as well as receptor-mediated cytolytic activity and calcium responses. Surprisingly, the R/G mutant still activated MAPKs and the NF-kappaB pathway and selectively stimulated the production of MIP1alpha, but not that of IFN-gamma or IL-8. In conclusion, we provide evidence that the activating functions of 2DL4 can be compartmentalized into two distinct structural modules: 1) through transmembrane association with FcepsilonRI-gamma; and 2) through another receptor domain independent of the transmembrane arginine.

  19. Protein kinase Cδ signaling downstream of the EGF receptor mediates migration and invasiveness of prostate cancer cells

    International Nuclear Information System (INIS)

    Kharait, Sourabh; Dhir, Rajiv; Lauffenburger, Douglas; Wells, Alan

    2006-01-01

    Tumor progression to the invasive phenotype occurs secondary to upregulated signaling from growth factor receptors that drive key cellular responses like proliferation, migration, and invasion. We hypothesized that Protein kinase Cδ (PKCδ)-mediated transcellular contractility is required for migration and invasion of prostate tumor cells. Two invasive human prostate cancer cell lines, DU145 cells overexpressing wildtype human EGFR (DU145WT) and PC3 cells, were studied. PKCδ is overexpressed in these cells relative to normal prostate epithelial cells, and is activated downstream of EGFR leading to cell motility via modulation of myosin light chain activity. Abrogation of PKCδ using Rottlerin and specific siRNA significantly decreased migration and invasion of both cell lines in vitro. Both PKCδ and phosphorylated PKCδ protein levels were higher in human prostate cancer tissue relative to normal donor prostate as assessed by Western blotting and immunohistochemistry. Thus, we conclude that PKCδ inhibition can limit migration and invasion of prostate cancer cells

  20. The brassinosteroid receptor BRI1 can generate cGMP enabling cGMP-dependent downstream signaling

    CSIR Research Space (South Africa)

    Wheeler, J

    2017-06-01

    Full Text Available ) with the ll PickUp Injection mode using the loading pump at 15 ll min�1 flow rate for 3 min. Samples were then loaded on a RSLC, 75 lm 9 500 mm, nanoVi- per, C18, 2 lm, 100 �A column (Acclaim, PepMap) retrofitted to an EASY-spray source with a flow rate of 300... receptor BRI1 can generate cGMP enabling cGMP-dependent downstream signaling Janet I. Wheeler1,2,†, Aloysius Wong3,4, Claudius Marondedze3,5, Arnoud J. Groen5, Lusisizwe Kwezi1,6, Lubna Freihat1, Jignesh Vyas1, Misjudeen A. Raji7, Helen R. Irving1...

  1. Four MicroRNAs Promote Prostate Cell Proliferation with Regulation of PTEN and Its Downstream Signals In Vitro

    Science.gov (United States)

    Xue, Jing-lun; Chen, Jin-zhong

    2013-01-01

    Background Phosphatase and tensin homologue (PTEN), as a tumor suppressor, plays vital roles in tumorigenesis and progression of prostate cancer. However, the mechanisms of PTEN regulation still need further investigation. We here report that a combination of four microRNAs (miR-19b, miR-23b, miR-26a and miR-92a) promotes prostate cell proliferation by regulating PTEN and its downstream signals in vitro. Methodology/Principal Findings We found that the four microRNAs (miRNAs) could effectively suppress PTEN expression by directly interacting with its 3’ UTR in prostate epithelial and cancer cells. Under-expression of the four miRNAs by antisense neutralization up-regulates PTEN expression, while overexpression of the four miRNAs accelerates epithelial and prostate cancer cell proliferation. Furthermore, the expression of the four miRNAs could, singly or jointly, alter the expression of the key components in the phosphoinositide 3-kinase (PI3K)/Akt pathway, including PIK3CA, PIK3CD, PIK3R1 and Akt, along with their downstream signal, cyclin D1. Conclusions These results suggested that the four miRNAs could promote prostate cancer cell proliferation by co-regulating the expression of PTEN, PI3K/Akt pathway and cyclin D1 in vitro. These findings increase understanding of the molecular mechanisms of prostate carcinogenesis and progression, even provide valuable insights into the diagnosis, prognosis, and rational design of novel therapeutics for prostate cancer. PMID:24098737

  2. Neurotrophin Promotes Neurite Outgrowth by Inhibiting Rif GTPase Activation Downstream of MAPKs and PI3K Signaling.

    Science.gov (United States)

    Tian, Xiaoxia; Yan, Huijuan; Li, Jiayi; Wu, Shuang; Wang, Junyu; Fan, Lifei

    2017-01-13

    Members of the well-known semaphorin family of proteins can induce both repulsive and attractive signaling in neural network formation and their cytoskeletal effects are mediated in part by small guanosine 5'-triphosphatase (GTPases). The aim of this study was to investigate the cellular role of Rif GTPase in the neurotrophin-induced neurite outgrowth. By using PC12 cells which are known to cease dividing and begin to show neurite outgrowth responding to nerve growth factor (NGF), we found that semaphorin 6A was as effective as nerve growth factor at stimulating neurite outgrowth in PC12 cells, and that its neurotrophic effect was transmitted through signaling by mitogen-activated protein kinases (MAPKs) and phosphatidylinositol-3-kinase (PI3K). We further found that neurotrophin-induced neurite formation in PC12 cells could be partially mediated by inhibition of Rif GTPase activity downstream of MAPKs and PI3K signaling. In conclusion, we newly identified Rif as a regulator of the cytoskeletal rearrangement mediated by semaphorins.

  3. Nonmuscle Myosin II Is Required for Internalization of the Epidermal Growth Factor Receptor and Modulation of Downstream Signaling*

    Science.gov (United States)

    Kim, Jong Hyun; Wang, Aibing; Conti, Mary Anne; Adelstein, Robert S.

    2012-01-01

    Ligand-induced internalization of the epidermal growth factor receptor (EGFR) is an important process for regulating signal transduction, cellular dynamics, and cell-cell communication. Here, we demonstrate that nonmuscle myosin II (NM II) is required for the internalization of the EGFR and to trigger the EGFR-dependent activation of ERK and AKT. The EGFR was identified as a protein that interacts with NM II by co-immunoprecipitation and mass spectrometry analysis. This interaction requires both the regulatory light chain 20 (RLC20) of NM II and the kinase domain of the EGFR. Two paralogs of NM II, NM II-A, and NM II-B can act to internalize the EGFR, depending on the cell type and paralog content of the cell line. Loss (siRNA) or inhibition (25 μm blebbistatin) of NM II attenuates the internalization of the EGFR and impairs EGFR-dependent activation of ERK and AKT. Both internalization of the EGFR and downstream signaling to ERK and AKT can be partially restored in siRNA-treated cells by introduction of wild type (WT) GFP-NM II, but cannot be restored by motor mutant NM II. Taken together, these results suggest that NM II plays a role in the internalization of the EGFR and EGFR-mediated signaling pathways. PMID:22718763

  4. Effect of Wnt-1 inducible signaling pathway protein-2 (WISP-2/CCN5), a downstream protein of Wnt signaling, on adipocyte differentiation

    International Nuclear Information System (INIS)

    Inadera, Hidekuni; Shimomura, Akiko; Tachibana, Shinjiro

    2009-01-01

    Wnt signaling negatively regulates adipocyte differentiation, and ectopic expression of Wnt-1 in 3T3-L1 cells induces several downstream molecules of Wnt signaling, including Wnt-1 inducible signaling pathway protein (WISP)-2. In this study, we examined the role of WISP-2 in the process of adipocyte differentiation using an in vitro cell culture system. In the differentiation of 3T3-L1 cells, WISP-2 expression was observed in growing cells and declined thereafter. In the mitotic clonal expansion phase of adipocyte differentiation, WISP-2 expression was transiently down-regulated concurrently with up-regulation of CCAAT/enhancer-binding protein δ expression. Treatment of 3T3-L1 cells in the differentiation medium with lithium, an activator of Wnt signaling, inhibited the differentiation process with concomitant induction of WISP-2. Treatment of differentiated cells with lithium induced de-differentiation as evidenced by profound reduction of peroxisome proliferator-activator receptor γ expression and concomitant induction of WISP-2. However, de-differentiation of differentiated cells induced by tumor necrosis factor-α did not induce WISP-2 expression. To directly examine the effect of WISP-2 on adipocyte differentiation, 3T3-L1 cells were infected with a retrovirus carrying WISP-2. Although forced expression of WISP-2 inhibited preadipocyte proliferation, it had no effect on adipocyte differentiation. Thus, although WISP-2 is a downstream protein of Wnt signaling, the role of WISP-2 on adipocyte differentiation may be marginal, at least in this in vitro culture model.

  5. Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition

    Science.gov (United States)

    Frost, Julianty; Galdeano, Carles; Soares, Pedro; Gadd, Morgan S.; Grzes, Katarzyna M.; Ellis, Lucy; Epemolu, Ola; Shimamura, Satoko; Bantscheff, Marcus; Grandi, Paola; Read, Kevin D.; Cantrell, Doreen A.; Rocha, Sonia; Ciulli, Alessio

    2016-11-01

    Chemical strategies to using small molecules to stimulate hypoxia inducible factors (HIFs) activity and trigger a hypoxic response under normoxic conditions, such as iron chelators and inhibitors of prolyl hydroxylase domain (PHD) enzymes, have broad-spectrum activities and off-target effects. Here we disclose VH298, a potent VHL inhibitor that stabilizes HIF-α and elicits a hypoxic response via a different mechanism, that is the blockade of the VHL:HIF-α protein-protein interaction downstream of HIF-α hydroxylation by PHD enzymes. We show that VH298 engages with high affinity and specificity with VHL as its only major cellular target, leading to selective on-target accumulation of hydroxylated HIF-α in a concentration- and time-dependent fashion in different cell lines, with subsequent upregulation of HIF-target genes at both mRNA and protein levels. VH298 represents a high-quality chemical probe of the HIF signalling cascade and an attractive starting point to the development of potential new therapeutics targeting hypoxia signalling.

  6. Inhibition of Spinal Interlukin-33/ST2 Signaling and Downstream ERK and JNK Pathways in Electroacupuncture Analgesia in Formalin Mice.

    Directory of Open Access Journals (Sweden)

    Ping Han

    Full Text Available Although acupuncture is widely used to manage pain, it remains highly controversial, largely due to the lack of a clear mechanism for its benefits. Here, we investigated the role of IL-33, a novel interleukin (IL-1 family member, and its receptor ST2 in the analgesic effects of electroacupuncture (EA on formalin-induced inflammatory pain. The results showed that 1 EA stimulation of ipsilateral Zusanli (ST 36 and Yanglingquan (GB 34 acupoints for 30 min remarkably suppressed the two phases of formalin-induced spontaneous pain; 2 subcutaneous or intrathecal administration of recombinant IL-33 (rIL-33 significantly inhibited the analgesic effect of EA, whereas the ST2 antibody potentiated EA analgesia in formalin mice; 3 EA treatment decreased the up-regulation of IL-33 and ST2 protein following formalin injection; and 4 the suppression of the formalin-induced expression of spinal phosphorylated ERK and JNK induced by EA treatment was significantly attenuated following subcutaneous rIL-33 delivery, and was further decreased by the ST2 antibody. These data suggest that EA alleviates formalin-induced inflammatory pain, at least partially, by inhibiting of spinal IL-33/ST2 signaling and the downstream ERK and JNK pathways.

  7. Inhibition of Spinal Interlukin-33/ST2 Signaling and Downstream ERK and JNK Pathways in Electroacupuncture Analgesia in Formalin Mice

    Science.gov (United States)

    Zhao, Jing; Wang, Yanqing; Wu, Gencheng; Mi, Wenli

    2015-01-01

    Although acupuncture is widely used to manage pain, it remains highly controversial, largely due to the lack of a clear mechanism for its benefits. Here, we investigated the role of IL-33, a novel interleukin (IL)-1 family member, and its receptor ST2 in the analgesic effects of electroacupuncture (EA) on formalin-induced inflammatory pain. The results showed that 1) EA stimulation of ipsilateral Zusanli (ST 36) and Yanglingquan (GB 34) acupoints for 30 min remarkably suppressed the two phases of formalin-induced spontaneous pain; 2) subcutaneous or intrathecal administration of recombinant IL-33 (rIL-33) significantly inhibited the analgesic effect of EA, whereas the ST2 antibody potentiated EA analgesia in formalin mice; 3) EA treatment decreased the up-regulation of IL-33 and ST2 protein following formalin injection; and 4) the suppression of the formalin-induced expression of spinal phosphorylated ERK and JNK induced by EA treatment was significantly attenuated following subcutaneous rIL-33 delivery, and was further decreased by the ST2 antibody. These data suggest that EA alleviates formalin-induced inflammatory pain, at least partially, by inhibiting of spinal IL-33/ST2 signaling and the downstream ERK and JNK pathways. PMID:26067287

  8. Pituitary adenylate cyclase activating polypeptide (PACAP signalling exerts chondrogenesis promoting and protecting effects: implication of calcineurin as a downstream target.

    Directory of Open Access Journals (Sweden)

    Tamás Juhász

    Full Text Available Pituitary adenylate cyclase activating polypeptide (PACAP is an important neurotrophic factor influencing differentiation of neuronal elements and exerting protecting role during traumatic injuries or inflammatory processes of the central nervous system. Although increasing evidence is available on its presence and protecting function in various peripheral tissues, little is known about the role of PACAP in formation of skeletal components. To this end, we aimed to map elements of PACAP signalling in developing cartilage under physiological conditions and during oxidative stress. mRNAs of PACAP and its receptors (PAC1,VPAC1, VPAC2 were detectable during differentiation of chicken limb bud-derived chondrogenic cells in micromass cell cultures. Expression of PAC1 protein showed a peak on days of final commitment of chondrogenic cells. Administration of either the PAC1 receptor agonist PACAP 1-38, or PACAP 6-38 that is generally used as a PAC1 antagonist, augmented cartilage formation, stimulated cell proliferation and enhanced PAC1 and Sox9 protein expression. Both variants of PACAP elevated the protein expression and activity of the Ca-calmodulin dependent Ser/Thr protein phosphatase calcineurin. Application of PACAPs failed to rescue cartilage formation when the activity of calcineurin was pharmacologically inhibited with cyclosporine A. Moreover, exogenous PACAPs prevented diminishing of cartilage formation and decrease of calcineurin activity during oxidative stress. As an unexpected phenomenon, PACAP 6-38 elicited similar effects to those of PACAP 1-38, although to a different extent. On the basis of the above results, we propose calcineurin as a downstream target of PACAP signalling in differentiating chondrocytes either in normal or pathophysiological conditions. Our observations imply the therapeutical perspective that PACAP can be applied as a natural agent that may have protecting effect during joint inflammation and/or may promote

  9. Suramin blocks interaction between human FGF1 and FGFR2 D2 domain and reduces downstream signaling activity

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Zong-Sian, E-mail: gary810426@hotmail.com [Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan (China); Liu, Che Fu, E-mail: s9823002@m98.nthu.edu.tw [Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan (China); Fu, Brian, E-mail: brianfu9@gmail.com [Northwood High School, Irvine, CA (United States); Chou, Ruey-Hwang, E-mail: rhchou@mail.cmu.edu.tw [Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung 40402, Taiwan (China); Department of Biotechnology, Asia University, Taiwan (China); Yu, Chin, E-mail: cyu.nthu@gmail.com [Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan (China)

    2016-09-02

    The extracellular portion of the human fibroblast growth factor receptor2 D2 domain (FGFR2 D2) interacts with human fibroblast growth factor 1 (hFGF1) to activate a downstream signaling cascade that ultimately affects mitosis and differentiation. Suramin is an antiparasiticdrug and a potent inhibitor of FGF-induced angiogenesis. Suramin has been shown to bind to hFGF1, and might block the interaction between hFGF1 and FGFR2 D2. Here, we titrated hFGF1 with FGFR2 D2 and suramin to elucidate their interactions using the detection of NMR. The docking results of both hFGF1-FGFR2 D2 domain and hFGF1-suramin complex were superimposed. The results indicate that suramin blocks the interaction between hFGF1 and FGFR2 D2. We used the PyMOL software to show the hydrophobic interaction of hFGF1-suramin. In addition, we used a Water-soluble Tetrazolium salts assay (WST1) to assess hFGF1 bioactivity. The results will be useful for the development of new antimitogenic activity drugs. - Highlights: • The interfacial residues on hFGF1-FGFR2 D2 and hFGF1-Suramin contact surface were mapped by {sup 1}H-{sup 15}N HSQC experiments. • hFGF1-FGFR2 D2 and hFGF1-Suramin complex models were generated from NMR restraints by using HADDOCK program. • We analyzed hFGF1-Suramin complex models and found the interaction between hFGF1-Suramin is hydrophobic. • The bioactivity of the hFGF1-FGFR2 D2 and hFGF1-Suramin complex was studied by using WST1 assay.

  10. Suramin blocks interaction between human FGF1 and FGFR2 D2 domain and reduces downstream signaling activity

    International Nuclear Information System (INIS)

    Wu, Zong-Sian; Liu, Che Fu; Fu, Brian; Chou, Ruey-Hwang; Yu, Chin

    2016-01-01

    The extracellular portion of the human fibroblast growth factor receptor2 D2 domain (FGFR2 D2) interacts with human fibroblast growth factor 1 (hFGF1) to activate a downstream signaling cascade that ultimately affects mitosis and differentiation. Suramin is an antiparasiticdrug and a potent inhibitor of FGF-induced angiogenesis. Suramin has been shown to bind to hFGF1, and might block the interaction between hFGF1 and FGFR2 D2. Here, we titrated hFGF1 with FGFR2 D2 and suramin to elucidate their interactions using the detection of NMR. The docking results of both hFGF1-FGFR2 D2 domain and hFGF1-suramin complex were superimposed. The results indicate that suramin blocks the interaction between hFGF1 and FGFR2 D2. We used the PyMOL software to show the hydrophobic interaction of hFGF1-suramin. In addition, we used a Water-soluble Tetrazolium salts assay (WST1) to assess hFGF1 bioactivity. The results will be useful for the development of new antimitogenic activity drugs. - Highlights: • The interfacial residues on hFGF1-FGFR2 D2 and hFGF1-Suramin contact surface were mapped by "1H-"1"5N HSQC experiments. • hFGF1-FGFR2 D2 and hFGF1-Suramin complex models were generated from NMR restraints by using HADDOCK program. • We analyzed hFGF1-Suramin complex models and found the interaction between hFGF1-Suramin is hydrophobic. • The bioactivity of the hFGF1-FGFR2 D2 and hFGF1-Suramin complex was studied by using WST1 assay.

  11. Effects of mutant human Ki-rasG12C gene dosage on murine lung tumorigenesis and signaling to its downstream effectors

    International Nuclear Information System (INIS)

    Dance-Barnes, Stephanie T.; Kock, Nancy D.; Floyd, Heather S.; Moore, Joseph E.; Mosley, Libyadda J.; D'Agostino, Ralph B.; Pettenati, Mark J.; Miller, Mark Steven

    2008-01-01

    Studies in cell culture have suggested that the level of RAS expression can influence the transformation of cells and the signaling pathways stimulated by mutant RAS expression. However, the levels of RAS expression in vivo appear to be subject to feedback regulation, limiting the total amount of RAS protein that can be expressed. We utilized a bitransgenic mouse lung tumor model that expressed the human Ki-ras G12C allele in a tetracycline-inducible, lung-specific manner. Treatment for 12 months with 500 μg/ml of doxycycline (DOX) allowed for maximal expression of the human Ki-ras G12C allele in the lung, and resulted in the development of focal hyperplasia and adenomas. We determined if different levels of mutant RAS expression would influence the phenotype of the lung lesions. Treatment with 25, 100 and 500 μg/ml of DOX resulted in dose-dependent increases in transgene expression and tumor multiplicity. Microscopic analysis of the lungs of mice treated with the 25 μg/ml dose of DOX revealed infrequent foci of hyperplasia, whereas mice treated with the 100 and 500 μg/ml doses exhibited numerous hyperplastic foci and also adenomas. Immunohistochemical and RNA analysis of the downstream effector pathways demonstrated that different levels of mutant RAS transgene expression resulted in differences in the expression and/or phosphorylation of specific signaling molecules. Our results suggest that the molecular alterations driving tumorigenesis may differ at different levels of mutant Ki-ras G12C expression, and this should be taken into consideration when inducible transgene systems are utilized to promote tumorigenesis in mouse models

  12. Signal Recovery in Compressive Sensing via Multiple Sparsifying Bases

    DEFF Research Database (Denmark)

    Wijewardhana, U. L.; Belyaev, Evgeny; Codreanu, M.

    2017-01-01

    is sparse is the key assumption utilized by such algorithms. However, the basis in which the signal is the sparsest is unknown for many natural signals of interest. Instead there may exist multiple bases which lead to a compressible representation of the signal: e.g., an image is compressible in different...... wavelet transforms. We show that a significant performance improvement can be achieved by utilizing multiple estimates of the signal using sparsifying bases in the context of signal reconstruction from compressive samples. Further, we derive a customized interior-point method to jointly obtain multiple...... estimates of a 2-D signal (image) from compressive measurements utilizing multiple sparsifying bases as well as the fact that the images usually have a sparse gradient....

  13. Direct Position Determination of Multiple Radio Signals

    Directory of Open Access Journals (Sweden)

    Weiss Anthony J

    2005-01-01

    Full Text Available The most common methods for position determination of radio signal emitters such as communications or radar transmitters are based on measuring a specified parameter such as angle of arrival (AOA or time of arrival (TOA of the signal. The measured parameters are then used to estimate the transmitter's location. Since the measurements are done at each base station independently, without using the constraint that the AOA/TOA estimates at different base stations should correspond to the same transmitter's location, this is a suboptimal location determination technique. Further, if the number of array elements at each base station is , and the signal waveforms are unknown, the number of cochannel simultaneous transmitters that can be localized by AOA is limited to . Also, most AOA algorithms fail when the sources are not well angularly separated. We propose a technique that uses exactly the same data as the common AOA methods but the position determination is direct. The proposed method can handle more than cochannel simultaneous signals. Although there are many stray parameters, only a two-dimensional search is required for a planar geometry. The technique provides a natural solution to the measurements sources association problem that is encountered in AOA-based location systems. In addition to new algorithms, we provide analytical performance analysis, Cramér-Rao bounds and Monte Carlo simulations. We demonstrate that the proposed approach frequently outperforms the traditional AOA methods for unknown as well as known signal waveforms.

  14. Dissection of Signaling Events Downstream of the c-Mpl Receptor in Murine Hematopoietic Stem Cells Via Motif-Engineered Chimeric Receptors.

    Science.gov (United States)

    Saka, Koichiro; Lai, Chen-Yi; Nojima, Masanori; Kawahara, Masahiro; Otsu, Makoto; Nakauchi, Hiromitsu; Nagamune, Teruyuki

    2018-02-01

    Hematopoietic stem cells (HSCs) are a valuable resource in transplantation medicine. Cytokines are often used to culture HSCs aiming at better clinical outcomes through enhancement of HSC reconstitution capability. Roles for each signal molecule downstream of receptors in HSCs, however, remain puzzling due to complexity of the cytokine-signaling network. Engineered receptors that are non-responsive to endogenous cytokines represent an attractive tool for dissection of signaling events. We here tested a previously developed chimeric receptor (CR) system in primary murine HSCs, target cells that are indispensable for analysis of stem cell activity. Each CR contains tyrosine motifs that enable selective activation of signal molecules located downstream of the c-Mpl receptor upon stimulation by an artificial ligand. Signaling through a control CR with a wild-type c-Mpl cytoplasmic tail sufficed to enhance HSC proliferation and colony formation in cooperation with stem cell factor (SCF). Among a series of CRs, only one compatible with selective Stat5 activation showed similar positive effects. The HSCs maintained ex vivo in these environments retained long-term reconstitution ability following transplantation. This ability was also demonstrated in secondary recipients, indicating effective transmission of stem cell-supportive signals into HSCs via these artificial CRs during culture. Selective activation of Stat5 through CR ex vivo favored preservation of lymphoid potential in long-term reconstituting HSCs, but not of myeloid potential, exemplifying possible dissection of signals downstream of c-Mpl. These CR systems therefore offer a useful tool to scrutinize complex signaling pathways in HSCs.

  15. Brassinosteriod Insensitive 2 (BIN2) acts as a downstream effector of the Target of Rapamycin (TOR) signaling pathway to regulate photoautotrophic growth in Arabidopsis.

    Science.gov (United States)

    Xiong, Fangjie; Zhang, Rui; Meng, Zhigang; Deng, Kexuan; Que, Yumei; Zhuo, Fengping; Feng, Li; Guo, Sundui; Datla, Raju; Ren, Maozhi

    2017-01-01

    The components of the target of rapamycin (TOR) signaling pathway have been well characterized in heterotrophic organisms from yeast to humans. However, because of rapamycin insensitivity, embryonic lethality in tor null mutants and a lack of reliable ways of detecting TOR protein kinase in higher plants, the key players upstream and downstream of TOR remain largely unknown in plants. Using engineered rapamycin-sensitive Binding Protein 12-2 (BP12-2) plants, the present study showed that combined treatment with rapamycin and active-site TOR inhibitors (asTORis) results in synergistic inhibition of TOR activity and plant growth in Arabidopsis. Based on this system, we revealed that TOR signaling plays a crucial role in modulating the transition from heterotrophic to photoautotrophic growth in Arabidopsis. Ribosomal protein S6 kinase 2 (S6K2) was identified as a direct downstream target of TOR, and the growth of TOR-suppressed plants could be rescued by up-regulating S6K2. Systems, genetic, and biochemical analyses revealed that Brassinosteriod Insensitive 2 (BIN2) acts as a novel downstream effector of S6K2, and the phosphorylation of BIN2 depends on TOR-S6K2 signaling in Arabidopsis. By combining pharmacological with genetic and biochemical approaches, we determined that the TOR-S6K2-BIN2 signaling pathway plays important roles in regulating the photoautotrophic growth of Arabidopsis. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

  16. Adaptive Arrays for Multiple Simultaneous Desired Signals.

    Science.gov (United States)

    1983-08-01

    weights [Equation (4)]. Using Equation (6), the inverse of the covariance matrix is given by 5 4 i *ŕm * T ". -1 1 I d Z dij (7) L -I + UT U* 4 di x di...Equations (11) and (12) p k = A k Ik d (14) dk aki*~~* ( ~ dk LJk Udk) and 1 t IjI II di l() 27 x = (1 + t UT U*) Thus, the output SNR of the kth desired...signals are assumed to be of the same frequency. There is no jammer 9 0 dB SIGNAL 10 dB SIGNAL 90 % 90 180 Fiur .dptdpatrnofalier rayo tn strpc lmet

  17. Terminal investment in multiple sexual signals

    DEFF Research Database (Denmark)

    Nielsen, Mattias Lange; Holman, Luke

    2012-01-01

    1. Trade-offs between current and future resource allocation can select for elevated reproductive effort in individuals facing mortality. Males are predicted to benefit from increasing investment in costly sexually selected signals after experiencing an acute life span reduction, although few...... immune challenge in a fashion that made them more attractive to females. 4. The results suggest that males terminally invest in both short- and medium-range pheromones when they perceive reduced future survival. Moreover, the constitutive and inducible aspects of male and female CHC production...

  18. Wireless Energy Harvesting Using Signals from Multiple Fading Channels

    KAUST Repository

    Chen, Yunfei; Zhao, Nan; Alouini, Mohamed-Slim

    2017-01-01

    fading or Gamma-shadowed Rician fading. The received signals are then harvested by using either a single harvester for simultaneous transmissions or multiple harvesters for transmissions at different frequencies, antennas or time slots. Both linear

  19. Inhibition of the Ras-ERK pathway in mitotic COS7 cells is due to the inability of EGFR/Raf to transduce EGF signaling to downstream proteins.

    Science.gov (United States)

    Shi, Huaiping; Zhang, Tianying; Yi, Yongqing; Ma, Yue

    2016-06-01

    Although previous studies have shown that Ras-ERK signaling in mitosis is closed due to the inhibition of signal transduction, the events involved in the molecular mechanisms are still unclear. In the present study, we investigated the Ras-ERK signaling pathway in mitotic COS7 cells. The results demonstrated that treatment with epidermal growth factor (EGF) failed to increase the endocytosis of EGF-EGFR (EGF receptor) complexes in mitotic COS7 cells, although a large amount of endosomes were found in asynchronous COS7 cells. Clathrin expression levels in mitotic COS7 cells were inhibited whereas caveolin expression levels in mitotic COS7 cells were almost unaffected. Y1068 and Y1086 residues of EGFR in the mitotic COS7 cells were activated. However, Grb2 and Shc in the mitotic COS7 cells did not bind to activated EGFR. Ras activity was inhibited in the mitotic COS7 cells whereas its downstream protein, Raf, was obviously phosphorylated by EGF in mitosis. Treatment with phorbol 12-myristate 13-acetate (PMA) also increased the phosphorylation levels of Raf in the mitotic COS7 cells. Nevertheless, Raf phosphorylation in mitosis was significantly inhibited by AG1478. Lastly, activation of EGF-mediated MEK and ERK in the mitotic COS7 cells was obviously inhibited. In summary, our results suggest that the Ras-ERK pathway is inhibited in mitotic COS7 cells which may be the dual result of the difficulty in the transduction of EGF signaling by EGFR or Raf to downstream proteins.

  20. DDX3 directly regulates TRAF3 ubiquitination and acts as a scaffold to co-ordinate assembly of signalling complexes downstream from MAVS.

    Science.gov (United States)

    Gu, Lili; Fullam, Anthony; McCormack, Niamh; Höhn, Yvette; Schröder, Martina

    2017-02-15

    The human DEAD-box helicase 3 (DDX3) has been shown to contribute to type I interferon (IFN) induction downstream from antiviral pattern recognition receptors. It binds to TANK-binding kinase 1 and IκB-kinase-ε (IKKε), the two key kinases mediating activation of IFN regulatory factor (IRF) 3 and IRF7. We previously demonstrated that DDX3 facilitates IKKε activation downstream from RIG-I and then links the activated kinase to IRF3. In the present study, we probed the interactions between DDX3 and other key signalling molecules in the RIG-I pathway and identified a novel direct interaction between DDX3 and TNF receptor-associated factor 3 (TRAF3) mediated by a TRAF-interaction motif in the N-terminus of DDX3, which was required for TRAF3 ubiquitination. Interestingly, we observed two waves of K63-linked TRAF3 ubiquitination following RIG-I activation by Sendai virus (SeV) infection, both of which were suppressed by DDX3 knockdown. We also investigated the spatiotemporal formation of endogenous downstream signalling complexes containing the mitochondrial antiviral signalling (MAVS) adaptor, DDX3, IκB-kinase-ε (IKKε), TRAF3 and IRF3. DDX3 was recruited to MAVS early after SeV infection, suggesting that it might mediate subsequent recruitment of other molecules. Indeed, knockdown of DDX3 prevented the formation of TRAF3-MAVS and TRAF3-IKKε complexes. Based on our data, we propose that early TRAF3 ubiquitination is required for the formation of a stable MAVS-TRAF3 complex, while the second wave of TRAF3 ubiquitination mediates IRF3 recruitment and activation. Our study characterises DDX3 as a multifunctional adaptor molecule that co-ordinates assembly of different TRAF3, IKKε and IRF3-containing signalling complexes downstream from MAVS. Additionally, it provides novel insights into the role of TRAF3 in RIG-I signalling. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

  1. The C-terminal tail of CRTH2 is a key molecular determinant that constrains GalphaI- and downstream-signaling cascade activation

    DEFF Research Database (Denmark)

    Schroeder, Ralf; Merten, Nicole; Mathiesen, Jesper Mosolff

    2009-01-01

    Prostaglandin D(2) activation of the seven transmembrane receptor CRTH2 regulates numerous cell functions that are important in inflammatory diseases such as asthma. Despite its disease implication, no studies to date aimed at identifying receptor domains governing signaling and surface expression......2 at the plasma membrane, presence of this domain confers a signaling-compromised conformation onto the receptor. Indeed, a mutant receptor lacking the major portion of its C-terminal tail displays paradoxically enhanced Galphai and ERK1/2 activation in spite of enhanced constitutive and agonist......-mediated internalization. Enhanced activation of Galphai proteins and downstream signaling cascades is likely due to the inability of the tail-truncated receptor to recruit beta-arrestin2 and undergo homologous desensitization. Unexpectedly, CRTH2 is not phosphorylated upon agonist-stimulation, a primary mechanism...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2010-05-10

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

  3. The C. elegans embryonic fate specification factor EGL-18 (GATA) is reutilized downstream of Wnt signaling to maintain a population of larval progenitor cells.

    Science.gov (United States)

    Gorrepati, Lakshmi; Eisenmann, David M

    2015-01-01

    In metazoans, stem cells in developing and adult tissues can divide asymmetrically to give rise to a daughter that differentiates and a daughter that retains the progenitor fate. Although the short-lived nematode C. elegans does not possess adult somatic stem cells, the lateral hypodermal seam cells behave in a similar manner: they divide once per larval stage to generate an anterior daughter that adopts a non-dividing differentiated fate and a posterior daughter that retains the seam fate and the ability to divide further. Wnt signaling pathway is known to regulate the asymmetry of these divisions and maintain the progenitor cell fate in one daughter, but how activation of the Wnt pathway accomplished this was unknown. We describe here our recent work that identified the GATA transcription factor EGL-18 as a downstream target of Wnt signaling necessary for maintenance of a progenitor population of larval seam cells. EGL-18 was previously shown to act in the initial specification of the seam cells in the embryo. Thus the acquisition of a Wnt-responsive cis-regulatory module allows an embryonic fate specification factor to be reutilized later in life downstream of a different regulator (Wnt signaling) to maintain a progenitor cell population. These results support the use of seam cell development in C. elegans as a simple model system for studying stem and progenitor cell biology.

  4. Using a Single VCSEL Source Employing OFDM Downstream Signal and Remodulated OOK Upstream Signal for Bi-directional Visible Light Communications.

    Science.gov (United States)

    Yeh, Chien-Hung; Wei, Liang-Yu; Chow, Chi-Wai

    2017-11-20

    In this work, we propose and demonstrate for the first time up to our knowledge, using a 682 nm visible vertical-cavity surface-emitting laser (VCSEL) applied in a bi-directional wavelength remodulated VLC system with a free space transmission distance of 3 m. To achieve a high VLC downstream traffic, spectral efficient orthogonal-frequency-division-multiplexing quadrature-amplitude-modulation (OFDM-QAM) with bit and power loading algorithms are applied on the VCSEL in the central office (CO). The OFDM downstream wavelength is remodulated by an acousto-optic modulator (AOM) with OOK modulation to produce the upstream traffic in the client side. Hence, only a single VCSEL laser is needed for the proposed bi-directional VLC system, achieving 10.6 Gbit/s OFDM downstream and 2 Mbit/s remodulated OOK upstream simultaneously. For the proposed system, as a single laser source with wavelength remodulation is used, the laser wavelength and temperature managements at the client side are not needed; and the whole system could be cost effective and energy efficient.

  5. Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling

    NARCIS (Netherlands)

    Ashton, Gabrielle H.; Morton, Jennifer P.; Myant, Kevin; Phesse, Toby J.; Ridgway, Rachel A.; Marsh, Victoria; Wilkins, Julie A.; Athineos, Dimitris; Muncan, Vanesa; Kemp, Richard; Neufeld, Kristi; Clevers, Hans; Brunton, Valerie; Winton, Douglas J.; Wang, Xiaoyan; Sears, Rosalie C.; Clarke, Alan R.; Frame, Margaret C.; Sansom, Owen J.

    2010-01-01

    The intestinal epithelium has a remarkable capacity to regenerate after injury and DNA damage. Here, we show that the integrin effector protein Focal Adhesion Kinase (FAK) is dispensable for normal intestinal homeostasis and DNA damage signaling, but is essential for intestinal regeneration

  6. G protein-coupled receptor kinase 2 negatively regulates chemokine signaling at a level downstream from G protein subunits

    NARCIS (Netherlands)

    Jimenez-Sainz, MC; Murga, C; Kavelaars, A; Jurado-Pueyo, M; Krakstad, BF; Heijnen, CJ; Mayor, F; Aragay, AM

    The G protein-coupled receptor kinase 2 (GRK2) phosphorylates and desensitizes ligand-activated G protein-coupled-receptors. Here, evidence is shown for a novel role of GRK2 in regulating chemokine-mediated signals. The presence of increased levels of GRK2 in human embryonic kidney (HEK) 293 cells

  7. Bcl-xL acts downstream of caspase-8 activation by the CD95 death-inducing signaling complex

    NARCIS (Netherlands)

    Medema, J. P.; Scaffidi, C.; Krammer, P. H.; Peter, M. E.

    1998-01-01

    The Bcl-2 family member Bcl-xL has often been correlated with apoptosis resistance. We have shown recently that in peripheral human T cells resistance to CD95-mediated apoptosis is characterized by a lack of caspase-8 recruitment to the CD95 death-inducing signaling complex (DISC) and by increased

  8. The Spalt transcription factors regulate cell proliferation, survival and epithelial integrity downstream of the Decapentaplegic signalling pathway

    Directory of Open Access Journals (Sweden)

    María F. Organista

    2012-10-01

    The expression of the spalt genes is regulated by the Decapentaplegic signalling pathway in the Drosophila wing. These genes participate in the patterning of the longitudinal wing veins by regulating the expression of vein-specific genes, and in the establishment of cellular affinities in the central region of the wing blade epithelium. The Spalt proteins act as transcription factors, most likely regulating gene expression by repression, but the identity of their target genes in the wing is still unknown. As a preliminary step to unravel the genetic hierarchy controlled by the Spalt proteins, we have analysed their requirements during wing development, and addressed to what extent they mediate all the functions of the Decapentaplegic pathway in this developmental system. We identify additional functions for Spalt in cell division, survival, and maintenance of epithelial integrity. Thus, Spalt activity is required to promote cell proliferation, acting in the G2/M transition of the cell cycle. The contribution of Spalt to cell division is limited to the central region of the wing blade, as they do not mediate the extra growth triggered by Decapentaplegic signalling in the peripheral regions of the wing disc. In addition, Spalt function is required to maintain cell viability in cells exposed to high levels of Decapentaplegic signalling. This aspect of Spalt function is related to the repression of JNK signalling in the spalt domain of expression. Finally, we further characterise the requirements of Spalt to maintain epithelial integrity by regulating cellular affinities between cells located in the central wing region. Our results indicate that Spalt function mediates most of the requirements identified for Decapentaplegic signalling, contributing to establish the cellular qualities that differentiate central versus peripheral territories in the wing blade.

  9. Illegitimate WNT signaling promotes proliferation of multiple myeloma cells

    Science.gov (United States)

    Derksen, Patrick W. B.; Tjin, Esther; Meijer, Helen P.; Klok, Melanie D.; Mac Gillavry, Harold D.; van Oers, Marinus H. J.; Lokhorst, Henk M.; Bloem, Andries C.; Clevers, Hans; Nusse, Roel; van der Neut, Ronald; Spaargaren, Marcel; Pals, Steven T.

    2004-01-01

    The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also influenced by signals from the environment. In multiple myeloma (MM), the factors and signals coming from the bone marrow microenvironment are possibly even essential for the growth of the tumor cells. As targets for intervention, these signals may be equally important as mutated oncogenes. Given their oncogenic potential, WNT signals form a class of paracrine growth factors that could act to influence MM cell growth. In this paper, we report that MM cells have hallmarks of active WNT signaling, whereas the cells have not undergone detectable mutations in WNT signaling genes such as adenomatous polyposis coli and β-catenin (CTNNB1). We show that the malignant MM plasma cells overexpress β-catenin, including its N-terminally unphosphorylated form, suggesting active β-catenin/T cell factor-mediated transcription. Further accumulation and nuclear localization of β-catenin, and/or increased cell proliferation, was achieved by stimulation of WNT signaling with either Wnt3a, LiCl, or the constitutively active S33Y mutant of β-catenin. In contrast, by blocking WNT signaling by dominant-negative T cell factor, we can interfere with the growth of MM cells. We therefore suggest that MM cells are dependent on an active WNT signal, which may have important implications for the management of this incurable form of cancer. PMID:15067127

  10. Disease-associated extracellular loop mutations in the adhesion G protein-coupled receptor G1 (ADGRG1; GPR56) differentially regulate downstream signaling.

    Science.gov (United States)

    Kishore, Ayush; Hall, Randy A

    2017-06-09

    Mutations to the adhesion G protein-coupled receptor ADGRG1 (G1; also known as GPR56) underlie the neurological disorder bilateral frontoparietal polymicrogyria. Disease-associated mutations in G1 studied to date are believed to induce complete loss of receptor function through disruption of either receptor trafficking or signaling activity. Given that N-terminal truncation of G1 and other adhesion G protein-coupled receptors has been shown to significantly increase the receptors' constitutive signaling, we examined two different bilateral frontoparietal polymicrogyria-inducing extracellular loop mutations (R565W and L640R) in the context of both full-length and N-terminally truncated (ΔNT) G1. Interestingly, we found that these mutations reduced surface expression of full-length G1 but not G1-ΔNT in HEK-293 cells. Moreover, the mutations ablated receptor-mediated activation of serum response factor luciferase, a classic measure of Gα 12/13 -mediated signaling, but had no effect on G1-mediated signaling to nuclear factor of activated T cells (NFAT) luciferase. Given these differential signaling results, we sought to further elucidate the pathway by which G1 can activate NFAT luciferase. We found no evidence that ΔNT activation of NFAT is dependent on Gα q/11 -mediated or β-arrestin-mediated signaling but rather involves liberation of Gβγ subunits and activation of calcium channels. These findings reveal that disease-associated mutations to the extracellular loops of G1 differentially alter receptor trafficking, depending on the presence of the N terminus, and differentially alter signaling to distinct downstream pathways. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Spargel/dPGC-1 is a new downstream effector in the insulin-TOR signaling pathway in Drosophila.

    Science.gov (United States)

    Mukherjee, Subhas; Duttaroy, Atanu

    2013-10-01

    Insulin and target of rapamycin (TOR) signaling pathways converge to maintain growth so a proportionate body form is attained. Insufficiency in either insulin or TOR results in developmental growth defects due to low ATP level. Spargel is the Drosophila homolog of PGC-1, which is an omnipotent transcriptional coactivator in mammals. Like its mammalian counterpart, Spargel/dPGC-1 is recognized for its role in energy metabolism through mitochondrial biogenesis. An earlier study demonstrated that Spargel/dPGC-1 is involved in the insulin-TOR signaling, but a comprehensive analysis is needed to understand exactly which step of this pathway Spargel/PGC-1 is essential. Using genetic epistasis analysis, we demonstrated that a Spargel gain of function can overcome the TOR and S6K mediated cell size and cell growth defects in a cell autonomous manner. Moreover, the tissue-restricted phenotypes of TOR and S6k mutants are rescued by Spargel overexpression. We have further elucidated that Spargel gain of function sets back the mitochondrial numbers in growth-limited TOR mutant cell clones, which suggests a possible mechanism for Spargel action on cells and tissue to attain normal size. Finally, excess Spargel can ameliorate the negative effect of FoxO overexpression only to a limited extent, which suggests that Spargel does not share all of the FoxO functions and consequently cannot significantly rescue the FoxO phenotypes. Together, our observation established that Spargel/dPGC-1 is indeed a terminal effector in the insulin-TOR pathway operating below TOR, S6K, Tsc, and FoxO. This led us to conclude that Spargel should be incorporated as a new member of this growth-signaling pathway.

  12. Downstream signaling mechanism of the C-terminal activation domain of transcriptional coactivator CoCoA

    OpenAIRE

    Kim, Jeong Hoon; Yang, Catherine K.; Stallcup, Michael R.

    2006-01-01

    The coiled-coil coactivator (CoCoA) is a transcriptional coactivator for nuclear receptors and enhances nuclear receptor function by the interaction with the bHLH-PAS domain (AD3) of p160 coactivators. The C-terminal activation domain (AD) of CoCoA possesses strong transactivation activity and is required for the coactivator function of CoCoA with nuclear receptors. To understand how CoCoA AD transmits its activating signal to the transcription machinery, we defined specific subregions, amino...

  13. Multiple Signal Classification for Gravitational Wave Burst Search

    Science.gov (United States)

    Cao, Junwei; He, Zhengqi

    2013-01-01

    This work is mainly focused on the application of the multiple signal classification (MUSIC) algorithm for gravitational wave burst search. This algorithm extracts important gravitational wave characteristics from signals coming from detectors with arbitrary position, orientation and noise covariance. In this paper, the MUSIC algorithm is described in detail along with the necessary adjustments required for gravitational wave burst search. The algorithm's performance is measured using simulated signals and noise. MUSIC is compared with the Q-transform for signal triggering and with Bayesian analysis for direction of arrival (DOA) estimation, using the Ω-pipeline. Experimental results show that MUSIC has a lower resolution but is faster. MUSIC is a promising tool for real-time gravitational wave search for multi-messenger astronomy.

  14. Honey bee foraging induces upregulation of early growth response protein 1, hormone receptor 38 and candidate downstream genes of the ecdysteroid signalling pathway.

    Science.gov (United States)

    Singh, A S; Shah, A; Brockmann, A

    2018-02-01

    In honey bees, continuous foraging at an artificial feeder induced a sustained upregulation of the immediate early genes early growth response protein 1 (Egr-1) and hormone receptor 38 (Hr38). This gene expression response was accompanied by an upregulation of several Egr-1 candidate downstream genes: ecdysone receptor (EcR), dopamine/ecdysteroid receptor (DopEcR), dopamine decarboxylase and dopamine receptor 2. Hr38, EcR and DopEcR are components of the ecdysteroid signalling pathway, which is highly probably involved in learning and memory processes in honey bees and other insects. Time-trained foragers still showed an upregulation of Egr-1 when the feeder was presented at an earlier time of the day, suggesting that the genomic response is more dependent on the food reward than training time. However, presentation of the feeder at the training time without food was still capable of inducing a transient increase in Egr-1 expression. Thus, learnt feeder cues, or even training time, probably affect Egr-1 expression. In contrast, whole brain Egr-1 expression changes did not differ between dancing and nondancing foragers. On the basis of our results we propose that food reward induced continuous foraging ultimately elicits a genomic response involving Egr-1 and Hr38 and their downstream genes. Furthermore this genomic response is highly probably involved in foraging-related learning and memory responses. © 2017 The Royal Entomological Society.

  15. Classification of Single and Multiple Disturbances in Electric Signals

    Directory of Open Access Journals (Sweden)

    Ribeiro Moisés Vidal

    2007-01-01

    Full Text Available This paper discusses and presents a different perspective for classifying single and multiple disturbances in electric signals, such as voltage and current ones. Basically, the principle of divide to conquer is applied to decompose the electric signals into what we call primitive signals or components from which primitive patterns can be independently recognized. A technique based on such concept is introduced to demonstrate the effectiveness of such idea. This technique decomposes the electric signals into three main primitive components. In each primitive component, few high-order-statistics- (HOS- based features are extracted. Then, Bayes' theory-based techniques are applied to verify the ocurrence or not of single or multiple disturbances in the electric signals. The performance analysis carried out on a large number of data indicates that the proposed technique outperforms the performance attained by the technique introduced by He and Starzyk. Additionally, the numerical results verify that the proposed technique is capable of offering interesting results when it is applied to classify several sets of disturbances if one cycle of the main frequency is considered, at least.

  16. Multiplicity counting from fission chamber signals in the current mode

    Energy Technology Data Exchange (ETDEWEB)

    Pázsit, I. [Chalmers University of Technology, Department of Physics, Division of Subatomic and Plasma Physics, SE-412 96 Göteborg (Sweden); Pál, L. [Centre for Energy Research, Hungarian Academy of Sciences, 114, POB 49, H-1525 Budapest (Hungary); Nagy, L. [Chalmers University of Technology, Department of Physics, Division of Subatomic and Plasma Physics, SE-412 96 Göteborg (Sweden); Budapest University of Technology and Economics, Institute of Nuclear Techniques, H-1111 Budapest (Hungary)

    2016-12-11

    In nuclear safeguards, estimation of sample parameters using neutron-based non-destructive assay methods is traditionally based on multiplicity counting with thermal neutron detectors in the pulse mode. These methods in general require multi-channel analysers and various dead time correction methods. This paper proposes and elaborates on an alternative method, which is based on fast neutron measurements with fission chambers in the current mode. A theory of “multiplicity counting” with fission chambers is developed by incorporating Böhnel's concept of superfission [1] into a master equation formalism, developed recently by the present authors for the statistical theory of fission chamber signals [2,3]. Explicit expressions are derived for the first three central auto- and cross moments (cumulants) of the signals of up to three detectors. These constitute the generalisation of the traditional Campbell relationships for the case when the incoming events represent a compound Poisson distribution. Because now the expressions contain the factorial moments of the compound source, they contain the same information as the singles, doubles and triples rates of traditional multiplicity counting. The results show that in addition to the detector efficiency, the detector pulse shape also enters the formulas; hence, the method requires a more involved calibration than the traditional method of multiplicity counting. However, the method has some advantages by not needing dead time corrections, as well as having a simpler and more efficient data processing procedure, in particular for cross-correlations between different detectors, than the traditional multiplicity counting methods.

  17. Id4 functions downstream of Bmp signaling to restrict TCF function in endocardial cells during atrioventricular valve development.

    Science.gov (United States)

    Ahuja, Suchit; Dogra, Deepika; Stainier, Didier Y R; Reischauer, Sven

    2016-04-01

    The atrioventricular canal (AVC) connects the atrial and ventricular chambers of the heart and its formation is critical for the development of the cardiac valves, chamber septation and formation of the cardiac conduction system. Consequently, problems in AVC formation can lead to congenital defects ranging from cardiac arrhythmia to incomplete cardiac septation. While our knowledge about early heart tube formation is relatively comprehensive, much remains to be investigated about the genes that regulate AVC formation. Here we identify a new role for the basic helix-loop-helix factor Id4 in zebrafish AVC valve development and function. id4 is first expressed in the AVC endocardium and later becomes more highly expressed in the atrial chamber. TALEN induced inactivation of id4 causes retrograde blood flow at the AV canal under heat induced stress conditions, indicating defects in AV valve function. At the molecular level, we found that id4 inactivation causes misexpression of several genes important for AVC and AV valve formation including bmp4 and spp1. We further show that id4 appears to control the number of endocardial cells that contribute to the AV valves by regulating Wnt signaling in the developing AVC endocardium. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Isolation of Fully Human Antagonistic RON Antibodies Showing Efficient Block of Downstream Signaling and Cell Migration1

    Science.gov (United States)

    Gunes, Zeynep; Zucconi, Adriana; Cioce, Mario; Meola, Annalisa; Pezzanera, Monica; Acali, Stefano; Zampaglione, Immacolata; De Pratti, Valeria; Bova, Luca; Talamo, Fabio; Demartis, Anna; Monaci, Paolo; La Monica, Nicola; Ciliberto, Gennaro; Vitelli, Alessandra

    2011-01-01

    RON belongs to the c-MET family of receptor tyrosine kinases. As its well-known family member MET, RON and its ligand macrophage-stimulating protein have been implicated in the progression and metastasis of tumors and have been shown to be overexpressed in cancer. We generated and tested a large number of human monoclonal antibodies (mAbs) against human RON. Our screening yielded three high-affinity antibodies that efficiently block ligand-dependent intracellular AKT and MAPK signaling. This effect correlates with the strong reduction of ligand-activated migration of T47D breast cancer cell line. By cross-competition experiments, we showed that the antagonistic antibodies fall into three distinct epitope regions of the RON extracellular Sema domain. Notably, no inhibition of tumor growth was observed in different epithelial tumor xenografts in nude mice with any of the antibodies. These results suggest that distinct properties beside ligand antagonism are required for anti-RON mAbs to exert antitumor effects in vivo. PMID:21286376

  19. Salicylic Acid Suppresses Jasmonic Acid Signaling Downstream of SCFCOI1-JAZ by Targeting GCC Promoter Motifs via Transcription Factor ORA59[C][W][OA

    Science.gov (United States)

    Van der Does, Dieuwertje; Leon-Reyes, Antonio; Koornneef, Annemart; Van Verk, Marcel C.; Rodenburg, Nicole; Pauwels, Laurens; Goossens, Alain; Körbes, Ana P.; Memelink, Johan; Ritsema, Tita; Van Wees, Saskia C.M.; Pieterse, Corné M.J.

    2013-01-01

    Antagonism between the defense hormones salicylic acid (SA) and jasmonic acid (JA) plays a central role in the modulation of the plant immune signaling network, but the molecular mechanisms underlying this phenomenon are largely unknown. Here, we demonstrate that suppression of the JA pathway by SA functions downstream of the E3 ubiquitin-ligase Skip-Cullin-F-box complex SCFCOI1, which targets JASMONATE ZIM-domain transcriptional repressor proteins (JAZs) for proteasome-mediated degradation. In addition, neither the stability nor the JA-induced degradation of JAZs was affected by SA. In silico promoter analysis of the SA/JA crosstalk transcriptome revealed that the 1-kb promoter regions of JA-responsive genes that are suppressed by SA are significantly enriched in the JA-responsive GCC-box motifs. Using GCC:GUS lines carrying four copies of the GCC-box fused to the β-glucuronidase reporter gene, we showed that the GCC-box motif is sufficient for SA-mediated suppression of JA-responsive gene expression. Using plants overexpressing the GCC-box binding APETALA2/ETHYLENE RESPONSE FACTOR (AP2/ERF) transcription factors ERF1 or ORA59, we found that SA strongly reduces the accumulation of ORA59 but not that of ERF1. Collectively, these data indicate that the SA pathway inhibits JA signaling downstream of the SCFCOI1-JAZ complex by targeting GCC-box motifs in JA-responsive promoters via a negative effect on the transcriptional activator ORA59. PMID:23435661

  20. Salicylic acid suppresses jasmonic acid signaling downstream of SCFCOI1-JAZ by targeting GCC promoter motifs via transcription factor ORA59.

    Science.gov (United States)

    Van der Does, Dieuwertje; Leon-Reyes, Antonio; Koornneef, Annemart; Van Verk, Marcel C; Rodenburg, Nicole; Pauwels, Laurens; Goossens, Alain; Körbes, Ana P; Memelink, Johan; Ritsema, Tita; Van Wees, Saskia C M; Pieterse, Corné M J

    2013-02-01

    Antagonism between the defense hormones salicylic acid (SA) and jasmonic acid (JA) plays a central role in the modulation of the plant immune signaling network, but the molecular mechanisms underlying this phenomenon are largely unknown. Here, we demonstrate that suppression of the JA pathway by SA functions downstream of the E3 ubiquitin-ligase Skip-Cullin-F-box complex SCF(COI1), which targets JASMONATE ZIM-domain transcriptional repressor proteins (JAZs) for proteasome-mediated degradation. In addition, neither the stability nor the JA-induced degradation of JAZs was affected by SA. In silico promoter analysis of the SA/JA crosstalk transcriptome revealed that the 1-kb promoter regions of JA-responsive genes that are suppressed by SA are significantly enriched in the JA-responsive GCC-box motifs. Using GCC:GUS lines carrying four copies of the GCC-box fused to the β-glucuronidase reporter gene, we showed that the GCC-box motif is sufficient for SA-mediated suppression of JA-responsive gene expression. Using plants overexpressing the GCC-box binding APETALA2/ETHYLENE RESPONSE FACTOR (AP2/ERF) transcription factors ERF1 or ORA59, we found that SA strongly reduces the accumulation of ORA59 but not that of ERF1. Collectively, these data indicate that the SA pathway inhibits JA signaling downstream of the SCF(COI1)-JAZ complex by targeting GCC-box motifs in JA-responsive promoters via a negative effect on the transcriptional activator ORA59.

  1. Khellin and visnagin differentially modulate AHR signaling and downstream CYP1A activity in human liver cells.

    Directory of Open Access Journals (Sweden)

    Radim Vrzal

    Full Text Available Khellin and visnagin are two furanochromones that can be frequently found in ethnomedical formulations in Asia and the Middle East. Both compounds possess anti-inflammatory and analgesic properties, therefore modern medicine uses these compounds or structurally related derivatives for treatment of vitiligo, bronchial asthma and renal colics. Despite their frequent usage, the potential toxic properties of visnagin and khellin are not well characterized up-to-now. Many natural compounds modulate the expression and activity of cytochrome P450 1A1 (CYP1A1, which is well-known to bioactivate pro-carcinogens. The expression of this enzyme is controlled by the aryl hydrocarbon receptor (AHR, a ligand-activated transcription factor and regulator of drug metabolism. Here, we investigated the influence of both furanochromones on AHR signaling in human HepG2 hepatocarcinoma cells and primary human hepatocytes. Both compounds transactivated xenobiotic response element (XRE-driven reporter gene activity in a dose-dependent manner and induced CYP1A1 transcription in HepG2 cells and primary hepatocytes. The latter was abolished in presence of a specific AHR antagonist. CYP1A enzyme activity assays done in HepG2 cells and primary hepatocytes revealed an inhibition of enzyme activity by both furanochromones, which may become relevant regarding the metabolism of xenobiotics and co-administered therapeutic drugs. The observed induction of several other members of the AHR gene battery, whose gene products are involved in regulation of cell growth, differentiation and migration, indicates that a further toxicological characterization of visnagin and khelllin is urgently required in order to minimize potential drug-drug interactions and other toxic side-effects that may occur during therapeutic usage of these furanochromones.

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

    Science.gov (United States)

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

    2016-01-01

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

  3. The Ste20 kinase misshapen regulates both photoreceptor axon targeting and dorsal closure, acting downstream of distinct signals.

    Science.gov (United States)

    Su, Y C; Maurel-Zaffran, C; Treisman, J E; Skolnik, E Y

    2000-07-01

    upstream signaling systems.

  4. On using the Multiple Signal Classification algorithm to study microbaroms

    Science.gov (United States)

    Marcillo, O. E.; Blom, P. S.; Euler, G. G.

    2016-12-01

    Multiple Signal Classification (MUSIC) (Schmidt, 1986) is a well-known high-resolution algorithm used in array processing for parameter estimation. We report on the application of MUSIC to infrasonic array data in a study of the structure of microbaroms. Microbaroms can be globally observed and display energy centered around 0.2 Hz. Microbaroms are an infrasonic signal generated by the non-linear interaction of ocean surface waves that radiate into the ocean and atmosphere as well as the solid earth in the form of microseisms. Microbaroms sources are dynamic and, in many cases, distributed in space and moving in time. We assume that the microbarom energy detected by an infrasonic array is the result of multiple sources (with different back-azimuths) in the same bandwidth and apply the MUSIC algorithm accordingly to recover the back-azimuth and trace velocity of the individual components. Preliminary results show that the multiple component assumption in MUSIC allows one to resolve the fine structure in the microbarom band that can be related to multiple ocean surface phenomena.

  5. Focal adhesion kinase, a downstream mediator of Raf-1 signaling, suppresses cellular adhesion, migration, and neuroendocrine markers in BON carcinoid cells.

    Science.gov (United States)

    Ning, Li; Chen, Herbert; Kunnimalaiyaan, Muthusamy

    2010-05-01

    We have recently reported that activation of the Raf-1/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase 1/2 (MEK1/2)/ERK1/2 signaling cascade in gastrointestinal carcinoid cell line (BON) alters cellular morphology and neuroendocrine phenotype. The mechanisms by which Raf-1 mediates these changes in carcinoid cells are unclear. Here, we report that activation of the Raf-1 signaling cascade in BON cells induced the expression of focal adhesion kinase (FAK) protein, suppressed the production of neuroendocrine markers, and resulted in significant decreases in cellular adhesion and migration. Importantly, inactivation of MEK1/2 by 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene or abolition of FAK induction in Raf-1-activated BON cells by targeted siRNA led to reversal of the Raf-1-mediated reduction in neuroendocrine markers and cellular adhesion and migration. Phosphorylation site-specific antibodies detected the phosphorylated FAK(Tyr407), but not FAK(Tyr397), in these Raf-1-activated cells, indicating that FAK(Tyr407) may be associated with changes in the neuroendocrine phenotype. Overexpression of constitutively active FAK plasmids (wild-type FAK or FAK(Tyr397) mutant) into BON cells reduced neuroendocrine markers, whereas the FAK(Tyr407) mutant plasmid did not show any decrease in the levels of neuroendocrine markers, indicating that phosphorylation of FAK at the Tyr(407) residue may be important for these effects. Our results showed for the first time that FAK is an essential downstream effector of the Raf-1/MEK1/2/ERK1/2 signaling cascade and negatively regulated the neuroendocrine and metastatic phenotype in BON cells. (c)2010 AACR.

  6. Signal Processing Algorithms for Down-Stream Traffic in Next Generation 10 Gbit/s Fixed-Grid Passive Optical Networks

    Directory of Open Access Journals (Sweden)

    Rameez Asif

    2014-01-01

    Full Text Available We have analyzed the impact of digital and optical signal processing algorithms, that is, Volterra equalization (VE, digital backpropagation (BP, and optical phase conjugation with nonlinearity module (OPC-NM, in next generation 10 Gbit/s (also referred to as XG DP-QPSK long haul WDM (fixed-grid passive optical network (PON without midspan repeaters over 120 km standard single mode fiber (SMF link for downstream signals. Due to the compensation of optical Kerr effects, the sensitivity penalty is improved by 2 dB by implementing BP algorithm, 1.5 dB by VE algorithm, and 2.69 dB by OPC-NM. Moreover, with the implementation of NL equalization technique, we are able to get the transmission distance of 126.6 km SMF for the 1 : 1024 split ratio at 5 GHz channel spacing in the nonlinear region.

  7. Ras1 interacts with multiple new signaling and cytoskeletal loci in Drosophila eggshell patterning and morphogenesis.

    Science.gov (United States)

    Schnorr, J D; Holdcraft, R; Chevalier, B; Berg, C A

    2001-10-01

    Little is known about the genes that interact with Ras signaling pathways to regulate morphogenesis. The synthesis of dorsal eggshell structures in Drosophila melanogaster requires multiple rounds of Ras signaling followed by dramatic epithelial sheet movements. We took advantage of this process to identify genes that link patterning and morphogenesis; we screened lethal mutations on the second chromosome for those that could enhance a weak Ras1 eggshell phenotype. Of 1618 lethal P-element mutations tested, 13 showed significant enhancement, resulting in forked and fused dorsal appendages. Our genetic and molecular analyses together with information from the Berkeley Drosophila Genome Project reveal that 11 of these lines carry mutations in previously characterized genes. Three mutations disrupt the known Ras1 cell signaling components Star, Egfr, and Blistered, while one mutation disrupts Sec61beta, implicated in ligand secretion. Seven lines represent cell signaling and cytoskeletal components that are new to the Ras1 pathway; these are Chickadee (Profilin), Tec29, Dreadlocks, POSH, Peanut, Smt3, and MESK2, a suppressor of dominant-negative Ksr. A twelfth insertion disrupts two genes, Nrk, a "neurospecific" receptor tyrosine kinase, and Tpp, which encodes a neuropeptidase. These results suggest that Ras1 signaling during oogenesis involves novel components that may be intimately associated with additional signaling processes and with the reorganization of the cytoskeleton. To determine whether these Ras1 Enhancers function upstream or downstream of the Egf receptor, four mutations were tested for their ability to suppress an activated Egfr construct (lambdatop) expressed in oogenesis exclusively in the follicle cells. Mutations in Star and l(2)43Bb had no significant effect upon the lambdatop eggshell defect whereas smt3 and dock alleles significantly suppressed the lambdatop phenotype.

  8. High congruence of isotope sewage signals in multiple marine taxa

    International Nuclear Information System (INIS)

    Connolly, Rod M.; Gorman, Daniel; Hindell, Jeremy S.; Kildea, Timothy N.; Schlacher, Thomas A.

    2013-01-01

    Highlights: • Sewage inputs are routinely mapped with stable isotopes ( 15 N) in organisms. • We tested whether choice of species influences spatial 15 N distributions. • Spatial gradients were consistent between algae, seagrasses, crabs, and fish. • A match of sewage-N signals in multiple marine taxa has not been reported before. • Spatially-coupled transfers in the food web produce the congruence of N imprints. -- Abstract: Assessments of sewage pollution routinely employ stable nitrogen isotope analysis (δ 15 N) in biota, but multiple taxa are rarely used. This single species focus leads to underreporting of whether derived spatial N patterns are consistent. Here we test the question of ‘reproducibility’, incorporating ‘taxonomic replication’ in the measurement of δ 15 N gradients in algae, seagrasses, crabs and fish with distance from a sewage outfall on the Adelaide coast (southern Australia). Isotopic sewage signals were equally strong in all taxa and declined at the same rate. This congruence amongst taxa has not been reported previously. It implies that sewage-N propagates to fish via a tight spatial coupling between production and consumption processes, resulting from limited animal movement that closely preserves the spatial pollution imprint. In situations such as this where consumers mirror pollution signals of primary producers, analyses of higher trophic levels will capture a broader ambit of ecological effects

  9. An Adaptive Model for Calculating the Correlation Degree of Multiple Adjacent Signalized Intersections

    Directory of Open Access Journals (Sweden)

    Linhong Wang

    2013-01-01

    Full Text Available As an important component of the urban adaptive traffic control system, subarea partition algorithm divides the road network into some small subareas and then determines the optimal signal control mode for each signalized intersection. Correlation model is the core of subarea partition algorithm because it can quantify the correlation degree of adjacent signalized intersections and decides whether these intersections can be grouped into one subarea. In most cases, there are more than two intersections in one subarea. However, current researches only focus on the correlation model for two adjacent intersections. The objective of this study is to develop a model which can calculate the correlation degree of multiple intersections adaptively. The cycle lengths, link lengths, number of intersections, and path flow between upstream and downstream coordinated phases were selected as the contributing factors of the correlation model. Their jointly impacts on the performance of the coordinated control mode relative to the isolated control mode were further studied using numerical experiments. The paper then proposed a correlation index (CI as an alternative to relative performance. The relationship between CI and the four contributing factors was established in order to predict the correlation, which determined whether adjacent intersections could be partitioned into one subarea. A value of 0 was set as the threshold of CI. If CI was larger than 0, multiple intersections could be partitioned into one subarea; otherwise, they should be separated. Finally, case studies were conducted in a real-life signalized network to evaluate the performance of the model. The results show that the CI simulates the relative performance well and could be a reliable index for subarea partition.

  10. C. elegans GATA factors EGL-18 and ELT-6 function downstream of Wnt signaling to maintain the progenitor fate during larval asymmetric divisions of the seam cells.

    Science.gov (United States)

    Gorrepati, Lakshmi; Thompson, Kenneth W; Eisenmann, David M

    2013-05-01

    The C. elegans seam cells are lateral epithelial cells arrayed in a single line from anterior to posterior that divide in an asymmetric, stem cell-like manner during larval development. These asymmetric divisions are regulated by Wnt signaling; in most divisions, the posterior daughter in which the Wnt pathway is activated maintains the progenitor seam fate, while the anterior daughter in which the Wnt pathway is not activated adopts a differentiated hypodermal fate. Using mRNA tagging and microarray analysis, we identified the functionally redundant GATA factor genes egl-18 and elt-6 as Wnt pathway targets in the larval seam cells. EGL-18 and ELT-6 have previously been shown to be required for initial seam cell specification in the embryo. We show that in larval seam cell asymmetric divisions, EGL-18 is expressed strongly in the posterior seam-fated daughter. egl-18 and elt-6 are necessary for larval seam cell specification, and for hypodermal to seam cell fate transformations induced by ectopic Wnt pathway overactivation. The TCF homolog POP-1 binds a site in the egl-18 promoter in vitro, and this site is necessary for robust seam cell expression in vivo. Finally, larval overexpression of EGL-18 is sufficient to drive expression of a seam marker in other hypodermal cells in wild-type animals, and in anterior hypodermal-fated daughters in a Wnt pathway-sensitized background. These data suggest that two GATA factors that are required for seam cell specification in the embryo independently of Wnt signaling are reused downstream of Wnt signaling to maintain the progenitor fate during stem cell-like divisions in larval development.

  11. Tuning Cell and Tissue Development by Combining Multiple Mechanical Signals.

    Science.gov (United States)

    Sinha, Ravi; Verdonschot, Nico; Koopman, Bart; Rouwkema, Jeroen

    2017-10-01

    Mechanical signals offer a promising way to control cell and tissue development. It has been established that cells constantly probe their mechanical microenvironment and employ force feedback mechanisms to modify themselves and when possible, their environment, to reach a homeostatic state. Thus, a correct mechanical microenvironment (external forces and mechanical properties and shapes of cellular surroundings) is necessary for the proper functioning of cells. In vitro or in the case of nonbiological implants in vivo, where cells are in an artificial environment, addition of the adequate mechanical signals can, therefore, enable the cells to function normally as in vivo. Hence, a wide variety of approaches have been developed to apply mechanical stimuli (such as substrate stretch, flow-induced shear stress, substrate stiffness, topography, and modulation of attachment area) to cells in vitro. These approaches have not just revealed the effects of the mechanical signals on cells but also provided ways for probing cellular molecules and structures that can provide a mechanistic understanding of the effects. However, they remain lower in complexity compared with the in vivo conditions, where the cellular mechanical microenvironment is the result of a combination of multiple mechanical signals. Therefore, combinations of mechanical stimuli have also been applied to cells in vitro. These studies have had varying focus-developing novel platforms to apply complex combinations of mechanical stimuli, observing the co-operation/competition between stimuli, combining benefits of multiple stimuli toward an application, or uncovering the underlying mechanisms of their action. In general, they provided new insights that could not have been predicted from previous knowledge. We present here a review of several such studies and the insights gained from them, thereby making a case for such studies to be continued and further developed.

  12. SignalSpider: Probabilistic pattern discovery on multiple normalized ChIP-Seq signal profiles

    KAUST Repository

    Wong, Kachun

    2014-09-05

    Motivation: Chromatin immunoprecipitation (ChIP) followed by high-throughput sequencing (ChIP-Seq) measures the genome-wide occupancy of transcription factors in vivo. Different combinations of DNA-binding protein occupancies may result in a gene being expressed in different tissues or at different developmental stages. To fully understand the functions of genes, it is essential to develop probabilistic models on multiple ChIP-Seq profiles to decipher the combinatorial regulatory mechanisms by multiple transcription factors. Results: In this work, we describe a probabilistic model (SignalSpider) to decipher the combinatorial binding events of multiple transcription factors. Comparing with similar existing methods, we found SignalSpider performs better in clustering promoter and enhancer regions. Notably, SignalSpider can learn higher-order combinatorial patterns from multiple ChIP-Seq profiles. We have applied SignalSpider on the normalized ChIP-Seq profiles from the ENCODE consortium and learned model instances. We observed different higher-order enrichment and depletion patterns across sets of proteins. Those clustering patterns are supported by Gene Ontology (GO) enrichment, evolutionary conservation and chromatin interaction enrichment, offering biological insights for further focused studies. We also proposed a specific enrichment map visualization method to reveal the genome-wide transcription factor combinatorial patterns from the models built, which extend our existing fine-scale knowledge on gene regulation to a genome-wide level. Availability and implementation: The matrix-algebra-optimized executables and source codes are available at the authors\\' websites: http://www.cs.toronto.edu/∼wkc/SignalSpider. Contact: Supplementary information: Supplementary data are available at Bioinformatics online.

  13. Wireless Energy Harvesting Using Signals from Multiple Fading Channels

    KAUST Repository

    Chen, Yunfei

    2017-08-01

    In this paper, we study the average, the probability density function and the cumulative distribution function of the harvested power. In the study, the signals are transmitted from multiple sources. The channels are assumed to be either Rician fading or Gamma-shadowed Rician fading. The received signals are then harvested by using either a single harvester for simultaneous transmissions or multiple harvesters for transmissions at different frequencies, antennas or time slots. Both linear and nonlinear models for the energy harvester at the receiver are examined. Numerical results are presented to show that, when a large amount of harvested power is required, a single harvester or the linear range of a practical nonlinear harvester are more efficient, to avoid power outage. Further, the power transfer strategy can be optimized for fixed total power. Specifically, for Rayleigh fading, the optimal strategy is to put the total power at the source with the best channel condition and switch off all other sources, while for general Rician fading, the optimum magnitudes and phases of the transmitting waveforms depend on the channel parameters.

  14. P38 pathway as a key downstream signal of connective tissue growth factor to regulate metastatic potential in non-small-cell lung cancer.

    Science.gov (United States)

    Kato, Shinichiro; Yokoyama, Satoru; Hayakawa, Yoshihiro; Li, Luhui; Iwakami, Yusuke; Sakurai, Hiroaki; Saiki, Ikuo

    2016-10-01

    Although the secretory matricellular protein connective tissue growth factor (CTGF) has been reported to be related to lung cancer metastasis, the precise mechanism by which CTGF regulates lung cancer metastasis has not been elucidated. In the present study, we show the molecular link between CTGF secretion and the p38 pathway in the invasive and metastatic potential of non-small-cell lung cancer (NSCLC). Among three different human NSCLC cell lines (PC-14, A549, and PC-9), their in vitro invasiveness was inversely correlated with the level of CTGF secretion. By supplementing or reducing CTGF secretion in NSCLC culture, dysregulation of the invasive and metastatic potential of NSCLC cell lines was largely compensated. By focusing on the protein kinases that are known to be regulated by CTGF, we found that the p38 pathway is a key downstream signal of CTGF to regulate the metastatic potential of NSCLC. Importantly, a negative correlation between CTGF and phosphorylation status of p38 was identified in The Cancer Genome Atlas lung adenocarcinoma dataset. In the context of the clinical importance of our findings, we showed that p38 inhibitor, SB203580, reduced the metastatic potential of NSCLC secreting low levels of CTGF. Collectively, our present findings indicate that the CTGF/p38 axis is a novel therapeutic target of NSCLC metastasis, particularly NSCLC secreting low levels of CTGF. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  15. Downstream components of RhoA required for signal pathway of superoxide formation during phagocytosis of serum opsonized zymosans in macrophages.

    Science.gov (United States)

    Kim, Jun Sub; Kim, Jae Gyu; Jeon, Chan Young; Won, Ha Young; Moon, Mi Young; Seo, Ji Yeon; Kim, Jong Il; Kim, Jaebong; Lee, Jae Yong; Choi, Soo Young; Park, Jinseu; Yoon Park, Jung Han; Ha, Kwon Soo; Kim, Pyeung Hyeun; Park, Jae Bong

    2005-12-31

    Rac1 and Rac2 are essential for the control of oxidative burst catalyzed by NADPH oxidase. It was also documented that Rho is associated with the superoxide burst reaction during phagocytosis of serum- (SOZ) and IgG-opsonized zymosan particles (IOZ). In this study, we attempted to reveal the signal pathway components in the superoxide formation regulated by Rho GTPase. Tat-C3 blocked superoxide production, suggesting that RhoA is essentially involved in superoxide formation during phagocytosis of SOZ. Conversely SOZ activated both RhoA and Rac1/2. Inhibition of RhoA-activated kinase (ROCK), an important downstream effector of RhoA, by Y27632 and myosin light chain kinase (MLCK) by ML-7 abrogated superoxide production by SOZ. Extracellular signaling-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) were activated during phagocytosis of SOZ, and Tat-C3 and SB203580 reduced ERK1/2 and p38 MAPK activation, suggesting that RhoA and p38 MAPK may be upstream regulators of ERK1/2. Inhibition of ERK1/2, p38 MAPK, phosphatidyl inositol 3-kinase did not block translocation of RhoA to membranes, suggesting that RhoA is upstream to these kinases. Inhibition of RhoA by Tat-C3 blocked phosphorylation of p47(PHOX). Taken together, RhoA, ROCK, p38MAPK, ERK1/2, and p47(PHOX) may be subsequently activated, leading to activation of NADPH oxidase to produce superoxide.

  16. Involvement of PI3K/Akt Signaling Pathway and Its Downstream Intracellular Targets in the Antidepressant-Like Effect of Creatine.

    Science.gov (United States)

    Cunha, Mauricio P; Budni, Josiane; Ludka, Fabiana K; Pazini, Francis L; Rosa, Julia Macedo; Oliveira, Ágatha; Lopes, Mark W; Tasca, Carla I; Leal, Rodrigo B; Rodrigues, Ana Lúcia S

    2016-07-01

    Creatine has been proposed to exert beneficial effects in the management of depression, but the cell signaling pathways implicated in its antidepressant effects are not well established. This study investigated the involvement of PI3K/Akt signaling pathway and its downstream intracellular targets in the antidepressant-like effect of creatine. The acute treatment of mice with creatine (1 mg/kg, po) increased the Akt and P70S6K phosphorylation, and HO-1, GPx and PSD95 immunocontents. The pretreatment of mice with LY294002 (10 nmol/mouse, icv, PI3K inhibitor), wortmannin (0.1 μg/mouse, icv, PI3K inhibitor), ZnPP (10 μg/mouse, icv, HO-1 inhibitor), or rapamycin (0.2 nmol/mouse, icv, mTOR inhibitor) prevented the antidepressant-like effect of creatine (1 mg/kg, po) in the TST. In addition, the administration of subeffective dose of either the selective GSK3 inhibitor AR-A014418 (0.01 μg/mouse, icv), the nonselective GSK3 inhibitor lithium chloride (10 mg/kg, po), or the HO-1 inductor CoPP (0.01 μg/mouse, icv), in combination with a subeffective dose of creatine (0.01 mg/kg, po) reduced the immobility time in the TST as compared with either drug alone. No treatment caused significant changes in the locomotor activity of mice. These results indicate that the antidepressant-like effect of creatine in the TST depends on the activation of Akt, Nrf2/HO-1, GPx, and mTOR, and GSK3 inhibition.

  17. Prevotella intermedia induces prostaglandin E2 via multiple signaling pathways.

    Science.gov (United States)

    Guan, S-M; Fu, S-M; He, J-J; Zhang, M

    2011-01-01

    Prostaglandin E(2) (PGE(2)) plays important roles in the bone resorption of inflammatory diseases such as rheumatoid arthritis and periodontitis via specific prostaglandin receptors (i.e., EP1-EP4). In this study, the authors examined whether Prevotella intermedia regulates PGE(2) production and EP expression in human periodontal ligament fibroblasts (hPDLs); they also explored the potential signaling pathways involved in PGE(2) production. P. intermedia induced PGE(2) production and cyclooxygenase-2 (COX-2) expression in a dose- and time-dependent manner. Indomethacin and NS-398 completely abrogated the P. intermedia-induced PGE(2) production without modulating COX-2 expression. Specific inhibitors of extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38, phosphatidylinositol 3-kinase, and protein kinase C--but not c-AMP and protein kinase A--significantly attenuated the P. intermedia-induced COX-2 and PGE(2) expression. P. intermedia reduced EP1 expression in a concentration- and time-dependent manner. The results indicate that the COX-2-dependent induction of PGE(2) by P. intermedia in hPDLs is mediated by multiple signaling pathways.

  18. Which downstream signal transduction pathway(s) of H-ras are necessary for the cellular response(s) to ionizing radiation? (Results of an astro research fellowship year)

    International Nuclear Information System (INIS)

    Rudoltz, Marc S.; Muschel, Ruth J.; McKenna, W. Gillies

    1996-01-01

    Purpose/Background: The H-ras oncogene encodes a protein which is an essential component of multiple downstream effector pathways required for induction of proliferation and differentiation. Ras plays a role in the control some of these signal transduction pathways, such as the MAP kinase pathway which controls gene expression and the Rac-Rho pathway which controls cell morphology. Previous work from our laboratory has associated H-ras expression with radiation resistance, a prolonged delay in G2 following exposure to ionizing radiation, and suppression of radiation-induced apoptosis. In addition, H-ras cooperates with myc in transformation. Recent work by White et al. (Cell 80:533-541, 1995) and Joneson et al. (Science 271: 810-812, 1996) describes three mutations in H-ras which were engineered to eliminate different downstream signal transduction pathways of H-ras. T35S contains a serine in place of threonine at amino acid 35 and is defective for ras-induced cytoskeletal changes and initiation of DNA synthesis. E37G contains a glutamic acid in place of glycine at amino acid 37 which eliminates interaction of H-ras with a GDP/GTP exchange factor. C40 contains a substitution of cysteine for tyrosine at amino acid 40 and is defective for H-ras induction of the MAP kinase pathway. We propose that by expressing these mutant H-ras proteins in immortalized cells the downstream pathways of H-ras which regulate the cellular response(s) to ionizing radiation may be determined. Materials and Methods: pHP-5 plasmids encoding these H-ras mutant genes (see White et al.) were transfected by calcium phosphate precipitation into MR4 cells, rat embryo fibroblasts immortalized by expression of v-myc. In this vector, the cDNA for H-ras is placed under the control of a CMV constitutive promoter, and selection is provided by hygromycin. The transfections performed were as follows: V12Ras (no mutation), T35S, E37G, C40, T35S + E37G, and T35S + C40. Twenty four hours after transfection

  19. Multiplicity counting from fission detector signals with time delay effects

    Science.gov (United States)

    Nagy, L.; Pázsit, I.; Pál, L.

    2018-03-01

    In recent work, we have developed the theory of using the first three auto- and joint central moments of the currents of up to three fission chambers to extract the singles, doubles and triples count rates of traditional multiplicity counting (Pázsit and Pál, 2016; Pázsit et al., 2016). The objective is to elaborate a method for determining the fissile mass, neutron multiplication, and (α, n) neutron emission rate of an unknown assembly of fissile material from the statistics of the fission chamber signals, analogous to the traditional multiplicity counting methods with detectors in the pulse mode. Such a method would be an alternative to He-3 detector systems, which would be free from the dead time problems that would be encountered in high counting rate applications, for example the assay of spent nuclear fuel. A significant restriction of our previous work was that all neutrons born in a source event (spontaneous fission) were assumed to be detected simultaneously, which is not fulfilled in reality. In the present work, this restriction is eliminated, by assuming an independent, identically distributed random time delay for all neutrons arising from one source event. Expressions are derived for the same auto- and joint central moments of the detector current(s) as in the previous case, expressed with the singles, doubles, and triples (S, D and T) count rates. It is shown that if the time-dispersion of neutron detections is of the same order of magnitude as the detector pulse width, as they typically are in measurements of fast neutrons, the multiplicity rates can still be extracted from the moments of the detector current, although with more involved calibration factors. The presented formulae, and hence also the performance of the proposed method, are tested by both analytical models of the time delay as well as with numerical simulations. Methods are suggested also for the modification of the method for large time delay effects (for thermalised neutrons).

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

    NARCIS (Netherlands)

    Martín, J.; Amo de Paz, L.; López, P.

    2008-01-01

    Multiple advertising sexual traits may either advertise different characteristics of male condition or be redundant to reinforce reliability of signals. Research has focused on multiple visual traits. However, in animals that use different multiple additional sensory systems, such as chemoreception,

  1. Curcumin mediates anticancer effects by modulating multiple cell signaling pathways.

    Science.gov (United States)

    Kunnumakkara, Ajaikumar B; Bordoloi, Devivasha; Harsha, Choudhary; Banik, Kishore; Gupta, Subash C; Aggarwal, Bharat B

    2017-08-01

    Curcumin, a component of a spice native to India, was first isolated in 1815 by Vogel and Pelletier from the rhizomes of Curcuma longa (turmeric) and, subsequently, the chemical structure of curcumin as diferuloylmethane was reported by Milobedzka et al. [(1910) 43., 2163-2170]. Since then, this polyphenol has been shown to exhibit antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, and antifungal activities. The current review primarily focuses on the anticancer potential of curcumin through the modulation of multiple cell signaling pathways. Curcumin modulates diverse transcription factors, inflammatory cytokines, enzymes, kinases, growth factors, receptors, and various other proteins with an affinity ranging from the pM to the mM range. Furthermore, curcumin effectively regulates tumor cell growth via modulation of numerous cell signaling pathways and potentiates the effect of chemotherapeutic agents and radiation against cancer. Curcumin can interact with most of the targets that are modulated by FDA-approved drugs for cancer therapy. The focus of this review is to discuss the molecular basis for the anticancer activities of curcumin based on preclinical and clinical findings. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  2. Inhibition of Dengue Virus Replication by a Class of Small-Molecule Compounds That Antagonize Dopamine Receptor D4 and Downstream Mitogen-Activated Protein Kinase Signaling

    Science.gov (United States)

    Smith, Jessica L.; Stein, David A.; Shum, David; Fischer, Matthew A.; Radu, Constantin; Bhinder, Bhavneet; Djaballah, Hakim; Nelson, Jay A.; Früh, Klaus

    2014-01-01

    ABSTRACT Dengue viruses (DENV) are endemic pathogens of tropical and subtropical regions that cause significant morbidity and mortality worldwide. To date, no vaccines or antiviral therapeutics have been approved for combating DENV-associated disease. In this paper, we describe a class of tricyclic small-molecule compounds—dihydrodibenzothiepines (DHBTs), identified through high-throughput screening—with potent inhibitory activity against DENV serotype 2. SKI-417616, a highly active representative of this class, displayed activity against all four serotypes of DENV, as well as against a related flavivirus, West Nile virus (WNV), and an alphavirus, Sindbis virus (SINV). This compound was characterized to determine its mechanism of antiviral activity. Investigation of the stage of the viral life cycle affected revealed that an early event in the life cycle is inhibited. Due to the structural similarity of the DHBTs to known antagonists of the dopamine and serotonin receptors, we explored the roles of two of these receptors, serotonin receptor 2A (5HTR2A) and the D4 dopamine receptor (DRD4), in DENV infection. Antagonism of DRD4 and subsequent downstream phosphorylation of epidermal growth factor receptor (EGFR)-related kinase (ERK) were found to impact DENV infection negatively, and blockade of signaling through this network was confirmed as the mechanism of anti-DENV activity for this class of compounds. IMPORTANCE The dengue viruses are mosquito-borne, reemerging human pathogens that are the etiological agents of a spectrum of febrile diseases. Currently, there are no approved therapeutic treatments for dengue-associated disease, nor is there a vaccine. This study identifies a small molecule, SKI-417616, with potent anti-dengue virus activity. Further analysis revealed that SKI-417616 acts through antagonism of the host cell dopamine D4 receptor and subsequent repression of the ERK phosphorylation pathway. These results suggest that SKI-417616, or other

  3. [Effects of Biejiajian Pills on Wnt signal pathway signal molecules β-catenin/TCF4 complex activities and downstream proteins cyclin D1 and MMP-2 in hepatocellular carcinoma cells].

    Science.gov (United States)

    Wen, Bin; Sun, Haitao; He, Songqi; Cheng, Yang; Jia, Wenyan; Fan, Eryan; Pang, Jie

    2014-12-01

    To study the effect of Biejiajian Pills on Wnt signal pathway and the mechanisms underlying its action to suppress the invasiveness of hepatocellular carcinoma. HepG2 cells cultured in the serum of rats fed with Biejiajian Pills for 48 h were examined for β-catenin expression using immunofluorescence, β-catenin/TCF4 complex activity with luciferase, and expressions of the downstream proteins cyclin D1 and MMP-2 using qRT-PCR. Biejiajian Pills-treated sera significantly reduced the expressions of cytoplasmic and nuclear β-catenin protein, cyclin D1 and MMP-2 proteins and lowered the activities of β-catenin/TCF4 complex. Biejiajian Pills may serve as a potential anti-tumor agent, whose effect might be mediated by inhibiting the Wnt/β-catenin pathway.

  4. Human Cytomegalovirus Immediate-Early 1 Protein Rewires Upstream STAT3 to Downstream STAT1 Signaling Switching an IL6-Type to an IFNγ-Like Response.

    Directory of Open Access Journals (Sweden)

    Thomas Harwardt

    2016-07-01

    Full Text Available The human cytomegalovirus (hCMV major immediate-early 1 protein (IE1 is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells induced to express IE1 exhibit global repression of IL6- and oncostatin M-responsive STAT3 target genes. This repression is followed by STAT1 phosphorylation and activation of STAT1 target genes normally induced by IFNγ. The observed repression and subsequent activation are both mediated through the same region (amino acids 410 to 445 in the C-terminal domain of IE1, and this region serves as a binding site for STAT3. Depletion of STAT3 phenocopies the STAT1-dependent IFNγ-like response to IE1. In contrast, depletion of the IL6 receptor (IL6ST or the STAT kinase JAK1 prevents this response. Accordingly, treatment with IL6 leads to prolonged STAT1 instead of STAT3 activation in wild-type IE1 expressing cells, but not in cells expressing a mutant protein (IE1dl410-420 deficient for STAT3 binding. A very similar STAT1-directed response to IL6 is also present in cells infected with a wild-type or revertant hCMV, but not an IE1dl410-420 mutant virus, and this response results in restricted viral replication. We conclude that IE1 is sufficient and necessary to rewire upstream IL6-type to downstream IFNγ-like signaling, two pathways linked to opposing actions, resulting in repressed STAT3- and activated STAT1-responsive genes. These findings relate transcriptional repressor and activator functions of IE1 and suggest unexpected outcomes relevant to viral pathogenesis in response to cytokines or growth factors that signal through the IL6ST-JAK1-STAT3 axis in hCMV-infected cells. Our results also reveal that IE1, a protein considered to be a key activator of the hCMV productive cycle, has an unanticipated role in tempering viral replication.

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

    Science.gov (United States)

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

    2014-10-01

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

  6. Encryption and validation of multiple signals for optical identification systems

    Energy Technology Data Exchange (ETDEWEB)

    Perez-Cabre, E [Universitat PoliteGcnica de Catalunya, Department Optica i Optometria, Violinista Vellsola 37, 08222 Terrassa (Spain); Millan, M S [Universitat PoliteGcnica de Catalunya, Department Optica i Optometria, Violinista Vellsola 37, 08222 Terrassa (Spain); Javidi, B [University of Connecticut, Electrical and Computer Engineering Department, 371 Fairfield Road, CT 06269 Storrs (United States)

    2007-07-15

    Multifactor encryption-authentication technique reinforces optical security by allowing the simultaneous A N D-verification of more than one primary image. Instead of basing the identification on a unique signature or piece of information, our goal is to authenticate a given person, object, vehicle by the simultaneous recognition of several factors. Some of them are intrinsic to the person and object or vehicle under control. Other factors, act as keys of the authentication step. Such a system is proposed for situations such as the access control to restricted areas, where the demand of security is high. The multifactor identification method involves double random-phase encoding, fully phase-based encryption and a combined nonlinear joint transform correlator and a classical 4f-correlator for simultaneous recognition and authentication of multiple images. The encoded signal fulfils the general requirements of invisible content, extreme difficulty in counterfeiting and real-time automatic verification. Four reference double-phase encoded images are compared with the retrieved input images obtained in situ from the person or the vehicle whose authentication is wanted and from a database. A recognition step based on the correlation between the signatures and the stored references determines the authentication or rejection of the person and object under surveillance.

  7. Encryption and validation of multiple signals for optical identification systems

    International Nuclear Information System (INIS)

    Perez-Cabre, E; Millan, M S; Javidi, B

    2007-01-01

    Multifactor encryption-authentication technique reinforces optical security by allowing the simultaneous A N D-verification of more than one primary image. Instead of basing the identification on a unique signature or piece of information, our goal is to authenticate a given person, object, vehicle by the simultaneous recognition of several factors. Some of them are intrinsic to the person and object or vehicle under control. Other factors, act as keys of the authentication step. Such a system is proposed for situations such as the access control to restricted areas, where the demand of security is high. The multifactor identification method involves double random-phase encoding, fully phase-based encryption and a combined nonlinear joint transform correlator and a classical 4f-correlator for simultaneous recognition and authentication of multiple images. The encoded signal fulfils the general requirements of invisible content, extreme difficulty in counterfeiting and real-time automatic verification. Four reference double-phase encoded images are compared with the retrieved input images obtained in situ from the person or the vehicle whose authentication is wanted and from a database. A recognition step based on the correlation between the signatures and the stored references determines the authentication or rejection of the person and object under surveillance

  8. Serotonergic neurons signal reward and punishment on multiple timescales

    Science.gov (United States)

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

    2015-01-01

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

  9. Fast modified signal-digit (MSD) multiplication technology and system

    Science.gov (United States)

    Sun, DeGui; He, Li-Ming; Wang, Na-Xin; Weng, Zhao-Heng

    1994-06-01

    In this paper, the carry-free property of modified-signed-digit (MSD) addition is analyzed with a space position logic encoding scheme. On this basis, MSD multiplication is discussed and a fast MSD multiplication system composed of optoelectronic logic technology and a multilayer optical interconnection architecture is propsed and studied. Finally, the effectivity of the fast MSD multiplication system is demostrated by using a 2X2 bit multiplication example and experimental results are given.

  10. Multiple running speed signals in medial entorhinal cortex

    Science.gov (United States)

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

    2016-01-01

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

  11. Ambiguity towards Multiple Historical Performance Information Signals: Evidence from Indonesian Open-Ended Mutual Fund Investors

    Directory of Open Access Journals (Sweden)

    Haris Pratama Loeis

    2015-10-01

    Full Text Available This study focuses on the behavior of open-ended mutual fund investors when encountered with multiple information signals of mutual fund’s historical performance. The behavior of investors can be reflected on their decision to subscribe or redeem their funds from mutual funds. Moreover, we observe the presence of ambiguity within investors due to multiple information signals, and also their reaction towards it. Our finding shows that open-ended mutual fund investors do not only have sensitivity towards past performance information signals, but also have additional sensitivity towards the ambiguity of multiple information signals. Because of the presence of ambiguity, investors give more consideration to negative information signals and the worst information signal in their investment decisions. Normal 0 false false false EN-US X-NONE X-NONE

  12. Sugar sensing by ChREBP/Mondo-Mlx-new insight into downstream regulatory networks and integration of nutrient-derived signals.

    Science.gov (United States)

    Havula, Essi; Hietakangas, Ville

    2018-04-01

    Animals regulate their physiology with respect to nutrient status, which requires nutrient sensing pathways. Simple carbohydrates, sugars, are sensed by the basic-helix-loop-helix leucine zipper transcription factors ChREBP/Mondo, together with their heterodimerization partner Mlx, which are well-established activators of sugar-induced lipogenesis. Loss of ChREBP/Mondo-Mlx in mouse and Drosophila leads to sugar intolerance, that is, inability to survive on sugar containing diet. Recent evidence has revealed that ChREBP/Mondo-Mlx responds to sugar and fatty acid-derived metabolites through several mechanisms and cross-connects with other nutrient sensing pathways. ChREBP/Mondo-Mlx controls several downstream transcription factors and hormones, which mediate not only readjustment of metabolic pathways, but also control feeding behavior, intestinal digestion, and circadian rhythm. Copyright © 2017. Published by Elsevier Ltd.

  13. Kidins220/ARMS as a functional mediator of multiple receptor signalling pathways.

    Science.gov (United States)

    Neubrand, Veronika E; Cesca, Fabrizia; Benfenati, Fabio; Schiavo, Giampietro

    2012-04-15

    An increasing body of evidence suggests that several membrane receptors--in addition to activating distinct signalling cascades--also engage in substantial crosstalk with each other, thereby adjusting their signalling outcome as a function of specific input information. However, little is known about the molecular mechanisms that control their coordination and integration of downstream signalling. A protein that is likely to have a role in this process is kinase-D-interacting substrate of 220 kDa [Kidins220, also known as ankyrin repeat-rich membrane spanning (ARMS), hereafter referred to as Kidins220/ARMS]. Kidins220/ARMS is a conserved membrane protein that is preferentially expressed in the nervous system and interacts with the microtubule and actin cytoskeleton. It interacts with neurotrophin, ephrin, vascular endothelial growth factor (VEGF) and glutamate receptors, and is a common downstream target of several trophic stimuli. Kidins220/ARMS is required for neuronal differentiation and survival, and its expression levels modulate synaptic plasticity. Kidins220/ARMS knockout mice show developmental defects mainly in the nervous and cardiovascular systems, suggesting a crucial role for this protein in modulating the cross talk between different signalling pathways. In this Commentary, we summarise existing knowledge regarding the physiological functions of Kidins220/ARMS, and highlight some interesting directions for future studies on the role of this protein in health and disease.

  14. Multiple roles and therapeutic implications of Akt signaling in cancer

    Directory of Open Access Journals (Sweden)

    Emiliano Calvo

    2009-06-01

    Full Text Available Emiliano Calvo1, Victoria Bolós2, Enrique Grande21Centro Integral Oncológico Clara Campal (CiOCC, Madrid. Spain; 2Pfizer Oncology, Alcobendas-Madrid, SpainAbstract: The prominence of the PI3K-Akt signaling pathway in several tumors indicates a relationship with tumor grade and proliferation. Critical cellular processes are driven through this pathway. More detailed knowledge of the pathogenesis of tumors would enable us to design targeted drugs to block both membrane tyrosine kinase receptors and the intracellular kinases involved in the transmission of the signal. The newly approved molecular inhibitors sunitinib (an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and other tyrosine kinase receptors, sorafenib (a serine–threonine kinase inhibitor that acts against B-Raf and temsirolimus (an mTOR inhibitor shown clinical activity in advanced kidney cancer. Chronic myeloid leukemia has changed its natural history thanks to imatinib and dasatinib, both of which inhibit the intracellular bcr/abl protein derived from the alteration in the Philadelphia chromosome. Intracellular pathways are still important in cancer development and their blockade directly affects outcome. Cross-talk has been observed but is not well understood. Vertical and horizontal pathway blockade are promising anticancer strategies. Indeed, preclinical and early clinical data suggest that combining superficial and intracellular blocking agents can synergize and leverage single-agent activity. The implication of the Akt signaling pathway in cancer is well established and has led to the development of new anticancer agents that block its activation.Keywords: Akt, cancer, therapeutic target, Akt inhibitors

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

    International Nuclear Information System (INIS)

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

    2015-01-01

    Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC 50 values of 10.8, 7.9 and 7.0 nm in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and β-catenin pro-survival pathways were inhibited. The decreased level of β-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies

  16. Gender differences in multiple sclerosis : induction of estrogen signaling in male and progesterone signaling in female lesions

    NARCIS (Netherlands)

    Luchetti, Sabina; van Eden, Corbert G; Schuurman, Karianne; van Strien, Miriam E; Swaab, Dick F; Huitinga, Inge

    The basis of gender differences in the prevalence and clinical progression of multiple sclerosis (MS) is not understood. Here, we identify gender-specific responses in steroid synthesis and signaling in the brains of MS patients as possible contributors to these differences. We investigated gene

  17. Ambiguity Towards Multiple Historical Performance Information Signals: Evidence From Indonesian Open-Ended Mutual Fund Investors

    OpenAIRE

    Haris Pratama Loeis; Ruslan Prijadi

    2015-01-01

    This study focuses on the behavior of open-ended mutual fund investors when encountered with multiple information signals of mutual fund’s historical performance. The behavior of investors can be reflected on their decision to subscribe or redeem their funds from mutual funds. Moreover, we observe the presence of ambiguity within investors due to multiple information signals, and also their reaction towards it. Our finding shows that open-ended mutual fund investors do not only have sen...

  18. Salicylic acid suppresses jasmonic acid signaling downstream of SCFCOI1-JAZ by targeting GCC promoter motifs via transcription factor ORA59

    NARCIS (Netherlands)

    Does, D. van der; Leon-Reyes, A.; Koornneef, A.; Verk, M.C. van; Rodenburg, N.; Pauwels, L.; Goossens, A.; Körbes, A.P.; Memelink, J.; Ritsema, T.; Wees, S.C.M. van; Pieterse, C.M.J.

    2013-01-01

    Antagonism between the defense hormones salicylic acid (SA) and jasmonic acid (JA) plays a central role in the modulation of the plant immune signaling network, but the molecular mechanisms underlying this phenomenon are largely unknown. Here, we demonstrate that suppression of the JA pathway by SA

  19. Signal transduction downstream of salicylic and jasmonic acid in herbivory-induced parasitoid attraction by Arabidopsis is independent of JAR1 and NPR1

    NARCIS (Netherlands)

    Poecke, van R.M.P.; Dicke, M.

    2003-01-01

    Plants can defend themselves indirectly against herbivores by emitting a volatile blend upon herbivory that attracts the natural enemies of these herbivores, either predators or parasitoids. Although signal transduction in plants from herbivory to induced volatile production depends on jasmonic acid

  20. Signal transduction in mitogenesis: Further evidence for multiple pathways

    International Nuclear Information System (INIS)

    Rozengurt, E.; Erusalimsky, J.; Mehmet, H.; Morris, C.; Nanberg, E.; Sinnett-Smith, J.

    1988-01-01

    Growth factors are implicated in a wide variety of physiological and pathological processes, including embryogenesis, hematopoiesis, would healing, immune responses, atherosclerosis, and neoplasia. An important link between growth factors and their receptors and oncogene products has also been established. Thus, the elucidation of the mechanism of action of growth factors has emerged as one of the fundamental problems in biology and may prove crucial for understanding the unrestrained proliferation of cancer cells. A new and intriguing development is the discovery that neuropeptides localized in neural and neuroendocrine cells of mammalian tissue can also act as growth factors for cells in culture. Furthermore, indirect evidence is accumulating that the mitogenic effects of neuropeptides may be relevant for a variety of long-term biological processes, including development and oncogenesis. In this context, the peptides of the bombesin family are of particular significance. These peptides are potent mitogens for Swiss 3T3 cells and may act as autocrine growth factors for small cell lung cancer. Here, the authors summarize their recent studies using bombesin-like peptides for elucidating the signal transduction pathways leading to mitogenesis and compare these pathways with those elicited by other growth factors

  1. Performance bounds for sparse signal reconstruction with multiple side information [arXiv

    DEFF Research Database (Denmark)

    Luong, Huynh Van; Seiler, Jurgen; Kaup, Andre

    2016-01-01

    In the context of compressive sensing (CS), this paper considers the problem of reconstructing sparse signals with the aid of other given correlated sources as multiple side information (SI). To address this problem, we propose a reconstruction algorithm with multiple SI (RAMSI) that solves...

  2. The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma.

    Science.gov (United States)

    Guillermet-Guibert, Julie; Bjorklof, Katja; Salpekar, Ashreena; Gonella, Cristiano; Ramadani, Faruk; Bilancio, Antonio; Meek, Stephen; Smith, Andrew J H; Okkenhaug, Klaus; Vanhaesebroeck, Bart

    2008-06-17

    The p110 isoforms of phosphoinositide 3-kinase (PI3K) are acutely regulated by extracellular stimuli. The class IA PI3K catalytic subunits (p110alpha, p110beta, and p110delta) occur in complex with a Src homology 2 (SH2) domain-containing p85 regulatory subunit, which has been shown to link p110alpha and p110delta to Tyr kinase signaling pathways. The p84/p101 regulatory subunits of the p110gamma class IB PI3K lack SH2 domains and instead couple p110gamma to G protein-coupled receptors (GPCRs). Here, we show, using small-molecule inhibitors with selectivity for p110beta and cells derived from a p110beta-deficient mouse line, that p110beta is not a major effector of Tyr kinase signaling but couples to GPCRs. In macrophages, both p110beta and p110gamma contributed to Akt activation induced by the GPCR agonist complement 5a, but not by the Tyr kinase ligand colony-stimulating factor-1. In fibroblasts, which express p110beta but not p110gamma, p110beta mediated Akt activation by the GPCR ligands stromal cell-derived factor, sphingosine-1-phosphate, and lysophosphatidic acid but not by the Tyr kinase ligands PDGF, insulin, and insulin-like growth factor 1. Introduction of p110gamma in these cells reduced the contribution of p110beta to GPCR signaling. Taken together, these data show that p110beta and p110gamma can couple redundantly to the same GPCR agonists. p110beta, which shows a much broader tissue distribution than the leukocyte-restricted p110gamma, could thus provide a conduit for GPCR-linked PI3K signaling in the many cell types where p110gamma expression is low or absent.

  3. The p110β isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110γ

    Science.gov (United States)

    Guillermet-Guibert, Julie; Bjorklof, Katja; Salpekar, Ashreena; Gonella, Cristiano; Ramadani, Faruk; Bilancio, Antonio; Meek, Stephen; Smith, Andrew J. H.; Okkenhaug, Klaus; Vanhaesebroeck, Bart

    2008-01-01

    The p110 isoforms of phosphoinositide 3-kinase (PI3K) are acutely regulated by extracellular stimuli. The class IA PI3K catalytic subunits (p110α, p110β, and p110δ) occur in complex with a Src homology 2 (SH2) domain-containing p85 regulatory subunit, which has been shown to link p110α and p110δ to Tyr kinase signaling pathways. The p84/p101 regulatory subunits of the p110γ class IB PI3K lack SH2 domains and instead couple p110γ to G protein-coupled receptors (GPCRs). Here, we show, using small-molecule inhibitors with selectivity for p110β and cells derived from a p110β-deficient mouse line, that p110β is not a major effector of Tyr kinase signaling but couples to GPCRs. In macrophages, both p110β and p110γ contributed to Akt activation induced by the GPCR agonist complement 5a, but not by the Tyr kinase ligand colony-stimulating factor-1. In fibroblasts, which express p110β but not p110γ, p110β mediated Akt activation by the GPCR ligands stromal cell-derived factor, sphingosine-1-phosphate, and lysophosphatidic acid but not by the Tyr kinase ligands PDGF, insulin, and insulin-like growth factor 1. Introduction of p110γ in these cells reduced the contribution of p110β to GPCR signaling. Taken together, these data show that p110β and p110γ can couple redundantly to the same GPCR agonists. p110β, which shows a much broader tissue distribution than the leukocyte-restricted p110γ, could thus provide a conduit for GPCR-linked PI3K signaling in the many cell types where p110γ expression is low or absent. PMID:18544649

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

    Lifescience Database Archive (English)

    Full Text Available 12213596 Multiple signaling pathways leading to the activation of interferon regula...(.html) (.csml) Show Multiple signaling pathways leading to the activation of interferon regulatoryfactor 3.... PubmedID 12213596 Title Multiple signaling pathways leading to the activation of

  5. Finding Multiple Peaks Signal in Fast Beam Conditions Monitor (BCM1F)

    CERN Document Server

    Bin Ab Maalek, Abu Ubaidah Amir; CERN. Geneva. EP Department

    2017-01-01

    Fast Beam Conditions Monitor (BCM1F) is diamond and silicon sensors based luminometer of CMS detector. The methods of finding multiple peaks signal in BCM1F is shown. Multiple peaks signal found at signal with width between 60 ns - 300 ns. Double peaks are counted as single hit in the constant threshold analysis and leads to underestimation in the luminosity. Therefore it should be estimated for different filling schemes and sensor types. The percentage of long width pulse in different sensor for different fill are calculated. About 30 \\% long width pulse found in sCVD sensor, 12 \\% in pCVD and no more than 1 \\% for silicon sensor.

  6. Target of rapamycin complex 2 signals to downstream effector yeast protein kinase 2 (Ypk2) through adheres-voraciously-to-target-of-rapamycin-2 protein 1 (Avo1) in Saccharomyces cerevisiae.

    Science.gov (United States)

    Liao, Hsien-Ching; Chen, Mei-Yu

    2012-02-24

    The conserved Ser/Thr kinase target of rapamycin (TOR) serves as a central regulator in controlling cell growth-related functions. There exist two distinct TOR complexes, TORC1 and TORC2, each coupling to specific downstream effectors and signaling pathways. In Saccharomyces cerevisiae, TORC2 is involved in regulating actin organization and maintaining cell wall integrity. Ypk2 (yeast protein kinase 2), a member of the cAMP-dependent, cGMP-dependent, and PKC (AGC) kinase family, is a TORC2 substrate known to participate in actin and cell wall regulation. Employing avo3(ts) mutants with defects in TORC2 functions that are suppressible by active Ypk2, we investigated the molecular interactions involved in mediating TORC2 signaling to Ypk2. GST pulldown assays in yeast lysates demonstrated physical interactions between Ypk2 and components of TORC2. In vitro binding assays revealed that Avo1 directly binds to Ypk2. In avo3(ts) mutants, the TORC2-Ypk2 interaction was reduced and could be restored by AVO1 overexpression, highlighting the important role of Avo1 in coupling TORC2 to Ypk2. The interaction was mapped to an internal region (amino acids 600-840) of Avo1 and a C-terminal region of Ypk2. Ypk2(334-677), a truncated form of Ypk2 containing the Avo1-interacting region, was able to interfere with Avo1-Ypk2 interaction in vitro. Overexpressing Ypk2(334-677) in yeast cells resulted in a perturbation of TORC2 functions, causing defective cell wall integrity, aberrant actin organization, and diminished TORC2-dependent Ypk2 phosphorylation evidenced by the loss of an electrophoretic mobility shift. Together, our data support the conclusion that the direct Avo1-Ypk2 interaction is crucial for TORC2 signaling to the downstream Ypk2 pathway.

  7. A speed guidance strategy for multiple signalized intersections based on car-following model

    Science.gov (United States)

    Tang, Tie-Qiao; Yi, Zhi-Yan; Zhang, Jian; Wang, Tao; Leng, Jun-Qiang

    2018-04-01

    Signalized intersection has great roles in urban traffic system. The signal infrastructure and the driving behavior near the intersection are paramount factors that have significant impacts on traffic flow and energy consumption. In this paper, a speed guidance strategy is introduced into a car-following model to study the driving behavior and the fuel consumption in a single-lane road with multiple signalized intersections. The numerical results indicate that the proposed model can reduce the fuel consumption and the average stop times. The findings provide insightful guidance for the eco-driving strategies near the signalized intersections.

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

    International Nuclear Information System (INIS)

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

    2014-01-01

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

  9. ANGUSTIFOLIA mediates one of the multiple SCRAMBLED signaling pathways regulating cell growth pattern in Arabidopsis thaliana.

    Science.gov (United States)

    Kwak, Su-Hwan; Song, Sang-Kee; Lee, Myeong Min; Schiefelbein, John

    2015-09-25

    In Arabidopsis thaliana, an atypical leucine-rich repeat receptor-like kinase, SCRAMBLED (SCM), is required for multiple developmental processes including root epidermal cell fate determination, silique dehiscence, inflorescence growth, ovule morphogenesis, and tissue morphology. Previous work suggested that SCM regulates these multiple pathways using distinct mechanisms via interactions with specific downstream factors. ANGUSTIFOLIA (AN) is known to regulate cell and tissue morphogenesis by influencing cortical microtubule arrangement, and recently, the AN protein was reported to interact with the SCM protein. Therefore, we examined whether AN might be responsible for mediating some of the SCM-dependent phenotypes. We discovered that both scm and an mutant lines cause an abnormal spiral or twisting growth of roots, but only the scm mutant affected root epidermal patterning. The siliques of the an and scm mutants also exhibited spiral growth, as previously reported, but only the scm mutant altered silique dehiscence. Interestingly, we discovered that the spiral growth of roots and siliques of the scm mutant is rescued by a truncated SCM protein that lacks its kinase domain, and that a juxtamembrane domain of SCM was sufficient for AN binding in the yeast two-hybrid analysis. These results suggest that the AN protein is one of the critical downstream factors of SCM pathways specifically responsible for mediating its effects on cell/tissue morphogenesis through cortical microtubule arrangement. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. MicroRNA-214 Reduces Insulin-like Growth Factor-1 (IGF-1) Receptor Expression and Downstream mTORC1 Signaling in Renal Carcinoma Cells*

    Science.gov (United States)

    Das, Falguni; Dey, Nirmalya; Bera, Amit; Kasinath, Balakuntalam S.; Ghosh-Choudhury, Nandini; Choudhury, Goutam Ghosh

    2016-01-01

    Elevated IGF-1/insulin-like growth factor-1 receptor (IGF-1R) autocrine/paracrine signaling in patients with renal cell carcinoma is associated with poor prognosis of the disease independent of their von Hippel-Lindau (VHL) status. Increased expression of IGF-1R in renal cancer cells correlates with their potency of tumor development and progression. The mechanism by which expression of IGF-1R is increased in renal carcinoma is not known. We report that VHL-deficient and VHL-positive renal cancer cells possess significantly decreased levels of mature, pre-, and pri-miR-214 than normal proximal tubular epithelial cells. We identified an miR-214 recognition element in the 3′UTR of IGF-1R mRNA and confirmed its responsiveness to miR-214. Overexpression of miR-214 decreased the IGF-1R protein levels, resulting in the inhibition of Akt kinase activity in both types of renal cancer cells. IGF-1 provoked phosphorylation and inactivation of PRAS40 in an Akt-dependent manner, leading to the activation of mTORC1 signal transduction to increase phosphorylation of S6 kinase and 4EBP-1. Phosphorylation-deficient mutants of PRAS40 and 4EBP-1 significantly inhibited IGF-1R-driven proliferation of renal cancer cells. Expression of miR-214 suppressed IGF-1R-induced phosphorylation of PRAS40, S6 kinase, and 4EBP-1, indicating inhibition of mTORC1 activity. Finally, miR-214 significantly blocked IGF-1R-forced renal cancer cell proliferation, which was reversed by expression of 3′UTR-less IGF-1R and constitutively active mTORC1. Together, our results identify a reciprocal regulation of IGF-1R levels and miR-214 expression in renal cancer cells independent of VHL status. Our data provide evidence for a novel mechanism for IGF-1R-driven renal cancer cell proliferation involving miR-214 and mTORC1. PMID:27226530

  11. IRF-3, IRF-5, and IRF-7 coordinately regulate the type I IFN response in myeloid dendritic cells downstream of MAVS signaling.

    Directory of Open Access Journals (Sweden)

    Helen M Lazear

    2013-01-01

    Full Text Available Although the transcription factors IRF-3 and IRF-7 are considered master regulators of type I interferon (IFN induction and IFN stimulated gene (ISG expression, Irf3(-/-×Irf7(-/- double knockout (DKO myeloid dendritic cells (mDC produce relatively normal levels of IFN-β after viral infection. We generated Irf3(-/-×Irf5(-/-×Irf7(-/- triple knockout (TKO mice to test whether IRF-5 was the source of the residual induction of IFN-β and ISGs in mDCs. In pathogenesis studies with two unrelated positive-sense RNA viruses (West Nile virus (WNV and murine norovirus, TKO mice succumbed at rates greater than DKO mice and equal to or approaching those of mice lacking the type I IFN receptor (Ifnar(-/-. In ex vivo studies, after WNV infection or exposure to Toll-like receptor agonists, TKO mDCs failed to produce IFN-β or express ISGs. In contrast, this response was sustained in TKO macrophages following WNV infection. To define IRF-regulated gene signatures, we performed microarray analysis on WNV-infected mDC from wild type (WT, DKO, TKO, or Ifnar(-/- mice, as well as from mice lacking the RIG-I like receptor adaptor protein MAVS. Whereas the gene induction pattern in DKO mDC was similar to WT cells, remarkably, almost no ISG induction was detected in TKO or Mavs(-/- mDC. The relative equivalence of TKO and Mavs(-/- responses suggested that MAVS dominantly regulates ISG induction in mDC. Moreover, we showed that MAVS-dependent induction of ISGs can occur through an IRF-5-dependent yet IRF-3 and IRF-7-independent pathway. Our results establish IRF-3, -5, and -7 as the key transcription factors responsible for mediating the type I IFN and ISG response in mDC during WNV infection and suggest a novel signaling link between MAVS and IRF-5.

  12. India's Downstream Petroleum Sector

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2010-07-01

    This study provides a holistic examination of pricing and investment dynamics in India's downstream petroleum sector. It analyses the current pricing practices, highlights the tremendous fiscal cost of current pricing and regulatory arrangements, and examines the sectoral investment dynamics. It also looks at potential paths towards market-based reform along which the Indian government may move, while at the same time protecting energy market access for India's large poor population.

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

    Science.gov (United States)

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

    2015-06-01

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

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

    Science.gov (United States)

    Effenberger, Frank; Liu, Xiang

    2015-05-18

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

  15. AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model

    International Nuclear Information System (INIS)

    Yao, H; Ashihara, E; Strovel, J W; Nakagawa, Y; Kuroda, J; Nagao, R; Tanaka, R; Yokota, A; Takeuchi, M; Hayashi, Y; Shimazaki, C; Taniwaki, M; Strand, K; Padia, J; Hirai, H; Kimura, S; Maekawa, T

    2011-01-01

    Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that β-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/β-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished β-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery

  16. DMPD: Suppressor of cytokine signaling (SOCS) 2, a protein with multiple functions. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17070092 Suppressor of cytokine signaling (SOCS) 2, a protein with multiple function...Epub 2006 Oct 27. (.png) (.svg) (.html) (.csml) Show Suppressor of cytokine signaling (SOCS) 2, a protein with multiple function...SOCS) 2, a protein with multiple functions. Authors Rico-Bautista E, Flores-Morales A, Fernandez-Perez L. Pu

  17. Thrombopoietin stimulates migration and activates multiple signaling pathways in hepatoblastoma cells

    DEFF Research Database (Denmark)

    Romanelli, Roberto G; Petrai, Ilaria; Robino, Gaia

    2005-01-01

    Thrombopoietin (TPO), a cytokine that participates in the differentiation and maturation of megakaryocytes, is produced in the liver, but only limited information is available on the biological response of liver-derived cells to TPO. In this study, we investigated whether HepG2 cells express c-Mpl......, the receptor for TPO, and whether TPO elicits biological responses and intracellular signaling in this cell type. Specific transcripts for c-Mpl were detected in HepG2 cells by RT-PCR, and expression of the protein was demonstrated by Western blot analysis and immunofluorescence. Exposure of HepG2 cells to TPO...... members of the MAPK family, including ERK and JNK, as assessed using phosphorylation-specific antibodies and immune complex kinase assays. TPO also activated phosphatidylinositol 3-kinase (PI3K) and the downstream kinase Akt in a time-dependent manner. Finally, activation of c-Mpl was associated...

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

    International Nuclear Information System (INIS)

    Vermare, L.; Hennequin, P.; Gürcan, Ö.D.

    2012-01-01

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

  19. Comprehending Multiple Documents on Scientific Controversies: Effects of Reading Goals and Signaling Rhetorical Relationships

    Science.gov (United States)

    Stadtler, Marc; Scharrer, Lisa; Skodzik, Timo; Bromme, Rainer

    2014-01-01

    Understanding conflicts between sources is an inherent part of science text comprehension. We examined whether readers' memories for conflicts and their situational interpretation of conflicts would be affected by reading goals and lexical cue phrases that signal rhetorical relationships. To this end, 198 undergraduates read multiple documents on…

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

    Energy Technology Data Exchange (ETDEWEB)

    Gupta, Sakshi [Laser Science and Technology Centre, Metcalfe House, Delhi 110054 (India); Instrument Design and Development Centre, Indian Institute of Technology, Hauz Khas, New Delhi 110016 (India); Ahmad, Azeem; Mehta, Dalip S., E-mail: mehtads@physics.iitd.ac.in [Department of Physics, Indian Institute of Technology, Hauz Khas, New Delhi 110016 (India); Gambhir, Vijayeta; Reddy, Martha N. [Laser Science and Technology Centre, Metcalfe House, Delhi 110054 (India)

    2015-08-31

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

  1. Klf5 deletion promotes Pten deletion-initiated luminal-type mouse prostate tumors through multiple oncogenic signaling pathways.

    Science.gov (United States)

    Xing, Changsheng; Ci, Xinpei; Sun, Xiaodong; Fu, Xiaoying; Zhang, Zhiqian; Dong, Eric N; Hao, Zhao-Zhe; Dong, Jin-Tang

    2014-11-01

    Krüppel-like factor 5 (KLF5) regulates multiple biologic processes. Its function in tumorigenesis appears contradictory though, showing both tumor suppressor and tumor promoting activities. In this study, we examined whether and how Klf5 functions in prostatic tumorigenesis using mice with prostate-specific deletion of Klf5 and phosphatase and tensin homolog (Pten), both of which are frequently inactivated in human prostate cancer. Histologic analysis demonstrated that when one Pten allele was deleted, which causes mouse prostatic intraepithelial neoplasia (mPIN), Klf5 deletion accelerated the emergence and progression of mPIN. When both Pten alleles were deleted, which causes prostate cancer, Klf5 deletion promoted tumor growth, increased cell proliferation, and caused more severe morphologic and molecular alterations. Homozygous deletion of Klf5 was more effective than hemizygous deletion. Unexpectedly, while Pten deletion alone expanded basal cell population in a tumor as reported, Klf5 deletion in the Pten-null background clearly reduced basal cell population while expanding luminal cell population. Global gene expression profiling, pathway analysis, and experimental validation indicate that multiple mechanisms could mediate the tumor-promoting effect of Klf5 deletion, including the up-regulation of epidermal growth factor and its downstream signaling molecules AKT and ERK and the inactivation of the p15 cell cycle inhibitor. KLF5 also appears to cooperate with several transcription factors, including CREB1, Sp1, Myc, ER and AR, to regulate gene expression. These findings validate the tumor suppressor function of KLF5. They also yield a mouse model that shares two common genetic alterations with human prostate cancer-mutation/deletion of Pten and deletion of Klf5.

  2. Multiple-failure signal validation in nuclear power plants using artificial neural networks

    International Nuclear Information System (INIS)

    Fantoni, P.F.; Mazzola, A.

    1996-01-01

    The possibility of using a neural network to validate process signals during normal and abnormal plant conditions is explored. In boiling water reactor plants, signal validation is used to generate reliable thermal limits calculation and to supply reliable inputs to other computerized systems that support the operator during accident scenarios. The way that autoassociative neural networks can promptly detect faulty process signal measurements and produce a best estimate of the actual process values even in multifailure situations is shown. A method was developed to train the network for multiple sensor-failure detection, based on a random failure simulation algorithm. Noise was artificially added to the input to evaluate the network's ability to respond in a very low signal-to-noise ratio environment. Training and test data sets were simulated by the real-time transient simulator code APROS

  3. Application of multiple signal classification algorithm to frequency estimation in coherent dual-frequency lidar

    Science.gov (United States)

    Li, Ruixiao; Li, Kun; Zhao, Changming

    2018-01-01

    Coherent dual-frequency Lidar (CDFL) is a new development of Lidar which dramatically enhances the ability to decrease the influence of atmospheric interference by using dual-frequency laser to measure the range and velocity with high precision. Based on the nature of CDFL signals, we propose to apply the multiple signal classification (MUSIC) algorithm in place of the fast Fourier transform (FFT) to estimate the phase differences in dual-frequency Lidar. In the presence of Gaussian white noise, the simulation results show that the signal peaks are more evident when using MUSIC algorithm instead of FFT in condition of low signal-noise-ratio (SNR), which helps to improve the precision of detection on range and velocity, especially for the long distance measurement systems.

  4. The Drosophila Perlecan gene trol regulates multiple signaling pathways in different developmental contexts

    Directory of Open Access Journals (Sweden)

    Perry Trinity L

    2007-11-01

    Full Text Available Abstract Background Heparan sulfate proteoglycans modulate signaling by a variety of growth factors. The mammalian proteoglycan Perlecan binds and regulates signaling by Sonic Hedgehog, Fibroblast Growth Factors (FGFs, Vascular Endothelial Growth Factor (VEGF and Platelet Derived Growth Factor (PDGF, among others, in contexts ranging from angiogenesis and cardiovascular development to cancer progression. The Drosophila Perlecan homolog trol has been shown to regulate the activity of Hedgehog and Branchless (an FGF homolog to control the onset of stem cell proliferation in the developing brain during first instar. Here we extend analysis of trol mutant phenotypes to show that trol is required for a variety of developmental events and modulates signaling by multiple growth factors in different situations. Results Different mutations in trol allow developmental progression to varying extents, suggesting that trol is involved in multiple cell-fate and patterning decisions. Analysis of the initiation of neuroblast proliferation at second instar demonstrated that trol regulates this event by modulating signaling by Hedgehog and Branchless, as it does during first instar. Trol protein is distributed over the surface of the larval brain, near the regulated neuroblasts that reside on the cortical surface. Mutations in trol also decrease the number of circulating plasmatocytes. This is likely to be due to decreased expression of pointed, the response gene for VEGF/PDGF signaling that is required for plasmatocyte proliferation. Trol is found on plasmatocytes, where it could regulate VEGF/PDGF signaling. Finally, we show that in second instar brains but not third instar brain lobes and eye discs, mutations in trol affect signaling by Decapentaplegic (a Transforming Growth Factor family member, Wingless (a Wnt growth factor and Hedgehog. Conclusion These studies extend the known functions of the Drosophila Perlecan homolog trol in both developmental and

  5. Probabilistic Inference on Multiple Normalized Signal Profiles from Next Generation Sequencing: Transcription Factor Binding Sites

    KAUST Repository

    Wong, Ka-Chun; Peng, Chengbin; Li, Yue

    2015-01-01

    With the prevalence of chromatin immunoprecipitation (ChIP) with sequencing (ChIP-Seq) technology, massive ChIP-Seq data has been accumulated. The ChIP-Seq technology measures the genome-wide occupancy of DNA-binding proteins in vivo. It is well-known that different DNA-binding protein occupancies may result in a gene being regulated in different conditions (e.g. different cell types). To fully understand a gene's function, it is essential to develop probabilistic models on multiple ChIP-Seq profiles for deciphering the gene transcription causalities. In this work, we propose and describe two probabilistic models. Assuming the conditional independence of different DNA-binding proteins' occupancies, the first method (SignalRanker) is developed as an intuitive method for ChIP-Seq genome-wide signal profile inference. Unfortunately, such an assumption may not always hold in some gene regulation cases. Thus, we propose and describe another method (FullSignalRanker) which does not make the conditional independence assumption. The proposed methods are compared with other existing methods on ENCODE ChIP-Seq datasets, demonstrating its regression and classification ability. The results suggest that FullSignalRanker is the best-performing method for recovering the signal ranks on the promoter and enhancer regions. In addition, FullSignalRanker is also the best-performing method for peak sequence classification. We envision that SignalRanker and FullSignalRanker will become important in the era of next generation sequencing. FullSignalRanker program is available on the following website: http://www.cs.toronto.edu/∼wkc/FullSignalRanker/ © 2015 IEEE.

  6. Probabilistic Inference on Multiple Normalized Signal Profiles from Next Generation Sequencing: Transcription Factor Binding Sites

    KAUST Repository

    Wong, Ka-Chun

    2015-04-20

    With the prevalence of chromatin immunoprecipitation (ChIP) with sequencing (ChIP-Seq) technology, massive ChIP-Seq data has been accumulated. The ChIP-Seq technology measures the genome-wide occupancy of DNA-binding proteins in vivo. It is well-known that different DNA-binding protein occupancies may result in a gene being regulated in different conditions (e.g. different cell types). To fully understand a gene\\'s function, it is essential to develop probabilistic models on multiple ChIP-Seq profiles for deciphering the gene transcription causalities. In this work, we propose and describe two probabilistic models. Assuming the conditional independence of different DNA-binding proteins\\' occupancies, the first method (SignalRanker) is developed as an intuitive method for ChIP-Seq genome-wide signal profile inference. Unfortunately, such an assumption may not always hold in some gene regulation cases. Thus, we propose and describe another method (FullSignalRanker) which does not make the conditional independence assumption. The proposed methods are compared with other existing methods on ENCODE ChIP-Seq datasets, demonstrating its regression and classification ability. The results suggest that FullSignalRanker is the best-performing method for recovering the signal ranks on the promoter and enhancer regions. In addition, FullSignalRanker is also the best-performing method for peak sequence classification. We envision that SignalRanker and FullSignalRanker will become important in the era of next generation sequencing. FullSignalRanker program is available on the following website: http://www.cs.toronto.edu/∼wkc/FullSignalRanker/ © 2015 IEEE.

  7. Use of multiple singular value decompositions to analyze complex intracellular calcium ion signals

    KAUST Repository

    Martinez, Josue G.

    2009-12-01

    We compare calcium ion signaling (Ca(2+)) between two exposures; the data are present as movies, or, more prosaically, time series of images. This paper describes novel uses of singular value decompositions (SVD) and weighted versions of them (WSVD) to extract the signals from such movies, in a way that is semi-automatic and tuned closely to the actual data and their many complexities. These complexities include the following. First, the images themselves are of no interest: all interest focuses on the behavior of individual cells across time, and thus, the cells need to be segmented in an automated manner. Second, the cells themselves have 100+ pixels, so that they form 100+ curves measured over time, so that data compression is required to extract the features of these curves. Third, some of the pixels in some of the cells are subject to image saturation due to bit depth limits, and this saturation needs to be accounted for if one is to normalize the images in a reasonably un-biased manner. Finally, the Ca(2+) signals have oscillations or waves that vary with time and these signals need to be extracted. Thus, our aim is to show how to use multiple weighted and standard singular value decompositions to detect, extract and clarify the Ca(2+) signals. Our signal extraction methods then lead to simple although finely focused statistical methods to compare Ca(2+) signals across experimental conditions.

  8. Neutron Detector Signal Processing to Calculate the Effective Neutron Multiplication Factor of Subcritical Assemblies

    Energy Technology Data Exchange (ETDEWEB)

    Talamo, Alberto [Argonne National Lab. (ANL), Argonne, IL (United States). Nuclear Engineering Division; Gohar, Yousry [Argonne National Lab. (ANL), Argonne, IL (United States). Nuclear Engineering Division

    2016-06-01

    This report describes different methodologies to calculate the effective neutron multiplication factor of subcritical assemblies by processing the neutron detector signals using MATLAB scripts. The subcritical assembly can be driven either by a spontaneous fission neutron source (e.g. californium) or by a neutron source generated from the interactions of accelerated particles with target materials. In the latter case, when the particle accelerator operates in a pulsed mode, the signals are typically stored into two files. One file contains the time when neutron reactions occur and the other contains the times when the neutron pulses start. In both files, the time is given by an integer representing the number of time bins since the start of the counting. These signal files are used to construct the neutron count distribution from a single neutron pulse. The built-in functions of MATLAB are used to calculate the effective neutron multiplication factor through the application of the prompt decay fitting or the area method to the neutron count distribution. If the subcritical assembly is driven by a spontaneous fission neutron source, then the effective multiplication factor can be evaluated either using the prompt neutron decay constant obtained from Rossi or Feynman distributions or the Modified Source Multiplication (MSM) method.

  9. Neutron Detector Signal Processing to Calculate the Effective Neutron Multiplication Factor of Subcritical Assemblies

    International Nuclear Information System (INIS)

    Talamo, Alberto; Gohar, Yousry

    2016-01-01

    This report describes different methodologies to calculate the effective neutron multiplication factor of subcritical assemblies by processing the neutron detector signals using MATLAB scripts. The subcritical assembly can be driven either by a spontaneous fission neutron source (e.g. californium) or by a neutron source generated from the interactions of accelerated particles with target materials. In the latter case, when the particle accelerator operates in a pulsed mode, the signals are typically stored into two files. One file contains the time when neutron reactions occur and the other contains the times when the neutron pulses start. In both files, the time is given by an integer representing the number of time bins since the start of the counting. These signal files are used to construct the neutron count distribution from a single neutron pulse. The built-in functions of MATLAB are used to calculate the effective neutron multiplication factor through the application of the prompt decay fitting or the area method to the neutron count distribution. If the subcritical assembly is driven by a spontaneous fission neutron source, then the effective multiplication factor can be evaluated either using the prompt neutron decay constant obtained from Rossi or Feynman distributions or the Modified Source Multiplication (MSM) method.

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

    Science.gov (United States)

    Flesia, C.; Schwendimann, P.

    1992-01-01

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

  11. Multiple Signaling Pathways Coordinately Regulate Forgetting of Olfactory Adaptation through Control of Sensory Responses in Caenorhabditis elegans.

    Science.gov (United States)

    Kitazono, Tomohiro; Hara-Kuge, Sayuri; Matsuda, Osamu; Inoue, Akitoshi; Fujiwara, Manabi; Ishihara, Takeshi

    2017-10-18

    Forgetting memories is important for animals to properly respond to continuously changing environments. To elucidate the mechanisms of forgetting, we used one of the behavioral plasticities of Caenorhabditis elegans hermaphrodite, olfactory adaptation to an attractive odorant, diacetyl, as a simple model of learning. In C. elegans, the TIR-1/JNK-1 pathway accelerates forgetting of olfactory adaptation by facilitating neural secretion from AWC sensory neurons. In this study, to identify the downstream effectors of the TIR-1/JNK-1 pathway, we conducted a genetic screen for suppressors of the gain-of-function mutant of tir-1 ( ok1052 ), which shows excessive forgetting. Our screening showed that three proteins-a membrane protein, MACO-1; a receptor tyrosine kinase, SCD-2; and its putative ligand, HEN-1-regulated forgetting downstream of the TIR-1/JNK-1 pathway. We further demonstrated that MACO-1 and SCD-2/HEN-1 functioned in parallel genetic pathways, and only MACO-1 regulated forgetting of olfactory adaptation to isoamyl alcohol, which is an attractive odorant sensed by different types of sensory neurons. In olfactory adaptation, odor-evoked Ca 2+ responses in olfactory neurons are attenuated by conditioning and recovered thereafter. A Ca 2+ imaging study revealed that this attenuation is sustained longer in maco-1 and scd-2 mutant animals than in wild-type animals like the TIR-1/JNK-1 pathway mutants. Furthermore, temporal silencing by histamine-gated chloride channels revealed that the neuronal activity of AWC neurons after conditioning is important for proper forgetting. We propose that distinct signaling pathways, each of which has a specific function, may coordinately and temporally regulate forgetting by controlling sensory responses. SIGNIFICANCE STATEMENT Active forgetting is an important process to understand the whole mechanisms of memories. Recent papers have reported that the noncell autonomous regulations are required for proper forgetting in

  12. Multiple Harmonics Fitting Algorithms Applied to Periodic Signals Based on Hilbert-Huang Transform

    Directory of Open Access Journals (Sweden)

    Hui Wang

    2013-01-01

    Full Text Available A new generation of multipurpose measurement equipment is transforming the role of computers in instrumentation. The new features involve mixed devices, such as kinds of sensors, analog-to-digital and digital-to-analog converters, and digital signal processing techniques, that are able to substitute typical discrete instruments like multimeters and analyzers. Signal-processing applications frequently use least-squares (LS sine-fitting algorithms. Periodic signals may be interpreted as a sum of sine waves with multiple frequencies: the Fourier series. This paper describes a new sine fitting algorithm that is able to fit a multiharmonic acquired periodic signal. By means of a “sinusoidal wave” whose amplitude and phase are both transient, the “triangular wave” can be reconstructed on the basis of Hilbert-Huang transform (HHT. This method can be used to test effective number of bits (ENOBs of analog-to-digital converter (ADC, avoiding the trouble of selecting initial value of the parameters and working out the nonlinear equations. The simulation results show that the algorithm is precise and efficient. In the case of enough sampling points, even under the circumstances of low-resolution signal with the harmonic distortion existing, the root mean square (RMS error between the sampling data of original “triangular wave” and the corresponding points of fitting “sinusoidal wave” is marvelously small. That maybe means, under the circumstances of any periodic signal, that ENOBs of high-resolution ADC can be tested accurately.

  13. Parameter Estimation of Multiple Frequency-Hopping Signals with Two Sensors

    Directory of Open Access Journals (Sweden)

    Le Zuo

    2018-04-01

    Full Text Available This paper essentially focuses on parameter estimation of multiple wideband emitting sources with time-varying frequencies, such as two-dimensional (2-D direction of arrival (DOA and signal sorting, with a low-cost circular synthetic array (CSA consisting of only two rotating sensors. Our basic idea is to decompose the received data, which is a superimposition of phase measurements from multiple sources into separated groups and separately estimate the DOA associated with each source. Motivated by joint parameter estimation, we propose to adopt the expectation maximization (EM algorithm in this paper; our method involves two steps, namely, the expectation-step (E-step and the maximization (M-step. In the E-step, the correspondence of each signal with its emitting source is found. Then, in the M-step, the maximum-likelihood (ML estimates of the DOA parameters are obtained. These two steps are iteratively and alternatively executed to jointly determine the DOAs and sort multiple signals. Closed-form DOA estimation formulae are developed by ML estimation based on phase data, which also realize an optimal estimation. Directional ambiguity is also addressed by another ML estimation method based on received complex responses. The Cramer-Rao lower bound is derived for understanding the estimation accuracy and performance comparison. The verification of the proposed method is demonstrated with simulations.

  14. Observer performance in detecting multiple radiographic signals: prediction and analysis using a generalized ROC approach

    International Nuclear Information System (INIS)

    Metz, C.E.; Starr, S.J.; Lusted, L.B.

    1975-01-01

    The theories of decision processes and signal detection provide a framework for the evaluation of observer performance. Some radiologic procedures involve a search for multiple similar lesions, as in gallstone or pneumoconiosis examinations. A model is presented which attempts to predict, from the conventional receiver operating characteristic (ROC) curve describing the detectability of a single visual signal in a radiograph, observer performance in an experiment requiring detection of more than one such signal. An experiment is described which tests the validity of this model for the case of detecting the presence of zero, one, or two low-contrast radiographic images of a two-mm.-diameter lucite bead embedded in radiographic mottle. Results from six observers, including three radiologists, confirm the validity of the model and suggest that human observer performance for relatively complex detection tasks can be predicted from the results of simpler experiments

  15. Multiple intracellular signaling pathways orchestrate adipocytic differentiation of human bone marrow stromal stem cells

    DEFF Research Database (Denmark)

    Ayesh Hafez Ali, Dalia; Abuelreich, Sarah; Alkeraishan, Nora

    2018-01-01

    during adipocyte differentiation of human bone marrow stromal (mesenchymal) stem cells (hMSCs) and identified 2,589 up-regulated and 2,583 down-regulated mRNA transcripts. Pathway analysis on the up-regulated gene list untraveled enrichment in multiple signaling pathways including insulin receptor......Bone marrow adipocyte formation plays a role in bone homeostasis and whole body energy metabolism. However, the transcriptional landscape and signaling pathways associated with adipocyte lineage commitment and maturation are not fully delineated. Thus, we performed global gene expression profiling...... signaling, focal Adhesion, metapathway biotransformation, a number of metabolic pathways e.g. selenium metabolism, Benzo(a)pyrene metabolism, fatty acid, triacylglycerol, ketone body metabolism, tryptophan metabolism, and catalytic cycle of mammalian flavin-containing monooxygenase (FMOs). On the other hand...

  16. DAG tales: the multiple faces of diacylglycerol--stereochemistry, metabolism, and signaling.

    Science.gov (United States)

    Eichmann, Thomas Oliver; Lass, Achim

    2015-10-01

    The neutral lipids diacylglycerols (DAGs) are involved in a plethora of metabolic pathways. They function as components of cellular membranes, as building blocks for glycero(phospho)lipids, and as lipid second messengers. Considering their central role in multiple metabolic processes and signaling pathways, cellular DAG levels require a tight regulation to ensure a constant and controlled availability. Interestingly, DAG species are versatile in their chemical structure. Besides the different fatty acid species esterified to the glycerol backbone, DAGs can occur in three different stereo/regioisoforms, each with unique biological properties. Recent scientific advances have revealed that DAG metabolizing enzymes generate and distinguish different DAG isoforms, and that only one DAG isoform holds signaling properties. Herein, we review the current knowledge of DAG stereochemistry and their impact on cellular metabolism and signaling. Further, we describe intracellular DAG turnover and its stereochemistry in a 3-pool model to illustrate the spatial and stereochemical separation and hereby the diversity of cellular DAG metabolism.

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

    Science.gov (United States)

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

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

    Directory of Open Access Journals (Sweden)

    Vieri Giuliano Santucci

    2013-11-01

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

  19. Endocannabinoid signaling within the basolateral amygdala integrates multiple stress hormone effects on memory consolidation.

    Science.gov (United States)

    Atsak, Piray; Hauer, Daniela; Campolongo, Patrizia; Schelling, Gustav; Fornari, Raquel V; Roozendaal, Benno

    2015-05-01

    Glucocorticoid hormones are known to act synergistically with other stress-activated neuromodulatory systems, such as norepinephrine and corticotropin-releasing factor (CRF), within the basolateral complex of the amygdala (BLA) to induce optimal strengthening of the consolidation of long-term memory of emotionally arousing experiences. However, as the onset of these glucocorticoid actions appear often too rapid to be explained by genomic regulation, the neurobiological mechanism of how glucocorticoids could modify the memory-enhancing properties of norepinephrine and CRF remained elusive. Here, we show that the endocannabinoid system, a rapidly activated retrograde messenger system, is a primary route mediating the actions of glucocorticoids, via a glucocorticoid receptor on the cell surface, on BLA neural plasticity and memory consolidation. Furthermore, glucocorticoids recruit downstream endocannabinoid activity within the BLA to interact with both the norepinephrine and CRF systems in enhancing memory consolidation. These findings have important implications for understanding the fine-tuned crosstalk between multiple stress hormone systems in the coordination of (mal)adaptive stress and emotional arousal effects on neural plasticity and memory consolidation.

  20. Detection of multiple AE signal by triaxial hodogram analysis; Sanjiku hodogram ho ni yoru taju acoustic emission no kenshutsu

    Energy Technology Data Exchange (ETDEWEB)

    Nagano, K; Yamashita, T [Muroran Institute of Technology, Hokkaido (Japan)

    1997-05-27

    In order to evaluate dynamic behavior of underground cracks, analysis and detection were attempted on multiple acoustic emission (AE) events. The multiple AE is a phenomenon in which multiple AE signals generated by underground cracks developed in an extremely short time interval are superimposed, and observed as one AE event. The multiple AE signal consists of two AE signals, whereas the second P-wave is supposed to have been inputted before the first S-wave is inputted. The first P-wave is inputted first, where linear three-dimensional particle movements are observed, but the movements are made random due to scattering and sensor characteristics. When the second P-wave is inputted, the linear particle movements are observed again, but are superimposed with the existing input signals and become multiple AE, which creates poor S/N ratio. The multiple AE detection determines it a multiple AE event when three conditions are met, i. e. a condition of equivalent time interval of a maximum value in a scalogram analysis, a condition of P-wave vibrating direction, and a condition of the linear particle movement. Seventy AE signals observed in the Kakkonda geothermal field were analyzed and AE signals that satisfy the multiple AE were detected. However, further development is required on an analysis method with high resolution for the time. 4 refs., 4 figs.

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

    Directory of Open Access Journals (Sweden)

    Siru Zhou

    2015-06-01

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

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

    Science.gov (United States)

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

    2015-12-15

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

  3. Effects of MiR-375-BMPR2 as a Key Factor Downstream of BMP15/GDF9 on the Smad1/5/8 and Smad2/3 Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Chang Liu

    2018-03-01

    Full Text Available Background/Aims: Bone morphogenetic protein 15 (BMP15 and growth differentiation factor 9 (GDF9, which are secreted by oocytes, are important regulators of follicular growth and development and ovarian function. These two factors can regulate the proliferation and apoptosis of cumulus cells via modulation of the Smad signaling pathway. Studies have shown that BMP15 and GDF9 can affect the level of miR-375, whereas the target gene of miR-375 is BMPR2, the type II receptor of BMP15 and GDF9. However, whether or how the BMP15/ GDF9-miR-375-BMPR2 pathway affects the proliferation and apoptosis of bovine cumulus cells through regulation of the Smad signaling pathway remains unclear. Methods: In this study, cumulus cells were first obtained from cumulus-oocyte complexes (COCs. Appropriate concentrations of BMP15 and GDF9 were added during the in vitro culture process. Cell Counting Kit-8 (CCK-8 analyses and flow cytometry were used to determine the effects of BMP15/GDF9 on bovine cumulus cells proliferation and apoptosis. Subsequently, miR-375 mimics, miR-375 inhibitor and BMPR2 siRNA were synthesized and used for transfection experiments. Western Blot analysis was used to detect changes before and after transfection in the expression levels of the BMP15/GDF9 type I receptors ALK4, ALK5 and ALK6; the phosphorylation levels of Smad2/3 and Smad1/5/8, which are key signaling pathway proteins downstream of BMP15/GDF9; the expression levels of PTX3, HAS2 and PTGS2, which are key genes involved in cumulus cells proliferation; and Bcl2/Bax, which are genes involved in apoptosis. Results: The addition of 100 ng/mL BMP15 or 200 ng/mL GDF9 or the combined addition of 50 ng/mL BMP15 and 100 ng/mL GDF9 effectively inhibited bovine cumulus cell apoptosis and promoted cell proliferation. BMP15/GDF9 negatively regulated miR-375 expression and positively regulated BMPR2 expression. High levels of miR-375 and inhibition of BMPR2 resulted in increased expression of ALK

  4. Signal Normalization Reduces Image Appearance Disparity Among Multiple Optical Coherence Tomography Devices.

    Science.gov (United States)

    Chen, Chieh-Li; Ishikawa, Hiroshi; Wollstein, Gadi; Bilonick, Richard A; Kagemann, Larry; Schuman, Joel S

    2017-02-01

    To assess the effect of the previously reported optical coherence tomography (OCT) signal normalization method on reducing the discrepancies in image appearance among spectral-domain OCT (SD-OCT) devices. Healthy eyes and eyes with various retinal pathologies were scanned at the macular region using similar volumetric scan patterns with at least two out of three SD-OCT devices at the same visit (Cirrus HD-OCT, Zeiss, Dublin, CA; RTVue, Optovue, Fremont, CA; and Spectralis, Heidelberg Engineering, Heidelberg, Germany). All the images were processed with the signal normalization. A set of images formed a questionnaire with 24 pairs of cross-sectional images from each eye with any combination of the three SD-OCT devices either both pre- or postsignal normalization. Observers were asked to evaluate the similarity of the two displayed images based on the image appearance. The effects on reducing the differences in image appearance before and after processing were analyzed. Twenty-nine researchers familiar with OCT images participated in the survey. Image similarity was significantly improved after signal normalization for all three combinations ( P ≤ 0.009) as Cirrus and RTVue combination became the most similar pair, followed by Cirrus and Spectralis, and RTVue and Spectralis. The signal normalization successfully minimized the disparities in the image appearance among multiple SD-OCT devices, allowing clinical interpretation and comparison of OCT images regardless of the device differences. The signal normalization would enable direct OCT images comparisons without concerning about device differences and broaden OCT usage by enabling long-term follow-ups and data sharing.

  5. Foraging Value, Risk Avoidance, and Multiple Control Signals: How the Anterior Cingulate Cortex Controls Value-based Decision-making.

    Science.gov (United States)

    Brown, Joshua W; Alexander, William H

    2017-10-01

    Recent work on the role of the ACC in cognition has focused on choice difficulty, action value, risk avoidance, conflict resolution, and the value of exerting control among other factors. A main underlying question is what are the output signals of ACC, and relatedly, what is their effect on downstream cognitive processes? Here we propose a model of how ACC influences cognitive processing in other brain regions that choose actions. The model builds on the earlier Predicted Response Outcome model and suggests that ACC learns to represent specifically the states in which the potential costs or risks of an action are high, on both short and long timescales. It then uses those cost signals as a basis to bias decisions to minimize losses while maximizing gains. The model simulates both proactive and reactive control signals and accounts for a variety of empirical findings regarding value-based decision-making.

  6. Threshold-Based Multiple Optical Signal Selection Scheme for Free-Space Optical Wavelength Division Multiplexing Systems

    KAUST Repository

    Nam, Sung Sik; Alouini, Mohamed-Slim; Zhang, Lin; Ko, Young-Chai

    2017-01-01

    We propose a threshold-based multiple optical signal selection scheme (TMOS) for free-space optical wavelength division multiplexing systems. With this scheme, we can obtain higher spectral efficiency while reducing the possible complexity

  7. Agmatine promotes the migration of murine brain endothelial cells via multiple signaling pathways.

    Science.gov (United States)

    Jung, Hyun-Joo; Jeon, Yong-Heui; Bokara, Kiran Kumar; Koo, Bon-Nyeo; Lee, Won Taek; Park, Kyung Ah; Lee, Jong-Eun

    2013-01-17

    The combination of adhesion and migration of endothelial cells (ECs) is an integral process for evolution, organization, repair and vessel formation in living organisms. Agmatine, a polycationic amine existing in brain, has been investigated to exert neuroprotective effects. Up to date, there are no studies reporting that agmatine modulates murine brain endothelial (bEnd.3) cells migration. In the present study, we intend to investigate the role of agmatine in bEnd.3 cells migration and the molecular mechanism mediating this action. The effect of agmatine on the bEnd.3 cells migration was examined by migration assay, and the mechanism involved for this effect was investigated by western blot analysis and NO contents measurements. Agmatine treatment (50, 100 and 200 μM) significantly accelerated bEnd.3 cells migration in a concentration-dependent manner. Western blotting revealed that agmatine treatment significantly induced vascular endothelial growth factor (VEGF), VEGF receptor 2 (Flk-1/KDR or VEGFR2), phosphatidylinositol 3-kinase (PI3K), Akt/protein kinase B (also known as PKB, PI3K downstream effector protein), endothelial nitric oxide synthase (eNOS) nitric oxide (NO; product by eNOS) and intercellular adhesion molecule 1 (ICAM-1) expressions during bEnd.3 cells migration. The expression of ICAM-1 and migration of bEnd.3 cells, induced by agmatine, were significantly attenuated by treatment of wortmannin, a specific PI3K inhibitor. Taken together, we provide the first evidence that activation of VEGF/VEGFR2 and the consequential PI3K/Akt/eNOS/NO/ICAM-1 signaling pathways are serial events, through which the treatment of agmatine could lead to bEnd.3 cells migration. Copyright © 2012 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

    Gao, Hui; Wang, Jianrong

    2016-02-01

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

  9. Signal Timing Optimization for Corridors with Multiple Highway-Rail Grade Crossings Using Genetic Algorithm

    Directory of Open Access Journals (Sweden)

    Yifeng Chen

    2018-01-01

    Full Text Available Safety and efficiency are two critical issues at highway-rail grade crossings (HRGCs and their nearby intersections. Standard traffic signal optimization programs are not designed to work on roadway networks that contain multiple HRGCs, because their underlying assumption is that the roadway traffic is in a steady-state. During a train event, steady-state conditions do not occur. This is particularly true for corridors that experience high train traffic (e.g., over 2 trains per hour. In this situation, the non-steady-state conditions predominate. This paper develops a simulation-based methodology for optimizing traffic signal timing plan on corridors of this kind. The primary goal is to maximize safety, and the secondary goal is to minimize delay. A Genetic Algorithm (GA was used as the optimization approach in the proposed methodology. A new transition preemption strategy for dual tracks (TPS_DT and a train arrival prediction model were integrated in the proposed methodology. An urban road network with multiple HRGCs in Lincoln, NE, was used as the study network. The microsimulation model VISSIM was used for evaluation purposes and was calibrated to local traffic conditions. A sensitivity analysis with different train traffic scenarios was conducted. It was concluded that the methodology can significantly improve both the safety and efficiency of traffic corridors with HRGCs.

  10. Retrieval of Droplet size Density Distribution from Multiple field of view Cross polarized Lidar Signals: Theory and Experimental Validation

    Science.gov (United States)

    2016-06-02

    Retrieval of droplet-size density distribution from multiple-field-of-view cross-polarized lidar signals: theory and experimental validation...Gilles Roy, Luc Bissonnette, Christian Bastille, and Gilles Vallee Multiple-field-of-view (MFOV) secondary-polarization lidar signals are used to...use secondary polarization. A mathematical relation among the PSD, the lidar fields of view, the scattering angles, and the angular depolarization

  11. Phosphoinositide protein kinase PDPK1 is a crucial cell signaling mediator in multiple myeloma.

    Science.gov (United States)

    Chinen, Yoshiaki; Kuroda, Junya; Shimura, Yuji; Nagoshi, Hisao; Kiyota, Miki; Yamamoto-Sugitani, Mio; Mizutani, Shinsuke; Sakamoto, Natsumi; Ri, Masaki; Kawata, Eri; Kobayashi, Tsutomu; Matsumoto, Yosuke; Horiike, Shigeo; Iida, Shinsuke; Taniwaki, Masafumi

    2014-12-15

    Multiple myeloma is a cytogenetically/molecularly heterogeneous hematologic malignancy that remains mostly incurable, and the identification of a universal and relevant therapeutic target molecule is essential for the further development of therapeutic strategy. Herein, we identified that 3-phosphoinositide-dependent protein kinase 1 (PDPK1), a serine threonine kinase, is expressed and active in all eleven multiple myeloma-derived cell lines examined regardless of the type of cytogenetic abnormality, the mutation state of RAS and FGFR3 genes, or the activation state of ERK and AKT. Our results revealed that PDPK1 is a pivotal regulator of molecules that are essential for myelomagenesis, such as RSK2, AKT, c-MYC, IRF4, or cyclin Ds, and that PDPK1 inhibition caused the growth inhibition and the induction of apoptosis with the activation of BIM and BAD, and augmented the in vitro cytotoxic effects of antimyeloma agents in myeloma cells. In the clinical setting, PDPK1 was active in myeloma cells of approximately 90% of symptomatic patients at diagnosis, and the smaller population of patients with multiple myeloma exhibiting myeloma cells without active PDPK1 showed a significantly less frequent proportion of the disease stage III by the International Staging System and a significantly more favorable prognosis, including the longer overall survival period and the longer progression-free survival period by bortezomib treatment, than patients with active PDPK1, suggesting that PDPK1 activation accelerates the disease progression and the resistance to treatment in multiple myeloma. Our study demonstrates that PDPK1 is a potent and a universally targetable signaling mediator in multiple myeloma regardless of the types of cytogenetic/molecular profiles. ©2014 American Association for Cancer Research.

  12. Evolution of multiple phosphodiesterase isoforms in stickleback involved in cAMP signal transduction pathway.

    Science.gov (United States)

    Sato, Yukuto; Hashiguchi, Yasuyuki; Nishida, Mutsumi

    2009-02-20

    Duplicate genes are considered to have evolved through the partitioning of ancestral functions among duplicates (subfunctionalization) and/or the acquisition of novel functions from a beneficial mutation (neofunctionalization). Additionally, an increase in gene dosage resulting from duplication may also confer an advantageous effect, as has been suggested for histone, tRNA, and rRNA genes. Currently, there is little understanding of the effect of increased gene dosage on subcellular networks like signal transduction pathways. Addressing this issue may provide further insights into the evolution by gene duplication. We analyzed the evolution of multiple stickleback phosphodiesterase (PDE, EC: 3.1.4.17) 1C genes involved in the cyclic nucleotide signaling pathway. Stickleback has 8-9 copies of this gene, whereas only one or two loci exist in other model vertebrates. Our phylogenetic and synteny analyses suggested that the multiple PDE1C genes in stickleback were generated by repeated duplications of >100-kbp chromosome segments. Sequence evolution analysis did not provide strong evidence for neofunctionalization in the coding sequences of stickleback PDE1C isoforms. On the other hand, gene expression analysis suggested that the derived isoforms acquired expression in new organs, implying their neofunctionalization in terms of expression patterns. In addition, at least seven isoforms of the stickleback PDE1C were co-expressed with olfactory-type G-proteins in the nose, suggesting that PDE1C dosage is increased in the stickleback olfactory transduction (OT) pathway. In silico simulations of OT implied that the increased PDE1C dosage extends the longevity of the depolarization signals of the olfactory receptor neuron. The predicted effect of the increase in PDE1C products on the OT pathway may play an important role in stickleback behavior and ecology. However, this possibility should be empirically examined. Our analyses imply that an increase in gene product sometimes

  13. Evolution of multiple phosphodiesterase isoforms in stickleback involved in cAMP signal transduction pathway

    Directory of Open Access Journals (Sweden)

    Nishida Mutsumi

    2009-02-01

    Full Text Available Abstract Background Duplicate genes are considered to have evolved through the partitioning of ancestral functions among duplicates (subfunctionalization and/or the acquisition of novel functions from a beneficial mutation (neofunctionalization. Additionally, an increase in gene dosage resulting from duplication may also confer an advantageous effect, as has been suggested for histone, tRNA, and rRNA genes. Currently, there is little understanding of the effect of increased gene dosage on subcellular networks like signal transduction pathways. Addressing this issue may provide further insights into the evolution by gene duplication. Results We analyzed the evolution of multiple stickleback phosphodiesterase (PDE, EC: 3.1.4.17 1C genes involved in the cyclic nucleotide signaling pathway. Stickleback has 8–9 copies of this gene, whereas only one or two loci exist in other model vertebrates. Our phylogenetic and synteny analyses suggested that the multiple PDE1C genes in stickleback were generated by repeated duplications of >100-kbp chromosome segments. Sequence evolution analysis did not provide strong evidence for neofunctionalization in the coding sequences of stickleback PDE1C isoforms. On the other hand, gene expression analysis suggested that the derived isoforms acquired expression in new organs, implying their neofunctionalization in terms of expression patterns. In addition, at least seven isoforms of the stickleback PDE1C were co-expressed with olfactory-type G-proteins in the nose, suggesting that PDE1C dosage is increased in the stickleback olfactory transduction (OT pathway. In silico simulations of OT implied that the increased PDE1C dosage extends the longevity of the depolarization signals of the olfactory receptor neuron. Conclusion The predicted effect of the increase in PDE1C products on the OT pathway may play an important role in stickleback behavior and ecology. However, this possibility should be empirically examined. Our

  14. The role of the PI3K-Akt signal transduction pathway in Autographa californica multiple nucleopolyhedrovirus infection of Spodoptera frugiperda cells

    International Nuclear Information System (INIS)

    Xiao Wei; Yang Yi; Weng Qingbei; Lin Tiehao; Yuan Meijin; Yang Kai; Pang Yi

    2009-01-01

    Many viruses activate the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway, thereby modulating diverse downstream signaling pathways associated with antiapoptosis, proliferation, cell cycling, protein synthesis and glucose metabolism, in order to augment their replication. To date, the role of the PI3K-Akt pathway in Baculovirus replication has not been defined. In the present study, we demonstrate that infection of Sf9 cells with Autographa californica multiple nucleopolyhedrovirus (AcMNPV) elevated cellular Akt phosphorylation at 1 h post-infection. The maximum Akt phosphorylation occurred at 6 h post-infection and remained unchanged until 18 h post-infection. The PI3K-specific inhibitor, LY294002, suppressed Akt phosphorylation in a dose-dependent manner, suggesting that AcMNPV-induced Akt phosphorylation is PI3K-dependent. The inhibition of PI3K-Akt activation by LY294002 significantly reduced the viral yield, including a reduction in budded viruses and occlusion bodies. The virus production was reduced only when the inhibitor was added within 24 h of infection, implying that activation of PI3K occurred early in infection. Correspondingly, both viral DNA replication and late (VP39) and very late (POLH) viral protein expression were impaired by LY294002 treatment; LY294002 had no effect on immediate-early (IE1) and early-late (GP64) protein expression. These results demonstrate that the PI3K-Akt pathway is required for efficient Baculovirus replication.

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

    Science.gov (United States)

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

    2015-01-01

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

  16. A threshold-based multiple optical signal selection scheme for WDM FSO systems

    KAUST Repository

    Nam, Sung Sik

    2017-07-20

    In this paper, we propose a threshold-based-multiple optical signal selection scheme (TMOS) for free-space optical systems based on wavelength division multiplexing. With the proposed TMOS, we can obtain higher spectral efficiency while reducing the potential increase in complexity of implementation caused by applying a selection-based beam selection scheme without a considerable performance loss. Here, to accurately characterize the performance of the proposed TMOS, we statistically analyze the characteristics with heterodyne detection technique over independent and identically distributed Log-normal turbulence conditions taking into considerations the impact of pointing error. Specifically, we derive exact closed-form expressions for the average bit error rate, and the average spectral efficiency by adopting an adaptive modulation. Some selected results shows that the average spectral efficiency can be increased with TMOS while the system requirement is satisfied.

  17. Multiple signaling pathways mediated by dopamine and calcium ionophore A23187 in human platelets

    International Nuclear Information System (INIS)

    Saeed, S.A.; Waqar, M.A.

    2009-01-01

    This study was undertaken to investigate the mechanism(s) of platelet aggregation induced by the synergistic action of dopamine (DA) and a Ca/sup +2/-ionophore, A23187. DA showed non significant effect on platelet aggregation over a wide range of concentrations (up to 500 micro M), but did potentiate the aggregation response of A23187. Aggregation induced by A23187 was inhibited by calcium channel blockers (diltiazem and verpamil), receptor blockers (chlorpromazine and haloperidol) and a cyclo-oxygenase inhibitor (indomethacin). However, the inhibitory effect of these blockers was more pronounced (with a selectivity ratio of 1.5-28) in the aggregation induced by synergistic effect of A23187 and DA. A phosphatidylinositol 3-kinase (P1 3-Kinase) inhibitor, wortmanin (1C/sub 50/. 25-30 nM), inhibited aggregation induced by either A23187 or DA and act synergistically. This synergistic effect on platelet aggregation is mediated through multiple signaling pathways. (author)

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

    International Nuclear Information System (INIS)

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

    2013-01-01

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

  19. A threshold-based multiple optical signal selection scheme for WDM FSO systems

    KAUST Repository

    Nam, Sung Sik; Alouini, Mohamed-Slim; Ko, Young-Chai; Cho, Sung Ho

    2017-01-01

    In this paper, we propose a threshold-based-multiple optical signal selection scheme (TMOS) for free-space optical systems based on wavelength division multiplexing. With the proposed TMOS, we can obtain higher spectral efficiency while reducing the potential increase in complexity of implementation caused by applying a selection-based beam selection scheme without a considerable performance loss. Here, to accurately characterize the performance of the proposed TMOS, we statistically analyze the characteristics with heterodyne detection technique over independent and identically distributed Log-normal turbulence conditions taking into considerations the impact of pointing error. Specifically, we derive exact closed-form expressions for the average bit error rate, and the average spectral efficiency by adopting an adaptive modulation. Some selected results shows that the average spectral efficiency can be increased with TMOS while the system requirement is satisfied.

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

    DEFF Research Database (Denmark)

    Bro-Jørgensen, Jakob; Dabelsteen, Torben

    2008-01-01

    frequency of the knee-clicking sound honestly indicated body size, a main determinant of fighting ability. In contrast, the dewlap size increased with estimated age rather than body size, suggesting that, by magnifying the silhouette of older bulls disproportionately, the dewlap acts as an indicator of age......Background: Given the costs of signalling, why do males often advertise their fighting ability to rivals using several signals rather than just one? Multiple signalling theories have developed largely in studies of sexual signals, and less is known about their applicability to intra-sexual...... agonistic signals in eland reflect three separate components of fighting ability: (1) body size, (2) age and (3) presumably androgen-related aggression, which is reflected in three backup signals. The study highlights how complex agonistic signalling systems can evolve through the simultaneous action...

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

    Science.gov (United States)

    Reimann, Tony

    2014-05-01

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

  2. Small Molecules Affect Human Dental Pulp Stem Cell Properties Via Multiple Signaling Pathways

    Science.gov (United States)

    Al-Habib, Mey; Yu, Zongdong

    2013-01-01

    One fundamental issue regarding stem cells for regenerative medicine is the maintenance of stem cell stemness. The purpose of the study was to test whether small molecules can enhance stem cell properties of mesenchymal stem cells (MSCs) derived from human dental pulp (hDPSCs), which have potential for multiple clinical applications. We identified the effects of small molecules (Pluripotin (SC1), 6-bromoindirubin-3-oxime and rapamycin) on the maintenance of hDPSC properties in vitro and the mechanisms involved in exerting the effects. Primary cultures of hDPSCs were exposed to optimal concentrations of these small molecules. Treated hDPSCs were analyzed for their proliferation, the expression levels of pluripotent and MSC markers, differentiation capacities, and intracellular signaling activations. We found that small molecule treatments decreased cell proliferation and increased the expression of STRO-1, NANOG, OCT4, and SOX2, while diminishing cell differentiation into odonto/osteogenic, adipogenic, and neurogenic lineages in vitro. These effects involved Ras-GAP-, ERK1/2-, and mTOR-signaling pathways, which may preserve the cell self-renewal capacity, while suppressing differentiation. We conclude that small molecules appear to enhance the immature state of hDPSCs in culture, which may be used as a strategy for adult stem cell maintenance and extend their capacity for regenerative applications. PMID:23573877

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

    Science.gov (United States)

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

    2014-01-01

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

  4. Distinct signaling mechanisms in multiple developmental pathways by the SCRAMBLED receptor of Arabidopsis.

    Science.gov (United States)

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

    2014-10-01

    SCRAMBLED (SCM), a leucine-rich repeat receptor-like kinase in Arabidopsis (Arabidopsis thaliana), is required for positional signaling in the root epidermis and for tissue/organ development in the shoot. To further understand SCM action, we generated a series of kinase domain variants and analyzed their ability to complement scm mutant defects. We found that the SCM kinase domain, but not kinase activity, is required for its role in root epidermal patterning, supporting the view that SCM is an atypical receptor kinase. We also describe a previously uncharacterized role for SCM in fruit dehiscence, because mature siliques from scm mutants fail to open properly. Interestingly, the kinase domain of SCM appears to be dispensable for this developmental process. Furthermore, we found that most of the SCM kinase domain mutations dramatically inhibit inflorescence development. Because this process is not affected in scm null mutants, it is likely that SCM acts redundantly to regulate inflorescence size. The importance of distinct kinase residues for these three developmental processes provides an explanation for the maintenance of the conserved kinase domain in the SCM protein, and it may generally explain its conservation in other atypical kinases. Furthermore, these results indicate that individual leucine-rich repeat receptor-like kinases may participate in multiple pathways using distinct signaling mechanisms to mediate diverse cellular communication events. © 2014 American Society of Plant Biologists. All Rights Reserved.

  5. The primary cilium as a multiple cellular signaling scaffold in development and disease

    Directory of Open Access Journals (Sweden)

    Hyuk Wan Ko*

    2012-08-01

    Full Text Available Primary cilia, single hair-like appendage on the surface of themost mammalian cells, were once considered to be vestigialcellular organelles for a past century because of their tinystructure and unknown function. Although they lack ancestralmotility function of cilia or flagella, they share common groundwith multiciliated motile cilia and flagella on internal structuresuch as microtubule based nine outer doublets nucleated from thebase of mother centrioles called basal body. Making cilia,ciliogenesis, in cells depends on the cell cycle stage due to reuseof centrioles for cell division forming mitotic spindle pole (Mphase and assembling cilia from basal body (starting G1 phaseand maintaining most of interphase. Ciliary assembly requiredtwo conflicting processes such as assembly and disassembly andbalance between these two processes determines the length ofcilia. Both process required highly conserved transport system tosupply needed substance to grow tip of cilia and bring ciliaryturnover product back to the base of cilia using motor protein,kinesin and dynein, and transport protein complex, IFT particles.Disruption of ciliary structure or function causes multiple humandisorder called ciliopathies affecting disease of diverse ciliatedtissues ranging from eye, kidney, respiratory tract and brain.Recent explosion of research on the primary cilia and theirinvolvement on animal development and disease attracts scientificinterest on how extensively the function of cilia related to specificcell physiology and signaling pathway. In this review, I introducegeneral features of primary cilia and recent progress inunderstanding of the ciliary length control and signaling pathwaystransduced through primary cilia in vertebrates.

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

    Science.gov (United States)

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

    2011-01-01

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

  7. Cyclophilins contribute to Stat3 signaling and survival of multiple myeloma cells.

    Science.gov (United States)

    Bauer, K; Kretzschmar, A K; Cvijic, H; Blumert, C; Löffler, D; Brocke-Heidrich, K; Schiene-Fischer, C; Fischer, G; Sinz, A; Clevenger, C V; Horn, F

    2009-08-06

    Signal transducer and activator of transcription 3 (Stat3) is the major mediator of interleukin-6 (IL-6) family cytokines. In addition, Stat3 is known to be involved in the pathophysiology of many malignancies. Here, we show that the cis-trans peptidyl-prolyl isomerase cyclophilin (Cyp) B specifically interacts with Stat3, whereas the highly related CypA does not. CypB knockdown inhibited the IL-6-induced transactivation potential but not the tyrosine phosphorylation of Stat3. Binding of CypB to Stat3 target promoters and alteration of the intranuclear localization of Stat3 on CypB depletion suggested a nuclear function of Stat3/CypB interaction. By contrast, CypA knockdown inhibited Stat3 IL-6-induced tyrosine phosphorylation and nuclear translocation. The Cyp inhibitor cyclosporine A (CsA) caused similar effects. However, Stat1 activation in response to IL-6 or interferon-gamma was not affected by Cyp silencing or CsA treatment. As a result, Cyp knockdown shifted IL-6 signaling to a Stat1-dominated pathway. Furthermore, Cyp depletion or treatment with CsA induced apoptosis in IL-6-dependent multiple myeloma cells, whereas an IL-6-independent line was not affected. Thus, Cyps support the anti-apoptotic action of Stat3. Taken together, CypA and CypB both play pivotal roles, yet at different signaling levels, for Stat3 activation and function. These data also suggest a novel mechanism of CsA action.

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

    Energy Technology Data Exchange (ETDEWEB)

    Marshall, Kris S.; Cohen, Michael J.; Fonseca, Greg J.; Todorovic, Biljana; King, Cason R. [Department of Microbiology and Immunology, Western University, London Regional Cancer Program, London, ON, Canada N6A 4L6 (Canada); Yousef, Ahmed F. [Department of Chemical and Environmental Engineering, Masdar Institute, Abu Dhabi (United Arab Emirates); Zhang, Zhiying [College of Animal Science and Technologies, Northwest A and F University, Yangling, Shaanxi 712100 (China); Mymryk, Joe S., E-mail: jmymryk@uwo.ca [Department of Microbiology and Immunology, Western University, London Regional Cancer Program, London, ON, Canada N6A 4L6 (Canada); Department of Oncology, Western University, London Regional Cancer Program, London, ON, Canada N6A 4L6 (Canada)

    2014-04-15

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

  9. Multiple Signal Classification Algorithm Based Electric Dipole Source Localization Method in an Underwater Environment

    Directory of Open Access Journals (Sweden)

    Yidong Xu

    2017-10-01

    Full Text Available A novel localization method based on multiple signal classification (MUSIC algorithm is proposed for positioning an electric dipole source in a confined underwater environment by using electric dipole-receiving antenna array. In this method, the boundary element method (BEM is introduced to analyze the boundary of the confined region by use of a matrix equation. The voltage of each dipole pair is used as spatial-temporal localization data, and it does not need to obtain the field component in each direction compared with the conventional fields based localization method, which can be easily implemented in practical engineering applications. Then, a global-multiple region-conjugate gradient (CG hybrid search method is used to reduce the computation burden and to improve the operation speed. Two localization simulation models and a physical experiment are conducted. Both the simulation results and physical experiment result provide accurate positioning performance, with the help to verify the effectiveness of the proposed localization method in underwater environments.

  10. Two zebrafish G2A homologs activate multiple intracellular signaling pathways in acidic environment

    Energy Technology Data Exchange (ETDEWEB)

    Ichijo, Yuta; Mochimaru, Yuta [Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571 (Japan); Azuma, Morio [Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, 3190-Gofuku, Toyama 930-8555 (Japan); Satou, Kazuhiro; Negishi, Jun [Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571 (Japan); Nakakura, Takashi [Department of Anatomy, Graduate School of Medicine, Teikyo University, 2-11-1 Itabashi-Ku, Tokyo 173-8605 (Japan); Oshima, Natsuki [Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571 (Japan); Mogi, Chihiro; Sato, Koichi [Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512 (Japan); Matsuda, Kouhei [Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, 3190-Gofuku, Toyama 930-8555 (Japan); Okajima, Fumikazu [Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512 (Japan); Tomura, Hideaki, E-mail: tomurah@meiji.ac.jp [Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571 (Japan)

    2016-01-01

    Human G2A is activated by various stimuli such as lysophosphatidylcholine (LPC), 9-hydroxyoctadecadienoic acid (9-HODE), and protons. The receptor is coupled to multiple intracellular signaling pathways, including the G{sub s}-protein/cAMP/CRE, G{sub 12/13}-protein/Rho/SRE, and G{sub q}-protein/phospholipase C/NFAT pathways. In the present study, we examined whether zebrafish G2A homologs (zG2A-a and zG2A-b) could respond to these stimuli and activate multiple intracellular signaling pathways. We also examined whether histidine residue and basic amino acid residue in the N-terminus of the homologs also play roles similar to those played by human G2A residues if the homologs sense protons. We found that the zG2A-a showed the high CRE, SRE, and NFAT activities, however, zG2A-b showed only the high SRE activity under a pH of 8.0. Extracellular acidification from pH 7.4 to 6.3 ameliorated these activities in zG2A-a-expressing cells. On the other hand, acidification ameliorated the SRE activity but not the CRE and NFAT activities in zG2A-b-expressing cells. LPC or 9-HODE did not modify any activity of either homolog. The substitution of histidine residue at the 174{sup th} position from the N-terminus of zG2A-a to asparagine residue attenuated proton-induced CRE and NFAT activities but not SRE activity. The substitution of arginine residue at the 32nd position from the N-terminus of zG2A-a to the alanine residue also attenuated its high and the proton-induced CRE and NFAT activities. On the contrary, the substitution did not attenuate SRE activity. The substitution of the arginine residue at the 10th position from the N-terminus of zG2A-b to the alanine residue also did not attenuate its high or the proton-induced SRE activity. These results indicate that zebrafish G2A homologs were activated by protons but not by LPC and 9-HODE, and the activation mechanisms of the homologs were similar to those of human G2A. - Highlights: • Zebrafish two G2A homologs are proton

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

    Directory of Open Access Journals (Sweden)

    Dabelsteen Torben

    2008-11-01

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

  12. Improving seasonal forecasts of hydroclimatic variables through the state of multiple large-scale climate signals

    Science.gov (United States)

    Castelletti, A.; Giuliani, M.; Block, P. J.

    2017-12-01

    Increasingly uncertain hydrologic regimes combined with more frequent and intense extreme events are challenging water systems management worldwide, emphasizing the need of accurate medium- to long-term predictions to timely prompt anticipatory operations. Despite modern forecasts are skillful over short lead time (from hours to days), predictability generally tends to decrease on longer lead times. Global climate teleconnection, such as El Niño Southern Oscillation (ENSO), may contribute in extending forecast lead times. However, ENSO teleconnection is well defined in some locations, such as Western USA and Australia, while there is no consensus on how it can be detected and used in other regions, particularly in Europe, Africa, and Asia. In this work, we generalize the Niño Index Phase Analysis (NIPA) framework by contributing the Multi Variate Niño Index Phase Analysis (MV-NIPA), which allows capturing the state of multiple large-scale climate signals (i.e. ENSO, North Atlantic Oscillation, Pacific Decadal Oscillation, Atlantic Multi-decadal Oscillation, Indian Ocean Dipole) to forecast hydroclimatic variables on a seasonal time scale. Specifically, our approach distinguishes the different phases of the considered climate signals and, for each phase, identifies relevant anomalies in Sea Surface Temperature (SST) that influence the local hydrologic conditions. The potential of the MV-NIPA framework is demonstrated through an application to the Lake Como system, a regulated lake in northern Italy which is mainly operated for flood control and irrigation supply. Numerical results show high correlations between seasonal SST values and one season-ahead precipitation in the Lake Como basin. The skill of the resulting MV-NIPA forecast outperforms the one of ECMWF products. This information represents a valuable contribution to partially anticipate the summer water availability, especially during drought events, ultimately supporting the improvement of the Lake Como

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

    Science.gov (United States)

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

    2016-01-01

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

  14. Multiple signal transduction pathways in okadaic acid induced apoptosis in HeLa cells

    International Nuclear Information System (INIS)

    Jayaraj, R.; Gupta, Nimesh; Rao, P.V. Lakshmana

    2009-01-01

    Okadaic acid (OA) is the major component of diarrhetic shell fish poisoning toxins and a potent inhibitor of protein phosphatase 1 and 2A. We investigated the signal transduction pathways involved in OA induced cell death in HeLa cells. OA induced cytotoxicity and apoptosis at IC50 of 100 nM. OA treatment resulted in time dependent increase in reactive oxygen species and depleted intracellular glutathione levels. Loss of mitochondrial membrane permeability led to translocation of bax, cytochrome-c and AIF from mitochondria to cytosol. The cells under fluorescence microscope showed typical apoptotic morphology with condensed chromatin, and nuclear fragmentation. We investigated the mitochondrial-mediated caspase cascade. The time dependent activation and cleavage of of bax, caspases-8, 10, 9, 3 and 7 was observed in Western blot analysis. In addition to caspase-dependent pathway AIF mediated caspase-independent pathway was involved in OA mediated cell death. OA also caused time dependent inhibition of protein phosphatase 2A activity and phosphorylation of p38 and p42/44 MAP kinases. Inhibitor studies with Ac-DEVO-CHO and Z-VAD-FMK could not prevent the phosphorylation of p38 and p42/44 MAP kinases. Our experiments with caspase inhibitors Ac-DEVD-CHO, Z-IETD-FMK and Z-VAD-FMK inhibited capsase-3, 8 cleavages but did not prevent OA-induced apoptosis and DNA fragmentation. Similarly, pretreatment with cyclosporin-A and N-acetylcysteine could not prevent the DNA fragmentation. In summary, the results of our study show that OA induces multiple signal transduction pathways acting either independently or simultaneously leading to apoptosis

  15. Raman database of amino acids solutions: A critical study of Extended Multiplicative Signal Correction

    KAUST Repository

    Candeloro, Patrizio

    2013-01-01

    The Raman spectra of biological materials always exhibit complex profiles, constituting several peaks and/or bands which arise due to the large variety of biomolecules. The extraction of quantitative information from these spectra is not a trivial task. While qualitative information can be retrieved from the changes in peaks frequencies or from the appearance/disappearance of some peaks, quantitative analysis requires an examination of peak intensities. Unfortunately in biological samples it is not easy to identify a reference peak for normalizing intensities, and this makes it very difficult to study the peak intensities. In the last decades a more refined mathematical tool, the extended multiplicative signal correction (EMSC), has been proposed for treating infrared spectra, which is also capable of providing quantitative information. From the mathematical and physical point of view, EMSC can also be applied to Raman spectra, as recently proposed. In this work the reliability of the EMSC procedure is tested by application to a well defined biological system: the 20 standard amino acids and their combination in peptides. The first step is the collection of a Raman database of these 20 amino acids, and subsequently EMSC processing is applied to retrieve quantitative information from amino acids mixtures and peptides. A critical review of the results is presented, showing that EMSC has to be carefully handled for complex biological systems. © 2013 The Royal Society of Chemistry.

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

    International Nuclear Information System (INIS)

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

    2010-01-01

    The natural product sesamin has been known to act as a potent antioxidant and prevent endothelial dysfunction. We here found that sesamin increased in vitro angiogenic processes, such as endothelial cell proliferation, migration, and tube formation, as well as neovascularization in an animal model. This compound elicited the activation of multiple angiogenic signal modulators, such as ERK, Akt, endothelial nitric oxide synthase (eNOS), NO production, FAK, and p38 MAPK, but not Src. The MEK inhibitor PD98059 and the PI3K inhibitor Wortmannin specifically inhibited sesamin-induced activation of the ERK and Akt/eNOS pathways. These inhibitors reduced angiogenic events, with high specificity for MEK/ERK-dependent cell proliferation and migration and PI3K/Akt-mediated tube formation. Moreover, inhibition of p38 MAPK effectively inhibited sesamin-induced cell migration. The angiogenic activity of sesamin was not associated with VEGF expression. Furthermore, this compound did not induce vascular permeability and upregulated ICAM-1 and VCAM-1 expression, which are hallmarks of vascular inflammation. These results suggest that sesamin stimulates angiogenesis in vitro and in vivo through the activation of MEK/ERK-, PI3K/Akt/eNOS-, p125 FAK -, and p38 MAPK-dependent pathways, without increasing vascular inflammation, and may be used for treating ischemic diseases and tissue regeneration.

  17. PKA/AMPK signaling in relation to adiponectin's antiproliferative effect on multiple myeloma cells.

    Science.gov (United States)

    Medina, E A; Oberheu, K; Polusani, S R; Ortega, V; Velagaleti, G V N; Oyajobi, B O

    2014-10-01

    Obesity increases the risk of developing multiple myeloma (MM). Adiponectin is a cytokine produced by adipocytes, but paradoxically decreased in obesity, that has been implicated in MM progression. Herein, we evaluated how prolonged exposure to adiponectin affected the survival of MM cells as well as putative signaling mechanisms. Adiponectin activates protein kinase A (PKA), which leads to decreased AKT activity and increased AMP-activated protein kinase (AMPK) activation. AMPK, in turn, induces cell cycle arrest and apoptosis. Adiponectin-induced apoptosis may be mediated, at least in part, by the PKA/AMPK-dependent decline in the expression of the enzyme acetyl-CoA-carboxylase (ACC), which is essential to lipogenesis. Supplementation with palmitic acid, the preliminary end product of fatty acid synthesis, rescues MM cells from adiponectin-induced apoptosis. Furthermore, 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), an ACC inhibitor, exhibited potent antiproliferative effects on MM cells that could also be inhibited by fatty acid supplementation. Thus, adiponectin's ability to reduce survival of MM cells appears to be mediated through its ability to suppress lipogenesis. Our findings suggest that PKA/AMPK pathway activators, or inhibitors of ACC, may be useful adjuvants to treat MM. Moreover, the antimyeloma effect of adiponectin supports the concept that hypoadiponectinemia, as occurs in obesity, promotes MM tumor progression.

  18. Locating seismicity on the Arctic plate boundary using multiple-event techniques and empirical signal processing

    Science.gov (United States)

    Gibbons, S. J.; Harris, D. B.; Dahl-Jensen, T.; Kværna, T.; Larsen, T. B.; Paulsen, B.; Voss, P. H.

    2017-12-01

    The oceanic boundary separating the Eurasian and North American plates between 70° and 84° north hosts large earthquakes which are well recorded teleseismically, and many more seismic events at far lower magnitudes that are well recorded only at regional distances. Existing seismic bulletins have considerable spread and bias resulting from limited station coverage and deficiencies in the velocity models applied. This is particularly acute for the lower magnitude events which may only be constrained by a small number of Pn and Sn arrivals. Over the past two decades there has been a significant improvement in the seismic network in the Arctic: a difficult region to instrument due to the harsh climate, a sparsity of accessible sites (particularly at significant distances from the sea), and the expense and difficult logistics of deploying and maintaining stations. New deployments and upgrades to stations on Greenland, Svalbard, Jan Mayen, Hopen, and Bjørnøya have resulted in a sparse but stable regional seismic network which results in events down to magnitudes below 3 generating high-quality Pn and Sn signals on multiple stations. A catalogue of several hundred events in the region since 1998 has been generated using many new phase readings on stations on both sides of the spreading ridge in addition to teleseismic P phases. A Bayesian multiple event relocation has resulted in a significant reduction in the spread of hypocentre estimates for both large and small events. Whereas single event location algorithms minimize vectors of time residuals on an event-by-event basis, the Bayesloc program finds a joint probability distribution of origins, hypocentres, and corrections to traveltime predictions for large numbers of events. The solutions obtained favour those event hypotheses resulting in time residuals which are most consistent over a given source region. The relocations have been performed with different 1-D velocity models applicable to the Arctic region and

  19. Monitoring the Simultaneous Presentation of Multiple Spatialized Speech Signals in the Free Field

    National Research Council Canada - National Science Library

    Nelson, W. T; Bolia, Robert S; Ericson, Mark A; McKinley, Richard L

    1998-01-01

    .... Factorial combinations of three variables, including the number of localized speech signals, the location of the speech signals along the horizontal plane, and the sex of the talker were employed...

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

    Science.gov (United States)

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

    2015-02-01

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

  1. Morbillivirus v proteins exhibit multiple mechanisms to block type 1 and type 2 interferon signalling pathways.

    Directory of Open Access Journals (Sweden)

    Senthil K Chinnakannan

    Full Text Available Morbilliviruses form a closely related group of pathogenic viruses which encode three non-structural proteins V, W and C in their P gene. Previous studies with rinderpest virus (RPV and measles virus (MeV have demonstrated that these non-structural proteins play a crucial role in blocking type I (IFNα/β and type II (IFNγ interferon action, and various mechanisms have been proposed for these effects. We have directly compared four important morbilliviruses, rinderpest (RPV, measles virus (MeV, peste des petits ruminants virus (PPRV and canine distemper virus (CDV. These viruses and their V proteins could all block type I IFN action. However, the viruses and their V proteins had varying abilities to block type II IFN action. The ability to block type II IFN-induced gene transcription correlated with co-precipitation of STAT1 with the respective V protein, but there was no correlation between co-precipitation of either STAT1 or STAT2 and the abilities of the V proteins to block type I IFN-induced gene transcription or the creation of the antiviral state. Further study revealed that the V proteins of RPV, MeV, PPRV and CDV could all interfere with phosphorylation of the interferon-receptor-associated kinase Tyk2, and the V protein of highly virulent RPV could also block the phosphorylation of another such kinase, Jak1. Co-precipitation studies showed that morbillivirus V proteins all form a complex containing Tyk2 and Jak1. This study highlights the ability of morbillivirus V proteins to target multiple components of the IFN signalling pathways to control both type I and type II IFN action.

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

    Directory of Open Access Journals (Sweden)

    Cao Hui

    2010-12-01

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

  3. Continuous downstream processing of biopharmaceuticals.

    Science.gov (United States)

    Jungbauer, Alois

    2013-08-01

    Continuous manufacturing has been applied in many different industries but has been pursued reluctantly in biotechnology where the batchwise process is still the standard. A shift to continuous operation can improve productivity of a process and substantially reduce the footprint. Continuous operation also allows robust purification of labile biomolecules. A full set of unit operations is available to design continuous downstream processing of biopharmaceuticals. Chromatography, the central unit operation, is most advanced in respect to continuous operation. Here, the problem of 'batch' definition has been solved. This has also paved the way for implementation of continuous downstream processing from a regulatory viewpoint. Economic pressure, flexibility, and parametric release considerations will be the driving force to implement continuous manufacturing strategies in future. Copyright © 2013 Elsevier Ltd. All rights reserved.

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

    Energy Technology Data Exchange (ETDEWEB)

    Voss, Kelsey; Amaya, Moushimi [National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, 10650 Pyramid Place, Manassas, VA (United States); Mueller, Claudius [Center for Applied Proteomics and Personalized Medicine, George Mason University, 10900 University Boulevard, Manassas, VA (United States); Roberts, Brian [Leidos Health Life Sciences, 5202 Presidents Court, Suite 110, Frederick, MD (United States); Kehn-Hall, Kylene; Bailey, Charles [National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, 10650 Pyramid Place, Manassas, VA (United States); Petricoin, Emanuel [Center for Applied Proteomics and Personalized Medicine, George Mason University, 10900 University Boulevard, Manassas, VA (United States); Narayanan, Aarthi, E-mail: anaraya1@gmu.edu [National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, 10650 Pyramid Place, Manassas, VA (United States)

    2014-11-15

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

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

    International Nuclear Information System (INIS)

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

    2014-01-01

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

  6. Multiple sexual signals: Calls over colors for mate attraction in an aposematic, color-diverse poison frog

    Directory of Open Access Journals (Sweden)

    Corinna Eva Dreher

    2014-06-01

    Full Text Available Sexual signals indicate species identity and mate quality, and their importance for mate attraction is largely recognized. Recently, research in animal communication has started to integrate multiple signal modalities and evaluate their interactions. However, mate choice experiments across animal taxa have been limited to laboratory conditions, and assessments of multiple sexual signals under field conditions are still lacking. We take advantage of the divergence in visual and acoustic signals among populations of the Neotropical poison frog Oophaga pumilio to evaluate the importance of male advertisement calls and color patterns in female mate selection. Previous mate choice experiments in this species suggested color-assortative female mate preferences across many populations. Nevertheless, acoustic signals are crucial for sexual selection in frogs, and males of O. pumilio use advertisement calls to attract females. We hypothesize that both advertisement calls and coloration affects female mate selection in O.pumilio. To test this hypothesis we tested 452 receptive females from six populations in Costa Rica and Panama in their natural home ranges for preferences regarding local vs. non-local advertisement calls and color patterns. Overall, the calls overrode the effect of coloration, whereby most females preferred local over non-local calls. We found a tendency to prefer brighter (but not necessarily local males in two populations. Furthermore the strength of preferences varied geographically, and thus might be involved in prezygotic isolation among populations. The stronger effect of calls on mate attraction is associated with acoustic divergence between genetic groups in the species, while colour pattern diversity is mostly located within one genetic group, i.e. not linked to large-scale population structure. Finally our data highlights the importance to consider an array of signal modalities in multiple wild populations in studies of

  7. Stochastic resonance and stability for a stochastic metapopulation system subjected to non-Gaussian noise and multiplicative periodic signal

    International Nuclear Information System (INIS)

    Kang-Kang, Wang; Xian-Bin, Liu; Yu, Zhou

    2015-01-01

    In this paper, the stability and stochastic resonance (SR) phenomenon induced by the multiplicative periodic signal for a metapopulation system driven by the additive Gaussian noise, multiplicative non-Gaussian noise and noise correlation time is investigated. By using the fast descent method, unified colored noise approximation and McNamara and Wiesenfeld’s SR theory, the analytical expressions of the stationary probability distribution function and signal-to-noise ratio (SNR) are derived in the adiabatic limit. Via numerical calculations, each effect of the addictive noise intensity, the multiplicative noise intensity and the correlation time upon the steady state probability distribution function and the SNR is discussed, respectively. It is shown that multiplicative, additive noises and the departure parameter from the Gaussian noise can all destroy the stability of the population system. However, the noise correlation time can consolidate the stability of the system. On the other hand, the correlation time always plays an important role in motivating the SR and enhancing the SNR. Under different parameter conditions of the system, the multiplicative, additive noises and the departure parameter can not only excite SR phenomenon, but also restrain the SR phenomenon, which demonstrates the complexity of different noises upon the nonlinear system. (paper)

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

    Directory of Open Access Journals (Sweden)

    Lucía eLopez

    2012-09-01

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

  9. Direction of Radio Finding via MUSIC (Multiple Signal Classification) Algorithm for Hardware Design System

    Science.gov (United States)

    Zhang, Zheng

    2017-10-01

    Concept of radio direction finding systems, which use radio direction finding is based on digital signal processing algorithms. Thus, the radio direction finding system becomes capable to locate and track signals by the both. Performance of radio direction finding significantly depends on effectiveness of digital signal processing algorithms. The algorithm uses the Direction of Arrival (DOA) algorithms to estimate the number of incidents plane waves on the antenna array and their angle of incidence. This manuscript investigates implementation of the DOA algorithms (MUSIC) on the uniform linear array in the presence of white noise. The experiment results exhibit that MUSIC algorithm changed well with the radio direction.

  10. Operational optimization in the downstream; Otimizacao operacional no downstream

    Energy Technology Data Exchange (ETDEWEB)

    Silberman, Luis; Cunha, Filipe Silveira Ramos da [Petroleo Ipiranga, Porto Alegre, RS (Brazil)

    2004-07-01

    On the present competitive down stream's market, there is a great necessity of optimization aiming to guarantee the best price and quality of our clients. Our goal is to attend these expectations while we guarantee an efficient operation. The greatest question is how far we are from the ideal model. This way, a lot of projects have been executed during the last years aiming the operational optimization of all our activities. We divide the projects in 4 areas: Logistic (new modals distribution), Transport (transport optimization - quality and more deliveries with less trucks), Client Support (Internet Ipiranga and Support Center), Distribution Terminals Productivity (automation and environment). This work intend to present our ideal, perfect and complete Downstream Operation model. We will talk about how close we are of this ideal model and we will present the projects that we had already developed and implanted on the automation of the terminals and the logistics area. (author)

  11. Multiple logistic regression model of signalling practices of drivers on urban highways

    Science.gov (United States)

    Puan, Othman Che; Ibrahim, Muttaka Na'iya; Zakaria, Rozana

    2015-05-01

    Giving signal is a way of informing other road users, especially to the conflicting drivers, the intention of a driver to change his/her movement course. Other users are exposed to hazard situation and risks of accident if the driver who changes his/her course failed to give signal as required. This paper describes the application of logistic regression model for the analysis of driver's signalling practices on multilane highways based on possible factors affecting driver's decision such as driver's gender, vehicle's type, vehicle's speed and traffic flow intensity. Data pertaining to the analysis of such factors were collected manually. More than 2000 drivers who have performed a lane changing manoeuvre while driving on two sections of multilane highways were observed. Finding from the study shows that relatively a large proportion of drivers failed to give any signals when changing lane. The result of the analysis indicates that although the proportion of the drivers who failed to provide signal prior to lane changing manoeuvre is high, the degree of compliances of the female drivers is better than the male drivers. A binary logistic model was developed to represent the probability of a driver to provide signal indication prior to lane changing manoeuvre. The model indicates that driver's gender, type of vehicle's driven, speed of vehicle and traffic volume influence the driver's decision to provide a signal indication prior to a lane changing manoeuvre on a multilane urban highway. In terms of types of vehicles driven, about 97% of motorcyclists failed to comply with the signal indication requirement. The proportion of non-compliance drivers under stable traffic flow conditions is much higher than when the flow is relatively heavy. This is consistent with the data which indicates a high degree of non-compliances when the average speed of the traffic stream is relatively high.

  12. Effects of multiple enzyme–substrate interactions in basic units of cellular signal processing

    International Nuclear Information System (INIS)

    Seaton, D D; Krishnan, J

    2012-01-01

    Covalent modification cycles are a ubiquitous feature of cellular signalling networks. In these systems, the interaction of an active enzyme with the unmodified form of its substrate is essential for signalling to occur. However, this interaction is not necessarily the only enzyme–substrate interaction possible. In this paper, we analyse the behaviour of a basic model of signalling in which additional, non-essential enzyme–substrate interactions are possible. These interactions include those between the inactive form of an enzyme and its substrate, and between the active form of an enzyme and its product. We find that these additional interactions can result in increased sensitivity and biphasic responses, respectively. The dynamics of the responses are also significantly altered by the presence of additional interactions. Finally, we evaluate the consequences of these interactions in two variations of our basic model, involving double modification of substrate and scaffold-mediated signalling, respectively. We conclude that the molecular details of protein–protein interactions are important in determining the signalling properties of enzymatic signalling pathways. (paper)

  13. Downstream flow top width prediction in a river system | Choudhury ...

    African Journals Online (AJOL)

    ANFIS, ARIMA and Hybrid Multiple Inflows Muskingum models (HMIM) were applied to simulate and forecast downstream discharge and flow top widths in a river system. The ANFIS model works on a set of linguistic rules while the ARIMA model uses a set of past values to predict the next value in a time series. The HMIM ...

  14. Integrated QSAR study for inhibitors of Hedgehog Signal Pathway against multiple cell lines:a collaborative filtering method.

    Science.gov (United States)

    Gao, Jun; Che, Dongsheng; Zheng, Vincent W; Zhu, Ruixin; Liu, Qi

    2012-07-31

    The Hedgehog Signaling Pathway is one of signaling pathways that are very important to embryonic development. The participation of inhibitors in the Hedgehog Signal Pathway can control cell growth and death, and searching novel inhibitors to the functioning of the pathway are in a great demand. As the matter of fact, effective inhibitors could provide efficient therapies for a wide range of malignancies, and targeting such pathway in cells represents a promising new paradigm for cell growth and death control. Current research mainly focuses on the syntheses of the inhibitors of cyclopamine derivatives, which bind specifically to the Smo protein, and can be used for cancer therapy. While quantitatively structure-activity relationship (QSAR) studies have been performed for these compounds among different cell lines, none of them have achieved acceptable results in the prediction of activity values of new compounds. In this study, we proposed a novel collaborative QSAR model for inhibitors of the Hedgehog Signaling Pathway by integration the information from multiple cell lines. Such a model is expected to substantially improve the QSAR ability from single cell lines, and provide useful clues in developing clinically effective inhibitors and modifications of parent lead compounds for target on the Hedgehog Signaling Pathway. In this study, we have presented: (1) a collaborative QSAR model, which is used to integrate information among multiple cell lines to boost the QSAR results, rather than only a single cell line QSAR modeling. Our experiments have shown that the performance of our model is significantly better than single cell line QSAR methods; and (2) an efficient feature selection strategy under such collaborative environment, which can derive the commonly important features related to the entire given cell lines, while simultaneously showing their specific contributions to a specific cell-line. Based on feature selection results, we have proposed several

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

    Science.gov (United States)

    Liu, Hong Xiang; Ermilov, Alexandre; Grachtchouk, Marina; Li, Libo; Gumucio, Deborah L; Dlugosz, Andrzej A; Mistretta, Charalotte M

    2013-10-01

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

  16. Downstream behavior of fission products

    International Nuclear Information System (INIS)

    Johnson, I.; Farahat, M.K.; Settle, J.L.; Johnson, C.E.; Ritzman, R.

    1986-01-01

    The downstream behavior of fission products has been investigated by injecting mixtures of CsOH, CsI, and Te into a flowing steam/hydrogen stream and determining the physical and chemical changes that took place as the gaseous mixture flowed down a reaction duct on which a temperature gradient (1000 0 to 200 0 C) had been imposed. Deposition on the wall of the duct occurred by vapor condensation in the higher temperature regions and by aerosol deposition in the remainder of the duct. Reactions in the gas stream between CsOH and CsI and between CsOH and Te had an effect on the vapor condensation. The aerosol was characterized by the use of impingement tabs placed in the gas stream

  17. The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways.

    Science.gov (United States)

    Youns, Mаhmoud; Abdel Halim Hegazy, Wael

    2017-01-01

    Digestive cancers are major causes of mortality and morbidity worldwide. Fisetin, a naturally occurring flavonoid, has been previously shown anti-proliferative, anti-cancer, neuroprotective, and antioxidant activities. In our study, the anti-tumor activities in addition to regulatory effects of fisetin on some cancer cell lines were investigated. Data presented here showed that fisetin induces growth inhibition, and apoptosis in hepatic (HepG-2), colorectal (Caco-2) and pancreatic (Suit-2) cancer cell lines. Gene expression results showed that 1307 genes were significantly regulated in their expression in hepatic and pancreatic cell lines. 350 genes were commonly up-regulated and 353 genes were commonly down-regulated. Additionally, 604 genes were oppositely expressed in both tumor cells. CDK5 signaling, NRF2-mediated oxidative stress response, glucocorticoid signaling, and ERK/MAPK signaling were among most prominent signaling pathways modulating the growth inhibitory effects of fisetin on hepatic and pancreatic cancer cells. The present analysis showed, for the first time, that the anti-tumor effect of fisetin was mediated mainly through modulation of multiple signaling pathways and via activation of CDKN1A, SEMA3E, GADD45B and GADD45A and down-regulation of TOP2A, KIF20A, CCNB2 and CCNB1 genes.

  18. The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways.

    Directory of Open Access Journals (Sweden)

    Mаhmoud Youns

    Full Text Available Digestive cancers are major causes of mortality and morbidity worldwide. Fisetin, a naturally occurring flavonoid, has been previously shown anti-proliferative, anti-cancer, neuroprotective, and antioxidant activities. In our study, the anti-tumor activities in addition to regulatory effects of fisetin on some cancer cell lines were investigated. Data presented here showed that fisetin induces growth inhibition, and apoptosis in hepatic (HepG-2, colorectal (Caco-2 and pancreatic (Suit-2 cancer cell lines. Gene expression results showed that 1307 genes were significantly regulated in their expression in hepatic and pancreatic cell lines. 350 genes were commonly up-regulated and 353 genes were commonly down-regulated. Additionally, 604 genes were oppositely expressed in both tumor cells. CDK5 signaling, NRF2-mediated oxidative stress response, glucocorticoid signaling, and ERK/MAPK signaling were among most prominent signaling pathways modulating the growth inhibitory effects of fisetin on hepatic and pancreatic cancer cells. The present analysis showed, for the first time, that the anti-tumor effect of fisetin was mediated mainly through modulation of multiple signaling pathways and via activation of CDKN1A, SEMA3E, GADD45B and GADD45A and down-regulation of TOP2A, KIF20A, CCNB2 and CCNB1 genes.

  19. The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways

    Science.gov (United States)

    Youns, Mаhmoud; Abdel Halim Hegazy, Wael

    2017-01-01

    Digestive cancers are major causes of mortality and morbidity worldwide. Fisetin, a naturally occurring flavonoid, has been previously shown anti-proliferative, anti-cancer, neuroprotective, and antioxidant activities. In our study, the anti-tumor activities in addition to regulatory effects of fisetin on some cancer cell lines were investigated. Data presented here showed that fisetin induces growth inhibition, and apoptosis in hepatic (HepG-2), colorectal (Caco-2) and pancreatic (Suit-2) cancer cell lines. Gene expression results showed that 1307 genes were significantly regulated in their expression in hepatic and pancreatic cell lines. 350 genes were commonly up-regulated and 353 genes were commonly down-regulated. Additionally, 604 genes were oppositely expressed in both tumor cells. CDK5 signaling, NRF2-mediated oxidative stress response, glucocorticoid signaling, and ERK/MAPK signaling were among most prominent signaling pathways modulating the growth inhibitory effects of fisetin on hepatic and pancreatic cancer cells. The present analysis showed, for the first time, that the anti-tumor effect of fisetin was mediated mainly through modulation of multiple signaling pathways and via activation of CDKN1A, SEMA3E, GADD45B and GADD45A and down-regulation of TOP2A, KIF20A, CCNB2 and CCNB1 genes. PMID:28052097

  20. Integrating Multiple Types of Data for Signaling Research: Challenges and Opportunities

    Energy Technology Data Exchange (ETDEWEB)

    Wiley, H. S.

    2011-02-15

    New technologies promise to provide unprecedented amounts of information that can provide a foundation for creating predictive models of cell signaling pathways. To be useful, however, this information must be integrated into a coherent framework. In addition, the sheer volume of data gathered from the new technologies requires computational approaches for its analysis. Unfortunately, there are many barriers to data integration and analysis, mostly because of a lack of adequate data standards and their inconsistent use by scientists. However, solving the fundamental issues of data sharing will enable the investigation of entirely new areas of cell signaling research.

  1. Zebrafish con/disp1 reveals multiple spatiotemporal requirements for Hedgehog-signaling in craniofacial development

    Directory of Open Access Journals (Sweden)

    Schwend Tyler

    2009-11-01

    Full Text Available Abstract Background The vertebrate head skeleton is derived largely from cranial neural crest cells (CNCC. Genetic studies in zebrafish and mice have established that the Hedgehog (Hh-signaling pathway plays a critical role in craniofacial development, partly due to the pathway's role in CNCC development. Disruption of the Hh-signaling pathway in humans can lead to the spectral disorder of Holoprosencephaly (HPE, which is often characterized by a variety of craniofacial defects including midline facial clefting and cyclopia 12. Previous work has uncovered a role for Hh-signaling in zebrafish dorsal neurocranium patterning and chondrogenesis, however Hh-signaling mutants have not been described with respect to the ventral pharyngeal arch (PA skeleton. Lipid-modified Hh-ligands require the transmembrane-spanning receptor Dispatched 1 (Disp1 for proper secretion from Hh-synthesizing cells to the extracellular field where they act on target cells. Here we study chameleon mutants, lacking a functional disp1(con/disp1. Results con/disp1 mutants display reduced and dysmorphic mandibular and hyoid arch cartilages and lack all ceratobranchial cartilage elements. CNCC specification and migration into the PA primorida occurs normally in con/disp1 mutants, however disp1 is necessary for post-migratory CNCC patterning and differentiation. We show that disp1 is required for post-migratory CNCC to become properly patterned within the first arch, while the gene is dispensable for CNCC condensation and patterning in more posterior arches. Upon residing in well-formed pharyngeal epithelium, neural crest condensations in the posterior PA fail to maintain expression of two transcription factors essential for chondrogenesis, sox9a and dlx2a, yet continue to robustly express other neural crest markers. Histology reveals that posterior arch residing-CNCC differentiate into fibrous-connective tissue, rather than becoming chondrocytes. Treatments with Cyclopamine, to

  2. PDGFRα depletion attenuates glioblastoma stem cells features by modulation of STAT3, RB1 and multiple oncogenic signals.

    Science.gov (United States)

    Cenciarelli, Carlo; Marei, Hany E; Felsani, Armando; Casalbore, Patrizia; Sica, Gigliola; Puglisi, Maria Ausiliatrice; Cameron, Angus J M; Olivi, Alessandro; Mangiola, Annunziato

    2016-08-16

    Platelet derived growth factor receptors (PDGFRs) play an important role in tumor pathogenesis, and they are frequently overexpressed in glioblastoma (GBM). Earlier we have shown a higher protein expression of PDGFR isoforms (α and β) in peritumoral-tissue derived cancer stem cells (p-CSC) than in tumor core (c-CSC) of several GBM affected patients. In the current study, in order to assess the activity of PDGFRα/PDGF-AA signaling axis, we performed time course experiments to monitor the effects of exogenous PDGF-AA on the expression of downstream target genes in c-CSC vs p-CSC. Interestingly, in p-CSC we detected the upregulation of Y705-phosphorylated Stat3, concurrent with a decrement of Rb1 protein in its active state, within minutes of PDGF-AA addition. This finding prompted us to elucidate the role of PDGFRα in self-renewal, invasion and differentiation in p-CSC by using short hairpin RNA depletion of PDGFRα expression. Notably, in PDGFRα-depleted cells, protein analysis revealed attenuation of stemness-related and glial markers expression, alongside early activation of the neuronal marker MAP2a/b that correlated with the induction of tumor suppressor Rb1. The in vitro reduction of the invasive capacity of PDGFRα-depleted CSC as compared to parental cells correlated with the downmodulation of markers of epithelial-mesenchymal transition phenotype and angiogenesis. Surprisingly, we observed the induction of anti-apoptotic proteins and compensatory oncogenic signals such as EDN1, EDNRB, PRKCB1, PDGF-C and PDGF-D. To conclude, we hypothesize that the newly discovered PDGFRα/Stat3/Rb1 regulatory axis might represent a potential therapeutic target for GBM treatment.

  3. Fiber nonlinearity compensation of an 8-channel WDM PDM-QPSK signal using multiple phase conjugations

    DEFF Research Database (Denmark)

    Hu, Hao; Jopson, R. M.; Dinu, M.

    2013-01-01

    We demonstrate compensation of fiber nonlinearities using optical phase conjugation of an 8-chamiel WDM 32-Gbaud PDM QPSK signal. Conjugating phase every 600 km in a fiber loop enabled a 6000 km transmission over True Wave fiber. © 2013 Optical Society of America....

  4. Use of multiple singular value decompositions to analyze complex intracellular calcium ion signals

    KAUST Repository

    Martinez, Josue G.; Huang, Jianhua Z.; Burghardt, Robert C.; Barhoumi, Rola; Carroll, Raymond J.

    2009-01-01

    ) to extract the signals from such movies, in a way that is semi-automatic and tuned closely to the actual data and their many complexities. These complexities include the following. First, the images themselves are of no interest: all interest focuses

  5. Climatic signals in multiple highly resolved stable isotope records from Greenland

    DEFF Research Database (Denmark)

    Vinther, Bo Møllesøe; Dahl-Jensen, Dorthe; Johnsen, Sigfus Johann

    2010-01-01

    are found to correspond better with winter stable isotope data than with summer or annual average stable isotope data it is suggested that a strong local Greenland temperature signal can be extracted from the winter stable isotope data even on centennial to millennial time scales. Udgivelsesdato: Feb....

  6. A novel Modulation Topology for Power Converters utilizing Multiple Carrier Signals

    DEFF Research Database (Denmark)

    Knott, Arnold; Pfaffinger, Gerhard; Andersen, Michael Andreas E.

    2008-01-01

    Power converters are known to generate spectral components in the range of interest of electromagnetic compatibility measurements. Common approaches to manipulate some selected components in these frequency ranges are shown here. These approaches add components to the input signal of the modulato...

  7. Multiple roles of the prostaglandin D2 signaling pathway in reproduction.

    Science.gov (United States)

    Rossitto, Moïra; Ujjan, Safdar; Poulat, Francis; Boizet-Bonhoure, Brigitte

    2015-01-01

    Prostaglandins signaling molecules are involved in numerous physiological processes. They are produced by several enzyme-limited reactions upon fatty acids, which are catalyzed by two cyclooxygenases and prostaglandin synthases. In particular, the prostaglandins E2 (PGE2), D2 (PGD2), and F2 (PGF2 α) have been shown to be involved in female reproductive mechanisms. Furthermore, widespread expression of lipocalin- and hematopoietic-PGD2 synthases in the male reproductive tract supports the purported roles of PGD2 in the development of both embryonic and adult testes, sperm maturation, and spermatogenesis. In this review, we summarize the putative roles of PGD2 signaling and the roles of both PGD2 synthases in testicular formation and function. We review the data reporting the involvement of PGD2 signaling in the differentiation of Sertoli and germ cells of the embryonic testis. Furthermore, we discuss the roles of lipocalin-PGD2 synthase in steroidogenesis and spermatogenesis, in terms of lipid molecule transport and PGD2 production. Finally, we discuss the hypothesis that PGD2 signaling may be affected in certain reproductive diseases, such as infertility, cryptorchidism, and testicular cancer. © 2015 Society for Reproduction and Fertility.

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

    Science.gov (United States)

    Vergallo, P.; Lay-Ekuakille, A.

    2013-08-01

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

  9. Ion energy characteristics downstream of a high power helicon

    International Nuclear Information System (INIS)

    Prager, James; Winglee, Robert; Ziemba, Tim; Roberson, B Race; Quetin, Gregory

    2008-01-01

    The High Power Helicon eXperiment operates at higher powers (37 kW) and lower background neutral pressure than other helicon experiments. The ion velocity distribution function (IVDF) has been measured at multiple locations downstream of the helicon source and a mach 3-6 flowing plasma was observed. The helicon antenna has a direct effect in accelerating the plasma downstream of the source. Also, the IVDF is affected by the cloud of neutrals from the initial gas puff, which keeps the plasma speed low at early times near the source.

  10. Ion energy characteristics downstream of a high power helicon

    Energy Technology Data Exchange (ETDEWEB)

    Prager, James; Winglee, Robert; Ziemba, Tim; Roberson, B Race; Quetin, Gregory [University of Washington, Johnson Hall 070, Box 351310, 4000 15th Avenue NE, Seattle, WA 98195-1310 (United States)], E-mail: jprager@u.washington.edu

    2008-05-01

    The High Power Helicon eXperiment operates at higher powers (37 kW) and lower background neutral pressure than other helicon experiments. The ion velocity distribution function (IVDF) has been measured at multiple locations downstream of the helicon source and a mach 3-6 flowing plasma was observed. The helicon antenna has a direct effect in accelerating the plasma downstream of the source. Also, the IVDF is affected by the cloud of neutrals from the initial gas puff, which keeps the plasma speed low at early times near the source.

  11. The representation of inflammatory signals in the brain: A model for subjective fatigue in multiple sclerosis

    NARCIS (Netherlands)

    Hanken, K.; Eling, P.A.T.M.; Hildebrandt, H.

    2014-01-01

    In multiple sclerosis (MS) patients, fatigue is rated as one of the most common and disabling symptoms. However, the pathophysiology underlying this fatigue is not yet clear. Several lines of evidence suggest that immunological factors, such as elevated levels of pro-inflammatory cytokines, may

  12. Long-term music training tunes how the brain temporally binds signals from multiple senses

    OpenAIRE

    Lee, HweeLing; Noppeney, Uta

    2011-01-01

    Practicing a musical instrument is a rich multisensory experience involving the integration of visual, auditory, and tactile inputs with motor responses. This combined psychophysics–fMRI study used the musician's brain to investigate how sensory-motor experience molds temporal binding of auditory and visual signals. Behaviorally, musicians exhibited a narrower temporal integration window than nonmusicians for music but not for speech. At the neural level, musicians showed increased audiovisua...

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

    OpenAIRE

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

    2016-01-01

    In the year 2000, Hanahan and Weinberg (1) defined the six Hallmarks of Cancer as: self-sufficiency in growth signals, evasion of apoptosis, insensitivity to antigrowth mechanisms, tissue invasion and metastasis, limitless replicative potential, and sustained angiogenesis. Eleven years later, two new Hallmarks were added to the list (avoiding immune destruction and reprograming energy metabolism) and two new tumor characteristics (tumor-promoting inflammation and genome instability and mutati...

  14. A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway.

    Science.gov (United States)

    Salašová, Alena; Yokota, Chika; Potěšil, David; Zdráhal, Zbyněk; Bryja, Vítězslav; Arenas, Ernest

    2017-07-11

    /PCP signaling pathway through its interaction to multiple WNT/PCP components. We suggest that LRRK2 regulates the balance between WNT/β-catenin and WNT/PCP signaling, depending on the binding partners. Since this balance is crucial for homeostasis of midbrain dopaminergic neurons, we hypothesize that its alteration may contribute to the pathophysiology of Parkinson's disease.

  15. Intramolecular 13C analysis of tree rings provides multiple plant ecophysiology signals covering decades.

    Science.gov (United States)

    Wieloch, Thomas; Ehlers, Ina; Yu, Jun; Frank, David; Grabner, Michael; Gessler, Arthur; Schleucher, Jürgen

    2018-03-22

    Measurements of carbon isotope contents of plant organic matter provide important information in diverse fields such as plant breeding, ecophysiology, biogeochemistry and paleoclimatology. They are currently based on 13 C/ 12 C ratios of specific, whole metabolites, but we show here that intramolecular ratios provide higher resolution information. In the glucose units of tree-ring cellulose of 12 tree species, we detected large differences in 13 C/ 12 C ratios (>10‰) among carbon atoms, which provide isotopically distinct inputs to major global C pools, including wood and soil organic matter. Thus, considering position-specific differences can improve characterisation of soil-to-atmosphere carbon fluxes and soil metabolism. In a Pinus nigra tree-ring archive formed from 1961 to 1995, we found novel 13 C signals, and show that intramolecular analysis enables more comprehensive and precise signal extraction from tree rings, and thus higher resolution reconstruction of plants' responses to climate change. Moreover, we propose an ecophysiological mechanism for the introduction of a 13 C signal, which links an environmental shift to the triggered metabolic shift and its intramolecular 13 C signature. In conclusion, intramolecular 13 C analyses can provide valuable new information about long-term metabolic dynamics for numerous applications.

  16. Insulin regulates multiple signaling pathways leading to monocyte/macrophage chemotaxis into the wound tissue

    Directory of Open Access Journals (Sweden)

    Yan Liu

    2018-01-01

    Full Text Available Wound healing is a complex process that involves sequential phases that overlap in time and space and affect each other dynamically at the gene and protein levels. We previously showed that insulin accelerates wound healing by stimulating faster and regenerative healing. One of the processes that insulin stimulates is an increase in monocyte/macrophage chemotaxis. In this study, we performed experiments in vivo and in vitro to elucidate the signaling transduction pathways that are involved in insulin-induced monocyte/macrophage chemotaxis. We found that insulin stimulates THP-1 cell chemotaxis in a dose-dependent and insulin receptor-dependent manner. We also show that the kinases PI3K-Akt, SPAK/JNK, and p38 MAPK are key molecules in the insulin-induced signaling pathways that lead to chemoattraction of the THP-1 cell. Furthermore, both PI3K-Akt and SPAK/JNK signaling involve Rac1 activation, an important molecule in regulating cell motility. Indeed, topical application of Rac1 inhibitor at an early stage during the healing process caused delayed and impaired healing even in the presence of insulin. These results delineate cell and molecular mechanisms involved in insulin-induced chemotaxis of monocyte/macrophage, cells that are critical for proper healing.

  17. A downstream voyage with mercury

    Science.gov (United States)

    Heinz, Gary

    2016-01-01

    Retrospective essay for the Bulletin of Environmental Contamination and Toxicology.As I look back on my paper, “Effects of Low Dietary Levels of Methyl Mercury on Mallard Reproduction,” published in 1974 in the Bulletin of Environmental Contamination and Toxicology, a thought sticks in my mind. I realize just how much my mercury research was not unlike a leaf in a stream, carried this way and that, sometimes stalled in an eddy, restarted, and carried downstream at a pace and path that was not completely under my control. I was hired in 1969 by the Patuxent Wildlife Research Center to study the effects of environmental pollutants on the behavior of wildlife. A colleague was conducting a study on the reproductive effects of methylmercury on mallards (Anas platyrhynchos), and he offered to give me some of the ducklings. I conducted a pilot study, testing how readily ducklings approached a tape-recorded maternal call. Sample sizes were small, but the results suggested that ducklings from mercury-treated parents behaved differently than controls. That’s how I got into mercury research—pretty much by chance.

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

    Science.gov (United States)

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

    2016-01-15

    The DELLA family of transcription regulators functions as master growth repressors in plants by inhibiting phytohormone gibberellin (GA) signaling in response to developmental and environmental cues. DELLAs also play a central role in mediating cross-talk between GA and other signaling pathways via antagonistic direct interactions with key transcription factors. However, how these crucial protein-protein interactions can be dynamically regulated during plant development remains unclear. Here, we show that DELLAs are modified by the O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) SECRET AGENT (SEC) in Arabidopsis. O-GlcNAcylation of the DELLA protein REPRESSOR OF ga1-3 (RGA) inhibits RGA binding to four of its interactors-PHYTOCHROME-INTERACTING FACTOR3 (PIF3), PIF4, JASMONATE-ZIM DOMAIN1, and BRASSINAZOLE-RESISTANT1 (BZR1)-that are key regulators in light, jasmonate, and brassinosteroid signaling pathways, respectively. Consistent with this, the sec-null mutant displayed reduced responses to GA and brassinosteroid and showed decreased expression of several common target genes of DELLAs, BZR1, and PIFs. Our results reveal a direct role of OGT in repressing DELLA activity and indicate that O-GlcNAcylation of DELLAs provides a fine-tuning mechanism in coordinating multiple signaling activities during plant development. © 2016 Zentella et al.; Published by Cold Spring Harbor Laboratory Press.

  19. The high risk HPV16 L2 minor capsid protein has multiple transport signals that mediate its nucleocytoplasmic traffic

    International Nuclear Information System (INIS)

    Mamoor, Shahan; Onder, Zeynep; Karanam, Balasubramanyam; Kwak, Kihyuck; Bordeaux, Jennifer; Crosby, Lauren; Roden, Richard B.S.; Moroianu, Junona

    2012-01-01

    In this study we examined the transport signals contributing to HPV16 L2 nucleocytoplasmic traffic using confocal microscopy analysis of enhanced green fluorescent protein—L2 (EGFP-L2) fusions expressed in HeLa cells. We confirmed that both nuclear localization signals (NLSs), the nNLS (1MRHKRSAKRTKR12) and cNLS (456RKRRKR461), previously characterized in vitro (Darshan et al., 2004), function independently in vivo. We discovered that a middle region rich in arginine residues (296SRRTGIRYSRIGNKQTLRTRS316) functions as a nuclear retention sequence (NRS), as mutagenesis of critical arginine residues within this NRS reduced the fraction of L2 in the nucleus despite the presence of both NLSs. Significantly, the infectivity of HPV16 pseudoviruses containing either RR297AA or RR297EE within the L2 NRS was strongly reduced both in HaCaT cells and in a murine challenge model. Experiments using Ratjadone A nuclear export inhibitor and mutation-localization analysis lead to the discovery of a leucine-rich nuclear export signal ( 462 LPYFFSDVSL) mediating 16L2 nuclear export. These data indicate that HPV16 L2 nucleocytoplasmic traffic is dependent on multiple functional transport signals.

  20. The high risk HPV16 L2 minor capsid protein has multiple transport signals that mediate its nucleocytoplasmic traffic

    Energy Technology Data Exchange (ETDEWEB)

    Mamoor, Shahan; Onder, Zeynep [Biology Department, Boston College, Chestnut Hill, MA 02467 (United States); Karanam, Balasubramanyam; Kwak, Kihyuck [Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231 (United States); Bordeaux, Jennifer; Crosby, Lauren [Biology Department, Boston College, Chestnut Hill, MA 02467 (United States); Roden, Richard B.S. [Department of Pathology, The Johns Hopkins University, Baltimore, MD 21231 (United States); Moroianu, Junona, E-mail: moroianu@bc.edu [Biology Department, Boston College, Chestnut Hill, MA 02467 (United States)

    2012-01-20

    In this study we examined the transport signals contributing to HPV16 L2 nucleocytoplasmic traffic using confocal microscopy analysis of enhanced green fluorescent protein-L2 (EGFP-L2) fusions expressed in HeLa cells. We confirmed that both nuclear localization signals (NLSs), the nNLS (1MRHKRSAKRTKR12) and cNLS (456RKRRKR461), previously characterized in vitro (Darshan et al., 2004), function independently in vivo. We discovered that a middle region rich in arginine residues (296SRRTGIRYSRIGNKQTLRTRS316) functions as a nuclear retention sequence (NRS), as mutagenesis of critical arginine residues within this NRS reduced the fraction of L2 in the nucleus despite the presence of both NLSs. Significantly, the infectivity of HPV16 pseudoviruses containing either RR297AA or RR297EE within the L2 NRS was strongly reduced both in HaCaT cells and in a murine challenge model. Experiments using Ratjadone A nuclear export inhibitor and mutation-localization analysis lead to the discovery of a leucine-rich nuclear export signal ({sub 462}LPYFFSDVSL) mediating 16L2 nuclear export. These data indicate that HPV16 L2 nucleocytoplasmic traffic is dependent on multiple functional transport signals.

  1. An ecological method for the sampling of nonverbal signalling behaviours of young children with profound and multiple learning disabilities (PMLD).

    Science.gov (United States)

    Atkin, Keith; Lorch, Marjorie Perlman

    2016-08-01

    Profound and multiple learning disabilities (PMLD) are a complex range of disabilities that affect the general health and well-being of the individual and their capacity to interact and learn. We developed a new methodology to capture the non-symbolic signalling behaviours of children with PMLD within the context of a face-to-face interaction with a caregiver to provide analysis at a micro-level of descriptive detail incorporating the use of the ELAN digital video software. The signalling behaviours of participants in a natural, everyday interaction can be better understood with the use of this innovation in methodology, which is predicated on the ecology of communication. Recognition of the developmental ability of the participants is an integral factor within that ecology. The method presented establishes an advanced account of the modalities through which a child affected by PMLD is able to communicate.

  2. DOA Estimation of Low Altitude Target Based on Adaptive Step Glowworm Swarm Optimization-multiple Signal Classification Algorithm

    Directory of Open Access Journals (Sweden)

    Zhou Hao

    2015-06-01

    Full Text Available The traditional MUltiple SIgnal Classification (MUSIC algorithm requires significant computational effort and can not be employed for the Direction Of Arrival (DOA estimation of targets in a low-altitude multipath environment. As such, a novel MUSIC approach is proposed on the basis of the algorithm of Adaptive Step Glowworm Swarm Optimization (ASGSO. The virtual spatial smoothing of the matrix formed by each snapshot is used to realize the decorrelation of the multipath signal and the establishment of a fullorder correlation matrix. ASGSO optimizes the function and estimates the elevation of the target. The simulation results suggest that the proposed method can overcome the low altitude multipath effect and estimate the DOA of target readily and precisely without radar effective aperture loss.

  3. Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells

    DEFF Research Database (Denmark)

    Zub, Kamila Anna; Sousa, Mirta Mittelstedt Leal de; Sarno, Antonio

    2015-01-01

    of the AKR1C family involved in prostaglandin synthesis contribute to the resistant phenotype. Finally, selected metabolic and oxidative stress response enzymes were targeted by inhibitors, several of which displayed a selective cytotoxicity against the melphalan-resistant cells and should be further...... and pathways not previously associated with melphalan resistance in multiple myeloma cells, including a metabolic switch conforming to the Warburg effect (aerobic glycolysis), and an elevated oxidative stress response mediated by VEGF/IL8-signaling. In addition, up-regulated aldo-keto reductase levels...

  4. Trichurs suis ova theraphy in relapsing multiple sclerosis is safe but without signals of beneficial effect

    DEFF Research Database (Denmark)

    Voldsgaard, A.; Bager, P.; Garde, E.

    2015-01-01

    revealed 6 new or enlarged T2 lesions in the run-in period, 7 lesions in the early period and 21 lesions in the late treatment period. Two patients suffered a relapse before treatment and two during treatment. Eight patients developed eosinophilia. The expression of cytokines and transcription factors did...... not change. CONCLUSIONS: In a small group of relapsing multiple sclerosis patients, Trichuris suis oral therapy was well tolerated but without beneficial effect....

  5. Multiple interactions between maternally-activated signalling pathways control Xenopus nodal-related genes.

    Science.gov (United States)

    Rex, Maria; Hilton, Emma; Old, Robert

    2002-03-01

    We have investigated the induction of the six Xenopus nodal-related genes, Xnr1-Xnr6, by maternal determinants. The beta-catenin pathway was modelled by stimulation using Xwnt8, activin-like signalling was modelled by activin, and VegT action was studied by overexpression in animal cap explants. Combinations of factors were examined, and previously unrecognised interactions were revealed in animal caps and whole embryos. For the induction of Xnr5 and Xnr6 in whole embryos, using a beta-catenin antisense morpholino oligonucleotide or a dominant negative XTcf3, we have demonstrated an absolute permissive requirement for the beta-catenin/Tcf pathway, in addition to the requirement for VegT action. In animal caps Xnr5 and Xnr6 are induced in response to VegT overexpression, and this induction is dependent upon the concomitant activation of the beta-catenin pathway that VegT initiates in animal caps. For the induction of Xnr3, VegT interacts negatively so as to inhibit the induction otherwise observed with wnt-signalling alone. The negative effect of VegT is not the result of a general inhibition of wnt-signalling, and does not result from an inhibition of wnt-induced siamois expression. A 294 bp proximal promoter fragment of the Xnr3 gene is sufficient to mediate the negative effect of VegT. Further experiments, employing cycloheximide to examine the dependence of Xnr gene expression upon proteins translated after the mid-blastula stage, demonstrated that Xnrs 4, 5 and 6 are 'primary' Xnr genes whose expression in the late blastula is solely dependent upon factors present before the mid-blastula stage.

  6. Multiple signal amplified electrochemiluminescent immunoassay for brombuterol detection using gold nanoparticles and polyamidoamine dendrimers-silver nanoribbon

    Energy Technology Data Exchange (ETDEWEB)

    Dong, Tiantian; Hu, Liuyi; Zhao, Kang; Deng, Anping, E-mail: denganping@suda.edu.cn; Li, Jianguo, E-mail: lijgsd@suda.edu.cn

    2016-11-16

    Electrochemiluminescent (ECL) immunosensor with multiple signal amplification was designed based on gold nanoparticles (AuNPs), polyamidoamine dendrimers (PAMAM) and silver-cysteine hybrid nanoribbon (SNR). Low toxic L-cysteine capped CdSe QDs was chosen as the ECL signal probe. To verify the proposed ultrasensitive ECL immunosensor for β-adrenergic agonists (β-AA), we detected Brombuterol (Brom) as a proof-of-principle analyte. Therein, AuNPs as the substrate can simplify the experiment process, accelerate the electron transfer rate, and carry more coating antigen (Ag-OVA) to enlarge ECL signal. On one hand, SNR on the surface of electrode can avoid the aggregation of AuNPs, and SNR-PAMAM-AuNPs also can be acted as a good accelerator for electron transfer. On the other hand, PAMAM (16 -NH{sub 2}) functionalized SNR (SNR-PAMAM) with numerous amino groups could be employed to bond abundant actived QDs to further amplify ECL signal. The new immunosensor can offer a simple, reliable, rapid, and selective detection for Brom, which have a dynamic range of 0.005–700 ng mL{sup −1} with a low detection limit at 1.5 pg mL{sup −1}. The proposed biosensor will extend the application of nanomaterials in ECL immunoassays and open a new road for the detection of Brom and other β-AA in the future. - Highlights: • A multiple signal amplification ECL immunosensor of eco-friendly CdSe QDs for brombuterol determination was developed. • Besides substrates, AuNPs and PAMAM-SNR were creatively used to accelerate the electron transport between electrode and QDs. • SNR-PAMAM with numerous amino groups also could be employed to bond abundant actived QDs to amplify ECL signal. • Competitive immunoassay was performed with ECL to detect small molecules of brombuterol. • It provided a method for detecting Brom and enlarged the usage of QDs, AuNPs and SNR-PAMAM in ECL biosensing.

  7. Multiple signal amplified electrochemiluminescent immunoassay for brombuterol detection using gold nanoparticles and polyamidoamine dendrimers-silver nanoribbon

    International Nuclear Information System (INIS)

    Dong, Tiantian; Hu, Liuyi; Zhao, Kang; Deng, Anping; Li, Jianguo

    2016-01-01

    Electrochemiluminescent (ECL) immunosensor with multiple signal amplification was designed based on gold nanoparticles (AuNPs), polyamidoamine dendrimers (PAMAM) and silver-cysteine hybrid nanoribbon (SNR). Low toxic L-cysteine capped CdSe QDs was chosen as the ECL signal probe. To verify the proposed ultrasensitive ECL immunosensor for β-adrenergic agonists (β-AA), we detected Brombuterol (Brom) as a proof-of-principle analyte. Therein, AuNPs as the substrate can simplify the experiment process, accelerate the electron transfer rate, and carry more coating antigen (Ag-OVA) to enlarge ECL signal. On one hand, SNR on the surface of electrode can avoid the aggregation of AuNPs, and SNR-PAMAM-AuNPs also can be acted as a good accelerator for electron transfer. On the other hand, PAMAM (16 -NH_2) functionalized SNR (SNR-PAMAM) with numerous amino groups could be employed to bond abundant actived QDs to further amplify ECL signal. The new immunosensor can offer a simple, reliable, rapid, and selective detection for Brom, which have a dynamic range of 0.005–700 ng mL"−"1 with a low detection limit at 1.5 pg mL"−"1. The proposed biosensor will extend the application of nanomaterials in ECL immunoassays and open a new road for the detection of Brom and other β-AA in the future. - Highlights: • A multiple signal amplification ECL immunosensor of eco-friendly CdSe QDs for brombuterol determination was developed. • Besides substrates, AuNPs and PAMAM-SNR were creatively used to accelerate the electron transport between electrode and QDs. • SNR-PAMAM with numerous amino groups also could be employed to bond abundant actived QDs to amplify ECL signal. • Competitive immunoassay was performed with ECL to detect small molecules of brombuterol. • It provided a method for detecting Brom and enlarged the usage of QDs, AuNPs and SNR-PAMAM in ECL biosensing.

  8. Rare earth industries: Downstream business

    International Nuclear Information System (INIS)

    2011-01-01

    The value chain of the rare earths business involves mining, extraction, processing, refining and the manufacture of an extensive range of downstream products which find wide applications in such industries including aerospace, consumer electronics, medical, military, automotive, renewable wind and solar energy and telecommunications. In fact the entire gamut of the high-tech industries depends on a sustainable supply of rare earths elements. The explosive demand in mobile phones is an excellent illustration of the massive potential that the rare earths business offers. In a matter of less than 20 years, the number of cell phones worldwide has reached a staggering 5 billion. Soon, going by the report of their growth in sales, the world demand for cell phones may even exceed the global population. Admittedly, the rare earths business does pose certain risks. Top among the risks are the health and safety risks. The mining, extraction and refining of rare earths produce residues and wastes which carry health and safety risks. The residues from the extraction and refining are radioactive, while their effluent waste streams do pose pollution risks to the receiving rivers and waterways. But, as clearly elaborated in a recent report by IAEA experts, there are technologies and systems available to efficiently mitigate such risks. The risks are Rare Earth manageable. However, it is crucial that the risk and waste management procedures are strictly followed and adhered to. This is where effective monitoring and surveillance throughout the life of all such rare earths facilities is crucial. Fortunately, Malaysia's regulatory standards on rare earths follow international standards. In some areas, Malaysia's regulatory regime is even more stringent than the international guidelines. (author)

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

    Science.gov (United States)

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

    2011-01-01

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

  10. Detection and localization of multiple short range targets using FMCW radar signal

    KAUST Repository

    Jardak, Seifallah

    2016-07-26

    In this paper, a 24 GHz frequency-modulated continuous wave radar is used to detect and localize both stationary and moving targets. Depending on the application, the implemented software offers different modes of operation. For example, it can simply output raw data samples for advanced offline processing or directly carry out a two dimensional fast Fourier transform to estimate the location and velocity of multiple targets. To suppress clutter and detect only moving targets, two methods based on the background reduction and the slow time processing techniques are implemented. A trade-off between the two methods is presented based on their performance and the required processing time. © 2016 IEEE.

  11. Noise Reduction Effect of Multiple-Sampling-Based Signal-Readout Circuits for Ultra-Low Noise CMOS Image Sensors

    Directory of Open Access Journals (Sweden)

    Shoji Kawahito

    2016-11-01

    Full Text Available This paper discusses the noise reduction effect of multiple-sampling-based signal readout circuits for implementing ultra-low-noise image sensors. The correlated multiple sampling (CMS technique has recently become an important technology for high-gain column readout circuits in low-noise CMOS image sensors (CISs. This paper reveals how the column CMS circuits, together with a pixel having a high-conversion-gain charge detector and low-noise transistor, realizes deep sub-electron read noise levels based on the analysis of noise components in the signal readout chain from a pixel to the column analog-to-digital converter (ADC. The noise measurement results of experimental CISs are compared with the noise analysis and the effect of noise reduction to the sampling number is discussed at the deep sub-electron level. Images taken with three CMS gains of two, 16, and 128 show distinct advantage of image contrast for the gain of 128 (noise(median: 0.29 e−rms when compared with the CMS gain of two (2.4 e−rms, or 16 (1.1 e−rms.

  12. Robust heart rate estimation from multiple asynchronous noisy sources using signal quality indices and a Kalman filter

    International Nuclear Information System (INIS)

    Li, Q; Mark, R G; Clifford, G D

    2008-01-01

    Physiological signals such as the electrocardiogram (ECG) and arterial blood pressure (ABP) in the intensive care unit (ICU) are often severely corrupted by noise, artifact and missing data, which lead to large errors in the estimation of the heart rate (HR) and ABP. A robust HR estimation method is described that compensates for these problems. The method is based upon the concept of fusing multiple signal quality indices (SQIs) and HR estimates derived from multiple electrocardiogram (ECG) leads and an invasive ABP waveform recorded from ICU patients. Physiological SQIs were obtained by analyzing the statistical characteristics of each waveform and their relationships to each other. HR estimates from the ECG and ABP are tracked with separate Kalman filters, using a modified update sequence based upon the individual SQIs. Data fusion of each HR estimate was then performed by weighting each estimate by the Kalman filters' SQI-modified innovations. This method was evaluated on over 6000 h of simultaneously acquired ECG and ABP from a 437 patient subset of ICU data by adding real ECG and realistic artificial ABP noise. The method provides an accurate HR estimate even in the presence of high levels of persistent noise and artifact, and during episodes of extreme bradycardia and tachycardia

  13. A Signal Detection Approach in a Multiple Cohort Study: Different Admission Tools Uniquely Select Different Successful Students

    Directory of Open Access Journals (Sweden)

    Linda van Ooijen-van der Linden

    2018-05-01

    Full Text Available Using multiple admission tools in university admission procedures is common practice. This is particularly useful if different admission tools uniquely select different subgroups of students who will be successful in university programs. A signal-detection approach was used to investigate the accuracy of Secondary School grade point average (SSGPA, an admission test score (ACS, and a non-cognitive score (NCS in uniquely selecting successful students. This was done for three consecutive first year cohorts of a broad psychology program. Each applicant's score on SSGPA, ACS, or NCS alone—and on seven combinations of these scores, all considered separate “admission tools”—was compared at two different (medium and high cut-off scores (criterion levels. Each of the tools selected successful students who were not selected by any of the other tools. Both sensitivity and specificity were enhanced by implementing multiple tools. The signal-detection approach distinctively provided useful information for decisions on admission instruments and cut-off scores.

  14. Targeting multiple pro-apoptotic signaling pathways with curcumin in prostate cancer cells

    Science.gov (United States)

    Rivera, Mariela; Ramos, Yanilda; Rodríguez-Valentín, Madeline; López-Acevedo, Sheila; Cubano, Luis A.; Zou, Jin; Zhang, Qiang; Wang, Guangdi

    2017-01-01

    Curcumin, an extract from the turmeric rhizome (Curcuma longa), is known to exhibit anti-inflammatory, antioxidant, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Accumulative data indicate that curcumin may induce cancer cell death. However, the detailed mechanism underlying its pro-apoptotic and anti-cancer effects remains to be elucidated. In the present study, we examined the signaling pathways triggered by curcumin, specifically, the exact molecular mechanisms of curcumin-induced apoptosis in highly metastatic human prostate cancer cells. The effect of curcumin was evaluated using for the first time in prostate cancer, a gel-free shotgun quantitative proteomic analysis coupled with Tandem Mass Tag isobaric labeling-based-signaling networks. Results were confirmed at the gene expression level by qRT-PCR and at the protein expression level by western blot and flow cytometry. Our findings revealed that curcumin induced an Endoplasmic Reticulum stress-mediated apoptosis in PC3. The mechanisms by which curcumin promoted cell death in these cells were associated with cell cycle arrest, increased reactive oxygen species, autophagy and the Unfolded Protein Response. Furthermore, the upregulation of ER stress was measured using key indicators of ER stress: Glucose-Regulated Protein 78, Inositol-Requiring Enzyme 1 alpha, Protein Disulfide isomerase and Calreticulin. Chronic ER stress induction was concomitant with the upregulation of pro-apoptotic markers (caspases 3,9,12) and Poly (ADP-ribose) polymerase. The downregulated proteins include anti-apoptotic and anti-tumor markers, supporting their curcumin-induced pro-apoptotic role in prostate cancer cells. Taken together, these data suggest that curcumin may serve as a promising anticancer agent by inducing a chronic ER stress mediated cell death and activation of cell cycle arrest, UPR, autophagy and oxidative stress responses. PMID:28628644

  15. Targeting multiple pro-apoptotic signaling pathways with curcumin in prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Mariela Rivera

    Full Text Available Curcumin, an extract from the turmeric rhizome (Curcuma longa, is known to exhibit anti-inflammatory, antioxidant, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Accumulative data indicate that curcumin may induce cancer cell death. However, the detailed mechanism underlying its pro-apoptotic and anti-cancer effects remains to be elucidated. In the present study, we examined the signaling pathways triggered by curcumin, specifically, the exact molecular mechanisms of curcumin-induced apoptosis in highly metastatic human prostate cancer cells. The effect of curcumin was evaluated using for the first time in prostate cancer, a gel-free shotgun quantitative proteomic analysis coupled with Tandem Mass Tag isobaric labeling-based-signaling networks. Results were confirmed at the gene expression level by qRT-PCR and at the protein expression level by western blot and flow cytometry. Our findings revealed that curcumin induced an Endoplasmic Reticulum stress-mediated apoptosis in PC3. The mechanisms by which curcumin promoted cell death in these cells were associated with cell cycle arrest, increased reactive oxygen species, autophagy and the Unfolded Protein Response. Furthermore, the upregulation of ER stress was measured using key indicators of ER stress: Glucose-Regulated Protein 78, Inositol-Requiring Enzyme 1 alpha, Protein Disulfide isomerase and Calreticulin. Chronic ER stress induction was concomitant with the upregulation of pro-apoptotic markers (caspases 3,9,12 and Poly (ADP-ribose polymerase. The downregulated proteins include anti-apoptotic and anti-tumor markers, supporting their curcumin-induced pro-apoptotic role in prostate cancer cells. Taken together, these data suggest that curcumin may serve as a promising anticancer agent by inducing a chronic ER stress mediated cell death and activation of cell cycle arrest, UPR, autophagy and oxidative stress responses.

  16. Insulin stimulates the expression of the SHARP-1 gene via multiple signaling pathways.

    Science.gov (United States)

    Takagi, K; Asano, K; Haneishi, A; Ono, M; Komatsu, Y; Yamamoto, T; Tanaka, T; Ueno, H; Ogawa, W; Tomita, K; Noguchi, T; Yamada, K

    2014-06-01

    The rat enhancer of split- and hairy-related protein-1 (SHARP-1) is a basic helix-loop-helix transcription factor. An issue of whether SHARP-1 is an insulin-inducible transcription factor was examined. Insulin rapidly increased the level of SHARP-1 mRNA both in vivo and in vitro. Then, signaling pathways involved with the increase of SHARP-1 mRNA by insulin were determined in H4IIE rat hepatoma cells. Pretreatments with LY294002, wortmannin, and staurosporine completely blocked the induction effect, suggesting the involvement of both phosphoinositide 3-kinase (PI 3-K) and protein kinase C (PKC) pathways. In fact, overexpression of a dominant negative form of atypical protein kinase C lambda (aPKCλ) significantly decreased the induction of the SHARP-1 mRNA. In addition, inhibitors for the small GTPase Rac or Jun N-terminal kinase (JNK) also blocked the induction of SHARP-1 mRNA by insulin. Overexpression of a dominant negative form of Rac1 prevented the activation by insulin. Furthermore, actinomycin D and cycloheximide completely blocked the induction of SHARP-1 mRNA by insulin. Finally, when a SHARP-1 expression plasmid was transiently transfected with various reporter plasmids into H4IIE cells, the promoter activity of PEPCK reporter plasmid was specifically decreased. Thus, we conclude that insulin induces the SHARP-1 gene expression at the transcription level via a both PI 3-K/aPKCλ/JNK- and a PI 3-K/Rac/JNK-signaling pathway; protein synthesis is required for this induction; and that SHARP-1 is a potential repressor of the PEPCK gene expression. © Georg Thieme Verlag KG Stuttgart · New York.

  17. Induction of functional Fc receptors in P388 leukemia cells. Requirement for multiple differentiation signals.

    Science.gov (United States)

    Cohen, D A; Stotelmyer, N L; Kaplan, A M

    1985-04-01

    The development of functional Fc receptors (FcR) during induced differentiation with the tumor promoter, phorbol myristate acetate (PMA), was studied in the murine tumor cell line, P388. PMA induced the appearance of FcR on the membranes of P388 cells as indicated by the binding of IgG-coated sheep red blood cells (IgG-SRBC). Concentrations of PMA as low as 1 ng/ml were sufficient to induce the expression of FcR as well as to inhibit cellular division and to induce adherence in the P388 tumor cell line; however, optimal FcR induction occurred at PMA concentrations of 10-100 ng/ml. Immunofluorescent analysis with heat-aggregated myeloma proteins indicated that PMA induced FcR which were capable of binding IgG2a and IgG2b immunoglobulins, but not IgG1. Adherence to a substratum was determined to be a second required signal for expression of FcR, since PMA induction of P388 tumor cells in teflon dishes failed to fully develop FcR and adherence of P388 cells to poly-L-lysine-coated culture dishes in the absence of PMA was insufficient for FcR expression. FcR which appeared after PMA induction were non-functional in the sense that membrane-bound IgG-SRBC were not ingested to any significant extent by the tumor cells. However, if FcR induction occurred in the presence conA-induced rat spleen cell culture supernatants, phagocytosis of membrane-bound erythrocytes occurred. These findings suggest that for the expression of FcR which are capable of particle internalization, at least three identifiable membrane-transmitted signals are required during differentiation.

  18. Small molecule inhibitors of the Candida albicans budded-to-hyphal transition act through multiple signaling pathways.

    Directory of Open Access Journals (Sweden)

    John Midkiff

    Full Text Available The ability of the pathogenic yeast Candida albicans to interconvert between budded and hyphal growth states, herein termed the budded-to-hyphal transition (BHT, is important for C. albicans development and virulence. The BHT is under the control of multiple cell signaling pathways that respond to external stimuli, including nutrient availability, high temperature, and pH. Previous studies identified 21 small molecules that could inhibit the C. albicans BHT in response to carbon limitation in Spider media. However, the studies herein show that the BHT inhibitors had varying efficacies in other hyphal-inducing media, reflecting their varying abilities to block signaling pathways associated with the different media. Chemical epistasis analyses suggest that most, but not all, of the BHT inhibitors were acting through either the Efg1 or Cph1 signaling pathways. Notably, the BHT inhibitor clozapine, a FDA-approved drug used to treat atypical schizophrenia by inhibiting G-protein-coupled dopamine receptors in the brain, and several of its functional analogs were shown to act at the level of the Gpr1 G-protein-coupled receptor. These studies are the first step in determining the target and mechanism of action of these BHT inhibitors, which may have therapeutic anti-fungal utility in the future.

  19. Electrochemical immunosensor with nanocellulose-Au composite assisted multiple signal amplification for detection of avian leukosis virus subgroup J.

    Science.gov (United States)

    Liu, Chao; Dong, Jing; Waterhouse, Geoffrey I N; Cheng, Ziqiang; Ai, Shiyun

    2018-03-15

    A sensitive sandwich-type electrochemical immunosensor was developed for the detection of avian leukosis virus subgroup J (ALV-J), which benefitted from multiple signal amplification involving graphene-perylene-3,4,9,10-tetracarboxylic acid nanocomposites (GR-PTCA), nanocellulose-Au NP composites (NC-Au) and the alkaline phosphatase (ALP) catalytic reaction. GR-PTCA nanocomposites on glassy carbon electrodes served as the immunosensor platform. Due to their excellent electrical conductivity and abundant polycarboxylic sites, the GR-PTCA nanocomposites allowed fast electron transfer and good immobilization of primary antibodies, thereby affording a strong immunosensor signal in the presence of ALV-J. The detected signal could be further amplified by the introduction of NC-Au composites as a carrier of secondary antibodies (Ab 2 ) and by harnessing the catalytic properties of Au and ALP. Under optimized testing conditions, the electrochemical immunosensor displayed excellent analytical performance for the detection of ALV-J, showing a linear current response from 10 2.08 to 10 4.0 TCID 50 /mL (TCID 50 : 50% tissue culture infective dose) with a low detection limit of 10 1.98 TCID 50 /mL (S/N = 3). In addition to high sensitivity, the immunosensor showed very good selectivity, reproducibility and operational stability, demonstrating potential application for the quantitative detection of ALV-J in clinical diagnosis. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Seasonal climate signals from multiple tree ring metrics: A case study of Pinus ponderosa in the upper Columbia River Basin

    Science.gov (United States)

    Dannenberg, Matthew P.; Wise, Erika K.

    2016-04-01

    Projected changes in the seasonality of hydroclimatic regimes are likely to have important implications for water resources and terrestrial ecosystems in the U.S. Pacific Northwest. The tree ring record, which has frequently been used to position recent changes in a longer-term context, typically relies on signals embedded in the total ring width of tree rings. Additional climatic inferences at a subannual temporal scale can be made using alternative tree ring metrics such as earlywood and latewood widths and the density of tree ring latewood. Here we examine seasonal precipitation and temperature signals embedded in total ring width, earlywood width, adjusted latewood width, and blue intensity chronologies from a network of six Pinus ponderosa sites in and surrounding the upper Columbia River Basin of the U.S. Pacific Northwest. We also evaluate the potential for combining multiple tree ring metrics together in reconstructions of past cool- and warm-season precipitation. The common signal among all metrics and sites is related to warm-season precipitation. Earlywood and latewood widths differ primarily in their sensitivity to conditions in the year prior to growth. Total and earlywood widths from the lowest elevation sites also reflect cool-season moisture. Effective correlation analyses and composite-plus-scale tests suggest that combining multiple tree ring metrics together may improve reconstructions of warm-season precipitation. For cool-season precipitation, total ring width alone explains more variance than any other individual metric or combination of metrics. The composite-plus-scale tests show that variance-scaled precipitation reconstructions in the upper Columbia River Basin may be asymmetric in their ability to capture extreme events.

  1. Relevancies of multiple-interaction events and signal-to-noise ratio for Anger-logic based PET detector designs

    Science.gov (United States)

    Peng, Hao

    2015-10-01

    A fundamental challenge for PET block detector designs is to deploy finer crystal elements while limiting the number of readout channels. The standard Anger-logic scheme including light sharing (an 8 by 8 crystal array coupled to a 2×2 photodetector array with an optical diffuser, multiplexing ratio: 16:1) has been widely used to address such a challenge. Our work proposes a generalized model to study the impacts of two critical parameters on spatial resolution performance of a PET block detector: multiple interaction events and signal-to-noise ratio (SNR). The study consists of the following three parts: (1) studying light output profile and multiple interactions of 511 keV photons within crystal arrays of different crystal widths (from 4 mm down to 1 mm, constant height: 20 mm); (2) applying the Anger-logic positioning algorithm to investigate positioning/decoding uncertainties (i.e., "block effect") in terms of peak-to-valley ratio (PVR), with light sharing, multiple interactions and photodetector SNR taken into account; and (3) studying the dependency of spatial resolution on SNR in the context of modulation transfer function (MTF). The proposed model can be used to guide the development and evaluation of a standard Anger-logic based PET block detector including: (1) selecting/optimizing the configuration of crystal elements for a given photodetector SNR; and (2) predicting to what extent additional electronic multiplexing may be implemented to further reduce the number of readout channels.

  2. [HSP90 Inhibitor 17-AAG Inhibits Multiple Myeloma Cell Proliferation by Down-regulating Wnt/β-Catenin Signaling Pathway].

    Science.gov (United States)

    Chen, Kan-Kan; He, Zheng-Mei; Ding, Bang-He; Chen, Yue; Zhang, Li-Juan; Yu, Liang; Gao, Jian

    2016-02-01

    To investigate the inhibitory effect of HSP90 inhibitory 17-AAG on proliferation of multiple myeloma cells and its main mechanism. The multiple myeloma cells U266 were treated with 17-AAG of different concentrations (200, 400, 600 and 800 nmol/L) for 24, 48, and 72 hours respectively, then the proliferation rate, expression levels of β-catenin and C-MYC protein, as well as cell cycle of U266 cells were treated with 17-AAG and were detected by MTT method, Western blot and flow cytometry, respectively. The 17-AAG showed inhibitory effect on the proliferation of U266 cells in dose- and time-depetent manners (r = -0.518, P AAG displayed no inhibitory effect on proliferation of U266 cells (P > 0.05). The result of culturing U266 cells for 72 hours by 17-AAG of different concentrations showed that the more high of 17-AAG concentration, the more low level of β-catenin and C-MYC proteins (P AAG concentration, the more high of cell ratio in G1 phase (P AAG, the more long time of culture, the more high of cell ratio in G1 phase (P AAG can inhibit the proliferation of multiple myeloma cells, the down-regulation of Wnt/β-catenin signaling pathway and inhibition of HSP90 expression may be the main mechnisms of 17-AAG effect.

  3. SENP1 inhibition induces apoptosis and growth arrest of multiple myeloma cells through modulation of NF-κB signaling

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Jun [Graduate School of Anhui Medical University, Hefei (China); Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Sun, Hui-Yan; Xiao, Feng-Jun; Wang, Hua [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Yang, Yang [Department of Hematology, General Hospital of Air Force, Beijing (China); Wang, Lu; Gao, Chun-Ji [Department of Hematology, PLA General Hospital, Beijing (China); Guo, Zi-Kuan [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Wu, Chu-Tse [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Wang, Li-Sheng, E-mail: Wangls@bmi.ac.cn [Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing 100850 (China); Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu (China)

    2015-05-01

    SUMO/sentrin specific protease 1 (Senp1) is an important regulation protease in the protein sumoylation, which affects the cell cycle, proliferation and differentiation. The role of Senp1 mediated protein desumoylation in pathophysiological progression of multiple myeloma is unknown. In this study, we demonstrated that Senp1 is overexpressed and induced by IL-6 in multiple myeloma cells. Lentivirus-mediated Senp1 knockdown triggers apoptosis and reduces viability, proliferation and colony forming ability of MM cells. The NF-κB family members including P65 and inhibitor protein IkBα play important roles in regulation of MM cell survival and proliferation. We further demonstrated that Senp1 inhibition decreased IL-6-induced P65 and IkBα phosphorylation, leading to inactivation of NF-kB signaling in MM cells. These results delineate a key role for Senp1in IL-6 induced proliferation and survival of MM cells, suggesting it may be a potential new therapeutic target in MM. - Highlights: • Senp1 is overexpressed and induced by IL-6 in multiple myeloma cells. • Senp1 knockdown triggers apoptosis and reduces proliferation of MM cells. • Senp1 inhibition decreased IL-6-induced P65 and IkBα phosphorylation.

  4. SENP1 inhibition induces apoptosis and growth arrest of multiple myeloma cells through modulation of NF-κB signaling

    International Nuclear Information System (INIS)

    Xu, Jun; Sun, Hui-Yan; Xiao, Feng-Jun; Wang, Hua; Yang, Yang; Wang, Lu; Gao, Chun-Ji; Guo, Zi-Kuan; Wu, Chu-Tse; Wang, Li-Sheng

    2015-01-01

    SUMO/sentrin specific protease 1 (Senp1) is an important regulation protease in the protein sumoylation, which affects the cell cycle, proliferation and differentiation. The role of Senp1 mediated protein desumoylation in pathophysiological progression of multiple myeloma is unknown. In this study, we demonstrated that Senp1 is overexpressed and induced by IL-6 in multiple myeloma cells. Lentivirus-mediated Senp1 knockdown triggers apoptosis and reduces viability, proliferation and colony forming ability of MM cells. The NF-κB family members including P65 and inhibitor protein IkBα play important roles in regulation of MM cell survival and proliferation. We further demonstrated that Senp1 inhibition decreased IL-6-induced P65 and IkBα phosphorylation, leading to inactivation of NF-kB signaling in MM cells. These results delineate a key role for Senp1in IL-6 induced proliferation and survival of MM cells, suggesting it may be a potential new therapeutic target in MM. - Highlights: • Senp1 is overexpressed and induced by IL-6 in multiple myeloma cells. • Senp1 knockdown triggers apoptosis and reduces proliferation of MM cells. • Senp1 inhibition decreased IL-6-induced P65 and IkBα phosphorylation

  5. Chronic anthropogenic noise disrupts glucocorticoid signaling and has multiple effects on fitness in an avian community.

    Science.gov (United States)

    Kleist, Nathan J; Guralnick, Robert P; Cruz, Alexander; Lowry, Christopher A; Francis, Clinton D

    2018-01-23

    Anthropogenic noise is a pervasive pollutant that decreases environmental quality by disrupting a suite of behaviors vital to perception and communication. However, even within populations of noise-sensitive species, individuals still select breeding sites located within areas exposed to high noise levels, with largely unknown physiological and fitness consequences. We use a study system in the natural gas fields of northern New Mexico to test the prediction that exposure to noise causes glucocorticoid-signaling dysfunction and decreases fitness in a community of secondary cavity-nesting birds. In accordance with these predictions, and across all species, we find strong support for noise exposure decreasing baseline corticosterone in adults and nestlings and, conversely, increasing acute stressor-induced corticosterone in nestlings. We also document fitness consequences with increased noise in the form of reduced hatching success in the western bluebird ( Sialia mexicana ), the species most likely to nest in noisiest environments. Nestlings of all three species exhibited accelerated growth of both feathers and body size at intermediate noise amplitudes compared with lower or higher amplitudes. Our results are consistent with recent experimental laboratory studies and show that noise functions as a chronic, inescapable stressor. Anthropogenic noise likely impairs environmental risk perception by species relying on acoustic cues and ultimately leads to impacts on fitness. Our work, when taken together with recent efforts to document noise across the landscape, implies potential widespread, noise-induced chronic stress coupled with reduced fitness for many species reliant on acoustic cues.

  6. Small leucine rich proteoglycan family regulates multiple signalling pathways in neural development and maintenance.

    Science.gov (United States)

    Dellett, Margaret; Hu, Wanzhou; Papadaki, Vasiliki; Ohnuma, Shin-ichi

    2012-04-01

    The small leucine-rich repeat proteoglycan (SLRPs) family of proteins currently consists of five classes, based on their structural composition and chromosomal location. As biologically active components of the extracellular matrix (ECM), SLRPs were known to bind to various collagens, having a role in regulating fibril assembly, organization and degradation. More recently, as a function of their diverse proteins cores and glycosaminoglycan side chains, SLRPs have been shown to be able to bind various cell surface receptors, growth factors, cytokines and other ECM components resulting in the ability to influence various cellular functions. Their involvement in several signaling pathways such as Wnt, transforming growth factor-β and epidermal growth factor receptor also highlights their role as matricellular proteins. SLRP family members are expressed during neural development and in adult neural tissues, including ocular tissues. This review focuses on describing SLRP family members involvement in neural development with a brief summary of their role in non-neural ocular tissues and in response to neural injury. © 2012 The Authors Development, Growth & Differentiation © 2012 Japanese Society of Developmental Biologists.

  7. Downstream targets of WRKY33

    DEFF Research Database (Denmark)

    Petersen, Klaus; Fiil, Berthe Katrine; Mundy, John

    2008-01-01

    Innate immunity signaling pathways in both animals and plants are regulated by mitogen-activated protein kinase (MAPK) cascades. In a recent publication we show that MPK4 and its substrate MKS1 interact with WRKY33 in vivo, and that WRKY33 is released from complexes with MPK4 upon infection....... Transcriptome analysis of a wrky33 loss-of-function mutant identified a subset of defense-related genes as putative targets of WRKY33. These genes include PAD3 and CYP71A13, which encode cytochrome P450 monoxygenases required for synthesis of the antimicrobial phytoalexin camalexin. Chromatin...... immunoprecipitation confirmed that WRKY33 bound the promoter of PAD3 when plants were inoculated with pathogens. Here we further discuss the involvement of two other targets of WRKY33, NUDT6 and ROF2 in defense responses against invading pathogens....

  8. A microfluidic device for studying cell signaling with multiple inputs and adjustable amplitudes and frequencies

    Science.gov (United States)

    Ningsih, Zubaidah; Chon, James W. M.; Clayton, Andrew H. A.

    2013-12-01

    Cell function is largely controlled by an intricate web of macromolecular interactions called signaling networks. It is known that the type and the intensity (concentration) of stimulus affect cell behavior. However, the temporal aspect of the stimulus is not yet fully understood. Moreover, the process of distinguishing between two stimuli by a cell is still not clear. A microfluidic device enables the delivery of a precise and exact stimulus to the cell due to the laminar flow established inside its micro-channel. The slow stream delivers a constant stimulus which is adjustable according to the experiment set up. Moreover, with controllable inputs, microfluidic facilitates the stimuli delivery according to a certain pattern with adjustable amplitude, frequency and phase. Several designs of PDMS microfluidic device has been produced in this project via photolithography and soft lithography processes. To characterize the microfluidic performance, two experiments has been conducted. First, by comparing the fluorescence intensity and the lifetime of fluorescein in the present of KI, mixing extent between two inputs was observed using Frequency Lifetime Imaging Microscopy (FLIM). Furthermore, the input-output relationship of fluorescein concentration delivered was also drawn to characterize the amplitude, frequency and phase of the inputs. Second experiment involved the cell culturing inside microfluidic. Using NG108-15 cells, proliferation and differentiation were observed based on the cell number and cell physiological changes. Our results demonstrate that hurdle design gives 86% mixing of fluorescein and buffer. Relationship between inputoutput fluorescein concentrations delivered has also been demonstrated and cells were successfully cultured inside the microfluidic.

  9. Multiple frequency audio signal communication as a mechanism for neurophysiology and video data synchronization.

    Science.gov (United States)

    Topper, Nicholas C; Burke, Sara N; Maurer, Andrew Porter

    2014-12-30

    Current methods for aligning neurophysiology and video data are either prepackaged, requiring the additional purchase of a software suite, or use a blinking LED with a stationary pulse-width and frequency. These methods lack significant user interface for adaptation, are expensive, or risk a misalignment of the two data streams. A cost-effective means to obtain high-precision alignment of behavioral and neurophysiological data is obtained by generating an audio-pulse embedded with two domains of information, a low-frequency binary-counting signal and a high, randomly changing frequency. This enabled the derivation of temporal information while maintaining enough entropy in the system for algorithmic alignment. The sample to frame index constructed using the audio input correlation method described in this paper enables video and data acquisition to be aligned at a sub-frame level of precision. Traditionally, a synchrony pulse is recorded on-screen via a flashing diode. The higher sampling rate of the audio input of the camcorder enables the timing of an event to be detected with greater precision. While on-line analysis and synchronization using specialized equipment may be the ideal situation in some cases, the method presented in the current paper presents a viable, low cost alternative, and gives the flexibility to interface with custom off-line analysis tools. Moreover, the ease of constructing and implements this set-up presented in the current paper makes it applicable to a wide variety of applications that require video recording. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Constraints on signaling network logic reveal functional subgraphs on Multiple Myeloma OMIC data.

    Science.gov (United States)

    Miannay, Bertrand; Minvielle, Stéphane; Magrangeas, Florence; Guziolowski, Carito

    2018-03-21

    The integration of gene expression profiles (GEPs) and large-scale biological networks derived from pathways databases is a subject which is being widely explored. Existing methods are based on network distance measures among significantly measured species. Only a small number of them include the directionality and underlying logic existing in biological networks. In this study we approach the GEP-networks integration problem by considering the network logic, however our approach does not require a prior species selection according to their gene expression level. We start by modeling the biological network representing its underlying logic using Logic Programming. This model points to reachable network discrete states that maximize a notion of harmony between the molecular species active or inactive possible states and the directionality of the pathways reactions according to their activator or inhibitor control role. Only then, we confront these network states with the GEP. From this confrontation independent graph components are derived, each of them related to a fixed and optimal assignment of active or inactive states. These components allow us to decompose a large-scale network into subgraphs and their molecular species state assignments have different degrees of similarity when compared to the same GEP. We apply our method to study the set of possible states derived from a subgraph from the NCI-PID Pathway Interaction Database. This graph links Multiple Myeloma (MM) genes to known receptors for this blood cancer. We discover that the NCI-PID MM graph had 15 independent components, and when confronted to 611 MM GEPs, we find 1 component as being more specific to represent the difference between cancer and healthy profiles.

  11. Analysis of signal transducer and activator of transcription 3 (Stat 3) pathway in multiple myeloma: Stat 3 activation and cyclin D1 dysregulation are mutually exclusive events.

    Science.gov (United States)

    Quintanilla-Martinez, Leticia; Kremer, Marcus; Specht, Katja; Calzada-Wack, Julia; Nathrath, Michaela; Schaich, Robert; Höfler, Heinz; Fend, Falko

    2003-05-01

    The signal transducer and activator of transcription molecules (Stats) play key roles in cytokine-induced signal transduction. Recently, it was proposed that constitutively activated Stat 3 (Stat 3 phosphorylated) contributes to the pathogenesis of multiple myeloma (MM) by preventing apoptosis and inducing proliferation. The study aim was to investigate Stat 3 activation in a series of multiple myeloma (MM) cases and its effect on downstream targets such as the anti-apoptotic proteins Bcl-xL, Mcl-1, and Bcl-2, and the cell-cycle protein cyclin D1. Forty-eight cases of MM were analyzed. Immunohistochemistry was performed on paraffin sections using antibodies against cyclin D1, Bcl-2, Bcl-xL, Mcl-1, p21, Stat 3, and Stat 3 phosphorylated (P). Their specificity was corroborated by Western blot analysis using eight human MM cell lines as control. The proliferation rate was assessed with the antibody MiB1. In addition, the mRNA levels of cyclin D1 and Stat 3 were determined by quantitative real-time reverse transcriptase-polymerase chain reaction of paraffin-embedded microdissected tissue. Three different groups determined by the expression of Stat 3P and cyclin D1 (protein and mRNA) were identified: group 1, Stat 3-activated (23 cases, 48%). All cases revealed nuclear expression of Stat 3P. No elevation of Stat 3 mRNA was identified in any of the cases. Three cases in this group showed intermediate to low cyclin D1 protein and mRNA expression. Group 2 included 15 (31%) cases with cyclin D1 staining and lack of Stat 3P. All cases showed intermediate to high levels of cyclin D1 mRNA expression. Group 3 included 10 (21%) cases with no expression of either cyclin D1 or Stat 3P. High levels of anti-apoptotic proteins Bcl-xL and Mcl-1 were identified in 89% and 100% of all cases, respectively. In contrast to Bcl-xL and Mcl-1, the expression of Bcl-2 showed an inverse correlation with proliferation rate (P: 0.0003). No significant differences were found between the three

  12. RGMs : Structural Insights, Molecular Regulation, and Downstream Signaling

    NARCIS (Netherlands)

    Siebold, Christian; Yamashita, Toshihide; Monnier, Philippe P.; Mueller, Bernhard K.; Pasterkamp, R. Jeroen

    Although originally discovered as neuronal growth cone-collapsing factors, repulsive guidance molecules (RGMs) are now known as key players in many fundamental processes, such as cell migration, differentiation, iron homeostasis, and apoptosis, during the development and homeostasis of many tissues

  13. Threshold-Based Multiple Optical Signal Selection Scheme for Free-Space Optical Wavelength Division Multiplexing Systems

    KAUST Repository

    Nam, Sung Sik

    2017-11-13

    We propose a threshold-based multiple optical signal selection scheme (TMOS) for free-space optical wavelength division multiplexing systems. With this scheme, we can obtain higher spectral efficiency while reducing the possible complexity of implementation caused by the beam-selection scheme and without a considerable performance loss. To characterize the performance of our scheme, we statistically analyze the operation characteristics under conventional detection conditions (i.e., heterodyne detection and intensity modulation/direct detection techniques) with log-normal turbulence while taking into consideration the impact of pointing error. More specifically, we derive exact closed-form expressions for the outage probability, the average bit error rate, and the average spectral efficiency while adopting an adaptive modulation. Some selected results show that TMOS increases the average spectral efficiency while maintaining a minimum average bit error rate requirement.

  14. Wide range of interacting partners of pea Gβ subunit of G-proteins suggests its multiple functions in cell signalling.

    Science.gov (United States)

    Bhardwaj, Deepak; Lakhanpaul, Suman; Tuteja, Narendra

    2012-09-01

    Climate change is a major concern especially in view of the increasing global population and food security. Plant scientists need to look for genetic tools whose appropriate usage can contribute to sustainable food availability. G-proteins have been identified as some of the potential genetic tools that could be useful for protecting plants from various stresses. Heterotrimeric G-proteins consisting of three subunits Gα, Gβ and Gγ are important components of a number of signalling pathways. Their structure and functions are already well studied in animals but their potential in plants is now gaining attention for their role in stress tolerance. Earlier we have reported that over expressing pea Gβ conferred heat tolerance in tobacco plants. Here we report the interacting partners (proteins) of Gβ subunit of Pisum sativum and their putative role in stress and development. Out of 90 transformants isolated from the yeast-two-hybrid (Y2H) screening, seven were chosen for further investigation due to their recurrence in multiple experiments. These interacting partners were confirmed using β-galactosidase colony filter lift and ONPG (O-nitrophenyl-β-D-galactopyranoside) assays. These partners include thioredoxin H, histidine-containing phosphotransfer protein 5-like, pathogenesis-related protein, glucan endo-beta-1, 3-glucosidase (acidic isoform), glycine rich RNA binding protein, cold and drought-regulated protein (corA gene) and soluble inorganic pyrophosphatase 1. This study suggests the role of pea Gβ subunit in stress signal transduction and development pathways owing to its capability to interact with a wide range of proteins of multiple functions. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  15. Improved statistical signal detection in pharmacovigilance by combining multiple strength-of-evidence aspects in vigiRank.

    Science.gov (United States)

    Caster, Ola; Juhlin, Kristina; Watson, Sarah; Norén, G Niklas

    2014-08-01

    Detection of unknown risks with marketed medicines is key to securing the optimal care of individual patients and to reducing the societal burden from adverse drug reactions. Large collections of individual case reports remain the primary source of information and require effective analytics to guide clinical assessors towards likely drug safety signals. Disproportionality analysis is based solely on aggregate numbers of reports and naively disregards report quality and content. However, these latter features are the very fundament of the ensuing clinical assessment. Our objective was to develop and evaluate a data-driven screening algorithm for emerging drug safety signals that accounts for report quality and content. vigiRank is a predictive model for emerging safety signals, here implemented with shrinkage logistic regression to identify predictive variables and estimate their respective contributions. The variables considered for inclusion capture different aspects of strength of evidence, including quality and clinical content of individual reports, as well as trends in time and geographic spread. A reference set of 264 positive controls (historical safety signals from 2003 to 2007) and 5,280 negative controls (pairs of drugs and adverse events not listed in the Summary of Product Characteristics of that drug in 2012) was used for model fitting and evaluation; the latter used fivefold cross-validation to protect against over-fitting. All analyses were performed on a reconstructed version of VigiBase(®) as of 31 December 2004, at around which time most safety signals in our reference set were emerging. The following aspects of strength of evidence were selected for inclusion into vigiRank: the numbers of informative and recent reports, respectively; disproportional reporting; the number of reports with free-text descriptions of the case; and the geographic spread of reporting. vigiRank offered a statistically significant improvement in area under the receiver

  16. Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling

    KAUST Repository

    Zeis, T.

    2015-04-01

    Emerging as an important correlate of neurological dysfunction in Multiple Sclerosis (MS), extended focal and diffuse gray matter abnormalities have been found and linked to clinical manifestations such as seizures, fatigue and cognitive dysfunction. To investigate possible underlying mechanisms we analyzed the molecular alterations in histopathological normal appearing cortical gray matter (NAGM) in MS. By performing a differential gene expression analysis of NAGM of control and MS cases we identified reduced transcription of astrocyte specific genes involved in the astrocyte–neuron lactate shuttle (ANLS) and the glutamate–glutamine cycle (GGC). Additional quantitative immunohistochemical analysis demonstrating a CX43 loss in MS NAGM confirmed a crucial involvement of astrocytes and emphasizes their importance in MS pathogenesis. Concurrently, a Toll-like/IL-1β signaling expression signature was detected in MS NAGM, indicating that immune-related signaling might be responsible for the downregulation of ANLS and GGC gene expression in MS NAGM. Indeed, challenging astrocytes with immune stimuli such as IL-1β and LPS reduced their ANLS and GGC gene expression in vitro. The detected upregulation of IL1B in MS NAGM suggests inflammasome priming. For this reason, astrocyte cultures were treated with ATP and ATP/LPS as for inflammasome activation. This treatment led to a reduction of ANLS and GGC gene expression in a comparable manner. To investigate potential sources for ANLS and GGC downregulation in MS NAGM, we first performed an adjuvant-driven stimulation of the peripheral immune system in C57Bl/6 mice in vivo. This led to similar gene expression changes in spinal cord demonstrating that peripheral immune signals might be one source for astrocytic gene expression changes in the brain. IL1B upregulation in MS NAGM itself points to a possible endogenous signaling process leading to ANLS and GGC downregulation. This is supported by our findings that, among others

  17. Differential effects of multiplicity of infection on Helicobacter pylori-induced signaling pathways and interleukin-8 gene transcription.

    Science.gov (United States)

    Ritter, Birgit; Kilian, Petra; Reboll, Marc Rene; Resch, Klaus; DiStefano, Johanna Kay; Frank, Ronald; Beil, Winfried; Nourbakhsh, Mahtab

    2011-02-01

    Interleukin-8 (IL-8) plays a central role in the pathogenesis of Helicobacter pylori infection. We used four different H. pylori strains isolated from patients with gastritis or duodenal ulcer disease to examine their differential effects on signaling pathways and IL-8 gene response in gastric epithelial cells. IL-8 mRNA level is elevated in response to high (100) multiplicity of infection (MOI) independent of cagA, vacA, and dupA gene characteristics. By lower MOIs (1 or 10), only cagA ( + ) strains significantly induce IL-8 gene expression. This is based on differential regulation of IL-8 promoter activity. Analysis of intracellular signaling pathways indicates that H. pylori clinical isolates induce IL-8 gene transcription through NF-κB p65, but by a MOI-dependent differential activation of MAPK pathways. Thus, the major virulence factors of H. pylori CagA, VacA, and DupA might play a minor role in the level of IL-8 gene response to a high bacterial load.

  18. The effect of S1P receptor signaling pathway on the survival and drug resistance in multiple myeloma cells.

    Science.gov (United States)

    Fu, Di; Li, Yingchun; Li, Jia; Shi, Xiaoyan; Yang, Ronghui; Zhong, Yuan; Wang, Huihan; Liao, Aijun

    2017-01-01

    Multiple myeloma (MM) remains incurable by conventional chemotherapy. Sphingosine-1-phosphate (S1P) receptor-mediated signaling has been recently demonstrated to have critical roles in cell survival and drug resistance in a number of hematological malignancies. To dissect the roles of S1P receptor pathway in MM, we systematically examined cell viability and protein expression associated with cell survival and drug resistance in MM cell lines upon treatment with either pathway activator (S1P) or inhibitor (FTY720). Our results reveal that FTY720 inhibits cell proliferation by downregulating expression of target genes, while S1P has an opposite effect. Knocking down of S1P receptor S1P5R results in a reduction of cell survival-related gene expression; however, it does not have impacts on expression of drug resistance genes. These results suggest that S1P signaling plays a role in cell proliferation and drug resistance in MM, and targeting this pathway will provide a new therapeutic direction for MM management.

  19. Experimental Verification of a New Model Describing the Influence of Incomplete Signal Extinction Ratio on the Sensitivity Degradation due to Multiple Interferometric Crosstalk

    DEFF Research Database (Denmark)

    Liu, Fenghai; Rasmussen, Christian Jørgen; Pedersen, Rune Johan Skullerud

    1999-01-01

    Larger optical penalties than predicted by a Gaussian crosstalk model are found both in our experiments and in the literature when investigating signals including multiple interferometric crosstalk contributions. We attribute this to an imperfect signal extinction ratio. In this letter, simple...... analytical relations for crosstalk induced power penalties are derived taking the signal extinction ratio into account and excellent agreement with 10-Gb/s experiments is obtained. Both theory and experiment show the importance of the signal extinction ratio in connection with interferometric crosstalk....

  20. Theoretical analysis and simulation of a code division multiple access system (cdma for secure signal transmission in wideband channels

    Directory of Open Access Journals (Sweden)

    Stevan M. Berber

    2014-06-01

    Code Division Multiple Access (CDMA technique which allows communications of multiple users in the same communication system. This is achieved in such a way that each user is assigned a unique code sequence, which is used at the receiver side to discover the information dedicated to that user. These systems belong to the group of communication systems for direct sequence spread spectrum systems. Traditionally, CDMA systems use binary orthogonal spreading codes. In this paper, a mathematical model and simulation of a CDMA system based on the application of non-binary, precisely speaking, chaotic spreading sequences. In their nature, these sequences belong to random sequences with infinite periodicity, and due to that they are appropriate for applications in the systems that provide enhanced security against interception and secrecy in signal transmission. Numerous papers are dedicated to the development of CDMA systems in flat fading channels. This paper presents the results of these systems analysis for the case when frequency selective fading is present in the channel. In addition, the paper investigates a possibility of using interleaving techniques to mitigate fading in a wideband channel with the frequency selective fading. Basic structure of a CDMA communication system and its operation In this paper, a CDMA system block schematic is ppresented and the function of all blocks is explained. Notation  to be used in the paper is introduced. Chaotic sequences are defined and explained in accordance with the method of their generation. A wideband channel with frequency selective fading is defined by its impulse response function. Theoretical analysis of a CDMA system with flat fading in a narrowband channel A narrowband channel and flat fading are defined. A mathematical analysis of the system is conducted by presenting the signal expressions at vital points in the transmitter and receiver. The expression of the signal at the output of the sequence correlator is

  1. Targeting p53 via JNK pathway: a novel role of RITA for apoptotic signaling in multiple myeloma.

    Science.gov (United States)

    Saha, Manujendra N; Jiang, Hua; Yang, Yijun; Zhu, Xiaoyun; Wang, Xiaoming; Schimmer, Aaron D; Qiu, Lugui; Chang, Hong

    2012-01-01

    The low frequency of p53 alterations e.g., mutations/deletions (∼10%) in multiple myeloma (MM) makes this tumor type an ideal candidate for p53-targeted therapies. RITA is a small molecule which can induce apoptosis in tumor cells by activating the p53 pathway. We previously showed that RITA strongly activates p53 while selectively inhibiting growth of MM cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy in MM. However, the molecular mechanisms underlying the pro-apoptotic effect of RITA are largely undefined. Gene expression analysis by microarray identified a significant number of differentially expressed genes associated with stress response including c-Jun N-terminal kinase (JNK) signaling pathway. By Western blot analysis we further confirmed that RITA induced activation of p53 in conjunction with up-regulation of phosphorylated ASK-1, MKK-4 and c-Jun. These results suggest that RITA induced the activation of JNK signaling. Chromatin immunoprecipitation (ChIP) analysis showed that activated c-Jun binds to the activator protein-1 (AP-1) binding site of the p53 promoter region. Disruption of the JNK signal pathway by small interfering RNA (siRNA) against JNK or JNK specific inhibitor, SP-600125 inhibited the activation of p53 and attenuated apoptosis induced by RITA in myeloma cells carrying wild type p53. On the other hand, p53 transcriptional inhibitor, PFT-α or p53 siRNA not only inhibited the activation of p53 transcriptional targets but also blocked the activation of c-Jun suggesting the presence of a positive feedback loop between p53 and JNK. In addition, RITA in combination with dexamethasone, known as a JNK activator, displays synergistic cytotoxic responses in MM cell lines and patient samples. Our study unveils a previously undescribed mechanism of RITA-induced p53-mediated apoptosis through JNK signaling pathway and provides the rationale for combination of p53 activating drugs with JNK

  2. Targeting p53 via JNK pathway: a novel role of RITA for apoptotic signaling in multiple myeloma.

    Directory of Open Access Journals (Sweden)

    Manujendra N Saha

    Full Text Available The low frequency of p53 alterations e.g., mutations/deletions (∼10% in multiple myeloma (MM makes this tumor type an ideal candidate for p53-targeted therapies. RITA is a small molecule which can induce apoptosis in tumor cells by activating the p53 pathway. We previously showed that RITA strongly activates p53 while selectively inhibiting growth of MM cells without inducing genotoxicity, indicating its potential as a drug lead for p53-targeted therapy in MM. However, the molecular mechanisms underlying the pro-apoptotic effect of RITA are largely undefined. Gene expression analysis by microarray identified a significant number of differentially expressed genes associated with stress response including c-Jun N-terminal kinase (JNK signaling pathway. By Western blot analysis we further confirmed that RITA induced activation of p53 in conjunction with up-regulation of phosphorylated ASK-1, MKK-4 and c-Jun. These results suggest that RITA induced the activation of JNK signaling. Chromatin immunoprecipitation (ChIP analysis showed that activated c-Jun binds to the activator protein-1 (AP-1 binding site of the p53 promoter region. Disruption of the JNK signal pathway by small interfering RNA (siRNA against JNK or JNK specific inhibitor, SP-600125 inhibited the activation of p53 and attenuated apoptosis induced by RITA in myeloma cells carrying wild type p53. On the other hand, p53 transcriptional inhibitor, PFT-α or p53 siRNA not only inhibited the activation of p53 transcriptional targets but also blocked the activation of c-Jun suggesting the presence of a positive feedback loop between p53 and JNK. In addition, RITA in combination with dexamethasone, known as a JNK activator, displays synergistic cytotoxic responses in MM cell lines and patient samples. Our study unveils a previously undescribed mechanism of RITA-induced p53-mediated apoptosis through JNK signaling pathway and provides the rationale for combination of p53 activating drugs with

  3. Specific intracellular signal transduction pathways downstream of CSF-1 receptors: their relationship to breast cancer local recurrence and distant relapse in vivo. Potential targets for the development of new, specific anti-breast cancer therapies to improve local control and block metastatic spread?

    International Nuclear Information System (INIS)

    Kacinski, Barry M.; Sapi, Eva; Flick, Maryann B.; Turner, Bruce; Perrotta, Peter; Maher, M. Grey; Carter, Darryl; Haffy, Bruce

    1997-01-01

    Purpose/Objective: Several earlier studies have implicated CSF-1 and its receptor (CSF-1R) in the biology of mammary neoplasms and those of the female reproductive tract. CSF-1Rs are expressed by the majority (<80%) of invasive breast carcinomas and their activation as evidenced by co-expression of CSF-1 has been correlated with adverse prognosis both in breast and ovarian carcinomas. In the studies, summarized below, we attempt to further correlate expression of CSF-1R with prognosis in breast cancer. We have also attempted to better define the intracellular signal transduction pathways controlled by CSF-1R which are responsible for such clinically relevant phenotypes as protease production, invasiveness, and tumorigenicity and have designed immunological reagents capable of discriminating the activated tyrosine phosphorylated form of CSF-1R from its inactive, unphosphorylated precursor in fixed tissue. Materials and Methods and Results: To study the role of specific tyrosine phosphorylations on downstream signal transduction pathways, we transfected the murine mammary epithelial cell line HC11 with a wild-type murine CSF-1R and two mutant CSF-1Rs in which two of the earliest and most prominent sites of tyrosine autophosphorylation TYR-721 (which couples the receptor to PI-3' kinase and indirectly to pp70-S6kinase and PKC) and TYR-809 (which couples the receptor to RAS-GAP) were mutated to PHE. Transfection of HC11 cells with an unmutated, wild-type CSF-1R increased cellular synthesis of active urokinase and increased their ability to invade basement membrane analogues. It also rendered them competent for anchorage- independent growth in soft agar and able to form pulmonary metastases in isogenic C57 mice after intravenous injection. A TYR-721→PHE mutation completely abolished anchorage- independent growth in vitro and pulmonary metastatic tumorigenicity in vivo without any effects on urokinase production or on cellular ability to invade basement membrane

  4. A novel virtual hub approach for multisource downstream service integration

    Science.gov (United States)

    Previtali, Mattia; Cuca, Branka; Barazzetti, Luigi

    2016-08-01

    A large development of downstream services is expected to be stimulated starting from earth observations (EO) datasets acquired by Copernicus satellites. An important challenge connected with the availability of downstream services is the possibility for their integration in order to create innovative applications with added values for users of different categories level. At the moment, the world of geo-information (GI) is extremely heterogeneous in terms of standards and formats used, thus preventing a facilitated access and integration of downstream services. Indeed, different users and data providers have also different requirements in terms of communication protocols and technology advancement. In recent years, many important programs and initiatives have tried to address this issue even on trans-regional and international level (e.g. INSPIRE Directive, GEOSS, Eye on Earth and SEIS). However, a lack of interoperability between systems and services still exists. In order to facilitate the interaction between different downstream services, a new architectural approach (developed within the European project ENERGIC OD) is proposed in this paper. The brokering-oriented architecture introduces a new mediation layer (the Virtual Hub) which works as an intermediary to bridge the gaps linked to interoperability issues. This intermediation layer de-couples the server and the client allowing a facilitated access to multiple downstream services and also Open Data provided by national and local SDIs. In particular, in this paper an application is presented integrating four services on the topic of agriculture: (i) the service given by Space4Agri (providing services based on MODIS and Landsat data); (ii) Gicarus Lab (providing sample services based on Landsat datasets) and (iii) FRESHMON (providing sample services for water quality) and services from a several regional SDIs.

  5. Exploring transcriptional signalling mediated by OsWRKY13, a potential regulator of multiple physiological processes in rice

    Directory of Open Access Journals (Sweden)

    Li Xianghua

    2009-06-01

    Full Text Available Abstract Background Rice transcription regulator OsWRKY13 influences the functioning of more than 500 genes in multiple signalling pathways, with roles in disease resistance, redox homeostasis, abiotic stress responses, and development. Results To determine the putative transcriptional regulation mechanism of OsWRKY13, the putative cis-acting elements of OsWRKY13-influenced genes were analyzed using the whole genome expression profiling of OsWRKY13-activated plants generated with the Affymetrix GeneChip Rice Genome Array. At least 39 transcription factor genes were influenced by OsWRKY13, and 30 of them were downregulated. The promoters of OsWRKY13-upregulated genes were overrepresented with W-boxes for WRKY protein binding, whereas the promoters of OsWRKY13-downregulated genes were enriched with cis-elements putatively for binding of MYB and AP2/EREBP types of transcription factors. Consistent with the distinctive distribution of these cis-elements in up- and downregulated genes, nine WRKY genes were influenced by OsWRKY13 and the promoters of five of them were bound by OsWRKY13 in vitro; all seven differentially expressed AP2/EREBP genes and six of the seven differentially expressed MYB genes were suppressed by in OsWRKY13-activated plants. A subset of OsWRKY13-influenced WRKY genes were involved in host-pathogen interactions. Conclusion These results suggest that OsWRKY13-mediated signalling pathways are partitioned by different transcription factors. WRKY proteins may play important roles in the monitoring of OsWRKY13-upregulated genes and genes involved in pathogen-induced defence responses, whereas MYB and AP2/EREBP proteins may contribute most to the control of OsWRKY13-downregulated genes.

  6. Investigation of Pseudomonas aeruginosa quorum-sensing signaling system for identifying multiple inhibitors using molecular docking and structural analysis methodology.

    Science.gov (United States)

    Soheili, Vahid; Bazzaz, Bibi Sedigheh Fazly; Abdollahpour, Nooshin; Hadizadeh, Farzin

    2015-12-01

    Pseudomonas aeruginosa is an opportunistic human pathogen and a common Gram-negative bacterium in hospital-acquired infections. It causes death in many burn victims, cystic-fibrosis and neutropenic-cancer patients. It is known that P. aeruginosa biofilm maturation and production of cell-associated and extracellular virulence factors such as pyocyanin, elastase and rhamnolipids are under the control of a quorum-sensing (QS) system. Among several proteins involved in the Pseudomonas QS mechanism, LasR and PqsE play an important role in its cascade signaling system. They can cause increases in QS factors, biofilm maturation, and the production of virulence factors. Therefore, inhibition of these proteins can reduce the pathogenicity of P. aeruginosa. According to the structure of corresponding auto-inducers bound to these proteins, in silico calculations were performed with some non-steroidal anti-inflammatory drugs (NSAIDs) to estimate possible interactions and find the co-inhibitors of LasR and PqsE. The results showed that oxicams (Piroxicam and Meloxicam) can interact well with active sites of both proteins with the Ki of 119.43 nM and 4.0 μM for Meloxicam and 201.39 nM and 4.88 μM against LasR and PqsE, respectively. These findings suggested that Piroxicam and Meloxicam can be used as potential inhibitors for control of the P. aeruginosa QS signaling system and biofilm formation, and may be used in the design of multiple inhibitors. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Nitric oxide-induced murine hematopoietic stem cell fate involves multiple signaling proteins, gene expression, and redox modulation.

    Science.gov (United States)

    Nogueira-Pedro, Amanda; Dias, Carolina C; Regina, Helena; Segreto, C; Addios, Priscilla C; Lungato, Lisandro; D'Almeida, Vania; Barros, Carlos C; Higa, Elisa M S; Buri, Marcus V; Ferreira, Alice T; Paredes-Gamero, Edgar Julian

    2014-11-01

    There are a growing number of reports showing the influence of redox modulation in cellular signaling. Although the regulation of hematopoiesis by reactive oxygen species (ROS) and reactive nitrogen species (RNS) has been described, their direct participation in the differentiation of hematopoietic stem cells (HSCs) remains unclear. In this work, the direct role of nitric oxide (NO(•)), a RNS, in the modulation of hematopoiesis was investigated using two sources of NO(•) , one produced by endothelial cells stimulated with carbachol in vitro and another using the NO(•)-donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) in vivo. Two main NO(•) effects were observed: proliferation of HSCs-especially of the short-term HSCs-and its commitment and terminal differentiation to the myeloid lineage. NO(•)-induced proliferation was characterized by the increase in the number of cycling HSCs and hematopoietic progenitor cells positive to BrdU and Ki-67, upregulation of Notch-1, Cx43, PECAM-1, CaR, ERK1/2, Akt, p38, PKC, and c-Myc. NO(•)-induced HSCs differentiation was characterized by the increase in granulocytic-macrophage progenitors, granulocyte-macrophage colony forming units, mature myeloid cells, upregulation of PU.1, and C/EBPα genes concomitantly to the downregulation of GATA-3 and Ikz-3 genes, activation of Stat5 and downregulation of the other analyzed proteins mentioned above. Also, redox status modulation differed between proliferation and differentiation responses, which is likely associated with the transition of the proliferative to differentiation status. Our findings provide evidence of the role of NO(•) in inducing HSCs proliferation and myeloid differentiation involving multiple signaling. © 2014 AlphaMed Press.

  8. High-harmonic electron bunching in the field of a signal wave and the use of this effect in cyclotron masers with frequency multiplication

    Directory of Open Access Journals (Sweden)

    I. V. Bandurkin

    2005-01-01

    Full Text Available A method of organizing electron-wave interaction at the multiplied frequency of the signal wave is proposed. This type of electron-wave interaction provides multiplied-frequency electron bunching, which leads to formation of an intense harmonic of the electron current at a selected multiplied frequency of the signal wave. This effect is attractive for the use in klystron-type cyclotron masers with frequency multiplication as a way to increase the output frequency and improve the selectivity.

  9. Signaling through three chemokine receptors triggers the migration of transplanted neural precursor cells in a model of multiple sclerosis.

    Science.gov (United States)

    Cohen, Mikhal E; Fainstein, Nina; Lavon, Iris; Ben-Hur, Tamir

    2014-09-01

    Multiple sclerosis (MS) is a multifocal disease, and precursor cells need to migrate into the multiple lesions in order to exert their therapeutic effects. Therefore, cell migration is a crucial element in regenerative processes in MS, dictating the route of delivery, when cell transplantation is considered. We have previously shown that inflammation triggers migration of multi-potential neural precursor cells (NPCs) into the white matter of experimental autoimmune encephalomyelitis (EAE) rodents, a widely used model of MS. Here we investigated the molecular basis of this attraction. NPCs were grown from E13 embryonic mouse brains and transplanted into the lateral cerebral ventricles of EAE mice. Transplanted NPC migration was directed by three tissue-derived chemokines. Stromal cell-derived factor-1α, monocyte chemo-attractant protein-1 and hepatocyte growth factor were expressed in the EAE brain and specifically in microglia and astrocytes. Their cognate receptors, CXCR4, CCR2 or c-Met were constitutively expressed on NPCs. Selective blockage of CXCR4, CCR2 or c-Met partially inhibited NPC migration in EAE brains. Blocking all three receptors had an additive effect and resulted in profound inhibition of NPC migration, as compared to extensive migration of control NPCs. The inflammation-triggered NPC migration into white matter tracts was dependent on a motile NPC phenotype. Specifically, depriving NPCs from epidermal growth factor (EGF) prevented the induction of glial commitment and a motile phenotype (as indicated by an in vitro motility assay), hampering their response to neuroinflammation. In conclusion, signaling via three chemokine systems accounts for most of the inflammation-induced, tissue-derived attraction of transplanted NPCs into white matter tracts during EAE. Copyright © 2014. Published by Elsevier B.V.

  10. Proton density differences in signal characteristics of multiple sclerosis plaques versus white matter lesions of small vessel disease and vasculitis on high-field strength MR images

    International Nuclear Information System (INIS)

    Peyster, R.G.; Siegal, T.L.

    1990-01-01

    This paper determines if variations in signal intensity characteristics on multi-spin-echo images obtained with a high-field-strength magnet can be useful in differentiating demyelinating plaques of multiple sclerosis from other pathologic white matter processes due to small vessel disease and vasculities. Using the first of two multi-spin-echo images obtained with a General Electric 1.5-T magnet, the investigators compared signal intensity characteristics in 30 patients with a firm clinical diagnosis of multiple sclerosis versus a control group of 30 patients with a known clinical history of small-vessel disease and vasculitis are isodense to gray matter on proton-density images

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

    Energy Technology Data Exchange (ETDEWEB)

    Fan, Yu [Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Zhan, Qian [The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Xu, Hongying [Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Li, Lili; Li, Chen [Cancer Epigenetics Laboratory, Department of Clinical Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute (Hong Kong); Xiao, Qian; Xiang, Shili; Hui, Tianli [Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Xiang, Tingxiu, E-mail: larissaxiang@163.com [Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Ren, Guosheng, E-mail: rengs726@126.com [Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China)

    2016-06-10

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

  12. Butyrate induces profound changes in gene expression related to multiple signal pathways in bovine kidney epithelial cells

    Directory of Open Access Journals (Sweden)

    Li CongJun

    2006-09-01

    Full Text Available Abstract Background Global gene expression profiles of bovine kidney epithelial cells regulated by sodium butyrate were investigated with high-density oligonucleotide microarrays. The bovine microarray with 86,191 distinct 60mer oligonucleotides, each with 4 replicates, was designed and produced with Maskless Array Synthesizer technology. These oligonucleotides represent approximately 45,383 unique cattle sequences. Results 450 genes significantly regulated by butyrate with a median False Discovery Rate (FDR = 0 % were identified. The majority of these genes were repressed by butyrate and associated with cell cycle control. The expression levels of 30 selected genes identified by the microarray were confirmed using real-time PCR. The results from real-time PCR positively correlated (R = 0.867 with the results from the microarray. Conclusion This study presented the genes related to multiple signal pathways such as cell cycle control and apoptosis. The profound changes in gene expression elucidate the molecular basis for the pleiotropic effects of butyrate on biological processes. These findings enable better recognition of the full range of beneficial roles butyrate may play during cattle energy metabolism, cell growth and proliferation, and possibly in fighting gastrointestinal pathogens.

  13. Dexibuprofen prevents neurodegeneration and cognitive decline in APPswe/PS1dE9 through multiple signaling pathways

    Directory of Open Access Journals (Sweden)

    Miren Ettcheto

    2017-10-01

    Full Text Available The aim of the present study is to elucidate the neuronal pathways associated to NSAIDs causing a reduction of the risk and progression of Alzheimer's disease. The research was developed administering the active enantiomer of ibuprofen, dexibuprofen (DXI, in order to reduce associated gastric toxicity. DXI was administered from three to six-month-old female APPswe/PS1dE9 mice as a model of familial Alzheimer's disease. DXI treatment reduced the activation of glial cells and the cytokine release involved in the neurodegenerative process, especially TNFα. Moreover, DXI reduced soluble β-amyloid (Aβ1-42 plaque deposition by decreasing APP, BACE1 and facilitating Aβ degradation by enhancing insulin-degrading enzyme. DXI also decreased TAU hyperphosphorylation inhibiting c-Abl/CABLES/p-CDK5 activation signal pathway and prevented spatial learning and memory impairment in transgenic mice. Therefore, chronic DXI treatment could constitute a potential AD-modifying drug, both restoring cognitive functions and reversing multiple brain neuropathological hallmarks.

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

    International Nuclear Information System (INIS)

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

    2016-01-01

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

  15. Philippines' downstream sector poised for growth

    International Nuclear Information System (INIS)

    Anon.

    1992-01-01

    This paper reports that the Philippines' downstream sector is poised for sharp growth. Despite a slip in refined products demand in recent years, Philippines products demand will rebound sharply by 2000, East-West Center (EWC), Honolulu, predicts. Philippines planned refinery expansions are expected to meet that added demand, EWC Director Fereidun Fesharaki says. Like the rest of the Asia-Pacific region, product specifications are changing, but major refiners in the area expect to meet the changes without major case outlays. At the same time, Fesharaki says, push toward deregulation will further bolster the outlook for the Philippines downstream sector

  16. The MAPKK FgMkk1 of Fusarium graminearum regulates vegetative differentiation, multiple stress response, and virulence via the cell wall integrity and high-osmolarity glycerol signaling pathways.

    Science.gov (United States)

    Yun, Yingzi; Liu, Zunyong; Zhang, Jingze; Shim, Won-Bo; Chen, Yun; Ma, Zhonghua

    2014-07-01

    Mitogen-activated protein (MAP) kinases play crucial roles in regulating fungal development, growth and pathogenicity, and in responses to the environment. In this study, we characterized a MAP kinase kinase FgMkk1 in Fusarium graminearum, the causal agent of wheat head blight. Phenotypic analyses of the FgMKK1 mutant (ΔFgMKK1) showed that FgMkk1 is involved in the regulation of hyphal growth, pigmentation, conidiation, deoxynivalenol biosynthesis and virulence of F. graminearum. ΔFgMKK1 also showed increased sensitivity to cell wall-damaging agents, and to osmotic and oxidative stresses, but exhibited decreased sensitivity to the fungicides iprodione and fludioxonil. In addition, the mutant revealed increased sensitivity to a biocontrol agent, Trichoderma atroviride. Western blot assays revealed that FgMkk1 positively regulates phosphorylation of the MAP kinases Mgv1 and FgOs-2, the key component in the cell wall integrity (CWI) and high-osmolarity glycerol (HOG) signalling pathway respectively. Yeast two-hybrid assay indicated that Mgv1 interacts with a transcription factor FgRlm1. The FgRLM1 mutant (ΔFgRLM1) showed increased sensitivity to cell wall-damaging agents and exhibited decreased virulence. Taken together, our data indicated that FgMkk1 is an upstream component of Mgv1, and regulates vegetative differentiation, multiple stress response and virulence via the CWI and HOG signalling pathways. FgRlm1 may be a downstream component of Mgv1 in the CWI pathway in F. graminearum. © 2013 Society for Applied Microbiology and John Wiley & Sons Ltd.

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

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Peihao; Guo, Honggang [Department of Hematology, Navy General Hospital, Beijing 100048 (China); Li, Guangchao [School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006 (China); Han, Siqi [Department of Medical Oncology, Jinling Hospital, Nanjing 210002 (China); Luo, Fei [Department of Stomatology, Jinling Hospital, Nanjing 210002 (China); Liu, Yi, E-mail: liuyi2033@163.com [Department of Hematology, Navy General Hospital, Beijing 100048 (China)

    2015-03-06

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

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

    Directory of Open Access Journals (Sweden)

    Zhang Huiping

    2012-05-01

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

  19. Scleroglucan: Fermentative Production, Downstream Processing and Applications

    Directory of Open Access Journals (Sweden)

    Shrikant A. Survase

    2007-01-01

    Full Text Available Exopolysaccharides produced by a variety of microorganisms find multifarious industrial applications in foods, pharmaceutical and other industries as emulsifiers, stabilizers, binders, gelling agents, lubricants, and thickening agents. One such exopolysaccharide is scleroglucan, produced by pure culture fermentation from filamentous fungi of genus Sclerotium. The review discusses the properties, fermentative production, downstream processing and applications of scleroglucan.

  20. The downstream industry compared to market

    International Nuclear Information System (INIS)

    Chevallier, B.

    2010-01-01

    J.L. Schilansky introduces here the difficult question of the downstream industry compared to market in recalling the recent structural changes (behaviour of customers, behaviour of the USA- and China-governments), the increase of the European and French regulations, the climatic change and the conjectural impact of the crisis on the refining industry. (O.M.)

  1. Wavelength Tuning Free Transceiver Module in OLT Downstream Multicasting 4λ × 10 Gb/s TWDM-PON System

    OpenAIRE

    M. S. Salleh; A. S. M. Supa’at; S. M. Idrus; S. Yaakob; Z. M. Yusof

    2014-01-01

    We propose a new architecture of dynamic time-wavelength division multiplexing-passive optical network (TWDM-PON) system that employs integrated all-optical packet routing (AOPR) module using 4λ×10 Gbps downstream signal to support 20 km fiber transmission. This module has been designed to support high speed L2 aggregation and routing in the physical layer PON system by using multicasting cross-gain modulation (XGM) to route packet from any PON port to multiple PON links. Meanwhile, the fixed...

  2. Retroactive signaling in short signaling pathways.

    Directory of Open Access Journals (Sweden)

    Jacques-Alexandre Sepulchre

    Full Text Available In biochemical signaling pathways without explicit feedback connections, the core signal transduction is usually described as a one-way communication, going from upstream to downstream in a feedforward chain or network of covalent modification cycles. In this paper we explore the possibility of a new type of signaling called retroactive signaling, offered by the recently demonstrated property of retroactivity in signaling cascades. The possibility of retroactive signaling is analysed in the simplest case of the stationary states of a bicyclic cascade of signaling cycles. In this case, we work out the conditions for which variables of the upstream cycle are affected by a change of the total amount of protein in the downstream cycle, or by a variation of the phosphatase deactivating the same protein. Particularly, we predict the characteristic ranges of the downstream protein, or of the downstream phosphatase, for which a retroactive effect can be observed on the upstream cycle variables. Next, we extend the possibility of retroactive signaling in short but nonlinear signaling pathways involving a few covalent modification cycles.

  3. Space-division-multiplexed transmission of 3x3 multiple-input multiple-output wireless signals over conventional graded-index multimode fiber

    NARCIS (Netherlands)

    Lei, Yi; Li, Jianqiang; Fan, Yuting; Yu, Dawei; Fu, Songnian; Yin, Feifei; Dai, Yitang; Xu, Kun

    2016-01-01

    In this paper, we experimentally demonstrate space-division-multiplexed (SDM) transmission of IEEE 802.11ac-compliant 3-spatial-stream WLAN signals over 3 spatial modes of conventional 50um graded-index (GI) multimode fiber (MMF) employing non-mode-selective 3D-waveguide photonic lantern. Two kinds

  4. Effect of cAMP signaling on expression of glucocorticoid receptor, Bim and Bad in glucocorticoid-sensitive and resistant leukemic and multiple myeloma cells.

    Science.gov (United States)

    Dong, Hongli; Carlton, Michael E; Lerner, Adam; Epstein, Paul M

    2015-01-01

    Stimulation of cAMP signaling induces apoptosis in glucocorticoid-sensitive and resistant CEM leukemic and MM.1 multiple myeloma cell lines, and this effect is enhanced by dexamethasone in both glucocorticoid-sensitive cell types and in glucocorticoid-resistant CEM cells. Expression of the mRNA for the glucocorticoid receptor alpha (GR) promoters 1A3, 1B and 1C, expression of mRNA and protein for GR, and the BH3-only proapoptotic proteins, Bim and Bad, and the phosphorylation state of Bad were examined following stimulation of the cAMP and glucocorticoid signaling pathways. Expression levels of GR promoters were increased by cAMP and glucocorticoid signaling, but GR protein expression was little changed in CEM and decreased in MM.1 cells. Stimulation of these two signaling pathways induced Bim in CEM cells, induced Bad in MM.1 cells, and activated Bad, as indicated by its dephosphorylation on ser112, in both cell types. This study shows that leukemic and multiple myeloma cells, including those resistant to glucocorticoids, can be induced to undergo apoptosis by stimulating the cAMP signaling pathway, with enhancement by glucocorticoids, and the mechanism by which this occurs may be related to changes in Bim and Bad expression, and in all cases, to activation of Bad.

  5. Seasonal Climate Signals in Multiple Tree-Ring Parameters: A Pilot Study of Pinus ponderosa in the Columbia River Basin

    Science.gov (United States)

    Dannenberg, M.; Wise, E. K.; Keung, J. H.

    2014-12-01

    Proxy-based reconstructions of past climate have played an integral role in assessments of historical climate change, and tree-ring widths (TRW) have a long history of use in this paleoclimate research due to their annual resolution, widespread availability, and sensitivity of growth processes to variation in temperature and water availability. Increasingly, studies have shown that additional tree-ring metrics—including earlywood and latewood widths (EW and LW, respectively), maximum latewood density, and the intensity of reflected blue light from latewood (BI)—can provide additional information on seasonal climatic variability that is not present in TRW alone due to different processes that affect growth in different parts of the growing season. Studies of these additional tree-ring metrics highlight their utility in climate reconstructions, but to date they have mostly been limited to a few tree species and regions. Here, we extend the range of previous studies on alternative tree-ring metrics by evaluating the seasonal climate signals in TRW, EW, LW, and BI of Pinus ponderosa at six semiarid sites surrounding the Columbia River basin in the U.S. Pacific Northwest (PNW). Cores from each site were cross-dated and EW, LW, and TRW were measured using standard dendrochronological procedures. BI was obtained using a high-resolution flatbed scanner and CooRecorder software. To evaluate the unique climate processes and seasonalities contributing to different dendrochronological metrics, monthly temperature and precipitation from each site were obtained from the PRISM climate model and were correlated with each of the tree-ring metrics using the MATLAB program SEASCORR. We also evaluate the potential of using multiple tree-ring metrics (rather than a single proxy) in reconstructions of precipitation in the PNW. Initial results suggest that 1) tree growth at each site is water-limited but with substantial differences among the sites in the strength and seasonality of

  6. Sub-lethal irradiation of human colorectal tumor cells imparts enhanced and sustained susceptibility to multiple death receptor signaling pathways.

    Directory of Open Access Journals (Sweden)

    Victoria Ifeadi

    Full Text Available BACKGROUND: Death receptors (DR of the TNF family function as anti-tumor immune effector molecules. Tumor cells, however, often exhibit DR-signaling resistance. Previous studies indicate that radiation can modify gene expression within tumor cells and increase tumor cell sensitivity to immune attack. The aim of this study is to investigate the synergistic effect of sub-lethal doses of ionizing radiation in sensitizing colorectal carcinoma cells to death receptor-mediated apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: The ability of radiation to modulate the expression of multiple death receptors (Fas/CD95, TRAILR1/DR4, TRAILR2/DR5, TNF-R1 and LTβR was examined in colorectal tumor cells. The functional significance of sub-lethal doses of radiation in enhancing tumor cell susceptibility to DR-induced apoptosis was determined by in vitro functional sensitivity assays. The longevity of these changes and the underlying molecular mechanism of irradiation in sensitizing diverse colorectal carcinoma cells to death receptor-mediated apoptosis were also examined. We found that radiation increased surface expression of Fas, DR4 and DR5 but not LTβR or TNF-R1 in these cells. Increased expression of DRs was observed 2 days post-irradiation and remained elevated 7-days post irradiation. Sub-lethal tumor cell irradiation alone exhibited minimal cell death, but effectively sensitized three of three colorectal carcinoma cells to both TRAIL and Fas-induced apoptosis, but not LTβR-induced death. Furthermore, radiation-enhanced Fas and TRAIL-induced cell death lasted as long as 5-days post-irradiation. Specific analysis of intracellular sensitizers to apoptosis indicated that while radiation did reduce Bcl-X(L and c-FLIP protein expression, this reduction did not correlate with the radiation-enhanced sensitivity to Fas and/or TRAIL mediated apoptosis among the three cell types. CONCLUSIONS/SIGNIFICANCE: Irradiation of tumor cells can overcome Fas and TRAIL

  7. Multiple Drug Treatments That Increase cAMP Signaling Restore Long-Term Memory and Aberrant Signaling in Fragile X Syndrome Models

    Science.gov (United States)

    Choi, Catherine H.; Schoenfeld, Brian P.; Bell, Aaron J.; Hinchey, Joseph; Rosenfelt, Cory; Gertner, Michael J.; Campbell, Sean R.; Emerson, Danielle; Hinchey, Paul; Kollaros, Maria; Ferrick, Neal J.; Chambers, Daniel B.; Langer, Steven; Sust, Steven; Malik, Aatika; Terlizzi, Allison M.; Liebelt, David A.; Ferreiro, David; Sharma, Ali; Koenigsberg, Eric; Choi, Richard J.; Louneva, Natalia; Arnold, Steven E.; Featherstone, Robert E.; Siegel, Steven J.; Zukin, R. Suzanne; McDonald, Thomas V.; Bolduc, Francois V.; Jongens, Thomas A.; McBride, Sean M. J.

    2016-01-01

    Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model. PMID:27445731

  8. India's Downstream Petroleum Sector

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2010-07-01

    This study provides a holistic examination of pricing and investment dynamics in India's downstream petroleum sector. It analyses the current pricing practices, highlights the tremendous fiscal cost of current pricing and regulatory arrangements, and examines the sectoral investment dynamics. It also looks at potential paths towards market-based reform along which the Indian government may move, while at the same time protecting energy market access for India's large poor population.

  9. Space-division-multiplexed transmission of 3x3 multiple-input multiple-output wireless signals over conventional graded-index multimode fiber.

    Science.gov (United States)

    Lei, Yi; Li, Jianqiang; Fan, Yuting; Yu, Dawei; Fu, Songnian; Yin, Feifei; Dai, Yitang; Xu, Kun

    2016-12-12

    In this paper, we experimentally demonstrate space-division-multiplexed (SDM) transmission of IEEE 802.11ac-compliant 3-spatial-stream WLAN signals over 3 spatial modes of conventional 50um graded-index (GI) multimode fiber (MMF) employing non-mode-selective 3D-waveguide photonic lantern. Two kinds of scenarios, including fiber-only transmission and fiber-wireless hybrid transmission, were investigated by measuring error vector magnitude (EVM) performance for each stream and condition number (CN) of the channel matrix. The experimental results show that, SDM-based MMF link could offer a CNwireless MIMO signals over existing in-building commercially-available MMFs with enormous cost-saving.

  10. Fiber nonlinearity mitigation of WDM-PDM QPSK/16-QAM signals using fiber-optic parametric amplifiers based multiple optical phase conjugations

    DEFF Research Database (Denmark)

    Hu, Hao; Jopson, Robert M.; Gnauck, Alan H.

    2017-01-01

    We demonstrate fiber nonlinearity mitigation by using multiple optical phase conjugations (OPCs) in the WDM transmission systems of both 8 x 32-Gbaud PDM QPSK channels and 8 x 32-Gbaud PDM 16-QAM channels, showing improved performance over a single mid-span OPC and no OPC in terms of nonlinear...... threshold and a best achievable Q(2) factor after transmission. In addition, after an even number of OPCs, the signal wavelength can be preserved after transmission. The performance of multiple OPCs for fiber nonlinearity mitigation was evaluated independently for WDM PDM QPSK signals and WDM PDM 16QAM...... to 1 dB compared to the case of mid-span OPC. The improvements in the best achievable Q(2) factors were more modest, ranging from 0.2 dB to 1.1 dB for the results presented. (C) 2017 Optical Society of America...

  11. Karhunen-Loève (PCA) based detection of multiple oscillations in multiple measurement signals from large-scale process plants

    DEFF Research Database (Denmark)

    Odgaard, Peter Fogh; Wickerhauser, M.V.

    2007-01-01

     In the perspective of optimizing the control and operation of large scale process plants, it is important to detect and to locate oscillations in the plants. This paper presents a scheme for detecting and localizing multiple oscillations in multiple measurements from such a large-scale power plant....... The scheme is based on a Karhunen-Lo\\`{e}ve analysis of the data from the plant. The proposed scheme is subsequently tested on two sets of data: a set of synthetic data and a set of data from a coal-fired power plant. In both cases the scheme detects the beginning of the oscillation within only a few samples....... In addition the oscillation localization has also shown its potential by localizing the oscillations in both data sets....

  12. Increased signal intensities in the dentate nucleus and globus pallidus on unenhanced T1-weighted images: evidence in children undergoing multiple gadolinium MRI exams

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Houchun H.; Pokorney, Amber; Towbin, Richard B.; Miller, Jeffrey H. [Phoenix Children' s Hospital, Department of Medical Imaging and Radiology, Phoenix, AZ (United States)

    2016-10-15

    Recent reports have suggested residual gadolinium deposition in the brain in subjects undergoing multiple contrast-enhanced MRI exams. These findings have raised some concerns regarding gadolinium-based contrast agent (GBCA) usage and retention in brain tissues. To summarize findings of hyperintense brain structures on precontrast T1-weighted images in 21 children undergoing multiple GBCA MRI exams. This retrospective study involved 21 patients, each of whom received multiple MRI examinations (range: 5-37 exams) with GBCA over the course of their medical treatment (duration from first to most recent exam: 1.2-12.9 years). The patients were between 0.9 and 14.4 years of age at the time of their first GBCA exam. Regions of interest were drawn in the dentate nucleus and the globus pallidus on 2-D fast spin echo images acquired at 1.5 T. The signal intensities of these two structures were normalized by that of the corpus callosum genu. Signal intensity ratios from these patients were compared to control patients of similar ages who have never received GBCA. Signal intensity ratios increased between the first and the most recent MRI exam in all 21 patients receiving GBCA, with an increase of 18.6%±12.7% (range: 0.5% to 47.5%) for the dentate nucleus and 12.4%±7.4% (range: -1.2% to 33.7%) for the globus pallidus (P<0.0001). Signal intensity ratios were also higher in GBCA patients than in controls (P<0.01). The degree of signal intensity enhancement did not correlate with statistical significance to the cumulative number or volume of GBCA administrations each patient received, the patient's age or the elapsed time between the first and most recent GBCA MRI exams. These results in children are consistent with recent findings in adults, suggesting possible gadolinium deposition in the brain. (orig.)

  13. Parametric Phase-sensitive and Phase-insensitive All-optical Signal Processing on Multiple Nonlinear Platforms - Invited talk

    DEFF Research Database (Denmark)

    Peucheret, Christophe; Da Ros, Francesco; Vukovic, Dragana

    Parametric processes in materials presenting a second- or third-order nonlinearity have been widely used to demonstrate a wide range of all-optical signal processing functionalities, including amplication, wavelength conversion, regeneration, sampling, switching, modulation format conver- sion, o...

  14. Multiple signalling systems controlling expression of luminescence in Vibrio harveyi: sequence and function of genes encoding a second sensory pathway.

    Science.gov (United States)

    Bassler, B L; Wright, M; Silverman, M R

    1994-07-01

    Density-dependent expression of luminescence in Vibrio harveyi is regulated by the concentration of extracellular signal molecules (autoinducers) in the culture medium. One signal-response system is encoded by the luxL,M,N locus. The luxL and luxM genes are required for the production of an autoinducer (probably beta-hydroxybutyl homoserine lactone), and the luxN gene is required for the response to that autoinducer. Analysis of the phenotypes of LuxL,M and N mutants indicated that an additional signal-response system also controls density sensing. We report here the identification, cloning and analysis of luxP and luxQ, which encode functions required for a second density-sensing system. Mutants with defects in luxP and luxQ are defective in response to a second autoinducer substance. LuxQ, like LuxN, is similar to members of the family of two-component, signal transduction proteins and contains both a histidine protein kinase and a response regulator domain. Analysis of signalling mutant phenotypes indicates that there are at least two separate signal-response pathways which converge to regulate expression of luminescence in V. harveyi.

  15. Parametric modelling of cardiac system multiple measurement signals: an open-source computer framework for performance evaluation of ECG, PCG and ABP event detectors.

    Science.gov (United States)

    Homaeinezhad, M R; Sabetian, P; Feizollahi, A; Ghaffari, A; Rahmani, R

    2012-02-01

    The major focus of this study is to present a performance accuracy assessment framework based on mathematical modelling of cardiac system multiple measurement signals. Three mathematical algebraic subroutines with simple structural functions for synthetic generation of the synchronously triggered electrocardiogram (ECG), phonocardiogram (PCG) and arterial blood pressure (ABP) signals are described. In the case of ECG signals, normal and abnormal PQRST cycles in complicated conditions such as fascicular ventricular tachycardia, rate dependent conduction block and acute Q-wave infarctions of inferior and anterolateral walls can be simulated. Also, continuous ABP waveform with corresponding individual events such as systolic, diastolic and dicrotic pressures with normal or abnormal morphologies can be generated by another part of the model. In addition, the mathematical synthetic PCG framework is able to generate the S4-S1-S2-S3 cycles in normal and in cardiac disorder conditions such as stenosis, insufficiency, regurgitation and gallop. In the PCG model, the amplitude and frequency content (5-700 Hz) of each sound and variation patterns can be specified. The three proposed models were implemented to generate artificial signals with varies abnormality types and signal-to-noise ratios (SNR), for quantitative detection-delineation performance assessment of several ECG, PCG and ABP individual event detectors designed based on the Hilbert transform, discrete wavelet transform, geometric features such as area curve length (ACLM), the multiple higher order moments (MHOM) metric, and the principal components analysed geometric index (PCAGI). For each method the detection-delineation operating characteristics were obtained automatically in terms of sensitivity, positive predictivity and delineation (segmentation) error rms and checked by the cardiologist. The Matlab m-file script of the synthetic ECG, ABP and PCG signal generators are available in the Appendix.

  16. Performance analysis of spectral-phase-encoded optical code-division multiple-access system regarding the incorrectly decoded signal as a nonstationary random process

    Science.gov (United States)

    Yan, Meng; Yao, Minyu; Zhang, Hongming

    2005-11-01

    The performance of a spectral-phase-encoded (SPE) optical code-division multiple-access (OCDMA) system is analyzed. Regarding the incorrectly decoded signal (IDS) as a nonstationary random process, we derive a novel probability distribution for it. The probability distribution of the IDS is considered a chi-squared distribution with degrees of freedom r=1, which is more reasonable and accurate than in previous work. The bit error rate (BER) of an SPE OCDMA system under multiple-access interference is evaluated. Numerical results show that the system can sustain very low BER even when there are multiple simultaneous users, and as the code length becomes longer or the initial pulse becomes shorter, the system performs better.

  17. Metabolic gene expression changes in astrocytes in Multiple Sclerosis cerebral cortex are indicative of immune-mediated signaling

    KAUST Repository

    Zeis, T.; Allaman, I.; Gentner, M.; Schroder, K.; Tschopp, J.; Magistretti, Pierre J.; Schaeren-Wiemers, N.

    2015-01-01

    Emerging as an important correlate of neurological dysfunction in Multiple Sclerosis (MS), extended focal and diffuse gray matter abnormalities have been found and linked to clinical manifestations such as seizures, fatigue and cognitive dysfunction

  18. DOWNSTREAM ECOCIDE FROM UPSTREAM WATER PIRACY

    OpenAIRE

    Miah Muhammad Adel

    2012-01-01

    Upstream India and downstream Bangladesh share more than 50 international rivers. India has set up water diversion constructions in more than 50% of these rivers, the largest one being on the Bangladeshâs northwest upon the Ganges River, puts Bangladeshâs Gangetic ecosystem at stake. In some border rivers, India has set up groins on her side of river banks. Also, Indian side pumps Bangladesh river water stealthily from border-rivers. Further, India is constructing another dam and reservoir up...

  19. Tidal Influence on Water Quality of Kapuas Kecil River Downstream

    Science.gov (United States)

    Purnaini, Rizki; Sudarmadji; Purwono, Suryo

    2018-02-01

    The Kapuas Kecil River is strongly influenced by tidal, in the dry season the intrusion of surface water is often a problem for the WTP because it causes the change of raw water quality to be processed. The purpose of this study was to examine the effect of sea tides on water quality of the Kapuas Kecil River. The study was conducted in Kapuas River downstream along ± 30 km from the upper boundary to the estuary. Water sampling is carried out during the dry and rainy season, when the tidal conditions at 7 (seven) locations of the monitoring station. Descriptive analysis methods and regression-correlation statistics are used to determine the effect of tides on water quality in Kapuas River downstream. In general, the water quality of the Kapuas Kecil River has exceeded the criteria of first class water quality, ie water that can be used for drinking water. The status of water quality of the Kapuas Kecil River based on the pollution index calculation shows the condition of the river is "mild to medium pollutants". The result of multiple linear regression analysis got the value of coefficient of determination (adjusted R square) = 0,760, which in whole show that independent variable (tidal and distance) influence to dependent variable (value of TDS) equal to 76%.

  20. The Multiple Faces of Prostaglandin E2 G-Protein Coupled Receptor Signaling during the Dendritic Cell Life Cycle

    Directory of Open Access Journals (Sweden)

    Alessandra Cambi

    2013-03-01

    Full Text Available Many processes regulating immune responses are initiated by G-protein coupled receptors (GPCRs and report biochemical changes in the microenvironment. Dendritic cells (DCs are the most potent antigen-presenting cells and crucial for the regulation of innate and adaptive immune responses. The lipid mediator Prostaglandin E2 (PGE2 via four GPCR subtypes (EP1-4 critically regulates DC generation, maturation and migration. The role of PGE2 signaling in DC biology was unraveled by the characterization of EP receptor subtype expression in DC progenitor cells and DCs, the identification of the signaling pathways initiated by these GPCR subtypes and the classification of DC responses to PGE2 at different stages of differentiation. Here, we review the advances in PGE2 signaling in DCs and describe the efforts still to be made to understand the spatio-temporal fine-tuning of PGE2 responses by DCs.

  1. CellNOptR: a flexible toolkit to train protein signaling networks to data using multiple logic formalisms.

    Science.gov (United States)

    Terfve, Camille; Cokelaer, Thomas; Henriques, David; MacNamara, Aidan; Goncalves, Emanuel; Morris, Melody K; van Iersel, Martijn; Lauffenburger, Douglas A; Saez-Rodriguez, Julio

    2012-10-18

    Cells process signals using complex and dynamic networks. Studying how this is performed in a context and cell type specific way is essential to understand signaling both in physiological and diseased situations. Context-specific medium/high throughput proteomic data measured upon perturbation is now relatively easy to obtain but formalisms that can take advantage of these features to build models of signaling are still comparatively scarce. Here we present CellNOptR, an open-source R software package for building predictive logic models of signaling networks by training networks derived from prior knowledge to signaling (typically phosphoproteomic) data. CellNOptR features different logic formalisms, from Boolean models to differential equations, in a common framework. These different logic model representations accommodate state and time values with increasing levels of detail. We provide in addition an interface via Cytoscape (CytoCopteR) to facilitate use and integration with Cytoscape network-based capabilities. Models generated with this pipeline have two key features. First, they are constrained by prior knowledge about the network but trained to data. They are therefore context and cell line specific, which results in enhanced predictive and mechanistic insights. Second, they can be built using different logic formalisms depending on the richness of the available data. Models built with CellNOptR are useful tools to understand how signals are processed by cells and how this is altered in disease. They can be used to predict the effect of perturbations (individual or in combinations), and potentially to engineer therapies that have differential effects/side effects depending on the cell type or context.

  2. Assigning Quantitative Function to Post-Translational Modifications Reveals Multiple Sites of Phosphorylation That Tune Yeast Pheromone Signaling Output

    Energy Technology Data Exchange (ETDEWEB)

    Pincus, David; Ryan, Christopher J.; Smith, Richard D.; Brent, Roger; Resnekov, Orna; Hakimi, Mohamed Ali

    2013-03-12

    Cell signaling systems transmit information by post-­translationally modifying signaling proteins, often via phosphorylation. While thousands of sites of phosphorylation have been identified in proteomic studies, the vast majority of sites have no known function. Assigning functional roles to the catalog of uncharacterized phosphorylation sites is a key research challenge. Here we present a general approach to address this challenge and apply it to a prototypical signaling pathway, the pheromone response pathway in Saccharomyces cerevisiae. The pheromone pathway includes a mitogen activated protein kinase (MAPK) cascade activated by a G-­protein coupled receptor (GPCR). We used mass spectrometry-based proteomics to identify sites whose phosphorylation changed when the system was active, and evolutionary conservation to assign priority to a list of candidate MAPK regulatory sites. We made targeted alterations in those sites, and measured the effects of the mutations on pheromone pathway output in single cells. Our work identified six new sites that quantitatively tuned system output. We developed simple computational models to find system architectures that recapitulated the quantitative phenotypes of the mutants. Our results identify a number of regulated phosphorylation events that contribute to adjust the input-­output relationship of this model eukaryotic signaling system. We believe this combined approach constitutes a general means not only to reveal modification sites required to turn a pathway on and off, but also those required for more subtle quantitative effects that tune pathway output. Our results further suggest that relatively small quantitative influences from individual regulatory phosphorylation events endow signaling systems with plasticity that evolution may exploit to quantitatively tailor signaling outcomes.

  3. Defocused low-energy shock wave activates adipose tissue-derived stem cells in vitro via multiple signaling pathways.

    Science.gov (United States)

    Xu, Lina; Zhao, Yong; Wang, Muwen; Song, Wei; Li, Bo; Liu, Wei; Jin, Xunbo; Zhang, Haiyang

    2016-12-01

    We found defocused low-energy shock wave (DLSW) could be applied in regenerative medicine by activating mesenchymal stromal cells. However, the possible signaling pathways that participated in this process remain unknown. In the present study, DLSW was applied in cultured rat adipose tissue-derived stem cells (ADSCs) to explore its effect on ADSCs and the activated signaling pathways. After treating with DLSW, the cellular morphology and cytoskeleton of ADSCs were observed. The secretions of ADSCs were detected. The expressions of ADSC surface antigens were analyzed using flow cytometry. The expressions of proliferating cell nuclear antigen and Ki67 were analyzed using western blot. The expression of CXCR2 and the migrations of ADSCs in vitro and in vivo were detected. The phosphorylation of selected signaling pathways with or without inhibitors was also detected. DLSW did not change the morphology and phenotype of ADSCs, and could promote the secretion, proliferation and migration of ADSCs. The phosphorylation levels were significantly higher in mitogen-activated protein kinases (MAPK) pathway, phosphoinositide 3-kinase (PI-3K)/AKT pathway and nuclear factor-kappa B (NF-κB) signaling pathway but not in Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Furthermore, ADSCs were not activated by DLSW after adding the inhibitors of these pathways simultaneously. Our results demonstrated for the first time that DLSW could activate ADSCs through MAPK, PI-3K/AKT and NF-κB signaling pathways. Combination of DLSW and agonists targeting these pathways might improve the efficacy of ADSCs in regenerative medicine in the future. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  4. Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

    DEFF Research Database (Denmark)

    Amin Al Olama, Ali; Dadaev, Tokhir; Hazelett, Dennis J

    2015-01-01

    associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated...... identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have...

  5. The root hair assay facilitates the use of genetic and pharmacological tools in order to dissect multiple signalling pathways that lead to programmed cell death.

    Directory of Open Access Journals (Sweden)

    Joanna Kacprzyk

    Full Text Available The activation of programmed cell death (PCD is often a result of complex signalling pathways whose relationship and intersection are not well understood. We recently described a PCD root hair assay and proposed that it could be used to rapidly screen genetic or pharmacological modulators of PCD. To further assess the applicability of the root hair assay for studying multiple signalling pathways leading to PCD activation we have investigated the crosstalk between salicylic acid, autophagy and apoptosis-like PCD (AL-PCD in Arabidopsis thaliana. The root hair assay was used to determine rates of AL-PCD induced by a panel of cell death inducing treatments in wild type plants treated with chemical modulators of salicylic acid synthesis or autophagy, and in genetic lines defective in autophagy or salicylic acid signalling. The assay demonstrated that PCD induced by exogenous salicylic acid or fumonisin B1 displayed a requirement for salicylic acid signalling and was partially dependent on the salicylic acid signal transducer NPR1. Autophagy deficiency resulted in an increase in the rates of AL-PCD induced by salicylic acid and fumonisin B1, but not by gibberellic acid or abiotic stress. The phenylalanine ammonia lyase-dependent salicylic acid synthesis pathway contributed only to death induced by salicylic acid and fumonisin B1. 3-Methyladenine, which is commonly used as an inhibitor of autophagy, appeared to influence PCD induction in all treatments suggesting a possible secondary, non-autophagic, effect on a core component of the plant PCD pathway. The results suggest that salicylic acid signalling is negatively regulated by autophagy during salicylic acid and mycotoxin-induced AL-PCD. However, this crosstalk does not appear to be directly involved in PCD induced by gibberellic acid or abiotic stress. This study demonstrates that the root hair assay is an effective tool for relatively rapid investigation of complex signalling pathways leading to

  6. DARHT-II Downstream Transport Beamline

    International Nuclear Information System (INIS)

    Westenskow, G A; Bertolini, L R; Duffy, P T; Paul, A C

    2001-01-01

    This paper describes the mechanical design of the downstream beam transport line for the second axis of the Dual Axis Radiographic Hydrodynamic Test (DARHT II) Facility. The DARHT-II project is a collaboration between LANL, LBNL and LLNL. DARHT II is a 18.4-MeV, 2000-Amperes, 2-(micro)sec linear induction accelerator designed to generate short bursts of x-rays for the purpose of radiographing dense objects. The downstream beam transport line is approximately 22-meter long region extending from the end of the accelerator to the bremsstrahlung target. Within this proposed transport line there are 12 conventional solenoid, quadrupole and dipole magnets; as well as several specialty magnets, which transport and focus the beam to the target and to the beam dumps. There are two high power beam dumps, which are designed to absorb 80-kJ per pulse during accelerator start-up and operation. Aspects of the mechanical design of these elements are presented

  7. Research on Healthy Anomaly Detection Model Based on Deep Learning from Multiple Time-Series Physiological Signals

    Directory of Open Access Journals (Sweden)

    Kai Wang

    2016-01-01

    Full Text Available Health is vital to every human being. To further improve its already respectable medical technology, the medical community is transitioning towards a proactive approach which anticipates and mitigates risks before getting ill. This approach requires measuring the physiological signals of human and analyzes these data at regular intervals. In this paper, we present a novel approach to apply deep learning in physiological signals analysis that allows doctor to identify latent risks. However, extracting high level information from physiological time-series data is a hard problem faced by the machine learning communities. Therefore, in this approach, we apply model based on convolutional neural network that can automatically learn features from raw physiological signals in an unsupervised manner and then based on the learned features use multivariate Gauss distribution anomaly detection method to detect anomaly data. Our experiment is shown to have a significant performance in physiological signals anomaly detection. So it is a promising tool for doctor to identify early signs of illness even if the criteria are unknown a priori.

  8. Multiple pathways carry signals from short-wavelength-sensitive ('blue') cones to the middle temporal area of the macaque.

    Science.gov (United States)

    Jayakumar, Jaikishan; Roy, Sujata; Dreher, Bogdan; Martin, Paul R; Vidyasagar, Trichur R

    2013-01-01

    We recorded spike activity of single neurones in the middle temporal visual cortical area (MT or V5) of anaesthetised macaque monkeys. We used flashing, stationary spatially circumscribed, cone-isolating and luminance-modulated stimuli of uniform fields to assess the effects of signals originating from the long-, medium- or short- (S) wavelength-sensitive cone classes. Nearly half (41/86) of the tested MT neurones responded reliably to S-cone-isolating stimuli. Response amplitude in the majority of the neurones tested further (19/28) was significantly reduced, though not always completely abolished, during reversible inactivation of visuotopically corresponding regions of the ipsilateral primary visual cortex (striate cortex, area V1). Thus, the present data indicate that signals originating in S-cones reach area MT, either via V1 or via a pathway that does not go through area V1. We did not find a significant difference between the mean latencies of spike responses of MT neurones to signals that bypass V1 and those that do not; the considerable overlap we observed precludes the use of spike-response latency as a criterion to define the routes through which the signals reach MT.

  9. Robust frequency diversity based algorithm for clutter noise reduction of ultrasonic signals using multiple sub-spectrum phase coherence

    Energy Technology Data Exchange (ETDEWEB)

    Gongzhang, R.; Xiao, B.; Lardner, T.; Gachagan, A. [Centre for Ultrasonic Engineering, University of Strathclyde, Glasgow, G1 1XW (United Kingdom); Li, M. [School of Engineering, University of Glasgow, Glasgow, G12 8QQ (United Kingdom)

    2014-02-18

    This paper presents a robust frequency diversity based algorithm for clutter reduction in ultrasonic A-scan waveforms. The performance of conventional spectral-temporal techniques like Split Spectrum Processing (SSP) is highly dependent on the parameter selection, especially when the signal to noise ratio (SNR) is low. Although spatial beamforming offers noise reduction with less sensitivity to parameter variation, phased array techniques are not always available. The proposed algorithm first selects an ascending series of frequency bands. A signal is reconstructed for each selected band in which a defect is present when all frequency components are in uniform sign. Combining all reconstructed signals through averaging gives a probability profile of potential defect position. To facilitate data collection and validate the proposed algorithm, Full Matrix Capture is applied on the austenitic steel and high nickel alloy (HNA) samples with 5MHz transducer arrays. When processing A-scan signals with unrefined parameters, the proposed algorithm enhances SNR by 20dB for both samples and consequently, defects are more visible in B-scan images created from the large amount of A-scan traces. Importantly, the proposed algorithm is considered robust, while SSP is shown to fail on the austenitic steel data and achieves less SNR enhancement on the HNA data.

  10. Rice bacterial blight pathogen Xanthomonas oryzae pv. oryzae produces multiple DSF-family signals in regulation of virulence factor production

    Directory of Open Access Journals (Sweden)

    Cha Jae-Soon

    2010-07-01

    Full Text Available Abstract Background Xanthomonas oryzae pv. oryzae (Xoo is the causal agent of rice bacterial blight disease. Xoo produces a range of virulence factors, including EPS, extracellular enzyme, iron-chelating siderophores, and type III-secretion dependent effectors, which are collectively essential for virulence. Genetic and genomics evidence suggest that Xoo might use the diffusible signal factor (DSF type quorum sensing (QS system to regulate the virulence factor production. However, little is known about the chemical structure of the DSF-like signal(s produced by Xoo and the factors influencing the signal production. Results Xoo genome harbours an rpf cluster comprising rpfB, rpfF, rpfC and rpfG. The proteins encoded by these genes are highly homologous to their counterparts in X. campestris pv. campestris (Xcc, suggesting that Xcc and Xoo might use similar mechanisms for DSF biosynthesis and autoregulation. Consistent with in silico analysis, the rpfF mutant was DSF-deficient and the rpfC mutant produced about 25 times higher DSF-like activity than the wild type Xoo strain KACC10331. From the supernatants of rpfC mutant, we purified three compounds showing strong DSF-like activity. Mass spectrometry and NMR analysis revealed that two of them were the previously characterized DSF and BDSF; the third one was a novel unsaturated fatty acid with 2 double bonds and was designated as CDSF in this study. Further analysis showed that all the three DSF-family signals were synthesized via the enzyme RpfF encoded by Xoo2868. DSF and BDSF at a final concentration of 3 μM to the rpfF mutant could fully restore its extracellular xylanase activity and EPS production to the wild type level, but CDSF was less active than DSF and BDSF in induction of EPS and xylanase. DSF and CDSF shared a similar cell density-dependent production time course with the maximum production being detected at 42 h after inoculation, whereas the maximum production of BDSF was observed

  11. Evaluating lane-by-lane gap-out based signal control for isolated intersection under stop-line, single and multiple advance detection systems

    Directory of Open Access Journals (Sweden)

    Chandan Keerthi Kancharla

    2016-12-01

    Full Text Available In isolated intersection’s actuated signal control, inductive loop detector layout plays a crucial role in providingthe vehicle information to the signal controller. Based on vehicle actuations at the detector, the green time is extended till a pre-defined threshold gap-out occurs. The Federal Highway Administration (FHWA proposed various guidelines for detec-tor layouts on low-speed and high-speed approaches. This paper proposes single and multiple advance detection schemes for low-speed traffic movements, that utilizes vehicle actuations from advance detectors located upstream of the stop-line, which are able to detect spill-back queues. The proposed detection schemes operate with actuated signal control based on lane-by-lane gap-out criteria. The performance of the proposed schemes is compared with FHWA’s stop-line and single advance detection schemes in the VISSIM simulation tool. Results have shown that the proposed single advance detection schemes showed improved performance in reducing travel time delay and average number of stops per vehicle under low volumes while the multiple advance detection scheme performed well under high volumes.

  12. Fibroblast growth factor receptor 3 interacts with and activates TGFβ-activated kinase 1 tyrosine phosphorylation and NFκB signaling in multiple myeloma and bladder cancer.

    Directory of Open Access Journals (Sweden)

    Lisa Salazar

    Full Text Available Cancer is a major public health problem worldwide. In the United States alone, 1 in 4 deaths is due to cancer and for 2013 a total of 1,660,290 new cancer cases and 580,350 cancer-related deaths are projected. Comprehensive profiling of multiple cancer genomes has revealed a highly complex genetic landscape in which a large number of altered genes, varying from tumor to tumor, impact core biological pathways and processes. This has implications for therapeutic targeting of signaling networks in the development of treatments for specific cancers. The NFκB transcription factor is constitutively active in a number of hematologic and solid tumors, and many signaling pathways implicated in cancer are likely connected to NFκB activation. A critical mediator of NFκB activity is TGFβ-activated kinase 1 (TAK1. Here, we identify TAK1 as a novel interacting protein and target of fibroblast growth factor receptor 3 (FGFR3 tyrosine kinase activity. We further demonstrate that activating mutations in FGFR3 associated with both multiple myeloma and bladder cancer can modulate expression of genes that regulate NFκB signaling, and promote both NFκB transcriptional activity and cell adhesion in a manner dependent on TAK1 expression in both cancer cell types. Our findings suggest TAK1 as a potential therapeutic target for FGFR3-associated cancers, and other malignancies in which TAK1 contributes to constitutive NFκB activation.

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

    International Nuclear Information System (INIS)

    Rhee, Yun-Hee; Jeong, Soo-Jin; Lee, Hyo-Jeong; Lee, Hyo-Jung; Koh, Wonil; Jung, Ji Hoon; Kim, Sun-Hee; Sung-Hoon, Kim

    2012-01-01

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

  14. Transcriptome Profiling Reveals the Negative Regulation of Multiple Plant Hormone Signaling Pathways Elicited by Overexpression of C-Repeat Binding Factors

    Directory of Open Access Journals (Sweden)

    Aixin Li

    2017-09-01

    Full Text Available C-repeat binding factors (CBF are a subfamily of AP2 transcription factors that play critical roles in the regulation of plant cold tolerance and growth in low temperature. In the present work, we sought to perform a detailed investigation into global transcriptional regulation of plant hormone signaling associated genes in transgenic plants engineered with CBF genes. RNA samples from Arabidopsis thaliana plants overexpressing two CBF genes, CBF2 and CBF3, were subjected to Illumina HiSeq 2000 RNA sequencing (RNA-Seq. Our results showed that more than half of the hormone associated genes that were differentially expressed in CBF2 or CBF3 transgenic plants were related to auxin signal transduction and metabolism. Most of these alterations in gene expression could lead to repression of auxin signaling. Accordingly, the IAA content was significantly decreased in young tissues of plants overexpressing CBF2 and CBF3 compared with wild type. In addition, genes associated with the biosynthesis of Jasmonate (JA and Salicylic acid (SA, as well as the signal sensing of Brassinolide (BR and SA, were down-regulated, while genes associated with Gibberellin (GA deactivation were up-regulated. In general, overexpression of CBF2 and CBF3 negatively affects multiple plant hormone signaling pathways in Arabidopsis. The transcriptome analysis using CBF2 and CBF3 transgenic plants provides novel and integrated insights into the interaction between CBFs and plant hormones, particularly the modulation of auxin signaling, which may contribute to the improvement of crop yields under abiotic stress via molecular engineering using CBF genes.

  15. Signaling Architectures that Transmit Unidirectional Information Despite Retroactivity.

    Science.gov (United States)

    Shah, Rushina; Del Vecchio, Domitilla

    2017-08-08

    A signaling pathway transmits information from an upstream system to downstream systems, ideally in a unidirectional fashion. A key obstacle to unidirectional transmission is retroactivity, the additional reaction flux that affects a system once its species interact with those of downstream systems. This raises the fundamental question of whether signaling pathways have developed specialized architectures that overcome retroactivity and transmit unidirectional signals. Here, we propose a general procedure based on mathematical analysis that provides an answer to this question. Using this procedure, we analyze the ability of a variety of signaling architectures to transmit one-way (from upstream to downstream) signals, as key biological parameters are tuned. We find that single stage phosphorylation and phosphotransfer systems that transmit signals from a kinase show a stringent design tradeoff that hampers their ability to overcome retroactivity. Interestingly, cascades of these architectures, which are highly represented in nature, can overcome this tradeoff and thus enable unidirectional transmission. By contrast, phosphotransfer systems, and single and double phosphorylation cycles that transmit signals from a substrate, are unable to mitigate retroactivity effects, even when cascaded, and hence are not well suited for unidirectional information transmission. These results are largely independent of the specific reaction-rate constant values, and depend on the topology of the architectures. Our results therefore identify signaling architectures that, allowing unidirectional transmission of signals, embody modular processes that conserve their input/output behavior across multiple contexts. These findings can be used to decompose natural signal transduction networks into modules, and at the same time, they establish a library of devices that can be used in synthetic biology to facilitate modular circuit design. Copyright © 2017 Biophysical Society. Published by

  16. Correction of inhomogeneous RF field using multiple SPGR signals for high-field spin-echo MRI

    International Nuclear Information System (INIS)

    Ishimori, Yoshiyuki; Monma, Masahiko; Yamada, Kazuhiro; Kimura, Hirohiko; Uematsu, Hidemasa; Fujiwara, Yasuhiro; Yamaguchi, Isao

    2007-01-01

    The purpose of this study was to propose a simple and useful method for correcting nonuniformity of high-field (3 Tesla) T 1 -weighted spin-echo (SE) images based on a B1 field map estimated from gradient recalled echo (GRE) signals. The method of this study was to estimate B1 inhomogeneity, spoiled gradient recalled echo (SPGR) images were collected using a fixed repetition time of 70 ms, flip angles of 45 and 90 degrees, and echo times of 4.8 and 10.4 ms. Selection of flip angles was based on the observation that the relative intensity changes in SPGR signals were very similar among different tissues at larger flip angles than the Ernst angle. Accordingly, spatial irregularity that was observed on a signal ratio map of the SPGR images acquired with these 2 flip angles was ascribed to inhomogeneity of the B1 field. Dual echo time was used to eliminate T 2 * effects. The ratio map that was acquired was scaled to provide an intensity correction map for SE images. Both phantom and volunteer studies were performed using a 3T magnetic resonance scanner to validate the method. In the phantom study, the uniformity of the T 1 -weighted SE image improved by 23%. Images of human heads also showed practically sufficient improvement in the image uniformity. The present method improves the image uniformity of high-field T 1 -weighted SE images. (author)

  17. Gene Expression Profile Reveals Abnormalities of Multiple Signaling Pathways in Mesenchymal Stem Cell Derived from Patients with Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Yu Tang

    2012-01-01

    Full Text Available We aimed to compare bone-marrow-derived mesenchymal stem cells (BMMSCs between systemic lupus erythematosus (SLE and normal controls by means of cDNA microarray, immunohistochemistry, immunofluorescence, and immunoblotting. Our results showed there were a total of 1, 905 genes which were differentially expressed by BMMSCs derived from SLE patients, of which, 652 genes were upregulated and 1, 253 were downregulated. Gene ontology (GO analysis showed that the majority of these genes were related to cell cycle and protein binding. Pathway analysis exhibited that differentially regulated signal pathways involved actin cytoskeleton, focal adhesion, tight junction, and TGF-β pathway. The high protein level of BMP-5 and low expression of Id-1 indicated that there might be dysregulation in BMP/TGF-β signaling pathway. The expression of Id-1 in SLE BMMSCs was reversely correlated with serum TNF-α levels. The protein level of cyclin E decreased in the cell cycling regulation pathway. Moreover, the MAPK signaling pathway was activated in BMMSCs from SLE patients via phosphorylation of ERK1/2 and SAPK/JNK. The actin distribution pattern of BMMSCs from SLE patients was also found disordered. Our results suggested that there were distinguished differences of BMMSCs between SLE patients and normal controls.

  18. Downstream process options for the ABE fermentation.

    Science.gov (United States)

    Friedl, Anton

    2016-05-01

    Butanol is a very interesting substance both for the chemical industry and as a biofuel. The classical distillation process for the removal of butanol is far too energy demanding, at a factor of 220% of the energy content of butanol. Alternative separation processes studied are hybrid processes of gas-stripping, liquid-liquid extraction and pervaporation with distillation and a novel adsorption/drying/desorption hybrid process. Compared with the energy content of butanol, the resulting energy demand for butanol separation and concentration of optimized hybrid processes is 11%-22% for pervaporation/distillation and 11%-17% for liquid-liquid extraction/distillation. For a novel adsorption/drying/desorption process, the energy demand is 9.4%. But all downstream process options need further proof of industrial applicability. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  19. The jet membrane-experiment: downstream sampling

    International Nuclear Information System (INIS)

    Campargue, R.

    1976-01-01

    The invasion separation effect of the free jet structure was found in 1966 at Saclay. In the Downstream Sampling Configuration patended by Campargue (1967), the light fraction is withdrawn from the supersonic central core, by skimming the separating free jet. From experimental and theoretical results obtained for gas and isotopic mixtures, the following points linked to operation and equipment costs, are considered: system description; influence of mass ratio, expansion ratio, nature of separating gas, ratio of upflow to separating jet flow, rarefaction. Fron an uninteresting aspect of Jet Membrane (elimination of background penetration), a new principle has been discovered to produce nozzle beams which may be of great interest for other separation processes involving free jets and/or molecular beams [fr

  20. Suppressor of cytokine signaling 2 (SOCS2) deletion protects against multiple low dose streptozotocin-induced type 1 diabetes in adult male mice

    DEFF Research Database (Denmark)

    Alkharusi, Amira; Mirecki-Garrido, Mercedes; Ma, Zuheng

    2016-01-01

    Background: Diabetes type 1 is characterized by the failure of beta cells to produce insulin. Suppressor of cytokine signaling (SOCS) proteins are important regulators of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Previous studies have shown that GH can...... prevent the development of type I diabetes in mice and that SOCS2 deficiency mimics a state of increased GH sensitivity. Methodology: The elevated sensitivity of SOCS2-/- mice to GH and possibly to PRL was the rationale to analyze the effects of multiple low dose streptozotocin (MLDSTZ)-induced diabetes...... in SOCS2-/- mice. Results: We show that 6-month-old SOCS2-/- mice, but not 2-month-old mice, were less sensitive to MLDSTZ-induced diabetes, compared to controls. MLDSTZ treatment induced glucose intolerance in both SOCS2+/+ and SOCS2-/- mice, as shown by glucose tolerance tests, with SOCS2+/+ mice...

  1. Systems-wide analysis of BCR signalosomes and downstream phosphorylation and ubiquitylation

    DEFF Research Database (Denmark)

    Satpathy, Shankha; Wagner, Sebastian A; Beli, Petra

    2015-01-01

    B-cell receptor (BCR) signaling is essential for the development and function of B cells; however, the spectrum of proteins involved in BCR signaling is not fully known. Here we used quantitative mass spectrometry-based proteomics to monitor the dynamics of BCR signaling complexes (signalosomes......) and to investigate the dynamics of downstream phosphorylation and ubiquitylation signaling. We identify most of the previously known components of BCR signaling, as well as many proteins that have not yet been implicated in this system. BCR activation leads to rapid tyrosine phosphorylation and ubiquitylation...... of the receptor-proximal signaling components, many of which are co-regulated by both the modifications. We illustrate the power of multilayered proteomic analyses for discovering novel BCR signaling components by demonstrating that BCR-induced phosphorylation of RAB7A at S72 prevents its association...

  2. ß-cell specific overexpression of suppressor of cytokine signalling-3 does not protect against multiple low dose streptozotocin induced type 1 diabetes in mice

    DEFF Research Database (Denmark)

    Börjesson, A; Rønn, S G; Karlsen, A E

    2011-01-01

    We investigated the impact of ß-cell specific overexpression of suppressor of cytokine signalling-3 (SOCS-3) on the development of multiple low dose streptozotocin (MLDSTZ) induced Type 1 diabetes and the possible mechanisms involved. MLDSTZ treatment was administered to RIP-SOCS-3 transgenic......RNA in islet cells and secretion of IL-1Ra into culture medium. MLDSTZ treatment caused gradual hyperglycemia both in the wt mice and in the transgenic mice with the latter tending to be more sensitive. In vitro experiments on wt and transgenic islets did not reveal any differences in sensitivity to damaging...

  3. C, N, P export regimes from headwater catchments to downstream reaches

    Science.gov (United States)

    Dupas, R.; Musolff, A.; Jawitz, J. W.; Rao, P. S.; Jaeger, C. G.; Fleckenstein, J. H.; Rode, M.; Borchardt, D.

    2017-12-01

    Excessive amounts of nutrients and dissolved organic matter in freshwater bodies affect aquatic ecosystems. In this study, the spatial and temporal variability in nitrate (NO3), dissolved organic carbon (DOC) and soluble reactive phosphorus (SRP) was analyzed in the Selke river continuum from headwaters draining 1 - 3 km² catchments to downstream reaches representing spatially integrated signals from 184 - 456 km² catchments (part of TERENO - Terrestrial Environmental Observatories, in Germany). Three headwater catchments were selected as archetypes of the main landscape units (land use x lithology) present in the Selke catchment. Export regimes in headwater catchments were interpreted in terms of NO3, DOC and SRP land-to-stream transfer processes. Headwater signals were subtracted from downstream signals, with the differences interpreted in terms of in-stream processes and contribution of point-source emissions. The seasonal dynamics for NO3 were opposite those of DOC and SRP in all three headwater catchments, and spatial differences also showed NO3 contrasting with DOC and SRP. These dynamics were interpreted as the result of the interplay of hydrological and biogeochemical processes, for which riparian zones were hypothesized to play a determining role. In the two downstream reaches, NO3 was transported almost conservatively, whereas DOC was consumed and produced in the upper and lower river sections, respectively. The natural export regime of SRP in the three headwater catchments mimicked a point-source signal, which may lead to overestimation of domestic contributions in the downstream reaches. Monitoring the river continuum from headwaters to downstream reaches proved effective to investigate jointly land-to-stream and in-stream transport and transformation processes.

  4. Multiple roles for nuclear localization signal (NLS, aa 442-472) of receptor interacting protein 3 (RIP3)

    International Nuclear Information System (INIS)

    Li Mei; Feng Shanshan; Wu Mian

    2008-01-01

    RIP3, a Ser/Thr kinase of RIP (Receptor Interacting Protein) family, is recruited to the TNFR1 signaling complex through RIP and has been shown to mediate apoptosis induction and NF-κB activation. RIP3 is a nucleocytoplasmic shuttling protein and its unconventional nuclear localization signal (NLS, 442-472 aa) is sufficient to trigger apoptosis in the nucleus. In this study, we demonstrate that this NLS exhibits several other roles besides apoptotic function. Firstly, this NLS was found to be required for both RIP3-induced apoptosis and RIP3-mediated NF-κB activation. Next, similar to RHIM motif (RIP homotypic interaction motif), NLS of RIP3 was found to be involved in RIP3-RIP interaction. Furthermore, this NLS was found to be both sufficient and necessary for RIP3 self-association. Our primary data also showed that RIP3 might form a homodimer within cells, and its apoptotic activity may not be required for this dimerization, rather the intactness of NLS determines RIP3-induced apoptosis, since a point mutation at amino acid residue 452 (Ile to Ala) within NLS greatly reduced its apoptotic ability, despite that RIP3 point mutant RIP3/I452A is able to dimerize with wild type RIP3 or itself

  5. Optogenetic analysis of a nociceptor neuron and network reveals ion channels acting downstream of primary sensors

    Science.gov (United States)

    Husson, Steven J.; Costa, Wagner Steuer; Wabnig, Sebastian; Stirman, Jeffrey N.; Watson, Joseph D.; Spencer, W. Clay; Akerboom, Jasper; Looger, Loren L.; Treinin, Millet; Miller, David M.; Lu, Hang; Gottschalk, Alexander

    2012-01-01

    Summary Background Nociception generally evokes rapid withdrawal behavior in order to protect the tissue from harmful insults. Most nociceptive neurons responding to mechanical insults display highly branched dendrites, an anatomy shared by Caenorhabditis elegans FLP and PVD neurons, which mediate harsh touch responses. Although several primary molecular nociceptive sensors have been characterized, less is known about modulation and amplification of noxious signals within nociceptor neurons. First, we analyzed the FLP/PVD network by optogenetics and studied integration of signals from these cells in downstream interneurons. Second, we investigated which genes modulate PVD function, based on prior single neuron mRNA profiling of PVD. Results Selectively photoactivating PVD, FLP and downstream interneurons using Channelrhodopsin-2 (ChR2) enabled functionally dissecting this nociceptive network, without interfering signals by other mechanoreceptors. Forward or reverse escape behaviors were determined by PVD and FLP, via integration by command interneurons. To identify mediators of PVD function, acting downstream of primary nocisensor molecules, we knocked down PVD-specific transcripts by RNAi and quantified light-evoked PVD-dependent behavior. Cell-specific disruption of synaptobrevin or voltage-gated Ca2+-channels (VGCCs) showed that PVD signals chemically to command interneurons. Knocking down the DEG/ENaC channel ASIC-1 and the TRPM channel GTL-1 indicated that ASIC-1 may extend PVD’s dynamic range and that GTL-1 may amplify its signals. These channels act cell-autonomously in PVD, downstream of primary mechanosensory molecules. Conclusions Our work implicates TRPM channels in modifying excitability of, and DEG/ENaCs in potentiating signal output from a mechano-nociceptor neuron. ASIC-1 and GTL-1 homologues, if functionally conserved, may denote valid targets for novel analgesics. PMID:22483941

  6. Adenylate Kinase and AMP Signaling Networks: Metabolic Monitoring, Signal Communication and Body Energy Sensing

    Directory of Open Access Journals (Sweden)

    Andre Terzic

    2009-04-01

    Full Text Available Adenylate kinase and downstream AMP signaling is an integrated metabolic monitoring system which reads the cellular energy state in order to tune and report signals to metabolic sensors. A network of adenylate kinase isoforms (AK1-AK7 are distributed throughout intracellular compartments, interstitial space and body fluids to regulate energetic and metabolic signaling circuits, securing efficient cell energy economy, signal communication and stress response. The dynamics of adenylate kinase-catalyzed phosphotransfer regulates multiple intracellular and extracellular energy-dependent and nucleotide signaling processes, including excitation-contraction coupling, hormone secretion, cell and ciliary motility, nuclear transport, energetics of cell cycle, DNA synthesis and repair, and developmental programming. Metabolomic analyses indicate that cellular, interstitial and blood AMP levels are potential metabolic signals associated with vital functions including body energy sensing, sleep, hibernation and food intake. Either low or excess AMP signaling has been linked to human disease such as diabetes, obesity and hypertrophic cardiomyopathy. Recent studies indicate that derangements in adenylate kinase-mediated energetic signaling due to mutations in AK1, AK2 or AK7 isoforms are associated with hemolytic anemia, reticular dysgenesis and ciliary dyskinesia. Moreover, hormonal, food and antidiabetic drug actions are frequently coupled to alterations of cellular AMP levels and associated signaling. Thus, by monitoring energy state and generating and distributing AMP metabolic signals adenylate kinase represents a unique hub within the cellular homeostatic network.

  7. Downstream Processing of Synechocystis for Biofuel Production

    Science.gov (United States)

    Sheng, Jie

    Lipids and free fatty acids (FFA) from cyanobacterium Synechocystis can be used for biofuel (e.g. biodiesel or renewable diesel) production. In order to utilize and scale up this technique, downstream processes including culturing and harvest, cell disruption, and extraction were studied. Several solvents/solvent systems were screened for lipid extraction from Synechocystis. Chloroform + methanol-based Folch and Bligh & Dyer methods were proved to be "gold standard" for small-scale analysis due to their highest lipid recoveries that were confirmed by their penetration of the cell membranes, higher polarity, and stronger interaction with hydrogen bonds. Less toxic solvents, such as methanol and MTBE, or direct transesterification of biomass (without preextraction step) gave only slightly lower lipid-extraction yields and can be considered for large-scale application. Sustained exposure to high and low temperature extremes severely lowered the biomass and lipid productivity. Temperature stress also triggered changes of lipid quality such as the degree of unsaturation; thus, it affected the productivities and quality of Synechocystis-derived biofuel. Pulsed electric field (PEF) was evaluated for cell disruption prior to lipid extraction. A treatment intensity > 35 kWh/m3 caused significant damage to the plasma membrane, cell wall, and thylakoid membrane, and it even led to complete disruption of some cells into fragments. Treatment by PEF enhanced the potential for the low-toxicity solvent isopropanol to access lipid molecules during subsequent solvent extraction, leading to lower usage of isopropanol for the same extraction efficiency. Other cell-disruption methods also were tested. Distinct disruption effects to the cell envelope, plasma membrane, and thylakoid membranes were observed that were related to extraction efficiency. Microwave and ultrasound had significant enhancement of lipid extraction. Autoclaving, ultrasound, and French press caused significant

  8. MEG (Magnetoencephalography) multipolar modeling of distributed sources using RAP-MUSIC (Recursively Applied and Projected Multiple Signal Characterization)

    Energy Technology Data Exchange (ETDEWEB)

    Mosher, J. C. (John C.); Baillet, S. (Sylvain); Jerbi, K. (Karim); Leahy, R. M. (Richard M.)

    2001-01-01

    We describe the use of truncated multipolar expansions for producing dynamic images of cortical neural activation from measurements of the magnetoencephalogram. We use a signal-subspace method to find the locations of a set of multipolar sources, each of which represents a region of activity in the cerebral cortex. Our method builds up an estimate of the sources in a recursive manner, i.e. we first search for point current dipoles, then magnetic dipoles, and finally first order multipoles. The dynamic behavior of these sources is then computed using a linear fit to the spatiotemporal data. The final step in the procedure is to map each of the multipolar sources into an equivalent distributed source on the cortical surface. The method is illustrated through an application to epileptic interictal MEG data.

  9. The microRNA-132/212 family fine-tunes multiple targets in Angiotensin II signalling in cardiac fibroblasts

    DEFF Research Database (Denmark)

    Eskildsen, Tilde V; Schneider, Mikael; Sandberg, Maria B

    2015-01-01

    INTRODUCTION: MicroRNAs (miRNAs) are emerging as key regulators of cardiovascular development and disease; however, the cardiac miRNA target molecules are not well understood. We and others have described the Angiotensin II (AngII)-induced miR-132/212 family as novel regulators of cardiovascular...... in silico and in vitro experiments to identify miR-132/212 molecular targets in primary rat cardiac fibroblasts. RESULTS: MiR-132/212 overexpression increased fibroblast cell size and mRNA arrays detected several hundred genes that were differentially expressed, including a wide panel of receptors...... pathways that fine-tuned by miR-132/212, suggesting a role for this miRNA family as master signalling switches in cardiac fibroblasts. Our data underscore the potential for miRNA tools to manipulate a large array of molecules and thereby control biological function....

  10. Methods and Apparatus for Aggregation of Multiple Pulse Code Modulation Channels into a Signal Time Division Multiplexing Stream

    Science.gov (United States)

    Chang, Chen J. (Inventor); Liaghati, Jr., Amir L. (Inventor); Liaghati, Mahsa L. (Inventor)

    2018-01-01

    Methods and apparatus are provided for telemetry processing using a telemetry processor. The telemetry processor can include a plurality of communications interfaces, a computer processor, and data storage. The telemetry processor can buffer sensor data by: receiving a frame of sensor data using a first communications interface and clock data using a second communications interface, receiving an end of frame signal using a third communications interface, and storing the received frame of sensor data in the data storage. After buffering the sensor data, the telemetry processor can generate an encapsulated data packet including a single encapsulated data packet header, the buffered sensor data, and identifiers identifying telemetry devices that provided the sensor data. A format of the encapsulated data packet can comply with a Consultative Committee for Space Data Systems (CCSDS) standard. The telemetry processor can send the encapsulated data packet using a fourth and a fifth communications interfaces.

  11. Low Oxygen Modulates Multiple Signaling Pathways, Increasing Self-Renewal, While Decreasing Differentiation, Senescence, and Apoptosis in Stromal MIAMI Cells

    Science.gov (United States)

    Rios, Carmen; D'Ippolito, Gianluca; Curtis, Kevin M.; Delcroix, Gaëtan J.-R.; Gomez, Lourdes A.; El Hokayem, Jimmy; Rieger, Megan; Parrondo, Ricardo; de las Pozas, Alicia; Perez-Stable, Carlos; Howard, Guy A.

    2016-01-01

    Human bone marrow multipotent mesenchymal stromal cell (hMSC) number decreases with aging. Subpopulations of hMSCs can differentiate into cells found in bone, vasculature, cartilage, gut, and other tissues and participate in their repair. Maintaining throughout adult life such cell subpopulations should help prevent or delay the onset of age-related degenerative conditions. Low oxygen tension, the physiological environment in progenitor cell-rich regions of the bone marrow microarchitecture, stimulates the self-renewal of marrow-isolated adult multilineage inducible (MIAMI) cells and expression of Sox2, Nanog, Oct4a nuclear accumulation, Notch intracellular domain, notch target genes, neuronal transcriptional repressor element 1 (RE1)-silencing transcription factor (REST), and hypoxia-inducible factor-1 alpha (HIF-1α), and additionally, by decreasing the expression of (i) the proapoptotic proteins, apoptosis-inducing factor (AIF) and Bak, and (ii) senescence-associated p53 expression and β-galactosidase activity. Furthermore, low oxygen increases canonical Wnt pathway signaling coreceptor Lrp5 expression, and PI3K/Akt pathway activation. Lrp5 inhibition decreases self-renewal marker Sox2 mRNA, Oct4a nuclear accumulation, and cell numbers. Wortmannin-mediated PI3K/Akt pathway inhibition leads to increased osteoblastic differentiation at both low and high oxygen tension. We demonstrate that low oxygen stimulates a complex signaling network involving PI3K/Akt, Notch, and canonical Wnt pathways, which mediate the observed increase in nuclear Oct4a and REST, with simultaneous decrease in p53, AIF, and Bak. Collectively, these pathway activations contribute to increased self-renewal with concomitant decreased differentiation, cell cycle arrest, apoptosis, and/or senescence in MIAMI cells. Importantly, the PI3K/Akt pathway plays a central mechanistic role in the oxygen tension-regulated self-renewal versus osteoblastic differentiation of progenitor cells. PMID:27059084

  12. The epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/β-catenin signaling and is frequently silenced in multiple tumors.

    Directory of Open Access Journals (Sweden)

    Xing-sheng Shu

    Full Text Available BACKGROUND: PRDM (PRDI-BF1 and RIZ domain containing proteins are zinc finger proteins involved in multiple cellular regulations by acting as epigenetic modifiers. We studied a recently identified PRDM member PRDM5 for its epigenetic abnormality and tumor suppressive functions in multiple tumorigeneses. METHODOLOGY/PRINCIPAL FINDINGS: Semi-quantitative RT-PCR showed that PRDM5 was broadly expressed in human normal tissues, but frequently silenced or downregulated in multiple carcinoma cell lines due to promoter CpG methylation, including 80% (4/5 nasopharyngeal, 44% (8/18 esophageal, 76% (13/17 gastric, 50% (2/4 cervical, and 25% (3/12 hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell lines. PRDM5 expression could be restored by 5-aza-2'-deoxycytidine demethylation treatment in silenced cell lines. PRDM5 methylation was frequently detected by methylation-specific PCR (MSP in multiple primary tumors, including 93% (43/46 nasopharyngeal, 58% (25/43 esophageal, 88% (37/42 gastric and 63% (29/46 hepatocellular tumors. PRDM5 was further found a stress-responsive gene, but its response was impaired when the promoter was methylated. Ectopic PRDM5 expression significantly inhibited tumor cell clonogenicity, accompanied by the inhibition of TCF/β-catenin-dependent transcription and downregulation of CDK4, TWIST1 and MDM2 oncogenes, while knocking down of PRDM5 expression lead to increased cell proliferation. ChIP assay showed that PRDM5 bound to its target gene promoters and suppressed their transcription. An inverse correlation between the expression of PRDM5 and activated β-catenin was also observed in cell lines. CONCLUSIONS/SIGNIFICANCE: PRDM5 functions as a tumor suppressor at least partially through antagonizing aberrant WNT/β-catenin signaling and oncogene expression. Frequent epigenetic silencing of PRDM5 is involved in multiple tumorigeneses, which could serve as a tumor biomarker.

  13. Microbial production of scleroglucan and downstream processing

    Directory of Open Access Journals (Sweden)

    Natalia Alejandra Castillo

    2015-10-01

    Full Text Available Synthetic petroleum-based polymers and natural plant polymers have the disadvantage of restricted sources, in addition to the non-biodegradability of the former ones. In contrast, eco-sustainable microbial polysaccharides, of low-cost and standardized production, represent an alternative to address this situation. With a strong global market, they attracted worldwide attention because of their novel and unique physico-chemical properties as well as varied industrial applications, and many of them are promptly becoming economically competitive. Scleroglucan, a beta-1,3-beta-1,6-glucan secreted by Sclerotium fungi, exhibits high potential for commercialization and may show different branching frequency, side-chain length and/or molecular weight depending on the producing strain or culture conditions. Water-solubility, viscosifying ability and wide stability over temperature, pH and salinity make scleroglucan useful for different biotechnological (enhanced oil recovery, food additives, drug delivery, cosmetic and pharmaceutical products, biocompatible materials, etc., and biomedical (immunoceutical, antitumor, etc. applications. It can be copiously produced at bioreactor scale under standardized conditions, where a high EPS concentration normally governs the process optimization. Operative and nutritional conditions, as well as the incidence of scleroglucan downstream processing will be discussed in this chapter. The relevance of using standardized inocula from selected strains and experiences concerning the intricate scleroglucan scaling-up will be also herein outlined.

  14. NAViGaTing the micronome--using multiple microRNA prediction databases to identify signalling pathway-associated microRNAs.

    Directory of Open Access Journals (Sweden)

    Elize A Shirdel

    2011-02-01

    Full Text Available MicroRNAs are a class of small RNAs known to regulate gene expression at the transcript level, the protein level, or both. Since microRNA binding is sequence-based but possibly structure-specific, work in this area has resulted in multiple databases storing predicted microRNA:target relationships computed using diverse algorithms. We integrate prediction databases, compare predictions to in vitro data, and use cross-database predictions to model the microRNA:transcript interactome--referred to as the micronome--to study microRNA involvement in well-known signalling pathways as well as associations with disease. We make this data freely available with a flexible user interface as our microRNA Data Integration Portal--mirDIP (http://ophid.utoronto.ca/mirDIP.mirDIP integrates prediction databases to elucidate accurate microRNA:target relationships. Using NAViGaTOR to produce interaction networks implicating microRNAs in literature-based, KEGG-based and Reactome-based pathways, we find these signalling pathway networks have significantly more microRNA involvement compared to chance (p<0.05, suggesting microRNAs co-target many genes in a given pathway. Further examination of the micronome shows two distinct classes of microRNAs; universe microRNAs, which are involved in many signalling pathways; and intra-pathway microRNAs, which target multiple genes within one signalling pathway. We find universe microRNAs to have more targets (p<0.0001, to be more studied (p<0.0002, and to have higher degree in the KEGG cancer pathway (p<0.0001, compared to intra-pathway microRNAs.Our pathway-based analysis of mirDIP data suggests microRNAs are involved in intra-pathway signalling. We identify two distinct classes of microRNAs, suggesting a hierarchical organization of microRNAs co-targeting genes both within and between pathways, and implying differential involvement of universe and intra-pathway microRNAs at the disease level.

  15. Signal intensity change on unenhanced T1-weighted images in dentate nucleus following gadobenate dimeglumine in patients with and without previous multiple administrations of gadodiamide

    Energy Technology Data Exchange (ETDEWEB)

    Ramalho, Joana [University of North Carolina Hospital, Chapel Hill, NC (United States); Centro Hospitalar de Lisboa Central, Lisbon (Portugal); Semelka, Richard C.; Castillo, Mauricio [University of North Carolina Hospital, Chapel Hill, NC (United States); AlObaidy, Mamdoh [University of North Carolina Hospital, Chapel Hill, NC (United States); King Faisal Specialist Hospital and Research Center, Riyadh (Saudi Arabia); Ramalho, Miguel [University of North Carolina Hospital, Chapel Hill, NC (United States); Hospital Garcia de Orta, Almada (Portugal); Nunes, Renato H. [University of North Carolina Hospital, Chapel Hill, NC (United States); Santa Casa de Misericordia de Sao Paulo, Sao Paulo (Brazil)

    2016-11-15

    To evaluate the impact of previous administration of gadodiamide and neural tissue gadolinium deposition in patients who received gadobenate dimeglumine. Our population included 62 patients who underwent at least three administrations of gadobenate dimeglumine, plus an additional contrast-enhanced last MRI for reference, divided into two groups: group 1, patients who in addition to gadobenate dimeglumine administrations had prior exposure to multiple doses of gadodiamide; group 2, patients without previous exposure to other gadolinium-based contrast agent (GBCAs). Quantitative analysis was performed on the first and last gadobenate dimeglumine MRIs in both groups. Dentate nucleus-to-middle cerebellar peduncle signal intensity ratios (DN/MCP) and relative change (RC) in signal over time were calculated and compared between groups using generalized additive model. Group 1 showed significant increase in baseline and follow-up DN/MCP compared to group 2 (p < 0.0001). The RC DN/MCP showed a non-statistically significant trend towards an increase in patients who underwent previous gadodiamide (p = 0.0735). There is increased T1 signal change over time in patients who underwent gadobenate dimeglumine and had received prior gadodiamide compared to those without known exposure to previous gadodiamide. A potentiating effect from prior gadodiamide on subsequent administered gadobenate dimeglumine may occur. (orig.)

  16. Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome–associated Sos1 mutation

    Science.gov (United States)

    Chen, Peng-Chieh; Wakimoto, Hiroko; Conner, David; Araki, Toshiyuki; Yuan, Tao; Roberts, Amy; Seidman, Christine E.; Bronson, Roderick; Neel, Benjamin G.; Seidman, Jonathan G.; Kucherlapati, Raju

    2010-01-01

    Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, unique facial features, and congenital heart disease. About 10%–15% of individuals with NS have mutations in son of sevenless 1 (SOS1), which encodes a RAS and RAC guanine nucleotide exchange factor (GEF). To understand the role of SOS1 in the pathogenesis of NS, we generated mice with the NS-associated Sos1E846K gain-of-function mutation. Both heterozygous and homozygous mutant mice showed many NS-associated phenotypes, including growth delay, distinctive facial dysmorphia, hematologic abnormalities, and cardiac defects. We found that the Ras/MAPK pathway as well as Rac and Stat3 were activated in the mutant hearts. These data provide in vivo molecular and cellular evidence that Sos1 is a GEF for Rac under physiological conditions and suggest that Rac and Stat3 activation might contribute to NS phenotypes. Furthermore, prenatal administration of a MEK inhibitor ameliorated the embryonic lethality, cardiac defects, and NS features of the homozygous mutant mice, demonstrating that this signaling pathway might represent a promising therapeutic target for NS. PMID:21041952

  17. Novel signal-dependent filter bank method for identification of multiple basal ganglia nuclei in Parkinsonian patients

    Science.gov (United States)

    Pinzon-Morales, R. D.; Orozco-Gutierrez, A. A.; Castellanos-Dominguez, G.

    2011-06-01

    Microelectrode recordings are a valuable tool for assisting localization targets during deep brain stimulation procedures in Parkinson's disease neurosurgery. Attempts to automate and standardize this process have been limited by variability in patient neurophysiology and strong dynamics of microelectrode recordings. In this paper, a methodology for the identification of basal ganglia nuclei is presented that is based on a signal-dependent filter bank method using microelectrode recordings. The method is a customized realization of the discrete wavelet transform via the lifting scheme that is optimally tuned by genetic algorithms. Using this method, unique mother wavelet functions that exhibit an adaptable spectrum to the microelectrode recording dynamic are generated. Additionally, by extracting morphological features from the space-transformed microelectrode recording, it is possible to integrate them into three-dimensional (3D) feature spaces with maximum class separability. Finally, high discriminant feature spaces are fed into basic classifiers to recognize up to four basal nuclei. Comparison with several existing wavelets highlights the characteristics of new mother wavelets. Additionally, classification results show that identification of addressed nuclei in the basal ganglia can be performed with 95% confidence.

  18. Physiological and Pathogenic Roles of Prolyl Isomerase Pin1 in Metabolic Regulations via Multiple Signal Transduction Pathway Modulations

    Directory of Open Access Journals (Sweden)

    Yusuke Nakatsu

    2016-09-01

    Full Text Available Prolyl isomerases are divided into three groups, the FKBP family, Cyclophilin and the Parvulin family (Pin1 and Par14. Among these isomerases, Pin1 is a unique prolyl isomerase binding to the motif including pSer/pThr-Pro that is phosphorylated by kinases. Once bound, Pin1 modulates the enzymatic activity, protein stability or subcellular localization of target proteins by changing the cis- and trans-formations of proline. Several studies have examined the roles of Pin1 in the pathogenesis of cancers and Alzheimer’s disease. On the other hand, recent studies have newly demonstrated Pin1 to be involved in regulating glucose and lipid metabolism. Interestingly, while Pin1 expression is markedly increased by high-fat diet feeding, Pin1 KO mice are resistant to diet-induced obesity, non-alcoholic steatohepatitis and diabetic vascular dysfunction. These phenomena result from the binding of Pin1 to several key factors regulating metabolic functions, which include insulin receptor substrate-1, AMPK, Crtc2 and NF-κB p65. In this review, we focus on recent advances in elucidating the physiological roles of Pin1 as well as the pathogenesis of disorders involving this isomerase, from the viewpoint of the relationships between signal transductions and metabolic functions.

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

    Directory of Open Access Journals (Sweden)

    Silke Neumann

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

  20. Receptor activity modifying proteins (RAMPs) interact with the VPAC1 receptor: evidence for differential RAMP modulation of multiple signalling pathways

    International Nuclear Information System (INIS)

    Christopoulos, G.; Morfis, M.; Sexton, P.M.; Christopoulos, A.; Laburthe, M.; Couvineau, A.

    2001-01-01

    Full text: Receptor activity modifying proteins (RAMP) constitute a family of three accessory proteins that affect the expression and/or phenotype of the calcitonin receptor (CTR) or CTR-like receptor (CRLR). In this study we screened a range of class II G protein-coupled receptors (PTH1, PTH2, GHRH, VPAC1, VPAC2 receptors) for possible RAMP interactions by measurement of receptor-induced translocation of c-myc tagged RAMP1 or HA tagged RAMP3. Of these, only the VPAC1 receptor caused significant translocation of c-myc-RAMP1 or HA-RAMP3 to the cell surface. Co-transfection of VPAC1 and RAMPs did not alter 125 I-VIP binding and specificity. VPAC1 receptor function was subsequently analyzed through parallel determinations of cAMP accumulation and phosphoinositide (PI) hydrolysis in the presence and absence of each of the three RAMPs. In contrast to CTR-RAMP interaction, where there was an increase in cAMP Pharmacologisand a decrease in PI hydrolysis, VPAC1-RAMP interaction was characterized by a specific increase in agonist-mediated PI hydrolysis when co-transfected with RAMP2. This change was due to an enhancement of Emax with no change in EC 50 value for VIP. No significant change in cAMP accumulation was observed. This is the first demonstration of an interaction of RAMPs with a G protein-coupled receptor outside the CTR family and may suggest a more generalized role for RAMPs in modulating G protein-coupled receptor signaling. Copyright (2001) Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists

  1. Multiple, disparate roles for calcium signaling in apoptosis of human prostate and cervical cancer cells exposed to diindolylmethane.

    Science.gov (United States)

    Savino, John A; Evans, Jodi F; Rabinowitz, Dorianne; Auborn, Karen J; Carter, Timothy H

    2006-03-01

    Diindolylmethane (DIM), derived from indole-3-carbinol in cruciferous vegetables, causes growth arrest and apoptosis of cancer cells in vitro. DIM also induces endoplasmic reticulum (ER) stress, and thapsigargin, a specific inhibitor of the sarcoplasmic reticulum/ER calcium-dependent ATPase, enhances this effect. We asked whether elevated cytosolic free calcium [Ca2+]i is required for cytotoxicity of DIM and thapsigargin in two cancer cells lines (C33A, from cervix, and DU145, from prostate). [Ca2+]i was measured in real-time by FURA-2 fluorescence. We tested whether DIM, thapsigargin, and DIM + thapsigargin cause apoptosis, measured by nucleosome release, under conditions that prevented elevation of [Ca2+]i, using both cell-permeable and cell-impermeable forms of the specific calcium chelator BAPTA. DIM, like thapsigargin, rapidly mobilized ER calcium. C33A and DU145 responded differently to perturbations in Ca2+ homeostasis, suggesting that DIM induces apoptosis by different mechanisms in these two cell lines and/or that calcium mobilization also activates different survival pathways in C33A and DU145. Apoptosis in C33A was independent of increased [Ca2+]i, suggesting that depletion of ER Ca2+ stores may be sufficient for cell killing, whereas apoptosis in DU145 required elevated [Ca2+]i for full response. Inhibitor studies using cyclosporin A and KN93 showed that Ca2+ signaling is important for cell survival but the characteristics of this response also differed in the two cell lines. Our results underscore the complex and variable nature of cellular responses to disrupted Ca2+ homeostasis and suggest that alteration Ca2+ homeostasis in the ER can induce cellular apoptosis by both calcium-dependent and calcium-independent mechanisms.

  2. Circadian rhythms in healthy aging--effects downstream from the pacemaker

    Science.gov (United States)

    Monk, T. H.; Kupfer, D. J.

    2000-01-01

    Using both previously published findings and entirely new data, we present evidence in support of the argument that the circadian dysfunction of advancing age in the healthy human is primarily one of failing to transduce the circadian signal from the circadian timing system (CTS) to rhythms "downstream" from the pacemaker rather than one of failing to generate the circadian signal itself. Two downstream rhythms are considered: subjective alertness and objective performance. For subjective alertness, we show that in both normal nychthemeral (24 h routine, sleeping at night) and unmasking (36 h of constant wakeful bed rest) conditions, advancing age, especially in men, leads to flattening of subjective alertness rhythms, even when circadian temperature rhythms are relatively robust. For objective performance, an unmasking experiment involving manual dexterity, visual search, and visual vigilance tasks was used to demonstrate that the relationship between temperature and performance is strong in the young, but not in older subjects (and especially not in older men).

  3. Associations of mRNA:microRNA for the shared downstream molecules of EGFR and alternative tyrosine kinase receptors in Non-Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Fengfeng Wang

    2016-10-01

    Full Text Available Lung cancer is the top cancer killer worldwide with high mortality rate. Majority belong to non-small cell lung cancers (NSCLCs. The epidermal growth factor receptor (EGFR has been broadly explored as a drug target for therapy. However, the drug responses are not durable due to the acquired resistance. MicroRNAs (miRNAs are small noncoding and endogenous molecules that can inhibit mRNA translation initiation and degrade mRNAs. We wonder if some downstream molecules shared by EGFR and the other tyrosine kinase receptors (TKRs further transduce the signals alternatively, and some miRNAs play the key roles in affecting the expression of these downstream molecules. In this study, we investigated the mRNA:miRNA associations for the direct EGFR downstream molecules in the EGFR signaling pathway shared with the other TKRs, including c-MET (hepatocyte growth factor receptor, Ron (a protein tyrosine kinase related to c-MET, PDGFR (platelet-derived growth factor receptor, and IGF-1R (insulin-like growth factor receptor-1. The multiple linear regression and support vector regression (SVR models were used to discover the statistically significant and the best weighted miRNAs regulating the mRNAs of these downstream molecules. These two models revealed the similar mRNA:miRNA associations. It was found that the miRNAs significantly affecting the mRNA expressions in the multiple regression model were also those with the largest weights in the SVR model. To conclude, we effectively identified a list of meaningful mRNA:miRNA associations: phospholipase C, gamma 1 (PLCG1 with miR-34a, phosphoinositide-3-kinase, regulatory subunit 2 (PIK3R2 with miR-30a-5p, growth factor receptor-bound protein 2 (GRB2 with miR-27a, and Janus kinase 1 (JAK1 with miR-302b and miR-520e. These associations could make great contributions to explore new mechanism in NSCLCs. These candidate miRNAs may be regarded as the potential drug targets for treating NSCLCs with acquired drug

  4. A low-cost, high-performance, digital signal processor-based lock-in amplifier capable of measuring multiple frequency sweeps simultaneously

    International Nuclear Information System (INIS)

    Sonnaillon, Maximiliano Osvaldo; Bonetto, Fabian Jose

    2005-01-01

    A high-performance digital lock-in amplifier implemented in a low-cost digital signal processor (DSP) board is described. This lock in is capable of measuring simultaneously multiple frequencies that change in time as frequency sweeps (chirps). The used 32-bit DSP has enough computing power to generate N=3 simultaneous reference signals and accurately measure the N=3 responses, operating as three lock ins connected in parallel to a linear system. The lock in stores the measured values in memory until they are downloaded to the a personal computer (PC). The lock in works in stand-alone mode and can be programmed and configured through the PC serial port. Downsampling and multiple filter stages were used in order to obtain a sharp roll off and a long time constant in the filters. This makes measurements possible in presence of high-noise levels. Before each measurement, the lock in performs an autocalibration that measures the frequency response of analog output and input circuitry in order to compensate for the departure from ideal operation. Improvements from previous lock-in implementations allow measuring the frequency response of a system in a short time. Furthermore, the proposed implementation can measure how the frequency response changes with time, a characteristic that is very important in our biotechnological application. The number of simultaneous components that the lock in can generate and measure can be extended, without reprogramming, by only using other DSPs of the same family that are code compatible and work at higher clock frequencies

  5. A low-cost, high-performance, digital signal processor-based lock-in amplifier capable of measuring multiple frequency sweeps simultaneously

    Energy Technology Data Exchange (ETDEWEB)

    Sonnaillon, Maximiliano Osvaldo; Bonetto, Fabian Jose [Laboratorio de Cavitacion y Biotecnologia, San Carlos de Bariloche (8400) (Argentina)

    2005-02-01

    A high-performance digital lock-in amplifier implemented in a low-cost digital signal processor (DSP) board is described. This lock in is capable of measuring simultaneously multiple frequencies that change in time as frequency sweeps (chirps). The used 32-bit DSP has enough computing power to generate N=3 simultaneous reference signals and accurately measure the N=3 responses, operating as three lock ins connected in parallel to a linear system. The lock in stores the measured values in memory until they are downloaded to the a personal computer (PC). The lock in works in stand-alone mode and can be programmed and configured through the PC serial port. Downsampling and multiple filter stages were used in order to obtain a sharp roll off and a long time constant in the filters. This makes measurements possible in presence of high-noise levels. Before each measurement, the lock in performs an autocalibration that measures the frequency response of analog output and input circuitry in order to compensate for the departure from ideal operation. Improvements from previous lock-in implementations allow measuring the frequency response of a system in a short time. Furthermore, the proposed implementation can measure how the frequency response changes with time, a characteristic that is very important in our biotechnological application. The number of simultaneous components that the lock in can generate and measure can be extended, without reprogramming, by only using other DSPs of the same family that are code compatible and work at higher clock frequencies.

  6. Prevotella intermedia stimulates tissue-type plasminogen activator and plasminogen activator inhibitor-2 expression via multiple signaling pathways in human periodontal ligament cells.

    Science.gov (United States)

    Guan, Su-Min; He, Jian-Jun; Zhang, Ming; Shu, Lei

    2011-06-01

    Prevotella intermedia is an important periodontal pathogen that induces various inflammatory and immune responses. In this study, we investigated the effects of P. intermedia on the plasminogen system in human periodontal ligament (hPDL) cells and explored the signaling pathways involved. Using semi-quantitative reverse transcription (RT)-PCR and quantitative real-time RT-qPCR, we demonstrated that P. intermedia challenge increased tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor (PAI)-2 expression in a concentration- and time-dependent manner, but exerted no influence on urokinase-type plasminogen activator and PAI-1mRNA expression in hPDL cells. Prevotella intermedia stimulation also enhanced tPA protein secretion as confirmed by enzyme-linked immunosorbent assay. Western blot results revealed that P. intermedia treatment increased phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 kinase (p38). ERK, JNK and protein kinase C inhibitors significantly attenuated the P. intermedia-induced tPA and PAI-2 expression. Furthermore, p38 and phosphatidylinositol 3-kinase inhibitors markedly decreased PAI-2 expression, whereas they showed no or little inhibition on tPA expression. In contrast, inhibition of protein kinase A greatly enhanced the upregulatory effect of P. intermedia on tPA and PAI-2 expression. Our results suggest that P. intermedia may contribute to periodontal tissue destruction by upregulating tPA and PAI-2 expression in hPDL cells via multiple signaling pathways. © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

  7. Signal intensity change on unenhanced T1-weighted images in dentate nucleus and globus pallidus after multiple administrations of gadoxetate disodium: an intraindividual comparative study

    Energy Technology Data Exchange (ETDEWEB)

    Conte, Giorgio; Minotti, Marta; De Piano, Francesca [Universita degli Studi di Milano, Postgraduation School in Radiodiagnostics, Milan (Italy); Preda, Lorenzo [Universita degli Studi di Pavia, Department of Clinical-Surgical Diagnostic and Pediatric Sciences, Pavia (Italy); National Center of Oncological Hadrontherapy (CNAO Foundation), Division of Radiology, Pavia (Italy); Cocorocchio, Emilia; Ferrucci, Pier Francesco [European Institute of Oncology, Melanoma and Sarcoma Medical Oncology Division, Milan (Italy); Raimondi, Sara [European Institute of Oncology, Division of Epidemiology and Biostatistics, Milan (Italy); Giannitto, Caterina; Petralia, Giuseppe [European Institute of Oncology, Division of Radiology, Milan (Italy); Bellomi, Massimo [European Institute of Oncology, Division of Radiology, Milan (Italy); Universita degli Studi di Milano, Oncology and Haematology/Oncology Department, Milan (Italy)

    2017-10-15

    To investigate whether there is an increased signal intensity (SI) of dentate nucleus (DN) and globus pallidus (GP) on unenhanced T1-weighted magnetic resonance imaging (MRI), in patients who had undergone multiple administrations of gadoxetate disodium. We retrospectively included stage III melanoma patients, who had been previously enrolled in a trial of adjuvant therapy and who had undergone whole-body contrast-enhanced MRIs with gadoxetate disodium every three months for their follow-up. The SI ratios of DN-to-pons and GP-to-thalamus on unenhanced T1-weighted images were calculated. The difference in SI ratios between the first and the last MRI examinations was assessed and a linear mixed model was performed to detect how SI ratios varied with the number of administrations. Eighteen patients were included in our study. The number of gadoxetate disodium administrations ranged from 2 to 18. Paired t-test did not show any significant difference in DN-to-pons (p=0.21) and GP-to-thalamus (p=0.09) SI ratios by the end of the study. DN-to-pons SI ratio and GP-to-thalamus SI ratio did not significantly increase with increasing the number of administrations (p=0.14 and p=0.06, respectively). Multiple administrations of gadoxetate disodium are not associated with increased SI in DN and GP in the brain. (orig.)

  8. Increasing the number and signal-to-noise ratio of OBS traces with supervirtual refraction interferometry and free-surface multiples

    KAUST Repository

    Bharadwaj, P.; Wang, X.; Schuster, Gerard T.; McIntosh, K.

    2013-01-01

    The theory of supervirtual interferometry is modified so that free-surface related multiple refractions can be used to enhance the signal-to-noise ratio (SNR) of primary refraction events by a factor proportional to√Ns, where Ns is the number of post-critical sources for a specified refraction multiple. We also show that refraction multiples can be transformed into primary refraction events recorded at virtual hydrophones located between the actual hydrophones. Thus, data recorded by a coarse sampling of ocean bottom seismic (OBS) stations can be transformed, in principle, into a virtual survey with P times more OBS stations, where P is the order of the visible free-surface related multiple refractions. The key assumption is that the refraction arrivals are those of head waves, not pure diving waves. The effectiveness of this method is validated with both synthetic OBS data and an OBS data set recorded offshore from Taiwan. Results show the successful reconstruction of far-offset traces out to a source-receiver offset of 120 km. The primary supervirtual traces increase the number of pickable first arrivals from approximately 1600 to more than 3100 for a subset of the OBS data set where the source is only on one side of the recording stations. In addition, the head waves associated with the first-order free-surface refraction multiples allow for the creation of six new common receiver gathers recorded at virtual OBS station located about half way between the actual OBS stations. This doubles the number of OBS stations compared to the original survey and increases the total number of pickable traces from approximately 1600 to more than 6200. In summary, our results with the OBS data demonstrate that refraction interferometry can sometimes more than quadruple the number of usable traces, increase the source-receiver offsets, fill in the receiver line with a denser distribution of OBS stations, and provide more reliable picking of first arrivals. Apotential liability

  9. Increasing the number and signal-to-noise ratio of OBS traces with supervirtual refraction interferometry and free-surface multiples

    KAUST Repository

    Bharadwaj, P.

    2013-01-10

    The theory of supervirtual interferometry is modified so that free-surface related multiple refractions can be used to enhance the signal-to-noise ratio (SNR) of primary refraction events by a factor proportional to√Ns, where Ns is the number of post-critical sources for a specified refraction multiple. We also show that refraction multiples can be transformed into primary refraction events recorded at virtual hydrophones located between the actual hydrophones. Thus, data recorded by a coarse sampling of ocean bottom seismic (OBS) stations can be transformed, in principle, into a virtual survey with P times more OBS stations, where P is the order of the visible free-surface related multiple refractions. The key assumption is that the refraction arrivals are those of head waves, not pure diving waves. The effectiveness of this method is validated with both synthetic OBS data and an OBS data set recorded offshore from Taiwan. Results show the successful reconstruction of far-offset traces out to a source-receiver offset of 120 km. The primary supervirtual traces increase the number of pickable first arrivals from approximately 1600 to more than 3100 for a subset of the OBS data set where the source is only on one side of the recording stations. In addition, the head waves associated with the first-order free-surface refraction multiples allow for the creation of six new common receiver gathers recorded at virtual OBS station located about half way between the actual OBS stations. This doubles the number of OBS stations compared to the original survey and increases the total number of pickable traces from approximately 1600 to more than 6200. In summary, our results with the OBS data demonstrate that refraction interferometry can sometimes more than quadruple the number of usable traces, increase the source-receiver offsets, fill in the receiver line with a denser distribution of OBS stations, and provide more reliable picking of first arrivals. Apotential liability

  10. Downstream-based Scheduling for Energy Conservation in Green EPONs

    KAUST Repository

    Chen, Shen; Dhaini, Ahmad R.; Ho, Pin-Han; Shihada, Basem; Shen, Gangxiang; Lin, Chih-Hao

    2012-01-01

    the ONU sleep time, it jeopardizes the quality of service (QoS) performance of the network, especially for downstream traffic in case the overlapping is based on the upstream time slot. In this paper, we study the downstream traffic performance in green

  11. A floating trap for sampling downstream migrant fishes.

    Science.gov (United States)

    Carl E. McLemore; Fred H. Everest; William R. Humphreys; Mario F. Solazzi

    1989-01-01

    Fishery scientists and managers are interested in obtaining information about downstream movements of fish species for biological and economic reasons. Different types of nets and traps have been used for this purpose with only partial success. The floating, self-cleaning downstream migrant trap described here proved successful for sampling several salmoniform and...

  12. Empirical investigation on the dependence of TCP downstream throughput on SNR in an IEEE802.11b WLAN system

    Directory of Open Access Journals (Sweden)

    Ikponmwosa Oghogho

    2017-04-01

    Full Text Available The dependence of TCP downstream throughput (TCPdownT on signal to noise ratio (SNR in an IEEE802.11b WLAN system was investigated in various environments and varieties of QoS traffic. TCPdownT was measured for various SNR observed. An Infrastructure based IEEE802.11b WLAN system having networked computers on which measurement software were installed, was set up consecutively in various environments (open corridor, small offices with block walls and plaster boards and free space. Empirical models describing TCPdownT against SNR for different signal ranges (all ranges of signals, strong signals only, grey signals only and weak signals only were statistically generated and validated. As the SNR values changed from high (strong signals through low (grey signals to very low (weak signals, our results show a strong dependence of TCPdownT on the received SNR. Our models showed lower RMS errors when compared with other similar models. We observed RMS errors of 0.6734791 Mbps, 0.472209 Mbps, 0.9111563 Mbps and 0.5764460 Mbps for general (all SNR model, strong signals model, grey signals model and Weak signals model respectively. Our models will provide researchers and WLAN systems users with a tool to estimate the TCP downstream throughput in a real network in various environments by monitoring the received SNR.

  13. Cellular prion protein is required for neuritogenesis: fine-tuning of multiple signaling pathways involved in focal adhesions and actin cytoskeleton dynamics

    Directory of Open Access Journals (Sweden)

    Alleaume-Butaux A

    2013-07-01

    Full Text Available Aurélie Alleaume-Butaux,1,2 Caroline Dakowski,1,2 Mathéa Pietri,1,2 Sophie Mouillet-Richard,1,2 Jean-Marie Launay,3,4 Odile Kellermann,1,2 Benoit Schneider1,2 1INSERM, UMR-S 747, 2Paris Descartes University, Sorbonne Paris Cité, UMR-S 747, 3Public Hospital of Paris, Department of Biochemistry, INSERM UMR-S 942, Lariboisière Hospital, Paris, France; 4Pharma Research Department, Hoffmann La Roche Ltd, Basel, Switzerland Abstract: Neuritogenesis is a dynamic phenomenon associated with neuronal differentiation that allows a rather spherical neuronal stem cell to develop dendrites and axon, a prerequisite for the integration and transmission of signals. The acquisition of neuronal polarity occurs in three steps: (1 neurite sprouting, which consists of the formation of buds emerging from the postmitotic neuronal soma; (2 neurite outgrowth, which represents the conversion of buds into neurites, their elongation and evolution into axon or dendrites; and (3 the stability and plasticity of neuronal polarity. In neuronal stem cells, remodeling and activation of focal adhesions (FAs associated with deep modifications of the actin cytoskeleton is a prerequisite for neurite sprouting and subsequent neurite outgrowth. A multiple set of growth factors and interactors located in the extracellular matrix and the plasma membrane orchestrate neuritogenesis by acting on intracellular signaling effectors, notably small G proteins such as RhoA, Rac, and Cdc42, which are involved in actin turnover and the dynamics of FAs. The cellular prion protein (PrPC, a glycosylphosphatidylinositol (GPI-anchored membrane protein mainly known for its role in a group of fatal neurodegenerative diseases, has emerged as a central player in neuritogenesis. Here, we review the contribution of PrPC to neuronal polarization and detail the current knowledge on the signaling pathways fine-tuned by PrPC to promote neurite sprouting, outgrowth, and maintenance. We emphasize that Pr

  14. NSP-CAS Protein Complexes: Emerging Signaling Modules in Cancer.

    Science.gov (United States)

    Wallez, Yann; Mace, Peter D; Pasquale, Elena B; Riedl, Stefan J

    2012-05-01

    The CAS (CRK-associated substrate) family of adaptor proteins comprises 4 members, which share a conserved modular domain structure that enables multiple protein-protein interactions, leading to the assembly of intracellular signaling platforms. Besides their physiological role in signal transduction downstream of a variety of cell surface receptors, CAS proteins are also critical for oncogenic transformation and cancer cell malignancy through associations with a variety of regulatory proteins and downstream effectors. Among the regulatory partners, the 3 recently identified adaptor proteins constituting the NSP (novel SH2-containing protein) family avidly bind to the conserved carboxy-terminal focal adhesion-targeting (FAT) domain of CAS proteins. NSP proteins use an anomalous nucleotide exchange factor domain that lacks catalytic activity to form NSP-CAS signaling modules. Additionally, the NSP SH2 domain can link NSP-CAS signaling assemblies to tyrosine-phosphorylated cell surface receptors. NSP proteins can potentiate CAS function by affecting key CAS attributes such as expression levels, phosphorylation state, and subcellular localization, leading to effects on cell adhesion, migration, and invasion as well as cell growth. The consequences of these activities are well exemplified by the role that members of both families play in promoting breast cancer cell invasiveness and resistance to antiestrogens. In this review, we discuss the intriguing interplay between the NSP and CAS families, with a particular focus on cancer signaling networks.

  15. A novel acetylation cycle of transcription co-activator Yes-associated protein that is downstream of Hippo pathway is triggered in response to SN2 alkylating agents.

    Science.gov (United States)

    Hata, Shoji; Hirayama, Jun; Kajiho, Hiroaki; Nakagawa, Kentaro; Hata, Yutaka; Katada, Toshiaki; Furutani-Seiki, Makoto; Nishina, Hiroshi

    2012-06-22

    Yes-associated protein (YAP) is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes. Although cytoplasmic retention of YAP is known to be mediated by Hippo pathway-dependent phosphorylation, post-translational modifications that regulate YAP in the nucleus remain unclear. Here we report the discovery of a novel cycle of acetylation/deacetylation of nuclear YAP induced in response to S(N)2 alkylating agents. We show that after treatment of cells with the S(N)2 alkylating agent methyl methanesulfonate, YAP phosphorylation mediated by the Hippo pathway is markedly reduced, leading to nuclear translocation of YAP and its acetylation. This YAP acetylation occurs on specific and highly conserved C-terminal lysine residues and is mediated by the nuclear acetyltransferases CBP (CREB binding protein) and p300. Conversely, the nuclear deacetylase SIRT1 is responsible for YAP deacetylation. Intriguingly, we found that YAP acetylation is induced specifically by S(N)2 alkylating agents and not by other DNA-damaging stimuli. These results identify a novel YAP acetylation cycle that occurs in the nucleus downstream of the Hippo pathway. Intriguingly, our findings also indicate that YAP acetylation is involved in responses to a specific type of DNA damage.

  16. A Novel Acetylation Cycle of Transcription Co-activator Yes-associated Protein That Is Downstream of Hippo Pathway Is Triggered in Response to SN2 Alkylating Agents*

    Science.gov (United States)

    Hata, Shoji; Hirayama, Jun; Kajiho, Hiroaki; Nakagawa, Kentaro; Hata, Yutaka; Katada, Toshiaki; Furutani-Seiki, Makoto; Nishina, Hiroshi

    2012-01-01

    Yes-associated protein (YAP) is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes. Although cytoplasmic retention of YAP is known to be mediated by Hippo pathway-dependent phosphorylation, post-translational modifications that regulate YAP in the nucleus remain unclear. Here we report the discovery of a novel cycle of acetylation/deacetylation of nuclear YAP induced in response to SN2 alkylating agents. We show that after treatment of cells with the SN2 alkylating agent methyl methanesulfonate, YAP phosphorylation mediated by the Hippo pathway is markedly reduced, leading to nuclear translocation of YAP and its acetylation. This YAP acetylation occurs on specific and highly conserved C-terminal lysine residues and is mediated by the nuclear acetyltransferases CBP (CREB binding protein) and p300. Conversely, the nuclear deacetylase SIRT1 is responsible for YAP deacetylation. Intriguingly, we found that YAP acetylation is induced specifically by SN2 alkylating agents and not by other DNA-damaging stimuli. These results identify a novel YAP acetylation cycle that occurs in the nucleus downstream of the Hippo pathway. Intriguingly, our findings also indicate that YAP acetylation is involved in responses to a specific type of DNA damage. PMID:22544757

  17. Comparative analysis of the pituitary and ovarian GnRH systems in the leopard gecko: signaling crosstalk between multiple receptor subtypes in ovarian follicles.

    Science.gov (United States)

    Ikemoto, Tadahiro; Park, Min Kyun

    2007-02-01

    GnRH regulates reproductive functions through interaction with its pituitary receptor in vertebrates. The present study demonstrated that the leopard gecko possessed two and three genes for GnRH ligands and receptors, respectively, though one of the three receptor subtypes had long been thought not to exist in reptiles. Each receptor subtype showed a distinct pharmacology. All types of ligands and receptors showed different expression patterns, and were widely expressed both inside and outside the brain. This report also shows a comparison of the pituitary and ovarian GnRH systems in the leopard gecko during and after the egg-laying season. All three receptor subtypes were expressed in both the whole pituitary and ovary; however, only one receptor subtype could be detected in the anterior pituitary gland. In situ hybridization showed spatial expression patterns of ovarian receptors, and suggested co-expression of multiple receptor subtypes in granulosa cells of larger follicles. Co-transfection of receptor subtypes showed a distinct pharmacology in COS-7 cells compared with those of single transfections. These results suggest that distinct signaling mechanisms are involved in the pituitary and ovarian GnRH systems. Seasonal and developmental variations in receptor expression in the anterior pituitary gland and ovarian follicles may contribute to the seasonal breeding of this animal.

  18. Wave and particle evolution downstream of quasi-perpendicular shocks

    Science.gov (United States)

    Mckean, M. E.; Omidi, N.; Krauss-Varban, D.; Karimabadi, H.

    1995-01-01

    Distributions of ions heated in quasi-perpendicular bow shocks have large perpendicular temperature anisotropies that provide free energy for the growth of Alfven ion cyclotron (AIC) and mirror waves. These modes are often obsreved in the Earth's magnetosheath. Using two-dimensional hybrid simulations, we show that these waves are produced near the shock front and convected downstream rather than being produced locally downstream. The wave activity reduces the proton anisotropy to magnetosheath levels within a few tens of gyroradii of the shock but takes significantly longer to reduce the anisotropy of He(++) ions. The waves are primarily driven by proton anisotropy and the dynamics of the helium ions is controlled by the proton waves. Downstream of high Mach number shocks, mirror waves compete effectively with AIC waves. Downstream of low Mach number shocks, AIC waves dominate.

  19. Downstream-based Scheduling for Energy Conservation in Green EPONs

    KAUST Repository

    Chen, Shen

    2012-05-01

    Maximizing the optical network unit’s (ONU) sleep time is an effective approach for achieving maximum energy conservation in green Ethernet passive optical networks (EPONs). While overlapping downstream and upstream ONU transmissions can maximize the ONU sleep time, it jeopardizes the quality of service (QoS) performance of the network, especially for downstream traffic in case the overlapping is based on the upstream time slot. In this paper, we study the downstream traffic performance in green EPONs under the limited service discipline and the upstream-based overlapped time window. Specifically, we first derive the expected mean packet delay, and then present a closed-form expression of the ONU sleep time, setting identical upstream/downstream transmission cycle times based on a maximum downstream traffic delay re-quirement. With the proposed system model, we present a novel downstream bandwidth allocation scheme for energy conservation in green EPONs. Simulation results verify the proposed model and highlight the advantages of our scheme over conventional approaches.

  20. Control of Delta Avulsion by Downstream Sediment Sinks

    Science.gov (United States)

    Salter, Gerard; Paola, Chris; Voller, Vaughan R.

    2018-01-01

    Understanding how fluxes are partitioned at delta bifurcations is critical for predicting patterns of land loss and gain in deltas worldwide. Although the dynamics of river deltas are influenced from both upstream and downstream, previous studies of bifurcations have focused on upstream controls. Using a quasi-1-D bifurcation model, we show that flow switching in bifurcations is strongly influenced by downstream sediment sinks. We find that coupling between upstream and downstream feedbacks can lead to oscillations in water and sediment flux partitioning. The frequency and initial rate of growth/decay of the oscillations depend on both upstream and downstream conditions, with dimensionless bifurcate length and bypass fraction emerging as key downstream parameters. With a strong offshore sink, causing bypass in the bifurcate branches, we find that bifurcation dynamics become "frozen"; that is, the bifurcation settles on a permanent discharge ratio. In contrast, under depositional conditions, we identify three dynamical regimes: symmetric; soft avulsion, where both branches remain open but the dominant branch switches; and full avulsion. Finally, we show that differential subsidence alters these regimes, with the difference in average sediment supply to each branch exactly compensating for the difference in accommodation generation. Additionally, the model predicts that bifurcations with shorter branches are less asymmetric than bifurcations with longer branches, all else equal, providing a possible explanation for the difference between backwater length distributaries, which tend to be avulsive, and relatively stable mouth-bar-scale networks. We conclude that bifurcations are sensitive both quantitatively and qualitatively to downstream sinks.

  1. Wind-Driven Ecological Flow Regimes Downstream from Hydropower Dams

    Science.gov (United States)

    Kern, J.; Characklis, G. W.

    2012-12-01

    Conventional hydropower can be turned on and off quicker and less expensively than thermal generation (coal, nuclear, or natural gas). These advantages enable hydropower utilities to respond to rapid fluctuations in energy supply and demand. More recently, a growing renewable energy sector has underlined the need for flexible generation capacity that can complement intermittent renewable resources such as wind power. While wind power entails lower variable costs than other types of generation, incorporating it into electric power systems can be problematic. Due to variable and unpredictable wind speeds, wind power is difficult to schedule and must be used when available. As a result, integrating large amounts of wind power into the grid may result in atypical, swiftly changing demand patterns for other forms of generation, placing a premium on sources that can be rapidly ramped up and down. Moreover, uncertainty in wind power forecasts will stipulate increased levels of 'reserve' generation capacity that can respond quickly if real-time wind supply is less than expected. These changes could create new hourly price dynamics for energy and reserves, altering the short-term financial signals that hydroelectric dam operators use to schedule water releases. Traditionally, hourly stream flow patterns below hydropower dams have corresponded in a very predictable manner to electricity demand, whose primary factors are weather (hourly temperature) and economic activity (workday hours). Wind power integration has the potential to yield more variable, less predictable flows at hydro dams, flows that at times could resemble reciprocal wind patterns. An existing body of research explores the impacts of standard, demand-following hydroelectric dams on downstream ecological flows; but weighing the benefits of increased reliance on wind power against further impacts to ecological flows may be a novel challenge for the environmental community. As a preliminary step in meeting this

  2. Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Pratheeshkumar, Poyil; Son, Young-Ok; Divya, Sasidharan Padmaja; Roy, Ram Vinod; Hitron, John Andrew; Wang, Lei [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Kim, Donghern; Dai, Jin [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Asha, Padmaja [National Centre for Aquatic Animal Health, Cochin University of Science and Technology, Cochin (India); Zhang, Zhuo [Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Wang, Yitao [State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau (China); Shi, Xianglin, E-mail: xshi5@email.uky.edu [Center for Research on Environmental Disease, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States); Graduate Center for Toxicology, University of Kentucky, 1095 VA Drive, Lexington, KY 40536 (United States)

    2014-12-01

    Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5 μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis. - Highlights: • Luteolin inhibited Cr(VI)-induced oxidative stress. • Luteolin inhibited chronic Cr(VI)-induced malignant transformation.

  3. Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways

    International Nuclear Information System (INIS)

    Pratheeshkumar, Poyil; Son, Young-Ok; Divya, Sasidharan Padmaja; Roy, Ram Vinod; Hitron, John Andrew; Wang, Lei; Kim, Donghern; Dai, Jin; Asha, Padmaja; Zhang, Zhuo; Wang, Yitao; Shi, Xianglin

    2014-01-01

    Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5 μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis. - Highlights: • Luteolin inhibited Cr(VI)-induced oxidative stress. • Luteolin inhibited chronic Cr(VI)-induced malignant transformation.

  4. Sweet Taste Receptor Signaling Network: Possible Implication for Cognitive Functioning

    Directory of Open Access Journals (Sweden)

    Menizibeya O. Welcome

    2015-01-01

    Full Text Available Sweet taste receptors are transmembrane protein network specialized in the transmission of information from special “sweet” molecules into the intracellular domain. These receptors can sense the taste of a range of molecules and transmit the information downstream to several acceptors, modulate cell specific functions and metabolism, and mediate cell-to-cell coupling through paracrine mechanism. Recent reports indicate that sweet taste receptors are widely distributed in the body and serves specific function relative to their localization. Due to their pleiotropic signaling properties and multisubstrate ligand affinity, sweet taste receptors are able to cooperatively bind multiple substances and mediate signaling by other receptors. Based on increasing evidence about the role of these receptors in the initiation and control of absorption and metabolism, and the pivotal role of metabolic (glucose regulation in the central nervous system functioning, we propose a possible implication of sweet taste receptor signaling in modulating cognitive functioning.

  5. Essential roles of Gab1 tyrosine phosphorylation in growth factor-mediated signaling and angiogenesis.

    Science.gov (United States)

    Wang, Weiye; Xu, Suowen; Yin, Meimei; Jin, Zheng Gen

    2015-02-15

    Growth factors and their downstream receptor tyrosine kinases (RTKs) mediate a number of biological processes controlling cell function. Adaptor (docking) proteins, which consist exclusively of domains and motifs that mediate molecular interactions, link receptor activation to downstream effectors. Recent studies have revealed that Grb2-associated-binders (Gab) family members (including Gab1, Gab2, and Gab3), when phosphorylated on tyrosine residues, provide binding sites for multiple effector proteins, such as Src homology-2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) and phosphatidylinositol 3-kinase (PI3K) regulatory subunit p85, thereby playing important roles in transducing RTKs-mediated signals into pathways with diversified biological functions. Here, we provide an up-to-date overview on the domain structure and biological functions of Gab1, the most intensively studied Gab family protein, in growth factor signaling and biological functions, with a special focus on angiogenesis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  6. Investigation of wall mass transfer characteristics downstream of an orifice

    International Nuclear Information System (INIS)

    El-Gammal, M.; Ahmed, W.H.; Ching, C.Y.

    2012-01-01

    Highlights: ► Numerical simulations were performed for the mass transfer downstream of an orifice. ► The Low Reynolds Number K-ε turbulence model was used. ► The numerical results were in good agreement with existing experimental results. ► The maximum Sherwood number downstream of the orifice was significantly affected by the Reynolds number. ► The Sherwood number profile was well correlated with the turbulence kinetic energy profile close to the wall. - Abstract: Numerical simulations were performed to determine the effect of Reynolds number and orifice to pipe diameter ratio (d o /d) on the wall mass transfer rate downstream of an orifice. The simulations were performed for d o /d of 0.475 for Reynolds number up to 70,000. The effect of d o /d was determined by performing simulations at a Reynolds number of 70,000 for d o /d of 0.375, 0.475 and 0.575. The momentum and mass transport equations were solved using the Low Reynolds Number (LRN) K-ε turbulence model. The Sherwood number (Sh) profile downstream of the orifice was in relatively good agreement with existing experimental results. The Sh increases sharply downstream of the orifice, reaching a maximum within 1–2 diameters downstream of the orifice, before relaxing back to the fully developed pipe flow value. The Sh number well downstream of the orifice was in good agreement with results for fully developed pipe flow estimated from the correlation of . The peak Sh numbers from the simulations were higher than that predicted from and .

  7. Results of the Simulator smart against synthetic signals using a model of reduced order of BWR with additive and multiplicative noise; Resultados del simulador smart frente a senales sinteticas utilizando un modelo de orden reducido de BWR con ruido aditivo y multiplicativo

    Energy Technology Data Exchange (ETDEWEB)

    Munoz-Cobo, J. L.; Montesino, M. E.; Pena, J.; Escriva, A.; Melara, J.

    2011-07-01

    Results of SMART-simulator front of synthetic signals with models of reduced order of BWR with additive and multiplicative noise Under the SMART project, which aims to monitor the signals Cofrentes nuclear plant, we have developed a signal generator of synthetics BWR that will allow together real signals of plant the validation of the monitor.

  8. Highly sensitive photoelectrochemical biosensor for kinase activity detection and inhibition based on the surface defect recognition and multiple signal amplification of metal-organic frameworks.

    Science.gov (United States)

    Wang, Zonghua; Yan, Zhiyong; Wang, Feng; Cai, Jibao; Guo, Lei; Su, Jiakun; Liu, Yang

    2017-11-15

    A turn-on photoelectrochemical (PEC) biosensor based on the surface defect recognition and multiple signal amplification of metal-organic frameworks (MOFs) was proposed for highly sensitive protein kinase activity analysis and inhibitor evaluation. In this strategy, based on the phosphorylation reaction in the presence of protein kinase A (PKA), the Zr-based metal-organic frameworks (UiO-66) accommodated with [Ru(bpy) 3 ] 2+ photoactive dyes in the pores were linked to the phosphorylated kemptide modified TiO 2 /ITO electrode through the chelation between the Zr 4+ defects on the surface of UiO-66 and the phosphate groups in kemptide. Under visible light irradiation, the excited electrons from [Ru(bpy) 3 ] 2+ adsorbed in the pores of UiO-66 injected into the TiO 2 conduction band to generate photocurrent, which could be utilized for protein kinase activities detection. The large surface area and high porosities of UiO-66 facilitated a large number of [Ru(bpy) 3 ] 2+ that increased the photocurrent significantly, and afforded a highly sensitive PEC analysis of kinase activity. The detection limit of the as-proposed PEC biosensor was 0.0049UmL -1 (S/N!=!3). The biosensor was also applied for quantitative kinase inhibitor evaluation and PKA activities detection in MCF-7 cell lysates. The developed visible-light PEC biosensor provides a simple detection procedure and a cost-effective manner for PKA activity assays, and shows great potential in clinical diagnosis and drug discoveries. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Acoustic MIMO signal processing

    CERN Document Server

    Huang, Yiteng; Chen, Jingdong

    2006-01-01

    A timely and important book addressing a variety of acoustic signal processing problems under multiple-input multiple-output (MIMO) scenarios. It uniquely investigates these problems within a unified framework offering a novel and penetrating analysis.

  10. Mortality of zebra mussel, Dreissena polymorpha, veligers during downstream transport

    Science.gov (United States)

    Horvath, T.G.; Lamberti, G.A.

    1999-01-01

    1. Streams flowing from lakes which contain zebra mussels, Dreissena polymorpha, provide apparently suitable habitats for mussel colonization and downstream range expansion, yet most such streams contain few adult mussels. We postulated that mussel veligers experience high mortality during dispersal via downstream transport. They tested this hypothesis in Christiana Creek, a lake-outlet stream in south-western Michigan, U.S.A., in which adult mussel density declined exponentially with distance downstream. 2. A staining technique using neutral red was developed and tested to distinguish quickly live and dead veligers. Live and dead veligers were distinguishable after an exposure of fresh samples to 13.3 mg L-1 of neutral red for 3 h. 3. Neutral red was used to determine the proportion of live veligers in samples taken longitudinally along Christiana Creek. The proportion of live veligers (mean ?? SE) declined from 90 ?? 3% at the lake outlet to 40 ?? 8% 18 km downstream. 4. Veligers appear to be highly susceptible to damage by physical forces (e.g. shear), and therefore, mortality in turbulent streams could be an important mechanism limiting zebra mussel dispersal to downstream reaches. Predictions of zebra mussel spread and population growth should consider lake-stream linkages and high mortality in running waters.

  11. Downstream Yangtze River levels impacted by Three Gorges Dam

    International Nuclear Information System (INIS)

    Wang, Jida; Sheng, Yongwei; Gleason, Colin J; Wada, Yoshihide

    2013-01-01

    Changes in the Yangtze River level induced by large-scale human water regulation have profound implications on the inundation dynamics of surrounding lakes/wetlands and the integrity of related ecosystems. Using in situ measurements and hydrological simulation, this study reveals an altered Yangtze level regime downstream from the Three Gorges Dam (TGD) to the Yangtze estuary in the East China Sea as a combined result of (i) TGD’s flow regulation and (ii) Yangtze channel erosion due to reduced sediment load. During the average annual cycle of TGD’s regular flow control in 2009–2012, downstream Yangtze level variations were estimated to have been reduced by 3.9–13.5% at 15 studied gauging stations, manifested as evident level decrease in fall and increase in winter and spring. The impacts on Yangtze levels generally diminished in a longitudinal direction from the TGD to the estuary, with a total time lag of ∼9–12 days. Chronic Yangtze channel erosion since the TGD closure has lowered water levels in relation to flows at most downstream stations, which in turn counteracts the anticipated level increase by nearly or over 50% in winter and spring while reinforcing the anticipated level decrease by over 20% in fall. Continuous downstream channel erosion in the near future may further counteract the benefit of increased Yangtze levels during TGD’s water supplement in winter and accelerate the receding of inundation areas/levels of downstream lakes in fall. (letter)

  12. The Orphan G Protein-coupled Receptor GPR17 Negatively Regulates Oligodendrocyte Differentiation via Gαi/o and Its Downstream Effector Molecules.

    Science.gov (United States)

    Simon, Katharina; Hennen, Stephanie; Merten, Nicole; Blättermann, Stefanie; Gillard, Michel; Kostenis, Evi; Gomeza, Jesus

    2016-01-08

    Recent studies have recognized G protein-coupled receptors as important regulators of oligodendrocyte development. GPR17, in particular, is an orphan G protein-coupled receptor that has been identified as oligodendroglial maturation inhibitor because its stimulation arrests primary mouse oligodendrocytes at a less differentiated stage. However, the intracellular signaling effectors transducing its activation remain poorly understood. Here, we use Oli-neu cells, an immortalized cell line derived from primary murine oligodendrocytes, and primary rat oligodendrocyte cultures as model systems to identify molecular targets that link cell surface GPR17 to oligodendrocyte maturation blockade. We demonstrate that stimulation of GPR17 by the small molecule agonist MDL29,951 (2-carboxy-4,6-dichloro-1H-indole-3-propionic acid) decreases myelin basic protein expression levels mainly by triggering the Gαi/o signaling pathway, which in turn leads to reduced activity of the downstream cascade adenylyl cyclase-cAMP-PKA-cAMP response element-binding protein (CREB). In addition, we show that GPR17 activation also diminishes myelin basic protein abundance by lessening stimulation of the exchange protein directly activated by cAMP (EPAC), thus uncovering a previously unrecognized role for EPAC to regulate oligodendrocyte differentiation. Together, our data establish PKA and EPAC as key downstream effectors of GPR17 that inhibit oligodendrocyte maturation. We envisage that treatments augmenting PKA and/or EPAC activity represent a beneficial approach for therapeutic enhancement of remyelination in those demyelinating diseases where GPR17 is highly expressed, such as multiple sclerosis. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  13. Critical effects of downstream boundary conditions on vortex breakdown

    Science.gov (United States)

    Kandil, Osama; Kandil, Hamdy A.; Liu, C. H.

    1992-01-01

    The unsteady, compressible, full Navier-Stokes (NS) equations are used to study the critical effects of the downstream boundary conditions on the supersonic vortex breakdown. The present study is applied to two supersonic vortex breakdown cases. In the first case, quasi-axisymmetric supersonic swirling flow is considered in a configured circular duct, and in the second case, quasi-axisymmetric supersonic swirling jet, that is issued from a nozzle into a supersonic jet of lower Mach number, is considered. For the configured duct flow, four different types of downstream boundary conditions are used, and for the swirling jet flow from the nozzle, two types of downstream boundary conditions are used. The solutions are time accurate which are obtained using an implicit, upwind, flux-difference splitting, finite-volume scheme.

  14. Downstream Processability of Crystal Habit-Modified Active Pharmaceutical Ingredient

    DEFF Research Database (Denmark)

    Pudasaini, Nawin; Upadhyay, Pratik Pankaj; Parker, Christian Richard

    2017-01-01

    Efficient downstream processing of active pharmaceutical ingredients (APIs) can depend strongly on their particulate properties, such as size and shape distributions. Especially in drug products with high API content, needle-like crystal habit of an API may show compromised flowability and tablet......Efficient downstream processing of active pharmaceutical ingredients (APIs) can depend strongly on their particulate properties, such as size and shape distributions. Especially in drug products with high API content, needle-like crystal habit of an API may show compromised flowability...

  15. Signal Diversity of Receptor for Advanced Glycation End Products.

    Science.gov (United States)

    Sakaguchi, Masakiyo; Kinoshita, Rie; Putranto, Endy Widya; Ruma, I Made Winarsa; Sumardika, I Wayan; Youyi, Chen; Tomonobu, Naoko; Yamamoto, Ken-Ichi; Murata, Hitoshi

    2017-12-01

    The receptor for advanced glycation end products (RAGE) is involved in inflammatory pathogenesis. It functions as a receptor to multiple ligands such as AGEs, HMGB1 and S100 proteins, activating multiple intracellular signaling pathways with each ligand binding. The molecular events by which ligand-activated RAGE controls diverse signaling are not well understood, but some progress was made recently. Accumulating evidence revealed that RAGE has multiple binding partners within the cytoplasm and on the plasma membrane. It was first pointed out in 2008 that RAGE's cytoplasmic tail is able to recruit Diaphanous-1 (Dia-1), resulting in the acquisition of increased cellular motility through Rac1/Cdc42 activation. We also observed that within the cytosol, RAGE's cytoplasmic tail behaves similarly to a Toll-like receptor (TLR4)-TIR domain, interacting with TIRAP and MyD88 adaptor molecules that in turn activate multiple downstream signals. Subsequent studies demonstrated the presence of an alternative adaptor molecule, DAP10, on the plasma membrane. The coupling of RAGE with DAP10 is critical for enhancing the RAGE-mediated survival signal. Interestingly, RAGE interaction on the membrane was not restricted to DAP10 alone. The chemotactic G-protein-coupled receptors (GPCRs) formyl peptide receptors1 and 2 (FPR1 and FPR2) also interacted with RAGE on the plasma membrane. Binding interaction between leukotriene B4 receptor 1 (BLT1) and RAGE was also demonstrated. All of the interactions affected the RAGE signal polarity. These findings indicate that functional interactions between RAGE and various molecules within the cytoplasmic area or on the membrane area coordinately regulate multiple ligand-mediated RAGE responses, leading to typical cellular phenotypes in several pathological settings. Here we review RAGE's signaling diversity, to contribute to the understanding of the elaborate functions of RAGE in physiological and pathological contexts.

  16. Combined inadequacies of multiple B-vitamins amplify colonic Wnt-signaling and promote intestinal tumorigenesis in BAT-LacZ X Apc1638N mice

    Science.gov (United States)

    The Wnt pathway is a pivotal signaling cascade in colorectal carcinogenesis. The purpose of this work is to determine whether depletion of folate and other metabolically-related one-carbon vitamins induces in vivo activation of intestinal Wnt signaling, and whether this occurs in parallel with incre...

  17. Combined inadequacies of multiple B-vitamins amplify colonic Wnt-signaling and promote intestinal tumorigenesis in BAT-LacZxApc1368N mice

    Science.gov (United States)

    The Wnt pathway is a pivotal signaling cascade in colorectal carcinogenesis. The purpose of this work is to determine whether depletion of folate and other metabolically-related one-carbon vitamins induces in vivo activation of intestinal Wnt signaling, and whether this occurs in parallel with incre...

  18. Model Insensitive and Calibration Independent Method for Determination of the Downstream Neutral Hydrogen Density Through Ly-alpha Glow Observations

    Science.gov (United States)

    Gangopadhyay, P.; Judge, D. L.

    1996-01-01

    Our knowledge of the various heliospheric phenomena (location of the solar wind termination shock, heliopause configuration and very local interstellar medium parameters) is limited by uncertainties in the available heliospheric plasma models and by calibration uncertainties in the observing instruments. There is, thus, a strong motivation to develop model insensitive and calibration independent methods to reduce the uncertainties in the relevant heliospheric parameters. We have developed such a method to constrain the downstream neutral hydrogen density inside the heliospheric tail. In our approach we have taken advantage of the relative insensitivity of the downstream neutral hydrogen density profile to the specific plasma model adopted. We have also used the fact that the presence of an asymmetric neutral hydrogen cavity surrounding the sun, characteristic of all neutral densities models, results in a higher multiple scattering contribution to the observed glow in the downstream region than in the upstream region. This allows us to approximate the actual density profile with one which is spatially uniform for the purpose of calculating the downstream backscattered glow. Using different spatially constant density profiles, radiative transfer calculations are performed, and the radial dependence of the predicted glow is compared with the observed I/R dependence of Pioneer 10 UV data. Such a comparison bounds the large distance heliospheric neutral hydrogen density in the downstream direction to a value between 0.05 and 0.1/cc.

  19. Imaging for monitoring downstream processing of fermentation broths

    DEFF Research Database (Denmark)

    Moiseyenko, Rayisa; Baum, Andreas; Jørgensen, Thomas Martini

    In relation to downstream processing of a fermentation broth coagulation/flocculation is a typical pretreatment method for separating undesirable particles/impurities from the wanted product. In the coagulation process the negatively charged impurities are destabilized by adding of a clarifying...

  20. DENSITY FLUCTUATIONS UPSTREAM AND DOWNSTREAM OF INTERPLANETARY SHOCKS

    Energy Technology Data Exchange (ETDEWEB)

    Pitňa, A.; Šafránková, J.; Němeček, Z.; Goncharov, O.; Němec, F.; Přech, L. [Charles University, Faculty of Mathematics and Physics, V Holešovičkách 2, 180 00 Prague 8 (Czech Republic); Chen, C. H. K. [Department of Physics, Imperial College London, London SW7 2AZ (United Kingdom); Zastenker, G. N., E-mail: jana.safrankova@mff.cuni.cz [Space Research Institute of Russian Academy of Sciences, Moscow, Russia, Profsoyuznaya ul. 84/32, Moscow 117997 (Russian Federation)

    2016-03-01

    Interplanetary (IP) shocks as typical large-scale disturbances arising from processes such as stream–stream interactions or Interplanetary Coronal Mass Ejection (ICME) launching play a significant role in the energy redistribution, dissipation, particle heating, acceleration, etc. They can change the properties of the turbulent cascade on shorter scales. We focus on changes of the level and spectral properties of ion flux fluctuations upstream and downstream of fast forward oblique shocks. Although the fluctuation level increases by an order of magnitude across the shock, the spectral slope in the magnetohydrodynamic range is conserved. The frequency spectra upstream of IP shocks are the same as those in the solar wind (if not spoiled by foreshock waves). The spectral slopes downstream are roughly proportional to the corresponding slopes upstream, suggesting that the properties of the turbulent cascade are conserved across the shock; thus, the shock does not destroy the shape of the spectrum as turbulence passes through it. Frequency spectra downstream of IP shocks often exhibit “an exponential decay” in the ion kinetic range that was earlier reported at electron scales in the solar wind or at ion scales in the interstellar medium. We suggest that the exponential shape of ion flux spectra in this range is caused by stronger damping of the fluctuations in the downstream region.

  1. Lateral and vertical distribution of downstream migrating juvenile sea lamprey

    Science.gov (United States)

    Sotola, V. Alex; Miehls, Scott M.; Simard, Lee G.; Marsden, J. Ellen

    2018-01-01

    Sea lamprey is considered an invasive and nuisance species in the Laurentian Great Lakes, Lake Champlain, and the Finger Lakes of New York and is a major focus of control efforts. Currently, management practices focus on limiting the area of infestation using barriers to block migratory adults, and lampricides to kill ammocoetes in infested tributaries. No control efforts currently target the downstream-migrating post-metamorphic life stage which could provide another management opportunity. In order to apply control methods to this life stage, a better understanding of their downstream movement patterns is needed. To quantify spatial distribution of downstream migrants, we deployed fyke and drift nets laterally and vertically across the stream channel in two tributaries of Lake Champlain. Sea lamprey was not randomly distributed across the stream width and lateral distribution showed a significant association with discharge. Results indicated that juvenile sea lamprey is most likely to be present in the thalweg and at midwater depths of the stream channel. Further, a majority of the catch occurred during high flow events, suggesting an increase in downstream movement activity when water levels are higher than base flow. Discharge and flow are strong predictors of the distribution of out-migrating sea lamprey, thus managers will need to either target capture efforts in high discharge areas of streams or develop means to guide sea lamprey away from these areas.

  2. Extreme wave phenomena in down-stream running modulated waves

    NARCIS (Netherlands)

    Andonowati, A.; Karjanto, N.; van Groesen, Embrecht W.C.

    Modulational, Benjamin-Feir, instability is studied for the down-stream evolution of surface gravity waves. An explicit solution, the soliton on finite background, of the NLS equation in physical space is used to study various phenomena in detail. It is shown that for sufficiently long modulation

  3. Downstream processing of Isochrysis galbana: a step towards microalgal biorefinery

    NARCIS (Netherlands)

    Gilbert-López, B.; Mendiola, J.A.; Fontecha, J.; Broek, van den L.A.M.; Sijtsma, L.; Cifuentes, A.; Herrero, M.; Ibáñez, E.

    2015-01-01

    An algae-based biorefinery relies on the efficient use of algae biomass through its fractionation of several valuable/bioactive compounds that can be used in industry. If this biorefinery includes green platforms as downstream processing technologies able to fulfill the requirements of green

  4. Patents and Downstream Innovation Suppression - Facts or Fiction?

    DEFF Research Database (Denmark)

    Howells, John

    the value of Kitch's prospect theory of patents, a theory that the social value of patents is that they enable the efficient coordination of technological development.    I re-examine history and legal sources bearing on Merges and Nelson's illustrative cases and find no case to illustrate downstream...

  5. Reactive oxygen species signaling and stomatal movement: Current updates and future perspectives

    Directory of Open Access Journals (Sweden)

    Rachana Singh

    2017-04-01

    Full Text Available Reactive oxygen species (ROS, a by-product of aerobic metabolism were initially studied in context to their damaging effect but recent decades witnessed significant advancements in understanding the role of ROS as signaling molecules. Contrary to earlier views, it is becoming evident that ROS production is not necessarily a symptom of cellular dysfunction but it might represent a necessary signal in adjusting the cellular machinery according to the altered conditions. Stomatal movement is controlled by multifaceted signaling network in response to endogenous and environmental signals. Furthermore, the stomatal aperture is regulated by a coordinated action of signaling proteins, ROS-generating enzymes, and downstream executors like transporters, ion pumps, plasma membrane channels, which control the turgor pressure of the guard cell. The earliest hallmarks of stomatal closure are ROS accumulation in the apoplast and chloroplasts and thereafter, there is a successive increase in cytoplasmic Ca2+ level which rules the multiple kinases activity that in turn regulates the activity of ROS-generating enzymes and various ion channels. In addition, ROS also regulate the action of multiple proteins directly by oxidative post translational modifications to adjust guard cell signaling. Notwithstanding, an active progress has been made with ROS signaling mechanism but the regulatory action for ROS signaling processes in stomatal movement is still fragmentary. Therefore, keeping in view the above facts, in this mini review the basic concepts and role of ROS signaling in the stomatal movement have been presented comprehensively along with recent highlights.

  6. The role of headwater streams in downstream water quality

    Science.gov (United States)

    Alexander, R.B.; Boyer, E.W.; Smith, R.A.; Schwarz, G.E.; Moore, R.B.

    2007-01-01

    Knowledge of headwater influences on the water-quality and flow conditions of downstream waters is essential to water-resource management at all governmental levels; this includes recent court decisions on the jurisdiction of the Federal Clean Water Act (CWA) over upland areas that contribute to larger downstream water bodies. We review current watershed research and use a water-quality model to investigate headwater influences on downstream receiving waters. Our evaluations demonstrate the intrinsic connections of headwaters to landscape processes and downstream waters through their influence on the supply, transport, and fate of water and solutes in watersheds. Hydrological processes in headwater catchments control the recharge of subsurface water stores, flow paths, and residence times of water throughout landscapes. The dynamic coupling of hydrological and biogeochemical processes in upland streams further controls the chemical form, timing, and longitudinal distances of solute transport to downstream waters. We apply the spatially explicit, mass-balance watershed model SPARROW to consider transport and transformations of water and nutrients throughout stream networks in the northeastern United States. We simulate fluxes of nitrogen, a primary nutrient that is a water-quality concern for acidification of streams and lakes and eutrophication of coastal waters, and refine the model structure to include literature observations of nitrogen removal in streams and lakes. We quantify nitrogen transport from headwaters to downstream navigable waters, where headwaters are defined within the model as first-order, perennial streams that include flow and nitrogen contributions from smaller, intermittent and ephemeral streams. We find that first-order headwaters contribute approximately 70% of the mean-annual water volume and 65% of the nitrogen flux in second-order streams. Their contributions to mean water volume and nitrogen flux decline only marginally to about 55% and

  7. Methylation of Hg downstream from the Bonanza Hg mine, Oregon

    Science.gov (United States)

    Gray, John E.; Hines, Mark E.; Krabbenhoft, David P.; Thoms, Bryn

    2012-01-01

    Speciation of Hg and conversion to methyl-Hg were evaluated in stream sediment, stream water, and aquatic snails collected downstream from the Bonanza Hg mine, Oregon. Total production from the Bonanza mine was >1360t of Hg, during mining from the late 1800s to 1960, ranking it as an intermediate sized Hg mine on an international scale. The primary objective of this study was to evaluate the distribution, transport, and methylation of Hg downstream from a Hg mine in a coastal temperate climatic zone. Data shown here for methyl-Hg, a neurotoxin hazardous to humans, are the first reported for sediment and water from this area. Stream sediment collected from Foster Creek flowing downstream from the Bonanza mine contained elevated Hg concentrations that ranged from 590 to 71,000ng/g, all of which (except the most distal sample) exceeded the probable effect concentration (PEC) of 1060ng/g, the Hg concentration above which harmful effects are likely to be observed in sediment-dwelling organisms. Concentrations of methyl-Hg in stream sediment collected from Foster Creek varied from 11 to 62ng/g and were highly elevated compared to regional baseline concentrations (0.11-0.82ng/g) established in this study. Methyl-Hg concentrations in stream sediment collected in this study showed a significant correlation with total organic C (TOC, R2=0.62), generally indicating increased methyl-Hg formation with increasing TOC in sediment. Isotopic-tracer methods indicated that several samples of Foster Creek sediment exhibited high rates of Hg-methylation. Concentrations of Hg in water collected downstream from the mine varied from 17 to 270ng/L and were also elevated compared to baselines, but all were below the 770ng/L Hg standard recommended by the USEPA to protect against chronic effects to aquatic wildlife. Concentrations of methyl-Hg in the water collected from Foster Creek ranged from 0.17 to 1.8ng/L, which were elevated compared to regional baseline sites upstream and downstream

  8. Temperature field downstream of an heated bundle mock-up results for different power distribution

    International Nuclear Information System (INIS)

    Girard, J.P.; Buravand, Y.

    1982-10-01

    The aim of these peculiar experiments performed on the ML4 loop in ISPRA is to evaluate the characteristics of the temperature field over a length of 20 to 30 dias downstream of a rod bundle for different temperatures profiles at the bundle outlet. The final purpose of this work will be to establish either directly or through models whether it is possible or not to detect subassembly failures using suitable of the subassembly outlet temperature signal. 15 hours of digital and analog recording were taped for five different power distributions in the bundle. The total power dissipation remained constant during the whole run. Two flow rates and seven axial location were investigated. It is shown that the different temperature profiles produce slight differences in the variance and skewness of the temperature signal measured along the axis of the pipe over 20 dias

  9. Gene network analysis shows immune-signaling and ERK1/2 as novel genetic markers for multiple addiction phenotypes: alcohol, smoking and opioid addiction.

    Science.gov (United States)

    Reyes-Gibby, Cielito C; Yuan, Christine; Wang, Jian; Yeung, Sai-Ching J; Shete, Sanjay

    2015-06-05

    Addictions to alcohol and tobacco, known risk factors for cancer, are complex heritable disorders. Addictive behaviors have a bidirectional relationship with pain. We hypothesize that the associations between alcohol, smoking, and opioid addiction observed in cancer patients have a genetic basis. Therefore, using bioinformatics tools, we explored the underlying genetic basis and identified new candidate genes and common biological pathways for smoking, alcohol, and opioid addiction. Literature search showed 56 genes associated with alcohol, smoking and opioid addiction. Using Core Analysis function in Ingenuity Pathway Analysis software, we found that ERK1/2 was strongly interconnected across all three addiction networks. Genes involved in immune signaling pathways were shown across all three networks. Connect function from IPA My Pathway toolbox showed that DRD2 is the gene common to both the list of genetic variations associated with all three addiction phenotypes and the components of the brain neuronal signaling network involved in substance addiction. The top canonical pathways associated with the 56 genes were: 1) calcium signaling, 2) GPCR signaling, 3) cAMP-mediated signaling, 4) GABA receptor signaling, and 5) G-alpha i signaling. Cancer patients are often prescribed opioids for cancer pain thus increasing their risk for opioid abuse and addiction. Our findings provide candidate genes and biological pathways underlying addiction phenotypes, which may be future targets for treatment of addiction. Further study of the variations of the candidate genes could allow physicians to make more informed decisions when treating cancer pain with opioid analgesics.

  10. Suppressor of cytokine signalling (SOCS)-3 protects beta cells against IL-1beta-mediated toxicity through inhibition of multiple nuclear factor-kappaB-regulated proapoptotic pathways

    DEFF Research Database (Denmark)

    Karlsen, Allan Ertman; Heding, P E; Frobøse, H

    2004-01-01

    The proinflammatory cytokine IL-1beta induces apoptosis in pancreatic beta cells via pathways dependent on nuclear factor-kappaB (NF-kappaB), mitogen-activated protein kinase, and protein kinase C. We recently showed suppressor of cytokine signalling (SOCS)-3 to be a natural negative feedback reg...... regulator of IL-1beta- and IFN-gamma-mediated signalling in rat islets and beta cell lines, preventing their deleterious effects. However, the mechanisms underlying SOCS-3 inhibition of IL-1beta signalling and prevention against apoptosis remain unknown....

  11. Msx genes are important apoptosis effectors downstream of the Shh/Gli3 pathway in the limb.

    Science.gov (United States)

    Lallemand, Yvan; Bensoussan, Vardina; Cloment, Cécile Saint; Robert, Benoît

    2009-07-15

    In tetrapods, the anteroposterior (AP) patterning of the limb is under the control of the antagonistic activities of the secreted factor Sonic hedgehog (Shh) and Gli3R, the truncated repressor form of the transcription factor Gli3. In this report, we show that Msx1 and Msx2 are targets and downstream effectors of Gli3R. Consequently, in Shh null mutants, Msx genes are overexpressed and, furthermore, partially responsible for the limb phenotype. This is exemplified by the fact that reducing Msx activity in Shh mutants partially restores a normal limb development. Finally, we show that the main action of the Msx genes, in both normal and Shh(-/-) limb development, is to control cell death in the mesenchyme. We propose that, in the limb, Msx genes act downstream of the Shh/Gli3 pathway by transducing BMP signaling and that, in the absence of Shh signaling, their deregulation contributes to the extensive apoptosis that impairs limb development.

  12. Profound blockage of CXCR4 signaling at multiple points using the synergy between plerixafor, mirtazapine, and clotrimazole as a new glioblastoma treatment adjunct.

    Science.gov (United States)

    Kast, Richard E

    2010-10-01

    CXCL12 signaling at CXCR4 is important in glioblastoma growth promotion as a migration-directing chemokine and as a mitosis-stimulating cytokine system. Recent developments in other areas of medicine may have made it now possible to comprehensively block glioblastoma's use of CXCL12 signaling. CXCL12 signaling at CXCR4 requires an active intermediate conductance Ca2+-activated K+ channel to function. Plerixafor (AMD3100) is a new small molecular weight inhibitor of CXCR4, FDA approved to aid in stem cell mobilization. Inhibition of CXCR4 by plerixafor is expected to inhibit particularly the glioblastoma stem cell population by inhibiting that sub-population's homing to the protective hypoxic niche. Histamine signals through the H1 receptor in glioblastoma cells to activate the intermediate conductance Ca2+-activated K+ channel also, thereby forming a potential bypass for inhibition of CXCR4-initiated signaling. The antidepressant mirtazapine is perhaps the most potent H1 antagonist in common clinical use. By inhibiting H1 stimulation of intermediate conductance Ca2+-activated K+ channels, it could prevent circumvention of CXCR4 inhibition by that path. The anti-fungal clotrimazole directly inhibits the intermediate conductance Ca2+- activated K+ channel at clinically achievable and well-tolerated doses. These three drugs used simultaneously are potential low morbidity paths to deeply inhibit CXCR4/CXCL12 signaling during cytotoxic glioblastoma treatment.

  13. Effect of boundary conditions on downstream vorticity from counter-rotating swirlers

    Directory of Open Access Journals (Sweden)

    Weiye Huo

    2015-02-01

    Full Text Available Particle image velocimetry (PIV is utilized to measure the non-reacting flow field in a reflow combustor with multiple and single swirlers. The velocity field, vortex structure and total vorticity levels are experimentally obtained using two different boundary conditions, representing a single confined swirler and multiple swirlers in an annular combustor. The influence of the boundary conditions on the flow field at several locations downstream of the swirlers is experimentally investigated, showing that the central vortex in the multi-swirler case is more concentrated than in the single-swirler case. The vorticity of the central vortex and average cross-sectional vorticity are relatively low at the swirler outlet in both cases. Both of these statistics gradually increase to the maximum values near 20 mm downstream of the swirler outlet, and subsequently decrease. It is also found that the central vortex in the multi-swirler case is consistently greater than the single-swirler case. These results demonstrate the critical influence of boundary conditions on flow characteristic of swirling flow, providing insight into the difference of the experiments on test-bed combustor and the full-scale annular combustors.

  14. Bidirectional 3.125 Gbps downstream / 2 Gbps upstream impulse radio ultrawide-band (UWB) over combined fiber and wireless link

    DEFF Research Database (Denmark)

    Jensen, Jesper Bevensee; Gibbon, Timothy Braidwood; Yu, Xianbin

    2010-01-01

    We demonstrate bidirectional fiber and wireless transmission of impulse radio ultra-wideband at 3.125 Gbps downstream and 2 Gbps upstream. After transmission over 50 km fiber and 1.85 m wireless link both signals are recovered without errors.......We demonstrate bidirectional fiber and wireless transmission of impulse radio ultra-wideband at 3.125 Gbps downstream and 2 Gbps upstream. After transmission over 50 km fiber and 1.85 m wireless link both signals are recovered without errors....

  15. Interleukin-34 Regulates Th1 and Th17 Cytokine Production by Activating Multiple Signaling Pathways through CSF-1R in Chicken Cell Lines

    Directory of Open Access Journals (Sweden)

    Anh Duc Truong

    2018-06-01

    Full Text Available Interleukin-34 (IL-34 is a newly recognized cytokine with functions similar to macrophage colony-stimulating factor 1. It is expressed in macrophages and fibroblasts, where it induces cytokine production; however, the mechanism of chicken IL-34 (chIL-34 signaling has not been identified to date. The aim of this study was to analyze the signal transduction pathways and specific biological functions associated with chIL-34 in chicken macrophage (HD11 and fibroblast (OU2 cell lines. We found that IL-34 is a functional ligand for the colony-stimulating factor receptor (CSF-1R in chicken cell lines. Treatment with chIL-34 increased the expression of Th1 and Th17 cytokines through phosphorylation of tyrosine and serine residues in Janus kinase (JAK 2, tyrosine kinase 2 (TYK2, signal transducer and activator of transcription (STAT 1, STAT3, and Src homology 2-containing tyrosine phosphatase 2 (SHP-2, which also led to phosphorylation of NF-κB1, p-mitogen-activated protein kinase kinase kinase 7 (TAK1, MyD88, suppressor of cytokine signaling 1 (SOCS1, and extracellular signal-regulated kinase 1 and 2 (ERK1/2. Taken together, these results suggest that chIL-34 functions by binding to CSF-1R and activating the JAK/STAT, nuclear factor κ B (NF-κB, and mitogen-activated protein kinase signaling pathways; these signaling events regulate cytokine expression and suggest roles for chIL-34 in innate and adaptive immunity.

  16. Dead zone area at the downstream flow of barrages

    Directory of Open Access Journals (Sweden)

    Mohamed F. Sauida

    2016-12-01

    Full Text Available Flow separation is a natural phenomenon encountered at some cases downstream of barrages. The main flow is divided into current and dead zone flows. The percentage area of dead zone flow must be taken into consideration downstream of barrages, due to its negative effect on flow characteristics. Experimental studies were conducted in the Hydraulic Research Institute (HRI, on a physical regulator model with five vents. Theoretically the separation zone is described as a part of an ellipse which is practically verified by plotting velocity vectors. The results show that the percentage area of dead zone to the area through length of separation depends mainly on the expansion ratio [channel width to width of opened vents], with maximum value of 81% for operated side gates. A statistical analysis was derived, to predict the percentage area of dead zone flow to the area through length of separation.

  17. Upstream-downstream cooperation approach in Guanting Reservoir watershed.

    Science.gov (United States)

    Yang, Zhi-Feng; Zhang, Wen-Guo

    2005-01-01

    A case study is introduced and discussed concerning water dispute of misuse and pollution between up- and down-stream parts. The relations between water usage and local industrial structures are analyzed. Results show it is important to change industrial structures of the target region along with controlling water pollution by technical and engineering methods. Three manners of upstream-downstream cooperation are presented and discussed based on the actual conditions of Guangting Reservoir watershed. Two typical scenarios are supposed and studied along with the local plan on water resources development. The best solution for this cooperation presents a good way to help the upstream developing in a new pattern of eco-economy.

  18. OGJ group weathered tough times upstream and downstream in 1991

    International Nuclear Information System (INIS)

    Biggs, J.B.; Price, R.B.

    1992-01-01

    With an upstream sector hit by low oil and gas prices and downstream operations squeezed by weak petroleum demand, 1991, was a tough year for the group of 22 major integrated U.S. companies Oil and Gas Journal tracks. This paper reports that the brief respite caused by the oil price spike in second half 1990 ended abruptly early in first half 1991, and it turned into a year of buckling down for most companies. They shed non-core assets, implemented strategic restructuring moves, and reduced staff. Although low prices slowed overall drilling activity for the group, oil and gas production increased slightly, and most companies reported reserves gains. Recession in the U.S. and Europe depressed demand for the group's fined products enough to pinch downstream earnings even as buoyant Asia-Pacific demand helped jack up world product sales

  19. Downstream management practices of transnational companies in institutionally vulnerable countries

    DEFF Research Database (Denmark)

    Jørgensen, Michael Søgaard; Milanez, Bruno

    2017-01-01

    Analyses of social and environmental management in transnational product chains focus often upstream on suppliers in socially and institutionally vulnerable countries and these suppliers' hazardous processes. Furthermore focus is on transnational companies' responsibility when they source from...... such suppliers. On the contrary, not much focus has been on transnational companies' downstream export of hazardous products to vulnerable countries and the product use in those countries. The article uses pesticides as case of hazardous products and identifies mechanisms in the downstream social...... and environmental management of a Danish pesticide company in vulnerable countries and especially in Brazil. The identified mechanisms are: the transnational company's on-going interpretation of the regulatory and ethical obligations for development and use of its hazardous products in vulnerable countries, path...

  20. International Retailing Operations: Downstream Entry and Expansion via Franchising

    OpenAIRE

    Petersen, Bent; Welch, Lawrence S.

    1999-01-01

    In this article, the shift into international franchising from other forms of operation, rather than the typical home market franchising base is explored. The focus is international retail franchising, based on a study of the Danish clothing and footwear industry. In this study it was found that Danish companies were moving into international franchising as an outcome of a more general shift from upstream wholesaling and subcontracting activities to downstream involvement in retailing activit...

  1. The Drosophila FoxA ortholog Fork head regulates growth and gene expression downstream of Target of rapamycin.

    Directory of Open Access Journals (Sweden)

    Margret H Bülow

    2010-12-01

    Full Text Available Forkhead transcription factors of the FoxO subfamily regulate gene expression programs downstream of the insulin signaling network. It is less clear which proteins mediate transcriptional control exerted by Target of rapamycin (TOR signaling, but recent studies in nematodes suggest a role for FoxA transcription factors downstream of TOR. In this study we present evidence that outlines a similar connection in Drosophila, in which the FoxA protein Fork head (FKH regulates cellular and organismal size downstream of TOR. We find that ectopic expression and targeted knockdown of FKH in larval tissues elicits different size phenotypes depending on nutrient state and TOR signaling levels. FKH overexpression has a negative effect on growth under fed conditions, and this phenotype is not further exacerbated by inhibition of TOR via rapamycin feeding. Under conditions of starvation or low TOR signaling levels, knockdown of FKH attenuates the size reduction associated with these conditions. Subcellular localization of endogenous FKH protein is shifted from predominantly cytoplasmic on a high-protein diet to a pronounced nuclear accumulation in animals with reduced levels of TOR or fed with rapamycin. Two putative FKH target genes, CG6770 and cabut, are transcriptionally induced by rapamycin or FKH expression, and silenced by FKH knockdown. Induction of both target genes in heterozygous TOR mutant animals is suppressed by mutations in fkh. Furthermore, TOR signaling levels and FKH impact on transcription of the dFOXO target gene d4E-BP, implying a point of crosstalk with the insulin pathway. In summary, our observations show that an alteration of FKH levels has an effect on cellular and organismal size, and that FKH function is required for the growth inhibition and target gene induction caused by low TOR signaling levels.

  2. Analysis of Petroleum Downstream Industry Potential in Riau Province

    Directory of Open Access Journals (Sweden)

    Tomi Erfando

    2017-06-01

    Full Text Available Petroleum downstream industry in Riau Province is still not optimal. The data shows that from 98,892,755 barrels lifting oil each year only 62,050,000 barrels could be processed in refinery unit II Dumai operated by PT Pertamina. There is a potential of 35-40% of downstream industry. Indonesian Government through The Ministry of Energy and Mineral Resources declared the construction of a mini refinery to boost oil processing output in the downstream sector. A feasibility study of development plan mini refinery is needed. The study includes production capacity analysis, product analysis, development & operational refinery  analysis and economic analysis. The results obtained by the mini refinery capacity is planned to process crude oil 6000 BOPD with the products produced are gasoline, kerosene, diesel and oil. Investment cost consist of is capital cost US $ 104419784 and operating cost US $ 13766734 each year with net profit earned US $ 12330063/year and rate of return from investment 11.63%

  3. Broad-Complex acts downstream of Met in juvenile hormone signaling to coordinate primitive holometabolan metamorphosis

    Czech Academy of Sciences Publication Activity Database

    Konopová, Barbora; Jindra, Marek

    2008-01-01

    Roč. 135, č. 3 (2008), s. 559-568 ISSN 0950-1991 R&D Projects: GA ČR(CZ) GA204/07/1032; GA AV ČR IAA5007305; GA MŠk LC07032 Institutional research plan: CEZ:AV0Z50070508 Keywords : metamorphosis * juvenile hormone * broad-complex Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.812, year: 2008

  4. Zika virus inhibits type‐I interferon production and downstream signaling

    OpenAIRE

    Kumar, Anil; Hou, Shangmei; Airo, Adriana M; Limonta, Daniel; Mancinelli, Valeria; Branton, William; Power, Christopher; Hobman, Tom C

    2016-01-01

    Zika virus is an emerging mosquito‐borne pathogen that is associated with Guillain–Barré syndrome in adults and microcephaly and other neurological defects in newborns. Despite being declared an international emergency by the World Health Organization, comparatively little is known about its biology. Here, we investigate the strategies employed by the virus to suppress the host antiviral response. We observe that once established, Zika virus infection is impervious to interferon treatment sug...

  5. Regulatory Network Identification by Genetical Genomics: Signaling Downstream of the Arabidopsis Receptor-Like Kinase ERECTA

    NARCIS (Netherlands)

    Terpstra, I.R.; Snoek, L.B.; Keurentjes, J.J.B.; Peeters, A.J.M.; Ackerveken, van den G.

    2010-01-01

    Gene expression differences between individuals within a species can be largely explained by differences in genetic background. The effect of genetic variants (alleles) of genes on expression can be studied in a multifactorial way by application of genetical genomics or expression quantitative trait

  6. Ran GTPase promotes cancer progression via Met receptor-mediated downstream signaling

    Science.gov (United States)

    Yuen, Hiu-Fung; Chan, Ka-Kui; Platt-Higgins, Angela; Dakir, El-Habib; Matchett, Kyle B.; Haggag, Yusuf Ahmed; Jithesh, Puthen V.; Habib, Tanwir; Faheem, Ahmed; Dean, Fennell A.; Morgan, Richard; Rudland, Philip S.; El-Tanani, Mohamed

    2016-01-01

    It has been shown previously that cancer cells with an activated oncogenic pathway, including Met activation, require Ran for growth and survival. Here, we show that knockdown of Ran leads to a reduction of Met receptor expression in several breast and lung cancer cell lines. This, in turn suppressed HGF expression and the Met-mediated activation of the Akt pathway, as well as cell adhesion, migration, and invasion. In a cell line model where Met amplification has previously been shown to contribute to gefitinib resistance, Ran knockdown sensitized cells to gefitinib-mediated inhibition of Akt and ERK1/2 phosphorylation and consequently reduced cell proliferation. We further demonstrate that Met reduction-mediated by knockdown of Ran, occurs at the post-transcriptional level, probably via a matrix metalloproteinase. Moreover, the level of immunoreactive Ran and Met are positively associated in human breast cancer specimens, suggesting that a high level of Ran may be a pre-requisite for Met overexpression. Interestingly, a high level of immunoreactive Ran dictates the prognostic significance of Met, indicating that the co-overexpression of Met and Ran may be associated with cancer progression and could be used in combination as a prognostic indicator. PMID:27716616

  7. Signaling Role of Fructose Mediated by FINS1/FBP in Arabidopsis thaliana

    Science.gov (United States)

    Cho, Young-Hee; Yoo, Sang-Dong

    2011-01-01

    Sugars are evolutionarily conserved signaling molecules that regulate the growth and development of both unicellular and multicellular organisms. As sugar-producing photosynthetic organisms, plants utilize glucose as one of their major signaling molecules. However, the details of other sugar signaling molecules and their regulatory factors have remained elusive, due to the complexity of the metabolite and hormone interactions that control physiological and developmental programs in plants. We combined information from a gain-of-function cell-based screen and a loss-of-function reverse-genetic analysis to demonstrate that fructose acts as a signaling molecule in Arabidopsis thaliana. Fructose signaling induced seedling developmental arrest and interacted with plant stress hormone signaling in a manner similar to that of glucose. For fructose signaling responses, the plant glucose sensor HEXOKINASE1 (HXK1) was dispensable, while FRUCTOSE INSENSITIVE1 (FINS1), a putative FRUCTOSE-1,6-BISPHOSPHATASE, played a crucial role. Interestingly, FINS1 function in fructose signaling appeared to be independent of its catalytic activity in sugar metabolism. Genetic analysis further indicated that FINS1–dependent fructose signaling may act downstream of the abscisic acid pathway, in spite of the fact that HXK1–dependent glucose signaling works upstream of hormone synthesis. Our findings revealed that multiple layers of controls by fructose, glucose, and abscisic acid finely tune the plant autotrophic transition and modulate early seedling establishment after seed germination. PMID:21253566

  8. Survey of activated FLT3 signaling in leukemia.

    Directory of Open Access Journals (Sweden)

    Ting-lei Gu

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

  9. Propagation of temperature disturbances in bounded flows downstream of a nozzle block

    International Nuclear Information System (INIS)

    Krebs, L.

    1979-12-01

    The early detection of cooling disturbances in a fuel element of a sodium cooled reactor is a must for safety reasons. One possibility of achieving this goal is by measuring and analyzing the coolant temperature at the fuel element outlet. Assessment of the potential of this method requires knowledge of the flow phenomena downstream of the fuel element. As a fluid dynamics model of a fuel element a nozzle block is used, the bores of which correspond to the subchannels between the fuel rods. The studies are conducted in water which has kinematic properties comparable to those of sodium. The velocity and temperature fields downstream of the nozzle block are examined for two REYNOLDS numbers. To simulate a disturbed cooling condition, water with a temperature higher by ΔT anti T = 10 K is injected through one subchannel of the nozzle block. At the same time, the volume injected is varied. The central channel and one side channel close to the wall are selected as injection sites. Statisticl analysis of the measured velocity and temperature signals covers the following parameters: Linear averages, intensities, probability densities, spectral power densities, autocorrelation functions, integral turbulence lengths, dissipation lengths, dissipation, skewness and flatness values. On the basis of FOURIER's differential equation of heat conduction a theoretical model is developed to describe both the average temperature field and the intensity field in the flow downstream of the nozzle block. Comparison of measurements and calculations furnishes good agreement and indicates that extrapolation of the model to sodium as a fluid is possible. Supplementary to the measurements and calculations details of the water test rig and the anemometer measuring system used for velocity and temperature measurements are shown in the Appendix. (orig.) 891 GL/orig. 892 KN [de

  10. Near-infrared spectra of Penicillium camemberti strains separated by extended multiplicative signal correction improved prediction of physical and chemical variations

    DEFF Research Database (Denmark)

    Decker, Marianne; Nielsen, Per Væggemose; Martens, Harald

    2005-01-01

    signal correction (TWEMSC) preprocessing, whereby three patterns of variation in near-infrared (NIR) log(1/R) spectra of fungal colonies could be separated mathematically: (1) physical light scattering and its wavelength dependency, (2) differences in light absorption of water due to varying sample...

  11. Fragile X mental retardation protein regulates trans-synaptic signaling in Drosophila

    Directory of Open Access Journals (Sweden)

    Samuel H. Friedman

    2013-11-01

    Fragile X syndrome (FXS, the most common inherited determinant of intellectual disability and autism spectrum disorders, is caused by loss of the fragile X mental retardation 1 (FMR1 gene product (FMRP, an mRNA-binding translational repressor. A number of conserved FMRP targets have been identified in the well-characterized Drosophila FXS disease model, but FMRP is highly pleiotropic in function and the full spectrum of FMRP targets has yet to be revealed. In this study, screens for upregulated neural proteins in Drosophila fmr1 (dfmr1 null mutants reveal strong elevation of two synaptic heparan sulfate proteoglycans (HSPGs: GPI-anchored glypican Dally-like protein (Dlp and transmembrane Syndecan (Sdc. Our recent work has shown that Dlp and Sdc act as co-receptors regulating extracellular ligands upstream of intracellular signal transduction in multiple trans-synaptic pathways that drive synaptogenesis. Consistently, dfmr1 null synapses exhibit altered WNT signaling, with changes in both Wingless (Wg ligand abundance and downstream Frizzled-2 (Fz2 receptor C-terminal nuclear import. Similarly, a parallel anterograde signaling ligand, Jelly belly (Jeb, and downstream ERK phosphorylation (dpERK are depressed at dfmr1 null synapses. In contrast, the retrograde BMP ligand Glass bottom boat (Gbb and downstream signaling via phosphorylation of the transcription factor MAD (pMAD seem not to be affected. To determine whether HSPG upregulation is causative for synaptogenic defects, HSPGs were genetically reduced to control levels in the dfmr1 null background. HSPG correction restored both (1 Wg and Jeb trans-synaptic signaling, and (2 synaptic architecture and transmission strength back to wild-type levels. Taken together, these data suggest that FMRP negatively regulates HSPG co-receptors controlling trans-synaptic signaling during synaptogenesis, and that loss of this regulation causes synaptic structure and function defects characterizing the FXS disease state.

  12. Trehalose-6-phosphate synthesis controls yeast gluconeogenesis downstream and independent of SNF1.

    Science.gov (United States)

    Deroover, Sofie; Ghillebert, Ruben; Broeckx, Tom; Winderickx, Joris; Rolland, Filip

    2016-06-01

    Trehalose-6-P (T6P), an intermediate of trehalose biosynthesis, was identified as an important regulator of yeast sugar metabolism and signaling. tps1Δ mutants, deficient in T6P synthesis (TPS), are unable to grow on rapidly fermentable medium with uncontrolled influx in glycolysis, depletion of ATP and accumulation of sugar phosphates. However, the exact molecular mechanisms involved are not fully understood. We show that SNF1 deletion restores the tps1Δ growth defect on glucose, suggesting that lack of TPS hampers inactivation of SNF1 or SNF1-regulated processes. In addition to alternative, non-fermentable carbon metabolism, SNF1 controls two major processes: respiration and gluconeogenesis. The tps1Δ defect appears to be specifically associated with deficient inhibition of gluconeogenesis, indicating more downstream effects. Consistently, Snf1 dephosphorylation and inactivation on glucose medium are not affected, as confirmed with an in vivo Snf1 activity reporter. Detailed analysis shows that gluconeogenic Pck1 and Fbp1 expression, protein levels and activity are not repressed upon glucose addition to tps1Δ cells, suggesting a link between the metabolic defect and persistent gluconeogenesis. While SNF1 is essential for induction of gluconeogenesis, T6P/TPS is required for inactivation of gluconeogenesis in the presence of glucose, downstream and independent of SNF1 activity and the Cat8 and Sip4 transcription factors. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  13. Experimental Study of Particle Separation in a L Kr Ionization Chamber by Multiple Measuring of dE/d x Using the Shape Analysis of Signal

    International Nuclear Information System (INIS)

    Cantoni, P.; Frabetti, P.L.; Stagni, L.

    1994-01-01

    Charged particle (π - k) separation in the momentum range 0.5 - 0.7 GeV/c using a new method of shape analysis of the signal from a liquid krypton (L Kr) ionization chamber has been experimentally studied. The detector has been exposed to pions and protons at T11 test beam at the CERN PS. The shape of the preamplifier output signal was recorded by a waveform digitizer, then it was doubly 'differentiated' to obtain few measurements of dE/d x inside a 2 cm gap. This permits an increase of the boundary momentum of 2 σ separation from 0.6 GeV/c to 0.68 GeV/c. The comparison with the Monte Carlo result shows good agreement. (author). 11 refs.; 9 figs

  14. Flow behavior of droplets downstream of the spacer

    International Nuclear Information System (INIS)

    Kodama, Eiichiro; Morishita, Kiyohide; Aritomi, Masanori; Yano, Takashi

    1998-01-01

    The fuel spacer, of which role is to maintain an appropriate rod-to-rod clearance, is one of the components of a Boiling Water Reactor (BWR) fuel rod bundles. The fuel spacer influences flow characteristics of the liquid film in fuel rod bundles, so that its geometry influences greatly thermal hydraulics such as critical power and pressure drop therein. The purpose of this study is to clarify the effect of the spacer geometry on the core flow split downstream of the spacer. Phase Doppler Anemometry (PDA) was used for their meausrement under the conditions of a small amount of droplets in mist flows. From the experimental results, the normalized droplet velocity profiles with a spacer were split by the spacer and were different between a wider and a narrower regions in the channel, however, they became uniform at the distance far 100mm from the spacer. In the case without a spacer, the velocity was monotonously increasing nearer the rod surface with going toward the center of the channel. In the case with a spacer, the velocity profile downstream of the spacer changed in the narrower region of the channel. This tendency became more remarkable with thickening the spacer and widening clearance between the spacer and the wall. In this paper, 'drift' velocity effect was applied for the spacer model, due to the gas flows were split by the spacer which is based on the momentum balance between the narrower and wider channels. This model was confirmed from the experimental results that the droplet flowed from a wider region to a narrower one. This drift effect appeared more strongly as the spacer became thicker and the clearance did narrower. The analytical results explained qualitatively the measured ones. It is clarified that the drift effect proposed in this work was a dominant factor on droplet deposition downstream of the spacer

  15. Climate change issue table : petroleum downstream sector industry foundation paper

    International Nuclear Information System (INIS)

    Crandall, G.R.; Kelly, S.J.; Kromm, R.B.; Prime, M.G.

    1999-01-01

    An analysis of the impact of the Kyoto Protocol on the Canadian downstream petroleum industry is presented. The downstream sector includes petroleum refining, plus all activities regarding distribution, marketing and retailing of petroleum products. In 1990, the carbon dioxide (CO 2 ) emissions resulting from the production and consumption of petroleum products were about 207 megatons which is about 45 per cent of total Canadian CO 2 emissions. This report includes the analysis of the Base Case and the Kyoto Case. The Base Case is premised on the implementation of fuel sulphur reductions to meet cleaner fuels requirements and an enhanced program of refinery efficiency initiatives. Under the Base Case assumptions the CO 2 emissions from refinery operations in 2010 would be about 3.4 below 1990 levels. The Kyoto Case was developed on the basis of reductions in Canadian petroleum product demand that would be sufficient to achieve a 6 per cent reduction in GHG emissions from the production and consumption of petroleum products relative to 1990 levels. The model demonstrates the dramatic economic impact of the Kyoto Case reductions on the Canadian downstream petroleum sector. Investment requirements for capital improvements to further distillate production and to further desulphurization are estimated at $ 1.5 billion between 2005 and 2015. The reduced volume of gasoline sales would be expected to result in rationalization of retail outlets, resulting in the closure of some 2,000 retail outlets with a combined loss of about 12,000 jobs. It is suggested that similar impact in other countries that are signatory to the Kyoto Protocol could result in the shift of refining, refining industry jobs and related economic benefits to countries which are not participants in the Kyoto Protocol. 14 tabs., 6 figs., 5 appendices

  16. Alfven waves and associated energetic ions downstream from Uranus

    International Nuclear Information System (INIS)

    Zhang, Ming; Belcher, J.W.; Richardson, J.D.; Smith, C.W.

    1991-01-01

    The authors report the observation of low-frequency waves in the solar wind downstream from Uranus. These waves are observed by the Voyager spacecraft for more than 2 weeks after the encounter with Uranus and are present during this period whenever the interplanetary magnetic field is oriented such that the field lines intersect the Uranian bow shock. The magnetic field and velocity components transverse to the background field are strongly correlated, consistent with the interpretation that these waves are Alfvenic and/or fast-mode waves. The waves have a spacecraft frame frequency of about 10 -3 Hz, and when first observed near the bow shock have an amplitude comparable to the background field. As the spacecraft moves farther from Uranus, the amplitude decays. The waves appear to propagate along the magnetic field lines outward from Uranus and are right-hand polarized. Theory suggests that these waves are generated in the upstream region by a resonant instability with a proton beam streaming along the magnetic field lines. The solar wind subsequently carries these waves downstream to the spacecraft location. These waves are associated with the presence of energetic (> 28 keV) ions observed by the low-energy charged particle instrument. These ions appear two days after the start of the wave activity and occur thereafter whenever the Alfven waves occur, increasing in intensity away from Uranus. The ions are argued to originate in the Uranian magnetosphere, but pitch-angle scattering in the upstream region is required to bring them downstream to the spacecraft location

  17. Signal characteristics of focal bone marrow lesions in patients with multiple myeloma using whole body T1w-TSE, T2w-STIR and diffusion-weighted imaging with background suppression

    Energy Technology Data Exchange (ETDEWEB)

    Sommer, Gregor; Bongartz, Georg; Winter, Leopold [University of Basel Hospital, Department of Radiology, Basel (Switzerland); Klarhoefer, Markus; Lenz, Claudia; Scheffler, Klaus [University of Basel Hospital, Department of Radiology, Division of Radiological Physics, Basel (Switzerland)

    2011-04-15

    This study analyses the diagnostic potential of Diffusion-Weighted Imaging with Background Suppression (DWIBS) in the detection of focal bone marrow lesions from multiple myeloma. The signal and contrast properties of DWIBS are evaluated in correlation with the serum concentration of M-component (MC) and compared with established T1- and T2-weighted sequences. Data from 103 consecutive studies in 81 patients are analysed retrospectively. Signal intensities and apparent Diffusion Coefficients (ADC) of 79 focal lesions in the lumbar spine or pelvis of 38 patients are determined and contrast-to-noise-ratio (CNR) is calculated. Data from patients with low (<20 g/L) and high (>20 g/dL) MC are evaluated separately. Signal intensities of focal myeloma lesions on T2w-STIR vary significantly depending on the MC, which leads to a loss in CNR in patients with high MC. No signal variation is observed for T1w-TSE and DWIBS. The CNR values provided by DWIBS in patients with high MC are slightly higher than those of T2w-STIR. ADC values in patients with low MC are significantly higher than in patients with high MC. Whole-body DWIBS has the potential to improve the conspicuity of focal myeloma lesions and provides additional biological information by ADC quantification. (orig.)

  18. Flow diagnostics downstream of a tribladed rotor model

    DEFF Research Database (Denmark)

    Naumov, I. V.; Rahmanov, V. V.; Okulov, Valery

    2012-01-01

    This paper presents results of a study of vortex wake structures and measurements of instantaneous 3D velocity fields downstream of a triblade turbine model. Two operation modes of flow around the rotor with different tip speed ratios were tested. Initially the wake structures were visualized...... and subsequently quantitative data were recorded through velocity field restoration from particle tracks using a stereo PIV system.The study supplied flow diagnostics and recovered the instantaneous 3D velocity fields in the longitudinal cross section behind a tribladed rotor at different values of tip speed ratio...

  19. Recent Molecular Advances on Downstream Plant Responses to Abiotic Stress

    Directory of Open Access Journals (Sweden)

    Cláudia Regina Batista de Souza

    2012-07-01

    Full Text Available Abiotic stresses such as extremes of temperature and pH, high salinity and drought, comprise some of the major factors causing extensive losses to crop production worldwide. Understanding how plants respond and adapt at cellular and molecular levels to continuous environmental changes is a pre-requisite for the generation of resistant or tolerant plants to abiotic stresses. In this review we aimed to present the recent advances on mechanisms of downstream plant responses to abiotic stresses and the use of stress-related genes in the development of genetically engineered crops.

  20. 'Patents and Downstream Innovation Suppression - Fact or Fiction?'

    DEFF Research Database (Denmark)

    Howells, John

    Merges and Nelson have provided an empirically grounded argument that firms use pioneer patents of 'broad' scope to block downstream technological development (Merges and Nelson 1990). If this is a regular occurrence then, as they claim, they have faulted Kitch's 'prospect theory' of patents (Kitch...... 1977), a theory that is a version of the classic justification for the award of the exclusive right - that it should protect the incentive to develop property. Merges and Nelson insist that their thesis should be supported by empirical evidence and they turn to historical accounts as an important form...

  1. WRKY transcription factors: key components in abscisic acid signalling.

    Science.gov (United States)

    Rushton, Deena L; Tripathi, Prateek; Rabara, Roel C; Lin, Jun; Ringler, Patricia; Boken, Ashley K; Langum, Tanner J; Smidt, Lucas; Boomsma, Darius D; Emme, Nicholas J; Chen, Xianfeng; Finer, John J; Shen, Qingxi J; Rushton, Paul J

    2012-01-01

    WRKY transcription factors (TFs) are key regulators of many plant processes, including the responses to biotic and abiotic stresses, senescence, seed dormancy and seed germination. For over 15 years, limited evidence has been available suggesting that WRKY TFs may play roles in regulating plant responses to the phytohormone abscisic acid (ABA), notably some WRKY TFs are ABA-inducible repressors of seed germination. However, the roles of WRKY TFs in other aspects of ABA signalling, and the mechanisms involved, have remained unclear. Recent significant progress in ABA research has now placed specific WRKY TFs firmly in ABA-responsive signalling pathways, where they act at multiple levels. In Arabidopsis, WRKY TFs appear to act downstream of at least two ABA receptors: the cytoplasmic PYR/PYL/RCAR-protein phosphatase 2C-ABA complex and the chloroplast envelope-located ABAR-ABA complex. In vivo and in vitro promoter-binding studies show that the target genes for WRKY TFs that are involved in ABA signalling include well-known ABA-responsive genes such as ABF2, ABF4, ABI4, ABI5, MYB2, DREB1a, DREB2a and RAB18. Additional well-characterized stress-inducible genes such as RD29A and COR47 are also found in signalling pathways downstream of WRKY TFs. These new insights also reveal that some WRKY TFs are positive regulators of ABA-mediated stomatal closure and hence drought responses. Conversely, many WRKY TFs are negative regulators of seed germination, and controlling seed germination appears a common function of a subset of WRKY TFs in flowering plants. Taken together, these new data demonstrate that WRKY TFs are key nodes in ABA-responsive signalling networks. © 2011 The Authors. Plant Biotechnology Journal © 2011 Society for Experimental Biology, Association of Applied Biologists and Blackwell Publishing Ltd.

  2. A method to synchronize signals from multiple patient monitoring devices through a single input channel for inclusion in list-mode acquisitions

    International Nuclear Information System (INIS)

    O’Connor, J. Michael; Pretorius, P. Hendrik; Johnson, Karen; King, Michael A.

    2013-01-01

    Purpose: This technical note documents a method that the authors developed for combining a signal to synchronize a patient-monitoring device with a second physiological signal for inclusion into list-mode acquisition. Our specific application requires synchronizing an external patient motion-tracking system with a medical imaging system by multiplexing the tracking input with the ECG input. The authors believe that their methodology can be adapted for use in a variety of medical imaging modalities including single photon emission computed tomography (SPECT) and positron emission tomography (PET). Methods: The authors insert a unique pulse sequence into a single physiological input channel. This sequence is then recorded in the list-mode acquisition along with the R-wave pulse used for ECG gating. The specific form of our pulse sequence allows for recognition of the time point being synchronized even when portions of the pulse sequence are lost due to collisions with R-wave pulses. This was achieved by altering our software used in binning the list-mode data to recognize even a portion of our pulse sequence. Limitations on heart rates at which our pulse sequence could be reliably detected were investigated by simulating the mixing of the two signals as a function of heart rate and time point during the cardiac cycle at which our pulse sequence is mixed with the cardiac signal. Results: The authors have successfully achieved accurate temporal synchronization of our motion-tracking system with acquisition of SPECT projections used in 17 recent clinical research cases. In our simulation analysis the authors determined that synchronization to enable compensation for body and respiratory motion could be achieved for heart rates up to 125 beats-per-minute (bpm). Conclusions: Synchronization of list-mode acquisition with external patient monitoring devices such as those employed in motion-tracking can reliably be achieved using a simple method that can be implemented using

  3. A method to synchronize signals from multiple patient monitoring devices through a single input channel for inclusion in list-mode acquisitions

    Energy Technology Data Exchange (ETDEWEB)

    O’Connor, J. Michael; Pretorius, P. Hendrik; Johnson, Karen; King, Michael A., E-mail: Michael.King@umassmed.edu [Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655 (United States)

    2013-12-15

    Purpose: This technical note documents a method that the authors developed for combining a signal to synchronize a patient-monitoring device with a second physiological signal for inclusion into list-mode acquisition. Our specific application requires synchronizing an external patient motion-tracking system with a medical imaging system by multiplexing the tracking input with the ECG input. The authors believe that their methodology can be adapted for use in a variety of medical imaging modalities including single photon emission computed tomography (SPECT) and positron emission tomography (PET). Methods: The authors insert a unique pulse sequence into a single physiological input channel. This sequence is then recorded in the list-mode acquisition along with the R-wave pulse used for ECG gating. The specific form of our pulse sequence allows for recognition of the time point being synchronized even when portions of the pulse sequence are lost due to collisions with R-wave pulses. This was achieved by altering our software used in binning the list-mode data to recognize even a portion of our pulse sequence. Limitations on heart rates at which our pulse sequence could be reliably detected were investigated by simulating the mixing of the two signals as a function of heart rate and time point during the cardiac cycle at which our pulse sequence is mixed with the cardiac signal. Results: The authors have successfully achieved accurate temporal synchronization of our motion-tracking system with acquisition of SPECT projections used in 17 recent clinical research cases. In our simulation analysis the authors determined that synchronization to enable compensation for body and respiratory motion could be achieved for heart rates up to 125 beats-per-minute (bpm). Conclusions: Synchronization of list-mode acquisition with external patient monitoring devices such as those employed in motion-tracking can reliably be achieved using a simple method that can be implemented using

  4. Estimating the wake deflection downstream of a wind turbine in different atmospheric stabilities: an LES study

    Directory of Open Access Journals (Sweden)

    L. Vollmer

    2016-09-01

    Full Text Available An intentional yaw misalignment of wind turbines is currently discussed as one possibility to increase the overall energy yield of wind farms. The idea behind this control is to decrease wake losses of downstream turbines by altering the wake trajectory of the controlled upwind turbines. For an application of such an operational control, precise knowledge about the inflow wind conditions, the magnitude of wake deflection by a yawed turbine and the propagation of the wake is crucial. The dependency of the wake deflection on the ambient wind conditions as well as the uncertainty of its trajectory are not sufficiently covered in current wind farm control models. In this study we analyze multiple sources that contribute to the uncertainty of the estimation of the wake deflection downstream of yawed wind turbines in different ambient wind conditions. We find that the wake shapes and the magnitude of deflection differ in the three evaluated atmospheric boundary layers of neutral, stable and unstable thermal stability. Uncertainty in the wake deflection estimation increases for smaller temporal averaging intervals. We also consider the choice of the method to define the wake center as a source of uncertainty as it modifies the result. The variance of the wake deflection estimation increases with decreasing atmospheric stability. Control of the wake position in a highly convective environment is therefore not recommended.

  5. Wash functions downstream of Rho1 GTPase in a subset of Drosophila immune cell developmental migrations

    Science.gov (United States)

    Verboon, Jeffrey M.; Rahe, Travis K.; Rodriguez-Mesa, Evelyn; Parkhurst, Susan M.

    2015-01-01

    Drosophila immune cells, the hemocytes, undergo four stereotypical developmental migrations to populate the embryo, where they provide immune reconnoitering, as well as a number of non–immune-related functions necessary for proper embryogenesis. Here, we describe a role for Rho1 in one of these developmental migrations in which posteriorly located hemocytes migrate toward the head. This migration requires the interaction of Rho1 with its downstream effector Wash, a Wiskott–Aldrich syndrome family protein. Both Wash knockdown and a Rho1 transgene harboring a mutation that prevents Wash binding exhibit the same developmental migratory defect as Rho1 knockdown. Wash activates the Arp2/3 complex, whose activity is needed for this migration, whereas members of the WASH regulatory complex (SWIP, Strumpellin, and CCDC53) are not. Our results suggest a WASH complex–independent signaling pathway to regulate the cytoskeleton during a subset of hemocyte developmental migrations. PMID:25739458

  6. A metabolic switch controls intestinal differentiation downstream of Adenomatous polyposis coli (APC).

    Science.gov (United States)

    Sandoval, Imelda T; Delacruz, Richard Glenn C; Miller, Braden N; Hill, Shauna; Olson, Kristofor A; Gabriel, Ana E; Boyd, Kevin; Satterfield, Christeena; Remmen, Holly Van; Rutter, Jared; Jones, David A

    2017-04-11

    Elucidating signaling pathways that regulate cellular metabolism is essential for a better understanding of normal development and tumorigenesis. Recent studies have shown that mitochondrial pyruvate carrier 1 (MPC1) , a crucial player in pyruvate metabolism, is downregulated in colon adenocarcinomas. Utilizing zebrafish to examine the genetic relationship between MPC1 and Adenomatous polyposis coli (APC), a key tumor suppressor in colorectal cancer, we found that apc controls the levels of mpc1 and that knock down of mpc1 recapitulates phenotypes of impaired apc function including failed intestinal differentiation. Exogenous human MPC1 RNA rescued failed intestinal differentiation in zebrafish models of apc deficiency. Our data demonstrate a novel role for apc in pyruvate metabolism and that pyruvate metabolism dictates intestinal cell fate and differentiation decisions downstream of apc .

  7. Cdc42 and phosphoinositide 3-kinase drive Rac-mediated actin polymerization downstream of c-Met in distinct and common pathways

    DEFF Research Database (Denmark)

    Bosse, Tanja; Ehinger, Julia; Czuchra, Aleksandra

    2007-01-01

    -WASP. Instead, actin polymerization was driven by Arp2/3 complex activation through the WAVE complex downstream of Rac. Together, our data establish an intricate signaling network comprising as key molecules Cdc42 and PI3-kinase, which converge on Rac-mediated actin reorganization essential for Listeria...

  8. Tolerance to drought and salt stress in plants: Unraveling the signaling networks

    Directory of Open Access Journals (Sweden)

    Dortje eGolldack

    2014-04-01

    Full Text Available Tolerance of plants to abiotic stressors such as drought and salinity is triggered by complex multicomponent signaling pathways to restore cellular homeostasis and promote survival. Major plant transcription factor families such as bZIP, NAC, AP2/ERF and MYB orchestrate regulatory networks underlying abiotic stress tolerance. Sucrose nonfermenting 1-related protein kinase 2 (SnRK2 and MAPK pathways contribute to initiation of stress adaptive downstream responses and promote plant growth and development. As a convergent point of multiple abiotic cues, cellular effects of environmental stresses are not only imbalances of ionic and osmotic homeostasis but also impaired photosynthesis, cellular energy depletion, and redox imbalances. Recent evidence of regulatory systems that link sensing and signaling of environmental conditions and the intracellular redox status have shed light on interfaces of stress and energy signaling. ROS (reactive oxygen species cause severe cellular damage by peroxidation and de-esterification of membrane lipids, however, current models also define a pivotal signaling function of ROS in triggering tolerance against stress. Recent research advances suggest and support a regulatory role of ROS in the cross talks of stress triggered hormonal signaling such as the abscisic acid (ABA pathway and endogenously induced redox and metabolite signals. Here, we discuss and review the versatile molecular convergence in the abiotic stress responsive signaling networks in the context of ROS and lipid derived signals and the specific role of stomatal signaling.

  9. Increasing signal intensity within the dentate nucleus and globus pallidus on unenhanced T1W magnetic resonance images in patients with relapsing-remitting multiple sclerosis: correlation with cumulative dose of a macrocyclic gadolinium-based contrast agent, gadobutrol

    Energy Technology Data Exchange (ETDEWEB)

    Stojanov, Dragan A. [University of Nis, Faculty of Medicine, Nis (Serbia); Clinical Center Nis, Center for Radiology, Nis (Serbia); Aracki-Trenkic, Aleksandra [Clinical Center Nis, Center for Radiology, Nis (Serbia); Vojinovic, Slobodan; Ljubisavljevic, Srdjan [University of Nis, Faculty of Medicine, Nis (Serbia); Clinical Center Nis, Clinic for Neurology, Nis (Serbia); Benedeto-Stojanov, Daniela [University of Nis, Faculty of Medicine, Nis (Serbia)

    2016-03-15

    To evaluate correlation between cumulative dose of gadobutrol and signal intensity (SI) within dentate nucleus and globus pallidus on unenhanced T1-weighted images in patients with relapsing-remitting multiple sclerosis (RRMS). Dentate nucleus-to-pons and globus pallidus-to-thalamus SI ratios, and renal and liver functions, were evaluated after multiple intravenous administrations of 0.1 mmol/kg gadobutrol at 27, 96-98, and 168 weeks. We compared SI ratios based on the number of administrations, total amount of gadobutrol administered, and time between injections. Globus pallidus-to-thalamus (p = 0.025) and dentate nucleus-to-pons (p < 0.001) SI ratios increased after multiple gadobutrol administrations, correlated with the number of administrations (ρ = 0.263, p = 0.046, respectively) and depended on the length of administration (p = 0.017, p = 0.037, respectively). Patients receiving gadobutrol at 27 weeks showed the greatest increase in both SI ratios (p = 0.006; p = 0.014, respectively, versus 96-98 weeks). GGT increased at the end of the study (p = 0.004). In patients with RRMS, SI within the dentate nucleus and globus pallidus increased on unenhanced T1-weighted images after multiple gadobutrol injections. Administration of the same total amount of gadobutrol over a shorter period caused greater SI increase. (orig.)

  10. Turbulence downstream of subcoronary stentless and stented aortic valves.

    Science.gov (United States)

    Funder, Jonas Amstrup; Frost, Markus Winther; Wierup, Per; Klaaborg, Kaj-Erik; Hjortdal, Vibeke; Nygaard, Hans; Hasenkam, J Michael

    2011-08-11

    Regions of turbulence downstream of bioprosthetic heart valves may cause damage to blood components, vessel wall as well as to aortic valve leaflets. Stentless aortic heart valves are known to posses several hemodynamic benefits such as larger effective orifice areas, lower aortic transvalvular pressure difference and faster left ventricular mass regression compared with their stented counterpart. Whether this is reflected by diminished turbulence formation, remains to be shown. We implanted either stented pericardial valve prostheses (Mitroflow), stentless valve prostheses (Solo or Toronto SPV) in pigs or they preserved their native valves. Following surgery, blood velocity was measured in the cross sectional area downstream of the valves using 10MHz ultrasonic probes connected to a dedicated pulsed Doppler equipment. As a measure of turbulence, Reynolds normal stress (RNS) was calculated at two different blood pressures (baseline and 50% increase). We found no difference in maximum RNS measurements between any of the investigated valve groups. The native valve had significantly lower mean RNS values than the Mitroflow (p=0.004), Toronto SPV (p=0.008) and Solo valve (p=0.02). There were no statistically significant differences between the artificial valve groups (p=0.3). The mean RNS was significantly larger when increasing blood pressure (p=0.0006). We, thus, found no advantages for the stentless aortic valves compared with stented prosthesis in terms of lower maximum or mean RNS values. Native valves have a significantly lower mean RNS value than all investigated bioprostheses. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Natural Origin Lycopene and Its "Green" Downstream Processing.

    Science.gov (United States)

    Papaioannou, Emmanouil H; Liakopoulou-Kyriakides, Maria; Karabelas, Anastasios J

    2016-01-01

    Lycopene is an abundant natural carotenoid pigment with several biological functions (well-known for its antioxidant properties) which is under intensive investigation in recent years. Lycopene chemistry, its natural distribution, bioavailability, biological significance, and toxicological effects are briefly outlined in the first part of this review. The second, major part, deals with various modern downstream processing techniques, which are assessed in order to identify promising approaches for the recovery of lycopene and of similar lipophilic compounds. Natural lycopene is synthesized in plants and by microorganisms, with main representatives of these two categories (for industrial production) tomato and its by-products and the fungus Blakeslea trispora, respectively. Currently, there is a great deal of effort to develop efficient downstream processing for large scale production of natural-origin lycopene, with trends strongly indicating the necessity for "green" and mild extraction conditions. In this review, emphasis is placed on final product safety and ecofriendly processing, which are expected to totally dominate in the field of natural-origin lycopene extraction and purification.

  12. Kappa-Electrons Downstream of the Solar Wind Termination Shock

    Science.gov (United States)

    Fahr, H. J.

    2017-12-01

    A theoretical description of the solar wind electron distribution function downstream of the termination shock under the influence of the shock-induced injection of overshooting KeV-energetic electrons will be presented. A kinetic phasespace transport equation in the bulk frame of the heliosheath plasma flow is developed for the solar wind electrons, taking into account shock-induced electron injection, convective changes, magnetic cooling processes and whistler wave-induced energy diffusion. Assuming that the local electron distribution under the prevailing Non-LTE conditions can be represented by a local kappa function with a local kappa parameter that varies with the streamline coordinates, we determine the parameters of the resulting, initial kappa distribution for the downstream electrons. From this initial function spectral electron fluxes can be derived and can be compared with those measured by the VOYAGER-1 spacecraft in the range between 40 to 70 KeV. It can then be shown that with kappa values around kappa = 6 one can in fact fit these data very satisfactorily. In addition it is shown that for isentropic electron flows kappa-distributed electrons have to undergo simultaneous changes of both parameters, i.e. kappa and theta, of the electron kappa function. It is also shown then that under the influence of energy sinks and sources the electron flux becomes non-isentropic with electron entropies changing along the streamline.

  13. Atrazine enhances progesterone production through activation of multiple signaling pathways in FSH-stimulated rat granulosa cells: evidence for premature luteinization.

    Science.gov (United States)

    Pogrmic-Majkic, Kristina; Samardzija, Dragana; Fa, Svetlana; Hrubik, Jelena; Glisic, Branka; Kaisarevic, Sonja; Andric, Nebojsa

    2014-11-01

    Premature luteinization is a possible cause of infertility in women. It is currently unknown whether environmental chemicals can induce changes associated with premature luteinization. Using rat granulosa cells (GC) in vitro, we demonstrated that exposure to atrazine (ATR), a widely used herbicide, causes GC phenotype that resembles that of human premature luteinization. At the end of the 48-h stimulation with FSH, ATR-exposed GC showed (1) higher levels of progesterone, (2) overexpression of luteal markers (Star and Cyp11a1), and (3) an increase in progesterone:estradiol ratio above 1. Mechanistic experiments were conducted to understand the signaling events engaged by ATR that lead to this phenotype. Western blot analysis revealed prolonged phosphorylation of protein kinase B (AKT) and cAMP response element-binding protein (CREB) in ATR- and FSH-exposed GC. An increased level of ERK1/2-dependent transcriptional factor CCATT/enhancer-binding protein beta (CEBPB) was observed after 4 h of ATR exposure. Inhibitors of PI3K (wortmannin) and MEK (U0126) prevented ATR-induced rise in progesterone level and expression of luteal markers in FSH-stimulated GC. Atrazine intensified AKT and CEBPB signaling and caused Star overexpression in forskolin-stimulated GC but not in epidermal growth factor (EGF)-stimulated GC. In the presence of rolipram, a specific inhibitor of phosphodiesterase 4 (PDE4), ATR was not able to further elevate AKT phosphorylation, CEBPB protein level, and Star mRNA in FSH-stimulated GC, suggesting that ATR inhibits PDE4. Overall, this study showed that ATR acts as a FSH sensitizer leading to enhanced cAMP, AKT, and CEBPB signaling and progesterone biosynthesis, which promotes premature luteinization phenotype in GC. © 2014 by the Society for the Study of Reproduction, Inc.

  14. AHP2, AHP3, and AHP5 act downstream of CKI1 in Arabidopsis female gametophyte development.

    Science.gov (United States)

    Liu, Zhenning; Yuan, Li; Song, Xiaoya; Yu, Xiaolin; Sundaresan, Venkatesan

    2017-06-15

    Histidine phosphotransfer proteins (HPs) are key elements of the two-component signaling system, which act as a shuttle to transfer phosphorylation signals from histidine kinases (HKs) to response regulators (RRs). CYTOKININ INDEPENDENT 1 (CKI1), a key regulator of central cell specification in the Arabidopsis female gametophyte, activates the cytokinin signaling pathway through the Arabidopsis histidine phosphotransfer proteins (AHPs). There are five HP genes in Arabidopsis, AHP1-AHP5, but it remains unknown which AHP genes act downstream of CKI1 in Arabidopsis female gametophyte development. Promoter activity analysis of AHP1-AHP5 in embryo sacs revealed AHP1, AHP2, AHP3, and AHP5 expression in the central cell. Phenotypic studies of various combinations of ahp mutants showed that triple mutations in AHP2, AHP3, and AHP5 resulted in defective embryo sac development. Using cell-specific single and double markers in the female gametophyte, the ahp2-2 ahp3 ahp5-2/+ triple mutant ovules showed loss of central cell and antipodal cell fates and gain of egg cell or synergid cell attributes, resembling the cki1 mutant phenotypes. These data suggest that AHP2, AHP3, and AHP5 are the major factors acting downstream of CKI1 in the two-component cytokinin signaling pathway to promote Arabidopsis female gametophyte development. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  15. A theoretical study of mixing downstream of transverse injection into a supersonic boundary layer

    Science.gov (United States)

    Baker, A. J.; Zelazny, S. W.

    1972-01-01

    A theoretical and analytical study was made of mixing downstream of transverse hydrogen injection, from single and multiple orifices, into a Mach 4 air boundary layer over a flat plate. Numerical solutions to the governing three-dimensional, elliptic boundary layer equations were obtained using a general purpose computer program. Founded upon a finite element solution algorithm. A prototype three-dimensional turbulent transport model was developed using mixing length theory in the wall region and the mass defect concept in the outer region. Excellent agreement between the computed flow field and experimental data for a jet/freestream dynamic pressure ratio of unity was obtained in the centerplane region of the single-jet configuration. Poorer agreement off centerplane suggests an inadequacy of the extrapolated two-dimensional turbulence model. Considerable improvement in off-centerplane computational agreement occured for a multi-jet configuration, using the same turbulent transport model.

  16. Ned-19 inhibition of parasite growth and multiplication suggests a role for NAADP mediated signalling in the asexual development of Plasmodium falciparum.

    Science.gov (United States)

    Suárez-Cortés, Pablo; Gambara, Guido; Favia, Annarita; Palombi, Fioretta; Alano, Pietro; Filippini, Antonio

    2017-09-12

    Although malaria is a preventable and curable human disease, millions of people risk to be infected by the Plasmodium parasites and to develop this illness. Therefore, there is an urgent need to identify new anti-malarial drugs. Ca 2+ signalling regulates different processes in the life cycle of Plasmodium falciparum, representing a suitable target for the development of new drugs. This study investigated for the first time the effect of a highly specific inhibitor of nicotinic acid adenine dinucleotide phosphate (NAADP)-induced Ca 2+ release (Ned-19) on P. falciparum, revealing the inhibitory effect of this compound on the blood stage development of this parasite. Ned-19 inhibits both the transition of the parasite from the early to the late trophozoite stage and the ability of the late trophozoite to develop to the multinucleated schizont stage. In addition, Ned-19 affects spontaneous intracellular Ca 2+ oscillations in ring and trophozoite stage parasites, suggesting that the observed inhibitory effects may be associated to regulation of intracellular Ca 2+ levels. This study highlights the inhibitory effect of Ned-19 on progression of the asexual life cycle of P. falciparum. The observation that Ned-19 inhibits spontaneous Ca 2+ oscillations suggests a potential role of NAADP in regulating Ca 2+ signalling of P. falciparum.

  17. Downstream mixing of sediment and tracers in agricultural catchments: Evidence of changing sediment sources and fluvial processes?

    Science.gov (United States)

    Ralph, Timothy; Wethered, Adam; Smith, Hugh; Heijnis, Henk

    2014-05-01

    Land clearance, soil tillage and grazing in agricultural catchments have liberated sediment and altered hydrological connectivity between hillslopes and channels, leading to increased sediment availability, mobilisation and delivery to rivers. The type and amount of sediment supplied to rivers is critical for fluvial geomorphology and aquatic ecosystem health. Contemporary sediment dynamics are routinely investigated using environmental radionuclides such as caesium-137 (Cs-137) and excess lead-210 (Pb-210ex), which can provide information regarding sediment source types and fluvial processes if sediment sources can be distinguished from one another and mixing models applied to representative samples. However, downstream transport, mixing and dilution of radionuclide-labelled sediment (especially from sources with low initial concentrations) can obliterate the tracer signal; sometimes before anything of geomorphological importance happens in the catchment. Can these findings be used as evidence of sediment source variations and fluvial processes when the limits of detection (of Cs-137 in particular) are being exceeded so rapidly downstream? Sediment sources and downstream sediment dynamics were investigated in Coolbaggie Creek, a major supplier of sediment to the Macquarie River in an agricultural catchment with temperate to semi-arid climate in Australia. Radionuclides were used to discriminate between the banks and gullies (Cs-137 1.45 +/- 0.47 Bq/kg; Pb-210ex 4.67 +/- 1.93 Bq/kg). Within the trunk stream, suspended sediment, organic matter and Cs-137 and Pb-210ex concentrations declined downstream. Results from a mixing model suggest that agricultural topsoils account for 95% of fine sediment entering the channel in the upper reach (200 m2) downstream, with channel expansion and gullies contributing fine sediment to the system. A lack of topsoil being supplied to the channel suggests minimal lateral connectivity between the catchment and the trunk stream in all

  18. The best-laid plans go oft awry: synaptogenic growth factor signaling in neuropsychiatric disease

    Directory of Open Access Journals (Sweden)

    Aislinn Joanmarie Williams

    2014-03-01

    Full Text Available Growth factors play important roles in synapse formation. Mouse models of neuropsychiatric diseases suggest that defects in synaptogenic growth factors, their receptors, and signaling pathways can lead to disordered neural development and various behavioral phenotypes, including anxiety, memory problems, and social deficits. Genetic association studies in humans have found evidence for similar relationships between growth factor signaling pathways and neuropsychiatric phenotypes. Accumulating data suggest that dysfunction in neuronal circuitry, caused by defects in growth factor-mediated synapse formation, contributes to the susceptibility to multiple neuropsychiatric diseases, including epilepsy, autism, and disorders of thought and mood (e.g. schizophrenia and bipolar disorder, respectively. In this review, we will focus on how specific synaptogenic growth factors and their downstream signaling pathways might be involved in the development of neuropsychiatric diseases.

  19. Characterization of membrane protein trafficking and cellular signaling at the primary cilium

    DEFF Research Database (Denmark)

    Mogensen, Johanne Bay

    Primary cilia are microtubule-based, non-motile, sensory organelles emerging in a single copy from the surface of most quiescent cells in vertebrates. They emanate from the centrosomal mother centriole and are assembled and maintained by a bidirectional transport process termed intraflagellar...... transport. Specific receptors, ion channels and downstream signaling components are localized along the cilium-centrosome axis, enabling the cilium to function as a hot spot for the balanced coordination of multiple signaling pathways to control cell cycle entry, differentiation and migration during...... differentiation of mouse stem cells into cardiomyocytes. These results support the conclusion that Tab2 functions at the primary cilium to coordinate specified signaling events, which when defective may lead to congenital heart disease Collectively, the results presented in this PhD thesis provide new insights...

  20. Pollutant Transport and Fate: Relations Between Flow-paths and Downstream Impacts of Human Activities

    Science.gov (United States)

    Thorslund, J.; Jarsjo, J.; Destouni, G.

    2017-12-01

    The quality of freshwater resources is increasingly impacted by human activities. Humans also extensively change the structure of landscapes, which may alter natural hydrological processes. To manage and maintain freshwater of good water quality, it is critical to understand how pollutants are released into, transported and transformed within the hydrological system. Some key scientific questions include: What are net downstream impacts of pollutants across different hydroclimatic and human disturbance conditions, and on different scales? What are the functions within and between components of the landscape, such as wetlands, on mitigating pollutant load delivery to downstream recipients? We explore these questions by synthesizing results from several relevant case study examples of intensely human-impacted hydrological systems. These case study sites have been specifically evaluated in terms of net impact of human activities on pollutant input to the aquatic system, as well as flow-path distributions trough wetlands as a potential ecosystem service of pollutant mitigation. Results shows that although individual wetlands have high retention capacity, efficient net retention effects were not always achieved at a larger landscape scale. Evidence suggests that the function of wetlands as mitigation solutions to pollutant loads is largely controlled by large-scale parallel and circular flow-paths, through which multiple wetlands are interconnected in the landscape. To achieve net mitigation effects at large scale, a large fraction of the polluted large-scale flows must be transported through multiple connected wetlands. Although such large-scale flow interactions are critical for assessing water pollution spreading and fate through the landscape, our synthesis shows a frequent lack of knowledge at such scales. We suggest ways forward for addressing the mismatch between the large scales at which key pollutant pressures and water quality changes take place and the

  1. Roles of STATs signaling in cardiovascular diseases.

    Science.gov (United States)

    Kishore, Raj; Verma, Suresh K

    2012-04-01

    In cardiac and many other systems, chronic stress activates avfamily of structurally and functionally conserved receptors and their downstream signaling molecules that entail tyrosine, serine or threonine phosphorylation to transfer the messages to the genetic machinery. However, the activation of the Janus kinases (JAKs) and their downstream signal transducer and activator of transcription (STATs) proteins is both characteristic of and unique to cytokine and growth factor signaling which plays a central role in heart physiology. Dysregulation of JAK-STAT signaling is associated with various cardiovascular diseases. The molecular signaling and specificity of the JAK-STAT pathway are modulated at many levels by distinct regulatory proteins. Here, we review recent studies on the regulation of the STAT signaling pathway that will enhance our ability to design rational therapeutic strategies for stress-induced heart failure.

  2. The Role of nAChR and Calcium Signaling in Pancreatic Cancer Initiation and Progression

    Energy Technology Data Exchange (ETDEWEB)

    Schaal, Courtney [Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 (United States); Padmanabhan, Jaya [Department of Molecular Medicine and USF Health Byrd Alzheimer’s Institute, University of South Florida, 4001 E. Fletcher Ave., Tampa, FL 33612 (United States); Chellappan, Srikumar, E-mail: Srikumar.Chellappan@moffitt.org [Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 (United States)

    2015-07-31

    Pancreatic cancer shows a strong correlation with smoking and the current therapeutic strategies have been relatively ineffective in improving the survival of patients. Efforts have been made over the past many years to understand the molecular events that drive the initiation and progression of pancreatic cancer, especially in the context of smoking. It has become clear that components of tobacco smoke not only initiate these cancers, especially pancreatic ductal adenocarcinomas (PDACs) through their mutagenic properties, but can also promote the growth and metastasis of these tumors by stimulating cell proliferation, angiogenesis, invasion and epithelial-mesenchymal transition. Studies in cell culture systems, animal models and human samples have shown that nicotinic acetylcholine receptor (nAChR) activation enhances these tumor-promoting events by channeling signaling through multiple pathways. In this context, signaling through calcium channels appear to facilitate pancreatic cancer growth by itself or downstream of nAChRs. This review article highlights the role of nAChR downstream signaling events and calcium signaling in the growth, metastasis as well as drug resistance of pancreatic cancer.

  3. The Role of nAChR and Calcium Signaling in Pancreatic Cancer Initiation and Progression

    International Nuclear Information System (INIS)

    Schaal, Courtney; Padmanabhan, Jaya; Chellappan, Srikumar

    2015-01-01

    Pancreatic cancer shows a strong correlation with smoking and the current therapeutic strategies have been relatively ineffective in improving the survival of patients. Efforts have been made over the past many years to understand the molecular events that drive the initiation and progression of pancreatic cancer, especially in the context of smoking. It has become clear that components of tobacco smoke not only initiate these cancers, especially pancreatic ductal adenocarcinomas (PDACs) through their mutagenic properties, but can also promote the growth and metastasis of these tumors by stimulating cell proliferation, angiogenesis, invasion and epithelial-mesenchymal transition. Studies in cell culture systems, animal models and human samples have shown that nicotinic acetylcholine receptor (nAChR) activation enhances these tumor-promoting events by channeling signaling through multiple pathways. In this context, signaling through calcium channels appear to facilitate pancreatic cancer growth by itself or downstream of nAChRs. This review article highlights the role of nAChR downstream signaling events and calcium signaling in the growth, metastasis as well as drug resistance of pancreatic cancer

  4. Detecting robust signals of interannual variability of gross primary productivity in Asia from multiple terrestrial carbon cycle models and long-term satellite-based vegetation data

    Science.gov (United States)

    Ichii, K.; Kondo, M.; Ueyama, M.; Kato, T.; Ito, A.; Sasai, T.; Sato, H.; Kobayashi, H.; Saigusa, N.

    2014-12-01

    Long term record of satellite-based terrestrial vegetation are important to evaluate terrestrial carbon cycle models. In this study, we demonstrate how multiple satellite observation can be used for evaluating past changes in gross primary productivity (GPP) and detecting robust anomalies in terrestrial carbon cycle in Asia through our model-data synthesis analysis, Asia-MIP. We focused on the two different temporal coverages: long-term (30 years; 1982-2011) and decadal (10 years; 2001-2011; data intensive period) scales. We used a NOAA/AVHRR NDVI record for long-term analysis and multiple satellite data and products (e.g. Terra-MODIS, SPOT-VEGETATION) as historical satellite data, and multiple terrestrial carbon cycle models (e.g. BEAMS, Biome-BGC, ORCHIDEE, SEIB-DGVM, and VISIT). As a results of long-term (30 years) trend analysis, satellite-based time-series data showed that approximately 40% of the area has experienced a significant increase in the NDVI, while only a few areas have experienced a significant decreasing trend over the last 30 years. The increases in the NDVI were dominant in the sub-continental regions of Siberia, East Asia, and India. Simulations using the terrestrial biosphere models also showed significant increases in GPP, similar to the results for the NDVI, in boreal and temperate regions. A modeled sensitivity analysis showed that the increases in GPP are explained by increased temperature and precipitation in Siberia. Precipitation, solar radiation, CO2fertilization and land cover changes are important factors in the tropical regions. However, the relative contributions of each factor to GPP changes are different among the models. Year-to-year variations of terrestrial GPP were overall consistently captured by the satellite data and terrestrial carbon cycle models if the anomalies are large (e.g. 2003 summer GPP anomalies in East Asia and 2002 spring GPP anomalies in mid to high latitudes). The behind mechanisms can be consistently

  5. Downstream ecological effects of dams: A geomorphic perspective

    International Nuclear Information System (INIS)

    Ligon, F.K.; Dietrich, W.E.; Trush, W.J.

    1995-01-01

    The damming of a river changes the flow of water, sediment, nutrients, energy, and biota, interrupting and altering most of a river's ecological processes. This article discusses the importance of geomorphological analysis in river conservation and management. To illustrate how subtle geomorphological adjustments may profoundly influence the ecological relationships downstream from dames, three case studies are presented. Then a geomorphically based approach for assessing and possibly mitigating some of the environmental effects of dams by tailoring dam designed and operation is outlined. The cases are as follows: channel simplification and salmon decline on the McKenzie River in Oregon; Channel incision and reduced floodplain inundation on the Oconee river in Georgia; Increased stability of a braided river in New Zealand's south island. 41 refs., 10 figs., 1 tab

  6. Continuous downstream processing for high value biological products: A Review.

    Science.gov (United States)

    Zydney, Andrew L

    2016-03-01

    There is growing interest in the possibility of developing truly continuous processes for the large-scale production of high value biological products. Continuous processing has the potential to provide significant reductions in cost and facility size while improving product quality and facilitating the design of flexible multi-product manufacturing facilities. This paper reviews the current state-of-the-art in separations technology suitable for continuous downstream bioprocessing, focusing on unit operations that would be most appropriate for the production of secreted proteins like monoclonal antibodies. This includes cell separation/recycle from the perfusion bioreactor, initial product recovery (capture), product purification (polishing), and formulation. Of particular importance are the available options, and alternatives, for continuous chromatographic separations. Although there are still significant challenges in developing integrated continuous bioprocesses, recent technological advances have provided process developers with a number of attractive options for development of truly continuous bioprocessing operations. © 2015 Wiley Periodicals, Inc.

  7. Downstream and upstream extension of the House of Quality

    DEFF Research Database (Denmark)

    Holmen, Elsebeth; Kristensen, Preben Sander

    . The transformation processes and characteristics constituting this fan were based on the knowledge possessed by the company before entering into development interaction with suppliers. If it is these characteristics which are used to express the demands of the company in the subsequent interaction process, much......Executive summary 1. During 1993-94 the authors followed a product development process in a Danish butter cookie company. The process was structured according to the Quality Function Deployment technique House of Quality. Originally, the intention was to study the prototyping process that we...... a discussion in a diabetics end-user focus group. During a series of meetings, the production manager and the sales manager transformed attributes int characteristics and constructed Houses of Quality for a sugar-free cookie. 2. Downstream on its way to the end-user, the product passes through a chain of users...

  8. Mergers and acquisitions of downstream facilities by producing countries

    Energy Technology Data Exchange (ETDEWEB)

    Ligon, D.R.

    1988-01-01

    The author discusses a phenomenon that he calls the ''re-integration'' or ''re-coupling'' of the worldwide oil industry, as foreign, particularly OPEC, producers are becoming directly involved with downstream operations in their most important markets. This phenomenon already has produced some far-reaching consequences that will become even more important and pervasive in the near future. First, he describes the factors and logic that led to these arrangements. Next, he outlines some of their practical considerations and implications. While some of the market factors described are applicable to any non-integrated producer, he spends most of his time discussing OPEC and ''neo-OPEC'' producers such as Mexico. These are the people doing the deals and are therefore probably of greatest interest.

  9. Curcumin and emodin down-regulate TGF-β signaling pathway in human cervical cancer cells.

    Directory of Open Access Journals (Sweden)

    Pooja Chandrakant Thacker

    Full Text Available Cervical cancer is the major cause of cancer related deaths in women, especially in developing countries and Human Papilloma Virus infection in conjunction with multiple deregulated signaling pathways leads to cervical carcinogenesis. TGF-β signaling in later stages of cancer is known to induce epithelial to mesenchymal transition promoting tumor growth. Phytochemicals, curcumin and emodin, are effective as chemopreventive and chemotherapeutic compounds against several cancers including cervical cancer. The main objective of this work was to study the effect of curcumin and emodin on TGF-β signaling pathway and its functional relevance to growth, migration and invasion in two cervical cancer cell lines, SiHa and HeLa. Since TGF-β and Wnt/β-catenin signaling pathways are known to cross talk having common downstream targets, we analyzed the effect of TGF-β on β-catenin (an important player in Wnt/β-catenin signaling and also studied whether curcumin and emodin modulate them. We observed that curcumin and emodin effectively down regulate TGF-β signaling pathway by decreasing the expression of TGF-β Receptor II, P-Smad3 and Smad4, and also counterbalance the tumorigenic effects of TGF-β by inhibiting the TGF-β-induced migration and invasion. Expression of downstream effectors of TGF-β signaling pathway, cyclinD1, p21 and Pin1, was inhibited along with the down regulation of key mesenchymal markers (Snail and Slug upon curcumin and emodin treatment. Curcumin and emodin were also found to synergistically inhibit cell population and migration in SiHa and HeLa cells. Moreover, we found that TGF-β activates Wnt/β-catenin signaling pathway in HeLa cells, and curcumin and emodin down regulate the pathway by inhibiting β-catenin. Taken together our data provide a mechanistic basis for the use of curcumin and emodin in the treatment of cervical cancer.