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Sample records for downstream signalling components

  1. 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.

  2. Evaluation of Intracellular Signaling Downstream Chimeric Antigen Receptors.

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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.

  4. 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.

  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. 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....

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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)

  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. Evolutionary conservation of plant gibberellin signalling pathway components

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    Reski Ralf

    2007-11-01

    Full Text Available Abstract Background: Gibberellins (GA are plant hormones that can regulate germination, elongation growth, and sex determination. They ubiquitously occur in seed plants. The discovery of gibberellin receptors, together with advances in understanding the function of key components of GA signalling in Arabidopsis and rice, reveal a fairly short GA signal transduction route. The pathway essentially consists of GID1 gibberellin receptors that interact with F-box proteins, which in turn regulate degradation of downstream DELLA proteins, suppressors of GA-controlled responses. Results: Arabidopsis sequences of the gibberellin signalling compounds were used to screen databases from a variety of plants, including protists, for homologues, providing indications for the degree of conservation of the pathway. The pathway as such appears completely absent in protists, the moss Physcomitrella patens shares only a limited homology with the Arabidopsis proteins, thus lacking essential characteristics of the classical GA signalling pathway, while the lycophyte Selaginella moellendorffii contains a possible ortholog for each component. The occurrence of classical GA responses can as yet not be linked with the presence of homologues of the signalling pathway. Alignments and display in neighbour joining trees of the GA signalling components confirm the close relationship of gymnosperms, monocotyledonous and dicotyledonous plants, as suggested from previous studies. Conclusion: Homologues of the GA-signalling pathway were mainly found in vascular plants. The GA signalling system may have its evolutionary molecular onset in Physcomitrella patens, where GAs at higher concentrations affect gravitropism and elongation growth.

  14. 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.

  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. High Frequency Components Recovery in Music Signals

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    V. Sebesta

    1999-04-01

    Full Text Available A new technique is presented which improves the subjective quality of band-limited music by recovery of high frequency components. Sequences of harmonics are found in the band-limited signal and these sequences are expanded to the high frequency band to estimate the lost part of spectrum. High frequency signal is generated to match this estimation and is added to the band-limited signal.

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

    Science.gov (United States)

    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.

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

    Science.gov (United States)

    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.

  19. 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.

  20. 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

  1. 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

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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).

  8. 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

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. Extracellular matrix component signaling in cancer

    DEFF Research Database (Denmark)

    Multhaupt, Hinke A. B.; Leitinger, Birgit; Gullberg, Donald

    2016-01-01

    Cell responses to the extracellular matrix depend on specific signaling events. These are important from early development, through differentiation and tissue homeostasis, immune surveillance, and disease pathogenesis. Signaling not only regulates cell adhesion cytoskeletal organization and motil...... as well as matrix constitution and protein crosslinking. Here we summarize roles of the three major matrix receptor types, with emphasis on how they function in tumor progression. [on SciFinder(R)]...

  17. 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

  18. 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...

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. 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...

  5. 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.

  6. 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

  7. 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.

  8. Two Component Signal Transduction in Desulfovibrio Species

    Energy Technology Data Exchange (ETDEWEB)

    Luning, Eric; Rajeev, Lara; Ray, Jayashree; Mukhopadhyay, Aindrila

    2010-05-17

    The environmentally relevant Desulfovibrio species are sulfate-reducing bacteria that are of interest in the bioremediation of heavy metal contaminated water. Among these, the genome of D. vulgaris Hildenborough encodes a large number of two component systems consisting of 72 putative response regulators (RR) and 64 putative histidinekinases (HK), the majority of which are uncharacterized. We classified the D. vulgaris Hildenborough RRs based on their output domains and compared the distribution of RRs in other sequenced Desulfovibrio species. We have successfully purified most RRs and several HKs as His-tagged proteins. We performed phospho-transfer experiments to verify relationships between cognate pairs of HK and RR, and we have also mapped a few non-cognate HK-RR pairs. Presented here are our discoveries from the Desulfovibrio RR categorization and results from the in vitro studies using purified His tagged D. vulgaris HKs and RRs.

  9. Source Signals Separation and Reconstruction Following Principal Component Analysis

    Directory of Open Access Journals (Sweden)

    WANG Cheng

    2014-02-01

    Full Text Available For separation and reconstruction of source signals from observed signals problem, the physical significance of blind source separation modal and independent component analysis is not very clear, and its solution is not unique. Aiming at these disadvantages, a new linear and instantaneous mixing model and a novel source signals separation reconstruction solving method from observed signals based on principal component analysis (PCA are put forward. Assumption of this new model is statistically unrelated rather than independent of source signals, which is different from the traditional blind source separation model. A one-to-one relationship between linear and instantaneous mixing matrix of new model and linear compound matrix of PCA, and a one-to-one relationship between unrelated source signals and principal components are demonstrated using the concept of linear separation matrix and unrelated of source signals. Based on this theoretical link, source signals separation and reconstruction problem is changed into PCA of observed signals then. The theoretical derivation and numerical simulation results show that, in despite of Gauss measurement noise, wave form and amplitude information of unrelated source signal can be separated and reconstructed by PCA when linear mixing matrix is column orthogonal and normalized; only wave form information of unrelated source signal can be separated and reconstructed by PCA when linear mixing matrix is column orthogonal but not normalized, unrelated source signal cannot be separated and reconstructed by PCA when mixing matrix is not column orthogonal or linear.

  10. 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.

  11. 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.

  12. 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.

  13. Signal-dependent independent component analysis by tunable mother wavelets

    International Nuclear Information System (INIS)

    Seo, Kyung Ho

    2006-02-01

    The objective of this study is to improve the standard independent component analysis when applied to real-world signals. Independent component analysis starts from the assumption that signals from different physical sources are statistically independent. But real-world signals such as EEG, ECG, MEG, and fMRI signals are not statistically independent perfectly. By definition, standard independent component analysis algorithms are not able to estimate statistically dependent sources, that is, when the assumption of independence does not hold. Therefore before independent component analysis, some preprocessing stage is needed. This paper started from simple intuition that wavelet transformed source signals by 'well-tuned' mother wavelet will be simplified sufficiently, and then the source separation will show better results. By the correlation coefficient method, the tuning process between source signal and tunable mother wavelet was executed. Gamma component of raw EEG signal was set to target signal, and wavelet transform was executed by tuned mother wavelet and standard mother wavelets. Simulation results by these wavelets was shown

  14. 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.

  15. Plant immune and growth receptors share common signalling components but localise to distinct plasma membrane nanodomains.

    Science.gov (United States)

    Bücherl, Christoph A; Jarsch, Iris K; Schudoma, Christian; Segonzac, Cécile; Mbengue, Malick; Robatzek, Silke; MacLean, Daniel; Ott, Thomas; Zipfel, Cyril

    2017-03-06

    Cell surface receptors govern a multitude of signalling pathways in multicellular organisms. In plants, prominent examples are the receptor kinases FLS2 and BRI1, which activate immunity and steroid-mediated growth, respectively. Intriguingly, despite inducing distinct signalling outputs, both receptors employ common downstream signalling components, which exist in plasma membrane (PM)-localised protein complexes. An important question is thus how these receptor complexes maintain signalling specificity. Live-cell imaging revealed that FLS2 and BRI1 form PM nanoclusters. Using single-particle tracking we could discriminate both cluster populations and we observed spatiotemporal separation between immune and growth signalling platforms. This finding was confirmed by visualising FLS2 and BRI1 within distinct PM nanodomains marked by specific remorin proteins and differential co-localisation with the cytoskeleton. Our results thus suggest that signalling specificity between these pathways may be explained by the spatial separation of FLS2 and BRI1 with their associated signalling components within dedicated PM nanodomains.

  16. 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.

  17. 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

  18. 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

  19. 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.

  20. 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.

  1. WRKY Transcription Factors: Key Components in Abscisic Acid Signaling

    Science.gov (United States)

    2011-01-01

    networks that take inputs from numerous stimuli and that they are involved in mediating responses to numerous phytohormones including salicylic acid ... jasmonic acid , ABA and GA. These roles in multiple signalling pathways may in turn partly explain the pleiotropic effects commonly seen when TF genes are...Review article WRKY transcription factors: key components in abscisic acid signalling Deena L. Rushton1, Prateek Tripathi1, Roel C. Rabara1, Jun Lin1

  2. PRAS40 is an integral regulatory component of erythropoietin mTOR signaling and cytoprotection.

    Directory of Open Access Journals (Sweden)

    Zhao Zhong Chong

    Full Text Available Emerging strategies that center upon the mammalian target of rapamycin (mTOR signaling for neurodegenerative disorders may bring effective treatment for a number of difficult disease entities. Here we show that erythropoietin (EPO, a novel agent for nervous system disorders, prevents apoptotic SH-SY5Y cell injury in an oxidative stress model of oxygen-glucose deprivation through phosphatidylinositol-3-kinase (PI 3-K/protein kinase B (Akt dependent activation of mTOR signaling and phosphorylation of the downstream pathways of p70 ribosomal S6 kinase (p70S6K, eukaryotic initiation factor 4E-binding protein 1 (4EBP1, and proline rich Akt substrate 40 kDa (PRAS40. PRAS40 is an important regulatory component either alone or in conjunction with EPO signal transduction that can determine cell survival through apoptotic caspase 3 activation. EPO and the PI 3-K/Akt pathways control cell survival and mTOR activity through the inhibitory post-translational phosphorylation of PRAS40 that leads to subcellular binding of PRAS40 to the cytoplasmic docking protein 14-3-3. However, modulation and phosphorylation of PRAS40 is independent of other protective pathways of EPO that involve extracellular signal related kinase (ERK 1/2 and signal transducer and activator of transcription (STAT5. Our studies highlight EPO and PRAS40 signaling in the mTOR pathway as potential therapeutic strategies for development against degenerative disorders that lead to cell demise.

  3. 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.

  4. 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.

  5. 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.

  6. 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...

  7. Physiological responses to taste signals of functional food components.

    Science.gov (United States)

    Narukawa, Masataka

    2018-02-01

    The functions of food have three categories: nutrition, palatability, and bioregulation. As the onset of lifestyle-related diseases has increased, many people have shown interest in functional foods that are beneficial to bioregulation. We believe that functional foods should be highly palatable for increased acceptance from consumers. In order to design functional foods with a high palatability, we have investigated about the palatability, especially in relation to the taste of food. In this review, we discuss (1) the identification of taste receptors that respond to functional food components; (2) an analysis of the peripheral taste transduction system; and (3) the investigation of the relationship between physiological functions and taste signals.

  8. 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.

  9. 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.

  10. 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

  11. 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

  12. 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

  13. Linearmycins Activate a Two-Component Signaling System Involved in Bacterial Competition and Biofilm Morphology

    Science.gov (United States)

    2017-01-01

    ABSTRACT Bacteria use two-component signaling systems to adapt and respond to their competitors and changing environments. For instance, competitor bacteria may produce antibiotics and other bioactive metabolites and sequester nutrients. To survive, some species of bacteria escape competition through antibiotic production, biofilm formation, or motility. Specialized metabolite production and biofilm formation are relatively well understood for bacterial species in isolation. How bacteria control these functions when competitors are present is not well studied. To address fundamental questions relating to the competitive mechanisms of different species, we have developed a model system using two species of soil bacteria, Bacillus subtilis and Streptomyces sp. strain Mg1. Using this model, we previously found that linearmycins produced by Streptomyces sp. strain Mg1 cause lysis of B. subtilis cells and degradation of colony matrix. We identified strains of B. subtilis with mutations in the two-component signaling system yfiJK operon that confer dual phenotypes of specific linearmycin resistance and biofilm morphology. We determined that expression of the ATP-binding cassette (ABC) transporter yfiLMN operon, particularly yfiM and yfiN, is necessary for biofilm morphology. Using transposon mutagenesis, we identified genes that are required for YfiLMN-mediated biofilm morphology, including several chaperones. Using transcriptional fusions, we found that YfiJ signaling is activated by linearmycins and other polyene metabolites. Finally, using a truncated YfiJ, we show that YfiJ requires its transmembrane domain to activate downstream signaling. Taken together, these results suggest coordinated dual antibiotic resistance and biofilm morphology by a single multifunctional ABC transporter promotes competitive fitness of B. subtilis. IMPORTANCE DNA sequencing approaches have revealed hitherto unexplored diversity of bacterial species in a wide variety of environments that

  14. 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.

  15. 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.

  16. 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.

  17. 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...

  18. 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.

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. 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.

  4. 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.

  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. Orphan receptor GPR179 forms macromolecular complexes with components of metabotropic signaling cascade in retina ON-bipolar neurons.

    Science.gov (United States)

    Orlandi, Cesare; Cao, Yan; Martemyanov, Kirill A

    2013-10-29

    In the mammalian retina, synaptic transmission between light-excited rod photoreceptors and downstream ON-bipolar neurons is indispensable for dim vision, and disruption of this process leads to congenital stationary night blindness in human patients. The ON-bipolar neurons use the metabotropic signaling cascade, initiated by the mGluR6 receptor, to generate depolarizing responses to light-induced changes in neurotransmitter glutamate release from the photoreceptor axonal terminals. Evidence for the identity of the components involved in transducing these signals is growing rapidly. Recently, the orphan receptor, GPR179, a member of the G protein-coupled receptor (GPCR) superfamily, has been shown to be indispensable for the synaptic responses of ON-bipolar cells. In our study, we investigated the interaction of GPR179 with principle components of the signal transduction cascade. We used immunoprecipitation and proximity ligation assays in transfected cells and native retinas to characterize the protein-protein interactions involving GPR179. The influence of cascade components on GPR179 localization was examined through immunohistochemical staining of the retinas from genetic mouse models. We demonstrated that, in mouse retinas, GPR179 forms physical complexes with the main components of the metabotropic cascade, recruiting mGluR6, TRPM1, and the RGS proteins. Elimination of mGluR6 or RGS proteins, but not TRPM1, detrimentally affects postsynaptic targeting or GPR179 expression. These observations suggest that the mGluR6 signaling cascade is scaffolded as a macromolecular complex in which the interactions between the components ensure the optimal spatiotemporal characteristics of signal transduction.

  7. 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.

  8. 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.

  9. PSM/SH2-B distributes selected mitogenic receptor signals to distinct components in the PI3-kinase and MAP kinase signaling pathways.

    Science.gov (United States)

    Deng, Youping; Xu, Hu; Riedel, Heimo

    2007-02-15

    The Pro-rich, PH, and SH2 domain containing mitogenic signaling adapter PSM/SH2-B has been implicated as a cellular partner of various mitogenic receptor tyrosine kinases and related signaling mechanisms. Here, we report in a direct comparison of three peptide hormones, that PSM participates in the assembly of distinct mitogenic signaling complexes in response to insulin or IGF-I when compared to PDGF in cultured normal fibroblasts. The complex formed in response to insulin or IGF-I involves the respective peptide hormone receptor and presumably the established components leading to MAP kinase activation. However, our data suggest an alternative link from the PDGF receptor via PSM directly to MEK1/2 and consequently also to p44/42 activation, possibly through a scaffold protein. At least two PSM domains participate, the SH2 domain anticipated to link PSM to the respective receptor and the Pro-rich region in an association with an unidentified downstream component resulting in direct MEK1/2 and p44/42 regulation. The PDGF receptor signaling complex formed in response to PDGF involves PI 3-kinase in addition to the same components and interactions as described for insulin or IGF-I. PSM associates with PI 3-kinase via p85 and in addition the PSM PH domain participates in the regulation of PI 3-kinase activity, presumably through membrane interaction. In contrast, the PSM Pro-rich region appears to participate only in the MAP kinase signal. Both pathways contribute to the mitogenic response as shown by cell proliferation, survival, and focus formation. PSM regulates p38 MAP kinase activity in a pathway unrelated to the mitogenic response.

  10. Exploring fMRI Data for Periodic Signal Components

    DEFF Research Database (Denmark)

    Hansen, Lars Kai; Nielsen, Finn Årup; Larsen, Jan

    2002-01-01

    We use a Bayesian framework to detect periodic components in fMRI data. The resulting detector is sensitive to periodic components with a flexible number of harmonics and with arbitrary amplitude and phases of the harmonics. It is possible to detect the correct number of harmonics in periodic sig...

  11. 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.

  12. 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

  13. 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.

  14. 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

  15. Signalling components of the house mouse mate recognition system

    Czech Academy of Sciences Publication Activity Database

    Bímová, Barbora; Albrecht, Tomáš; Macholán, Miloš; Piálek, Jaroslav

    2009-01-01

    Roč. 80, č. 1 (2009), s. 20-27 ISSN 0376-6357 R&D Projects: GA AV ČR IAA600930506 Institutional research plan: CEZ:AV0Z60930519; CEZ:AV0Z50450515 Keywords : Faeces * Olfactory communication * Salivary and rogen binding protein * Sexual preferences * Urinary signals Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.527, year: 2009

  16. 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

  17. [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.

  18. 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.

  19. Actin is an essential component of plant gravitropic signaling pathways

    Science.gov (United States)

    Braun, Markus; Hauslage, Jens; Limbach, Christoph

    2003-08-01

    A role of the actin cytoskeleton in the different phases of gravitropism in higher plant organs seems obvious, but experimental evidence is still inconclusive and contradictory. In gravitropically tip-growing rhizoids and protonemata, however, it is well documented that actin is an essential component of the tip-growth machinery and is involved either in the cellular mechanisms that lead to gravity sensing and in the processes of the graviresponses that result in the reorientation of the growth direction. All these processes depend on a complexly organized and highly dynamic organization of actin filaments whose diverse functions are coordinated by numerous associated proteins. Actin filaments and myosins mediate the transport of secretory vehicles to the growing tip and precisely control the delivery of cell wall material. In addition, both cell types use a very efficient actomyosin-based system to control and correct the position of their statoliths and to direct sedimenting statoliths to confined graviperception sites at the plasma membrane. The studies presented in this paper provide evidence for the essential role of actin in plant gravity sensing and the gravitropic responses. A unique actin-organizing center exists in the tip of characean rhizoids and protonemata which is associated with and dynamically regulated by a specific set of actin-dynamizing proteins. It is concluded that this highly dynamic apical actin array is an essential prerequisite for gravity sensing and gravity-oriented tip growth.

  20. Perceived Synchrony of Frog Multimodal Signal Components Is Influenced by Content and Order.

    Science.gov (United States)

    Taylor, Ryan C; Page, Rachel A; Klein, Barrett A; Ryan, Michael J; Hunter, Kimberly L

    2017-10-01

    Multimodal signaling is common in communication systems. Depending on the species, individual signal components may be produced synchronously as a result of physiological constraint (fixed) or each component may be produced independently (fluid) in time. For animals that rely on fixed signals, a basic prediction is that asynchrony between the components should degrade the perception of signal salience, reducing receiver response. Male túngara frogs, Physalaemus pustulosus, produce a fixed multisensory courtship signal by vocalizing with two call components (whines and chucks) and inflating a vocal sac (visual component). Using a robotic frog, we tested female responses to variation in the temporal arrangement between acoustic and visual components. When the visual component lagged a complex call (whine + chuck), females largely rejected this asynchronous multisensory signal in favor of the complex call absent the visual cue. When the chuck component was removed from one call, but the robofrog inflation lagged the complex call, females responded strongly to the asynchronous multimodal signal. When the chuck component was removed from both calls, females reversed preference and responded positively to the asynchronous multisensory signal. When the visual component preceded the call, females responded as often to the multimodal signal as to the call alone. These data show that asynchrony of a normally fixed signal does reduce receiver responsiveness. The magnitude and overall response, however, depend on specific temporal interactions between the acoustic and visual components. The sensitivity of túngara frogs to lagging visual cues, but not leading ones, and the influence of acoustic signal content on the perception of visual asynchrony is similar to those reported in human psychophysics literature. Virtually all acoustically communicating animals must conduct auditory scene analyses and identify the source of signals. Our data suggest that some basic

  1. Motile cilia of human airway epithelia contain hedgehog signaling components that mediate noncanonical hedgehog signaling.

    Science.gov (United States)

    Mao, Suifang; Shah, Alok S; Moninger, Thomas O; Ostedgaard, Lynda S; Lu, Lin; Tang, Xiao Xiao; Thornell, Ian M; Reznikov, Leah R; Ernst, Sarah E; Karp, Philip H; Tan, Ping; Keshavjee, Shaf; Abou Alaiwa, Mahmoud H; Welsh, Michael J

    2018-02-06

    Differentiated airway epithelia produce sonic hedgehog (SHH), which is found in the thin layer of liquid covering the airway surface. Although previous studies showed that vertebrate HH signaling requires primary cilia, as airway epithelia mature, the cells lose primary cilia and produce hundreds of motile cilia. Thus, whether airway epithelia have apical receptors for SHH has remained unknown. We discovered that motile cilia on airway epithelial cells have HH signaling proteins, including patched and smoothened. These cilia also have proteins affecting cAMP-dependent signaling, including Gα i and adenylyl cyclase 5/6. Apical SHH decreases intracellular levels of cAMP, which reduces ciliary beat frequency and pH in airway surface liquid. These results suggest that apical SHH may mediate noncanonical HH signaling through motile cilia to dampen respiratory defenses at the contact point between the environment and the lung, perhaps counterbalancing processes that stimulate airway defenses. Copyright © 2018 the Author(s). Published by PNAS.

  2. Female preferences for aposematic signal components in a polymorphic poison frog

    NARCIS (Netherlands)

    Maan, Martine E.; Cummings, Molly E.

    Aposematic signals may be subject to conflicting selective pressures from predators and conspecifics. We studied female preferences for different components of aposematic coloration in the polymorphic poison frog Oophaga pumilio across several phenotypically distinct populations. This frog shows

  3. Denoising of chaotic signal using independent component analysis and empirical mode decomposition with circulate translating

    International Nuclear Information System (INIS)

    Wang Wen-Bo; Zhang Xiao-Dong; Chang Yuchan; Wang Xiang-Li; Wang Zhao; Chen Xi; Zheng Lei

    2016-01-01

    In this paper, a new method to reduce noises within chaotic signals based on ICA (independent component analysis) and EMD (empirical mode decomposition) is proposed. The basic idea is decomposing chaotic signals and constructing multidimensional input vectors, firstly, on the base of EMD and its translation invariance. Secondly, it makes the independent component analysis on the input vectors, which means that a self adapting denoising is carried out for the intrinsic mode functions (IMFs) of chaotic signals. Finally, all IMFs compose the new denoised chaotic signal. Experiments on the Lorenz chaotic signal composed of different Gaussian noises and the monthly observed chaotic sequence on sunspots were put into practice. The results proved that the method proposed in this paper is effective in denoising of chaotic signals. Moreover, it can correct the center point in the phase space effectively, which makes it approach the real track of the chaotic attractor. (paper)

  4. Soy Components Genistein and Lunasin Regulate E-Cadherin and Wnt Signaling in Mammary Epithelial Cells

    Science.gov (United States)

    Enhanced Wnt/beta-catenin signaling and loss of E-cadherin expression are considered hallmarks of tumorigenesis. We previously showed by microarray gene profiling that dietary intake of soy-based AIN-93G diets altered components of Wnt/beta-catenin signaling in rat mammary epithelial cells. To furth...

  5. Phosphate sink containing two-component signaling systems as tunable threshold devices

    DEFF Research Database (Denmark)

    Amin, Munia; Kothamachu, Varun B; Feliu, Elisenda

    2014-01-01

    Synthetic biology aims to design de novo biological systems and reengineer existing ones. These efforts have mostly focused on transcriptional circuits, with reengineering of signaling circuits hampered by limited understanding of their systems dynamics and experimental challenges. Bacterial two......-component signaling systems offer a rich diversity of sensory systems that are built around a core phosphotransfer reaction between histidine kinases and their output response regulator proteins, and thus are a good target for reengineering through synthetic biology. Here, we explore the signal-response relationship...... rapid signal termination, whereby one of the RRs acts as a phosphate sink towards the other RR (i.e. the output RR), but also implements a sigmoidal signal-response relationship. We identify two mathematical conditions on system parameters that are necessary for sigmoidal signal-response relationships...

  6. Analysis of market signals in a competitive electricity market using components of network rental

    International Nuclear Information System (INIS)

    Amarasinghe, L.Y.C.; Annakkage, U.D.

    2009-01-01

    In the competitive electricity market, Locational Marginal Prices (LMPs) are important pricing signals for the participants as the effects of transmission losses and binding constraints are embedded in LMPs. While these LMPs provide valuable information at each location, they do not provide a detailed description in terms of contributing terms. The LMP components, on the other hand, show the explicit decomposition of LMP into contributing components, and thus, can be considered as better market signals. However, the effects of transmission losses cannot be explicitly seen from the LMP components. In this paper, the components of network rental is proposed to be used as a method in analyzing market signals, by decomposing the network rental into contributing components among the consumers. Since, the network rental is the surplus paid by all the consumers, components of network rental show how each consumer has actually overpaid due to losses and each binding constraint separately. A case study is also presented to demonstrate the potential of this proposed method in market signal analysis. (author)

  7. Non-stationary component extraction in noisy multicomponent signal using polynomial chirping Fourier transform.

    Science.gov (United States)

    Lu, Wenlong; Xie, Junwei; Wang, Heming; Sheng, Chuan

    2016-01-01

    Inspired by track-before-detection technology in radar, a novel time-frequency transform, namely polynomial chirping Fourier transform (PCFT), is exploited to extract components from noisy multicomponent signal. The PCFT combines advantages of Fourier transform and polynomial chirplet transform to accumulate component energy along a polynomial chirping curve in the time-frequency plane. The particle swarm optimization algorithm is employed to search optimal polynomial parameters with which the PCFT will achieve a most concentrated energy ridge in the time-frequency plane for the target component. The component can be well separated in the polynomial chirping Fourier domain with a narrow-band filter and then reconstructed by inverse PCFT. Furthermore, an iterative procedure, involving parameter estimation, PCFT, filtering and recovery, is introduced to extract components from a noisy multicomponent signal successively. The Simulations and experiments show that the proposed method has better performance in component extraction from noisy multicomponent signal as well as provides more time-frequency details about the analyzed signal than conventional methods.

  8. : Signal Decomposition of High Resolution Time Series River data to Separate Local and Regional Components of Conductivity

    Science.gov (United States)

    Signal processing techniques were applied to high-resolution time series data obtained from conductivity loggers placed upstream and downstream of a wastewater treatment facility along a river. Data was collected over 14-60 days, and several seasons. The power spectral densit...

  9. Signal Decomposition of High Resolution Time Series River Data to Separate Local and Regional Components of Conductivity

    Science.gov (United States)

    Signal processing techniques were applied to high-resolution time series data obtained from conductivity loggers placed upstream and downstream of an oil and gas wastewater treatment facility along a river. Data was collected over 14-60 days. The power spectral density was us...

  10. Complex Signal Kurtosis and Independent Component Analysis for Wideband Radio Frequency Interference Detection

    Science.gov (United States)

    Schoenwald, Adam; Mohammed, Priscilla; Bradley, Damon; Piepmeier, Jeffrey; Wong, Englin; Gholian, Armen

    2016-01-01

    Radio-frequency interference (RFI) has negatively implicated scientific measurements across a wide variation passive remote sensing satellites. This has been observed in the L-band radiometers SMOS, Aquarius and more recently, SMAP [1, 2]. RFI has also been observed at higher frequencies such as K band [3]. Improvements in technology have allowed wider bandwidth digital back ends for passive microwave radiometry. A complex signal kurtosis radio frequency interference detector was developed to help identify corrupted measurements [4]. This work explores the use of ICA (Independent Component Analysis) as a blind source separation technique to pre-process radiometric signals for use with the previously developed real and complex signal kurtosis detectors.

  11. The Role of Cgrp-Receptor Component Protein (Rcp in Cgrp-Mediated Signal Transduction

    Directory of Open Access Journals (Sweden)

    M. A. Prado

    2001-01-01

    Full Text Available The calcitonin gene-related peptide (CGRP-receptor component protein (RCP is a 17-kDa intracellular peripheral membrane protein required for signal transduction at CGRP receptors. To determine the role of RCP in CGRP-mediated signal transduction, RCP was depleted from NIH3T3 cells using antisense strategy. Loss of RCP protein correlated with loss of cAMP production by CGRP in the antisense cells. In contrast, loss of RCP had no effect on CGRP-mediated binding; therefore RCP is not acting as a chaperone for the CGRP receptor. Instead, RCP is a novel signal transduction molecule that couples the CGRP receptor to the cellular signal transduction machinery. RCP thus represents a prototype for a new class of signal transduction proteins that are required for regulation of G protein-coupled receptors.

  12. A simple iterative independent component analysis algorithm for vibration source signal identification of complex structures

    Directory of Open Access Journals (Sweden)

    Dong-Sup Lee

    2015-01-01

    Full Text Available Independent Component Analysis (ICA, one of the blind source separation methods, can be applied for extracting unknown source signals only from received signals. This is accomplished by finding statistical independence of signal mixtures and has been successfully applied to myriad fields such as medical science, image processing, and numerous others. Nevertheless, there are inherent problems that have been reported when using this technique: insta- bility and invalid ordering of separated signals, particularly when using a conventional ICA technique in vibratory source signal identification of complex structures. In this study, a simple iterative algorithm of the conventional ICA has been proposed to mitigate these problems. The proposed method to extract more stable source signals having valid order includes an iterative and reordering process of extracted mixing matrix to reconstruct finally converged source signals, referring to the magnitudes of correlation coefficients between the intermediately separated signals and the signals measured on or nearby sources. In order to review the problems of the conventional ICA technique and to vali- date the proposed method, numerical analyses have been carried out for a virtual response model and a 30 m class submarine model. Moreover, in order to investigate applicability of the proposed method to real problem of complex structure, an experiment has been carried out for a scaled submarine mockup. The results show that the proposed method could resolve the inherent problems of a conventional ICA technique.

  13. Hedgehog Signaling Components Are Expressed in Choroidal Neovascularization in Laser-induced Retinal Lesion

    International Nuclear Information System (INIS)

    Nochioka, Katsunori; Okuda, Hiroaki; Tatsumi, Kouko; Morita, Shoko; Ogata, Nahoko; Wanaka, Akio

    2016-01-01

    Choroidal neovascularization is one of the major pathological changes in age-related macular degeneration, which causes devastating blindness in the elderly population. The molecular mechanism of choroidal neovascularization has been under extensive investigation, but is still an open question. We focused on sonic hedgehog signaling, which is implicated in angiogenesis in various organs. Laser-induced injuries to the mouse retina were made to cause choroidal neovascularization. We examined gene expression of sonic hedgehog, its receptors (patched1, smoothened, cell adhesion molecule down-regulated by oncogenes (Cdon) and biregional Cdon-binding protein (Boc)) and downstream transcription factors (Gli1-3) using real-time RT-PCR. At seven days after injury, mRNAs for Patched1 and Gli1 were upregulated in response to injury, but displayed no upregulation in control retinas. Immunohistochemistry revealed that Patched1 and Gli1 proteins were localized to CD31-positive endothelial cells that cluster between the wounded retina and the pigment epithelium layer. Treatment with the hedgehog signaling inhibitor cyclopamine did not significantly decrease the size of the neovascularization areas, but the hedgehog agonist purmorphamine made the areas significantly larger than those in untreated retina. These results suggest that the hedgehog-signaling cascade may be a therapeutic target for age-related macular degeneration

  14. 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.

  15. Low dose gamma irradiation enhances defined signaling components of intercellular reactive oxygen-mediated apoptosis induction

    International Nuclear Information System (INIS)

    Bauer, G

    2011-01-01

    Transformed cells are selectively removed by intercellular ROS-mediated induction of apoptosis. Signaling is based on the HOCl and the NO/peroxynitrite pathway (major pathways) and the nitryl chloride and the metal-catalyzed Haber-Weiss pathway (minor pathways). During tumor progression, resistance against intercellular induction of apoptosis is acquired through expression of membrane-associated catalase. Low dose radiation of nontransformed cells has been shown to enhance intercellular induction of apoptosis. The present study was performed to define the signaling components which are modulated by low dose gamma irradiation. Low dose radiation induced the release of peroxidase from nontransformed, transformed and tumor cells. Extracellular superoxide anion generation was strongly enhanced in the case of transformed cells and tumor cells, but not in nontransformed cells. Enhancement of peroxidase release and superoxide anion generation either increased intercellular induction of apoptosis of transformed cells, or caused a partial protection under specific signaling conditions. In tumor cells, low dose radiation enhanced the production of major signaling components, but this had no effect on apoptosis induction, due to the strong resistance mechanism of tumor cells. Our data specify the nature of low dose radiation-induced effects on specific signaling components of intercellular induction of apoptosis at defined stages of multistep carcinogenesis.

  16. Expression of insulin signalling components in the sensory epithelium of the human saccule

    DEFF Research Database (Denmark)

    Degerman, Eva; Rauch, Uwe; Lindberg, Sven

    2013-01-01

    signalling components in the inner ear is sparce. Our immunohistochemistry approach has shown that the insulin receptor, insulin receptor substrate 1 (IRS1), protein kinase B (PKB) and insulin-sensitive glucose transporter (GLUT4) are expressed in the sensory epithelium of the human saccule, which also...

  17. Denoising of chaotic signal using independent component analysis and empirical mode decomposition with circulate translating

    Science.gov (United States)

    Wen-Bo, Wang; Xiao-Dong, Zhang; Yuchan, Chang; Xiang-Li, Wang; Zhao, Wang; Xi, Chen; Lei, Zheng

    2016-01-01

    In this paper, a new method to reduce noises within chaotic signals based on ICA (independent component analysis) and EMD (empirical mode decomposition) is proposed. The basic idea is decomposing chaotic signals and constructing multidimensional input vectors, firstly, on the base of EMD and its translation invariance. Secondly, it makes the independent component analysis on the input vectors, which means that a self adapting denoising is carried out for the intrinsic mode functions (IMFs) of chaotic signals. Finally, all IMFs compose the new denoised chaotic signal. Experiments on the Lorenz chaotic signal composed of different Gaussian noises and the monthly observed chaotic sequence on sunspots were put into practice. The results proved that the method proposed in this paper is effective in denoising of chaotic signals. Moreover, it can correct the center point in the phase space effectively, which makes it approach the real track of the chaotic attractor. Project supported by the National Science and Technology, China (Grant No. 2012BAJ15B04), the National Natural Science Foundation of China (Grant Nos. 41071270 and 61473213), the Natural Science Foundation of Hubei Province, China (Grant No. 2015CFB424), the State Key Laboratory Foundation of Satellite Ocean Environment Dynamics, China (Grant No. SOED1405), the Hubei Provincial Key Laboratory Foundation of Metallurgical Industry Process System Science, China (Grant No. Z201303), and the Hubei Key Laboratory Foundation of Transportation Internet of Things, Wuhan University of Technology, China (Grant No.2015III015-B02).

  18. Signal extraction and wave field separation in tunnel seismic prediction by independent component analysis

    Science.gov (United States)

    Yue, Y.; Jiang, T.; Zhou, Q.

    2017-12-01

    In order to ensure the rationality and the safety of tunnel excavation, the advanced geological prediction has been become an indispensable step in tunneling. However, the extraction of signal and the separation of P and S waves directly influence the accuracy of geological prediction. Generally, the raw data collected in TSP system is low quality because of the numerous disturb factors in tunnel projects, such as the power interference and machine vibration interference. It's difficult for traditional method (band-pass filtering) to remove interference effectively as well as bring little loss to signal. The power interference, machine vibration interference and the signal are original variables and x, y, z component as observation signals, each component of the representation is a linear combination of the original variables, which satisfy applicable conditions of independent component analysis (ICA). We perform finite-difference simulations of elastic wave propagation to synthetic a tunnel seismic reflection record. The method of ICA was adopted to process the three-component data, and the results show that extract the estimates of signal and the signals are highly correlated (the coefficient correlation is up to more than 0.93). In addition, the estimates of interference that separated from ICA and the interference signals are also highly correlated, and the coefficient correlation is up to more than 0.99. Thus, simulation results showed that the ICA is an ideal method for extracting high quality data from mixed signals. For the separation of P and S waves, the conventional separation techniques are based on physical characteristics of wave propagation, which require knowledge of the near-surface P and S waves velocities and density. Whereas the ICA approach is entirely based on statistical differences between P and S waves, and the statistical technique does not require a priori information. The concrete results of the wave field separation will be presented in

  19. Experimental study on engine gas-path component fault monitoring using exhaust gas electrostatic signal

    International Nuclear Information System (INIS)

    Sun, Jianzhong; Zuo, Hongfu; Liu, Pengpeng; Wen, Zhenhua

    2013-01-01

    This paper presents the recent development in engine gas-path components health monitoring using electrostatic sensors in combination with signal-processing techniques. Two ground-based engine electrostatic monitoring experiments are reported and the exhaust gas electrostatic monitoring signal-based fault-detection method is proposed. It is found that the water washing, oil leakage and combustor linear cracking result in an increase in the activity level of the electrostatic monitoring signal, which can be detected by the electrostatic monitoring system. For on-line health monitoring of the gas-path components, a baseline model-based fault-detection method is proposed and the multivariate state estimation technique is used to establish the baseline model for the electrostatic monitoring signal. The method is applied to a data set from a turbo-shaft engine electrostatic monitoring experiment. The results of the case study show that the system with the developed method is capable of detecting the gas-path component fault in an on-line fashion. (paper)

  20. The reduced kinome of Ostreococcus tauri: core eukaryotic signalling components in a tractable model species.

    Science.gov (United States)

    Hindle, Matthew M; Martin, Sarah F; Noordally, Zeenat B; van Ooijen, Gerben; Barrios-Llerena, Martin E; Simpson, T Ian; Le Bihan, Thierry; Millar, Andrew J

    2014-08-02

    The current knowledge of eukaryote signalling originates from phenotypically diverse organisms. There is a pressing need to identify conserved signalling components among eukaryotes, which will lead to the transfer of knowledge across kingdoms. Two useful properties of a eukaryote model for signalling are (1) reduced signalling complexity, and (2) conservation of signalling components. The alga Ostreococcus tauri is described as the smallest free-living eukaryote. With less than 8,000 genes, it represents a highly constrained genomic palette. Our survey revealed 133 protein kinases and 34 protein phosphatases (1.7% and 0.4% of the proteome). We conducted phosphoproteomic experiments and constructed domain structures and phylogenies for the catalytic protein-kinases. For each of the major kinases families we review the completeness and divergence of O. tauri representatives in comparison to the well-studied kinomes of the laboratory models Arabidopsis thaliana and Saccharomyces cerevisiae, and of Homo sapiens. Many kinase clades in O. tauri were reduced to a single member, in preference to the loss of family diversity, whereas TKL and ABC1 clades were expanded. We also identified kinases that have been lost in A. thaliana but retained in O. tauri. For three, contrasting eukaryotic pathways - TOR, MAPK, and the circadian clock - we established the subset of conserved components and demonstrate conserved sites of substrate phosphorylation and kinase motifs. We conclude that O. tauri satisfies our two central requirements. Several of its kinases are more closely related to H. sapiens orthologs than S. cerevisiae is to H. sapiens. The greatly reduced kinome of O. tauri is therefore a suitable model for signalling in free-living eukaryotes.

  1. 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

  2. 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

  3. 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.

  4. 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

  5. A study on the crack inspection signal characteristics for power plant components by phased array UT

    International Nuclear Information System (INIS)

    Cho, Yong Sang; Lim, Sang Gyu; Kil, Du Song

    2001-01-01

    Phased array ultrasonic testing system has become available for practical application in complicated geometry such as turbine blade root, tenon, disc in power industry. This research describes the characteristics of phased array UT signal for various type of blade roots in thermal Power Plant turbines. This application of Phased array ultrasonic testing system has been promoted mainly to save inspection time and labor cost of turbine inspection. The characteristic of phase array UT signal for power plant component is very simple to understand but to difficult for perform the inspection. Since our sophisticated inspection technique and systems are essential for the inspection of steam turbine blade roots that require high reliability, we intend to develop new technology and improve phased array technique based on the wide and much experience for the inspection of turbine components.

  6. 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...

  7. Blind Extraction of Chaotic Signals by Using the Fast Independent Component Analysis Algorithm

    International Nuclear Information System (INIS)

    Hong-Bin, Chen; Jiu-Chao, Feng; Yong, Fang

    2008-01-01

    We report the results of using the fast independent component analysis (FastICA) algorithm to realize blind extraction of chaotic signals. Two cases are taken into consideration: namely, the mixture is noiseless or contaminated by noise. Pre-whitening is employed to reduce the effect of noise before using the FastICA algorithm. The correlation coefficient criterion is adopted to evaluate the performance, and the success rate is defined as a new criterion to indicate the performance with respect to noise or different mixing matrices. Simulation results show that the FastICA algorithm can extract the chaotic signals effectively. The impact of noise, the length of a signal frame, the number of sources and the number of observed mixtures on the performance is investigated in detail. It is also shown that regarding a noise as an independent source is not always correct

  8. Blind Separation of Acoustic Signals Combining SIMO-Model-Based Independent Component Analysis and Binary Masking

    Directory of Open Access Journals (Sweden)

    Hiekata Takashi

    2006-01-01

    Full Text Available A new two-stage blind source separation (BSS method for convolutive mixtures of speech is proposed, in which a single-input multiple-output (SIMO-model-based independent component analysis (ICA and a new SIMO-model-based binary masking are combined. SIMO-model-based ICA enables us to separate the mixed signals, not into monaural source signals but into SIMO-model-based signals from independent sources in their original form at the microphones. Thus, the separated signals of SIMO-model-based ICA can maintain the spatial qualities of each sound source. Owing to this attractive property, our novel SIMO-model-based binary masking can be applied to efficiently remove the residual interference components after SIMO-model-based ICA. The experimental results reveal that the separation performance can be considerably improved by the proposed method compared with that achieved by conventional BSS methods. In addition, the real-time implementation of the proposed BSS is illustrated.

  9. Analysis and Classification of Acoustic Emission Signals During Wood Drying Using the Principal Component Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Ho Yang [Korea Research Institute of Standards and Science, Daejeon (Korea, Republic of); Kim, Ki Bok [Chungnam National University, Daejeon (Korea, Republic of)

    2003-06-15

    In this study, acoustic emission (AE) signals due to surface cracking and moisture movement in the flat-sawn boards of oak (Quercus Variablilis) during drying under the ambient conditions were analyzed and classified using the principal component analysis. The AE signals corresponding to surface cracking showed higher in peak amplitude and peak frequency, and shorter in rise time than those corresponding to moisture movement. To reduce the multicollinearity among AE features and to extract the significant AE parameters, correlation analysis was performed. Over 99% of the variance of AE parameters could be accounted for by the first to the fourth principal components. The classification feasibility and success rate were investigated in terms of two statistical classifiers having six independent variables (AE parameters) and six principal components. As a result, the statistical classifier having AE parameters showed the success rate of 70.0%. The statistical classifier having principal components showed the success rate of 87.5% which was considerably than that of the statistical classifier having AE parameters

  10. Analysis and Classification of Acoustic Emission Signals During Wood Drying Using the Principal Component Analysis

    International Nuclear Information System (INIS)

    Kang, Ho Yang; Kim, Ki Bok

    2003-01-01

    In this study, acoustic emission (AE) signals due to surface cracking and moisture movement in the flat-sawn boards of oak (Quercus Variablilis) during drying under the ambient conditions were analyzed and classified using the principal component analysis. The AE signals corresponding to surface cracking showed higher in peak amplitude and peak frequency, and shorter in rise time than those corresponding to moisture movement. To reduce the multicollinearity among AE features and to extract the significant AE parameters, correlation analysis was performed. Over 99% of the variance of AE parameters could be accounted for by the first to the fourth principal components. The classification feasibility and success rate were investigated in terms of two statistical classifiers having six independent variables (AE parameters) and six principal components. As a result, the statistical classifier having AE parameters showed the success rate of 70.0%. The statistical classifier having principal components showed the success rate of 87.5% which was considerably than that of the statistical classifier having AE parameters

  11. Molecular characterization of banana NAC transcription factors and their interactions with ethylene signalling component EIL during fruit ripening.

    Science.gov (United States)

    Shan, Wei; Kuang, Jian-fei; Chen, Lei; Xie, Hui; Peng, Huan-huan; Xiao, Yun-yi; Li, Xue-ping; Chen, Wei-xin; He, Quan-guang; Chen, Jian-ye; Lu, Wang-jin

    2012-09-01

    The plant-specific NAC (NAM, ATAF1/2, and CUC2) transcription factors (TFs) play important roles in plant growth, development, and stress responses. However, the precise role of NAC TFs in relation to fruit ripening is poorly understood. In this study, six NAC genes, designated MaNAC1-MaNAC6, were isolated and characterized from banana fruit. Subcellular localization showed that MaNAC1-MaNAC5 proteins localized preferentially to the nucleus, while MaNAC6 was distributed throughout the entire cell. A transactivation assay in yeast demonstrated that MaNAC4 and MaNAC6, as well as their C-terminal regions, possessed trans-activation activity. Gene expression profiles in fruit with four different ripening characteristics, including natural, ethylene-induced, 1-methylcyclopropene (1-MCP)-delayed, and a combination of 1-MCP with ethylene treatment, revealed that the MaNAC genes were differentially expressed in peel and pulp during post-harvest ripening. MaNAC1 and MaNAC2 were apparently upregulated by ethylene in peel and pulp, consistent with the increase in ethylene production. In contrast, MaNAC3 in peel and pulp and MaNAC5 in peel were constitutively expressed, and transcripts of MaNAC4 in peel and pulp and MaNAC6 in peel decreased, while MaNAC5 or MaNAC6 in pulp increased slightly during fruit ripening. Furthermore, the MaNAC2 promoter was activated after ethylene application, further enhancing the involvement of MaNAC2 in fruit ripening. More importantly, yeast two-hybrid and bimolecular fluorescence complementation analyses confirmed that MaNAC1/2 physically interacted with a downstream component of ethylene signalling, ethylene insensitive 3 (EIN3)-like protein, termed MaEIL5, which was downregulated during ripening. Taken together, these results suggest that MaNACs such as MaNAC1/MaNAC2, may be involved in banana fruit ripening via interaction with ethylene signalling components.

  12. 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

  13. SNMP is a signaling component required for pheromone sensitivity in Drosophila.

    Science.gov (United States)

    Jin, Xin; Ha, Tal Soo; Smith, Dean P

    2008-08-05

    The only known volatile pheromone in Drosophila, 11-cis-vaccenyl acetate (cVA), mediates a variety of behaviors including aggregation, mate recognition, and sexual behavior. cVA is detected by a small set of olfactory neurons located in T1 trichoid sensilla on the antennae of males and females. Two components known to be required for cVA reception are the odorant receptor Or67d and the extracellular pheromone-binding protein LUSH. Using a genetic screen for cVA-insensitive mutants, we have identified a third component required for cVA reception: sensory neuron membrane protein (SNMP). SNMP is a homolog of CD36, a scavenger receptor important for lipoprotein binding and uptake of cholesterol and lipids in vertebrates. In humans, loss of CD36 is linked to a wide range of disorders including insulin resistance, dyslipidemia, and atherosclerosis, but how CD36 functions in lipid transport and signal transduction is poorly understood. We show that SNMP is required in pheromone-sensitive neurons for cVA sensitivity but is not required for sensitivity to general odorants. Using antiserum to SNMP infused directly into the sensillum lymph, we show that SNMP function is required on the dendrites of cVA-sensitive neurons; this finding is consistent with a direct role in cVA signal transduction. Therefore, pheromone perception in Drosophila should serve as an excellent model to elucidate the role of CD36 members in transmembrane signaling.

  14. Cloning of a two-component signal transduction system of Xanthomonas campestris pv. phaseoli var. fuscans strain BXPF65

    DEFF Research Database (Denmark)

    Chan, JWYF; Maynard, Scott; Goodwin, PH

    1998-01-01

    A putative two-component signal transduction system was amplified and cloned from the plant pathogenic bacterium Xanthomonas campestris pv. phaseoli var. fuscans isolate BXPF65. The 620 bp amplified fragment was sequenced and analyzed with the BLAST Enhanced Alignment Utility (BEAUTY). BEAUTY...... that the putative histidine kinase has homology with conserved “transmitter” domains of sensor proteins in two-component signal transduction systems. RFLP analysis using the putative signal transduction system showed polymorphisms among the strains....

  15. 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.

  16. Separation of PbWO4 and BGO signals into Cerenkov and scintillation components

    International Nuclear Information System (INIS)

    Voena, C

    2009-01-01

    We present results from beam tests performed in 2007 on PbWO 4 and BGO crystals in the context of the DREAM project. Signals from high energy electrons and pions are analyzed and the possibility of separating the contributions from Cerenkov (C) and scintillation (S) light for individual events is investigated. Different methods exploiting the difference in timing, in the spectra and in the directionality of the two types of light have been developed to determine the contribution of the two components. In the BGO crystal, Cerenkov signals have been enhanced with the use of optical filters and the ratio C/S is measured with good precision (∼20-30% for energy deposits less than 1 GeV).

  17. Real-time classification of signals from three-component seismic sensors using neural nets

    Science.gov (United States)

    Bowman, B. C.; Dowla, F.

    1992-05-01

    Adaptive seismic data acquisition systems with capabilities of signal discrimination and event classification are important in treaty monitoring, proliferation, and earthquake early detection systems. Potential applications include monitoring underground chemical explosions, as well as other military, cultural, and natural activities where characteristics of signals change rapidly and without warning. In these applications, the ability to detect and interpret events rapidly without falling behind the influx of the data is critical. We developed a system for real-time data acquisition, analysis, learning, and classification of recorded events employing some of the latest technology in computer hardware, software, and artificial neural networks methods. The system is able to train dynamically, and updates its knowledge based on new data. The software is modular and hardware-independent; i.e., the front-end instrumentation is transparent to the analysis system. The software is designed to take advantage of the multiprocessing environment of the Unix operating system. The Unix System V shared memory and static RAM protocols for data access and the semaphore mechanism for interprocess communications were used. As the three-component sensor detects a seismic signal, it is displayed graphically on a color monitor using X11/Xlib graphics with interactive screening capabilities. For interesting events, the triaxial signal polarization is computed, a fast Fourier Transform (FFT) algorithm is applied, and the normalized power spectrum is transmitted to a backpropagation neural network for event classification. The system is currently capable of handling three data channels with a sampling rate of 500 Hz, which covers the bandwidth of most seismic events. The system has been tested in laboratory setting with artificial events generated in the vicinity of a three-component sensor.

  18. Electrical Signal Path Study and Component Assay for the MAJORANA N-Type Segmented Contact Detector

    Energy Technology Data Exchange (ETDEWEB)

    Amman, Mark; Bergevin, Marc; Chan, Yuen-Dat; Detwiler, Jason A.; Fujikawa, Brian .; Lesko, Kevin T.; Luke, Paul N.; Prior, Gersende; Poon, Alan W.; Smith, Alan R.; Vetter, Kai; Yaver, Harold; Zimmermann, Sergio

    2009-02-24

    The purpose of the present electrical signal path study is to explore the various issues related to the deployment of highly-segmented low-background Ge detectors for the MAJORANA double-beta decay experiment. A significant challenge is to simultaneously satisfy competing requirements for the mechanical design, electrical readout performance, and radiopurity specifications from the MAJORANA project. Common to all rare search experiments, there is a very stringent limit on the acceptable radioactivity level of all the electronics components involved. Some of the findings are summarized in this report.

  19. Electrical Signal Path Study and Component Assay for the MAJORANA N-Type Segmented Contact Detector

    International Nuclear Information System (INIS)

    Amman, Mark; Bergevin, Marc; Chan, Yuen-Dat; Detwiler, Jason A.; Fujikawa, Brian; Lesko, Kevin T.; Luke, Paul N.; Prior, Gersende; Poon, Alan W.; Smith, Alan R.; Vetter, Kai; Yaver, Harold; Zimmermann, Sergio

    2009-01-01

    The purpose of the present electrical signal path study is to explore the various issues related to the deployment of highly-segmented low-background Ge detectors for the MAJORANA double-beta decay experiment. A significant challenge is to simultaneously satisfy competing requirements for the mechanical design, electrical readout performance, and radiopurity specifications from the MAJORANA project. Common to all rare search experiments, there is a very stringent limit on the acceptable radioactivity level of all the electronics components involved. Some of the findings are summarized in this report.

  20. 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.

  1. Altered Expression of Wnt Signaling Pathway Components in Osteogenesis of Mesenchymal Stem Cells in Osteoarthritis Patients.

    Science.gov (United States)

    Tornero-Esteban, Pilar; Peralta-Sastre, Ascensión; Herranz, Eva; Rodríguez-Rodríguez, Luis; Mucientes, Arkaitz; Abásolo, Lydia; Marco, Fernando; Fernández-Gutiérrez, Benjamín; Lamas, José Ramón

    2015-01-01

    Osteoarthritis (OA) is characterized by altered homeostasis of joint cartilage and bone, whose functional properties rely on chondrocytes and osteoblasts, belonging to mesenchymal stem cells (MSCs). WNT signaling acts as a hub integrating and crosstalking with other signaling pathways leading to the regulation of MSC functions. The aim of this study was to evaluate the existence of a differential signaling between Healthy and OA-MSCs during osteogenesis. MSCs of seven OA patients and six healthy controls were isolated, characterised and expanded. During in vitro osteogenesis, cells were recovered at days 1, 10 and 21. RNA and protein content was obtained. Expression of WNT pathway genes was evaluated using RT-qPCR. Functional studies were also performed to study the MSC osteogenic commitment and functional and post-traslational status of β-catenin and several receptor tyrosine kinases. Several genes were downregulated in OA-MSCs during osteogenesis in vitro. These included soluble Wnts, inhibitors, receptors, co-receptors, several kinases and transcription factors. Basal levels of β-catenin were higher in OA-MSCs, but calcium deposition and expression of osteogenic genes was similar between Healthy and OA-MSCs. Interestingly an increased phosphorylation of p44/42 MAPK (ERK1/2) signaling node was present in OA-MSCs. Our results point to the existence in OA-MSCs of alterations in expression of Wnt pathway components during in vitro osteogenesis that are partially compensated by post-translational mechanisms modulating the function of other pathways. We also point the relevance of other signaling pathways in OA pathophysiology suggesting their role in the maintenance of joint homeostasis through modulation of MSC osteogenic potential.

  2. TRPM5, a taste-signaling transient receptor potential ion-channel, is a ubiquitous signaling component in chemosensory cells

    Directory of Open Access Journals (Sweden)

    Hofmann Thomas

    2007-07-01

    Full Text Available Abstract Background A growing number of TRP channels have been identified as key players in the sensation of smell, temperature, mechanical forces and taste. TRPM5 is known to be abundantly expressed in taste receptor cells where it participates in sweet, amino acid and bitter perception. A role of TRPM5 in other sensory systems, however, has not been studied so far. Results Here, we systematically investigated the expression of TRPM5 in rat and mouse tissues. Apart from taste buds, where we found TRPM5 to be predominantly localized on the basolateral surface of taste receptor cells, TRPM5 immunoreactivity was seen in other chemosensory organs – the main olfactory epithelium and the vomeronasal organ. Most strikingly, we found solitary TRPM5-enriched epithelial cells in all parts of the respiratory and gastrointestinal tract. Based on their tissue distribution, the low cell density, morphological features and co-immunostaining with different epithelial markers, we identified these cells as brush cells (also known as tuft, fibrillovesicular, multivesicular or caveolated cells. In terms of morphological characteristics, brush cells resemble taste receptor cells, while their origin and biological role are still under intensive debate. Conclusion We consider TRPM5 to be an intrinsic signaling component of mammalian chemosensory organs, and provide evidence for brush cells being an important cellular correlate in the periphery.

  3. Two-Component Signal Transduction System SaeRS Positively Regulates Staphylococcus epidermidis Glucose Metabolism

    Directory of Open Access Journals (Sweden)

    Qiang Lou

    2014-01-01

    Full Text Available Staphylococcus epidermidis, which is a causative pathogen of nosocomial infection, expresses its virulent traits such as biofilm and autolysis regulated by two-component signal transduction system SaeRS. In this study, we performed a proteomic analysis of differences in expression between the S. epidermidis 1457 wild-type and saeRS mutant to identify candidates regulated by saeRS using two-dimensional gel electrophoresis (2-DE combined with matrix-assisted laser desorption/lonization mass spectrometry (MALDI-TOF-MS. Of 55 identified proteins that significantly differed in expression between the two strains, 15 were upregulated and 40 were downregulated. The downregulated proteins included enzymes related to glycolysis and TCA cycle, suggesting that glucose is not properly utilized in S. epidermidis when saeRS was deleted. The study will be helpful for treatment of S. epidermidis infection from the viewpoint of metabolic modulation dependent on two-component signal transduction system SaeRS.

  4. Physiological modules for generating discrete and rhythmic movements: component analysis of EMG signals.

    Science.gov (United States)

    Bengoetxea, Ana; Leurs, Françoise; Hoellinger, Thomas; Cebolla, Ana Maria; Dan, Bernard; Cheron, Guy; McIntyre, Joseph

    2014-01-01

    A central question in Neuroscience is that of how the nervous system generates the spatiotemporal commands needed to realize complex gestures, such as handwriting. A key postulate is that the central nervous system (CNS) builds up complex movements from a set of simpler motor primitives or control modules. In this study we examined the control modules underlying the generation of muscle activations when performing different types of movement: discrete, point-to-point movements in eight different directions and continuous figure-eight movements in both the normal, upright orientation and rotated 90°. To test for the effects of biomechanical constraints, movements were performed in the frontal-parallel or sagittal planes, corresponding to two different nominal flexion/abduction postures of the shoulder. In all cases we measured limb kinematics and surface electromyographic activity (EMG) signals for seven different muscles acting around the shoulder. We first performed principal component analysis (PCA) of the EMG signals on a movement-by-movement basis. We found a surprisingly consistent pattern of muscle groupings across movement types and movement planes, although we could detect systematic differences between the PCs derived from movements performed in each shoulder posture and between the principal components associated with the different orientations of the figure. Unexpectedly we found no systematic differences between the figure eights and the point-to-point movements. The first three principal components could be associated with a general co-contraction of all seven muscles plus two patterns of reciprocal activation. From these results, we surmise that both "discrete-rhythmic movements" such as the figure eight, and discrete point-to-point movement may be constructed from three different fundamental modules, one regulating the impedance of the limb over the time span of the movement and two others operating to generate movement, one aligned with the

  5. Combining RNA interference and kinase inhibitors against cell signalling components involved in cancer

    International Nuclear Information System (INIS)

    O'Grady, Michael; Raha, Debasish; Hanson, Bonnie J; Bunting, Michaeline; Hanson, George T

    2005-01-01

    The transcription factor activator protein-1 (AP-1) has been implicated in a large variety of biological processes including oncogenic transformation. The tyrosine kinases of the epidermal growth factor receptor (EGFR) constitute the beginning of one signal transduction cascade leading to AP-1 activation and are known to control cell proliferation and differentiation. Drug discovery efforts targeting this receptor and other pathway components have centred on monoclonal antibodies and small molecule inhibitors. Resistance to such inhibitors has already been observed, guiding the prediction of their use in combination therapies with other targeted agents such as RNA interference (RNAi). This study examines the use of RNAi and kinase inhibitors for qualification of components involved in the EGFR/AP-1 pathway of ME180 cells, and their inhibitory effects when evaluated individually or in tandem against multiple components of this important disease-related pathway. AP-1 activation was assessed using an ME180 cell line stably transfected with a beta-lactamase reporter gene under the control of AP-1 response element following epidermal growth factor (EGF) stimulation. Immunocytochemistry allowed for further quantification of small molecule inhibition on a cellular protein level. RNAi and RT-qPCR experiments were performed to assess the amount of knockdown on an mRNA level, and immunocytochemistry was used to reveal cellular protein levels for the targeted pathway components. Increased potency of kinase inhibitors was shown by combining RNAi directed towards EGFR and small molecule inhibitors acting at proximal or distal points in the pathway. After cellular stimulation with EGF and analysis at the level of AP-1 activation using a β-lactamase reporter gene, a 10–12 fold shift or 2.5–3 fold shift toward greater potency in the IC 50 was observed for EGFR and MEK-1 inhibitors, respectively, in the presence of RNAi targeting EGFR. EGFR pathway components were qualified as

  6. 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.

  7. Bioelectric signal classification using a recurrent probabilistic neural network with time-series discriminant component analysis.

    Science.gov (United States)

    Hayashi, Hideaki; Shima, Keisuke; Shibanoki, Taro; Kurita, Yuichi; Tsuji, Toshio

    2013-01-01

    This paper outlines a probabilistic neural network developed on the basis of time-series discriminant component analysis (TSDCA) that can be used to classify high-dimensional time-series patterns. TSDCA involves the compression of high-dimensional time series into a lower-dimensional space using a set of orthogonal transformations and the calculation of posterior probabilities based on a continuous-density hidden Markov model that incorporates a Gaussian mixture model expressed in the reduced-dimensional space. The analysis can be incorporated into a neural network so that parameters can be obtained appropriately as network coefficients according to backpropagation-through-time-based training algorithm. The network is considered to enable high-accuracy classification of high-dimensional time-series patterns and to reduce the computation time taken for network training. In the experiments conducted during the study, the validity of the proposed network was demonstrated for EEG signals.

  8. Non-Intrusive Load Monitoring of HVAC Components using Signal Unmixing

    Energy Technology Data Exchange (ETDEWEB)

    Rahimpour, Alireza [University of Tennessee, Knoxville (UTK); Qi, Hairong [ORNL; Fugate, David L [ORNL; Kuruganti, Teja [ORNL

    2015-01-01

    Heating, Ventilating and Air Conditioning units (HVAC) are a major electrical energy consumer in buildings. Monitoring of the operation and energy consumption of HVAC would increase the awareness of building owners and maintenance service providers of the condition and quality of performance of these units, enabling conditioned-based maintenance which would help achieving higher energy efficiency. In this paper, a novel non-intrusive load monitoring method based on group constrained non-negative matrix factorization is proposed for monitoring the different components of HVAC unit by only measuring the whole building aggregated power signal. At the first level of this hierarchical approach, power consumption of the building is decomposed to energy consumption of the HVAC unit and all the other electrical devices operating in the building such as lighting and plug loads. Then, the estimated power signal of the HVAC is used for estimating the power consumption profile of the HVAC major electrical loads such as compressors, condenser fans and indoor blower. Experiments conducted on real data collected from a building testbed maintained at the Oak Ridge National Laboratory (ORNL) demonstrate high accuracy on the disaggregation task.

  9. The PP2A Regulatory Subunit Tap46, a Component of the TOR Signaling Pathway, Modulates Growth and Metabolism in Plants[W

    Science.gov (United States)

    Ahn, Chang Sook; Han, Jeong-A; Lee, Ho-Seok; Lee, Semi; Pai, Hyun-Sook

    2011-01-01

    Tap42/α4, a regulatory subunit of protein phosphatase 2A, is a downstream effector of the target of rapamycin (TOR) protein kinase, which regulates cell growth in coordination with nutrient and environmental conditions in yeast and mammals. In this study, we characterized the functions and phosphatase regulation of plant Tap46. Depletion of Tap46 resulted in growth arrest and acute plant death with morphological markers of programmed cell death. Tap46 interacted with PP2A and PP2A-like phosphatases PP4 and PP6. Tap46 silencing modulated cellular PP2A activities in a time-dependent fashion similar to TOR silencing. Immunoprecipitated full-length and deletion forms of Arabidopsis thaliana TOR phosphorylated recombinant Tap46 protein in vitro, supporting a functional link between Tap46 and TOR. Tap46 depletion reproduced the signature phenotypes of TOR inactivation, such as dramatic repression of global translation and activation of autophagy and nitrogen mobilization, indicating that Tap46 may act as a positive effector of TOR signaling in controlling those processes. Additionally, Tap46 silencing in tobacco (Nicotiana tabacum) BY-2 cells caused chromatin bridge formation at anaphase, indicating its role in sister chromatid segregation. These findings suggest that Tap46, in conjunction with associated phosphatases, plays an essential role in plant growth and development as a component of the TOR signaling pathway. PMID:21216945

  10. Detection of oscillatory components in noise signals and its application to fast detection of sodium boiling in LMFBR's

    International Nuclear Information System (INIS)

    Ehrhardt, J.

    1975-09-01

    In general, the surveillance of technical plants is performed by observating the mean value of measured signals. In this method not all information included in these signals is used. On the other hand - for example in a reactor - disturbances are possible which generate small oscillatory components in the measured signals. In general, these oscillatory components do not influence the mean value of the signals and consequently do not activate the conventional control system; however they can be found by analysis of the signal's noise component. For the detection of these oscillatory signals the observation of the frequency spectra of the noise signals is particularly advantageous because they produce peaks at the oscillation frequencies. In this paper a new detection system for the fast detection of suddenly appearing peaks in the frequency spectra of noise signals is presented. The prototype of a compact detection unit was developed which continuously computes the power spectral density (PSD) of noise signals and simultaneously supervises the PSD for peaks in the relevant frequency range. The detection method is not affected by the frequency dependance of the PSD and is applicable to any noise signal. General criteria were developed to enable the determination of the optimal detection system and its sensitivity. The upper limits of false alarm rate and detection time were taken into account. The detection criteria are applicable to all noise signals with approximately normally distributed amplitudes. Theoretical results were confirmed in a number of experiments; special experimental and theoretical parameter studies were done for the optimal detection of sodium boiling in LMFBR's. Computations based on these results showed that local and integral sodium boiling can be detected in a wide core range of SNR 300 by observing fluctuations of the neutron flux. In this connection it is important to point out that no additional core instrumentation is necessary because the

  11. Convergent RANK- and c-Met-mediated signaling components predict survival of patients with prostate cancer: an interracial comparative study.

    Science.gov (United States)

    Hu, Peizhen; Chung, Leland W K; Berel, Dror; Frierson, Henry F; Yang, Hua; Liu, Chunyan; Wang, Ruoxiang; Li, Qinlong; Rogatko, Andre; Zhau, Haiyen E

    2013-01-01

    We reported (PLoS One 6 (12):e28670, 2011) that the activation of c-Met signaling in RANKL-overexpressing bone metastatic LNCaP cell and xenograft models increased expression of RANK, RANKL, c-Met, and phosphorylated c-Met, and mediated downstream signaling. We confirmed the significance of the RANK-mediated signaling network in castration resistant clinical human prostate cancer (PC) tissues. In this report, we used a multispectral quantum dot labeling technique to label six RANK and c-Met convergent signaling pathway mediators simultaneously in formalin fixed paraffin embedded (FFPE) tissue specimens, quantify the intensity of each expression at the sub-cellular level, and investigated their potential utility as predictors of patient survival in Caucasian-American, African-American and Chinese men. We found that RANKL and neuropilin-1 (NRP-1) expression predicts survival of Caucasian-Americans with PC. A Gleason score ≥ 8 combined with nuclear p-c-Met expression predicts survival in African-American PC patients. Neuropilin-1, p-NF-κB p65 and VEGF are predictors for the overall survival of Chinese men with PC. These results collectively support interracial differences in cell signaling networks that can predict the survival of PC patients.

  12. Convergent RANK- and c-Met-mediated signaling components predict survival of patients with prostate cancer: an interracial comparative study.

    Directory of Open Access Journals (Sweden)

    Peizhen Hu

    Full Text Available We reported (PLoS One 6 (12:e28670, 2011 that the activation of c-Met signaling in RANKL-overexpressing bone metastatic LNCaP cell and xenograft models increased expression of RANK, RANKL, c-Met, and phosphorylated c-Met, and mediated downstream signaling. We confirmed the significance of the RANK-mediated signaling network in castration resistant clinical human prostate cancer (PC tissues. In this report, we used a multispectral quantum dot labeling technique to label six RANK and c-Met convergent signaling pathway mediators simultaneously in formalin fixed paraffin embedded (FFPE tissue specimens, quantify the intensity of each expression at the sub-cellular level, and investigated their potential utility as predictors of patient survival in Caucasian-American, African-American and Chinese men. We found that RANKL and neuropilin-1 (NRP-1 expression predicts survival of Caucasian-Americans with PC. A Gleason score ≥ 8 combined with nuclear p-c-Met expression predicts survival in African-American PC patients. Neuropilin-1, p-NF-κB p65 and VEGF are predictors for the overall survival of Chinese men with PC. These results collectively support interracial differences in cell signaling networks that can predict the survival of PC patients.

  13. A signal-substrate match in the substrate-borne component of a multimodal courtship display

    Directory of Open Access Journals (Sweden)

    Damian O. ELIAS, Andrew C. MASON, Eileen A. HEBETS

    2010-06-01

    Full Text Available The environment can impose strong limitations on the efficacy of signal transmission. In particular, for vibratory communication, the signaling environment is often extremely heterogeneous at very small scales. Nevertheless, natural selection is expected to select for signals well-suited to effective transmission. Here, we test for substrate-dependent signal efficacy in the wolf spider Schizocosa stridulans Stratton 1991. We first explore the transmission characteristics of this important signaling modality by playing recorded substrate-borne signals through three different substrates (leaf litter, pine litter, and red clay and measuring the propagated signal. We found that the substrate-borne signal of S. stridulans attenuates the least on leaf litter, the substrate upon which the species is naturally found. Next, by assessing mating success with artificially muted and non-muted males across different signaling substrates (leaf litter, pine litter, and sand, we explored the relationship between substrate-borne signaling and substrate for mating success. We found that muted males were unsuccessful in obtaining copulations regardless of substrate, while mating success was dependent on the signaling substrate for non-muted males. For non-muted males, more males copulated on leaf litter than any other substrate. Taken together, these results confirm the importance of substrate-borne signaling in S. stridulans and suggest a match between signal properties and signal efficacy – leaf litter transmits the signal most effectively and males are most successful in obtaining copulations on leaf litter [Current Zoology 56 (3: 370–378, 2010].

  14. The Removal of EOG Artifacts From EEG Signals Using Independent Component Analysis and Multivariate Empirical Mode Decomposition.

    Science.gov (United States)

    Wang, Gang; Teng, Chaolin; Li, Kuo; Zhang, Zhonglin; Yan, Xiangguo

    2016-09-01

    The recorded electroencephalography (EEG) signals are usually contaminated by electrooculography (EOG) artifacts. In this paper, by using independent component analysis (ICA) and multivariate empirical mode decomposition (MEMD), the ICA-based MEMD method was proposed to remove EOG artifacts (EOAs) from multichannel EEG signals. First, the EEG signals were decomposed by the MEMD into multiple multivariate intrinsic mode functions (MIMFs). The EOG-related components were then extracted by reconstructing the MIMFs corresponding to EOAs. After performing the ICA of EOG-related signals, the EOG-linked independent components were distinguished and rejected. Finally, the clean EEG signals were reconstructed by implementing the inverse transform of ICA and MEMD. The results of simulated and real data suggested that the proposed method could successfully eliminate EOAs from EEG signals and preserve useful EEG information with little loss. By comparing with other existing techniques, the proposed method achieved much improvement in terms of the increase of signal-to-noise and the decrease of mean square error after removing EOAs.

  15. Attenuation of artifacts in EEG signals measured inside an MRI scanner using constrained independent component analysis

    International Nuclear Information System (INIS)

    Rasheed, Tahir; Lee, Young-Koo; Lee, Soo Yeol; Kim, Tae-Seong

    2009-01-01

    Integration of electroencephalography (EEG) and functional magnetic imaging (fMRI) resonance will allow analysis of the brain activities at superior temporal and spatial resolution. However simultaneous acquisition of EEG and fMRI is hindered by the enhancement of artifacts in EEG, the most prominent of which are ballistocardiogram (BCG) and electro-oculogram (EOG) artifacts. The situation gets even worse if the evoked potentials are measured inside MRI for their minute responses in comparison to the spontaneous brain responses. In this study, we propose a new method of attenuating these artifacts from the spontaneous and evoked EEG data acquired inside an MRI scanner using constrained independent component analysis with a priori information about the artifacts as constraints. With the proposed techniques of reference function generation for the BCG and EOG artifacts as constraints, our new approach performs significantly better than the averaged artifact subtraction (AAS) method. The proposed method could be an alternative to the conventional ICA method for artifact attenuation, with some advantages. As a performance measure we have achieved much improved normalized power spectrum ratios (INPS) for continuous EEG and correlation coefficient (cc) values with outside MRI visual evoked potentials for visual evoked EEG, as compared to those obtained with the AAS method. The results show that our new approach is more effective than the conventional methods, almost fully automatic, and no extra ECG signal measurements are involved

  16. Adaptation to Environmental Stimuli within the Host: Two-Component Signal Transduction Systems of Mycobacterium tuberculosis

    Science.gov (United States)

    Bretl, Daniel J.; Demetriadou, Chrystalla; Zahrt, Thomas C.

    2011-01-01

    Summary: Pathogenic microorganisms encounter a variety of environmental stresses following infection of their respective hosts. Mycobacterium tuberculosis, the etiological agent of tuberculosis, is an unusual bacterial pathogen in that it is able to establish lifelong infections in individuals within granulomatous lesions that are formed following a productive immune response. Adaptation to this highly dynamic environment is thought to be mediated primarily through transcriptional reprogramming initiated in response to recognition of stimuli, including low-oxygen tension, nutrient depletion, reactive oxygen and nitrogen species, altered pH, toxic lipid moieties, cell wall/cell membrane-perturbing agents, and other environmental cues. To survive continued exposure to these potentially adverse factors, M. tuberculosis encodes a variety of regulatory factors, including 11 complete two-component signal transduction systems (TCSSs) and several orphaned response regulators (RRs) and sensor kinases (SKs). This report reviews our current knowledge of the TCSSs present in M. tuberculosis. In particular, we discuss the biochemical and functional characteristics of individual RRs and SKs, the environmental stimuli regulating their activation, the regulons controlled by the various TCSSs, and the known or postulated role(s) of individual TCSSs in the context of M. tuberculosis physiology and/or pathogenesis. PMID:22126994

  17. 3D Organotypic Culture Model to Study Components of ERK Signaling.

    Science.gov (United States)

    Chioni, Athina-Myrto; Bajwa, Rabia Tayba; Grose, Richard

    2017-01-01

    Organotypic models are 3D in vitro representations of an in vivo environment. Their complexity can range from an epidermal replica to the establishment of a cancer microenvironment. These models have been used for many years, in an attempt to mimic the structure and function of cells and tissues found inside the body. Methods for developing 3D organotypic models differ according to the tissue of interest and the experimental design. For example, cultures may be grown submerged in culture medium and or at an air-liquid interface. Our group is focusing on an air-liquid interface 3D organotypic model. These cultures are grown on a nylon membrane-covered metal grid with the cells embedded in a Collagen-Matrigel gel. This allows cells to grow in an air-liquid interface to enable diffusion and nourishment from the medium below. Subsequently, the organotypic cultures can be used for immunohistochemical staining of various components of ERK signaling, which is a key player in mediating communication between cells and their microenvironment.

  18. Thrombopoietin/MPL participates in initiating and maintaining RUNX1-ETO acute myeloid leukemia via PI3K/AKT signaling

    NARCIS (Netherlands)

    J.A. Pulikkan (John); D. Madera (Dmitri); L. Xue (Liting); P. Bradley (Paul); S.F. Landrette (Sean Francis); Y.-H. Kuo (Ya-Huei); S. Abbas (Saman); L.J. Zhu (Lihua Julie); P.J.M. Valk (Peter); L.H. Castilla (Lucio)

    2012-01-01

    textabstractOncogenic mutations in components of cytokine signaling pathways elicit ligand-independent activation of downstream signaling, enhancing proliferation and survival in acute myeloid leukemia (AML). The myeloproliferative leukemia virus oncogene, MPL, a homodimeric receptor activated by

  19. Fetal ECG Extraction from Abdominal Signals: A Review on Suppression of Fundamental Power Line Interference Component and Its Harmonics

    OpenAIRE

    Ţarălungă, Dragoş-Daniel; Ungureanu, Georgeta-Mihaela; Gussi, Ilinca; Strungaru, Rodica; Wolf, Werner

    2014-01-01

    Interference of power line (PLI) (fundamental frequency and its harmonics) is usually present in biopotential measurements. Despite all countermeasures, the PLI still corrupts physiological signals, for example, electromyograms (EMG), electroencephalograms (EEG), and electrocardiograms (ECG). When analyzing the fetal ECG (fECG) recorded on the maternal abdomen, the PLI represents a particular strong noise component, being sometimes 10 times greater than the fECG signal, and thus impairing the...

  20. Characterization of sur-2, a Novel Ras-Mediated Signal Transduction Component in C. elegans

    National Research Council Canada - National Science Library

    DesJardins, Edward

    1998-01-01

    ... (oncogenes). A subset of proto-oncogenes comprise the RAS signal transduction pathway. Vulval development in the nematode worm Caenorhabditis elegans is controlled by a RAS signal transduction pathway...

  1. Characterization of sur-2, a Novel Ras-Mediated Signal Transduction Component in C. elegans

    National Research Council Canada - National Science Library

    DesJardins, Edward

    1999-01-01

    ... (oncogenes). A subset of proto-oncogenes comprise the RAS signal transduction pathway. Vulval development in the nematode worm Caenorhabditis elegans is controlled by a RAS signal transduction pathway. C...

  2. Preliminary study on electron paramagnetic resonance (EPR) signal properties of mobile phone components for dose estimation in radiation accident

    Energy Technology Data Exchange (ETDEWEB)

    Park, Byeong Ryong; Ha, Wi Ho; Park, Sun Hoo; Lee, Jin Kyeong; Lee, Seung Sook [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2015-12-15

    We have investigated the EPR signal properties in 12 components of two mobile phones (LCD, OLED) using electron paramagnetic resonance (EPR) spectrometer in this study.EPR measurements were performed at normal atmospheric conditions using Bruker EXEXSYS-II E500 spectrometer with X-band bridge, and samples were irradiated by {sup 137}C{sub s} gamma-ray source. To identify the presence of radiation-induced signal (RIS), the EPR spectra of each sample were measured unirradiated and irradiated at 50 Gy. Then, dose-response curve and signal intensity variating by time after irradiation were measured. As a result, the signal intensity increased after irradiation in all samples except the USIM plastic and IC chip. Among the samples, cover glass(CG), lens, light guide plate(LGP) and diffusion sheet have shown fine linearity (R{sup 2} > 0.99). Especially, the LGP had ideal characteristics for dosimetry because there were no signal in 0 Gy and high rate of increase in RIS. However, this sample showed weakness in fading. Signal intensity of LGP and Diffusion Sheet decreased by 50% within 72 hours after irradiation, while signals of Cover Glass and Lens were stably preserved during the short period of time. In order to apply rapidly EPR dosimetry using mobile phone components in large-scale radiation accidents, further studies on signal differences for same components of the different mobile phone, fading, pretreatment of samples and processing of background signal are needed. However, it will be possible to do dosimetry by dose-additive method or comparative method using unirradiated same product in small-scale accident.

  3. Extraction of fast neuronal changes from multichannel functional near-infrared spectroscopy signals using independent component analysis

    Science.gov (United States)

    Morren, Geert; Wolf, Martin; Lemmerling, Philippe; Wolf, Ursula; Choi, Jee H.; Gratton, Enrico; De Lathauwer, Lieven; Van Huffel, Sabine

    2002-06-01

    Fast changes in the range of milliseconds in the optical properties of cerebral tissue, which are associated with brain activity, can be detected using non-invasive near-infrared spectroscopy (NIRS). These changes in light scattering are due to an alteration in the refractive index at neuronal membranes. The aim of this study was to develop highly sensitive data analysis algorithms to detect this fast signal, which is small compared to other physiological signals. A frequency-domain tissue oximeter, whose laser diodes were modulated at 110MHz was used. The amplitude, mean intensity and phase of the modulated optical signal was measured at 96Hz sample rate. The probe consisting of 4 crossed source detector pairs was placed above the motor cortex, contralateral to the hand performing a tapping exercise consisting of alternating rest- and tapping periods of 20s each. The tapping frequency, which was set to 3.55Hz or 2.5 times the heart rate of the subject to avoid the influence of harmonics on the signal, could not be observed in any of the individual signals measured by the detectors. An adaptive filter was used to remove the arterial pulsatility from the optical signals. Independent Component Analysis allowed to separate signal components in which the tapping frequency was clearly visible.

  4. 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

  5. Acquisition of electrical signals using commercial electronic components for detection system of Lead ion in distilled water

    Science.gov (United States)

    Pujiyanto; Yasin, M.; Rusydi, F.

    2018-03-01

    Development of lead ion detection systems is expected to have an advantage in terms of simplicity of the device and easy for concentration analysis of a lead ion with very high performance. One important part of lead ion detection systems are electrical signal acquisition parts. The electrical signal acquisition part uses the main electronic components: non inverting op-amplifier, instrumentation amplifier, multiplier circuit and logarithmic amplifier. Here will be shown the performance of lead ion detection systems when the existing electrical signal processors use commercial electronic components. The results that can be drawn from this experimental were the lead ion sensor that has been developed can be used to detect lead ions with a sensitivity of 10.48 mV/ppm with the linearity 97.11% and had a measurement range of 0.1 ppm to 80 ppm.

  6. The human keratinocyte two-dimensional gel protein database (update 1995): mapping components of signal transduction pathways

    DEFF Research Database (Denmark)

    Celis, J E; Rasmussen, H H; Gromov, P

    1995-01-01

    identified (protein name, organelle components, etc.) using a procedure or a combination of procedures that include (i) comigration with known human proteins, (ii) 2-D gel immunoblotting using specific antibodies, (iii) microsequencing of Coomassie Brilliant Blue stained proteins, (iv) mass spectrometry, (v......)vaccinia virus expression of full length cDNAs, and (vi) in vitro transcription/translation of full-length cDNAs. This year, special emphasis has been given to the identification of signal transduction components by using 2-D gel immunoblotting of crude keratinocyte lysates in combination with enhanced......--through a systematic study of ekeratinocytes--qualitative and quantitative information on proteins and their genes that may allow us to identify abnormal patterns of gene expression and to pinpoint signaling pathways and components affected in various skin diseases, cancer included. Udgivelsesdato: 1995-Dec...

  7. Non-destructive testing of high heat flux components of fusion devices by infrared thermography: modeling and signal processing

    International Nuclear Information System (INIS)

    Cismondi, Fabio

    2007-01-01

    In Plasma Facing Components (PFCs) the joint of the CFC armour material onto the metallic CuCrZr heat sink needs to be significant defects free. Detection of material flaws is a major issue of the PFCs acceptance protocol. A Non-Destructive Technique (NDT) based upon active infrared thermography allows testing PFCs on SATIR tests bed in Cadarache. Up to now defect detection was based on the comparison of the surface temperature evolution of the inspected component with that of a supposed 'defect-free' one (used as a reference element). This work deals with improvement of thermal signal processing coming from SATIR. In particular the contributions of the thermal modelling and statistical signal processing converge in this work. As for thermal modelling, the identification of a sensitive parameter to defect presence allows improving the quantitative estimation of defect Otherwise Finite Element (FE) modeling of SATIR allows calculating the so called deterministic numerical tile. Statistical approach via the Monte Carlo technique extends the numerical tile concept to the numerical population concept. As for signal processing, traditional statistical treatments allow a better localization of the bond defect processing thermo-signal by itself, without utilising a reference signal. Moreover the problem of detection and classification of random signals can be solved by maximizing the signal-to-noise ratio. Two filters maximizing the signal-to-noise ratio are optimized: the stochastic matched filter aims at detects detection and the constrained stochastic matched filter aims at defects classification. Performances are quantified and methods are compared via the ROC curves. (author)

  8. Complement component 1, q subcomponent binding protein (C1QBP) in lipid rafts mediates hepatic metastasis of pancreatic cancer by regulating IGF-1/IGF-1R signaling.

    Science.gov (United States)

    Shi, Haojun; Fang, Winston; Liu, Minda; Fu, Deliang

    2017-10-01

    Pancreatic cancer shows a remarkable predilection for hepatic metastasis. Complement component 1, q subcomponent binding protein (C1QBP) can mediate growth factor-induced cancer cell chemotaxis and distant metastasis by activation of receptor tyrosine kinases. Coincidentally, insulin-like growth factor-1 (IGF-1) derived from the liver and cancer cells itself has been recognized as a critical inducer of hepatic metastasis. However, the mechanism underlying IGF-1-dependent hepatic metastasis of pancreatic cancer, in which C1QBP may be involved, remains unknown. In the study, we demonstrated a significant association between C1QBP expression and hepatic metastasis in patients with pancreatic cancer. IGF-1 induced the translocation of C1QBP from cytoplasm to lipid rafts and further drove the formation of CD44 variant 6 (CD44v6)/C1QBP complex in pancreatic cancer cells. C1QBP interacting with CD44v6 in lipid rafts promoted phosphorylation of IGF-1R and thus activated downstream PI3K and MAPK signaling pathways which mediated metastatic potential of pancreatic cancer cells including proliferation, apoptosis, invasion, adhesion and energy metabolism. Furthermore, C1QBP knockdown suppressed hepatic metastasis of pancreatic cancer cells in nude mice. We therefore conclude that C1QBP in lipid rafts serves a key regulator of IGF-1/IGF-1R-induced hepatic metastasis from pancreatic cancer. Our findings about C1QBP in lipid rafts provide a novel strategy to block IGF-1/IGF-1R signaling in pancreatic cancer and a reliable premise for more efficient combined modality therapies. © 2017 UICC.

  9. Performance comparison of independent component analysis algorithms for fetal cardiac signal reconstruction: a study on synthetic fMCG data

    International Nuclear Information System (INIS)

    Mantini, D; II, K E Hild; Alleva, G; Comani, S

    2006-01-01

    Independent component analysis (ICA) algorithms have been successfully used for signal extraction tasks in the field of biomedical signal processing. We studied the performances of six algorithms (FastICA, CubICA, JADE, Infomax, TDSEP and MRMI-SIG) for fetal magnetocardiography (fMCG). Synthetic datasets were used to check the quality of the separated components against the original traces. Real fMCG recordings were simulated with linear combinations of typical fMCG source signals: maternal and fetal cardiac activity, ambient noise, maternal respiration, sensor spikes and thermal noise. Clusters of different dimensions (19, 36 and 55 sensors) were prepared to represent different MCG systems. Two types of signal-to-interference ratios (SIR) were measured. The first involves averaging over all estimated components and the second is based solely on the fetal trace. The computation time to reach a minimum of 20 dB SIR was measured for all six algorithms. No significant dependency on gestational age or cluster dimension was observed. Infomax performed poorly when a sub-Gaussian source was included; TDSEP and MRMI-SIG were sensitive to additive noise, whereas FastICA, CubICA and JADE showed the best performances. Of all six methods considered, FastICA had the best overall performance in terms of both separation quality and computation times

  10. 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

    Autosomal-dominant mutations in the Park8 gene encoding Leucine-rich repeat kinase 2 (LRRK2) have been identified to cause up to 40% of the genetic forms of Parkinson's disease. However, the function and molecular pathways regulated by LRRK2 are largely unknown. It has been shown that LRRK2 serves as a scaffold during activation of WNT/β-catenin signaling via its interaction with the β-catenin destruction complex, DVL1-3 and LRP6. In this study, we examine whether LRRK2 also interacts with signaling components of the WNT/Planar Cell Polarity (WNT/PCP) pathway, which controls the maturation of substantia nigra dopaminergic neurons, the main cell type lost in Parkinson's disease patients. Co-immunoprecipitation and tandem mass spectrometry was performed in a mouse substantia nigra cell line (SN4741) and human HEK293T cell line in order to identify novel LRRK2 binding partners. Inhibition of the WNT/β-catenin reporter, TOPFlash, was used as a read-out of WNT/PCP pathway activation. The capacity of LRRK2 to regulate WNT/PCP signaling in vivo was tested in Xenopus laevis' early development. Our proteomic analysis identified that LRRK2 interacts with proteins involved in WNT/PCP signaling such as the PDZ domain-containing protein GIPC1 and Integrin-linked kinase (ILK) in dopaminergic cells in vitro and in the mouse ventral midbrain in vivo. Moreover, co-immunoprecipitation analysis revealed that LRRK2 binds to two core components of the WNT/PCP signaling pathway, PRICKLE1 and CELSR1, as well as to FLOTILLIN-2 and CULLIN-3, which regulate WNT secretion and inhibit WNT/β-catenin signaling, respectively. We also found that PRICKLE1 and LRRK2 localize in signalosomes and act as dual regulators of WNT/PCP and β-catenin signaling. Accordingly, analysis of the function of LRRK2 in vivo, in X. laevis revelaed that LRKK2 not only inhibits WNT/β-catenin pathway, but induces a classical WNT/PCP phenotype in vivo. Our study shows for the first time that LRRK2 activates the WNT

  11. [Detection of quadratic phase coupling between EEG signal components by nonparamatric and parametric methods of bispectral analysis].

    Science.gov (United States)

    Schmidt, K; Witte, H

    1999-11-01

    Recently the assumption of the independence of individual frequency components in a signal has been rejected, for example, for the EEG during defined physiological states such as sleep or sedation [9, 10]. Thus, the use of higher-order spectral analysis capable of detecting interrelations between individual signal components has proved useful. The aim of the present study was to investigate the quality of various non-parametric and parametric estimation algorithms using simulated as well as true physiological data. We employed standard algorithms available for the MATLAB. The results clearly show that parametric bispectral estimation is superior to non-parametric estimation in terms of the quality of peak localisation and the discrimination from other peaks.

  12. Separating movement and gravity components in an acceleration signal and implications for the assessment of human daily physical activity.

    Directory of Open Access Journals (Sweden)

    Vincent T van Hees

    Full Text Available INTRODUCTION: Human body acceleration is often used as an indicator of daily physical activity in epidemiological research. Raw acceleration signals contain three basic components: movement, gravity, and noise. Separation of these becomes increasingly difficult during rotational movements. We aimed to evaluate five different methods (metrics of processing acceleration signals on their ability to remove the gravitational component of acceleration during standardised mechanical movements and the implications for human daily physical activity assessment. METHODS: An industrial robot rotated accelerometers in the vertical plane. Radius, frequency, and angular range of motion were systematically varied. Three metrics (Euclidian norm minus one [ENMO], Euclidian norm of the high-pass filtered signals [HFEN], and HFEN plus Euclidean norm of low-pass filtered signals minus 1 g [HFEN+] were derived for each experimental condition and compared against the reference acceleration (forward kinematics of the robot arm. We then compared metrics derived from human acceleration signals from the wrist and hip in 97 adults (22-65 yr, and wrist in 63 women (20-35 yr in whom daily activity-related energy expenditure (PAEE was available. RESULTS: In the robot experiment, HFEN+ had lowest error during (vertical plane rotations at an oscillating frequency higher than the filter cut-off frequency while for lower frequencies ENMO performed better. In the human experiments, metrics HFEN and ENMO on hip were most discrepant (within- and between-individual explained variance of 0.90 and 0.46, respectively. ENMO, HFEN and HFEN+ explained 34%, 30% and 36% of the variance in daily PAEE, respectively, compared to 26% for a metric which did not attempt to remove the gravitational component (metric EN. CONCLUSION: In conclusion, none of the metrics as evaluated systematically outperformed all other metrics across a wide range of standardised kinematic conditions. However, choice

  13. Separating movement and gravity components in an acceleration signal and implications for the assessment of human daily physical activity.

    Science.gov (United States)

    van Hees, Vincent T; Gorzelniak, Lukas; Dean León, Emmanuel Carlos; Eder, Martin; Pias, Marcelo; Taherian, Salman; Ekelund, Ulf; Renström, Frida; Franks, Paul W; Horsch, Alexander; Brage, Søren

    2013-01-01

    Human body acceleration is often used as an indicator of daily physical activity in epidemiological research. Raw acceleration signals contain three basic components: movement, gravity, and noise. Separation of these becomes increasingly difficult during rotational movements. We aimed to evaluate five different methods (metrics) of processing acceleration signals on their ability to remove the gravitational component of acceleration during standardised mechanical movements and the implications for human daily physical activity assessment. An industrial robot rotated accelerometers in the vertical plane. Radius, frequency, and angular range of motion were systematically varied. Three metrics (Euclidian norm minus one [ENMO], Euclidian norm of the high-pass filtered signals [HFEN], and HFEN plus Euclidean norm of low-pass filtered signals minus 1 g [HFEN+]) were derived for each experimental condition and compared against the reference acceleration (forward kinematics) of the robot arm. We then compared metrics derived from human acceleration signals from the wrist and hip in 97 adults (22-65 yr), and wrist in 63 women (20-35 yr) in whom daily activity-related energy expenditure (PAEE) was available. In the robot experiment, HFEN+ had lowest error during (vertical plane) rotations at an oscillating frequency higher than the filter cut-off frequency while for lower frequencies ENMO performed better. In the human experiments, metrics HFEN and ENMO on hip were most discrepant (within- and between-individual explained variance of 0.90 and 0.46, respectively). ENMO, HFEN and HFEN+ explained 34%, 30% and 36% of the variance in daily PAEE, respectively, compared to 26% for a metric which did not attempt to remove the gravitational component (metric EN). In conclusion, none of the metrics as evaluated systematically outperformed all other metrics across a wide range of standardised kinematic conditions. However, choice of metric explains different degrees of variance in

  14. Evolutionary Recycling of Light Signaling Components in Fleshy Fruits: New Insights on the Role of Pigments to Monitor Ripening

    OpenAIRE

    Llorente, Briardo; D?Andrea, Lucio; Rodr?guez-Concepci?n, Manuel

    2016-01-01

    Besides an essential source of energy, light provides environmental information to plants. Photosensory pathways are thought to have occurred early in plant evolution, probably at the time of the Archaeplastida ancestor, or perhaps even earlier. Manipulation of individual components of light perception and signaling networks in tomato (Solanum lycopersicum) affects the metabolism of ripening fruit at several levels. Most strikingly, recent experiments have shown that some of the molecular mec...

  15. Fetal ECG Extraction from Abdominal Signals: A Review on Suppression of Fundamental Power Line Interference Component and Its Harmonics

    Directory of Open Access Journals (Sweden)

    Dragoş-Daniel Ţarălungă

    2014-01-01

    Full Text Available Interference of power line (PLI (fundamental frequency and its harmonics is usually present in biopotential measurements. Despite all countermeasures, the PLI still corrupts physiological signals, for example, electromyograms (EMG, electroencephalograms (EEG, and electrocardiograms (ECG. When analyzing the fetal ECG (fECG recorded on the maternal abdomen, the PLI represents a particular strong noise component, being sometimes 10 times greater than the fECG signal, and thus impairing the extraction of any useful information regarding the fetal health state. Many signal processing methods for cancelling the PLI from biopotentials are available in the literature. In this review study, six different principles are analyzed and discussed, and their performance is evaluated on simulated data (three different scenarios, based on five quantitative performance indices.

  16. Fetal ECG extraction from abdominal signals: a review on suppression of fundamental power line interference component and its harmonics.

    Science.gov (United States)

    Ţarălungă, Dragoş-Daniel; Ungureanu, Georgeta-Mihaela; Gussi, Ilinca; Strungaru, Rodica; Wolf, Werner

    2014-01-01

    Interference of power line (PLI) (fundamental frequency and its harmonics) is usually present in biopotential measurements. Despite all countermeasures, the PLI still corrupts physiological signals, for example, electromyograms (EMG), electroencephalograms (EEG), and electrocardiograms (ECG). When analyzing the fetal ECG (fECG) recorded on the maternal abdomen, the PLI represents a particular strong noise component, being sometimes 10 times greater than the fECG signal, and thus impairing the extraction of any useful information regarding the fetal health state. Many signal processing methods for cancelling the PLI from biopotentials are available in the literature. In this review study, six different principles are analyzed and discussed, and their performance is evaluated on simulated data (three different scenarios), based on five quantitative performance indices.

  17. Identification of the feedforward component in manual control with predictable target signals.

    Science.gov (United States)

    Drop, Frank M; Pool, Daan M; Damveld, Herman J; van Paassen, Marinus M; Mulder, Max

    2013-12-01

    In the manual control of a dynamic system, the human controller (HC) often follows a visible and predictable reference path. Compared with a purely feedback control strategy, performance can be improved by making use of this knowledge of the reference. The operator could effectively introduce feedforward control in conjunction with a feedback path to compensate for errors, as hypothesized in literature. However, feedforward behavior has never been identified from experimental data, nor have the hypothesized models been validated. This paper investigates human control behavior in pursuit tracking of a predictable reference signal while being perturbed by a quasi-random multisine disturbance signal. An experiment was done in which the relative strength of the target and disturbance signals were systematically varied. The anticipated changes in control behavior were studied by means of an ARX model analysis and by fitting three parametric HC models: two different feedback models and a combined feedforward and feedback model. The ARX analysis shows that the experiment participants employed control action on both the error and the target signal. The control action on the target was similar to the inverse of the system dynamics. Model fits show that this behavior can be modeled best by the combined feedforward and feedback model.

  18. 454 Transcriptome sequencing suggests a role for two-component signalling in cellularization and differentiation of barley endosperm transfer cells.

    Science.gov (United States)

    Thiel, Johannes; Hollmann, Julien; Rutten, Twan; Weber, Hans; Scholz, Uwe; Weschke, Winfriede

    2012-01-01

    Cell specification and differentiation in the endosperm of cereals starts at the maternal-filial boundary and generates the endosperm transfer cells (ETCs). Besides the importance in assimilate transfer, ETCs are proposed to play an essential role in the regulation of endosperm differentiation by affecting development of proximate endosperm tissues. We attempted to identify signalling elements involved in early endosperm differentiation by using a combination of laser-assisted microdissection and 454 transcriptome sequencing. 454 sequencing of the differentiating ETC region from the syncytial state until functionality in transfer processes captured a high proportion of novel transcripts which are not available in existing barley EST databases. Intriguingly, the ETC-transcriptome showed a high abundance of elements of the two-component signalling (TCS) system suggesting an outstanding role in ETC differentiation. All components and subfamilies of the TCS, including distinct kinds of membrane-bound receptors, have been identified to be expressed in ETCs. The TCS system represents an ancient signal transduction system firstly discovered in bacteria and has previously been shown to be co-opted by eukaryotes, like fungi and plants, whereas in animals and humans this signalling route does not exist. Transcript profiling of TCS elements by qRT-PCR suggested pivotal roles for specific phosphorelays activated in a coordinated time flow during ETC cellularization and differentiation. ETC-specificity of transcriptionally activated TCS phosphorelays was assessed for early differentiation and cellularization contrasting to an extension of expression to other grain tissues at the beginning of ETC maturation. Features of candidate genes of distinct phosphorelays and transcriptional activation of genes putatively implicated in hormone signalling pathways hint at a crosstalk of hormonal influences, putatively ABA and ethylene, and TCS signalling. Our findings suggest an integral

  19. Processing of pulse oximeter signals using adaptive filtering and autocorrelation to isolate perfusion and oxygenation components

    Science.gov (United States)

    Ibey, Bennett; Subramanian, Hariharan; Ericson, Nance; Xu, Weijian; Wilson, Mark; Cote, Gerard L.

    2005-03-01

    A blood perfusion and oxygenation sensor has been developed for in situ monitoring of transplanted organs. In processing in situ data, motion artifacts due to increased perfusion can create invalid oxygenation saturation values. In order to remove the unwanted artifacts from the pulsatile signal, adaptive filtering was employed using a third wavelength source centered at 810nm as a reference signal. The 810 nm source resides approximately at the isosbestic point in the hemoglobin absorption curve where the absorbance of light is nearly equal for oxygenated and deoxygenated hemoglobin. Using an autocorrelation based algorithm oxygenation saturation values can be obtained without the need for large sampling data sets allowing for near real-time processing. This technique has been shown to be more reliable than traditional techniques and proven to adequately improve the measurement of oxygenation values in varying perfusion states.

  20. A procedure to correct the effects of a relative delay between the quadrature components of radar signals at base band

    Directory of Open Access Journals (Sweden)

    Grydeland

    2005-01-01

    Full Text Available The real and imaginary parts of baseband signals are obtained from a real narrow-band signal by quadrature mixing, i.e. by mixing with cosine and sine signals at the narrow band's selected center frequency. We address the consequences of a delay between the outputs of the quadrature mixer, which arise when digital samples of the quadrature baseband signals are not synchronised, i.e. when the real and imaginary components have been shifted by one or more samples with respect to each other. Through analytical considerations and simulations of such an error on different synthetic signals, we show how this error can be expected to afflict different measurements. In addition, we show the effect of the error on actual incoherent scatter radar data obtained by two different digital receiver systems used in parallel at the EISCAT Svalbard Radar (ESR. The analytical considerations indicate a procedure to correct the error, albeit with some limitations due to a small singular region. We demonstrate the correction procedure on actually afflicted data and compare the results to simultaneously acquired unafflicted data. We also discuss the possible data analysis strategies, including some that avoid dealing directly with the singular region mentioned above.

  1. Signal-to-noise contribution of principal component loads in reconstructed near-infrared Raman tissue spectra.

    Science.gov (United States)

    Grimbergen, M C M; van Swol, C F P; Kendall, C; Verdaasdonk, R M; Stone, N; Bosch, J L H R

    2010-01-01

    The overall quality of Raman spectra in the near-infrared region, where biological samples are often studied, has benefited from various improvements to optical instrumentation over the past decade. However, obtaining ample spectral quality for analysis is still challenging due to device requirements and short integration times required for (in vivo) clinical applications of Raman spectroscopy. Multivariate analytical methods, such as principal component analysis (PCA) and linear discriminant analysis (LDA), are routinely applied to Raman spectral datasets to develop classification models. Data compression is necessary prior to discriminant analysis to prevent or decrease the degree of over-fitting. The logical threshold for the selection of principal components (PCs) to be used in discriminant analysis is likely to be at a point before the PCs begin to introduce equivalent signal and noise and, hence, include no additional value. Assessment of the signal-to-noise ratio (SNR) at a certain peak or over a specific spectral region will depend on the sample measured. Therefore, the mean SNR over the whole spectral region (SNR(msr)) is determined in the original spectrum as well as for spectra reconstructed from an increasing number of principal components. This paper introduces a method of assessing the influence of signal and noise from individual PC loads and indicates a method of selection of PCs for LDA. To evaluate this method, two data sets with different SNRs were used. The sets were obtained with the same Raman system and the same measurement parameters on bladder tissue collected during white light cystoscopy (set A) and fluorescence-guided cystoscopy (set B). This method shows that the mean SNR over the spectral range in the original Raman spectra of these two data sets is related to the signal and noise contribution of principal component loads. The difference in mean SNR over the spectral range can also be appreciated since fewer principal components can

  2. The Signaling Role of CD40 Ligand in Platelet Biology and in Platelet Component Transfusion

    Science.gov (United States)

    Aoui, Chaker; Prigent, Antoine; Sut, Caroline; Tariket, Sofiane; Hamzeh-Cognasse, Hind; Pozzetto, Bruno; Richard, Yolande; Cognasse, Fabrice; Laradi, Sandrine; Garraud, Olivier

    2014-01-01

    The CD40 ligand (CD40L) is a transmembrane molecule of crucial interest in cell signaling in innate and adaptive immunity. It is expressed by a variety of cells, but mainly by activated T-lymphocytes and platelets. CD40L may be cleaved into a soluble form (sCD40L) that has a cytokine-like activity. Both forms bind to several receptors, including CD40. This interaction is necessary for the antigen specific immune response. Furthermore, CD40L and sCD40L are involved in inflammation and a panoply of immune related and vascular pathologies. Soluble CD40L is primarily produced by platelets after activation, degranulation and cleavage, which may present a problem for transfusion. Soluble CD40L is involved in adverse transfusion events including transfusion related acute lung injury (TRALI). Although platelet storage designed for transfusion occurs in sterile conditions, platelets are activated and release sCD40L without known agonists. Recently, proteomic studies identified signaling pathways activated in platelet concentrates. Soluble CD40L is a good candidate for platelet activation in an auto-amplification loop. In this review, we describe the immunomodulatory role of CD40L in physiological and pathological conditions. We will focus on the main signaling pathways activated by CD40L after binding to its different receptors. PMID:25479079

  3. Extraction of a Weak Co-Channel Interfering Communication Signal Using Complex Independent Component Analysis

    Science.gov (United States)

    2013-06-01

    zarzoso/ biblio /tnn10.pdf"> % "Robust independent component analysis by iterative maximization</a> % <a href = "http://www.i3s.unice.fr/~zarzoso... biblio /tnn10.pdf"> % of the kurtosis contrast with algebraic optimal step size"</a>, % IEEE Transactions on Neural Networks, vol. 21, no. 2, % pp

  4. Independent component analysis based digital signal processing in coherent optical fiber communication systems

    Science.gov (United States)

    Li, Xiang; Luo, Ming; Qiu, Ying; Alphones, Arokiaswami; Zhong, Wen-De; Yu, Changyuan; Yang, Qi

    2018-02-01

    In this paper, channel equalization techniques for coherent optical fiber transmission systems based on independent component analysis (ICA) are reviewed. The principle of ICA for blind source separation is introduced. The ICA based channel equalization after both single-mode fiber and few-mode fiber transmission for single-carrier and orthogonal frequency division multiplexing (OFDM) modulation formats are investigated, respectively. The performance comparisons with conventional channel equalization techniques are discussed.

  5. Attenuation of spin resonance signals in media with the multi-component system of collectivized electrons

    International Nuclear Information System (INIS)

    Vojtenko, V.A.

    1995-01-01

    Universal relaxation theory of spectral line form at electron scattering light with spin flip at scattering of neutrons and at electron paramagnetic resonance, is plotted. Signals of spin resonances are shown to be subjected to strong attenuation caused by mutual transformations of various current carriers in multicomponent spin systems contained in intermetallic actinides with heavy fermions, in HTSC-crystals, in indirect highly alloyed semiconductors, solid solutions and superlattices. Physical reasons of observation of light strong scattering with spin flip in intermetallic actinides with semi-width independent of the wave vector are discussed. 19 refs

  6. The fast ratio: A rapid measure for testing the dominance of the fast component in the initial OSL signal from quartz

    International Nuclear Information System (INIS)

    Durcan, Julie A.; Duller, Geoff A.T.

    2011-01-01

    The signal from the fast component is usually considered preferable for quartz optically stimulated luminescence (OSL) dating, however its presence in a continuous wave (CW) OSL signal is often assumed, rather than verified. This paper presents an objective measure (termed the fast ratio) for testing the dominance of the fast component in the initial part of a quartz OSL signal. The ratio is based upon the photo ionisation cross-sections of the fast and medium components and the power of the measurement equipment used to record the OSL signal, and it compares parts of the OSL signal selected to represent the fast and medium components. The ability of the fast ratio to distinguish between samples whose CW-OSL signal is dominated by the fast and non-fast components is demonstrated by comparing the fast ratio with the contribution of the fast component calculated from curve deconvolution of measured OSL signals and from simulated data. The ratio offers a rapid method for screening a large number of OSL signals obtained for individual equivalent dose estimates, it can be calculated and applied as easily as other routine screening methods, and is transferrable between different aliquots, samples and measurement equipment. - Highlights: → Fast ratio is a measure which tests dominance of fast component in quartz OSL signals. → A fast ratio above 20 implies a CW-OSL signal is dominated by fast component. → Fast ratio can be easily and rapidly applied to a large number of OSL signals. → Uses include signal comparison, data screening, identify need for further analysis.

  7. Shared and unique components of human population structure and genome-wide signals of positive selection in South Asia.

    Science.gov (United States)

    Metspalu, Mait; Romero, Irene Gallego; Yunusbayev, Bayazit; Chaubey, Gyaneshwer; Mallick, Chandana Basu; Hudjashov, Georgi; Nelis, Mari; Mägi, Reedik; Metspalu, Ene; Remm, Maido; Pitchappan, Ramasamy; Singh, Lalji; Thangaraj, Kumarasamy; Villems, Richard; Kivisild, Toomas

    2011-12-09

    South Asia harbors one of the highest levels genetic diversity in Eurasia, which could be interpreted as a result of its long-term large effective population size and of admixture during its complex demographic history. In contrast to Pakistani populations, populations of Indian origin have been underrepresented in previous genomic scans of positive selection and population structure. Here we report data for more than 600,000 SNP markers genotyped in 142 samples from 30 ethnic groups in India. Combining our results with other available genome-wide data, we show that Indian populations are characterized by two major ancestry components, one of which is spread at comparable frequency and haplotype diversity in populations of South and West Asia and the Caucasus. The second component is more restricted to South Asia and accounts for more than 50% of the ancestry in Indian populations. Haplotype diversity associated with these South Asian ancestry components is significantly higher than that of the components dominating the West Eurasian ancestry palette. Modeling of the observed haplotype diversities suggests that both Indian ancestry components are older than the purported Indo-Aryan invasion 3,500 YBP. Consistent with the results of pairwise genetic distances among world regions, Indians share more ancestry signals with West than with East Eurasians. However, compared to Pakistani populations, a higher proportion of their genes show regionally specific signals of high haplotype homozygosity. Among such candidates of positive selection in India are MSTN and DOK5, both of which have potential implications in lipid metabolism and the etiology of type 2 diabetes. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  8. Identification and characterization of novel defence and PCD signalling components in Arabidopsis

    DEFF Research Database (Denmark)

    Xie, Wenjun

    rescued syp121 syp122 ssdx (suppressor of syntaxin-related death) lines were collected. SSD genes are typically required for pathogen defence. In this PhD project, using some of these triple mutant lines, SSD6 and SSD12 were identified to be novel genes by Mutmap and complementation test. SSD6 encode...... a large protein with at least six domains with predicted functions, and mutations in five of these showed that they are important for the lesion mimic phenotype of syp121 syp122. Subcellular localization showed SSD6 to function on the ER. In the project, a split-GFP Gateway vector system was developed...... for topology studies of membrane proteins, and SSD6 was found to be an ER membrane-anchored cytosolic protein. The position of SSD6 in the defence signalling network was studied using syp121 syp122 ssd6 ssdy quadruple mutants, which suggested that SSD6 is not involved in any known signalling pathway. All...

  9. A short study to assess the potential of independent component analysis for motion artifact separation in wearable pulse oximeter signals.

    Science.gov (United States)

    Yao, Jianchu; Warren, Steve

    2005-01-01

    Motion artifact reduction and separation become critical when medical sensors are used in wearable monitoring scenarios. Previous research has demonstrated that independent component analysis (ICA) can be applied to pulse oximeter signals to separate photoplethysmographic (PPG) data from motion artifacts, ambient light, and other interference in low-motion environments. However, ICA assumes that all source signal component pairs are mutually independent. It is important to assess the statistical independence of the source components in PPG data, especially if ICA is to be applied in ambulatory monitoring environments, where motion artifacts can have a substantial effect on the quality of data received from light-based sensors. This paper addresses the statistical relationship between motion artifacts and PPG data by calculating the correlation coefficients between arterial volume variations and motion over a range of stationary to high-motion conditions. Analyses indicate that motion significantly affects arterial flow, so care must be taken when applying ICA to light-based sensor data acquired from wearable platforms.

  10. Influence of a component of solar irradiance on radon signals at 1000 meter depth at the Gran Sasso Laboratory, Italy

    Science.gov (United States)

    Gazit-Yaari (Charit-Yaari), N.; Steinitz, G.; Piatibratova, O.

    2012-04-01

    Exploratory monitoring of radon is conducted at one site at the deep underground Gran Sasso National Laboratory (LNGS; 1,000m below the surface). Monitoring is performed in a small secluded space separated by a sealed partition from the entirety of the laboratory environment in air in contact with the exposed surrounding calcareous country rock. Overall radon levels are low (0.45 kBq/m3). Utilizing both alpha and gamma-ray detectors measurements (15-minute resolution) cover a time span of ca. 600 days. Systematic and recurring radon signals are recorded consisting of two primary signal types: a) non-periodic Multi-Day (MD) signals lasting 2-10 days, and b) Daily Radon (DR) signals - which are of a periodic nature exhibiting a primary 24-hour cycle. Temperature in the closed enclosure is stable (11.5±0.3 °C) and pressure reflects above surface barometric variations. Analysis and comparison in the time and frequency domains (FFT) of local environmental data (P, T) indicates that these do not drive radon variation in air at the site. The phenomenology of the MD and DR signals is similar to situations encountered at other locations where radon is monitored with a high time resolution in geogas at upper crustal levels. Using the Continuous Wavelet Transform analysis tool a different variation pattern is observed for time series consisting of day-time and night-time measurement of the gamma radiation from radon progeny. Applying the same analysis to the time series of local air pressure does not reveal a day-time and night-time difference. The observation of a differing day/night pattern in the gamma radiation from radon at LNGS is similar to further occurrences at other subsurface locations. Production of a day/night pattern must be related to rotation of Earth around its axis. This phenomenon is a further confirmation of the recent proposition as to the influence of a component of solar irradiance on the nuclear radiation from radon in air. The occurrence of these

  11. Convergence of PASTA kinase and two-component signaling in response to cell wall stress in Enterococcus faecalis.

    Science.gov (United States)

    Kellogg, Stephanie L; Kristich, Christopher J

    2018-04-09

    Two common signal transduction mechanisms used by bacteria to sense and respond to changing environments are two-component systems (TCSs) and eukaryotic-like Ser/Thr kinases and phosphatases (eSTK/Ps). Enterococcus faecalis is a Gram-positive bacterium and serious opportunistic pathogen that relies on both a TCS and an eSTK/P pathway for intrinsic resistance to cell wall-targeting antibiotics. The TCS consists of a histidine kinase (CroS) and response regulator (CroR) that become activated upon exposure of cells to cell wall-targeting antibiotics, leading to modulation of gene expression. The eSTK/P pathway consists of a transmembrane kinase (IreK) and its cognate phosphatase (IreP), which act antagonistically to mediate antibiotic resistance through an unknown mechanism. Because both CroS/R and IreK/P contribute to enterococcal resistance towards cell wall-targeting antibiotics, we hypothesized these signaling systems are intertwined. To test this hypothesis, we analyzed CroR phosphorylation and CroS/R-dependent gene expression to probe the influence of IreK and IreP on CroS/R signaling. In addition, we analyzed the phosphorylation state of CroS which revealed IreK-dependent phosphorylation of a Thr residue important for CroS function. Our results are consistent with a model in which IreK positively influences CroR-dependent gene expression through phosphorylation of CroS to promote antimicrobial resistance in E. faecalis Importance Two-component signaling systems (TCSs) and eukaryotic-like Ser/Thr kinases (eSTKs) are used by bacteria to sense and adapt to changing environments. Understanding how these pathways are regulated to promote bacterial survival is critical for a more complete understanding of bacterial stress responses and physiology. The opportunistic pathogen Enterococcus faecalis relies on both a TCS (CroS/R) and an eSTK (IreK) for intrinsic resistance to cell wall-targeting antibiotics. We probed the relationship between CroS/R and IreK, revealing

  12. Rhythmic Components in Extracranial Brain Signals Reveal Multifaceted Task Modulation of Overlapping Neuronal Activity.

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    Roemer van der Meij

    Full Text Available Oscillatory neuronal activity is implicated in many cognitive functions, and its phase coupling between sensors may reflect networks of communicating neuronal populations. Oscillatory activity is often studied using extracranial recordings and compared between experimental conditions. This is challenging, because there is overlap between sensor-level activity generated by different sources, and this can obscure differential experimental modulations of these sources. Additionally, in extracranial data, sensor-level phase coupling not only reflects communicating populations, but can also be generated by a current dipole, whose sensor-level phase coupling does not reflect source-level interactions. We present a novel method, which is capable of separating and characterizing sources on the basis of their phase coupling patterns as a function of space, frequency and time (trials. Importantly, this method depends on a plausible model of a neurobiological rhythm. We present this model and an accompanying analysis pipeline. Next, we demonstrate our approach, using magnetoencephalographic (MEG recordings during a cued tactile detection task as a case study. We show that the extracted components have overlapping spatial maps and frequency content, which are difficult to resolve using conventional pairwise measures. Because our decomposition also provides trial loadings, components can be readily contrasted between experimental conditions. Strikingly, we observed heterogeneity in alpha and beta sources with respect to whether their activity was suppressed or enhanced as a function of attention and performance, and this happened both in task relevant and irrelevant regions. This heterogeneity contrasts with the common view that alpha and beta amplitude over sensory areas are always negatively related to attention and performance.

  13. Combination of Empirical Mode Decomposition Components of HRV Signals for Discriminating Emotional States

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    Ateke Goshvarpour

    2016-06-01

    Full Text Available Introduction Automatic human emotion recognition is one of the most interesting topics in the field of affective computing. However, development of a reliable approach with a reasonable recognition rate is a challenging task. The main objective of the present study was to propose a robust method for discrimination of emotional responses thorough examination of heart rate variability (HRV. In the present study, considering the non-stationary and non-linear characteristics of HRV, empirical mode decomposition technique was utilized as a feature extraction approach. Materials and Methods In order to induce the emotional states, images indicating four emotional states, i.e., happiness, peacefulness, sadness, and fearfulness were presented. Simultaneously, HRV was recorded in 47 college students. The signals were decomposed into some intrinsic mode functions (IMFs. For each IMF and different IMF combinations, 17 standard and non-linear parameters were extracted. Wilcoxon test was conducted to assess the difference between IMF parameters in different emotional states. Afterwards, a probabilistic neural network was used to classify the features into emotional classes. Results Based on the findings, maximum classification rates were achieved when all IMFs were fed into the classifier. Under such circumstances, the proposed algorithm could discriminate the affective states with sensitivity, specificity, and correct classification rate of 99.01%, 100%, and 99.09%, respectively. In contrast, the lowest discrimination rates were attained by IMF1 frequency and its combinations. Conclusion The high performance of the present approach indicated that the proposed method is applicable for automatic emotion recognition.

  14. Speckle noise reduction technique for Lidar echo signal based on self-adaptive pulse-matching independent component analysis

    Science.gov (United States)

    Xu, Fan; Wang, Jiaxing; Zhu, Daiyin; Tu, Qi

    2018-04-01

    Speckle noise has always been a particularly tricky problem in improving the ranging capability and accuracy of Lidar system especially in harsh environment. Currently, effective speckle de-noising techniques are extremely scarce and should be further developed. In this study, a speckle noise reduction technique has been proposed based on independent component analysis (ICA). Since normally few changes happen in the shape of laser pulse itself, the authors employed the laser source as a reference pulse and executed the ICA decomposition to find the optimal matching position. In order to achieve the self-adaptability of algorithm, local Mean Square Error (MSE) has been defined as an appropriate criterion for investigating the iteration results. The obtained experimental results demonstrated that the self-adaptive pulse-matching ICA (PM-ICA) method could effectively decrease the speckle noise and recover the useful Lidar echo signal component with high quality. Especially, the proposed method achieves 4 dB more improvement of signal-to-noise ratio (SNR) than a traditional homomorphic wavelet method.

  15. Evolutionary recycling of light signaling components in fleshy fruits: new insights on the role of pigments to monitor ripening

    Directory of Open Access Journals (Sweden)

    Briardo eLlorente

    2016-03-01

    Full Text Available Besides an essential source of energy, light provides environmental information to plants. Photosensory pathways are thought to have occurred early in plant evolution, probably at the time of the Archaeplastida ancestor, or perhaps even earlier. Manipulation of individual components of light perception and signaling networks in tomato (Solanum lycopersicum affects the metabolism of ripening fruit at several levels. Most strikingly, recent experiments have shown that some of the molecular mechanisms originally devoted to sense and respond to environmental light cues have been re-adapted during evolution to provide plants with useful information on fruit ripening progression. In particular, the presence of chlorophylls in green fruit can strongly influence the spectral composition of the light filtered through the fruit pericarp. The concomitant changes in light quality can be perceived and transduced by phytochromes and phytochrome-interacting factors, respectively, to regulate gene expression and in turn modulate the production of carotenoids, a family of metabolites that are relevant for the final pigmentation of ripe fruits. We raise the hypothesis that the evolutionary recycling of light-signaling components to finely adjust pigmentation to the actual ripening stage of the fruit may have represented a selective advantage for primeval fleshy-fruited plants even before the extinction of dinosaurs.

  16. Evolutionary Recycling of Light Signaling Components in Fleshy Fruits: New Insights on the Role of Pigments to Monitor Ripening.

    Science.gov (United States)

    Llorente, Briardo; D'Andrea, Lucio; Rodríguez-Concepción, Manuel

    2016-01-01

    Besides an essential source of energy, light provides environmental information to plants. Photosensory pathways are thought to have occurred early in plant evolution, probably at the time of the Archaeplastida ancestor, or perhaps even earlier. Manipulation of individual components of light perception and signaling networks in tomato (Solanum lycopersicum) affects the metabolism of ripening fruit at several levels. Most strikingly, recent experiments have shown that some of the molecular mechanisms originally devoted to sense and respond to environmental light cues have been re-adapted during evolution to provide plants with useful information on fruit ripening progression. In particular, the presence of chlorophylls in green fruit can strongly influence the spectral composition of the light filtered through the fruit pericarp. The concomitant changes in light quality can be perceived and transduced by phytochromes (PHYs) and PHY-interacting factors, respectively, to regulate gene expression and in turn modulate the production of carotenoids, a family of metabolites that are relevant for the final pigmentation of ripe fruits. We raise the hypothesis that the evolutionary recycling of light-signaling components to finely adjust pigmentation to the actual ripening stage of the fruit may have represented a selective advantage for primeval fleshy-fruited plants even before the extinction of dinosaurs.

  17. 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.

  18. Independent component analysis for the extraction of reliable protein signal profiles from MALDI-TOF mass spectra.

    Science.gov (United States)

    Mantini, Dante; Petrucci, Francesca; Del Boccio, Piero; Pieragostino, Damiana; Di Nicola, Marta; Lugaresi, Alessandra; Federici, Giorgio; Sacchetta, Paolo; Di Ilio, Carmine; Urbani, Andrea

    2008-01-01

    Independent component analysis (ICA) is a signal processing technique that can be utilized to recover independent signals from a set of their linear mixtures. We propose ICA for the analysis of signals obtained from large proteomics investigations such as clinical multi-subject studies based on MALDI-TOF MS profiling. The method is validated on simulated and experimental data for demonstrating its capability of correctly extracting protein profiles from MALDI-TOF mass spectra. The comparison on peak detection with an open-source and two commercial methods shows its superior reliability in reducing the false discovery rate of protein peak masses. Moreover, the integration of ICA and statistical tests for detecting the differences in peak intensities between experimental groups allows to identify protein peaks that could be indicators of a diseased state. This data-driven approach demonstrates to be a promising tool for biomarker-discovery studies based on MALDI-TOF MS technology. The MATLAB implementation of the method described in the article and both simulated and experimental data are freely available at http://www.unich.it/proteomica/bioinf/.

  19. Modular and coordinated expression of immune system regulatory and signaling components in the developing and adult nervous system.

    Science.gov (United States)

    Monzón-Sandoval, Jimena; Castillo-Morales, Atahualpa; Crampton, Sean; McKelvey, Laura; Nolan, Aoife; O'Keeffe, Gerard; Gutierrez, Humberto

    2015-01-01

    During development, the nervous system (NS) is assembled and sculpted through a concerted series of neurodevelopmental events orchestrated by a complex genetic programme. While neural-specific gene expression plays a critical part in this process, in recent years, a number of immune-related signaling and regulatory components have also been shown to play key physiological roles in the developing and adult NS. While the involvement of individual immune-related signaling components in neural functions may reflect their ubiquitous character, it may also reflect a much wider, as yet undescribed, genetic network of immune-related molecules acting as an intrinsic component of the neural-specific regulatory machinery that ultimately shapes the NS. In order to gain insights into the scale and wider functional organization of immune-related genetic networks in the NS, we examined the large scale pattern of expression of these genes in the brain. Our results show a highly significant correlated expression and transcriptional clustering among immune-related genes in the developing and adult brain, and this correlation was the highest in the brain when compared to muscle, liver, kidney and endothelial cells. We experimentally tested the regulatory clustering of immune system (IS) genes by using microarray expression profiling in cultures of dissociated neurons stimulated with the pro-inflammatory cytokine TNF-alpha, and found a highly significant enrichment of immune system-related genes among the resulting differentially expressed genes. Our findings strongly suggest a coherent recruitment of entire immune-related genetic regulatory modules by the neural-specific genetic programme that shapes the NS.

  20. Two-Component Signal Transduction Systems That Regulate the Temporal and Spatial Expression of Myxococcus xanthus Sporulation Genes.

    Science.gov (United States)

    Sarwar, Zaara; Garza, Anthony G

    2016-02-01

    When starved for nutrients, Myxococcus xanthus produces a biofilm that contains a mat of rod-shaped cells, known as peripheral rods, and aerial structures called fruiting bodies, which house thousands of dormant and stress-resistant spherical spores. Because rod-shaped cells differentiate into spherical, stress-resistant spores and spore differentiation occurs only in nascent fruiting bodies, many genes and multiple levels of regulation are required. Over the past 2 decades, many regulators of the temporal and spatial expression of M. xanthus sporulation genes have been uncovered. Of these sporulation gene regulators, two-component signal transduction circuits, which typically contain a histidine kinase sensor protein and a transcriptional regulator known as response regulator, are among the best characterized. In this review, we discuss prototypical two-component systems (Nla6S/Nla6 and Nla28S/Nla28) that regulate an early, preaggregation phase of sporulation gene expression during fruiting body development. We also discuss orphan response regulators (ActB and FruA) that regulate a later phase of sporulation gene expression, which begins during the aggregation stage of fruiting body development. In addition, we summarize the research on a complex two-component system (Esp) that is important for the spatial regulation of sporulation. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  1. Verification of γ-Amino-Butyric Acid (GABA) Signaling System Components in Periodontal Ligament Cells In Vivo and In Vitro.

    Science.gov (United States)

    Konermann, Anna; Kantarci, Alpdogan; Wilbert, Steven; Van Dyke, Thomas; Jäger, Andreas

    2016-11-01

    CNS key neurotransmitter γ-amino-butyric acid (GABA) and its signaling components are likewise detectable in non-neuronal tissues displaying inter alia immunomodulatory functions. This study aimed at identifying potential glutamate decarboxylase (GAD)65 and GABA receptor expression in periodontal ligament (PDL) cells in vivo and in vitro, with particular regard to inflammation and mechanical loading. Gene expression was analyzed in human PDL cells at rest or in response to IL-1ß (5 ng/ml) or TNFα (5 ng/ml) challenge via qRT-PCR. Western blot determined constitutive receptor expression, and confocal laser scanning fluorescence microscopy visualized expression changes induced by inflammation. ELISA quantified GAD65 release. Immunocytochemistry was performed for GABA component detection in vitro on mechanically loaded PDL cells, and in vivo on rat upper jaw biopsies with mechanically induced root resorptions. Statistical significance was set at p GABA B1 , GABA B2 , GABA A1 , and GABA A3 were ubiquitously expressed both on gene and protein level. GABA A2 and GAD65 were undetectable in resting cells, but induced by inflammation. GABA B1 exhibited the highest basal gene expression (6.97 % ± 0.16). IL-1ß markedly increased GABA B2 on a transcriptional (57.28-fold ± 12.40) and protein level seen via fluorescence microscopy. TNFα-stimulated PDL cells released GAD65 (3.68 pg/ml ± 0.17 after 24 h, 5.77 pg/ml ± 0.65 after 48 h). Immunocytochemistry revealed GAD65 expression in mechanically loaded PDL cells. In vivo, GABA components were varyingly expressed in an inflammatory periodontal environment. PDL cells differentially express GABA signaling components and secrete GAD65. Inflammation and mechanical loading regulate these neurotransmitter molecules, which are also detectable in vivo and are potentially involved in periodontal pathophysiology.

  2. Quantitative evaluation of deep and shallow tissue layers' contribution to fNIRS signal using multi-distance optodes and independent component analysis.

    Science.gov (United States)

    Funane, Tsukasa; Atsumori, Hirokazu; Katura, Takusige; Obata, Akiko N; Sato, Hiroki; Tanikawa, Yukari; Okada, Eiji; Kiguchi, Masashi

    2014-01-15

    To quantify the effect of absorption changes in the deep tissue (cerebral) and shallow tissue (scalp, skin) layers on functional near-infrared spectroscopy (fNIRS) signals, a method using multi-distance (MD) optodes and independent component analysis (ICA), referred to as the MD-ICA method, is proposed. In previous studies, when the signal from the shallow tissue layer (shallow signal) needs to be eliminated, it was often assumed that the shallow signal had no correlation with the signal from the deep tissue layer (deep signal). In this study, no relationship between the waveforms of deep and shallow signals is assumed, and instead, it is assumed that both signals are linear combinations of multiple signal sources, which allows the inclusion of a "shared component" (such as systemic signals) that is contained in both layers. The method also assumes that the partial optical path length of the shallow layer does not change, whereas that of the deep layer linearly increases along with the increase of the source-detector (S-D) distance. Deep- and shallow-layer contribution ratios of each independent component (IC) are calculated using the dependence of the weight of each IC on the S-D distance. Reconstruction of deep- and shallow-layer signals are performed by the sum of ICs weighted by the deep and shallow contribution ratio. Experimental validation of the principle of this technique was conducted using a dynamic phantom with two absorbing layers. Results showed that our method is effective for evaluating deep-layer contributions even if there are high correlations between deep and shallow signals. Next, we applied the method to fNIRS signals obtained on a human head with 5-, 15-, and 30-mm S-D distances during a verbal fluency task, a verbal working memory task (prefrontal area), a finger tapping task (motor area), and a tetrametric visual checker-board task (occipital area) and then estimated the deep-layer contribution ratio. To evaluate the signal separation

  3. MAVS dimer is a crucial signaling component of innate immunity and the target of hepatitis C virus NS3/4A protease.

    Science.gov (United States)

    Baril, Martin; Racine, Marie-Eve; Penin, François; Lamarre, Daniel

    2009-02-01

    The mitochondrial antiviral signaling (MAVS) protein plays a central role in innate antiviral immunity. Upon recognition of a virus, intracellular receptors of the RIG-I-like helicase family interact with MAVS to trigger a signaling cascade. In this study, we investigate the requirement of the MAVS structure for enabling its signaling by structure-function analyses and resonance energy transfer approaches in live cells. We now report the essential role of the MAVS oligomer in signal transduction and map the transmembrane domain as the main determinant of dimerization. A combination of mutagenesis and computational methods identified a cluster of residues making favorable van der Waals interactions at the MAVS dimer interface. We also correlated the activation of IRF3 and NF-kappaB with MAVS oligomerization rather than its mitochondrial localization. Finally, we demonstrated that MAVS oligomerization is disrupted upon expression of HCV NS3/4A protease, suggesting a mechanism for the loss of antiviral signaling. Altogether, our data suggest that the MAVS oligomer is essential in the formation of a multiprotein membrane-associated signaling complex and enables downstream activation of IRF3 and NF-kappaB in antiviral innate immunity.

  4. Immunocytochemical evidence for co-expression of Type III IP3 receptor with signaling components of bitter taste transduction

    Directory of Open Access Journals (Sweden)

    Kinnamon Sue C

    2001-04-01

    Full Text Available Abstract Background Taste receptor cells are responsible for transducing chemical stimuli into electrical signals that lead to the sense of taste. An important second messenger in taste transduction is IP3, which is involved in both bitter and sweet transduction pathways. Several components of the bitter transduction pathway have been identified, including the T2R/TRB taste receptors, phospholipase C β2, and the G protein subunits α-gustducin, β3, and γ13. However, the identity of the IP3 receptor subtype in this pathway is not known. In the present study we used immunocytochemistry on rodent taste tissue to identify the IP3 receptors expressed in taste cells and to examine taste bud expression patterns for IP3R3. Results Antibodies against Type I, II, and III IP3 receptors were tested on sections of rat and mouse circumvallate papillae. Robust cytoplasmic labeling for the Type III IP3 receptor (IP3R3 was found in a large subset of taste cells in both species. In contrast, little or no immunoreactivity was seen with antibodies against the Type I or Type II IP3 receptors. To investigate the potential role of IP3R3 in bitter taste transduction, we used double-label immunocytochemistry to determine whether IP3R3 is expressed in the same subset of cells expressing other bitter signaling components. IP3R3 immunoreactive taste cells were also immunoreactive for PLCβ2 and γ13. Alpha-gustducin immunoreactivity was present in a subset of IP3R3, PLCβ2, and γ13 positive cells. Conclusions IP3R3 is the dominant form of the IP3 receptor expressed in taste cells and our data suggest it plays an important role in bitter taste transduction.

  5. Expression of factors and key components associated with the PI3K signaling pathway in colon cancer.

    Science.gov (United States)

    Chen, Hua; Gao, Junyi; Du, Zhenhua; Zhang, Xuequn; Yang, Fei; Gao, Wei

    2018-04-01

    The pathophysiology of colorectal cancer (CRC) has not been fully elucidated. The dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway frequently contributes to the tumorigenesis and progression of human cancer. The aim of the present study was to explore the expression and clinical significance of a number of associated factors and key components of the PI3K signaling pathway, including phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (p110α), phosphorylated protein kinase B (p-Akt) Ser473, p-mammalian target of rapamycin (mTOR) Ser2448, cyclin D1, cyclin dependent kinase (CDK)4, RELA proto-oncogene, nuclear factor-κβ subunit (p65), Ras and extracellular signal-regulated kinase (ERK)1/2 in human CRC. The expression of target proteins was detected using immunohistochemistry (IHC) in 65 CRC cases and 15 colonic adenoma cases. The association between the expression of target proteins and clinical pathological parameters was analyzed using a χ 2 test. IHC results revealed that the expression of all target proteins was significantly increased in CRC tissues compared with in colonic adenoma tissues (P0.05). Cyclin D1, CDK4 and Ras were revealed to be expressed significantly higher in poorly differentiated CRC compared with moderately differentiated CRC (Pcancer tissues with lymph node metastasis compared with cancer tissues without lymph node metastasis (P<0.05). These results suggest that the target proteins may all participate in the tumorigenesis of CRC. Furthermore, cyclin D1, CDK4, Ras, p65 and ERK1/2 may be important in the progression of CRC. The results of the present study may provide novel predictive factors and therapeutic targets for CRC.

  6. 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)

  7. 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

  8. Minor abnormalities of testis development in mice lacking the gene encoding the MAPK signalling component, MAP3K1.

    Directory of Open Access Journals (Sweden)

    Nick Warr

    2011-05-01

    Full Text Available In mammals, the Y chromosome is a dominant male determinant, causing the bipotential gonad to develop as a testis. Recently, cases of familial and spontaneous 46,XY disorders of sex development (DSD have been attributed to mutations in the human gene encoding mitogen-activated protein kinase kinase kinase 1, MAP3K1, a component of the mitogen-activated protein kinase (MAPK signal transduction pathway. In individuals harbouring heterozygous mutations in MAP3K1, dysregulation of MAPK signalling was observed in lymphoblastoid cell lines, suggesting a causal role for these mutations in disrupting XY sexual development. Mice lacking the cognate gene, Map3k1, are viable and exhibit the eyes open at birth (EOB phenotype on a mixed genetic background, but on the C57BL/6J genetic background most mice die at around 14.5 dpc due to a failure of erythropoiesis in the fetal liver. However, no systematic examination of sexual development in Map3k1-deficient mice has been described, an omission that is especially relevant in the case of C57BL/6J, a genetic background that is sensitized to disruptions to testis determination. Here, we report that on a mixed genetic background mice lacking Map3k1 are fertile and exhibit no overt abnormalities of testis development. On C57BL/6J, significant non-viability is observed with very few animals surviving to adulthood. However, an examination of development in Map3k1-deficient XY embryos on this genetic background revealed no significant defects in testis determination, although minor abnormalities were observed, including an increase in gonadal length. Based on these observations, we conclude that MAP3K1 is not required for mouse testis determination. We discuss the significance of these data for the functional interpretation of sex-reversing MAP3K1 mutations in humans.

  9. 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.

  10. Frizzled 2 is a key component in the regulation of TOR signaling-mediated egg production in the mosquito Aedes aegypti.

    Science.gov (United States)

    Weng, Shih-Che; Shiao, Shin-Hong

    2015-06-01

    The Wnt signaling pathway was first discovered as a key event in embryonic development and cell polarity in Drosophila. Recently, several reports have shown that Wnt stimulates translation and cell growth by activating the mTOR pathway in mammals. Previous studies have demonstrated that the Target of Rapamycin (TOR) pathway plays an important role in mosquito vitellogenesis. However, the interactions between these two pathways are poorly understood in the mosquito. In this study, we hypothesized that factors from the TOR and Wnt signaling pathways interacted synergistically in mosquito vitellogenesis. Our results showed that silencing Aedes aegypti Frizzled 2 (AaFz2), a transmembrane receptor of the Wnt signaling pathway, decreased the fecundity of mosquitoes. We showed that AaFz2 was highly expressed at the transcriptional and translational levels in the female mosquito 6 h after a blood meal, indicating amino acid-stimulated expression of AaFz2. Notably, the phosphorylation of S6K, a downstream target of the TOR pathway, and the expression of vitellogenin were inhibited in the absence of AaFz2. A direct link was found in this study between Wnt and TOR signaling in the regulation of mosquito reproduction. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Performance comparison of six independent components analysis algorithms for fetal signal extraction from real fMCG data

    International Nuclear Information System (INIS)

    Hild, Kenneth E; Alleva, Giovanna; Nagarajan, Srikantan; Comani, Silvia

    2007-01-01

    In this study we compare the performance of six independent components analysis (ICA) algorithms on 16 real fetal magnetocardiographic (fMCG) datasets for the application of extracting the fetal cardiac signal. We also compare the extraction results for real data with the results previously obtained for synthetic data. The six ICA algorithms are FastICA, CubICA, JADE, Infomax, MRMI-SIG and TDSEP. The results obtained using real fMCG data indicate that the FastICA method consistently outperforms the others in regard to separation quality and that the performance of an ICA method that uses temporal information suffers in the presence of noise. These two results confirm the previous results obtained using synthetic fMCG data. There were also two notable differences between the studies based on real and synthetic data. The differences are that all six ICA algorithms are independent of gestational age and sensor dimensionality for synthetic data, but depend on gestational age and sensor dimensionality for real data. It is possible to explain these differences by assuming that the number of point sources needed to completely explain the data is larger than the dimensionality used in the ICA extraction

  12. The AtNFXL1 gene functions as a signaling component of the type A trichothecene-dependent response

    Science.gov (United States)

    Asano, Tomoya; Yasuda, Michiko; Nakashita, Hideo; Kimura, Makoto; Yamaguchi1, Kazuo

    2008-01-01

    Phytopathogenic Fusarium species produce the trichothecene family of phytotoxins, which function as a virulence factor during infection of plants. Trichothecenes are classifiable into four major groups by their chemical structures. Recently, the AtNFXL1 gene was reported as a type A trichothecene T-2 toxin-inducible gene. The AtNFXL1 gene encodes a putative transcription factor with similarity to the human transcription repressor NF-X1. The atnfxl1 mutant exhibited hypersensitivity phenotype to T-2 toxin but not to type B deoxynivalenol (DON) in comparison with wild type when Arabidopsis thaliana grew on agar medium containing trichothecenes. The absence or presence of a carbonyl group at the C8 position distinguishes type A and type B. Growth defect by another type A trichothecene diacetoxyscirpenol (DAS), was weakly enhanced in the atnfxl1 mutant. Diacetoxyscirpenol is distinguishable from T-2 toxin only by the absence of an isovaleryl group at the C8 position. Correspondingly, the AtNFXL1 promoter activity was apparently induced in T-2 toxin-treated and DAS-treated plants. In contrast, DON failed to induce the AtNFXL1 promoter activity. Consequently, the AtNFXL1 gene functions as a signaling component of the type A trichothecene-dependent response in Arabidopsis. In addition, the C8 position of trichothecenes might be closely related to the function of AtNFXL1 gene. PMID:19704430

  13. 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.

  14. 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)

  15. MUSIC-CONTENT-ADAPTIVE ROBUST PRINCIPAL COMPONENT ANALYSIS FOR A SEMANTICALLY CONSISTENT SEPARATION OF FOREGROUND AND BACKGROUND IN MUSIC AUDIO SIGNALS

    OpenAIRE

    Papadopoulos , Hélène; Ellis , Daniel P.W.

    2014-01-01

    International audience; Robust Principal Component Analysis (RPCA) is a technique to decompose signals into sparse and low rank components, and has recently drawn the attention of the MIR field for the problem of separating leading vocals from accompaniment, with appealing re-sults obtained on small excerpts of music. However, the perfor-mance of the method drops when processing entire music tracks. We present an adaptive formulation of RPCA that incorporates music content information to guid...

  16. Classification Technique for Ultrasonic Weld Inspection Signals using a Neural Network based on 2-dimensional fourier Transform and Principle Component Analysis

    International Nuclear Information System (INIS)

    Kim, Jae Joon

    2004-01-01

    Neural network-based signal classification systems are increasingly used in the analysis of large volumes of data obtained in NDE applications. Ultrasonic inspection methods on the other hand are commonly used in the nondestructive evaluation of welds to detect flaws. An important characteristic of ultrasonic inspection is the ability to identify the type of discontinuity that gives rise to a peculiar signal. Standard techniques rely on differences in individual A-scans to classify the signals. This paper proposes an ultrasonic signal classification technique based on the information tying in the neighboring signals. The approach is based on a 2-dimensional Fourier transform and the principal component analysis to generate a reduced dimensional feature vector for classification. Results of applying the technique to data obtained from the inspection of actual steel welds are presented

  17. Tyrosine kinase signalling in breast cancer: Modulation of tyrosine kinase signalling in human breast cancer through altered expression of signalling intermediates

    International Nuclear Information System (INIS)

    Kairouz, Rania; Daly, Roger J

    2000-01-01

    The past decade has seen the definition of key signalling pathways downstream of receptor tyrosine kinases (RTKs) in terms of their components and the protein-protein interactions that facilitate signal transduction. Given the strong evidence that links signalling by certain families of RTKs to the progression of breast cancer, it is not surprising that the expression profile of key downstream signalling intermediates in this disease has also come under scrutiny, particularly because some exhibit transforming potential or amplify mitogenic signalling pathways when they are overexpressed. Reflecting the diverse cellular processes regulated by RTKs, it is now clear that altered expression of such signalling proteins in breast cancer may influence not only cellular proliferation (eg Grb2) but also the invasive properties of the cancer cells (eg EMS1/cortactin)

  18. Evolutionary history of the OmpR/IIIA family of signal transduction two component systems in Lactobacillaceae and Leuconostocaceae

    Directory of Open Access Journals (Sweden)

    González-Candelas Fernando

    2011-02-01

    Full Text Available Abstract Background Two component systems (TCS are signal transduction pathways which typically consist of a sensor histidine kinase (HK and a response regulator (RR. In this study, we have analyzed the evolution of TCS of the OmpR/IIIA family in Lactobacillaceae and Leuconostocaceae, two families belonging to the group of lactic acid bacteria (LAB. LAB colonize nutrient-rich environments such as foodstuffs, plant materials and the gastrointestinal tract of animals thus driving the study of this group of both basic and applied interest. Results The genomes of 19 strains belonging to 16 different species have been analyzed. The number of TCS encoded by the strains considered in this study varied between 4 in Lactobacillus helveticus and 17 in Lactobacillus casei. The OmpR/IIIA family was the most prevalent in Lactobacillaceae accounting for 71% of the TCS present in this group. The phylogenetic analysis shows that no new TCS of this family has recently evolved in these Lactobacillaceae by either lineage-specific gene expansion or domain shuffling. Furthermore, no clear evidence of non-orthologous replacements of either RR or HK partners has been obtained, thus indicating that coevolution of cognate RR and HKs has been prevalent in Lactobacillaceae. Conclusions The results obtained suggest that vertical inheritance of TCS present in the last common ancestor and lineage-specific gene losses appear as the main evolutionary forces involved in their evolution in Lactobacillaceae, although some HGT events cannot be ruled out. This would agree with the genomic analyses of Lactobacillales which show that gene losses have been a major trend in the evolution of this group.

  19. Spinal glutamatergic neurons defined by EphA4 signaling are essential components of normal locomotor circuits

    DEFF Research Database (Denmark)

    Borgius, Lotta; Nishimaru, Hiroshi; Caldeira, Vanessa

    2014-01-01

    EphA4 signaling is essential for the spatiotemporal organization of neuronal circuit formation. In mice, deletion of this signaling pathway causes aberrant midline crossing of axons from both brain and spinal neurons and the complete knock-outs (KOs) exhibit a pronounced change in motor behavior...

  20. 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....

  1. 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

  2. The effect of irradiation dose and storage time on the ESR signal in the cuticle of different components of the exoskeleton of Norway lobster (Nephrops norvegicus)

    Energy Technology Data Exchange (ETDEWEB)

    Stewart, E.M. (Queen' s Univ., Belfast, Northern Ireland (United Kingdom)); Stevenson, M.H. (Department of Agriculture for Northern Ireland (United Kingdom). Food and Agricultural Chemistry Research Div. Queen' s Univ., Belfast, Northern Ireland (United Kingdom)); Gray, R. (Department for Agriculture for Northern Ireland (United Kingdom). Food and Agricultural Chemistry Research Div.)

    This paper examines the potential of ESR spectroscopy too determine if Norway lobsters have been irradiated. Ninety samples, each containing 3 whole Norway lobsters, were prepared, thirty were used as controls while the remaining sixty were given irradiation doses of approximately either 1 or 3 kGy. Following irradiation the samples were stored at 1[sup o]C for 0, 7, 14, 21 or 28 d. After each storage period the cuticle of the tail, carapace, claws and walking legs was removed, freeze-dried and ground prior to analysis using ESR spectroscopy. The control spectra were subtracted from their respective irradiated spectra thereby leaving the radiation-induced signal. Peak heights of the signals were measured. The ESR signals derived from the different components of the exoskeleton were similar in shape and varied only in their intensities. The claw samples gave the most intense signal while that from the walking legs was the weakest. There was a significant decay in the signal intensity over the storage period with the signal derived from cuticle of the claws showing the greatest diminution (44%) and that of the tail the least (17%). The signal intensities of the walking legs and carapace decreased by 22% and 30% respectively. In conclusion ESR spectroscopy is a useful technique for the qualitative detection of irradiated Norway lobster and shows considerable potential for quantification of dose received. (author).

  3. The effect of irradiation dose and storage time on the ESR signal in the cuticle of different components of the exoskeleton of Norway lobster (Nephrops norvegicus)

    International Nuclear Information System (INIS)

    Stewart, E.M.; Stevenson, M.H.; Gray, R.

    1993-01-01

    This paper examines the potential of ESR spectroscopy too determine if Norway lobsters have been irradiated. Ninety samples, each containing 3 whole Norway lobsters, were prepared, thirty were used as controls while the remaining sixty were given irradiation doses of approximately either 1 or 3 kGy. Following irradiation the samples were stored at 1 o C for 0, 7, 14, 21 or 28 d. After each storage period the cuticle of the tail, carapace, claws and walking legs was removed, freeze-dried and ground prior to analysis using ESR spectroscopy. The control spectra were subtracted from their respective irradiated spectra thereby leaving the radiation-induced signal. Peak heights of the signals were measured. The ESR signals derived from the different components of the exoskeleton were similar in shape and varied only in their intensities. The claw samples gave the most intense signal while that from the walking legs was the weakest. There was a significant decay in the signal intensity over the storage period with the signal derived from cuticle of the claws showing the greatest diminution (44%) and that of the tail the least (17%). The signal intensities of the walking legs and carapace decreased by 22% and 30% respectively. In conclusion ESR spectroscopy is a useful technique for the qualitative detection of irradiated Norway lobster and shows considerable potential for quantification of dose received. (author)

  4. 10-Hydroxy-2-decenoic Acid, the Major Lipid Component of Royal Jelly, Extends the Lifespan of Caenorhabditis elegans through Dietary Restriction and Target of Rapamycin Signaling

    Directory of Open Access Journals (Sweden)

    Yoko Honda

    2015-01-01

    Full Text Available Royal jelly (RJ produced by honeybees has been reported to possess diverse health-beneficial properties and has been implicated to have a function in longevity across diverse species as well as honeybees. 10-Hydroxy-2-decenoic acid (10-HDA, the major lipid component of RJ produced by honeybees, was previously shown to increase the lifespan of Caenorhabditis elegans. The objective of this study is to elucidate signaling pathways that are involved in the lifespan extension by 10-HDA. 10-HDA further extended the lifespan of the daf-2 mutants, which exhibit long lifespan through reducing insulin-like signaling (ILS, indicating that 10-HDA extended lifespan independently of ILS. On the other hand, 10-HDA did not extend the lifespan of the eat-2 mutants, which show long lifespan through dietary restriction caused by a food-intake defect. This finding indicates that 10-HDA extends lifespan through dietary restriction signaling. We further found that 10-HDA did not extend the lifespan of the long-lived mutants in daf-15, which encodes Raptor, a target of rapamycin (TOR components, indicating that 10-HDA shared some longevity control mechanisms with TOR signaling. Additionally, 10-HDA was found to confer tolerance against thermal and oxidative stress. 10-HDA increases longevity not through ILS but through dietary restriction and TOR signaling in C. elegans.

  5. 10-Hydroxy-2-decenoic Acid, the Major Lipid Component of Royal Jelly, Extends the Lifespan of Caenorhabditis elegans through Dietary Restriction and Target of Rapamycin Signaling.

    Science.gov (United States)

    Honda, Yoko; Araki, Yoko; Hata, Taketoshi; Ichihara, Kenji; Ito, Masafumi; Tanaka, Masashi; Honda, Shuji

    2015-01-01

    Royal jelly (RJ) produced by honeybees has been reported to possess diverse health-beneficial properties and has been implicated to have a function in longevity across diverse species as well as honeybees. 10-Hydroxy-2-decenoic acid (10-HDA), the major lipid component of RJ produced by honeybees, was previously shown to increase the lifespan of Caenorhabditis elegans. The objective of this study is to elucidate signaling pathways that are involved in the lifespan extension by 10-HDA. 10-HDA further extended the lifespan of the daf-2 mutants, which exhibit long lifespan through reducing insulin-like signaling (ILS), indicating that 10-HDA extended lifespan independently of ILS. On the other hand, 10-HDA did not extend the lifespan of the eat-2 mutants, which show long lifespan through dietary restriction caused by a food-intake defect. This finding indicates that 10-HDA extends lifespan through dietary restriction signaling. We further found that 10-HDA did not extend the lifespan of the long-lived mutants in daf-15, which encodes Raptor, a target of rapamycin (TOR) components, indicating that 10-HDA shared some longevity control mechanisms with TOR signaling. Additionally, 10-HDA was found to confer tolerance against thermal and oxidative stress. 10-HDA increases longevity not through ILS but through dietary restriction and TOR signaling in C. elegans.

  6. The Drosophila Duox maturation factor is a key component of a positive feedback loop that sustains regeneration signaling.

    Science.gov (United States)

    Khan, Sumbul Jawed; Abidi, Syeda Nayab Fatima; Skinner, Andrea; Tian, Yuan; Smith-Bolton, Rachel K

    2017-07-01

    Regenerating tissue must initiate the signaling that drives regenerative growth, and sustain that signaling long enough for regeneration to complete. How these key signals are sustained is unclear. To gain a comprehensive view of the changes in gene expression that occur during regeneration, we performed whole-genome mRNAseq of actively regenerating tissue from damaged Drosophila wing imaginal discs. We used genetic tools to ablate the wing primordium to induce regeneration, and carried out transcriptional profiling of the regeneration blastema by fluorescently labeling and sorting the blastema cells, thus identifying differentially expressed genes. Importantly, by using genetic mutants of several of these differentially expressed genes we have confirmed that they have roles in regeneration. Using this approach, we show that high expression of the gene moladietz (mol), which encodes the Duox-maturation factor NIP, is required during regeneration to produce reactive oxygen species (ROS), which in turn sustain JNK signaling during regeneration. We also show that JNK signaling upregulates mol expression, thereby activating a positive feedback signal that ensures the prolonged JNK activation required for regenerative growth. Thus, by whole-genome transcriptional profiling of regenerating tissue we have identified a positive feedback loop that regulates the extent of regenerative growth.

  7. Comparative Analysis of the Clinical Significance of Oscillatory Components in the Rhythmic Structure of Pulse Signal in the Diagnostics of Psychosomatic Disorders in School Age Children.

    Science.gov (United States)

    Desova, A A; Dorofeyuk, A A; Anokhin, A M

    2017-01-01

    We performed a comparative analysis of the types of spectral density typical of various parameters of pulse signal. The experimental material was obtained during the examination of school age children with various psychosomatic disorders. We also performed a typological analysis of the spectral density functions corresponding to the time series of different parameters of a single oscillation of pulse signals; the results of their comparative analysis are presented. We determined the most significant spectral components for two disordersin children: arterial hypertension and mitral valve prolapse.

  8. Task completion report for investigating why output signal-variable values differ from their output component-parameter values in test problem MST2

    International Nuclear Information System (INIS)

    Steinke, R.G.

    1997-01-01

    Signal-variable values and their component-parameter values differ in an end-of-timestep edit to the TRCOUT and TRCGRF files because signal variables have beginning-of-timestep values, and component parameters have end-of-timestep values. Oscillatory divergence in the MST2 standard test problem after 9000 s occurs because of TRAC-P's numerical evaluation at a 1000 material Courant number. The magnitude of that divergence has diminished by a factor of 3.5 from Version 5.3.01 to 5.4.15 and by a factor of 25 from Version 5.4.15 to 5.4.28. That divergence can be eliminated by evaluating MST2 with a maximum material Courant number of 500

  9. Multichannel Signals Reconstruction Based on Tunable Q-Factor Wavelet Transform-Morphological Component Analysis and Sparse Bayesian Iteration for Rotating Machines

    Directory of Open Access Journals (Sweden)

    Qing Li

    2018-04-01

    Full Text Available High-speed remote transmission and large-capacity data storage are difficult issues in signals acquisition of rotating machines condition monitoring. To address these concerns, a novel multichannel signals reconstruction approach based on tunable Q-factor wavelet transform-morphological component analysis (TQWT-MCA and sparse Bayesian iteration algorithm combined with step-impulse dictionary is proposed under the frame of compressed sensing (CS. To begin with, to prevent the periodical impulses loss and effectively separate periodical impulses from the external noise and additive interference components, the TQWT-MCA method is introduced to divide the raw vibration signal into low-resonance component (LRC, i.e., periodical impulses and high-resonance component (HRC, thus, the periodical impulses are preserved effectively. Then, according to the amplitude range of generated LRC, the step-impulse dictionary atom is designed to match the physical structure of periodical impulses. Furthermore, the periodical impulses and HRC are reconstructed by the sparse Bayesian iteration combined with step-impulse dictionary, respectively, finally, the final reconstructed raw signals are obtained by adding the LRC and HRC, meanwhile, the fidelity of the final reconstructed signals is tested by the envelop spectrum and error analysis, respectively. In this work, the proposed algorithm is applied to simulated signal and engineering multichannel signals of a gearbox with multiple faults. Experimental results demonstrate that the proposed approach significantly improves the reconstructive accuracy compared with the state-of-the-art methods such as non-convex Lq (q = 0.5 regularization, spatiotemporal sparse Bayesian learning (SSBL and L1-norm, etc. Additionally, the processing time, i.e., speed of storage and transmission has increased dramatically, more importantly, the fault characteristics of the gearbox with multiple faults are detected and saved, i.e., the

  10. Cumulative and Synergistic Effects of Physical, Biological, and Acoustic Signals on Marine Mammal Habitat Use Physical Oceanography Component: Soundscapes Under Sea Ice: Can We Listen for Open Water?

    Science.gov (United States)

    2013-09-30

    Physical, Biological, and Acoustic Signals on Marine Mammal Habitat Use Physical Oceanography Component: Soundscapes Under Sea Ice: Can we listen for... Soundscapes Under Sea Ice: Can we listen for open water? 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d...the source. These different sounds can be described as “ soundscapes ”, and graphically represented by comparing two or more features of the sound

  11. 10-Hydroxy-2-decenoic Acid, the Major Lipid Component of Royal Jelly, Extends the Lifespan of Caenorhabditis elegans through Dietary Restriction and Target of Rapamycin Signaling

    OpenAIRE

    Honda, Yoko; Araki, Yoko; Hata, Taketoshi; Ichihara, Kenji; Ito, Masafumi; Tanaka, Masashi; Honda, Shuji

    2015-01-01

    Royal jelly (RJ) produced by honeybees has been reported to possess diverse health-beneficial properties and has been implicated to have a function in longevity across diverse species as well as honeybees. 10-Hydroxy-2-decenoic acid (10-HDA), the major lipid component of RJ produced by honeybees, was previously shown to increase the lifespan of Caenorhabditis elegans. The objective of this study is to elucidate signaling pathways that are involved in the lifespan extension by 10-HDA. 10-HDA f...

  12. 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

  13. Loss of nitrate reductases NIA1 and NIA2 impairs stomatal closure by altering genes of core ABA signaling components in Arabidopsis.

    Science.gov (United States)

    Zhao, Chenchen; Cai, Shengguan; Wang, Yizhou; Chen, Zhong-Hua

    2016-06-02

    Nitrate reductases NIA1 and NIA2 determine NO production in plants and are critical to abscisic acid (ABA)-induced stomatal closure. However, the role for NIA1 and NIA2 in ABA signaling has not been paid much attention in nitrate reductase loss-of-function mutant nia1nia2. Recently, we have demonstrated that ABA-inhibited K(+)in current and ABA-enhanced slow anion current were absent in nia1nia2. Exogenous NO restored regulation of these channels for stomatal closure in nia1nia2. In this study, we found that mutating NIA1 and NIA2 impaired nearly all the key components of guard cell ABA signaling pathway in Arabidopsis. We also propose a simplified model for ABA signaling in the nia1nia2 mutant.

  14. Modulation of Ras signaling alters the toxicity of hydroquinone, a benzene metabolite and component of cigarette smoke

    International Nuclear Information System (INIS)

    North, Matthew; Shuga, Joe; Fromowitz, Michele; Loguinov, Alexandre; Shannon, Kevin; Zhang, Luoping; Smith, Martyn T; Vulpe, Chris D

    2014-01-01

    Benzene is an established human leukemogen, with a ubiquitous environmental presence leading to significant population exposure. In a genome-wide functional screen in the yeast Saccharomyces cerevisiae, inactivation of IRA2, a yeast ortholog of the human tumor suppressor gene NF1 (Neurofibromin), enhanced sensitivity to hydroquinone, an important benzene metabolite. Increased Ras signaling is implicated as a causal factor in the increased pre-disposition to leukemia of individuals with mutations in NF1. Growth inhibition of yeast by hydroquinone was assessed in mutant strains exhibiting varying levels of Ras activity. Subsequently, effects of hydroquinone on both genotoxicity (measured by micronucleus formation) and proliferation of WT and Nf1 null murine hematopoietic precursors were assessed. Here we show that the Ras status of both yeast and mammalian cells modulates hydroquinone toxicity, indicating potential synergy between Ras signaling and benzene toxicity. Specifically, enhanced Ras signaling increases both hydroquinone-mediated growth inhibition in yeast and genotoxicity in mammalian hematopoetic precursors as measured by an in vitro erythroid micronucleus assay. Hydroquinone also increases proliferation of CFU-GM progenitor cells in mice with Nf1 null bone marrow relative to WT, the same cell type associated with benzene-associated leukemia. Together our findings show that hydroquinone toxicity is modulated by Ras signaling. Individuals with abnormal Ras signaling could be more vulnerable to developing myeloid diseases after exposure to benzene. We note that hydroquinone is used cosmetically as a skin-bleaching agent, including by individuals with cafe-au-lait spots (which may be present in individuals with neurofibromatosis who have a mutation in NF1), which could be unadvisable given our findings

  15. Detection of gear cracks in a complex gearbox of wind turbines using supervised bounded component analysis of vibration signals collected from multi-channel sensors

    Science.gov (United States)

    Li, Zhixiong; Yan, Xinping; Wang, Xuping; Peng, Zhongxiao

    2016-06-01

    In the complex gear transmission systems, in wind turbines a crack is one of the most common failure modes and can be fatal to the wind turbine power systems. A single sensor may suffer with issues relating to its installation position and direction, resulting in the collection of weak dynamic responses of the cracked gear. A multi-channel sensor system is hence applied in the signal acquisition and the blind source separation (BSS) technologies are employed to optimally process the information collected from multiple sensors. However, literature review finds that most of the BSS based fault detectors did not address the dependence/correlation between different moving components in the gear systems; particularly, the popular used independent component analysis (ICA) assumes mutual independence of different vibration sources. The fault detection performance may be significantly influenced by the dependence/correlation between vibration sources. In order to address this issue, this paper presents a new method based on the supervised order tracking bounded component analysis (SOTBCA) for gear crack detection in wind turbines. The bounded component analysis (BCA) is a state of art technology for dependent source separation and is applied limitedly to communication signals. To make it applicable for vibration analysis, in this work, the order tracking has been appropriately incorporated into the BCA framework to eliminate the noise and disturbance signal components. Then an autoregressive (AR) model built with prior knowledge about the crack fault is employed to supervise the reconstruction of the crack vibration source signature. The SOTBCA only outputs one source signal that has the closest distance with the AR model. Owing to the dependence tolerance ability of the BCA framework, interfering vibration sources that are dependent/correlated with the crack vibration source could be recognized by the SOTBCA, and hence, only useful fault information could be preserved in

  16. ON THE SOLAR ORIGIN OF THE SIGNAL AT 220.7 μHz: A POSSIBLE COMPONENT OF A g-MODE?

    International Nuclear Information System (INIS)

    Jimenez, A.; Garcia, R. A.

    2009-01-01

    Gravity modes in the Sun have been the object of a long and difficult search in recent decades. Thanks to the data accumulated with the last generation of instruments (BiSON, GONG, and three helioseismic instruments aboard the Solar and Heliospheric Observatory (SOHO)), scientists have been able to find signatures of their presence. However, the individual detection of such modes remains evasive. In this article, we study the signal at 220.7 μHz which is a peak that is present in most of the helioseismic data of the last 10 years. This signal has already been identified as being a component of a g-mode candidate detected in the GOLF Doppler velocity signal. The nature of this peak is studied in particular using the VIRGO/SPM instrument aboard SOHO. First we analyze all the available instrumental data of VIRGO and SOHO (housekeeping) to reject any possible instrumental origin. No relation was found, implying that the signal has a solar origin. Using Monte Carlo simulations, we find, with more than 99% confidence level, that the signal found in VIRGO/SPM is very unlikely to be due to pure noise.

  17. Low levels of strigolactones in roots as a component of the systemic signal of drought stress in tomato

    Czech Academy of Sciences Publication Activity Database

    Visentin, I.; Vitali, M.; Ferrero, M.; Zhang, Y.; Ruyter-Spira, C.; Novák, Ondřej; Strnad, Miroslav; Lovisolo, C.; Schubert, A.; Cardinale, F.

    2016-01-01

    Roč. 212, č. 4 (2016), s. 954-963 ISSN 0028-646X R&D Projects: GA MŠk(CZ) LO1204 Institutional support: RVO:61389030 Keywords : abscisic-acid * plant-responses * lotus-japonicus * biosynthesis * arabidopsis * pea * hormone * growth * xylem * soil * abscisic acid (ABA) * drought * strigolactones (SL) * systemic signalling * tomato (Solanum lycopersicum) Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.330, year: 2016

  18. A Conserved Two-Component Signal Transduction System Controls the Response to Phosphate Starvation in Bifidobacterium breve UCC2003.

    NARCIS (Netherlands)

    Alvarez-Martin, P.; Fernandez, M.; O'Connell-Motherway, M.; O'Connell, K.J.; Sauvageot, N.; Fitzgerald, G.F.; Macsharry, J.; Zomer, A.L.; Sinderen, D. van

    2012-01-01

    This work reports on the identification and molecular characterization of the two-component regulatory system (2CRS) PhoRP, which controls the response to inorganic phosphate (P(i)) starvation in Bifidobacterium breve UCC2003. The response regulator PhoP was shown to bind to the promoter region of

  19. Independent component analysis using prior information for signal detection in a functional imaging system of the retina

    NARCIS (Netherlands)

    Barriga, E. Simon; Pattichis, Marios; Ts’o, Dan; Abramoff, Michael; Kardon, Randy; Kwon, Young; Soliz, Peter

    2011-01-01

    Independent component analysis (ICA) is a statistical technique that estimates a set of sources mixed by an unknown mixing matrix using only a set of observations. For this purpose, the only assumption is that the sources are statistically independent. In many applications, some information about

  20. Novel processing of Barkhausen noise signal for assessment of residual stress in surface ground components exhibiting poor magnetic response

    International Nuclear Information System (INIS)

    Vashista, M.; Paul, S.

    2011-01-01

    The Barkhausen Noise Analysis (BNA) technique has been utilised to assess surface integrity of steels. But the BNA technique is not very successful in evaluating surface integrity of ground steels that exhibit poor micro-magnetic response. A new approach has been proposed for the processing of BN signal and two newly proposed parameters, namely 'count' and 'event', have been shown to correlate linearly with the residual stress upon grinding, with judicious choice of user defined 'threshold', even when the micro-magnetic response of the work material is poor. In the present study, residual stress induced upon conventional plunge surface grinding of hardened bearing steel has been investigated along with unhardened bearing steel for benchmarking. Moreover, similar correlation has been established, when primarily compressive stress is induced upon high speed grinding using cBN wheel with moderately deep cut suppressing the micro-magnetic response from the ground medium carbon steel as the work material. - Highlights: → The problem of work materials exhibiting poor BN response and poor Barkhausen Noise response is identified. → A novel signal processing strategy is introduced to address the issue of poor micro-magnetic response of some ferromagnetic material. → Potential of newly introduced BN parameters has been studied. → These two BN parameters exhibited linear correlation with residual stress for work material with poor micro-magnetic response.

  1. Developmental programming: effect of prenatal steroid excess on intraovarian components of insulin signaling pathway and related proteins in sheep.

    Science.gov (United States)

    Ortega, Hugo H; Rey, Florencia; Velazquez, Melisa M L; Padmanabhan, Vasantha

    2010-06-01

    Prenatal testosterone (T) excess increases ovarian follicular recruitment, follicular persistence, insulin resistance, and compensatory hyperinsulinemia. Considering the importance of insulin in ovarian physiology, in this study, using prenatal T- and dihydrotestosterone (DHT, a nonaromatizable androgen)-treated female sheep, we tested the hypothesis that prenatal androgen excess alters the intraovarian insulin signaling cascade and metabolic mediators that have an impact on insulin signaling. Changes in ovarian insulin receptor (INSRB), insulin receptor substrate 1 (IRS1), mammalian target of rapamycin (MTOR), phosphatidylinositol 3-kinase (PIK3), peroxisome proliferator-activated receptor-gamma (PPARG), and adiponectin proteins were determined at fetal (Days 90 and 140), postpubertal (10 mo), and adult (21 mo) ages by immunohistochemistry. Results indicated that these proteins were expressed in granulosa, theca, and stromal compartments, with INSRB, IRS1, PPARG, and adiponectin increasing in parallel with advanced follicular differentiation. Importantly, prenatal T excess induced age-specific changes in PPARG and adiponectin expression, with increased PPARG expression evident during fetal life and decreased antral follicular adiponectin expression during adult life. Comparison of developmental changes in prenatal T and DHT-treated females found that the effects on PPARG were programmed by androgenic actions of T, whereas the effects on adiponectin were likely by its estrogenic action. These results suggest a role for PPARG in the programming of ovarian disruptions by prenatal T excess, including a decrease in antral follicular adiponectin expression and a contributory role for adiponectin in follicular persistence and ovulatory failure.

  2. 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

  3. Brain insulin signaling: a key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes

    Science.gov (United States)

    McNay, Ewan C.; Recknagel, Andrew K.

    2011-01-01

    Understanding of the role of insulin in the brain has gradually expanded, from initial conceptions of the brain as insulin-insensitive through identification of a role in regulation of feeding to recent demonstration of insulin as a key component of hippocampal memory processes. Conversely, systemic insulin resistance such as that seen in type 2 diabetes is associated with a range of cogntive and neural deficits. Here we review the evidence for insulin as a cognitive and neural modulator, including potential effector mechanisms, and examine the impact that type 2 diabetes has on these mechanisms in order to identify likely bases for the cognitive impairments seen in type 2 diabetic patients. PMID:21907815

  4. Seven novel probe systems for real-time PCR provide absolute single-base discrimination, higher signaling, and generic components.

    Science.gov (United States)

    Murray, James L; Hu, Peixu; Shafer, David A

    2014-11-01

    We have developed novel probe systems for real-time PCR that provide higher specificity, greater sensitivity, and lower cost relative to dual-labeled probes. The seven DNA Detection Switch (DDS)-probe systems reported here employ two interacting polynucleotide components: a fluorescently labeled probe and a quencher antiprobe. High-fidelity detection is achieved with three DDS designs: two internal probes (internal DDS and Flip probes) and a primer probe (ZIPR probe), wherein each probe is combined with a carefully engineered, slightly mismatched, error-checking antiprobe. The antiprobe blocks off-target detection over a wide range of temperatures and facilitates multiplexing. Other designs (Universal probe, Half-Universal probe, and MacMan probe) use generic components that enable low-cost detection. Finally, single-molecule G-Force probes employ guanine-mediated fluorescent quenching by forming a hairpin between adjacent C-rich and G-rich sequences. Examples provided show how these probe technologies discriminate drug-resistant Mycobacterium tuberculosis mutants, Escherichia coli O157:H7, oncogenic EGFR deletion mutations, hepatitis B virus, influenza A/B strains, and single-nucleotide polymorphisms in the human VKORC1 gene. Copyright © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

  5. 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.

  6. 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.)

  7. Measuring, processing and evaluation of dynamic signal components of diagnostic systems and instrumentation and control systems at the Temelin NPP

    International Nuclear Information System (INIS)

    Stulik, P.; Sipek, B.

    2005-10-01

    The quality of the RVMS measuring chains was examined during an outage of the Temelin-1 reactor unit. This consisted of a defined measurement of the measuring chain output of the ionization chambers of the power zone and thermocouples by the RVMS system, processing of the time series obtained, and evaluation of the spectral parameters within the given frequency band. The results of evaluation were classified for the transfer function values along with their differences and for the phase shift values. The dynamic components of the resistance thermometers on the primary loops of the Temelin-1 and 2 reactor units were measured and the measurements were evaluated. The results in the frequency region, in the form of spectral characteristics for both the hot and cold legs, indicate that the non-invasive determination of the dynamics of the resistance thermometer measuring chains can serve as a promising basic tool for the diagnosis and life monitoring of this important in-service measurement

  8. Statistical and time domain signal analysis of the thermal behaviour of wind turbine drive train components under dynamic operation conditions

    International Nuclear Information System (INIS)

    Nienhaus, K; Baltes, R; Bernet, C; Hilbert, M

    2012-01-01

    Gearboxes and generators are fundamental components of all electrical machines and the backbone of all electricity generation. Since the wind energy represents one of the key energy sources of the future, the number of wind turbines installed worldwide is rapidly increasing. Unlike in the past wind turbines are more often positioned in arctic as well as in desert like regions, and thereby exposed to harsh environmental conditions. Especially the temperature in those regions is a key factor that defines the design and choice of components and materials of the drive train. To optimize the design and health monitoring under varying temperatures it is important to understand the thermal behaviour dependent on environmental and machine parameters. This paper investigates the behaviour of the stator temperature of the double fed induction generator of a wind turbine. Therefore, different scenarios such as start of the turbine after a long period of no load, stop of the turbine after a long period of full load and others are isolated and analysed. For each scenario the dependences of the temperature on multiple wind turbine parameters such as power, speed and torque are studied. With the help of the regression analysis for multiple variables, it is pointed out which parameters have high impact on the thermal behaviour. Furthermore, an analysis was done to study the dependences in the time domain. The research conducted is based on 10 months of data of a 2 MW wind turbine using an adapted data acquisition system for high sampled data. The results appear promising, and lead to a better understanding of the thermal behaviour of a wind turbine drive train. Furthermore, the results represent the base of future research of drive trains under harsh environmental conditions, and it can be used to improve the fault diagnosis and design of electrical machines.

  9. Protein arginine methyltransferase 5 is an essential component of the hypoxia-inducible factor 1 signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Ji-Hong; Choi, Yong-Joon; Cho, Chung-Hyun [Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799 (Korea, Republic of); Park, Jong-Wan, E-mail: parkjw@snu.ac.kr [Department of Pharmacology, Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799 (Korea, Republic of)

    2012-02-10

    Highlights: Black-Right-Pointing-Pointer HIF-1{alpha} is expressed PRMT5-dependently in hypoxic cancer cells. Black-Right-Pointing-Pointer The HIF-1 regulation of hypoxia-induced genes is attenuated in PRMT5-knocked-down cells. Black-Right-Pointing-Pointer The de novo synthesis of HIF-1{alpha} depends on PRMT5. Black-Right-Pointing-Pointer PRMT5 is involved in the HIF-1{alpha} translation initiated by 5 Prime UTR of HIF-1{alpha} mRNA. -- Abstract: Protein arginine methyltransferase 5 (PRMT5) is an enzyme that transfers one or two methyl groups to the arginine residues of histones or non-histone proteins, and that plays critical roles in cellular processes as diverse as receptor signaling and gene expression. Furthermore, PRMT5 is highly expressed in tumors, where it may be associated with tumor growth. Although much research has been conducted on PRMT5, little is known regarding its role in adaption to hypoxia. As hypoxia-inducible factor 1 (HIF-1) is a key player in hypoxic response, we examined the possible involvement of PRMT5 in the HIF-1 signaling pathway. Of the siRNAs targeting PRMT1-8, only PRMT5 siRNA attenuated the hypoxic induction of HIF-1{alpha} in A549 cells, and this result was reproducible in all three cancer cell lines examined. PRMT5 knock-down also repressed the promoter activities and the transcript levels of HIF-1-governed genes. Mechanistically, de novo synthesis of HIF-1{alpha} protein was reduced in PRMT5-knocked-down A549 cells, and this was rescued by PRMT5 restoration. In contrast, HIF-1{alpha} transcription, RNA processing, and protein stability were unaffected by PRMT5 knock-down. Furthermore, PRMT5 was found to be essential for the HIF-1{alpha} translation initiated by the 5 Prime UTR of HIF-1{alpha} mRNA. Given our results and previous reports, we believe that PRMT5 probably promotes tumor growth by stimulating cell proliferation and by participating in the construction of a tumor-favorable microenvironment via HIF-1 activation.

  10. Protein arginine methyltransferase 5 is an essential component of the hypoxia-inducible factor 1 signaling pathway

    International Nuclear Information System (INIS)

    Lim, Ji-Hong; Choi, Yong-Joon; Cho, Chung-Hyun; Park, Jong-Wan

    2012-01-01

    Highlights: ► HIF-1α is expressed PRMT5-dependently in hypoxic cancer cells. ► The HIF-1 regulation of hypoxia-induced genes is attenuated in PRMT5-knocked-down cells. ► The de novo synthesis of HIF-1α depends on PRMT5. ► PRMT5 is involved in the HIF-1α translation initiated by 5′ UTR of HIF-1α mRNA. -- Abstract: Protein arginine methyltransferase 5 (PRMT5) is an enzyme that transfers one or two methyl groups to the arginine residues of histones or non-histone proteins, and that plays critical roles in cellular processes as diverse as receptor signaling and gene expression. Furthermore, PRMT5 is highly expressed in tumors, where it may be associated with tumor growth. Although much research has been conducted on PRMT5, little is known regarding its role in adaption to hypoxia. As hypoxia-inducible factor 1 (HIF-1) is a key player in hypoxic response, we examined the possible involvement of PRMT5 in the HIF-1 signaling pathway. Of the siRNAs targeting PRMT1–8, only PRMT5 siRNA attenuated the hypoxic induction of HIF-1α in A549 cells, and this result was reproducible in all three cancer cell lines examined. PRMT5 knock-down also repressed the promoter activities and the transcript levels of HIF-1-governed genes. Mechanistically, de novo synthesis of HIF-1α protein was reduced in PRMT5-knocked-down A549 cells, and this was rescued by PRMT5 restoration. In contrast, HIF-1α transcription, RNA processing, and protein stability were unaffected by PRMT5 knock-down. Furthermore, PRMT5 was found to be essential for the HIF-1α translation initiated by the 5′ UTR of HIF-1α mRNA. Given our results and previous reports, we believe that PRMT5 probably promotes tumor growth by stimulating cell proliferation and by participating in the construction of a tumor-favorable microenvironment via HIF-1 activation.

  11. SPL8 Acts Together with the Brassinosteroid-Signaling Component BIM1 in Controlling Arabidopsis thaliana Male Fertility

    Directory of Open Access Journals (Sweden)

    Shuping Xing

    2013-06-01

    Full Text Available The non-miR156 targeted SBP-box gene SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 8 (SPL8, plays an important role in Arabidopsis anther development, where its loss-of-function results in a semi-sterile phenotype. Fully male-sterile plants are obtained when a spl8 loss-of-function mutation is introduced into a 35S:MIR156 genetic background, thereby revealing functional redundancy between SPL8 and miR156-targeted SBP-box genes. Here, we show that BIM1, a gene encoding a bHLH protein involved in brassinosteroid signaling and embryonic patterning, functions redundantly with SPL8 in its requirement for male fertility. Although bim1 single mutants displayed a mild fertility problem due to shortened filaments in some flowers, mutation of BIM1 significantly enhanced the semi-sterile phenotype of the spl8 mutant. Expression of both SPL8 and BIM1 was detected in overlapping expression domains during early anther developmental stages. Our data suggest that in regulating anther development, SPL8 and BIM1 function cooperatively in a common complex or in synergistic pathways. Phylogenetic analysis supports the idea of an evolutionary conserved function for both genes in angiosperm anther development.

  12. 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.

  13. Ras signaling in aging and metabolic regulation.

    Science.gov (United States)

    Slack, Cathy

    2017-12-07

    Aberrant signal transduction downstream of the Ras GTPase has a well-established role in tumorigenesis. Mutations that result in hyperactivation of Ras are responsible for a third of all human cancers. Hence, small molecule inhibitors of the Ras signal transduction cascade have been under intense focus as potential cancer treatments. In both invertebrate and mammalian models, emerging evidence has also implicated components of the Ras signaling pathway in aging and metabolic regulation. Here, I review the current evidence for Ras signaling in these newly discovered roles highlighting the interactions between the Ras pathway and other longevity assurance mechanisms. Defining the role of Ras signaling in maintaining age-related health may have important implications for the development of interventions that could not only increase lifespan but also delay the onset and/or progression of age-related functional decline.

  14. A conserved two-component signal transduction system controls the response to phosphate starvation in Bifidobacterium breve UCC2003.

    Science.gov (United States)

    Alvarez-Martin, Pablo; Fernández, Matilde; O'Connell-Motherway, Mary; O'Connell, Kerry Joan; Sauvageot, Nicolas; Fitzgerald, Gerald F; MacSharry, John; Zomer, Aldert; van Sinderen, Douwe

    2012-08-01

    This work reports on the identification and molecular characterization of the two-component regulatory system (2CRS) PhoRP, which controls the response to inorganic phosphate (P(i)) starvation in Bifidobacterium breve UCC2003. The response regulator PhoP was shown to bind to the promoter region of pstSCAB, specifying a predicted P(i) transporter system, as well as that of phoU, which encodes a putative P(i)-responsive regulatory protein. This interaction is assumed to cause transcriptional modulation under conditions of P(i) limitation. Our data suggest that the phoRP genes are subject to positive autoregulation and, together with pstSCAB and presumably phoU, represent the complete regulon controlled by the phoRP-encoded 2CRS in B. breve UCC2003. Determination of the minimal PhoP binding region combined with bioinformatic analysis revealed the probable recognition sequence of PhoP, designated here as the PHO box, which together with phoRP is conserved among many high-GC-content Gram-positive bacteria. The importance of the phoRP 2CRS in the response of B. breve to P(i) starvation conditions was confirmed by analysis of a B. breve phoP insertion mutant which exhibited decreased growth under phosphate-limiting conditions compared to its parent strain UCC2003.

  15. Evidence for the Induction of Key Components of the NOTCH Signaling Pathway via Deltamethrin and Azamethiphos Treatment in the Sea Louse Caligus rogercresseyi

    Directory of Open Access Journals (Sweden)

    Sebastian Boltaña

    2016-05-01

    Full Text Available The extensive use of organophosphates and pyrethroids in the aquaculture industry has negatively impacted parasite sensitivity to the delousing effects of these antiparasitics, especially among sea lice species. The NOTCH signaling pathway is a positive regulator of ABC transporter subfamily C expression and plays a key role in the generation and modulation of pesticide resistance. However, little is known about the molecular mechanisms behind pesticide resistance, partly due to the lack of genomic and molecular information on the processes involved in the resistance mechanism of sea lice. Next-generation sequencing technologies provide an opportunity for rapid and cost-effective generation of genome-scale data. The present study, through RNA-seq analysis, determined that the sea louse Caligus rogercresseyi (C. rogercresseyi specifically responds to the delousing drugs azamethiphos and deltamethrin at the transcriptomic level by differentially activating mRNA of the NOTCH signaling pathway and of ABC genes. These results suggest that frequent antiparasitic application may increase the activity of inhibitory mRNA components, thereby promoting inhibitory NOTCH output and conditions for increased resistance to delousing drugs. Moreover, data analysis underscored that key functions of NOTCH/ABC components were regulated during distinct phases of the drug response, thus indicating resistance modifications in C. rogercresseyi resulting from the frequent use of organophosphates and pyrethroids.

  16. Evaluation of expression of the Wnt signaling components in canine mammary tumors via RT2 Profiler PCR Array and immunochemistry assays.

    Science.gov (United States)

    Yu, Fang; Rasotto, Roberta; Zhang, Hong; Pei, Shimin; Zhou, Bin; Yang, Xu; Jin, Yipeng; Zhang, Di; Lin, Degui

    2017-09-30

    The Wnt signaling pathway and its key component β-catenin have critical roles in the development of diseases such as tumors in mammals. However, little has been reported about involvement of the Wnt/β-catenin signaling pathway in canine mammary tumors (CMTs). The present study detected expression of 30 Wnt signaling pathway-related genes in CMTs; the results are potentially useful for molecular-based diagnosis of CMTs and the development of new targeted therapies. Significant upregulations of dickkopf-1 protein, secreted frizzled-related sequence protein 1 (SFRP1), frizzled 3, β-catenin, and lymphoid enhancer-binding factor 1 (LEF1) were detected in highly malignant CMTs compared to levels in normal mammary gland tissues; moreover, highly significant upregulation of WNT5A was observed in low malignancy CMTs. Downregulation was only detected for SFRP4 in malignant CMT samples. The subcellular location of β-catenin and cyclin D1 in 100 CMT samples was investigated via immunohistochemical analysis, and significantly increased expressions of β-catenin in cytoplasm and cyclin D1 in nuclei were revealed. Western blotting analysis revealed that the expression of β-catenin and LEF1 increased in in the majority of CMT samples. Taken together, the results provide important evidence of the activation status of the Wnt pathway in CMTs and valuable clues to identifying biomarkers for molecular-based diagnosis of CMT.

  17. Non-linear multivariate and multiscale monitoring and signal denoising strategy using Kernel Principal Component Analysis combined with Ensemble Empirical Mode Decomposition method

    Science.gov (United States)

    Žvokelj, Matej; Zupan, Samo; Prebil, Ivan

    2011-10-01

    The article presents a novel non-linear multivariate and multiscale statistical process monitoring and signal denoising method which combines the strengths of the Kernel Principal Component Analysis (KPCA) non-linear multivariate monitoring approach with the benefits of Ensemble Empirical Mode Decomposition (EEMD) to handle multiscale system dynamics. The proposed method which enables us to cope with complex even severe non-linear systems with a wide dynamic range was named the EEMD-based multiscale KPCA (EEMD-MSKPCA). The method is quite general in nature and could be used in different areas for various tasks even without any really deep understanding of the nature of the system under consideration. Its efficiency was first demonstrated by an illustrative example, after which the applicability for the task of bearing fault detection, diagnosis and signal denosing was tested on simulated as well as actual vibration and acoustic emission (AE) signals measured on purpose-built large-size low-speed bearing test stand. The positive results obtained indicate that the proposed EEMD-MSKPCA method provides a promising tool for tackling non-linear multiscale data which present a convolved picture of many events occupying different regions in the time-frequency plane.

  18. The AutoAssociative Neural Network in signal analysis: II. Application to on-line monitoring of a simulated BWR component

    International Nuclear Information System (INIS)

    Marseguerra, M.; Zoia, A.

    2005-01-01

    In this paper, Robust AutoAssociative Neural Networks (RAANN) are applied to a series of signals produced by the Halden simulator of the 1200MWe BWR Forsmark-3 plant in Sweden. The applications concern: - correction of drifts and gross errors in sensors, for diagnostic and control purposes, - cluster analysis, to individuate a failed component and the intensity of the failure, - forecasting system signals, for safety or economic purposes, - reconstruction of unmeasured signals (virtual sensors). In the attainment of the above results, the geometric interpretation of the mapping performed by the network, propounded in Part I of this work, has provided a reasoned choice of the most critical free parameter, i.e., the number f of nodes of the bottleneck layer, thus allowing a deep understanding of the network functioning and also avoiding the traditional and troubling procedure of selection by trial-and-error. The theoretical basis of this analysis, discussed in details in the companion paper, is founded on the idea of dimension and in particular of fractal dimension, which has been used as a numerical estimator of f

  19. Induction of biogenic magnetization and redox control by a component of the target of rapamycin complex 1 signaling pathway.

    Directory of Open Access Journals (Sweden)

    Keiji Nishida

    Full Text Available Most organisms are simply diamagnetic, while magnetotactic bacteria and migratory animals are among organisms that exploit magnetism. Biogenic magnetization not only is of fundamental interest, but also has industrial potential. However, the key factor(s that enable biogenic magnetization in coordination with other cellular functions and metabolism remain unknown. To address the requirements for induction and the application of synthetic bio-magnetism, we explored the creation of magnetism in a simple model organism. Cell magnetization was first observed by attraction towards a magnet when normally diamagnetic yeast Saccharomyces cerevisiae were grown with ferric citrate. The magnetization was further enhanced by genetic modification of iron homeostasis and introduction of ferritin. The acquired magnetizable properties enabled the cells to be attracted to a magnet, and be trapped by a magnetic column. Superconducting quantum interference device (SQUID magnetometry confirmed and quantitatively characterized the acquired paramagnetism. Electron microscopy and energy-dispersive X-ray spectroscopy showed electron-dense iron-containing aggregates within the magnetized cells. Magnetization-based screening of gene knockouts identified Tco89p, a component of TORC1 (Target of rapamycin complex 1, as important for magnetization; loss of TCO89 and treatment with rapamycin reduced magnetization in a TCO89-dependent manner. The TCO89 expression level positively correlated with magnetization, enabling inducible magnetization. Several carbon metabolism genes were also shown to affect magnetization. Redox mediators indicated that TCO89 alters the intracellular redox to an oxidized state in a dose-dependent manner. Taken together, we demonstrated that synthetic induction of magnetization is possible and that the key factors are local redox control through carbon metabolism and iron supply.

  20. Progesterone signaling mediated through progesterone receptor membrane component-1 in ovarian cells with special emphasis on ovarian cancer.

    Science.gov (United States)

    Peluso, John J

    2011-08-01

    Various ovarian cell types including granulosa cells and ovarian surface epithelial cells express the progesterone (P4) binding protein, progesterone receptor membrane component-1 (PGRMC1). PGRMC1 is also expressed in ovarian tumors. PGRMC1 plays an essential role in promoting the survival of both normal and cancerous ovarian cell in vitro. Given the clinical significance of factors that regulate the viability of ovarian cancer, this review will focus on the role of PGRMC1 in ovarian cancer, while drawing insights into the mechanism of PGRMC1's action from cell lines derived from healthy ovaries as well as ovarian tumors. Studies using PGRMC1siRNA demonstrated that P4's ability to inhibit ovarian cells from undergoing apoptosis in vitro is dependent on PGRMC1. To confirm the importance of PGRMC1, the ability of PGRMC1-deplete ovarian cancer cell lines to form tumors in intact nude mice was assessed. Compared to PGRMC1-expressing ovarian cancer cells, PGRMC1-deplete ovarian cancer cells formed tumors in fewer mice (80% compared to 100% for controls). Moreover, the number of tumors derived from PGRMC1-deplete ovarian cancer cells was 50% of that observed in controls. Finally, the tumors that formed from PGRMC1-deplete ovarian cancer cells were about a fourth the size of tumors derived from ovarian cancer cells with normal levels of PGRMC1. One reason for PGRMC1-deplete tumors being smaller is that they had a poorly developed microvasculature system. How PGRMC1 regulates cell viability and in turn tumor growth is not known but part of the mechanism likely involves the regulation of genes that promote cell survival and inhibit apoptosis. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. Surface mu heavy chain signals down-regulation of the V(D)J-recombinase machinery in the absence of surrogate light chain components.

    Science.gov (United States)

    Galler, Gunther R; Mundt, Cornelia; Parker, Mathew; Pelanda, Roberta; Mårtensson, Inga-Lill; Winkler, Thomas H

    2004-06-07

    Early B cell development is characterized by stepwise, ordered rearrangement of the immunoglobulin (Ig) heavy (HC) and light (LC) chain genes. Only one of the two alleles of these genes is used to produce a receptor, a phenomenon referred to as allelic exclusion. It has been suggested that pre-B cell receptor (pre-BCR) signals are responsible for down-regulation of the VDJH-recombinase machinery (Rag1, Rag2, and terminal deoxynucleotidyl transferase [TdT]), thereby preventing further rearrangement on the second HC allele. Using a mouse model, we show that expression of an inducible muHC transgene in Rag2-/- pro-B cells induces down-regulation of the following: (a) TdT protein, (b) a transgenic green fluorescent protein reporter reflecting endogenous Rag2 expression, and (c) Rag1 primary transcripts. Similar effects were also observed in the absence of surrogate LC (SLC) components, but not in the absence of the signaling subunit Ig-alpha. Furthermore, in wild-type mice and in mice lacking either lambda5, VpreB1/2, or the entire SLC, the TdT protein is down-regulated in muHC+LC- pre-B cells. Surprisingly, muHC without LC is expressed on the surface of pro-/pre-B cells from lambda5-/-, VpreB1-/-VpreB2-/-, and SLC-/- mice. Thus, SLC or LC is not required for muHC cell surface expression and signaling in these cells. Therefore, these findings offer an explanation for the occurrence of HC allelic exclusion in mice lacking SLC components.

  2. Magnitude And Distance Determination From The First Few Seconds Of One Three Components Seismological Station Signal Using Support Vector Machine Regression Methods

    Science.gov (United States)

    Ochoa Gutierrez, L. H.; Vargas Jimenez, C. A.; Niño Vasquez, L. F.

    2011-12-01

    The "Sabana de Bogota" (Bogota Savannah) is the most important social and economical center of Colombia. Almost the third of population is concentrated in this region and generates about the 40% of Colombia's Internal Brute Product (IBP). According to this, the zone presents an elevated vulnerability in case that a high destructive seismic event occurs. Historical evidences show that high magnitude events took place in the past with a huge damage caused to the city and indicate that is probable that such events can occur in the next years. This is the reason why we are working in an early warning generation system, using the first few seconds of a seismic signal registered by three components and wide band seismometers. Such system can be implemented using Computational Intelligence tools, designed and calibrated to the particular Geological, Structural and environmental conditions present in the region. The methods developed are expected to work on real time, thus suitable software and electronic tools need to be developed. We used Support Vector Machines Regression (SVMR) methods trained and tested with historic seismic events registered by "EL ROSAL" Station, located near Bogotá, calculating descriptors or attributes as the input of the model, from the first 6 seconds of signal. With this algorithm, we obtained less than 10% of mean absolute error and correlation coefficients greater than 85% in hypocentral distance and Magnitude estimation. With this results we consider that we can improve the method trying to have better accuracy with less signal time and that this can be a very useful model to be implemented directly in the seismological stations to generate a fast characterization of the event, broadcasting not only raw signal but pre-processed information that can be very useful for accurate Early Warning Generation.

  3. 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.

  4. The auditory-evoked N2 and P3 components in the stop-signal task: indices of inhibition, response-conflict or error-detection?

    Science.gov (United States)

    Dimoska, Aneta; Johnstone, Stuart J; Barry, Robert J

    2006-11-01

    The N2 and P3 components have been separately associated with response inhibition in the stop-signal task, and more recently, the N2 has been implicated in the detection of response-conflict. To isolate response inhibition activity from early sensory processing, the present study compared processing of the stop-signal with that of a task-irrelevant tone, which subjects were instructed to ignore. Stop-signals elicited a larger N2 on failed-stop trials and a larger P3 on successful-stop trials, relative to ignore-signal trials, likely reflecting activity related to failed and successful stopping, respectively. ERPs between fast and slow reaction-time (RT) groups were also examined as it was hypothesised that greater inhibitory activation to stop faster responses would manifest in the component reflecting this process. Successful-stop P3 showed the anticipated effect (globally larger amplitude in the fast than slow RT group), supporting its association with the stopping of an ongoing response. In contrast, N2 was larger in the slow than fast RT group, and in contrast to the predictions of the response-conflict hypothesis, successful-stop N2 and the response-locked error-negativity (Ne) differed in scalp distribution. These findings indicate that the successful-stop N2 may be better explained as a deliberate form of response control or selection, which the slow RT group employed as a means of increasing the likelihood of a successful-stop. Finally, a comparison of stimulus and response-locked ERPs revealed that the failed-stop N2 and P3 appeared to reflect error-related activity, best observed in the response-locked Ne and error-positivity (Pe). Together these findings indicate that the successful-stop N2 and P3 reflect functionally distinct aspects of response control that are dependent upon performance strategies, while failed-stop N2 and P3 reflect error-related activity.

  5. Identification of potential genetic components involved in the deviant quorum-sensing signaling pathways of Burkholderia glumae through a functional genomics approach

    Directory of Open Access Journals (Sweden)

    Ruoxi eChen

    2015-03-01

    Full Text Available Burkholderia glumae is the chief causal agent for bacterial panicle blight of rice. The acyl-homoserine lactone (AHL-mediated quorum-sensing (QS system dependent on a pair of luxI and luxR homologs, tofI and tofR, is the primary cell-to-cell signaling mechanism determining the virulence of this bacterium. Production of toxoflavin, a major virulence factor of B. glumae, is known to be dependent on the tofI/tofR QS system. In our previous study, however, it was observed that B. glumae mutants defective in tofI or tofR produced toxoflavin if they grew on the surface of a solid medium, suggesting that alternative signaling pathways independent of tofI or tofR are activated in that growth condition for the production of toxoflavin. In this study, potential genetic components involved in the tofI- and tofR-independent signaling pathways for toxoflavin production were sought through screening random mini-Tn5 mutants of B. glumae to better understand the intercellular signaling pathways of this pathogen. Fifteen and three genes were initially identified as the potential genetic elements of the tofI- and tofR-independent pathways, respectively. Especially, the ORF (bglu_2g06320 divergently transcribed from toxJ, which encodes an orphan LuxR protein and controls toxoflavin biosynthesis, was newly identified in this study as a gene required for the tofR-independent toxoflavin production and named as toxK. Among those genes, flhD, dgcB, and wyzB were further studied to validate their functions in the tofI-independent toxoflavin production, and similar studies were also conducted with qsmR and toxK for their functions in the tofR-independent toxoflavin production. This work provides a foundation for future comprehensive studies of the intercellular signaling systems of B. glumae and other related pathogenic bacteria.

  6. Activation by insulin and amino acids of signaling components leading to translation initiation in skeletal muscle of neonatal pigs is developmentally regulated.

    Science.gov (United States)

    Suryawan, Agus; Orellana, Renan A; Nguyen, Hanh V; Jeyapalan, Asumthia S; Fleming, Jillian R; Davis, Teresa A

    2007-12-01

    Insulin and amino acids act independently to stimulate protein synthesis in skeletal muscle of neonatal pigs, and the responses decrease with development. The purpose of this study was to compare the separate effects of fed levels of INS and AA on the activation of signaling components leading to translation initiation and how these responses change with development. Overnight-fasted 6- (n = 4/group) and 26-day-old (n = 6/ group) pigs were studied during 1) euinsulinemic-euglycemiceuaminoacidemic conditions (controls), 2) euinsulinemic-euglycemichyperaminoacidemic clamps (AA), and 3) hyperinsulinemic-euglycemic-euaminoacidemic clamps (INS). INS, but not AA, increased the phosphorylation of protein kinase B (PKB) and tuberous sclerosis 2 (TSC2). Both INS and AA increased protein synthesis and the phosphorylation of mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase-1, and eukaryotic initiation factor (eIF)4E-binding protein 1 (4E-BP1), and these responses were higher in 6-day-old compared with 26-day-old pigs. Both INS and AA decreased the binding of 4E-BP1 to eIF4E and increased eIF4E binding to eIF4G; these effects were greater in 6-day-old than in 26-day-old pigs. Neither INS nor AA altered the composition of mTORC1 (raptor, mTOR, and GbetaL) or mTORC2 (rictor, mTOR, and GbetaL) complexes. Furthermore, neither INS, AA, nor age had any effect on the abundance of Rheb and the phosphorylation of AMP-activated protein kinase and eukaryotic elongation factor 2. Our results suggest that the activation by insulin and amino acids of signaling components leading to translation initiation is developmentally regulated and parallels the developmental decline in protein synthesis in skeletal muscle of neonatal pigs.

  7. Load-induced modulation of signal transduction networks.

    Science.gov (United States)

    Jiang, Peng; Ventura, Alejandra C; Sontag, Eduardo D; Merajver, Sofia D; Ninfa, Alexander J; Del Vecchio, Domitilla

    2011-10-11

    Biological signal transduction networks are commonly viewed as circuits that pass along information--in the process amplifying signals, enhancing sensitivity, or performing other signal-processing tasks--to transcriptional and other components. Here, we report on a "reverse-causality" phenomenon, which we call load-induced modulation. Through a combination of analytical and experimental tools, we discovered that signaling was modulated, in a surprising way, by downstream targets that receive the signal and, in doing so, apply what in physics is called a load. Specifically, we found that non-intuitive changes in response dynamics occurred for a covalent modification cycle when load was present. Loading altered the response time of a system, depending on whether the activity of one of the enzymes was maximal and the other was operating at its minimal rate or whether both enzymes were operating at submaximal rates. These two conditions, which we call "limit regime" and "intermediate regime," were associated with increased or decreased response times, respectively. The bandwidth, the range of frequency in which the system can process information, decreased in the presence of load, suggesting that downstream targets participate in establishing a balance between noise-filtering capabilities and a circuit's ability to process high-frequency stimulation. Nodes in a signaling network are not independent relay devices, but rather are modulated by their downstream targets.

  8. Unlimited multistability and Boolean logic in microbial signalling

    DEFF Research Database (Denmark)

    Kothamachu, Varun B; Feliu, Elisenda; Cardelli, Luca

    2015-01-01

    The ability to map environmental signals onto distinct internal physiological states or programmes is critical for single-celled microbes. A crucial systems dynamics feature underpinning such ability is multistability. While unlimited multistability is known to arise from multi-site phosphorylation...... seen in the signalling networks of eukaryotic cells, a similarly universal mechanism has not been identified in microbial signalling systems. These systems are generally known as two-component systems comprising histidine kinase (HK) receptors and response regulator proteins engaging in phosphotransfer...... further prove that sharing of downstream components allows a system with n multi-domain hybrid HKs to attain 3n steady states. We find that such systems, when sensing distinct signals, can readily implement Boolean logic functions on these signals. Using two experimentally studied examples of two...

  9. Salinity-induced inhibition of growth in the aquatic pteridophyte Azolla microphylla primarily involves inhibition of photosynthetic components and signaling molecules as revealed by proteome analysis.

    Science.gov (United States)

    Thagela, Preeti; Yadav, Ravindra Kumar; Mishra, Vagish; Dahuja, Anil; Ahmad, Altaf; Singh, Pawan Kumar; Tiwari, Budhi Sagar; Abraham, Gerard

    2017-01-01

    Salinity stress causes adverse physiological and biochemical changes in the growth and productivity of a plant. Azolla, a symbiotic pteridophyte and potent candidate for biofertilizer due to its nitrogen fixation ability, shows reduced growth and nitrogen fixation during saline stress. To better understand regulatory components involved in salinity-induced physiological changes, in the present study, Azolla microphylla plants were exposed to NaCl (6.74 and 8.61 ds/m) and growth, photochemical reactions of photosynthesis, ion accumulation, and changes in cellular proteome were studied. Maximum dry weight was accumulated in control and untreated plant while a substantial decrease in dry weight was observed in the plants exposed to salinity. Exposure of the organism to different concentrations of salt in hydroponic conditions resulted in differential level of Na + and K + ion accumulation. Comparative analysis of salinity-induced proteome changes in A. microphylla revealed 58 salt responsive proteins which were differentially expressed during the salt exposure. Moreover, 42 % spots among differentially expressed proteins were involved in different signaling events. The identified proteins are involved in photosynthesis, energy metabolism, amino acid biosynthesis, protein synthesis, and defense. Downregulation of these key metabolic proteins appears to inhibit the growth of A. microphylla in response to salinity. Altogether, the study revealed that in Azolla, increased salinity primarily affected signaling and photosynthesis that in turn leads to reduced biomass.

  10. Determination of Magnitude and Location of Earthquakes With Only Five Seconds of a Three Component Broadband Sensor Signal Located Near Bogota, Colombia Using Support Vector Machines

    Science.gov (United States)

    Ochoa Gutierrez, L. H.; Vargas Jiménez, C. A.; Niño Vasquez, L. F., Sr.

    2017-12-01

    Early warning generation for earthquakes that occur near the city of Bogotá-Colombia is extremely important. Using the information of a broadband and three component station, property of the Servicio Geológico Colombiano (SGC), called El Rosal, which is located very near the city, we developed a model based on support vector machines techniques (SVM), with a standardized polynomial kernel, using as descriptors or input data, seismic signal features, complemented by the hipocentral parameters calculated for each one of the reported events. The model was trained and evaluated by cross correlation and was used to predict, with only five seconds of signal, the magnitude and location of a seismic event. With the proposed model we calculated local magnitude with an accuracy of 0.19 units of magnitude, epicentral distance with an accuracy of about 11 k, depth with a precision of approximately 40 km and the azimuth of arrival with a precision of 45°. This research made a significant contribution for early warning generation for the country, in particular for the city of Bogotá. These models will be implemented in the future in the "Red Sismológica de la Sabana de Bogotá y sus Alrededores (RSSB)" which belongs to the Universidad Nacional de Colombia.

  11. Systems level analysis of two-component signal transduction systems in Erwinia amylovora: Role in virulence, regulation of amylovoran biosynthesis and swarming motility

    Directory of Open Access Journals (Sweden)

    Sundin George W

    2009-05-01

    Full Text Available Abstract Background Two-component signal transduction systems (TCSTs, consisting of a histidine kinase (HK and a response regulator (RR, represent a major paradigm for signal transduction in prokaryotes. TCSTs play critical roles in sensing and responding to environmental conditions, and in bacterial pathogenesis. Most TCSTs in Erwinia amylovora have either not been identified or have not yet been studied. Results We used a systems approach to identify TCST and related signal transduction genes in the genome of E. amylovora. Comparative genomic analysis of TCSTs indicated that E. amylovora TCSTs were closely related to those of Erwinia tasmaniensis, a saprophytic enterobacterium isolated from apple flowers, and to other enterobacteria. Forty-six TCST genes in E. amylovora including 17 sensor kinases, three hybrid kinases, 20 DNA- or ligand-binding RRs, four RRs with enzymatic output domain (EAL-GGDEF proteins, and two kinases were characterized in this study. A systematic TCST gene-knockout experiment was conducted, generating a total of 59 single-, double-, and triple-mutants. Virulence assays revealed that five of these mutants were non-pathogenic on immature pear fruits. Results from phenotypic characterization and gene expression experiments indicated that several groups of TCST systems in E. amylovora control amylovoran biosynthesis, one of two major virulence factors in E. amylovora. Both negative and positive regulators of amylovoran biosynthesis were identified, indicating a complex network may control this important feature of pathogenesis. Positive (non-motile, EnvZ/OmpR, negative (hypermotile, GrrS/GrrA, and intermediate regulators for swarming motility in E. amylovora were also identified. Conclusion Our results demonstrated that TCSTs in E. amylovora played major roles in virulence on immature pear fruit and in regulating amylovoran biosynthesis and swarming motility. This suggested presence of regulatory networks governing

  12. The Arabidopsis KH-Domain RNA-Binding Protein ESR1 Functions in Components of Jasmonate Signalling, Unlinking Growth Restraint and Resistance to Stress.

    Directory of Open Access Journals (Sweden)

    Louise F Thatcher

    Full Text Available Glutathione S-transferases (GSTs play important roles in the protection of cells against toxins and oxidative damage where one Arabidopsis member, GSTF8, has become a commonly used marker gene for early stress and defense responses. A GSTF8 promoter fragment fused to the luciferase reporter gene was used in a forward genetic screen for Arabidopsis mutants with up-regulated GSTF8 promoter activity. This identified the esr1-1 (enhanced stress response 1 mutant which also conferred increased resistance to the fungal pathogen Fusarium oxysporum. Through positional cloning, the ESR1 gene was found to encode a KH-domain containing RNA-binding protein (At5g53060. Whole transcriptome sequencing of esr1-1 identified altered expression of genes involved in responses to biotic and abiotic stimuli, hormone signaling pathways and developmental processes. In particular was an overall significant enrichment for jasmonic acid (JA mediated processes in the esr1-1 down-regulated dataset. A subset of these genes were tested for MeJA inducibility and we found the expression of some but not all were reduced in esr1-1. The esr1-1 mutant was not impaired in other aspects of JA-signalling such as JA- sensitivity or development, suggesting ESR1 functions in specific components of the JA-signaling pathway. Examination of salicylic acid (SA regulated marker genes in esr1-1 showed no increase in basal or SA induced expression suggesting repression of JA-regulated genes is not due to antagonistic SA-JA crosstalk. These results define new roles for KH-domain containing proteins with ESR1 unlinking JA-mediated growth and defense responses.

  13. Equation-free analysis of two-component system signalling model reveals the emergence of co-existing phenotypes in the absence of multistationarity.

    Directory of Open Access Journals (Sweden)

    Rebecca B Hoyle

    Full Text Available Phenotypic differences of genetically identical cells under the same environmental conditions have been attributed to the inherent stochasticity of biochemical processes. Various mechanisms have been suggested, including the existence of alternative steady states in regulatory networks that are reached by means of stochastic fluctuations, long transient excursions from a stable state to an unstable excited state, and the switching on and off of a reaction network according to the availability of a constituent chemical species. Here we analyse a detailed stochastic kinetic model of two-component system signalling in bacteria, and show that alternative phenotypes emerge in the absence of these features. We perform a bifurcation analysis of deterministic reaction rate equations derived from the model, and find that they cannot reproduce the whole range of qualitative responses to external signals demonstrated by direct stochastic simulations. In particular, the mixed mode, where stochastic switching and a graded response are seen simultaneously, is absent. However, probabilistic and equation-free analyses of the stochastic model that calculate stationary states for the mean of an ensemble of stochastic trajectories reveal that slow transcription of either response regulator or histidine kinase leads to the coexistence of an approximate basal solution and a graded response that combine to produce the mixed mode, thus establishing its essential stochastic nature. The same techniques also show that stochasticity results in the observation of an all-or-none bistable response over a much wider range of external signals than would be expected on deterministic grounds. Thus we demonstrate the application of numerical equation-free methods to a detailed biochemical reaction network model, and show that it can provide new insight into the role of stochasticity in the emergence of phenotypic diversity.

  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. 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

  16. 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...

  17. Active Components with Inhibitory Activities on IFN-γ/STAT1 and IL-6/STAT3 Signaling Pathways from Caulis Trachelospermi

    Directory of Open Access Journals (Sweden)

    Xiao-Ting Liu

    2014-08-01

    Full Text Available Initial investigation for new active herbal extract with inhibiting activity on JAK/STAT signaling pathway revealed that the extract of Caulis Trachelospermi, which was separated by 80% alcohol extraction and subsequent HP-20 macroporous resin column chromatography, was founded to strongly inhibit IFN-γ-induced STAT1-responsive luciferase activity (IFN-γ/STAT1 with IC50 value of 2.43 μg/mL as well as inhibiting IL-6-induced STAT3-responsive luciferase activity (IL-6/STAT3 with IC50 value of 1.38 μg/mL. Subsequent study on its active components led to the isolation and identification of two new dibenzylbutyrolactone lignans named 4-demethyltraxillaside (1 and nortrachelogenin 4-O-β-d-glucopyranoside (2, together with six known compounds. The lignan compounds 1–4 together with other lignan compounds isolated in previous study were tested the activities on IFN-γ/STAT1 and IL-6/STAT3 pathways. The following result showed that the main components trachelogenin and arctigenin had corresponding activities on IFN-γ/STAT1 pathway with IC50 values of 3.14 μM and 9.46 μM as well as trachelogenin, arctigenin and matairesinol strongly inhibiting IL-6/STAT3 pathway with IC50 values of 3.63 μM, 6.47 μM and 2.92 μM, respectively.

  18. The Meckel syndrome- associated protein MKS1 functionally interacts with components of the BBSome and IFT complexes to mediate ciliary trafficking and hedgehog signaling

    Science.gov (United States)

    Barrington, Chloe L.; Katsanis, Nicholas

    2017-01-01

    The importance of primary cilia in human health is underscored by the link between ciliary dysfunction and a group of primarily recessive genetic disorders with overlapping clinical features, now known as ciliopathies. Many of the proteins encoded by ciliopathy-associated genes are components of a handful of multi-protein complexes important for the transport of cargo to the basal body and/or into the cilium. A key question is whether different complexes cooperate in cilia formation, and whether they participate in cilium assembly in conjunction with intraflagellar transport (IFT) proteins. To examine how ciliopathy protein complexes might function together, we have analyzed double mutants of an allele of the Meckel syndrome (MKS) complex protein MKS1 and the BBSome protein BBS4. We find that Mks1; Bbs4 double mutant mouse embryos exhibit exacerbated defects in Hedgehog (Hh) dependent patterning compared to either single mutant, and die by E14.5. Cells from double mutant embryos exhibit a defect in the trafficking of ARL13B, a ciliary membrane protein, resulting in disrupted ciliary structure and signaling. We also examined the relationship between the MKS complex and IFT proteins by analyzing double mutant between Mks1 and a hypomorphic allele of the IFTB component Ift172. Despite each single mutant surviving until around birth, Mks1; Ift172avc1 double mutants die at mid-gestation, and exhibit a dramatic failure of cilia formation. We also find that Mks1 interacts genetically with an allele of Dync2h1, the IFT retrograde motor. Thus, we have demonstrated that the MKS transition zone complex cooperates with the BBSome to mediate trafficking of specific trans-membrane receptors to the cilium. Moreover, the genetic interaction of Mks1 with components of IFT machinery suggests that the transition zone complex facilitates IFT to promote cilium assembly and structure. PMID:28291807

  19. The Meckel syndrome- associated protein MKS1 functionally interacts with components of the BBSome and IFT complexes to mediate ciliary trafficking and hedgehog signaling.

    Directory of Open Access Journals (Sweden)

    Sarah C Goetz

    Full Text Available The importance of primary cilia in human health is underscored by the link between ciliary dysfunction and a group of primarily recessive genetic disorders with overlapping clinical features, now known as ciliopathies. Many of the proteins encoded by ciliopathy-associated genes are components of a handful of multi-protein complexes important for the transport of cargo to the basal body and/or into the cilium. A key question is whether different complexes cooperate in cilia formation, and whether they participate in cilium assembly in conjunction with intraflagellar transport (IFT proteins. To examine how ciliopathy protein complexes might function together, we have analyzed double mutants of an allele of the Meckel syndrome (MKS complex protein MKS1 and the BBSome protein BBS4. We find that Mks1; Bbs4 double mutant mouse embryos exhibit exacerbated defects in Hedgehog (Hh dependent patterning compared to either single mutant, and die by E14.5. Cells from double mutant embryos exhibit a defect in the trafficking of ARL13B, a ciliary membrane protein, resulting in disrupted ciliary structure and signaling. We also examined the relationship between the MKS complex and IFT proteins by analyzing double mutant between Mks1 and a hypomorphic allele of the IFTB component Ift172. Despite each single mutant surviving until around birth, Mks1; Ift172avc1 double mutants die at mid-gestation, and exhibit a dramatic failure of cilia formation. We also find that Mks1 interacts genetically with an allele of Dync2h1, the IFT retrograde motor. Thus, we have demonstrated that the MKS transition zone complex cooperates with the BBSome to mediate trafficking of specific trans-membrane receptors to the cilium. Moreover, the genetic interaction of Mks1 with components of IFT machinery suggests that the transition zone complex facilitates IFT to promote cilium assembly and structure.

  20. 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.

  1. 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

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

    Science.gov (United States)

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

    2015-07-31

    The pH-responsive one-component signaling system CadC in Escherichia coli belongs to the family of ToxR-like proteins, whose members share a conserved modular structure, with an N-terminal cytoplasmic winged helix-turn-helix DNA-binding domain being followed by a single transmembrane helix and a C-terminal periplasmic pH-sensing domain. In E. coli CadC, a cytoplasmic linker comprising approximately 50 amino acids is essential for transmission of the signal from the sensor to the DNA-binding domain. However, the mechanism of transduction is poorly understood. Using NMR spectroscopy, we demonstrate here that the linker region is intrinsically disordered in solution. Furthermore, mutational analyses showed that it tolerates a range of amino acid substitutions (altering polarity, rigidity and α-helix-forming propensity), is robust to extension but is sensitive to truncation. Indeed, truncations either reversed the expression profile of the target operon cadBA or decoupled expression from external pH altogether. CadC dimerizes via its periplasmic domain, but light-scattering analysis provided no evidence for dimerization of the isolated DNA-binding domain, with or without the linker region. However, bacterial two-hybrid analysis revealed that CadC forms stable dimers in a stimulus- and linker-dependent manner, interacting only at pHpH. Thus, we propose that the disordered CadC linker is required for transducing the pH-dependent response of the periplasmic sensor into a structural rearrangement that facilitates dimerization of the cytoplasmic CadC DNA-binding domain. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. 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.

  4. 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

  5. Forward modeling of fluctuating dietary 13C signals to validate 13C turnover models of milk and milk components from a diet-switch experiment.

    Directory of Open Access Journals (Sweden)

    Alexander Braun

    Full Text Available Isotopic variation of food stuffs propagates through trophic systems. But, this variation is dampened in each trophic step, due to buffering effects of metabolic and storage pools. Thus, understanding of isotopic variation in trophic systems requires knowledge of isotopic turnover. In animals, turnover is usually quantified in diet-switch experiments in controlled conditions. Such experiments usually involve changes in diet chemical composition, which may affect turnover. Furthermore, it is uncertain if diet-switch based turnover models are applicable under conditions with randomly fluctuating dietary input signals. Here, we investigate if turnover information derived from diet-switch experiments with dairy cows can predict the isotopic composition of metabolic products (milk, milk components and feces under natural fluctuations of dietary isotope and chemical composition. First, a diet-switch from a C3-grass/maize diet to a pure C3-grass diet was used to quantify carbon turnover in whole milk, lactose, casein, milk fat and feces. Data were analyzed with a compartmental mixed effects model, which allowed for multiple pools and intra-population variability, and included a delay between feed ingestion and first tracer appearance in outputs. The delay for milk components and whole milk was ~12 h, and that of feces ~20 h. The half-life (t½ for carbon in the feces was 9 h, while lactose, casein and milk fat had a t½ of 10, 18 and 19 h. The (13C kinetics of whole milk revealed two pools, a fast pool with a t½ of 10 h (likely representing lactose, and a slower pool with a t½ of 21 h (likely including casein and milk fat. The diet-switch based turnover information provided a precise prediction (RMSE ~0.2 ‰ of the natural (13C fluctuations in outputs during a 30 days-long period when cows ingested a pure C3 grass with naturally fluctuating isotope composition.

  6. Mutation of the Streptococcus gordonii Thiol-Disulfide Oxidoreductase SdbA Leads to Enhanced Biofilm Formation Mediated by the CiaRH Two-Component Signaling System.

    Directory of Open Access Journals (Sweden)

    Lauren Davey

    Full Text Available Streptococcus gordonii is a commensal inhabitant of human oral biofilms. Previously, we identified an enzyme called SdbA that played an important role in biofilm formation by S. gordonii. SdbA is thiol-disulfide oxidoreductase that catalyzes disulfide bonds in secreted proteins. Surprisingly, inactivation of SdbA results in enhanced biofilm formation. In this study we investigated the basis for biofilm formation by the ΔsdbA mutant. The results revealed that biofilm formation was mediated by the interaction between the CiaRH and ComDE two-component signalling systems. Although it did not affect biofilm formation by the S. gordonii parent strain, CiaRH was upregulated in the ΔsdbA mutant and it was essential for the enhanced biofilm phenotype. The biofilm phenotype was reversed by inactivation of CiaRH or by the addition of competence stimulating peptide, the production of which is blocked by CiaRH activity. Competition assays showed that the enhanced biofilm phenotype also corresponded to increased oral colonization in mice. Thus, the interaction between SdbA, CiaRH and ComDE affects biofilm formation both in vitro and in vivo.

  7. Principal component and discriminant analyses as powerful tools to support taxonomic identification and their use for functional and phylogenetic signal detection of isolated fossil shark teeth.

    Directory of Open Access Journals (Sweden)

    Giuseppe Marramà

    Full Text Available Identifying isolated teeth of fossil selachians only based on qualitative characters is sometimes hindered by similarity in their morphology, resulting often in heated taxonomic debates. On the other hand, the use of quantitative characters (i.e. measurements has been often neglected or underestimated in characterization and identification of fossil teeth of selachians. Here we show that, employing a robust methodological protocol based on principal component and discriminant analyses on a sample of 175 isolated fossil teeth of lamniform sharks, the traditional morphometrics can be useful to support and complement the classic taxonomic identification made on qualitative features. Furthermore, we show that discriminant analysis can be successfully useful to assign indeterminate isolated shark teeth to a certain taxon. Finally, the degree of separation of the clusters might be used to predict functional and probably also phylogenetic signals in lamniform shark teeth. However, this needs to be tested in the future employing teeth of more extant and extinct lamniform sharks and it must be pointed out that this approach does not replace in any way the qualitative analysis, but it is intended to complement and support it.

  8. A Fusion Approach to Feature Extraction by Wavelet Decomposition and Principal Component Analysis in Transient Signal Processing of SAW Odor Sensor Array

    Directory of Open Access Journals (Sweden)

    Prashant SINGH

    2011-03-01

    Full Text Available This paper presents theoretical analysis of a new approach for development of surface acoustic wave (SAW sensor array based odor recognition system. The construction of sensor array employs a single polymer interface for selective sorption of odorant chemicals in vapor phase. The individual sensors are however coated with different thicknesses. The idea of sensor coating thickness variation is for terminating solvation and diffusion kinetics of vapors into polymer up to different stages of equilibration on different sensors. This is expected to generate diversity in information content of the sensors transient. The analysis is based on wavelet decomposition of transient signals. The single sensor transients have been used earlier for generating odor identity signatures based on wavelet approximation coefficients. In the present work, however, we exploit variability in diffusion kinetics due to polymer thicknesses for making odor signatures. This is done by fusion of the wavelet coefficients from different sensors in the array, and then applying the principal component analysis. We find that the present approach substantially enhances the vapor class separability in feature space. The validation is done by generating synthetic sensor array data based on well-established SAW sensor theory.

  9. 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.

  10. 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

  11. Autophosphorylation is essential for the in vivo function of the Lotus japonicus Nod factor receptor 1 and receptor-mediated signalling in cooperation with Nod factor receptor 5

    DEFF Research Database (Denmark)

    Madsen, Esben B; Antolín-Llovera, Meritxell; Grossmann, Christina

    2011-01-01

    and cloning of downstream components, little is known about the activation and signalling mechanisms of the Nod-factor receptors themselves. Here we show that both receptor proteins localize to the plasma membrane, and present evidence for heterocomplex formation initiating downstream signalling. Expression...... of NFR1 and NFR5 in Nicotiana benthamiana and Allium ampeloprasum (leek) cells caused a rapid cell-death response. The signalling leading to cell death was abrogated using a kinase-inactive variant of NFR1. In these surviving cells, a clear interaction between NFR1 and NFR5 was detected in vivo through...

  12. 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

  13. Downstream-Conditioned Maximum Entropy Method for Exit Boundary Conditions in the Lattice Boltzmann Method

    Directory of Open Access Journals (Sweden)

    Javier A. Dottori

    2015-01-01

    Full Text Available A method for modeling outflow boundary conditions in the lattice Boltzmann method (LBM based on the maximization of the local entropy is presented. The maximization procedure is constrained by macroscopic values and downstream components. The method is applied to fully developed boundary conditions of the Navier-Stokes equations in rectangular channels. Comparisons are made with other alternative methods. In addition, the new downstream-conditioned entropy is studied and it was found that there is a correlation with the velocity gradient during the flow development.

  14. 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.

  15. TGF beta-1 dependent fast stimulation of ATM and p53 phosphorylation following exposure to ionizing radiation does not involve TGF beta-receptor I signalling

    NARCIS (Netherlands)

    Wiegman, Erwin M.; Blaese, Marcet A.; Loeffler, Heidi; Coppes, Rob P.; Rodemann, H. Peter

    Background and purpose: It has been proposed that radiation induced stimulation of ATM and downstream components involves activation of TGF beta-1 and that this may be due to TGF beta-1-receptor I-Smad signalling. Therefore, the aim of this study was to clarify the distinct role of TGF

  16. Corrosion impact of reductant on DWPF and downstream facilities

    Energy Technology Data Exchange (ETDEWEB)

    Mickalonis, J. I. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Imrich, K. J. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Jantzen, C. M. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Murphy, T. H. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL); Wilderman, J. E. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2014-12-01

    Glycolic acid is being evaluated as an alternate reductant in the preparation of high level waste for the Defense Waste Processing Facility (DWPF) at the Savannah River Site (SRS). During processing, the glycolic acid is not completely consumed and small quantities of the glycolate anion are carried forward to other high level waste (HLW) facilities. The impact of the glycolate anion on the corrosion of the materials of construction throughout the waste processing system has not been previously evaluated. A literature review had revealed that corrosion data in glycolate-bearing solution applicable to SRS systems were not available. Therefore, testing was recommended to evaluate the materials of construction of vessels, piping and components within DWPF and downstream facilities. The testing, conducted in non-radioactive simulants, consisted of both accelerated tests (electrochemical and hot-wall) with coupons in laboratory vessels and prototypical tests with coupons immersed in scale-up and mock-up test systems. Eight waste or process streams were identified in which the glycolate anion might impact the performance of the materials of construction. These streams were 70% glycolic acid (DWPF feed vessels and piping), SRAT/SME supernate (Chemical Processing Cell (CPC) vessels and piping), DWPF acidic recycle (DWPF condenser and recycle tanks and piping), basic concentrated recycle (HLW tanks, evaporators, and transfer lines), salt processing (ARP, MCU, and Saltstone tanks and piping), boric acid (MCU separators), and dilute waste (HLW evaporator condensate tanks and transfer line and ETF components). For each stream, high temperature limits and worst-case glycolate concentrations were identified for performing the recommended tests. Test solution chemistries were generally based on analytical results of actual waste samples taken from the various process facilities or of prototypical simulants produced in the laboratory. The materials of construction for most vessels

  17. Role of the two component signal transduction system CpxAR in conferring cefepime and chloramphenicol resistance in Klebsiella pneumoniae NTUH-K2044.

    Directory of Open Access Journals (Sweden)

    Vijaya Bharathi Srinivasan

    Full Text Available BACKGROUND: Klebsiella pneumoniae is a gram-negative, non-motile, facultative anaerobe belonging to the Enterobacteriaceae family of the γ-Proteobacteria class in the phylum Proteobacteria. Multidrug resistant K. pneumoniae have caused major therapeutic problems worldwide due to emergence of extended-spectrum β-lactamase producing strains. Two-component systems serve as a basic stimulus-response coupling mechanism to allow organisms to sense and respond to changes in many different environmental conditions including antibiotic stress. PRINCIPAL FINDINGS: In the present study, we investigated the role of an uncharacterized cpxAR operon in bacterial physiology and antimicrobial resistance by generating isogenic mutant (ΔcpxAR deficient in the CpxA/CpxR component derived from the hyper mucoidal K1 strain K. pneumoniae NTUH-K2044. The behaviour of ΔcpxAR was determined under hostile conditions, reproducing stresses encountered in the gastrointestinal environment and deletion resulted in higher sensitivity to bile, osmotic and acid stresses. The ΔcpxAR was more susceptible to β-lactams and chloramphenicol than the wild-type strain, and complementation restored the altered phenotypes. The relative change in expression of acrB, acrD, eefB efflux genes were decreased in cpxAR mutant as evidenced by qRT-PCR. Comparison of outer membrane protein profiles indicated a conspicuous difference in the knock out background. Gel shift assays demonstrated direct binding of CpxR(KP to promoter region of ompC(KP in a concentration dependent manner. CONCLUSIONS AND SIGNIFICANCE: The Cpx envelope stress response system is known to be activated by alterations in pH, membrane composition and misfolded proteins, and this systematic investigation reveals its direct involvement in conferring antimicrobial resistance against clinically significant antibiotics for the very first time. Overall results displayed in this report reflect the pleiotropic role of the Cpx

  18. Areca nut components stimulate ADAM17, IL-1α, PGE2 and 8-isoprostane production in oral keratinocyte: role of reactive oxygen species, EGF and JAK signaling.

    Science.gov (United States)

    Chang, Mei-Chi; Chan, Chiu-Po; Chen, Yi-Jane; Hsien, Hsiang-Chi; Chang, Ya-Ching; Yeung, Sin-Yuet; Jeng, Po-Yuan; Cheng, Ru-Hsiu; Hahn, Liang-Jiunn; Jeng, Jiiang-Huei

    2016-03-29

    Betel quid (BQ) chewing is an etiologic factor of oral submucous fibrosis (OSF) and oral cancer. There are 600 million BQ chewers worldwide. The mechanisms for the toxic and inflammatory responses of BQ are unclear. In this study, both areca nut (AN) extract (ANE) and arecoline stimulated epidermal growth factor (EGF) and interleukin-1α (IL-1α) production of gingival keratinocytes (GKs), whereas only ANE can stimulate a disintegrin and metalloproteinase 17 (ADAM17), prostaglandin E2 (PGE2) and 8-isoprostane production. ANE-induced EGF production was inhibited by catalase. Addition of anti-EGF neutralizing antibody attenuated ANE-induced cyclooxygenase-2 (COX-2), mature ADAM9 expression and PGE2 and 8-isoprostane production. ANE-induced IL-1α production was inhibited by catalase, anti-EGF antibody, PD153035 (EGF receptor antagonist) and U0126 (MEK inhibitor) but not by α-naphthoflavone (cytochrome p450-1A1 inhibitor). ANE-induced ADAM17 production was inhibited by pp2 (Src inhibitor), U0126, α-naphthoflavone and aspirin. AG490 (JAK inhibitor) prevented ANE-stimulated ADAM17, IL-1α, PGE2 production, COX-2 expression, ADAM9 maturation, and the ANE-induced decline in keratin 5 and 14, but showed little effect on cdc2 expression and EGF production. Moreover, ANE-induced 8-isoprostane production by GKs was inhibited by catalase, anti-EGF antibody, AG490, pp2, U0126, α-naphthoflavone, Zinc protoporphyrin (ZnPP) and aspirin. These results indicate that AN components may involve in BQ-induced oral cancer by induction of reactive oxygen species, EGF/EGFR, IL-1α, ADAMs, JAK, Src, MEK/ERK, CYP1A1, and COX signaling pathways, and the aberration of cell cycle and differentiation. Various blockers against ROS, EGF, IL-1α, ADAM, JAK, Src, MEK, CYP1A1, and COX can be used for prevention or treatment of BQ chewing-related diseases.

  19. Cladding Heatup Prediction between Spacer Grids for the Downstream Effect Evaluation

    International Nuclear Information System (INIS)

    Park, J. Y.; Kim, M. W.

    2009-01-01

    Since a recirculation sump clogging issue by debris generated from high energy pipe line break had been invoked as GSI-191 in the US, many researches on this issue have been undertaken. Previous researches on this topic are well summarized in Bang et al. Due to comprehensive nature of the issue, it includes many area of research and one of them is the area of downstream effect evaluation. The downstream effect is involved with adverse effects of debris passing the sump screen on the downstream systems, components and piping including core and it can be further divided into an ex-vessel downstream effect and an in-vessel downstream effect. In the ex-vessel downstream effect, focus is laid on plugging of spray nozzle, wearing and abrasion of moving parts of pump and valve and etc. Otherwise, a debris effect on reactor core is focused in the in-vessel downstream effect. Since debris can be ingested in the core or the systems of downstream of sump screen during recirculation, basically the downstream effect influences long-term core cooling phase. With respect to the in-vessel downstream effect, an up-to-date evaluation methodology is well summarized in a topical report submitted to the US nuclear regulatory commission by the pressurized water reactor owners group (PWROG). The report evaluates various aspects of debris ingestion in the core such as blockage at the core inlet, collection of debris on fuel grids, plating-out of fuel, chemical precipitants, protective coatings effect and etc. Most of them are evaluated qualitative manner based on previous research results and geometrical consideration on fuel rod bundles but some of them are also backed up by quantitative calculations to corroborate the qualitative decisions. One of them is a cladding heatup calculation between spacer grids. This is done to demonstrate that the cladding temperature of a fuel rod between grids with debris deposited on the clad surface in a post- LOCA recirculation environment is below

  20. Combined 15N-Labeling and TandemMOAC Quantifies Phosphorylation of MAP Kinase Substrates Downstream of MKK7 in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Nicola V. Huck

    2017-12-01

    Full Text Available Reversible protein phosphorylation is a widespread posttranslational modification that plays a key role in eukaryotic signal transduction. Due to the dynamics of protein abundance, low stoichiometry and transient nature of protein phosphorylation, the detection and accurate quantification of substrate phosphorylation by protein kinases remains a challenge in phosphoproteome research. Here, we combine tandem metal-oxide affinity chromatography (tandemMOAC with stable isotope 15N metabolic labeling for the measurement and accurate quantification of low abundant, transiently phosphorylated peptides by mass spectrometry. Since tandemMOAC is not biased toward the enrichment of acidophilic, basophilic, or proline-directed kinase substrates, the method is applicable to identify targets of all these three types of protein kinases. The MKK7-MPK3/6 module, for example, is involved in the regulation of plant development and plant basal and systemic immune responses, but little is known about downstream cascade components. Using our here described phosphoproteomics approach we identified several MPK substrates downstream of the MKK7-MPK3/6 phosphorylation cascade in Arabidopsis. The identification and validation of dynamin-related protein 2 as a novel phosphorylation substrate of the MKK7-MPK3/6 module establishes a novel link between MPK signaling and clathrin-mediated vesicle trafficking.

  1. Structural characterization of the heme-based oxygen sensor, AfGcHK, its interactions with the cognate response regulator, and their combined mechanism of action in a bacterial two-component signaling system

    Czech Academy of Sciences Publication Activity Database

    Stráňava, M.; Martínek, V.; Man, Petr; Fojtíková, V.; Kavan, Daniel; Vaněk, O.; Shimizu, T.; Martínková, M.

    2016-01-01

    Roč. 84, č. 10 (2016), s. 1375-1389 ISSN 1097-0134 R&D Projects: GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61388971 Keywords : heme-based oxygen sensor * histidine kinase * two-component signal transduction system Subject RIV: CE - Biochemistry

  2. 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.

  3. 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).

  4. 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

  5. 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...

  6. 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.

  7. Evolution of Abscisic Acid Synthesis and Signaling Mechanisms

    Science.gov (United States)

    Hauser, Felix; Waadt, Rainer; Schroeder, Julian I.

    2011-01-01

    The plant hormone abscisic acid (ABA) mediates seed dormancy, controls seedling development and triggers tolerance to abiotic stresses, including drought. Core ABA signaling components consist of a recently identified group of ABA receptor proteins of the PYRABACTIN RESISTANCE (PYR)/REGULATORY COMPONENT OF ABA RECEPTOR (RCAR) family that act as negative regulators of members of the PROTEIN PHOSPHATASE 2C (PP2C) family. Inhibition of PP2C activity enables activation of SNF1-RELATED KINASE 2 (SnRK2) protein kinases, which target downstream components, including transcription factors, ion channels and NADPH oxidases. These and other components form a complex ABA signaling network. Here, an in depth analysis of the evolution of components in this ABA signaling network shows that (i) PYR/RCAR ABA receptor and ABF-type transcription factor families arose during land colonization of plants and are not found in algae and other species, (ii) ABA biosynthesis enzymes have evolved to plant- and fungal-specific forms, leading to different ABA synthesis pathways, (iii) existing stress signaling components, including PP2C phosphatases and SnRK kinases, were adapted for novel roles in this plant-specific network to respond to water limitation. In addition, evolutionarily conserved secondary structures in the PYR/RCAR ABA receptor family are visualized. PMID:21549957

  8. Processing oscillatory signals by incoherent feedforward loops

    Science.gov (United States)

    Zhang, Carolyn; Wu, Feilun; Tsoi, Ryan; Shats, Igor; You, Lingchong

    From the timing of amoeba development to the maintenance of stem cell pluripotency,many biological signaling pathways exhibit the ability to differentiate between pulsatile and sustained signals in the regulation of downstream gene expression.While networks underlying this signal decoding are diverse,many are built around a common motif, the incoherent feedforward loop (IFFL),where an input simultaneously activates an output and an inhibitor of the output.With appropriate parameters,this motif can generate temporal adaptation,where the system is desensitized to a sustained input.This property serves as the foundation for distinguishing signals with varying temporal profiles.Here,we use quantitative modeling to examine another property of IFFLs,the ability to process oscillatory signals.Our results indicate that the system's ability to translate pulsatile dynamics is limited by two constraints.The kinetics of IFFL components dictate the input range for which the network can decode pulsatile dynamics.In addition,a match between the network parameters and signal characteristics is required for optimal ``counting''.We elucidate one potential mechanism by which information processing occurs in natural networks with implications in the design of synthetic gene circuits for this purpose. This work was partially supported by the National Science Foundation Graduate Research Fellowship (CZ).

  9. Guard Cell Signal Transduction Network: Advances in Understanding Abscisic Acid, CO2, and Ca2+ Signaling

    KAUST Repository

    Kim, Tae-Houn

    2010-05-04

    Stomatal pores are formed by pairs of specialized epidermal guard cells and serve as major gateways for both CO2 influx into plants from the atmosphere and transpirational water loss of plants. Because they regulate stomatal pore apertures via integration of both endogenous hormonal stimuli and environmental signals, guard cells have been highly developed as a model system to dissect the dynamics and mechanisms of plant-cell signaling. The stress hormone ABA and elevated levels of CO2 activate complex signaling pathways in guard cells that are mediated by kinases/phosphatases, secondary messengers, and ion channel regulation. Recent research in guard cells has led to a new hypothesis for how plants achieve specificity in intracellular calcium signaling: CO2 and ABA enhance (prime) the calcium sensitivity of downstream calcium-signaling mechanisms. Recent progress in identification of early stomatal signaling components are reviewed here, including ABA receptors and CO2-binding response proteins, as well as systems approaches that advance our understanding of guard cell-signaling mechanisms.

  10. Guard Cell Signal Transduction Network: Advances in Understanding Abscisic Acid, CO2, and Ca2+ Signaling

    KAUST Repository

    Kim, Tae-Houn; Bö hmer, Maik; Hu, Honghong; Nishimura, Noriyuki; Schroeder, Julian I.

    2010-01-01

    Stomatal pores are formed by pairs of specialized epidermal guard cells and serve as major gateways for both CO2 influx into plants from the atmosphere and transpirational water loss of plants. Because they regulate stomatal pore apertures via integration of both endogenous hormonal stimuli and environmental signals, guard cells have been highly developed as a model system to dissect the dynamics and mechanisms of plant-cell signaling. The stress hormone ABA and elevated levels of CO2 activate complex signaling pathways in guard cells that are mediated by kinases/phosphatases, secondary messengers, and ion channel regulation. Recent research in guard cells has led to a new hypothesis for how plants achieve specificity in intracellular calcium signaling: CO2 and ABA enhance (prime) the calcium sensitivity of downstream calcium-signaling mechanisms. Recent progress in identification of early stomatal signaling components are reviewed here, including ABA receptors and CO2-binding response proteins, as well as systems approaches that advance our understanding of guard cell-signaling mechanisms.

  11. 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.

  12. 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.

  13. 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.

  14. Nasal chemosensory cells use bitter taste signaling to detect irritants and bacterial signals.

    Science.gov (United States)

    Tizzano, Marco; Gulbransen, Brian D; Vandenbeuch, Aurelie; Clapp, Tod R; Herman, Jake P; Sibhatu, Hiruy M; Churchill, Mair E A; Silver, Wayne L; Kinnamon, Sue C; Finger, Thomas E

    2010-02-16

    The upper respiratory tract is continually assaulted with harmful dusts and xenobiotics carried on the incoming airstream. Detection of such irritants by the trigeminal nerve evokes protective reflexes, including sneezing, apnea, and local neurogenic inflammation of the mucosa. Although free intra-epithelial nerve endings can detect certain lipophilic irritants (e.g., mints, ammonia), the epithelium also houses a population of trigeminally innervated solitary chemosensory cells (SCCs) that express T2R bitter taste receptors along with their downstream signaling components. These SCCs have been postulated to enhance the chemoresponsive capabilities of the trigeminal irritant-detection system. Here we show that transduction by the intranasal solitary chemosensory cells is necessary to evoke trigeminally mediated reflex reactions to some irritants including acyl-homoserine lactone bacterial quorum-sensing molecules, which activate the downstream signaling effectors associated with bitter taste transduction. Isolated nasal chemosensory cells respond to the classic bitter ligand denatonium as well as to the bacterial signals by increasing intracellular Ca(2+). Furthermore, these same substances evoke changes in respiration indicative of trigeminal activation. Genetic ablation of either G alpha-gustducin or TrpM5, essential elements of the T2R transduction cascade, eliminates the trigeminal response. Because acyl-homoserine lactones serve as quorum-sensing molecules for gram-negative pathogenic bacteria, detection of these substances by airway chemoreceptors offers a means by which the airway epithelium may trigger an epithelial inflammatory response before the bacteria reach population densities capable of forming destructive biofilms.

  15. Development of Adaptive AE Signal Pattern Recognition Program and Application to Classification of Defects in Metal Contact Regions of Rotating Component

    International Nuclear Information System (INIS)

    Lee, K. Y.; Lee, C. M.; Kim, J. S.

    1996-01-01

    In this study, the artificial defects in rotary compressor are classified using pattern recognition of acoustic emission signal. For this purpose the computer program is developed. The neural network classifier is compared with the statistical classifier such as the linear discriminant function classifier and empirical Bayesian classifier. It is concluded that the former is better. It is possible to acquire the recognition rate of above 99% by neural network classifier

  16. Noise Reduction, Atmospheric Pressure Admittance Estimation and Long-Period Component Extraction in Time-Varying Gravity Signals Using Ensemble Empirical Mode Decomposition

    Directory of Open Access Journals (Sweden)

    Linsong Wang

    2015-01-01

    Full Text Available Time-varying gravity signals, with their nonlinear, non-stationary and multi-scale characteristics, record the physical responses of various geodynamic processes and consist of a blend of signals with various periods and amplitudes, corresponding to numerous phenomena. Superconducting gravimeter (SG records are processed in this study using a multi-scale analytical method and corrected for known effects to reduce noise, to study geodynamic phenomena using their gravimetric signatures. Continuous SG (GWR-C032 gravity and barometric data are decomposed into a series of intrinsic mode functions (IMFs using the ensemble empirical mode decomposition (EEMD method, which is proposed to alleviate some unresolved issues (the mode mixing problem and the end effect of the empirical mode decomposition (EMD. Further analysis of the variously scaled signals is based on a dyadic filter bank of the IMFs. The results indicate that removing the high-frequency IMFs can reduce the natural and man-made noise in the data, which are caused by electronic device noise, Earth background noise and the residual effects of pre-processing. The atmospheric admittances based on frequency changes are estimated from the gravity and the atmospheric pressure IMFs in various frequency bands. These time- and frequency-dependent admittance values can be used effectively to improve the atmospheric correction. Using the EEMD method as a filter, the long-period IMFs are extracted from the SG time-varying gravity signals spanning 7 years. The resulting gravity residuals are well correlated with the gravity effect caused by the _ polar motion after correcting for atmospheric effects.

  17. Spectral components of laser Doppler flowmetry signals recorded in healthy and type 1 diabetic subjects at rest and during a local and progressive cutaneous pressure application: scalogram analyses

    International Nuclear Information System (INIS)

    Humeau, Anne; Koitka, Audrey; Abraham, Pierre; Saumet, Jean-Louis; L'Huillier, Jean-Pierre

    2004-01-01

    A significant transient increase in laser Doppler flowmetry (LDF) signals is observed in response to a local and progressive cutaneous pressure application in healthy subjects. This reflex may be impaired in diabetic patients. The work presents a signal processing providing the clarification of this phenomenon. Scalogram analyses of LDF signals recorded at rest and during a local and progressive cutaneous pressure application are performed on healthy and type 1 diabetic subjects. Three frequency bands, corresponding to myogenic, neurogenic and endothelial related metabolic activities, are studied. The results show that, at rest, the scalogram energy of each frequency band is significantly lower for diabetic patients than for healthy subjects, but the scalogram relative energies do not show any statistical difference between the two groups. Moreover, the neurogenic and endothelial related metabolic activities are significantly higher during the progressive pressure than at rest, in healthy and diabetic subjects. However, the relative contribution of the endothelial related metabolic activity is significantly higher during the progressive pressure than at rest, in the interval 200-400 s following the beginning of the pressure application, but only for healthy subjects. These results may improve knowledge on cutaneous microvascular responses to injuries or local pressures initiating diabetic complications

  18. Spectral components of laser Doppler flowmetry signals recorded in healthy and type 1 diabetic subjects at rest and during a local and progressive cutaneous pressure application: scalogram analyses

    Energy Technology Data Exchange (ETDEWEB)

    Humeau, Anne [Groupe ISAIP-ESAIP, 18 rue du 8 mai 1945, BP 80022, 49180 Saint Barthelemy d' Anjou cedex (France); Koitka, Audrey [Laboratoire de Physiologie et d' Explorations Vasculaires, Centre Hospitalier Universitaire d' Angers, 49033 Angers cedex 01 (France); Abraham, Pierre [Laboratoire de Physiologie et d' Explorations Vasculaires, Centre Hospitalier Universitaire d' Angers, 49033 Angers cedex 01 (France); Saumet, Jean-Louis [Laboratoire de Physiologie et d' Explorations Vasculaires, Centre Hospitalier Universitaire d' Angers, 49033 Angers cedex 01 (France); L' Huillier, Jean-Pierre [Ecole Nationale Superieure d' Arts et Metiers (ENSAM), Laboratoire Procedes-Materiaux-Instrumentation (LPMI), 2 boulevard du Ronceray, BP 3525, 49035 Angers cedex (France)

    2004-09-07

    A significant transient increase in laser Doppler flowmetry (LDF) signals is observed in response to a local and progressive cutaneous pressure application in healthy subjects. This reflex may be impaired in diabetic patients. The work presents a signal processing providing the clarification of this phenomenon. Scalogram analyses of LDF signals recorded at rest and during a local and progressive cutaneous pressure application are performed on healthy and type 1 diabetic subjects. Three frequency bands, corresponding to myogenic, neurogenic and endothelial related metabolic activities, are studied. The results show that, at rest, the scalogram energy of each frequency band is significantly lower for diabetic patients than for healthy subjects, but the scalogram relative energies do not show any statistical difference between the two groups. Moreover, the neurogenic and endothelial related metabolic activities are significantly higher during the progressive pressure than at rest, in healthy and diabetic subjects. However, the relative contribution of the endothelial related metabolic activity is significantly higher during the progressive pressure than at rest, in the interval 200-400 s following the beginning of the pressure application, but only for healthy subjects. These results may improve knowledge on cutaneous microvascular responses to injuries or local pressures initiating diabetic complications.

  19. Downstream reduction of rural channel size with contrasting urban effects in small coastal streams of southeastern Australia

    Science.gov (United States)

    Nanson, G. C.; Young, R. W.

    1981-07-01

    Although most streams show a downstream increase in channel size corresponding to a downstream increase in flood discharges, those flowing off the Illawarra escarpment of New South Wales show a marked reduction of channel size, accompanied by a down-stream increase in flood frequency in their lower reaches. Within the confined and steeply sloping valleys of the escarpment foothills, bed and bank sediments are relatively coarse and uncohesive, and channels increase in size, corresponding to increasing discharge downstream. However, once these streams emerge into more open rural valleys at lower slopes and are accompanied by extensive floodplains formed of fine cohesive sediment, there is a dramatic reduction in channel size. This decrease in channel size apparently results from a sudden decline in channel slope and associated stream power, the cohesive nature of downstream alluvium, its retention on the channel banks by a dense cover of pasture grasses, and the availability of an extensive floodplain to carry displaced floodwater. Under these conditions floodwaters very frequently spill out over the floodplain and the downstream channel-flow becomes a relatively unimportant component of the total peak discharge. This emphasizes the importance of these floodplains as a part of the total channel system. In situations where urban development has increased peak runoff and reduced the available area of effective floodplain, stream channels formed in this fine alluvium rapidly entrench and increase in cross-sectional area by 2-3 times. Minor man-induced channel alteration and maintenance appears to trigger this enlargement.

  20. 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

  1. Beam Halo on the LHC TCDQ Diluter System and Thermal Load on the Downstream Superconducting Magnets

    CERN Document Server

    Goddard, B; Presland, A; Redaelli, S; Robert-Démolaize, G; Sarchiapone, L; Weiler, T; Weterings, W

    2006-01-01

    The moveable single-jawed graphite TCDQ diluter must be positioned very close to the circulating LHC beam in order to prevent damage to downstream components in the event of an unsynchronised beam abort. A two-jawed graphite TCS.IR6 collimator forms part of the TCDQ system. The requirement to place the jaws close to the beam means that the system can intercept a substantial beam halo load. Initial investigations indicated a worryingly high heat load on the Q4 coils. This paper presents the updated load cases, shielding and simulation geometry, and the results of simulations of the energy deposition in the TCDQ system and in the downstream superconducting Q4 magnet. The implications for the operation of the LHC are discussed.

  2. 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 .

  3. Hsp90 inhibition differentially destabilises MAP kinase and TGF-beta signalling components in cancer cells revealed by kinase-targeted chemoproteomics

    International Nuclear Information System (INIS)

    Haupt, Armin; Dahl, Andreas; Lappe, Michael; Lehrach, Hans; Gonzalez, Cayetano; Drewes, Gerard; Lange, Bodo MH; Joberty, Gerard; Bantscheff, Marcus; Fröhlich, Holger; Stehr, Henning; Schweiger, Michal R; Fischer, Axel; Kerick, Martin; Boerno, Stefan T

    2012-01-01

    The heat shock protein 90 (Hsp90) is required for the stability of many signalling kinases. As a target for cancer therapy it allows the simultaneous inhibition of several signalling pathways. However, its inhibition in healthy cells could also lead to severe side effects. This is the first comprehensive analysis of the response to Hsp90 inhibition at the kinome level. We quantitatively profiled the effects of Hsp90 inhibition by geldanamycin on the kinome of one primary (Hs68) and three tumour cell lines (SW480, U2OS, A549) by affinity proteomics based on immobilized broad spectrum kinase inhibitors ('kinobeads'). To identify affected pathways we used the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway classification. We combined Hsp90 and proteasome inhibition to identify Hsp90 substrates in Hs68 and SW480 cells. The mutational status of kinases from the used cell lines was determined using next-generation sequencing. A mutation of Hsp90 candidate client RIPK2 was mapped onto its structure. We measured relative abundances of > 140 protein kinases from the four cell lines in response to geldanamycin treatment and identified many new potential Hsp90 substrates. These kinases represent diverse families and cellular functions, with a strong representation of pathways involved in tumour progression like the BMP, MAPK and TGF-beta signalling cascades. Co-treatment with the proteasome inhibitor MG132 enabled us to classify 64 kinases as true Hsp90 clients. Finally, mutations in 7 kinases correlate with an altered response to Hsp90 inhibition. Structural modelling of the candidate client RIPK2 suggests an impact of the mutation on a proposed Hsp90 binding domain. We propose a high confidence list of Hsp90 kinase clients, which provides new opportunities for targeted and combinatorial cancer treatment and diagnostic applications

  4. CB1 Receptor-Mediated Signaling Underlies the Hippocampal Synaptic, Learning and Memory Deficits Following Treatment with JWH-081, a New Component of Spice/K2 Preparations

    OpenAIRE

    Basavarajappa, Balapal S.; Subbanna, Shivakumar

    2014-01-01

    Recently, synthetic cannabinoids have been sprayed onto plant material, which is subsequently packaged and sold as “Spice” or “K2” to mimic the effects of marijuana. A recent report identified several synthetic additives in samples of “Spice/K2”, including JWH-081, a synthetic ligand for the cannabinoid receptor 1 (CB1). The deleterious effects of JWH-081 on brain function are not known, particularly on CB1 signaling, synaptic plasticity, learning and memory. Here, we evaluated the effects of...

  5. An SVM-Based Classifier for Estimating the State of Various Rotating Components in Agro-Industrial Machinery with a Vibration Signal Acquired from a Single Point on the Machine Chassis

    Directory of Open Access Journals (Sweden)

    Ruben Ruiz-Gonzalez

    2014-11-01

    Full Text Available The goal of this article is to assess the feasibility of estimating the state of various rotating components in agro-industrial machinery by employing just one vibration signal acquired from a single point on the machine chassis. To do so, a Support Vector Machine (SVM-based system is employed. Experimental tests evaluated this system by acquiring vibration data from a single point of an agricultural harvester, while varying several of its working conditions. The whole process included two major steps. Initially, the vibration data were preprocessed through twelve feature extraction algorithms, after which the Exhaustive Search method selected the most suitable features. Secondly, the SVM-based system accuracy was evaluated by using Leave-One-Out cross-validation, with the selected features as the input data. The results of this study provide evidence that (i accurate estimation of the status of various rotating components in agro-industrial machinery is possible by processing the vibration signal acquired from a single point on the machine structure; (ii the vibration signal can be acquired with a uniaxial accelerometer, the orientation of which does not significantly affect the classification accuracy; and, (iii when using an SVM classifier, an 85% mean cross-validation accuracy can be reached, which only requires a maximum of seven features as its input, and no significant improvements are noted between the use of either nonlinear or linear kernels.

  6. Degenerative Suspensory Ligament Desmitis (DSLD in Peruvian Paso Horses Is Characterized by Altered Expression of TGFβ Signaling Components in Adipose-Derived Stromal Fibroblasts.

    Directory of Open Access Journals (Sweden)

    Wei Luo

    Full Text Available Equine degenerative suspensory ligament desmitis (DSLD in Peruvian Paso horses typically presents at 7-15 years and is characterized by lameness, focal disorganization of collagen fibrils, and chondroid deposition in the body of the ligament. With the aim of developing a test for disease risk (that can be used to screen horses before breeding we have quantified the expression of 76 TGFβ-signaling target genes in adipose-derived stromal fibroblasts (ADSCs from six DSLD-affected and five unaffected Paso horses. Remarkably, 35 of the genes showed lower expression (p<0.05 in cells from DSLD-affected animals and this differential was largely eliminated by addition of exogenous TGFβ1. Moreover, TGFβ1-mediated effects on expression were prevented by the TGFβR1/2 inhibitor LY2109761, showing that the signaling was via a TGFβR1/2 complex. The genes affected by the pathology indicate that it is associated with a generalized metabolic disturbance, since some of those most markedly altered in DSLD cells (ATF3, MAPK14, ACVRL1 (ALK1, SMAD6, FOS, CREBBP, NFKBIA, and TGFBR2 represent master-regulators in a wide range of cellular metabolic responses.

  7. Membrane-associated proteomics of chickpea identifies Sad1/UNC-84 protein (CaSUN1), a novel component of dehydration signaling

    Science.gov (United States)

    Jaiswal, Dinesh Kumar; Mishra, Poonam; Subba, Pratigya; Rathi, Divya; Chakraborty, Subhra; Chakraborty, Niranjan

    2014-02-01

    Dehydration affects almost all the physiological processes including those that result in the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which in turn elicits a highly conserved signaling, the unfolded protein response (UPR). We investigated the dehydration-responsive membrane-associated proteome of a legume, chickpea, by 2-DE coupled with mass spectrometry. A total of 184 protein spots were significantly altered over a dehydration treatment of 120 h. Among the differentially expressed proteins, a non-canonical SUN domain protein, designated CaSUN1 (Cicer arietinum Sad1/UNC-84), was identified. CaSUN1 localized to the nuclear membrane and ER, besides small vacuolar vesicles. The transcripts were downregulated by both abiotic and biotic stresses, but not by abscisic acid treatment. Overexpression of CaSUN1 conferred stress tolerance in transgenic Arabidopsis. Furthermore, functional complementation of the yeast mutant, slp1, could rescue its growth defects. We propose that the function of CaSUN1 in stress response might be regulated via UPR signaling.

  8. 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.

  9. 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)

  10. CB1 receptor-mediated signaling underlies the hippocampal synaptic, learning, and memory deficits following treatment with JWH-081, a new component of spice/K2 preparations.

    Science.gov (United States)

    Basavarajappa, Balapal S; Subbanna, Shivakumar

    2014-02-01

    Recently, synthetic cannabinoids have been sprayed onto plant material, which is subsequently packaged and sold as "Spice" or "K2" to mimic the effects of marijuana. A recent report identified several synthetic additives in samples of "Spice/K2", including JWH-081, a synthetic ligand for the cannabinoid receptor 1 (CB1). The deleterious effects of JWH-081 on brain function are not known, particularly on CB1 signaling, synaptic plasticity, learning and memory. Here, we evaluated the effects of JWH-081 on pCaMKIV, pCREB, and pERK1/2 signaling events followed by long-term potentiation (LTP), hippocampal-dependent learning and memory tasks using CB1 receptor wild-type (WT) and knockout (KO) mice. Acute administration of JWH-081 impaired CaMKIV phosphorylation in a dose-dependent manner, whereas inhibition of CREB phosphorylation in CB1 receptor WT mice was observed only at higher dose of JWH-081 (1.25 mg/kg). JWH-081 at higher dose impaired CaMKIV and CREB phosphorylation in a time-dependent manner in CB1 receptor WT mice but not in KO mice and failed to alter ERK1/2 phosphorylation. In addition, SR treated or CB1 receptor KO mice have a lower pCaMKIV/CaMKIV ratio and higher pCREB/CREB ratio compared with vehicle or WT littermates. In hippocampal slices, JWH-081 impaired LTP in CB1 receptor WT but not in KO littermates. Furthermore, JWH-081 at higher dose impaired object recognition, spontaneous alternation and spatial memory on the Y-maze in CB1 receptor WT mice but not in KO mice. Collectively our findings suggest that deleterious effects of JWH-081 on hippocampal function involves CB1 receptor mediated impairments in CaMKIV and CREB phosphorylation, LTP, learning and memory in mice. © 2013 Wiley Periodicals, Inc.

  11. 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.

  12. 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.

  13. 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.

  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. Ric-8A, a Gα protein guanine nucleotide exchange factor potentiates taste receptor signaling

    Directory of Open Access Journals (Sweden)

    Claire J Fenech

    2009-10-01

    Full Text Available Taste receptors for sweet, bitter and umami tastants are G-protein coupled receptors (GPCRs. While much effort has been devoted to understanding G-protein-receptor interactions and identifying the components of the signalling cascade downstream of these receptors, at the level of the G-protein the modulation of receptor signal transduction remains relatively unexplored. In this regard a taste-specific regulator of G-protein signaling (RGS, RGS21, has recently been identified. To study whether guanine nucleotide exchange factors (GEFs are involved in the transduction of the signal downstream of the taste GPCRs we investigated the expression of Ric-8A and Ric-8B in mouse taste cells and their interaction with G-protein subunits found in taste buds. Mammalian Ric-8 proteins were initially identified as potent GEFs for a range of Gα subunits and Ric-8B has recently been shown to amplify olfactory signal transduction. We find that both Ric-8A and Ric-8B are expressed in a large portion of taste bud cells and that most of these cells contain IP3R-3 a marker for sweet, umami and bitter taste receptor cells. Ric-8A interacts with Gα-gustducin and Gαi2 through which it amplifies the signal transduction of hTas2R16, a receptor for bitter compounds. Overall, these findings are consistent with a role for Ric-8 in mammalian taste signal transduction.

  16. Environmental radiological studies downstream from the Rancho Seco Nuclear Power Generating Station, 1985

    International Nuclear Information System (INIS)

    Noshkin, V.E.; Wong, K.M.; Eagle, R.J.; Brunk, J.L.; Jokela, T.A.

    1986-01-01

    Information compiled in 1985 while assessing the environmental impact of radionuclides previously discharged with aqueous releases from the Rancho Seco Nuclear Power Generating Plant is presented. In October 1984, the quantities of gamma-emitting radionuclides in water discharged to Clay Creek from the plant were reduced below operationally defined detection limits for liquid effluents. However, radionuclides previously discharged persist in the downstream environment and are found in many aquatic dietary components. 134 Cs and 137 Cs are the primary gamma-emitting radionuclides detected in the edible flesh of different fish, crayfish, and frogs. Coefficients for exponential equations are generated, from a least square analysis, that relate the change in concentration of 137 Cs in fish to distance downstream and time between March and October 1985. Concentrations of 137 Cs in surface creek sediments also decreased in the downstream direction much in the same manner as concentrations decreased in fish. However, there was no significant difference in the radiocesium concentrations in surface sediements collected from comparable locations during both 1984 and 1985

  17. Lipids as tumoricidal components of human α-lactalbumin made lethal to tumor cells (HAMLET): unique and shared effects on signaling and death.

    Science.gov (United States)

    Ho, James C S; Storm, Petter; Rydström, Anna; Bowen, Ben; Alsin, Fredrik; Sullivan, Louise; Ambite, Inès; Mok, K H; Northen, Trent; Svanborg, Catharina

    2013-06-14

    Long-chain fatty acids are internalized by receptor-mediated mechanisms or receptor-independent diffusion across cytoplasmic membranes and are utilized as nutrients, building blocks, and signaling intermediates. Here we describe how the association of long-chain fatty acids to a partially unfolded, extracellular protein can alter the presentation to target cells and cellular effects. HAMLET (human α-lactalbumin made lethal to tumor cells) is a tumoricidal complex of partially unfolded α-lactalbumin and oleic acid (OA). As OA lacks independent tumoricidal activity at concentrations equimolar to HAMLET, the contribution of the lipid has been debated. We show by natural abundance (13)C NMR that the lipid in HAMLET is deprotonated and by chromatography that oleate rather than oleic acid is the relevant HAMLET constituent. Compared with HAMLET, oleate (175 μm) showed weak effects on ion fluxes and gene expression. Unlike HAMLET, which causes metabolic paralysis, fatty acid metabolites were less strongly altered. The functional overlap increased with higher oleate concentrations (500 μm). Cellular responses to OA were weak or absent, suggesting that deprotonation favors cellular interactions of fatty acids. Fatty acids may thus exert some of their essential effects on host cells when in the deprotonated state and when presented in the context of a partially unfolded protein.

  18. Downstream and soaring interfaces and vortices in 2-D stratified wakes and their impact on transport of contaminants

    Directory of Open Access Journals (Sweden)

    Y. D. Chashechkin

    2006-01-01

    Full Text Available The flow of continuously stratified fluids past obstacles was studied analytically, numerically, and experimentally. The obstacles discussed here include a flat strip, aligned with the flow, inclined or transverse to the flow and a horizontal cylinder. In the flow pattern, transient and attached (lee internal waves, downstream wakes with submerged interfaces and vortices, soaring singular interfaces, soaring vortices and vortex systems are distinguished. New components of laminar flow past a horizontally towed strip are presented. Fine transverse streaky structures on the strip in the downstream wake were visualized. Soaring isolated interfaces, which are internal boundary layers forming inside the downstream attached wave field past bluff bodies were observed. With increasing of the body velocity a vortex pair was formed directly at the leading edge of this interface.

  19. Transcriptional regulatory networks downstream of TAL1/SCL in T-cell acute lymphoblastic leukemia

    OpenAIRE

    Palomero, Teresa; Odom, Duncan T.; O'Neil, Jennifer; Ferrando, Adolfo A.; Margolin, Adam; Neuberg, Donna S.; Winter, Stuart S.; Larson, Richard S.; Li, Wei; Liu, X. Shirley; Young, Richard A.; Look, A. Thomas

    2006-01-01

    Aberrant expression of 1 or more transcription factor oncogenes is a critical component of the molecular pathogenesis of human T-cell acute lymphoblastic leukemia (T-ALL); however, oncogenic transcriptional programs downstream of T-ALL oncogenes are mostly unknown. TAL1/SCL is a basic helix-loop-helix (bHLH) transcription factor oncogene aberrantly expressed in 60% of human T-ALLs. We used chromatin immunoprecipitation (ChIP) on chip to identify 71 direct transcriptional targets of TAL1/SCL. ...

  20. Smad signaling pathway is a pivotal component of tissue inhibitor of metalloproteinases-3 regulation by transforming growth factor beta in human chondrocytes.

    Science.gov (United States)

    Qureshi, Hamid Yaqoob; Ricci, Gemma; Zafarullah, Muhammad

    2008-09-01

    Transforming growth factor beta (TGF-beta1) promotes cartilage matrix synthesis and induces tissue inhibitor of metalloproteinases-3 (TIMP-3), which inhibits matrix metalloproteinases, aggrecanases and TNF-alpha-converting enzyme implicated in articular cartilage degradation and joint inflammation. TGF-beta1 activates Akt, ERK and Smad2 pathways in chondrocytes. Here we investigated previously unexplored roles of specific Smads in TGF-beta1 induction of TIMP-3 gene by pharmacological and genetic knockdown approaches. TGF-beta1-induced Smad2 phosphorylation and TIMP-3 protein expression could be inhibited by the Smad2/3 phosphorylation inhibitors, PD169316 and SB203580 and by Smad2-specific siRNA. Specific inhibitor of Smad3 (SIS3) and Smad3 siRNA abolished TGF-beta induction of TIMP-3. Smad2/3 siRNAs also down regulated TIMP-3 promoter-driven luciferase activities, suggesting transcriptional regulation. SiRNA-driven co-Smad4 knockdown abrogated TIMP-3 augmentation by TGF-beta. TIMP-3 promoter deletion analysis revealed that -828 deletion retains the original promoter activity while -333 and -167 deletions display somewhat reduced activity suggesting that most of the TGF-beta-responsive, cis-acting elements are found in the -333 fragment. Chromatin Immunoprecipitation (ChIP) analysis confirmed binding of Smad2 and Smad4 with the -940 and -333 promoter sequences. These results suggest that receptor-activated Smad2 and Smad3 and co-Smad4 critically mediate TGF-beta-stimulated TIMP-3 expression in human chondrocytes and TIMP-3 gene is a target of Smad signaling pathway.

  1. Downstream approaches to phosphorus management in agricultural landscapes: regional applicability and use.

    Science.gov (United States)

    Kröger, R; Dunne, E J; Novak, J; King, K W; McLellan, E; Smith, D R; Strock, J; Boomer, K; Tomer, M; Noe, G B

    2013-01-01

    This review provides a critical overview of conservation practices that are aimed at improving water quality by retaining phosphorus (P) downstream of runoff genesis. The review is structured around specific downstream practices that are prevalent in various parts of the United States. Specific practices that we discuss include the use of controlled drainage, chemical treatment of waters and soils, receiving ditch management, and wetlands. The review also focuses on the specific hydrology and biogeochemistry associated with each of those practices. The practices are structured sequentially along flowpaths as you move through the landscape, from the edge-of-field, to adjacent aquatic systems, and ultimately to downstream P retention. Often practices are region specific based on geology, cropping practices, and specific P related problems and thus require a right practice, and right place mentality to management. Each practice has fundamental P transport and retention processes by systems that can be optimized by management with the goal of reducing downstream P loading after P has left agricultural fields. The management of P requires a system-wide assessment of the stability of P in different biogeochemical forms (particulate vs. dissolved, organic vs. inorganic), in different storage pools (soil, sediment, streams etc.), and under varying biogeochemical and hydrological conditions that act to convert P from one form to another and promote its retention in or transport out of different landscape components. There is significant potential of hierarchically placing practices in the agricultural landscape and enhancing the associated P mitigation. But an understanding is needed of short- and long-term P retention mechanisms within a certain practice and incorporating maintenance schedules if necessary to improve P retention times and minimize exceeding retention capacity. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. 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...

  3. 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.

  4. 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.

  5. 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

  6. 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

  7. 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...

  8. 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 ...

  9. 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

  10. 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

  11. 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

  12. 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.

  13. Two-Component Signaling System VgrRS Directly Senses Extracytoplasmic and Intracellular Iron to Control Bacterial Adaptation under Iron Depleted Stress.

    Directory of Open Access Journals (Sweden)

    Li Wang

    2016-12-01

    Full Text Available Both iron starvation and excess are detrimental to cellular life, especially for animal and plant pathogens since they always live in iron-limited environments produced by host immune responses. However, how organisms sense and respond to iron is incompletely understood. Herein, we reveal that in the phytopathogenic bacterium Xanthomonas campestris pv. campestris, VgrS (also named ColS is a membrane-bound receptor histidine kinase that senses extracytoplasmic iron limitation in the periplasm, while its cognate response regulator, VgrR (ColR, detects intracellular iron excess. Under iron-depleted conditions, dissociation of Fe3+ from the periplasmic sensor region of VgrS activates the VgrS autophosphorylation and subsequent phosphotransfer to VgrR, an OmpR-family transcription factor that regulates bacterial responses to take up iron. VgrR-VgrS regulon and the consensus DNA binding motif of the transcription factor VgrR were dissected by comparative proteomic and ChIP-seq analyses, which revealed that in reacting to iron-depleted environments, VgrR directly or indirectly controls the expressions of hundreds of genes that are involved in various physiological cascades, especially those associated with iron-uptake. Among them, we demonstrated that the phosphorylated VgrR tightly represses the transcription of a special TonB-dependent receptor gene, tdvA. This regulation is a critical prerequisite for efficient iron uptake and bacterial virulence since activation of tdvA transcription is detrimental to these processes. When the intracellular iron accumulates, the VgrR-Fe2+ interaction dissociates not only the binding between VgrR and the tdvA promoter, but also the interaction between VgrR and VgrS. This relieves the repression in tdvA transcription to impede continuous iron uptake and avoids possible toxic effects of excessive iron accumulation. Our results revealed a signaling system that directly senses both extracytoplasmic and intracellular

  14. Comparative proteomics of oxalate downregulated tomatoes points towards cross talk of signal components and metabolic consequences during post-harvest storage

    Directory of Open Access Journals (Sweden)

    Kanika Narula

    2016-08-01

    Full Text Available Fruits of angiosperms evolved intricate regulatory machinery for sensorial attributes and storage quality after harvesting. Organic acid composition of storage organs forms the molecular and biochemical basis of organoleptic and nutritional qualities with metabolic specialization. Of these, oxalic acid (OA, determines the post-harvest quality in fruits. Tomato (Solanum lycopersicum fruit have distinctive feature to undergo a shift from heterotrophic metabolism to carbon assimilation partitioning during storage. We have earlier shown that decarboxylative degradation of OA by FvOXDC leads to acid homeostasis besides increased fungal tolerance in E8.2-OXDC tomato. Here, we elucidate the metabolic consequences of oxalate down-regulation and molecular mechanisms that determine organoleptic features, signaling and hormonal regulation in E8.2-OXDC fruit during post-harvest storage. A comparative proteomics approach has been applied between wild-type and E8.2-OXDC tomato in temporal manner. The MS/MS analyses led to the identification of 32 and 39 differentially abundant proteins associated with primary and secondary metabolism, assimilation, biogenesis, and development in wild-type and E8.2-OXDC tomatoes, respectively. Next, we interrogated the proteome data using correlation network analysis that identified significant functional hubs pointing toward storage related coinciding processes through a common mechanism of function and modulation. Furthermore, physiochemical analyses exhibited reduced oxalic acid content with concomitant increase in citric acid, lycopene and marginal decrease in malic acid in E8.2-OXDC fruit. Nevertheless, E8.2-OXDC fruit maintained an optimal pH and a steady state acid pool. These might contribute to reorganization of pectin constituent, reduced membrane leakage and improved fruit firmness in E8.2-OXDC fruit with that of wild-type tomato during storage. Collectively, our study provides insights into kinetically controlled

  15. 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.

  16. Phylogenetic diversity of stress signalling pathways in fungi

    Directory of Open Access Journals (Sweden)

    Stansfield Ian

    2009-02-01

    Full Text Available Abstract Background Microbes must sense environmental stresses, transduce these signals and mount protective responses to survive in hostile environments. In this study we have tested the hypothesis that fungal stress signalling pathways have evolved rapidly in a niche-specific fashion that is independent of phylogeny. To test this hypothesis we have compared the conservation of stress signalling molecules in diverse fungal species with their stress resistance. These fungi, which include ascomycetes, basidiomycetes and microsporidia, occupy highly divergent niches from saline environments to plant or mammalian hosts. Results The fungi displayed significant variation in their resistance to osmotic (NaCl and sorbitol, oxidative (H2O2 and menadione and cell wall stresses (Calcofluor White and Congo Red. There was no strict correlation between fungal phylogeny and stress resistance. Rather, the human pathogens tended to be more resistant to all three types of stress, an exception being the sensitivity of Candida albicans to the cell wall stress, Calcofluor White. In contrast, the plant pathogens were relatively sensitive to oxidative stress. The degree of conservation of osmotic, oxidative and cell wall stress signalling pathways amongst the eighteen fungal species was examined. Putative orthologues of functionally defined signalling components in Saccharomyces cerevisiae were identified by performing reciprocal BLASTP searches, and the percent amino acid identities of these orthologues recorded. This revealed that in general, central components of the osmotic, oxidative and cell wall stress signalling pathways are relatively well conserved, whereas the sensors lying upstream and transcriptional regulators lying downstream of these modules have diverged significantly. There was no obvious correlation between the degree of conservation of stress signalling pathways and the resistance of a particular fungus to the corresponding stress. Conclusion Our

  17. The role of membrane microdomains in transmembrane signaling through the epithelial glycoprotein Gp140/CDCP1

    Science.gov (United States)

    Alvares, Stacy M.; Dunn, Clarence A.; Brown, Tod A.; Wayner, Elizabeth E.; Carter, William G.

    2008-01-01

    Cell adhesion to the extracellular matrix (ECM) via integrin adhesion receptors initiates signaling cascades leading to changes in cell behavior. While integrin clustering is necessary to initiate cell attachment to the matrix, additional membrane components are necessary to mediate the transmembrane signals and the cell adhesion response that alter downstream cell behavior. Many of these signaling components reside in glycosphingolipid-rich and cholesterol-rich membrane domains such as Tetraspanin Enriched Microdomains (TEMs)/Glycosynapse 3 and Detergent-Resistant Microdomains (DRMs), also known as lipid rafts. In the following article, we will review examples of how components in these membrane microdomains modulate integrin adhesion after initial attachment to the ECM. Additionally, we will present data on a novel adhesion-responsive transmembrane glycoprotein Gp140/CUB Domain Containing Protein 1, which clusters in epithelial cell-cell contacts. Gp140 can then be phosphorylated by Src Family Kinases at tyrosine 734 in response to outside-in signals- possibly through interactions involving the extracellular CUB domains. Data presented here suggests that outside-in signals through Gp140 in cell-cell contacts assemble membrane clusters that associate with membrane microdomains to recruit and activate SFKs. Active SFKs then mediate phosphorylation of Gp140, SFK and PKCδ with Gp140 acting as a transmembrane scaffold for these kinases. We propose that the clustering of Gp140 and signaling components in membrane microdomains in cell-cell contacts contributes to changes in cell behavior. PMID:18269919

  18. 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....

  19. Loads Bias Genetic and Signaling Switches in Synthetic and Natural Systems

    Science.gov (United States)

    Medford, June; Prasad, Ashok

    2014-01-01

    Biological protein interactions networks such as signal transduction or gene transcription networks are often treated as modular, allowing motifs to be analyzed in isolation from the rest of the network. Modularity is also a key assumption in synthetic biology, where it is similarly expected that when network motifs are combined together, they do not lose their essential characteristics. However, the interactions that a network module has with downstream elements change the dynamical equations describing the upstream module and thus may change the dynamic and static properties of the upstream circuit even without explicit feedback. In this work we analyze the behavior of a ubiquitous motif in gene transcription and signal transduction circuits: the switch. We show that adding an additional downstream component to the simple genetic toggle switch changes its dynamical properties by changing the underlying potential energy landscape, and skewing it in favor of the unloaded side, and in some situations adding loads to the genetic switch can also abrogate bistable behavior. We find that an additional positive feedback motif found in naturally occurring toggle switches could tune the potential energy landscape in a desirable manner. We also analyze autocatalytic signal transduction switches and show that a ubiquitous positive feedback switch can lose its switch-like properties when connected to a downstream load. Our analysis underscores the necessity of incorporating the effects of downstream components when understanding the physics of biochemical network motifs, and raises the question as to how these effects are managed in real biological systems. This analysis is particularly important when scaling synthetic networks to more complex organisms. PMID:24676102

  20. The genome sequence of the protostome Daphnia pulex encodes respective orthologues of a neurotrophin, a Trk and a p75NTR: Evolution of neurotrophin signaling components and related proteins in the bilateria

    Directory of Open Access Journals (Sweden)

    Wilson Karen HS

    2009-10-01

    Full Text Available Abstract Background Neurotrophins and their Trk and p75NTR receptors play an important role in the nervous system. To date, neurotrophins, Trk and p75NTR have only been found concomitantly in deuterostomes. In protostomes, homologues to either neurotrophin, Trk or p75NTR are reported but their phylogenetic relationship to deuterostome neurotrophin signaling components is unclear. Drosophila has neurotrophin homologues called Spätzles (Spz, some of which were recently renamed neurotrophins, but direct proof that these are deuterostome neurotrophin orthologues is lacking. Trks belong to the receptor tyrosine kinase (RTK family and among RTKs, Trks and RORs are closest related. Flies lack Trks but have ROR and ROR-related proteins called NRKs playing a neurotrophic role. Mollusks have so far the most similar proteins to Trks (Lymnaea Trk and Aplysia Trkl but the exact phylogenetic relationship of mollusk Trks to each other and to vertebrate Trks is unknown. p75NTR belongs to the tumor necrosis factor receptor (TNFR superfamily. The divergence of the TNFR families in vertebrates has been suggested to parallel the emergence of the adaptive immune system. Only one TNFR representative, the Drosophila Wengen, has been found in protostomes. To clarify the evolution of neurotrophin signaling components in bilateria, this work analyzes the genome of the crustacean Daphnia pulex as well as new genetic data from protostomes. Results The Daphnia genome encodes a neurotrophin, p75NTR and Trk orthologue together with Trkl, ROR, and NRK-RTKs. Drosophila Spz1, 2, 3, 5, 6 orthologues as well as two new groups of Spz proteins (Spz7 and 8 are also found in the Daphnia genome. Searching genbank and the genomes of Capitella, Helobdella and Lottia reveals neurotrophin signaling components in other protostomes. Conclusion It appears that a neurotrophin, Trk and p75NTR existed at the protostome/deuterostome split. In protostomes, a "neurotrophin superfamily" includes

  1. Resolution of thermal striping issue downstream of a horizontal pipe elbow in stratified pipe flow

    International Nuclear Information System (INIS)

    Kuzay, T.M.; Kasza, K.E.

    1985-01-01

    A thermally stratified pipe flow produced by a thermal transient when passing through a horizontal elbow as a result of secondary flow gives rise to large thermal fluctuations on the inner curvature wall of the downstream piping. These fluctuations were measured in a specially instrumented horizontal pipe and elbow system on a test set-up using water in the Mixing Components Technology Facility (MCTF) at Argonne National Laboratory (ANL). This study is part of a larger program which is studying the influence of thermal buoyancy on general reactor component performance. This paper discusses the influence of pipe flow generated thermal oscillations on the thermal stresses induced in the pipe walls. The instrumentation was concentrated around the exit plane of the 90 0 sweep elbow, since prior tests had indicated that the largest thermal fluctuations would occur within about one hydraulic diameter downstream of the elbow exit. The thermocouples were located along the inner curvature of the piping and measured the near surface fluid temperature. The test matrix involved thermal downramps under turbulent flow conditions

  2. Resolution of thermal striping issue downstream of a horizontal pipe elbow in stratified pipe flow. [LMFBR

    Energy Technology Data Exchange (ETDEWEB)

    Kuzay, T.M.; Kasza, K.E.

    1985-01-01

    A thermally stratified pipe flow produced by a thermal transient when passing through a horizontal elbow as a result of secondary flow gives rise to large thermal fluctuations on the inner curvature wall of the downstream piping. These fluctuations were measured in a specially instrumented horizontal pipe and elbow system on a test set-up using water in the Mixing Components Technology Facility (MCTF) at Argonne National Laboratory (ANL). This study is part of a larger program which is studying the influence of thermal buoyancy on general reactor component performance. This paper discusses the influence of pipe flow generated thermal oscillations on the thermal stresses induced in the pipe walls. The instrumentation was concentrated around the exit plane of the 90/sup 0/ sweep elbow, since prior tests had indicated that the largest thermal fluctuations would occur within about one hydraulic diameter downstream of the elbow exit. The thermocouples were located along the inner curvature of the piping and measured the near surface fluid temperature. The test matrix involved thermal downramps under turbulent flow conditions.

  3. 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.

  4. 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.

  5. 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

  6. 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...

  7. 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...

  8. 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.

  9. 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%

  10. 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

  11. 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...

  12. 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

  13. 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

  14. PI3K: A Crucial Piece in the RAS Signaling Puzzle.

    Science.gov (United States)

    Krygowska, Agata Adelajda; Castellano, Esther

    2018-06-01

    RAS proteins are key signaling switches essential for control of proliferation, differentiation, and survival of eukaryotic cells. RAS proteins are mutated in 30% of human cancers. In addition, mutations in upstream or downstream signaling components also contribute to oncogenic activation of the pathway. RAS proteins exert their functions through activation of several signaling pathways and dissecting the contributions of these effectors in normal cells and in cancer is an ongoing challenge. In this review, we summarize our current knowledge about how RAS regulates type I phosphatidylinositol 3-kinase (PI3K), one of the main RAS effectors. RAS signaling through PI3K is necessary for normal lymphatic vasculature development and for RAS-induced transformation in vitro and in vivo, especially in lung cancer, where it is essential for tumor initiation and necessary for tumor maintenance. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

  15. Hedgehog signaling acts with the temporal cascade to promote neuroblast cell cycle exit.

    Directory of Open Access Journals (Sweden)

    Phing Chian Chai

    Full Text Available In Drosophila postembryonic neuroblasts, transition in gene expression programs of a cascade of transcription factors (also known as the temporal series acts together with the asymmetric division machinery to generate diverse neurons with distinct identities and regulate the end of neuroblast proliferation. However, the underlying mechanism of how this "temporal series" acts during development remains unclear. Here, we show that Hh signaling in the postembryonic brain is temporally regulated; excess (earlier onset of Hh signaling causes premature neuroblast cell cycle exit and under-proliferation, whereas loss of Hh signaling causes delayed cell cycle exit and excess proliferation. Moreover, the Hh pathway functions downstream of Castor but upstream of Grainyhead, two components of the temporal series, to schedule neuroblast cell cycle exit. Interestingly, hh is likely a target of Castor. Hence, Hh signaling provides a link between the temporal series and the asymmetric division machinery in scheduling the end of neurogenesis.

  16. How a mycoparasite employs g-protein signaling: using the example of trichoderma.

    Science.gov (United States)

    Omann, Markus; Zeilinger, Susanne

    2010-01-01

    Mycoparasitic Trichoderma spp. act as potent biocontrol agents against a number of plant pathogenic fungi, whereupon the mycoparasitic attack includes host recognition followed by infection structure formation and secretion of lytic enzymes and antifungal metabolites leading to the host's death. Host-derived signals are suggested to be recognized by receptors located on the mycoparasite's cell surface eliciting an internal signal transduction cascade which results in the transcription of mycoparasitism-relevant genes. Heterotrimeric G proteins of fungi transmit signals originating from G-protein-coupled receptors mainly to the cAMP and the MAP kinase pathways resulting in regulation of downstream effectors. Components of the G-protein signaling machinery such as Gα subunits and G-protein-coupled receptors were recently shown to play crucial roles in Trichoderma mycoparasitism as they govern processes such as the production of extracellular cell wall lytic enzymes, the secretion of antifungal metabolites, and the formation of infection structures.

  17. YAP regulates neuronal differentiation through Sonic hedgehog signaling pathway

    International Nuclear Information System (INIS)

    Lin, Yi-Ting; Ding, Jing-Ya; Li, Ming-Yang; Yeh, Tien-Shun; Wang, Tsu-Wei; Yu, Jenn-Yah

    2012-01-01

    Tight regulation of cell numbers by controlling cell proliferation and apoptosis is important during development. Recently, the Hippo pathway has been shown to regulate tissue growth and organ size in Drosophila. In mammalian cells, it also affects cell proliferation and differentiation in various tissues, including the nervous system. Interplay of several signaling cascades, such as Notch, Wnt, and Sonic Hedgehog (Shh) pathways, control cell proliferation during neuronal differentiation. However, it remains unclear whether the Hippo pathway coordinates with other signaling cascades in regulating neuronal differentiation. Here, we used P19 cells, a mouse embryonic carcinoma cell line, as a model to study roles of YAP, a core component of the Hippo pathway, in neuronal differentiation. P19 cells can be induced to differentiate into neurons by expressing a neural bHLH transcription factor gene Ascl1. Our results showed that YAP promoted cell proliferation and inhibited neuronal differentiation. Expression of Yap activated Shh but not Wnt or Notch signaling activity during neuronal differentiation. Furthermore, expression of Yap increased the expression of Patched homolog 1 (Ptch1), a downstream target of the Shh signaling. Knockdown of Gli2, a transcription factor of the Shh pathway, promoted neuronal differentiation even when Yap was over-expressed. We further demonstrated that over-expression of Yap inhibited neuronal differentiation in primary mouse cortical progenitors and Gli2 knockdown rescued the differentiation defect in Yap over-expressing cells. In conclusion, our study reveals that Shh signaling acts downstream of YAP in regulating neuronal differentiation. -- Highlights: ► YAP promotes cell proliferation and inhibits neuronal differentiation in P19 cells. ► YAP promotes Sonic hedgehog signaling activity during neuronal differentiation. ► Knockdown of Gli2 rescues the Yap-overexpression phenotype in P19 cells. ► Knockdown of Gli2 rescues the Yap

  18. YAP regulates neuronal differentiation through Sonic hedgehog signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Yi-Ting; Ding, Jing-Ya [Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Li, Ming-Yang [Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan (China); Yeh, Tien-Shun [Department of Anatomy and Cell Biology, National Yang-Ming University, Taipei 112, Taiwan (China); Wang, Tsu-Wei [Department of Life Science, National Taiwan Normal University, Taipei 116, Taiwan (China); Yu, Jenn-Yah [Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan (China); Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan (China)

    2012-09-10

    Tight regulation of cell numbers by controlling cell proliferation and apoptosis is important during development. Recently, the Hippo pathway has been shown to regulate tissue growth and organ size in Drosophila. In mammalian cells, it also affects cell proliferation and differentiation in various tissues, including the nervous system. Interplay of several signaling cascades, such as Notch, Wnt, and Sonic Hedgehog (Shh) pathways, control cell proliferation during neuronal differentiation. However, it remains unclear whether the Hippo pathway coordinates with other signaling cascades in regulating neuronal differentiation. Here, we used P19 cells, a mouse embryonic carcinoma cell line, as a model to study roles of YAP, a core component of the Hippo pathway, in neuronal differentiation. P19 cells can be induced to differentiate into neurons by expressing a neural bHLH transcription factor gene Ascl1. Our results showed that YAP promoted cell proliferation and inhibited neuronal differentiation. Expression of Yap activated Shh but not Wnt or Notch signaling activity during neuronal differentiation. Furthermore, expression of Yap increased the expression of Patched homolog 1 (Ptch1), a downstream target of the Shh signaling. Knockdown of Gli2, a transcription factor of the Shh pathway, promoted neuronal differentiation even when Yap was over-expressed. We further demonstrated that over-expression of Yap inhibited neuronal differentiation in primary mouse cortical progenitors and Gli2 knockdown rescued the differentiation defect in Yap over-expressing cells. In conclusion, our study reveals that Shh signaling acts downstream of YAP in regulating neuronal differentiation. -- Highlights: Black-Right-Pointing-Pointer YAP promotes cell proliferation and inhibits neuronal differentiation in P19 cells. Black-Right-Pointing-Pointer YAP promotes Sonic hedgehog signaling activity during neuronal differentiation. Black-Right-Pointing-Pointer Knockdown of Gli2 rescues the Yap

  19. 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

  20. Other components

    International Nuclear Information System (INIS)

    Anon.

    1993-01-01

    This chapter includes descriptions of electronic and mechanical components which do not merit a chapter to themselves. Other hardware requires mention because of particularly high tolerance or intolerance of exposure to radiation. A more systematic analysis of radiation responses of structures which are definable by material was given in section 3.8. The components discussed here are field effect transistors, transducers, temperature sensors, magnetic components, superconductors, mechanical sensors, and miscellaneous electronic components

  1. 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.

  2. Areca nut components affect COX-2, cyclin B1/cdc25C and keratin expression, PGE2 production in keratinocyte is related to reactive oxygen species, CYP1A1, Src, EGFR and Ras signaling.

    Directory of Open Access Journals (Sweden)

    Mei-Chi Chang

    Full Text Available Chewing of betel quid (BQ increases the risk of oral cancer and oral submucous fibrosis (OSF, possibly by BQ-induced toxicity and induction of inflammatory response in oral mucosa.Primary gingival keratinocytes (GK cells were exposed to areca nut (AN components with/without inhibitors. Cytotoxicity was measured by 3-(4,5-dimethyl- thiazol- 2-yl-2,5-diphenyl-tetrazolium bromide (MTT assay. mRNA and protein expression was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR and western blotting. PGE2/PGF2α production was measured by enzyme-linked immunosorbent assays.Areca nut extract (ANE stimulated PGE2/PGF2α production, and upregulated the expression of cyclooxygenase-2 (COX-2, cytochrome P450 1A1 (CYP1A1 and hemeoxygenase-1 (HO-1, but inhibited expression of keratin 5/14, cyclinB1 and cdc25C in GK cells. ANE also activated epidermal growth factor receptor (EGFR, Src and Ras signaling pathways. ANE-induced COX-2, keratin 5, keratin 14 and cdc25C expression as well as PGE2 production were differentially regulated by α-naphthoflavone (a CYP 1A1/1A2 inhibitor, PD153035 (EGFR inhibitor, pp2 (Src inhibitor, and manumycin A (a Ras inhibitor. ANE-induced PGE2 production was suppressed by piper betle leaf (PBL extract and hydroxychavicol (two major BQ components, dicoumarol (aQuinone Oxidoreductase--NQO1 inhibitor and curcumin. ANE-induced cytotoxicity was inhibited by catalase and enhanced by dicoumarol, suggesting that AN components may contribute to the pathogenesis of OSF and oral cancer via induction of aberrant differentiation, cytotoxicity, COX-2 expression, and PGE2/PGF2α production.CYP4501A1, reactive oxygen species (ROS, EGFR, Src and Ras signaling pathways could all play a role in ANE-induced pathogenesis of oral cancer. Addition of PBL into BQ and curcumin consumption could inhibit the ANE-induced inflammatory response.

  3. Necroptotic signaling in adaptive and innate immunity.

    Science.gov (United States)

    Lu, Jennifer V; Chen, Helen C; Walsh, Craig M

    2014-11-01

    The vertebrate immune system is highly dependent on cell death for efficient responsiveness to microbial pathogens and oncogenically transformed cells. Cell death pathways are vital to the function of many immune cell types during innate, humoral and cellular immune responses. In addition, cell death regulation is imperative for proper adaptive immune self-tolerance and homeostasis. While apoptosis has been found to be involved in several of these roles in immunity, recent data demonstrate that alternative cell death pathways are required. Here, we describe the involvement of a programmed form of cellular necrosis called "necroptosis" in immunity. We consider the signaling pathways that promote necroptosis downstream of death receptors, type I transmembrane proteins of the tumor necrosis factor (TNF) receptor family. The involvement of necroptotic signaling through a "RIPoptosome" assembled in response to innate immune stimuli or genotoxic stress is described. We also characterize the induction of necroptosis following antigenic stimulation in T cells lacking caspase-8 or FADD function. While necroptotic signaling remains poorly understood, it is clear that this pathway is an essential component to effective vertebrate immunity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. 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

  5. Control of striatal signaling by G protein regulators

    Directory of Open Access Journals (Sweden)

    Keqiang eXie

    2011-08-01

    Full Text Available Signaling via heterotrimeric G proteins plays a crucial role in modulating the responses of striatal neurons that ultimately shape core behaviors mediated by the basal ganglia circuitry, such as reward valuation, habit formation and movement coordination. Activation of G-protein-coupled receptors (GPCRs by extracellular signals activates heterotrimeric G proteins by promoting the binding of GTP to their α subunits. G proteins exert their effects by influencing the activity of key effector proteins in this region, including ion channels, second messenger enzymes and protein kinases. Striatal neurons express a staggering number of GPCRs whose activation results in the engagement of downstream signaling pathways and cellular responses with unique profiles but common molecular mechanisms. Studies over the last decade have revealed that the extent and duration of GPCR signaling are controlled by a conserved protein family named Regulator of G protein Signaling (RGS. RGS proteins accelerate GTP hydrolysis by the α subunits of G proteins, thus promoting deactivation of GPCR signaling. In this review, we discuss the progress made in understanding the roles of RGS proteins in controlling striatal G protein signaling and providing integration and selectivity of signal transmission. We review evidence on the formation of a macromolecular complex between RGS proteins and other components of striatal signaling pathways, their molecular regulatory mechanisms and impacts on GPCR signaling in the striatum obtained from biochemical studies and experiments involving genetic mouse models. Special emphasis is placed on RGS9-2, a member of the RGS family that is highly enriched in the striatum and plays critical roles in drug addiction and motor control.

  6. 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...

  7. 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.

  8. '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...

  9. Small larvae in large rivers: observations on downstream movement of European grayling Thymallus thymallus during early life stages.

    Science.gov (United States)

    Van Leeuwen, C H A; Dokk, T; Haugen, T O; Kiffney, P M; Museth, J

    2017-06-01

    Behaviour of early life stages of the salmonid European grayling Thymallus thymallus was investigated by assessing the timing of larval downstream movement from spawning areas, the depth at which larvae moved and the distribution of juvenile fish during summer in two large connected river systems in Norway. Trapping of larvae moving downstream and electrofishing surveys revealed that T. thymallus larvae emerging from the spawning gravel moved downstream predominantly during the night, despite light levels sufficient for orientation in the high-latitude study area. Larvae moved in the water mostly at the bottom layer close to the substratum, while drifting debris was caught in all layers of the water column. Few young-of-the-year still resided close to the spawning areas in autumn, suggesting large-scale movement (several km). Together, these observations show that there may be a deliberate, active component to downstream movement of T. thymallus during early life stages. This research signifies the importance of longitudinal connectivity for T. thymallus in Nordic large river systems. Human alterations of flow regimes and the construction of reservoirs for hydropower may not only affect the movement of adult fish, but may already interfere with active movement behaviour of fish during early life stages. © 2017 The Fisheries Society of the British Isles.

  10. 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

  11. 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 .

  12. 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...

  13. Downstream element determines RNase Y cleavage of the saePQRS operon in Staphylococcus aureus.

    Science.gov (United States)

    Marincola, Gabriella; Wolz, Christiane

    2017-06-02

    In gram-positive bacteria, RNase J1, RNase J2 and RNase Y are thought to be major contributors to mRNA degradation and maturation. In Staphylococcus aureus, RNase Y activity is restricted to regulating the mRNA decay of only certain transcripts. Here the saePQRS operon was used as a model to analyze RNase Y specificity in living cells. A RNase Y cleavage site is located in an intergenic region between saeP and saeQ. This cleavage resulted in rapid degradation of the upstream fragment and stabilization of the downstream fragment. Thereby, the expression ratio of the different components of the operon was shifted towards saeRS, emphasizing the regulatory role of RNase Y activity. To assess cleavage specificity different regions surrounding the sae CS were cloned upstream of truncated gfp, and processing was analyzed in vivo using probes up- and downstream of CS. RNase Y cleavage was not determined by the cleavage site sequence. Instead a 24-bp double-stranded recognition structure was identified that was required to initiate cleavage 6 nt upstream. The results indicate that RNase Y activity is determined by secondary structure recognition determinants, which guide cleavage from a distance. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

  14. Electronic components

    CERN Document Server

    Colwell, Morris A

    1976-01-01

    Electronic Components provides a basic grounding in the practical aspects of using and selecting electronics components. The book describes the basic requirements needed to start practical work on electronic equipment, resistors and potentiometers, capacitance, and inductors and transformers. The text discusses semiconductor devices such as diodes, thyristors and triacs, transistors and heat sinks, logic and linear integrated circuits (I.C.s) and electromechanical devices. Common abbreviations applied to components are provided. Constructors and electronics engineers will find the book useful

  15. 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%.

  16. 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.

  17. 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.

  18. A Review: Molecular Aberrations within Hippo Signaling in Bone and Soft Tissue Sarcomas

    Directory of Open Access Journals (Sweden)

    Michael D Deel

    2015-09-01

    Full Text Available The Hippo signaling pathway is an evolutionarily conserved developmental network vital for the regulation of organ size, tissue homeostasis, repair and regeneration, and cell fate. The Hippo pathway has also been shown to have tumor suppressor properties. Hippo transduction involves a series of kinases and scaffolding proteins that are intricately connected to proteins in developmental cascades and in the tissue microenvironment. This network governs the downstream Hippo transcriptional coactivators YAP and TAZ, which bind to and activate the output of TEADs, as well as other transcription factors responsible for cellular proliferation, self-renewal, differentiation, and survival. Surprisingly, there are few oncogenic mutations within the core components of the Hippo pathway. Instead, dysregulated Hippo signaling is a versatile accomplice to commonly mutated cancer pathways. For example, YAP and TAZ can be activated by oncogenic signaling from other pathways, or serve as coactivators for classical oncogenes. Emerging evidence suggests that Hippo signaling couples cell density and cytoskeletal structural changes to morphogenic signals, and conveys a mesenchymal phenotype. While much of Hippo biology has been described in epithelial cell systems, it is clear that dysregulated Hippo signaling also contributes to malignancies of mesenchymal origin. This review will summarize the known molecular alterations within the Hippo pathway in sarcomas, and highlight how several pharmacologic compounds have shown activity in modulating Hippo components, providing proof-of-principle that Hippo signaling may be harnessed for therapeutic application in sarcomas.

  19. Intercellular signaling pathways active during and after growth and differentiation of the lumbar vertebral growth plate.

    Science.gov (United States)

    Dahia, Chitra Lekha; Mahoney, Eric J; Durrani, Atiq A; Wylie, Christopher

    2011-06-15

    Vertebral growth plates at different postnatal ages were assessed for active intercellular signaling pathways. To generate a spatial and temporal map of the major signaling pathways active in the postnatal mouse lumbar vertebral growth plate. The growth of all long bones is known to occur by cartilaginous growth plates. The growth plate is composed of layers of chondrocyets that actively proliferate, differentiate, die and, are replaced by bone. The role of major cell signaling pathways has been suggested for regulation of the fetal long bones. But not much is known about the molecular or cellular signals that control the postnatal vertebral growth plate and hence postnatal vertebral bone growth. Understanding such molecular mechanisms will help design therapeutic treatments for vertebral growth disorders such as scoliosis. Antibodies against activated downstream intermediates were used to identify cells in the growth plate responding to BMP, TGFβ, and FGF in cryosections of lumbar vertebrae from different postnatal age mice to identify the zones that were responding to these signals. Reporter mice were used to identify the chondrocytes responding to hedgehog (Ihh), and Wnt signaling. We present a spatial/temporal map of these signaling pathways during growth, and differentiation of the mouse lumbar vertebral growth plate. During growth and differentiation of the vertebral growth plate, its different components respond at different times to different intercellular signaling ligands. Response to most of these signals is dramatically downregulated at the end of vertebral growth.

  20. 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

  1. Destabilization of strigolactone receptor DWARF14 by binding of ligand and E3-ligase signaling effector DWARF3

    Science.gov (United States)

    Zhao, Li-Hua; Zhou, X Edward; Yi, Wei; Wu, Zhongshan; Liu, Yue; Kang, Yanyong; Hou, Li; de Waal, Parker W; Li, Suling; Jiang, Yi; Scaffidi, Adrian; Flematti, Gavin R; Smith, Steven M; Lam, Vinh Q; Griffin, Patrick R; Wang, Yonghong; Li, Jiayang; Melcher, Karsten; Xu, H Eric

    2015-01-01

    Strigolactones (SLs) are endogenous hormones and exuded signaling molecules in plant responses to low levels of mineral nutrients. Key mediators of the SL signaling pathway in rice include the α/β-fold hydrolase DWARF 14 (D14) and the F-box component DWARF 3 (D3) of the ubiquitin ligase SCFD3 that mediate ligand-dependent degradation of downstream signaling repressors. One perplexing feature is that D14 not only functions as the SL receptor but is also an active enzyme that slowly hydrolyzes diverse natural and synthetic SLs including GR24, preventing the crystallization of a binary complex of D14 with an intact SL as well as the ternary D14/SL/D3 complex. Here we overcome these barriers to derive a structural model of D14 bound to intact GR24 and identify the interface that is required for GR24-mediated D14-D3 interaction. The mode of GR24-mediated signaling, including ligand recognition, hydrolysis by D14, and ligand-mediated D14-D3 interaction, is conserved in structurally diverse SLs. More importantly, D14 is destabilized upon the binding of ligands and D3, thus revealing an unusual mechanism of SL recognition and signaling, in which the hormone, the receptor, and the downstream effectors are systematically destabilized during the signal transduction process. PMID:26470846

  2. Interaction of TGFβ and BMP signaling pathways during chondrogenesis.

    Directory of Open Access Journals (Sweden)

    Bettina Keller

    2011-01-01

    Full Text Available TGFβ and BMP signaling pathways exhibit antagonistic activities during the development of many tissues. Although the crosstalk between BMP and TGFβ signaling pathways is well established in bone development, the relationship between these two pathways is less well defined during cartilage development and postnatal homeostasis. We generated hypomorphic mouse models of cartilage-specific loss of BMP and TGFβ signaling to assess the interaction of these pathways in postnatal growth plate homeostasis. We further used the chondrogenic ATDC5 cell line to test effects of BMP and TGFβ signaling on each other's downstream targets. We found that conditional deletion of Smad1 in chondrocytes resulted in a shortening of the growth plate. The addition of Smad5 haploinsufficiency led to a more severe phenotype with shorter prehypertrophic and hypertrophic zones and decreased chondrocyte proliferation. The opposite growth plate phenotype was observed in a transgenic mouse model of decreased chondrocytic TGFβ signaling that was generated by expressing a dominant negative form of the TGFβ receptor I (ΔTβRI in cartilage. Histological analysis demonstrated elongated growth plates with enhanced Ihh expression, as well as an increased proliferation rate with altered production of extracellular matrix components. In contrast, in chondrogenic ATDC5 cells, TGFβ was able to enhance BMP signaling, while BMP2 significantly reduces levels of TGF signaling. In summary, our data demonstrate that during endochondral ossification, BMP and TGFβ signaling can have antagonistic effects on chondrocyte proliferation and differentiation in vivo. We also found evidence of direct interaction between the two signaling pathways in a cell model of chondrogenesis in vitro.

  3. 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.

  4. Synaptic membrane rafts: traffic lights for local neurotrophin signaling?

    Science.gov (United States)

    Zonta, Barbara; Minichiello, Liliana

    2013-10-18

    Lipid rafts, cholesterol and lipid rich microdomains, are believed to play important roles as platforms for the partitioning of transmembrane and synaptic proteins involved in synaptic signaling, plasticity, and maintenance. There is increasing evidence of a physical interaction between post-synaptic densities and post-synaptic lipid rafts. Localization of proteins within lipid rafts is highly regulated, and therefore lipid rafts may function as traffic lights modulating and fine-tuning neuronal signaling. The tyrosine kinase neurotrophin receptors (Trk) and the low-affinity p75 neurotrophin receptor (p75(NTR)) are enriched in neuronal lipid rafts together with the intermediates of downstream signaling pathways, suggesting a possible role of rafts in neurotrophin signaling. Moreover, neurotrophins and their receptors are involved in the regulation of cholesterol metabolism. Cholesterol is an important component of lipid rafts and its depletion leads to gradual loss of synapses, underscoring the importance of lipid rafts for proper neuronal function. Here, we review and discuss the idea that translocation of neurotrophin receptors in synaptic rafts may account for the selectivity of their transduced signals.

  5. Synaptic membrane rafts: traffic lights for local neurotrophin signalling?

    Directory of Open Access Journals (Sweden)

    Barbara eZonta

    2013-10-01

    Full Text Available Lipid rafts, cholesterol and lipid rich microdomains, are believed to play important roles as platforms for the partitioning of transmembrane and synaptic proteins involved in synaptic signalling, plasticity and maintenance. There is increasing evidence of a physical interaction between post-synaptic densities and post-synaptic lipid rafts. Localization of proteins within lipid rafts is highly regulated, and therefore lipid rafts may function as traffic lights modulating and fine-tuning neuronal signalling. The tyrosine kinase neurotrophin receptors (Trk and the low-affinity p75 neurotrophin receptor (p75NTR are enriched in neuronal lipid rafts together with the intermediates of downstream signalling pathways, suggesting a possible role of rafts in neurotrophin signalling. Moreover, neurotrophins and their receptors are involved in the regulation of cholesterol metabolism. Cholesterol is an important component of lipid rafts and its depletion leads to gradual loss of synapses, underscoring the importance of lipid rafts for proper neuronal function. Here, we review and discuss the idea that translocation of neurotrophin receptors in synaptic rafts may account for the selectivity of their transduced signals.

  6. Limonin, a Component of Dictamni Radicis Cortex, Inhibits Eugenol-Induced Calcium and cAMP Levels and PKA/CREB Signaling Pathway in Non-Neuronal 3T3-L1 Cells

    Directory of Open Access Journals (Sweden)

    Yeo Cho Yoon

    2015-12-01

    Full Text Available Limonin, one of the major components in dictamni radicis cortex (DRC, has been shown to play various biological roles in cancer, inflammation, and obesity in many different cell types and tissues. Recently, the odorant-induced signal transduction pathway (OST has gained attention not only because of its function in the perception of smell but also because of its numerous physiological functions in non-neuronal cells. However, little is known about the effects of limonin and DRC on the OST pathway in non-neuronal cells. We investigated odorant-stimulated increases in Ca2+ and cAMP, major second messengers in the OST pathway, in non-neuronal 3T3-L1 cells pretreated with limonin and ethanol extracts of DRC. Limonin and the extracts significantly decreased eugenol-induced Ca2+ and cAMP levels and upregulated phosphorylation of CREB and PKA. Our results demonstrated that limonin and DRC extract inhibit the OST pathway in non-neuronal cells by modulating Ca2+ and cAMP levels and phosphorylation of CREB.

  7. 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

  8. 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.

  9. 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...

  10. 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.

  11. 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...

  12. The downstream externalities of harvesting rainwater in semi-arid watersheds: an Indian case study

    NARCIS (Netherlands)

    Bouma, J.A.; Biggs, T.W.; Bouwer, L.M.

    2011-01-01

    Water-related investment projects affect downstream water availability, and therefore should account for these externalities. Few projects do, however, owing to lack of awareness, lack of data and difficulty in linking upstream investments to downstream effects. This article assesses the downstream

  13. From gravel to sand. Downstream fining of bed sediments in the lower river Rhine

    NARCIS (Netherlands)

    Frings, R.M.

    2007-01-01

    A common characteristic of many rivers is the tendency for bed sediments to become finer in downstream direction. This phenomenon, which is generally known as downstream fining, has a strong effect on the morphologic and hydrodynamic behaviour of a river. The fundamental causes of downstream

  14. Operating multireservoir hydropower systems for downstream water quality

    International Nuclear Information System (INIS)

    Hayes, D.F.

    1990-01-01

    Hydropower reservoir operations often impact tailwater quality and water quality in the stream or river below the impoundment for many miles. Determining optimal operating strategies for a system of hydropower reservoirs involves solving a highly dimensional nonlinear, nonconvex optimization problem. This research adds the additional complexities of downstream water quality considerations within the optimization formulation to determine operating strategies for a system of hydropower reservoirs operating in series (tandem) or parallel. The formulation was used to determine operating strategies for six reservoirs of the upper Cumberland river basin in Tennessee and Kentucky. Significant dissolved oxygen (DO) violations occur just upstream of Nashville, Tennessee below Old Hickory dam during the months of August and September. Daily reservoir releases were determined for the period of June through September which would produce the maximum hydropower revenue while meeting downstream water quality objectives. Optimal releases for three operational strategies were compared to historical operations for the years 1985, 1986, and 1988. These strategies included: spilling as necessary to meet water quality criteria, near normal operation (minimal spills), and drawdown of reservoirs as necessary to meet criteria without spills. Optimization results showed an 8% to 15% hydropower loss may be necessary to meet water quality criteria through spills and a 2% to 9% improvement in DO below Old Hickory may be possible without significant spills. Results also showed that substantial increases in initial headwater elevations would be necessary to meet daily DO criteria and avoid spills. The optimal control theory algorithm used to solve the problem proved to be an efficient and robust solver of this large optimization problem

  15. Downstream cumulative effects of land use on freshwater communities

    Science.gov (United States)

    Kuglerová, L.; Kielstra, B. W.; Moore, D.; Richardson, J. S.

    2015-12-01

    Many streams and rivers are subject to disturbance from intense land use such as urbanization and agriculture, and this is especially obvious for small headwaters. Streams are spatially organized into networks where headwaters represent the tributaries and provide water, nutrients, and organic material to the main stems. Therefore perturbations within the headwaters might be cumulatively carried on downstream. Although we know that the disturbance of headwaters in urban and agricultural landscapes poses threats to downstream river reaches, the magnitude and severity of these changes for ecological communities is less known. We studied stream networks along a gradient of disturbance connected to land use intensity, from urbanized watersheds to watersheds placed in agricultural settings in the Greater Toronto Area. Further, we compared the patterns and processes found in the modified watershed to a control watershed, situated in a forested, less impacted landscape. Preliminary results suggest that hydrological modifications (flash floods), habitat loss (drainage and sewer systems), and water quality issues of small streams in urbanized and agricultural watersheds represent major disturbances and threats for aquatic and riparian biota on local as well as larger spatial scales. For example, communities of riparian plants are dominated by species typical of the land use on adjacent uplands as well as the dominant land use on the upstream contributing area, instead of riparian obligates commonly found in forested watersheds. Further, riparian communities in disturbed environments are dominated by invasive species. The changes in riparian communities are vital for various functions of riparian vegetation. Bank erosion control is suppressed, leading to severe channel transformations and sediment loadings in urbanized watersheds. Food sources for instream biota and thermal regimes are also changed, which further triggers alterations of in-stream biological communities

  16. Electrostatic quasi-monochromatic waves in the downstream region of the Earth's bow shock based on Geotail observations

    Science.gov (United States)

    Shin, K.; Kojima, H.; Matsumoto, H.; Mukai, T.

    2007-02-01

    Geotail plasma wave observations show the existence of intense electrostatic quasi-monochromatic (EQM) waves in the downstream region of the Earth's bow shock. They oscillate parallel to the ambient magnetic field and appear at frequencies between the electron plasma and ion plasma frequencies. Although these waves have been believed to be Doppler-shifted ion acoustic waves, the typical plasma parameters observed in the downstream region do not support the generation conditions for ion acoustic waves. In this paper, the existence of cold electron beam-like components accompanying EQM waves is considered based on waveform and statistical analyses. Linear dispersion analyses using realistic plasma parameters revealed that the cold electron beams cause destabilization of electron acoustic waves at frequencies consistent with those of observed EQM waves. The results of observations and linear analyses suggest that EQM waves are generated by the destabilization of the electron acoustic mode.

  17. Syndecans – key regulators of cell signaling and biological functions

    DEFF Research Database (Denmark)

    Afratis, Nikolaos A.; Nikitovic, Dragana; Multhaupt, Hinke A.B.

    2017-01-01

    molecules during cancer initiation and progression. Particularly syndecans interact with other cell surface receptors, such as growth factor receptors and integrins, which lead to activation of downstream signaling pathways, which are critical for the cellular behavior. Moreover, this review describes...

  18. 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.

  19. 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

  20. Wnt/β-catenin and LIF-Stat3 signaling pathways converge on Sp5 to promote mouse embryonic stem cell self-renewal.

    Science.gov (United States)

    Ye, Shoudong; Zhang, Dongming; Cheng, Fei; Wilson, Daniel; Mackay, Jeffrey; He, Kan; Ban, Qian; Lv, Feng; Huang, Saifei; Liu, Dahai; Ying, Qi-Long

    2016-01-15

    Activation of leukemia inhibitor factor (LIF)-Stat3 or Wnt/β-catenin signaling promotes mouse embryonic stem cell (mESC) self-renewal. A myriad of downstream targets have been identified in the individual signal pathways, but their common targets remain largely elusive. In this study, we found that the LIF-Stat3 and Wnt/β-catenin signaling pathways converge on Sp5 to promote mESC self-renewal. Forced Sp5 expression can reproduce partial effects of Wnt/β-catenin signaling but mimics most features of LIF-Stat3 signaling to maintain undifferentiated mESCs. Moreover, Sp5 is able to convert mouse epiblast stem cells into a naïve pluripotent state. Thus, Sp5 is an important component of the regulatory network governing mESC naïve pluripotency. © 2016. Published by The Company of Biologists Ltd.

  1. Analysis of signal transduction in cell-free extracts and rafts of Xenopus eggs.

    Science.gov (United States)

    Tokmakov, Alexander A; Iwasaki, Tetsushi; Sato, Ken-Ichi; Fukami, Yasuo

    2010-05-01

    Intracellular signaling during egg activation/fertilization has been extensively studied using intact eggs, which can be manipulated by microinjection of different mRNAs, proteins, or chemical drugs. Furthermore, egg extracts, which retain high CSF activity (CSF-arrested extracts), were developed for studying fertilization/activation signal transduction, which have significant advantages as a model system. The addition of calcium to CSF-arrested extracts initiates a plethora of signaling events that take place during egg activation. Hence, the signaling downstream of calcium mobilization has been successfully studied in the egg extracts. Moreover, despite disruption of membrane-associated signaling compartments and ordered compartmentalization during extract preparation, CSF-arrested extracts can be successfully used to study early signaling events, which occur upstream of calcium release during egg activation/fertilization. In combination with the CSF-arrested extracts, activated egg rafts can reproduce some events of egg activation, including PLCgamma activation, IP3 production, transient calcium release, MAPK inactivation, and meiotic exit. This becomes possible due to complementation of the sperm-induced egg activation signaling machinery present in the rafts with the components of signal transduction system localized in the extracts. Herein, we describe protocols for studying molecular mechanisms of egg fertilization/activation using cell-free extracts and membrane rafts prepared from metaphase-arrested Xenopus eggs.

  2. Porcine Circovirus-Like Virus P1 Inhibits Wnt Signaling Pathway in Vivo and in Vitro.

    Science.gov (United States)

    Zhu, Xuejiao; Wen, Libin; Sheng, Shaoyang; Wang, Wei; Xiao, Qi; Qu, Meng; Hu, Yiyi; Liu, Chuanmin; He, Kongwang

    2018-01-01

    Porcine circovirus-like virus P1 is an important pathogen of the current pig industry, the infection mechanism is not entirely clear. Wnt signaling pathway plays an important role in the growth of young animals and infection of some viruses. This study was designed to demonstrate the effects of P1 infection on the Wnt signaling pathway. In vivo experiments, we demonstrated the down-regulatory effects of P1 infection in piglets and mice on the downstream components expression levels of Wnt signaling pathway, and the effects of Wnt signaling pathway activation on the pathogenesis of P1. In vitro studies, we found P1 infection down-regulated protein level of β-catenin and mRNA level of mmp2, prevented the β-catenin from entering into nucleus, abolished the TCF/LEF promoter activity, proved that P1 could inhibit the activation of Wnt signaling pathway in vitro . Finally, we found that VP1 of P1 virus also had the inhibitory effects on Wnt signaling pathway in vitro , elucidated the mechanism of P1's inhibitory effects on the Wnt signaling pathway and offered the possibility that the suppression of Wnt signaling pathway was involved in the post-weaning multisystemic wasting syndrome (PMWS), laying a foundation for elucidating the pathogenesis of P1.

  3. Porcine Circovirus-Like Virus P1 Inhibits Wnt Signaling Pathway in Vivo and in Vitro

    Directory of Open Access Journals (Sweden)

    Xuejiao Zhu

    2018-03-01

    Full Text Available Porcine circovirus-like virus P1 is an important pathogen of the current pig industry, the infection mechanism is not entirely clear. Wnt signaling pathway plays an important role in the growth of young animals and infection of some viruses. This study was designed to demonstrate the effects of P1 infection on the Wnt signaling pathway. In vivo experiments, we demonstrated the down-regulatory effects of P1 infection in piglets and mice on the downstream components expression levels of Wnt signaling pathway, and the effects of Wnt signaling pathway activation on the pathogenesis of P1. In vitro studies, we found P1 infection down-regulated protein level of β-catenin and mRNA level of mmp2, prevented the β-catenin from entering into nucleus, abolished the TCF/LEF promoter activity, proved that P1 could inhibit the activation of Wnt signaling pathway in vitro. Finally, we found that VP1 of P1 virus also had the inhibitory effects on Wnt signaling pathway in vitro, elucidated the mechanism of P1’s inhibitory effects on the Wnt signaling pathway and offered the possibility that the suppression of Wnt signaling pathway was involved in the post-weaning multisystemic wasting syndrome (PMWS, laying a foundation for elucidating the pathogenesis of P1.

  4. Multimodal signal variation in space and time : how important is matching a signal with its signaler?

    OpenAIRE

    Taylor, Ryan C.; Klein, Barrett; Stein, Joey; Ryan, Michael J.

    2011-01-01

    Multimodal signals (acoustic+visual) are known to be used by many anuran amphibians during courtship displays. The relative degree to which each signal component influences female mate choice, however, remains poorly understood. In this study we used a robotic frog with an inflating vocal sac and acoustic playbacks to document responses of female túngara frogs to unimodal signal components (acoustic and visual). We then tested female responses to a synchronous multimodal signal. Finally, we t...

  5. Abscisic Acid and abiotic stress signaling.

    Science.gov (United States)

    Tuteja, Narendra

    2007-05-01

    Abiotic stress is severe environmental stress, which impairs crop production on irrigated land worldwide. Overall, the susceptibility or tolerance to the stress in plants is a coordinated action of multiple stress responsive genes, which also cross-talk with other components of stress signal transduction pathways. Plant responses to abiotic stress can be determined by the severity of the stress and by the metabolic status of the plant. Abscisic acid (ABA) is a phytohormone critical for plant growth and development and plays an important role in integrating various stress signals and controlling downstream stress responses. Plants have to adjust ABA levels constantly in responce to changing physiological and environmental conditions. To date, the mechanisms for fine-tuning of ABA levels remain elusive. The mechanisms by which plants respond to stress include both ABA-dependent and ABA-independent processes. Various transcription factors such as DREB2A/2B, AREB1, RD22BP1 and MYC/MYB are known to regulate the ABA-responsive gene expression through interacting with their corrosponding cis-acting elements such as DRE/CRT, ABRE and MYCRS/MYBRS, respectively. Understanding these mechanisms is important to improve stress tolerance in crops plants. This article first describes the general pathway for plant stress response followed by roles of ABA and transcription factors in stress tolerance including the regulation of ABA biosynthesis.

  6. Specific components of face perception in the human fusiform gyrus studied by tomographic estimates of magnetoencephalographic signals: a tool for the evaluation of non-verbal communication in psychosomatic paradigms

    Directory of Open Access Journals (Sweden)

    Ioannides Andreas A

    2007-12-01

    Full Text Available Abstract Aims The aim of this study was to determine the specific spatiotemporal activation patterns of face perception in the fusiform gyrus (FG. The FG is a key area in the specialized brain system that makes possible the recognition of face with ease and speed in our daily life. Characterization of FG response provides a quantitative method for evaluating the fundamental functions that contribute to non-verbal communication in various psychosomatic paradigms. Methods The MEG signal was recorded during passive visual stimulus presentation with three stimulus types – Faces, Hands and Shoes. The stimuli were presented separately to the central and peripheral visual fields. We performed statistical parametric mapping (SPM analysis of tomographic estimates of activity to compare activity between a pre- and post-stimulus period in the same object (baseline test, and activity between objects (active test. The time course of regional activation curves was analyzed for each stimulus condition. Results The SPM baseline test revealed a response to each stimulus type, which was very compact at the initial segment of main MFG170. For hands and shoes the area of significant change remains compact. For faces the area expanded widely within a few milliseconds and its boundaries engulfed the other object areas. The active test demonstrated that activity for faces was significantly larger than the activity for hands. The same face specific compact area as in the baseline test was identified, and then again expanded widely. For each stimulus type and presentation in each one of the visual fields locations, the analysis of the time course of FG activity identified three components in the FG: MFG100, MFG170, and MFG200 – all showed preference for faces. Conclusion Early compact face-specific activity in the FG expands widely along the occipito-ventral brain within a few milliseconds. The significant difference between faces and the other object stimuli in MFG

  7. Downstream process development in biotechnological itaconic acid manufacturing.

    Science.gov (United States)

    Magalhães, Antonio Irineudo; de Carvalho, Júlio Cesar; Medina, Jesus David Coral; Soccol, Carlos Ricardo

    2017-01-01

    Itaconic acid is a promising chemical that has a wide range of applications and can be obtained in large scale using fermentation processes. One of the most important uses of this biomonomer is the environmentally sustainable production of biopolymers. Separation of itaconic acid from the fermented broth has a considerable impact in the total production cost. Therefore, optimization and high efficiency downstream processes are technological challenges to make biorefineries sustainable and economically viable. This review describes the current state of the art in recovery and purification for itaconic acid production via bioprocesses. Previous studies on the separation of itaconic acid relying on operations such as crystallization, precipitation, extraction, electrodialysis, diafiltration, pertraction, and adsorption. Although crystallization is a typical method of itaconic acid separation from fermented broth, other methods such as membrane separation and reactive extraction are promising as a recovery steps coupled to the fermentation, potentially enhancing the overall process yield. Another approach is adsorption in fixed bed columns, which efficiently separates itaconic acid. Despite recent advances in separation and recovery methods, there is still space for improvement in IA recovery and purification.

  8. Simulation of hanging dams downstream of Ossauskoski power plant

    Energy Technology Data Exchange (ETDEWEB)

    Aaltonen, J.; Huokuna, M. [Finnish Environment Inst., Helsinki (Finland); Severinkangas, K.; Talvensaari, M. [Kemijoki Oy, Rovaniemi (Finland)

    2008-07-01

    Sixteen power plants have been constructed along Finland's Kemijoki River for hydroelectric power production. The Ossauskoski facility has recently undergone major renovations and upgrade, making it the sixth largest hydroelectric power plant in Finland, with a new capacity of 124 MW and an annual energy output of 501 GWh. The increase in power output and discharge may cause changes in ice conditions downstream of the power plant. The section of the river is already subjected to frazil ice problems and hanging dam formation. Discharges and adverse effects of frazil ice phenomena are likely to increase due to climate change, resulting in harm for hydropower production and the environment, particularly in flow regulated rivers where winter discharges are higher than natural discharges. As such, a study was launched to investigate a dredge plan suggested by by the electric utility Kemijoki Oy. The project involved mapping the river bed topography to identify the location and extent of hanging dams. A sounding device and ground penetrating radar was used to find the thaw regions in the ice cover. The JJT numerical river ice model was effectively used to study the effect of hanging dams on water levels. However, the ice bridging phenomena was not modelled in a reliable way by the JJT model and will be modelled in the future using the CRISSP2D numerical model. 5 refs., 11 figs.

  9. Energy taxes and subsidies downstream: transparency and dissemination

    International Nuclear Information System (INIS)

    Aissaour, A.

    2001-01-01

    The reasons why governments levy taxes are discussed with special reference to the energy sector. The article focuses on the quantitative aspect of policies and gives a guide to the relevant statistical sources. It summarises the basis of taxes and subsidies and discusses the incidence of energy taxation together with the structure of taxes and subsidies in energy downstream. It reviews the main sources of data and issues highlighted by published statistics and the impact of taxes levied on the consumption of energy products and other taxes (e.g. VAT) which directly affect end-user prices. Production-based levies such as royalties, petroleum revenue taxes, windfall taxes and import and export taxes on fuels are not discussed. The paper is presented under the sub-headings of (i) theoretical foundations in a nutshell; (ii) the incidence of taxation; (iii) the structure and main features of energy taxation (iv) base rate and level of taxation (v) sources of data and methods and (vi) observability and comparability

  10. Gellan Gum: Fermentative Production, Downstream Processing and Applications

    Directory of Open Access Journals (Sweden)

    Ishwar B. Bajaj

    2007-01-01

    Full Text Available The microbial exopolysaccharides are water-soluble polymers secreted by microorganisms during fermentation. The biopolymer gellan gum is a relatively recent addition to the family of microbial polysaccharides that is gaining much importance in food, pharmaceutical and chemical industries due to its novel properties. It is commercially produced by C. P. Kelco in Japan and the USA. Further research and development in biopolymer technology is expected to expand its use. This article presents a critical review of the available information on the gellan gum synthesized by Sphingomonas paucimobilis with special emphasis on its fermentative production and downstream processing. Rheological behaviour of fermentation broth during fermentative production of gellan gum and problems associated with mass transfer have been addressed. Information on the biosynthetic pathway of gellan gum, enzymes and precursors involved in gellan gum production and application of metabolic engineering for enhancement of yield of gellan gum has been specified. Characteristics of gellan gum with respect to its structure, physicochemical properties, rheology of its solutions and gel formation behaviour are discussed. An attempt has also been made to review the current and potential applications of gellan gum in food, pharmaceutical and other industries.

  11. Glomerular prostaglandins modulate vascular reactivity of the downstream efferent arterioles.

    Science.gov (United States)

    Arima, S; Ren, Y; Juncos, L A; Carretero, O A; Ito, S

    1994-03-01

    The balance of vascular resistance in afferent (Af-) and efferent arterioles (Ef-Arts) is a crucial factor that determines glomerular hemodynamics. We have recently reported that when Ef-Arts were perfused from the distal end of the Af-Art through the glomerulus (orthograde perfusion; OP), both angiotensin II (Ang II) and norepinephrine (NE) induced much weaker constriction than they did when Ef-Arts were perfused from the distal end (retrograde perfusion; RP). This difference was not affected by inhibiting synthesis of nitric oxide. In the present study, we tested the hypothesis that glomerular prostaglandins (PGs) may modulate vascular reactivity of the downstream Ef-Art. In addition, we examined the possible modulatory role of PGs in the Af-Art responses to Ang II or NE. Both Ang II and NE caused dose-dependent constriction of Ef-Arts with either OP or RP; however, the constriction was stronger in RP. At 10(-8) M, Ang II decreased Ef-Art diameter by 35 +/- 3.5% in OP (N = 9) compared to 73 +/- 3.9% in RP (N = 5), while 10(-6) M NE decreased the diameter by 25 +/- 3.6% in OP (N = 9) compared to 62 +/- 7.2% in RP (N = 5). Pretreatment with 5 x 10(-5) M indomethacin (Indo) did not alter basal diameter with either method of perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

  12. Flume experiments on scour downstream of wood stream restoration structures

    Science.gov (United States)

    Pagliara, Stefano; Kurdistani, Sahameddin Mahmoudi

    2017-02-01

    River restoration aims to improve physical natural form and processes of a river. Techniques to control the riverbed, stabilize channel alignment, protect stream banks, and rebuild the natural habitat are an important part of river restoration projects. Rivers can be stabilized and habitat restored through techniques such as rebuilding meanders and pool-riffle sequences and managing large wood. Structures that limit channel width to accelerate the normal flows through the constricted section are referred to as stream deflectors. Single-wing, double-wing and triangular deflectors are the most commonly used types of this measure. Log-frame deflectors consist of a triangular log frame filled with rock. Deflector constructions singly or in series in low gradient meandering streams, divert base flows toward the center of the channel and, under certain conditions, increase the depth and velocity of flow thereby creating scour pools and enhancing fish habitat. Scour characteristics and morphologies downstream of log-frame deflectors have been analyzed at the hydraulic laboratory of the University of Pisa. All experiments have been carried out in clear water conditions. The results showed that the tailwater depth plays an important role on scour characteristics. In addition, it was experimentally proven that using log-frame deflectors instead of log-deflectors result in a better river bank protection. In this case, for all the tested hydraulic conditions, the scour hole never occurred close to the channel bank. Useful empirical relationships have been proposed in order to evaluate the main features of the scour geometry.

  13. Incidental potable water reuse in a Catalonian basin: living downstream

    Directory of Open Access Journals (Sweden)

    R. Mujeriego

    2017-09-01

    Full Text Available A preliminary assessment of incidental potable water reuse (IPR in the Llobregat River basin has been conducted by estimating the dilution factor of treated effluent discharges upstream of six river flow measurement sections. IPR in the Llobregat River basin is an everyday occurrence, because of the systematic discharge of treated effluents upstream of river sections used as drinking water sources. Average river flows at the Sant Joan Despí measurement section increased from 400,000 m3/d (2007 to 864,000 m3/d (2008 and to 931,000 m3/d (2013, while treated effluent discharges upstream of that section ranged from 109,000 m3/d to 114,000 m3/d in those years. The highest degree of IPR occurs downstream of the Abrera and Sant Joan Despí flow measurement sections, from where about half of the drinking water supplied to the Barcelona Metropolitan Area is abstracted. Based on average annual flows, the likelihood that drinking water produced from that river stretch contained treated effluent varied from 25% (2007 to 13% (2008 and to 12% (2013. Water agencies and drinking water production utilities have strived for decades to ensure that drinking water production satisfies applicable quality requirements and provides the required public health protection.

  14. Downstream Processing, Formulation Development and Antithrombotic Evaluation of Microbial Nattokinase.

    Science.gov (United States)

    Kapoor, Rohit; Harde, Harshad; Jain, Sanyog; Panda, Amulya Kumar; Panda, Bibhu Prasad

    2015-07-01

    The present research work describes the downstreaming of nattokinase (NK) produced by Bacillus subtilis under solid state fermentation; and the role of efficient oral formulation of purified NK in the management of thrombotic disorders. Molecular weight of purified NK was estimated to be 28 kDa with specific activity of 504.4 FU/mg. Acid stable nattokinase loaded chitosan nanoparticles (sNLCN) were fabricated for oral delivery of this enzyme. Box-Behnken design (BBD) was employed to investigate and validate the effect of process (independent) variables on the quality attributes (dependent variables) of nanoparticles. The integrity, conformational stability and preservation of fibrinolytic activity of NK (in both free and sNLCN forms) were established by SDS-PAGE, CD analysis and in vitro clot lytic examination, respectively. A 'tail thrombosis model' demonstrated significant decrease in frequency of thrombosis in Wistar rats upon peroral administration of sNLCN in comparison with negative control and free NK group. Furthermore, coagulation analysis, namely the measurement of prothrombin and activated partial thromboplastin time illustrated that sNLCN showed significantly (p < 0.001) higher anti-thrombotic potential in comparison to the free NK. Further, sNLCN showed anti-thrombotic profile similar to warfarin. This study signifies the potential of sNLCN in oral delivery of NK for the management of thrombotic disorders.

  15. Principal components

    NARCIS (Netherlands)

    Hallin, M.; Hörmann, S.; Piegorsch, W.; El Shaarawi, A.

    2012-01-01

    Principal Components are probably the best known and most widely used of all multivariate analysis techniques. The essential idea consists in performing a linear transformation of the observed k-dimensional variables in such a way that the new variables are vectors of k mutually orthogonal

  16. The IRS-1 signaling system.

    Science.gov (United States)

    Myers, M G; Sun, X J; White, M F

    1994-07-01

    Insulin-receptor substrate 1 (IRS-1) is a principal substrate of the receptor tyrosine kinase for insulin and insulin-like growth factor 1, and a substrate for a tyrosine kinase activated by interleukin 4. IRS-1 undergoes multisite tyrosine phosphorylation and mediates downstream signals by 'docking' various proteins that contain Src homology 2 domains. IRS-1 appears to be a unique molecule; however, 4PS, a protein found mainly in hemopoietic cells, may represent another member of this family.

  17. Environmental radiological studies downstream from Rancho Seco Nuclear Power Generating Station

    International Nuclear Information System (INIS)

    Noshkin, V.E.; Wong, K.M.; Eagle, R.J.; Dawson, J.W.; Brunk, J.L.; Jokela, T.A.

    1985-01-01

    This report summarizes the information compiled in 1984 while assessing the environmental impact of radionuclides in aquatic releases from the Rancho Seco Nuclear Power Generating Station. Gamma-emitting radionuclides discharged since 1981 are found in many of the dietary components derived from the creeks receiving the effluent wastewater. Some soils and crops are found to contain radionuclides that originate from the contaminated water that was transferred to land during the irrigation season. 134 Cs and 137 Cs are the primary gamma-emitting radionuclides detected in the edible flesh of fish from the creeks. Concentrations in the flesh of fish decreased exponentially with distance from the plant. No significant differences in the 137 Cs activity were found between male and female fish of equal size, but concentrations may vary in fish of different size, with the season and diet. 21% of the total 137 Cs and 134 Cs discharged between 1981 and 1984 is associated with the creek sediments to a distance of 27 km from the plant. Fractions of the missing inventory have been transferred to land during the irrigation season or to downstream regions more distant than 27 km from the plant. The radiocesium content of the sediments in 1984 decreased significantly in a downstream direction, much in the same manner as concentrations decreased in fish. Radioactivity originating from the plant was not above detection limits in any terrestrial food item sampled beyond 6.5 km from the plant. Based on the usage factors provided by individuals interviewed in a 1984 survey, the fish and aquatic-organism ingestion pathway contributed the largest radiological dose to humans utilizing products contaminated with the radionuclides in the liquid wastes discharged from the Rancho Seco Nuclear Power Generating Station in 1984

  18. 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

  19. Differences in sedge fen vegetation upstream and downstream from a managed impoundment

    Science.gov (United States)

    Kowalski, Kurt P.; Wilcox, Douglas A.

    2003-01-01

    The U.S. Fish and Wildlife Service proposed the restoration of wetlands impacted by a series of drainage ditches and pools located in an extensive undeveloped peatland in the Seney National Wildlife Refuge, Michigan. This study examined the nature and extent of degradation to the Marsh Creek wetlands caused by alteration of natural hydrology by a water-storage pool (C-3 Pool) that intersects the Marsh Creek channel. We tested the hypothesis that a reduction in moderate-intensity disturbance associated with natural water-level fluctuations below the C-3 dike contributed to lower species richness, reduced floristic quality and a larger tree and shrub component than vegetation upstream from the pool. Wetland plant communities were sampled quantitatively and analyzed for species richness, floristic quality and physiognomy. Aerial photographs, GIS databases and GPS data contributed to the characterization and analysis of the Marsh Creek wetlands. Results showed that there was lower species richness in vegetated areas downstream from the pool, but not the anticipated growth in shrubs. Wetland vegetation upstream and downstream from the pool had similar floristic quality, except for a greater number of weedy taxa above the pool. Seepage through the pool dike and localized ground-water discharge created conditions very similar to those observed around beaver dams in Marsh Creek. In essence, the dike containing the C-3 Pool affected hydrology and wetland plant communities in a manner similar to an enormous beaver dam, except that it did not allow seasonal flooding episodes to occur. Management actions to release water from the pool into the original Marsh Creek channel at certain times and in certain amounts that mimic the natural flow regime would be expected to promote greater plant species richness and minimize the negative impacts of the dike.

  20. A functional screen reveals an extensive layer of transcriptional and splicing control underlying RAS/MAPK signaling in Drosophila.

    Directory of Open Access Journals (Sweden)

    Dariel Ashton-Beaucage

    2014-03-01

    Full Text Available The small GTPase RAS is among the most prevalent oncogenes. The evolutionarily conserved RAF-MEK-MAPK module that lies downstream of RAS is one of the main conduits through which RAS transmits proliferative signals in normal and cancer cells. Genetic and biochemical studies conducted over the last two decades uncovered a small set of factors regulating RAS/MAPK signaling. Interestingly, most of these were found to control RAF activation, thus suggesting a central regulatory role for this event. Whether additional factors are required at this level or further downstream remains an open question. To obtain a comprehensive view of the elements functionally linked to the RAS/MAPK cascade, we used a quantitative assay in Drosophila S2 cells to conduct a genome-wide RNAi screen for factors impacting RAS-mediated MAPK activation. The screen led to the identification of 101 validated hits, including most of the previously known factors associated to this pathway. Epistasis experiments were then carried out on individual candidates to determine their position relative to core pathway components. While this revealed several new factors acting at different steps along the pathway--including a new protein complex modulating RAF activation--we found that most hits unexpectedly work downstream of MEK and specifically influence MAPK expression. These hits mainly consist of constitutive splicing factors and thereby suggest that splicing plays a specific role in establishing MAPK levels. We further characterized two representative members of this group and surprisingly found that they act by regulating mapk alternative splicing. This study provides an unprecedented assessment of the factors modulating RAS/MAPK signaling in Drosophila. In addition, it suggests that pathway output does not solely rely on classical signaling events, such as those controlling RAF activation, but also on the regulation of MAPK levels. Finally, it indicates that core splicing

  1. Endocrinology and the brain: corticotropin-releasing hormone signaling.

    Science.gov (United States)

    Inda, Carolina; Armando, Natalia G; Dos Santos Claro, Paula A; Silberstein, Susana

    2017-08-01

    Corticotropin-releasing hormone (CRH) is a key player of basal and stress-activated responses in the hypothalamic-pituitary-adrenal axis (HPA) and in extrahypothalamic circuits, where it functions as a neuromodulator to orchestrate humoral and behavioral adaptive responses to stress. This review describes molecular components and cellular mechanisms involved in CRH signaling downstream of its G protein-coupled receptors (GPCRs) CRHR1 and CRHR2 and summarizes recent findings that challenge the classical view of GPCR signaling and impact on our understanding of CRHRs function. Special emphasis is placed on recent studies of CRH signaling that revealed new mechanistic aspects of cAMP generation and ERK1/2 activation in physiologically relevant contexts of the neurohormone action. In addition, we present an overview of the pathophysiological role of the CRH system, which highlights the need for a precise definition of CRHRs signaling at molecular level to identify novel targets for pharmacological intervention in neuroendocrine tissues and specific brain areas involved in CRH-related disorders. © 2017 The authors.

  2. Water Scarcity Hotspots Travel Downstream Due to Human Interventions in the 20th and 21st Century

    Science.gov (United States)

    Veldkamp, T. I. E.; Wada, Y.; Aerts, J. C. J. H.; Doell, P.; Gosling, S. N.; Liu, J.; Masaki, Y.; Oki, T.; Ostberg, S.; Pokhrel, Y.; hide

    2017-01-01

    Water scarcity is rapidly increasing in many regions. In a novel, multi-model assessment, we examine how human interventions (HI: land use and land cover change, man-made reservoirs and human water use) affected monthly river water availability and water scarcity over the period 1971 - 2010. Here we show that HI drastically change the critical dimensions of water scarcity, aggravating water scarcity for 8.8%(7.4 - 16.5 %) ) of the global population but alleviating it for another 8.3 % (6.4 -15.8 %). Positive impacts of HI mostly occur upstream, whereas HI aggravate water scarcity downstream; HI cause water scarcity to travel downstream. Attribution of water scarcity changes to HI components is complex and varies among the hydrological models. Seasonal variation in impacts and dominant HI components is also substantial. A thorough consideration of the spatially and temporally varying interactions among HI components and of uncertainties is therefore crucial for the success of water scarcity adaptation by HI.

  3. Water scarcity hotspots travel downstream due to human interventions in the 20th and 21st century

    Science.gov (United States)

    Veldkamp, T. I. E.; Wada, Y.; Aerts, J. C. J. H.; Döll, P.; Gosling, S. N.; Liu, J.; Masaki, Y.; Oki, T.; Ostberg, S.; Pokhrel, Y.; Satoh, Y.; Kim, H.; Ward, P. J.

    2017-06-01

    Water scarcity is rapidly increasing in many regions. In a novel, multi-model assessment, we examine how human interventions (HI: land use and land cover change, man-made reservoirs and human water use) affected monthly river water availability and water scarcity over the period 1971-2010. Here we show that HI drastically change the critical dimensions of water scarcity, aggravating water scarcity for 8.8% (7.4-16.5%) of the global population but alleviating it for another 8.3% (6.4-15.8%). Positive impacts of HI mostly occur upstream, whereas HI aggravate water scarcity downstream; HI cause water scarcity to travel downstream. Attribution of water scarcity changes to HI components is complex and varies among the hydrological models. Seasonal variation in impacts and dominant HI components is also substantial. A thorough consideration of the spatially and temporally varying interactions among HI components and of uncertainties is therefore crucial for the success of water scarcity adaptation by HI.

  4. Evolution of JAK-STAT pathway components: mechanisms and role in immune system development.

    Directory of Open Access Journals (Sweden)

    Clifford Liongue

    Full Text Available BACKGROUND: Lying downstream of a myriad of cytokine receptors, the Janus kinase (JAK-Signal transducer and activator of transcription (STAT pathway is pivotal for the development and function of the immune system, with additional important roles in other biological systems. To gain further insight into immune system evolution, we have performed a comprehensive bioinformatic analysis of the JAK-STAT pathway components, including the key negative regulators of this pathway, the SH2-domain containing tyrosine phosphatase (SHP, Protein inhibitors against Stats (PIAS, and Suppressor of cytokine signaling (SOCS proteins across a diverse range of organisms. RESULTS: Our analysis has demonstrated significant expansion of JAK-STAT pathway components co-incident with the emergence of adaptive immunity, with whole genome duplication being the principal mechanism for generating this additional diversity. In contrast, expansion of upstream cytokine receptors appears to be a pivotal driver for the differential diversification of specific pathway components. CONCLUSION: Diversification of JAK-STAT pathway components during early vertebrate development occurred concurrently with a major expansion of upstream cytokine receptors and two rounds of whole genome duplications. This produced an intricate cell-cell communication system that has made a significant contribution to the evolution of the immune system, particularly the emergence of adaptive immunity.

  5. Haploinsufficiency for Core Exon Junction Complex Components Disrupts Embryonic Neurogenesis and Causes p53-Mediated Microcephaly.

    Directory of Open Access Journals (Sweden)

    Hanqian Mao

    2016-09-01

    Full Text Available The exon junction complex (EJC is an RNA binding complex comprised of the core components Magoh, Rbm8a, and Eif4a3. Human mutations in EJC components cause neurodevelopmental pathologies. Further, mice heterozygous for either Magoh or Rbm8a exhibit aberrant neurogenesis and microcephaly. Yet despite the requirement of these genes for neurodevelopment, the pathogenic mechanisms linking EJC dysfunction to microcephaly remain poorly understood. Here we employ mouse genetics, transcriptomic and proteomic analyses to demonstrate that haploinsufficiency for each of the 3 core EJC components causes microcephaly via converging regulation of p53 signaling. Using a new conditional allele, we first show that Eif4a3 haploinsufficiency phenocopies aberrant neurogenesis and microcephaly of Magoh and Rbm8a mutant mice. Transcriptomic and proteomic analyses of embryonic brains at the onset of neurogenesis identifies common pathways altered in each of the 3 EJC mutants, including ribosome, proteasome, and p53 signaling components. We further demonstrate all 3 mutants exhibit defective splicing of RNA regulatory proteins, implying an EJC dependent RNA regulatory network that fine-tunes gene expression. Finally, we show that genetic ablation of one downstream pathway, p53, significantly rescues microcephaly of all 3 EJC mutants. This implicates p53 activation as a major node of neurodevelopmental pathogenesis following EJC impairment. Altogether our study reveals new mechanisms to help explain how EJC mutations influence neurogenesis and underlie neurodevelopmental disease.

  6. Impact on Water Quality of Nandoni Water Reservoir Downstream of Municipal Sewage Plants in Vhembe District, South Africa

    Directory of Open Access Journals (Sweden)

    Jabulani Ray Gumbo

    2016-06-01

    Full Text Available The deterioration of water quality in our freshwater sources is on the increase worldwide and, in South Africa, mostly due to the discharge of municipal sewage effluent. Here we report on the use of principal component analysis, coupled with factor and cluster analysis, to study the similarities and differences between upstream and downstream sampling sites that are downstream of municipal sewage plants. The contribution of climatic variables, air temperature, humidity, and rainfall were also evaluated with respect to variations in water quality at the sampling sites. The physicochemical and microbial values were higher than the Department of Water Affairs and Forestry (DWAF and World Health Organization (WHO guidelines. The cluster analysis showed the presence of two clusters for each of the Mvudi, Dzindi, and Luvuvhu Rivers and Nandoni reservoir sampling sites. The principal component analysis (PCA accounted for 40% of the water quality variation and was associated strongly with pH, electrical conductivity, calcium, magnesium, chloride, bromide, nitrate, and total coliform, and negatively with rainfall, which represented Mvudi downstream and was attributed to the Thohoyandou sewage plant. The PCA accounted for 54% of the variation and was associated strongly with electrical conductivity, sulfate; total dissolved solids, fluoride, turbidity, nitrate, manganese, alkalinity, magnesium, and total coliform represented Dzindi downstream, with inflows from the Vuwani sewage plant and agriculture. The PCA accounted for 30% of the variation and was associated strongly with total dissolved solids, electrical conductivity, magnesium, fluoride, nitrate, sulfate, total coliform average air temperature, and total rainfall, and negatively associated with manganese and bromide represented Luvuvhu upstream and was associated with commercial agriculture. The PCA accounted for 21% of the variation and was associated strongly with turbidity, alkalinity, magnesium

  7. Solid state lighting component

    Energy Technology Data Exchange (ETDEWEB)

    Yuan, Thomas; Keller, Bernd; Tarsa, Eric; Ibbetson, James; Morgan, Frederick; Dowling, Kevin; Lys, Ihor

    2017-10-17

    An LED component according to the present invention comprising an array of LED chips mounted on a submount with the LED chips capable of emitting light in response to an electrical signal. The array can comprise LED chips emitting at two colors of light wherein the LED component emits light comprising the combination of the two colors of light. A single lens is included over the array of LED chips. The LED chip array can emit light of greater than 800 lumens with a drive current of less than 150 milli-Amps. The LED chip component can also operate at temperatures less than 3000 degrees K. In one embodiment, the LED array is in a substantially circular pattern on the submount.

  8. Cognitive Component Analysis

    DEFF Research Database (Denmark)

    Feng, Ling

    2008-01-01

    This dissertation concerns the investigation of the consistency of statistical regularities in a signaling ecology and human cognition, while inferring appropriate actions for a speech-based perceptual task. It is based on unsupervised Independent Component Analysis providing a rich spectrum...... of audio contexts along with pattern recognition methods to map components to known contexts. It also involves looking for the right representations for auditory inputs, i.e. the data analytic processing pipelines invoked by human brains. The main ideas refer to Cognitive Component Analysis, defined...... as the process of unsupervised grouping of generic data such that the ensuing group structure is well-aligned with that resulting from human cognitive activity. Its hypothesis runs ecologically: features which are essentially independent in a context defined ensemble, can be efficiently coded as sparse...

  9. Improved intake design for downstream migrating fish at hydropower plants

    International Nuclear Information System (INIS)

    Mih, W.C.

    1991-01-01

    This paper reports on hydroelectric power projects on the Columbia River which provided low-cost electricity to the Pacific Northwest. However, they are detrimental to anadromous fisheries resources. Anadromous fish are migratory. They begin their life in shallow mountain streams. After several months, they migrate to the ocean, where the fish grow to maturity before their return migration. Remarkably, most anadromous fish return to spawn in their natal streams. At dams, the upstream migration of grown salmon and steelhead is accomplished through fishways. The downstream migration of juveniles remains a serious problem. Juvenile fish follow the water flow during their sea-ward migration. When passing through a turbine, fish can be severely injured due to the sudden pressure drop, high velocity shear zones, and rotating turbine blades. Stunned fish that survive the gauntlet of the turbine are easy prey for sea gulls and squawfish in the tailrace of the powerhouse. Fish mortality per turbine passage is estimated at 15 percent. With nine hydropower projected on the main steam of the Columbia River, their combined mortality is very serious. The historical Columbia River anadromous run of about 12 million fish has declined to 2.5 million in recent years. Modern high-output hydraulic turbines are designed to be placed at a lower elevation to minimize cavitation damage to turbine blades. The modern design trend of deep intake submergence has caused parallel and unsteady vortex flow patterns in the forebay, resulting in a decrease in the guiding efficiency of the screens, such as at Bonneville Second Powerhouse and at Rocky Reach Project

  10. Downstream impacts of dams: shifts in benthic invertivorous fish assemblages

    Science.gov (United States)

    Granzotti, Rafaela Vendrametto; Miranda, Leandro E.; Agostinho, Angelo A.; Gomes, Luiz Carlos

    2018-01-01

    Impoundments alter connectivity, sediment transport and water discharge in rivers and floodplains, affecting recruitment, habitat and resource availability for fish including benthic invertivorous fish, which represent an important link between primary producers and higher trophic levels in tropical aquatic ecosystems. We investigated long-term changes to water regime, water quality, and invertivorous fish assemblages pre and post impoundment in three rivers downstream of Porto Primavera Reservoir in south Brazil: Paraná, Baía and Ivinhema rivers. Impacts were distinct in the Paraná River, which is fully obstructed by the dam, less evident in the Baía River which is partially obstructed by the dam, but absent in the unimpounded Ivinhema River. Changes in water regime were reflected mainly as changes in water-level fluctuation with little effect on timing. Water transparency increased in the Paraná River post impoundment but did not change in the Baía and Ivinhema rivers. Changes in fish assemblages included a decrease in benthic invertivorous fish in the Paraná River and a shift in invertivorous fish assemblage structure in the Baía and Paraná rivers but not in the unimpounded Ivinhema River. Changes in water regime and water transparency, caused by impoundment, directly or indirectly impacted invertivorous fish assemblages. Alterations of fish assemblages following environmental changes have consequences over the entire ecosystem, including a potential decrease in the diversity of mechanisms for energy flow. We suggest that keeping existing unimpounded tributaries free of dams, engineering artificial floods, and intensive management of fish habitat within the floodplain may preserve native fish assemblages and help maintain functionality and ecosystem services in highly impounded rivers.

  11. Low cost energy in Canada: The view from downstream

    International Nuclear Information System (INIS)

    Irving, K.

    1993-01-01

    The key cost determinants of energy in Canada are analyzed and recommendations are made to ensure the competitiveness of Canadian energy costs and energy-consuming industries in the North American and world markets. Oil supplies 45% of world energy and has a key role in determining prices of all other energy forms since it serves as an incremental source of energy: its consumption changes according to economic growth, changes in weather patterns, and other factors. North America currently accounts for about a third of world oil consumption. North American oil demand is expected to remain flat over the next few decades. As Canada only produces ca 3% of world oil supply, it cannot determine oil prices. However, with an efficient downstream industry, Canada can influence the end-user price of energy. The cost structure of refined products in Canada is analyzed. The cost of raw materials is the single biggest determinant of the final product cost, followed by taxes, operating costs, and profit margin. For gasoline in Ontario, taxes account for half the retail cost, crude oil prices ca 30%, and refining costs ca 4%. Refining costs comprise about two thirds labor costs and one third energy costs. Refiner margins have not exceeded 2 cents/l since 1981, creating reluctance to invest in the refining sector. By 1994, some 200,000 bbl/d of refining capacity is expected to be shut down in Canada. Compared to refineries in the USA, Canadian refineries are smaller and have a much lower capacity to upgrade residual fuel oil to light products. Future challenges to the industry include a projected need for $5 billion in investment, largely to fund new environmental initiatives. Such an investment cannot be met through current industry profits. 12 figs., 3 tabs

  12. Phospholipase D and phosphatidic acid in plant defence response: from protein–protein and lipid–protein interactions to hormone signalling

    Science.gov (United States)

    Zhao, Jian

    2015-01-01

    Phospholipase Ds (PLDs) and PLD-derived phosphatidic acids (PAs) play vital roles in plant hormonal and environmental responses and various cellular dynamics. Recent studies have further expanded the functions of PLDs and PAs into plant–microbe interaction. The molecular diversities and redundant functions make PLD–PA an important signalling complex regulating lipid metabolism, cytoskeleton dynamics, vesicle trafficking, and hormonal signalling in plant defence through protein–protein and protein–lipid interactions or hormone signalling. Different PLD–PA signalling complexes and their targets have emerged as fast-growing research topics for understanding their numerous but not yet established roles in modifying pathogen perception, signal transduction, and downstream defence responses. Meanwhile, advanced lipidomics tools have allowed researchers to reveal further the mechanisms of PLD–PA signalling complexes in regulating lipid metabolism and signalling, and their impacts on jasmonic acid/oxylipins, salicylic acid, and other hormone signalling pathways that essentially mediate plant defence responses. This review attempts to summarize the progress made in spatial and temporal PLD/PA signalling as well as PLD/PA-mediated modification of plant defence. It presents an in-depth discussion on the functions and potential mechanisms of PLD–PA complexes in regulating actin filament/microtubule cytoskeleton, vesicle trafficking, and hormonal signalling, and in influencing lipid metabolism-derived metabolites as critical signalling components in plant defence responses. The discussion puts PLD–PA in a broader context in order to guide future research. PMID:25680793

  13. Signal Words

    Science.gov (United States)

    SIGNAL WORDS TOPIC FACT SHEET NPIC fact sheets are designed to answer questions that are commonly asked by the ... making decisions about pesticide use. What are Signal Words? Signal words are found on pesticide product labels, ...

  14. Measuring displacement signal with an accelerometer

    International Nuclear Information System (INIS)

    Han, Sang Bo

    2010-01-01

    An effective and simple way to reconstruct displacement signal from a measured acceleration signal is proposed in this paper. To reconstruct displacement signal by means of double-integrating the time domain acceleration signal, the Nyquist frequency of the digital sampling of the acceleration signal should be much higher than the highest frequency component of the signal. On the other hand, to reconstruct displacement signal by taking the inverse Fourier transform, the magnitude of the significant frequency components of the Fourier transform of the acceleration signal should be greater than the 6 dB increment line along the frequency axis. With a predetermined resolution in time and frequency domain, determined by the sampling rate to measure and record the original signal, reconstructing high-frequency signals in the time domain and reconstructing low-frequency signals in the frequency domain will produce biased errors. Furthermore, because of the DC components inevitably included in the sampling process, low-frequency components of the signals are overestimated when displacement signals are reconstructed from the Fourier transform of the acceleration signal. The proposed method utilizes curve-fitting around the significant frequency components of the Fourier transform of the acceleration signal before it is inverse-Fourier transformed. Curve-fitting around the dominant frequency components provides much better results than simply ignoring the insignificant frequency components of the signal

  15. GEFs: Dual regulation of Rac1 signaling.

    Science.gov (United States)

    Marei, Hadir; Malliri, Angeliki

    2017-04-03

    GEFs play a critical role in regulating Rac1 signaling. They serve as signaling nodes converting upstream signals into downstream Rac1-driven cellular responses. Through associating with membrane-bound Rac1, GEFs facilitate the exchange of GDP for GTP, thereby activating Rac1. As a result, Rac1 undergoes conformational changes that mediate its interaction with downstream effectors, linking Rac1 to a multitude of physiological and pathological processes. Interestingly, there are at least 20 GEFs involved in Rac1 activation, suggesting a more complex role of GEFs in regulating Rac1 signaling apart from promoting the exchange of GDP for GTP. Indeed, accumulating evidence implicates GEFs in directing the specificity of Rac1-driven signaling cascades, although the underlying mechanisms were poorly defined. Recently, through conducting a comparative study, we highlighted the role of 2 Rac-specific GEFs, Tiam1 and P-Rex1, in dictating the biological outcome downstream of Rac1. Importantly, further proteomic analysis uncovered a GEF activity-independent function for both GEFs in modulating the Rac1 interactome, which results in the stimulation of GEF-specific signaling cascades. Here, we provide an overview of our recent findings and discuss the role of GEFs as master regulators of Rac1 signaling with a particular focus on GEF-mediated modulation of cell migration following Rac1 activation.

  16. Downstream processing and chromatography based analytical methods for production of vaccines, gene therapy vectors, and bacteriophages

    Science.gov (United States)

    Kramberger, Petra; Urbas, Lidija; Štrancar, Aleš

    2015-01-01

    Downstream processing of nanoplexes (viruses, virus-like particles, bacteriophages) is characterized by complexity of the starting material, number of purification methods to choose from, regulations that are setting the frame for the final product and analytical methods for upstream and downstream monitoring. This review gives an overview on the nanoplex downstream challenges and chromatography based analytical methods for efficient monitoring of the nanoplex production. PMID:25751122

  17. Transcriptional regulation of SlPYL, SlPP2C, and SlSnRK2 gene families encoding ABA signal core components during tomato fruit development and drought stress.

    Science.gov (United States)

    Sun, Liang; Wang, Yan-Ping; Chen, Pei; Ren, Jie; Ji, Kai; Li, Qian; Li, Ping; Dai, Sheng-Jie; Leng, Ping

    2011-11-01

    In order to characterize the potential transcriptional regulation of core components of abscisic acid (ABA) signal transduction in tomato fruit development and drought stress, eight SlPYL (ABA receptor), seven SlPP2C (type 2C protein phosphatase), and eight SlSnRK2 (subfamily 2 of SNF1-related kinases) full-length cDNA sequences were isolated from the tomato nucleotide database of NCBI GenBank. All SlPYL, SlPP2C, and SlSnRK2 genes obtained are homologous to Arabidopsis AtPYL, AtPP2C, and AtSnRK2 genes, respectively. Based on phylogenetic analysis, SlPYLs and SlSnRK2s were clustered into three subfamilies/subclasses, and all SlPP2Cs belonged to PP2C group A. Within the SlPYL gene family, SlPYL1, SlPYL2, SlPYL3, and SlPYL6 were the major genes involved in the regulation of fruit development. Among them, SlPYL1 and SlPYL2 were expressed at high levels throughout the process of fruit development and ripening; SlPYL3 was strongly expressed at the immature green (IM) and mature green (MG) stages, while SlPYL6 was expressed strongly at the IM and red ripe (RR) stages. Within the SlPP2C gene family, the expression of SlPP2C, SlPP2C3, and SlPP2C4 increased after the MG stage; SlPP2C1 and SlPP2C5 peaked at the B3 stage, while SlPP2C2 and SlPP2C6 changed little during fruit development. Within the SlSnRK2 gene family, the expression of SlSnRK2.2, SlSnRK2.3, SlSnRK2.4, and SlSnRK2C was higher than that of other members during fruit development. Additionally, most SlPYL genes were down-regulated, while most SlPP2C and SlSnRK2 genes were up-regulated by dehydration in tomato leaf.

  18. In vivo RNAi screen reveals neddylation genes as novel regulators of Hedgehog signaling.

    Directory of Open Access Journals (Sweden)

    Juan Du

    Full Text Available Hedgehog (Hh signaling is highly conserved in all metazoan animals and plays critical roles in many developmental processes. Dysregulation of the Hh signaling cascade has been implicated in many diseases, including cancer. Although key components of the Hh pathway have been identified, significant gaps remain in our understanding of the regulation of individual Hh signaling molecules. Here, we report the identification of novel regulators of the Hh pathway, obtained from an in vivo RNA interference (RNAi screen in Drosophila. By selectively targeting critical genes functioning in post-translational modification systems utilizing ubiquitin (Ub and Ub-like proteins, we identify two novel genes (dUba3 and dUbc12 that negatively regulate Hh signaling activity. We provide in vivo and in vitro evidence illustrating that dUba3 and dUbc12 are essential components of the neddylation pathway; they function in an enzyme cascade to conjugate the ubiquitin-like NEDD8 modifier to Cullin proteins. Neddylation activates the Cullin-containing ubiquitin ligase complex, which in turn promotes the degradation of Cubitus interruptus (Ci, the downstream transcription factor of the Hh pathway. Our study reveals a conserved molecular mechanism of the neddylation pathway in Drosophila and sheds light on the complex post-translational regulations in Hh signaling.

  19. Wnt signaling in cancer

    Science.gov (United States)

    Zhan, T; Rindtorff, N; Boutros, M

    2017-01-01

    Wnt signaling is one of the key cascades regulating development and stemness, and has also been tightly associated with cancer. The role of Wnt signaling in carcinogenesis has most prominently been described for colorectal cancer, but aberrant Wnt signaling is observed in many more cancer entities. Here, we review current insights into novel components of Wnt pathways and describe their impact on cancer development. Furthermore, we highlight expanding functions of Wnt signaling for both solid and liquid tumors. We also describe current findings how Wnt signaling affects maintenance of cancer stem cells, metastasis and immune control. Finally, we provide an overview of current strategies to antagonize Wnt signaling in cancer and challenges that are associated with such approaches. PMID:27617575

  20. CesRK, a two-component signal transduction system in Listeria monocytogenes, responds to the presence of cell wall-acting antibiotics and affects beta-lactam resistance

    DEFF Research Database (Denmark)

    Kallipolitis, Birgitte H; Ingmer, Hanne; Gahan, Cormac G

    2003-01-01

    Listeria monocytogenes is a food-borne pathogen that can cause a variety of illnesses ranging from gastroenteritis to life-threatening septicemia. The beta-lactam antibiotic ampicillin remains the drug of choice for the treatment of listeriosis. We have previously identified a response regulator...... of L. monocytogenes to tolerate ethanol and cell wall-acting antibiotics of the beta-lactam family. Furthermore, CesRK controls the expression of a putative extracellular peptide encoded by the orf2420 gene, located immediately downstream from cesRK. Inactivation of orf2420 revealed that it contributes...... to ethanol tolerance and pathogenesis in mice. Interestingly, we found that transcription of orf2420 was strongly induced by subinhibitory concentrations of various cell wall-acting antibiotics, ethanol, and lysozyme. The induction of orf2420 expression was abolished in the absence of CesRK. Our data suggest...

  1. MET signalling in primary colon epithelial cells leads to increased transformation irrespective of aberrant Wnt signalling

    Science.gov (United States)

    Boon, E M J; Kovarikova, M; Derksen, P W B; van der Neut, R

    2005-01-01

    It has been shown that in hereditary and most sporadic colon tumours, components of the Wnt pathway are mutated. The Wnt target MET has been implicated in the development of colon cancer. Here, we show that overexpression of wild-type or a constitutively activated form of MET in colon epithelial cells leads to increased transformation irrespective of Wnt signalling. Fetal human colon epithelial cells without aberrant Wnt signalling were transfected with wild-type or mutated MET constructs. Expression of these constructs leads to increased phosphorylation of MET and its downstream targets PKB and MAPK. Upon stimulation with HGF, the expression of E-cadherin is downregulated in wild-type MET-transfected cells, whereas cells expressing mutated MET show low E-cadherin levels independent of stimulation with ligand. This implies a higher migratory propensity of these cells. Furthermore, fetal human colon epithelial cells expressing the mutated form of MET have colony-forming capacity in soft agar, while cells expressing wild-type MET show an intermediate phenotype. Subcutaneous injection of mutated MET-transfected cells in nude mice leads to the formation of tumours within 12 days in all mice injected. At this time point, mock-transfected cells do not form tumours, while wild-type MET-transfected cells form subcutaneous tumours in one out of five mice. We thus show that MET signalling can lead to increased transformation of colon epithelial cells independent of Wnt signalling and in this way could play an essential role in the onset and progression of colorectal cancer. PMID:15785735

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

    Directory of Open Access Journals (Sweden)

    Hanselman Keaton B

    2006-10-01

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

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

    Science.gov (United States)

    Gami, Minaxi S; Iser, Wendy B; Hanselman, Keaton B; Wolkow, Catherine A

    2006-10-04

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

  4. Lithium inhibits tumorigenic potential of PDA cells through targeting hedgehog-GLI signaling pathway.

    Directory of Open Access Journals (Sweden)

    Zhonglu Peng

    Full Text Available Hedgehog signaling pathway plays a critical role in the initiation and development of pancreatic ductal adenocarcinoma (PDA and represents an attractive target for PDA treatment. Lithium, a clinical mood stabilizer for mental disorders, potently inhibits the activity of glycogen synthase kinase 3β (GSK3β that promotes the ubiquitin-dependent proteasome degradation of GLI1, an important downstream component of hedgehog signaling. Herein, we report that lithium inhibits cell proliferation, blocks G1/S cell-cycle progression, induces cell apoptosis and suppresses tumorigenic potential of PDA cells through down-regulation of the expression and activity of GLI1. Moreover, lithium synergistically enhances the anti-cancer effect of gemcitabine. These findings further our knowledge of mechanisms of action for lithium and provide a potentially new therapeutic strategy for PDA through targeting GLI1.

  5. Tenebrio molitor Gram-negative-binding protein 3 (TmGNBP3) is essential for inducing downstream antifungal Tenecin 1 gene expression against infection with Beauveria bassiana JEF-007.

    Science.gov (United States)

    Yang, Yi-Ting; Lee, Mi Rong; Lee, Se Jin; Kim, Sihyeon; Nai, Yu-Shin; Kim, Jae Su

    2017-05-23

    The Toll signaling pathway is responsible for defense against both Gram-positive bacteria and fungi. Gram-negative binding protein 3 (GNBP3) has a strong affinity for the fungal cell wall component, β-1,3-glucan, which can activate the prophenoloxidase (proPO) cascade and induce the Toll signaling pathway. Myeloid differentiation factor 88 (MyD88) is an intracellular adaptor protein involved in the Toll signaling pathway. In this study, we monitored the response of 5 key genes (TmGNBP3, TmMyD88, and Tenecin 1, 2, and 3) in the Toll pathway of the mealworm Tenebrio molitor immune system against the fungus Beauveria bassiana JEF-007 using RT-PCR. TmGNBP3, Tenecin 1, and Tenecin 2 were significantly upregulated after fungal infection. To better understand the roles of the Toll signaling pathway in the mealworm immune system, TmGNBP3 and TmMyD88 were knocked down by RNAi silencing. Target gene expression levels decreased at 2 d postknockdown and were dramatically reduced at 6 d post-dsRNA injection. Therefore, mealworms were compromised by B. bassiana JEF-007 at 6 d post-dsRNA injection. Silencing of TmMyD88 and TmGNBP3 resulted in reduced resistance of the host to fungal infection. Particularly, reducing TmGNBP3 levels obviously downregulated Tenecin 1 and Tenecin 2 expression levels, whereas silencing TmMyD88 expression resulted in decreased Tenecin 2 expression. These results indicate that TmGNBP3 is essential to induce downstream antifungal peptide Tenecin 1 expression against B. bassiana JEF-007. © 2017 Institute of Zoology, Chinese Academy of Sciences.

  6. Method of signal analysis

    International Nuclear Information System (INIS)

    Berthomier, Charles

    1975-01-01

    A method capable of handling the amplitude and the frequency time laws of a certain kind of geophysical signals is described here. This method is based upon the analytical signal idea of Gabor and Ville, which is constructed either in the time domain by adding an imaginary part to the real signal (in-quadrature signal), or in the frequency domain by suppressing negative frequency components. The instantaneous frequency of the initial signal is then defined as the time derivative of the phase of the analytical signal, and his amplitude, or envelope, as the modulus of this complex signal. The method is applied to three types of magnetospheric signals: chorus, whistlers and pearls. The results obtained by analog and numerical calculations are compared to results obtained by classical systems using filters, i.e. based upon a different definition of the concept of frequency. The precision with which the frequency-time laws are determined leads then to the examination of the principle of the method and to a definition of instantaneous power density spectrum attached to the signal, and to the first consequences of this definition. In this way, a two-dimensional representation of the signal is introduced which is less deformed by the analysis system properties than the usual representation, and which moreover has the advantage of being obtainable practically in real time [fr

  7. 40 CFR 80.210 - What sulfur standards apply to gasoline downstream from refineries and importers?

    Science.gov (United States)

    2010-07-01

    ... combined with non-S-RGAS for the sole purpose of producing midgrade gasoline. (6) Where S-RGAS is being... of the gasoline. (f) Downstream standards applicable to S-RGAS when produced or imported. (1) The downstream standard applicable to any gasoline classified as S-RGAS when produced or imported shall be...

  8. Hydrodynamic properties and distribution of bait downstream of a zooplankton trap

    DEFF Research Database (Denmark)

    Selander, Erik; Heuschele, Jan; Larsson, Ann I.

    2017-01-01

    The flow regime around a chemically baited trap is crucial for the trapping process and distribution of bait downstream of traps. We measured the flow field downstream of a trap prototype in flume experiments and mapped the distribution of bait using laser induced fluorescence. The trap produced ...

  9. 40 CFR 80.220 - What are the downstream standards for GPA gasoline?

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 16 2010-07-01 2010-07-01 false What are the downstream standards for GPA gasoline? 80.220 Section 80.220 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... downstream location other than at a retail outlet or wholesale purchaser-consumer facility, and during the...

  10. Investigation of changes to the operation of Keenleyside Dam to reduce supersaturation of dissolved gases downstream

    International Nuclear Information System (INIS)

    Nunn, J.O.H.; Fidler, L.E.; Northcott, P.

    1993-01-01

    Keenlyside Dam is located on the Columbia River in southeast British Columbia. It impounds Arrow Lakes Reservoir, which has a live storage of 8.8 billion m 3 . The dam is used for flood control and to increase power generation in the USA. Recent field measurements have shown that the current operation of the dam often creates high levels of total gas pressure (TGP) downstream of the dam, with supersaturation levels occasionally reaching as high as 140%. It appeared that these increased levels were associated with the use of the spillway. High levels of dissolved gases may have adverse effects on aquatic life. Therefore, a comprehensive study was initiated to investigate ways of reducing TGP levels. The discharge facilities at the dam are described, along with the effects of dissolved gas supersaturation on fish. Current studies include measurement of field TGP levels, development of a model to predict TGP levels for different modes of operation of the discharge facilities, assessing the effects of TGP on different fish species at different life stages, field testing of the discharge facilities, and assessment of long-term impacts of various operating alternatives on the dam structures and equipment. Preliminary results indicate that the north low-level ports of the spillway increase the TGP level significantly less than the other two components of the discharge facilities. Current operating practice therefore maximizes use of the north ports within current operating limits. 9 refs., 4 figs

  11. Rethinking downstream regulation: California's opportunity to engage households in reducing greenhouse gases

    International Nuclear Information System (INIS)

    Niemeier, D.; Gould, Gregory; Karner, Alex; Hixson, Mark; Bachmann, Brooke; Okma, Carrie; Lang, Ziv; Heres Del Valle, David

    2008-01-01

    With the passage of the Global Warming Solutions Act of 2006 (AB32), California has begun an ambitious journey to reduce in-state GHG emissions to 1990 levels by 2020. Under the direction of executive order S-20-06, a mandated Market Advisory Committee (MAC) charged with studying market-based mechanisms to reduce GHG emissions, including cap and trade systems, has recommended taking an 'upstream' approach to GHG emissions regulation, arguing that upstream regulation will reduce administrative costs because there are fewer agents. In this paper, we argue that, the total costs to society of a GHG cap and trade scheme can be minimized though downstream regulation, rather than the widely proposed upstream approach. We propose a household carbon trading system with four major components: a state allocation to households, household-to-household trading, households to utility company credit transfers, and utility companies to government credit transfers. The proposed system can also be considered more equitable than carbon taxes and upstream cap and trade systems to control GHG emissions from residential energy use and is consistent with AB32

  12. Unravelling pathways downstream Sox6 induction in K562 erythroid cells by proteomic analysis

    KAUST Repository

    Barbarani, Gloria

    2017-10-20

    The Sox6 transcription factor is crucial for terminal maturation of definitive red blood cells. Sox6-null mouse fetuses present misshapen and nucleated erythrocytes, due to impaired actin assembly and cytoskeleton stability. These defects are accompanied with a reduced survival of Sox6-/- red blood cells, resulting in a compensated anemia. Sox6-overexpression in K562 cells and in human primary ex vivo erythroid cultures enhances erythroid differentiation and leads to hemoglobinization, the hallmark of erythroid maturation. To obtain an overview on processes downstream to Sox6 expression, we performed a differential proteomic analysis on human erythroid K562 cells overexpressing Sox6. Sox6-overexpression induces dysregulation of 64 proteins, involved in cytoskeleton remodeling and in protein synthesis, folding and trafficking, key processes for erythroid maturation. Moreover, 43 out of 64 genes encoding for differentially expressed proteins contain within their proximal regulatory regions sites that are bound by SOX6 according to ENCODE ChIP-seq datasets and are possible direct SOX6 targets. SAR1B, one of the most induced proteins upon Sox6 overexpression, shares a conserved regulatory module, composed by a double SOX6 binding site and a GATA1 consensus, with the adjacent SEC24 A gene. Since both genes encode for COPII components, this element could concur to the coordinated expression of these proteins during erythropoiesis.

  13. Wake Measurement Downstream of a Hybrid Wing Body Model with Blown Flaps

    Science.gov (United States)

    Lin, John C.; Jones, Gregory S.; Allan, Brian G.; Westra, Bryan W.; Collins, Scott W.; Zeune, Cale H.

    2010-01-01

    Flow-field measurements were obtained in the wake of a full-span Hybrid Wing Body model with internally blown flaps. The test was performed at the NASA Langley 14 x 22 Foot Subsonic Tunnel at low speeds. Off-body measurements were obtained with a 7-hole probe rake survey system. Three model configurations were investigated. At 0deg angle of attack the surveys were completed with 0deg and 60deg flap deflections. At 10deg angle of attack the wake surveys were completed with a slat and a 60deg flap deflection. The 7-hole probe results further quantified two known swirling regions (downstream of the outboard flap edge and the inboard/outboard flap juncture) for the 60deg flap cases with blowing. Flowfield results and the general trends are very similar for the two blowing cases at nozzle pressure ratios of 1.37 and 1.56. High downwash velocities correlated with the enhanced lift for the 60deg flap cases with blowing. Jet-induced effects are the largest at the most inboard station for all (three) velocity components due in part to the larger inboard slot height. The experimental data are being used to improve computational tools for high-lift wings with integrated powered-lift technologies.

  14. Asymmetric cell division during T cell development controls downstream fate

    Science.gov (United States)

    Pham, Kim; Shimoni, Raz; Charnley, Mirren; Ludford-Menting, Mandy J.; Hawkins, Edwin D.; Ramsbottom, Kelly; Oliaro, Jane; Izon, David; Ting, Stephen B.; Reynolds, Joseph; Lythe, Grant; Molina-Paris, Carmen; Melichar, Heather; Robey, Ellen; Humbert, Patrick O.; Gu, Min

    2015-01-01

    During mammalian T cell development, the requirement for expansion of many individual T cell clones, rather than merely expansion of the entire T cell population, suggests a possible role for asymmetric cell division (ACD). We show that ACD of developing T cells controls cell fate through differential inheritance of cell fate determinants Numb and α-Adaptin. ACD occurs specifically during the β-selection stage of T cell development, and subsequent divisions are predominantly symmetric. ACD is controlled by interaction with stromal cells and chemokine receptor signaling and uses a conserved network of polarity regulators. The disruption of polarity by deletion of the polarity regulator, Scribble, or the altered inheritance of fate determinants impacts subsequent fate decisions to influence the numbers of DN4 cells arising after the β-selection checkpoint. These findings indicate that ACD enables the thymic microenvironment to orchestrate fate decisions related to differentiation and self-renewal. PMID:26370500

  15. A conserved PHD finger protein and endogenous RNAi modulate insulin signaling in Caenorhabditis elegans.

    Science.gov (United States)

    Mansisidor, Andres R; Cecere, Germano; Hoersch, Sebastian; Jensen, Morten B; Kawli, Trupti; Kennedy, Lisa M; Chavez, Violeta; Tan, Man-Wah; Lieb, Jason D; Grishok, Alla

    2011-09-01

    Insulin signaling has a profound effect on longevity and the oxidative stress resistance of animals. Inhibition of insulin signaling results in the activation of DAF-16/FOXO and SKN-1/Nrf transcription factors and increased animal fitness. By studying the biological functions of the endogenous RNA interference factor RDE-4 and conserved PHD zinc finger protein ZFP-1 (AF10), which regulate overlapping sets of genes in Caenorhabditis elegans, we identified an important role for these factors in the negative modulation of transcription of the insulin/PI3 signaling-dependent kinase PDK-1. Consistently, increased expression of pdk-1 in zfp-1 and rde-4 mutants contributed to their reduced lifespan and sensitivity to oxidative stress and pathogens due to the reduction in the expression of DAF-16 and SKN-1 targets. We found that the function of ZFP-1 in modulating pdk-1 transcription was important for the extended lifespan of the age-1(hx546) reduction-of-function PI3 kinase mutant, since the lifespan of the age-1; zfp-1 double mutant strain was significantly shorter compared to age-1(hx546). We further demonstrate that overexpression of ZFP-1 caused an increased resistance to oxidative stress in a DAF-16-dependent manner. Our findings suggest that epigenetic regulation of key upstream signaling components in signal transduction pathways through chromatin and RNAi may have a large impact on the outcome of signaling and expression of numerous downstream genes.

  16. TMEM59 potentiates Wnt signaling by promoting signalosome formation.

    Science.gov (United States)

    Gerlach, Jan P; Jordens, Ingrid; Tauriello, Daniele V F; van 't Land-Kuper, Ineke; Bugter, Jeroen M; Noordstra, Ivar; van der Kooij, Johanneke; Low, Teck Y; Pimentel-Muiños, Felipe X; Xanthakis, Despina; Fenderico, Nicola; Rabouille, Catherine; Heck, Albert J R; Egan, David A; Maurice, Madelon M

    2018-04-09

    Wnt/β-catenin signaling controls development and adult tissue homeostasis by regulating cell proliferation and cell fate decisions. Wnt binding to its receptors Frizzled (FZD) and low-density lipoprotein-related 6 (LRP6) at the cell surface initiates a signaling cascade that leads to the transcription of Wnt target genes. Upon Wnt binding, the receptors assemble into large complexes called signalosomes that provide a platform for interactions with downstream effector proteins. The molecular basis of signalosome formation and regulation remains elusive, largely due to the lack of tools to analyze its endogenous components. Here, we use internally tagged Wnt3a proteins to isolate and characterize activated, endogenous Wnt receptor complexes by mass spectrometry-based proteomics. We identify the single-span membrane protein TMEM59 as an interactor of FZD and LRP6 and a positive regulator of Wnt signaling. Mechanistically, TMEM59 promotes the formation of multimeric Wnt-FZD assemblies via intramembrane interactions. Subsequently, these Wnt-FZD-TMEM59 clusters merge with LRP6 to form mature Wnt signalosomes. We conclude that the assembly of multiprotein Wnt signalosomes proceeds along well-ordered steps that involve regulated intramembrane interactions. Copyright © 2018 the Author(s). Published by PNAS.

  17. Metazoan-like signaling in a unicellular receptor tyrosine kinase

    Directory of Open Access Journals (Sweden)

    Schultheiss Kira P

    2013-02-01

    Full Text Available Abstract Background Receptor tyrosine kinases (RTKs are crucial com