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Sample records for paracrine signal determines

  1. Paracrine signaling in a bacterium.

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    López, Daniel; Vlamakis, Hera; Losick, Richard; Kolter, Roberto

    2009-07-15

    Cellular differentiation is triggered by extracellular signals that cause target cells to adopt a particular fate. Differentiation in bacteria typically involves autocrine signaling in which all cells in the population produce and respond to the same signal. Here we present evidence for paracrine signaling in bacterial populations-some cells produce a signal to which only certain target cells respond. Biofilm formation in Bacillus involves two centrally important signaling molecules, ComX and surfactin. ComX triggers the production of surfactin. In turn, surfactin causes a subpopulation of cells to produce an extracellular matrix. Cells that produced surfactin were themselves unable to respond to it. Likewise, once surfactin-responsive cells commenced matrix production, they no longer responded to ComX and could not become surfactin producers. Insensitivity to ComX was the consequence of the extracellular matrix as mutant cells unable to make matrix responded to both ComX and surfactin. Our results demonstrate that extracellular signaling was unidirectional, with one subpopulation producing a signal and a different subpopulation responding to it. Paracrine signaling in a bacterial population ensures the maintenance, over generations, of particular cell types even in the presence of molecules that would otherwise cause those cells to differentiate into other cell types.

  2. Probing Embryonic Stem Cell Autocrine and Paracrine Signaling Using Microfluidics

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    Przybyla, Laralynne; Voldman, Joel

    2012-07-01

    Although stem cell fate is traditionally manipulated by exogenously altering the cells' extracellular signaling environment, the endogenous autocrine and paracrine signals produced by the cells also contribute to their two essential processes: self-renewal and differentiation. Autocrine and/or paracrine signals are fundamental to both embryonic stem cell self-renewal and early embryonic development, but the nature and contributions of these signals are often difficult to fully define using conventional methods. Microfluidic techniques have been used to explore the effects of cell-secreted signals by controlling cell organization or by providing precise control over the spatial and temporal cellular microenvironment. Here we review how such techniques have begun to be adapted for use with embryonic stem cells, and we illustrate how many remaining questions in embryonic stem cell biology could be addressed using microfluidic technologies.

  3. Biology of primate relaxin: A paracrine signal in early pregnancy?

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    Hayes Eric S

    2004-06-01

    Full Text Available Abstract Relaxin is a peptide hormone that exerts numerous effects in a variety of tissues across a broad range of species. Although first identified more than 75 years ago interest in relaxin biology has waxed and waned over the years consistent with peaks and troughs of new experimental data on its wide-ranging biological effects and advances in relaxin enabling technologies. Recent insights into species-dependent differences in relaxin biology during pregnancy have once again stimulated a relative surge of interest in the study of relaxin's reproductive biology. Identification and pharmacological characterization of orphaned relaxin receptors and exploration of its paracrine effects on pregnancy using genomic and proteomic technologies have succeeded in fueling current interest in relaxin research. Primates and non-primate vertebrates exhibit very disparate profiles of relaxin genomics, proteomics and functional biology. Non-human primates appear to exhibit a very close similarity to humans with respect to relaxin reproductive biology but the similarities and subtle differences are only just beginning to be understood. We, and others, have shown that relaxin produces significant changes to the non-human primate endometrium during the peri-implantation period that are consistent with relaxin's long perceived role as a paracrine modulator of pregnancy. The purpose of this review is to summarize the reproductive biology of relaxin in non-human primates with a specific emphasis on the paracrine role of ovarian and endometrial relaxin during embryo implantation and early pregnancy.

  4. Predictions for optimal mitigation of paracrine inhibitory signalling in haemopoietic stem cell cultures.

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    Berry, Joseph D; Godara, Pankaj; Liovic, Petar; Haylock, David N

    2015-04-16

    Recent studies in the literature have highlighted the critical role played by cell signalling in determining haemopoietic stem cell (HSC) fate within ex vivo culture systems. Stimulatory signals can enhance proliferation and promote differentiation, whilst inhibitory signals can significantly limit culture output. Numerical models of various mitigation strategies are presented and applied to determine effectiveness of these strategies toward mitigation of paracrine inhibitory signalling inherent in these culture systems. The strategies assessed include mixing, media-exchange, fed-batch and perfusion. The models predict that significant spatial concentration gradients exist in typical cell cultures, with important consequences for subsequent cell expansion. Media exchange is shown to be the most effective mitigation strategy, but remains labour intensive and difficult to scale-up for large culture systems. The fed-batch strategy is only effective at very small Peclet number, and its effect is diminished as the cell culture volume grows. Conversely, mixing is effective at high Peclet number, and ineffective at low Peclet number. The models predict that cell expansion in fed-batch cultures becomes independent of increasing dilution rate, consistent with experimental results previously reported in the literature. In contrast, the models predict that increasing the flow rate in perfused cultures will lead to increased cell expansion, indicating the suitability of perfusion for use as an automated, tunable strategy. The effect of initial cell seeding density is also investigated, with the model showing that perfusion outperforms dilution for all densities considered. The models predict that the impact of inhibitory signalling in HSC cultures can be mitigated against using media manipulation strategies, with the optimal strategy dependent upon the protein diffusion time-scale relative to the media manipulation time-scale. The key messages from this study can be applied to

  5. Cellular observations enabled by microculture: paracrine signaling and population demographics†

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    Domenech, Maribella; Yu, Hongmei; Warrick, Jay; Badders, Nisha M.; Meyvantsson, Ivar; Alexander, Caroline M.; Beebe, David J.

    2009-01-01

    The cellular microenvironment plays a critical role in shaping and directing the process of communication between the cells. Soluble signals are responsible for many cellular behaviors such as cell survival, proliferation and differentiation. Despite the importance of soluble signals, canonical methods are not well suited to the study of soluble factor interactions between multiple cell types. Macro-scale technology often puts cells into a convective environment that can wash away and dilute soluble signals from their targets, minimizing local concentrations of important factors. In addition, current methods such as transwells, require large numbers of cells and are limited to studying just two cell types. Here, we present data supporting the use of microchannels to study soluble factor signaling providing improved sensitivity as well as the ability to move beyond existing co-culture and conditioned medium paradigms. In addition, we present data suggesting that microculture can be used to unmask effects of population demographics. In this example the data support the hypothesis that a growth promoting subpopulation of cells exists in the mouse mammary gland. PMID:20011455

  6. Cellular observations enabled by microculture: paracrine signaling and population demographics.

    Science.gov (United States)

    Domenech, Maribella; Yu, Hongmei; Warrick, Jay; Badders, Nisha M; Meyvantsson, Ivar; Alexander, Caroline M; Beebe, David J

    2009-03-01

    The cellular microenvironment plays a critical role in shaping and directing the process of communication between the cells. Soluble signals are responsible for many cellular behaviors such as cell survival, proliferation and differentiation. Despite the importance of soluble signals, canonical methods are not well suited to the study of soluble factor interactions between multiple cell types. Macro-scale technology often puts cells into a convective environment that can wash away and dilute soluble signals from their targets, minimizing local concentrations of important factors. In addition, current methods such as transwells, require large numbers of cells and are limited to studying just two cell types. Here, we present data supporting the use of microchannels to study soluble factor signaling providing improved sensitivity as well as the ability to move beyond existing co-culture and conditioned medium paradigms. In addition, we present data suggesting that microculture can be used to unmask effects of population demographics. In this example the data support the hypothesis that a growth promoting subpopulation of cells exists in the mouse mammary gland.

  7. Ciliopathy proteins regulate paracrine signaling by modulating proteasomal degradation of mediators

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    Liu, Yangfan P.; Tsai, I-Chun; Morleo, Manuela; Oh, Edwin C.; Leitch, Carmen C.; Massa, Filomena; Lee, Byung-Hoon; Parker, David S.; Finley, Daniel; Zaghloul, Norann A.; Franco, Brunella; Katsanis, Nicholas

    2014-01-01

    Cilia are critical mediators of paracrine signaling; however, it is unknown whether proteins that contribute to ciliopathies converge on multiple paracrine pathways through a common mechanism. Here, we show that loss of cilopathy-associated proteins Bardet-Biedl syndrome 4 (BBS4) or oral-facial-digital syndrome 1 (OFD1) results in the accumulation of signaling mediators normally targeted for proteasomal degradation. In WT cells, several BBS proteins and OFD1 interacted with proteasomal subunits, and loss of either BBS4 or OFD1 led to depletion of multiple subunits from the centrosomal proteasome. Furthermore, overexpression of proteasomal regulatory components or treatment with proteasomal activators sulforaphane (SFN) and mevalonolactone (MVA) ameliorated signaling defects in cells lacking BBS1, BBS4, and OFD1, in morphant zebrafish embryos, and in induced neurons from Ofd1-deficient mice. Finally, we tested the hypothesis that other proteasome-dependent pathways not known to be associated with ciliopathies are defective in the absence of ciliopathy proteins. We found that loss of BBS1, BBS4, or OFD1 led to decreased NF-κB activity and concomitant IκBβ accumulation and that these defects were ameliorated with SFN treatment. Taken together, our data indicate that basal body proteasomal regulation governs paracrine signaling pathways and suggest that augmenting proteasomal function might benefit ciliopathy patients. PMID:24691443

  8. Role of Stromal Paracrine Signals in Proliferative Diseases of the Aging Human Prostate

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    Kenichiro Ishii

    2018-04-01

    Full Text Available Androgens are essential for the development, differentiation, growth, and function of the prostate through epithelial–stromal interactions. However, androgen concentrations in the hypertrophic human prostate decrease significantly with age, suggesting an inverse correlation between androgen levels and proliferative diseases of the aging prostate. In elderly males, age- and/or androgen-related stromal remodeling is spontaneously induced, i.e., increased fibroblast and myofibroblast numbers, but decreased smooth muscle cell numbers in the prostatic stroma. These fibroblasts produce not only growth factors, cytokines, and extracellular matrix proteins, but also microRNAs as stromal paracrine signals that stimulate prostate epithelial cell proliferation. Surgical or chemical castration is the standard systemic therapy for patients with advanced prostate cancer. Androgen deprivation therapy induces temporary remission, but the majority of patients eventually progress to castration-resistant prostate cancer, which is associated with a high mortality rate. Androgen deprivation therapy-induced stromal remodeling may be involved in the development and progression of castration-resistant prostate cancer. In the tumor microenvironment, activated fibroblasts stimulating prostate cancer cell proliferation are called carcinoma-associated fibroblasts. In this review, we summarize the role of stromal paracrine signals in proliferative diseases of the aging human prostate and discuss the potential clinical applications of carcinoma-associated fibroblast-derived exosomal microRNAs as promising biomarkers.

  9. STAT3 can be activated through paracrine signaling in breast epithelial cells

    International Nuclear Information System (INIS)

    Lieblein, Jacqueline C; Ball, Sarah; Hutzen, Brian; Sasser, A Kate; Lin, Huey-Jen; Huang, Tim HM; Hall, Brett M; Lin, Jiayuh

    2008-01-01

    Many cancers, including breast cancer, have been identified with increased levels of phosphorylated or the active form of Signal Transducers and Activators of Transcription 3 (STAT3) protein. However, whether the tumor microenvironment plays a role in this activation is still poorly understood. Conditioned media, which contains soluble factors from MDA-MB-231 and MDA-MB-468 breast cancer cells and breast cancer associated fibroblasts, was added to MCF-10A breast epithelial and MDA-MB-453 breast cancer cells. The stimulation of phosphorylated STAT3 (p-STAT3) levels by conditioned media was assayed by Western blot in the presence or absence of neutralized IL-6 antibody, or a JAK/STAT3 inhibitor, JSI-124. The stimulation of cell proliferation in MCF-10A cells by conditioned media in the presence or absence of JSI-124 was subjected to MTT analysis. IL-6, IL-10, and VEGF levels were determined by ELISA analysis. Our results demonstrated that conditioned media from cell lines with constitutively active STAT3 are sufficient to induce p-STAT3 levels in various recipients that do not possess elevated p-STAT3 levels. This signaling occurs through the JAK/STAT3 pathway, leading to STAT3 phosphorylation as early as 30 minutes and is persistent for at least 24 hours. ELISA analysis confirmed a correlation between elevated levels of IL-6 production and p-STAT3. Neutralization of the IL-6 ligand or gp130 was sufficient to block increased levels of p-STAT3 (Y705) in treated cells. Furthermore, soluble factors within the MDA-MB-231 conditioned media were also sufficient to stimulate an increase in IL-6 production from MCF-10A cells. These results demonstrate STAT3 phosphorylation in breast epithelial cells can be stimulated by paracrine signaling through soluble factors from both breast cancer cells and breast cancer associated fibroblasts with elevated STAT3 phosphorylation. The induction of STAT3 phosphorylation is through the IL-6/JAK pathway and appears to be associated with

  10. Paracrine effect of carbon monoxide - astrocytes promote neuroprotection through purinergic signaling in mice.

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    Queiroga, Cláudia S F; Alves, Raquel M A; Conde, Sílvia V; Alves, Paula M; Vieira, Helena L A

    2016-08-15

    The neuroprotective role of carbon monoxide (CO) has been studied in a cell-autonomous mode. Herein, a new concept is disclosed - CO affects astrocyte-neuron communication in a paracrine manner to promote neuroprotection. Neuronal survival was assessed when co-cultured with astrocytes that had been pre-treated or not with CO. The CO-pre-treated astrocytes reduced neuronal cell death, and the cellular mechanisms were investigated, focusing on purinergic signaling. CO modulates astrocytic metabolism and extracellular ATP content in the co-culture medium. Moreover, several antagonists of P1 adenosine and P2 ATP receptors partially reverted CO-induced neuroprotection through astrocytes. Likewise, knocking down expression of the neuronal P1 adenosine receptor A2A-R (encoded by Adora2a) reverted the neuroprotective effects of CO-exposed astrocytes. The neuroprotection of CO-treated astrocytes also decreased following prevention of ATP or adenosine release from astrocytic cells and inhibition of extracellular ATP metabolism into adenosine. Finally, the neuronal downstream event involves TrkB (also known as NTRK2) receptors and BDNF. Pharmacological and genetic inhibition of TrkB receptors reverts neuroprotection triggered by CO-treated astrocytes. Furthermore, the neuronal ratio of BDNF to pro-BDNF increased in the presence of CO-treated astrocytes and decreased whenever A2A-R expression was silenced. In summary, CO prevents neuronal cell death in a paracrine manner by targeting astrocytic metabolism through purinergic signaling. © 2016. Published by The Company of Biologists Ltd.

  11. The Role of Paracrine and Autocrine Signaling in the Early Phase of Adipogenic Differentiation of Adipose-derived Stem Cells

    DEFF Research Database (Denmark)

    Hemmingsen, Mette; Vedel, Søren; Skafte-Pedersen, Peder

    2013-01-01

    Using different cell densities and microfluidic perfusion cell cultures to suppress the effects of cell-released factors, we have demonstrated the significant role played by auto- or paracrine signaling in adipocyte differentiation. The cell-released factor(s) were shown to act in the recruitment...

  12. Paracrine and autocrine signals promoting full chondrogenic differentiation of a mesoblastic cell line.

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    Locker, Morgane; Kellermann, Odile; Boucquey, Marie; Khun, Huot; Huerre, Michel; Poliard, Anne

    2004-01-01

    The pluripotent mesoblastic C1 cell line was used under serum-free culture conditions to investigate how paracrine and autocrine signals cooperate to drive chondrogenesis. Sequential addition of two systemic hormones, dexamethasone and triiodothyronine, permits full chondrogenic differentiation. The cell intrinsic activation of the BMP signaling pathway and Sox9 expression occurring on mesoblastic condensation is insufficient for recruitment of the progenitors. Dexamethasone-dependent Sox9 upregulation is essential for chondrogenesis. Differentiation of lineage stem cells relies on cell autonomous regulations modulated by external signals. We used the pluripotent mesoblastic C1 cell line under serum-free culture conditions to investigate how paracrine and autocrine signals cooperate to induce differentiation of a precursor clone along the chondrogenic lineage. C1 cells, cultured as aggregates, were induced toward chondrogenesis by addition of 10(-7) M dexamethasone in serum-free medium. After 30 days, dexamethasone was replaced by 10 nM triiodothyronine to promote final hypertrophic conversion. Mature and hypertrophic phenotypes were characterized by immunocytochemistry using specific antibodies against types II and X collagens, respectively. Type II collagen, bone morphogenetic proteins (BMPs), BMP receptors, Smads, and Sox9 expression were monitored by reverse transcriptase-polymerase chain reaction (RT-PCR), Northern blot, and/or Western blot analysis. Once C1 cells have formed nodules, sequential addition of two systemic hormones is sufficient to promote full chondrogenic differentiation. In response to dexamethasone, nearly 100% of the C1 precursors engage in chondrogenesis and convert within 30 days into mature chondrocytes, which triggers a typical cartilage matrix. On day 25, a switch in type II procollagen mRNA splicing acted as a limiting step in the acquisition of the mature chondrocyte phenotype. On day 30, substitution of dexamethasone with

  13. Osteoblast-secreted collagen upregulates paracrine Sonic hedgehog signaling by prostate cancer cells and enhances osteoblast differentiation

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    Zunich Samantha M

    2012-07-01

    Full Text Available Abstract Background Induction of osteoblast differentiation by paracrine Sonic hedgehog (Shh signaling may be a mechanism through which Shh-expressing prostate cancer cells initiate changes in the bone microenvironment and promote metastases. A hallmark of osteoblast differentiation is the formation of matrix whose predominant protein is type 1 collagen. We investigated the formation of a collagen matrix by osteoblasts cultured with prostate cancer cells, and its effects on interactions between prostate cancer cells and osteoblasts. Results In the presence of exogenous ascorbic acid (AA, a co-factor in collagen synthesis, mouse MC3T3 pre-osteoblasts in mixed cultures with human LNCaP prostate cancer cells or LNCaP cells modified to overexpress Shh (LNShh cells formed collagen matrix with distinct fibril ultrastructural characteristics. AA increased the activity of alkaline phosphatase and the expression of the alkaline phosphatase gene Akp2, markers of osteoblast differentiation, in MC3T3 pre-osteoblasts cultured with LNCaP or LNShh cells. However, the AA-stimulated increase in Akp2 expression in MC3T3 pre-osteoblasts cultured with LNShh cells far exceeded the levels observed in MC3T3 cells cultured with either LNCaP cells with AA or LNShh cells without AA. Therefore, AA and Shh exert a synergistic effect on osteoblast differentiation. We determined whether the effect of AA on LNShh cell-induced osteoblast differentiation was mediated by Shh signaling. AA increased the expression of Gli1 and Ptc1, target genes of the Shh pathway, in MC3T3 pre-osteoblasts cultured with LNShh cells to at least twice their levels without AA. The ability of AA to upregulate Shh signaling and enhance alkaline phosphatase activity was blocked in MC3T3 cells that expressed a dominant negative form of the transcription factor GLI1. The AA-stimulated increase in Shh signaling and Shh-induced osteoblast differentiation was also inhibited by the specific collagen synthesis

  14. Msx homeobox genes critically regulate embryo implantation by controlling paracrine signaling between uterine stroma and epithelium.

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    Shanmugasundaram Nallasamy

    Full Text Available The mammalian Msx homeobox genes, Msx1 and Msx2, encode transcription factors that control organogenesis and tissue interactions during embryonic development. We observed overlapping expression of these factors in uterine epithelial and stromal compartments of pregnant mice prior to embryo implantation. Conditional ablation of both Msx1 and Msx2 in the uterus resulted in female infertility due to a failure in implantation. In these mutant mice (Msx1/2(d/d, the uterine epithelium exhibited persistent proliferative activity and failed to attach to the embryos. Gene expression profiling of uterine epithelium and stroma of Msx1/2(d/d mice revealed an elevated expression of several members of the Wnt gene family in the preimplantation uterus. Increased canonical Wnt signaling in the stromal cells activated β-catenin, stimulating the production of a subset of fibroblast growth factors (FGFs in these cells. The secreted FGFs acted in a paracrine manner via the FGF receptors in the epithelium to promote epithelial proliferation, thereby preventing differentiation of this tissue and creating a non-receptive uterus refractory to implantation. Collectively, these findings delineate a unique signaling network, involving Msx1/2, Wnts, and FGFs, which operate in the uterus at the time of implantation to control the mesenchymal-epithelial dialogue critical for successful establishment of pregnancy.

  15. Msx homeobox genes critically regulate embryo implantation by controlling paracrine signaling between uterine stroma and epithelium.

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    Nallasamy, Shanmugasundaram; Li, Quanxi; Bagchi, Milan K; Bagchi, Indrani C

    2012-01-01

    The mammalian Msx homeobox genes, Msx1 and Msx2, encode transcription factors that control organogenesis and tissue interactions during embryonic development. We observed overlapping expression of these factors in uterine epithelial and stromal compartments of pregnant mice prior to embryo implantation. Conditional ablation of both Msx1 and Msx2 in the uterus resulted in female infertility due to a failure in implantation. In these mutant mice (Msx1/2(d/d)), the uterine epithelium exhibited persistent proliferative activity and failed to attach to the embryos. Gene expression profiling of uterine epithelium and stroma of Msx1/2(d/d) mice revealed an elevated expression of several members of the Wnt gene family in the preimplantation uterus. Increased canonical Wnt signaling in the stromal cells activated β-catenin, stimulating the production of a subset of fibroblast growth factors (FGFs) in these cells. The secreted FGFs acted in a paracrine manner via the FGF receptors in the epithelium to promote epithelial proliferation, thereby preventing differentiation of this tissue and creating a non-receptive uterus refractory to implantation. Collectively, these findings delineate a unique signaling network, involving Msx1/2, Wnts, and FGFs, which operate in the uterus at the time of implantation to control the mesenchymal-epithelial dialogue critical for successful establishment of pregnancy.

  16. Human Wharton's jelly mesenchymal stem cells promote skin wound healing through paracrine signaling.

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    Arno, Anna I; Amini-Nik, Saeid; Blit, Patrick H; Al-Shehab, Mohammed; Belo, Cassandra; Herer, Elaine; Tien, Col Homer; Jeschke, Marc G

    2014-02-24

    The prevalence of nonhealing wounds is predicted to increase due to the growing aging population. Despite the use of novel skin substitutes and wound dressings, poorly vascularized wound niches impair wound repair. Mesenchymal stem cells (MSCs) have been reported to provide paracrine signals to promote wound healing, but the effect of human Wharton's jelly-derived MSCs (WJ-MSCs) has not yet been described in human normal skin. Human WJ-MSCs and normal skin fibroblasts were isolated from donated umbilical cords and normal adult human skin. Fibroblasts were treated with WJ-MSC-conditioned medium (WJ-MSC-CM) or nonconditioned medium. Expression of genes involved in re-epithelialization (transforming growth factor-β2), neovascularization (hypoxia-inducible factor-1α) and fibroproliferation (plasminogen activator inhibitor-1) was upregulated in WJ-MSC-CM-treated fibroblasts (P≤0.05). WJ-MSC-CM enhanced normal skin fibroblast proliferation (P≤0.001) and migration (P≤0.05), and promoted wound healing in an excisional full-thickness skin murine model. Under our experimental conditions, WJ-MSCs enhanced skin wound healing in an in vivo mouse model.

  17. Both Autocrine Signaling and Paracrine Signaling of HB-EGF Enhance Ocular Neovascularization.

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    Inoue, Yuki; Shimazawa, Masamitsu; Nakamura, Shinsuke; Takata, Shinsuke; Hashimoto, Yuhei; Izawa, Hiroshi; Masuda, Tomomi; Tsuruma, Kazuhiro; Sakaue, Tomohisa; Nakayama, Hironao; Higashiyama, Shigeki; Hara, Hideaki

    2018-01-01

    The incidence of blindness is increasing because of the increase in abnormal ocular neovascularization. Anti-VEGF (vascular endothelial growth factor) therapies have led to good results, although they are not a cure for the blindness. The purpose of this study was to determine what role HB-EGF (heparin-binding epidermal growth factor-like growth factor) plays in ocular angiogenesis. We examined the role played by HB-EGF in ocular neovascularization in 2 animal models of neovascularization: laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy. We also studied human retinal microvascular endothelial cells in culture. Our results showed that the neovascularization was decreased in both the CNV and oxygen-induced retinopathy models in HB-EGF conditional knockout mice compared with that in wild-type mice. Moreover, the expressions of HB-EGF and VEGF were increased after laser-induced CNV and oxygen-induced retinopathy, and their expression sites were located around the neovascular areas. Exposure of human retinal microvascular endothelial cells to HB-EGF and VEGF increased their proliferation and migration, and CRM-197 (cross-reactive material-197), an HB-EGF inhibitor, decreased the HB-EGF-induced and VEGF-induced cell proliferation and migration. VEGF increased the expression of HB-EGF mRNA. VEGF-dependent activation of EGFR (epidermal growth factor receptor)/ERK1/2 (extracellular signal-regulated kinase 1/2) signaling and cell proliferation of endothelial cells required stimulation of the ADAM17 (a disintegrin and metalloprotease) and ADAM12. CRM-197 decreased the grades of the fluorescein angiograms and size of the CNV areas in marmoset monkeys. These findings suggest that HB-EGF plays an important role in the development of CNV. Therefore, further investigations of HB-EGF are needed as a potential therapeutic target in the treatment of exudative age-related macular degeneration. © 2017 American Heart Association, Inc.

  18. Interleukin-6: a bone marrow stromal cell paracrine signal that induces neuroendocrine differentiation and modulates autophagy in bone metastatic PCa cells.

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    Delk, Nikki A; Farach-Carson, Mary C

    2012-04-01

    Autophagy reallocates nutrients and clears normal cells of damaged proteins and organelles. In the context of metastatic disease, invading cancer cells hijack autophagic processes to survive and adapt in the host microenvironment. We sought to understand how autophagy is regulated in the metastatic niche for prostate cancer (PCa) cells where bone marrow stromal cell (BMSC) paracrine signaling induces PCa neuroendocrine differentiation (NED). In PCa, this transdifferentiation of metastatic PCa cells to neuronal-like cells correlates with advanced disease. Because autophagy provides a survival advantage for cancer cells and promotes cell differentiation, we hypothesized that autophagy mediates PCa NED in the bone. Thus, we determined the ability of paracrine factors in conditioned media (CM) from two separate BMSC subtypes, HS5 and HS27a, to induce autophagy in C4-2 and C4-2B bone metastatic PCa cells by characterizing the autophagy marker, LC3. Unlike HS27a CM, HS5 CM induced LC3 accumulation in PCa cells, suggesting autophagy was induced and indicating that HS5 and HS27a secrete a different milieu of paracrine factors that influence PCa autophagy. We identified interleukin-6 (IL-6), a cytokine more highly expressed in HS5 cells than in HS27a cells, as a paracrine factor that regulates PCa autophagy. Pharmacological inhibition of STAT3 activity did not attenuate LC3 accumulation, implying that IL-6 regulates NED and autophagy through different pathways. Finally, chloroquine inhibition of autophagic flux blocked PCa NED; hence autophagic flux maintains NED. Our studies imply that autophagy is cytoprotective for PCa cells in the bone, thus targeting autophagy is a potential therapeutic strategy.

  19. XIAP gene expression and function is regulated by autocrine and paracrine TGF-β signaling

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    Van Themsche Céline

    2010-08-01

    Full Text Available Abstract Background X-linked inhibitor of apoptosis protein (XIAP is often overexpressed in cancer cells, where it plays a key role in survival and also promotes invasiveness. To date however, the extracellular signals and intracellular pathways regulating its expression and activity remain incompletely understood. We have previously showed that exposure to each of the three TGF-β (transforming growth factor beta isoforms upregulates XIAP protein content in endometrial carcinoma cells in vitro. In the present study, we have investigated the clinical relevance of TGF-β isoforms in endometrial tumours and the mechanisms through which TGF-β isoforms regulate XIAP content in uterine cancer cells. Methods TGF-β isoforms immunoreactivity in clinical samples from endometrial tumours was assessed using immunofluorescence. Two model cancer cell lines (KLE endometrial carcinoma cells and HeLa cervical cancer cells and pharmacological inhibitors were used to investigate the signalling pathways regulating XIAP expression and activity in response to autocrine and paracrine TGF-β in cancer cell. Results We have found immunoreactivity for each TGF-β isoform in clinical samples from endometrial tumours, localizing to both stromal and epithelial/cancer cells. Blockade of autocrine TGF-β signaling in KLE endometrial carcinoma cells and HeLa cervical cancer cells reduced endogenous XIAP mRNA and protein levels. In addition, each TGF-β isoform upregulated XIAP gene expression when given exogenously, in a Smad/NF-κB dependent manner. This resulted in increased polyubiquitination of PTEN (phosphatase and tensin homolog on chromosome ten, a newly identified substrate for XIAP E3 ligase activity, and in a XIAP-dependent decrease of PTEN protein levels. Although each TGF-β isoform decreased PTEN content in a XIAP- and a Smad-dependent manner, decrease of PTEN levels in response to only one isoform, TGF-β3, was blocked by PI3-K inhibitor LY294002. Conclusions

  20. Decidual Stromal Cell Response to Paracrine Signals from the Trophoblast: Amplification of Immune and Angiogenic Modulators

    DEFF Research Database (Denmark)

    Hess, AP; Hamilton, AE; Talbi, S

    2007-01-01

    During the invasive phase of implantation, trophoblasts and maternal decidual stromal cells secrete products that regulate trophoblast differentiation and migration into the maternal endometrium. Paracrine interactions between the extravillous trophoblast and the maternal decidua are important...... a functional genomics approach to investigate these paracrine interactions. Human endometrial stromal cells were decidualized with progesterone and were further treated with conditioned media (CM) from human trophoblasts (TCM) or, as a control, with conditioned media (CCM) from non-decidualized stromal cells...... regulated groups. The data demonstrate a significant induction of pro-inflammatory cytokines and chemokines, as well as angiogenic/static factors in decidualized endometrial stromal cells in response to trophoblast-secreted products. The data suggest that the trophoblast acts to alter the local immune...

  1. Subgroup-Elimination Transcriptomics Identifies Signaling Proteins that Define Subclasses of TRPV1-Positive Neurons and a Novel Paracrine Circuit

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    Isensee, Jörg; Wenzel, Carsten; Buschow, Rene; Weissmann, Robert; Kuss, Andreas W.; Hucho, Tim

    2014-01-01

    Normal and painful stimuli are detected by specialized subgroups of peripheral sensory neurons. The understanding of the functional differences of each neuronal subgroup would be strongly enhanced by knowledge of the respective subgroup transcriptome. The separation of the subgroup of interest, however, has proven challenging as they can hardly be enriched. Instead of enriching, we now rapidly eliminated the subgroup of neurons expressing the heat-gated cation channel TRPV1 from dissociated rat sensory ganglia. Elimination was accomplished by brief treatment with TRPV1 agonists followed by the removal of compromised TRPV1(+) neurons using density centrifugation. By differential microarray and sequencing (RNA-Seq) based expression profiling we compared the transcriptome of all cells within sensory ganglia versus the same cells lacking TRPV1 expressing neurons, which revealed 240 differentially expressed genes (adj. p1.5). Corroborating the specificity of the approach, many of these genes have been reported to be involved in noxious heat or pain sensitization. Beyond the expected enrichment of ion channels, we found the TRPV1 transcriptome to be enriched for GPCRs and other signaling proteins involved in adenosine, calcium, and phosphatidylinositol signaling. Quantitative population analysis using a recent High Content Screening (HCS) microscopy approach identified substantial heterogeneity of expressed target proteins even within TRPV1-positive neurons. Signaling components defined distinct further subgroups within the population of TRPV1-positive neurons. Analysis of one such signaling system showed that the pain sensitizing prostaglandin PGD2 activates DP1 receptors expressed predominantly on TRPV1(+) neurons. In contrast, we found the PGD2 producing prostaglandin D synthase to be expressed exclusively in myelinated large-diameter neurons lacking TRPV1, which suggests a novel paracrine neuron-neuron communication. Thus, subgroup analysis based on the elimination

  2. Paracrine-mediated osteoclastogenesis by the osteosarcoma MG63 cell line: is RANKL/RANK signalling really important?

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    Costa-Rodrigues, J; Teixeira, C A; Fernandes, M H

    2011-08-01

    Although in the past little attention has been paid to the influence of osteosarcoma cells in osteoclast function, recent studies suggest a close relationship between osteosarcoma aggressiveness and osteoclastic activity. The present study addresses the paracrine effects of MG63 cells, a human osteosarcoma-derived cell line, on the differentiation of peripheral blood osteoclast precursor cells (PBMC). PBMC were cultured for 21 days in the presence of conditioned media from MG63 cell cultures (CM) collected at 48 h (CM_MG1), 7 days (CM_MG2) and 14 days (CM_MG3). MG63 cell cultures displayed the expression of ALP and BMP-2 and, also, the osteoclastogenic genes M-CSF and RANKL, although with a low expression of RANKL. PBMC cultures supplemented with CM presented an evident osteoclastogenic behavior, which was dependent on the culture period of the MG63 cells. The inductive effect appeared to be more relevant for the differentiation and activation genes, c-myc and c-src, and lower for genes associated with osteoclast function. In addition, PBMC cultures displayed increased functional parameters, including calcium phosphate resorbing activity. Assessment of the PBMC cultures in the presence of U0126, PDTC, and indomethacin suggested that in addition to MEK and NFkB pathways, other signaling mechanisms, probably not involving RANKL/RANK interaction, might be activated in the presence of conditioned medium from MG63. In conclusion, MG63 cell line appears to induce a significant paracrine-mediated osteoclastogenic response. Understanding the mechanisms underlying the interaction of osteosarcoma cells and osteoclasts may contribute to the development of new potential approaches in the treatment of such bone metabolic diseases.

  3. The Role of Paracrine and Autocrine Signaling in the Early Phase of Adipogenic Differentiation of Adipose-derived Stem Cells

    Science.gov (United States)

    Hemmingsen, Mette; Vedel, Søren; Skafte-Pedersen, Peder; Sabourin, David; Collas, Philippe; Bruus, Henrik; Dufva, Martin

    2013-01-01

    Introduction High cell density is known to enhance adipogenic differentiation of mesenchymal stem cells, suggesting secretion of signaling factors or cell-contact-mediated signaling. By employing microfluidic biochip technology, we have been able to separate these two processes and study the secretion pathways. Methods and results Adipogenic differentiation of human adipose-derived stem cells (ASCs) cultured in a microfluidic system was investigated under perfusion conditions with an adipogenic medium or an adipogenic medium supplemented with supernatant from differentiating ASCs (conditioned medium). Conditioned medium increased adipogenic differentiation compared to adipogenic medium with respect to accumulation of lipid-filled vacuoles and gene expression of key adipogenic markers (C/EBPα, C/EBPβ, C/EBPδ, PPARγ, LPL and adiponectin). The positive effects of conditioned medium were observed early in the differentiation process. Conclusions Using different cell densities and microfluidic perfusion cell cultures to suppress the effects of cell-released factors, we have demonstrated the significant role played by auto- or paracrine signaling in adipocyte differentiation. The cell-released factor(s) were shown to act in the recruitment phase of the differentiation process. PMID:23723991

  4. The role of paracrine and autocrine signaling in the early phase of adipogenic differentiation of adipose-derived stem cells.

    Directory of Open Access Journals (Sweden)

    Mette Hemmingsen

    Full Text Available INTRODUCTION: High cell density is known to enhance adipogenic differentiation of mesenchymal stem cells, suggesting secretion of signaling factors or cell-contact-mediated signaling. By employing microfluidic biochip technology, we have been able to separate these two processes and study the secretion pathways. METHODS AND RESULTS: Adipogenic differentiation of human adipose-derived stem cells (ASCs cultured in a microfluidic system was investigated under perfusion conditions with an adipogenic medium or an adipogenic medium supplemented with supernatant from differentiating ASCs (conditioned medium. Conditioned medium increased adipogenic differentiation compared to adipogenic medium with respect to accumulation of lipid-filled vacuoles and gene expression of key adipogenic markers (C/EBPα, C/EBPβ, C/EBPδ, PPARγ, LPL and adiponectin. The positive effects of conditioned medium were observed early in the differentiation process. CONCLUSIONS: Using different cell densities and microfluidic perfusion cell cultures to suppress the effects of cell-released factors, we have demonstrated the significant role played by auto- or paracrine signaling in adipocyte differentiation. The cell-released factor(s were shown to act in the recruitment phase of the differentiation process.

  5. c-kitpos GATA-4 high rat cardiac stem cells foster adult cardiomyocyte survival through IGF-1 paracrine signalling.

    Directory of Open Access Journals (Sweden)

    Nanako Kawaguchi

    2010-12-01

    Full Text Available Resident c-kit positive (c-kitpos cardiac stem cells (CSCs could be considered the most appropriate cell type for myocardial regeneration therapies. However, much is still unknown regarding their biological properties and potential.We produced clones of high and low expressing GATA-4 CSCs from long-term bulk-cultured c-kitpos CSCs isolated from adult rat hearts. When c-kitpos GATA-4 high expressing clonal CSCs (cCSCs were co-cultured with adult rat ventricular cardiomyocytes, we observed increased survival and contractility of the cardiomyocytes, compared to cardiomyocytes cultured alone, co-cultured with fibroblasts or c-kitpos GATA-4 low expressing cCSCs. When analysed by ELISA, the concentration of IGF-1 was significantly increased in the c-kitpos GATA-4 high cCSC/cardiomyocyte co-cultures and there was a significant correlation between IGF-1 concentration and cardiomyocyte survival. We showed the activation of the IGF-1 receptor and its downstream molecular targets in cardiomyocytes co-cultured with c-kitpos GATA-4 high cCSCs but not in cardiomyocytes that were cultured alone, co-cultured with fibroblasts or c-kitpos GATA-4 low cCSCs. Addition of a blocking antibody specific to the IGF-1 receptor inhibited the survival of cardiomyocytes and prevented the activation of its signalling in cardiomyocytes in the c-kitpos GATA-4 high cCSC/cardiomyocyte co-culture system. IGF-1 supplementation or IGF-1 high conditioned medium taken from the co-culture of c-kitpos GATA-4 high cCSCs plus cardiomyocytes did extend the survival and contractility of cardiomyocytes cultured alone and cardiomyocytes co-cultured with c-kitpos GATA-4 low cCSCs.c-kitpos GATA-4 high cCSCs exert a paracrine survival effect on cardiomyocytes through induction of the IGF-1R and signalling pathway.

  6. Retinol dehydrogenase-10 regulates pancreas organogenesis and endocrine cell differentiation via paracrine retinoic acid signalling

    DEFF Research Database (Denmark)

    Arregi, Igor; Climent, Maria; Iliev, Dobromir

    2016-01-01

    Vitamin A-derived retinoic acid (RA) signals are critical for the development of several organs, including the pancreas. However, the tissue-specific control of RA synthesis in organ and cell lineage development has only poorly been addressed in vivo. Here we show that Retinol dehydrogenase-10 (Rdh......10), a key enzyme in embryonic RA production, has important functions in pancreas organogenesis and endocrine cell differentiation. Rdh10 was expressed in the developing pancreas epithelium and surrounding mesenchyme. Rdh10 null mutant mouse embryos exhibited dorsal pancreas agenesis...... and a hypoplastic ventral pancreas with retarded tubulogenesis and branching. Conditional disruption of Rdh10 from the endoderm caused increased mortality, reduced body weight and lowered blood glucose levels after birth. Endodermal Rdh10 deficiency led to a smaller dorsal pancreas with a reduced density of early...

  7. The effects of high dose ionizing radiation on transcriptional regulation and paracrine signaling in human peripheral blood mononuclear cells

    International Nuclear Information System (INIS)

    Beer, L.

    2015-01-01

    While it has long been accepted that direct cell-cell interactions and the replacement of injured tissues with injected cells exerts therapeutic effects, it is currently believed that, in addition, paracrine factors released from different cell types activate cytoprotective and regenerative processes. Cells are now seen as bioreactors that produce and release soluble factors which might be used as therapeutics. We have previously shown that peripheral blood mononuclear cells (PBMCs) release a plethora of paracrine factors that enhance wound healing, attenuate myocardial damage following acute myocardial infarction, abolish microvascular obstruction, improve neurological outcome after acute ischemic stroke and spinal cord injury and protect mice from experimental autoimmune myocarditis. These PBMC derived paracrine factors may exert their effects via the induction of cytoprotective pathways, augmentation of angiogenesis, induction of NO-depended vasodilation and inhibition of VASP dependent platelet aggregation, as well as driving auto-reactive CD4+ cells into apoptosis. To enhance the cellular secretory capacity, treatments which induce stress responses, such as hypoxic preconditioning or ionizing irradiation (IR), have been developed. Although these effects have been evaluated in several disease states there is little data available on the cellular effects of ionizing irradiation on human PBMCs and their secretome. In this study, we have thus undertaken to investigate the effects of IR on human PBMCs in terms of the induction of transcriptional changes and release of pleiotropic paracrine factors. There are three primary aims of this doctoral thesis: 1. To investigate cellular processes activated or repressed in human PBMCs following high dose ionizing radiation (60Gy) and high density cell cultivation (25*10"6 cells/ml) for up to 24 hours. 2. To identify paracrine factors released from these cells using a multi-methodical biochemical/bioinformatics approach. 3

  8. Adipose-derived stem cells enhance myogenic differentiation in the mdx mouse model of muscular dystrophy via paracrine signaling

    Directory of Open Access Journals (Sweden)

    Ji-qing Cao

    2016-01-01

    Full Text Available Adipose-derived stem cells have been shown to promote peripheral nerve regeneration through the paracrine secretion of neurotrophic factors. However, it is unclear whether these cells can promote myogenic differentiation in muscular dystrophy. Adipose-derived stem cells (6 × 10 6 were injected into the gastrocnemius muscle of mdx mice at various sites. Dystrophin expression was found in the muscle fibers. Phosphorylation levels of Akt, mammalian target of rapamycin (mTOR, eIF-4E binding protein 1 and S6 kinase 1 were increased, and the Akt/mTOR pathway was activated. Simultaneously, myogenin levels were increased, whereas cleaved caspase 3 and vimentin levels were decreased. Necrosis and fibrosis were reduced in the muscle fibers. These findings suggest that adipose-derived stem cells promote the regeneration and survival of muscle cells by inhibiting apoptosis and fibrosis, thereby alleviating muscle damage in muscular dystrophy.

  9. EMMPRIN regulates tumor growth and metastasis by recruiting bone marrow-derived cells through paracrine signaling of SDF-1 and VEGF.

    Science.gov (United States)

    Chen, Yanke; Gou, Xingchun; Kong, Derek Kai; Wang, Xiaofei; Wang, Jianhui; Chen, Zeming; Huang, Chen; Zhou, Jiangbing

    2015-10-20

    EMMPRIN, a cell adhesion molecule highly expressed in a variety of tumors, is associated with poor prognosis in cancer patients. Mechanistically, EMMPRIN has been characterized to contribute to tumor development and progression by controlling the expression of MMPs and VEGF. In the present study, by using fluorescently labeled bone marrow-derived cells (BMDCs), we found that the down-regulation of EMMPRIN expression in cancer cells reduces tumor growth and metastasis, and is associated with the reduced recruitment of BMDCs. Further protein profiling studies suggest that EMMPRIN controls BMDC recruitment through regulating the secretion of soluble factors, notably, VEGF and SDF-1. We demonstrate that the expression and secretion of SDF-1 in tumor cells are regulated by EMMPRIN. This study reveals a novel mechanism by which EMMPRIN promotes tumor growth and metastasis by recruitment of BMDCs through controlling secretion and paracrine signaling of SDF-1 and VEGF.

  10. Prognostic factors of craniopharyngioma with special reference to autocrine/paracrine signaling: underestimated implication of growth hormone receptor.

    Science.gov (United States)

    Ogawa, Yoshikazu; Watanabe, Mika; Tominaga, Teiji

    2015-10-01

    Craniopharyngioma is a slow-growing tumor classified as benign, but tight adhesion and significant local infiltration to the vital structures are common. In spite of improvement of modern microsurgery techniques and precise anatomical understanding not few cases of this tumor recur, and long-term tumor control and maintenance of quality of life are sometimes difficult. However, very little is known about the effects of the molecular characters of craniopharyngioma on the prognosis. Ninety eight cases of craniopharyngioma surgically treated at the Department of Neurosurgery, Tohoku University Hospital and Kohnan Hospital from April 1996 to May 2014, 45 males and 53 females aged from 2 to 80 years (mean, 40.84 years) were retrospectively reviewed, and postoperative outcomes and the possible involvement of the autocrine/paracrine mechanism were investigated. The patients were followed up at intervals of 6 months to assess tumor recurrence, and clinical outcomes were correlated with the findings of immunohistochemical examinations used growth hormone receptor (GHR) and downstream hormones. The follow-up period ranged from 3 to 209 months. Hormone expression was examined in 88 patients, of which 46 specimens (52.3 %) showed high expression of GHR. The GHR high expression group had a significantly shorter duration of postoperative stable disease compared with the low expression group (logrank test, p = 0.007). Simultaneous high expression of growth hormone (GH) and GHR was found in 33 specimens (37.5 %), and the high expression group had a significantly shorter duration of postoperative stable disease compared with the low expression group (logrank test, p = 0.011). No other hormones showed statistically significant differences in outcomes. High expression of GHR is associated with shorter duration of postoperative stable disease in patients with craniopharyngioma. If the surgical specimens were craniopharyngiomas with high GHR expression, GH supplementation

  11. Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment

    Science.gov (United States)

    Xiao, Deyi; Barry, Samantha; Kmetz, Daniel; Egger, Michael; Pan, Jianmin; Rai, Shesh N; Qu, Jifu; McMasters, Kelly M.; Hao, Hongying

    2016-01-01

    The tumor microenvironment is abundant with exosomes that are secreted by the cancer cells themselves. Exosomes are nanosized, organelle-like membranous structures that are increasingly being recognized as major contributors in the progression of malignant neoplasms. A critical element in melanoma progression is its propensity to metastasize, but little is known about how melanoma cell-derived exosomes modulate the microenvironment to optimize conditions for tumor progression and metastasis. Here, we provide evidence that melanoma cell-derived exosomes promote phenotype switching in primary melanocytes through paracrine/autocrine signaling. We found that the mitogen-activated protein kinase (MAPK) signaling pathway was activated during the exosome-mediated epithelial-to-mesenchymal transition (EMT)-resembling process, which promotes metastasis. Let-7i, an miRNA modulator of EMT, was also involved in this process. We further defined two other miRNA modulators of EMT (miR-191 and let-7a) in serum exosomes for differentiating stage I melanoma patients from non-melanoma subjects. These results provide the first strong molecular evidence that melanoma cell-derived exosomes promote the EMT-resembling process in the tumor microenvironment. Thus, novel strategies targeting EMT and modulating the tumor microenvironment may emerge as important approaches for the treatment of metastatic melanoma. PMID:27063098

  12. Conjugated linoleic acid induces human adipocyte delipidation: autocrine/paracrine regulation of MEK/ERK signaling by adipocytokines

    DEFF Research Database (Denmark)

    Brown, J Mark; Boysen, Maria Sandberg; Chung, Soonkyu

    2004-01-01

    of MEK/ERK could be attenuated by pretreatment with U0126 and pertussis toxin. In parallel, pretreatment with U0126 blocked the ability of trans-10, cis-12 CLA to alter gene expression and attenuate glucose and fatty acid uptake of the cultures. Intriguingly, the induction by CLA of MEK/ERK signaling...

  13. IL1-and TGF beta-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine 'Bystander senescence'

    Czech Academy of Sciences Publication Activity Database

    Hubáčková, Soňa; Krejčíková, Kateřina; Bartek, Jiří; Hodný, Zdeněk

    2012-01-01

    Roč. 4, č. 12 (2012), 932-951 ISSN 1945-4589 R&D Projects: GA ČR GA204/08/1418; GA ČR GAP301/10/1525 Institutional support: RVO:68378050 Keywords : senescence-associated secretome * DNA damage response * cytokines * JAK/STAT3 * TGF beta * NF kappa B * IL6 * IL beta * Nox4 * autocrine and paracrine signaling * tumor Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.696, year: 2012

  14. n-3 Polyunsaturated Fatty Acids and Mechanisms to Mitigate Inflammatory Paracrine Signaling in Obesity-Associated Breast Cancer

    Directory of Open Access Journals (Sweden)

    Jennifer M. Monk

    2014-10-01

    Full Text Available Globally, the prevalence of obesity is increasing which subsequently increases the risk of the development of obesity-related chronic diseases. Low-grade chronic inflammation and dysregulated adipose tissue inflammatory mediator/adipokine secretion are well-established in obesity, and these factors increase the risk of developing inflammation-associated cancer. Breast cancer is of particular interest given that increased inflammation within the subcutaneous mammary adipose tissue depot can alter the local tissue inflammatory microenvironment such that it resembles that of obese visceral adipose tissue. Therefore, in obese women with breast cancer, increased inflammatory mediators both locally and systemically can perpetuate inflammation-associated pro-carcinogenic signaling pathways, thereby increasing disease severity. Herein, we discuss some of these inflammation-associated pro-carcinogenic mechanisms of the combined obese breast cancer phenotype and offer evidence that dietary long chain n-3 polyunsaturated fatty acids (PUFA may have utility in mitigating the severity of obesity-associated inflammation and breast cancer.

  15. Microbioreactor arrays for full factorial screening of exogenous and paracrine factors in human embryonic stem cell differentiation.

    Directory of Open Access Journals (Sweden)

    Drew M Titmarsh

    Full Text Available Timed exposure of pluripotent stem cell cultures to exogenous molecules is widely used to drive differentiation towards desired cell lineages. However, screening differentiation conditions in conventional static cultures can become impractical in large parameter spaces, and is intrinsically limited by poor spatiotemporal control of the microenvironment that also makes it impossible to determine whether exogenous factors act directly or through paracrine-dependent mechanisms. We detail here the development of a continuous flow microbioreactor array platform that combines full-factorial multiplexing of input factors with progressive accumulation of paracrine factors through serially-connected culture chambers, and further, the use of this system to explore the combinatorial parameter space of both exogenous and paracrine factors involved in human embryonic stem cell (hESC differentiation to a MIXL1-GFP(+ primitive streak-like population. We show that well known inducers of primitive streak (BMP, Activin and Wnt signals do not simply act directly on hESC to induce MIXL1 expression, but that this requires accumulation of surplus, endogenous factors; and, that conditioned medium or FGF-2 supplementation is able to offset this. Our approach further reveals the presence of a paracrine, negative feedback loop to the MIXL1-GFP(+ population, which can be overcome with GSK-3β inhibitors (BIO or CHIR99021, implicating secreted Wnt inhibitory signals such as DKKs and sFRPs as candidate effectors. Importantly, modulating paracrine effects identified in microbioreactor arrays by supplementing FGF-2 and CHIR in conventional static culture vessels resulted in improved differentiation outcomes. We therefore demonstrate that this microbioreactor array platform uniquely enables the identification and decoding of complex soluble factor signalling hierarchies, and that this not only challenges prevailing strategies for extrinsic control of hESC differentiation, but

  16. Direct Position Determination of Multiple Radio Signals

    Directory of Open Access Journals (Sweden)

    Weiss Anthony J

    2005-01-01

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

  17. Autocrine and Paracrine Mechanisms Promoting Chemoresistance in Cholangiocarcinoma

    Directory of Open Access Journals (Sweden)

    Massimiliano Cadamuro

    2017-01-01

    Full Text Available Resistance to conventional chemotherapeutic agents, a typical feature of cholangiocarcinoma, prevents the efficacy of the therapeutic arsenal usually used to combat malignancy in humans. Mechanisms of chemoresistance by neoplastic cholangiocytes include evasion of drug-induced apoptosis mediated by autocrine and paracrine cues released in the tumor microenvironment. Here, recent evidence regarding molecular mechanisms of chemoresistance is reviewed, as well as associations between well-developed chemoresistance and activation of the cancer stem cell compartment. It is concluded that improved understanding of the complex interplay between apoptosis signaling and the promotion of cell survival represent potentially productive areas for active investigation, with the ultimate aim of encouraging future studies to unveil new, effective strategies able to overcome current limitations on treatment.

  18. Sex determining signal in Drosophila melanogaster

    Indian Academy of Sciences (India)

    Administrator

    Addition of almost any segment of the X chromosome pro- duced a shift towards ... It is now well established that the X/A signal acts to set the functional state ... tionally related because a defect in one of them can be partly. COMMENTARY ON ...

  19. Alternative method for determining the constant offset in lidar signal

    Science.gov (United States)

    Vladimir A. Kovalev; Cyle Wold; Alexander Petkov; Wei Min Hao

    2009-01-01

    We present an alternative method for determining the total offset in lidar signal created by a daytime background-illumination component and electrical or digital offset. Unlike existing techniques, here the signal square-range-correction procedure is initially performed using the total signal recorded by lidar, without subtraction of the offset component. While...

  20. Low-Frequency Beacon Signal Strength Determination.

    Science.gov (United States)

    1980-01-01

    Radio Frequency List , RIS AF-6050-12 [141. Using this value and assum- ing performance for these facilities as indicatcd in FAA Handbook 6050.10, ERP...FAA Handbook 6050. 10 for facilities of appropriate transmitter power, determined from FAA Master Radio Frequency List 6050-12, April 1979...these facilities has not been directly measured and, therefore, values corresponding to transmitter powers given in FAA Master Radio Frequency List , RIS

  1. The endocrine and paracrine control of menstruation.

    Science.gov (United States)

    Henriet, Patrick; Gaide Chevronnay, Héloïse P; Marbaix, Etienne

    2012-07-25

    During the reproductive life, the human endometrium undergoes cycles of substantial remodeling including, at menstruation, a massive but delimited tissue breakdown immediately followed by scarless repair. The present review aims at summarizing the current knowledge on the endocrine and paracrine control of menstruation in the light of recent observations that undermine obsolete dogmas. Menstruation can be globally considered as a response to falling progesterone concentration. However, tissue breakdown is heterogeneous and tightly controlled in space and time by a complex network of regulators and effectors, including cytokines, chemokines, proteases and various components of an inflammatory response. Moreover, menstruation must be regarded as part of a complex and integrated mechanism of tissue remodeling including features that precede and follow tissue lysis, i.e. decidualization and immediate post-menstrual regeneration. The understanding of the regulation of menstruation is of major basic and clinical interest. Indeed, these mechanisms largely overlap with those controlling other histopathological occurrences of tissue remodeling, such as development and cancer, and inappropriate control of menstrual features is a major potential cause of two frequent endometrial pathologies (i.e. abnormal uterine bleeding and endometriosis). Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  2. Endothelial cells activate the cancer stem cell-associated NANOGP8 pathway in colorectal cancer cells in a paracrine fashion.

    Science.gov (United States)

    Wang, Rui; Bhattacharya, Rajat; Ye, Xiangcang; Fan, Fan; Boulbes, Delphine R; Xia, Ling; Ellis, Lee M

    2017-08-01

    In colorectal cancer (CRC), cancer stem cells (CSCs) have been hypothesized to mediate cell survival and chemoresistance. Previous studies from our laboratory described a role for liver parenchymal endothelial cells (LPECs) in mediating the CSC phenotype in CRC cells in a paracrine/angiocrine fashion. The objectives of this study were to determine whether endothelial cells (ECs) from different organs can induce the CSC phenotype in CRC cells and to elucidate the signaling pathways involved. We treated a newly developed CRC cell line (HCP-1) and established CRC cell lines (HT29 and SW480) with conditioned medium (CM) from primary ECs isolated from nonmalignant liver, lung, colon mucosa, and kidney. Our results showed that CM from ECs from all organs increased the number of CSCs, as determined by sphere formation, and protein levels of NANOG and OCT4 in CRC cells. With the focus of further elucidating the role of the liver vascular network in mediating the CSC phenotype, we demonstrated that CM from LPECs increased resistance to 5-fluorouracil in CRC cells. Moreover, we showed that LPEC CM specifically induced NANOGP8 expression in CRC cells by specific enzyme digestion and a luciferase reporter assay using a vector containing the NANOGP8 promoter. Lastly, we found that LPEC CM-induced NANOGP8 expression and sphere formation were mediated by AKT activation. Our studies demonstrated a paracrine role for ECs in regulating the CSC phenotype and chemoresistance in CRC cells by AKT-mediated induction of NANOGP8. These studies suggest a more specific approach to target CSCs by blocking the expression of NANOGP8 in cancer cells. © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

  3. Morphogen and community effects determine cell fates in response to BMP4 signaling in human embryonic stem cells.

    Science.gov (United States)

    Nemashkalo, Anastasiia; Ruzo, Albert; Heemskerk, Idse; Warmflash, Aryeh

    2017-09-01

    Paracrine signals maintain developmental states and create cell fate patterns in vivo and influence differentiation outcomes in human embryonic stem cells (hESCs) in vitro Systematic investigation of morphogen signaling is hampered by the difficulty of disentangling endogenous signaling from experimentally applied ligands. Here, we grow hESCs in micropatterned colonies of 1-8 cells ('µColonies') to quantitatively investigate paracrine signaling and the response to external stimuli. We examine BMP4-mediated differentiation in µColonies and standard culture conditions and find that in µColonies, above a threshold concentration, BMP4 gives rise to only a single cell fate, contrary to its role as a morphogen in other developmental systems. Under standard culture conditions BMP4 acts as a morphogen but this requires secondary signals and particular cell densities. We find that a 'community effect' enforces a common fate within µColonies, both in the state of pluripotency and when cells are differentiated, and that this effect allows a more precise response to external signals. Using live cell imaging to correlate signaling histories with cell fates, we demonstrate that interactions between neighbors result in sustained, homogenous signaling necessary for differentiation. © 2017. Published by The Company of Biologists Ltd.

  4. Autocrine and Paracrine Hh Signaling Regulate Prostate Development

    Science.gov (United States)

    2010-09-01

    Rev. Mol. Cell. Biol. 6, 306–317 7. Wang, B. E., Shou, J., Ross, S., Koeppen, H., De Sauvage, F. J., and Gao, W. Q. (2003) J. Biol. Chem. 278, 18506...and Placzek, M. (2006) Nat. Rev. Genet. 7, 841–850 13. Callahan, C. A., Ofstad, T., Horng, L.,Wang, J. K., Zhen, H. H., Coulombe , P. A., and Oro, A. E...Albig, A. R., and Schiemann, W. P. (2005)Mol. Biol. Cell 16, 609–625 45. Olsen, M. W., Ley , C. D., Junker, N., Hansen, A. J., Lund, E. L., and Krist

  5. Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals

    OpenAIRE

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

    2005-01-01

    In diabetic LDLR–/– mice, an ectopic BMP2-Msx2 gene regulatory program is upregulated in association with vascular calcification. We verified the procalcific actions of aortic Msx2 expression in vivo. CMV-Msx2 transgenic (CMV-Msx2Tg+) mice expressed 3-fold higher levels of aortic Msx2 than nontransgenic littermates. On high-fat diets, CMV-Msx2Tg+ mice exhibited marked cardiovascular calcification involving aortic and coronary tunica media. This corresponded to regions of Msx2 immunoreactivity...

  6. Plant natriuretic peptides are apoplastic and paracrine stress response molecules

    KAUST Repository

    Wang, Yuhua

    2011-04-07

    Higher plants contain biologically active proteins that are recognized by antibodies against human atrial natriuretic peptide (ANP). We identified and isolated two Arabidopsis thaliana immunoreactive plant natriuretic peptide (PNP)-encoding genes, AtPNP-A and AtPNP-B, which are distantly related members of the expansin superfamily and have a role in the regulation of homeostasis in abiotic and biotic stresses, and have shown that AtPNP-A modulates the effects of ABA on stomata. Arabidopsis PNP (PNP-A) is mainly expressed in leaf mesophyll cells, and in protoplast assays we demonstrate that it is secreted using AtPNP-A:green fluorescent protein (GFP) reporter constructs and flow cytometry. Transient reporter assays provide evidence that AtPNP-A expression is enhanced by heat, osmotica and salt, and that AtPNP-A itself can enhance its own expression, thereby generating a response signature diagnostic for paracrine action and potentially also autocrine effects. Expression of native AtPNP-A is enhanced by osmotica and transiently by salt. Although AtPNP-A expression is induced by salt and osmotica, ABA does not significantly modulate AtPNP-A levels nor does recombinant AtPNP-A affect reporter expression of the ABA-responsive RD29A gene. Together, these results provide experimental evidence that AtPNP-A is stress responsive, secreted into the apoplastic space and can enhance its own expression. Furthermore, our findings support the idea that AtPNP-A, together with ABA, is an important component in complex plant stress responses and that, much like in animals, peptide signaling molecules can create diverse and modular signals essential for growth, development and defense under rapidly changing environmental conditions. © 2011 The Author.

  7. Bone Marrow Mesenchymal Stromal Cells Stimulate Skeletal Myoblast Proliferation through the Paracrine Release of VEGF

    Science.gov (United States)

    Chellini, Flaminia; Mazzanti, Benedetta; Nistri, Silvia; Nosi, Daniele; Saccardi, Riccardo; Quercioli, Franco; Zecchi-Orlandini, Sandra; Formigli, Lucia

    2012-01-01

    Mesenchymal stromal cells (MSCs) are the leading cell candidates in the field of regenerative medicine. These cells have also been successfully used to improve skeletal muscle repair/regeneration; however, the mechanisms responsible for their beneficial effects remain to be clarified. On this basis, in the present study, we evaluated in a co-culture system, the ability of bone-marrow MSCs to influence C2C12 myoblast behavior and analyzed the cross-talk between the two cell types at the cellular and molecular level. We found that myoblast proliferation was greatly enhanced in the co-culture as judged by time lapse videomicroscopy, cyclin A expression and EdU incorporation. Moreover, myoblasts immunomagnetically separated from MSCs after co-culture expressed higher mRNA and protein levels of Notch-1, a key determinant of myoblast activation and proliferation, as compared with the single culture. Notch-1 intracellular domain and nuclear localization of Hes-1, a Notch-1 target gene, were also increased in the co-culture. Interestingly, the myoblastic response was mainly dependent on the paracrine release of vascular endothelial growth factor (VEGF) by MSCs. Indeed, the addition of MSC-derived conditioned medium (CM) to C2C12 cells yielded similar results as those observed in the co-culture and increased the phosphorylation and expression levels of VEGFR. The treatment with the selective pharmacological VEGFR inhibitor, KRN633, resulted in a marked attenuation of the receptor activation and concomitantly inhibited the effects of MSC-CM on C2C12 cell growth and Notch-1 signaling. In conclusion, this study provides novel evidence for a role of MSCs in stimulating myoblast cell proliferation and suggests that the functional interaction between the two cell types may be exploited for the development of new and more efficient cell-based skeletal muscle repair strategies. PMID:22815682

  8. Interaction Dynamics Determine Signaling and Output Pathway Responses

    Directory of Open Access Journals (Sweden)

    Klement Stojanovski

    2017-04-01

    Full Text Available The understanding of interaction dynamics in signaling pathways can shed light on pathway architecture and provide insights into targets for intervention. Here, we explored the relevance of kinetic rate constants of a key upstream osmosensor in the yeast high-osmolarity glycerol-mitogen-activated protein kinase (HOG-MAPK pathway to signaling output responses. We created mutant pairs of the Sln1-Ypd1 complex interface that caused major compensating changes in the association (kon and dissociation (koff rate constants (kinetic perturbations but only moderate changes in the overall complex affinity (Kd. Yeast cells carrying a Sln1-Ypd1 mutant pair with moderate increases in kon and koff displayed a lower threshold of HOG pathway activation than wild-type cells. Mutants with higher kon and koff rates gave rise to higher basal signaling and gene expression but impaired osmoadaptation. Thus, the kon and koff rates of the components in the Sln1 osmosensor determine proper signaling dynamics and osmoadaptation.

  9. Autocrine-paracrine regulation of the mammary gland.

    Science.gov (United States)

    Weaver, S R; Hernandez, L L

    2016-01-01

    The mammary gland has a remarkable capacity for regulation at a local level, particularly with respect to its main function: milk secretion. Regulation of milk synthesis has significant effects on animal and human health, at the level of both the mother and the neonate. Control by the mammary gland of its essential function, milk synthesis, is an evolutionary necessity and is therefore tightly regulated at a local level. For at least the last 60 yr, researchers have been interested in elucidating the mechanisms underpinning the mammary gland's ability to self-regulate, largely without the influence from systemic hormones or signals. By the 1960s, scientists realized the importance of milk removal in the capacity of the gland to produce milk and that the dynamics of this removal, including emptying of the alveolar spaces and frequency of milking, were controlled locally as opposed to traditional systemic hormonal regulation. Using both in vitro systems and various mammalian species, including goats, marsupials, humans, and dairy cows, it has been demonstrated that the mammary gland is largely self-regulating in its capacity to support the young, which is the evolutionary basis for milk production. Local control occurs at the level of the mammary epithelial cell through pressure and stretching negative-feedback mechanisms, and also in an autocrine fashion through bioactive factors within the milk which act as inhibitors, regulating milk secretion within the alveoli themselves. It is only within the last 20 to 30 yr that potential candidates for these bioactive factors have been examined at a molecular level. Several, including parathyroid hormone-related protein, growth factors (transforming growth factor, insulin-like growth factor, epidermal growth factor), and serotonin, are synthesized within and act upon the gland and possess dynamic receptor activity resulting in diverse effects on growth, calcium homeostasis, and milk composition. This review will focus on the

  10. Angiotensin peptides in the non-gravid uterus: Paracrine actions beyond circulation.

    Science.gov (United States)

    Casalechi, Maíra; Dela Cruz, Cynthia; Lima, Luiza C; Maciel, Luciana P; Pereira, Virgínia M; Reis, Fernando M

    2018-03-01

    The renin-angiotensin system (RAS) involves a complex network of precursors, peptides, enzymes and receptors comprising a systemic (endocrine) and a local (paracrine/autocrine) system. The local RAS plays important roles in tissue modulation and may operate independently of or in close interaction with the circulatory RAS, acting in a complementary fashion. Angiotensin (Ang) II, its receptor AT 1 and Ang-(1-7) expression in the endometrium vary with menstrual cycle, and stromal cell decidualization in vitro is accompanied by local synthesis of angiotensinogen and prorenin. Mas receptor is unlikely to undergo marked changes accompanying the cyclic ovarian steroid hormone fluctuations. Studies investigating the functional relevance of the RAS in the non-gravid uterus show a number of paracrine effects beyond circulation and suggest that RAS peptides may be involved in the pathophysiology of proliferative and fibrotic diseases. Endometrial cancer is associated with increased expression of Ang II, Ang-converting enzyme 1 and AT 1 in the tumoral tissue compared to neighboring non-neoplastic endometrium, and also with a gene polymorphism that enhances AT 1 signal. Ang II induces human endometrial cells to transdifferentiate into cells with myofibroblast phenotype and to synthetize extracellular matrix components that might contribute to endometrial fibrosis. Altogether, these findings point to a fully operating RAS within the uterus, but since many concepts rely on preliminary evidence further studies are needed to clarify the role of the local RAS in uterine physiology and pathophysiology. Copyright © 2018 Elsevier Inc. All rights reserved.

  11. Paracrine control of vascularization and neurogenesis by neurotrophins.

    Science.gov (United States)

    Emanueli, Costanza; Schratzberger, Peter; Kirchmair, Rudolf; Madeddu, Paolo

    2003-10-01

    The neuronal system plays a fundamental role in the maturation of primitive embryonic vascular network by providing a paracrine template for blood vessel branching and arterial differentiation. Furthermore, postnatal vascular and neural regeneration cooperate in the healing of damaged tissue. Neurogenesis continues in adulthood although confined to specific brain regions. Following ischaemic insult, neural staminal cells contribute towards the healing process through the stimulation of neurogenesis and vasculogenesis. Evidence indicates that nerves and blood vessels exert a reciprocal control of their own growth by paracrine mechanisms. For instance, guidance factors, including vascular endothelial growth factor A (VEGF-A) and semaphorins, which share the ability of binding neuropilin receptors, play a pivotal role in the tridimensional growth pattern of arterial vessels and nerves. Animal models and clinical studies have demonstrated a role of VEGF-A in the pathogenesis of ischaemic and diabetic neuropathies. Further, supplementation with VEGF-A ameliorates neuronal recovery by exerting protective effects on nerves and stimulating reparative neovascularization. Human tissue kallikrein, a recently discovered angiogenic and arteriogenic factor, accelerates neuronal recovery by stimulating the growth of vasa nervorum. Conversely, the neurotrophin nerve growth factor, known to regulate neuronal survival and differentiation, is now regarded as a stimulator of angiogenesis and arteriogenesis. These results indicate that angiogenesis and neurogenesis are paracrinally regulated by growth factors released by endothelial cells and neurons. Supplementation of these growth factors, alone or in combination, could benefit the treatment of ischaemic diseases and neuropathies.

  12. Effect of Serum and Oxygen Concentration on Gene Expression and Secretion of Paracrine Factors by Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    Patrick Page

    2014-01-01

    Full Text Available Mesenchymal stem cells (MSC secrete paracrine factors that may exert a protective effect on the heart after coronary artery occlusion. This study was done to determine the effect of hypoxia and serum levels on the mRNA expression and secretion of paracrine factors. Mouse bone marrow MSC were cultured with 5% or 20% serum and in either normoxic (21% O2 or hypoxic (1% O2 conditions. Expression of mRNA for vascular endothelial growth factor (VEGF, monocyte chemotactic protein-1 (MCP-1, macrophage inflammatory protein-1α (MIP-1α, MIP-1β, and matrix metalloproteinase-2 (MMP-2 was determined by RT-qPCR. Secretion into the culture media was determined by ELISA. Hypoxia caused a reduction in gene expression for MCP-1 and an increase for VEGF (5% serum, MIP-1α, MIP-1β, and MMP-2. Serum reduction lowered gene expression for VEGF (normoxia, MCP-1 (hypoxia, MIP-1α (hypoxia, MIP-1β (hypoxia, and MMP-2 (hypoxia and increased gene expression for MMP-2 (normoxia. The level of secretion of these factors into the media generally paralleled gene expression with some exceptions. These data demonstrate that serum and oxygen levels have a significant effect on the gene expression and secretion of paracrine factors by MSC which will affect how MSC interact in vivo during myocardial ischemia.

  13. Determination of signal intensity affected by Gaussian noise

    International Nuclear Information System (INIS)

    Blostein, Jeronimo J.; Bennun, Leonardo

    1999-01-01

    A methodology based on maximum likelihood criteria, to identify and quantify an arbitrary signal affected by Gaussian noise is shown. To use this methodology it is necessary to know the position in the spectrum where the signal of interest should appear, and the shape of the signal when the background is null or unappreciable. (author)

  14. Hedgehog-mediated paracrine interaction between hepatic stellate cells and marrow-derived mesenchymal stem cells

    International Nuclear Information System (INIS)

    Lin Nan; Tang Zhaofeng; Deng Meihai; Zhong Yuesi; Lin Jizong; Yang Xuhui; Xiang Peng; Xu Ruiyun

    2008-01-01

    During liver injury, bone marrow-derived mesenchymal stem cells (MSCs) can migrate and differentiate into hepatocytes. Hepatic stellate cell (SC) activation is a pivotal event in the development of liver fibrosis. Therefore, we hypothesized that SCs may play an important role in regulating MSC proliferation and differentiation through the paracrine signaling pathway. We demonstrate that MSCs and SCs both express hedgehog (Hh) pathway components, including its ligands, receptors, and target genes. Transwell co-cultures of SCs and MSCs showed that the SCs produced sonic hedgehog (Shh), which enhanced the proliferation and differentiation of MSCs. These findings demonstrate that SCs indirectly modulate the activity of MSCs in vitro via the Hh pathway, and provide a plausible explanation for the mechanisms of transplanted MSCs in the treatment of liver fibrosis

  15. Mechanically stimulated bone cells secrete paracrine factors that regulate osteoprogenitor recruitment, proliferation, and differentiation

    International Nuclear Information System (INIS)

    Brady, Robert T.; O'Brien, Fergal J.; Hoey, David A.

    2015-01-01

    Bone formation requires the recruitment, proliferation and osteogenic differentiation of mesenchymal progenitors. A potent stimulus driving this process is mechanical loading, yet the signalling mechanisms underpinning this are incompletely understood. The objective of this study was to investigate the role of the mechanically-stimulated osteocyte and osteoblast secretome in coordinating progenitor contributions to bone formation. Initially osteocytes (MLO-Y4) and osteoblasts (MC3T3) were mechanically stimulated for 24hrs and secreted factors within the conditioned media were collected and used to evaluate mesenchymal stem cell (MSC) and osteoblast recruitment, proliferation and osteogenesis. Paracrine factors secreted by mechanically stimulated osteocytes significantly enhanced MSC migration, proliferation and osteogenesis and furthermore significantly increased osteoblast migration and proliferation when compared to factors secreted by statically cultured osteocytes. Secondly, paracrine factors secreted by mechanically stimulated osteoblasts significantly enhanced MSC migration but surprisingly, in contrast to the osteocyte secretome, inhibited MSC proliferation when compared to factors secreted by statically cultured osteoblasts. A similar trend was observed in osteoblasts. This study provides new information on mechanically driven signalling mechanisms in bone and highlights a contrasting secretome between cells at different stages in the bone lineage, furthering our understanding of loading-induced bone formation and indirect biophysical regulation of osteoprogenitors. - Highlights: • Physically stimulated osteocytes secrete factors that regulate osteoprogenitors. • These factors enhance recruitment, proliferation and osteogenic differentiation. • Physically stimulated osteoblasts secrete factors that also regulate progenitors. • These factors enhance recruitment but inhibit proliferation of osteoprogenitors. • This study highlights a contrasting

  16. Mechanically stimulated bone cells secrete paracrine factors that regulate osteoprogenitor recruitment, proliferation, and differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Brady, Robert T. [Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (Ireland); Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin (Ireland); Advanced Materials and BioEngineering Research Centre (AMBER), Trinity College Dublin & Royal College of Surgeons in Ireland (Ireland); Dept. of Mechanical, Aeronautical and Biomedical Engineering, University of Limerick (Ireland); O' Brien, Fergal J. [Tissue Engineering Research Group, Dept. of Anatomy, Royal College of Surgeons in Ireland (Ireland); Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin (Ireland); Advanced Materials and BioEngineering Research Centre (AMBER), Trinity College Dublin & Royal College of Surgeons in Ireland (Ireland); Hoey, David A., E-mail: david.hoey@ul.ie [Trinity Centre for Bioengineering, School of Engineering, Trinity College Dublin (Ireland); Dept. of Mechanical, Aeronautical and Biomedical Engineering, University of Limerick (Ireland); The Centre for Applied Biomedical Engineering Research, University of Limerick (Ireland); Materials & Surface Science Institute, University of Limerick (Ireland)

    2015-03-27

    Bone formation requires the recruitment, proliferation and osteogenic differentiation of mesenchymal progenitors. A potent stimulus driving this process is mechanical loading, yet the signalling mechanisms underpinning this are incompletely understood. The objective of this study was to investigate the role of the mechanically-stimulated osteocyte and osteoblast secretome in coordinating progenitor contributions to bone formation. Initially osteocytes (MLO-Y4) and osteoblasts (MC3T3) were mechanically stimulated for 24hrs and secreted factors within the conditioned media were collected and used to evaluate mesenchymal stem cell (MSC) and osteoblast recruitment, proliferation and osteogenesis. Paracrine factors secreted by mechanically stimulated osteocytes significantly enhanced MSC migration, proliferation and osteogenesis and furthermore significantly increased osteoblast migration and proliferation when compared to factors secreted by statically cultured osteocytes. Secondly, paracrine factors secreted by mechanically stimulated osteoblasts significantly enhanced MSC migration but surprisingly, in contrast to the osteocyte secretome, inhibited MSC proliferation when compared to factors secreted by statically cultured osteoblasts. A similar trend was observed in osteoblasts. This study provides new information on mechanically driven signalling mechanisms in bone and highlights a contrasting secretome between cells at different stages in the bone lineage, furthering our understanding of loading-induced bone formation and indirect biophysical regulation of osteoprogenitors. - Highlights: • Physically stimulated osteocytes secrete factors that regulate osteoprogenitors. • These factors enhance recruitment, proliferation and osteogenic differentiation. • Physically stimulated osteoblasts secrete factors that also regulate progenitors. • These factors enhance recruitment but inhibit proliferation of osteoprogenitors. • This study highlights a contrasting

  17. Adult mouse epicardium modulates myocardial injury by secreting paracrine factors

    Science.gov (United States)

    Zhou, Bin; Honor, Leah B.; He, Huamei; Ma, Qing; Oh, Jin-Hee; Butterfield, Catherine; Lin, Ruei-Zeng; Melero-Martin, Juan M.; Dolmatova, Elena; Duffy, Heather S.; von Gise, Alexander; Zhou, Pingzhu; Hu, Yong Wu; Wang, Gang; Zhang, Bing; Wang, Lianchun; Hall, Jennifer L.; Moses, Marsha A.; McGowan, Francis X.; Pu, William T.

    2011-01-01

    The epicardium makes essential cellular and paracrine contributions to the growth of the fetal myocardium and the formation of the coronary vasculature. However, whether the epicardium has similar roles postnatally in the normal and injured heart remains enigmatic. Here, we have investigated this question using genetic fate-mapping approaches in mice. In uninjured postnatal heart, epicardial cells were quiescent. Myocardial infarction increased epicardial cell proliferation and stimulated formation of epicardium-derived cells (EPDCs), which remained in a thickened layer on the surface of the heart. EPDCs did not adopt cardiomyocyte or coronary EC fates, but rather differentiated into mesenchymal cells expressing fibroblast and smooth muscle cell markers. In vitro and in vivo assays demonstrated that EPDCs secreted paracrine factors that strongly promoted angiogenesis. In a myocardial infarction model, EPDC-conditioned medium reduced infarct size and improved heart function. Our findings indicate that epicardium modulates the cardiac injury response by conditioning the subepicardial environment, potentially offering a new therapeutic strategy for cardiac protection. PMID:21505261

  18. Aberrant Hedgehog ligands induce progressive pancreatic fibrosis by paracrine activation of myofibroblasts and ductular cells in transgenic zebrafish.

    Directory of Open Access Journals (Sweden)

    In Hye Jung

    Full Text Available Hedgehog (Hh signaling is frequently up-regulated in fibrogenic pancreatic diseases including chronic pancreatitis and pancreatic cancer. Although recent series suggest exclusive paracrine activation of stromal cells by Hh ligands from epithelial components, debates still exist on how Hh signaling works in pathologic conditions. To explore how Hh signaling affects the pancreas, we investigated transgenic phenotypes in zebrafish that over-express either Indian Hh or Sonic Hh along with green fluorescence protein (GFP to enable real-time observation, or GFP alone as control, at the ptf1a domain. Transgenic embryos and zebrafish were serially followed for transgenic phenotypes, and investigated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR, in situ hybridization, and immunohistochemistry. Over-expression of Ihh or Shh reveals virtually identical phenotypes. Hh induces morphologic changes in a developing pancreas without derangement in acinar differentiation. In older zebrafish, Hh induces progressive pancreatic fibrosis intermingled with proliferating ductular structures, which is accompanied by the destruction of the acinar structures. Both myofibroblasts and ductular are activated and proliferated by paracrine Hh signaling, showing restricted expression of Hh downstream components including Patched1 (Ptc1, Smoothened (Smo, and Gli1/2 in those Hh-responsive cells. Hh ligands induce matrix metalloproteinases (MMPs, especially MMP9 in all Hh-responsive cells, and transform growth factor-ß1 (TGFß1 only in ductular cells. Aberrant Hh over-expression, however, does not induce pancreatic tumors. On treatment with inhibitors, embryonic phenotypes are reversed by either cyclopamine or Hedgehog Primary Inhibitor-4 (HPI-4. Pancreatic fibrosis is only prevented by HPI-4. Our study provides strong evidence of Hh signaling which induces pancreatic fibrosis through paracrine activation of Hh-responsive cells in vivo. Induction of

  19. Paracrine Pathways in Uterine Leiomyoma Stem Cells Involve Insulinlike Growth Factor 2 and Insulin Receptor A.

    Science.gov (United States)

    Moravek, Molly B; Yin, Ping; Coon, John S; Ono, Masanori; Druschitz, Stacy A; Malpani, Saurabh S; Dyson, Matthew T; Rademaker, Alfred W; Robins, Jared C; Wei, Jian-Jun; Kim, J Julie; Bulun, Serdar E

    2017-05-01

    Uterine leiomyomas (fibroids) are the most common benign tumors in women. Recently, three populations of leiomyoma cells were discovered on the basis of CD34 and CD49b expression, but molecular differences between these populations remain unknown. To define differential gene expression and signaling pathways in leiomyoma cell populations. Cells from human leiomyoma tissue were sorted by flow cytometry into three populations: CD34+/CD49b+, CD34+/CD49b-, and CD34-/CD49b-. Microarray gene expression profiling and pathway analysis were performed. To investigate the insulinlike growth factor (IGF) pathway, real-time quantitative polymerase chain reaction, immunoblotting, and 5-ethynyl-2'-deoxyuridine incorporation studies were performed in cells isolated from fresh leiomyoma. Research laboratory. Eight African American women. None. Gene expression patterns, cell proliferation, and differentiation. A total of 1164 genes were differentially expressed in the three leiomyoma cell populations, suggesting a hierarchical differentiation order whereby CD34+/CD49b+ stem cells differentiate to CD34+/CD49b- intermediary cells, which then terminally differentiate to CD34-/CD49b- cells. Pathway analysis revealed differential expression of several IGF signaling pathway genes. IGF2 was overexpressed in CD34+/CD49b- vs CD34-/CD49b- cells (83-fold; P leiomyoma stem cell proliferation and may represent paracrine signaling between leiomyoma cell types. Therapies targeting the IGF pathway should be investigated for both treatment and prevention of leiomyomas. Copyright © 2017 by the Endocrine Society

  20. Magnetic resonance signal moment determination using the Earth's magnetic field

    KAUST Repository

    Fridjonsson, Einar Orn; Creber, Sarah A.; Vrouwenvelder, Johannes S.; Johns, Michael L.

    2015-01-01

    We demonstrate a method to manipulate magnetic resonance data such that the moments of the signal spatial distribution are readily accessible. Usually, magnetic resonance imaging relies on data acquired in so-called k-space which is subsequently Fourier transformed to render an image. Here, via analysis of the complex signal in the vicinity of the centre of k-space we are able to access the first three moments of the signal spatial distribution, ultimately in multiple directions. This is demonstrated for biofouling of a reverse osmosis (RO) membrane module, rendering unique information and an early warning of the onset of fouling. The analysis is particularly applicable for the use of mobile magnetic resonance spectrometers; here we demonstrate it using an Earth's magnetic field system.

  1. Magnetic resonance signal moment determination using the Earth's magnetic field

    KAUST Repository

    Fridjonsson, Einar Orn

    2015-03-01

    We demonstrate a method to manipulate magnetic resonance data such that the moments of the signal spatial distribution are readily accessible. Usually, magnetic resonance imaging relies on data acquired in so-called k-space which is subsequently Fourier transformed to render an image. Here, via analysis of the complex signal in the vicinity of the centre of k-space we are able to access the first three moments of the signal spatial distribution, ultimately in multiple directions. This is demonstrated for biofouling of a reverse osmosis (RO) membrane module, rendering unique information and an early warning of the onset of fouling. The analysis is particularly applicable for the use of mobile magnetic resonance spectrometers; here we demonstrate it using an Earth\\'s magnetic field system.

  2. The paracrine effect of exogenous growth hormone alleviates dysmorphogenesis caused by tbx5 deficiency in zebrafish (Danio rerio embryos

    Directory of Open Access Journals (Sweden)

    Tsai Tzu-Chun

    2012-07-01

    Full Text Available Abstract Background Dysmorphogenesis and multiple organ defects are well known in zebrafish (Danio rerio embryos with T-box transcription factor 5 (tbx5 deficiencies, mimicking human Holt-Oram syndrome. Methods Using an oligonucleotide-based microarray analysis to study the expression of special genes in tbx5 morphants, we demonstrated that GH and some GH-related genes were markedly downregulated. Zebrafish embryos microinjected with tbx5-morpholino (MO antisense RNA and mismatched antisense RNA in the 1-cell stage served as controls, while zebrafish embryos co-injected with exogenous growth hormone (GH concomitant with tbx5-MO comprised the treatment group. Results The attenuating effects of GH in tbx5-MO knockdown embryos were quantified and observed at 24, 30, 48, 72, and 96 h post-fertilization. Though the understanding of mechanisms involving GH in the tbx5 functioning complex is limited, exogenous GH supplied to tbx5 knockdown zebrafish embryos is able to enhance the expression of downstream mediators in the GH and insulin-like growth factor (IGF-1 pathway, including igf1, ghra, and ghrb, and signal transductors (erk1, akt2, and eventually to correct dysmorphogenesis in various organs including the heart and pectoral fins. Supplementary GH also reduced apoptosis as determined by a TUNEL assay and decreased the expression of apoptosis-related genes and proteins (bcl2 and bad according to semiquantitative reverse-transcription polymerase chain reaction and immunohistochemical analysis, respectively, as well as improving cell cycle-related genes (p27 and cdk2 and cardiomyogenetic genes (amhc, vmhc, and cmlc2. Conclusions Based on our results, tbx5 knockdown causes a pseudo GH deficiency in zebrafish during early embryonic stages, and supplementation of exogenous GH can partially restore dysmorphogenesis, apoptosis, cell growth inhibition, and abnormal cardiomyogenesis in tbx5 knockdown zebrafish in a paracrine manner.

  3. Determine the Role of Canonical Wnt Signaling in Ovarian Tumorigenesis

    Science.gov (United States)

    2015-12-01

    Cancer Res, 2007. 13(14): p. 4042-5. 10. Mann, B., et al., Target genes of beta-catenin-T cell -factor/ lymphoid -enhancer- factor signaling in human...triggers innate immunity. Cell Host Microbe 12(4): 558–570. 34. Lundholm M, et al. (2014) Prostate tumor-derived exosomes down-regulate NKG2D... cell -extrinsic pathway through which natural killer cells eliminate cancer cells . Nat Cell Biol 15(7):818–828. 57. Ishii KJ, Akira S (2006) Innate

  4. c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae

    Science.gov (United States)

    Skartsis, Nikolaos; Martinez, Laisel; Duque, Juan Camilo; Tabbara, Marwan; Velazquez, Omaida C.; Asif, Arif; Andreopoulos, Fotios; Salman, Loay H.

    2014-01-01

    Stenosis of arteriovenous (A-V) fistulae secondary to neointimal hyperplasia (NIH) compromises dialysis delivery, which worsens patients' quality of life and increases medical costs associated with the maintenance of vascular accesses. In the present study, we evaluated the role of the receptor tyrosine kinase c-Kit in A-V fistula neointima formation. Initially, c-Kit was found in the neointima and adventitia of human brachiobasilic fistulae, whereas it was barely detectable in control veins harvested at the time of access creation. Using the rat A-V fistula model to study venous vascular remodeling, we analyzed the spatial and temporal pattern of c-Kit expression in the fistula wall. Interestingly, c-Kit immunoreactivity increased with time after anastomosis, which concurred with the accumulation of cells in the venous intima. In addition, c-Kit expression in A-V fistulae was positively altered by chronic kidney failure conditions. Both blockade of c-Kit with imatinib mesylate (Gleevec) and inhibition of stem cell factor production with a specific short hairpin RNA prevented NIH in the outflow vein of experimental fistulae. In agreement with these data, impaired c-Kit activity compromised the development of NIH in A-V fistulae created in c-KitW/Wv mutant mice. These results suggest that targeting of the c-Kit signaling pathway may be an effective approach to prevent postoperative NIH in A-V fistulae. PMID:25186298

  5. Zinc as a paracrine effector in pancreatic islet cell death.

    Science.gov (United States)

    Kim, B J; Kim, Y H; Kim, S; Kim, J W; Koh, J Y; Oh, S H; Lee, M K; Kim, K W; Lee, M S

    2000-03-01

    Because of a huge amount of Zn2+ in secretory granules of pancreatic islet beta-cells, Zn2+ released in certain conditions might affect the function or survival of islet cells. We studied potential paracrine effects of endogenous Zn2+ on beta-cell death. Zn2+ induced insulinoma/islet cell death in a dose-dependent manner. Chelation of released endogenous Zn2+ by CaEDTA significantly decreased streptozotocin (STZ)-induced islet cell death in an in vitro culture system simulating in vivo circumstances but not in the conventional culture system. Zn2+ chelation in vivo by continuous CaEDTA infusion significantly decreased the incidence of diabetes after STZ administration. N-(6-methoxy-quinolyl)-para-toluene-sulfonamide staining revealed that Zn2+ was densely deposited in degenerating islet cells 24 h after STZ treatment, which was decreased by CaEDTA infusion. We show here that Zn2+ is not a passive element for insulin storage but an active participant in islet cell death in certain conditions, which in time might contribute to the development of diabetes in aged people.

  6. A method for detecting nonlinear determinism in normal and epileptic brain EEG signals.

    Science.gov (United States)

    Meghdadi, Amir H; Fazel-Rezai, Reza; Aghakhani, Yahya

    2007-01-01

    A robust method of detecting determinism for short time series is proposed and applied to both healthy and epileptic EEG signals. The method provides a robust measure of determinism through characterizing the trajectories of the signal components which are obtained through singular value decomposition. Robustness of the method is shown by calculating proposed index of determinism at different levels of white and colored noise added to a simulated chaotic signal. The method is shown to be able to detect determinism at considerably high levels of additive noise. The method is then applied to both intracranial and scalp EEG recordings collected in different data sets for healthy and epileptic brain signals. The results show that for all of the studied EEG data sets there is enough evidence of determinism. The determinism is more significant for intracranial EEG recordings particularly during seizure activity.

  7. Paracrine Maturation and Migration of SH-SY5Y Cells by Dental Pulp Stem Cells.

    Science.gov (United States)

    Gervois, P; Wolfs, E; Dillen, Y; Hilkens, P; Ratajczak, J; Driesen, R B; Vangansewinkel, T; Bronckaers, A; Brône, B; Struys, T; Lambrichts, I

    2017-06-01

    Neurological disorders are characterized by neurodegeneration and/or loss of neuronal function, which cannot be adequately repaired by the host. Therefore, there is need for novel treatment options such as cell-based therapies that aim to salvage or reconstitute the lost tissue or that stimulate host repair. The present study aimed to evaluate the paracrine effects of human dental pulp stem cells (hDPSCs) on the migration and neural maturation of human SH-SY5Y neuroblastoma cells. The hDPSC secretome had a significant chemoattractive effect on SH-SY5Y cells as shown by a transwell assay. To evaluate neural maturation, SH-SY5Y cells were first induced toward neuronal cells, after which they were exposed to the hDPSC secretome. In addition, SH-SY5Y cells subjected to the hDPSC secretome showed increased neuritogenesis compared with nonexposed cells. Maturated cells were shown to increase immune reactivity for neuronal markers compared with controls. Ultrastructurally, retinoic acid (RA) signaling and subsequent exposure to the hDPSC secretome induced a gradual rise in metabolic activity and neuronal features such as multivesicular bodies and cytoskeletal elements associated with cellular communication. In addition, electrophysiological recordings of differentiating cells demonstrated a transition toward a neuronal electrophysiological profile based on the maximum tetrodotoxin (TTX)-sensitive, Na + current. Moreover, conditioned medium (CM)-hDPSC-maturated SH-SY5Y cells developed distinct features including, Cd 2+ -sensitive currents, which suggests that CM-hDPSC-maturated SH-SY5Y acquired voltage-gated Ca 2+ channels. The results reported in this study demonstrate the potential of hDPSCs to support differentiation and recruitment of cells with neuronal precursor characteristics in a paracrine manner. Moreover, this in vitro experimental design showed that the widely used SH-SY5Y cell line can improve and simplify the preclinical in vitro research on the molecular

  8. Biomaterials that promote cell-cell interactions enhance the paracrine function of MSCs.

    Science.gov (United States)

    Qazi, Taimoor H; Mooney, David J; Duda, Georg N; Geissler, Sven

    2017-09-01

    Mesenchymal stromal cells (MSCs) secrete paracrine factors that play crucial roles during tissue regeneration. Whether this paracrine function is influenced by the properties of biomaterials in general, and those used for cell delivery in particular, largely remains unexplored. Here, we investigated if three-dimensional culture in distinct microenvironments - nanoporous hydrogels (mean pore size ∼5 nm) and macroporous scaffolds (mean pore size ∼120 μm) - affects the secretion pattern of MSCs, and consequently leads to differential paracrine effects on target progenitor cells such as myoblasts. We report that compared to MSCs encapsulated in hydrogels, scaffold seeded MSCs show an enhanced secretion profile and exert beneficial paracrine effects on various myoblast functions including migration and proliferation. Additionally, we show that the heightened paracrine effects of scaffold seeded cells can in part be attributed to N-cadherin mediated cell-cell interactions during culture. In hydrogels, this physical interaction between cells is prevented by the encapsulating matrix. Functionally blocking N-cadherin negatively affected the secretion profile and paracrine effects of MSCs on myoblasts, with stronger effects observed for scaffold seeded compared to hydrogel encapsulated cells. Together, these findings demonstrate that the therapeutic potency of MSCs can be enhanced by biomaterials that promote cell-cell interactions. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Microbiota promote secretory cell determination in the intestinal epithelium by modulating host Notch signaling.

    Science.gov (United States)

    Troll, Joshua V; Hamilton, M Kristina; Abel, Melissa L; Ganz, Julia; Bates, Jennifer M; Stephens, W Zac; Melancon, Ellie; van der Vaart, Michiel; Meijer, Annemarie H; Distel, Martin; Eisen, Judith S; Guillemin, Karen

    2018-02-23

    Resident microbes promote many aspects of host development, although the mechanisms by which microbiota influence host tissues remain unclear. We showed previously that the microbiota is required for allocation of appropriate numbers of secretory cells in the zebrafish intestinal epithelium. Because Notch signaling is crucial for secretory fate determination, we conducted epistasis experiments to establish whether the microbiota modulates host Notch signaling. We also investigated whether innate immune signaling transduces microbiota cues via the Myd88 adaptor protein. We provide the first evidence that microbiota-induced, Myd88-dependent signaling inhibits host Notch signaling in the intestinal epithelium, thereby promoting secretory cell fate determination. These results connect microbiota activity via innate immune signaling to the Notch pathway, which also plays crucial roles in intestinal homeostasis throughout life and when impaired can result in chronic inflammation and cancer. © 2018. Published by The Company of Biologists Ltd.

  10. A two-step recognition of signal sequences determines the translocation efficiency of proteins.

    OpenAIRE

    Belin, D; Bost, S; Vassalli, J D; Strub, K

    1996-01-01

    The cytosolic and secreted, N-glycosylated, forms of plasminogen activator inhibitor-2 (PAI-2) are generated by facultative translocation. To study the molecular events that result in the bi-topological distribution of proteins, we determined in vitro the capacities of several signal sequences to bind the signal recognition particle (SRP) during targeting, and to promote vectorial transport of murine PAI-2 (mPAI-2). Interestingly, the six signal sequences we compared (mPAI-2 and three mutated...

  11. Stationary analysis of signals and ratio decay determination in BWR type reactors by neuronal network

    International Nuclear Information System (INIS)

    Sanchis, R.; Palomo, M. J.; Munoz-Cobo, J. L.

    1998-01-01

    The signals registered in the nuclear plants have non stationary characteristics, in numerous times. This made difficult the application of the methods of analysis. There are determinate temporal intervals in that the signal is stationary with determinate mean, value together of zones with corrupt registers, and other zones with mean value distinct, but stationary during a temporal interval. The methodology consist in a stationary analysis to the signal received of the nuclear plant. With the Gabor Transformation are determined the temporal intervals of the stationary signals, synthesised it, as previous phase to the application of the methods of the analysis of stability parameters with methods ARMA, SVD, Neural Net,... to the reconstructed signal. 4 refs. (Author)

  12. Photodynamic therapy potentiates the paracrine endothelial stimulation by colorectal cancer

    Science.gov (United States)

    Lamberti, María Julia; Florencia Pansa, María; Emanuel Vera, Renzo; Belén Rumie Vittar, Natalia; Rivarola, Viviana Alicia

    2014-11-01

    Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer death worldwide. Recurrence is a major problem and is often the ultimate cause of death. In this context, the tumor microenvironment influences tumor progression and is considered as a new essential feature that clearly impacts on treatment outcome, and must therefore be taken into consideration. Photodynamic therapy (PDT), oxygen, light and drug-dependent, is a novel treatment modality when CRC patients are inoperable. Tumor vasculature and parenchyma cells are both potential targets of PDT damage modulating tumor-stroma interactions. In biological activity assessment in photodynamic research, three-dimensional (3D) cultures are essential to integrate biomechanical, biochemical, and biophysical properties that better predict the outcome of oxygen- and drug-dependent medical therapies. Therefore, the objective of this study was to investigate the antitumor effect of methyl 5-aminolevulinic acid-PDT using a light emitting diode for the treatment of CRC cells in a scenario that mimics targeted tissue complexity, providing a potential bridge for the gap between 2D cultures and animal models. Since photodynamic intervention of the tumor microenvironment can effectively modulate the tumor-stroma interaction, it was proposed to characterize the endothelial response to CRC paracrine communication, if one of these two populations is photosensitized. In conclusion, we demonstrated that the dialogue between endothelial and tumor populations when subjected to lethal PDT conditions induces an increase in angiogenic phenotype, and we think that it should be carefully considered for the development of PDT therapeutic protocols.

  13. Oxygen Tension Regulates Human Mesenchymal Stem Cell Paracrine Functions.

    Science.gov (United States)

    Paquet, Joseph; Deschepper, Mickael; Moya, Adrien; Logeart-Avramoglou, Delphine; Boisson-Vidal, Catherine; Petite, Hervé

    2015-07-01

    : Mesenchymal stem cells (MSCs) have captured the attention and research endeavors of the scientific world because of their differentiation potential. However, there is accumulating evidence suggesting that the beneficial effects of MSCs are predominantly due to the multitude of bioactive mediators secreted by these cells. Because the paracrine potential of MSCs is closely related to their microenvironment, the present study investigated and characterized select aspects of the human MSC (hMSC) secretome and assessed its in vitro and in vivo bioactivity as a function of oxygen tension, specifically near anoxia (0.1% O2) and hypoxia (5% O2), conditions that reflect the environment to which MSCs are exposed during MSC-based therapies in vivo. In contrast to supernatant conditioned media (CM) obtained from hMSCs cultured at either 5% or 21% of O2, CM from hMSCs cultured under near anoxia exhibited significantly (p mesenchymal stem cell (hMSC) secretome and assessed its in vitro and in vivo biological bioactivity as a function of oxygen tension, specifically near anoxia (0.1% O2) and hypoxia (5% O2), conditions that reflect the environment to which MSCs are exposed during MSC-based therapies in vivo. The present study provided the first evidence of a shift of the hMSC cytokine signature induced by oxygen tension, particularly near anoxia (0.1% O2). Conditioned media obtained from hMSCs cultured under near anoxia exhibited significantly enhanced chemotactic and proangiogenic properties and a significant decrease in the inflammatory mediator content. These findings provide new evidence that elucidates aspects of great importance for the use of MSCs in regenerative medicine, could contribute to improving the efficacy of such therapies, and most importantly highlighted the interest in using conditioned media in therapeutic modalities. ©AlphaMed Press.

  14. Plant natriuretic peptides are apoplastic and paracrine stress response molecules

    KAUST Repository

    Wang, Yuhua; Gehring, Christoph A; Irving, Helen R.

    2011-01-01

    plant stress responses and that, much like in animals, peptide signaling molecules can create diverse and modular signals essential for growth, development and defense under rapidly changing environmental conditions. © 2011 The Author.

  15. Paracrine action of HO-1-modified mesenchymal stem cells mediates cardiac protection and functional improvement.

    Science.gov (United States)

    Zeng, Bin; Ren, Xiaofeng; Lin, Guosheng; Zhu, Chengang; Chen, Honglei; Yin, Jiechao; Jiang, Hong; Yang, Bo; Ding, Danhua

    2008-10-01

    The aim has been to determine whether the supernatants of mesenchymal stem cells (MSCs) transfected with adenovirus carrying human heme oxygenase-1 (hHO-1) gene protect cardiomyocytes from ischemic injury. We have found that hHO-1 infected MSCs (hHO-1-MSCs) increased expression of hHO-1 protein. Apoptosis of cultured hHO-1-MSCs exposed to hypoxia was suppressed. Several cytokines, including HGF, bFGF, TGF-beta, VEGF and IL-1beta, were produced by hHO-1-MSCs, some being significantly enhanced under hypoxia stimulation. Meanwhile, those cytokines reduced caspase-3 level and activity in cultured adult rat ventricular cardiomyocytes (ARVCs) exposed to hypoxia. Supernatants obtained from hHO-1-MSCs improved left ventricular function, limited myocardial infarct size, increased microvessel density, and inhibited apoptosis of cardiomyocytes in rat myocardial infarction. It can be concluded hHO-1-modified MSCs prevent myocardial cell injury via secretion of paracrine-acting mediators.

  16. Endothelin-3 production by human rhabdomyosarcoma: a possible new marker with a paracrine role.

    Science.gov (United States)

    Palladini, Arianna; Astolfi, Annalisa; Croci, Stefania; De Giovanni, Carla; Nicoletti, Giordano; Rosolen, Angelo; Sartori, Francesca; Lollini, Pier-Luigi; Landuzzi, Lorena; Nanni, Patrizia

    2006-03-01

    Several autocrine and paracrine growth factor circuits have been found in human rhabdomyosarcoma cells. In this study we show that endothelin-3 (ET-3), a vasoactive peptide, is produced by human rhabdomyosarcoma cell lines, whereas it is not expressed by human sarcoma cell lines of non-muscle origin. We did not find evidence of a significant autocrine loop; nevertheless ET-3 produced by rhabdomyosarcoma cells can act as a paracrine factor, since it promotes migration of endothelial cells. Moreover ET-3 is present in plasma of mice bearing xenografts of human rhabdomyosarcoma cells, and may be potential new marker of the human rhabdomyosarcoma to be studied further.

  17. Evidence for autocrine and paracrine regulation of allergen-induced mast cell mediator release in the guinea pig airways.

    Science.gov (United States)

    Yu, Li; Liu, Qi; Canning, Brendan J

    2018-03-05

    Mast cells play an essential role in immediate type hypersensitivity reactions and in chronic allergic diseases of the airways, including asthma. Mast cell mediator release can be modulated by locally released autacoids and circulating hormones, but surprisingly little is known about the autocrine effects of mediators released upon mast cell activation. We thus set out to characterize the autocrine and paracrine effects of mast cell mediators on mast cell activation in the guinea pig airways. By direct measures of histamine, cysteinyl-leukotriene and thromboxane release and with studies of allergen-evoked contractions of airway smooth muscle, we describe a complex interplay amongst these autacoids. Notably, we observed an autocrine effect of the cysteinyl-leukotrienes acting through cysLT 1 receptors on mast cell leukotriene release. We confirmed the results of previous studies demonstrating a marked enhancement of mast cell mediator release following cyclooxygenase inhibition, but we have extended these results by showing that COX-2 derived eicosanoids inhibit cysteinyl-leukotriene release and yet are without effect on histamine release. Given the prominent role of COX-1 inhibition in aspirin-sensitive asthma, these data implicate preformed mediators stored in granules as the initial drivers of these adverse reactions. Finally, we describe the paracrine signaling cascade leading to thromboxane synthesis in the guinea pig airways following allergen challenge, which occurs indirectly, secondary to cysLT 1 receptor activation on structural cells and/ or leukocytes within the airway wall, and a COX-2 dependent synthesis of the eicosanoid. The results highlight the importance of cell-cell and autocrine interactions in regulating allergic responses in the airways. Copyright © 2017. Published by Elsevier B.V.

  18. Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination.

    Directory of Open Access Journals (Sweden)

    Yuna Kim

    2006-06-01

    Full Text Available The genes encoding members of the wingless-related MMTV integration site (WNT and fibroblast growth factor (FGF families coordinate growth, morphogenesis, and differentiation in many fields of cells during development. In the mouse, Fgf9 and Wnt4 are expressed in gonads of both sexes prior to sex determination. Loss of Fgf9 leads to XY sex reversal, whereas loss of Wnt4 results in partial testis development in XX gonads. However, the relationship between these signals and the male sex-determining gene, Sry, was unknown. We show through gain- and loss-of-function experiments that fibroblast growth factor 9 (FGF9 and WNT4 act as opposing signals to regulate sex determination. In the mouse XY gonad, Sry normally initiates a feed-forward loop between Sox9 and Fgf9, which up-regulates Fgf9 and represses Wnt4 to establish the testis pathway. Surprisingly, loss of Wnt4 in XX gonads is sufficient to up-regulate Fgf9 and Sox9 in the absence of Sry. These data suggest that the fate of the gonad is controlled by antagonism between Fgf9 and Wnt4. The role of the male sex-determining switch--Sry in the case of mammals--is to tip the balance between these underlying patterning signals. In principle, sex determination in other vertebrates may operate through any switch that introduces an imbalance between these two signaling pathways.

  19. A New Wavelet Threshold Determination Method Considering Interscale Correlation in Signal Denoising

    Directory of Open Access Journals (Sweden)

    Can He

    2015-01-01

    Full Text Available Due to simple calculation and good denoising effect, wavelet threshold denoising method has been widely used in signal denoising. In this method, the threshold is an important parameter that affects the denoising effect. In order to improve the denoising effect of the existing methods, a new threshold considering interscale correlation is presented. Firstly, a new correlation index is proposed based on the propagation characteristics of the wavelet coefficients. Then, a threshold determination strategy is obtained using the new index. At the end of the paper, a simulation experiment is given to verify the effectiveness of the proposed method. In the experiment, four benchmark signals are used as test signals. Simulation results show that the proposed method can achieve a good denoising effect under various signal types, noise intensities, and thresholding functions.

  20. Determination of the X, Y coordinates of a pulsed ultrasonic source of signals

    International Nuclear Information System (INIS)

    Sokolov, B.V.; Shemyakin, V.V.

    1975-01-01

    A range of problems in predicting the emergency state of large-scale vessel housings are determined for subsequent solution involving acoustic emission phenomena. The authors specify the position of a given problem and present substantial grounds for selecting the minimum number of group signal receivers for unambiguous calculation of the location of the source. Relationships are obtained between X, Y - the coordinates of the pulse signal source - and experimentally measured time differences in recording of signals by group receivers. A criterion is given for selecting the true signal group combination when the receivers simultaneously record waves from several sources. Specific suggestions are made regarding the experimental information to be stored in a central computer for subsequent processing [ru

  1. Analysis Sparse Representation for Nonnegative Signals Based on Determinant Measure by DC Programming

    Directory of Open Access Journals (Sweden)

    Yujie Li

    2018-01-01

    Full Text Available Analysis sparse representation has recently emerged as an alternative approach to the synthesis sparse model. Most existing algorithms typically employ the l0-norm, which is generally NP-hard. Other existing algorithms employ the l1-norm to relax the l0-norm, which sometimes cannot promote adequate sparsity. Most of these existing algorithms focus on general signals and are not suitable for nonnegative signals. However, many signals are necessarily nonnegative such as spectral data. In this paper, we present a novel and efficient analysis dictionary learning algorithm for nonnegative signals with the determinant-type sparsity measure which is convex and differentiable. The analysis sparse representation can be cast in three subproblems, sparse coding, dictionary update, and signal update, because the determinant-type sparsity measure would result in a complex nonconvex optimization problem, which cannot be easily solved by standard convex optimization methods. Therefore, in the proposed algorithms, we use a difference of convex (DC programming scheme for solving the nonconvex problem. According to our theoretical analysis and simulation study, the main advantage of the proposed algorithm is its greater dictionary learning efficiency, particularly compared with state-of-the-art algorithms. In addition, our proposed algorithm performs well in image denoising.

  2. Halo-independent determination of the unmodulated WIMP signal in DAMA: the isotropic case

    Energy Technology Data Exchange (ETDEWEB)

    Gondolo, Paolo [Department of Physics, University of Utah, 115 South 1400 East #201, Salt Lake City, Utah 84112-0830 (United States); Scopel, Stefano, E-mail: paolo.gondolo@utah.edu, E-mail: scopel@sogang.ac.kr [Department of Physics, Sogang University, Seoul 121-742 (Korea, Republic of)

    2017-09-01

    We present a halo-independent determination of the unmodulated signal corresponding to the DAMA modulation if interpreted as due to dark matter weakly interacting massive particles (WIMPs). First we show how a modulated signal gives information on the WIMP velocity distribution function in the Galactic rest frame from which the unmodulated signal descends. Then we describe a mathematically-sound profile likelihood analysis in which the likelihood is profiled over a continuum of nuisance parameters (namely, the WIMP velocity distribution). As a first application of the method, which is very general and valid for any class of velocity distributions, we restrict the analysis to velocity distributions that are isotropic in the Galactic frame. In this way we obtain halo-independent maximum-likelihood estimates and confidence intervals for the DAMA unmodulated signal. We find that the estimated unmodulated signal is in line with expectations for a WIMP-induced modulation and is compatible with the DAMA background+signal rate. Specifically, for the isotropic case we find that the modulated amplitude ranges between a few percent and about 25% of the unmodulated amplitude, depending on the WIMP mass.

  3. A two-step recognition of signal sequences determines the translocation efficiency of proteins.

    Science.gov (United States)

    Belin, D; Bost, S; Vassalli, J D; Strub, K

    1996-02-01

    The cytosolic and secreted, N-glycosylated, forms of plasminogen activator inhibitor-2 (PAI-2) are generated by facultative translocation. To study the molecular events that result in the bi-topological distribution of proteins, we determined in vitro the capacities of several signal sequences to bind the signal recognition particle (SRP) during targeting, and to promote vectorial transport of murine PAI-2 (mPAI-2). Interestingly, the six signal sequences we compared (mPAI-2 and three mutated derivatives thereof, ovalbumin and preprolactin) were found to have the differential activities in the two events. For example, the mPAI-2 signal sequence first binds SRP with moderate efficiency and secondly promotes the vectorial transport of only a fraction of the SRP-bound nascent chains. Our results provide evidence that the translocation efficiency of proteins can be controlled by the recognition of their signal sequences at two steps: during SRP-mediated targeting and during formation of a committed translocation complex. This second recognition may occur at several time points during the insertion/translocation step. In conclusion, signal sequences have a more complex structure than previously anticipated, allowing for multiple and independent interactions with the translocation machinery.

  4. Nanohertz frequency determination for the gravity probe B high frequency superconducting quantum interference device signal.

    Science.gov (United States)

    Salomon, M; Conklin, J W; Kozaczuk, J; Berberian, J E; Keiser, G M; Silbergleit, A S; Worden, P; Santiago, D I

    2011-12-01

    In this paper, we present a method to measure the frequency and the frequency change rate of a digital signal. This method consists of three consecutive algorithms: frequency interpolation, phase differencing, and a third algorithm specifically designed and tested by the authors. The succession of these three algorithms allowed a 5 parts in 10(10) resolution in frequency determination. The algorithm developed by the authors can be applied to a sampled scalar signal such that a model linking the harmonics of its main frequency to the underlying physical phenomenon is available. This method was developed in the framework of the gravity probe B (GP-B) mission. It was applied to the high frequency (HF) component of GP-B's superconducting quantum interference device signal, whose main frequency f(z) is close to the spin frequency of the gyroscopes used in the experiment. A 30 nHz resolution in signal frequency and a 0.1 pHz/s resolution in its decay rate were achieved out of a succession of 1.86 s-long stretches of signal sampled at 2200 Hz. This paper describes the underlying theory of the frequency measurement method as well as its application to GP-B's HF science signal.

  5. Compensatory Paracrine Mechanisms That Define The Urothelial Response to Injury in Partial Bladder Outlet Obstruction

    Energy Technology Data Exchange (ETDEWEB)

    Bassuk, James; Lendvay, Thomas S.; Sweet, Robert; Han, Chang-Hee; Soygur, Tarkan; Cheng, Jan-Fang; Plaire, J. Chadwick; Charleston, Jay S.; Charleston, Lynne B.; Bagai, Shelly; Cochrane, Kimberly; Rubio, Eric; Bassuk, James A.; Fuchs, Elaine

    2007-06-21

    Diseases and conditions affecting the lower urinary tract are a leading cause of dysfunctional sexual health, incontinence, infection, and kidney failure. The growth, differentiation, and repair of the bladder's epithelial lining are regulated, in part, by fibroblast growth factor (FGF)-7 and -10 via a paracrine cascade originating in the mesenchyme (lamina propria) and targeting the receptor for FGF-7 and -10 within the transitional epithelium (urothelium). The FGF-7 gene is located at the 15q15-q21.1 locus on chromosome 15 and four exons generate a 3.852-kb mRNA. Five duplicated FGF-7 gene sequences that localized to chromosome 9 were predicted not to generate functional protein products, thus validating the use of FGF-7-null mice as an experimental model. Recombinant FGF-7 and -10 induced proliferation of human urothelial cells in vitro and transitional epithelium of wild-type and FGF-7-null mice in vivo.To determine the extent that induction of urothelial cell proliferation during the bladder response to injury is dependent on FGF-7, an animal model of partial bladder outlet obstruction was developed. Unbiased stereology was used to measure the percentage of proliferating urothelial cells between obstructed groups of wild-type and FGF-7-null mice. The stereological analysis indicated that a statistical significant difference did not exist between the two groups, suggesting that FGF-7 is not essential for urothelial cell proliferation in response to partial outlet obstruction. In contrast, a significant increase in FGF-10 expression was observed in the obstructed FGF-7-null group, indicating that the compensatory pathway that functions in this model results in urothelial repair.

  6. Cell fate in the Arabidopsis root meristem determined by directional signalling.

    Science.gov (United States)

    van den Berg, C; Willemsen, V; Hage, W; Weisbeek, P; Scheres, B

    1995-11-02

    Postembryonic development in plants is achieved by apical meristems. Surgical studies and clonal analysis have revealed indirectly that cells in shoot meristems have no predictable destiny and that position is likely to play a role in the acquisition of cell identity. In contrast to animal systems, there has been no direct evidence for inductive signalling in plants until now. Here we present evidence for such signalling using laser ablation of cells in the root meristem of Arabidopsis thaliana. Although these cells show rigid clonal relationships, we now demonstrate that it is positional control that is most important in the determination of cell fate. Positional signals can be perpetuated from more mature to initial cells to guide the pattern of meristem cell differentiation. This offers an alternative to the general opinion that meristems are the source of patterning information.

  7. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells

    International Nuclear Information System (INIS)

    Dontu, Gabriela; Jackson, Kyle W; McNicholas, Erin; Kawamura, Mari J; Abdallah, Wissam M; Wicha, Max S

    2004-01-01

    Notch signaling has been implicated in the regulation of cell-fate decisions such as self-renewal of adult stem cells and differentiation of progenitor cells along a particular lineage. Moreover, depending on the cellular and developmental context, the Notch pathway acts as a regulator of cell survival and cell proliferation. Abnormal expression of Notch receptors has been found in different types of epithelial metaplastic lesions and neoplastic lesions, suggesting that Notch may act as a proto-oncogene. The vertebrate Notch1 and Notch4 homologs are involved in normal development of the mammary gland, and mutated forms of these genes are associated with development of mouse mammary tumors. In order to determine the role of Notch signaling in mammary cell-fate determination, we have utilized a newly described in vitro system in which mammary stem/progenitor cells can be cultured in suspension as nonadherent 'mammospheres'. Notch signaling was activated using exogenous ligands, or was inhibited using previously characterized Notch signaling antagonists. Utilizing this system, we demonstrate that Notch signaling can act on mammary stem cells to promote self-renewal and on early progenitor cells to promote their proliferation, as demonstrated by a 10-fold increase in secondary mammosphere formation upon addition of a Notch-activating DSL peptide. In addition to acting on stem cells, Notch signaling is also able to act on multipotent progenitor cells, facilitating myoepithelial lineage-specific commitment and proliferation. Stimulation of this pathway also promotes branching morphogenesis in three-dimensional Matrigel cultures. These effects are completely inhibited by a Notch4 blocking antibody or a gamma secretase inhibitor that blocks Notch processing. In contrast to the effects of Notch signaling on mammary stem/progenitor cells, modulation of this pathway has no discernable effect on fully committed, differentiated, mammary epithelial cells. These studies

  8. Mechanisms of cytolysin-induced cell damage -- a role for auto- and paracrine signalling

    DEFF Research Database (Denmark)

    Skals, Marianne Gerberg; Prætorius, Helle

    2013-01-01

    Cytolysins inflict cell damage by forming pores in the plasma membrane. The Na(+) conductivity of these pores results in an ion influx that exceeds the capacity of the Na(+) /K(+) -pump to extrude Na(+) . This net load of intracellular osmolytes results in swelling and eventual lysis of the attac...

  9. alpha-Tocopheryl succinate inhibits angiogenesis by disrupting paracrine FGF2 signalling

    Czech Academy of Sciences Publication Activity Database

    Neužil, Jiří; Swettenham, E.; Wang, X.F.; Dong, L.F.; Stapelberg, M.

    2007-01-01

    Roč. 581, č. 24 (2007), s. 4611-4615 ISSN 0014-5793 Institutional research plan: CEZ:AV0Z50520514; CEZ:AV0Z50520701 Keywords : mitocans * proliferating endothelial cells * apoptosis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.263, year: 2007

  10. Blocking Hedgehog release from pancreatic cancer cells increases paracrine signaling potency

    NARCIS (Netherlands)

    Damhofer, Helene; Veenstra, Veronique L.; Tol, Johanna A. M. G.; van Laarhoven, Hanneke W. M.; Medema, Jan Paul; Bijlsma, Maarten F.

    2015-01-01

    Members of the Hedgehog (Hh) family of morphogens play crucial roles in development but are also involved in the progression of certain types of cancer. Despite being synthesized as hydrophobic dually lipid-modified molecules, and thus being strongly membrane-associated, Hh ligands are able to

  11. Relation between stability and resilience determines the performance of early warning signals under different environmental drivers.

    Science.gov (United States)

    Dai, Lei; Korolev, Kirill S; Gore, Jeff

    2015-08-11

    Shifting patterns of temporal fluctuations have been found to signal critical transitions in a variety of systems, from ecological communities to human physiology. However, failure of these early warning signals in some systems calls for a better understanding of their limitations. In particular, little is known about the generality of early warning signals in different deteriorating environments. In this study, we characterized how multiple environmental drivers influence the dynamics of laboratory yeast populations, which was previously shown to display alternative stable states [Dai et al., Science, 2012]. We observed that both the coefficient of variation and autocorrelation increased before population collapse in two slowly deteriorating environments, one with a rising death rate and the other one with decreasing nutrient availability. We compared the performance of early warning signals across multiple environments as "indicators for loss of resilience." We find that the varying performance is determined by how a system responds to changes in a specific driver, which can be captured by a relation between stability (recovery rate) and resilience (size of the basin of attraction). Furthermore, we demonstrate that the positive correlation between stability and resilience, as the essential assumption of indicators based on critical slowing down, can break down in this system when multiple environmental drivers are changed simultaneously. Our results suggest that the stability-resilience relation needs to be better understood for the application of early warning signals in different scenarios.

  12. Comparison of signaling interactions determining annual and perennial plant growth in response to low temperature

    Directory of Open Access Journals (Sweden)

    Astrid eWingler

    2015-01-01

    Full Text Available Low temperature inhibits plant growth despite the fact that considerable rates of photosynthetic activity can be maintained. Instead of lower rates of photosynthesis, active inhibition of cell division and expansion is primarily responsible for reduced growth. This results in sink limitation and enables plants to accumulate carbohydrates that act as compatible solutes or are stored throughout the winter to enable re-growth in spring. Regulation of growth in response to temperature therefore requires coordination with carbon metabolism, e.g. via the signaling metabolite trehalose-6-phosphate. The phytohormones gibberellins (GA and jasmonate (JA play an important role in regulating growth in response to temperature. Growth restriction at low temperature is mainly mediated by DELLA proteins, whose degradation is promoted by GA. For annual plants, it has been shown that the GA/DELLA pathway interacts with JA signaling and C-repeat binding factor (CBF dependent cold acclimation, but these interactions have not been explored in detail for perennials. Growth regulation in response to seasonal factors is, however, particularly important in perennials, especially at high latitudes. In autumn, growth cessation in trees is caused by shortening of the daylength in interaction with phytohormone signaling. In perennial grasses seasonal differences in the sensitivity to GA may enable enhanced growth in spring. This review provides an overview of the signaling interactions that determine plant growth at low temperature and highlights gaps in our knowledge, especially concerning the seasonality of signaling responses in perennial plants.

  13. Automatic Threshold Determination for a Local Approach of Change Detection in Long-Term Signal Recordings

    Directory of Open Access Journals (Sweden)

    David Hewson

    2007-01-01

    Full Text Available CUSUM (cumulative sum is a well-known method that can be used to detect changes in a signal when the parameters of this signal are known. This paper presents an adaptation of the CUSUM-based change detection algorithms to long-term signal recordings where the various hypotheses contained in the signal are unknown. The starting point of the work was the dynamic cumulative sum (DCS algorithm, previously developed for application to long-term electromyography (EMG recordings. DCS has been improved in two ways. The first was a new procedure to estimate the distribution parameters to ensure the respect of the detectability property. The second was the definition of two separate, automatically determined thresholds. One of them (lower threshold acted to stop the estimation process, the other one (upper threshold was applied to the detection function. The automatic determination of the thresholds was based on the Kullback-Leibler distance which gives information about the distance between the detected segments (events. Tests on simulated data demonstrated the efficiency of these improvements of the DCS algorithm.

  14. Determination of noise sources and space-dependent reactor transfer functions from measured output signals only

    Energy Technology Data Exchange (ETDEWEB)

    Hoogenboom, J.E.; van Dam, H.; Kleiss, E.B.J.; van Uitert, G.C.; Veldhuis, D.

    1982-01-01

    The measured cross power spectral densities of the signals from three neutron detectors and the displacement of the control rod of the 2 MW research reactor HOR at Delft have been used to determine the space-dependent reactor transfer function, the transfer function of the automatic reactor control system and the noise sources influencing the measured signals. From a block diagram of the reactor with control system and noise sources expressions were derived for the measured cross power spectral densities, which were adjusted to satisfy the requirements following from the adopted model. Then for each frequency point the required transfer functions and noise sources could be derived. The results are in agreement with those of autoregressive modelling of the reactor control feed-back loop. A method has been developed to determine the non-linear characteristics of the automatic reactor control system by analysing the non-gaussian probability density function of the power fluctuations.

  15. Determination of noise sources and space-dependent reactor transfer functions from measured output signals only

    International Nuclear Information System (INIS)

    Hoogenboom, J.E.

    1982-01-01

    The measured cross power spectral densities of the signals from three neutron detectors and the displacement of the control rod of the 2 MW research reactor HOR at Delft have been used to determine the space-dependent reactor transfer function, the transfer function of the automatic reactor control system and the noise sources influencing the measured signals. From a block diagram of the reactor with control system and noise sources expressions were derived for the measured cross power spectral densities, which were adjusted to satisfy the requirements following from the adopted model. Then for each frequency point the required transfer functions and noise sources could be derived. The results are in agreement with those of autoregressive modelling of the reactor control feed-back loop. A method has been developed to determine the non-linear characteristics of the automatic reactor control system by analysing the non-gaussian probability density function of the power fluctuations. (author)

  16. Band extension in digital methods of transfer function determinationsignal conditioners asymmetry error corrections

    Directory of Open Access Journals (Sweden)

    Zbigniew Staroszczyk

    2014-12-01

    Full Text Available [b]Abstract[/b]. In the paper, the calibrating method for error correction in transfer function determination with the use of DSP has been proposed. The correction limits/eliminates influence of transfer function input/output signal conditioners on the estimated transfer functions in the investigated object. The method exploits frequency domain conditioning paths descriptor found during training observation made on the known reference object.[b]Keywords[/b]: transfer function, band extension, error correction, phase errors

  17. Satellite single-axis attitude determination based on Automatic Dependent Surveillance - Broadcast signals

    Science.gov (United States)

    Zhou, Kaixing; Sun, Xiucong; Huang, Hai; Wang, Xinsheng; Ren, Guangwei

    2017-10-01

    The space-based Automatic Dependent Surveillance - Broadcast (ADS-B) is a new technology for air traffic management. The satellite equipped with spaceborne ADS-B system receives the broadcast signals from aircraft and transfers the message to ground stations, so as to extend the coverage area of terrestrial-based ADS-B. In this work, a novel satellite single-axis attitude determination solution based on the ADS-B receiving system is proposed. This solution utilizes the signal-to-noise ratio (SNR) measurement of the broadcast signals from aircraft to determine the boresight orientation of the ADS-B receiving antenna fixed on the satellite. The basic principle of this solution is described. The feasibility study of this new attitude determination solution is implemented, including the link budget and the access analysis. On this basis, the nonlinear least squares estimation based on the Levenberg-Marquardt method is applied to estimate the single-axis orientation. A full digital simulation has been carried out to verify the effectiveness and performance of this solution. Finally, the corresponding results are processed and presented minutely.

  18. Activation of cardiac progenitor cells through paracrine effects of mesenchymal stem cells

    International Nuclear Information System (INIS)

    Nakanishi, Chiaki; Yamagishi, Masakazu; Yamahara, Kenichi; Hagino, Ikuo; Mori, Hidezo; Sawa, Yoshiki; Yagihara, Toshikatsu; Kitamura, Soichiro; Nagaya, Noritoshi

    2008-01-01

    Mesenchymal stem cells (MSC) transplantation has been proved to be promising strategy to treat the failing heart. The effect of MSC transplantation is thought to be mediated mainly in a paracrine manner. Recent reports have suggested that cardiac progenitor cells (CPC) reside in the heart. In this study, we investigated whether MSC had paracrine effects on CPC in vitro. CPC were isolated from the neonatal rat heart using an explant method. MSC were isolated from the adult rat bone marrow. MSC-derived conditioned medium promoted proliferation of CPC and inhibited apoptosis of CPC induced by hypoxia and serum starvation. Chemotaxis chamber assay demonstrated that MSC-derived conditioned medium enhanced migration of CPC. Furthermore, MSC-derived conditioned medium upregulated expression of cardiomyocyte-related genes in CPC such as β-myosin heavy chain (β-MHC) and atrial natriuretic peptide (ANP). In conclusion, MSC-derived conditioned medium had protective effects on CPC and enhanced their migration and differentiation

  19. Determination of outdoor signal propagation via visibility analysis in outdoor wireless networks

    Directory of Open Access Journals (Sweden)

    Mustafa Coşar

    2017-02-01

    Full Text Available Wireless networks on university campuses has gained importance in recent years. These networks in major areas such as university campuses, are faced with many problems during the planning, design and establishment. These problems are among the first that comes to mind, the physical properties of the campus and is selected according to the characteristics of network equipment. There is no doubt at all points of a wireless network set up in order to provide uninterrupted service and quality of the signal is expected to be good. However, it should be understood literally cannot meet these expectations. Therefore, to solve many problems to campus planning and design can be made to have acceptable signal distribution will have the appropriate use of and satisfaction with increasing effect. In this study, due to the start of construction on the North Campus of Hitit University, wireless signal spread using the current spread has been determined with the help of geographic information systems visibility analysis. An area of 56 hectares, with the total of 9 AP the acceptable signal distribution was obtained.

  20. Use of generator substitution to determine the real attenuation of informative signals in the compromising emanation

    Directory of Open Access Journals (Sweden)

    Alexander A. Golyakhov

    2018-05-01

    Full Text Available A determination of real attenuation of information signal's radiation on a way from the source to a possible location of intelligence devices is considered to be the most difficult operation while assessing information security against leakage of electromagnetic emanation. In this context the problem of automation of this kind of measurement is of great interest. It takes considerable effort and time to measure the attenuation by existing automated systems. That is why the measurements are generally taken within the limited range of frequencies only. Along with that, a spectre of a single information impulse has a leaf-structure and is solid on every frequency leaf. So electromagnetic field intensity attenuation measurement carried on the some preselected frequencies is not able to represent the complete attenuation characteristics. The measurements of attenuation in the whole informative signal spectre within the given frequency range requires a few thousand measurements, which makes the current method ineffective and time consuming. The relevant specialized automatized measurement systems of security verification has active protection system noise measurement mode, which can be used to measure the real attenuation. In this article a rather exact method of real attenuation of informative signal of video subsystem of electron-ray tube monitor measurement is described and confirmed in experiment. The measurements were made using specialized automatized system “Sigurd” and video subsystem informative signal noise generator. The described method allows a significant reduction of  the time needed for specialized investigations of security verification on electromagnetic emanation.

  1. Roles for gut vagal sensory signals in determining energy availability and energy expenditure.

    Science.gov (United States)

    Schwartz, Gary J

    2018-08-15

    The gut sensory vagus transmits a wide range of meal-related mechanical, chemical and gut peptide signals from gastrointestinal and hepatic tissues to the central nervous system at the level of the caudal brainstem. Results from studies using neurophysiological, behavioral physiological and metabolic approaches that challenge the integrity of this gut-brain axis support an important role for these gut signals in the negative feedback control of energy availability by limiting food intake during a meal. These experimental approaches have now been applied to identify important and unanticipated contributions of the vagal sensory gut-brain axis to the control of two additional effectors of overall energy balance: the feedback control of endogenous energy availability through hepatic glucose production and metabolism, and the control of energy expenditure through brown adipose tissue thermogenesis. Taken together, these studies reveal the pleiotropic influences of gut vagal meal-related signals on energy balance, and encourage experimental efforts aimed at understanding how the brainstem represents, organizes and coordinates gut vagal sensory signals with these three determinants of energy homeostasis. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. Interplay between glucose and leptin signalling determines the strength of GABAergic synapses at POMC neurons.

    Science.gov (United States)

    Lee, Dong Kun; Jeong, Jae Hoon; Chun, Sung-Kun; Chua, Streamson; Jo, Young-Hwan

    2015-03-26

    Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis. Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important. Here we show that leptin's action on GABA release to POMC neurons is influenced by glucose levels. Leptin stimulates the JAK2-PI3K pathway in both presynaptic GABAergic terminals and postsynaptic POMC neurons. Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose. However, postsynaptic TRPC channel opening by the PI3K-PLC signalling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose. High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin. Our data indicate that the interplay between glucose and leptin signalling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons.

  3. Interplay between glucose and leptin signaling determines the strength of GABAergic synapses at POMC neurons

    Science.gov (United States)

    Lee, Dong Kun; Jeong, Jae Hoon; Chun, Sung-Kun; Chua, Streamson; Jo, Young-Hwan

    2015-01-01

    Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis. Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important. Here we show that leptin’s action on GABA release to POMC neurons is influenced by glucose levels. Leptin stimulates the JAK2-PI3K pathway in both presynaptic GABAergic terminals and postsynaptic POMC neurons. Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose. However, postsynaptic TRPC channel opening by the PI3K-PLC signaling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose. High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin. Our data indicate that the interplay between glucose and leptin signaling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons. PMID:25808323

  4. ALFY-Controlled DVL3 Autophagy Regulates Wnt Signaling, Determining Human Brain Size.

    Directory of Open Access Journals (Sweden)

    Rotem Kadir

    2016-03-01

    Full Text Available Primary microcephaly is a congenital neurodevelopmental disorder of reduced head circumference and brain volume, with fewer neurons in the cortex of the developing brain due to premature transition between symmetrical and asymmetrical cellular division of the neuronal stem cell layer during neurogenesis. We now show through linkage analysis and whole exome sequencing, that a dominant mutation in ALFY, encoding an autophagy scaffold protein, causes human primary microcephaly. We demonstrate the dominant effect of the mutation in drosophila: transgenic flies harboring the human mutant allele display small brain volume, recapitulating the disease phenotype. Moreover, eye-specific expression of human mutant ALFY causes rough eye phenotype. In molecular terms, we demonstrate that normally ALFY attenuates the canonical Wnt signaling pathway via autophagy-dependent removal specifically of aggregates of DVL3 and not of Dvl1 or Dvl2. Thus, autophagic attenuation of Wnt signaling through removal of Dvl3 aggregates by ALFY acts in determining human brain size.

  5. Disentangling evolutionary signals: conservation, specificity determining positions and coevolution. Implication for catalytic residue prediction

    DEFF Research Database (Denmark)

    Teppa, Elin; Wilkins, Angela D.; Nielsen, Morten

    2012-01-01

    Background: A large panel of methods exists that aim to identify residues with critical impact on protein function based on evolutionary signals, sequence and structure information. However, it is not clear to what extent these different methods overlap, and if any of the methods have higher...... predictive potential compared to others when it comes to, in particular, the identification of catalytic residues (CR) in proteins. Using a large set of enzymatic protein families and measures based on different evolutionary signals, we sought to break up the different components of the information content......-value Evolutionary Trace (rvET) methods and conservation, another containing mutual information (MI) methods, and the last containing methods designed explicitly for the identification of specificity determining positions (SDPs): integer-value Evolutionary Trace (ivET), SDPfox, and XDET. In terms of prediction of CR...

  6. Paracrine Mechanisms of Intravenous Bone Marrow-Derived Mononuclear Stem Cells in Chronic Ischemic Stroke

    Directory of Open Access Journals (Sweden)

    Ashu Bhasin

    2016-10-01

    Full Text Available Background: The emerging role of stem cell technology and transplantation has helped scientists to study their potential role in neural repair and regeneration. The fate of stem cells is determined by their niche, consisting of surrounding cells and the secreted trophic growth factors. This interim report evaluates the safety, feasibility and efficacy (if any of bone marrow-derived mononuclear stem cells (BM-MNC in chronic ischemic stroke by studying the release of serum vascular endothelial growth factor (VEGF and brain-derived neurotrophic growth factor (BDNF. Methods: Twenty stroke patients and 20 age-matched healthy controls were recruited with the following inclusion criteria: 3 months to 1.5 years from the index event, Medical Research Council (MRC grade of hand muscles of at least 2, Brunnstrom stage 2-5, conscious, and comprehendible. They were randomized to one group receiving autologous BM-MNC (mean 60-70 million and to another group receiving saline infusion (placebo. All patients were administered a neuromotor rehabilitation regime for 8 weeks. Clinical assessments [Fugl Meyer scale (FM, modified Barthel index (mBI, MRC grade, Ashworth tone scale] were carried out and serum VEGF and BDNF levels were assessed at baseline and at 8 weeks. Results: No serious adverse events were observed during the study. There was no statistically significant clinical improvement between the groups (FM: 95% CI 15.2-5.35, p = 0.25; mBI: 95% CI 14.3-4.5, p = 0.31. VEGF and BDNF expression was found to be greater in group 1 compared to group 2 (VEGF: 442.1 vs. 400.3 pg/ml, p = 0.67; BDNF: 21.3 vs. 19.5 ng/ml without any statistically significant difference. Conclusion: Autologous mononuclear stem cell infusion is safe and tolerable by chronic ischemic stroke patients. The released growth factors (VEGF and BDNF in the microenvironment could be due to the paracrine hypothesis of stem cell niche and neurorehabilitation regime.

  7. Immunohistochemical evidence for an endocrine/paracrine role for ghrelin in the reproductive tissues of sheep

    Directory of Open Access Journals (Sweden)

    Brown Yvonne A

    2005-10-01

    Full Text Available Abstract Background The gut hormone, ghrelin, is involved in the neuroendocrine and metabolic responses to hunger. In monogastric species, circulating ghrelin levels show clear meal-related and body weight-related changes. The pattern of secretion and its role in ruminant species is less clear. Ghrelin acts via growth hormone secretagogue receptors (GHSR-1a to alter food intake, fat utilization, and cellular proliferation. There is also evidence that ghrelin is involved in reproductive function. In the present study we used immunohistochemistry to investigate the presence of ghrelin and GHSR-1a in sheep reproductive tissues. In addition, we examined whether ghrelin and GHSR-1a protein expression is developmentally regulated in the adult and fetal ovine testis, and whether there is an association with markers of cellular proliferation, i.e. stem cell factor (SCF and proliferating cell nuclear antigen (PCNA. Methods Antibodies raised against ghrelin and its functional receptor, GHSR-type 1a, were used in standard immunohistochemical protocols on various reproductive tissues collected from adult and fetal sheep. GHSR-1a mRNA presence was also confirmed by in situ hybridisation. SCF and PCNA immunoexpression was investigated in fetal testicular samples. Adult and fetal testicular immunostaining for ghrelin, GHSR-1a, SCF and PCNA was analysed using computer-aided image analysis. Image analysis data were subjected to one-way ANOVA, with differences in immunostaining between time-points determined by Fisher's least significant difference. Results In adult sheep tissue, ghrelin and GHSR-1a immunostaining was detected in the stomach (abomasum, anterior pituitary gland, testis, ovary, and hypothalamic and hindbrain regions of the brain. In the adult testis, there was a significant effect of season (photoperiod on the level of immunostaining for ghrelin (p Conclusion Evidence is presented for the presence of ghrelin and its receptor in various reproductive

  8. The Role of Retinal Determination Gene Network (RDGN) in Hormone Signaling Transduction and Prostate Tumorigenes

    Science.gov (United States)

    2015-12-01

    S, Zhang W, Zhou J, Wang J, Ertel A, Li Z, Rui H, Quong A, Lisanti MP, Tozeren A, Tanes C, Addya S, Gormley M, Wang C, McMahon SB, Pestell RG...MP, Wang C, Pestell RG. Acetylation of the cell-fate factor dachshund determines p53 binding and signaling modules in breast cancer. Oncotarget...MP, Quong A, Ertel A, Pestell RG. Cell fate factor DACH1 represses YB-1-mediated oncogenic transcription and translation. Cancer Res. 2014;74(3):829

  9. Attitude determination for small satellites using GPS signal-to-noise ratio

    Science.gov (United States)

    Peters, Daniel

    An embedded system for GPS-based attitude determination (AD) using signal-to-noise (SNR) measurements was developed for CubeSat applications. The design serves as an evaluation testbed for conducting ground based experiments using various computational methods and antenna types to determine the optimum AD accuracy. Raw GPS data is also stored to non-volatile memory for downloading and post analysis. Two low-power microcontrollers are used for processing and to display information on a graphic screen for real-time performance evaluations. A new parallel inter-processor communication protocol was developed that is faster and uses less power than existing standard protocols. A shorted annular patch (SAP) antenna was fabricated for the initial ground-based AD experiments with the testbed. Static AD estimations with RMS errors in the range of 2.5° to 4.8° were achieved over a range of off-zenith attitudes.

  10. Micro-earthquake signal analysis and hypocenter determination around Lokon volcano complex

    Energy Technology Data Exchange (ETDEWEB)

    Firmansyah, Rizky, E-mail: rizkyfirmansyah@hotmail.com [Geophysical Engineering, Faculty of Mining and Petroleum Engineering, Institut Teknologi Bandung, Bandung, 40132 (Indonesia); Nugraha, Andri Dian, E-mail: nugraha@gf.itb.ac.id [Global Geophysical Group, Faculty of Mining and Petroleum Engineering, Institut Teknologi Bandung, Bandung, 40132 (Indonesia); Kristianto, E-mail: kris@vsi.esdm.go.id [Center for Volcanology and Geological Hazard Mitigation (CVGHM), Geological Agency, Bandung, 40122 (Indonesia)

    2015-04-24

    Mount Lokon is one of five active volcanoes which is located in the North Sulawesi region. Since June 26{sup th}, 2011, standby alert set by the Center for Volcanology and Geological Hazard Mitigation (CVGHM) for this mountain. The Mount Lokon volcano erupted on July 4{sup th}, 2011 and still continuously erupted until August 28{sup th}, 2011. Due to its high seismic activity, this study is focused to analysis of micro-earthquake signal and determine the micro-earthquake hypocenter location around the complex area of Lokon-Empung Volcano before eruption phase in 2011 (time periods of January, 2009 up to March, 2010). Determination of the hypocenter location was conducted with Geiger Adaptive Damping (GAD) method. We used initial model from previous study in Volcan de Colima, Mexico. The reason behind the model selection was based on the same characteristics that shared between Mount Lokon and Colima including andesitic stratovolcano and small-plinian explosions volcanian types. In this study, a picking events was limited to the volcano-tectonics of A and B types, hybrid, long-period that has a clear signal onset, and local tectonic with different maximum S – P time are not more than three seconds. As a result, we observed the micro-earthquakes occurred in the area north-west of Mount Lokon region.

  11. Micro-earthquake signal analysis and hypocenter determination around Lokon volcano complex

    International Nuclear Information System (INIS)

    Firmansyah, Rizky; Nugraha, Andri Dian; Kristianto

    2015-01-01

    Mount Lokon is one of five active volcanoes which is located in the North Sulawesi region. Since June 26 th , 2011, standby alert set by the Center for Volcanology and Geological Hazard Mitigation (CVGHM) for this mountain. The Mount Lokon volcano erupted on July 4 th , 2011 and still continuously erupted until August 28 th , 2011. Due to its high seismic activity, this study is focused to analysis of micro-earthquake signal and determine the micro-earthquake hypocenter location around the complex area of Lokon-Empung Volcano before eruption phase in 2011 (time periods of January, 2009 up to March, 2010). Determination of the hypocenter location was conducted with Geiger Adaptive Damping (GAD) method. We used initial model from previous study in Volcan de Colima, Mexico. The reason behind the model selection was based on the same characteristics that shared between Mount Lokon and Colima including andesitic stratovolcano and small-plinian explosions volcanian types. In this study, a picking events was limited to the volcano-tectonics of A and B types, hybrid, long-period that has a clear signal onset, and local tectonic with different maximum S – P time are not more than three seconds. As a result, we observed the micro-earthquakes occurred in the area north-west of Mount Lokon region

  12. Net Analyte Signal Standard Additions Method for Simultaneous Determination of Sulfamethoxazole and Trimethoprim in Pharmaceutical Formulations and Biological Fluids

    OpenAIRE

    Givianrad, M. H.; Mohagheghian, M.

    2012-01-01

    The applicability of a novel net analyte signal standard addition method (NASSAM) to the resolving of overlapping spectra corresponding to the sulfamethoxazole and trimethoprim was verified by UV-visible spectrophotometry. The results confirmed that the net analyte signal standard additions method with simultaneous addition of both analytes is suitable for the simultaneous determination of sulfamethoxazole and trimethoprim in aqueous media. Moreover, applying the net analyte signal standard a...

  13. Adipocyte activation of cancer stem cell signaling in breast cancer

    Institute of Scientific and Technical Information of China (English)

    Benjamin; Wolfson; Gabriel; Eades; Qun; Zhou

    2015-01-01

    Signaling within the tumor microenvironment has a critical role in cancer initiation and progression. Adipocytes, one of the major components of the breast microenvironment,have been shown to provide pro-tumorigenic signals that promote cancer cell proliferation and invasiveness in vitro and tumorigenicity in vivo. Adipocyte secreted factors such as leptin and interleukin-6(IL-6) have a paracrine effect on breast cancer cells. In adipocyte-adjacent breast cancer cells, the leptin and IL-6 signaling pathways activate janus kinase 2/signal transducer and activatorof transcription 5, promoting the epithelial-mesenchymal transition, and upregulating stemness regulators such as Notch, Wnt and the Sex determining region Y-box 2/octamer binding transcription factor 4/Nanog signaling axis. In this review we will summarize the major signaling pathways that regulate cancer stem cells in breast cancer and describe the effects that adipocyte secreted IL-6 and leptin have on breast cancer stem cell signaling. Finally we will introduce a new potential treatment paradigm of inhibiting the adipocyte-breast cancer cell signaling via targeting the IL-6 or leptin pathways.

  14. Paracrine Maturation and Migration of SH-SY5Y Cells by Dental Pulp Stem Cells

    OpenAIRE

    Gervois, Pascal; Wolfs, Esther; Dillen, Yörg; Hilkens, Petra; Ratajczak, Jessica; Driesen, Ronald; Vangansewinkel, Tim; Bronckaers, Annelies; Brône, Bert; Struys, Tom; Lambrichts, Ivo

    2017-01-01

    Neurological disorders are characterized by neurodegeneration and/or loss of neuronal function, which cannot be adequately repaired by the host. Therefore, there is need for novel treatment options such as cell-based therapies that aim to salvage or reconstitute the lost tissue or that stimulate host repair. The present study aimed to evaluate the paracrine effects of human dental pulp stem cells (hDPSCs) on the migration and neural maturation of human SH-SY5Y neuroblastoma cells. The hDPSC s...

  15. Direct Position Determination of Unknown Signals in the Presence of Multipath Propagation.

    Science.gov (United States)

    Du, Jianping; Wang, Ding; Yu, Wanting; Yu, Hongyi

    2018-03-17

    A novel geolocation architecture, termed "Multiple Transponders and Multiple Receivers for Multiple Emitters Positioning System (MTRE)" is proposed in this paper. Existing Direct Position Determination (DPD) methods take advantage of a rather simple channel assumption (line of sight channels with complex path attenuations) and a simplified MUltiple SIgnal Classification (MUSIC) algorithm cost function to avoid the high dimension searching. We point out that the simplified assumption and cost function reduce the positioning accuracy because of the singularity of the array manifold in a multi-path environment. We present a DPD model for unknown signals in the presence of Multi-path Propagation (MP-DPD) in this paper. MP-DPD adds non-negative real path attenuation constraints to avoid the mistake caused by the singularity of the array manifold. The Multi-path Propagation MUSIC (MP-MUSIC) method and the Active Set Algorithm (ASA) are designed to reduce the dimension of searching. A Multi-path Propagation Maximum Likelihood (MP-ML) method is proposed in addition to overcome the limitation of MP-MUSIC in the sense of a time-sensitive application. An iterative algorithm and an approach of initial value setting are given to make the MP-ML time consumption acceptable. Numerical results validate the performances improvement of MP-MUSIC and MP-ML. A closed form of the Cramér-Rao Lower Bound (CRLB) is derived as a benchmark to evaluate the performances of MP-MUSIC and MP-ML.

  16. Induction of type I interferon signaling determines the relative pathogenicity of Staphylococcus aureus strains.

    Directory of Open Access Journals (Sweden)

    Dane Parker

    2014-02-01

    Full Text Available The tremendous success of S. aureus as a human pathogen has been explained primarily by its array of virulence factors that enable the organism to evade host immunity. Perhaps equally important, but less well understood, is the importance of the intensity of the host response in determining the extent of pathology induced by S. aureus infection, particularly in the pathogenesis of pneumonia. We compared the pathogenesis of infection caused by two phylogenetically and epidemiologically distinct strains of S. aureus whose behavior in humans has been well characterized. Induction of the type I IFN cascade by strain 502A, due to a NOD2-IRF5 pathway, was the major factor in causing severe pneumonia and death in a murine model of pneumonia and was associated with autolysis and release of peptidogylcan. In contrast to USA300, 502A was readily eliminated from epithelial surfaces in vitro. Nonetheless, 502A caused significantly increased tissue damage due to the organisms that were able to invade systemically and trigger type I IFN responses, and this was ameliorated in Ifnar⁻/⁻ mice. The success of USA300 to cause invasive infection appears to depend upon its resistance to eradication from epithelial surfaces, but not production of specific toxins. Our studies illustrate the important and highly variable role of type I IFN signaling within a species and suggest that targeted immunomodulation of specific innate immune signaling cascades may be useful to prevent the excessive morbidity associated with S. aureus pneumonia.

  17. A set of enhanced green fluorescent protein concatemers for quantitative determination of nuclear localization signal strength.

    Science.gov (United States)

    Böhm, Jennifer; Thavaraja, Ramya; Giehler, Susanne; Nalaskowski, Marcus M

    2017-09-15

    Regulated transport of proteins between nucleus and cytoplasm is an important process in the eukaryotic cell. In most cases, active nucleo-cytoplasmic protein transport is mediated by nuclear localization signal (NLS) and/or nuclear export signal (NES) motifs. In this study, we developed a set of vectors expressing enhanced GFP (EGFP) concatemers ranging from 2 to 12 subunits (2xEGFP to 12xEGFP) for analysis of NLS strength. As shown by in gel GFP fluorescence analysis and αGFP Western blotting, EGFP concatemers are expressed as fluorescent full-length proteins in eukaryotic cells. As expected, nuclear localization of concatemeric EGFPs decreases with increasing molecular weight. By oligonucleotide ligation this set of EGFP concatemers can be easily fused to NLS motifs. After determination of intracellular localization of EGFP concatemers alone and fused to different NLS motifs we calculated the size of a hypothetic EGFP concatemer showing a defined distribution of EGFP fluorescence between nucleus and cytoplasm (n/c ratio = 2). Clear differences of the size of the hypothetic EGFP concatemer depending on the fused NLS motif were observed. Therefore, we propose to use the size of this hypothetic concatemer as quantitative indicator for comparing strength of different NLS motifs. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Distinct Phosphorylation Clusters Determine the Signaling Outcome of Free Fatty Acid Receptor 4/G Protein-Coupled Receptor 120

    DEFF Research Database (Denmark)

    Prihandoko, Rudi; Alvarez-Curto, Elisa; Hudson, Brian D

    2016-01-01

    of these phosphoacceptor sites to alanine completely prevented phosphorylation of mFFA4 but did not limit receptor coupling to extracellular signal regulated protein kinase 1 and 2 (ERK1/2) activation. Rather, an inhibitor of Gq/11proteins completely prevented receptor signaling to ERK1/2. By contrast, the recruitment...... activation. These unique observations define differential effects on signaling mediated by phosphorylation at distinct locations. This hallmark feature supports the possibility that the signaling outcome of mFFA4 activation can be determined by the pattern of phosphorylation (phosphorylation barcode...

  19. A Paracrine Role for IL6 in Prostate Cancer Patients: Lack of Production by Primary or Metastatic Tumor Cells

    Science.gov (United States)

    Yu, Shu-Han; Zheng, Qizhi; Esopi, David; Macgregor-Das, Anne; Luo, Jun; Antonarakis, Emmanuel S.; Drake, Charles G.; Vessella, Robert; Morrissey, Colm; De Marzo, Angelo M.; Sfanos, Karen S.

    2015-01-01

    Correlative human studies suggest that the pleiotropic cytokine interleukin-6 (IL6) contributes to the development and/or progression of prostate cancer. However, the source of IL6 production in the prostate microenvironment in patients has yet to be determined. The cellular origin of IL6 in primary and metastatic prostate cancer was examined in formalin-fixed, paraffin-embedded (FFPE) tissues using a highly sensitive and specific chromogenic in situ hybridization (CISH) assay that underwent extensive analytical validation. Quantitative RT-PCR (q-RT-PCR) showed that benign prostate tissues often had higher expression of IL6 mRNA than matched tumor specimens. CISH analysis further indicated that both primary and metastatic prostate adenocarcinoma cells do not express IL6 mRNA. IL6 expression was highly heterogeneous across specimens and was nearly exclusively restricted to the prostate stromal compartment – including endothelial cells and macrophages among other cell types. The number of IL6-expressing cells correlated positively with the presence of acute inflammation. In metastatic disease, tumor cells were negative in all lesions examined and IL6 expression was restricted to endothelial cells within the vasculature of bone metastases. Finally, IL6 was not detected in any cells in soft tissue metastases. These data suggest that, in prostate cancer patients, paracrine rather than autocrine IL6 production is likely associated with any role for the cytokine in disease progression. PMID:26048576

  20. Determination of elastic mechanical characteristics of surface coatings from analysis of signals obtained by impulse excitation

    Science.gov (United States)

    Nyaguly, E.; Craştiu, I.; Deac, S.; Gozman-Pop, C.; Drăgănescu, G.; Bereteu, L.

    2018-01-01

    Most of the surface coatings are based on the synthetic polymers, which are substances composed from very large molecules that form tough, flexible, adhesive films when applied to surfaces. The other components of surface coverings materials are pigments that provide colour, opacity, gloss and other properties. Surface coatings are two-phase composite materials: constitute a polymer matrix on the one side, and on the other side of the pigments and additives dispersed in the matrix. Their role is not only aesthetically but also to ensure anticorrosive protection or even improve some mechanical properties of coated surfaces. In this paper it will follow, starting from the mechanical properties of the substrate, the metallic sheet in general, to determine the new properties of the assembly of substrate and the two coating layers, also the determination of mechanical properties of the layers. From the analysis of vibroacoustic signals obtained by the impulse excitation of the sample, one can determine the elasticity modulus. These results come to validate the results based on finite element analysis (FEA) of the same samples.

  1. Use of high frequency analysis of acoustic emission signals to determine rolling element bearing condition

    International Nuclear Information System (INIS)

    Cockerill, A; Holford, K M; Pullin, R; Clarke, A; Bradshaw, T; Cole, P

    2015-01-01

    Acoustic Emission (AE) sensors were used to detect signals arising from a cylindrical roller bearing with artificial defects seeded onto the outer raceway. An SKF N204ECP roller bearing was placed between two double row spherical roller bearings, type SKF 22202E, and loaded between 0.29 and 1.79kN. Speed was constant at 5780rpm. High frequency analysis allowed insight into the condition of the bearings through the determination of an increase in the structural resonances of the system as the size of an artificial defect was increased. As higher loads were applied, frequencies around 100kHz were excited, indicating the release of AE possibly attributed to friction and the plastic deformation as peaks, induced through engraving of the raceway, were flattened and worn down. Sensitivity of AE to this level in bearings indicates the potential of the technique to detect the early stages of bearing failure during life tests. (paper)

  2. A method to determine the necessity for global signal regression in resting-state fMRI studies.

    Science.gov (United States)

    Chen, Gang; Chen, Guangyu; Xie, Chunming; Ward, B Douglas; Li, Wenjun; Antuono, Piero; Li, Shi-Jiang

    2012-12-01

    In resting-state functional MRI studies, the global signal (operationally defined as the global average of resting-state functional MRI time courses) is often considered a nuisance effect and commonly removed in preprocessing. This global signal regression method can introduce artifacts, such as false anticorrelated resting-state networks in functional connectivity analyses. Therefore, the efficacy of this technique as a correction tool remains questionable. In this article, we establish that the accuracy of the estimated global signal is determined by the level of global noise (i.e., non-neural noise that has a global effect on the resting-state functional MRI signal). When the global noise level is low, the global signal resembles the resting-state functional MRI time courses of the largest cluster, but not those of the global noise. Using real data, we demonstrate that the global signal is strongly correlated with the default mode network components and has biological significance. These results call into question whether or not global signal regression should be applied. We introduce a method to quantify global noise levels. We show that a criteria for global signal regression can be found based on the method. By using the criteria, one can determine whether to include or exclude the global signal regression in minimizing errors in functional connectivity measures. Copyright © 2012 Wiley Periodicals, Inc.

  3. Multi-signal sedimentation velocity analysis with mass conservation for determining the stoichiometry of protein complexes.

    Directory of Open Access Journals (Sweden)

    Chad A Brautigam

    Full Text Available Multi-signal sedimentation velocity analytical ultracentrifugation (MSSV is a powerful tool for the determination of the number, stoichiometry, and hydrodynamic shape of reversible protein complexes in two- and three-component systems. In this method, the evolution of sedimentation profiles of macromolecular mixtures is recorded simultaneously using multiple absorbance and refractive index signals and globally transformed into both spectrally and diffusion-deconvoluted component sedimentation coefficient distributions. For reactions with complex lifetimes comparable to the time-scale of sedimentation, MSSV reveals the number and stoichiometry of co-existing complexes. For systems with short complex lifetimes, MSSV reveals the composition of the reaction boundary of the coupled reaction/migration process, which we show here may be used to directly determine an association constant. A prerequisite for MSSV is that the interacting components are spectrally distinguishable, which may be a result, for example, of extrinsic chromophores or of different abundances of aromatic amino acids contributing to the UV absorbance. For interacting components that are spectrally poorly resolved, here we introduce a method for additional regularization of the spectral deconvolution by exploiting approximate knowledge of the total loading concentrations. While this novel mass conservation principle does not discriminate contributions to different species, it can be effectively combined with constraints in the sedimentation coefficient range of uncomplexed species. We show in theory, computer simulations, and experiment, how mass conservation MSSV as implemented in SEDPHAT can enhance or even substitute for the spectral discrimination of components. This should broaden the applicability of MSSV to the analysis of the composition of reversible macromolecular complexes.

  4. Linear signal noise summer accurately determines and controls S/N ratio

    Science.gov (United States)

    Sundry, J. L.

    1966-01-01

    Linear signal noise summer precisely controls the relative power levels of signal and noise, and mixes them linearly in accurately known ratios. The S/N ratio accuracy and stability are greatly improved by this technique and are attained simultaneously.

  5. Human umbilical cord mesenchymal stem cells promote peripheral nerve repair via paracrine mechanisms

    Directory of Open Access Journals (Sweden)

    Zhi-yuan Guo

    2015-01-01

    Full Text Available Human umbilical cord-derived mesenchymal stem cells (hUCMSCs represent a promising young-state stem cell source for cell-based therapy. hUCMSC transplantation into the transected sciatic nerve promotes axonal regeneration and functional recovery. To further clarify the paracrine effects of hUCMSCs on nerve regeneration, we performed human cytokine antibody array analysis, which revealed that hUCMSCs express 14 important neurotrophic factors. Enzyme-linked immunosorbent assay and immunohistochemistry showed that brain-derived neurotrophic factor, glial-derived neurotrophic factor, hepatocyte growth factor, neurotrophin-3, basic fibroblast growth factor, type I collagen, fibronectin and laminin were highly expressed. Treatment with hUCMSC-conditioned medium enhanced Schwann cell viability and proliferation, increased nerve growth factor and brain-derived neurotrophic factor expression in Schwann cells, and enhanced neurite growth from dorsal root ganglion explants. These findings suggest that paracrine action may be a key mechanism underlying the effects of hUCMSCs in peripheral nerve repair.

  6. Bone marrow transplantation rescues intestinal mucosa after whole body radiation via paracrine mechanisms

    International Nuclear Information System (INIS)

    Chang, Ya Hui; Lin, Li-Mei; Lou, Chi-Wen; Chou, Chuan-Kai; Ch’ang, Hui-Ju

    2012-01-01

    Purpose: Our previous study reveals bone marrow transplantation (BMT) recruits host marrow-derived myelomonocytic cells to radiation-injured intestine, enhancing stromal proliferation, leading secondarily to epithelial regeneration. In this study, we propose BMT ameliorates intestinal damage via paracrine mechanisms. Materials and methods: Angiogenic cytokines within the intestinal mucosa of mice after whole body irradiation (WBI) with or without BMT were measured by cytokine array and ELISA. BM conditioned medium (BMCM) with or without treatment with neutralizing antibodies to angiogenic cytokines were continuously infused into mice for three days after radiation. Carrageenan was used to deplete myelomonocytic cells of mice. Results: BMT increased VEGF, bFGF and other angiogenic and chemotactic cytokines in the intestinal mucosa within 24 h after WBI. Infusion of BMCM ameliorated radiation-induced intestinal damage with improved stromal activity and prolonged survival of mice. Neutralization of bFGF, PDGF and other angiogenic cytokines within BMCM abolished the mitigating effect to the intestine. Pretreatment of carrageenan to recipient mice reversed some of the cytokine levels, including VEGF, bFGF and IGF within the intestinal mucosa after BMT. Conclusions: Our result suggests BMT recruits host myelomonocytic cells and enhances intestinal stroma proliferation after radiation by secreting cytokines enhancing angiogenesis and chemotaxis. Host myelomonocytic cells further uplift the paracrine effect to enhance intestinal mucosal recovery.

  7. Lung-derived growth factors: possible paracrine effectors of fetal lung development

    International Nuclear Information System (INIS)

    Montes, A.M.

    1985-01-01

    A potential role for paracrine secretions in lung organogenesis has been hypothesized (Alescio and Piperno, 1957). These studies present direct support for the paracrine model by demonstrating the presence of locally produced mitogenic/maturational factors in fetal rat lung tissue. Conditioned serum free medium (CSFM) from nineteen-day fetal rat lung cultures was shown to contain several bioactive peptides as detected by 3 H-Thymidine incorporation into chick embryo and rat lung fibroblasts, as well as 14 C-choline incorporation into surfactant in mixed cell cultures. Using ion-exchange chromatography and Sephadex gel filtration, a partially purified mitogen, 11-III, was obtained. The partially purified 11-III stimulates mitosis in chick embryo fibroblasts and post-natal rat lung fibroblasts. Multiplication in fetal rat lung fibroblasts cultures is stimulated only when these are pre-incubated with a competence factor or unprocessed CSFM. This suggests the existence of an endogenously produced competence factor important in the regulation of fetal lung growth. Preparation 11-III does not possess surfactant stimulating activity as assessed by 3 H-choline incorporation into lipids in predominantly type-II cell cultures. These data demonstrate the presence of a maturational/mitogenic factor, influencing type-II mixed cell cultures. In addition, 11-III had been shown to play an autocrine role stimulating the proliferation of fetal lung fibroblasts. Finally, these data suggest the existence of a local produced competence factor

  8. A low-density culture method of cerebellar granule neurons with paracrine support applicable for the study of neuronal morphogenesis.

    Science.gov (United States)

    Kubota, Kenta; Seno, Takeshi; Konishi, Yoshiyuki

    2013-11-20

    Cerebellar granule neuronal cultures have been used to study the molecular mechanisms underlying neuronal functions, including neuronal morphogenesis. However, a limitation of this system is the difficulty to analyze isolated neurons because these are required to be maintained at a high density. Therefore, in the present study, we aimed to develop a simple and cost-effective method for culturing low-density cerebellar granule neurons. Cerebellar granule cells at two different densities (low- and high-density) were co-cultivated in order for the low-density culture to be supported by the paracrine signals from the high-density culture. This method enabled morphology analysis of isolated cerebellar granule neurons without astrocytic feeder cultures or supplements such as B27. Using this method, we investigated the function of a polarity factor. Studies using hippocampal neurons suggested that glycogen synthase kinase-3 (GSK-3) is an essential regulator of neuronal polarity, and inhibition of GSK-3 results in the formation of multiple axons. Pharmacological inhibitors for GSK-3 (6-bromoindirubin-3'-oxime and lithium chloride) did not cause the formation of multiple axons of cerebellar granule neurons but significantly reduced their length. Consistent results were obtained by introducing kinase-dead form of GSK-3 beta (K85A). These results indicated that GSK-3 is not directly involved in the control of neuronal polarity in cerebellar granule neurons. Overall, this study provides a simple method for culturing low-density cerebellar granule neurons and insights in to the neuronal-type dependent function of GSK-3 in neuronal morphogenesis. © 2013 Elsevier B.V. All rights reserved.

  9. Turnover of amyloid precursor protein family members determines their nuclear signaling capability.

    Science.gov (United States)

    Gersbacher, Manuel T; Goodger, Zoë V; Trutzel, Annette; Bundschuh, Diana; Nitsch, Roger M; Konietzko, Uwe

    2013-01-01

    The amyloid precursor protein (APP) as well as its homologues, APP-like protein 1 and 2 (APLP1 and APLP2), are cleaved by α-, β-, and γ-secretases, resulting in the release of their intracellular domains (ICDs). We have shown that the APP intracellular domain (AICD) is transported to the nucleus by Fe65 where they jointly bind the histone acetyltransferase Tip60 and localize to spherical nuclear complexes (AFT complexes), which are thought to be sites of transcription. We have now analyzed the subcellular localization and turnover of the APP family members. Similarly to AICD, the ICD of APLP2 localizes to spherical nuclear complexes together with Fe65 and Tip60. In contrast, the ICD of APLP1, despite binding to Fe65, does not translocate to the nucleus. In addition, APLP1 predominantly localizes to the plasma membrane, whereas APP and APLP2 are detected in vesicular structures. APLP1 also demonstrates a much slower turnover of the full-length protein compared to APP and APLP2. We further show that the ICDs of all APP family members are degraded by the proteasome and that the N-terminal amino acids of ICDs determine ICD degradation rate. Together, our results suggest that different nuclear signaling capabilities of APP family members are due to different rates of full-length protein processing and ICD proteasomal degradation. Our results provide evidence in support of a common nuclear signaling function for APP and APLP2 that is absent in APLP1, but suggest that APLP1 has a regulatory role in the nuclear translocation of APP family ICDs due to the sequestration of Fe65.

  10. Direct Position Determination of Unknown Signals in the Presence of Multipath Propagation

    Science.gov (United States)

    Yu, Hongyi

    2018-01-01

    A novel geolocation architecture, termed “Multiple Transponders and Multiple Receivers for Multiple Emitters Positioning System (MTRE)” is proposed in this paper. Existing Direct Position Determination (DPD) methods take advantage of a rather simple channel assumption (line of sight channels with complex path attenuations) and a simplified MUltiple SIgnal Classification (MUSIC) algorithm cost function to avoid the high dimension searching. We point out that the simplified assumption and cost function reduce the positioning accuracy because of the singularity of the array manifold in a multi-path environment. We present a DPD model for unknown signals in the presence of Multi-path Propagation (MP-DPD) in this paper. MP-DPD adds non-negative real path attenuation constraints to avoid the mistake caused by the singularity of the array manifold. The Multi-path Propagation MUSIC (MP-MUSIC) method and the Active Set Algorithm (ASA) are designed to reduce the dimension of searching. A Multi-path Propagation Maximum Likelihood (MP-ML) method is proposed in addition to overcome the limitation of MP-MUSIC in the sense of a time-sensitive application. An iterative algorithm and an approach of initial value setting are given to make the MP-ML time consumption acceptable. Numerical results validate the performances improvement of MP-MUSIC and MP-ML. A closed form of the Cramér–Rao Lower Bound (CRLB) is derived as a benchmark to evaluate the performances of MP-MUSIC and MP-ML. PMID:29562601

  11. Direct Position Determination of Unknown Signals in the Presence of Multipath Propagation

    Directory of Open Access Journals (Sweden)

    Jianping Du

    2018-03-01

    Full Text Available A novel geolocation architecture, termed “Multiple Transponders and Multiple Receivers for Multiple Emitters Positioning System (MTRE” is proposed in this paper. Existing Direct Position Determination (DPD methods take advantage of a rather simple channel assumption (line of sight channels with complex path attenuations and a simplified MUltiple SIgnal Classification (MUSIC algorithm cost function to avoid the high dimension searching. We point out that the simplified assumption and cost function reduce the positioning accuracy because of the singularity of the array manifold in a multi-path environment. We present a DPD model for unknown signals in the presence of Multi-path Propagation (MP-DPD in this paper. MP-DPD adds non-negative real path attenuation constraints to avoid the mistake caused by the singularity of the array manifold. The Multi-path Propagation MUSIC (MP-MUSIC method and the Active Set Algorithm (ASA are designed to reduce the dimension of searching. A Multi-path Propagation Maximum Likelihood (MP-ML method is proposed in addition to overcome the limitation of MP-MUSIC in the sense of a time-sensitive application. An iterative algorithm and an approach of initial value setting are given to make the MP-ML time consumption acceptable. Numerical results validate the performances improvement of MP-MUSIC and MP-ML. A closed form of the Cramér–Rao Lower Bound (CRLB is derived as a benchmark to evaluate the performances of MP-MUSIC and MP-ML.

  12. Brain serotonin signaling does not determine sexual preference in male mice.

    Directory of Open Access Journals (Sweden)

    Mariana Angoa-Pérez

    Full Text Available It was reported recently that male mice lacking brain serotonin (5-HT lose their preference for females (Liu et al., 2011, Nature, 472, 95-100, suggesting a role for 5-HT signaling in sexual preference. Regulation of sex preference by 5-HT lies outside of the well established roles in this behavior established for the vomeronasal organ (VNO and the main olfactory epithelium (MOE. Presently, mice with a null mutation in the gene for tryptophan hydroxylase 2 (TPH2, which are depleted of brain 5-HT, were tested for sexual preference. When presented with inanimate (urine scents from male or estrous female or animate (male or female mouse in estrus sexual stimuli, TPH2-/- males show a clear preference for female over male stimuli. When a TPH2-/- male is offered the simultaneous choice between an estrous female and a male mouse, no sexual preference is expressed. However, when confounding behaviors that are seen among 3 mice in the same cage are controlled, TPH2-/- mice, like their TPH2+/+ counterparts, express a clear preference for female mice. Female TPH2-/- mice are preferred by males over TPH2+/+ females but this does not lead to increased pregnancy success. In fact, if one or both partners in a mating pair are TPH2-/- in genotype, pregnancy success rates are significantly decreased. Finally, expression of the VNO-specific cation channel TRPC2 and of CNGA2 in the MOE of TPH2-/- mice is normal, consistent with behavioral findings that sexual preference of TPH2-/- males for females is intact. In conclusion, 5-HT signaling in brain does not determine sexual preference in male mice. The use of pharmacological agents that are non-selective for the 5-HT neuronal system and that have serious adverse effects may have contributed historically to the stance that 5-HT regulates sexual behavior, including sex partner preference.

  13. Processing and display of nuclear magnetism logging signals: application to residual oil determination

    International Nuclear Information System (INIS)

    Brown, R.J.S.; Neuman, C.H.

    1980-01-01

    A presentation is made of a series of computations and signal displays which help to show the nature of NML signals in general as well as to show the response to particular formation, hole, and tool conditions. Such processing of digitally recorded signals enables improved accuracy and bed resolution over that presented with the raw log. The treatment of drilling mud filtrate to eliminate NML signal from the brine phase in the invaded zone is described. Logs are shown as recorded before and after invasion of treated mud filtrate. This treatment causes the NML signal to correspond to residual oil only, enabling accurate and relatively inexpensive measurement of residual oil. 24 refs

  14. GPCR-Mediated Signaling of Metabolites

    DEFF Research Database (Denmark)

    Husted, Anna Sofie; Trauelsen, Mette; Rudenko, Olga

    2017-01-01

    microbiota target primarily enteroendocrine, neuronal, and immune cells in the lamina propria of the gut mucosa and the liver and, through these tissues, the rest of the body. In contrast, metabolites from the intermediary metabolism act mainly as metabolic stress-induced autocrine and paracrine signals...... and obesity. The concept of key metabolites as ligands for specific GPCRs has broadened our understanding of metabolic signaling significantly and provides a number of novel potential drug targets....

  15. Overview of frequency bandwidth determination techniques of useful signal in case of leaks detection by correlation method

    International Nuclear Information System (INIS)

    Faerman, V A; Avramchuk, V S; Luneva, E E

    2014-01-01

    In this paper an overview of useful signal detection methods on the background of intense noise and limits determination methods of useful signal is presented. The following features are considered: peculiarities of usage of correlation analysis, cross-amplitude spectrum, coherence function, cross-phase spectrum, time-frequency correlation function in case of frequency limits determination as well as leaks detection in pipelines. The possibility of using time-frequency correlation function for solving above named issues is described. Time- frequency correlation function provides information about the signals correlation for each of the investigated frequency bands. Data about location of peaks on the surface plot of a time- frequency correlation function allows making an assumption about the spectral composition of useful signal and its frequency boundaries

  16. Determination of the wavelength dependence of the differential pathlength factor from near-infrared pulse signals

    Science.gov (United States)

    Kohl, Matthias; Nolte, Christian; Heekeren, Hauke R.; Horst, Susanne; Scholz, Udo; Obrig, Hellmuth; Villringer, Arno

    1998-06-01

    For the calculation of changes in oxyhaemoglobin, deoxyhaemoglobin and the redox state of cytochrome-c-oxidase from attenuation data via a modified Beer-Lambert equation the wavelength dependence of the differential pathlength factor (DPF) has to be taken into account. The DPF, i.e. the ratio of the mean optical pathlength and the physical light source-detector separation at each wavelength, determines the crosstalk between the different concentrations and is therefore essential for a sensitive detection of chromophore changes. Here a simple method is suggested to estimate the wavelength dependence of the DPF from pulse-induced attenuation changes measured on the head of adult humans. The essence is that the DPF is the ratio of the attenuation changes over absorption coefficient changes, and that the spectral form of the pulse correlated absorption coefficient change can be assumed to be proportional to the extinction coefficient of blood. Indicators for the validity of the DPF derived for wavelengths between 700 and 970 nm are the stability of the calculated haemoglobin and cytochrome signals with variations of the wavelength range included for their calculation and its overall agreement with the data available from the literature.

  17. Analyzing surface EMG signals to determine relationship between jaw imbalance and arm strength loss

    Directory of Open Access Journals (Sweden)

    Truong Quang Dang Khoa

    2012-08-01

    Full Text Available Abstract Background This study investigated the relationship between dental occlusion and arm strength; in particular, the imbalance in the jaw can cause loss in arm strength phenomenon. One of the goals of this study was to record the maximum forces that the subjects can resist against the pull-down force on their hands while biting a spacer of adjustable height on the right or left side of the jaw. Then EMG measurement was used to determine the EMG-Force relationship of the jaw, neck and arms muscles. This gave us useful insights on the arms strength loss due to the biomechanical effects of the imbalance in the jaw mechanism. Methods In this study to determine the effects of the imbalance in the jaw to the strength of the arms, we conducted experiments with a pool of 20 healthy subjects of both genders. The subjects were asked to resist a pull down force applied on the contralateral arm while biting on a firm spacer using one side of the jaw. Four different muscles – masseter muscles, deltoid muscles, bicep muscles and trapezoid muscles – were involved. Integrated EMG (iEMG and Higuchi fractal dimension (HFD were used to analyze the EMG signals. Results The results showed that (1 Imbalance in the jaw causes loss of arm strength contra-laterally; (2 The loss is approximately a linear function of the height of the spacers. Moreover, the iEMG showed the intensity of muscle activities decreased when the degrees of jaw imbalance increased (spacer thickness increased. In addition, the tendency of Higuchi fractal dimension decreased for all muscles. Conclusions This finding indicates that muscle fatigue and the decrease in muscle contraction level leads to the loss of arm strength.

  18. Net Analyte Signal Standard Additions Method for Simultaneous Determination of Sulfamethoxazole and Trimethoprim in Pharmaceutical Formulations and Biological Fluids

    Directory of Open Access Journals (Sweden)

    M. H. Givianrad

    2012-01-01

    Full Text Available The applicability of a novel net analyte signal standard addition method (NASSAM to the resolving of overlapping spectra corresponding to the sulfamethoxazole and trimethoprim was verified by UV-visible spectrophotometry. The results confirmed that the net analyte signal standard additions method with simultaneous addition of both analytes is suitable for the simultaneous determination of sulfamethoxazole and trimethoprim in aqueous media. Moreover, applying the net analyte signal standard additions method revealed that the two drugs could be determined simultaneously with the concentration ratios of sulfamethoxazole to trimethoprim varying from 1:35 to 60:1 in the mixed samples. In addition, the limits of detections were 0.26 and 0.23 μmol L-1 for sulfamethoxazole and trimethoprim, respectively. The proposed method has been effectively applied to the simultaneous determination of sulfamethoxazole and trimethoprim in some synthetic, pharmaceutical formulation and biological fluid samples.

  19. Increased Paracrine Immunomodulatory Potential of Mesenchymal Stromal Cells in Three-Dimensional Culture

    DEFF Research Database (Denmark)

    Follin, Bjarke; Juhl, Morten; Cohen, Smadar

    2016-01-01

    Mesenchymal stromal/stem cells (MSCs) have been investigated extensively through the past years, proving to have great clinical therapeutic potential. In vitro cultivation of MSCs in three-dimensional (3D) culture systems, such as scaffolds, hydrogels, or spheroids, have recently gained attention...... for tissue engineering applications. Studies on MSC spheroids demonstrated that such cultivation increased the paracrine immunomodulatory potential of the MSCs, accompanied by phenotypic alterations. In this review, we gather results from recent experimental studies on the immunomodulatory abilities of MSCs...... when cultured as spheroids or in biomaterials like scaffolds or hydrogels compared to regular two-dimensional (2D) culture and show that alterations occurring to MSCs in spheroids also occur in MSCs in biomaterials. We provide a brief description of known mechanisms of MSC immunomodulatory capacity...

  20. Bone Marrow Stem Cell Derived Paracrine Factors for Regenerative Medicine: Current Perspectives and Therapeutic Potential

    Directory of Open Access Journals (Sweden)

    Tom J. Burdon

    2011-01-01

    Full Text Available During the past several years, there has been intense research in the field of bone marrow-derived stem cell (BMSC therapy to facilitate its translation into clinical setting. Although a lot has been accomplished, plenty of challenges lie ahead. Furthermore, there is a growing body of evidence showing that administration of BMSC-derived conditioned media (BMSC-CM can recapitulate the beneficial effects observed after stem cell therapy. BMSCs produce a wide range of cytokines and chemokines that have, until now, shown extensive therapeutic potential. These paracrine mechanisms could be as diverse as stimulating receptor-mediated survival pathways, inducing stem cell homing and differentiation or regulating the anti-inflammatory effects in wounded areas. The current review reflects the rapid shift of interest from BMSC to BMSC-CM to alleviate many logistical and technical issues regarding cell therapy and evaluates its future potential as an effective regenerative therapy.

  1. Paracrine Apoptotic Effect of p53 Mediated by Tumor Suppressor Par-4

    Directory of Open Access Journals (Sweden)

    Ravshan Burikhanov

    2014-01-01

    Full Text Available The guardian of the genome, p53, is often mutated in cancer and may contribute to therapeutic resistance. Given that p53 is intact and functional in normal tissues, we harnessed its potential to inhibit the growth of p53-deficient cancer cells. Specific activation of p53 in normal fibroblasts selectively induced apoptosis in p53-deficient cancer cells. This paracrine effect was mediated by p53-dependent secretion of the tumor suppressor Par-4. Accordingly, the activation of p53 in normal mice, but not p53−/− or Par-4−/− mice, caused systemic elevation of Par-4, which induced apoptosis of p53-deficient tumor cells. Mechanistically, p53 induced Par-4 secretion by suppressing the expression of its binding partner, UACA, which sequesters Par-4. Thus, normal cells can be empowered by p53 activation to induce Par-4 secretion for the inhibition of therapy-resistant tumors.

  2. Hyperplasia of epithelium adjacent to transitional cell carcinoma can be induced by growth factors through paracrine pathways

    NARCIS (Netherlands)

    W.I. de Boer (Pim); J.M.J. Rebel (Annemarie); C.D.E.M. Thijssen (C. D E M); M. Vermey; Th.H. van der Kwast (Theo); A.J.M. van den Eijnden-van Raaij (Janny)

    1994-01-01

    textabstractHyperplasia of transitional cell epithelium adjacent to human transitional cell carcinomas (TCC) is a common finding in pathology. This hyperplasia may be a precancerous aberration. Alternatively, it has been suggested that the hyperplasia is due to paracrine action of tumour-derived

  3. The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms.

    Science.gov (United States)

    Bavik, Claes; Coleman, Ilsa; Dean, James P; Knudsen, Beatrice; Plymate, Steven; Nelson, Peter S

    2006-01-15

    The greatest risk factor for developing carcinoma of the prostate is advanced age. Potential molecular and physiologic contributors to the frequency of cancer occurrence in older individuals include the accumulation of somatic mutations through defects in genome maintenance, epigenetic gene silencing, oxidative stress, loss of immune surveillance, telomere dysfunction, chronic inflammation, and alterations in tissue microenvironment. In this context, the process of prostate carcinogenesis can be influenced through interactions between intrinsic cellular alterations and the extrinsic microenvironment and macroenvironment, both of which change substantially as a consequence of aging. In this study, we sought to characterize the molecular alterations that occur during the process of prostate fibroblast senescence to identify factors in the aged tissue microenvironment capable of promoting the proliferation and potentially the neoplastic progression of prostate epithelium. We evaluated three mechanisms leading to cell senescence: oxidative stress, DNA damage, and replicative exhaustion. We identified a consistent program of gene expression that includes a subset of paracrine factors capable of influencing adjacent prostate epithelial growth. Both direct coculture and conditioned medium from senescent prostate fibroblasts stimulated epithelial cell proliferation, 3-fold and 2-fold, respectively. The paracrine-acting proteins fibroblast growth factor 7, hepatocyte growth factor, and amphiregulin (AREG) were elevated in the extracellular environment of senescent prostate fibroblasts. Exogenous AREG alone stimulated prostate epithelial cell growth, and neutralizing antibodies and small interfering RNA targeting AREG attenuated, but did not completely abrogate the growth-promoting effects of senescent fibroblast conditioned medium. These results support the concept that aging-related changes in the prostate microenvironment may contribute to the progression of prostate

  4. Molecular imaging of the paracrine proangiogenic effects of progenitor cell therapy in limb ischemia.

    Science.gov (United States)

    Ryu, Jae Choon; Davidson, Brian P; Xie, Aris; Qi, Yue; Zha, Daogang; Belcik, J Todd; Caplan, Evan S; Woda, Juliana M; Hedrick, Catherine C; Hanna, Richard N; Lehman, Nicholas; Zhao, Yan; Ting, Anthony; Lindner, Jonathan R

    2013-02-12

    Stem cells are thought to enhance vascular remodeling in ischemic tissue in part through paracrine effects. Using molecular imaging, we tested the hypothesis that treatment of limb ischemia with multipotential adult progenitor cells (MAPCs) promotes recovery of blood flow through the recruitment of proangiogenic monocytes. Hind-limb ischemia was produced in mice by iliac artery ligation, and MAPCs were administered intramuscularly on day 1. Optical imaging of luciferase-transfected MAPCs indicated that cells survived for 1 week. Contrast-enhanced ultrasound on days 3, 7, and 21 showed a more complete recovery of blood flow and greater expansion of microvascular blood volume in MAPC-treated mice than in controls. Fluorescent microangiography demonstrated more complete distribution of flow to microvascular units in MAPC-treated mice. On ultrasound molecular imaging, expression of endothelial P-selectin and intravascular recruitment of CX(3)CR-1-positive monocytes were significantly higher in MAPC-treated mice than in the control groups at days 3 and 7 after arterial ligation. Muscle immunohistology showed a >10-fold-greater infiltration of monocytes in MAPC-treated than control-treated ischemic limbs at all time points. Intravital microscopy of ischemic or tumor necrosis factor-α-treated cremaster muscle demonstrated that MAPCs migrate to perimicrovascular locations and potentiate selectin-dependent leukocyte rolling. In vitro migration of human CD14(+) monocytes was 10-fold greater in response to MAPC-conditioned than basal media. In limb ischemia, MAPCs stimulate the recruitment of proangiogenic monocytes through endothelial activation and enhanced chemotaxis. These responses are sustained beyond the MAPC lifespan, suggesting that paracrine effects promote flow recovery by rebalancing the immune response toward a more regenerative phenotype.

  5. Paracrine action of mesenchymal stromal cells delivered by microspheres contributes to cutaneous wound healing and prevents scar formation in mice.

    Science.gov (United States)

    Huang, Sha; Wu, Yan; Gao, Dongyun; Fu, Xiaobing

    2015-07-01

    Accumulating evidence suggests that mesenchymal stromal cells (MSCs) participate in wound healing to favor tissue regeneration and inhibit fibrotic tissue formation. However, the evidence of MSCs to suppress cutaneous scar is extremely rare, and the mechanism remains unidentified. This study aimed to demonstrate whether MSCs-as the result of their paracrine actions on damaged tissues-would accelerate wound healing and prevent cutaneous fibrosis. For efficient delivery of MSCs to skin wounds, microspheres were used to maintain MSC potency. Whether MSCs can accelerate wound healing and alleviate cutaneous fibrosis through paracrine action was investigated with the use of a Transwell co-culture system in vitro and a murine model in vivo. MSCs cultured on gelatin microspheres fully retained their cell surface marker expression profile, proliferation, differentiation and paracrine potential. Co-cultures of MSCs and fibroblasts indicated that the benefits of MSCs on suppressing fibroblast proliferation and its fibrotic behavior induced by inflammatory cytokines probably were caused by paracrine actions. Importantly, microspheres successfully delivered MSCs into wound margins and significantly accelerated wound healing and concomitantly reduced the fibrotic activities of cells within the wounds and excessive accumulation of extracellular matrix as well as the transforming growth factor-β1/transforming growth factor-β3 ratio. This study provides insight into what we believe to be a previously undescribed, multifaceted role of MSC-released protein in reducing cutaneous fibrotic formation. Paracrine action of MSCs delivered by microspheres may thus qualify as a promising strategy to enhance tissue repair and to prevent excessive fibrosis during cutaneous wound healing. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  6. Substance P enhances proliferation and paracrine potential of adipose-derived stem cells in vitro

    International Nuclear Information System (INIS)

    Kim, Suna; Piao, Jiyuan; Son, Youngsook; Hong, Hyun Sook

    2017-01-01

    Stem cells have tremendous promise to treat intractable diseases. Notably, adipose-derived stem cells (ADSCs) are actively being investigated because of ease of sampling and high repopulation capacity in vitro. ADSCs can exert a therapeutic effect through differentiation and paracrine potential, and these actions have been proven in many diseases, including cutaneous and inflammatory diseases. Transplantation of ADSCs necessitates therapeutic quantities and thus, long term ex vivo culture of ADSCs. However, this procedure can impair the activity of ADSCs and provoke cellular senescence, leading to low efficacy in vivo. Accordingly, strategies to restore cellular activity and inhibit senescence of stem cells during ex vivo culture are needed for stem cell-based therapies. This study evaluated a potential supplementary role of Substance P (SP) in ADSC ex vivo culture. After confirming that the ADSC cell cycle was damaged by passage 6 (p6), ADSCs at p6 were cultured with SP, and their proliferation rates, cumulative cell numbers, cytokine profiles, and impact on T/endothelial cells were assessed. Long-term culture weakened proliferation ability and secretion of the cytokines, transforming growth factor-beta 1 (TGF-beta1), vascular endothelial growth factor (VEGF), and stromal cell derived factor-1 alpha (SDF-1alpha) in ADSCs. However, SP treatment reduced the population doubling time (PDT), enabling gain of a sufficient number of ADSCs at early passages. In addition, SP restored cytokine secretion, enhancing the ADSC-mediated paracrine effect on T cell and human umbilical vein endothelial cells (HUVECs). Taken together, these results suggest that SP can retain the therapeutic effect of ADSCs by elevating their proliferative and paracrine potential in ex vivo culture. - Highlights: • Long-term culture of ADSCs leads to cell senescence. • Paracrine potential of ADSC decreases as passage number increases. • SP enhances the weakened proliferation capacity of

  7. Intra-Tumour Signalling Entropy Determines Clinical Outcome in Breast and Lung Cancer

    Science.gov (United States)

    Banerji, Christopher R. S.; Severini, Simone; Caldas, Carlos; Teschendorff, Andrew E.

    2015-01-01

    The cancer stem cell hypothesis, that a small population of tumour cells are responsible for tumorigenesis and cancer progression, is becoming widely accepted and recent evidence has suggested a prognostic and predictive role for such cells. Intra-tumour heterogeneity, the diversity of the cancer cell population within the tumour of an individual patient, is related to cancer stem cells and is also considered a potential prognostic indicator in oncology. The measurement of cancer stem cell abundance and intra-tumour heterogeneity in a clinically relevant manner however, currently presents a challenge. Here we propose signalling entropy, a measure of signalling pathway promiscuity derived from a sample’s genome-wide gene expression profile, as an estimate of the stemness of a tumour sample. By considering over 500 mixtures of diverse cellular expression profiles, we reveal that signalling entropy also associates with intra-tumour heterogeneity. By analysing 3668 breast cancer and 1692 lung adenocarcinoma samples, we further demonstrate that signalling entropy correlates negatively with survival, outperforming leading clinical gene expression based prognostic tools. Signalling entropy is found to be a general prognostic measure, valid in different breast cancer clinical subgroups, as well as within stage I lung adenocarcinoma. We find that its prognostic power is driven by genes involved in cancer stem cells and treatment resistance. In summary, by approximating both stemness and intra-tumour heterogeneity, signalling entropy provides a powerful prognostic measure across different epithelial cancers. PMID:25793737

  8. Intra-tumour signalling entropy determines clinical outcome in breast and lung cancer.

    Directory of Open Access Journals (Sweden)

    Christopher R S Banerji

    2015-03-01

    Full Text Available The cancer stem cell hypothesis, that a small population of tumour cells are responsible for tumorigenesis and cancer progression, is becoming widely accepted and recent evidence has suggested a prognostic and predictive role for such cells. Intra-tumour heterogeneity, the diversity of the cancer cell population within the tumour of an individual patient, is related to cancer stem cells and is also considered a potential prognostic indicator in oncology. The measurement of cancer stem cell abundance and intra-tumour heterogeneity in a clinically relevant manner however, currently presents a challenge. Here we propose signalling entropy, a measure of signalling pathway promiscuity derived from a sample's genome-wide gene expression profile, as an estimate of the stemness of a tumour sample. By considering over 500 mixtures of diverse cellular expression profiles, we reveal that signalling entropy also associates with intra-tumour heterogeneity. By analysing 3668 breast cancer and 1692 lung adenocarcinoma samples, we further demonstrate that signalling entropy correlates negatively with survival, outperforming leading clinical gene expression based prognostic tools. Signalling entropy is found to be a general prognostic measure, valid in different breast cancer clinical subgroups, as well as within stage I lung adenocarcinoma. We find that its prognostic power is driven by genes involved in cancer stem cells and treatment resistance. In summary, by approximating both stemness and intra-tumour heterogeneity, signalling entropy provides a powerful prognostic measure across different epithelial cancers.

  9. Assessing the osteoblast transcriptome in a model of enhanced bone formation due to constitutive G{sub s}–G protein signaling in osteoblasts

    Energy Technology Data Exchange (ETDEWEB)

    Wattanachanya, Lalita, E-mail: lalita_md@yahoo.com [Endocrine Research Unit, Veterans Affairs Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, CA (United States); Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok (Thailand); Wang, Liping, E-mail: lipingwang05@yahoo.com [Endocrine Research Unit, Veterans Affairs Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, CA (United States); Millard, Susan M., E-mail: susan.millard@mater.uq.edu.au [Endocrine Research Unit, Veterans Affairs Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, CA (United States); Lu, Wei-Dar, E-mail: weidar_lu@yahoo.com [Endocrine Research Unit, Veterans Affairs Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, CA (United States); O’Carroll, Dylan, E-mail: dylancocarroll@gmail.com [Endocrine Research Unit, Veterans Affairs Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, CA (United States); Hsiao, Edward C., E-mail: Edward.Hsiao@ucsf.edu [Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, CA (United States); Conklin, Bruce R., E-mail: bconklin@gladstone.ucsf.edu [Gladstone Institute of Cardiovascular Disease, San Francisco, CA (United States); Department of Medicine, University of California, San Francisco, CA (United States); Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA (United States); Nissenson, Robert A., E-mail: Robert.Nissenson@ucsf.edu [Endocrine Research Unit, Veterans Affairs Medical Center and Departments of Medicine and Physiology, University of California, San Francisco, CA (United States)

    2015-05-01

    G protein-coupled receptor (GPCR) signaling in osteoblasts (OBs) is an important regulator of bone formation. We previously described a mouse model expressing Rs1, an engineered constitutively active G{sub s}-coupled GPCR, under the control of the 2.3 kb Col I promoter. These mice showed a dramatic age-dependent increase in trabecular bone of femurs. Here, we further evaluated the effects of enhanced G{sub s} signaling in OBs on intramembranous bone formation by examining calvariae of 1- and 9-week-old Col1(2.3)/Rs1 mice and characterized the in vivo gene expression specifically occurring in osteoblasts with activated G{sub s} G protein-coupled receptor signaling, at the cellular level rather than in a whole bone. Rs1 calvariae displayed a dramatic increase in bone volume with partial loss of cortical structure. By immunohistochemistry, Osterix was detected in cells throughout the inter-trabecular space while Osteocalcin was expressed predominantly in cells along bone surfaces, suggesting the role of paracrine mediators secreted from OBs driven by 2.3 kb Col I promoter could influence early OB commitment, differentiation, and/or proliferation. Gene expression analysis of calvarial OBs revealed that genes affected by Rs1 signaling include those encoding proteins important for cell differentiation, cytokines and growth factors, angiogenesis, coagulation, and energy metabolism. The set of G{sub s}-GPCRs and other GPCRs that may contribute to the observed skeletal phenotype and candidate paracrine mediators of the effect of G{sub s} signaling in OBs were also determined. Our results identify novel detailed in vivo cellular changes of the anabolic response of the skeleton to G{sub s} signaling in mature OBs. - Highlights: • OB expression of an engineered G{sub s}-coupled receptor dramatically increases bone mass. • We investigated the changes in gene expression in vivo in enhanced OB G{sub s} signaling. • Genes in cell cycle and transcription were increased in

  10. Determinants of cell-to-cell variability in protein kinase signaling.

    Science.gov (United States)

    Jeschke, Matthias; Baumgärtner, Stephan; Legewie, Stefan

    2013-01-01

    Cells reliably sense environmental changes despite internal and external fluctuations, but the mechanisms underlying robustness remain unclear. We analyzed how fluctuations in signaling protein concentrations give rise to cell-to-cell variability in protein kinase signaling using analytical theory and numerical simulations. We characterized the dose-response behavior of signaling cascades by calculating the stimulus level at which a pathway responds ('pathway sensitivity') and the maximal activation level upon strong stimulation. Minimal kinase cascades with gradual dose-response behavior show strong variability, because the pathway sensitivity and the maximal activation level cannot be simultaneously invariant. Negative feedback regulation resolves this trade-off and coordinately reduces fluctuations in the pathway sensitivity and maximal activation. Feedbacks acting at different levels in the cascade control different aspects of the dose-response curve, thereby synergistically reducing the variability. We also investigated more complex, ultrasensitive signaling cascades capable of switch-like decision making, and found that these can be inherently robust to protein concentration fluctuations. We describe how the cell-to-cell variability of ultrasensitive signaling systems can be actively regulated, e.g., by altering the expression of phosphatase(s) or by feedback/feedforward loops. Our calculations reveal that slow transcriptional negative feedback loops allow for variability suppression while maintaining switch-like decision making. Taken together, we describe design principles of signaling cascades that promote robustness. Our results may explain why certain signaling cascades like the yeast pheromone pathway show switch-like decision making with little cell-to-cell variability.

  11. Determinants of cell-to-cell variability in protein kinase signaling.

    Directory of Open Access Journals (Sweden)

    Matthias Jeschke

    Full Text Available Cells reliably sense environmental changes despite internal and external fluctuations, but the mechanisms underlying robustness remain unclear. We analyzed how fluctuations in signaling protein concentrations give rise to cell-to-cell variability in protein kinase signaling using analytical theory and numerical simulations. We characterized the dose-response behavior of signaling cascades by calculating the stimulus level at which a pathway responds ('pathway sensitivity' and the maximal activation level upon strong stimulation. Minimal kinase cascades with gradual dose-response behavior show strong variability, because the pathway sensitivity and the maximal activation level cannot be simultaneously invariant. Negative feedback regulation resolves this trade-off and coordinately reduces fluctuations in the pathway sensitivity and maximal activation. Feedbacks acting at different levels in the cascade control different aspects of the dose-response curve, thereby synergistically reducing the variability. We also investigated more complex, ultrasensitive signaling cascades capable of switch-like decision making, and found that these can be inherently robust to protein concentration fluctuations. We describe how the cell-to-cell variability of ultrasensitive signaling systems can be actively regulated, e.g., by altering the expression of phosphatase(s or by feedback/feedforward loops. Our calculations reveal that slow transcriptional negative feedback loops allow for variability suppression while maintaining switch-like decision making. Taken together, we describe design principles of signaling cascades that promote robustness. Our results may explain why certain signaling cascades like the yeast pheromone pathway show switch-like decision making with little cell-to-cell variability.

  12. LIF-activated Jak signaling determines Esrrb expression during late-stage reprogramming

    Directory of Open Access Journals (Sweden)

    Delun Huang

    2018-01-01

    Full Text Available The regulatory process of naïve-state induced pluripotent stem cell (iPSC generation is not well understood. Leukemia inhibitory factor (LIF-activated Janus kinase/signal transducer and activator of transcription 3 (Jak/Stat3 is the master regulator for naïve-state pluripotency achievement and maintenance. The estrogen-related receptor beta (Esrrb serves as a naïve-state marker gene regulating self-renewal of embryonic stem cells (ESCs. However, the interconnection between Esrrb and LIF signaling for pluripotency establishment in reprogramming is unclear. We screened the marker genes critical for complete reprogramming during mouse iPSC generation, and identified genes including Esrrb that are responsive to LIF/Jak pathway signaling. Overexpression of Esrrb resumes the reprogramming halted by inhibition of Jak activity in partially reprogrammed cells (pre-iPSCs, and leads to the generation of pluripotent iPSCs. We further show that neither overexpression of Nanog nor stimulation of Wnt signaling, two upstream regulators of Esrrb in ESCs, stimulates the expression of Esrrb in reprogramming when LIF or Jak activity is blocked. Our study demonstrates that Esrrb is a specific reprogramming factor regulated downstream of the LIF/Jak signaling pathway. These results shed new light on the regulatory role of LIF pathway on complete pluripotency establishment during iPSC generation.

  13. Equivalent dose determination in foraminifera: analytical description of the CO2--signal dose-response curve

    International Nuclear Information System (INIS)

    Hoffmann, D.; Woda, C.; Mangini, A.

    2003-01-01

    The dose-response of the CO 2 - signal (g=2.0006) in foraminifera with ages between 19 and 300 ka is investigated. The sum of two exponential saturation functions is an adequate function to describe the dose-response curve up to an additional dose of 8000 Gy. It yields excellent dating results but requires an artificial doses of at least 5000 Gy. For small additional doses of about 500 Gy the single exponential saturation function can be used to calculate a reliable equivalent dose D E , although it does not describ the dose-response for higher doses. The CO 2 - -signal dose-response indicates that the signal has two components of which one is less stable than the other

  14. Determination of Lineaments of the Sea of Marmara using Normalized Derivatives and Analytic Signals

    International Nuclear Information System (INIS)

    Oruc, B.

    2007-01-01

    The normalized derivatives and analytic signals calculated from magnetic anomaly map present useful results for the structural interpretation. The effectiveness of the methods on the solutions of lineaments has been tested for the edges of the thin-plate model. In the field data, magnetic anomaly map observed in the middle section of Marmara Sea has been used. The approximate solutions have been obtained for the lineaments of the area related in North Anatolia Fault from the characteristic images of the normalized derivatives and horizontal derivative analytic signals

  15. The Role of Retinal Determination Gene Network (RDGN) in Hormone Signaling Transduction and Prostate Tumorigenesis

    Science.gov (United States)

    2012-10-01

    PI3K/ Akt and MAPK/Erk signaling. We identified the A-type cyclin, cyclin A1 as an important downstream target of PI3K/ Akt (59); 3) autocrine IL-6...DACH1 inhibits transforming growth factor-beta signaling through binding Smad4 . J Biol Chem. 2003; 278(51):51673- 84. 33. Le Grand F, Grifone R, Mourikis...androgen receptor. Endocr Relat Cancer. 2009; 16(1):155-69. 59. Wegiel B, Bjartell A, Culig Z, Persson JL. Interleukin-6 activates PI3K/ Akt pathway

  16. Cytoplasmic organelles determine complexity and specificity of calcium signalling in adrenal chromaffin cells

    Czech Academy of Sciences Publication Activity Database

    Garsia-Sancho, J.; Verkhratsky, Alexei

    2008-01-01

    Roč. 192, č. 2 (2008), s. 263-271 ISSN 1748-1708 Institutional research plan: CEZ:AV0Z50390512 Keywords : Ca2+ signalling * calcium microdomains * chromaffin cells Subject RIV: JE - Non-nuclear Energetics, Energy Consumption ; Use Impact factor: 2.455, year: 2008

  17. Biochar and microbial signaling: production conditions determine effects on microbial communication

    Science.gov (United States)

    Masiello, Caroline A.; Chen, Ye; Gao, Xiaodong; Liu, Shirley; Cheng, Hsiao-Ying; Bennett, Matthew R.; Rudgers, Jennifer A.; Wagner, Daniel S.; Zygourakis, Kyriacos; Silberg, Jonathan J.

    2013-01-01

    Charcoal has a long soil residence time, which has resulted in its production and use as a carbon sequestration technique (biochar). A range of biological effects can be triggered by soil biochar that can positively and negatively influence carbon storage, such as changing the decomposition rate of organic matter and altering plant biomass production. Sorption of cellular signals has been hypothesized to underlie some of these effects, but it remains unknown whether the binding of biochemical signals occurs, and if so, on time scales relevant to microbial growth and communication. We examined biochar sorption of N-3-oxo-dodecanoyl-L-homoserine lactone, an acyl-homoserine lactone (AHL) intercellular signaling molecule used by many gram-negative soil microbes to regulate gene expression. We show that wood biochars disrupt communication within a growing multicellular system that is made up of sender cells that synthesize AHL and receiver cells that express green fluorescent protein in response to an AHL signal. However, biochar inhibition of AHL-mediated cell-cell communication varied, with the biochar prepared at 700°C (surface area of 301 m2/g) inhibiting cellular communication 10-fold more than an equivalent mass of biochar prepared at 300°C (surface area of 3 m2/g). These findings provide the first direct evidence that biochars elicit a range of effects on gene expression dependent on intercellular signaling, implicating the method of biochar preparation as a parameter that could be tuned to regulate microbial-dependent soil processes, like nitrogen fixation and pest attack of root crops. PMID:24066613

  18. Biochar and microbial signaling: production conditions determine effects on microbial communication.

    Science.gov (United States)

    Masiello, Caroline A; Chen, Ye; Gao, Xiaodong; Liu, Shirley; Cheng, Hsiao-Ying; Bennett, Matthew R; Rudgers, Jennifer A; Wagner, Daniel S; Zygourakis, Kyriacos; Silberg, Jonathan J

    2013-10-15

    Charcoal has a long soil residence time, which has resulted in its production and use as a carbon sequestration technique (biochar). A range of biological effects can be triggered by soil biochar that can positively and negatively influence carbon storage, such as changing the decomposition rate of organic matter and altering plant biomass production. Sorption of cellular signals has been hypothesized to underlie some of these effects, but it remains unknown whether the binding of biochemical signals occurs, and if so, on time scales relevant to microbial growth and communication. We examined biochar sorption of N-3-oxo-dodecanoyl-L-homoserine lactone, an acyl-homoserine lactone (AHL) intercellular signaling molecule used by many gram-negative soil microbes to regulate gene expression. We show that wood biochars disrupt communication within a growing multicellular system that is made up of sender cells that synthesize AHL and receiver cells that express green fluorescent protein in response to an AHL signal. However, biochar inhibition of AHL-mediated cell-cell communication varied, with the biochar prepared at 700 °C (surface area of 301 m(2)/g) inhibiting cellular communication 10-fold more than an equivalent mass of biochar prepared at 300 °C (surface area of 3 m(2)/g). These findings provide the first direct evidence that biochars elicit a range of effects on gene expression dependent on intercellular signaling, implicating the method of biochar preparation as a parameter that could be tuned to regulate microbial-dependent soil processes, like nitrogen fixation and pest attack of root crops.

  19. A threshold model for receptor tyrosine kinase signaling specificity and cell fate determination [version 1; referees: 4 approved

    Directory of Open Access Journals (Sweden)

    Allen Zinkle

    2018-06-01

    Full Text Available Upon ligand engagement, the single-pass transmembrane receptor tyrosine kinases (RTKs dimerize to transmit qualitatively and quantitatively different intracellular signals that alter the transcriptional landscape and thereby determine the cellular response. The molecular mechanisms underlying these fundamental events are not well understood. Considering recent insights into the structural biology of fibroblast growth factor signaling, we propose a threshold model for RTK signaling specificity in which quantitative differences in the strength/longevity of ligand-induced receptor dimers on the cell surface lead to quantitative differences in the phosphorylation of activation loop (A-loop tyrosines as well as qualitative differences in the phosphorylation of tyrosines mediating substrate recruitment. In this model, quantitative differences on A-loop tyrosine phosphorylation result in gradations in kinase activation, leading to the generation of intracellular signals of varying amplitude/duration. In contrast, qualitative differences in the pattern of tyrosine phosphorylation on the receptor result in the recruitment/activation of distinct substrates/intracellular pathways. Commensurate with both the dynamics of the intracellular signal and the types of intracellular pathways activated, unique transcriptional signatures are established. Our model provides a framework for engineering clinically useful ligands that can tune receptor dimerization stability so as to bias the cellular transcriptome to achieve a desired cellular output.

  20. Interplay between Dioxin-Mediated Signaling and Circadian Clock: A Possible Determinant in Metabolic Homeostasis

    Directory of Open Access Journals (Sweden)

    Chun Wang

    2014-07-01

    Full Text Available The rotation of the earth on its axis creates the environment of a 24 h solar day, which organisms on earth have used to their evolutionary advantage by integrating this timing information into their genetic make-up in the form of a circadian clock. This intrinsic molecular clock is pivotal for maintenance of synchronized homeostasis between the individual organism and the external environment to allow coordinated rhythmic physiological and behavioral function. Aryl hydrocarbon receptor (AhR is a master regulator of dioxin-mediated toxic effects, and is, therefore, critical in maintaining adaptive responses through regulating the expression of phase I/II drug metabolism enzymes. AhR expression is robustly rhythmic, and physiological cross-talk between AhR signaling and circadian rhythms has been established. Increasing evidence raises a compelling argument that disruption of endogenous circadian rhythms contributes to the development of disease, including sleep disorders, metabolic disorders and cancers. Similarly, exposure to environmental pollutants through air, water and food, is increasingly cited as contributory to these same problems. Thus, a better understanding of interactions between AhR signaling and the circadian clock regulatory network can provide critical new insights into environmentally regulated disease processes. This review highlights recent advances in the understanding of the reciprocal interactions between dioxin-mediated AhR signaling and the circadian clock including how these pathways relate to health and disease, with emphasis on the control of metabolic function.

  1. Carvacrol promotes angiogenic paracrine potential and endothelial differentiation of human mesenchymal stem cells at low concentrations.

    Science.gov (United States)

    Matluobi, Danial; Araghi, Atefeh; Maragheh, Behnaz Faramarzian Azimi; Rezabakhsh, Aysa; Soltani, Sina; Khaksar, Majid; Siavashi, Vahid; Feyzi, Adel; Bagheri, Hesam Saghaei; Rahbarghazi, Reza; Montazersaheb, Soheila

    2018-01-01

    Phenolic monoterpene compound, named Carvacrol, has been found to exert different biological outcomes. It has been accepted that the angiogenic activity of human mesenchymal stem cells was crucial in the pursuit of appropriate regeneration. In the current experiment, we investigated the contribution of Carvacrol on the angiogenic behavior of primary human mesenchymal stem cells. Mesenchymal stem cells were exposed to Carvacrol in a dose ranging from 25 to 200μM for 48h. We measured cell survival rate by MTT assay and migration rate by a scratch test. The oxidative status was monitored by measuring SOD, GPx activity. The endothelial differentiation was studied by evaluating the level of VE-cadherin and vWF by real-time PCR and ELISA analyses. The content of VEGF and tubulogenesis behavior was monitored in vitro. We also conducted Matrigel plug in vivo CAM assay to assess the angiogenic potential of conditioned media from human mesenchymal stem cells after exposure to Carvacrol. Carvacrol was able to increase mesenchymal stem cell survival and migration rate (pcells by detecting vWF and VE-cadherin expression (pmesenchymal stem cells conditioned media improved angiogenesis tube formation in vitro (pmesenchymal stem cells by modulating cell differentiation and paracrine angiogenic response. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Paracrine interactions of cancer-associated fibroblasts, macrophages and endothelial cells: tumor allies and foes.

    Science.gov (United States)

    Ronca, Roberto; Van Ginderachter, Jo A; Turtoi, Andrei

    2018-01-01

    Tumor stroma is composed of many cellular subtypes, of which the most abundant are fibroblasts, macrophages and endothelial cells. During the process of tissue injury, these three cellular subtypes must coordinate their activity to efficiently contribute to tissue regeneration. In tumor, this mechanism is hijacked by cancer cells, which rewire the interaction of stromal cells to benefit tumor development. The present review aims at summarizing most relevant information concerning both pro-tumorigenic and anti-tumorigenic actions implicating the three stromal cell subtypes as well as their mutual interactions. Although stromal cells are generally regarded as tumor-supportive and at will manipulated by cancer cells, several novel studies point at many defaults in cancer cell-mediated stromal reprograming. Indeed, parts of initial tissue-protective and homeostatic functions of the stromal cells remain in place even after tumor development. Both tumor-supportive and tumor-suppressive functions have been well described for macrophages, whereas similar results are emerging for fibroblasts and endothelial cells. Recent success of immunotherapies have finally brought the long awaited proof that stroma is key for efficient tumor targeting. However, a better understanding of paracrine stromal interactions is needed in order to encourage drug development not only aiming at disruption of tumor-supportive communication but also re-enforcing, existing, tumor-suppressive mechanisms.

  3. MCP-1 expressed by osteoclasts stimulates osteoclastogenesis in an autocrine/paracrine manner

    International Nuclear Information System (INIS)

    Miyamoto, Kana; Ninomiya, Ken; Sonoda, Koh-Hei; Miyauchi, Yoshiteru; Hoshi, Hiroko; Iwasaki, Ryotaro; Miyamoto, Hiroya

    2009-01-01

    Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that plays a critical role in the recruitment and activation of leukocytes. Here, we describe that multinuclear osteoclast formation was significantly inhibited in cells derived from MCP-1-deficient mice. MCP-1 has been implicated in the regulation of osteoclast cell-cell fusion; however defects of multinuclear osteoclast formation in the cells from mice deficient in DC-STAMP, a seven transmembrane receptor essential for osteoclast cell-cell fusion, was not rescued by recombinant MCP-1. The lack of MCP-1 in osteoclasts resulted in a down-regulation of DC-STAMP, NFATc1, and cathepsin K, all of which were highly expressed in normal osteoclasts, suggesting that osteoclast differentiation was inhibited in MCP-1-deficient cells. MCP-1 alone did not induce osteoclastogenesis, however, the inhibition of osteoclastogenesis in MCP-1-deficient cells was restored by addition of recombinant MCP-1, indicating that osteoclastogenesis was regulated in an autocrine/paracrine manner by MCP-1 under the stimulation of RANKL in osteoclasts.

  4. Determination of pseudo multi-pulse production rate in GM counters by correlation analysis between signal pulses

    International Nuclear Information System (INIS)

    Hashimoto, Kengo; Ueda, Taizou

    1996-01-01

    A technique, based on the correlation analysis of signal pulses in time sequence, is proposed to determine the production rate of the pseudo multi-pulse in Geiger-Mueller (GM) counter. With a multi-channel scaler initiated by a signal pulse, subsequent pulses are recorded in sequence. The production of the multi-pulse increases the counting probability immediately after the initiation. By examining the deviation of the measured probability from the ideal counting probability, the production rate and the average lag time to produce the multi-pulse can be determined. By the use of the present technique, the production rate and the average lag time were obtained for the various GM tubes. These results indicate that the consumption of the quench gas results in a significant increase in the production rate but little variation in the lag time, and that the lag time strongly depends on the tube diameter. (author)

  5. Paracrine effects of bone marrow-derived endothelial progenitor cells: cyclooxygenase-2/prostacyclin pathway in pulmonary arterial hypertension.

    Directory of Open Access Journals (Sweden)

    Dong-Mei Jiang

    Full Text Available BACKGROUND: Endothelial dysfunction is the pathophysiological characteristic of pulmonary arterial hypertension (PAH. Some paracrine factors secreted by bone marrow-derived endothelial progenitor cells (BMEPCs have the potential to strengthen endothelial integrity and function. This study investigated whether BMEPCs have the therapeutic potential to improve monocrotaline (MCT-induced PAH via producing vasoprotective substances in a paracrine fashion. METHODS AND RESULTS: Bone marrow-derived mononuclear cells were cultured for 7 days to yield BMEPCs. 24 hours or 3 weeks after exposure to BMEPCs in vitro or in vivo, the vascular reactivity, cyclooxygenase-2 (COX-2 expression, prostacyclin (PGI2 and cAMP release in isolated pulmonary arteries were examined respectively. Treatment with BMEPCs could improve the relaxation of pulmonary arteries in MCT-induced PAH and BMEPCs were grafted into the pulmonary bed. The COX-2/prostacyclin synthase (PGIS and its progenies PGI2/cAMP were found to be significantly increased in BMEPCs treated pulmonary arteries, and this action was reversed by a selective COX-2 inhibitor, NS398. Moreover, the same effect was also observed in conditioned medium obtained from BMEPCs culture. CONCLUSIONS: Implantation of BMEPCs effectively ameliorates MCT-induced PAH. Factors secreted in a paracrine fashion from BMEPCs promote vasoprotection by increasing the release of PGI2 and level of cAMP.

  6. Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance.

    Science.gov (United States)

    Bertolino, Alessandro; Taurisano, Paolo; Pisciotta, Nicola Marco; Blasi, Giuseppe; Fazio, Leonardo; Romano, Raffaella; Gelao, Barbara; Lo Bianco, Luciana; Lozupone, Madia; Di Giorgio, Annabella; Caforio, Grazia; Sambataro, Fabio; Niccoli-Asabella, Artor; Papp, Audrey; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadee, Wolfgang; Rubini, Giuseppe

    2010-02-22

    Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway.

  7. Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance.

    Directory of Open Access Journals (Sweden)

    Alessandro Bertolino

    2010-02-01

    Full Text Available Variation of the gene coding for D2 receptors (DRD2 has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560 predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic and D2L (mainly post-synaptic. However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known.Thirty-seven healthy subjects were genotyped for rs1076560 (G>T and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors, as well as BOLD fMRI during N-Back working memory.Subjects carrying the T allele (previously associated with reduced D2S expression had striatal reductions of [123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT.Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic-cortical pathway.

  8. The Role of Retinal Determination Gene Network (RDGN) in Hormone Signaling Transduction and Prostate Tumorigenesis

    Science.gov (United States)

    2013-10-01

    Wu K, Wang L, Jiao X, Ju X, Li Z, Ertel A, Addya S, McCue P, Lisanti MP, Wang C, Davis RJ, Mardon G, Pestell RG. Androgen therapy resistant...Li Z, Hu J, Chen K, Wu J, Pestell RG. DACH1 inhibited prostate cancer cellular proliferation and Interleukon-6 signaling. AACR 103rd Annual Meeting...March 31 – April 4, 2012, Chicago, IL.  Wang J, Cai S, Chen K, Sun Y, Li S, Pestell RG, Wu K. Regulation of AR transcriptional activity and

  9. Structural and functional mapping of Rtg2p determinants involved in retrograde signaling and aging of Saccharomyces cerevisiae.

    Directory of Open Access Journals (Sweden)

    Rafaela Maria Rios-Anjos

    Full Text Available In Saccharomyces cerevisiae mitochondrial dysfunction induces retrograde signaling, a pathway of communication from mitochondria to the nucleus that promotes a metabolic remodeling to ensure sufficient biosynthetic precursors for replication. Rtg2p is a positive modulator of this pathway that is also required for cellular longevity. This protein belongs to the ASKHA superfamily, and contains a putative N-terminal ATP-binding domain, but there is no detailed structural and functional map of the residues in this domain that accounts for their contribution to retrograde signaling and aging. Here we use Decomposition of Residue Correlation Networks and site-directed mutagenesis to identify Rtg2p structural determinants of retrograde signaling and longevity. We found that most of the residues involved in retrograde signaling surround the ATP-binding loops, and that Rtg2p N-terminus is divided in three regions whose mutants have different aging phenotypes. We also identified E137, D158 and S163 as possible residues involved in stabilization of ATP at the active site. The mutants shown here may be used to map other Rtg2p activities that crosstalk to other pathways of the cell related to genomic stability and aging.

  10. Theoretical Study of Molecular Determinants Involved in Signal Binding to the TraR Protein of Agrobacterium tumefaciens

    Directory of Open Access Journals (Sweden)

    N. Kumar

    2005-10-01

    Full Text Available N-acylated homoserine lactone (AHL mediated cell-cell communication in bacteria is dependent on the recognition of the cognate signal by its receptor. This interaction allows the receptor-ligand complex to act as a transcriptional activator, controlling the expression of a range of bacterial phenotypes, including virulence factor expression and biofilm formation. One approach to determine the key features of signal- binding is to model the intermolecular interactions between the receptor and ligand using computational-based modeling software (LigandFit. In this communication, we have modeled the crystal structure of the AHL receptor protein TraR and its AHL signal N-(3- oxooctanoyl-homoserine lactone from Agrobacterium tumefaciens and compared it to the previously reported antagonist behaviour of a number of AHL analogues, in an attempt to determine structural constraints for ligand binding. We conclude that (i a common conformation of the AHL in the hydrophobic and hydrophilic region exists for ligand-binding, (ii a tail chain length threshold of 8 carbons is most favourable for ligand-binding affinity, (iii the positive correlation in the docking studies could be used a virtual screening tool.

  11. Stimulated human mast cells secrete mitochondrial components that have autocrine and paracrine inflammatory actions.

    Directory of Open Access Journals (Sweden)

    Bodi Zhang

    Full Text Available Mast cells are hematopoietically-derived tissue immune cells that participate in acquired and innate immunity, as well as in inflammation through release of many chemokines and cytokines, especially in response to the pro-inflammatory peptide substance P (SP. Inflammation is critical in the pathogenesis of many diseases, but the trigger(s is often unknown. We investigated if mast cell stimulation leads to secretion of mitochondrial components and whether these could elicit autocrine and/or paracrine inflammatory effects. Here we show that human LAD2 mast cells stimulated by IgE/anti-IgE or by the SP led to secretion of mitochondrial particles, mitochondrial (mt mtDNA and ATP without cell death. Mitochondria purified from LAD2 cells and, when mitochondria added to mast cells trigger degranulation and release of histamine, PGD(2, IL-8, TNF, and IL-1β. This stimulatory effect is partially inhibited by an ATP receptor antagonist and by DNAse. These results suggest that the mitochondrial protein fraction may also contribute. Purified mitochondria also stimulate IL-8 and vascular endothelial growth factor (VEGF release from cultured human keratinocytes, and VEGF release from primary human microvascular endothelial cells. In order to investigate if mitochondrial components could be secreted in vivo, we injected rats intraperiotoneally (ip with compound 48/80, which mimicks the action of SP. Peritoneal mast cells degranulated and mitochondrial particles were documented by transimission electron microscopy outside the cells. We also wished to investigate if mitochondrial components secreted locally could reach the systemic circulation. Administration ip of mtDNA isolated from LAD2 cells in rats was detected in their serum within 4 hr, indicating that extravascular mtDNA could enter the systemic circulation. Secretion of mitochondrial components from stimulated live mast cells may act as "autopathogens" contributing to the pathogenesis of inflammatory

  12. Determination of scattering center of multipath signals using geometric optics and Fresnel zone concepts

    Directory of Open Access Journals (Sweden)

    Kamil Yavuz Kapusuz

    2014-06-01

    Full Text Available In this study, a method for determining scattering center (or center of scattering points of a multipath is proposed, provided that the direction of arrival of the multipath is known by the receiver. The method is based on classical electromagnetic wave principles in order to determine scattering center over irregular terrain. Geometrical optics (GO along with Fresnel zone concept is employed, as the receiver, the transmitter positions and irregular terrain data are assumed to be provided. The proposed method could be used at UHF bands, especially, operations of radars and electronic warfare applications.

  13. Evidence for paracrine/autocrine regulation of GLP-1-producing cells

    DEFF Research Database (Denmark)

    Kappe, Camilla; Zhang, Qimin; Holst, Jens Juul

    2013-01-01

    Glucagon-like peptide-1 (GLP-1), secreted from gut L cells upon nutrient intake, forms the basis for novel drugs against type 2 diabetes (T2D). Secretion of GLP-1 has been suggested to be impaired in T2D and in conditions associated with hyperlipidemia and insulin resistance. Further, recent...... studies support lipotoxicity of GLP-1-producing cells in vitro. However, little is known about the regulation of L-cell viability/function, the effects of insulin signaling, or the potential effects of stable GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors. We determined effects of insulin...... as well as possible autocrine action of GLP-1 on viability/apoptosis of GLP-1-secreting cells in the presence/absence of palmitate, while also assessing direct effects on function. The studies were performed using the GLP-1-secreting cell line GLUTag, and palmitate was used to simulate hyperlipidemia. Our...

  14. Auxin transport, metabolism, and signalling during nodule initiation: indeterminate and determinate nodules

    NARCIS (Netherlands)

    Kohlen, W.; Ng, Jason Liang Pin; Deinum, E.E.; Mathesius, Ulrike

    2018-01-01

    Most legumes can form a unique type of lateral organ on their roots: root nodules. These structures host symbiotic nitrogen-fixing bacteria called rhizobia. Several different types of nodules can be found in nature, but the two best-studied types are called indeterminate and determinate nodules.

  15. Dynamics Determine Signaling in a Multicomponent System Associated with Rheumatoid Arthritis.

    Science.gov (United States)

    Lindgren, Cecilia; Tyagi, Mohit; Viljanen, Johan; Toms, Johannes; Ge, Changrong; Zhang, Naru; Holmdahl, Rikard; Kihlberg, Jan; Linusson, Anna

    2018-05-24

    Strategies that target multiple components are usually required for treatment of diseases originating from complex biological systems. The multicomponent system consisting of the DR4 major histocompatibility complex type II molecule, the glycopeptide CII259-273 from type II collagen, and a T-cell receptor is associated with development of rheumatoid arthritis (RA). We introduced non-native amino acids and amide bond isosteres into CII259-273 and investigated the effect on binding to DR4 and the subsequent T-cell response. Molecular dynamics simulations revealed that complexes between DR4 and derivatives of CII259-273 were highly dynamic. Signaling in the overall multicomponent system was found to depend on formation of an appropriate number of dynamic intramolecular hydrogen bonds between DR4 and CII259-273, together with the positioning of the galactose moiety of CII259-273 in the DR4 binding groove. Interestingly, the system tolerated modifications at several positions in CII259-273, indicating opportunities to use analogues to increase our understanding of how rheumatoid arthritis develops and for evaluation as vaccines to treat RA.

  16. Signal quality indices and data fusion for determining clinical acceptability of electrocardiograms

    International Nuclear Information System (INIS)

    Clifford, G D; Behar, J; Li, Q; Rezek, I

    2012-01-01

    A completely automated algorithm to detect poor-quality electrocardiograms (ECGs) is described. The algorithm is based on both novel and previously published signal quality metrics, originally designed for intensive care monitoring. The algorithms have been adapted for use on short (5–10 s) single- and multi-lead ECGs. The metrics quantify spectral energy distribution, higher order moments and inter-channel and inter-algorithm agreement. Seven metrics were calculated for each channel (84 features in all) and presented to either a multi-layer perceptron artificial neural network or a support vector machine (SVM) for training on a multiple-annotator labelled and adjudicated training dataset. A single-lead version of the algorithm was also developed in a similar manner. Data were drawn from the PhysioNet Challenge 2011 dataset where binary labels were available, on 1500 12-lead ECGs indicating whether the entire recording was acceptable or unacceptable for clinical interpretation. We re-annotated all the leads in both the training set (1000 labelled ECGs) and test dataset (500 12-lead ECGs where labels were not publicly available) using two independent annotators, and a third for adjudication of differences. We found that low-quality data accounted for only 16% of the ECG leads. To balance the classes (between high and low quality), we created extra noisy data samples by adding noise from PhysioNet’s noise stress test database to some of the clean 12-lead ECGs. No data were shared between training and test sets. A classification accuracy of 98% on the training data and 97% on the test data were achieved. Upon inspection, incorrectly classified data were found to be borderline cases which could be classified either way. If these cases were more consistently labelled, we expect our approach to achieve an accuracy closer to 100%. (paper)

  17. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer.

    Science.gov (United States)

    Priceman, Saul J; Gerdts, Ethan A; Tilakawardane, Dileshni; Kennewick, Kelly T; Murad, John P; Park, Anthony K; Jeang, Brook; Yamaguchi, Yukiko; Yang, Xin; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E; Wu, Anna M; Brown, Christine E; Forman, Stephen J

    2018-01-01

    Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with "on-target off-tumor" activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies.

  18. Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer

    Science.gov (United States)

    Priceman, Saul J.; Gerdts, Ethan A.; Tilakawardane, Dileshni; Kennewick, Kelly T.; Murad, John P.; Park, Anthony K.; Jeang, Brook; Yamaguchi, Yukiko; Urak, Ryan; Weng, Lihong; Chang, Wen-Chung; Wright, Sarah; Pal, Sumanta; Reiter, Robert E.; Brown, Christine E.; Forman, Stephen J.

    2018-01-01

    ABSTRACT Advancing chimeric antigen receptor (CAR)-engineered adoptive T cells for the treatment of solid cancers is a major focus in the field of immunotherapy, given impressive recent clinical responses in hematological malignancies. Prostate cancer may be amenable to T cell-based immunotherapy since several tumor antigens, including prostate stem-cell antigen (PSCA), are widely over-expressed in metastatic disease. While antigen selectivity of CARs for solid cancers is crucial, it is problematic due to the absence of truly restricted tumor antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we show that the intracellular co-stimulatory signaling domain can determine a CAR's sensitivity for tumor antigen expression. A 4-1BB intracellular co-stimulatory signaling domain in PSCA-CARs confers improved selectivity for higher tumor antigen density, reduced T cell exhaustion phenotype, and equivalent tumor killing ability compared to PSCA-CARs containing the CD28 co-stimulatory signaling domain. PSCA-CARs exhibit robust in vivo anti-tumor activity in patient-derived bone-metastatic prostate cancer xenograft models, and 4-1BB-containing CARs show superior T cell persistence and control of disease compared with CD28-containing CARs. Our study demonstrates the importance of co-stimulation in defining an optimal CAR T cell, and also highlights the significance of clinically relevant models in developing solid cancer CAR T cell therapies. PMID:29308300

  19. Highly sensitive determination of atropine using cobalt oxide nanostructures: Influence of functional groups on the signal sensitivity

    Energy Technology Data Exchange (ETDEWEB)

    Soomro, Razium Ali, E-mail: raziumsoomro@gmail.com [Interface Analysis Centre, School of Physics, University of Bristol, Bristol, BS8 1TL (United Kingdom); National Centre of Excellence in Analytical Chemistry, University of Sindh, Jamshoro, 76080 (Pakistan); Nafady, Ayman [Department of Chemistry, College of Science, King Saud University, Riyadh (Saudi Arabia); Department of Chemistry, Faculty of Science, Sohag University, Sohag (Egypt); Hallam, Keith Richard [Interface Analysis Centre, School of Physics, University of Bristol, Bristol, BS8 1TL (United Kingdom); Jawaid, Sana [National Centre of Excellence in Analytical Chemistry, University of Sindh, Jamshoro, 76080 (Pakistan); Al Enizi, Abdullah [Department of Chemistry, College of Science, King Saud University, Riyadh (Saudi Arabia); Sherazi, Syed Tufail Hussain; Sirajuddin [National Centre of Excellence in Analytical Chemistry, University of Sindh, Jamshoro, 76080 (Pakistan); Ibupoto, Zafar Hussain [Dr M.A. Kazi Institute of Chemistry, University of Sindh, Jamshoro, 76080 (Pakistan); Willander, Magnus [Department of Science and Technology, Campus Norrkoping, Linkoping University, SE-60174, Norrkoping (Sweden)

    2016-12-15

    This study describes sensitive determination of atropine using glassy carbon electrodes (GCE) modified with Co{sub 3}O{sub 4} nanostructures. The as-synthesised nanostructures were grown using cysteine (CYS), glutathione (GSH) and histidine (HYS) as effective templates under hydrothermal action. The obtained morphologies revealed interesting structural features, including both cavity-based and flower-shaped structures. The as-synthesised morphologies were noted to actively participate in electro-catalysis of atropine (AT) drug where GSH-assisted structures exhibited the best signal response in terms of current density and over-potential value. The study also discusses the influence of functional groups on the signal sensitivity of atropine electro-oxidation. The functionalisation was carried with the amino acids originally used as effective templates for the growth of Co{sub 3}O{sub 4} nanostructures. The highest increment was obtained when GSH was used as the surface functionalising agent. The GSH-functionalised Co{sub 3}O{sub 4}-modified electrode was utilised for the electro-chemical sensing of AT in a concentration range of 0.01–0.46 μM. The developed sensor exhibited excellent working linearity (R{sup 2} = 0.999) and signal sensitivity up to 0.001 μM of AT. The noted high sensitivity of the sensor is associated with the synergy of superb surface architectures and favourable interaction facilitating the electron transfer kinetics for the electro-catalytic oxidation of AT. Significantly, the developed sensor demonstrated excellent working capability when used for AT detection in human urine samples with strong anti-interference potential against common co-existing species, such as glucose, fructose, cysteine, uric acid, dopamine and ascorbic acid. - Highlights: • Template-assisted growth of Co{sub 3}O{sub 4} nanostructures. • Shape-dependent electro-catalysis of atropine. • Effect of functionalisation of signal sensitivity.

  20. Net analyte signal standard addition method for simultaneous determination of sulphadiazine and trimethoprim in bovine milk and veterinary medicines.

    Science.gov (United States)

    Hajian, Reza; Mousavi, Esmat; Shams, Nafiseh

    2013-06-01

    Net analyte signal standard addition method has been used for the simultaneous determination of sulphadiazine and trimethoprim by spectrophotometry in some bovine milk and veterinary medicines. The method combines the advantages of standard addition method with the net analyte signal concept which enables the extraction of information concerning a certain analyte from spectra of multi-component mixtures. This method has some advantages such as the use of a full spectrum realisation, therefore it does not require calibration and prediction step and only a few measurements require for the determination. Cloud point extraction based on the phenomenon of solubilisation used for extraction of sulphadiazine and trimethoprim in bovine milk. It is based on the induction of micellar organised media by using Triton X-100 as an extraction solvent. At the optimum conditions, the norm of NAS vectors increased linearly with concentrations in the range of 1.0-150.0 μmolL(-1) for both sulphadiazine and trimethoprim. The limits of detection (LOD) for sulphadiazine and trimethoprim were 0.86 and 0.92 μmolL(-1), respectively. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. Tumors initiated by constitutive Cdk2 activation exhibit transforming growth factor beta resistance and acquire paracrine mitogenic stimulation during progression

    DEFF Research Database (Denmark)

    Corsino, P.; Davis, B.; Law, M.

    2007-01-01

    ) promoter results in mammary gland hyperplasia and fibrosis, and mammary tumors. Cell lines isolated from MMTV-cyclin D1-Cdk2 (MMTV-D1K2) tumors exhibit Rb and p130 hyperphosphorylation and up-regulation of the protein products of E2F-dependent genes. These results suggest that cyclin D1/Cdk2 complexes may...... sites. Together, these results suggest that deregulation of the Cdk/Rb/E2F axis reprograms mammary epithelial cells to initiate a paracrine loop with tumor-associated fibroblasts involving TGF beta and HGF, resulting in desmoplasia. The MMTV-DIK2 mice should provide a useful model system...

  2. Determination of PWR core water level using ex-core detectors signals

    International Nuclear Information System (INIS)

    Bernal, Alvaro; Abarca, Agustin; Miro, Rafael; Verdu, Gumersindo

    2013-01-01

    The core water level provides relevant neutronic and thermalhydraulic information of the reactor such as power, k eff and cooling ability; in fact, core water level monitoring could be used to predict LOCA and cooling reduction which may deal with core damage. Although different detection equipment is used to monitor several parameters such as the power, core water level monitoring is not an evident task. However, ex-core detectors can measure the fast neutrons leaking the core and several studies demonstrate the existence of a relationship between fast neutron leakage and core water level due to the shielding effect of the water. In addition, new ex-core detectors are being developed, such as silicon carbide semiconductor radiation detectors, monitoring the neutron flux with higher accuracy and in higher temperatures conditions. Therefore, a methodology to determine this relationship has been developed based on a Monte Carlo calculation using MCNP code and applying variance reduction with adjoint functions based on the adjoint flux obtained with the discrete ordinates code TORT. (author)

  3. Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models.

    Science.gov (United States)

    Cristofaro, Brunella; Shi, Yu; Faria, Marcella; Suchting, Steven; Leroyer, Aurelie S; Trindade, Alexandre; Duarte, Antonio; Zovein, Ann C; Iruela-Arispe, M Luisa; Nih, Lina R; Kubis, Nathalie; Henrion, Daniel; Loufrani, Laurent; Todiras, Mihail; Schleifenbaum, Johanna; Gollasch, Maik; Zhuang, Zhen W; Simons, Michael; Eichmann, Anne; le Noble, Ferdinand

    2013-04-01

    Arteriogenesis requires growth of pre-existing arteriolar collateral networks and determines clinical outcome in arterial occlusive diseases. Factors responsible for the development of arteriolar collateral networks are poorly understood. The Notch ligand Delta-like 4 (Dll4) promotes arterial differentiation and restricts vessel branching. We hypothesized that Dll4 may act as a genetic determinant of collateral arterial networks and functional recovery in stroke and hind limb ischemia models in mice. Genetic loss- and gain-of-function approaches in mice showed that Dll4-Notch signaling restricts pial collateral artery formation by modulating arterial branching morphogenesis during embryogenesis. Adult Dll4(+/-) mice showed increased pial collateral numbers, but stroke volume upon middle cerebral artery occlusion was not reduced compared with wild-type littermates. Likewise, Dll4(+/-) mice showed reduced blood flow conductance after femoral artery occlusion, and, despite markedly increased angiogenesis, tissue ischemia was more severe. In peripheral arteries, loss of Dll4 adversely affected excitation-contraction coupling in arterial smooth muscle in response to vasopressor agents and arterial vessel wall adaption in response to increases in blood flow, collectively contributing to reduced flow reserve. We conclude that Dll4-Notch signaling modulates native collateral formation by acting on vascular branching morphogenesis during embryogenesis. Dll4 furthermore affects tissue perfusion by acting on arterial function and structure. Loss of Dll4 stimulates collateral formation and angiogenesis, but in the context of ischemic diseases such beneficial effects are overruled by adverse functional changes, demonstrating that ischemic recovery is not solely determined by collateral number but rather by vessel functionality.

  4. Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models

    Science.gov (United States)

    Cristofaro, Brunella; Shi, Yu; Faria, Marcella; Suchting, Steven; Leroyer, Aurelie S.; Trindade, Alexandre; Duarte, Antonio; Zovein, Ann C.; Iruela-Arispe, M. Luisa; Nih, Lina R.; Kubis, Nathalie; Henrion, Daniel; Loufrani, Laurent; Todiras, Mihail; Schleifenbaum, Johanna; Gollasch, Maik; Zhuang, Zhen W.; Simons, Michael; Eichmann, Anne; le Noble, Ferdinand

    2013-01-01

    Arteriogenesis requires growth of pre-existing arteriolar collateral networks and determines clinical outcome in arterial occlusive diseases. Factors responsible for the development of arteriolar collateral networks are poorly understood. The Notch ligand Delta-like 4 (Dll4) promotes arterial differentiation and restricts vessel branching. We hypothesized that Dll4 may act as a genetic determinant of collateral arterial networks and functional recovery in stroke and hind limb ischemia models in mice. Genetic loss- and gain-of-function approaches in mice showed that Dll4-Notch signaling restricts pial collateral artery formation by modulating arterial branching morphogenesis during embryogenesis. Adult Dll4+/- mice showed increased pial collateral numbers, but stroke volume upon middle cerebral artery occlusion was not reduced compared with wild-type littermates. Likewise, Dll4+/- mice showed reduced blood flow conductance after femoral artery occlusion, and, despite markedly increased angiogenesis, tissue ischemia was more severe. In peripheral arteries, loss of Dll4 adversely affected excitation-contraction coupling in arterial smooth muscle in response to vasopressor agents and arterial vessel wall adaption in response to increases in blood flow, collectively contributing to reduced flow reserve. We conclude that Dll4-Notch signaling modulates native collateral formation by acting on vascular branching morphogenesis during embryogenesis. Dll4 furthermore affects tissue perfusion by acting on arterial function and structure. Loss of Dll4 stimulates collateral formation and angiogenesis, but in the context of ischemic diseases such beneficial effects are overruled by adverse functional changes, demonstrating that ischemic recovery is not solely determined by collateral number but rather by vessel functionality. PMID:23533173

  5. Signals that determine internationalisation

    OpenAIRE

    Aryee, Esmeralda Na Momo; Henriquez Parodi, Massiel Carolina

    2017-01-01

    Master's thesis Business Administration BE501 - University of Agder 2017 International franchising business model is extensively and increasingly being used by entrepreneurs and firms seeking growth through geographic expansion. Thus, continued research efforts are needed to help entrepreneurs make wise choices when attracting investors into the business. Two popular theories (agency and resource scarcity) have been the basis on which international franchising has been explaine...

  6. Accurate determination of interfacial protein secondary structure by combining interfacial-sensitive amide I and amide III spectral signals.

    Science.gov (United States)

    Ye, Shuji; Li, Hongchun; Yang, Weilai; Luo, Yi

    2014-01-29

    Accurate determination of protein structures at the interface is essential to understand the nature of interfacial protein interactions, but it can only be done with a few, very limited experimental methods. Here, we demonstrate for the first time that sum frequency generation vibrational spectroscopy can unambiguously differentiate the interfacial protein secondary structures by combining surface-sensitive amide I and amide III spectral signals. This combination offers a powerful tool to directly distinguish random-coil (disordered) and α-helical structures in proteins. From a systematic study on the interactions between several antimicrobial peptides (including LKα14, mastoparan X, cecropin P1, melittin, and pardaxin) and lipid bilayers, it is found that the spectral profiles of the random-coil and α-helical structures are well separated in the amide III spectra, appearing below and above 1260 cm(-1), respectively. For the peptides with a straight backbone chain, the strength ratio for the peaks of the random-coil and α-helical structures shows a distinct linear relationship with the fraction of the disordered structure deduced from independent NMR experiments reported in the literature. It is revealed that increasing the fraction of negatively charged lipids can induce a conformational change of pardaxin from random-coil to α-helical structures. This experimental protocol can be employed for determining the interfacial protein secondary structures and dynamics in situ and in real time without extraneous labels.

  7. Hollow nanogold microsphere-signalized lateral flow immuno dipstick for the sensitive determination of the neurotoxin brevetoxin B

    International Nuclear Information System (INIS)

    Zhang, Kangyao; Wu, Jiachang; Li, Yineng; Wu, Yarong; Huang, Tianfu; Tang, Dianping

    2014-01-01

    We report on a new membrane-based lateral-flow assay for the rapid determination of the algal biotoxin brevetoxin B (BrevTox) that can be found in fish. Hollow nanogold microspheres (HGMS) with an average size of 45 nm were synthesized by using the reverse micelle method, followed by functionalization with monoclonal mouse anti-BrevTox antibody (mAb-HGMS). They served as the signalling reagent. Bovine serum albumin-BrevTox conjugate and rabbit anti-mouse IgG antibody were manually spotted on the nitrocellulose membrane and served as reagents for the test line and control line, respectively. Both spherical gold nanoparticle-labeled anti-BrevTox antibody (mAb-AuNP) and mAb-HGMS conjugate were investigated with respect to their suitability as signal-transduction tags, and the latter was found to give improved analytical features. The HGMS-based labeling method was then also studied in terms of performance in the immuno dipstick assay. Under optimal conditions, the visual detection limit (cut-off value) of the mAb-AuNP based assay is 1.5 ng mL −1 , while the sensitivity of the mAb-HGMS based assay is as low as 0.1 ng mL −1 . Yes/no decisions can be made within 10 min without the need for expensive instrumentation. The results for the analysis of target BrevTox in spiked fish samples showed a good correlation with data obtained with the commercial ELISA. Importantly, the assay gave no false negative results. (author)

  8. Photoplethysmography Signal Analysis for Optimal Region-of-Interest Determination in Video Imaging on a Built-In Smartphone under Different Conditions

    Directory of Open Access Journals (Sweden)

    Yunyoung Nam

    2017-10-01

    Full Text Available Smartphones and tablets are widely used in medical fields, which can improve healthcare and reduce healthcare costs. Many medical applications for smartphones and tablets have already been developed and widely used by both health professionals and patients. Specifically, video recordings of fingertips made using a smartphone camera contain a pulsatile component caused by the cardiac pulse equivalent to that present in a photoplethysmographic signal. By performing peak detection on the pulsatile signal, it is possible to estimate a continuous heart rate and a respiratory rate. To estimate the heart rate and respiratory rate accurately, which pixel regions of the color bands give the most optimal signal quality should be investigated. In this paper, we investigate signal quality to determine the best signal quality by the largest amplitude values for three different smartphones under different conditions. We conducted several experiments to obtain reliable PPG signals and compared the PPG signal strength in the three color bands when the flashlight was both on and off. We also evaluated the intensity changes of PPG signals obtained from the smartphones with motion artifacts and fingertip pressure force. Furthermore, we have compared the PSNR of PPG signals of the full-size images with that of the region of interests (ROIs.

  9. Liver heterotopia in the head of a patient with osteosarcoma of the maxilla. A paracrine tumor-induced hepatogenesis?

    Science.gov (United States)

    Corsi, Alessandro; Riminucci, Mara

    2017-02-01

    Heterotopia of liver tissue is uncommon. It has been reported at various sites, more frequently near the orthotopic liver, including gallbladder, hepatic ligaments, omentum, and retroperitoneum, rarely within the diaphragm and the thoracic cavity, and never within the head. We report here a 22-year-old patient surgically treated for a maxillary osteosarcoma in which microscopic liver tissue islands were incidentally detected in the respiratory mucosa of the surgical margin. The islands comprised well-differentiated HepPar-1-positive hepatocytes and were surrounded by cytokeratin-7- and cytokeratin-19-positive bile duct-like structures. This case, which is unique in the medical literature, may suggest an inductive paracrine effect of the osteosarcoma cells by secretion of factors promoting hepatocyte specification of primitive endodermal progenitors and subsequent liver morphogenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. The paracrine feedback loop between vitamin D₃ (1,25(OH)₂D₃) and PTHrP in prehypertrophic chondrocytes

    NARCIS (Netherlands)

    Bach, Frances C; Rutten, Kirsten; Hendriks, Kristyanne; Riemers, Frank M; Cornelissen, Peter; de Bruin, Alain; Arkesteijn, Ger J; Wubbolts, Richard; Horton, William A; Penning, Louis C; Tryfonidou, Marianna A

    2014-01-01

    The endocrine feedback loop between vitamin D3(1,25(OH)2D3) and parathyroid hormone (PTH) plays a central role in skeletal development. PTH-related protein (PTHrP) shares homology and its receptor (PTHR1) with PTH. The aim of this study was to investigate whether there is a functional paracrine

  11. Suppression of DHT-induced paracrine stimulation of endothelial cell growth by estrogens via prostate cancer cells.

    Science.gov (United States)

    Wen, Juan; Zhao, Yuan; Li, Jinghe; Weng, Chunyan; Cai, Jingjing; Yang, Kan; Yuan, Hong; Imperato-McGinley, Julianne; Zhu, Yuan-Shan

    2013-07-01

    Androgen modulation of angiogenesis in prostate cancer may be not directly mediated by androgen receptor (AR) as AR is not detected in the prostatic endothelial cells. We examined the paracrine stimulation of cell proliferation by prostate tumor cells and its modulation by androgen and estrogens in a murine endothelial cell line (MEC) that does not express AR. Tumor cell conditioned media (TCM) collected from LAPC-4 or LNCaP prostatic tumor cells produced a time- and concentration-dependent induction of cell growth in MECs, which was parallel to the VEGF concentration in the TCM. This TCM-induced cell growth in MECs was enhanced by the treatment of prostatic tumor cells with dihydrotestosterone (DHT). Both the TCM-stimulation and DHT-enhancement effects in MECs were completely blocked by SU5416, a specific VEGF receptor antagonist. Co-administration of 17α-estradiol or 17β-estradiol with DHT in prostatic tumor cells completely inhibited the DHT-enhancement effect while treatment with DHT, 17α-estradiol or 17β-estradiol did not produce any significant direct effect in MECs. Moreover, administration of 17α-estradiol or 17β-estradiol in xenograft animals with LAPC-4 or LNCaP prostate tumor significantly decreased the microvessel number in the tumor tissues. Our study indicated that prostate tumor cells regulate endothelial cell growth through a paracrine mechanism, which is mainly mediated by VEGF; and DHT is able to modulate endothelial cell growth via tumor cells, which is inhibited by 17α-estradiol and 17β-estradiol. Thus, both17α-estradiol and 17β-estradiol are potential agents for anti-angiogenesis therapy in androgen-responsive prostate cancer. Copyright © 2013 Wiley Periodicals, Inc.

  12. Attenuation of radiation-induced DNA damage due to paracrine interactions between normal human epithelial and stromal cells

    International Nuclear Information System (INIS)

    Saenko, V.A.; Nakazawa, Yu.; Rogounovitch, T.I.; Suzuki, K.; Mitsutake, N.; Matsuse, M.; Yamashita, S.

    2007-01-01

    Complete text of publication follows. Objective: Developmentally, every tissue accommodates different types of cells, such as epitheliocytes and stromal cells in parenchymal organs. To better understand the complexity of radiation response, it is necessary to evaluate possible cross-talk between different tissue components. This work was set out to investigate reciprocal influence of normal human epithelial cells and fibroblasts on the extent of radiation-induced DNA damage. Methods: Model cultures of primary human thyrocytes (PT), normal diploid fibroblasts (BJ), PT/BJ cell co-culture and conditioned medium transfer were used to examine DNA damage in terms of γ-H2AX foci number per cell or by Comet assay after exposure to different doses of γ-rays. Results: In co-cultures, the kinetics of γ-H2AX foci number change was dose-dependent and similar to that in individual PT and BJ cultures. The number of γ-H2AX foci in co-cultures was significantly lower (∼25%) in both types of cells comparing to individual cultures. Reciprocal conditioned medium transfer to individual counterpart cells prior to irradiation resulted in approximately 35% reduction in the number γ-H2AX foci at 1 Gy and lower doses in both PT and BJ demonstrating the role of paracrine soluble factors. Comet assay corroborated the results of γ-H2AX foci counting in conditioned medium transfer experiments. In contrast to medium conditioned on PT cells, conditioned medium collected from several human thyroid cancer cell lines failed to establish DNA-protected state in BJ fibroblasts. In its turn, medium conditioned on BJ cells did not change the extent of radiation-induced DNA damage in cancer cell lines tested. Conclusion: The results imply the existence of a network of soluble factor-mediated paracrine interactions between normal epithelial and stromal cells that could be a part of natural mechanism by which cells protect DNA from genotoxic stress.

  13. Curcumin Triggers p16-Dependent Senescence in Active Breast Cancer-Associated Fibroblasts and Suppresses Their Paracrine Procarcinogenic Effects

    Directory of Open Access Journals (Sweden)

    Siti-Fauziah Hendrayani

    2013-06-01

    Full Text Available Activated cancer-associated fibroblasts (CAFs or myofibroblasts not only facilitate tumor growth and spread but also affect tumor response to therapeutic agents. Therefore, it became clear that efficient therapeutic regimens should also take into account the presence of these supportive cells and inhibit their paracrine effects. To this end, we tested the effect of low concentrations of curcumin, a pharmacologically safe natural product, on patient-derived primary breast CAF cells. We have shown that curcumin treatment upregulates p16INK4A and other tumor suppressor proteins while inactivates the JAK2/STAT3 pathway. This reduced the level of alpha-smooth muscle actin (α-SMA and the migration/invasion abilities of these cells. Furthermore, curcumin suppressed the expression/secretion of stromal cell-derived factor-1 (SDF-1, interleukin-6 (IL-6, matrix metalloproteinase-2 (MMP-2, MMP-9, and transforming growth factor-β, which impeded their paracrine procarcinogenic potential. Intriguingly, these effects were sustained even after curcumin withdrawal and cell splitting. Therefore, using different markers of senescence [senescence-associated β-galactosidase (SA-β-gal activity, Ki-67 and Lamin B1 levels, and bromodeoxyuridine incorporation], we have shown that curcumin markedly suppresses Lamin B1 and triggers DNA damage-independent senescence in proliferating but not quiescent breast stromal fibroblasts. Importantly, this curcumin-related senescence was p16INK4A-dependent and occurred with no associated inflammatory secretory phenotype. These results indicate the possible inactivation of cancer-associated myofibroblasts and present the first indication that curcumin can trigger DNA damage-independent and safe senescence in stromal fibroblasts.

  14. Chemokine CXCL3 mediates prostate cancer cells proliferation, migration and gene expression changes in an autocrine/paracrine fashion.

    Science.gov (United States)

    Xin, Hua; Cao, Yu; Shao, Ming-Liang; Zhang, Wei; Zhang, Chun-Bin; Wang, Jing-Tao; Liang, Li-Chun; Shao, Wen-Wu; Qi, Ya-Ling; Li, Yue; Zhang, Ze-Yu; Yang, Zhe; Sun, Yu-Hong; Zhang, Peng-Xia; Jia, Lin-Lin; Wang, Wei-Qun

    2018-05-01

    We have previously indicated that CXCL3 was upregulated in the tissues of prostate cancer, and exogenous administration of CXCL3 played a predominant role in the tumorigenicity of prostate cancer cells. In the present study, we further explored the role and the underlying mechanism of CXCL3 overexpression in the oncogenic potential of prostate cancer in an autocrine/paracrine fashion. CXCL3-overexpressing prostate cancer cell line PC-3 and immortalized prostate stromal cell line WPMY-1 were established by gene transfection. CCK-8, transwell assays and growth of tumor xenografts were conducted to characterize the effects of CXCL3 on PC-3 cells' proliferation and migration. Western blotting was conducted to test whether CXCL3 could affect the expression of tumorigenesis-associated genes. The results showed that CXCL3 overexpression in PC-3 cells and the PC-3 cells treated with the supernatants of CXCL3-transfected WPMY-1 cells stimulated the proliferation and migration of PC-3 cells in vitro and in a nude mouse xenograft model. Western blotting revealed higher levels of p-ERK, Akt and Bcl-2 and lower levels of Bax in the tumor xenografts transplanted with CXCL3-transfected PC-3 cells. Moreover, the tumor xenografts derived from the PC-3 cells treated with supernatants of CXCL3-transfected WPMY-1 cells showed higher expression of ERK, Akt and Bcl-2 and lower expression of Bax. These findings suggest that CXCL3 autocrine/paracrine pathways are involved in the development of prostate cancer by regulating the expression of the target genes that are related to the progression of malignancies.

  15. Endocrine and paracrine regulation of zebrafish spermatogenesis : The Sertoli cell perspective

    NARCIS (Netherlands)

    Schulz, R. W.; Nóbrega, R. H.; Vidal de Souza Morais, Roberto Daltro; De Waal, P. P.; França, L. R.; Bogerd, J.

    2015-01-01

    Spermatogonial stem cells (SSCs) either self-renew or differentiate into spermatogonia that further develop into spermatozoa. Self-renewal occurs when residing in a specific micro-environment (niche) while displacement from the niche would tip the signalling balance towards differentiation.

  16. Cysteamine induces cholecystokinin release from the duodenum. Evidence for somatostatin as an inhibitory paracrine regulator of cholecystokinin secretion in the rat

    International Nuclear Information System (INIS)

    Abucham, J.; Reichlin, S.

    1990-01-01

    To determine whether cholecystokinin secretion is regulated by endogenous somatostatin, somatostatin deficiency was induced in vivo with cysteamine (250 mg/kg body wt, IV) or anti-somatostatin antiserum in anaesthetized rats and in vitro with cysteamine (30 micrograms/mL) in a rat duodenum-incubation system. Cholecystokinin secretion was assessed in vivo by measuring amylase in duodenal perfusates collected at 10-minute intervals for 1 hour and in vitro by a carboxy-terminal radioimmunoassay. Cysteamine induced a marked decrease in duodenal immunoreactive somatostatin both in vivo (50%) and in vitro (60%). The rate of amylase secretion increased from 9.7 +/- 2.1 U (mean +/- SE) to 28.0 +/- 4.8 U at 20 minutes (P less than 0.001). The cholecystokinin-receptor antagonist CR-1392 abolished amylase response for 30 minutes, whereas the more potent antagonists Asperlicin (18.0 mg/kg body wt, IV) and L-364,718 (0.25 mg/kg body wt, IV) caused prolonged blockade. The rate of amylase secretion in gastrectomized animals increased from 7.2 +/- 2.0 U to 15.0 +/- 2.2 U 20 minutes after cysteamine administration (P less than 0.01), indicating that the effect was not due to the presence of gastrin. In vitro, cysteamine caused a nearly fourfold increase in cholecystokinin secretion compared with controls (63.1 +/- 4.9 vs. 15.2 +/- 3.7, respectively; P less than 0.001). In vivo immunoneutralization of circulating somatostatin with a high-affinity and high-capacity antiserum produced no significant change in the rate of amylase secretion. These results suggest that cholecystokinin secretion is tonically inhibited by somatostatin and that this effect is mediated by locally secreted (paracrine) but not by circulating somatostatin

  17. Determining dark matter properties with a XENONnT/LZ signal and LHC Run 3 monojet searches

    Science.gov (United States)

    Baum, Sebastian; Catena, Riccardo; Conrad, Jan; Freese, Katherine; Krauss, Martin B.

    2018-04-01

    We develop a method to forecast the outcome of the LHC Run 3 based on the hypothetical detection of O (100 ) signal events at XENONnT. Our method relies on a systematic classification of renormalizable single-mediator models for dark matter-quark interactions and is valid for dark matter candidates of spin less than or equal to one. Applying our method to simulated data, we find that at the end of the LHC Run 3 only two mutually exclusive scenarios would be compatible with the detection of O (100 ) signal events at XENONnT. In the first scenario, the energy distribution of the signal events is featureless, as for canonical spin-independent interactions. In this case, if a monojet signal is detected at the LHC, dark matter must have spin 1 /2 and interact with nucleons through a unique velocity-dependent operator. If a monojet signal is not detected, dark matter interacts with nucleons through canonical spin-independent interactions. In a second scenario, the spectral distribution of the signal events exhibits a bump at nonzero recoil energies. In this second case, a monojet signal can be detected at the LHC Run 3; dark matter must have spin 1 /2 and interact with nucleons through a unique momentum-dependent operator. We therefore conclude that the observation of O (100 ) signal events at XENONnT combined with the detection, or the lack of detection, of a monojet signal at the LHC Run 3 would significantly narrow the range of possible dark matter-nucleon interactions. As we argued above, it can also provide key information on the dark matter particle spin.

  18. Characterization of HGF/Met Signaling in Cell Lines Derived From Urothelial Carcinoma of the Bladder

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Young H. [Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Apolo, Andrea B. [Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Agarwal, Piyush K.; Bottaro, Donald P., E-mail: dbottaro@helix.nih.gov [Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States)

    2014-11-25

    There is mounting evidence of oncogenic hepatocyte growth factor (HGF)/Met signaling in urothelial carcinoma (UC) of the bladder. The effects of three kinase inhibitors, cabozantinib, crizotinib and EMD1214063, on HGF-driven signaling and cell growth, invasion and tumorigenicity were analyzed in cultured UC cell lines. SW780 xenograft growth in SCID and human HGF knock-in SCID (hHGF/SCID) mice treated with cabozantinib or vehicle, as well as tumor levels of Met and pMet, were also determined. Met content was robust in most UC-derived cell lines. Basal pMet content and effector activation state in quiescent cells were low, but significantly enhanced by added HGF, as were cell invasion, proliferation and anchorage independent growth. These HGF-driven effects were reversed by Met inhibitor treatment. Tumor xenograft growth was significantly higher in hHGF/SCID mice vs. SCID mice and significantly inhibited by cabozantinib, as was tumor phospho-Met content. These studies indicate the prevalence and functionality of the HGF/Met signaling pathway in UC cells, suggest that paracrine HGF may contribute to UC tumor growth and progression, and that support further preclinical investigation of Met inhibitors for the treatment of UC is warranted.

  19. The satiety signaling neuropeptide perisulfakinin inhibits the activity of central neurons promoting general activity

    Directory of Open Access Journals (Sweden)

    Dieter Wicher

    2007-12-01

    Full Text Available The metabolic state is one of the determinants of the general activity level. Satiety is related to resting or sleep whereas hunger correlates to wakefulness and activity. The counterpart to the mammalian satiety signal cholecystokinin (CCK in insects are the sulfakinins. The aim of this study was to resolve the mechanism by which the antifeedant activity of perisulfakinin (PSK in Periplaneta americana is mediated. We identified the sources of PSK which is used both as hormone and as paracrine messenger. PSK is found in the neurohemal organ of the brain and in nerve endings throughout the central nervous system. To correlate the distributions of PSK and its receptor (PSKR, we cloned the gene coding for PSKR and provide evidence for its expression within the nervous system. It occurs only in a few neurons, among them are the dorsal unpaired median (DUM neurons which release octopamine thereby regulating the general level of activity. Application of PSK to DUM neurons attenuated the spiking frequency (EC50=11pM due to reduction of a pacemaker Ca2+ current through cAMP-inhibited pTRPγ channels. PSK increased the intracellular cAMP level while decreasing the intracellular Ca2+ concentration in DUM neurons. Thus, the satiety signal conferred by PSK acts antagonistically to the hunger signal, provided by the adipokinetic hormone (AKH: PSK depresses the electrical activity of DUM neurons by inhibiting the pTRPγ channel that is activated by AKH under conditions of food shortage.

  20. How the turtle forms its shell: a paracrine hypothesis of carapace formation.

    Science.gov (United States)

    Cebra-Thomas, Judith; Tan, Fraser; Sistla, Seeta; Estes, Eileen; Bender, Gunes; Kim, Christine; Riccio, Paul; Gilbert, Scott F

    2005-11-15

    We propose a two-step model for the evolutionary origin of the turtle shell. We show here that the carapacial ridge (CR) is critical for the entry of the ribs into the dorsal dermis. Moreover, we demonstrate that the maintenance of the CR and its ability to attract the migrating rib precursor cells depend upon fibroblast growth factor (FGF) signaling. Inhibitors of FGF allow the CR to degenerate, with the consequent migration of ribs along the ventral body wall. Beads containing FGF10 can rearrange rib migration in the chick, suggesting that the CR FGF10 plays an important role in attracting the rib rudiments. The co-ordinated growth of the carapacial plate and the ribs may be a positive feedback loop (similar to that of the limbs) caused by the induction of Fgf8 in the distal tips of the ribs by the FGF10-secreting mesenchyme of the CR. Once in the dermis, the ribs undergo endochrondral ossification. We provide evidence that the ribs act as signaling centers for the dermal ossification and that this ossification is due to bone morphogenetic proteins secreted by the rib. Thus, once the ribs are within the dermis, the ossification of the dermis is not difficult to achieve. This relatively rapid means of carapace formation would allow for the appearance of turtles in the fossil record without obvious intermediates. Copyright 2005 Wiley-Liss, Inc.

  1. Ghrelin is involved in the paracrine communication between neurons and glial cells.

    Science.gov (United States)

    Avau, B; De Smet, B; Thijs, T; Geuzens, A; Tack, J; Vanden Berghe, P; Depoortere, I

    2013-09-01

    Ghrelin is the only known peripherally active orexigenic hormone produced by the stomach that activates vagal afferents to stimulate food intake and to accelerate gastric emptying. Vagal sensory neurons within the nodose ganglia are surrounded by glial cells, which are able to receive and transmit chemical signals. We aimed to investigate whether ghrelin activates or influences the interaction between both types of cells. The effect of ghrelin was compared with that of leptin and cholecystokinin (CCK). Cultures of rat nodose ganglia were characterized by immunohistochemistry and the functional effects of peptides, neurotransmitters, and pharmacological blockers were measured by Ca(2+) imaging using Fluo-4-AM as an indicator. Neurons responded to KCl and were immunoreactive for PGP-9.5 whereas glial cells responded to lysophosphatidic acid and had the typical SOX-10-positive nuclear staining. Neurons were only responsive to CCK (31 ± 5%) whereas glial cells responded equally to the applied stimuli: ghrelin (27 ± 2%), leptin (21 ± 2%), and CCK (30 ± 2%). In contrast, neurons stained more intensively for the ghrelin receptor than glial cells. ATP induced [Ca(2+) ]i rises in 90% of the neurons whereas ACh and the NO donor, SIN-1, mainly induced [Ca(2+) ]i changes in glial cells (41 and 51%, respectively). The percentage of ghrelin-responsive glial cells was not affected by pretreatment with suramin, atropine, hexamethonium or 1400 W, but was reduced by l-NAME and by tetrodotoxin. Neurons were shown to be immunoreactive for neuronal NO-synthase (nNOS). Our data show that ghrelin induces Ca(2+) signaling in glial cells of the nodose ganglion via the release of NO originating from the neurons. © 2013 John Wiley & Sons Ltd.

  2. Diverse in- and output polarities and high complexity of local synaptic and nonsynaptic signalling within a chemically defined class of peptidergic Drosophila neurons

    Science.gov (United States)

    Peptidergic neurons are not easily integrated into current connectomics concepts, since their peptide messages can be distributed via non-synaptic paracrine signaling or even via volume transmission. Moreover, and especially in insects, the polarity of peptidergic interneurons in terms of in- and o...

  3. Paracrine effects and heterogeneity of marrow-derived stem/progenitor cells: relevance for the treatment of respiratory diseases.

    Science.gov (United States)

    Conese, Massimo; Carbone, Annalucia; Castellani, Stefano; Di Gioia, Sante

    2013-01-01

    Stem cell-based treatment may represent a hope for the treatment of acute lung injury and pulmonary fibrosis, and other chronic lung diseases, such as cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). It is well established in preclinical models that bone marrow-derived stem and progenitor cells exert beneficial effects on inflammation, immune responses and repairing of damage in virtually all lung-borne diseases. While it was initially thought that the positive outcome was due to a direct engraftment of these cells into the lung as endothelial and epithelial cells, paracrine factors are now considered the main mechanism through which stem and progenitor cells exert their therapeutic effect. This knowledge has led to the clinical use of marrow cells in pulmonary hypertension with endothelial progenitor cells (EPCs) and in COPD with mesenchymal stromal (stem) cells (MSCs). Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells, MSCs, EPCs and fibrocytes, encompass a wide array of cell subsets with different capacities of engraftment and injured tissue-regenerating potential. The characterization/isolation of the stem cell subpopulations represents a major challenge to improve the efficacy of transplantation protocols used in regenerative medicine and applied to lung disorders. Copyright © 2013 S. Karger AG, Basel.

  4. Omentum-derived stromal cells improve myocardial regeneration in pig post-infarcted heart through a potent paracrine mechanism

    Energy Technology Data Exchange (ETDEWEB)

    De Siena, Rocco; Balducci, Luigi; Blasi, Antonella; Montanaro, Manuela Gessica; Saldarelli, Marilisa [Medestea Research and Production Laboratories, Consorzio Carso, 70010 Valenzano, Bari (Italy); Saponaro, Vittorio [Department of Veterinary Medicine, University of Bari, 70010 Valenzano, Bari (Italy); Martino, Carmela [Medestea Research and Production Laboratories, Consorzio Carso, 70010 Valenzano, Bari (Italy); Logrieco, Gaetano [Department of Surgery, Hospital ' F. Miulli' 70021 AcquaViva delle Fonti, Bari (Italy); Soleti, Antonio; Fiobellot, Simona [Medestea Research and Production Laboratories, Consorzio Carso, 70010 Valenzano, Bari (Italy); Madeddu, Paolo [Experimental Cardiovascular Medicine, Bristol Heart Institute, Bristol BS2 8WH (United Kingdom); Rossi, Giacomo [Department of Pathology, University of Camerino, 63100 Ascoli Piceno (Italy); Ribatti, Domenico [Department of Human Anatomy, University of Bari, 70125 Bari (Italy); Crovace, Antonio [Department of Veterinary Medicine, University of Bari, 70010 Valenzano, Bari (Italy); Cristini, Silvia; Invernici, Gloria; Parati, Eugenio Agostino [Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, Fondazione IRCCS Neurological Institute ' Carlo Besta' , 20133 Milan (Italy); Alessandri, Giulio, E-mail: cisiamo2@yahoo.com [Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, Fondazione IRCCS Neurological Institute ' Carlo Besta' , 20133 Milan (Italy)

    2010-07-01

    Cell-based therapy could be a valid option to treat myocardial infarct (MI). Adipose-derived stromal cells (ADStCs) have demonstrated tissue regenerative potential including cardiomyogenesis. Omentum is an extremely rich source of visceral fat and its accumulation seems to correlate with cardiovascular diseases. We investigated the capacity of human fat Omentum-derived StCs (FOStCs) to affect heart function upon acute infarct in pigs induced by permanent ligation of the anterior interventricular artery (IVA). We demonstrated for the first time that the local injection of 50 x 10{sup 6} of FOStCs ameliorates the functional parameters of post-infarct heart. Most importantly, histology of FOStCs treated hearts demonstrated a substantial improvement of cardiomyogenesis. In culture, FOStCs produced an impressive number and amount of angiogenic factors and cytokines. Moreover, the conditioned medium of FOStCs (FOStCs-CM) stimulates in vitro cardiac endothelial cells (ECs) proliferation and vascular morphogenesis and inhibits monocytes, EC activation and cardiomyocyte apoptosis. Since FOStCs in vivo did not trans-differentiate into cardiomyocyte-like cells, we conclude that FOStCs efficacy was presumably mediated by a potent paracrine mechanism involving molecules that concomitantly improved angiogenesis, reduced inflammation and prevented cardiomyocytes death. Our results highlight for the first time the important role that human FOStCs may have in cardiac regeneration.

  5. The mir-279/996 cluster represses receptor tyrosine kinase signaling to determine cell fates in the Drosophila eye.

    Science.gov (United States)

    Duan, Hong; de Navas, Luis F; Hu, Fuqu; Sun, Kailiang; Mavromatakis, Yannis E; Viets, Kayla; Zhou, Cyrus; Kavaler, Joshua; Johnston, Robert J; Tomlinson, Andrew; Lai, Eric C

    2018-04-09

    Photoreceptors in the crystalline Drosophila eye are recruited by receptor tyrosine kinase (RTK)/Ras signaling mediated by Epidermal growth factor receptor (EGFR) and the Sevenless (Sev) receptor. Analyses of an allelic deletion series of the mir-279/996 locus, along with a panel of modified genomic rescue transgenes, show that Drosophila eye patterning depends on both miRNAs. Transcriptional reporter and activity sensor transgenes reveal expression and function of miR-279/996 in non-neural cells of the developing eye. Moreover, mir-279/996 mutants exhibit substantial numbers of ectopic photoreceptors, particularly of R7, and cone cell loss. These miRNAs restrict RTK signaling in the eye, since mir-279/996 nulls are dominantly suppressed by positive components of the EGFR pathway and enhanced by heterozygosity for an EGFR repressor. miR-279/996 limit photoreceptor recruitment by targeting multiple positive RTK/Ras signaling components that promote photoreceptor/R7 specification. Strikingly, deletion of mir-279/996 sufficiently derepresses RTK/Ras signaling so as to rescue a population of R7 cells in R7-specific RTK null mutants boss and sev , which otherwise completely lack this cell fate. Altogether, we reveal a rare setting of developmental cell specification that involves substantial miRNA control. © 2018. Published by The Company of Biologists Ltd.

  6. Kinetics in Signal Transduction Pathways Involving Promiscuous Oligomerizing Receptors Can Be Determined by Receptor Specificity : Apoptosis Induction by TRAIL

    NARCIS (Netherlands)

    Szegezdi, Eva; van der Sloot, Almer M.; Mahalingam, Devalingam; O'Leary, Lynda; Cool, Robbert H.; Munoz, Ines G.; Montoya, Guillermo; Quax, Wim J.; de Jong, Steven; Samali, Afshin; Serrano, Luis

    Here we show by computer modeling that kinetics and outcome of signal transduction in case of hetero-oligomerizing receptors of a promiscuous ligand largely depend on the relative amounts of its receptors. Promiscuous ligands can trigger the formation of nonproductive receptor complexes, which slows

  7. Tyrosine kinase signalling in breast cancer

    International Nuclear Information System (INIS)

    Hynes, Nancy E

    2000-01-01

    Cells are continuously exposed to diverse stimuli ranging from soluble endocrine and paracrine factors to signalling molecules on neighbouring cells. Receptors of the tyrosine kinase family play an important role in the integration and interpretation of these external stimuli, allowing a cell to respond appropriately to its environment. The activation of receptor tyrosine kinases (RTKs) is tightly controlled, allowing a normal cell to correctly integrate its external environment with internal signal transduction pathways. In contrast, due to numerous molecular alterations arising during the course of malignancy, a tumour is characterized by an abnormal response to its environment, which allows cancer cells to evade the normal mechanisms controlling cellular proliferation. Alterations in the expression of various RTKs, in their activation, and in the signalling molecules lying downstream of the receptors play important roles in the development of cancer. This topic is the major focus of the thematic review section of this issue of Breast Cancer Research

  8. Insulin-like growth factor-1 suppresses the Myostatin signaling pathway during myogenic differentiation

    International Nuclear Information System (INIS)

    Retamales, A.; Zuloaga, R.; Valenzuela, C.A.; Gallardo-Escarate, C.; Molina, A.; Valdés, J.A.

    2015-01-01

    Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway. This study reports on a novel functional crosstalk between the IGF-1 and MSTN signaling pathways, as mediated through interaction between PI3K/Akt and Smad3. Stimulation of skeletal myoblasts with MSTN resulted in a transient increase in the pSmad3:Smad3 ratio and Smad-dependent transcription. Moreover, MSTN inhibited myod gene expression and myoblast fusion in an Activin receptor-like kinase/Smad3-dependent manner. Preincubation of skeletal myoblasts with IGF-1 blocked MSTN-induced Smad3 activation, promoting myod expression and myoblast differentiation. This inhibitory effect of IGF-1 on the MSTN signaling pathway was dependent on IGF-1 receptor, PI3K, and Akt activities. Finally, immunoprecipitation assay analysis determined that IGF-1 pretreatment increased Akt and Smad3 interaction. These results demonstrate that the IGF-1/PI3K/Akt pathway may inhibit MSTN signaling during myoblast differentiation, providing new insight to existing knowledge on the complex crosstalk between both growth factors. - Highlights: • IGF-1 inhibits Myostatin canonical signaling pathway through IGF-1R/PI3K/Akt pathway. • IGF-1 promotes myoblast differentiation through a direct blocking of Myostatin signaling pathway. • IGF-1 induces the interaction of Akt with Smad3 in skeletal myoblast

  9. Insulin-like growth factor-1 suppresses the Myostatin signaling pathway during myogenic differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Retamales, A.; Zuloaga, R.; Valenzuela, C.A. [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Gallardo-Escarate, C. [Laboratory of Biotechnology and Aquatic Genomics, Universidad de Concepción, Concepción (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile); Molina, A. [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile); Valdés, J.A., E-mail: jvaldes@unab.cl [Laboratorio de Biotecnología Molecular, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago (Chile); Interdisciplinary Center for Aquaculture Research (INCAR), P.O. Box 160-C, Concepción (Chile)

    2015-08-21

    Myogenic differentiation is a complex and well-coordinated process for generating mature skeletal muscle fibers. This event is autocrine/paracrine regulated by growth factors, principally Myostatin (MSTN) and Insulin-like Growth Factor-1 (IGF-1). Myostatin, a member of the transforming growth factor-β superfamily, is a negative regulator of skeletal muscle growth in vertebrates that exerts its inhibitory function by activating Smad transcription factors. In contrast, IGF-1 promotes the differentiation of skeletal myoblasts by activating the PI3K/Akt signaling pathway. This study reports on a novel functional crosstalk between the IGF-1 and MSTN signaling pathways, as mediated through interaction between PI3K/Akt and Smad3. Stimulation of skeletal myoblasts with MSTN resulted in a transient increase in the pSmad3:Smad3 ratio and Smad-dependent transcription. Moreover, MSTN inhibited myod gene expression and myoblast fusion in an Activin receptor-like kinase/Smad3-dependent manner. Preincubation of skeletal myoblasts with IGF-1 blocked MSTN-induced Smad3 activation, promoting myod expression and myoblast differentiation. This inhibitory effect of IGF-1 on the MSTN signaling pathway was dependent on IGF-1 receptor, PI3K, and Akt activities. Finally, immunoprecipitation assay analysis determined that IGF-1 pretreatment increased Akt and Smad3 interaction. These results demonstrate that the IGF-1/PI3K/Akt pathway may inhibit MSTN signaling during myoblast differentiation, providing new insight to existing knowledge on the complex crosstalk between both growth factors. - Highlights: • IGF-1 inhibits Myostatin canonical signaling pathway through IGF-1R/PI3K/Akt pathway. • IGF-1 promotes myoblast differentiation through a direct blocking of Myostatin signaling pathway. • IGF-1 induces the interaction of Akt with Smad3 in skeletal myoblast.

  10. Determination of the influence of asymmetry of the electric field distribution in gaseous proportional counters on their signal amplitude

    International Nuclear Information System (INIS)

    Jagusztyn, W.

    1976-01-01

    A method is described of establishing the influence of the asymmetry of the electric field distribution in gaseous proportional counters on the amplitude of their voltage signal. A numerical evaluation of this effect demands performing calculations of the electric field in the vicinity of the anode. Using the described method of numerical solution of the Laplace equation in polar coordinates with logarythmically scaled radial dimension, it is possible to achieve the required accuracy. In the calculations of differences in amplitudes of voltage signals, for chosen trajektories of electrons liberated in the process of primary ionization, changes in the gaseous amplification factors and drift velocities of positive ions are taken into account. Experimental results prove the validity of presented theory. The results obtained are accurate enough to be applied to the design of proportional counters of non-cylindrical geometries. (author)

  11. A computerized traffic control algorithm to determine optimal traffic signal settings. Ph.D. Thesis - Toledo Univ.

    Science.gov (United States)

    Seldner, K.

    1977-01-01

    An algorithm was developed to optimally control the traffic signals at each intersection using a discrete time traffic model applicable to heavy or peak traffic. Off line optimization procedures were applied to compute the cycle splits required to minimize the lengths of the vehicle queues and delay at each intersection. The method was applied to an extensive traffic network in Toledo, Ohio. Results obtained with the derived optimal settings are compared with the control settings presently in use.

  12. IGF-1 Receptor and adhesion signaling: an important axis in determining cancer cell phenotype and therapy resistance.

    Directory of Open Access Journals (Sweden)

    Orla T Cox

    2015-07-01

    Full Text Available IGF-1R expression and activation levels generally cannot be correlated in cancer cells, suggesting that cellular proteins may modulate IGF-1R activity. Strong candidates for such modulation are found in cell-matrix and cell-cell adhesion signaling complexes. Activated IGF-1R is present at focal adhesions, where it can stabilize β1 integrin and participate in signaling complexes that promote invasiveness associated with epithelial mesenchymal transition (EMT, and resistance to therapy. Whether IGF-1R contributes to EMT or to non-invasive tumor growth may be strongly influenced by the degree of ECM engagement and the presence or absence of key proteins in IGF-1R-cell adhesion complexes. One such protein is PDLIM2, which promotes both cell polarization and EMT by regulating the stability of transcription factors including NFκB, STATs and beta catenin. PDLIM2 exhibits tumor suppressor activity, but is also highly expressed in certain invasive cancers. It is likely that distinct adhesion complex proteins modulate IGF-1R signaling during cancer progression or adaptive responses to therapy. Thus, identifying the key modulators will be important for developing effective therapeutic strategies and predictive biomarkers.

  13. Glioblastoma Stem Cells Microenvironment: The Paracrine Roles of the Niche in Drug and Radioresistance

    Directory of Open Access Journals (Sweden)

    Alessia Fidoamore

    2016-01-01

    Full Text Available Among all solid tumors, the high-grade glioma appears to be the most vascularized one. In fact, “microvascular hyperplasia” is a hallmark of GBM. An altered vascular network determines irregular blood flow, so that tumor cells spread rapidly beyond the diffusion distance of oxygen in the tissue, with the consequent formation of hypoxic or anoxic areas, where the bulk of glioblastoma stem cells (GSCs reside. The response to this event is the induction of angiogenesis, a process mediated by hypoxia inducible factors. However, this new capillary network is not efficient in maintaining a proper oxygen supply to the tumor mass, thereby causing an oxygen gradient within the neoplastic zone. This microenvironment helps GSCs to remain in a “quiescent” state preserving their potential to proliferate and differentiate, thus protecting them by the effects of chemo- and radiotherapy. Recent evidences suggest that responses of glioblastoma to standard therapies are determined by the microenvironment of the niche, where the GSCs reside, allowing a variety of mechanisms that contribute to the chemo- and radioresistance, by preserving GSCs. It is, therefore, crucial to investigate the components/factors of the niche in order to formulate new adjuvant therapies rendering more efficiently the gold standard therapies for this neoplasm.

  14. Determination of the off-shell Higgs boson signal strength in the high-mass $ZZ$ and $WW$ final states with the ATLAS detector

    CERN Document Server

    Aad, Georges; Abdallah, Jalal; Abdinov, Ovsat; Aben, Rosemarie; Abolins, Maris; AbouZeid, Ossama; Abramowicz, Halina; Abreu, Henso; Abreu, Ricardo; Abulaiti, Yiming; Acharya, Bobby Samir; Adamczyk, Leszek; Adams, David; Adelman, Jahred; Adomeit, Stefanie; Adye, Tim; Affolder, Tony; Agatonovic-Jovin, Tatjana; Aguilar-Saavedra, Juan Antonio; Agustoni, Marco; Ahlen, Steven; Ahmadov, Faig; Aielli, Giulio; Akerstedt, Henrik; Åkesson, Torsten Paul Ake; Akimoto, Ginga; Akimov, Andrei; Alberghi, Gian Luigi; Albert, Justin; Albrand, Solveig; Alconada Verzini, Maria Josefina; Aleksa, Martin; Aleksandrov, Igor; Alexa, Calin; Alexander, Gideon; Alexopoulos, Theodoros; Alhroob, Muhammad; Alimonti, Gianluca; Alio, Lion; Alison, John; Allbrooke, Benedict; Allport, Phillip; Aloisio, Alberto; Alonso, Alejandro; Alonso, Francisco; Alpigiani, Cristiano; Altheimer, Andrew David; Alvarez Gonzalez, Barbara; Άlvarez Piqueras, Damián; Alviggi, Mariagrazia; Amako, Katsuya; Amaral Coutinho, Yara; Amelung, Christoph; Amidei, Dante; Amor Dos Santos, Susana Patricia; Amorim, Antonio; Amoroso, Simone; Amram, Nir; Amundsen, Glenn; Anastopoulos, Christos; Ancu, Lucian Stefan; Andari, Nansi; Andeen, Timothy; Anders, Christoph Falk; Anders, Gabriel; Anderson, Kelby; Andreazza, Attilio; Andrei, George Victor; Angelidakis, Stylianos; Angelozzi, Ivan; Anger, Philipp; Angerami, Aaron; Anghinolfi, Francis; Anisenkov, Alexey; Anjos, Nuno; Annovi, Alberto; Antonelli, Mario; Antonov, Alexey; Antos, Jaroslav; Anulli, Fabio; Aoki, Masato; Aperio Bella, Ludovica; Arabidze, Giorgi; Arai, Yasuo; Araque, Juan Pedro; Arce, Ayana; Arduh, Francisco Anuar; Arguin, Jean-Francois; Argyropoulos, Spyridon; Arik, Metin; Armbruster, Aaron James; Arnaez, Olivier; Arnal, Vanessa; Arnold, Hannah; Arratia, Miguel; Arslan, Ozan; Artamonov, Andrei; Artoni, Giacomo; Asai, Shoji; Asbah, Nedaa; Ashkenazi, Adi; Åsman, Barbro; Asquith, Lily; Assamagan, Ketevi; Astalos, Robert; Atkinson, Markus; Atlay, Naim Bora; Auerbach, Benjamin; Augsten, Kamil; Aurousseau, Mathieu; Avolio, Giuseppe; Axen, Bradley; Ayoub, Mohamad Kassem; Azuelos, Georges; Baak, Max; Baas, Alessandra; Bacci, Cesare; Bachacou, Henri; Bachas, Konstantinos; Backes, Moritz; Backhaus, Malte; Badescu, Elisabeta; Bagiacchi, Paolo; Bagnaia, Paolo; Bai, Yu; Bain, Travis; Baines, John; Baker, Oliver Keith; Balek, Petr; Balestri, Thomas; Balli, Fabrice; Banas, Elzbieta; Banerjee, Swagato; Bannoura, Arwa A E; Bansil, Hardeep Singh; Barak, Liron; Baranov, Sergei; Barberio, Elisabetta Luigia; Barberis, Dario; Barbero, Marlon; Barillari, Teresa; Barisonzi, Marcello; Barklow, Timothy; Barlow, Nick; Barnes, Sarah Louise; Barnett, Bruce; Barnett, Michael; Barnovska, Zuzana; Baroncelli, Antonio; Barone, Gaetano; Barr, Alan; Barreiro, Fernando; Barreiro Guimarães da Costa, João; Bartoldus, Rainer; Barton, Adam Edward; Bartos, Pavol; Bassalat, Ahmed; Basye, Austin; Bates, Richard; Batista, Santiago Juan; Batley, Richard; Battaglia, Marco; Bauce, Matteo; Bauer, Florian; Bawa, Harinder Singh; Beacham, James Baker; Beattie, Michael David; Beau, Tristan; Beauchemin, Pierre-Hugues; Beccherle, Roberto; Bechtle, Philip; Beck, Hans Peter; Becker, Anne Kathrin; Becker, Maurice; Becker, Sebastian; Beckingham, Matthew; Becot, Cyril; Beddall, Andrew; Beddall, Ayda; Bednyakov, Vadim; Bee, Christopher; Beemster, Lars; Beermann, Thomas; Begel, Michael; Behr, Katharina; Belanger-Champagne, Camille; Bell, Paul; Bell, William; Bella, Gideon; Bellagamba, Lorenzo; Bellerive, Alain; Bellomo, Massimiliano; Belotskiy, Konstantin; Beltramello, Olga; Benary, Odette; Benchekroun, Driss; Bender, Michael; Bendtz, Katarina; Benekos, Nektarios; Benhammou, Yan; Benhar Noccioli, Eleonora; Benitez Garcia, Jorge-Armando; Benjamin, Douglas; Bensinger, James; Bentvelsen, Stan; Beresford, Lydia; Beretta, Matteo; Berge, David; Bergeaas Kuutmann, Elin; Berger, Nicolas; Berghaus, Frank; Beringer, Jürg; Bernard, Clare; Bernard, Nathan Rogers; Bernius, Catrin; Bernlochner, Florian Urs; Berry, Tracey; Berta, Peter; Bertella, Claudia; Bertoli, Gabriele; Bertolucci, Federico; Bertsche, Carolyn; Bertsche, David; Besana, Maria Ilaria; Besjes, Geert-Jan; Bessidskaia Bylund, Olga; Bessner, Martin Florian; Besson, Nathalie; Betancourt, Christopher; Bethke, Siegfried; Bevan, Adrian John; Bhimji, Wahid; Bianchi, Riccardo-Maria; Bianchini, Louis; Bianco, Michele; Biebel, Otmar; Bieniek, Stephen Paul; Biglietti, Michela; Bilbao De Mendizabal, Javier; Bilokon, Halina; Bindi, Marcello; Binet, Sebastien; Bingul, Ahmet; Bini, Cesare; Black, Curtis; Black, James; Black, Kevin; Blackburn, Daniel; Blair, Robert; Blanchard, Jean-Baptiste; Blanco, Jacobo Ezequiel; Blazek, Tomas; Bloch, Ingo; Blocker, Craig; Blum, Walter; Blumenschein, Ulrike; Bobbink, Gerjan; Bobrovnikov, Victor; Bocchetta, Simona Serena; Bocci, Andrea; Bock, Christopher; Boehler, Michael; Bogaerts, Joannes Andreas; Bogdanchikov, Alexander; Bohm, Christian; Boisvert, Veronique; Bold, Tomasz; Boldea, Venera; Boldyrev, Alexey; Bomben, Marco; Bona, Marcella; Boonekamp, Maarten; Borisov, Anatoly; Borissov, Guennadi; Borroni, Sara; Bortfeldt, Jonathan; Bortolotto, Valerio; Bos, Kors; Boscherini, Davide; Bosman, Martine; Boudreau, Joseph; Bouffard, Julian; Bouhova-Thacker, Evelina Vassileva; Boumediene, Djamel Eddine; Bourdarios, Claire; Bousson, Nicolas; Boutouil, Sara; Boveia, Antonio; Boyd, James; Boyko, Igor; Bozic, Ivan; Bracinik, Juraj; Brandt, Andrew; Brandt, Gerhard; Brandt, Oleg; Bratzler, Uwe; Brau, Benjamin; Brau, James; Braun, Helmut; Brazzale, Simone Federico; Brendlinger, Kurt; Brennan, Amelia Jean; Brenner, Lydia; Brenner, Richard; Bressler, Shikma; Bristow, Kieran; Bristow, Timothy Michael; Britton, Dave; Britzger, Daniel; Brochu, Frederic; Brock, Ian; Brock, Raymond; Bronner, Johanna; Brooijmans, Gustaaf; Brooks, Timothy; Brooks, William; Brosamer, Jacquelyn; Brost, Elizabeth; Brown, Jonathan; Bruckman de Renstrom, Pawel; Bruncko, Dusan; Bruneliere, Renaud; Bruni, Alessia; Bruni, Graziano; Bruschi, Marco; Bryngemark, Lene; Buanes, Trygve; Buat, Quentin; Buchholz, Peter; Buckley, Andrew; Buda, Stelian Ioan; Budagov, Ioulian; Buehrer, Felix; Bugge, Lars; Bugge, Magnar Kopangen; Bulekov, Oleg; Burckhart, Helfried; Burdin, Sergey; Burghgrave, Blake; Burke, Stephen; Burmeister, Ingo; Busato, Emmanuel; Büscher, Daniel; Büscher, Volker; Bussey, Peter; Buszello, Claus-Peter; Butler, John; Butt, Aatif Imtiaz; Buttar, Craig; Butterworth, Jonathan; Butti, Pierfrancesco; Buttinger, William; Buzatu, Adrian; Buzykaev, Aleksey; Cabrera Urbán, Susana; Caforio, Davide; Cakir, Orhan; Calafiura, Paolo; Calandri, Alessandro; Calderini, Giovanni; Calfayan, Philippe; Caloba, Luiz; Calvet, David; Calvet, Samuel; Camacho Toro, Reina; Camarda, Stefano; Cameron, David; Caminada, Lea Michaela; Caminal Armadans, Roger; Campana, Simone; Campanelli, Mario; Campoverde, Angel; Canale, Vincenzo; Canepa, Anadi; Cano Bret, Marc; Cantero, Josu; Cantrill, Robert; Cao, Tingting; Capeans Garrido, Maria Del Mar; Caprini, Irinel; Caprini, Mihai; Capua, Marcella; Caputo, Regina; Cardarelli, Roberto; Carli, Tancredi; Carlino, Gianpaolo; Carminati, Leonardo; Caron, Sascha; Carquin, Edson; Carrillo-Montoya, German D; Carter, Janet; Carvalho, João; Casadei, Diego; Casado, Maria Pilar; Casolino, Mirkoantonio; Castaneda-Miranda, Elizabeth; Castelli, Angelantonio; Castillo Gimenez, Victoria; Castro, Nuno Filipe; Catastini, Pierluigi; Catinaccio, Andrea; Catmore, James; Cattai, Ariella; Caudron, Julien; Cavaliere, Viviana; Cavalli, Donatella; Cavalli-Sforza, Matteo; Cavasinni, Vincenzo; Ceradini, Filippo; Cerio, Benjamin; Cerny, Karel; Santiago Cerqueira, Augusto; Cerri, Alessandro; Cerrito, Lucio; Cerutti, Fabio; Cerv, Matevz; Cervelli, Alberto; Cetin, Serkant Ali; Chafaq, Aziz; Chakraborty, Dhiman; Chalupkova, Ina; Chang, Philip; Chapleau, Bertrand; Chapman, John Derek; Charlton, Dave; Chau, Chav Chhiv; Chavez Barajas, Carlos Alberto; Cheatham, Susan; Chegwidden, Andrew; Chekanov, Sergei; Chekulaev, Sergey; Chelkov, Gueorgui; Chelstowska, Magda Anna; Chen, Chunhui; Chen, Hucheng; Chen, Karen; Chen, Liming; Chen, Shenjian; Chen, Xin; Chen, Ye; Cheng, Hok Chuen; Cheng, Yangyang; Cheplakov, Alexander; Cheremushkina, Evgenia; Cherkaoui El Moursli, Rajaa; Chernyatin, Valeriy; Cheu, Elliott; Chevalier, Laurent; Chiarella, Vitaliano; Childers, John Taylor; Chiodini, Gabriele; Chisholm, Andrew; Chislett, Rebecca Thalatta; Chitan, Adrian; Chizhov, Mihail; Choi, Kyungeon; Chouridou, Sofia; Chow, Bonnie Kar Bo; Christodoulou, Valentinos; Chromek-Burckhart, Doris; Chu, Ming-Lee; Chudoba, Jiri; Chuinard, Annabelle Julia; Chwastowski, Janusz; Chytka, Ladislav; Ciapetti, Guido; Ciftci, Abbas Kenan; Cinca, Diane; Cindro, Vladimir; Cioara, Irina Antonela; Ciocio, Alessandra; Citron, Zvi Hirsh; Ciubancan, Mihai; Clark, Allan G; Clark, Brian Lee; Clark, Philip James; Clarke, Robert; Cleland, Bill; Clement, Christophe; Coadou, Yann; Cobal, Marina; Coccaro, Andrea; Cochran, James H; Coffey, Laurel; Cogan, Joshua Godfrey; Cole, Brian; Cole, Stephen; Colijn, Auke-Pieter; Collot, Johann; Colombo, Tommaso; Compostella, Gabriele; Conde Muiño, Patricia; Coniavitis, Elias; Connell, Simon Henry; Connelly, Ian; Consonni, Sofia Maria; Consorti, Valerio; Constantinescu, Serban; Conta, Claudio; Conti, Geraldine; Conventi, Francesco; Cooke, Mark; Cooper, Ben; Cooper-Sarkar, Amanda; Copic, Katherine; Cornelissen, Thijs; Corradi, Massimo; Corriveau, Francois; Corso-Radu, Alina; Cortes-Gonzalez, Arely; Cortiana, Giorgio; Costa, Giuseppe; Costa, María José; Costanzo, Davide; Côté, David; Cottin, Giovanna; Cowan, Glen; Cox, Brian; Cranmer, Kyle; Cree, Graham; Crépé-Renaudin, Sabine; Crescioli, Francesco; Cribbs, Wayne Allen; Crispin Ortuzar, Mireia; Cristinziani, Markus; Croft, Vince; Crosetti, Giovanni; Cuhadar Donszelmann, Tulay; Cummings, Jane; Curatolo, Maria; Cuthbert, Cameron; Czirr, Hendrik; Czodrowski, Patrick; D'Auria, Saverio; D'Onofrio, Monica; Da Cunha Sargedas De Sousa, Mario Jose; Da Via, Cinzia; Dabrowski, Wladyslaw; Dafinca, Alexandru; Dai, Tiesheng; Dale, Orjan; Dallaire, Frederick; Dallapiccola, Carlo; Dam, Mogens; Dandoy, Jeffrey Rogers; Daniells, Andrew Christopher; Danninger, Matthias; Dano Hoffmann, Maria; Dao, Valerio; Darbo, Giovanni; Darmora, Smita; Dassoulas, James; Dattagupta, Aparajita; Davey, Will; David, Claire; Davidek, Tomas; Davies, Eleanor; Davies, Merlin; Davison, Peter; Davygora, Yuriy; Dawe, Edmund; Dawson, Ian; Daya-Ishmukhametova, Rozmin; De, Kaushik; de Asmundis, Riccardo; De Castro, Stefano; De Cecco, Sandro; De Groot, Nicolo; de Jong, Paul; De la Torre, Hector; De Lorenzi, Francesco; De Nooij, Lucie; De Pedis, Daniele; De Salvo, Alessandro; De Sanctis, Umberto; De Santo, Antonella; De Vivie De Regie, Jean-Baptiste; Dearnaley, William James; Debbe, Ramiro; Debenedetti, Chiara; Dedovich, Dmitri; Deigaard, Ingrid; Del Peso, Jose; Del Prete, Tarcisio; Delgove, David; Deliot, Frederic; Delitzsch, Chris Malena; Deliyergiyev, Maksym; Dell'Acqua, Andrea; Dell'Asta, Lidia; Dell'Orso, Mauro; Della Pietra, Massimo; della Volpe, Domenico; Delmastro, Marco; Delsart, Pierre-Antoine; Deluca, Carolina; DeMarco, David; Demers, Sarah; Demichev, Mikhail; Demilly, Aurelien; Denisov, Sergey; Derendarz, Dominik; Derkaoui, Jamal Eddine; Derue, Frederic; Dervan, Paul; Desch, Klaus Kurt; Deterre, Cecile; Deviveiros, Pier-Olivier; Dewhurst, Alastair; Dhaliwal, Saminder; Di Ciaccio, Anna; Di Ciaccio, Lucia; Di Domenico, Antonio; Di Donato, Camilla; Di Girolamo, Alessandro; Di Girolamo, Beniamino; Di Mattia, Alessandro; Di Micco, Biagio; Di Nardo, Roberto; Di Simone, Andrea; Di Sipio, Riccardo; Di Valentino, David; Diaconu, Cristinel; Diamond, Miriam; Dias, Flavia; Diaz, Marco Aurelio; Diehl, Edward; Dietrich, Janet; Diglio, Sara; Dimitrievska, Aleksandra; Dingfelder, Jochen; Dittus, Fridolin; Djama, Fares; Djobava, Tamar; Djuvsland, Julia Isabell; Barros do Vale, Maria Aline; Dobos, Daniel; Dobre, Monica; Doglioni, Caterina; Dohmae, Takeshi; Dolejsi, Jiri; Dolezal, Zdenek; Dolgoshein, Boris; Donadelli, Marisilvia; Donati, Simone; Dondero, Paolo; Donini, Julien; Dopke, Jens; Doria, Alessandra; Dova, Maria-Teresa; Doyle, Tony; Drechsler, Eric; Dris, Manolis; Dubreuil, Emmanuelle; Duchovni, Ehud; Duckeck, Guenter; Ducu, Otilia Anamaria; Duda, Dominik; Dudarev, Alexey; Duflot, Laurent; Duguid, Liam; Dührssen, Michael; Dunford, Monica; Duran Yildiz, Hatice; Düren, Michael; Durglishvili, Archil; Duschinger, Dirk; Dwuznik, Michal; Dyndal, Mateusz; Eckardt, Christoph; Ecker, Katharina Maria; Edson, William; Edwards, Nicholas Charles; Ehrenfeld, Wolfgang; Eifert, Till; Eigen, Gerald; Einsweiler, Kevin; Ekelof, Tord; El Kacimi, Mohamed; Ellert, Mattias; Elles, Sabine; Ellinghaus, Frank; Elliot, Alison; Ellis, Nicolas; Elmsheuser, Johannes; Elsing, Markus; Emeliyanov, Dmitry; Enari, Yuji; Endner, Oliver Chris; Endo, Masaki; Engelmann, Roderich; Erdmann, Johannes; Ereditato, Antonio; Ernis, Gunar; Ernst, Jesse; Ernst, Michael; Errede, Steven; Ertel, Eugen; Escalier, Marc; Esch, Hendrik; Escobar, Carlos; Esposito, Bellisario; Etienvre, Anne-Isabelle; Etzion, Erez; Evans, Hal; Ezhilov, Alexey; Fabbri, Laura; Facini, Gabriel; Fakhrutdinov, Rinat; Falciano, Speranza; Falla, Rebecca Jane; Faltova, Jana; Fang, Yaquan; Fanti, Marcello; Farbin, Amir; Farilla, Addolorata; Farooque, Trisha; Farrell, Steven; Farrington, Sinead; Farthouat, Philippe; Fassi, Farida; Fassnacht, Patrick; Fassouliotis, Dimitrios; Favareto, Andrea; Fayard, Louis; Federic, Pavol; Fedin, Oleg; Fedorko, Wojciech; Feigl, Simon; Feligioni, Lorenzo; Feng, Cunfeng; Feng, Eric; Feng, Haolu; Fenyuk, Alexander; Fernandez Martinez, Patricia; Fernandez Perez, Sonia; Ferrag, Samir; Ferrando, James; Ferrari, Arnaud; Ferrari, Pamela; Ferrari, Roberto; Ferreira de Lima, Danilo Enoque; Ferrer, Antonio; Ferrere, Didier; Ferretti, Claudio; Ferretto Parodi, Andrea; Fiascaris, Maria; Fiedler, Frank; Filipčič, Andrej; Filipuzzi, Marco; Filthaut, Frank; Fincke-Keeler, Margret; Finelli, Kevin Daniel; Fiolhais, Miguel; Fiorini, Luca; Firan, Ana; Fischer, Adam; Fischer, Cora; Fischer, Julia; Fisher, Wade Cameron; Fitzgerald, Eric Andrew; Flechl, Martin; Fleck, Ivor; Fleischmann, Philipp; Fleischmann, Sebastian; Fletcher, Gareth Thomas; Fletcher, Gregory; Flick, Tobias; Floderus, Anders; Flores Castillo, Luis; Flowerdew, Michael; Formica, Andrea; Forti, Alessandra; Fournier, Daniel; Fox, Harald; Fracchia, Silvia; Francavilla, Paolo; Franchini, Matteo; Francis, David; Franconi, Laura; Franklin, Melissa; Fraternali, Marco; Freeborn, David; French, Sky; Friedrich, Felix; Froidevaux, Daniel; Frost, James; Fukunaga, Chikara; Fullana Torregrosa, Esteban; Fulsom, Bryan Gregory; Fuster, Juan; Gabaldon, Carolina; Gabizon, Ofir; Gabrielli, Alessandro; Gabrielli, Andrea; Gadatsch, Stefan; Gadomski, Szymon; Gagliardi, Guido; Gagnon, Pauline; Galea, Cristina; Galhardo, Bruno; Gallas, Elizabeth; Gallop, Bruce; Gallus, Petr; Galster, Gorm Aske Gram Krohn; Gan, KK; Gao, Jun; Gao, Yanyan; Gao, Yongsheng; Garay Walls, Francisca; Garberson, Ford; García, Carmen; García Navarro, José Enrique; Garcia-Sciveres, Maurice; Gardner, Robert; Garelli, Nicoletta; Garonne, Vincent; Gatti, Claudio; Gaudiello, Andrea; Gaudio, Gabriella; Gaur, Bakul; Gauthier, Lea; Gauzzi, Paolo; Gavrilenko, Igor; Gay, Colin; Gaycken, Goetz; Gazis, Evangelos; Ge, Peng; Gecse, Zoltan; Gee, Norman; Geerts, Daniël Alphonsus Adrianus; Geich-Gimbel, Christoph; Geisler, Manuel Patrice; Gemme, Claudia; Genest, Marie-Hélène; Gentile, Simonetta; George, Matthias; George, Simon; Gerbaudo, Davide; Gershon, Avi; Ghazlane, Hamid; Ghodbane, Nabil; Giacobbe, Benedetto; Giagu, Stefano; Giangiobbe, Vincent; Giannetti, Paola; Gibbard, Bruce; Gibson, Stephen; Gilchriese, Murdock; Gillam, Thomas; Gillberg, Dag; Gilles, Geoffrey; Gingrich, Douglas; Giokaris, Nikos; Giordani, MarioPaolo; Giorgi, Filippo Maria; Giorgi, Francesco Michelangelo; Giraud, Pierre-Francois; Giromini, Paolo; Giugni, Danilo; Giuliani, Claudia; Giulini, Maddalena; Gjelsten, Børge Kile; Gkaitatzis, Stamatios; Gkialas, Ioannis; Gkougkousis, Evangelos Leonidas; Gladilin, Leonid; Glasman, Claudia; Glatzer, Julian; Glaysher, Paul; Glazov, Alexandre; Goblirsch-Kolb, Maximilian; Goddard, Jack Robert; Godlewski, Jan; Goldfarb, Steven; Golling, Tobias; Golubkov, Dmitry; Gomes, Agostinho; Gonçalo, Ricardo; Goncalves Pinto Firmino Da Costa, Joao; Gonella, Laura; González de la Hoz, Santiago; Gonzalez Parra, Garoe; Gonzalez-Sevilla, Sergio; Goossens, Luc; Gorbounov, Petr Andreevich; Gordon, Howard; Gorelov, Igor; Gorini, Benedetto; Gorini, Edoardo; Gorišek, Andrej; Gornicki, Edward; Goshaw, Alfred; Gössling, Claus; Gostkin, Mikhail Ivanovitch; Goujdami, Driss; Goussiou, Anna; Govender, Nicolin; Grabas, Herve Marie Xavier; Graber, Lars; Grabowska-Bold, Iwona; Grafström, Per; Grahn, Karl-Johan; Gramling, Johanna; Gramstad, Eirik; Grancagnolo, Sergio; Grassi, Valerio; Gratchev, Vadim; Gray, Heather; Graziani, Enrico; Greenwood, Zeno Dixon; Gregersen, Kristian; Gregor, Ingrid-Maria; Grenier, Philippe; Griffiths, Justin; Grillo, Alexander; Grimm, Kathryn; Grinstein, Sebastian; Gris, Philippe Luc Yves; Grishkevich, Yaroslav; Grivaz, Jean-Francois; Grohs, Johannes Philipp; Grohsjean, Alexander; Gross, Eilam; Grosse-Knetter, Joern; Grossi, Giulio Cornelio; Grout, Zara Jane; Guan, Liang; Guenther, Jaroslav; Guescini, Francesco; Guest, Daniel; Gueta, Orel; Guido, Elisa; Guillemin, Thibault; Guindon, Stefan; Gul, Umar; Gumpert, Christian; Guo, Jun; Gupta, Shaun; Gutierrez, Phillip; Gutierrez Ortiz, Nicolas Gilberto; Gutschow, Christian; Guyot, Claude; Gwenlan, Claire; Gwilliam, Carl; Haas, Andy; Haber, Carl; Hadavand, Haleh Khani; Haddad, Nacim; Haefner, Petra; Hageböck, Stephan; Hajduk, Zbigniew; Hakobyan, Hrachya; Haleem, Mahsana; Haley, Joseph; Hall, David; Halladjian, Garabed; Hallewell, Gregory David; Hamacher, Klaus; Hamal, Petr; Hamano, Kenji; Hamer, Matthias; Hamilton, Andrew; Hamilton, Samuel; Hamity, Guillermo Nicolas; Hamnett, Phillip George; Han, Liang; Hanagaki, Kazunori; Hanawa, Keita; Hance, Michael; Hanke, Paul; Hanna, Remie; Hansen, Jørgen Beck; Hansen, Jorn Dines; Hansen, Maike Christina; Hansen, Peter Henrik; Hara, Kazuhiko; Hard, Andrew; Harenberg, Torsten; Hariri, Faten; Harkusha, Siarhei; Harrington, Robert; Harrison, Paul Fraser; Hartjes, Fred; Hasegawa, Makoto; Hasegawa, Satoshi; Hasegawa, Yoji; Hasib, A; Hassani, Samira; Haug, Sigve; Hauser, Reiner; Hauswald, Lorenz; Havranek, Miroslav; Hawkes, Christopher; Hawkings, Richard John; Hawkins, Anthony David; Hayashi, Takayasu; Hayden, Daniel; Hays, Chris; Hays, Jonathan Michael; Hayward, Helen; Haywood, Stephen; Head, Simon; Heck, Tobias; Hedberg, Vincent; Heelan, Louise; Heim, Sarah; Heim, Timon; Heinemann, Beate; Heinrich, Lukas; Hejbal, Jiri; Helary, Louis; Hellman, Sten; Hellmich, Dennis; Helsens, Clement; Henderson, James; Henderson, Robert; Heng, Yang; Hengler, Christopher; Henrichs, Anna; Henriques Correia, Ana Maria; Henrot-Versille, Sophie; Herbert, Geoffrey Henry; Hernández Jiménez, Yesenia; Herrberg-Schubert, Ruth; Herten, Gregor; Hertenberger, Ralf; Hervas, Luis; Hesketh, Gavin Grant; Hessey, Nigel; Hetherly, Jeffrey Wayne; Hickling, Robert; Higón-Rodriguez, Emilio; Hill, Ewan; Hill, John; Hiller, Karl Heinz; Hillier, Stephen; Hinchliffe, Ian; Hines, Elizabeth; Hinman, Rachel Reisner; Hirose, Minoru; Hirschbuehl, Dominic; Hobbs, John; Hod, Noam; Hodgkinson, Mark; Hodgson, Paul; Hoecker, Andreas; Hoeferkamp, Martin; Hoenig, Friedrich; Hohlfeld, Marc; Hohn, David; Holmes, Tova Ray; Hong, Tae Min; Hooft van Huysduynen, Loek; Hopkins, Walter; Horii, Yasuyuki; Horton, Arthur James; Hostachy, Jean-Yves; Hou, Suen; Hoummada, Abdeslam; Howard, Jacob; Howarth, James; Hrabovsky, Miroslav; Hristova, Ivana; Hrivnac, Julius; Hryn'ova, Tetiana; Hrynevich, Aliaksei; Hsu, Catherine; Hsu, Pai-hsien Jennifer; Hsu, Shih-Chieh; Hu, Diedi; Hu, Qipeng; Hu, Xueye; Huang, Yanping; Hubacek, Zdenek; Hubaut, Fabrice; Huegging, Fabian; Huffman, Todd Brian; Hughes, Emlyn; Hughes, Gareth; Huhtinen, Mika; Hülsing, Tobias Alexander; Huseynov, Nazim; Huston, Joey; Huth, John; Iacobucci, Giuseppe; Iakovidis, Georgios; Ibragimov, Iskander; Iconomidou-Fayard, Lydia; Ideal, Emma; Idrissi, Zineb; Iengo, Paolo; Igonkina, Olga; Iizawa, Tomoya; Ikegami, Yoichi; Ikematsu, Katsumasa; Ikeno, Masahiro; Ilchenko, Iurii; Iliadis, Dimitrios; Ilic, Nikolina; Inamaru, Yuki; Ince, Tayfun; Ioannou, Pavlos; Iodice, Mauro; Iordanidou, Kalliopi; Ippolito, Valerio; Irles Quiles, Adrian; Isaksson, Charlie; Ishino, Masaya; Ishitsuka, Masaki; Ishmukhametov, Renat; Issever, Cigdem; Istin, Serhat; Iturbe Ponce, Julia Mariana; Iuppa, Roberto; Ivarsson, Jenny; Iwanski, Wieslaw; Iwasaki, Hiroyuki; Izen, Joseph; Izzo, Vincenzo; Jabbar, Samina; Jackson, Brett; Jackson, Matthew; Jackson, Paul; Jaekel, Martin; Jain, Vivek; Jakobs, Karl; Jakobsen, Sune; Jakoubek, Tomas; Jakubek, Jan; Jamin, David Olivier; Jana, Dilip; Jansen, Eric; Jansky, Roland; Janssen, Jens; Janus, Michel; Jarlskog, Göran; Javadov, Namig; Javůrek, Tomáš; Jeanty, Laura; Jejelava, Juansher; Jeng, Geng-yuan; Jennens, David; Jenni, Peter; Jentzsch, Jennifer; Jeske, Carl; Jézéquel, Stéphane; Ji, Haoshuang; Jia, Jiangyong; Jiang, Yi; Jimenez Pena, Javier; Jin, Shan; Jinaru, Adam; Jinnouchi, Osamu; Joergensen, Morten Dam; Johansson, Per; Johns, Kenneth; Jon-And, Kerstin; Jones, Graham; Jones, Roger; Jones, Tim; Jongmanns, Jan; Jorge, Pedro; Joshi, Kiran Daniel; Jovicevic, Jelena; Ju, Xiangyang; Jung, Christian; Jussel, Patrick; Juste Rozas, Aurelio; Kaci, Mohammed; Kaczmarska, Anna; Kado, Marumi; Kagan, Harris; Kagan, Michael; Kahn, Sebastien Jonathan; Kajomovitz, Enrique; Kalderon, Charles William; Kama, Sami; Kamenshchikov, Andrey; Kanaya, Naoko; Kaneda, Michiru; Kaneti, Steven; Kantserov, Vadim; Kanzaki, Junichi; Kaplan, Benjamin; Kapliy, Anton; Kar, Deepak; Karakostas, Konstantinos; Karamaoun, Andrew; Karastathis, Nikolaos; Kareem, Mohammad Jawad; Karnevskiy, Mikhail; Karpov, Sergey; Karpova, Zoya; Karthik, Krishnaiyengar; Kartvelishvili, Vakhtang; Karyukhin, Andrey; Kashif, Lashkar; Kass, Richard; Kastanas, Alex; Kataoka, Yousuke; Katre, Akshay; Katzy, Judith; Kawagoe, Kiyotomo; Kawamoto, Tatsuo; Kawamura, Gen; Kazama, Shingo; Kazanin, Vassili; Kazarinov, Makhail; Keeler, Richard; Kehoe, Robert; Keil, Markus; Keller, John; Kempster, Jacob Julian; Keoshkerian, Houry; Kepka, Oldrich; Kerševan, Borut Paul; Kersten, Susanne; Keyes, Robert; Khalil-zada, Farkhad; Khandanyan, Hovhannes; Khanov, Alexander; Kharlamov, Alexey; Khoo, Teng Jian; Khoriauli, Gia; Khovanskiy, Valery; Khramov, Evgeniy; Khubua, Jemal; Kim, Hee Yeun; Kim, Hyeon Jin; Kim, Shinhong; Kim, Young-Kee; Kimura, Naoki; Kind, Oliver Maria; King, Barry; King, Matthew; King, Robert Steven Beaufoy; King, Samuel Burton; Kirk, Julie; Kiryunin, Andrey; Kishimoto, Tomoe; Kisielewska, Danuta; Kiss, Florian; Kiuchi, Kenji; Kladiva, Eduard; Klein, Matthew Henry; Klein, Max; Klein, Uta; Kleinknecht, Konrad; Klimek, Pawel; Klimentov, Alexei; Klingenberg, Reiner; Klinger, Joel Alexander; Klioutchnikova, Tatiana; Klok, Peter; Kluge, Eike-Erik; Kluit, Peter; Kluth, Stefan; Kneringer, Emmerich; Knoops, Edith; Knue, Andrea; Kobayashi, Dai; Kobayashi, Tomio; Kobel, Michael; Kocian, Martin; Kodys, Peter; Koffas, Thomas; Koffeman, Els; Kogan, Lucy Anne; Kohlmann, Simon; Kohout, Zdenek; Kohriki, Takashi; Koi, Tatsumi; Kolanoski, Hermann; Koletsou, Iro; Komar, Aston; Komori, Yuto; Kondo, Takahiko; Kondrashova, Nataliia; Köneke, Karsten; König, Adriaan; König, Sebastian; Kono, Takanori; Konoplich, Rostislav; Konstantinidis, Nikolaos; Kopeliansky, Revital; Koperny, Stefan; Köpke, Lutz; Kopp, Anna Katharina; Korcyl, Krzysztof; Kordas, Kostantinos; Korn, Andreas; Korol, Aleksandr; Korolkov, Ilya; Korolkova, Elena; Kortner, Oliver; Kortner, Sandra; Kosek, Tomas; Kostyukhin, Vadim; Kotov, Vladislav; Kotwal, Ashutosh; Kourkoumeli-Charalampidi, Athina; Kourkoumelis, Christine; Kouskoura, Vasiliki; Koutsman, Alex; Kowalewski, Robert Victor; Kowalski, Tadeusz; Kozanecki, Witold; Kozhin, Anatoly; Kramarenko, Viktor; Kramberger, Gregor; Krasnopevtsev, Dimitriy; Krasny, Mieczyslaw Witold; Krasznahorkay, Attila; Kraus, Jana; Kravchenko, Anton; Kreiss, Sven; Kretz, Moritz; Kretzschmar, Jan; Kreutzfeldt, Kristof; Krieger, Peter; Krizka, Karol; Kroeninger, Kevin; Kroha, Hubert; Kroll, Joe; Kroseberg, Juergen; Krstic, Jelena; Kruchonak, Uladzimir; Krüger, Hans; Krumnack, Nils; Krumshteyn, Zinovii; Kruse, Amanda; Kruse, Mark; Kruskal, Michael; Kubota, Takashi; Kucuk, Hilal; Kuday, Sinan; Kuehn, Susanne; Kugel, Andreas; Kuger, Fabian; Kuhl, Andrew; Kuhl, Thorsten; Kukhtin, Victor; Kulchitsky, Yuri; Kuleshov, Sergey; Kuna, Marine; Kunigo, Takuto; Kupco, Alexander; Kurashige, Hisaya; Kurochkin, Yurii; Kurumida, Rie; Kus, Vlastimil; Kuwertz, Emma Sian; Kuze, Masahiro; Kvita, Jiri; Kwan, Tony; Kyriazopoulos, Dimitrios; La Rosa, Alessandro; La Rosa Navarro, Jose Luis; La Rotonda, Laura; Lacasta, Carlos; Lacava, Francesco; Lacey, James; Lacker, Heiko; Lacour, Didier; Lacuesta, Vicente Ramón; Ladygin, Evgueni; Lafaye, Remi; Laforge, Bertrand; Lagouri, Theodota; Lai, Stanley; Lambourne, Luke; Lammers, Sabine; Lampen, Caleb; Lampl, Walter; Lançon, Eric; Landgraf, Ulrich; Landon, Murrough; Lang, Valerie Susanne; Lange, J örn Christian; Lankford, Andrew; Lanni, Francesco; Lantzsch, Kerstin; Laplace, Sandrine; Lapoire, Cecile; Laporte, Jean-Francois; Lari, Tommaso; Lasagni Manghi, Federico; Lassnig, Mario; Laurelli, Paolo; Lavrijsen, Wim; Law, Alexander; Laycock, Paul; Le Dortz, Olivier; Le Guirriec, Emmanuel; Le Menedeu, Eve; LeCompte, Thomas; Ledroit-Guillon, Fabienne Agnes Marie; Lee, Claire Alexandra; Lee, Shih-Chang; Lee, Lawrence; Lefebvre, Guillaume; Lefebvre, Michel; Legger, Federica; Leggett, Charles; Lehan, Allan; Lehmann Miotto, Giovanna; Lei, Xiaowen; Leight, William Axel; Leisos, Antonios; Leister, Andrew Gerard; Leite, Marco Aurelio Lisboa; Leitner, Rupert; Lellouch, Daniel; Lemmer, Boris; Leney, Katharine; Lenz, Tatjana; Lenzen, Georg; Lenzi, Bruno; Leone, Robert; Leone, Sandra; Leonidopoulos, Christos; Leontsinis, Stefanos; Leroy, Claude; Lester, Christopher; Levchenko, Mikhail; Levêque, Jessica; Levin, Daniel; Levinson, Lorne; Levy, Mark; Lewis, Adrian; Leyko, Agnieszka; Leyton, Michael; Li, Bing; Li, Haifeng; Li, Ho Ling; Li, Lei; Li, Liang; Li, Shu; Li, Yichen; Liang, Zhijun; Liao, Hongbo; Liberti, Barbara; Liblong, Aaron; Lichard, Peter; Lie, Ki; Liebal, Jessica; Liebig, Wolfgang; Limbach, Christian; Limosani, Antonio; Lin, Simon; Lin, Tai-Hua; Linde, Frank; Lindquist, Brian Edward; Linnemann, James; Lipeles, Elliot; Lipniacka, Anna; Lisovyi, Mykhailo; Liss, Tony; Lissauer, David; Lister, Alison; Litke, Alan; Liu, Bo; Liu, Dong; Liu, Jian; Liu, Jianbei; Liu, Kun; Liu, Lulu; Liu, Miaoyuan; Liu, Minghui; Liu, Yanwen; Livan, Michele; Lleres, Annick; Llorente Merino, Javier; Lloyd, Stephen; Lo Sterzo, Francesco; Lobodzinska, Ewelina; Loch, Peter; Lockman, William; Loebinger, Fred; Loevschall-Jensen, Ask Emil; Loginov, Andrey; Lohse, Thomas; Lohwasser, Kristin; Lokajicek, Milos; Long, Brian Alexander; Long, Jonathan; Long, Robin Eamonn; Looper, Kristina Anne; Lopes, Lourenco; Lopez Mateos, David; Lopez Paredes, Brais; Lopez Paz, Ivan; Lorenz, Jeanette; Lorenzo Martinez, Narei; Losada, Marta; Loscutoff, Peter; Lösel, Philipp Jonathan; Lou, XinChou; Lounis, Abdenour; Love, Jeremy; Love, Peter; Lu, Nan; Lubatti, Henry; Luci, Claudio; Lucotte, Arnaud; Luehring, Frederick; Lukas, Wolfgang; Luminari, Lamberto; Lundberg, Olof; Lund-Jensen, Bengt; Lungwitz, Matthias; Lynn, David; Lysak, Roman; Lytken, Else; Ma, Hong; Ma, Lian Liang; Maccarrone, Giovanni; Macchiolo, Anna; Macdonald, Calum Michael; Machado Miguens, Joana; Macina, Daniela; Madaffari, Daniele; Madar, Romain; Maddocks, Harvey Jonathan; Mader, Wolfgang; Madsen, Alexander; Maeland, Steffen; Maeno, Tadashi; Maevskiy, Artem; Magradze, Erekle; Mahboubi, Kambiz; Mahlstedt, Joern; Maiani, Camilla; Maidantchik, Carmen; Maier, Andreas Alexander; Maier, Thomas; Maio, Amélia; Majewski, Stephanie; Makida, Yasuhiro; Makovec, Nikola; Malaescu, Bogdan; Malecki, Pawel; Maleev, Victor; Malek, Fairouz; Mallik, Usha; Malon, David; Malone, Caitlin; Maltezos, Stavros; Malyshev, Vladimir; Malyukov, Sergei; Mamuzic, Judita; Mancini, Giada; Mandelli, Beatrice; Mandelli, Luciano; Mandić, Igor; Mandrysch, Rocco; Maneira, José; Manfredini, Alessandro; Manhaes de Andrade Filho, Luciano; Manjarres Ramos, Joany; Mann, Alexander; Manning, Peter; Manousakis-Katsikakis, Arkadios; Mansoulie, Bruno; Mantifel, Rodger; Mantoani, Matteo; Mapelli, Livio; March, Luis; Marchiori, Giovanni; Marcisovsky, Michal; Marino, Christopher; Marjanovic, Marija; Marroquim, Fernando; Marsden, Stephen Philip; Marshall, Zach; Marti, Lukas Fritz; Marti-Garcia, Salvador; Martin, Brian Thomas; Martin, Tim; Martin, Victoria Jane; Martin dit Latour, Bertrand; Martinez, Mario; Martin-Haugh, Stewart; Martoiu, Victor Sorin; Martyniuk, Alex; Marx, Marilyn; Marzano, Francesco; Marzin, Antoine; Masetti, Lucia; Mashimo, Tetsuro; Mashinistov, Ruslan; Masik, Jiri; Maslennikov, Alexey; Massa, Ignazio; Massa, Lorenzo; Massol, Nicolas; Mastrandrea, Paolo; Mastroberardino, Anna; Masubuchi, Tatsuya; Mättig, Peter; Mattmann, Johannes; Maurer, Julien; Maxfield, Stephen; Maximov, Dmitriy; Mazini, Rachid; Mazza, Simone Michele; Mazzaferro, Luca; Mc Goldrick, Garrin; Mc Kee, Shawn Patrick; McCarn, Allison; McCarthy, Robert; McCarthy, Tom; McCubbin, Norman; McFarlane, Kenneth; Mcfayden, Josh; Mchedlidze, Gvantsa; McMahon, Steve; McPherson, Robert; Medinnis, Michael; Meehan, Samuel; Mehlhase, Sascha; Mehta, Andrew; Meier, Karlheinz; Meineck, Christian; Meirose, Bernhard; Mellado Garcia, Bruce Rafael; Meloni, Federico; Mengarelli, Alberto; Menke, Sven; Meoni, Evelin; Mercurio, Kevin Michael; Mergelmeyer, Sebastian; Mermod, Philippe; Merola, Leonardo; Meroni, Chiara; Merritt, Frank; Messina, Andrea; Metcalfe, Jessica; Mete, Alaettin Serhan; Meyer, Carsten; Meyer, Christopher; Meyer, Jean-Pierre; Meyer, Jochen; Middleton, Robin; Miglioranzi, Silvia; Mijović, Liza; Mikenberg, Giora; Mikestikova, Marcela; Mikuž, Marko; Milesi, Marco; Milic, Adriana; Miller, David; Mills, Corrinne; Milov, Alexander; Milstead, David; Minaenko, Andrey; Minami, Yuto; Minashvili, Irakli; Mincer, Allen; Mindur, Bartosz; Mineev, Mikhail; Ming, Yao; Mir, Lluisa-Maria; Mitani, Takashi; Mitrevski, Jovan; Mitsou, Vasiliki A; Miucci, Antonio; Miyagawa, Paul; Mjörnmark, Jan-Ulf; Moa, Torbjoern; Mochizuki, Kazuya; Mohapatra, Soumya; Mohr, Wolfgang; Molander, Simon; Moles-Valls, Regina; Mönig, Klaus; Monini, Caterina; Monk, James; Monnier, Emmanuel; Montejo Berlingen, Javier; Monticelli, Fernando; Monzani, Simone; Moore, Roger; Morange, Nicolas; Moreno, Deywis; Moreno Llácer, María; Morettini, Paolo; Morgenstern, Marcus; Morii, Masahiro; Morisbak, Vanja; Moritz, Sebastian; Morley, Anthony Keith; Mornacchi, Giuseppe; Morris, John; Mortensen, Simon Stark; Morton, Alexander; Morvaj, Ljiljana; Moser, Hans-Guenther; Mosidze, Maia; Moss, Josh; Motohashi, Kazuki; Mount, Richard; Mountricha, Eleni; Mouraviev, Sergei; Moyse, Edward; Muanza, Steve; Mudd, Richard; Mueller, Felix; Mueller, James; Mueller, Klemens; Mueller, Ralph Soeren Peter; Mueller, Thibaut; Muenstermann, Daniel; Mullen, Paul; Munwes, Yonathan; Murillo Quijada, Javier Alberto; Murray, Bill; Musheghyan, Haykuhi; Musto, Elisa; Myagkov, Alexey; Myska, Miroslav; Nackenhorst, Olaf; Nadal, Jordi; Nagai, Koichi; Nagai, Ryo; Nagai, Yoshikazu; Nagano, Kunihiro; Nagarkar, Advait; Nagasaka, Yasushi; Nagata, Kazuki; Nagel, Martin; Nagy, Elemer; Nairz, Armin Michael; Nakahama, Yu; Nakamura, Koji; Nakamura, Tomoaki; Nakano, Itsuo; Namasivayam, Harisankar; Nanava, Gizo; Naranjo Garcia, Roger Felipe; Narayan, Rohin; Naumann, Thomas; Navarro, Gabriela; Nayyar, Ruchika; Neal, Homer; Nechaeva, Polina; Neep, Thomas James; Nef, Pascal Daniel; Negri, Andrea; Negrini, Matteo; Nektarijevic, Snezana; Nellist, Clara; Nelson, Andrew; Nemecek, Stanislav; Nemethy, Peter; Nepomuceno, Andre Asevedo; Nessi, Marzio; Neubauer, Mark; Neumann, Manuel; Neves, Ricardo; Nevski, Pavel; Newman, Paul; Nguyen, Duong Hai; Nickerson, Richard; Nicolaidou, Rosy; Nicquevert, Bertrand; Nielsen, Jason; Nikiforou, Nikiforos; Nikiforov, Andriy; Nikolaenko, Vladimir; Nikolic-Audit, Irena; Nikolopoulos, Konstantinos; Nilsen, Jon Kerr; Nilsson, Paul; Ninomiya, Yoichi; Nisati, Aleandro; Nisius, Richard; Nobe, Takuya; Nomachi, Masaharu; Nomidis, Ioannis; Nooney, Tamsin; Norberg, Scarlet; Nordberg, Markus; Novgorodova, Olga; Nowak, Sebastian; Nozaki, Mitsuaki; Nozka, Libor; Ntekas, Konstantinos; Nunes Hanninger, Guilherme; Nunnemann, Thomas; Nurse, Emily; Nuti, Francesco; O'Brien, Brendan Joseph; O'grady, Fionnbarr; O'Neil, Dugan; O'Shea, Val; Oakham, Gerald; Oberlack, Horst; Obermann, Theresa; Ocariz, Jose; Ochi, Atsuhiko; Ochoa, Ines; Oda, Susumu; Odaka, Shigeru; Ogren, Harold; Oh, Alexander; Oh, Seog; Ohm, Christian; Ohman, Henrik; Oide, Hideyuki; Okamura, Wataru; Okawa, Hideki; Okumura, Yasuyuki; Okuyama, Toyonobu; Olariu, Albert; Olivares Pino, Sebastian Andres; Oliveira Damazio, Denis; Oliver Garcia, Elena; Olszewski, Andrzej; Olszowska, Jolanta; Onofre, António; Onyisi, Peter; Oram, Christopher; Oreglia, Mark; Oren, Yona; Orestano, Domizia; Orlando, Nicola; Oropeza Barrera, Cristina; Orr, Robert; Osculati, Bianca; Ospanov, Rustem; Otero y Garzon, Gustavo; Otono, Hidetoshi; Ouchrif, Mohamed; Ouellette, Eric; Ould-Saada, Farid; Ouraou, Ahmimed; Oussoren, Koen Pieter; Ouyang, Qun; Ovcharova, Ana; Owen, Mark; Owen, Rhys Edward; Ozcan, Veysi Erkcan; Ozturk, Nurcan; Pachal, Katherine; Pacheco Pages, Andres; Padilla Aranda, Cristobal; Pagáčová, Martina; Pagan Griso, Simone; Paganis, Efstathios; Pahl, Christoph; Paige, Frank; Pais, Preema; Pajchel, Katarina; Palacino, Gabriel; Palestini, Sandro; Palka, Marek; Pallin, Dominique; Palma, Alberto; Pan, Yibin; Panagiotopoulou, Evgenia; Pandini, Carlo Enrico; Panduro Vazquez, William; Pani, Priscilla; Panitkin, Sergey; Paolozzi, Lorenzo; Papadopoulou, Theodora; Papageorgiou, Konstantinos; Paramonov, Alexander; Paredes Hernandez, Daniela; Parker, Michael Andrew; Parker, Kerry Ann; Parodi, Fabrizio; Parsons, John; Parzefall, Ulrich; Pasqualucci, Enrico; Passaggio, Stefano; Pastore, Fernanda; Pastore, Francesca; Pásztor, Gabriella; Pataraia, Sophio; Patel, Nikhul; Pater, Joleen; Pauly, Thilo; Pearce, James; Pearson, Benjamin; Pedersen, Lars Egholm; Pedersen, Maiken; Pedraza Lopez, Sebastian; Pedro, Rute; Peleganchuk, Sergey; Pelikan, Daniel; Peng, Haiping; Penning, Bjoern; Penwell, John; Perepelitsa, Dennis; Perez Codina, Estel; Pérez García-Estañ, María Teresa; Perini, Laura; Pernegger, Heinz; Perrella, Sabrina; Peschke, Richard; Peshekhonov, Vladimir; Peters, Krisztian; Peters, Yvonne; Petersen, Brian; Petersen, Troels; Petit, Elisabeth; Petridis, Andreas; Petridou, Chariclia; Petrolo, Emilio; Petrucci, Fabrizio; Pettersson, Nora Emilia; Pezoa, Raquel; Phillips, Peter William; Piacquadio, Giacinto; Pianori, Elisabetta; Picazio, Attilio; Piccaro, Elisa; Piccinini, Maurizio; Pickering, Mark Andrew; Piegaia, Ricardo; Pignotti, David; Pilcher, James; Pilkington, Andrew; Pina, João Antonio; Pinamonti, Michele; Pinfold, James; Pingel, Almut; Pinto, Belmiro; Pires, Sylvestre; Pitt, Michael; Pizio, Caterina; Plazak, Lukas; Pleier, Marc-Andre; Pleskot, Vojtech; Plotnikova, Elena; Plucinski, Pawel; Pluth, Daniel; Poettgen, Ruth; Poggioli, Luc; Pohl, David-leon; Polesello, Giacomo; Policicchio, Antonio; Polifka, Richard; Polini, Alessandro; Pollard, Christopher Samuel; Polychronakos, Venetios; Pommès, Kathy; Pontecorvo, Ludovico; Pope, Bernard; Popeneciu, Gabriel Alexandru; Popovic, Dragan; Poppleton, Alan; Pospisil, Stanislav; Potamianos, Karolos; Potrap, Igor; Potter, Christina; Potter, Christopher; Poulard, Gilbert; Poveda, Joaquin; Pozdnyakov, Valery; Pralavorio, Pascal; Pranko, Aliaksandr; Prasad, Srivas; Prell, Soeren; Price, Darren; Price, Joe; Price, Lawrence; Primavera, Margherita; Prince, Sebastien; Proissl, Manuel; Prokofiev, Kirill; Prokoshin, Fedor; Protopapadaki, Eftychia-sofia; Protopopescu, Serban; Proudfoot, James; Przybycien, Mariusz; Ptacek, Elizabeth; Puddu, Daniele; Pueschel, Elisa; Puldon, David; Purohit, Milind; Puzo, Patrick; Qian, Jianming; Qin, Gang; Qin, Yang; Quadt, Arnulf; Quarrie, David; Quayle, William; Queitsch-Maitland, Michaela; Quilty, Donnchadha; Radeka, Veljko; Radescu, Voica; Radhakrishnan, Sooraj Krishnan; Radloff, Peter; Rados, Pere; Ragusa, Francesco; Rahal, Ghita; Rajagopalan, Srinivasan; Rammensee, Michael; Rangel-Smith, Camila; Rauscher, Felix; Rave, Stefan; Ravenscroft, Thomas; Raymond, Michel; Read, Alexander Lincoln; Readioff, Nathan Peter; Rebuzzi, Daniela; Redelbach, Andreas; Redlinger, George; Reece, Ryan; Reeves, Kendall; Rehnisch, Laura; Reisin, Hernan; Relich, Matthew; Rembser, Christoph; Ren, Huan; Renaud, Adrien; Rescigno, Marco; Resconi, Silvia; Rezanova, Olga; Reznicek, Pavel; Rezvani, Reyhaneh; Richter, Robert; Richter, Stefan; Richter-Was, Elzbieta; Ricken, Oliver; Ridel, Melissa; Rieck, Patrick; Riegel, Christian Johann; Rieger, Julia; Rijssenbeek, Michael; Rimoldi, Adele; Rinaldi, Lorenzo; Ristić, Branislav; Ritsch, Elmar; Riu, Imma; Rizatdinova, Flera; Rizvi, Eram; Robertson, Steven; Robichaud-Veronneau, Andree; Robinson, Dave; Robinson, James; Robson, Aidan; Roda, Chiara; Roe, Shaun; Røhne, Ole; Rolli, Simona; Romaniouk, Anatoli; Romano, Marino; Romano Saez, Silvestre Marino; Romero Adam, Elena; Rompotis, Nikolaos; Ronzani, Manfredi; Roos, Lydia; Ros, Eduardo; Rosati, Stefano; Rosbach, Kilian; Rose, Peyton; Rosendahl, Peter Lundgaard; Rosenthal, Oliver; Rossetti, Valerio; Rossi, Elvira; Rossi, Leonardo Paolo; Rosten, Rachel; Rotaru, Marina; Roth, Itamar; Rothberg, Joseph; Rousseau, David; Royon, Christophe; Rozanov, Alexandre; Rozen, Yoram; Ruan, Xifeng; Rubbo, Francesco; Rubinskiy, Igor; Rud, Viacheslav; Rudolph, Christian; Rudolph, Matthew Scott; Rühr, Frederik; Ruiz-Martinez, Aranzazu; Rurikova, Zuzana; Rusakovich, Nikolai; Ruschke, Alexander; Russell, Heather; Rutherfoord, John; Ruthmann, Nils; Ryabov, Yury; Rybar, Martin; Rybkin, Grigori; Ryder, Nick; Saavedra, Aldo; Sabato, Gabriele; Sacerdoti, Sabrina; Saddique, Asif; Sadrozinski, Hartmut; Sadykov, Renat; Safai Tehrani, Francesco; Saimpert, Matthias; Sakamoto, Hiroshi; Sakurai, Yuki; Salamanna, Giuseppe; Salamon, Andrea; Saleem, Muhammad; Salek, David; Sales De Bruin, Pedro Henrique; Salihagic, Denis; Salnikov, Andrei; Salt, José; Salvatore, Daniela; Salvatore, Pasquale Fabrizio; Salvucci, Antonio; Salzburger, Andreas; Sampsonidis, Dimitrios; Sanchez, Arturo; Sánchez, Javier; Sanchez Martinez, Victoria; Sandaker, Heidi; Sandbach, Ruth Laura; Sander, Heinz Georg; Sanders, Michiel; Sandhoff, Marisa; Sandoval, Carlos; Sandstroem, Rikard; Sankey, Dave; Sansoni, Andrea; Santoni, Claudio; Santonico, Rinaldo; Santos, Helena; Santoyo Castillo, Itzebelt; Sapp, Kevin; Sapronov, Andrey; Saraiva, João; Sarrazin, Bjorn; Sasaki, Osamu; Sasaki, Yuichi; Sato, Koji; Sauvage, Gilles; Sauvan, Emmanuel; Savage, Graham; Savard, Pierre; Sawyer, Craig; Sawyer, Lee; Saxon, James; Sbarra, Carla; Sbrizzi, Antonio; Scanlon, Tim; Scannicchio, Diana; Scarcella, Mark; Scarfone, Valerio; Schaarschmidt, Jana; Schacht, Peter; Schaefer, Douglas; Schaefer, Ralph; Schaeffer, Jan; Schaepe, Steffen; Schaetzel, Sebastian; Schäfer, Uli; Schaffer, Arthur; Schaile, Dorothee; Schamberger, R~Dean; Scharf, Veit; Schegelsky, Valery; Scheirich, Daniel; Schernau, Michael; Schiavi, Carlo; Schillo, Christian; Schioppa, Marco; Schlenker, Stefan; Schmidt, Evelyn; Schmieden, Kristof; Schmitt, Christian; Schmitt, Sebastian; Schmitt, Stefan; Schneider, Basil; Schnellbach, Yan Jie; Schnoor, Ulrike; Schoeffel, Laurent; Schoening, Andre; Schoenrock, Bradley Daniel; Schopf, Elisabeth; Schorlemmer, Andre Lukas; Schott, Matthias; Schouten, Doug; Schovancova, Jaroslava; Schramm, Steven; Schreyer, Manuel; Schroeder, Christian; Schuh, Natascha; Schultens, Martin Johannes; Schultz-Coulon, Hans-Christian; Schulz, Holger; Schumacher, Markus; Schumm, Bruce; Schune, Philippe; Schwanenberger, Christian; Schwartzman, Ariel; Schwarz, Thomas Andrew; Schwegler, Philipp; Schwemling, Philippe; Schwienhorst, Reinhard; Schwindling, Jerome; Schwindt, Thomas; Schwoerer, Maud; Sciacca, Gianfranco; Scifo, Estelle; Sciolla, Gabriella; Scuri, Fabrizio; Scutti, Federico; Searcy, Jacob; Sedov, George; Sedykh, Evgeny; Seema, Pienpen; Seidel, Sally; Seiden, Abraham; Seifert, Frank; Seixas, José; Sekhniaidze, Givi; Sekula, Stephen; Selbach, Karoline Elfriede; Seliverstov, Dmitry; Semprini-Cesari, Nicola; Serfon, Cedric; Serin, Laurent; Serkin, Leonid; Serre, Thomas; Seuster, Rolf; Severini, Horst; Sfiligoj, Tina; Sforza, Federico; Sfyrla, Anna; Shabalina, Elizaveta; Shamim, Mansoora; Shan, Lianyou; Shang, Ruo-yu; Shank, James; Shapiro, Marjorie; Shatalov, Pavel; Shaw, Kate; Shcherbakova, Anna; Shehu, Ciwake Yusufu; Sherwood, Peter; Shi, Liaoshan; Shimizu, Shima; Shimmin, Chase Owen; Shimojima, Makoto; Shiyakova, Mariya; Shmeleva, Alevtina; Shoaleh Saadi, Diane; Shochet, Mel; Shojaii, Seyedruhollah; Shrestha, Suyog; Shulga, Evgeny; Shupe, Michael; Shushkevich, Stanislav; Sicho, Petr; Sidiropoulou, Ourania; Sidorov, Dmitri; Sidoti, Antonio; Siegert, Frank; Sijacki, Djordje; Silva, José; Silver, Yiftah; Silverstein, Samuel; Simak, Vladislav; Simard, Olivier; Simic, Ljiljana; Simion, Stefan; Simioni, Eduard; Simmons, Brinick; Simon, Dorian; Simoniello, Rosa; Sinervo, Pekka; Sinev, Nikolai; Siragusa, Giovanni; Sisakyan, Alexei; Sivoklokov, Serguei; Sjölin, Jörgen; Sjursen, Therese; Skinner, Malcolm Bruce; Skottowe, Hugh Philip; Skubic, Patrick; Slater, Mark; Slavicek, Tomas; Slawinska, Magdalena; Sliwa, Krzysztof; Smakhtin, Vladimir; Smart, Ben; Smestad, Lillian; Smirnov, Sergei; Smirnov, Yury; Smirnova, Lidia; Smirnova, Oxana; Smith, Matthew; Smizanska, Maria; Smolek, Karel; Snesarev, Andrei; Snidero, Giacomo; Snyder, Scott; Sobie, Randall; Socher, Felix; Soffer, Abner; Soh, Dart-yin; Solans, Carlos; Solar, Michael; Solc, Jaroslav; Soldatov, Evgeny; Soldevila, Urmila; Solodkov, Alexander; Soloshenko, Alexei; Solovyanov, Oleg; Solovyev, Victor; Sommer, Philip; Song, Hong Ye; Soni, Nitesh; Sood, Alexander; Sopczak, Andre; Sopko, Bruno; Sopko, Vit; Sorin, Veronica; Sosa, David; Sosebee, Mark; Sotiropoulou, Calliope Louisa; Soualah, Rachik; Soueid, Paul; Soukharev, Andrey; South, David; Spagnolo, Stefania; Spalla, Margherita; Spanò, Francesco; Spearman, William Robert; Spettel, Fabian; Spighi, Roberto; Spigo, Giancarlo; Spiller, Laurence Anthony; Spousta, Martin; Spreitzer, Teresa; St Denis, Richard Dante; Staerz, Steffen; Stahlman, Jonathan; Stamen, Rainer; Stamm, Soren; Stanecka, Ewa; Stanescu, Cristian; Stanescu-Bellu, Madalina; Stanitzki, Marcel Michael; Stapnes, Steinar; Starchenko, Evgeny; Stark, Jan; Staroba, Pavel; Starovoitov, Pavel; Staszewski, Rafal; Stavina, Pavel; Steinberg, Peter; Stelzer, Bernd; Stelzer, Harald Joerg; Stelzer-Chilton, Oliver; Stenzel, Hasko; Stern, Sebastian; Stewart, Graeme; Stillings, Jan Andre; Stockton, Mark; Stoebe, Michael; Stoicea, Gabriel; Stolte, Philipp; Stonjek, Stefan; Stradling, Alden; Straessner, Arno; Stramaglia, Maria Elena; Strandberg, Jonas; Strandberg, Sara; Strandlie, Are; Strauss, Emanuel; Strauss, Michael; Strizenec, Pavol; Ströhmer, Raimund; Strom, David; Stroynowski, Ryszard; Strubig, Antonia; Stucci, Stefania Antonia; Stugu, Bjarne; Styles, Nicholas Adam; Su, Dong; Su, Jun; Subramaniam, Rajivalochan; Succurro, Antonella; Sugaya, Yorihito; Suhr, Chad; Suk, Michal; Sulin, Vladimir; Sultansoy, Saleh; Sumida, Toshi; Sun, Siyuan; Sun, Xiaohu; Sundermann, Jan Erik; Suruliz, Kerim; Susinno, Giancarlo; Sutton, Mark; Suzuki, Shota; Suzuki, Yu; Svatos, Michal; Swedish, Stephen; Swiatlowski, Maximilian; Sykora, Ivan; Sykora, Tomas; Ta, Duc; Taccini, Cecilia; Tackmann, Kerstin; Taenzer, Joe; Taffard, Anyes; Tafirout, Reda; Taiblum, Nimrod; Takai, Helio; Takashima, Ryuichi; Takeda, Hiroshi; Takeshita, Tohru; Takubo, Yosuke; Talby, Mossadek; Talyshev, Alexey; Tam, Jason; Tan, Kong Guan; Tanaka, Junichi; Tanaka, Reisaburo; Tanaka, Satoshi; Tanaka, Shuji; Tannenwald, Benjamin Bordy; Tannoury, Nancy; Tapprogge, Stefan; Tarem, Shlomit; Tarrade, Fabien; Tartarelli, Giuseppe Francesco; Tas, Petr; Tasevsky, Marek; Tashiro, Takuya; Tassi, Enrico; Tavares Delgado, Ademar; Tayalati, Yahya; Taylor, Frank; Taylor, Geoffrey; Taylor, Wendy; Teischinger, Florian Alfred; Teixeira Dias Castanheira, Matilde; Teixeira-Dias, Pedro; Temming, Kim Katrin; Ten Kate, Herman; Teng, Ping-Kun; Teoh, Jia Jian; Tepel, Fabian-Phillipp; Terada, Susumu; Terashi, Koji; Terron, Juan; Terzo, Stefano; Testa, Marianna; Teuscher, Richard; Therhaag, Jan; Theveneaux-Pelzer, Timothée; Thomas, Juergen; Thomas-Wilsker, Joshuha; Thompson, Emily; Thompson, Paul; Thompson, Ray; Thompson, Stan; Thomsen, Lotte Ansgaard; Thomson, Evelyn; Thomson, Mark; Thun, Rudolf; Tibbetts, Mark James; Ticse Torres, Royer Edson; Tikhomirov, Vladimir; Tikhonov, Yury; Timoshenko, Sergey; Tiouchichine, Elodie; Tipton, Paul; Tisserant, Sylvain; Todorov, Theodore; Todorova-Nova, Sharka; Tojo, Junji; Tokár, Stanislav; Tokushuku, Katsuo; Tollefson, Kirsten; Tolley, Emma; Tomlinson, Lee; Tomoto, Makoto; Tompkins, Lauren; Toms, Konstantin; Torrence, Eric; Torres, Heberth; Torró Pastor, Emma; Toth, Jozsef; Touchard, Francois; Tovey, Daniel; Trefzger, Thomas; Tremblet, Louis; Tricoli, Alessandro; Trigger, Isabel Marian; Trincaz-Duvoid, Sophie; Tripiana, Martin; Trischuk, William; Trocmé, Benjamin; Troncon, Clara; Trottier-McDonald, Michel; Trovatelli, Monica; True, Patrick; Trzebinski, Maciej; Trzupek, Adam; Tsarouchas, Charilaos; Tseng, Jeffrey; Tsiareshka, Pavel; Tsionou, Dimitra; Tsipolitis, Georgios; Tsirintanis, Nikolaos; Tsiskaridze, Shota; Tsiskaridze, Vakhtang; Tskhadadze, Edisher; Tsukerman, Ilya; Tsulaia, Vakhtang; Tsuno, Soshi; Tsybychev, Dmitri; Tudorache, Alexandra; Tudorache, Valentina; Tuna, Alexander Naip; Tupputi, Salvatore; Turchikhin, Semen; Turecek, Daniel; Turra, Ruggero; Turvey, Andrew John; Tuts, Michael; Tykhonov, Andrii; Tylmad, Maja; Tyndel, Mike; Ueda, Ikuo; Ueno, Ryuichi; Ughetto, Michael; Ugland, Maren; Uhlenbrock, Mathias; Ukegawa, Fumihiko; Unal, Guillaume; Undrus, Alexander; Unel, Gokhan; Ungaro, Francesca; Unno, Yoshinobu; Unverdorben, Christopher; Urban, Jozef; Urquijo, Phillip; Urrejola, Pedro; Usai, Giulio; Usanova, Anna; Vacavant, Laurent; Vacek, Vaclav; Vachon, Brigitte; Valderanis, Chrysostomos; Valencic, Nika; Valentinetti, Sara; Valero, Alberto; Valery, Loic; Valkar, Stefan; Valladolid Gallego, Eva; Vallecorsa, Sofia; Valls Ferrer, Juan Antonio; Van Den Wollenberg, Wouter; Van Der Deijl, Pieter; van der Geer, Rogier; van der Graaf, Harry; Van Der Leeuw, Robin; van Eldik, Niels; van Gemmeren, Peter; Van Nieuwkoop, Jacobus; van Vulpen, Ivo; van Woerden, Marius Cornelis; Vanadia, Marco; Vandelli, Wainer; Vanguri, Rami; Vaniachine, Alexandre; Vannucci, Francois; Vardanyan, Gagik; Vari, Riccardo; Varnes, Erich; Varol, Tulin; Varouchas, Dimitris; Vartapetian, Armen; Varvell, Kevin; Vazeille, Francois; Vazquez Schroeder, Tamara; Veatch, Jason; Veloso, Filipe; Velz, Thomas; Veneziano, Stefano; Ventura, Andrea; Ventura, Daniel; Venturi, Manuela; Venturi, Nicola; Venturini, Alessio; Vercesi, Valerio; Verducci, Monica; Verkerke, Wouter; Vermeulen, Jos; Vest, Anja; Vetterli, Michel; Viazlo, Oleksandr; Vichou, Irene; Vickey, Trevor; Vickey Boeriu, Oana Elena; Viehhauser, Georg; Viel, Simon; Vigne, Ralph; Villa, Mauro; Villaplana Perez, Miguel; Vilucchi, Elisabetta; Vincter, Manuella; Vinogradov, Vladimir; Vivarelli, Iacopo; Vives Vaque, Francesc; Vlachos, Sotirios; Vladoiu, Dan; Vlasak, Michal; Vogel, Marcelo; Vokac, Petr; Volpi, Guido; Volpi, Matteo; von der Schmitt, Hans; von Radziewski, Holger; von Toerne, Eckhard; Vorobel, Vit; Vorobev, Konstantin; Vos, Marcel; Voss, Rudiger; Vossebeld, Joost; Vranjes, Nenad; Vranjes Milosavljevic, Marija; Vrba, Vaclav; Vreeswijk, Marcel; Vuillermet, Raphael; Vukotic, Ilija; Vykydal, Zdenek; Wagner, Peter; Wagner, Wolfgang; Wahlberg, Hernan; Wahrmund, Sebastian; Wakabayashi, Jun; Walder, James; Walker, Rodney; Walkowiak, Wolfgang; Wang, Chao; Wang, Fuquan; Wang, Haichen; Wang, Hulin; Wang, Jike; Wang, Jin; Wang, Kuhan; Wang, Rui; Wang, Song-Ming; Wang, Tan; Wang, Xiaoxiao; Wanotayaroj, Chaowaroj; Warburton, Andreas; Ward, Patricia; Wardrope, David Robert; Warsinsky, Markus; Washbrook, Andrew; Wasicki, Christoph; Watkins, Peter; Watson, Alan; Watson, Ian; Watson, Miriam; Watts, Gordon; Watts, Stephen; Waugh, Ben; Webb, Samuel; Weber, Michele; Weber, Stefan Wolf; Webster, Jordan S; Weidberg, Anthony; Weinert, Benjamin; Weingarten, Jens; Weiser, Christian; Weits, Hartger; Wells, Phillippa; Wenaus, Torre; Wengler, Thorsten; Wenig, Siegfried; Wermes, Norbert; Werner, Matthias; Werner, Per; Wessels, Martin; Wetter, Jeffrey; Whalen, Kathleen; Wharton, Andrew Mark; White, Andrew; White, Martin; White, Ryan; White, Sebastian; Whiteson, Daniel; Wickens, Fred; Wiedenmann, Werner; Wielers, Monika; Wienemann, Peter; Wiglesworth, Craig; Wiik-Fuchs, Liv Antje Mari; Wildauer, Andreas; Wilkens, Henric George; Williams, Hugh; Williams, Sarah; Willis, Christopher; Willocq, Stephane; Wilson, Alan; Wilson, John; Wingerter-Seez, Isabelle; Winklmeier, Frank; Winter, Benedict Tobias; Wittgen, Matthias; Wittkowski, Josephine; Wollstadt, Simon Jakob; Wolter, Marcin Wladyslaw; Wolters, Helmut; Wosiek, Barbara; Wotschack, Jorg; Woudstra, Martin; Wozniak, Krzysztof; Wu, Mengqing; Wu, Miles; Wu, Sau Lan; Wu, Xin; Wu, Yusheng; Wyatt, Terry Richard; Wynne, Benjamin; Xella, Stefania; Xu, Da; Xu, Lailin; Yabsley, Bruce; Yacoob, Sahal; Yakabe, Ryota; Yamada, Miho; Yamaguchi, Yohei; Yamamoto, Akira; Yamamoto, Shimpei; Yamanaka, Takashi; Yamauchi, Katsuya; Yamazaki, Yuji; Yan, Zhen; Yang, Haijun; Yang, Hongtao; Yang, Yi; Yao, Liwen; Yao, Weiming; Yasu, Yoshiji; Yatsenko, Elena; Yau Wong, Kaven Henry; Ye, Jingbo; Ye, Shuwei; Yeletskikh, Ivan; Yen, Andy L; Yildirim, Eda; Yorita, Kohei; Yoshida, Rikutaro; Yoshihara, Keisuke; Young, Charles; Young, Christopher John; Youssef, Saul; Yu, David Ren-Hwa; Yu, Jaehoon; Yu, Jiaming; Yu, Jie; Yuan, Li; Yurkewicz, Adam; Yusuff, Imran; Zabinski, Bartlomiej; Zaidan, Remi; Zaitsev, Alexander; Zalieckas, Justas; Zaman, Aungshuman; Zambito, Stefano; Zanello, Lucia; Zanzi, Daniele; Zeitnitz, Christian; Zeman, Martin; Zemla, Andrzej; Zengel, Keith; Zenin, Oleg; Ženiš, Tibor; Zerwas, Dirk; Zhang, Dongliang; Zhang, Fangzhou; Zhang, Jinlong; Zhang, Lei; Zhang, Ruiqi; Zhang, Xueyao; Zhang, Zhiqing; Zhao, Xiandong; Zhao, Yongke; Zhao, Zhengguo; Zhemchugov, Alexey; Zhong, Jiahang; Zhou, Bing; Zhou, Chen; Zhou, Lei; Zhou, Li; Zhou, Ning; Zhu, Cheng Guang; Zhu, Hongbo; Zhu, Junjie; Zhu, Yingchun; Zhuang, Xuai; Zhukov, Konstantin; Zibell, Andre; Zieminska, Daria; Zimine, Nikolai; Zimmermann, Christoph; Zimmermann, Robert; Zimmermann, Stephanie; Zinonos, Zinonas; Zinser, Markus; Ziolkowski, Michael; Živković, Lidija; Zobernig, Georg; Zoccoli, Antonio; zur Nedden, Martin; Zurzolo, Giovanni; Zwalinski, Lukasz

    2015-07-17

    Measurements of the $ZZ$ and $WW$ final states in the mass range above the $2m_Z$ and $2m_W$ thresholds provide a unique opportunity to measure the off-shell coupling strength of the Higgs boson. This paper presents a determination of the off-shell Higgs boson event yields normalised to the Standard Model prediction (signal strength) in the $ZZ \\rightarrow 4\\ell$, $ZZ\\rightarrow 2\\ell2\

  15. Signal-to-noise ratio and detective quantum efficiency determination by and alternative use of photographic detectors

    International Nuclear Information System (INIS)

    Burgudzhiev, Z.; Koleva, D.

    1986-01-01

    A known theoretical model of an alternative use of silver-halogenid pnotographic emulsions in which the number of the granulas forming the photographic image is used as a detector output instead of the microdensiometric blackening density is applied to some real photographic emulsions. It is found that by this use the Signal-to-Noise ratio of the photographic detector can be increased to about 5 times while its detective quantum efficiency can reach about 20%, being close to that of some photomultipliers

  16. Determination of Tobramycin in M9 Medium by LC-MS/MS: Signal Enhancement by Trichloroacetic Acid

    DEFF Research Database (Denmark)

    Huang, Liusheng; Haagensen, Janus Anders Juul; Verotta, Davide

    2018-01-01

    mM ammonium formate and 0.14% trifluoroacetic acid and acetonitrile containing 0.1% trifluoroacetic acid in a gradient mode. ESI+ and MRM with ion m/z 468 → 324 for tobramycin and m/z 473 -> 327 for the IS were used for quantification. The calibration curve concentration range was 50-25000 ng....../mL. Matrix effect from M9 media was not significant when compared with injection solvents, but signal enhancement by trichloroacetic acid was significant (∼ 3 fold). The method is simple, fast, and reliable. Using the method, the in vitro PK/PD model was tested with one bolus dose of tobramycin....

  17. A paracrine mechanism involving renal tubular cells, adipocytes and macrophages promotes kidney stone formation in a simulated metabolic syndrome environment.

    Science.gov (United States)

    Zuo, Li; Tozawa, Keiichi; Okada, Atsushi; Yasui, Takahiro; Taguchi, Kazumi; Ito, Yasuhiko; Hirose, Yasuhiko; Fujii, Yasuhiro; Niimi, Kazuhiro; Hamamoto, Shuzo; Ando, Ryosuke; Itoh, Yasunori; Zou, Jiangang; Kohri, Kenjiro

    2014-06-01

    We developed an in vitro system composed of renal tubular cells, adipocytes and macrophages to simulate metabolic syndrome conditions. We investigated the molecular communication mechanism of these cells and their involvement in kidney stone formation. Mouse renal tubular cells (M-1) were cocultured with adipocytes (3T3-L1) and/or macrophages (RAW264.7). Calcium oxalate monohydrate crystals were exposed to M-1 cells after 48-hour coculture and the number of calcium oxalate monohydrate crystals adherent to the cells was quantified. The expression of cocultured medium and M-1 cell inflammatory factors was analyzed by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. The inflammatory markers MCP-1, OPN and TNF-α were markedly up-regulated in cocultured M-1 cells. OPN expression increased in M-1 cells cocultured with RAW264.7 cells while MCP-1 and TNF-α were over expressed in M-1 cells cocultured with 3T3-L1 cells. Coculturing M-1 cells simultaneously with 3T3-L1 and RAW264.7 cells resulted in a significant increase in calcium oxalate monohydrate crystal adherence to M-1 cells. Inflammatory cytokine changes were induced by coculturing renal tubular cells with adipocytes and/or macrophages without direct contact, indicating that crosstalk between adipocytes/macrophages and renal tubular cells was mediated by soluble factors. The susceptibility to urolithiasis of patients with metabolic syndrome might be due to aggravated inflammation of renal tubular cells triggered by a paracrine mechanism involving these 3 cell types. Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  18. Paracrine effects of bone marrow soup restore organ function, regeneration, and repair in salivary glands damaged by irradiation.

    Directory of Open Access Journals (Sweden)

    Simon D Tran

    Full Text Available BACKGROUND: There are reports that bone marrow cell (BM transplants repaired irradiated salivary glands (SGs and re-established saliva secretion. However, the mechanisms of action behind these reports have not been elucidated. METHODS: To test if a paracrine mechanism was the main effect behind this reported improvement in salivary organ function, whole BM cells were lysed and its soluble intracellular contents (termed as "BM Soup" injected into mice with irradiation-injured SGs. The hypothesis was that BM Soup would protect salivary cells, increase tissue neovascularization, function, and regeneration. Two minor aims were also tested a comparing two routes of delivering BM Soup, intravenous (I.V. versus intra-glandular injections, and b comparing the age of the BM Soup's donors. The treatment-comparison group consisted of irradiated mice receiving injections of living whole BM cells. Control mice received irradiation and injections of saline or sham-irradiation. All mice were followed for 8 weeks post-irradiation. RESULTS: BM Soup restored salivary flow rates to normal levels, protected salivary acinar, ductal, myoepithelial, and progenitor cells, increased cell proliferation and blood vessels, and up-regulated expression of tissue remodeling/repair/regenerative genes (MMP2, CyclinD1, BMP7, EGF, NGF. BM Soup was as an efficient therapeutic agent as injections of live BM cells. Both intra-glandular or I.V. injections of BM Soup, and from both young and older mouse donors were as effective in repairing irradiated SGs. The intra-glandular route reduced injection frequency/dosage by four-fold. CONCLUSION: BM Soup, which contains only the cell by-products, can be advantageously used to repair irradiation-damaged SGs rather than transplanting whole live BM cells which carry the risk of differentiating into unwanted/tumorigenic cell types in SGs.

  19. Paracrine effects of bone marrow soup restore organ function, regeneration, and repair in salivary glands damaged by irradiation.

    Science.gov (United States)

    Tran, Simon D; Liu, Younan; Xia, Dengsheng; Maria, Ola M; Khalili, Saeed; Wang, Renee Wan-Jou; Quan, Vu-Hung; Hu, Shen; Seuntjens, Jan

    2013-01-01

    There are reports that bone marrow cell (BM) transplants repaired irradiated salivary glands (SGs) and re-established saliva secretion. However, the mechanisms of action behind these reports have not been elucidated. To test if a paracrine mechanism was the main effect behind this reported improvement in salivary organ function, whole BM cells were lysed and its soluble intracellular contents (termed as "BM Soup") injected into mice with irradiation-injured SGs. The hypothesis was that BM Soup would protect salivary cells, increase tissue neovascularization, function, and regeneration. Two minor aims were also tested a) comparing two routes of delivering BM Soup, intravenous (I.V.) versus intra-glandular injections, and b) comparing the age of the BM Soup's donors. The treatment-comparison group consisted of irradiated mice receiving injections of living whole BM cells. Control mice received irradiation and injections of saline or sham-irradiation. All mice were followed for 8 weeks post-irradiation. BM Soup restored salivary flow rates to normal levels, protected salivary acinar, ductal, myoepithelial, and progenitor cells, increased cell proliferation and blood vessels, and up-regulated expression of tissue remodeling/repair/regenerative genes (MMP2, CyclinD1, BMP7, EGF, NGF). BM Soup was as an efficient therapeutic agent as injections of live BM cells. Both intra-glandular or I.V. injections of BM Soup, and from both young and older mouse donors were as effective in repairing irradiated SGs. The intra-glandular route reduced injection frequency/dosage by four-fold. BM Soup, which contains only the cell by-products, can be advantageously used to repair irradiation-damaged SGs rather than transplanting whole live BM cells which carry the risk of differentiating into unwanted/tumorigenic cell types in SGs.

  20. ATP-dependent paracrine communication between enteric neurons and glia in a primary cell culture derived from embryonic mice.

    Science.gov (United States)

    Gomes, P; Chevalier, J; Boesmans, W; Roosen, L; van den Abbeel, V; Neunlist, M; Tack, J; Vanden Berghe, P

    2009-08-01

    The importance of dynamic interactions between glia and neurons is increasingly recognized, both in the central and enteric nervous system. However, apart from their protective role, little is known about enteric neuro-glia interaction. The aim was to investigate neuro-glia intercellular communication in a mouse culture model using optical techniques. Complete embryonic (E13) guts were enzymatically dissociated, seeded on coverslips and studied with immunohistochemistry and Ca(2+)-imaging. Putative progenitor-like cells (expressing both PGP9.5 and S-100) differentiated over approximately 5 days into glia or neurons expressing typical cell-specific markers. The glia-neuron ratio could be manipulated by specific supplements (N2, G5). Neurons and glia were functionally identified both by their Ca(2+)-response to either depolarization (high K(+)) or lysophosphatidic acid and by the expression of typical markers. Neurons responded to ACh, DMPP, 5-HT, ATP and electrical stimulation, while glia responded to ATP and ADPbetas. Inhibition of glial responses by MRS2179 suggests involvement of P2Y1 receptors. Neuronal stimulation also caused delayed glial responses, which were reduced by suramin and by exogenous apyrases that catalyse nucleotide breakdown. Conversely, glial responses were enhanced by ARL-67156, an ecto-ATPase inhibitor. In this mouse enteric co-culture, functional glia and neurons can be easily monitored using optical techniques. Glial cells can be activated directly by ATP or ADPbetas. Activation of neuronal cells (DMPP, K(+)) causes secondary responses in glial cells, which can be modulated by tuning ATP and ADP breakdown. This strongly supports the involvement of paracrine purinergic communication between enteric neurons and glia.

  1. Structural determination of importin alpha in complex with beak and feather disease virus capsid nuclear localization signal

    International Nuclear Information System (INIS)

    Patterson, Edward I.; Dombrovski, Andrew K.; Swarbrick, Crystall M.D.; Raidal, Shane R.; Forwood, Jade K.

    2013-01-01

    Highlights: •Circovirus capsid proteins contain large nuclear localization signals (NLS). •A method of nuclear import has not been elucidated. •Beak and feather disease virus (BFDV) capsid NLS was crystallized with importin α. •The structure showed BFDV NLS binding to the major site of importin α. •Result shows implications for mechanism of nuclear transport for all circoviruses. -- Abstract: Circoviruses represent a rapidly increasing genus of viruses that infect a variety of vertebrates. Replication requires shuttling viral molecules into the host cell nucleus, a process facilitated by capsid-associated protein (Cap). Whilst a nuclear localization signal (NLS) has been shown to mediate nuclear translocation, the mode of nuclear transport remains to be elucidated. To better understand this process, beak and feather disease virus (BFDV) Cap NLS was crystallized with nuclear import receptor importin-α (Impα). Diffraction yielded structural data to 2.9 Å resolution, and the binding site on both Impα and BFDV Cap NLS were well resolved. The binding mechanism for the major site is likely conserved across circoviruses as supported by the similarity of NLSs in circovirus Caps. This finding illuminates a crucial step for infection of host cells by this viral family, and provides a platform for rational drug design against the binding interface

  2. Persistence and dynamics of DNA damage signal amplification determined by microcolony formation and live-cell imaging

    International Nuclear Information System (INIS)

    Oka, Yasuyoshi; Yamauchi, Motohiro; Suzuki, Masatoshi; Yamashita, Shunichi; Suzuki, Keiji

    2011-01-01

    Cell cycle checkpoints are essential cellular process protecting the integrity of the genome from DNA damaging agents. In the present study, we developed a microcolony assay, in which normal human diploid fibroblast-like cells exposed to ionizing radiation, were plated onto coverslips at very low density (3 cells/cm 2 ). Cells were grown for up to 3 days, and phosphorylated ataxia-telangiectasia mutated (ATM) at Ser1981 and 53BP1 foci were analyzed as the markers for an amplified DNA damage signal. We observed a dose-dependent increase in the fraction of non-dividing cells, whose increase was compromised by knocking down p53 expression. While large persistent foci were predominantly formed in non-dividing cells, we observed some growing colonies that contained cells with large foci. As each microcolony was derived from a single cell, it appeared that some cells could proliferate with large foci. A live-imaging analysis using hTERT-immortalized normal human diploid cells transfected with the EGFP-tagged 53BP1 gene revealed that the formation of persistent large foci was highly dynamic. Delayed appearance and disappearance of large foci were frequently observed in exposed cells visualized 12-72 hours after X-irradiation. Thus, our results indicate that amplified DNA damage signal could be ignored, which may be explained in part by the dynamic nature of the amplification process. (author)

  3. Loss of Mitogen-Activated Protein Kinase Kinase Kinase 4 (MAP3K4) Reveals a Requirement for MAPK Signalling in Mouse Sex Determination

    Science.gov (United States)

    Bogani, Debora; Siggers, Pam; Brixey, Rachel; Warr, Nick; Beddow, Sarah; Edwards, Jessica; Williams, Debbie; Wilhelm, Dagmar; Koopman, Peter; Flavell, Richard A.; Chi, Hongbo; Ostrer, Harry; Wells, Sara; Cheeseman, Michael; Greenfield, Andy

    2009-01-01

    Sex determination in mammals is controlled by the presence or absence of the Y-linked gene SRY. In the developing male (XY) gonad, sex-determining region of the Y (SRY) protein acts to up-regulate expression of the related gene, SOX9, a transcriptional regulator that in turn initiates a downstream pathway of testis development, whilst also suppressing ovary development. Despite the requirement for a number of transcription factors and secreted signalling molecules in sex determination, intracellular signalling components functioning in this process have not been defined. Here we report a role for the phylogenetically ancient mitogen-activated protein kinase (MAPK) signalling pathway in mouse sex determination. Using a forward genetic screen, we identified the recessive boygirl (byg) mutation. On the C57BL/6J background, embryos homozygous for byg exhibit consistent XY gonadal sex reversal. The byg mutation is an A to T transversion causing a premature stop codon in the gene encoding MAP3K4 (also known as MEKK4), a mitogen-activated protein kinase kinase kinase. Analysis of XY byg/byg gonads at 11.5 d post coitum reveals a growth deficit and a failure to support mesonephric cell migration, both early cellular processes normally associated with testis development. Expression analysis of mutant XY gonads at the same stage also reveals a dramatic reduction in Sox9 and, crucially, Sry at the transcript and protein levels. Moreover, we describe experiments showing the presence of activated MKK4, a direct target of MAP3K4, and activated p38 in the coelomic region of the XY gonad at 11.5 d post coitum, establishing a link between MAPK signalling in proliferating gonadal somatic cells and regulation of Sry expression. Finally, we provide evidence that haploinsufficiency for Map3k4 accounts for T-associated sex reversal (Tas). These data demonstrate that MAP3K4-dependent signalling events are required for normal expression of Sry during testis development, and create a novel

  4. Loss of mitogen-activated protein kinase kinase kinase 4 (MAP3K4 reveals a requirement for MAPK signalling in mouse sex determination.

    Directory of Open Access Journals (Sweden)

    Debora Bogani

    2009-09-01

    Full Text Available Sex determination in mammals is controlled by the presence or absence of the Y-linked gene SRY. In the developing male (XY gonad, sex-determining region of the Y (SRY protein acts to up-regulate expression of the related gene, SOX9, a transcriptional regulator that in turn initiates a downstream pathway of testis development, whilst also suppressing ovary development. Despite the requirement for a number of transcription factors and secreted signalling molecules in sex determination, intracellular signalling components functioning in this process have not been defined. Here we report a role for the phylogenetically ancient mitogen-activated protein kinase (MAPK signalling pathway in mouse sex determination. Using a forward genetic screen, we identified the recessive boygirl (byg mutation. On the C57BL/6J background, embryos homozygous for byg exhibit consistent XY gonadal sex reversal. The byg mutation is an A to T transversion causing a premature stop codon in the gene encoding MAP3K4 (also known as MEKK4, a mitogen-activated protein kinase kinase kinase. Analysis of XY byg/byg gonads at 11.5 d post coitum reveals a growth deficit and a failure to support mesonephric cell migration, both early cellular processes normally associated with testis development. Expression analysis of mutant XY gonads at the same stage also reveals a dramatic reduction in Sox9 and, crucially, Sry at the transcript and protein levels. Moreover, we describe experiments showing the presence of activated MKK4, a direct target of MAP3K4, and activated p38 in the coelomic region of the XY gonad at 11.5 d post coitum, establishing a link between MAPK signalling in proliferating gonadal somatic cells and regulation of Sry expression. Finally, we provide evidence that haploinsufficiency for Map3k4 accounts for T-associated sex reversal (Tas. These data demonstrate that MAP3K4-dependent signalling events are required for normal expression of Sry during testis development, and

  5. CTNNB1 signaling in sertoli cells downregulates spermatogonial stem cell activity via WNT4.

    Directory of Open Access Journals (Sweden)

    Alexandre Boyer

    Full Text Available Constitutive activation of the WNT signaling effector CTNNB1 (β-catenin in the Sertoli cells of the Ctnnb1(tm1Mmt/+;Amhr2(tm3(creBhr/+ mouse model results in progressive germ cell loss and sterility. In this study, we sought to determine if this phenotype could be due to a loss of spermatogonial stem cell (SSC activity. Reciprocal SSC transplants between Ctnnb1(tm1Mmt/+;Amhr2(tm3(creBhr/+ and wild-type mice showed that SSC activity is lost in Ctnnb1(tm1Mmt/+;Amhr2(tm3(creBhr/+ testes over time, whereas the mutant testes could not support colonization by wild-type SSCs. Microarray analyses performed on cultured Sertoli cells showed that CTNNB1 induces the expression of genes associated with the female sex determination pathway, which was also found to occur in Ctnnb1(tm1Mmt/+;Amhr2(tm3(creBhr/+ testes. One CTNNB1 target gene encoded the secreted signaling molecule WNT4. We therefore tested the effects of WNT4 on SSC-enriched germ cell cultures, and found that WNT4 induced cell death and reduced SSC activity without affecting cell cycle. Conversely, conditional inactivation of Wnt4 in the Ctnnb1(tm1Mmt/+;Amhr2(tm3(creBhr/+ model rescued spermatogenesis and male fertility, indicating that WNT4 is the major effector downstream of CTNNB1 responsible for germ cell loss. Furthermore, WNT4 was found to signal via the CTNNB1 pathway in Sertoli cells, suggesting a self-reinforcing positive feedback loop. Collectively, these data indicate for the first time that ectopic activation of a signaling cascade in the stem cell niche depletes SSC activity through a paracrine factor. These findings may provide insight into the pathogenesis of male infertility, as well as embryonic gonadal development.

  6. Simultaneous determination of effective carrier lifetime and resistivity of Si wafers using the nonlinear nature of photocarrier radiometric signals

    Science.gov (United States)

    Sun, Qiming; Melnikov, Alexander; Wang, Jing; Mandelis, Andreas

    2018-04-01

    A rigorous treatment of the nonlinear behavior of photocarrier radiometric (PCR) signals is presented theoretically and experimentally for the quantitative characterization of semiconductor photocarrier recombination and transport properties. A frequency-domain model based on the carrier rate equation and the classical carrier radiative recombination theory was developed. The derived concise expression reveals different functionalities of the PCR amplitude and phase channels: the phase bears direct quantitative correlation with the carrier effective lifetime, while the amplitude versus the estimated photocarrier density dependence can be used to extract the equilibrium majority carrier density and thus, resistivity. An experimental ‘ripple’ optical excitation mode (small modulation depth compared to the dc level) was introduced to bypass the complicated ‘modulated lifetime’ problem so as to simplify theoretical interpretation and guarantee measurement self-consistency and reliability. Two Si wafers with known resistivity values were tested to validate the method.

  7. Energy determination of cosmic ray showers in surface arrays using signal inference at a single distance from the core

    Energy Technology Data Exchange (ETDEWEB)

    Ros, G. [Space Plasmas and AStroparticle Group, Dpto. Fisica, Universidad de Alcala Ctra, Madrid-Barcelona km. 33, Alcala de Henares E-28871 (Spain)], E-mail: germanrosmagan@yahoo.es; Medina-Tanco, G. [Instituto de Ciencias Nucleares, UNAM, Circuito Exteriror S/N, Ciudad Universitaria, Mexico D. F. 04510 (Mexico); Peral, L. del [Space Plasmas and AStroparticle Group, Dpto. Fisica, Universidad de Alcala Ctra, Madrid-Barcelona km. 33, Alcala de Henares E-28871 (Spain); D' Olivo, J.C. [Instituto de Ciencias Nucleares, UNAM, Circuito Exteriror S/N, Ciudad Universitaria, Mexico D. F. 04510 (Mexico); Arqueros, F. [Dpto. Fisica Atomica, Molecular y Nuclear, Facultad de Fisica, Universidad Complutense de Madrid, Ciudad Universitaria 28040, Madrid (Spain); Rodriguez-Frias, M.D. [Space Plasmas and AStroparticle Group, Dpto. Fisica, Universidad de Alcala Ctra, Madrid-Barcelona km. 33, Alcala de Henares E-28871 (Spain)

    2009-09-21

    In most high energy cosmic ray surface arrays, the primary energy is currently determined from the value of the lateral distribution function at a fixed distance from the shower core, r{sub 0}. The value of r{sub 0} is mainly related to the geometry of the array and is, therefore, considered as fixed independently of the shower energy or direction. We argue, however, that the dependence of r{sub 0} on energy and zenith angle is not negligible. Therefore, in the present work we propose a new characteristic distance, which we call r{sub opt}, specifically determined for each individual shower, with the objective of optimizing the energy reconstruction. This parameter may not only improve the energy determination, but also allow a more reliable reconstruction of the shape and position of rapidly varying spectral features. We show that the use of a specific r{sub opt} determined on a shower-to-shower basis, instead of using a fixed characteristic value, is of particular benefit in dealing with the energy reconstruction of events with saturated detectors, which are in general a large fraction of all the events detected by an array as energy increases. Furthermore, the r{sub opt} approach has the additional advantage of applying the same unified treatment for all detected events, regardless of whether they have saturated detectors or not.

  8. Basal-subtype and MEK-Pl3K feedback signaling determine susceptibility of breast cancer cells to MEK inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Mirzoeva, Olga K.; Das, Debopriya; Heiser, Laura M.; Bhattacharya, Sanchita; Siwak, Doris; Gendelman, Rina; Bayani, Nora; Wang, Nicholas J.; Neve, Richard M.; Knight, Zachary; Feiler, Heidi S.; Gascard, Philippe; Parvin, Bahram; Spellman, Paul T.; Shokat, Kevan M.; Wyrobek, Andrew J.; Bissell, Mina J.; McCormick, Frank; Kuo, Wen-Lin; Mills, Gordon B.; Gray, Joe W.; Korn, W. Michael

    2009-01-23

    Specific inhibitors of MEK have been developed that efficiently inhibit the oncogenic RAF-MEK-ERK pathway. We employed a systems-based approach to identify breast cancer subtypes particularly susceptible to MEK inhibitors and to understand molecular mechanisms conferring resistance to such compounds. Basal-type breast cancer cells were found to be particularly susceptible to growth-inhibition by small-molecule MEK inhibitors. Activation of the PI3 kinase pathway in response to MEK inhibition through a negative MEK-EGFR-PI3 kinase feedback loop was found to limit efficacy. Interruption of this feedback mechanism by targeting MEK and PI3 kinase produced synergistic effects, including induction of apoptosis and, in some cell lines, cell cycle arrest and protection from apoptosis induced by proapoptotic agents. These findings enhance our understanding of the interconnectivity of oncogenic signal transduction circuits and have implications for the design of future clinical trials of MEK inhibitors in breast cancer by guiding patient selection and suggesting rational combination therapies.

  9. Bone-derived mesenchymal stromal cells from HIV transgenic mice exhibit altered proliferation, differentiation capacity and paracrine functions along with impaired therapeutic potential in kidney injury

    International Nuclear Information System (INIS)

    Cheng, Kang; Rai, Partab; Lan, Xiqian; Plagov, Andrei; Malhotra, Ashwani; Gupta, Sanjeev; Singhal, Pravin C.

    2013-01-01

    Mesenchymal stem cells (MSCs) secrete paracrine factors that could be cytoprotective and serve roles in immunoregulation during tissue injury. Although MSCs express HIV receptors, and co-receptors, and are susceptible to HIV infection, whether HIV-1 may affect biological properties of MSCs needs more study. We evaluated cellular proliferation, differentiation and paracrine functions of MSCs isolated from compact bones of healthy control mice and Tg26 HIV-1 transgenic mice. The ability of MSCs to protect against cisplatin toxicity was studied in cultured renal tubular cells as well as in intact mice. We successfully isolated MSCs from healthy mice and Tg26 HIV-1 transgenic mice and found the latter expressed viral Nef, Vpu, NL4-3 and Vif genes. The proliferation and differentiation of Tg26 HIV-1 MSCs was inferior to MSCs from healthy mice. Moreover, transplantation of Tg26 HIV-1 MSCs less effectively improved outcomes compared with healthy MSCs in mice with acute kidney injury. Also, Tg26 HIV-1 MSCs secreted multiple cytokines, but at significantly lower levels than healthy MSCs, which resulted in failure of conditioned medium from these MSCs to protect cultured renal tubular cells from cisplatin toxicity. Therefore, HIV-1 had adverse biological effects on MSCs extending to their proliferation, differentiation, function, and therapeutic potential. These findings will help in advancing mechanistical insight in renal injury and repair in the setting of HIV-1 infection. -- Highlights: •MSCs isolated from HIV mice displayed HIV genes. •MSCs isolated from HIV mice exhibited attenuated growth and paracrine functions. •AKI mice with transplanted HIV-MSC displayed poor outcome. •HIV-1 MSC secreted multiple cytokines but at a lower level

  10. Bone-derived mesenchymal stromal cells from HIV transgenic mice exhibit altered proliferation, differentiation capacity and paracrine functions along with impaired therapeutic potential in kidney injury

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Kang; Rai, Partab; Lan, Xiqian; Plagov, Andrei; Malhotra, Ashwani [Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhassett, NY (United States); Gupta, Sanjeev [Departments of Medicine and Pathology, Marion Bessin Liver Research Center, Diabetes Center, Cancer Center, Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Institute for Clinical and Translational Research, Albert Einstein College of Medicine, Bronx, NY (United States); Singhal, Pravin C., E-mail: psinghal@nshs.edu [Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhassett, NY (United States)

    2013-08-15

    Mesenchymal stem cells (MSCs) secrete paracrine factors that could be cytoprotective and serve roles in immunoregulation during tissue injury. Although MSCs express HIV receptors, and co-receptors, and are susceptible to HIV infection, whether HIV-1 may affect biological properties of MSCs needs more study. We evaluated cellular proliferation, differentiation and paracrine functions of MSCs isolated from compact bones of healthy control mice and Tg26 HIV-1 transgenic mice. The ability of MSCs to protect against cisplatin toxicity was studied in cultured renal tubular cells as well as in intact mice. We successfully isolated MSCs from healthy mice and Tg26 HIV-1 transgenic mice and found the latter expressed viral Nef, Vpu, NL4-3 and Vif genes. The proliferation and differentiation of Tg26 HIV-1 MSCs was inferior to MSCs from healthy mice. Moreover, transplantation of Tg26 HIV-1 MSCs less effectively improved outcomes compared with healthy MSCs in mice with acute kidney injury. Also, Tg26 HIV-1 MSCs secreted multiple cytokines, but at significantly lower levels than healthy MSCs, which resulted in failure of conditioned medium from these MSCs to protect cultured renal tubular cells from cisplatin toxicity. Therefore, HIV-1 had adverse biological effects on MSCs extending to their proliferation, differentiation, function, and therapeutic potential. These findings will help in advancing mechanistical insight in renal injury and repair in the setting of HIV-1 infection. -- Highlights: •MSCs isolated from HIV mice displayed HIV genes. •MSCs isolated from HIV mice exhibited attenuated growth and paracrine functions. •AKI mice with transplanted HIV-MSC displayed poor outcome. •HIV-1 MSC secreted multiple cytokines but at a lower level.

  11. Determination of the critical bending speeds of a multy-rotor shaft from the vibration signal analysis

    Science.gov (United States)

    Crâştiu, I.; Nyaguly, E.; Deac, S.; Gozman-Pop, C.; Bârgău, A.; Bereteu, L.

    2018-01-01

    The purpose of this paper is the development and validation of an impulse excitation technique to determine flexural critical speeds of a single rotor shaft and multy-rotor shaft. The experimental measurement of the vibroacoustic response is carried out by using a condenser microphone as a transducer. By the means of Modal Analysis using Finite Element Method (FEM), the natural frequencies and shape modes of one rotor and three rotor specimens are determined. The vibration responses of the specimens, in simple supported conditions, are carried out using algorithms based on Fast Fourier Transform (FFT). To validate the results of the modal parameters estimated using Finite Element Analysis (FEA) these are compared with experimental ones.

  12. The Possible Role of Dentin as a Piezoelectric Signal Generator by Determining the Elec-tromechanical Coupling Factor of Dentin

    Directory of Open Access Journals (Sweden)

    Atabak Shahidi

    2011-08-01

    Full Text Available Introduction: This article aimed at calculation of the electromechanical coupling factor of dentin which is an indicator of the effectiveness with which a piezoelectric material converts electrical en-ergy into mechanical energy, or vice versa. The hypothesis: The electro-mechanical coupling factor of dentin was determined in mode 11 and 33 by calculating the ratio of the produced electrical energy to the stored elastic energy in dentin under applied pressure. This study showed that the electromechanical coupling factor of dentin was affected by the direction of the applied force and the moisture content of dentin. Also dentin was a weak electromechanical energy converter which might be categorized as a piezoelectric pressure sensor.Evaluation of the hypothesis: Determination of the electrome-chanical coupling factor of dentin and its other piezoelectric constants is essential to investigate the biologic role of piezoelectricity in tooth.

  13. Sequential injection titration method using second-order signals: determination of acidity in plant oils and biodiesel samples.

    Science.gov (United States)

    del Río, Vanessa; Larrechi, M Soledad; Callao, M Pilar

    2010-06-15

    A new concept of flow titration is proposed and demonstrated for the determination of total acidity in plant oils and biodiesel. We use sequential injection analysis (SIA) with a diode array spectrophotometric detector linked to chemometric tools such as multivariate curve resolution-alternating least squares (MCR-ALS). This system is based on the evolution of the basic specie of an acid-base indicator, alizarine, when it comes into contact with a sample that contains free fatty acids. The gradual pH change in the reactor coil due to diffusion and reaction phenomenona allows the sequential appearance of both species of the indicator in the detector coil, recording a data matrix for each sample. The SIA-MCR-ALS method helps to reduce the amounts of sample, the reagents and the time consumed. Each determination consumes 0.413ml of sample, 0.250ml of indicator and 3ml of carrier (ethanol) and generates 3.333ml of waste. The frequency of the analysis is high (12 samples h(-1) including all steps, i.e., cleaning, preparing and analysing). The utilized reagents are of common use in the laboratory and it is not necessary to use the reagents of perfect known concentration. The method was applied to determine acidity in plant oil and biodiesel samples. Results obtained by the proposed method compare well with those obtained by the official European Community method that is time consuming and uses large amounts of organic solvents.

  14. Dual-cyclical nucleic acid strand-displacement polymerization based signal amplification system for highly sensitive determination of p53 gene.

    Science.gov (United States)

    Xu, Jianguo; Wu, Zai-Sheng; Li, Hongling; Wang, Zhenmeng; Le, Jingqing; Zheng, Tingting; Jia, Lee

    2016-12-15

    In the present study, we proposed a novel dual-cyclical nucleic acid strand-displacement polymerization (dual-CNDP) based signal amplification system for highly sensitive determination of tumor suppressor genes. The system primarily consisted of a signaling hairpin probe (SHP), a label-free hairpin probe (LHP) and an initiating primer (IP). The presence of target DNA was able to induce one CNDP through continuous process of ligation, polymerization and nicking, leading to extensively accumulation of two nicked triggers (NT1 and NT2). Intriguingly, the NT1 could directly hybridize SHP, while the NT2 could act as the target analog to induce another CNDP. The resulting dual-CNDP contributed the striking signal amplification, and only a very weak blank noise existed since the ligation template of target was not involved. In this case, the target could be detected in a wide linear range (5 orders of magnitude), and a low detection limit (78 fM) was obtained, which is superior to most of the existing fluorescent methods. Moreover, the dual-CNDP sensing system provided a high selectivity towards target DNA against mismatched target and was successfully applied to analysis of target gene extracted from cancer cells or in human serum-contained samples, indicating its great potential for practical applications. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Short-range intercellular calcium signaling in bone

    DEFF Research Database (Denmark)

    Jørgensen, Niklas Rye

    2005-01-01

    different mechanisms for this propagation. One mechanism involves the secretion of a nucleotide, possibly ATP, acting in an autocrine action to purinergic P2Y2 receptors on the neighboring cells, leading to intracellular IP3 generation and subsequent release of calcium from intracellular stores. The other...... to osteoclasts as well. We demonstrated that paracrine action of ATP was responsible for the wave propagation, but now the purinergic P2X7 receptor was involved. Thus, the studies demonstrate that calcium signals can be propagated not only among osteoblasts, but also between osteoblasts and osteoclasts...

  16. Real-time determination of the signal-to-noise ratio of partly coherent seismic time series

    DEFF Research Database (Denmark)

    Kjeldsen, Peter Møller

    1994-01-01

    it is of great practical interest to be able to monitor the S/N while the traces are recorded an approach for fast real-time determination of the S/N of seismic time series is proposed. The described method is based on an iterative procedure utilizing the trace-to-trace coherence, but unlike procedures known so...... far it uses calculated initial guesses and stop criterions. This significantly reduces the computational burden of the procedure so that real-time capabilities are obtained...

  17. The function of endocytosis in Wnt signaling.

    Science.gov (United States)

    Brunt, Lucy; Scholpp, Steffen

    2018-03-01

    Wnt growth factors regulate one of the most important signaling networks during development, tissue homeostasis and disease. Despite the biological importance of Wnt signaling, the mechanism of endocytosis during this process is ill described. Wnt molecules can act as paracrine signals, which are secreted from the producing cells and transported through neighboring tissue to activate signaling in target cells. Endocytosis of the ligand is important at several stages of action: One central function of endocytic trafficking in the Wnt pathway occurs in the source cell. Furthermore, the β-catenin-dependent Wnt ligands require endocytosis for signal activation and to regulate gene transcription in the responding cells. Alternatively, Wnt/β-catenin-independent signaling regulates endocytosis of cell adherence plaques to control cell migration. In this comparative review, we elucidate these three fundamental interconnected functions, which together regulate cellular fate and cellular behavior. Based on established hypotheses and recent findings, we develop a revised picture for the complex function of endocytosis in the Wnt signaling network.

  18. Retinoic acid is a potential dorsalising signal in the late embryonic chick hindbrain

    Directory of Open Access Journals (Sweden)

    Maden Malcolm

    2007-12-01

    Full Text Available Abstract Background Human retinoic acid teratogenesis results in malformations of dorsally derived hindbrain structures such as the cerebellum, noradrenergic hindbrain neurons and the precerebellar system. These structures originate from the rhombic lip and adjacent dorsal precursor pools that border the fourth ventricle roofplate. While retinoic acid synthesis is known to occur in the meninges that blanket the hindbrain, the particular sensitivity of only dorsal structures to disruptions in retinoid signalling is puzzling. We therefore looked for evidence within the neural tube for more spatiotemporally specific signalling pathways using an in situ hybridisation screen of known retinoic acid pathway transcripts. Results We find that there are highly restricted domains of retinoic acid synthesis and breakdown within specific hindbrain nuclei as well as the ventricular layer and roofplate. Intriguingly, transcripts of cellular retinoic acid binding protein 1 are always found at the interface between dividing and post-mitotic cells. By contrast to earlier stages of development, domains of synthesis and breakdown in post-mitotic neurons are co-localised. At the rhombic lip, expression of the mRNA for retinoic acid synthesising and catabolising enzymes is spatially highly organised with respect to the Cath1-positive precursors of migratory precerebellar neurons. Conclusion The late developing hindbrain shows patterns of retinoic acid synthesis and use that are distinct from the well characterised phase of rostrocaudal patterning. Selected post-mitotic populations, such as the locus coeruleus, appear to both make and break down retinoic acid suggesting that a requirement for an autocrine, or at least a highly localised paracrine signalling network, might explain its acute sensitivity to retinoic acid disruption. At the rhombic lip, retinoic acid is likely to act as a dorsalising factor in parallel with other roofplate signalling pathways. While its

  19. Determining

    Directory of Open Access Journals (Sweden)

    Bahram Andarzian

    2015-06-01

    Full Text Available Wheat production in the south of Khuzestan, Iran is constrained by heat stress for late sowing dates. For optimization of yield, sowing at the appropriate time to fit the cultivar maturity length and growing season is critical. Crop models could be used to determine optimum sowing window for a locality. The objectives of this study were to evaluate the Cropping System Model (CSM-CERES-Wheat for its ability to simulate growth, development, grain yield of wheat in the tropical regions of Iran, and to study the impact of different sowing dates on wheat performance. The genetic coefficients of cultivar Chamran were calibrated for the CSM-CERES-Wheat model and crop model performance was evaluated with experimental data. Wheat cultivar Chamran was sown on different dates, ranging from 5 November to 9 January during 5 years of field experiments that were conducted in the Khuzestan province, Iran, under full and deficit irrigation conditions. The model was run for 8 sowing dates starting on 25 October and repeated every 10 days until 5 January using long-term historical weather data from the Ahvaz, Behbehan, Dezful and Izeh locations. The seasonal analysis program of DSSAT was used to determine the optimum sowing window for different locations as well. Evaluation with the experimental data showed that performance of the model was reasonable as indicated by fairly accurate simulation of crop phenology, biomass accumulation and grain yield against measured data. The normalized RMSE were 3%, 2%, 11.8%, and 3.4% for anthesis date, maturity date, grain yield and biomass, respectively. Optimum sowing window was different among locations. It was opened and closed on 5 November and 5 December for Ahvaz; 5 November and 15 December for Behbehan and Dezful;and 1 November and 15 December for Izeh, respectively. CERES-Wheat model could be used as a tool to evaluate the effect of sowing date on wheat performance in Khuzestan conditions. Further model evaluations

  20. Polycyclic aromatic hydrocarbons and dibutyl phthalate disrupt dorsal-ventral axis determination via the Wnt/{beta}-catenin signaling pathway in zebrafish embryos

    Energy Technology Data Exchange (ETDEWEB)

    Fairbairn, Elise A., E-mail: efairbairn@ucdavis.edu [University of California Davis, Bodega Marine Laboratory, P.O. Box 247, Bodega Bay, CA 94923 (United States); Bonthius, Jessica, E-mail: jessica.bonthius@gmail.com [University of California Davis, Bodega Marine Laboratory, P.O. Box 247, Bodega Bay, CA 94923 (United States); Cherr, Gary N., E-mail: gncherr@ucdavis.edu [University of California Davis, Bodega Marine Laboratory, P.O. Box 247, Bodega Bay, CA 94923 (United States); Department of Environmental Toxicology, University of California Davis, Davis, CA 95616 (United States); Department of Nutrition, University of California Davis, Davis, CA 95616 (United States)

    2012-11-15

    The canonical Wnt/{beta}-catenin signaling pathway is critical during early teleost development for establishing the dorsal-ventral axis. Within this pathway, GSK-3{beta}, a key regulatory kinase in the Wnt pathway, regulates {beta}-catenin degradation and thus the ability of {beta}-catenin to enter nuclei, where it can activate expression of genes that have been linked to the specification of the dorsal-ventral axis. In this study, we describe the morphological abnormalities that resulted in zebrafish embryos when axis determination was disrupted by environmental contaminants. These abnormalities were linked to abnormal nuclear accumulation of {beta}-catenin. Furthermore, we demonstrated that the developmental abnormalities and altered nuclear {beta}-catenin accumulation occurred when embryos were exposed to commercial GSK-3{beta} inhibitors. Zebrafish embryos were exposed to commercially available GSK-3 inhibitors (GSK-3 Inhibitor IX and 1-azakenpaullone), or common environmental contaminants (dibutyl phthalate or the polycyclic aromatic hydrocarbons phenanthrene and fluorene) from the 2 to 8-cell stage through the mid-blastula transition (MBT). These embryos displayed morphological abnormalities at 12.5 h post-fertilization (hpf) that were comparable to embryos exposed to lithium chloride (LiCl) (300 mM LiCl for 10 min, prior to the MBT), a classic disruptor of embryonic axis determination. Whole-mount immunolabeling and laser scanning confocal microscopy were used to localize {beta}-catenin. The commercial GSK-3 Inhibitors as well as LiCl, dibutyl phthalate, fluorene and phenanthrene all induced an increase in the levels of nuclear {beta}-catenin throughout the embryo, indicating that the morphological abnormalities were a result of disruption of Wnt/{beta}-catenin signaling during dorsal-ventral axis specification. The ability of environmental chemicals to directly or indirectly target GSK-3{beta} was assessed. Using Western blot analysis, the ability of these

  1. Engineered myocardium model to study the roles of HIF-1α and HIF1A-AS1 in paracrine-only signaling under pathological level oxidative stress.

    Science.gov (United States)

    Acun, Aylin; Zorlutuna, Pinar

    2017-08-01

    Studying heart tissue is critical for understanding and developing treatments for cardiovascular diseases. In this work, we fabricated precisely controlled and biomimetic engineered model tissues to study how cell-cell and cell-matrix interactions influence myocardial cell survival upon exposure to pathological level oxidative stress. Specifically, the interactions of endothelial cells (ECs) and cardiomyocytes (CMs), and the role of hypoxia inducible factor-1α (HIF-1α), with its novel alternative regulator, HIF-1α antisense RNA1 (HIF1A-AS1), in these interactions were investigated. We encapsulated CMs in photo-crosslinkable, biomimetic hydrogels with or without ECs, then exposed to oxidative stress followed by normoxia. With precisely controlled microenvironment provided by the model tissues, cell-cell interactions were restricted to be solely through the secreted factors. CM survival after oxidative stress was significantly improved, in the presence of ECs, when cells were in the model tissues that were functionalized with cell attachment motifs. Importantly, the cardioprotective effect of ECs was reduced when HIF-1α expression was knocked down suggesting that HIF-1α is involved in cardioprotection from oxidative damage, provided through secreted factors conferred by the ECs. Using model tissues, we showed that cell survival increased with increased cell-cell communication and enhanced cell-matrix interactions. In addition, whole genome transcriptome analysis showed, for the first time to our knowledge, a possible role for HIF1A-AS1 in oxidative regulation of HIF-1α. We showed that although HIF1A-AS1 knockdown helps CM survival, its effect is overridden by CM-EC bidirectional interactions as we showed that the conditioned media taken from the CM-EC co-cultures improved CM survival, regardless of HIF1A-AS1 expression. Cardiovascular diseases, most of which are associated with oxidative stress, is the most common cause of death worldwide. Thus, understanding the molecular events as well as the role of intercellular communication under oxidative stress is upmost importance in its prevention. In this study we used 3D engineered tissue models to investigate the role of HIF-1α and its regulation in EC-mediated cardioprotection. We showed that EC-mediated protection is only possible when there is a bidirectional crosstalk between ECs and CMs even without physical cell-cell contact. In addition, this protective effect is at least partially related to cell-ECM interactions and HIF-1α, which is regulated by HIF1A-AS1 under oxidative stress. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  2. An Lmx1b-miR135a2 regulatory circuit modulates Wnt1/Wnt signaling and determines the size of the midbrain dopaminergic progenitor pool.

    Directory of Open Access Journals (Sweden)

    Angela Anderegg

    Full Text Available MicroRNAs regulate gene expression in diverse physiological scenarios. Their role in the control of morphogen related signaling pathways has been less studied, particularly in the context of embryonic Central Nervous System (CNS development. Here, we uncover a role for microRNAs in limiting the spatiotemporal range of morphogen expression and function. Wnt1 is a key morphogen in the embryonic midbrain, and directs proliferation, survival, patterning and neurogenesis. We reveal an autoregulatory negative feedback loop between the transcription factor Lmx1b and a newly characterized microRNA, miR135a2, which modulates the extent of Wnt1/Wnt signaling and the size of the dopamine progenitor domain. Conditional gain of function studies reveal that Lmx1b promotes Wnt1/Wnt signaling, and thereby increases midbrain size and dopamine progenitor allocation. Conditional removal of Lmx1b has the opposite effect, in that expansion of the dopamine progenitor domain is severely compromised. Next, we provide evidence that microRNAs are involved in restricting dopamine progenitor allocation. Conditional loss of Dicer1 in embryonic stem cells (ESCs results in expanded Lmx1a/b+ progenitors. In contrast, forced elevation of miR135a2 during an early window in vivo phenocopies the Lmx1b conditional knockout. When En1::Cre, but not Shh::Cre or Nes::Cre, is used for recombination, the expansion of Lmx1a/b+ progenitors is selectively reduced. Bioinformatics and luciferase assay data suggests that miR135a2 targets Lmx1b and many genes in the Wnt signaling pathway, including Ccnd1, Gsk3b, and Tcf7l2. Consistent with this, we demonstrate that this mutant displays reductions in the size of the Lmx1b/Wnt1 domain and range of canonical Wnt signaling. We posit that microRNA modulation of the Lmx1b/Wnt axis in the early midbrain/isthmus could determine midbrain size and allocation of dopamine progenitors. Since canonical Wnt activity has recently been recognized as a key

  3. Triple-Frequency Code-Phase Combination Determination: A Comparison with the Hatch-Melbourne-Wübbena Combination Using BDS Signals

    Directory of Open Access Journals (Sweden)

    Chenlong Deng

    2018-02-01

    Full Text Available Considering the influence of the ionosphere, troposphere, and other systematic errors on double-differenced ambiguity resolution (AR, we present an optimal triple-frequency code-phase combination determination method driven by both the model and the real data. The new method makes full use of triple-frequency code measurements (especially the low-noise of the code on the B3 signal to minimize the total noise level and achieve the largest AR success rate (model-driven under different ionosphere residual situations (data-driven, thus speeding up the AR by directly rounding. With the triple-frequency Beidou Navigation Satellite System (BDS data collected at five stations from a continuously-operating reference station network in Guangdong Province of China, different testing scenarios are defined (a medium baseline, whose distance is between 20 km and 50 km; a medium-long baseline, whose distance is between 50 km and 100 km; and a long baseline, whose distance is larger than 100 km. The efficiency of the optimal code-phase combination on the AR success rate was compared with that of the geometry-free and ionosphere-free (GIF combination and the Hatch-Melbourne-Wübbena (HMW combination. Results show that the optimal combinations can always achieve better results than the HMW combination with B2 and B3 signals, especially when the satellite elevation angle is larger than 45°. For the wide-lane AR which aims to obtain decimeter-level kinematic positioning service, the standard deviation (STD of ambiguity residuals for the suboptimal combination are only about 0.2 cycles, and the AR success rate by directly rounding can be up to 99%. Compared with the HMW combinations using B1 and B2 signals and using B1 and B3 signals, the suboptimal combination achieves the best results in all baselines, with an overall improvement of about 40% and 20%, respectively. Additionally, the STD difference between the optimal and the GIF code-phase combinations decreases

  4. Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling

    International Nuclear Information System (INIS)

    Noda, Saori; Takahashi, Atsushi; Hayashi, Takeru; Tanuma, Sei-ichi; Hatakeyama, Masanori

    2016-01-01

    SHP2, encoded by the PTPN11 gene, is a protein tyrosine phosphatase that plays a key role in the proliferation of cells via RAS-ERK activation. SHP2 also promotes Wnt signaling by dephosphorylating parafibromin. Germline missense mutations of PTPN11 are found in more than half of patients with Noonan syndrome (NS) and LEOPARD syndrome (LS), both of which are congenital developmental disorders with multiple common symptoms. However, whereas NS-associated PTPN11 mutations give rise to gain-of-function SHP2 mutants, LS-associated SHP2 mutants are reportedly loss-of-function mutants. To determine the phosphatase activity of LS-associated SHP2 more appropriately, we performed an in vitro phosphatase assay using tyrosine-phosphorylated parafibromin, a biologically relevant substrate of SHP2 and the positive regulator of Wnt signaling that is activated through SHP2-mediated dephosphorylation. We found that LS-associated SHP2 mutants (Y279C, T468M, Q506P, and Q510E) exhibited a substantially reduced phosphatase activity toward parafibromin when compared with wild-type SHP2. Furthermore, each of the LS-associated mutants displayed a differential degree of decrease in phosphatase activity. Deviation of the SHP2 catalytic activity from a certain range, either too strong or too weak, may therefore lead to similar clinical outcomes in NS and LS, possibly through an imbalanced Wnt signal caused by inadequate dephosphorylation of parafibromin. - Highlights: • LS-associated SHP2 mutants dephosphorylate parafibromin on Y290, Y293, and Y315. • LS-associated SHP2 mutants display a reduced tyrosine phosphatase activity. • LS-specific SHP2-Y279C is catalytically less active than LS-specific SHP2-T468M. • NS/LS-associated SHP2-Q506P has both hyper- and hypomorphic enzymatic properties.

  5. Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling

    Energy Technology Data Exchange (ETDEWEB)

    Noda, Saori [Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba (Japan); Takahashi, Atsushi; Hayashi, Takeru [Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Tanuma, Sei-ichi [Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba (Japan); Hatakeyama, Masanori, E-mail: mhata@m.u-tokyo.ac.jp [Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan)

    2016-01-22

    SHP2, encoded by the PTPN11 gene, is a protein tyrosine phosphatase that plays a key role in the proliferation of cells via RAS-ERK activation. SHP2 also promotes Wnt signaling by dephosphorylating parafibromin. Germline missense mutations of PTPN11 are found in more than half of patients with Noonan syndrome (NS) and LEOPARD syndrome (LS), both of which are congenital developmental disorders with multiple common symptoms. However, whereas NS-associated PTPN11 mutations give rise to gain-of-function SHP2 mutants, LS-associated SHP2 mutants are reportedly loss-of-function mutants. To determine the phosphatase activity of LS-associated SHP2 more appropriately, we performed an in vitro phosphatase assay using tyrosine-phosphorylated parafibromin, a biologically relevant substrate of SHP2 and the positive regulator of Wnt signaling that is activated through SHP2-mediated dephosphorylation. We found that LS-associated SHP2 mutants (Y279C, T468M, Q506P, and Q510E) exhibited a substantially reduced phosphatase activity toward parafibromin when compared with wild-type SHP2. Furthermore, each of the LS-associated mutants displayed a differential degree of decrease in phosphatase activity. Deviation of the SHP2 catalytic activity from a certain range, either too strong or too weak, may therefore lead to similar clinical outcomes in NS and LS, possibly through an imbalanced Wnt signal caused by inadequate dephosphorylation of parafibromin. - Highlights: • LS-associated SHP2 mutants dephosphorylate parafibromin on Y290, Y293, and Y315. • LS-associated SHP2 mutants display a reduced tyrosine phosphatase activity. • LS-specific SHP2-Y279C is catalytically less active than LS-specific SHP2-T468M. • NS/LS-associated SHP2-Q506P has both hyper- and hypomorphic enzymatic properties.

  6. An Epstein-Barr virus encoded inhibitor of Colony Stimulating Factor-1 signaling is an important determinant for acute and persistent EBV infection.

    Directory of Open Access Journals (Sweden)

    Makoto Ohashi

    2012-12-01

    Full Text Available Acute Epstein-Barr virus (EBV infection is the most common cause of Infectious Mononucleosis. Nearly all adult humans harbor life-long, persistent EBV infection which can lead to development of cancers including Hodgkin Lymphoma, Burkitt Lymphoma, nasopharyngeal carcinoma, gastric carcinoma, and lymphomas in immunosuppressed patients. BARF1 is an EBV replication-associated, secreted protein that blocks Colony Stimulating Factor 1 (CSF-1 signaling, an innate immunity pathway not targeted by any other virus species. To evaluate effects of BARF1 in acute and persistent infection, we mutated the BARF1 homologue in the EBV-related herpesvirus, or lymphocryptovirus (LCV, naturally infecting rhesus macaques to create a recombinant rhLCV incapable of blocking CSF-1 (ΔrhBARF1. Rhesus macaques orally challenged with ΔrhBARF1 had decreased viral load indicating that CSF-1 is important for acute virus infection. Surprisingly, ΔrhBARF1 was also associated with dramatically lower virus setpoints during persistent infection. Normal acute viral load and normal viral setpoints during persistent rhLCV infection could be restored by Simian/Human Immunodeficiency Virus-induced immunosuppression prior to oral inoculation with ΔrhBARF1 or infection of immunocompetent animals with a recombinant rhLCV where the rhBARF1 was repaired. These results indicate that BARF1 blockade of CSF-1 signaling is an important immune evasion strategy for efficient acute EBV infection and a significant determinant for virus setpoint during persistent EBV infection.

  7. Insights into genetic and epigenetic determinants with impact on vitamin D signaling and cancer association studies: The case of thyroid cancer

    Directory of Open Access Journals (Sweden)

    Gregoire B Morand

    2014-11-01

    Full Text Available Vitamin D is a key regulator of calcium metabolism and has been implicated as a cancer preventive agent. However, clinical studies have revealed conflicting results on its cancer preventive properties, attributed in part to multiple metabolic and regulatory factors susceptible to affect individual responses to exogenous vitamin D. Vitamin D is obtained from dietary sources and sun exposure, which depends on numerous parameters such as skin type, latitude, and lifestyle factors. Focusing on thyroid cancer, we document that genetic and epigenetic determinants can greatly impact individual response to vitamin D and may outweigh the classical clinical correlative studies that focus on sun exposure/dietary intake factors. In particular, genetic determinants innate to host intrinsic metabolic pathways such as highly polymorphic cytochromes P450s responsible for the metabolic activation of vitamin D are expressed in many organs, including the thyroid gland and can impact vitamin D interaction with its nuclear receptor (VDR in thyroid tissue. Moreover, downstream regulatory pathways in vitamin D signalling as well as VDR are also subject to wide genetic variability among human populations as shown by genome-wide studies. These genetic variations in multiple components of vitamin D pathways are critical determinants for the re-valuation of the potential preventive and anticancer properties of vitamin D in thyroid cancer.

  8. Alternative SAIL-Trp for robust aromatic signal assignment and determination of the {chi}{sub 2} conformation by intra-residue NOEs

    Energy Technology Data Exchange (ETDEWEB)

    Miyanoiri, Yohei; Takeda, Mitsuhiro [Nagoya University, Graduate School of Science, Structural Biology Research Center (Japan); Jee, JunGoo; Ono, Akira M.; Okuma, Kosuke; Terauchi, Tsutomu [Tokyo Metropolitan University, Center for Priority Areas (Japan); Kainosho, Masatsune, E-mail: kainosho@nagoya-u.jp [Nagoya University, Graduate School of Science, Structural Biology Research Center (Japan)

    2011-12-15

    Tryptophan (Trp) residues are frequently found in the hydrophobic cores of proteins, and therefore, their side-chain conformations, especially the precise locations of the bulky indole rings, are critical for determining structures by NMR. However, when analyzing [U-{sup 13}C,{sup 15}N]-proteins, the observation and assignment of the ring signals are often hampered by excessive overlaps and tight spin couplings. These difficulties have been greatly alleviated by using stereo-array isotope labeled (SAIL) proteins, which are composed of isotope-labeled amino acids optimized for unambiguous side-chain NMR assignment, exclusively through the {sup 13}C-{sup 13}C and {sup 13}C-{sup 1}H spin coupling networks (Kainosho et al. in Nature 440:52-57, 2006). In this paper, we propose an alternative type of SAIL-Trp with the [{zeta}2,{zeta}3-{sup 2}H{sub 2}; {delta}1,{epsilon}3,{eta}2-{sup 13}C{sub 3}; {epsilon}1-{sup 15}N]-indole ring ([{sup 12}C{sub {gamma},}{sup 12}C{sub {epsilon}2}] SAIL-Trp), which provides a more robust way to correlate the {sup 1}H{sub {beta}}, {sup 1}H{sub {alpha}}, and {sup 1}H{sub N} to the {sup 1}H{sub {delta}1} and {sup 1}H{sub {epsilon}3} through the intra-residue NOEs. The assignment of the {sup 1}H{sub {delta}1}/{sup 13}C{sub {delta}1} and {sup 1}H{sub {epsilon}3}/{sup 13}C{sub {epsilon}3} signals can thus be transferred to the {sup 1}H{sub {epsilon}1}/{sup 15}N{sub {epsilon}1} and {sup 1}H{sub {eta}2}/{sup 13}C{sub {eta}2} signals, as with the previous type of SAIL-Trp, which has an extra {sup 13}C at the C{sub {gamma}} of the ring. By taking advantage of the stereospecific deuteration of one of the prochiral {beta}-methylene protons, which was {sup 1}H{sub {beta}2} in this experiment, one can determine the side-chain conformation of the Trp residue including the {chi}{sub 2} angle, which is especially important for Trp residues, as they can adopt three preferred conformations. We demonstrated the usefulness of [{sup 12}C{sub {gamma}},{sup 12}C

  9. Alternative SAIL-Trp for robust aromatic signal assignment and determination of the χ2 conformation by intra-residue NOEs

    International Nuclear Information System (INIS)

    Miyanoiri, Yohei; Takeda, Mitsuhiro; Jee, JunGoo; Ono, Akira M.; Okuma, Kosuke; Terauchi, Tsutomu; Kainosho, Masatsune

    2011-01-01

    Tryptophan (Trp) residues are frequently found in the hydrophobic cores of proteins, and therefore, their side-chain conformations, especially the precise locations of the bulky indole rings, are critical for determining structures by NMR. However, when analyzing [U– 13 C, 15 N]-proteins, the observation and assignment of the ring signals are often hampered by excessive overlaps and tight spin couplings. These difficulties have been greatly alleviated by using stereo-array isotope labeled (SAIL) proteins, which are composed of isotope-labeled amino acids optimized for unambiguous side-chain NMR assignment, exclusively through the 13 C– 13 C and 13 C– 1 H spin coupling networks (Kainosho et al. in Nature 440:52–57, 2006). In this paper, we propose an alternative type of SAIL-Trp with the [ζ2,ζ3- 2 H 2 ; δ1,ε3,η2- 13 C 3 ; ε1- 15 N]-indole ring ([ 12 C γ, 12 C ε2 ] SAIL-Trp), which provides a more robust way to correlate the 1 H β , 1 H α , and 1 H N to the 1 H δ1 and 1 H ε3 through the intra-residue NOEs. The assignment of the 1 H δ1 / 13 C δ1 and 1 H ε3 / 13 C ε3 signals can thus be transferred to the 1 H ε1 / 15 N ε1 and 1 H η2 / 13 C η2 signals, as with the previous type of SAIL-Trp, which has an extra 13 C at the C γ of the ring. By taking advantage of the stereospecific deuteration of one of the prochiral β-methylene protons, which was 1 H β2 in this experiment, one can determine the side-chain conformation of the Trp residue including the χ 2 angle, which is especially important for Trp residues, as they can adopt three preferred conformations. We demonstrated the usefulness of [ 12 C γ , 12 C ε2 ] SAIL-Trp for the 12 kDa DNA binding domain of mouse c-Myb protein (Myb-R2R3), which contains six Trp residues.

  10. Alternative SAIL-Trp for robust aromatic signal assignment and determination of the χ(2) conformation by intra-residue NOEs.

    Science.gov (United States)

    Miyanoiri, Yohei; Takeda, Mitsuhiro; Jee, JunGoo; Ono, Akira M; Okuma, Kosuke; Terauchi, Tsutomu; Kainosho, Masatsune

    2011-12-01

    Tryptophan (Trp) residues are frequently found in the hydrophobic cores of proteins, and therefore, their side-chain conformations, especially the precise locations of the bulky indole rings, are critical for determining structures by NMR. However, when analyzing [U-(13)C,(15)N]-proteins, the observation and assignment of the ring signals are often hampered by excessive overlaps and tight spin couplings. These difficulties have been greatly alleviated by using stereo-array isotope labeled (SAIL) proteins, which are composed of isotope-labeled amino acids optimized for unambiguous side-chain NMR assignment, exclusively through the (13)C-(13)C and (13)C-(1)H spin coupling networks (Kainosho et al. in Nature 440:52-57, 2006). In this paper, we propose an alternative type of SAIL-Trp with the [ζ2,ζ3-(2)H(2); δ1,ε3,η2-(13)C(3); ε1-(15)N]-indole ring ([(12)C (γ,) ( 12) C(ε2)] SAIL-Trp), which provides a more robust way to correlate the (1)H(β), (1)H(α), and (1)H(N) to the (1)H(δ1) and (1)H(ε3) through the intra-residue NOEs. The assignment of the (1)H(δ1)/(13)C(δ1) and (1)H(ε3)/(13)C(ε3) signals can thus be transferred to the (1)H(ε1)/(15)N(ε1) and (1)H(η2)/(13)C(η2) signals, as with the previous type of SAIL-Trp, which has an extra (13)C at the C(γ) of the ring. By taking advantage of the stereospecific deuteration of one of the prochiral β-methylene protons, which was (1)H(β2) in this experiment, one can determine the side-chain conformation of the Trp residue including the χ(2) angle, which is especially important for Trp residues, as they can adopt three preferred conformations. We demonstrated the usefulness of [(12)C(γ),(12)C(ε2)] SAIL-Trp for the 12 kDa DNA binding domain of mouse c-Myb protein (Myb-R2R3), which contains six Trp residues.

  11. Sweet Taste Receptor Signaling Network: Possible Implication for Cognitive Functioning

    Directory of Open Access Journals (Sweden)

    Menizibeya O. Welcome

    2015-01-01

    Full Text Available Sweet taste receptors are transmembrane protein network specialized in the transmission of information from special “sweet” molecules into the intracellular domain. These receptors can sense the taste of a range of molecules and transmit the information downstream to several acceptors, modulate cell specific functions and metabolism, and mediate cell-to-cell coupling through paracrine mechanism. Recent reports indicate that sweet taste receptors are widely distributed in the body and serves specific function relative to their localization. Due to their pleiotropic signaling properties and multisubstrate ligand affinity, sweet taste receptors are able to cooperatively bind multiple substances and mediate signaling by other receptors. Based on increasing evidence about the role of these receptors in the initiation and control of absorption and metabolism, and the pivotal role of metabolic (glucose regulation in the central nervous system functioning, we propose a possible implication of sweet taste receptor signaling in modulating cognitive functioning.

  12. Steroid signaling system responds differently to temperature and hormone manipulation in the red-eared slider turtle (Trachemys scripta elegans), a reptile with temperature-dependent sex determination.

    Science.gov (United States)

    Ramsey, M; Crews, D

    2007-01-01

    Many reptiles, including the red-eared slider turtle (Trachemys scripta elegans), exhibit temperature-dependent sex determination (TSD). Temperature determines gonadal sex during the middle of embryogenesis, or the temperature-sensitive period (TSP), when gonadal sex is labile to both temperature and hormones--particularly estrogen. The biological actions of steroid hormones are mediated by their receptors as defined here as the classic transcriptional regulation of target genes. To elucidate estrogen action during sex determination, we examined estrogen receptor alpha (Esr1, hereafter referred to as ERalpha), estrogen receptor beta (Esr2, hereafter referred to as ERbeta), and androgen receptor (Ar, hereafter referred to as AR) expression in slider turtle gonads before, during and after the TSP, as well as following sex reversal via temperature or steroid hormone manipulation. ERalpha and AR levels spike at the female-producing temperature while ovarian sex is determined, but none of the receptors exhibited sexually dimorphic localization within the gonad prior to morphological differentiation. All three receptors respond differentially to sex-reversing treatments. When shifted to female-producing temperatures, embryos maintain ERalpha and AR expression while ERbeta is reduced. When shifted to male-producing temperatures, medullary expression of all three receptors is reduced. Feminization via estradiol (E(2)) treatment at a male-producing temperature profoundly changed the expression patterns for all three receptors. ERalpha and ERbeta redirected to the cortex in E(2)-created ovaries, while AR medullary expression was transiently reduced. Although warmer incubation temperature and estrogen result in the same endpoint (ovarian development), our results indicate different steroid signaling patterns between temperature- and estrogen-induced feminization. 2007 S. Karger AG, Basel

  13. SKR-1, a homolog of Skp1 and a member of the SCFSEL-10 complex, regulates sex-determination and LIN-12/Notch signaling in C. elegans

    Science.gov (United States)

    Killian, Darrell J.; Harvey, Elizabeth; Johnson, Peter; Otori, Muneyoshi; Mitani, Shohei; Xue, Ding

    2008-01-01

    Sex-determination in C. elegans requires regulation of gene transcription and protein activity and stability. sel-10 encodes a WD40-repeat-containing F-box protein that likely mediates the ubiquitin-mediated degradation of important sex-determination factors. Loss of sel-10 results in a mild masculinization of hermaphrodites, whereas dominant alleles of sel-10, such as sel-10(n1074), cause a more severe masculinization, including a reversal of the life versus death decision in sex-specific neurons. To investigate about how sel-10 regulates sex-determination, we conducted a sel-10(n1074) suppressor screen and isolated a weak loss-of-function allele of skr-1, one of 21 Skp1-related genes in C. elegans. Skp1, Cullin, and F-box proteins, such as SEL-10, are components of the SCF E3 ubiquitin ligase complex. We present genetic evidence that the sel-10(n1074) masculinization phenotype is dependent upon skr-1 and cul-1 activity. Furthermore, we show that the SKR-1(M140I) weak loss-of-function mutation interferes with SKR-1/SEL-10 binding. Unexpectedly, we found that the G567E substitution in SEL-10 caused by the n1074 allele impairs the binding of SEL-10 to SKR-1 and the dimerization of SEL-10, which may be important for SEL-10 function. Our results suggest that SKR-1, CUL-1 and SEL-10 constitute an SCF E3 ligase complex that plays an important role in modulating sex-determination and LIN-12/Notch signaling in C. elegans. PMID:18718460

  14. Quantifying the passive gamma signal from spent nuclear fuel in support of determining the plutonium content in spent nuclear fuel with nondestructive assay

    Energy Technology Data Exchange (ETDEWEB)

    Fensin, Michael L [Los Alamos National Laboratory; Tobin, Steven J [Los Alamos National Laboratory; Menlove, Howard O [Los Alamos National Laboratory; Swinhoe, Martyn T [Los Alamos National Laboratory

    2009-01-01

    The objective of safeguarding nuclear material is to deter diversions of significant quantities of nuclear materials by timely monitoring and detection. There are a variety of motivations for quantifying plutonium in spent fuel (SF), by means of nondestructive assay (NDA), in order to meet this goal. These motivations include the following: strengthening the capabilities of the International Atomic Energy Agencies ability to safeguard nuclear facilities, shipper/receiver difference, input accountability at reprocessing facilities and burnup credit at repositories. Many NDA techniques exist for measuring signatures from SF; however, no single NDA technique can, in isolation, quantify elemental plutonium in SF. A study has been undertaken to determine the best integrated combination of 13 NDA techniques for characterizing Pu mass in spent fuel. This paper focuses on the development of a passive gamma measurement system in support the spent fuel assay system. Gamma ray detection for fresh nuclear fuel focuses on gamma ray emissions that directly coincide with the actinides of interest to the assay. For example, the 186-keV gamma ray is generally used for {sup 235}U assay and the 384-keV complex is generally used for assaying plutonium. In spent nuclear fuel, these signatures cannot be detected as the Compton continuum created from the fission products dominates the signal in this energy range. For SF, the measured gamma signatures from key fission products ({sup 134}Cs, {sup 137}Cs, {sup 154}Eu) are used to ascertain burnup, cooling time, and fissile content information. In this paper the Monte Carlo modeling set-up for a passive gamma spent fuel assay system will be described. The set-up of the system includes a germanium detector and an ion chamber and will be used to gain passive gamma information that will be integrated into a system for determining Pu in SF. The passive gamma signal will be determined from a library of {approx} 100 assemblies that have been

  15. Vasohibin 2 promotes human luminal breast cancer angiogenesis in a non-paracrine manner via transcriptional activation of fibroblast growth factor 2.

    Science.gov (United States)

    Tu, Min; Lu, Cheng; Lv, Nan; Wei, Jishu; Lu, Zipeng; Xi, Chunhua; Chen, Jianmin; Guo, Feng; Jiang, Kuirong; Li, Qiang; Wu, Junli; Song, Guoxin; Wang, Shui; Gao, Wentao; Miao, Yi

    2016-12-28

    Vasohibin 2 (VASH2) is an angiogenic factor and cancer-related protein that acts via paracrine mechanisms. Here, we investigated the angiogenic function and mechanism of action of VASH2 in 200 human breast cancer tissues by performing immunohistochemical staining, western blot, indirect sandwich enzyme-linked immunosorbent assay (ELISA), and a semi-quantitative sandwich-based antibody array. Breast cancer cells stably overexpressing VASH2 or with knocked-down VASH2 were established and used for in vivo and in vitro models. In human luminal tissue, but not in HER2-positive or basal-like breast cancer tissues, VASH2 was positively correlated with CD31-positive microvascular density, induced angiogenesis in xenograft tumors, and promoted human umbilical vein endothelial cell tube formation in vitro. VASH2 expression was absent in the concentrated conditioned medium collected from knocked-down VASH2 and VASH2-overexpressing luminal breast cancer cells. Further, VASH2 regulated the expression of fibroblast growth factor 2 (FGF2) in human luminal breast cancer cells, and the pro-angiogenic effect induced by VASH2 overexpression was blocked by FGF2 neutralization in vitro. Additionally, dual luciferase reporter assay and Chromatin immunoprecipitation analysis results showed that FGF2 promoter was transcriptionally activated by VASH2 via histone modifications. In conclusion, VASH2 expression is positively correlated with FGF2 expression and promotes angiogenesis in human luminal breast cancer by transcriptional activation of fibroblast growth factor 2 through non-paracrine mechanisms. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  16. Determination of the substrate repertoire of ADAMTS2, 3, and 14 significantly broadens their functions and identifies extracellular matrix organization and TGF-β signaling as primary targets.

    Science.gov (United States)

    Bekhouche, Mourad; Leduc, Cedric; Dupont, Laura; Janssen, Lauriane; Delolme, Frederic; Vadon-Le Goff, Sandrine; Smargiasso, Nicolas; Baiwir, Dominique; Mazzucchelli, Gabriel; Zanella-Cleon, Isabelle; Dubail, Johanne; De Pauw, Edwin; Nusgens, Betty; Hulmes, David J S; Moali, Catherine; Colige, Alain

    2016-05-01

    A disintegrin and metalloproteinase with thrombospondin type I motif (ADAMTS)2, 3, and 14 are collectively named procollagen N-proteinases (pNPs) because of their specific ability to cleave the aminopropeptide of fibrillar procollagens. Several reports also indicate that they could be involved in other biological processes, such as blood coagulation, development, and male fertility, but the potential substrates associated with these activities remain unknown. Using the recently described N-terminal amine isotopic labeling of substrate approach, we analyzed the secretomes of human fibroblasts and identified 8, 17, and 22 candidate substrates for ADAMTS2, 3, and 14, respectively. Among these newly identified substrates, many are components of the extracellular matrix and/or proteins related to cell signaling such as latent TGF-β binding protein 1, TGF-β RIII, and dickkopf-related protein 3. Candidate substrates for the 3 ADAMTS have been biochemically validated in different contexts, and the implication of ADAMTS2 in the control of TGF-β activity has been further demonstrated in human fibroblasts. Finally, the cleavage site specificity was assessed showing a clear and unique preference for nonpolar or slightly hydrophobic amino acids. This work shows that the activities of the pNPs extend far beyond the classically reported processing of the aminopropeptide of fibrillar collagens and that they should now be considered as multilevel regulators of matrix deposition and remodeling.-Bekhouche, M., Leduc, C., Dupont, L., Janssen, L., Delolme, F., Vadon-Le Goff, S., Smargiasso, N., Baiwir, D., Mazzucchelli, G., Zanella-Cleon, I., Dubail, J., De Pauw, E., Nusgens, B., Hulmes, D. J. S., Moali, C., Colige, A. Determination of the substrate repertoire of ADAMTS2, 3, and 14 significantly broadens their functions and identifies extracellular matrix organization and TGF-β signaling as primary targets. © FASEB.

  17. The platelet-derived growth factor signaling system in snapping turtle embryos, Chelydra serpentina: potential role in temperature-dependent sex determination and testis development.

    Science.gov (United States)

    Rhen, Turk; Jangula, Adam; Schroeder, Anthony; Woodward-Bosh, Rikki

    2009-05-01

    The platelet-derived growth factor (Pdgf) signaling system is known to play a significant role during embryonic and postnatal development of testes in mammals and birds. In contrast, genes that comprise the Pdgf system in reptiles have never been cloned or studied in any tissue, let alone developing gonads. To explore the potential role of PDGF ligands and their receptors during embryogenesis, we cloned cDNA fragments of Pdgf-A, Pdgf-B, and receptors PdgfR-alpha and PdgfR-beta in the snapping turtle, a reptile with temperature-dependent sex determination (TSD). We then compared gene expression profiles in gonads from embryos incubated at a male-producing temperature to those from embryos at a female-producing temperature, as well as between hatchling testes and ovaries. Expression of Pdgf-B mRNA in embryonic gonads was significantly higher at a male temperature than at a female temperature, but there was no difference between hatchling testes and ovaries. This developmental pattern was reversed for Pdgf-A and PdgfR-alpha mRNA: expression of these genes did not differ in embryos, but diverged in hatchling testes and ovaries. Levels of PdgfR-beta mRNA in embryonic gonads were not affected by temperature and did not differ between testes and ovaries. However, expression of both receptors increased at least an order of magnitude from the embryonic to the post-hatching period. Finally, we characterized expression of these genes in several other embryonic tissues. The brain, heart, and liver displayed unique expression patterns that distinguished these tissues from each other and from intestine, lung, and muscle. Incubation temperature had a significant effect on expression of PdgfR-alpha and PdgfR-beta in the heart but not other tissues. Together, these findings demonstrate that temperature has tissue specific effects on the Pdgf system and suggest that Pdgf signaling is involved in sex determination and the ensuing differentiation of testes in the snapping turtle.

  18. Illegitimate WNT signaling promotes proliferation of multiple myeloma cells

    Science.gov (United States)

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

    2004-01-01

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

  19. Voltammetric determination of paracetamole using a glassy carbon electrode modified with Prussian Blue and a molecularly imprinted polymer, and ratiometric read-out of two signals

    International Nuclear Information System (INIS)

    Dai, Yunlong; Li, Xueyan; Lu, Xiaojing; Kan, Xianwen

    2016-01-01

    The authors report on a ratiometric electrochemical sensor for paracetamole (PR) which was fabricated by successively electropolymerizing a layer of Prussian blue (PB) and a layer of molecularly imprinted polypyrrole (MIP) on the surface of a glassy carbon electrode (GCE). The binding of PR molecules to the MIP has two effects: The first is an increase of the oxidation current for PR at 0.42 V (vs. SCE), and the second is a decrease in the current for PB (at 0.18 V) due to partial blocking of the channels which results in reduced electron transmissivity. Both currents, and in particular their ratio, can serve as analytical information. Under optimized conditions, the sensor displays enhanced sensitivity for PR in the 1.0 nM to 0.1 mM concentration range and a 0.53 nM lower limit of detection. The sensor was applied to the determination of PR in tablets and urines where it gave recoveries in the range between 94.6 and 104.9 %. This dual-signal (ratiometric) detection scheme (using electro polymerized Prussian Blue and analyte-specific MIP) in our perception has a wide scope in that it may be applied to numerous other electro active species for which specific MIP can be made available. (author)

  20. Simultaneous determination of penicillin G salts by infrared spectroscopy: Evaluation of combining orthogonal signal correction with radial basis function-partial least squares regression

    Science.gov (United States)

    Talebpour, Zahra; Tavallaie, Roya; Ahmadi, Seyyed Hamid; Abdollahpour, Assem

    2010-09-01

    In this study, a new method for the simultaneous determination of penicillin G salts in pharmaceutical mixture via FT-IR spectroscopy combined with chemometrics was investigated. The mixture of penicillin G salts is a complex system due to similar analytical characteristics of components. Partial least squares (PLS) and radial basis function-partial least squares (RBF-PLS) were used to develop the linear and nonlinear relation between spectra and components, respectively. The orthogonal signal correction (OSC) preprocessing method was used to correct unexpected information, such as spectral overlapping and scattering effects. In order to compare the influence of OSC on PLS and RBF-PLS models, the optimal linear (PLS) and nonlinear (RBF-PLS) models based on conventional and OSC preprocessed spectra were established and compared. The obtained results demonstrated that OSC clearly enhanced the performance of both RBF-PLS and PLS calibration models. Also in the case of some nonlinear relation between spectra and component, OSC-RBF-PLS gave satisfactory results than OSC-PLS model which indicated that the OSC was helpful to remove extrinsic deviations from linearity without elimination of nonlinear information related to component. The chemometric models were tested on an external dataset and finally applied to the analysis commercialized injection product of penicillin G salts.

  1. Variation in the ovine cortisol response to systemic bacterial endotoxin challenge is predominantly determined by signalling within the hypothalamic-pituitary-adrenal axis

    International Nuclear Information System (INIS)

    You Qiumei; Karrow, Niel A.; Cao Honghe; Rodriguez, Alexander; Mallard, Bonnie A.; Boermans, Herman J.

    2008-01-01

    Bi-directional communication between the neuroendocrine and immune systems is designed, in part, to maintain or restore homeostasis during physiological stress. Exposure to endotoxin during Gram-negative bacterial infection for example, elicits the release of pro-inflammatory cytokines that activate the hypothalamic-pituitary-adrenal axis (HPAA). The secretion of adrenal glucocorticoids subsequently down regulates the host inflammatory response, minimizing potential tissue damage. Sequence and epigenetic variants in genes involved in regulating the neuroendocrine and immune systems are likely to contribute to individual differences in the HPAA response, and this may influence the host anti-inflammatory response to toxin exposure and susceptibility to inflammatory disease. In this study, high (HCR) and low (LCR) cortisol responders were selected from a normal population of 110 female sheep challenged iv with Escherichia coli endotoxin (400 ng/kg) to identify potential determinants that contribute to variation in the cortisol response phenotype. This phenotype was stable over several years in the HCR and LCR animals, and did not appear to be attributed to differences in expression of hepatic immune-related genes or systemic pro-inflammatory cytokine concentrations. Mechanistic studies using corticotrophin-releasing factor (0.5 μg/kg body weight), arginine vasopressin (0.5 μg/kg), and adrenocorticotropic hormone (0.5 μg/kg) administered iv demonstrated that variation in this phenotype is largely determined by signalling within the HPAA. Future studies will use this ovine HCR/LCR model to investigate potential genetic and epigenetic variants that may contribute to variation in cortisol responsiveness to bacterial endotoxin

  2. 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, ...

  3. Location and wavefield attributes of long-period signals at Villarrica volcano (Chile) determined by array and polarization-moveout analysis

    Science.gov (United States)

    Lehr, Johanna; Thorwart, Martin; Rabbel, Wolfgang

    2016-04-01

    Villarrica Volcano is the most active volcano in Chile whose latest eruption occurred in March 2015. Increasing the knowledge on its processes, structure and behavior is thus crucial to an effective monitoring and hazard assessment. In this context, long-period volcanic signals (LP) are considered to be a key to the understanding of fluid dynamics and volcanic plumbing systems, accessible by seismological observations. However, standard seismological location tools usually fail due to the emergent onset of the signal and its serious distortion caused by attenuation and scattering in a complex geology. Therefore, alternative methods are needed. In March 2012, a dense seismic network was installed at Villarrica for two weeks with 50 stations covering the volcanic edifice including 6 subarrays. About 400 LP events were identified. LP-events recorded on crater stations look similar to typical earthquakes arrivals with distinguishable P- and S-wave onsets indicating a source near the crater. But with increasing source distance waveforms gradually change into typical LP-events. To investigate how to locate these LP-events we tested two approaches at the basis of a show-case event. In a first trial, records of the subarrays were used to determine backazimuths and slowness by beamforming in the time domain. The analysis was performed in a moving window, using semblance to measure the beam quality. The epicenter was derived by intersecting azimuthal rays. It locates ca. 1 km southeast of the summit crater. Slownesses range from 0.5 s/km up to 2.0 s/km. At frequencies above 2 Hz, additional maxima appear in the semblance distribution of near-summit arrays which can be interpreted as side-scattered signals. Since the crossing points of the backazimuth rays showed some scattering we tested polarization analysis (applied to the subset of 3-component stations) as an alternative location method. Although the direct interpretation of the backazimuths was unreliable, we identified

  4. Paracrine interactions between LNCaP prostate cancer cells and bioengineered bone in 3D in vitro culture reflect molecular changes during bone metastasis.

    Science.gov (United States)

    Sieh, Shirly; Taubenberger, Anna V; Lehman, Melanie L; Clements, Judith A; Nelson, Colleen C; Hutmacher, Dietmar W

    2014-06-01

    As microenvironmental factors such as three-dimensionality and cell-matrix interactions are increasingly being acknowledged by cancer biologists, more complex 3D in vitro models are being developed to study tumorigenesis and cancer progression. To better understand the pathophysiology of bone metastasis, we have established and validated a 3D indirect co-culture model to investigate the paracrine interactions between prostate cancer (PCa) cells and human osteoblasts. Co-culture of the human PCa, LNCaP cells embedded within polyethylene glycol hydrogels with human osteoblasts in the form of a tissue engineered bone construct (TEB), resulted in reduced proliferation of LNCaP cells. LNCaP cells in both monoculture and co-culture were responsive to the androgen analog, R1881, as indicated by an increase in the expression (mRNA and/or protein induction) of androgen-regulated genes including prostate specific antigen and fatty acid synthase. Microarray gene expression analysis further revealed an up-regulation of bone markers and other genes associated with skeletal and vasculature development and a significant activation of transforming growth factor β1 downstream genes in LNCaP cells after co-culture with TEB. LNCaP cells co-cultured with TEB also unexpectedly showed similar changes in classical androgen-responsive genes under androgen-deprived conditions not seen in LNCaP monocultures. The molecular changes of LNCaP cells after co-culturing with TEBs suggest that osteoblasts exert a paracrine effect that may promote osteomimicry and modulate the expression of androgen-responsive genes in LNCaP cells. Taken together, we have presented a novel 3D in vitro model that allows the study of cellular and molecular changes occurring in PCa cells and osteoblasts that are relevant to metastatic colonization of bone. This unique in vitro model could also facilitate cancer biologists to dissect specific biological hypotheses via extensive genomic or proteomic assessments to

  5. A novel technique for determination of two dimensional signal-to-noise ratio improvement factor of an antiscatter grid in digital radiography

    Science.gov (United States)

    Nøtthellen, Jacob; Konst, Bente; Abildgaard, Andreas

    2014-08-01

    Purpose: to present a new and simplified method for pixel-wise determination of the signal-to-noise ratio improvement factor KSNR of an antiscatter grid, when used with a digital imaging system. The method was based on approximations of published formulas. The simplified estimate of K2SNR may be used as a decision tool for whether or not to use an antiscatter grid. Methods: the primary transmission of the grid Tp was determined with and without a phantom present using a pattern of beam stops. The Bucky factor B was measured with and without a phantom present. Hence K2SNR maps were created based on Tp and B. A formula was developed to calculate K2SNR from the measured Bs without using the measured Tp. The formula was applied on two exposures of anthropomorphic phantoms, adult legs and baby chest, and on two homogeneous poly[methyl methacrylate] (PMMA) phantoms, 5 cm and 10 cm thick. The results from anthropomorphic phantoms were compared to those based on the beam stop method. The results for the PMMA-phantoms were compared to a study that used a contrast-detail phantom. Results: 2D maps of K2SNR over the entire adult legs and baby chest phantoms were created. The maps indicate that it is advantageous to use the antiscatter grid for imaging of the adult legs. For baby chest imaging the antiscatter grid is not recommended if only the lung regions are of interest. The K2SNR maps based on the new method correspond to those from the beam stop method, and the K2SNR from the homogenous phantoms arising from two different approaches also agreed well with each other. Conclusion: a method to measure 2D K2SNR associated with grid use in digital radiography system was developed and validated. The proposed method requires four exposures and use of a simple formula. It is fast and provides adequate estimates for K2SNR.

  6. The hedgehog-signaling pathway is repressed during the osteogenic differentiation of dental follicle cells

    DEFF Research Database (Denmark)

    Morsczeck, Christian; Reck, A; Beck, H C

    2017-01-01

    of repressors of the hedgehog-signaling pathway such as Patched 1 (PTCH1), Suppressor of Fused (SUFU), and Parathyroid Hormone-Related Peptide (PTHrP). Previous studies suggested that hedgehog proteins induce the osteogenic differentiation of mesenchymal stem cells via a paracrine pathway. Indian hedgehog (IHH......) induced the expression of the osteogenic transcription factor RUNX2. However, a supplementation of the BMP2-based osteogenic differentiation medium with IHH did not induce the expression of RUNX2. Moreover, IHH inhibited slightly the ALP activity and the mineralization of osteogenic-differentiated DFCs...

  7. Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue

    Energy Technology Data Exchange (ETDEWEB)

    Santander, Ana M.; Lopez-Ocejo, Omar; Casas, Olivia; Agostini, Thais; Sanchez, Lidia; Lamas-Basulto, Eduardo; Carrio, Roberto [Department of Microbiology and Immunology, University of Miami Miller School of Medicine, 1600 NW 10th Ave, Miami, FL 33136 (United States); Cleary, Margot P. [Hormel Institute, University of Minnesota, Austin, MN 55912 (United States); Gonzalez-Perez, Ruben R. [Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30314 (United States); Torroella-Kouri, Marta, E-mail: mtorroella@med.miami.edu [Department of Microbiology and Immunology, University of Miami Miller School of Medicine, 1600 NW 10th Ave, Miami, FL 33136 (United States); Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1475 NW 12th Ave, Miami, FL 33136 (United States)

    2015-01-15

    The relationship between obesity and breast cancer (BC) has focused on serum factors. However, the mammary gland contains adipose tissue (AT) which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT) is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations). In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity.

  8. Paracrine Interactions between Adipocytes and Tumor Cells Recruit and Modify Macrophages to the Mammary Tumor Microenvironment: The Role of Obesity and Inflammation in Breast Adipose Tissue

    International Nuclear Information System (INIS)

    Santander, Ana M.; Lopez-Ocejo, Omar; Casas, Olivia; Agostini, Thais; Sanchez, Lidia; Lamas-Basulto, Eduardo; Carrio, Roberto; Cleary, Margot P.; Gonzalez-Perez, Ruben R.; Torroella-Kouri, Marta

    2015-01-01

    The relationship between obesity and breast cancer (BC) has focused on serum factors. However, the mammary gland contains adipose tissue (AT) which may enable the crosstalk between adipocytes and tumor cells contributing to tumor macrophage recruitment. We hypothesize that the breast AT (bAT) is inflamed in obese females and plays a major role in breast cancer development. The effects of this interplay on macrophage chemotaxis were examined in vitro, using co-cultures of mouse macrophages, mammary tumor cells and adipocytes. Macrophages were exposed to the adipocyte and tumor paracrine factors leptin, CCL2 and lauric acid (alone or in combinations). In cell supernatants Luminex identified additional molecules with chemotactic and other pro-tumor functions. Focus on the adipokine leptin, which has been shown to have a central role in breast cancer pathogenesis, indicated it modulates macrophage phenotypes and functions. In vivo experiments demonstrate that mammary tumors from obese mice are larger and that bAT from obese tumor-bearers contains higher numbers of macrophages/CLS and hypertrophic adipocytes than bAT from lean tumor-bearers, thus confirming it is more inflamed. Also, bAT distal from the tumor is more inflamed in obese than in lean mice. Our results reveal that bAT plays a role in breast cancer development in obesity

  9. Reciprocal Signaling between the Ectoderm and a Mesendodermal Left-Right Organizer Directs Left-Right Determination in the Sea Urchin Embryo

    Science.gov (United States)

    Bessodes, Nathalie; Haillot, Emmanuel; Duboc, Véronique; Röttinger, Eric; Lahaye, François; Lepage, Thierry

    2012-01-01

    During echinoderm development, expression of nodal on the right side plays a crucial role in positioning of the rudiment on the left side, but the mechanisms that restrict nodal expression to the right side are not known. Here we show that establishment of left-right asymmetry in the sea urchin embryo relies on reciprocal signaling between the ectoderm and a left-right organizer located in the endomesoderm. FGF/ERK and BMP2/4 signaling are required to initiate nodal expression in this organizer, while Delta/Notch signaling is required to suppress formation of this organizer on the left side of the archenteron. Furthermore, we report that the H+/K+-ATPase is critically required in the Notch signaling pathway upstream of the S3 cleavage of Notch. Our results identify several novel players and key early steps responsible for initiation, restriction, and propagation of left-right asymmetry during embryogenesis of a non-chordate deuterostome and uncover a functional link between the H+/K+-ATPase and the Notch signaling pathway. PMID:23271979

  10. The Crossroads of Synaptic Growth Signaling, Membrane Traffic and Neurological Disease: Insights from Drosophila.

    Science.gov (United States)

    Deshpande, Mugdha; Rodal, Avital A

    2016-02-01

    Neurons require target-derived autocrine and paracrine growth factors to maintain proper identity, innervation, homeostasis and survival. Neuronal growth factor signaling is highly dependent on membrane traffic, both for the packaging and release of the growth factors themselves, and for regulation of intracellular signaling by their transmembrane receptors. Here, we review recent findings from the Drosophila larval neuromuscular junction (NMJ) that illustrate how specific steps of intracellular traffic and inter-organelle interactions impinge on signaling, particularly in the bone morphogenic protein, Wingless and c-Jun-activated kinase pathways, regulating elaboration and stability of NMJ arbors, construction of synapses and synaptic transmission and homeostasis. These membrane trafficking and signaling pathways have been implicated in human motor neuron diseases including amyotrophic lateral sclerosis and hereditary spastic paraplegia, highlighting their importance for neuronal health and survival. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. 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...

  12. Paracrine GABA and insulin regulate pancreatic alpha cell proliferation in a mouse model of type 1 diabetes.

    Science.gov (United States)

    Feng, Allen L; Xiang, Yun-Yan; Gui, Le; Kaltsidis, Gesthika; Feng, Qingping; Lu, Wei-Yang

    2017-06-01

    This study aimed to elucidate the mechanism of increased proliferation of alpha cells in recent-onset type 1 diabetes. Pancreatic beta cells express GAD and produce γ-aminobutyric acid (GABA), which inhibits alpha cell secretion of glucagon. We explored the roles of GABA in alpha cell proliferation in conditions corresponding to type 1 diabetes in a mouse model and in vitro. Type 1 diabetes was induced by injecting the mice with streptozotocin (STZ). Some of the STZ-injected mice were treated with GABA (10 mg/kg daily) for 12 days. Isolated pancreatic islets were treated with STZ or STZ together with GABA for 2 days. The effects of GABA treatment on STZ-induced alpha cell proliferation in vivo and in vitro were assessed. The effect of muscimol, a GABA receptor agonist, on αTC1-6 cell proliferation was also examined. STZ injection substantially decreased levels of GAD, GABA and insulin in pancreatic beta cells 12 h after injection; this was followed by an upsurge of phosphorylated mechanistic target of rapamycin (p-mTOR) in the alpha cells at day 1, and a significant increase in alpha cell mass at day 3. Treating STZ-injected mice with GABA largely restored the immunodetectable levels of insulin and GAD in the beta cells and significantly decreased the number of aldehyde dehydrogenase 1 family, member A3 (ALDH1a3)-positive cells, alpha cell mass and hyperglucagonaemia. STZ treatment also increased alpha cell proliferation in isolated islets, which was reversed by co-treatment with GABA. Muscimol, together with insulin, significantly lowered the level of cytosolic Ca 2+ and p-mTOR, and decreased the proliferation rate of αTC1-6 cells. GABA signalling critically controls the alpha cell population in pancreatic islets. Low intraislet GABA may contribute to alpha cell hyperplasia in early type 1 diabetes.

  13. Antiseptic solutions modulate the paracrine-like activity of bone chips: differential impact of chlorhexidine and sodium hypochlorite.

    Science.gov (United States)

    Sawada, Kosaku; Caballé-Serrano, Jordi; Bosshardt, Dieter D; Schaller, Benoit; Miron, Richard J; Buser, Daniel; Gruber, Reinhard

    2015-09-01

    Chemical decontamination increases the availability of bone grafts; however, it remains unclear whether antiseptic processing changes the biological activity of bone. Bone chips were incubated with four different antiseptic solutions including (1) povidone-iodine (0.5%), (2) chlorhexidine diguluconate (0.2%), (3) hydrogen peroxide (1%) and (4) sodium hypochlorite (0.25%). After 10 min. of incubation, changes in the capacity of the bone-conditioned medium (BCM) to modulate gene expression of gingival fibroblasts was investigated. Conditioned medium obtained from freshly prepared bone chips increased the expression of TGF-β target genes interleukin 11 (IL11), proteoglycan4 (PRG4), NADPH oxidase 4 (NOX4), and decreased the expression of adrenomedullin (ADM), and pentraxin 3 (PTX3) in gingival fibroblasts. Incubation of bone chips with 0.2% chlorhexidine, followed by vigorously washing resulted in a BCM with even higher expression of IL11, PRG4 and NOX4. These findings were also detected with a decrease in cell viability and an activation of apoptosis signalling. Chlorhexidine alone, at low concentrations, increased IL11, PRG4 and NOX4 expression, independent of the TGF-β receptor I kinase activity. In contrast, 0.25% sodium hypochlorite almost entirely abolished the activity of BCM, whereas the other two antiseptic solutions, 1% hydrogen peroxide and 0.5% povidone-iodine, had relatively no impact respectively. These in vitro findings demonstrate that incubation of bone chips with chlorhexidine differentially affects the activity of the respective BCM compared to the other antiseptic solutions. The data further suggest that the main effects are caused by chlorhexidine remaining in the BCM after repeated washing of the bone chips. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Drought Signaling in Plants

    Indian Academy of Sciences (India)

    depending upon the source and nature of signaling: (i) hormone signal, (ii) .... plants to regulate the rate of transpiration through minor structural .... cell has to keep spending energy (in the form of A TP) to maintain a .... enzymes and proteins in the regulation of cellular metabolism can be determined by either inactivating.

  15. ATP signals

    DEFF Research Database (Denmark)

    Novak, Ivana

    2016-01-01

    The Department of Biology at the University of Copenhagen explains the function of ATP signalling in the pancreas......The Department of Biology at the University of Copenhagen explains the function of ATP signalling in the pancreas...

  16. Paracrine stimulation of P2X7 receptor by ATP activates a proliferative pathway in ovarian carcinoma cells.

    Science.gov (United States)

    Vázquez-Cuevas, Francisco G; Martínez-Ramírez, Angélica S; Robles-Martínez, Leticia; Garay, Edith; García-Carrancá, Alejandro; Pérez-Montiel, Delia; Castañeda-García, Carolina; Arellano, Rogelio O

    2014-11-01

    P2X7 is a purinergic receptor-channel; its activation by ATP elicits a broad set of cellular actions, from apoptosis to signals for survival. Here, P2X7 expression and function was studied in human ovarian carcinoma (OCA) cells, and biopsies from non-cancerous and cancer patients were analyzed by immunohistochemistry. Ovarian surface epithelium in healthy tissue expressed P2X7 at a high level that was maintained throughout the cancer. The cell lines SKOV-3 and CAOV-3 were used to investigate P2X7 functions in OCA. In SKOV-3 cells, selective stimulation of P2X7 by 2'(3')-O-(4-benzoylbenzoyl) adenosine-5'-triphosphate (BzATP) induced a dose-dependent increase of intracellular Ca(2+) concentration ([Ca(2+)](i)) but not cell death. Instead, BzATP increased the levels of phosphorylated ERK and AKT (pERK and pAKT), with an EC(50) of 44 ± 2 and 1.27 ± 0.5 μM, respectively; 10 μM BzATP evoked a maximum effect within 15 min that lasted for 120 min. Interestingly, basal levels of pERK and pAKT were decreased in the presence of apyrase in the medium, strongly suggesting an endogenous, ATP-mediated phenomenon. Accordingly: (i) mechanically stimulated cells generated a [Ca(2+)](i) increase that was abolished by apyrase; (ii) apyrase induced a decrease in culture viability, as measured by the MTS assay for mitochondrial activity; and (iii) incubation with 10 μM AZ10606120, a specific P2X7 antagonist and transfection with the dominant negative P2X7 mutant E496A, both reduced cell viability to 70.1 ± 8.9% and to 76.5 ± 5%, respectively, of control cultures. These observations suggested that P2X7 activity was auto-induced through ATP efflux; this increased pERK and pAKT levels that generated a positive feedback on cell viability. © 2014 Wiley Periodicals, Inc.

  17. Calcium alginate gels as stem cell matrix-making paracrine stem cell activity available for enhanced healing after surgery.

    Directory of Open Access Journals (Sweden)

    Andreas Schmitt

    Full Text Available Regeneration after surgery can be improved by the administration of anabolic growth factors. However, to locally maintain these factors at the site of regeneration is problematic. The aim of this study was to develop a matrix system containing human mesenchymal stem cells (MSCs which can be applied to the surgical site and allows the secretion of endogenous healing factors from the cells. Calcium alginate gels were prepared by a combination of internal and external gelation. The gelling behaviour, mechanical stability, surface adhesive properties and injectability of the gels were investigated. The permeability of the gels for growth factors was analysed using bovine serum albumin and lysozyme as model proteins. Human MSCs were isolated, cultivated and seeded into the alginate gels. Cell viability was determined by AlamarBlue assay and fluorescence microscopy. The release of human VEGF and bFGF from the cells was determined using an enzyme-linked immunoassay. Gels with sufficient mechanical properties were prepared which remained injectable through a syringe and solidified in a sufficient time frame after application. Surface adhesion was improved by the addition of polyethylene glycol 300,000 and hyaluronic acid. Humans MSCs remained viable for the duration of 6 weeks within the gels. Human VEGF and bFGF was found in quantifiable concentrations in cell culture supernatants of gels loaded with MSCs and incubated for a period of 6 weeks. This work shows that calcium alginate gels can function as immobilization matrices for human MSCs.

  18. Hedgehog signaling and therapeutics in pancreatic cancer.

    LENUS (Irish Health Repository)

    Kelleher, Fergal C

    2012-02-01

    OBJECTIVE: To conduct a systematic review of the role that the hedgehog signaling pathway has in pancreatic cancer tumorigenesis. METHOD: PubMed search (2000-2010) and literature based references. RESULTS: Firstly, in 2009 a genetic analysis of pancreatic cancers found that a core set of 12 cellular signaling pathways including hedgehog were genetically altered in 67-100% of cases. Secondly, in vitro and in vivo studies of treatment with cyclopamine (a naturally occurring antagonist of the hedgehog signaling pathway component; Smoothened) has shown that inhibition of hedgehog can abrogate pancreatic cancer metastasis. Thirdly, experimental evidence has demonstrated that sonic hedgehog (Shh) is correlated with desmoplasia in pancreatic cancer. This is important because targeting the Shh pathway potentially may facilitate chemotherapeutic drug delivery as pancreatic cancers tend to have a dense fibrotic stroma that extrinsically compresses the tumor vasculature leading to a hypoperfusing intratumoral circulation. It is probable that patients with locally advanced pancreatic cancer will derive the greatest benefit from treatment with Smoothened antagonists. Fourthly, it has been found that ligand dependent activation by hedgehog occurs in the tumor stromal microenvironment in pancreatic cancer, a paracrine effect on tumorigenesis. Finally, in pancreatic cancer, cells with the CD44+CD24+ESA+ immunophenotype select a population enriched for cancer initiating stem cells. Shh is increased 46-fold in CD44+CD24+ESA+ cells compared with normal pancreatic epithelial cells. Medications that destruct pancreatic cancer initiating stem cells are a potentially novel strategy in cancer treatment. CONCLUSIONS: Aberrant hedgehog signaling occurs in pancreatic cancer tumorigenesis and therapeutics that target the transmembrane receptor Smoothened abrogate hedgehog signaling and may improve the outcomes of patients with pancreatic cancer.

  19. Detection of the sulfhydryl groups in proteins with slow hydrogen exchange rates and determination of their proton/deuteron fractionation factors using the deuterium-induced effects on the 13C(beta) NMR signals.

    Science.gov (United States)

    Takeda, Mitsuhiro; Jee, JunGoo; Terauchi, Tsutomu; Kainosho, Masatsune

    2010-05-05

    A method for identifying cysteine (Cys) residues with sulfhydryl (SH) groups exhibiting slow hydrogen exchange rates has been developed for proteins in aqueous media. The method utilizes the isotope shifts of the C(beta) chemical shifts induced by the deuteration of the SH groups. The 18.2 kDa E. coli peptidyl prolyl cis-trans isomerase b (EPPIb), which was selectively labeled with [3-(13)C;3,3-(2)H(2)]Cys, showed much narrower line widths for the (13)C(beta) NMR signals, as compared to those of the proteins labeled with either [3-(13)C]Cys or (3R)-[3-(13)C;3-(2)H]Cys. The (13)C(beta) signals of the two Cys residues of EPPIb, i.e. Cys-31 and Cys-121, labeled with [3-(13)C;3,3-(2)H(2)]Cys, split into four signals in H(2)O/D(2)O (1:1) at 40 degrees C and pH 7.5, indicating that the exchange rates of the side-chain SH's and the backbone amides are too slow to average the chemical shift differences of the (13)C(beta) signals, due to the two- and three-bond isotope shifts. By virtue of the well-separated signals, the proton/deuteron fractional factors for both the SH and amide groups of the two Cys residues in EPPIb could be directly determined, as approximately 0.4-0.5 for [SD]/[SH] and 0.9-1.0 for [ND]/[NH], by the relative intensities of the NMR signals for the isotopomers. The proton NOE's of the two slowly exchanging SH's were clearly identified in the NOESY spectra and were useful for the determining the local structure of EPPIb around the Cys residues.

  20. Determining of the Parking Manoeuvre and the Taxi Blockage Adjustment Factor for the Saturation Flow Rate at the Outlet Legs of Signalized Intersections: Case Study from Rasht City (Iran)

    Science.gov (United States)

    Behbahani, Hamid; Jahangir Samet, Mehdi; Najafi Moghaddam Gilani, Vahid; Amini, Amir

    2017-10-01

    The presence of taxi stops within the area of signalized intersections at the outlet legs due to unnatural behaviour of the taxis, sudden change of lanes, parking manoeuvres activities and stopping the vehicle to discharge or pick up the passengers have led to reduction of saturation flow rate at the outlet leg of signalized intersections and increased delay as well as affecting the performance of a crossing lane. So far, in term of evaluating effective adjustment factors on saturation flow rate at the inlet legs of the signalized intersections, various studies have been carried out, however; there has not been any studies on effective adjustment factors on saturation flow rate at the inlet legs. Hence, the evaluating of the traffic effects of unique behaviours on the saturation flow rate of the outlet leg is very important. In this research the parking manoeuvre time and taxi blockage time were evaluated and analyzed based on the available lane width as well as determining the effective adjustment factors on the saturation flow rate using recording related data at four signalized intersections in Rasht city. The results show that the average parking manoeuvre time is a function of the lane width and is increased as the lane width is reduced. Also, it is suggested to use the values of 7.37 and 11.31 seconds, respectively for the average parking manoeuvre time and the average blockage time of taxies at the outlet legs of signalized intersections for the traffic designing in Rasht city.

  1. Bone marrow-derived mesenchymal stem cells repaired but did not prevent gentamicin-induced acute kidney injury through paracrine effects in rats.

    Directory of Open Access Journals (Sweden)

    Luciana A Reis

    Full Text Available This study evaluated the effects of bone marrow-derived mesenchymal stem cells (BMSCs or their conditioned medium (CM on the repair and prevention of Acute Kidney Injury (AKI induced by gentamicin (G. Animals received daily injections of G up to 20 days. On the 10(th day, injections of BMSCs, CM, CM+trypsin, CM+RNase or exosome-like microvesicles extracted from the CM were administered. In the prevention groups, the animals received the BMSCs 24 h before or on the 5(th day of G treatment. Creatinine (Cr, urea (U, FENa and cytokines were quantified. The kidneys were evaluated using hematoxylin/eosin staining and immunohystochemistry. The levels of Cr, U and FENa increased during all the periods of G treatment. The BMSC transplantation, its CM or exosome injections inhibited the increase in Cr, U, FENa, necrosis, apoptosis and also increased cell proliferation. The pro-inflammatory cytokines decreased while the anti-inflammatory cytokines increased compared to G. When the CM or its exosomes were incubated with RNase (but not trypsin, these effects were blunted. The Y chromosome was not observed in the 24-h prevention group, but it persisted in the kidney for all of the periods analyzed, suggesting that the injury is necessary for the docking and maintenance of BMSCs in the kidney. In conclusion, the BMSCs and CM minimized the G-induced renal damage through paracrine effects, most likely through the RNA carried by the exosome-like microvesicles. The use of the CM from BMSCs can be a potential therapeutic tool for this type of nephrotoxicity, allowing for the avoidance of cell transplantations.

  2. Aging exacerbates obesity-induced oxidative stress and inflammation in perivascular adipose tissue in mice: a paracrine mechanism contributing to vascular redox dysregulation and inflammation.

    Science.gov (United States)

    Bailey-Downs, Lora C; Tucsek, Zsuzsanna; Toth, Peter; Sosnowska, Danuta; Gautam, Tripti; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2013-07-01

    Obesity in the elderly individuals is increasing at alarming rates and there is evidence suggesting that elderly individuals are more vulnerable to the deleterious cardiovascular effects of obesity than younger individuals. However, the specific mechanisms through which aging and obesity interact to promote the development of cardiovascular disease remain unclear. The present study was designed to test the hypothesis that aging exacerbates obesity-induced inflammation in perivascular adipose tissue, which contributes to increased vascular oxidative stress and inflammation in a paracrine manner. To test this hypothesis, we assessed changes in the secretome, reactive oxygen species production, and macrophage infiltration in periaortic adipose tissue of young (7 month old) and aged (24 month old) high-fat diet-fed obese C57BL/6 mice. High-fat diet-induced vascular reactive oxygen species generation significantly increased in aged mice, which was associated with exacerbation of endothelial dysfunction and vascular inflammation. In young animals, high-fat diet-induced obesity promoted oxidative stress in the perivascular adipose tissue, which was associated with a marked proinflammatory shift in the profile of secreted cytokines and chemokines. Aging exacerbated obesity-induced oxidative stress and inflammation and significantly increased macrophage infiltration in periaortic adipose tissue. Using cultured arteries isolated from young control mice, we found that inflammatory factors secreted from the perivascular fat tissue of obese aged mice promote significant prooxidative and proinflammatory phenotypic alterations in the vascular wall, mimicking the aging phenotype. Overall, our findings support an important role for localized perivascular adipose tissue inflammation in exacerbation of vascular oxidative stress and inflammation in aging, an effect that likely enhances the risk for development of cardiovascular diseases from obesity in the elderly individuals.

  3. Paracrine effects of oocyte secreted factors and stem cell factor on porcine granulosa and theca cells in vitro

    Directory of Open Access Journals (Sweden)

    Webb Bob

    2003-08-01

    Full Text Available Abstract Oocyte control of granulosa and theca cell function may be mediated by several growth factors via a local feedback loop(s between these cell types. This study examined both the role of oocyte-secreted factors on granulosa and thecal cells, cultured independently and in co-culture, and the effect of stem cell factor (SCF; a granulosa cell derived peptide that appears to have multiple roles in follicle development. Granulosa and theca cells were isolated from 2–6 mm healthy follicles of mature porcine ovaries and cultured under serum-free conditions, supplemented with: 100 ng/ml LR3 IGF-1, 10 ng/ml insulin, 100 ng/ml testosterone, 0–10 ng/ml SCF, 1 ng/ml FSH (granulosa, 0.01 ng/ml LH (theca or 1 ng/ml FSH and 0.01 ng/ml LH (co-culture and with/without oocyte conditioned medium (OCM or 5 oocytes. Cells were cultured in 96 well plates for 144 h, after which viable cell numbers were determined. Medium was replaced every 48 h and spent medium analysed for steroids. Oocyte secreted factors were shown to stimulate both granulosa cell proliferation (P

  4. Red not dead: signaling in and from erythrocytes.

    Science.gov (United States)

    Sprague, Randy S; Stephenson, Alan H; Ellsworth, Mary L

    2007-11-01

    The oxygen required to meet metabolic needs of all tissues is delivered by the erythrocyte, a small, flexible cell which, in mammals, is devoid of a nucleus and mitochondria. Despite its simple appearance, this 'bag of hemoglobin' has an important role in its own distribution, enabling the delivery of oxygen to precisely meet localized metabolic need. When an erythrocyte enters an area in which tissue oxygen demand exceeds supply, a signaling pathway is activated resulting in the release of adenosine 5'-triphosphate (ATP). This ATP acts in a paracrine fashion to increase vascular caliber resulting in increased oxygen delivery. Defects in this pathway are found in erythrocytes of humans with type 2 diabetes (DM2) and could contribute to the perfusion abnormalities in skeletal muscle associated with this disease.

  5. 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

  6. 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.

  7. Sensitive electrochemical determination of α-fetoprotein using a glassy carbon electrode modified with in-situ grown gold nanoparticles, graphene oxide and MWCNTs acting as signal amplifiers

    International Nuclear Information System (INIS)

    Gao, Yan-Sha; Zhu, Xiao-Fei; Yang, Tao-Tao; Xu, Jing-Kun; Zhang, Kai-Xin; Lu, Li-Min

    2015-01-01

    The authors describe an electrochemical immunoassay for α-fetoprotein (α-FP) using a glassy carbon electrode (GCE) modified with a nanocomposite made from gold nanoparticles, graphene oxide and multi-walled carbon nanotubes (AuNPs/GO-MWCNTs) and acting as a signal amplification matrix. The nanocomposite was synthesized in a one-pot redox reaction between GO and HAuCl 4 without using an additional reductant. The stepwise assembly of the immunoelectrode was characterized by means of cyclic voltammetry and electrochemical impedance spectroscopy. The interaction of antigen and antibody on the surface of the electrode creates a barrier for electrons and causes retarded electron transfer, this resulting in decreased signals in differential pulse voltammetry of hexacyanoferrate which is added as an electrochemical probe. Using this strategy and by working at a potential of 0.2 V (vs. SCE), a wide analytical range (0.01 - 100 ng∙mL -1 ) is covered. The correlation coefficient is 0.9929, and the limit of detection is as low as 3 pg∙mL -1 at a signal-to-noise ratio of 3. This electrochemical immunoassay combines the specificity of an immunological detection scheme with the sensitivity of an electrode modified with AuNPs and GO-MWCNTs. (author)

  8. Signals of Ezh2, Src, and Akt Involve in Myostatin-Pax7 Pathways Regulating the Myogenic Fate Determination during the Sheep Myoblast Proliferation and Differentiation

    Science.gov (United States)

    Li, Li; Liu, Ruizao; Zhang, Li; Zhao, Fuping; Lu, Jian; Zhang, Xiaoning; Du, Lixin

    2015-01-01

    Myostatin and Pax7 have been well documented individually, however, the mechanism by which Myostatin regulates Pax7 is seldom reported. Here, based on muscle transcriptome analysis in Texel (Myostatin mutant) and Ujumqin (wild type) sheep across the five fetal stages, we constructed and examined the Myostatin-Pax7 pathways in muscle. Then we validated the signals by RNAi in the proliferating and differentiating sheep myoblasts in vitro at mRNA, protein, and cell morphological levels. We reveal that Myostatin signals to Pax7 at least through Ezh2, Src, and Akt during the sheep myoblast proliferation and differentiation. Other signals such as p38MAPK, mTOR, Erk1/2, Wnt, Bmp2, Smad, Tgfb1, and p21 are most probably involved in the Myostatin-affected myogenic events. Myostatin knockdown significantly reduces the counts of nucleus and myotube, but not the fusion index of myoblasts during cell differentiation. In addition, findings also indicate that Myostatin is required for normal myogenic differentiation of the sheep myoblasts, which is different from the C2C12 myoblasts. We expand the regulatory network of Myostatin-Pax7 pathways and first illustrate that Myostatin as a global regulator participates in the epigenetic events involved in myogenesis, which contributes to understand the molecular mechanism of Myostatin in regulation of myogenesis. PMID:25811841

  9. Paracrine Activation of the Wnt/β-Catenin Pathway by Bone Marrow Stem Cell Attenuates Cisplatin-Induced Kidney Injury

    Directory of Open Access Journals (Sweden)

    Xiaoyan Jiao

    2017-12-01

    Full Text Available Background/Aims: Cisplatin-induced acute kidney injury (AKI involves damage to tubular cells via excess reactive oxygen species (ROS generation. Stem cell-based therapies have shown great promise in AKI treatment. In this study, we aimed to assess the protective effect and mechanism of bone marrow mesenchymal stem cell (BMSC-derived conditioned medium (CM against cisplatin-induced AKI. Methods: In vitro, NRK-52E cells were incubated with cisplatin in the presence or absence of CM, followed by the assessment of cell viability, apoptosis and cell cycle distribution. Then, ICG-001 and IWR-1 were used to inhibit the wnt/β-catenin pathway. Furthermore, intracellular and mitochondrial ROS levels were evaluated using DCFH-DA and MitoSOX, respectively. In vivo, after cisplatin injection, rats were intravenously injected with CM or BMSCs. Sera and kidney tissues were collected on day 3 after cisplatin injection to evaluate changes in renal function and histology. Western blotting and qRT-PCR were employed to determine the expression of wnt/β-catenin pathway-related genes and proteins. Immunohistochemical staining was used to evaluate tubular β-catenin expression in kidney biopsy from AKI patients. Results: CM protected NRK-52E cells from cisplatin-induced injury by restoring the wnt4/β-catenin pathway. In response to ICG-001 and IWR-1, the protective effect of CM was attenuated, characterized by a decrease in cell proliferation and an increase in cell apoptosis and intracellular and mitochondrial ROS levels. Knockdown of β-catenin using siRNAs also suppressed the mitochondrial biogenesis regulators PGC-1α, TFAM and NRF-1. In the rat model, CM significantly alleviated renal function and histology associated with tubular injury and upregulated wnt4 and β-catenin. However, the renoprotective effect of CM was blocked by ICG-001, characterized by exacerbated renal function, suppressed PGC-1α expression and increased mitochondrial ROS. Clinical data

  10. Paracrine Activation of the Wnt/β-Catenin Pathway by Bone Marrow Stem Cell Attenuates Cisplatin-Induced Kidney Injury.

    Science.gov (United States)

    Jiao, Xiaoyan; Cai, Jieru; Yu, Xiaofang; Ding, Xiaoqiang

    2017-01-01

    Cisplatin-induced acute kidney injury (AKI) involves damage to tubular cells via excess reactive oxygen species (ROS) generation. Stem cell-based therapies have shown great promise in AKI treatment. In this study, we aimed to assess the protective effect and mechanism of bone marrow mesenchymal stem cell (BMSC)-derived conditioned medium (CM) against cisplatin-induced AKI. In vitro, NRK-52E cells were incubated with cisplatin in the presence or absence of CM, followed by the assessment of cell viability, apoptosis and cell cycle distribution. Then, ICG-001 and IWR-1 were used to inhibit the wnt/β-catenin pathway. Furthermore, intracellular and mitochondrial ROS levels were evaluated using DCFH-DA and MitoSOX, respectively. In vivo, after cisplatin injection, rats were intravenously injected with CM or BMSCs. Sera and kidney tissues were collected on day 3 after cisplatin injection to evaluate changes in renal function and histology. Western blotting and qRT-PCR were employed to determine the expression of wnt/β-catenin pathway-related genes and proteins. Immunohistochemical staining was used to evaluate tubular β-catenin expression in kidney biopsy from AKI patients. CM protected NRK-52E cells from cisplatin-induced injury by restoring the wnt4/β-catenin pathway. In response to ICG-001 and IWR-1, the protective effect of CM was attenuated, characterized by a decrease in cell proliferation and an increase in cell apoptosis and intracellular and mitochondrial ROS levels. Knockdown of β-catenin using siRNAs also suppressed the mitochondrial biogenesis regulators PGC-1α, TFAM and NRF-1. In the rat model, CM significantly alleviated renal function and histology associated with tubular injury and upregulated wnt4 and β-catenin. However, the renoprotective effect of CM was blocked by ICG-001, characterized by exacerbated renal function, suppressed PGC-1α expression and increased mitochondrial ROS. Clinical data showed that the tubular β-catenin level was lower in

  11. Selective Deletion of Leptin Signaling in Endothelial Cells Enhances Neointima Formation and Phenocopies the Vascular Effects of Diet-Induced Obesity in Mice.

    Science.gov (United States)

    Hubert, Astrid; Bochenek, Magdalena L; Schütz, Eva; Gogiraju, Rajinikanth; Münzel, Thomas; Schäfer, Katrin

    2017-09-01

    Obesity is associated with elevated circulating leptin levels and hypothalamic leptin resistance. Leptin receptors (LepRs) are expressed on endothelial cells, and leptin promotes neointima formation in a receptor-dependent manner. Our aim was to examine the importance of endothelial LepR (End.LepR) signaling during vascular remodeling and to determine whether the cardiovascular consequences of obesity are because of hyperleptinemia or endothelial leptin resistance. Mice with loxP-flanked LepR alleles were mated with mice expressing Cre recombinase controlled by the inducible endothelial receptor tyrosine kinase promoter. Obesity was induced with high-fat diet. Neointima formation was examined after chemical carotid artery injury. Morphometric quantification revealed significantly greater intimal hyperplasia, neointimal cellularity, and proliferation in End.LepR knockout mice, and similar findings were obtained in obese, hyperleptinemic End.LepR wild-type animals. Analysis of primary endothelial cells confirmed abrogated signal transducer and activator of transcription-3 phosphorylation in response to leptin in LepR knockout and obese LepR wild-type mice. Quantitative PCR, ELISA, and immunofluorescence analyses revealed increased expression and release of endothelin-1 in End.LepR-deficient and LepR-resistant cells, and ET receptor A/B antagonists abrogated their paracrine effects on murine aortic smooth muscle cell proliferation. Reduced expression of peroxisome proliferator-activated receptor-γ and increased nuclear activator protein-1 staining was observed in End.LepR-deficient and LepR-resistant cells, and peroxisome proliferator-activated receptor-γ antagonization increased endothelial endothelin-1 expression. Our findings suggest that intact endothelial leptin signaling limits neointima formation and that obesity represents a state of endothelial leptin resistance. These observations and the identification of endothelin-1 as soluble mediator of the

  12. Signaling aggression.

    Science.gov (United States)

    van Staaden, Moira J; Searcy, William A; Hanlon, Roger T

    2011-01-01

    From psychological and sociological standpoints, aggression is regarded as intentional behavior aimed at inflicting pain and manifested by hostility and attacking behaviors. In contrast, biologists define aggression as behavior associated with attack or escalation toward attack, omitting any stipulation about intentions and goals. Certain animal signals are strongly associated with escalation toward attack and have the same function as physical attack in intimidating opponents and winning contests, and ethologists therefore consider them an integral part of aggressive behavior. Aggressive signals have been molded by evolution to make them ever more effective in mediating interactions between the contestants. Early theoretical analyses of aggressive signaling suggested that signals could never be honest about fighting ability or aggressive intentions because weak individuals would exaggerate such signals whenever they were effective in influencing the behavior of opponents. More recent game theory models, however, demonstrate that given the right costs and constraints, aggressive signals are both reliable about strength and intentions and effective in influencing contest outcomes. Here, we review the role of signaling in lieu of physical violence, considering threat displays from an ethological perspective as an adaptive outcome of evolutionary selection pressures. Fighting prowess is conveyed by performance signals whose production is constrained by physical ability and thus limited to just some individuals, whereas aggressive intent is encoded in strategic signals that all signalers are able to produce. We illustrate recent advances in the study of aggressive signaling with case studies of charismatic taxa that employ a range of sensory modalities, viz. visual and chemical signaling in cephalopod behavior, and indicators of aggressive intent in the territorial calls of songbirds. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Extracellular ATP in the Exocrine Pancreas – ATP Release, Signalling and Metabolism

    DEFF Research Database (Denmark)

    Kowal, Justyna Magdalena

    release. So far, the contribution of duct cells in purinergic signalling has never been studied. This work presents that both acinar and duct cells are sources of extracellular ATP in the exocrine pancreas. Here we show that duct cells release ATP in response to several physiological......ATP plays an important role as an autocrine/paracrine signalling molecule, being released from a number of tissues, in response to physiological and pathophysiological stimuli. Released ATP induces Ca2+ - and/or cAMP - dependent cellular responses via activation of ubiquitously expressed P2X and P2......, particularly during Ca2+ stress conditions. In conclusion, these studies demonstrate a complex regulation of purinergic signalling in exocrine pancreas. A crucial role for duct cells in mediating extracellular nucleotides homeostasis, involving ATP release, subsequent hydrolysis and conversion via...

  14. The Role of (BETA)-Catenin in Androgen Receptor Signaling

    National Research Council Canada - National Science Library

    Bhowmick, Neil A

    2006-01-01

    .... Our preliminary data seem indicate stromally derived paracrine Wnt family members activate theepithelial frizzled receptor to enable prostate epithelial survival in an androgen deficient environment...

  15. cMyc/miR-125b-5p signalling determines sensitivity to bortezomib in preclinical model of cutaneous T-cell lymphomas

    DEFF Research Database (Denmark)

    Manfè, Valentina; Biskup, Edyta; Willumsgaard, Ayalah

    2013-01-01

    Successful/effective cancer therapy in low grade lymphoma is often hampered by cell resistance to anti-neoplastic agents. The crucial mechanisms responsible for this phenomenon are poorly understood. Overcoming resistance of tumor cells to anticancer agents, such as proteasome inhibitors, could...... improve their clinical efficacy. Using cutaneous T-cell lymphoma (CTCL) as a model of the chemotherapy-resistant peripheral lymphoid malignancy, we demonstrated that resistance to proteasome inhibition involved a signaling between the oncogene cMyc and miR-125b-5p. Bortezomib repressed c...

  16. FGF10: A multifunctional mesenchymal-epithelial signaling growth factor in development, health, and disease.

    Science.gov (United States)

    Itoh, Nobuyuki

    2016-04-01

    The FGF family comprises 22 members with diverse functions in development and health. FGF10 specifically activates FGFR2b in a paracrine manner with heparan sulfate as a co-factor. FGF10and FGFR2b are preferentially expressed in the mesenchyme and epithelium, respectively. FGF10 is a mesenchymal signaling molecule in the epithelium. FGF10 knockout mice die shortly after birth due to the complete absence of lungs as well as fore- and hindlimbs. FGF10 is also essential for the development of multiple organs. The phenotypes of Fgf10 knockout mice are very similar to those of FGFR2b knockout mice, indicating that FGF10 acts as a ligand that is specific to FGFR2b in mouse multi-organ development. FGF10 also plays roles in epithelial-mesenchymal transition, the repair of tissue injury, and embryonic stem cell differentiation. In humans, FGF10 loss-of-function mutations result in inherited diseases including aplasia of lacrimal and salivary gland, lacrimo-auriculo-dento-digital syndrome, and chronic obstructive pulmonary disease. FGF10 is also involved in the oncogenicity of pancreatic and breast cancers. Single nucleotide polymorphisms in FGF10 are also potential risk factors for limb deficiencies, cleft lip and palate, and extreme myopia. These findings indicate that FGF10 is a crucial paracrine signal from the mesenchyme to epithelium for development, health, and disease. Copyright © 2015. Published by Elsevier Ltd.

  17. 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.

  18. Scaled signal intensity of uterine fibroids based on T2-weighted MR images: a potential objective method to determine the suitability for magnetic resonance-guided focused ultrasound surgery of uterine fibroids.

    Science.gov (United States)

    Park, Hyun; Yoon, Sang-Wook; Sokolov, Amit

    2015-12-01

    Magnetic Resonance-guided Focused Ultrasound Surgery (MRgFUS) is a non-invasive method to treat uterine fibroids. To help determine the patient suitability for MRgFUS, we propose a new objective measure: the scaled signal intensity (SSI) of uterine fibroids in T2 weighted MR images (T2WI). Forty three uterine fibroids in 40 premenopausal women were included in this retrospective study. SSI of each fibroid was measured from the screening T2WI by standardizing its mean signal intensity to a 0-100 scale, using reference intensities of rectus abdominis muscle (0) and subcutaneous fat (100). Correlation between the SSI and the non-perfused volume (NPV) ratio (a measure for treatment success) was calculated. Pre-treatment SSI showed a significant inverse-correlation with post treatment NPV ratio (p < 0.05). When dichotomizing NPV ratio at 45 %, the optimal cut off value of the SSI was found to be 16.0. A fibroid with SSI value 16.0 or less can be expected to have optimal responses. The SSI of uterine fibroids in T2WI can be suggested as an objective parameter to help in patient selection for MRgFUS. • Signal intensity of fibroid in MR images predicts treatment response to MRgFUS. • Signal intensity is standardized into scaled form using adjacent tissues as references. • Fibroids with SSI less than 16.0 are expected to have optimal responses.

  19. Signal detection

    International Nuclear Information System (INIS)

    Tholomier, M.

    1985-01-01

    In a scanning electron microscope, whatever is the measured signal, the same set is found: incident beam, sample, signal detection, signal amplification. The resulting signal is used to control the spot luminosity with the observer cathodoscope. This is synchronized with the beam scanning on the sample; on the cathodoscope, the image in secondary electrons, backscattered electrons,... of the sample surface is reconstituted. The best compromise must be found between a register time low enough to remove eventual variations (under the incident beam) of the nature of the observed phenomenon, and a good spatial resolution of the image and a signal-to-noise ratio high enough. The noise is one of the basic limitations of the scanning electron microscope performance. The whose measurement line must be optimized to reduce it [fr

  20. Molecular and Cellular Signaling

    CERN Document Server

    Beckerman, Martin

    2005-01-01

    A small number of signaling pathways, no more than a dozen or so, form a control layer that is responsible for all signaling in and between cells of the human body. The signaling proteins belonging to the control layer determine what kinds of cells are made during development and how they function during adult life. Malfunctions in the proteins belonging to the control layer are responsible for a host of human diseases ranging from neurological disorders to cancers. Most drugs target components in the control layer, and difficulties in drug design are intimately related to the architecture of the control layer. Molecular and Cellular Signaling provides an introduction to molecular and cellular signaling in biological systems with an emphasis on the underlying physical principles. The text is aimed at upper-level undergraduates, graduate students and individuals in medicine and pharmacology interested in broadening their understanding of how cells regulate and coordinate their core activities and how diseases ...

  1. Interleukin-1β regulates fat-liver crosstalk in obesity by auto-paracrine modulation of adipose tissue inflammation and expandability.

    Directory of Open Access Journals (Sweden)

    Ori Nov

    Full Text Available The inflammasome has been recently implicated in obesity-associated dys-metabolism. However, of its products, the specific role of IL-1β was clinically demonstrated to mediate only the pancreatic beta-cell demise, and in mice mainly the intra-hepatic manifestations of obesity. Yet, it remains largely unknown if IL-1β, a cytokine believed to mainly function locally, could regulate dysfunctional inter-organ crosstalk in obesity. Here we show that High-fat-fed (HFF mice exhibited a preferential increase of IL-1β in portal compared to systemic blood. Moreover, portally-drained mesenteric fat transplantation from IL-1βKO donors resulted in lower pyruvate-glucose flux compared to mice receiving wild-type (WT transplant. These results raised a putative endocrine function for visceral fat-derived IL-1β in regulating hepatic gluconeogenic flux. IL-1βKO mice on HFF exhibited only a minor or no increase in adipose expression of pro-inflammatory genes (including macrophage M1 markers, Mac2-positive crown-like structures and CD11b-F4/80-double-positive macrophages, all of which were markedly increased in WT-HFF mice. Further consistent with autocrine/paracrine functions of IL-1β within adipose tissue, adipose tissue macrophage lipid content was increased in WT-HFF mice, but significantly less in IL-1βKO mice. Ex-vivo, adipose explants co-cultured with primary hepatocytes from WT or IL-1-receptor (IL-1RI-KO mice suggested only a minor direct effect of adipose-derived IL-1β on hepatocyte insulin resistance. Importantly, although IL-1βKOs gained weight similarly to WT-HFF, they had larger fat depots with similar degree of adipocyte hypertrophy. Furthermore, adipogenesis genes and markers (pparg, cepba, fabp4, glut4 that were decreased by HFF in WT, were paradoxically elevated in IL-1βKO-HFF mice. These local alterations in adipose tissue inflammation and expansion correlated with a lower liver size, less hepatic steatosis, and preserved insulin

  2. Three-dimensional spheroid cell culture of umbilical cord tissue-derived mesenchymal stromal cells leads to enhanced paracrine induction of wound healing.

    Science.gov (United States)

    Santos, Jorge M; Camões, Sérgio P; Filipe, Elysse; Cipriano, Madalena; Barcia, Rita N; Filipe, Mariana; Teixeira, Mariana; Simões, Sandra; Gaspar, Manuela; Mosqueira, Diogo; Nascimento, Diana S; Pinto-do-Ó, Perpétua; Cruz, Pedro; Cruz, Helder; Castro, Matilde; Miranda, Joana P

    2015-05-09

    The secretion of trophic factors by mesenchymal stromal cells has gained increased interest given the benefits it may bring to the treatment of a variety of traumatic injuries such as skin wounds. Herein, we report on a three-dimensional culture-based method to improve the paracrine activity of a specific population of umbilical cord tissue-derived mesenchymal stromal cells (UCX®) towards the application of conditioned medium for the treatment of cutaneous wounds. A UCX® three-dimensional culture model was developed and characterized with respect to spheroid formation, cell phenotype and cell viability. The secretion by UCX® spheroids of extracellular matrix proteins and trophic factors involved in the wound-healing process was analysed. The skin regenerative potential of UCX® three-dimensional culture-derived conditioned medium (CM3D) was also assessed in vitro and in vivo against UCX® two-dimensional culture-derived conditioned medium (CM2D) using scratch and tubulogenesis assays and a rat wound splinting model, respectively. UCX® spheroids kept in our three-dimensional system remained viable and multipotent and secreted considerable amounts of vascular endothelial growth factor A, which was undetected in two-dimensional cultures, and higher amounts of matrix metalloproteinase-2, matrix metalloproteinase-9, hepatocyte growth factor, transforming growth factor β1, granulocyte-colony stimulating factor, fibroblast growth factor 2 and interleukin-6, when compared to CM2D. Furthermore, CM3D significantly enhanced elastin production and migration of keratinocytes and fibroblasts in vitro. In turn, tubulogenesis assays revealed increased capillary maturation in the presence of CM3D, as seen by a significant increase in capillary thickness and length when compared to CM2D, and increased branching points and capillary number when compared to basal medium. Finally, CM3D-treated wounds presented signs of faster and better resolution when compared to untreated and CM

  3. Biased Gs Versus Gq Proteins and β-Arrestin Signaling in the NK1 Receptor Determined by Interactions in the Water Hydrogen Bond Network

    DEFF Research Database (Denmark)

    Valentin-Hansen, Louise; Frimurer, Thomas M; Mokrosinski, Jacek

    2015-01-01

    X-ray structures, molecular dynamics simulations, and mutational analysis have previously indicated that an extended water hydrogen bond network between trans-membranes I-III, VI, and VII constitutes an allosteric interface essential for stabilizing different active and inactive helical...... of the highly conserved AspII:10 (2.50). Here, we find that this GluII:10 occupies the space of a putative allosteric modulating Na(+) ion and makes direct inter-helical interactions in particular with SerIII:15 (3.39) and AsnVII:16 (7.49) of the NPXXY motif. Mutational changes in the interface between GluII:10....... It is concluded that the interface between position II:10 (2.50), III:15 (3.39), and VII:16 (7.49) in the center of the water hydrogen bond network constitutes a focal point for fine-tuning seven trans-membrane receptor conformations activating different signal transduction pathways....

  4. Guanylin peptides: cyclic GMP signaling mechanisms

    Directory of Open Access Journals (Sweden)

    Forte L.R.

    1999-01-01

    Full Text Available Guanylate cyclases (GC serve in two different signaling pathways involving cytosolic and membrane enzymes. Membrane GCs are receptors for guanylin and atriopeptin peptides, two families of cGMP-regulating peptides. Three subclasses of guanylin peptides contain one intramolecular disulfide (lymphoguanylin, two disulfides (guanylin and uroguanylin and three disulfides (E. coli stable toxin, ST. The peptides activate membrane receptor-GCs and regulate intestinal Cl- and HCO3- secretion via cGMP in target enterocytes. Uroguanylin and ST also elicit diuretic and natriuretic responses in the kidney. GC-C is an intestinal receptor-GC for guanylin and uroguanylin, but GC-C may not be involved in renal cGMP pathways. A novel receptor-GC expressed in the opossum kidney (OK-GC has been identified by molecular cloning. OK-GC cDNAs encode receptor-GCs in renal tubules that are activated by guanylins. Lymphoguanylin is highly expressed in the kidney and heart where it may influence cGMP pathways. Guanylin and uroguanylin are highly expressed in intestinal mucosa to regulate intestinal salt and water transport via paracrine actions on GC-C. Uroguanylin and guanylin are also secreted from intestinal mucosa into plasma where uroguanylin serves as an intestinal natriuretic hormone to influence body Na+ homeostasis by endocrine mechanisms. Thus, guanylin peptides control salt and water transport in the kidney and intestine mediated by cGMP via membrane receptors with intrinsic guanylate cyclase activity.

  5. Determination of the Average Native Background and the Light-Induced EPR Signals and their Variation in the Teeth Enamel Based on Large-Scale Survey of the Population

    International Nuclear Information System (INIS)

    Ivannikov, Alexander I.; Khailov, Artem M.; Orlenko, Sergey P.; Skvortsov, Valeri G.; Stepanenko, Valeri F.; Zhumadilov, Kassym Sh.; Williams, Benjamin B.; Flood, Ann B.; Swartz, Harold M.

    2016-01-01

    The aim of the study is to determine the average intensity and variation of the native background signal amplitude (NSA) and of the solar light-induced signal amplitude (LSA) in electron paramagnetic resonance (EPR) spectra of tooth enamel for different kinds of teeth and different groups of people. These values are necessary for determination of the intensity of the radiation-induced signal amplitude (RSA) by subtraction of the expected NSA and LSA from the total signal amplitude measured in L-band for in vivo EPR dosimetry. Variation of these signals should be taken into account when estimating the uncertainty of the estimated RSA. A new analysis of several hundred EPR spectra that were measured earlier at X-band in a large-scale examination of the population of the Central Russia was performed. Based on this analysis, the average values and the variation (standard deviation, SD) of the amplitude of the NSA for the teeth from different positions, as well as LSA in outer enamel of the front teeth for different population groups, were determined. To convert data acquired at X-band to values corresponding to the conditions of measurement at L-band, the experimental dependencies of the intensities of the RSA, LSA and NSA on the m.w. power, measured at both X and L-band, were analysed. For the two central upper incisors, which are mainly used in in vivo dosimetry, the mean LSA annual rate induced only in the outer side enamel and its variation were obtained as 10 ± 2 (SD = 8) mGy y"-"1, the same for X- and L-bands (results are presented as the mean ± error of mean). Mean NSA in enamel and its variation for the upper incisors was calculated at 2.0 ± 0.2 (SD = 0.5) Gy, relative to the calibrated RSA dose-response to gamma radiation measured under non-power saturation conditions at X-band. Assuming the same value for L-band under non-power saturating conditions, then for in vivo measurements at L-band at 25 mW (power saturation conditions), a mean NSA and its

  6. Determination of the Average Native Background and the Light-Induced EPR Signals and their Variation in the Teeth Enamel Based on Large-Scale Survey of the Population.

    Science.gov (United States)

    Ivannikov, Alexander I; Khailov, Artem M; Orlenko, Sergey P; Skvortsov, Valeri G; Stepanenko, Valeri F; Zhumadilov, Kassym Sh; Williams, Benjamin B; Flood, Ann B; Swartz, Harold M

    2016-12-01

    The aim of the study is to determine the average intensity and variation of the native background signal amplitude (NSA) and of the solar light-induced signal amplitude (LSA) in electron paramagnetic resonance (EPR) spectra of tooth enamel for different kinds of teeth and different groups of people. These values are necessary for determination of the intensity of the radiation-induced signal amplitude (RSA) by subtraction of the expected NSA and LSA from the total signal amplitude measured in L-band for in vivo EPR dosimetry. Variation of these signals should be taken into account when estimating the uncertainty of the estimated RSA. A new analysis of several hundred EPR spectra that were measured earlier at X-band in a large-scale examination of the population of the Central Russia was performed. Based on this analysis, the average values and the variation (standard deviation, SD) of the amplitude of the NSA for the teeth from different positions, as well as LSA in outer enamel of the front teeth for different population groups, were determined. To convert data acquired at X-band to values corresponding to the conditions of measurement at L-band, the experimental dependencies of the intensities of the RSA, LSA and NSA on the m.w. power, measured at both X and L-band, were analysed. For the two central upper incisors, which are mainly used in in vivo dosimetry, the mean LSA annual rate induced only in the outer side enamel and its variation were obtained as 10 ± 2 (SD = 8) mGy y -1 , the same for X- and L-bands (results are presented as the mean ± error of mean). Mean NSA in enamel and its variation for the upper incisors was calculated at 2.0 ± 0.2 (SD = 0.5) Gy, relative to the calibrated RSA dose-response to gamma radiation measured under non-power saturation conditions at X-band. Assuming the same value for L-band under non-power saturating conditions, then for in vivo measurements at L-band at 25 mW (power saturation conditions), a mean NSA and its

  7. Nitrate signals determine the sensing of nitrogen through differential expression of genes involved in nitrogen uptake and assimilation in finger millet.

    Science.gov (United States)

    Gupta, Alok Kumar; Gaur, Vikram Singh; Gupta, Sanjay; Kumar, Anil

    2013-06-01

    In order to understand the molecular basis of high nitrogen use efficiency of finger millet, five genes (EcHNRT2, EcLNRT1, EcNADH-NR, EcGS, and EcFd-GOGAT) involved in nitrate uptake and assimilation were isolated using conserved primer approaches. Expression profiles of these five genes along with the previously isolated EcDof1 was studied under increased KNO3 concentrations (0.15 to 1,500 μM) for 2 h as well as at 1.5 μM for 24 h in the roots and shoots of 25 days old nitrogen deprived two contrasting finger millet genotypes (GE-3885 and GE-1437) differing in grain protein content (13.76 and 6.15 %, respectively). Time kinetics experiment revealed that, all the five genes except EcHNRT2 in the leaves of GE-3885 were induced within 30 min of nitrate exposure indicating that there might be a greater nitrogen deficit in leaves and therefore quick transportation of nitrate signals to the leaves. Exposing the plants to increasing nitrate concentrations for 2 h showed that in roots of GE-3885, NR was strongly induced while GS was repressed; however, the pattern was found to be reversed in leaves of GE-1437 indicating that in GE-3885, most of the nitrate might be reduced in the roots but assimilated in leaves and vice-versa. Furthermore, compared with the low-protein genotype, expression of HNRT2 was strongly induced in both roots and shoots of high-protein genotype at the least nitrate concentration supplied. This further indicates that GE-3885 is a quick sensor of nitrogen compared with the low-protein genotype. Furthermore, expression of EcDof1 was also found to overlap the expression of NR, GS, and GOGAT indicating that Dof1 probably regulates the expression of these genes under different conditions by sensing the nitrogen fluctuations around the root zone.

  8. MRI-based liver iron content determination at 3 T in regularly transfused patients by signal intensity ratio using an alternative analysis approach based on R{sub 2}* theory

    Energy Technology Data Exchange (ETDEWEB)

    Wunderlich, A.P. [Universitaetsklinikum Ulm (Germany). Section for Experimental Radiology; Cario, H. [Universitaetsklinik Ulm (Germany). Children' s Hospital; Bommer, M. [Alb-Fils-Clinics, Goeppingen (Germany). Hematology and Oncology Dept.; Beer, M.; Schmidt, S.A. [Universitaetsklinikum Ulm (Germany). Dept. for Diagnostic and Interventional Radiology; Juchems, M.S. [Klinikum Konstanz (Germany). Diagnostic and Interventional Radiology

    2016-09-15

    To evaluate the feasibility of addressing liver iron content (LIC) in regularly transfused patients by MR imaging at 3 T based on the signal intensity ratio (SIR). An innovative data analysis approach was developed for this purpose. 47 consecutive examinations of regularly transfused patients were included. In all cases, we expected high LIC levels. Patients were scanned with MRI at 3 T with multi-echo gradient echo sequences (GRE) at four different flip angles between 20 and 90 with echo times (TE) ranging from 0.9 to 9.8 ms. Spin-echo protocols were acquired to determine the LIC with a reference MRI method working at 1.5 T. 3 T GRE data were analyzed using the liver-to-muscle SIR. Since the method known for 1.5 T was not expected to be applicable for analyzing 3 T data, theoretic dependence of the SIR on the LIC was derived from the equation describing R{sub 2}* signal decay. Obtained SIR values were correlated to reference LIC to get a relation for calculating LIC from SIR quantities. LIC values and their uncertainties were determined from GRE data and correlated to LIC reference values. For two LIC thresholds, the diagnostic accuracy was determined. LIC was reliably determined from SIR in our patient cohort even for large LIC values. Median of LIC uncertainties was 10%, and the diagnostic accuracy was 0.92 and 0.91, respectively. Determination of even high LIC, resulting in small SIR values, is feasible at 3 T using appropriate SIR analysis.

  9. Determination of eugenol in rat plasma by liquid chromatography-quadrupole ion trap mass spectrometry using a simple off-line dansyl chloride derivatization reaction to enhance signal intensity.

    Science.gov (United States)

    Beaudry, Francis; Guénette, Sarah Annie; Vachon, Pascal

    2006-11-01

    A rapid, selective and sensitive method was developed for the determination of eugenol concentration using an off-line dansyl chloride derivatization step to enhance signal intensity. The method consisted of a protein precipitation extraction followed by derivatization with dansyl chloride and analysis by full scan liquid chromatography electrospray quadrupole ion trap mass spectrometry (LC-ESI-QIT). The separation was achieved using a 100 x 2 mm C(8) analytical column combined with an isocratic mobile phase composed of 75:25 acetonitrile: 0.1% formic acid in water set at a flow rate of 0.25 mL/min. Signal intensity of the eugenol-dansyl chloride derivative was increased up to 100-fold as compared with the underivatized eugenol in positive electrospray mode. An analytical range of 100-20,000 ng/mL was used in the calibration curve of plasma and blood samples. The LOD observed was 0.5 pg injected on column. The novel method met all requirements of specificity, sensitivity, linearity, precision, accuracy and stability. In conclusion, a rapid and sensitive LC-ESI/MS/MS method using a derivatization agent was developed to enhance signal intensity of eugenol. Copyright (c) 2006 John Wiley & Sons, Ltd.

  10. Steroid Signaling and Temperature-Dependent Sex Determination – Reviewing the Evidence for Early Action of Estrogen during Ovarian Determination in the Red-Eared Slider Turtle (Trachemys scripta elegans)

    Science.gov (United States)

    Ramsey, Mary; Crews, David

    2009-01-01

    The developmental processes underlying gonadal differentiation are conserved across vertebrates, but the triggers initiating these trajectories are extremely variable. The red-eared slider turtle (Trachemys scripta elegans) exhibits temperature-dependent sex determination (TSD), a system where incubation temperature during a temperature-sensitive period of development determines offspring sex. However, gonadal sex is sensitive to both temperature and hormones during this period – particularly estrogen. We present a model for temperature-based differences in aromatase expression as a critical step in ovarian determination. Localized estrogen production facilitates ovarian development while inhibiting male-specific gene expression. At male-producing temperatures aromatase is not upregulated, thereby allowing testis development. PMID:18992835

  11. Source mechanism of Vulcanian degassing at Popocatépetl Volcano, Mexico, determined from waveform inversions of very long period signals

    Science.gov (United States)

    Chouet, Bernard A.; Dawson, Phillip B.; Arciniega-Ceballos, Alejandra

    2005-01-01

    The source mechanism of very long period (VLP) signals accompanying volcanic degassing bursts at Popocatépetl is analyzed in the 15–70 s band by minimizing the residual error between data and synthetics calculated for a point source embedded in a homogeneous medium. The waveforms of two eruptions (23 April and 23 May 2000) representative of mild Vulcanian activity are well reproduced by our inversion, which takes into account volcano topography. The source centroid is positioned 1500 m below the western perimeter of the summit crater, and the modeled source is composed of a shallow dipping crack (sill with easterly dip of 10°) intersecting a steeply dipping crack (northeast striking dike dipping 83° northwest), whose surface extension bisects the vent. Both cracks undergo a similar sequence of inflation, deflation, and reinflation, reflecting a cycle of pressurization, depressurization, and repressurization within a time interval of 3–5 min. The largest moment release occurs in the sill, showing a maximum volume change of 500–1000 m3, pressure drop of 3–5 MPa, and amplitude of recovered pressure equal to 1.2 times the amplitude of the pressure drop. In contrast, the maximum volume change in the dike is less (200–300 m3), with a corresponding pressure drop of 1–2 MPa and pressure recovery equal to the pressure drop. Accompanying these volumetric sources are single-force components with magnitudes of 108 N, consistent with melt advection in response to pressure transients. The source time histories of the volumetric components of the source indicate that significant mass movement starts within the sill and triggers a mass movement response in the dike within a few seconds. Such source behavior is consistent with the opening of a pathway for escape of pent-up gases from slow pressurization of the sill driven by magma crystallization. The opening of this pathway and associated rapid evacuation of volcanic gases induces the pressure drop. Pressure

  12. Role for herpes simplex virus 1 ICP27 in the inhibition of type I interferon signaling

    International Nuclear Information System (INIS)

    Johnson, Karen E.; Song, Byeongwoon; Knipe, David M.

    2008-01-01

    Host cells respond to viral infection by many mechanisms, including the production of type I interferons which act in a paracrine and autocrine manner to induce the expression of antiviral interferon-stimulated genes (ISGs). Viruses have evolved means to inhibit interferon signaling to avoid induction of the innate immune response. Herpes simplex virus 1 (HSV-1) has several mechanisms to inhibit type I interferon production, the activities of ISGs, and the interferon signaling pathway itself. We report that the inhibition of the Jak/STAT pathway by HSV-1 requires viral gene expression and that viral immediate-early protein ICP27 plays a role in downregulating STAT-1 phosphorylation and in preventing the accumulation of STAT-1 in the nucleus. We also show that expression of ICP27 by transfection causes an inhibition of IFN-induced STAT-1 nuclear accumulation. Therefore, ICP27 is necessary and sufficient for at least some of the effects of HSV infection on STAT-1

  13. Mesenchymal Stem Cell Conditioned Medium Promotes Proliferation and Migration of Alveolar Epithelial Cells under Septic Conditions In Vitro via the JNK-P38 Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Jie Chen

    2015-11-01

    Full Text Available Background/Aims: Mesenchymal stem cell (MSC based therapies may be useful for treating acute respiratory distress syndrome (ARDS, but the underlying mechanisms are incompletely understood. We investigated the impact of human umbilical cord Wharton's jelly-derived MSC (hUC-MSC secreted factors on alveolar epithelial cells under septic conditions and determined the relevant intracellular signaling pathways. Methods: Human alveolar epithelial cells (AEC and primary human small airway epithelial cells (SAEC were subjected to lipopolysaccharide (LPS with or without the presence of hUC-MSC-conditioned medium (CM. Proliferation and migration of AEC and SAEC were determined via an MTT assay, a wound healing assay and a transwell migration assay (only for AEC. Protein phosphorylation was determined by western blot and the experiments were repeated in presence of small-molecule inhibitors. The hMSC-secretory proteins were identified by LC-MS/MS mass spectrometry. Results: MSC-CM enhanced proliferation and migration. Activation of JNK and P38, but not ERK, was required for the proliferation and migration of AEC and SAEC. Pretreatment of AEC or SAEC with SP600125, an inhibitor of JNK1 or SB200358, an inhibitor of P38, significantly reduced cell proliferation and migration. An array of proteins including TGF-beta receptor type-1, TGF-beta receptor type-2, Ras-related C3 botulinum toxin substrate 1 and Ras-related C3 botulinum toxin substrate 2 which influencing the proliferation and migration of AEC and SAEC were detected in MSC-CM. Conclusion: Our data suggest MSC promote epithelial cell repair through releasing a repertoire of paracrine factors via activation of JNK and P38 MAPK.

  14. JNK1 induces hedgehog signaling from stellate cells to accelerate liver regeneration in mice.

    Science.gov (United States)

    Langiewicz, Magda; Graf, Rolf; Humar, Bostjan; Clavien, Pierre A

    2018-04-27

    To improve outcomes of two-staged hepatectomies for large/multiple liver tumors, portal vein ligation (PVL) has been combined with parenchymal transection (coined ALPPS; Associated Liver Partition and Portal vein ligation for Staged hepatectomy) to greatly accelerate liver regeneration. In a novel ALPPS mouse model, we have reported paracrine Indian hedgehog (IHH) signaling from stellate cells as an early contributor to augmented regeneration. Here, we sought to identify upstream regulators of IHH. ALPPS in mice was compared against PVL and additional control surgeries. Potential IHH regulators were identified through in silico mining of transcriptomic data. JNK1 activity was reduced through SP600125 to evaluate its effects on IHH signaling. Recombinant IHH was injected after JNK diminution to substantiate their relationship during accelerated liver regeneration. Mining linked Ihh to Mapk8. JNK1 upregulation after ALPPS was validated and preceded the IHH peak. On immunofluorescence, JNK1 and IHH co-localized in ASMA-positive non-parenchymal cells. Inhibition of JNK1 prior to ALPPS surgery reduced liver weight gain to PVL levels and was accompanied by downregulation of hepatocellular proliferation and the IHH-GLI1-CCND1 axis. In JNK1-inhibited mice, recombinant IHH restored ALPPS-like acceleration of regeneration and re-elevated JNK1 activity, suggesting the presence of a positive IHH-JNK1 feedback loop. JNK1-mediated induction of IHH paracrine signaling from HSCs is essential for accelerated regeneration of parenchymal mass. The JNK1-IHH axis is a mechanism unique to ALPPS surgery and may point to therapeutic alternatives for patients with insufficient regenerative capacity. ALPPS, a novel two-staged hepatectomy, induces an unprecedented acceleration of liver regeneration to enable treatment of unresectable liver tumors. Here, we demonstrate JNK1-IHH signaling as a mechanism underlying the regenerative acceleration induced by ALPPS. Copyright © 2018 European

  15. Signal Processing

    International Nuclear Information System (INIS)

    Anon.

    1992-01-01

    Signal processing techniques, extensively used nowadays to maximize the performance of audio and video equipment, have been a key part in the design of hardware and software for high energy physics detectors since pioneering applications in the UA1 experiment at CERN in 1979

  16. Live Cell Analysis and Mathematical Modeling Identify Determinants of Attenuation of Dengue Virus 2'-O-Methylation Mutant.

    Directory of Open Access Journals (Sweden)

    Bianca Schmid

    2015-12-01

    Full Text Available Dengue virus (DENV is the most common mosquito-transmitted virus infecting ~390 million people worldwide. In spite of this high medical relevance, neither a vaccine nor antiviral therapy is currently available. DENV elicits a strong interferon (IFN response in infected cells, but at the same time actively counteracts IFN production and signaling. Although the kinetics of activation of this innate antiviral defense and the timing of viral counteraction critically determine the magnitude of infection and thus disease, quantitative and kinetic analyses are lacking and it remains poorly understood how DENV spreads in IFN-competent cell systems. To dissect the dynamics of replication versus antiviral defense at the single cell level, we generated a fully viable reporter DENV and host cells with authentic reporters for IFN-stimulated antiviral genes. We find that IFN controls DENV infection in a kinetically determined manner that at the single cell level is highly heterogeneous and stochastic. Even at high-dose, IFN does not fully protect all cells in the culture and, therefore, viral spread occurs even in the face of antiviral protection of naïve cells by IFN. By contrast, a vaccine candidate DENV mutant, which lacks 2'-O-methylation of viral RNA is profoundly attenuated in IFN-competent cells. Through mathematical modeling of time-resolved data and validation experiments we show that the primary determinant for attenuation is the accelerated kinetics of IFN production. This rapid induction triggered by mutant DENV precedes establishment of IFN-resistance in infected cells, thus causing a massive reduction of virus production rate. In contrast, accelerated protection of naïve cells by paracrine IFN action has negligible impact. In conclusion, these results show that attenuation of the 2'-O-methylation DENV mutant is primarily determined by kinetics of autocrine IFN action on infected cells.

  17. Determination of the Anthropogenic Carbon Signal to the Total Change in Dissolved Carbon in the Coastal Upwelling Region Along the Washington-Oregon-California Continental Margin

    Science.gov (United States)

    Feely, R. A.

    2016-02-01

    The continental shelf region off the Washington-Oregon-California coast is seasonally exposed to water with a low aragonite saturation state by coastal upwelling of CO2-rich waters. To date, the spatial and temporal distribution of anthropogenic CO2 (Canthro) contribution to the CO2-rich waters is largely unknown. Here we use an adaptation of the linear regression approach described in Feely et al (2008) along with the GO-SHIP Repeat Hydrography data sets from the northeast Pacific to establish an annually updated relationship between Canthro and potential density. This relationship was then used with the NOAA Ocean Acidification Program west coast cruise data sets from 2007, 2011, 2012 and 2013 to determine the spatial variations of Canthro in the upwelled water. Our results show large spatial differences in Canthro in surface waters along the coast with the lowest surface values (40-45 µmol kg-1) in strong upwelling regions of off northern California and southern Oregon and higher values (50-70 µmol kg-1) to the north and south. Canthro contributes an average of about 70% of the increased amount of dissolved inorganic carbon in the upwelled waters at the surface. In contrast, at 50 m the Canthro contribution is approximately 31% and at 100 m it averages about 16%. The remaining contributions are primarily due to respiration processes in the water that was upwelled and transported to coastal regions or underwent respiration processes that occurred locally during the course of the upwelling season. The uptake of Canthro has caused the aragonite saturation horizon to shoal by approximately 30-50 m since preindustrial period so that the undersaturated waters are well within the regions that affect the biological communities on the continental shelf.

  18. CTRP9 ameliorates cellular senescence via PGC‑1α/AMPK signaling in mesenchymal stem cells.

    Science.gov (United States)

    Li, Qun; Zhu, Zhangzhang; Wang, Chengde; Cai, Lin; Lu, Jianglong; Wang, Yongchun; Xu, Jiadong; Su, Zhipeng; Zheng, Weiming; Chen, Xianbin

    2018-08-01

    Stroke is the second most common cause of death worldwide, and thus, it imposes great financial burdens on both individuals and society. Mesenchymal stem cell (MSC) therapy is a promising approach for ischemic brain injury. However, MSC treatment potential is progressively reduced with age, limiting their therapeutic efficacy for brain repair post‑stroke. C1q and tumor necrosis factor‑related protein 9 (CTRP9) is a novel cytoprotective cytokine with antioxidant effects, which is highly expressed in brain tissue. The present study tested the hypothesis that CTRP9 might act as an antisenescence factor to promote the rejuvenation of aged MSCs. MSCs were isolated from the bone marrow of young (8‑weeks‑old) and aged (18‑months‑old) male C57BL/6 mice. Cell proliferation was measured by Cell Counting Kit‑8 assay and cell viability was determined by MTT assay. Gene expression levels of interleukin (IL)‑6 and IL‑10 were evaluated with reverse transcription‑quantitative polymerase chain reaction, and secretion of vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor, and insulin‑like growth factor were measured by ELISA. The expression levels of proteins in the peroxisome proliferator‑activated receptor γcoactivator (PGC)‑1α/AMP‑activated protein kinase (AMPK) signaling pathway were investigated with western blotting. Oxidative stress was evaluated by detecting mitochondrial membrane potential, reactive oxygen species, superoxide dismutase activity and malondialdehyde. MSCs isolated from aged mice exhibited reduced proliferation and viability, and impaired immunoregulatory and paracrine abilities, compared with MSCs from younger mice. CTRP9 had a significant antisenescence effect in aged MSCs by activating PGC‑1α/AMPK signaling and decreasing the oxidative response. Silencing either PGC‑1α or AMPK abolished the above effects of CTRP9. These results suggest that CTRP9 may have a critical role in

  19. The Reparative Abilities of Menstrual Stem Cells Modulate the Wound Matrix Signals and Improve Cutaneous Regeneration

    Directory of Open Access Journals (Sweden)

    Jimena Cuenca

    2018-05-01

    Full Text Available Considerable advances have been made toward understanding the cellular and molecular mechanism of wound healing, however, treatments for chronic wounds remain elusive. Emerging concepts utilizing mesenchymal stem cells (MSCs from umbilical cord, adipose tissue and bone marrow have shown therapeutical advantages for wound healing. Based on this positive outcome, efforts to determine the optimal sources for MSCs are required in order to improve their migratory, angiogenic, immunomodulatory, and reparative abilities. An alternative source suitable for repetitive, non-invasive collection of MSCs is from the menstrual fluid (MenSCs, displaying a major practical advantage over other sources. This study aims to compare the biological functions and the transcriptomic pattern of MenSCs with umbilical cord MSCs in conditions resembling the wound microenvironment. Consequently, we correlate the specific gene expression signature from MenSCs with changes of the wound matrix signals in vivo. The direct comparison revealed a superior clonogenic and migratory potential of MenSCs as well as a beneficial effect of their secretome on human dermal fibroblast migration in vitro. Furthermore, MenSCs showed increased immunomodulatory properties, inhibiting T-cell proliferation in co-culture. We further, investigated the expression of selected genes involved in wound repair (growth factors, cytokines, chemokines, AMPs, MMPs and found considerably higher expression levels in MenSCs (ANGPT1 1.5-fold; PDGFA 1.8-fold; PDGFB 791-fold; MMP3 21.6-fold; ELN 13.4-fold; and MMP10 9.2-fold. This difference became more pronounced under a pro-inflammatory stimulation, resembling wound bed conditions. Locally applied in a murine excisional wound splinting model, MenSCs showed a significantly improved wound closure after 14 days, as well as enhanced neovascularization, compared to the untreated group. Interestingly, analysis of excised wound tissue revealed a significantly higher

  20. Cross-regulation of cytokine signalling: pro-inflammatory cytokines restrict IL-6 signalling through receptor internalisation and degradation.

    Science.gov (United States)

    Radtke, Simone; Wüller, Stefan; Yang, Xiang-ping; Lippok, Barbara E; Mütze, Barbara; Mais, Christine; de Leur, Hildegard Schmitz-Van; Bode, Johannes G; Gaestel, Matthias; Heinrich, Peter C; Behrmann, Iris; Schaper, Fred; Hermanns, Heike M

    2010-03-15

    The inflammatory response involves a complex interplay of different cytokines which act in an auto- or paracrine manner to induce the so-called acute phase response. Cytokines are known to crosstalk on multiple levels, for instance by regulating the mRNA stability of targeted cytokines through activation of the p38-MAPK pathway. In our study we discovered a new mechanism that answers the long-standing question how pro-inflammatory cytokines and environmental stress restrict immediate signalling of interleukin (IL)-6-type cytokines. We show that p38, activated by IL-1beta, TNFalpha or environmental stress, impairs IL-6-induced JAK/STAT signalling through phosphorylation of the common cytokine receptor subunit gp130 and its subsequent internalisation and degradation. We identify MK2 as the kinase that phosphorylates serine 782 in the cytoplasmic part of gp130. Consequently, inhibition of p38 or MK2, deletion of MK2 or mutation of crucial amino acids within the MK2 target site or the di-leucine internalisation motif blocks receptor depletion and restores IL-6-dependent STAT activation as well as gene induction. Hence, a novel negative crosstalk mechanism for cytokine signalling is described, where cytokine receptor turnover is regulated in trans by pro-inflammatory cytokines and stress stimuli to coordinate the inflammatory response.

  1. The role of the Hedgehog signaling pathway in cancer: A comprehensive review

    Directory of Open Access Journals (Sweden)

    Ana Marija Skoda

    2018-02-01

    Full Text Available The Hedgehog (Hh signaling pathway was first identified in the common fruit fly. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. The Hh signaling pathway plays an important role in the embryonic development. It exerts its biological effects through a signaling cascade that culminates in a change of balance between activator and repressor forms of glioma-associated oncogene (Gli transcription factors. The components of the Hh signaling pathway involved in the signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh], Patched receptor (Ptch1, Ptch2, Smoothened receptor (Smo, Suppressor of fused homolog (Sufu, kinesin protein Kif7, protein kinase A (PKA, and cyclic adenosine monophosphate (cAMP. The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1, PTCH2, and GLI1. Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas. The aberrant activation of the Hh signaling pathway is caused by mutations in the related genes (ligand-independent signaling or by the excessive expression of the Hh signaling molecules (ligand-dependent signaling – autocrine or paracrine. Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer treatment. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers.

  2. Scaled signal intensity of uterine fibroids based on T2-weighted MR images: a potential objective method to determine the suitability for magnetic resonance-guided focused ultrasound surgery of uterine fibroids

    Energy Technology Data Exchange (ETDEWEB)

    Park, Hyun [CHA University, Comprehensive Gynecologic Cancer Center, CHA Bundang Medical Center, Gyunggi-do (Korea, Republic of); Yoon, Sang-Wook [CHA University, Department of Diagnostic Radiology, CHA Bundang Medical Center, Sungnam-si, Gyunggi-do (Korea, Republic of); Sokolov, Amit [InSightec Ltd., Haifa (Israel)

    2015-12-15

    Magnetic Resonance-guided Focused Ultrasound Surgery (MRgFUS) is a non-invasive method to treat uterine fibroids. To help determine the patient suitability for MRgFUS, we propose a new objective measure: the scaled signal intensity (SSI) of uterine fibroids in T2 weighted MR images (T2WI). Forty three uterine fibroids in 40 premenopausal women were included in this retrospective study. SSI of each fibroid was measured from the screening T2WI by standardizing its mean signal intensity to a 0-100 scale, using reference intensities of rectus abdominis muscle (0) and subcutaneous fat (100). Correlation between the SSI and the non-perfused volume (NPV) ratio (a measure for treatment success) was calculated. Pre-treatment SSI showed a significant inverse-correlation with post treatment NPV ratio (p < 0.05). When dichotomizing NPV ratio at 45 %, the optimal cut off value of the SSI was found to be 16.0. A fibroid with SSI value 16.0 or less can be expected to have optimal responses. The SSI of uterine fibroids in T2WI can be suggested as an objective parameter to help in patient selection for MRgFUS. (orig.)

  3. Salicylic acid signaling inhibits apoplastic reactive oxygen species signaling.

    Science.gov (United States)

    Xu, Enjun; Brosché, Mikael

    2014-06-04

    Reactive oxygen species (ROS) are used by plants as signaling molecules during stress and development. Given the amount of possible challenges a plant face from their environment, plants need to activate and prioritize between potentially conflicting defense signaling pathways. Until recently, most studies on signal interactions have focused on phytohormone interaction, such as the antagonistic relationship between salicylic acid (SA)-jasmonic acid and cytokinin-auxin. In this study, we report an antagonistic interaction between SA signaling and apoplastic ROS signaling. Treatment with ozone (O3) leads to a ROS burst in the apoplast and induces extensive changes in gene expression and elevation of defense hormones. However, Arabidopsis thaliana dnd1 (defense no death1) exhibited an attenuated response to O3. In addition, the dnd1 mutant displayed constitutive expression of defense genes and spontaneous cell death. To determine the exact process which blocks the apoplastic ROS signaling, double and triple mutants involved in various signaling pathway were generated in dnd1 background. Simultaneous elimination of SA-dependent and SA-independent signaling components from dnd1 restored its responsiveness to O3. Conversely, pre-treatment of plants with SA or using mutants that constitutively activate SA signaling led to an attenuation of changes in gene expression elicited by O3. Based upon these findings, we conclude that plants are able to prioritize the response between ROS and SA via an antagonistic action of SA and SA signaling on apoplastic ROS signaling.

  4. Determination of the physical values of a plasma puff by analysis of the diamagnetic signals. 1. part: expansion model for the puff. 2. part: comparison of experimental results with the expansion model for the plasma puff

    International Nuclear Information System (INIS)

    Jacquinot, J.; Leloup, Ch.; Waelbroeck, F.; Poffe, J.P.

    1964-01-01

    The flow of a dense plasma puff, along the axis of a uniform magnetic field is examined, assuming the following hypotheses: the axial distribution of the line density can be described at any time by a gaussian function whose characteristic parameter is independent of the distance from the axis of the system; the β ratio is less than 0,6. An approximate solution of the magnetohydrodynamics equations is obtained. The evolution of the characteristic properties of the plasma (local velocity, temperature and density) can be calculated from a set of equations involving 5 plasma parameters. A method leading to the determination of these parameters is described. It uses 5 informations picked up from the diamagnetic signals induced by the plasma into a set of 4 compensated magnetic loops. (authors) [fr

  5. Integrin Signalling

    OpenAIRE

    Schelfaut, Roselien

    2005-01-01

    Integrins are receptors presented on most cells. By binding ligand they can generate signalling pathways inside the cell. Those pathways are a linkage to proteins in the cytosol. It is known that tumor cells can survive and proliferate in the absence of a solid support while normal cells need to be bound to ligand. To understand why tumour cells act that way, we first have to know how ligand-binding to integrins affect the cell. This research field includes studies on activation of proteins b...

  6. VLSI signal processing technology

    CERN Document Server

    Swartzlander, Earl

    1994-01-01

    This book is the first in a set of forthcoming books focussed on state-of-the-art development in the VLSI Signal Processing area. It is a response to the tremendous research activities taking place in that field. These activities have been driven by two factors: the dramatic increase in demand for high speed signal processing, especially in consumer elec­ tronics, and the evolving microelectronic technologies. The available technology has always been one of the main factors in determining al­ gorithms, architectures, and design strategies to be followed. With every new technology, signal processing systems go through many changes in concepts, design methods, and implementation. The goal of this book is to introduce the reader to the main features of VLSI Signal Processing and the ongoing developments in this area. The focus of this book is on: • Current developments in Digital Signal Processing (DSP) pro­ cessors and architectures - several examples and case studies of existing DSP chips are discussed in...

  7. Regulation of cellular communication by signaling microdomains in the blood vessel wall.

    Science.gov (United States)

    Billaud, Marie; Lohman, Alexander W; Johnstone, Scott R; Biwer, Lauren A; Mutchler, Stephanie; Isakson, Brant E

    2014-01-01

    It has become increasingly clear that the accumulation of proteins in specific regions of the plasma membrane can facilitate cellular communication. These regions, termed signaling microdomains, are found throughout the blood vessel wall where cellular communication, both within and between cell types, must be tightly regulated to maintain proper vascular function. We will define a cellular signaling microdomain and apply this definition to the plethora of means by which cellular communication has been hypothesized to occur in the blood vessel wall. To that end, we make a case for three broad areas of cellular communication where signaling microdomains could play an important role: 1) paracrine release of free radicals and gaseous molecules such as nitric oxide and reactive oxygen species; 2) role of ion channels including gap junctions and potassium channels, especially those associated with the endothelium-derived hyperpolarization mediated signaling, and lastly, 3) mechanism of exocytosis that has considerable oversight by signaling microdomains, especially those associated with the release of von Willebrand factor. When summed, we believe that it is clear that the organization and regulation of signaling microdomains is an essential component to vessel wall function.

  8. Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

    Science.gov (United States)

    Billaud, Marie; Lohman, Alexander W.; Johnstone, Scott R.; Biwer, Lauren A.; Mutchler, Stephanie; Isakson, Brant E.

    2014-01-01

    It has become increasingly clear that the accumulation of proteins in specific regions of the plasma membrane can facilitate cellular communication. These regions, termed signaling microdomains, are found throughout the blood vessel wall where cellular communication, both within and between cell types, must be tightly regulated to maintain proper vascular function. We will define a cellular signaling microdomain and apply this definition to the plethora of means by which cellular communication has been hypothesized to occur in the blood vessel wall. To that end, we make a case for three broad areas of cellular communication where signaling microdomains could play an important role: 1) paracrine release of free radicals and gaseous molecules such as nitric oxide and reactive oxygen species; 2) role of ion channels including gap junctions and potassium channels, especially those associated with the endothelium-derived hyperpolarization mediated signaling, and lastly, 3) mechanism of exocytosis that has considerable oversight by signaling microdomains, especially those associated with the release of von Willebrand factor. When summed, we believe that it is clear that the organization and regulation of signaling microdomains is an essential component to vessel wall function. PMID:24671377

  9. Clinical Implications of Hedgehog Pathway Signaling in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Daniel L. Suzman

    2015-09-01

    Full Text Available Activity in the Hedgehog pathway, which regulates GLI-mediated transcription, is important in organogenesis and stem cell regulation in self-renewing organs, but is pathologically elevated in many human malignancies. Mutations leading to constitutive activation of the pathway have been implicated in medulloblastoma and basal cell carcinoma, and inhibition of the pathway has demonstrated clinical responses leading to the approval of the Smoothened inhibitor, vismodegib, for the treatment of advanced basal cell carcinoma. Aberrant Hedgehog pathway signaling has also been noted in prostate cancer with evidence suggesting that it may render prostate epithelial cells tumorigenic, drive the epithelial-to-mesenchymal transition, and contribute towards the development of castration-resistance through autocrine and paracrine signaling within the tumor microenvironment and cross-talk with the androgen pathway. In addition, there are emerging clinical data suggesting that inhibition of the Hedgehog pathway may be effective in the treatment of recurrent and metastatic prostate cancer. Here we will review these data and highlight areas of active clinical research as they relate to Hedgehog pathway inhibition in prostate cancer.

  10. Modulation of taste sensitivity by GLP-1 signaling in taste buds.

    Science.gov (United States)

    Martin, Bronwen; Dotson, Cedrick D; Shin, Yu-Kyong; Ji, Sunggoan; Drucker, Daniel J; Maudsley, Stuart; Munger, Steven D

    2009-07-01

    Modulation of sensory function can help animals adjust to a changing external and internal environment. Even so, mechanisms for modulating taste sensitivity are poorly understood. Using immunohistochemical, biochemical, and behavioral approaches, we found that the peptide hormone glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) are expressed in mammalian taste buds. Furthermore, we found that GLP-1 signaling plays an important role in the modulation of taste sensitivity: GLP-1R knockout mice exhibit a dramatic reduction in sweet taste sensitivity as well as an enhanced sensitivity to umami-tasting stimuli. Together, these findings suggest a novel paracrine mechanism for the hormonal modulation of taste function in mammals.

  11. determination of gsm determination of gsm signal penetration loss

    African Journals Online (AJOL)

    eobe

    Mobile and wireless communications are a basic need in modern society. Statistics ... no direct line-of-sight path between the transmitting and the receiving antennas. ... measurements and over 276,000 instantaneous power measurements.

  12. Wrong signals

    International Nuclear Information System (INIS)

    Nillesen, P.H.L.; Telling, J.G.

    2001-01-01

    The Netherlands Electricity Regulatory Service (Dte, abbreviated in Dutch) bases the determination of the efficiency of electricity network businesses on the possibility of businesses to adjust their production capacity on a short term. In reality, however, the production capacity of electricity networks is fixed. By adjusting the model, by means of which the efficiency is determined, to the assumption of Dte, other efficiency scores will be produced. As a result of the output of the present model, many businesses receive the wrong stimuli. In this article the method of Dte is assessed. By putting the method in an international context it is determined whether the aim of the regulation is realized. The production process of the Dutch market is specified and compared internationally.1 ref

  13. Ion Channels of Pituitary Gonadotrophs and Their Roles in Signaling and Secretion

    Directory of Open Access Journals (Sweden)

    Stanko S. Stojilkovic

    2017-06-01

    Full Text Available Gonadotrophs are basophilic cells of the anterior pituitary gland specialized to secrete gonadotropins in response to elevation in intracellular calcium concentration. These cells fire action potentials (APs spontaneously, coupled with voltage-gated calcium influx of insufficient amplitude to trigger gonadotropin release. The spontaneous excitability of gonadotrophs reflects the expression of voltage-gated sodium, calcium, potassium, non-selective cation-conducting, and chloride channels at their plasma membrane (PM. These cells also express the hyperpolarization-activated and cyclic nucleotide-gated cation channels at the PM, as well as GABAA, nicotinic, and purinergic P2X channels gated by γ-aminobutyric acid (GABA, acetylcholine (ACh, and ATP, respectively. Activation of these channels leads to initiation or amplification of the pacemaking activity, facilitation of calcium influx, and activation of the exocytic pathway. Gonadotrophs also express calcium-conducting channels at the endoplasmic reticulum membranes gated by inositol trisphosphate and intracellular calcium. These channels are activated potently by hypothalamic gonadotropin-releasing hormone (GnRH and less potently by several paracrine calcium-mobilizing agonists, including pituitary adenylate cyclase-activating peptides, endothelins, ACh, vasopressin, and oxytocin. Activation of these channels causes oscillatory calcium release and a rapid gonadotropin release, accompanied with a shift from tonic firing of single APs to periodic bursting type of electrical activity, which accounts for a sustained calcium signaling and gonadotropin secretion. This review summarizes our current understanding of ion channels as signaling molecules in gonadotrophs, the role of GnRH and paracrine agonists in their gating, and the cross talk among channels.

  14. Connexins and M3 Muscarinic Receptors Contribute to Heterogeneous Ca2+ Signaling in Mouse Aortic Endothelium

    Directory of Open Access Journals (Sweden)

    François-Xavier Boittin

    2013-02-01

    Full Text Available Background/Aims: Smooth muscle tone is controlled by Ca2+ signaling in the endothelial layer. Mouse endothelial cells are interconnected by gap junctions made of Connexin40 (Cx40 and Cx37, which allow the exchange of signaling molecules to coordinate their activity. Here, we investigated the role of Cx40 in the endothelial Ca2+ signaling of the mouse aorta. Methods: Ca2+ imaging was performed on intact aortic endothelium from both wild type (Cx40+/+ and Connexin40-deficient (Cx40 -/- mice. Results: Acetylcholine (ACh induced early fast and high amplitude Ca2+ transients in a fraction of endothelial cells expressing the M3 muscarinic receptors. Inhibition of intercellular communication using carbenoxolone or octanol fully blocked the propagation of ACh-induced Ca2+ transients toward adjacent cells in WT and Cx40-/- mice. As compared to WT, Cx40-/- mice displayed a reduced propagation of ACh-induced Ca2+ waves, indicating that Cx40 contributes to the spreading of Ca2+ signals. The propagation of those Ca2+ responses was not blocked by suramin, a blocker of purinergic ATP receptors, indicating that there is no paracrine effect of ATP release on the Ca2+ waves. Conclusions: Altogether our data show that Cx40 and Cx37 contribute to the propagation and amplification of the Ca2+ signaling triggered by ACh in endothelial cells expressing the M3 muscarinic receptors.

  15. Canonical hedgehog signaling augments tumor angiogenesis by induction of VEGF-A in stromal perivascular cells

    Science.gov (United States)

    Chen, Weiwei; Tang, Tracy; Eastham-Anderson, Jeff; Dunlap, Debra; Alicke, Bruno; Nannini, Michelle; Gould, Stephen; Yauch, Robert; Modrusan, Zora; DuPree, Kelly J.; Darbonne, Walter C.; Plowman, Greg; de Sauvage, Frederic J.; Callahan, Christopher A.

    2011-01-01

    Hedgehog (Hh) signaling is critical to the patterning and development of a variety of organ systems, and both ligand-dependent and ligand-independent Hh pathway activation are known to promote tumorigenesis. Recent studies have shown that in tumors promoted by Hh ligands, activation occurs within the stromal microenvironment. Testing whether ligand-driven Hh signaling promotes tumor angiogenesis, we found that Hh antagonism reduced the vascular density of Hh-producing LS180 and SW480 xenografts. In addition, ectopic expression of sonic hedgehog in low-Hh–expressing DLD-1 xenografts increased tumor vascular density, augmented angiogenesis, and was associated with canonical Hh signaling within perivascular tumor stromal cells. To better understand the molecular mechanisms underlying Hh-mediated tumor angiogenesis, we established an Hh-sensitive angiogenesis coculture assay and found that fibroblast cell lines derived from a variety of human tissues were Hh responsive and promoted angiogenesis in vitro through a secreted paracrine signal(s). Affymetrix array analyses of cultured fibroblasts identified VEGF-A, hepatocyte growth factor, and PDGF-C as candidate secreted proangiogenic factors induced by Hh stimulation. Expression studies of xenografts and angiogenesis assays using combinations of Hh and VEGF-A inhibitors showed that it is primarily Hh-induced VEGF-A that promotes angiogenesis in vitro and augments tumor-derived VEGF to promote angiogenesis in vivo. PMID:21597001

  16. 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

  17. NMR signal transducer

    International Nuclear Information System (INIS)

    Kucheryaev, A.G.; Oliferchuk, N.L.

    1975-01-01

    A signal transducer of nuclear magnetic resonance for simultaneously measuring frequency and intensitivity of two various isotope signals, which are in one specimen is described. The transducer represents radiofrequency circuit with two resonance frequences, which is common for two autodyne generators. To decrease measuring time and to increase recording diagram stability the radiofrequency circuit has LC netork, in the inductivity of which investigated specimen is located; a circuit variable capacity is connected in parallel with one of the autodyne generators. Besides the radiofrequency circuit has an inductance coil in series with a standard specimen inside as well as a variable capacitor connected in parallel with the second autodyne generator. An amplitude of oscillation of each resonance frequency is controlled and adjusted separately. The transducer described can be used for the measurement of a nuclei concentration, isotope concentration and for the spin determination

  18. Intercellular signalling in Stigmatella aurantiaca.

    Science.gov (United States)

    Plaga, W; Ulrich, S H

    1999-12-01

    The myxobacterium Stigmatella aurantiaca is a prokaryotic model used to study intercellular signalling and the genetic determination of morphogenesis. Signalling factors and genes required for the generation of the elaborate multicellular fruiting body are to be identified. Recently, the structure of stigmolone, which is the pheromone necessary for fruiting body formation, was elucidated, and genes involved in development were characterised. Progress has also been made in the genetic accessibility of S. aurantiaca.

  19. Fast digitizing and digital signal processing of detector signals

    International Nuclear Information System (INIS)

    Hannaske, Roland

    2008-01-01

    A fast-digitizer data acquisition system recently installed at the neutron time-of-flight experiment nELBE, which is located at the superconducting electron accelerator ELBE of Forschungszentrum Dresden-Rossendorf, is tested with two different detector types. Preamplifier signals from a high-purity germanium detector are digitized, stored and finally processed. For a precise determination of the energy of the detected radiation, the moving-window deconvolution algorithm is used to compensate the ballistic deficit and different shaping algorithms are applied. The energy resolution is determined in an experiment with γ-rays from a 22 Na source and is compared to the energy resolution achieved with analogously processed signals. On the other hand, signals from the photomultipliers of barium fluoride and plastic scintillation detectors are digitized. These signals have risetimes of a few nanoseconds only. The moment of interaction of the radiation with the detector is determined by methods of digital signal processing. Therefore, different timing algorithms are implemented and tested with data from an experiment at nELBE. The time resolutions achieved with these algorithms are compared to each other as well as to reference values coming from analog signal processing. In addition to these experiments, some properties of the digitizing hardware are measured and a program for the analysis of stored, digitized data is developed. The analysis of the signals shows that the energy resolution achieved with the 10-bit digitizer system used here is not competitive to a 14-bit peak-sensing ADC, although the ballistic deficit can be fully corrected. However, digital methods give better result in sub-ns timing than analog signal processing. (orig.)

  20. Vitamin D Is a Multilevel Repressor of Wnt/β-Catenin Signaling in Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Larriba, María Jesús; González-Sancho, José Manuel; Barbáchano, Antonio; Niell, Núria; Ferrer-Mayorga, Gemma; Muñoz, Alberto, E-mail: amunoz@iib.uam.es [Instituto de Investigaciones Biomédicas “Alberto Sols”, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Arturo Duperier 4, Madrid 28029 (Spain)

    2013-10-21

    The Wnt/β-catenin signaling pathway is abnormally activated in most colorectal cancers and in a proportion of other neoplasias. This activation initiates or contributes to carcinogenesis by regulating the expression of a large number of genes in tumor cells. The active vitamin D metabolite 1α,25-dihydroxyvitamin D{sub 3} (1,25(OH){sub 2}D{sub 3}) inhibits Wnt/β-catenin signaling by several mechanisms at different points along the pathway. Additionally, paracrine actions of 1,25(OH){sub 2}D{sub 3} on stromal cells may also repress this pathway in neighbouring tumor cells. Here we review the molecular basis for the various mechanisms by which 1,25(OH){sub 2}D{sub 3} antagonizes Wnt/β-catenin signaling, preferentially in human colon carcinoma cells, and the consequences of this inhibition for the phenotype and proliferation rate. The effect of the vitamin D system on Wnt/β-catenin signaling and tumor growth in animal models will also be commented in detail. Finally, we revise existing data on the relation between vitamin D receptor expression and vitamin D status and the expression of Wnt/β-catenin pathway genes and targets in cancer patients.

  1. Inhibition of CXCL12/CXCR4 autocrine/paracrine loop reduces viability of human glioblastoma stem-like cells affecting self-renewal activity

    International Nuclear Information System (INIS)

    Gatti, Monica; Pattarozzi, Alessandra; Bajetto, Adriana; Würth, Roberto; Daga, Antonio; Fiaschi, Pietro; Zona, Gianluigi; Florio, Tullio; Barbieri, Federica

    2013-01-01

    Cancer stem cells (CSCs) or tumor initiating cells (TICs) drive glioblastoma (GBM) development, invasiveness and drug resistance. Distinct molecular pathways might regulate CSC biology as compared to cells in the bulk tumor mass, representing potential therapeutic targets. Chemokine CXCL12 and its receptor CXCR4 control proliferation, invasion and angiogenesis in GBM cell lines and primary cultures, but little is known about their activity in GBM CSCs. We demonstrate that CSCs, isolated from five human GBMs, express CXCR4 and release CXCL12 in vitro, although different levels of expression and secretion were observed in individual cultures, as expected for the heterogeneity of GBMs. CXCL12 treatment induced Akt-mediated significant pro-survival and self-renewal activities, while proliferation was induced at low extent. The role of CXCR4 signaling in CSC survival and self-renewal was further demonstrated using the CXCR4 antagonist AMD3100 that reduced self-renewal and survival with greater efficacy in the cultures that released higher CXCL12 amounts. The specificity of CXCL12 in sustaining CSC survival was demonstrated by the lack of AMD3100-dependent inhibition of viability in differentiated cells derived from the same GBMs. These findings, although performed on a limited number of tumor samples, suggest that the CXCL12/CXCR4 interaction mediates survival and self-renewal in GBM CSCs with high selectivity, thus emerging as a candidate system responsible for maintenance of cancer progenitors, and providing survival benefits to the tumor

  2. Neural stem cells induce bone-marrow-derived mesenchymal stem cells to generate neural stem-like cells via juxtacrine and paracrine interactions

    International Nuclear Information System (INIS)

    Alexanian, Arshak R.

    2005-01-01

    Several recent reports suggest that there is far more plasticity that previously believed in the developmental potential of bone-marrow-derived cells (BMCs) that can be induced by extracellular developmental signals of other lineages whose nature is still largely unknown. In this study, we demonstrate that bone-marrow-derived mesenchymal stem cells (MSCs) co-cultured with mouse proliferating or fixed (by paraformaldehyde or methanol) neural stem cells (NSCs) generate neural stem cell-like cells with a higher expression of Sox-2 and nestin when grown in NS-A medium supplemented with N2, NSC conditioned medium (NSCcm) and bFGF. These neurally induced MSCs eventually differentiate into β-III-tubulin and GFAP expressing cells with neuronal and glial morphology when grown an additional week in Neurobasal/B27 without bFGF. We conclude that juxtacrine interaction between NSCs and MSCs combined with soluble factors released from NSCs are important for generation of neural-like cells from bone-marrow-derived adherent MSCs

  3. Alteration of canonical and non-canonical WNT-signaling by crystalline silica in human lung epithelial cells

    International Nuclear Information System (INIS)

    Perkins, Timothy N.; Dentener, Mieke A.; Stassen, Frank R.; Rohde, Gernot G.; Mossman, Brooke T.; Wouters, Emiel F.M.; Reynaert, Niki L.

    2016-01-01

    Growth and development of the mature lung is a complex process orchestrated by a number of intricate developmental signaling pathways. Wingless-type MMTV-integration site (WNT) signaling plays critical roles in controlling branching morphogenesis cell differentiation, and formation of the conducting and respiratory airways. In addition, WNT pathways are often re-activated in mature lungs during repair and regeneration. WNT- signaling has been elucidated as a crucial contributor to the development of idiopathic pulmonary fibrosis as well as other hyper-proliferative lung diseases. Silicosis, a detrimental occupational lung disease caused by excessive inhalation of crystalline silica dust, is hallmarked by repeated cycles of damaging inflammation, epithelial hyperplasia, and formation of dense, hyalinized nodules of whorled collagen. However, mechanisms of epithelial cell hyperplasia and matrix deposition are not well understood, as most research efforts have focused on the pronounced inflammatory response. Microarray data from our previous studies has revealed a number of WNT-signaling and WNT-target genes altered by crystalline silica in human lung epithelial cells. In the present study, we utilize pathway analysis to designate connections between genes altered by silica in WNT-signaling networks. Furthermore, we confirm microarray findings by QRT-PCR and demonstrate both activation of canonical (β-catenin) and down-regulation of non-canonical (WNT5A) signaling in immortalized (BEAS-2B) and primary (PBEC) human bronchial epithelial cells. These findings suggest that WNT-signaling and cross-talk with other pathways (e.g. Notch), may contribute to proliferative, fibrogenic and inflammatory responses to silica in lung epithelial cells. - Highlights: • Pathway analysis reveals silica-induced WNT-signaling in lung epithelial cells. • Silica-induced canonical WNT-signaling is mediated by autocrine/paracrine signals. • Crystalline silica decreases non-canonical WNT

  4. Alteration of canonical and non-canonical WNT-signaling by crystalline silica in human lung epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Perkins, Timothy N.; Dentener, Mieke A. [Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands); Stassen, Frank R. [Department of Medical Microbiology, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands); Rohde, Gernot G. [Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands); Mossman, Brooke T. [Department of Pathology, University of Vermont College of Medicine, Burlington, VT (United States); Wouters, Emiel F.M. [Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands); Reynaert, Niki L., E-mail: n.reynaert@maastrichtuniversity.nl [Department of Respiratory Medicine, Maastricht University Medical Centre +, Maastricht University Maastricht (Netherlands)

    2016-06-15

    Growth and development of the mature lung is a complex process orchestrated by a number of intricate developmental signaling pathways. Wingless-type MMTV-integration site (WNT) signaling plays critical roles in controlling branching morphogenesis cell differentiation, and formation of the conducting and respiratory airways. In addition, WNT pathways are often re-activated in mature lungs during repair and regeneration. WNT- signaling has been elucidated as a crucial contributor to the development of idiopathic pulmonary fibrosis as well as other hyper-proliferative lung diseases. Silicosis, a detrimental occupational lung disease caused by excessive inhalation of crystalline silica dust, is hallmarked by repeated cycles of damaging inflammation, epithelial hyperplasia, and formation of dense, hyalinized nodules of whorled collagen. However, mechanisms of epithelial cell hyperplasia and matrix deposition are not well understood, as most research efforts have focused on the pronounced inflammatory response. Microarray data from our previous studies has revealed a number of WNT-signaling and WNT-target genes altered by crystalline silica in human lung epithelial cells. In the present study, we utilize pathway analysis to designate connections between genes altered by silica in WNT-signaling networks. Furthermore, we confirm microarray findings by QRT-PCR and demonstrate both activation of canonical (β-catenin) and down-regulation of non-canonical (WNT5A) signaling in immortalized (BEAS-2B) and primary (PBEC) human bronchial epithelial cells. These findings suggest that WNT-signaling and cross-talk with other pathways (e.g. Notch), may contribute to proliferative, fibrogenic and inflammatory responses to silica in lung epithelial cells. - Highlights: • Pathway analysis reveals silica-induced WNT-signaling in lung epithelial cells. • Silica-induced canonical WNT-signaling is mediated by autocrine/paracrine signals. • Crystalline silica decreases non-canonical WNT

  5. Basic digital signal processing

    CERN Document Server

    Lockhart, Gordon B

    1985-01-01

    Basic Digital Signal Processing describes the principles of digital signal processing and experiments with BASIC programs involving the fast Fourier theorem (FFT). The book reviews the fundamentals of the BASIC program, continuous and discrete time signals including analog signals, Fourier analysis, discrete Fourier transform, signal energy, power. The text also explains digital signal processing involving digital filters, linear time-variant systems, discrete time unit impulse, discrete-time convolution, and the alternative structure for second order infinite impulse response (IIR) sections.

  6. Inhibition of canonical WNT signaling pathway by β-catenin/CBP inhibitor ICG-001 ameliorates liver fibrosis in vivo through suppression of stromal CXCL12.

    Science.gov (United States)

    Akcora, Büsra Öztürk; Storm, Gert; Bansal, Ruchi

    2018-03-01

    Quiescent hepatic stellate cells (HSCs), in response to liver injury, undergo characteristic morphological transformation into proliferative, contractile and ECM-producing myofibroblasts. In this study, we investigated the implication of canonical Wnt signaling pathway in HSCs and liver fibrogenesis. Canonical Wnt signaling pathway activation and inhibition using β-catenin/CBP inhibitor ICG001 was examined in-vitro in TGFβ-activated 3T3, LX2, primary human HSCs, and in-vivo in CCl 4 -induced acute liver injury mouse model. Fibroblasts-conditioned medium studies were performed to assess the Wnt-regulated paracrine factors involved in crosstalk between HSCs-macrophages and HSCs-endothelial cells. Canonical Wnt signaling pathway components were significantly up-regulated in-vitro and in-vivo. In-vitro, ICG-001 significantly inhibited fibrotic parameters, 3D-collagen contractility and wound healing. Conditioned medium induced fibroblasts-mediated macrophage and endothelial cells activation was significantly inhibited by ICG-001. In-vivo, ICG-001 significantly attenuated collagen accumulation and HSC activation. Interestingly, ICG-001 drastically inhibited macrophage infiltration, intrahepatic inflammation and angiogenesis. We further analyzed the paracrine factors involved in Wnt-mediated effects and found CXCL12 was significantly suppressed both in-vitro and in-vivo following Wnt inhibition. Wnt-regulated CXCL12 secretion from activated HSCs potentiated macrophage infiltration and activation, and angiogenesis. Pharmacological inhibition of canonical Wnt signaling pathway via suppression of stromal CXCL12 suggests a potential therapeutic approach targeting activated HSCs in liver fibrosis. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  7. Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin

    Directory of Open Access Journals (Sweden)

    Shi Yandong

    2012-12-01

    Full Text Available Abstract Background Optimizing the safety and efficacy of standard chemotherapeutic agents such as cisplatin (CDDP is of clinical relevance. Serum starvation in vitro and short-term food starvation in vivo both stress cells by the sudden depletion of paracrine growth stimulation. Methods The effects of serum starvation on CDDP toxicity were investigated in normal and cancer cells by assessing proliferation, cell cycle distribution and activation of DNA-damage response and of AMPK, and were compared to effects observed in cells grown in serum-containing medium. The effects of short-term food starvation on CDDP chemotherapy were assessed in xenografts-bearing mice and were compared to effects on tumor growth and/or regression determined in mice with no diet alteration. Results We observed that serum starvation in vitro sensitizes cancer cells to CDDP while protecting normal cells. In detail, in normal cells, serum starvation resulted in a complete arrest of cellular proliferation, i.e. depletion of BrdU-incorporation during S-phase and accumulation of the cells in the G0/G1-phase of the cell cycle. Further analysis revealed that proliferation arrest in normal cells is due to p53/p21 activation, which is AMPK-dependent and ATM-independent. In cancer cells, serum starvation also decreased the fraction of S-phase cells but to a minor extent. In contrast to normal cells, serum starvation-induced p53 activation in cancer cells is both AMPK- and ATM-dependent. Combination of CDDP with serum starvation in vitro increased the activation of ATM/Chk2/p53 signaling pathway compared to either treatment alone resulting in an enhanced sensitization of cancer cells to CDDP. Finally, short-term food starvation dramatically increased the sensitivity of human tumor xenografts to cisplatin as indicated not only by a significant growth delay, but also by the induction of complete remission in 60% of the animals bearing mesothelioma xenografts, and in 40% of the

  8. Evaluation of diffuse diseases of the upper abdominal organs by MRI. Determination of a normal range in signal intensity ratio of each organ to the renal medulla in T1- and T2-weighted images and evaluation of diffuse diseases of an organ by using it

    International Nuclear Information System (INIS)

    Mitsuhashi, Hiroshi

    1995-01-01

    Diffuse diseases of the upper abdominal organs, including the liver, spleen, pancreas, and vertebral marrow, were evaluated by using signal intensity ratio of each organ to the renal medulla in T1- and T2-weighted images. Conventional T1- and T2-weighted images were obtained in 1.5 T MR system in 203 persons, including 122 controls and 81 patients with a diffuse disease in the upper abdominal organ. In controls, though there was neither sexual nor age difference in signal intensity ratios of the liver and pancreas, those of the spleen and vertebral marrow showed sexual and age difference, respectively. A normal range of signal intensity ratio of each organ in each image was determined in each decade of each sex by using controls. The signal intensity ratio of the liver was significantly low in T1- and T2-weighted images in patients with abundant iron deposit and within normal limits in patients with liver cirrhosis or scant iron deposit. The signal intensity ratio of the liver was significantly high only in a T2-weighted image in patients with fatty deposit in the liver, which was suspected to be due to inflammatory change in the liver with fatty deposit. The signal intensity ratios of the spleen, pancreas, and vertebral marrow were significantly low only in a T2-weighted image in patients with iron metabolic disturbance. The signal intensity ratio of the pancreas was significantly high in 40% of patients with acute and/or chronic pancreatitis, which was more sensitive in detection of pancreatitis than data in other studies. it can be concluded that the signal intensity ratio of each organ to the renal medulla in T1- and T2-weighted images is useful for detection of diffuse diseases of the upper abdominal organs by using the normal range in each decade of each sex. (S.Y.)

  9. Choline Phospholipid Metabolites of Human Vascular Endothelial Cells Altered by Cyclooxygenase Inhibition, Growth Factor Depletion, and Paracrine Factors Secreted by Cancer Cells

    Directory of Open Access Journals (Sweden)

    Noriko Mori

    2003-04-01

    Full Text Available Magnetic resonance studies have previously shown that solid tumors and cancer cells in culture typically exhibit high phosphocholine and total choline. Treatment of cancer cells with the anti-inflammatory agent, indomethacin (INDO, reverted the phenotype of choline phospholipid metabolites in cancer cells towards a less malignant phenotype. Since endothelial cells form a key component of tumor vasculature, in this study, we used MR spectroscopy to characterize the phenotype of choline phospholipid metabolites in human umbilical vein endothelial cells (HUVECs. We determined the effect of growth factors, the anti-inflammatory agent INDO, and conditioned media obtained from a malignant cell line, on choline phospholipid metabolites. Growth factor depletion or treatment with INDO induced similar changes in the choline phospholipid metabolites of HUVECs. Treatment with conditioned medium obtained from MDA-MB-231 cancer cells induced changes similar to the presence of growth factor supplements. These results suggest that cancer cells secrete growth factors and/or other molecules that influence the choline phospholipid metabolism of HUVECs. The ability of INDO to alter choline phospholipid metabolism in the presence of growth factor supplements suggests that the inflammatory response pathways of HUVECs may play a role in cancer cell-HUVEC interaction and in the response of HUVECs to growth factors.

  10. EUROmediCAT signal detection

    DEFF Research Database (Denmark)

    Given, Joanne E; Loane, Maria; Luteijn, Johannes Michiel

    2016-01-01

    AIMS: To evaluate congenital anomaly (CA)-medication exposure associations produced by the new EUROmediCAT signal detection system and determine which require further investigation. METHODS: Data from 15 EUROCAT registries (1995-2011) with medication exposures at the chemical substance (5th level...

  11. 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.

  12. Signal sciences workshop proceedings

    Energy Technology Data Exchange (ETDEWEB)

    Candy, J.V.

    1997-05-01

    This meeting is aimed primarily at signal processing and controls. The technical program for the 1997 Workshop includes a variety of efforts in the Signal Sciences with applications in the Microtechnology Area a new program at LLNL and a future area of application for both Signal/Image Sciences. Special sessions organized by various individuals in Seismic and Optical Signal Processing as well as Micro-Impulse Radar Processing highlight the program, while the speakers at the Signal Processing Applications session discuss various applications of signal processing/control to real world problems. For the more theoretical, a session on Signal Processing Algorithms was organized as well as for the more pragmatic, featuring a session on Real-Time Signal Processing.

  13. Signal sciences workshop. Proceedings

    International Nuclear Information System (INIS)

    Candy, J.V.

    1997-01-01

    This meeting is aimed primarily at signal processing and controls. The technical program for the 1997 Workshop includes a variety of efforts in the Signal Sciences with applications in the Microtechnology Area a new program at LLNL and a future area of application for both Signal/Image Sciences. Special sessions organized by various individuals in Seismic and Optical Signal Processing as well as Micro-Impulse Radar Processing highlight the program, while the speakers at the Signal Processing Applications session discuss various applications of signal processing/control to real world problems. For the more theoretical, a session on Signal Processing Algorithms was organized as well as for the more pragmatic, featuring a session on Real-Time Signal Processing

  14. ECG signal processing

    NARCIS (Netherlands)

    2009-01-01

    A system extracts an ECG signal from a composite signal (308) representing an electric measurement of a living subject. Identification means (304) identify a plurality of temporal segments (309) of the composite signal corresponding to a plurality of predetermined segments (202,204,206) of an ECG

  15. Optimal Signal Quality Index for Photoplethysmogram Signals

    Directory of Open Access Journals (Sweden)

    Mohamed Elgendi

    2016-09-01

    Full Text Available A photoplethysmogram (PPG is a noninvasive circulatory signal related to the pulsatile volume of blood in tissue and is typically collected by pulse oximeters. PPG signals collected via mobile devices are prone to artifacts that negatively impact measurement accuracy, which can lead to a significant number of misleading diagnoses. Given the rapidly increased use of mobile devices to collect PPG signals, developing an optimal signal quality index (SQI is essential to classify the signal quality from these devices. Eight SQIs were developed and tested based on: perfusion, kurtosis, skewness, relative power, non-stationarity, zero crossing, entropy, and the matching of systolic wave detectors. Two independent annotators annotated all PPG data (106 recordings, 60 s each and a third expert conducted the adjudication of differences. The independent annotators labeled each PPG signal with one of the following labels: excellent, acceptable or unfit for diagnosis. All indices were compared using Mahalanobis distance, linear discriminant analysis, quadratic discriminant analysis, and support vector machine with leave-one-out cross-validation. The skewness index outperformed the other seven indices in differentiating between excellent PPG and acceptable, acceptable combined with unfit, and unfit recordings, with overall F 1 scores of 86.0%, 87.2%, and 79.1%, respectively.

  16. Optimal Signal Quality Index for Photoplethysmogram Signals.

    Science.gov (United States)

    Elgendi, Mohamed

    2016-09-22

    A photoplethysmogram (PPG) is a noninvasive circulatory signal related to the pulsatile volume of blood in tissue and is typically collected by pulse oximeters. PPG signals collected via mobile devices are prone to artifacts that negatively impact measurement accuracy, which can lead to a significant number of misleading diagnoses. Given the rapidly increased use of mobile devices to collect PPG signals, developing an optimal signal quality index (SQI) is essential to classify the signal quality from these devices. Eight SQIs were developed and tested based on: perfusion, kurtosis, skewness, relative power, non-stationarity, zero crossing, entropy, and the matching of systolic wave detectors. Two independent annotators annotated all PPG data (106 recordings, 60 s each) and a third expert conducted the adjudication of differences. The independent annotators labeled each PPG signal with one of the following labels: excellent, acceptable or unfit for diagnosis. All indices were compared using Mahalanobis distance, linear discriminant analysis, quadratic discriminant analysis, and support vector machine with leave-one-out cross-validation. The skewness index outperformed the other seven indices in differentiating between excellent PPG and acceptable, acceptable combined with unfit, and unfit recordings, with overall F 1 scores of 86.0%, 87.2%, and 79.1%, respectively.

  17. 300 Area signal cable study

    International Nuclear Information System (INIS)

    Whattam, J.W.

    1994-01-01

    This report was prepared to discuss the alternatives available for removing the 300 Area overhead signal cable system. This system, installed in 1969, has been used for various monitoring and communication signaling needs throughout the 300 Area. Over the years this cabling system has deteriorated, has been continually reconfigured, and has been poorly documented to the point of nonreliability. The first step was to look at the systems utilizing the overhead signal cable that are still required for operation. Of the ten systems that once operated via the signal cable, only five are still required; the civil defense evacuation alarms, the public address (PA) system, the criticality alarms, the Pacific Northwest Laboratory Facilities Management Control System (FMCS), and the 384 annunciator panel. Of these five, the criticality alarms and the FMCS have been dealt with under other proposals. Therefore, this study focused on the alternatives available for the remaining three systems (evacuation alarms, PA system, and 384 panel) plus the accountability aid phones. Once the systems to be discussed were determined, then three alternatives for providing the signaling pathway were examined for each system: (1) re-wire using underground communication ducts, (2) use the Integrated Voice/Data Telecommunications System (IVDTS) already installed and operated by US West, and (3) use radio control. Each alternative was developed with an estimated cost, advantages, and disadvantages. Finally, a recommendation was provided for the best alternative for each system

  18. Signal analysis for failure detection

    International Nuclear Information System (INIS)

    Parpaglione, M.C.; Perez, L.V.; Rubio, D.A.; Czibener, D.; D'Attellis, C.E.; Brudny, P.I.; Ruzzante, J.E.

    1994-01-01

    Several methods for analysis of acoustic emission signals are presented. They are mainly oriented to detection of changes in noisy signals and characterization of higher amplitude discrete pulses or bursts. The aim was to relate changes and events with failure, crack or wear in materials, being the final goal to obtain automatic means of detecting such changes and/or events. Performance evaluation was made using both simulated and laboratory test signals. The methods being presented are the following: 1. Application of the Hopfield Neural Network (NN) model for classifying faults in pipes and detecting wear of a bearing. 2. Application of the Kohonnen and Back Propagation Neural Network model for the same problem. 3. Application of Kalman filtering to determine time occurrence of bursts. 4. Application of a bank of Kalman filters (KF) for failure detection in pipes. 5. Study of amplitude distribution of signals for detecting changes in their shape. 6. Application of the entropy distance to measure differences between signals. (author). 10 refs, 11 figs

  19. Stereotypical architecture of the stem cell niche is spatiotemporally established by miR-125-dependent coordination of Notch and steroid signaling.

    Science.gov (United States)

    Yatsenko, Andriy S; Shcherbata, Halyna R

    2018-02-08

    Stem cell niches act as signaling platforms that regulate stem cell self-renewal and sustain stem cells throughout life; however, the specific developmental events controlling their assembly are not well understood. Here, we show that during Drosophila ovarian germline stem cell niche formation, the status of Notch signaling in the cell can be reprogrammed. This is controlled via steroid-induced miR-125 , which targets a negative regulator of Notch signaling, Tom. Thus, miR-125 acts as a spatiotemporal coordinator between paracrine Notch and endocrine steroid signaling. Moreover, a dual security mechanism for Notch signaling activation exists to ensure the robustness of niche assembly. Particularly, stem cell niche cells can be specified either via lateral inhibition, in which a niche cell precursor acquires Notch signal-sending status randomly, or via peripheral induction, whereby Delta is produced by a specific cell. When one mechanism is perturbed due to mutations, developmental defects or environmental stress, the remaining mechanism ensures that the niche is formed, perhaps abnormally, but still functional. This guarantees that the germline stem cells will have their residence, thereby securing progressive oogenesis and, thus, organism reproduction. © 2018. Published by The Company of Biologists Ltd.

  20. 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

  1. Nonmyocyte ERK1/2 signaling contributes to load-induced cardiomyopathy in Marfan mice.

    Science.gov (United States)

    Rouf, Rosanne; MacFarlane, Elena Gallo; Takimoto, Eiki; Chaudhary, Rahul; Nagpal, Varun; Rainer, Peter P; Bindman, Julia G; Gerber, Elizabeth E; Bedja, Djahida; Schiefer, Christopher; Miller, Karen L; Zhu, Guangshuo; Myers, Loretha; Amat-Alarcon, Nuria; Lee, Dong I; Koitabashi, Norimichi; Judge, Daniel P; Kass, David A; Dietz, Harry C

    2017-08-03

    Among children with the most severe presentation of Marfan syndrome (MFS), an inherited disorder of connective tissue caused by a deficiency of extracellular fibrillin-1, heart failure is the leading cause of death. Here, we show that, while MFS mice (Fbn1C1039G/+ mice) typically have normal cardiac function, pressure overload (PO) induces an acute and severe dilated cardiomyopathy in association with fibrosis and myocyte enlargement. Failing MFS hearts show high expression of TGF-β ligands, with increased TGF-β signaling in both nonmyocytes and myocytes; pathologic ERK activation is restricted to the nonmyocyte compartment. Informatively, TGF-β, angiotensin II type 1 receptor (AT1R), or ERK antagonism (with neutralizing antibody, losartan, or MEK inhibitor, respectively) prevents load-induced cardiac decompensation in MFS mice, despite persistent PO. In situ analyses revealed an unanticipated axis of activation in nonmyocytes, with AT1R-dependent ERK activation driving TGF-β ligand expression that culminates in both autocrine and paracrine overdrive of TGF-β signaling. The full compensation seen in wild-type mice exposed to mild PO correlates with enhanced deposition of extracellular fibrillin-1. Taken together, these data suggest that fibrillin-1 contributes to cardiac reserve in the face of hemodynamic stress, critically implicate nonmyocytes in disease pathogenesis, and validate ERK as a therapeutic target in MFS-related cardiac decompensation.

  2. Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration.

    Science.gov (United States)

    Glaser, Talita; Cappellari, Angélica Regina; Pillat, Micheli Mainardi; Iser, Isabele Cristiana; Wink, Márcia Rosângela; Battastini, Ana Maria Oliveira; Ulrich, Henning

    2012-09-01

    Replacement of lost or dysfunctional tissues by stem cells has recently raised many investigations on therapeutic applications. Purinergic signaling has been shown to regulate proliferation, differentiation, cell death, and successful engraftment of stem cells originated from diverse origins. Adenosine triphosphate release occurs in a controlled way by exocytosis, transporters, and lysosomes or in large amounts from damaged cells, which is then subsequently degraded into adenosine. Paracrine and autocrine mechanisms induced by immune responses present critical factors for the success of stem cell therapy. While P1 receptors generally exert beneficial effects including anti-inflammatory activity, P2 receptor-mediated actions depend on the subtype of stimulated receptors and localization of tissue repair. Pro-inflammatory actions and excitatory tissue damages mainly result from P2X7 receptor activation, while other purinergic receptor subtypes participate in proliferation and differentiation, thereby providing adequate niches for stem cell engraftment and novel mechanisms for cell therapy and endogenous tissue repair. Therapeutic applications based on regulation of purinergic signaling are foreseen for kidney and heart muscle regeneration, Clara-like cell replacement for pulmonary and bronchial epithelial cells as well as for induction of neurogenesis in case of neurodegenerative diseases.

  3. Selective androgen receptor modulators (SARMs) negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling.

    Science.gov (United States)

    Narayanan, Ramesh; Ahn, Sunjoo; Cheney, Misty D; Yepuru, Muralimohan; Miller, Duane D; Steiner, Mitchell S; Dalton, James T

    2014-01-01

    The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER)-positive and 40-70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer. Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR) were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC) co-culture signaling studies were performed to understand the mechanisms of action. Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures. 1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.

  4. Selective androgen receptor modulators (SARMs negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling.

    Directory of Open Access Journals (Sweden)

    Ramesh Narayanan

    Full Text Available The androgen receptor (AR is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER-positive and 40-70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer.Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC co-culture signaling studies were performed to understand the mechanisms of action.Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures.1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.

  5. The Hippo signaling functions through the Notch signaling to regulate intrahepatic bile duct development in mammals

    Science.gov (United States)

    Wu, Nan; Nguyen, Quy; Wan, Ying; Zhou, Tiaohao; Venter, Julie; Frampton, Gabriel A; DeMorrow, Sharon; Pan, Duojia; Meng, Fanyin; Glaser, Shannon; Alpini, Gianfranco; Bai, Haibo

    2018-01-01

    The Hippo signaling pathway and the Notch signaling pathway are evolutionary conserved signaling cascades that have important roles in embryonic development of many organs. In murine liver, disruption of either pathway impairs intrahepatic bile duct development. Recent studies suggested that the Notch signaling receptor Notch2 is a direct transcriptional target of the Hippo signaling pathway effector YAP, and the Notch signaling is a major mediator of the Hippo signaling in maintaining biliary cell characteristics in adult mice. However, it remains to be determined whether the Hippo signaling pathway functions through the Notch signaling in intrahepatic bile duct development. We found that loss of the Hippo signaling pathway tumor suppressor Nf2 resulted in increased expression levels of the Notch signaling pathway receptor Notch2 in cholangiocytes but not in hepatocytes. When knocking down Notch2 on the background of Nf2 deficiency in mouse livers, the excessive bile duct development induced by Nf2 deficiency was suppressed by heterozygous and homozygous deletion of Notch2 in a dose-dependent manner. These results implicated that Notch signaling is one of the downstream effectors of the Hippo signaling pathway in regulating intrahepatic bile duct development. PMID:28581486

  6. Suppression of choriocarcinoma invasion and metastasis following blockade of BDNF/TrkB signaling

    International Nuclear Information System (INIS)

    Kawamura, Kazuhiro; Kawamura, Nanami; Okamoto, Naoki; Manabe, Motomu

    2013-01-01

    Brain-derived neurotrophic factor (BDNF) acts through its cognate receptor tyrosine kinase-B (TrkB) to regulate diverse physiological functions in reproductive and other tissues. In normal and malignant trophoblastic cells, the BDNF/TrkB signaling promotes cell growth. Due to the highly malignant nature of choriocarcinoma, we investigated possible involvement of this system in choriocarcinoma cell invasion and metastasis. We demonstrated that treatment of cultured choriocarcinoma cells, known to express both BDNF and TrkB, with a soluble TrkB ectodomain or a Trk receptor inhibitor K252a suppressed cell invasion accompanied with decreased expression of matrix metalloproteinase-2, a cell invasion marker. In vivo studies using a tumor xenograft model in athymic nude mice further showed inhibition of cell invasion from tumors to surrounding tissues following the suppression of endogenous TrkB signaling. For an in vivo model of choriocarcinoma metastasis, we performed intravenous injections of JAR cells expressing firefly luciferase into severe combined immunodeficiency (SCID) mice. Treatment with K252a inhibited metastasis of tumors to distant organs. In vivo K252a treatment also suppressed metastatic tumor growth as reflected by decreased cell proliferation and increased apoptosis and caspases-3/7 activities, together with reduced tissue levels of a tumor marker, human chorionic gonadotropin-β. In vivo suppression of TrkB signaling also led to decreased expression of angiogenic markers in metastatic tumor, including cluster of differentiation 31 and vascular endothelial growth factor A. Our findings suggested essential autocrine/paracrine roles of the BDNF/TrkB signaling system in choriocarcinoma invasion and metastasis. Inhibition of this signaling could serve as the basis to develop a novel therapy for patients with choriocarcinoma

  7. Second-hand signals

    DEFF Research Database (Denmark)

    Bergenholtz, Carsten

    2014-01-01

    Studies of signaling theory have traditionally focused on the dyadic link between the sender and receiver of the signal. Within a science‐based perspective this framing has led scholars to investigate how patents and publications of firms function as signals. I explore another important type...... used by various agents in their search for and assessment of products and firms. I conclude by arguing how this second‐hand nature of signals goes beyond a simple dyadic focus on senders and receivers of signals, and thus elucidates the more complex interrelations of the various types of agents...

  8. Estimation of neural energy in microelectrode signals

    Science.gov (United States)

    Gaumond, R. P.; Clement, R.; Silva, R.; Sander, D.

    2004-09-01

    We considered the problem of determining the neural contribution to the signal recorded by an intracortical electrode. We developed a linear least-squares approach to determine the energy fraction of a signal attributable to an arbitrary number of autocorrelation-defined signals buried in noise. Application of the method requires estimation of autocorrelation functions Rap(tgr) characterizing the action potential (AP) waveforms and Rn(tgr) characterizing background noise. This method was applied to the analysis of chronically implanted microelectrode signals from motor cortex of rat. We found that neural (AP) energy consisted of a large-signal component which grows linearly with the number of threshold-detected neural events and a small-signal component unrelated to the count of threshold-detected AP signals. The addition of pseudorandom noise to electrode signals demonstrated the algorithm's effectiveness for a wide range of noise-to-signal energy ratios (0.08 to 39). We suggest, therefore, that the method could be of use in providing a measure of neural response in situations where clearly identified spike waveforms cannot be isolated, or in providing an additional 'background' measure of microelectrode neural activity to supplement the traditional AP spike count.

  9. Pasture height at the beginning of deferment as a determinant of signal grass structure and potential selectivity by cattle - doi: 10.4025/actascianimsci.v35i4.20421

    Directory of Open Access Journals (Sweden)

    Manoel Eduardo Rozalino Santos

    2013-10-01

    Full Text Available Current experiment identified the height of signal grass {Urochloa decumbens (Stapf R. D. Webster cv. Basilisk [syn. Brachiaria decumbens Stapf cv. Basilisk]} at the beginning of deferment that provided an appropriate pasture structure and potential selectivity by cattle on deferred pastures. Four pasture heights at the beginning of deferment (10, 20, 30 and 40 cm and two forage samples (available on pasture and simulated grazing were studied. The experimental design was set in completely randomized blocks, with two replications, in a split-plot arrangement. Higher percentage of live leaf blades and lower percentage of live stems and senescent forage were recorded in the forage sample from simulated grazing. The increase in pasture height increased the percentage of senescent forage and reduced the percentage of live leaf blades in forage samples. Pasture height at the beginning of deferment did not affect the potential selectivity index by cattle for the percentage of live leaf blade. The potential selectivity index varied quadratically for the percentage of live stems and increased linearly for the percentage of senescent forage with pasture height. A 10-to-20 cm reduction in pasture height at the beginning of deferment improved the structure of deferred signal grass and optimized selectivity by cattle.  

  10. Orexin A/Hypocretin Modulates Leptin Receptor-Mediated Signaling by Allosteric Modulations Mediated by the Ghrelin GHS-R1A Receptor in Hypothalamic Neurons.

    Science.gov (United States)

    Medrano, Mireia; Aguinaga, David; Reyes-Resina, Irene; Canela, Enric I; Mallol, Josefa; Navarro, Gemma; Franco, Rafael

    2018-06-01

    The hypothalamus is a key integrator of nutrient-seeking signals in the form of hormones and metabolites originated in both the central nervous system and the periphery. The main autocrine and paracrine target of orexinergic-related hormones such as leptin, orexin/hypocretin, and ghrelin are neuropeptide Y neurons located in the arcuate nucleus of the hypothalamus. The aim of this study was to investigate the expression and the molecular and functional relationships between leptin, orexin/hypocretin and ghrelin receptors. Biophysical studies in a heterologous system showed physical interactions between them, with potential formation of heterotrimeric complexes. Functional assays showed robust allosteric interactions particularly different when the three receptors are expressed together. Further biochemical and pharmacological assays provided evidence of heterotrimer functional expression in primary cultures of hypothalamic neurons. These findings constitute evidence of close relationships in the action of the three hormones already starting at the receptor level in hypothalamic cells.

  11. Measurand transient signal suppressor

    Science.gov (United States)

    Bozeman, Richard J., Jr. (Inventor)

    1994-01-01

    A transient signal suppressor for use in a controls system which is adapted to respond to a change in a physical parameter whenever it crosses a predetermined threshold value in a selected direction of increasing or decreasing values with respect to the threshold value and is sustained for a selected discrete time interval is presented. The suppressor includes a sensor transducer for sensing the physical parameter and generating an electrical input signal whenever the sensed physical parameter crosses the threshold level in the selected direction. A manually operated switch is provided for adapting the suppressor to produce an output drive signal whenever the physical parameter crosses the threshold value in the selected direction of increasing or decreasing values. A time delay circuit is selectively adjustable for suppressing the transducer input signal for a preselected one of a plurality of available discrete suppression time and producing an output signal only if the input signal is sustained for a time greater than the selected suppression time. An electronic gate is coupled to receive the transducer input signal and the timer output signal and produce an output drive signal for energizing a control relay whenever the transducer input is a non-transient signal which is sustained beyond the selected time interval.

  12. 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

  13. Cooperative ethylene receptor signaling

    OpenAIRE

    Liu, Qian; Wen, Chi-Kuang

    2012-01-01

    The gaseous plant hormone ethylene is perceived by a family of five ethylene receptor members in the dicotyledonous model plant Arabidopsis. Genetic and biochemical studies suggest that the ethylene response is suppressed by ethylene receptor complexes, but the biochemical nature of the receptor signal is unknown. Without appropriate biochemical measures to trace the ethylene receptor signal and quantify the signal strength, the biological significance of the modulation of ethylene responses ...

  14. Traffic signal synchronization.

    Science.gov (United States)

    Huang, Ding-wei; Huang, Wei-neng

    2003-05-01

    The benefits of traffic signal synchronization are examined within the cellular automata approach. The microsimulations of traffic flow are obtained with different settings of signal period T and time delay delta. Both numerical results and analytical approximations are presented. For undersaturated traffic, the green-light wave solutions can be realized. For saturated traffic, the correlation among the traffic signals has no effect on the throughput. For oversaturated traffic, the benefits of synchronization are manifest only when stochastic noise is suppressed.

  15. Digital signal processing the Tevatron BPM signals

    International Nuclear Information System (INIS)

    Cancelo, G.; James, E.; Wolbers, S.

    2005-01-01

    The Beam Position Monitor (TeV BPM) readout system at Fermilab's Tevatron has been updated and is currently being commissioned. The new BPMs use new analog and digital hardware to achieve better beam position measurement resolution. The new system reads signals from both ends of the existing directional stripline pickups to provide simultaneous proton and antiproton measurements. The signals provided by the two ends of the BPM pickups are processed by analog band-pass filters and sampled by 14-bit ADCs at 74.3MHz. A crucial part of this work has been the design of digital filters that process the signal. This paper describes the digital processing and estimation techniques used to optimize the beam position measurement. The BPM electronics must operate in narrow-band and wide-band modes to enable measurements of closed-orbit and turn-by-turn positions. The filtering and timing conditions of the signals are tuned accordingly for the operational modes. The analysis and the optimized result for each mode are presented

  16. Nichtkontinuierliche (zeitdiskrete) Signale

    Science.gov (United States)

    Plaßmann, Wilfried

    Zeitdiskrete Signale werden häufig aus zeitkontinuierlichen Signalen durch Abtastung erzeugt. Dass beide Signale gleichwertig sind, zeigt das Abtasttheorem (Kap. 116) von Shannon, sofern die Bedingung nach (116.2), f_{ab}≈(2{,}2 {\\ldots} 4)\\cdot fg) eingehalten wird. Digitale Signale haben Vorteile: Einfache Speicherung, Weiterverarbeitung in Rechnern, wenig störanfällige Übertragung. Für die Bearbeitung dieser Signale dienen die im Kapitel dargestellten Hilfsmittel: Diskrete Fouriertransformation; Schnelle Fouriertransformation; z-Transformation: Darstellung, Sätze zur z-Transformation, Korrespondenzen zu Zeitfunktionen, Beispiele.

  17. Biomedical signals and systems

    CERN Document Server

    Tranquillo, Joseph V

    2013-01-01

    Biomedical Signals and Systems is meant to accompany a one-semester undergraduate signals and systems course. It may also serve as a quick-start for graduate students or faculty interested in how signals and systems techniques can be applied to living systems. The biological nature of the examples allows for systems thinking to be applied to electrical, mechanical, fluid, chemical, thermal and even optical systems. Each chapter focuses on a topic from classic signals and systems theory: System block diagrams, mathematical models, transforms, stability, feedback, system response, control, time

  18. Radiation signal processing system

    International Nuclear Information System (INIS)

    Bennett, M.; Knoll, G.; Strange, D.

    1980-01-01

    An improved signal processing system for radiation imaging apparatus comprises: a radiation transducer producing transducer signals proportional to apparent spatial coordinates of detected radiation events; means for storing true spatial coordinates corresponding to a plurality of predetermined apparent spatial coordinates relative to selected detected radiation events said means for storing responsive to said transducer signal and producing an output signal representative of said true spatial coordinates; and means for interpolating the true spatial coordinates of the detected radiation events located intermediate the stored true spatial coordinates, said means for interpolating communicating with said means for storing

  19. Digital signal processing

    CERN Document Server

    O'Shea, Peter; Hussain, Zahir M

    2011-01-01

    In three parts, this book contributes to the advancement of engineering education and that serves as a general reference on digital signal processing. Part I presents the basics of analog and digital signals and systems in the time and frequency domain. It covers the core topics: convolution, transforms, filters, and random signal analysis. It also treats important applications including signal detection in noise, radar range estimation for airborne targets, binary communication systems, channel estimation, banking and financial applications, and audio effects production. Part II considers sel

  20. Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling

    Science.gov (United States)

    Carpio, Lomeli R.; Bradley, Elizabeth W.; McGee-Lawrence, Meghan E.; Weivoda, Megan M.; Poston, Daniel D.; Dudakovic, Amel; Xu, Ming; Tchkonia, Tamar; Kirkland, James L.; van Wijnen, Andre J.; Oursler, Merry Jo; Westendorf, Jennifer J.

    2017-01-01

    Histone deacetylase (HDAC) inhibitors are efficacious epigenetic-based therapies for some cancers and neurological disorders; however, each of these drugs inhibits multiple HDACs and has detrimental effects on the skeleton. To better understand how HDAC inhibitors affect endochondral bone formation, we conditionally deleted one of their targets, Hdac3, pre- and postnatally in type II collagen α1 (Col2α1)–expressing chondrocytes. Embryonic deletion was lethal, but postnatal deletion of Hdac3 delayed secondary ossification center formation, altered maturation of growth plate chondrocytes, and increased osteoclast activity in the primary spongiosa. HDAC3-deficient chondrocytes exhibited increased expression of cytokine and matrix-degrading genes (Il-6, Mmp3, Mmp13, and Saa3) and a reduced abundance of genes related to extracellular matrix production, bone development, and ossification (Acan, Col2a1, Ihh, and Col10a1). Histone acetylation increased at and near genes that had increased expression. The acetylation and activation of nuclear factor κB (NF-κB) were also increased in HDAC3-deficient chondrocytes. Increased cytokine signaling promoted autocrine activation of Janus kinase (JAK)–signal transducer and activator of transcription (STAT) and NF-κB pathways to suppress chondrocyte maturation, as well as paracrine activation of osteoclasts and bone resorption. Blockade of interleukin-6 (IL-6)–JAK–STAT signaling, NF-κB signaling, and bromodomain extraterminal proteins, which recognize acetylated lysines and promote transcriptional elongation, significantly reduced Il-6 and Mmp13 expression in HDAC3-deficient chondrocytes and secondary activation in osteoclasts. The JAK inhibitor ruxolitinib also reduced osteoclast activity in Hdac3 conditional knockout mice. Thus, HDAC3 controls the temporal and spatial expression of tissue-remodeling genes and inflammatory responses in chondrocytes to ensure proper endochondral ossification during development. PMID

  1. Cell-autonomous intracellular androgen receptor signaling drives the growth of human prostate cancer initiating cells.

    Science.gov (United States)

    Vander Griend, Donald J; D'Antonio, Jason; Gurel, Bora; Antony, Lizamma; Demarzo, Angelo M; Isaacs, John T

    2010-01-01

    The lethality of prostate cancer is due to the continuous growth of cancer initiating cells (CICs) which are often stimulated by androgen receptor (AR) signaling. However, the underlying molecular mechanism(s) for such AR-mediated growth stimulation are not fully understood. Such mechanisms may involve cancer cell-dependent induction of tumor stromal cells to produce paracrine growth factors or could involve cancer cell autonomous autocrine and/or intracellular AR signaling pathways. We utilized clinical samples, animal models and a series of AR-positive human prostate cancer cell lines to evaluate AR-mediated growth stimulation of prostate CICs. The present studies document that stromal AR expression is not required for prostate cancer growth, since tumor stroma surrounding AR-positive human prostate cancer metastases (N = 127) are characteristically AR-negative. This lack of a requirement for AR expression in tumor stromal cells is also documented by the fact that human AR-positive prostate cancer cells grow equally well when xenografted in wild-type versus AR-null nude mice. AR-dependent growth stimulation was documented to involve secretion, extracellular binding, and signaling by autocrine growth factors. Orthotopic xenograft animal studies documented that the cellautonomous autocrine growth factors which stimulate prostate CIC growth are not the andromedins secreted by normal prostate stromal cells. Such cell autonomous and extracellular autocrine signaling is necessary but not sufficient for the optimal growth of prostate CICs based upon the response to anti-androgen plus/or minus preconditioned media. AR-induced growth stimulation of human prostate CICs requires AR-dependent intracellular pathways. The identification of such AR-dependent intracellular pathways offers new leads for the development of effective therapies for prostate cancer. (c) 2009 Wiley-Liss, Inc.

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

    Science.gov (United States)

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

    2013-10-01

    organs, the fungiform papilla and taste bud, and surrounding lingual cells. Shh signaling has roles in forming and maintaining fungiform papillae and taste buds, most likely via stage-specific autocrine and/or paracrine mechanisms, and by engaging epithelial/mesenchymal interactions. © 2013 Elsevier Inc. All rights reserved.

  3. Ubiquitination in apoptosis signaling

    NARCIS (Netherlands)

    van de Kooij, L.W.

    2014-01-01

    The work described in this thesis focuses on ubiquitination and protein degradation, with an emphasis on how these processes regulate apoptosis signaling. More specifically, our aims were: 1. To increase the understanding of ubiquitin-mediated regulation of apoptosis signaling. 2. To identify the E3

  4. Multiresolution signal decomposition schemes

    NARCIS (Netherlands)

    J. Goutsias (John); H.J.A.M. Heijmans (Henk)

    1998-01-01

    textabstract[PNA-R9810] Interest in multiresolution techniques for signal processing and analysis is increasing steadily. An important instance of such a technique is the so-called pyramid decomposition scheme. This report proposes a general axiomatic pyramid decomposition scheme for signal analysis

  5. SignalR blueprints

    CERN Document Server

    Ingebrigtsen, Einar

    2015-01-01

    This book is designed for software developers, primarily those with knowledge of C#, .NET, and JavaScript. Good knowledge and understanding of SignalR is assumed to allow efficient programming of core elements and applications in SignalR.

  6. Optimal fault signal estimation

    NARCIS (Netherlands)

    Stoorvogel, Antonie Arij; Niemann, H.H.; Saberi, A.; Sannuti, P.

    2002-01-01

    We consider here both fault identification and fault signal estimation. Regarding fault identification, we seek either exact or almost fault identification. On the other hand, regarding fault signal estimation, we seek either $H_2$ optimal, $H_2$ suboptimal or Hinfinity suboptimal estimation. By

  7. Signal sampling circuit

    NARCIS (Netherlands)

    Louwsma, S.M.; Vertregt, Maarten

    2011-01-01

    A sampling circuit for sampling a signal is disclosed. The sampling circuit comprises a plurality of sampling channels adapted to sample the signal in time-multiplexed fashion, each sampling channel comprising a respective track-and-hold circuit connected to a respective analogue to digital

  8. Signal sampling circuit

    NARCIS (Netherlands)

    Louwsma, S.M.; Vertregt, Maarten

    2010-01-01

    A sampling circuit for sampling a signal is disclosed. The sampling circuit comprises a plurality of sampling channels adapted to sample the signal in time-multiplexed fashion, each sampling channel comprising a respective track-and-hold circuit connected to a respective analogue to digital

  9. Bioelectric Signal Measuring System

    Science.gov (United States)

    Guadarrama-Santana, A.; Pólo-Parada, L.; García-Valenzuela, A.

    2015-01-01

    We describe a low noise measuring system based on interdigitated electrodes for sensing bioelectrical signals. The system registers differential voltage measurements in order of microvolts. The base noise during measurements was in nanovolts and thus, the sensing signals presented a very good signal to noise ratio. An excitation voltage of 1Vrms with 10 KHz frequency was applied to an interdigitated capacitive sensor without a material under test and to a mirror device simultaneously. The output signals of both devices was then subtracted in order to obtain an initial reference value near cero volts and reduce parasitic capacitances due to the electronics, wiring and system hardware as well. The response of the measuring system was characterized by monitoring temporal bioelectrical signals in real time of biological materials such as embryo chicken heart cells and bovine suprarenal gland cells.

  10. Acoustic Signals and Systems

    DEFF Research Database (Denmark)

    2008-01-01

    The Handbook of Signal Processing in Acoustics will compile the techniques and applications of signal processing as they are used in the many varied areas of Acoustics. The Handbook will emphasize the interdisciplinary nature of signal processing in acoustics. Each Section of the Handbook...... will present topics on signal processing which are important in a specific area of acoustics. These will be of interest to specialists in these areas because they will be presented from their technical perspective, rather than a generic engineering approach to signal processing. Non-specialists, or specialists...... from different areas, will find the self-contained chapters accessible and will be interested in the similarities and differences between the approaches and techniques used in different areas of acoustics....

  11. Adaptive signal processor

    Energy Technology Data Exchange (ETDEWEB)

    Walz, H.V.

    1980-07-01

    An experimental, general purpose adaptive signal processor system has been developed, utilizing a quantized (clipped) version of the Widrow-Hoff least-mean-square adaptive algorithm developed by Moschner. The system accommodates 64 adaptive weight channels with 8-bit resolution for each weight. Internal weight update arithmetic is performed with 16-bit resolution, and the system error signal is measured with 12-bit resolution. An adapt cycle of adjusting all 64 weight channels is accomplished in 8 ..mu..sec. Hardware of the signal processor utilizes primarily Schottky-TTL type integrated circuits. A prototype system with 24 weight channels has been constructed and tested. This report presents details of the system design and describes basic experiments performed with the prototype signal processor. Finally some system configurations and applications for this adaptive signal processor are discussed.

  12. Adaptive signal processor

    International Nuclear Information System (INIS)

    Walz, H.V.

    1980-07-01

    An experimental, general purpose adaptive signal processor system has been developed, utilizing a quantized (clipped) version of the Widrow-Hoff least-mean-square adaptive algorithm developed by Moschner. The system accommodates 64 adaptive weight channels with 8-bit resolution for each weight. Internal weight update arithmetic is performed with 16-bit resolution, and the system error signal is measured with 12-bit resolution. An adapt cycle of adjusting all 64 weight channels is accomplished in 8 μsec. Hardware of the signal processor utilizes primarily Schottky-TTL type integrated circuits. A prototype system with 24 weight channels has been constructed and tested. This report presents details of the system design and describes basic experiments performed with the prototype signal processor. Finally some system configurations and applications for this adaptive signal processor are discussed

  13. Zinc Signals and Immunity.

    Science.gov (United States)

    Maywald, Martina; Wessels, Inga; Rink, Lothar

    2017-10-24

    Zinc homeostasis is crucial for an adequate function of the immune system. Zinc deficiency as well as zinc excess result in severe disturbances in immune cell numbers and activities, which can result in increased susceptibility to infections and development of especially inflammatory diseases. This review focuses on the role of zinc in regulating intracellular signaling pathways in innate as well as adaptive immune cells. Main underlying molecular mechanisms and targets affected by altered zinc homeostasis, including kinases, caspases, phosphatases, and phosphodiesterases, will be highlighted in this article. In addition, the interplay of zinc homeostasis and the redox metabolism in affecting intracellular signaling will be emphasized. Key signaling pathways will be described in detail for the different cell types of the immune system. In this, effects of fast zinc flux, taking place within a few seconds to minutes will be distinguish from slower types of zinc signals, also designated as "zinc waves", and late homeostatic zinc signals regarding prolonged changes in intracellular zinc.

  14. Ambient temperature signalling in plants.

    Science.gov (United States)

    Wigge, Philip A

    2013-10-01

    Plants are exposed to daily and seasonal fluctuations in temperature. Within the 'ambient' temperature range (about 12-27°C for Arabidopsis) temperature differences have large effects on plant growth and development, disease resistance pathways and the circadian clock without activating temperature stress pathways. It is this developmental sensing and response to non-stressful temperatures that will be covered in this review. Recent advances have revealed key players in mediating temperature signals. The bHLH transcription factor PHYTOCHROME INTERACTING FACTOR4 (PIF4) has been shown to be a hub for multiple responses to warmer temperature in Arabidopsis, including flowering and hypocotyl elongation. Changes in chromatin state are involved in transmitting temperature signals to the transcriptome. Determining the precise mechanisms of temperature perception represents an exciting goal for the field. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. Fibroblast TGF-Beta Signaling in Breast Development and Cancer

    Science.gov (United States)

    2012-09-01

    3.1.1. Genetic stability and hormones...creating a permissive ‘ pasture ’ for the emerging malignant cell [4]. Stro- mal cells are though to be critical drivers of tumor progression in a...of a subpopulation of highly proliferative p53-null stromal cells through a paracrine mechanism [16]. 3.1.1. Genetic stability and hormones Although

  16. Orexin/Hypocretin Signaling.

    Science.gov (United States)

    Kukkonen, Jyrki P

    Orexin/hypocretin peptide (orexin-A and orexin-B) signaling is believed to take place via the two G-protein-coupled receptors (GPCRs), named OX 1 and OX 2 orexin receptors, as described in the previous chapters. Signaling of orexin peptides has been investigated in diverse endogenously orexin receptor-expressing cells - mainly neurons but also other types of cells - and in recombinant cells expressing the receptors in a heterologous manner. Findings in the different systems are partially convergent but also indicate cellular background-specific signaling. The general picture suggests an inherently high degree of diversity in orexin receptor signaling.In the current chapter, I present orexin signaling on the cellular and molecular levels. Discussion of the connection to (potential) physiological orexin responses is only brief since these are in focus of other chapters in this book. The same goes for the post-synaptic signaling mechanisms, which are dealt with in Burdakov: Postsynaptic actions of orexin. The current chapter is organized according to the tissue type, starting from the central nervous system. Finally, receptor signaling pathways are discussed across tissues, cell types, and even species.

  17. Schottky signal analysis: tune and chromaticity computation

    CERN Document Server

    Chanon, Ondine

    2016-01-01

    Schottky monitors are used to determine important beam parameters in a non-destructive way. The Schottky signal is due to the internal statistical fluctuations of the particles inside the beam. In this report, after explaining the different components of a Schottky signal, an algorithm to compute the betatron tune is presented, followed by some ideas to compute machine chromaticity. The tests have been performed with offline and/or online LHC data.

  18. Calibration of Galileo signals for time metrology.

    Science.gov (United States)

    Defraigne, Pascale; Aerts, Wim; Cerretto, Giancarlo; Cantoni, Elena; Sleewaegen, Jean-Marie

    2014-12-01

    Using global navigation satellite system (GNSS) signals for accurate timing and time transfer requires the knowledge of all electric delays of the signals inside the receiving system. GNSS stations dedicated to timing or time transfer are classically calibrated only for Global Positioning System (GPS) signals. This paper proposes a procedure to determine the hardware delays of a GNSS receiving station for Galileo signals, once the delays of the GPS signals are known. This approach makes use of the broadcast satellite inter-signal biases, and is based on the ionospheric delay measured from dual-frequency combinations of GPS and Galileo signals. The uncertainty on the so-determined hardware delays is estimated to 3.7 ns for each isolated code in the L5 frequency band, and 4.2 ns for the ionosphere-free combination of E1 with a code of the L5 frequency band. For the calibration of a time transfer link between two stations, another approach can be used, based on the difference between the common-view time transfer results obtained with calibrated GPS data and with uncalibrated Galileo data. It is shown that the results obtained with this approach or with the ionospheric method are equivalent.

  19. Neutrino signals from dark matter decay

    Energy Technology Data Exchange (ETDEWEB)

    Covi, Laura; Grefe, Michael [Deutsches Elektronen-Synchrotron (DESY), Hamburg (Germany); Ibarra, Alejandro; Tran, David [Technische Univ. Muenchen, Garching (Germany). Physik-Department T30d

    2009-12-15

    We investigate different neutrino signals from the decay of dark matter particles to determine the prospects for their detection, and more specifically if any spectral signature can be disentangled from the background in present and future neutrino observatories. If detected, such a signal could bring an independent confirmation of the dark matter interpretation of the dramatic rise in the positron fraction above 10 GeV recently observed by the PAMELA satellite experiment and offer the possibility of distinguishing between astrophysical sources and dark matter decay or annihilation. In combination with other signals, it may also be possible to distinguish among different dark matter decay channels. (orig.)

  20. Neutrino signals from dark matter decay

    International Nuclear Information System (INIS)

    Covi, Laura; Grefe, Michael; Ibarra, Alejandro; Tran, David

    2009-12-01

    We investigate different neutrino signals from the decay of dark matter particles to determine the prospects for their detection, and more specifically if any spectral signature can be disentangled from the background in present and future neutrino observatories. If detected, such a signal could bring an independent confirmation of the dark matter interpretation of the dramatic rise in the positron fraction above 10 GeV recently observed by the PAMELA satellite experiment and offer the possibility of distinguishing between astrophysical sources and dark matter decay or annihilation. In combination with other signals, it may also be possible to distinguish among different dark matter decay channels. (orig.)

  1. The importance of correcting for signal drift in diffusion MRI

    OpenAIRE

    Vos, Sjoerd B; Tax, Chantal M W; Luijten, Peter R; Ourselin, Sebastien; Leemans, Alexander; Froeling, Martijn

    2017-01-01

    PURPOSE: To investigate previously unreported effects of signal drift as a result of temporal scanner instability on diffusion MRI data analysis and to propose a method to correct this signal drift. METHODS: We investigated the signal magnitude of non-diffusion-weighted EPI volumes in a series of diffusion-weighted imaging experiments to determine whether signal magnitude changes over time. Different scan protocols and scanners from multiple vendors were used to verify this on phantom data, a...

  2. Signal flow analysis

    CERN Document Server

    Abrahams, J R; Hiller, N

    1965-01-01

    Signal Flow Analysis provides information pertinent to the fundamental aspects of signal flow analysis. This book discusses the basic theory of signal flow graphs and shows their relation to the usual algebraic equations.Organized into seven chapters, this book begins with an overview of properties of a flow graph. This text then demonstrates how flow graphs can be applied to a wide range of electrical circuits that do not involve amplification. Other chapters deal with the parameters as well as circuit applications of transistors. This book discusses as well the variety of circuits using ther

  3. L-Lactate protects neurons against excitotoxicity: implication of an ATP-mediated signaling cascade

    KAUST Repository

    Jourdain, P.

    2016-02-19

    Converging experimental data indicate a neuroprotective action of L-Lactate. Using Digital Holographic Microscopy, we observe that transient application of glutamate (100 μM; 2 min) elicits a NMDA-dependent death in 65% of mouse cortical neurons in culture. In the presence of L-Lactate (or Pyruvate), the percentage of neuronal death decreases to 32%. UK5099, a blocker of the Mitochondrial Pyruvate Carrier, fully prevents L-Lactate-mediated neuroprotection. In addition, L-Lactate-induced neuroprotection is not only inhibited by probenicid and carbenoxolone, two blockers of ATP channel pannexins, but also abolished by apyrase, an enzyme degrading ATP, suggesting that ATP produced by the Lactate/Pyruvate pathway is released to act on purinergic receptors in an autocrine/paracrine manner. Finally, pharmacological approaches support the involvement of the P2Y receptors associated to the PI3-kinase pathway, leading to activation of KATP channels. This set of results indicates that L-Lactate acts as a signalling molecule for neuroprotection against excitotoxicity through coordinated cellular pathways involving ATP production, release and activation of a P2Y/KATP cascade.

  4. Synaptic communication and signal processing among sensory cells in taste buds.

    Science.gov (United States)

    Chaudhari, Nirupa

    2014-08-15

    Taste buds (sensory structures embedded in oral epithelium) show a remarkable diversity of transmitters synthesized and secreted locally. The known transmitters accumulate in a cell type selective manner, with 5-HT and noradrenaline being limited to presynaptic cells, GABA being synthesized in both presynaptic and glial-like cells, and acetylcholine and ATP used for signalling by receptor cells. Each of these transmitters participates in local negative or positive feedback circuits that target particular cell types. Overall, the role of ATP is the best elucidated. ATP serves as a principal afferent transmitter, and also is the key trigger for autocrine positive feedback and paracrine circuits that result in potentiation (via adenosine) or inhibition (via GABA or 5-HT). While many of the cellular receptors and mechanisms for these circuits are known, their impact on sensory detection and perception remains to be elaborated in most instances. This brief review examines what is known, and some of the open questions and controversies surrounding the transmitters and circuits of the taste periphery. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

  5. L-Lactate protects neurons against excitotoxicity: implication of an ATP-mediated signaling cascade

    KAUST Repository

    Jourdain, P.; Allaman, I.; Rothenfusser, K.; Fiumelli, Hubert; Marquet, P.; Magistretti, Pierre J.

    2016-01-01

    Converging experimental data indicate a neuroprotective action of L-Lactate. Using Digital Holographic Microscopy, we observe that transient application of glutamate (100 μM; 2 min) elicits a NMDA-dependent death in 65% of mouse cortical neurons in culture. In the presence of L-Lactate (or Pyruvate), the percentage of neuronal death decreases to 32%. UK5099, a blocker of the Mitochondrial Pyruvate Carrier, fully prevents L-Lactate-mediated neuroprotection. In addition, L-Lactate-induced neuroprotection is not only inhibited by probenicid and carbenoxolone, two blockers of ATP channel pannexins, but also abolished by apyrase, an enzyme degrading ATP, suggesting that ATP produced by the Lactate/Pyruvate pathway is released to act on purinergic receptors in an autocrine/paracrine manner. Finally, pharmacological approaches support the involvement of the P2Y receptors associated to the PI3-kinase pathway, leading to activation of KATP channels. This set of results indicates that L-Lactate acts as a signalling molecule for neuroprotection against excitotoxicity through coordinated cellular pathways involving ATP production, release and activation of a P2Y/KATP cascade.

  6. Determination of the level of water in the core of reactors PWR using neutron detectors signal ex core; Determinacion del nivel del agua del nucleo de reactores PWR usando la senal de detectores neutronicos excore

    Energy Technology Data Exchange (ETDEWEB)

    Bernal, A.; Abarca, A.; Miro, R.; Verdu, G.

    2014-07-01

    The level of water from the core provides relevant information of the neutronic and thermal hydraulic of the reactor as the power, k EFF and cooling capacity. In fact, this level monitoring can be used for prediction of LOCA and reduction of cooling that can cause damage to the core. There are several teams that measure a variety of parameters of the reactor, as opposed to the level of the water of the core. However, the detectors 'excore' measure fast neutrons which escape from the core and there are studies that demonstrate the existence of a relationship between them and the water level of the kernel due to the water shield. Therefore, a methodology has been developed to determine this relationship, using the Monte Carlo method using the MCNP code and apply variance reduction techniques based on the attached flow that is obtained using the method of discrete ordinates using code TORT. (Author)

  7. Endothelial juxtaposition of distinct adult stem cells activates angiogenesis signaling molecules in endothelial cells.

    Science.gov (United States)

    Mohammadi, Elham; Nassiri, Seyed Mahdi; Rahbarghazi, Reza; Siavashi, Vahid; Araghi, Atefeh

    2015-12-01

    Efficacy of therapeutic angiogenesis needs a comprehensive understanding of endothelial cell (EC) function and biological factors and cells that interplay with ECs. Stem cells are considered the key components of pro- and anti-angiogenic milieu in a wide variety of physiopathological states, and interactions of EC-stem cells have been the subject of controversy in recent years. In this study, the potential effects of three tissue-specific adult stem cells, namely rat marrow-derived mesenchymal stem cells (rBMSCs), rat adipose-derived stem cells (rADSCs) and rat muscle-derived satellite cells (rSCs), on the endothelial activation of key angiogenic signaling molecules, including VEGF, Ang-2, VEGFR-2, Tie-2, and Tie2-pho, were investigated. Human umbilical vein endothelial cells (HUVECs) and rat lung microvascular endothelial cells (RLMECs) were cocultured with the stem cells or incubated with the stem cell-derived conditioned media on Matrigel. Following HUVEC-stem cell coculture, CD31-positive ECs were flow sorted and subjected to western blotting to analyze potential changes in the expression of the pro-angiogenic signaling molecules. Elongation and co-alignment of the stem cells were seen along the EC tubes in the EC-stem cell cocultures on Matrigel, with cell-to-cell dye communication in the EC-rBMSC cocultures. Moreover, rBMSCs and rADSCs significantly improved endothelial tubulogenesis in both juxtacrine and paracrine manners. These two latter stem cells dynamically up-regulated VEGF, Ang-2, VREGR-2, and Tie-2 but down-regulated Tie2-pho and the Tie2-pho/Tie-2 ratio in HUVECs. Induction of pro-angiogenic signaling in ECs by marrow- and adipose-derived MSCs further indicates the significance of stem cell milieu in angiogenesis dynamics.

  8. Underwater Acoustic Signal Processing

    National Research Council Canada - National Science Library

    Culver, Richard L; Sibul, Leon H; Bradley, David L

    2007-01-01

    .... The research is directed toward passive sonar detection and classification, continuous wave (CW) and broadband signals, shallow water operation, both platform-mounted and distributed systems, and frequencies below 1 kHz...

  9. Signals and systems

    CERN Document Server

    Rao, K Deergha

    2018-01-01

    This textbook covers the fundamental theories of signals and systems analysis, while incorporating recent developments from integrated circuits technology into its examples. Starting with basic definitions in signal theory, the text explains the properties of continuous-time and discrete-time systems and their representation by differential equations and state space. From those tools, explanations for the processes of Fourier analysis, the Laplace transform, and the z-Transform provide new ways of experimenting with different kinds of time systems. The text also covers the separate classes of analog filters and their uses in signal processing applications. Intended for undergraduate electrical engineering students, chapter sections include exercise for review and practice for the systems concepts of each chapter. Along with exercises, the text includes MATLAB-based examples to allow readers to experiment with signals and systems code on their own. An online repository of the MATLAB code from this textbook can...

  10. Topological signal processing

    CERN Document Server

    Robinson, Michael

    2014-01-01

    Signal processing is the discipline of extracting information from collections of measurements. To be effective, the measurements must be organized and then filtered, detected, or transformed to expose the desired information.  Distortions caused by uncertainty, noise, and clutter degrade the performance of practical signal processing systems. In aggressively uncertain situations, the full truth about an underlying signal cannot be known.  This book develops the theory and practice of signal processing systems for these situations that extract useful, qualitative information using the mathematics of topology -- the study of spaces under continuous transformations.  Since the collection of continuous transformations is large and varied, tools which are topologically-motivated are automatically insensitive to substantial distortion. The target audience comprises practitioners as well as researchers, but the book may also be beneficial for graduate students.

  11. Acoustic MIMO signal processing

    CERN Document Server

    Huang, Yiteng; Chen, Jingdong

    2006-01-01

    A timely and important book addressing a variety of acoustic signal processing problems under multiple-input multiple-output (MIMO) scenarios. It uniquely investigates these problems within a unified framework offering a novel and penetrating analysis.

  12. Ultrahigh bandwidth signal processing

    DEFF Research Database (Denmark)

    Oxenløwe, Leif Katsuo

    2016-01-01

    Optical time lenses have proven to be very versatile for advanced optical signal processing. Based on a controlled interplay between dispersion and phase-modulation by e.g. four-wave mixing, the processing is phase-preserving, an hence useful for all types of data signals including coherent multi......-level modulation founats. This has enabled processing of phase-modulated spectrally efficient data signals, such as orthogonal frequency division multiplexed (OFDM) signa In that case, a spectral telescope system was used, using two time lenses with different focal lengths (chirp rates), yielding a spectral...... regeneratio These operations require a broad bandwidth nonlinear platform, and novel photonic integrated nonlinear platform like aluminum gallium arsenide nano-waveguides used for 1.28 Tbaud optical signal processing will be described....

  13. Traffic Signal Cycle Lengths

    Data.gov (United States)

    Town of Chapel Hill, North Carolina — Traffic signal location list for the town of Chapel Hill. This data set includes light cycle information as well as as intersection information.The Town of Chapel...

  14. Foundations of signal processing

    CERN Document Server

    Vetterli, Martin; Goyal, Vivek K

    2014-01-01

    This comprehensive and engaging textbook introduces the basic principles and techniques of signal processing, from the fundamental ideas of signals and systems theory to real-world applications. Students are introduced to the powerful foundations of modern signal processing, including the basic geometry of Hilbert space, the mathematics of Fourier transforms, and essentials of sampling, interpolation, approximation and compression. The authors discuss real-world issues and hurdles to using these tools, and ways of adapting them to overcome problems of finiteness and localisation, the limitations of uncertainty and computational costs. Standard engineering notation is used throughout, making mathematical examples easy for students to follow, understand and apply. It includes over 150 homework problems and over 180 worked examples, specifically designed to test and expand students' understanding of the fundamentals of signal processing, and is accompanied by extensive online materials designed to aid learning, ...

  15. Source of seismic signals

    Energy Technology Data Exchange (ETDEWEB)

    Frankovskii, B.A.; Khor' yakov, K.A.

    1980-08-30

    Patented is a source of seismic signals consisting of a shock generator with a basic low-voltage and auxillary high-voltage stator coils, a capacitive transformer and control switches. To increase the amplitude of signal excitation a condensor battery and auxillary commutator are introduced into the device, which are connected in parallel and serially into the circuit of the main low-voltage stator coil.

  16. Redox signaling in plants.

    Science.gov (United States)

    Foyer, Christine H; Noctor, Graham

    2013-06-01

    Our aim is to deliver an authoritative and challenging perspective of current concepts in plant redox signaling, focusing particularly on the complex interface between the redox and hormone-signaling pathways that allow precise control of plant growth and defense in response to metabolic triggers and environmental constraints and cues. Plants produce significant amounts of singlet oxygen and other reactive oxygen species (ROS) as a result of photosynthetic electron transport and metabolism. Such pathways contribute to the compartment-specific redox-regulated signaling systems in plant cells that convey information to the nucleus to regulate gene expression. Like the chloroplasts and mitochondria, the apoplast-cell wall compartment makes a significant contribution to the redox signaling network, but unlike these organelles, the apoplast has a low antioxidant-buffering capacity. The respective roles of ROS, low-molecular antioxidants, redox-active proteins, and antioxidant enzymes are considered in relation to the functions of plant hormones such as salicylic acid, jasmonic acid, and auxin, in the composite control of plant growth and defense. Regulation of redox gradients between key compartments in plant cells such as those across the plasma membrane facilitates flexible and multiple faceted opportunities for redox signaling that spans the intracellular and extracellular environments. In conclusion, plants are recognized as masters of the art of redox regulation that use oxidants and antioxidants as flexible integrators of signals from metabolism and the environment.

  17. Transient-Switch-Signal Suppressor

    Science.gov (United States)

    Bozeman, Richard J., Jr.

    1995-01-01

    Circuit delays transmission of switch-opening or switch-closing signal until after preset suppression time. Used to prevent transmission of undesired momentary switch signal. Basic mode of operation simple. Beginning of switch signal initiates timing sequence. If switch signal persists after preset suppression time, circuit transmits switch signal to external circuitry. If switch signal no longer present after suppression time, switch signal deemed transient, and circuit does not pass signal on to external circuitry, as though no transient switch signal. Suppression time preset at value large enough to allow for damping of underlying pressure wave or other mechanical transient.

  18. Digital Signal Processing applied to Physical Signals

    CERN Document Server

    Alberto, Diego; Musa, L

    2011-01-01

    It is well known that many of the scientific and technological discoveries of the XXI century will depend on the capability of processing and understanding a huge quantity of data. With the advent of the digital era, a fully digital and automated treatment can be designed and performed. From data mining to data compression, from signal elaboration to noise reduction, a processing is essential to manage and enhance features of interest after every data acquisition (DAQ) session. In the near future, science will go towards interdisciplinary research. In this work there will be given an example of the application of signal processing to different fields of Physics from nuclear particle detectors to biomedical examinations. In Chapter 1 a brief description of the collaborations that allowed this thesis is given, together with a list of the publications co-produced by the author in these three years. The most important notations, definitions and acronyms used in the work are also provided. In Chapter 2, the last r...

  19. Prokineticin-1 (PROK1) modulates interleukin (IL)-11 expression via prokineticin receptor 1 (PROKR1) and the calcineurin/NFAT signalling pathway.

    Science.gov (United States)

    Cook, Ian H; Evans, Jemma; Maldonado-Pérez, David; Critchley, Hilary O; Sales, Kurt J; Jabbour, Henry N

    2010-03-01

    Prokineticin-1 (PROK1) is a multifunctional secreted protein which signals via the G-protein coupled receptor, PROKR1. Previous data from our laboratory using a human genome survey microarray showed that PROK1-prokineticin receptor 1 (PROKR1) signalling regulates numerous genes important for establishment of early pregnancy, including the cytokine interleukin (IL)-11. Here, we have shown that PROK1-PROKR1 induces the expression of IL-11 in PROKR1 Ishikawa cells and first trimester decidua via the calcium-calcineurin signalling pathway in a guanine nucleotide-binding protein (G(q/11)), extracellular signal-regulated kinases, Ca(2+) and calcineurin-nuclear factor of activated T cells dependent manner. Conversely, treatment of human decidua with a lentiviral miRNA to abolish endogenous PROK1 expression results in a significant reduction in IL-11 expression and secretion. Importantly, we have also shown a regulatory role for the regulator of calcineurin 1 isoform 4 (RCAN1-4). Overexpression of RCAN1-4 in PROKR1 Ishikawa cells using an adenovirus leads to a reduction in PROK1 induced IL-11 indicating that RCAN1-4 is a negative regulator in the calcineurin-mediated signalling to IL-11. Finally, we have shown the potential for both autocrine and paracrine signalling in the human endometrium by co-localizing IL-11, IL-11Ralpha and PROKR1 within the stromal and glandular epithelial cells of non-pregnant endometrium and first trimester decidua. Overall we have identified and characterized the signalling components of a novel PROK1-PROKR1 signalling pathway regulating IL-11.

  20. Wnt and β-Catenin Signaling and Skeletal Muscle Myogenesis in Response to Muscle Damage and Resistance Exercise and Training

    Directory of Open Access Journals (Sweden)

    Dan Newmire

    2015-10-01

    Full Text Available The factors that regulate skeletal muscle hypertrophy in human adults in response to resistance training (RT has largely focused on endogenous endocrine responses. However, the endocrine response to RT as having an obligatory role in muscle hypertrophy has come under scrutiny, as other mechanisms and pathways seem to also be involved in up-regulating muscle protein synthesis (MPS. Skeletal muscle myogenesis is a multifactorial process of tissue growth and repair in response to resistance training is regulated by many factors.  As a result, satellite cell-fused myogenesis is a possible factor in skeletal muscle regeneration and hypertrophy in response to RT.  The Wnt family ligands interact with various receptors and activate different downstream signaling pathways and have been classified as either canonical (β-catenin dependent or non-canonical (β-catenin independent.  Wnt is secreted from numerous tissues in a paracrine fashion. The Wnt/β-catenin signaling pathway is a highly-regulated and intricate pathway that is essential to skeletal muscle myogenesis.  The canonical Wnt/β-catenin pathway may influence satellite cells to myogenic commitment, differentiation, and fusion into muscle fibers in response to injury or trauma, self-renewal, and normal basal turnover.  The current literature has shown that, in response mechanical overload from acute resistance exercise and chronic resistance training, that the Wnt/β-catenin signaling pathway is stimulated which may actuate the process of muscle repair and hypertrophy in response to exercise-induced muscle damage. The purpose of this review is to elaborate on the Wnt/β-catenin signaling  pathway, the current literature investigating the relationship of the Wnt/β-catenin pathway and its effects on myogenesis is response to muscle damage and resistance exercise and training.      Keywords: skeletal muscle, hypertrophy, myogenesis, cell signaling, protein synthesis, resistance

  1. Social knowledge and signals in primates.

    Science.gov (United States)

    Bergman, Thore J; Sheehan, Michael J

    2013-07-01

    Primates are notable for having a rich and detailed understanding of their social environment and there has been great interest in the evolution and function of social knowledge in primates. Indeed, primates have been shown to have impressive understandings of not only other group members but also the complex relationships among them. To be useful, however, social knowledge requires memories from previous encounters and observations about individual traits that are stable. Here, we argue that social systems or traits that make social knowledge more costly or less accurate will favor signals that either supplement or replace social knowledge. Thus, the relationship between signals and social knowledge can be complementary or antagonistic depending on the type of signal. Our goal in this review is to elucidate the relationships between signals and social knowledge in primates. We categorize signals into three types, each with different relationships to social knowledge. (1) Identity signals directly facilitate social knowledge, (2) current-state signals supplement information gained through social knowledge, and (3) badges of status replace social knowledge. Primates rely extensively on identity information, but it remains to be determined to what extent this is based on receiver perception of individual variation or senders using identity signals. Primates frequently utilize current-state signals including signals of intent to augment their interactions with familiar individuals. Badges of status are rare in primates, and the cases where they are used point to a functional and evolutionary trade-off between badges of status and social knowledge. However, the nature of this relationship needs further exploration. © 2012 Wiley Periodicals, Inc.

  2. Cellular signalling properties in microcircuits

    DEFF Research Database (Denmark)

    Toledo-Rodriguez, Maria; El Manira, Abdeljabbar; Wallén, Peter

    2005-01-01

    Molecules and cells are the signalling elements in microcircuits. Recent studies have uncovered bewildering diversity in postsynaptic signalling properties in all areas of the vertebrate nervous system. Major effort is now being invested in establishing the specialized signalling properties...

  3. Signal integrity characterization techniques

    CERN Document Server

    Bogatin, Eric

    2009-01-01

    "Signal Integrity Characterization Techniques" addresses the gap between traditional digital and microwave curricula all while focusing on a practical and intuitive understanding of signal integrity effects within the data transmission channel. High-speed interconnects such as connectors, PCBs, cables, IC packages, and backplanes are critical elements of differential channels that must be designed using today's most powerful analysis and characterization tools.Both measurements and simulation must be done on the device under test, and both activities must yield data that correlates with each other. Most of this book focuses on real-world applications of signal integrity measurements - from backplane for design challenges to error correction techniques to jitter measurement technologies. The authors' approach wisely addresses some of these new high-speed technologies, and it also provides valuable insight into its future direction and will teach the reader valuable lessons on the industry.

  4. Quantum signaling game

    International Nuclear Information System (INIS)

    Frackiewicz, Piotr

    2014-01-01

    We present a quantum approach to a signaling game; a special kind of extensive game of incomplete information. Our model is based on quantum schemes for games in strategic form where players perform unitary operators on their own qubits of some fixed initial state and the payoff function is given by a measurement on the resulting final state. We show that the quantum game induced by our scheme coincides with a signaling game as a special case and outputs nonclassical results in general. As an example, we consider a quantum extension of the signaling game in which the chance move is a three-parameter unitary operator whereas the players' actions are equivalent to classical ones. In this case, we study the game in terms of Nash equilibria and refine the pure Nash equilibria adapting to the quantum game the notion of a weak perfect Bayesian equilibrium. (paper)

  5. Method for forecasting an earthquake from precursor signals

    International Nuclear Information System (INIS)

    Farnworth, D.F.

    1996-01-01

    A method for forecasting an earthquake from precursor signals by employing characteristic first electromagnetic signals, second, seismically induced electromagnetic signals, seismically induced mechanical signals, and infrasonic acoustic signals which have been observed to precede an earthquake. From a first electromagnetic signal, a magnitude, depth beneath the surface of the earth, distance, latitude, longitude, and first and second forecasts of the time of occurrence of the impending earthquake may be derived. From a second, seismically induced electromagnetic signal and the mechanical signal, third and fourth forecasts of the time of occurrence of an impending earthquake determined from the analysis above, a magnitude, depth beneath the surface of the earth and fourth and fifth forecasts of the time of occurrence of the impending earthquake may be derived. The forecasts of time available from the above analyses range from up to five weeks to substantially within one hour in advance of the earthquake. (author)

  6. PKD signaling and pancreatitis

    Science.gov (United States)

    Yuan, Jingzhen; Pandol, Stephen J.

    2016-01-01

    Background Acute pancreatitis is a serious medical disorder with no current therapies directed to the molecular pathogenesis of the disorder. Inflammation, inappropriate intracellular activation of digestive enzymes, and parenchymal acinar cell death by necrosis are the critical pathophysiologic processes of acute pancreatitis. Thus, it is necessary to elucidate the key molecular signals that mediate these pathobiologic processes and develop new therapeutic strategies to attenuate the appropriate signaling pathways in order to improve outcomes for this disease. A novel serine/threonine protein kinase D (PKD) family has emerged as key participants in signal transduction, and this family is increasingly being implicated in the regulation of multiple cellular functions and diseases. Methods This review summarizes recent findings of our group and others regarding the signaling pathway and the biological roles of the PKD family in pancreatic acinar cells. In particular, we highlight our studies of the functions of PKD in several key pathobiologic processes associated with acute pancreatitis in experimental models. Results Our findings reveal that PKD signaling is required for NF-κB activation/inflammation, intracellular zymogen activation, and acinar cell necrosis in rodent experimental pancreatitis. Novel small-molecule PKD inhibitors attenuate the severity of pancreatitis in both in vitro and in vivo experimental models. Further, this review emphasizes our latest advances in the therapeutic application of PKD inhibitors to experimental pancreatitis after the initiation of pancreatitis. Conclusions These novel findings suggest that PKD signaling is a necessary modulator in key initiating pathobiologic processes of pancreatitis, and that it constitutes a novel therapeutic target for treatments of this disorder. PMID:26879861

  7. Signal processing in microdosimetry

    International Nuclear Information System (INIS)

    Arbel, A.

    1984-01-01

    Signals occurring in microdosimetric measurements cover a dynamic range of 100 dB at a counting rate which normally stays below 10 4 but could increase significantly in case of an accident. The need for high resolution at low energies, non-linear signal processing to accommodate the specified dynamic range, easy calibration and thermal stability are conflicting requirements which pose formidable design problems. These problems are reviewed, and a practical approach to their solution is given employing a single processing channel. (author)

  8. Understanding signal integrity

    CERN Document Server

    Thierauf, Stephen C

    2010-01-01

    This unique book provides you with practical guidance on understanding and interpreting signal integrity (SI) performance to help you with your challenging circuit board design projects. You find high-level discussions of important SI concepts presented in a clear and easily accessible format, including question and answer sections and bulleted lists.This valuable resource features rules of thumb and simple equations to help you make estimates of critical signal integrity parameters without using circuit simulators of CAD (computer-aided design). The book is supported with over 120 illustratio

  9. Electronic signal conditioning

    CERN Document Server

    NEWBY, BRUCE

    1994-01-01

    At technician level, brief references to signal conditioning crop up in a fragmented way in various textbooks, but there has been no single textbook, until now!More advanced texts do exist but they are more mathematical and presuppose a higher level of understanding of electronics and statistics. Electronic Signal Conditioning is designed for HNC/D students and City & Guilds Electronics Servicing 2240 Parts 2 & 3. It will also be useful for BTEC National, Advanced GNVQ, A-level electronics and introductory courses at degree level.

  10. TOR signalling in plants.

    Science.gov (United States)

    Rexin, Daniel; Meyer, Christian; Robaglia, Christophe; Veit, Bruce

    2015-08-15

    Although the eukaryotic TOR (target of rapamycin) kinase signalling pathway has emerged as a key player for integrating nutrient-, energy- and stress-related cues with growth and metabolic outputs, relatively little is known of how this ancient regulatory mechanism has been adapted in higher plants. Drawing comparisons with the substantial knowledge base around TOR kinase signalling in fungal and animal systems, functional aspects of this pathway in plants are reviewed. Both conserved and divergent elements are discussed in relation to unique aspects associated with an autotrophic mode of nutrition and adaptive strategies for multicellular development exhibited by plants. © 2015 Authors; published by Portland Press Limited.

  11. Genomic signal processing

    CERN Document Server

    Shmulevich, Ilya

    2007-01-01

    Genomic signal processing (GSP) can be defined as the analysis, processing, and use of genomic signals to gain biological knowledge, and the translation of that knowledge into systems-based applications that can be used to diagnose and treat genetic diseases. Situated at the crossroads of engineering, biology, mathematics, statistics, and computer science, GSP requires the development of both nonlinear dynamical models that adequately represent genomic regulation, and diagnostic and therapeutic tools based on these models. This book facilitates these developments by providing rigorous mathema

  12. Processing of acoustic signal in rock desintegration

    Directory of Open Access Journals (Sweden)

    Futó Jozef

    2002-12-01

    Full Text Available For the determination of an effective rock disintegration for a given tool and rock type it is needed to define an optimal disintegration regime. Optimisation of the disintegration process by drilling denotes the finding out an appropriate couple of input parameters of disintegration, i.e. the thrust and revolutions for a quasi-equal rock environment. The disintegration process can be optimised to reach the maximum immediate drilling rate, to reach the minimum specific disintegration energy or to reach the maximum ratio of immediate drilling rate and specific disintegration energy. For the determination of the optimal thrust and revolutions it is needed to monitor the disintegration process. Monitoring of the disintegration process in real conditions is complicated by unfavourable factors, such as the presence of water, dust, vibrations etc. Following our present experience in the monitoring of drilling or full-profile driving, we try to replace the monitoring of input values by monitoring of the scanned acoustic signal. This method of monitoring can extend the optimisation of disintegration process in the technical practice. Its advantage consists in the registration of one acoustic signal by an appropriate microphone. Monitoring of acoustic signal is used also in monitoring of metal machining by milling and turning jobs. The research results of scanning of the acoustic signal in machining of metals are encouraging. Acoustic signal can be processed by different statistical parameters. The paper decribes some results of monitoring of the acoustic signal in rock disintegration on the drilling stand of the Institute of Geotechnics SAS in Košice. The acoustic signal has been registered and processed in no-load run of electric motor, in no-load run of electric motor with a drilling fluid, and in the Ruskov andesite drilling. Registration and processing of the acoustic signal is solved as a part of the research grant task within the basic research

  13. 4D MR imaging using robust internal respiratory signal

    International Nuclear Information System (INIS)

    Hui, CheukKai; Wen, Zhifei; Beddar, Sam; Stemkens, Bjorn; Tijssen, R H N; Van den Berg, C A T; Hwang, Ken-Pin

    2016-01-01

    The purpose of this study is to investigate the feasibility of using internal respiratory (IR) surrogates to sort four-dimensional (4D) magnetic resonance (MR) images. The 4D MR images were constructed by acquiring fast 2D cine MR images sequentially, with each slice scanned for more than one breathing cycle. The 4D volume was then sorted retrospectively using the IR signal. In this study, we propose to use multiple low-frequency components in the Fourier space as well as the anterior body boundary as potential IR surrogates. From these potential IR surrogates, we used a clustering algorithm to identify those that best represented the respiratory pattern to derive the IR signal. A study with healthy volunteers was performed to assess the feasibility of the proposed IR signal. We compared this proposed IR signal with the respiratory signal obtained using respiratory bellows. Overall, 99% of the IR signals matched the bellows signals. The average difference between the end inspiration times in the IR signal and bellows signal was 0.18 s in this cohort of matching signals. For the acquired images corresponding to the other 1% of non-matching signal pairs, the respiratory motion shown in the images was coherent with the respiratory phases determined by the IR signal, but not the bellows signal. This suggested that the IR signal determined by the proposed method could potentially correct the faulty bellows signal. The sorted 4D images showed minimal mismatched artefacts and potential clinical applicability. The proposed IR signal therefore provides a feasible alternative to effectively sort MR images in 4D. (paper)

  14. Expected Signal Observability at Future Experiments

    CERN Document Server

    Bartsch, Valeria

    2005-01-01

    Several methods to quantify the ''significance'' of an expected signal at future experiments have been used or suggested in literature. In this note, comparisons are presented with a method based on the likelihood ratio of the ''background hypothesis'' and the ''signal-plus-background hypothesis''. A large number of Monte Carlo experiments are performed to investigate the properties of the various methods and to check whether the probability of a background fluctuation having produced the claimed significance of the discovery is properly described. In addition, the best possible separation between the two hypotheses should be provided, in other words, the discovery potential of a future experiment be maximal. Finally, a practical method to apply a likelihood-based definition of the significance is suggested in this note. Signal and background contributions are determined from a likelihoo d fit based on shapes only, and the probability density distributions of the significance thus determined are found to be o...

  15. Lipopolysaccharide inhibits myogenic differentiation of C2C12 myoblasts through the Toll-like receptor 4-nuclear factor-κB signaling pathway and myoblast-derived tumor necrosis factor-α.

    Directory of Open Access Journals (Sweden)

    Yuko Ono

    Full Text Available Circulating lipopolysaccharide (LPS concentrations are often elevated in patients with sepsis or with various endogenous diseases that are associated with metabolic endotoxemia. Involuntary loss of skeletal muscle, termed muscle wasting, is commonly observed in these conditions, suggesting that circulating LPS might play an essential role in its development. Although impairment of muscle regeneration is an important determinant of skeletal muscle wasting, it is unclear whether LPS affects this process and, if so, by what mechanism. Here, we used the C2C12 myoblast cell line to investigate the effects of LPS on myogenesis.C2C12 myoblasts were grown to 80% confluence and induced to differentiate in the absence or presence of LPS (0.1 or 1 μg/mL; TAK-242 (1 μM, a specific inhibitor of Toll-like receptor 4 (TLR4 signaling; and a tumor necrosis factor (TNF-α neutralizing antibody (5 μg/mL. Expression of a skeletal muscle differentiation marker (myosin heavy chain II, two essential myogenic regulatory factors (myogenin and MyoD, and a muscle negative regulatory factor (myostatin was analyzed by western blotting. Nuclear factor-κB (NF-κB DNA-binding activity was measured using an enzyme-linked immunosorbent assay.LPS dose-dependently and significantly decreased the formation of multinucleated myotubes and the expression of myosin heavy chain II, myogenin, and MyoD, and increased NF-κB DNA-binding activity and myostatin expression. The inhibitory effect of LPS on myogenic differentiation was reversible, suggesting that it was not caused by nonspecific toxicity. Both TAK-242 and anti-TNF-α reduced the LPS-induced increase in NF-κB DNA-binding activity, downregulation of myogenic regulatory factors, and upregulation of myostatin, thereby partially rescuing the impairment of myogenesis.Our data suggest that LPS inhibits myogenic differentiation via a TLR4-NF-κB-dependent pathway and an autocrine/paracrine TNF-α-induced pathway. These pathways

  16. Television picture signal processing

    NARCIS (Netherlands)

    1998-01-01

    Field or frame memories are often used in television receivers for video signal processing functions, such as noise reduction and/or flicker reduction. Television receivers also have graphic features such as teletext, menu-driven control systems, multilingual subtitling, an electronic TV-Guide, etc.

  17. Signals: Applying Academic Analytics

    Science.gov (United States)

    Arnold, Kimberly E.

    2010-01-01

    Academic analytics helps address the public's desire for institutional accountability with regard to student success, given the widespread concern over the cost of higher education and the difficult economic and budgetary conditions prevailing worldwide. Purdue University's Signals project applies the principles of analytics widely used in…

  18. Communication Signals in Lizards.

    Science.gov (United States)

    Carpenter, Charles C.

    1983-01-01

    Discusses mechanisms and functional intent of visual communication signals in iguanid/agamid lizards. Demonstrated that lizards communicate with each other by using pushups and head nods and that each species does this in its own way, conveying different types of information. (JN)

  19. Modeling binaural signal detection

    NARCIS (Netherlands)

    Breebaart, D.J.

    2001-01-01

    With the advent of multimedia technology and powerful signal processing systems, audio processing and reproduction has gained renewed interest. Examples of products that have been developed are audio coding algorithms to efficiently store and transmit music and speech, or audio reproduction systems

  20. Quantum cloning and signaling

    International Nuclear Information System (INIS)

    Simon, C.; Weihs, G.; Zeilinger, A.

    1999-01-01

    We discuss the close connections between cloning of quantum states and superluminal signaling. We present an optimal universal cloning machine based on stimulated emission recently proposed by the authors. As an instructive example, we show how a scheme for superluminal communication based on this cloning machine fails. (Authors)

  1. "Utilizing" signal detection theory.

    Science.gov (United States)

    Lynn, Spencer K; Barrett, Lisa Feldman

    2014-09-01

    What do inferring what a person is thinking or feeling, judging a defendant's guilt, and navigating a dimly lit room have in common? They involve perceptual uncertainty (e.g., a scowling face might indicate anger or concentration, for which different responses are appropriate) and behavioral risk (e.g., a cost to making the wrong response). Signal detection theory describes these types of decisions. In this tutorial, we show how incorporating the economic concept of utility allows signal detection theory to serve as a model of optimal decision making, going beyond its common use as an analytic method. This utility approach to signal detection theory clarifies otherwise enigmatic influences of perceptual uncertainty on measures of decision-making performance (accuracy and optimality) and on behavior (an inverse relationship between bias magnitude and sensitivity optimizes utility). A "utilized" signal detection theory offers the possibility of expanding the phenomena that can be understood within a decision-making framework. © The Author(s) 2014.

  2. Activation of PDGFr-β Signaling Pathway after Imatinib and Radioimmunotherapy Treatment in Experimental Pancreatic Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Abe, Michio [Minamata City Hospital and Medical Center, Minamata City, Kumamoto 867 (Japan); Kortylewicz, Zbigniew P.; Enke, Charles A.; Mack, Elizabeth; Baranowska-Kortylewicz, Janina, E-mail: jbaranow@unmc.edu [Department of Radiation Oncology, J. Bruce Henriksen Cancer Research Laboratories, University of Nebraska Medical Center, Omaha, NE 68198 (United States)

    2011-05-25

    Pancreatic cancer does not respond to a single-agent imatinib therapy. Consequently, multimodality treatments are contemplated. Published data indicate that in colorectal cancer, imatinib and radioimmunotherapy synergize to delay tumor growth. In pancreatic cancer, the tumor response is additive. This disparity of outcomes merited further studies because interactions between these modalities depend on the imatinib-induced reduction of the tumor interstitial fluid pressure. The examination of human and murine PDGFr-β/PDGF-B pathways in SW1990 pancreatic cancer xenografts revealed that the human branch is practically dormant in untreated tumors but the insult on the stromal component produces massive responses of human cancer cells. Inhibition of the stromal PDGFr-β with imatinib activates human PDGFr-β/PDGF-B signaling loop, silent in untreated xenografts, via an apparent paracrine rescue pathway. Responses are treatment-and time-dependent. Soon after treatment, levels of human PDGFr-β, compared to untreated tumors, are 3.4×, 12.4×, and 5.7× higher in imatinib-, radioimmunotherapy + imatinib-, and radioimmunotherapy-treated tumors, respectively. A continuous 14-day irradiation of imatinib-treated xenografts reduces levels of PDGFr-β and phosphorylated PDGFr-β by 5.3× and 4×, compared to earlier times. Human PDGF-B is upregulated suggesting that the survival signaling via the autocrine pathway is also triggered after stromal injury. These findings indicate that therapies targeting pancreatic cancer stromal components may have unintended mitogenic effects and that these effects can be reversed when imatinib is used in conjunction with radioimmunotherapy.

  3. Fibroblast growth factor receptor signaling is essential for normal mammary gland development and stem cell function.

    Science.gov (United States)

    Pond, Adam C; Bin, Xue; Batts, Torey; Roarty, Kevin; Hilsenbeck, Susan; Rosen, Jeffrey M

    2013-01-01

    Fibroblast growth factor (FGF) signaling plays an important role in embryonic stem cells and adult tissue homeostasis, but the function of FGFs in mammary gland stem cells is less well defined. Both FGFR1 and FGFR2 are expressed in basal and luminal mammary epithelial cells (MECs), suggesting that together they might play a role in mammary gland development and stem cell dynamics. Previous studies have demonstrated that the deletion of FGFR2 resulted only in transient developmental defects in branching morphogenesis. Using a conditional deletion strategy, we investigated the consequences of FGFR1 deletion alone and then the simultaneous deletion of both FGFR1 and FGFR2 in the mammary epithelium. FGFR1 deletion using a keratin 14 promoter-driven Cre-recombinase resulted in an early, yet transient delay in development. However, no reduction in functional outgrowth potential was observed following limiting dilution transplantation analysis. In contrast, a significant reduction in outgrowth potential was observed upon the deletion of both FGFR1 and FGFR2 in MECs using adenovirus-Cre. Additionally, using a fluorescent reporter mouse model to monitor Cre-mediated recombination, we observed a competitive disadvantage following transplantation of both FGFR1/R2-null MECs, most prominently in the basal epithelial cells. This correlated with the complete loss of the mammary stem cell repopulating population in the FGFR1/R2-attenuated epithelium. FGFR1/R2-null MECs were partially rescued in chimeric outgrowths containing wild-type MECs, suggesting the potential importance of paracrine mechanisms involved in the maintenance of the basal epithelial stem cells. These studies document the requirement for functional FGFR signaling in mammary stem cells during development. Copyright © 2012 AlphaMed Press.

  4. Activation of PDGFr-β Signaling Pathway after Imatinib and Radioimmunotherapy Treatment in Experimental Pancreatic Cancer

    International Nuclear Information System (INIS)

    Abe, Michio; Kortylewicz, Zbigniew P.; Enke, Charles A.; Mack, Elizabeth; Baranowska-Kortylewicz, Janina

    2011-01-01

    Pancreatic cancer does not respond to a single-agent imatinib therapy. Consequently, multimodality treatments are contemplated. Published data indicate that in colorectal cancer, imatinib and radioimmunotherapy synergize to delay tumor growth. In pancreatic cancer, the tumor response is additive. This disparity of outcomes merited further studies because interactions between these modalities depend on the imatinib-induced reduction of the tumor interstitial fluid pressure. The examination of human and murine PDGFr-β/PDGF-B pathways in SW1990 pancreatic cancer xenografts revealed that the human branch is practically dormant in untreated tumors but the insult on the stromal component produces massive responses of human cancer cells. Inhibition of the stromal PDGFr-β with imatinib activates human PDGFr-β/PDGF-B signaling loop, silent in untreated xenografts, via an apparent paracrine rescue pathway. Responses are treatment-and time-dependent. Soon after treatment, levels of human PDGFr-β, compared to untreated tumors, are 3.4×, 12.4×, and 5.7× higher in imatinib-, radioimmunotherapy + imatinib-, and radioimmunotherapy-treated tumors, respectively. A continuous 14-day irradiation of imatinib-treated xenografts reduces levels of PDGFr-β and phosphorylated PDGFr-β by 5.3× and 4×, compared to earlier times. Human PDGF-B is upregulated suggesting that the survival signaling via the autocrine pathway is also triggered after stromal injury. These findings indicate that therapies targeting pancreatic cancer stromal components may have unintended mitogenic effects and that these effects can be reversed when imatinib is used in conjunction with radioimmunotherapy

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

    Science.gov (United States)

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

    2016-01-01

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

  6. Transcriptomic Analysis Of Purified Embryonic Neural Stem Cells From Zebrafish Embryos Reveals Signalling Pathways Involved In Glycine-dependent Neurogenesis

    Directory of Open Access Journals (Sweden)

    Eric eSAMARUT

    2016-03-01

    Full Text Available How is the initial set of neurons correctly established during the development of the vertebrate central nervous system? In the embryo, glycine and GABA are depolarizing due the immature chloride gradient, which is only reversed to become hyperpolarizing later in post-natal development. We previously showed that glycine regulates neurogenesis via paracrine signalling that promotes calcium transients in neural stem cells (NSCs and their differentiation into interneurons within the spinal cord of the zebrafish embryo. However, the subjacent molecular mechanisms are not yet understood. Our previous work suggests that early neuronal progenitors were not differentiating correctly in the developing spinal cord. As a result, we aimed at identifying the downstream molecular mechanisms involved specifically in NSCs during glycine-dependent embryonic neurogenesis. Using a gfap:GFP transgenic line, we successfully purified NSCs by fluorescence-activated cell sorting (FACS from whole zebrafish embryos and in embryos in which the glycine receptor was knocked down. The strength of this approach is that it focused on the NSC population while tackling the biological issue in an in vivo context in whole zebrafish embryos. After sequencing the transcriptome by RNA-sequencing, we analyzed the genes whose expression was changed upon disruption of glycine signalling and we confirmed the differential expression by independent RTqPCR assay. While over a thousand genes showed altered expression levels, through pathway analysis we identified 14 top candidate genes belonging to five different canonical signalling pathways (signalling by calcium, TGF-beta, sonic hedgehog, Wnt and p53-related apoptosis that are likely to mediate the promotion of neurogenesis by glycine.

  7. Wnt secretion and signaling in Caenorhabditis elegans

    NARCIS (Netherlands)

    Yang, P.T.

    2008-01-01

    Wnt proteins are a highly conserved family of signaling molecules that play a central role during development and in adult tissue homeostasis. Wnt proteins regulate a variety of biological processes, ranging from cell proliferation and cell fate determination to cell migration, axon guidance and

  8. Characterization of Radar Signals Using Neural Networks

    Science.gov (United States)

    1990-12-01

    e***e*e*eeeeeeeeeeeesseeeeeese*eee*e*e************s /* Function Name: load.input.ptterns Number: 4.1 /* Description: This function determines wether ...XSE.last.layer Number: 8.5 */ /* Description: The function determines wether to backpropate the *f /* parameter by the sigmoidal or linear update...Sigmoidal Function," Mathematics of Control, Signals and Systems, 2:303-314 (March 1989). 6. Dayhoff, Judith E. Neural Network Architectures. New York: Van

  9. Critical nodes in signalling pathways

    DEFF Research Database (Denmark)

    Taniguchi, Cullen M; Emanuelli, Brice; Kahn, C Ronald

    2006-01-01

    Physiologically important cell-signalling networks are complex, and contain several points of regulation, signal divergence and crosstalk with other signalling cascades. Here, we use the concept of 'critical nodes' to define the important junctions in these pathways and illustrate their unique role...... using insulin signalling as a model system....

  10. Sinusoidal Representation of Acoustic Signals

    Science.gov (United States)

    Honda, Masaaki

    Sinusoidal representation of acoustic signals has been an important tool in speech and music processing like signal analysis, synthesis and time scale or pitch modifications. It can be applicable to arbitrary signals, which is an important advantage over other signal representations like physical modeling of acoustic signals. In sinusoidal representation, acoustic signals are composed as sums of sinusoid (sine wave) with different amplitudes, frequencies and phases, which is based on the timedependent short-time Fourier transform (STFT). This article describes the principles of acoustic signal analysis/synthesis based on a sinusoid representation with focus on sine waves with rapidly varying frequency.

  11. The newest digital signal processing

    International Nuclear Information System (INIS)

    Lee, Chae Uk

    2002-08-01

    This book deal with the newest digital signal processing, which contains introduction on conception of digital signal processing, constitution and purpose, signal and system such as signal, continuos signal, discrete signal and discrete system, I/O expression on impress response, convolution, mutual connection of system and frequency character,z transform of definition, range, application of z transform and relationship with laplace transform, Discrete fourier, Fast fourier transform on IDFT algorithm and FFT application, foundation of digital filter of notion, expression, types, frequency characteristic of digital filter and design order of filter, Design order of filter, Design of FIR digital filter, Design of IIR digital filter, Adaptive signal processing, Audio signal processing, video signal processing and application of digital signal processing.

  12. Variable reflectivity signal mirrors and signal response measurements

    International Nuclear Information System (INIS)

    Vine, Glenn de; Shaddock, Daniel A; McClelland, David E

    2002-01-01

    Future gravitational wave detectors will include some form of signal mirror in order to alter the signal response of the device. We introduce interferometer configurations which utilize a variable reflectivity signal mirror allowing a tunable peak frequency and variable signal bandwidth. A detector configured with a Fabry-Perot cavity as the signal mirror is compared theoretically with one using a Michelson interferometer for a signal mirror. A system for the measurement of the interferometer signal responses is introduced. This technique is applied to a power-recycled Michelson interferometer with resonant sideband extraction. We present broadband measurements of the benchtop prototype's signal response for a range of signal cavity detunings. This technique is also applicable to most other gravitational wave detector configurations

  13. Variable reflectivity signal mirrors and signal response measurements

    CERN Document Server

    Vine, G D; McClelland, D E

    2002-01-01

    Future gravitational wave detectors will include some form of signal mirror in order to alter the signal response of the device. We introduce interferometer configurations which utilize a variable reflectivity signal mirror allowing a tunable peak frequency and variable signal bandwidth. A detector configured with a Fabry-Perot cavity as the signal mirror is compared theoretically with one using a Michelson interferometer for a signal mirror. A system for the measurement of the interferometer signal responses is introduced. This technique is applied to a power-recycled Michelson interferometer with resonant sideband extraction. We present broadband measurements of the benchtop prototype's signal response for a range of signal cavity detunings. This technique is also applicable to most other gravitational wave detector configurations.

  14. An optimal filter for short photoplethysmogram signals

    Science.gov (United States)

    Liang, Yongbo; Elgendi, Mohamed; Chen, Zhencheng; Ward, Rabab

    2018-01-01

    A photoplethysmogram (PPG) contains a wealth of cardiovascular system information, and with the development of wearable technology, it has become the basic technique for evaluating cardiovascular health and detecting diseases. However, due to the varying environments in which wearable devices are used and, consequently, their varying susceptibility to noise interference, effective processing of PPG signals is challenging. Thus, the aim of this study was to determine the optimal filter and filter order to be used for PPG signal processing to make the systolic and diastolic waves more salient in the filtered PPG signal using the skewness quality index. Nine types of filters with 10 different orders were used to filter 219 (2.1s) short PPG signals. The signals were divided into three categories by PPG experts according to their noise levels: excellent, acceptable, or unfit. Results show that the Chebyshev II filter can improve the PPG signal quality more effectively than other types of filters and that the optimal order for the Chebyshev II filter is the 4th order. PMID:29714722

  15. Lymphocyte signaling: beyond knockouts.

    Science.gov (United States)

    Saveliev, Alexander; Tybulewicz, Victor L J

    2009-04-01

    The analysis of lymphocyte signaling was greatly enhanced by the advent of gene targeting, which allows the selective inactivation of a single gene. Although this gene 'knockout' approach is often informative, in many cases, the phenotype resulting from gene ablation might not provide a complete picture of the function of the corresponding protein. If a protein has multiple functions within a single or several signaling pathways, or stabilizes other proteins in a complex, the phenotypic consequences of a gene knockout may manifest as a combination of several different perturbations. In these cases, gene targeting to 'knock in' subtle point mutations might provide more accurate insight into protein function. However, to be informative, such mutations must be carefully based on structural and biophysical data.

  16. Sphingosine signaling and atherogenesis

    DEFF Research Database (Denmark)

    Xu, Cang-bao; Hansen-Schwartz, Jacob; Edvinsson, Lars

    2004-01-01

    Sphingosine-1-phosphate (S1P) has diverse biological functions acting inside cells as a second messenger to regulate cell proliferation and survival, and extracellularly, as a ligand for a group of G protein-coupled receptors (GPCRs) named the endothelial differentiation gene (EDG) family. Five...... closely related GPCRs of EDG family (EDG1, EDG3, EDG5, EDG6, and EDG8) have recently been identified as high-affinity S1P receptors. These receptors are coupled via Gi, Gq, G12/13, and Rho. The signaling pathways are linked to vascular cell migration, proliferation, apoptosis, intracellular Ca2......+ mobilization, and expression of adhesion molecules. The formation of an atherosclerotic lesion occurs through activation of cellular events that include monocyte adhesion to the endothelium and vascular smooth muscle cell (VSMC) migration and proliferation. Thus, S1P signaling may play an important role...

  17. Determination of the physical values of a plasma puff by analysis of the diamagnetic signals. 1. part: expansion model for the puff. 2. part: comparison of experimental results with the expansion model for the plasma puff; Determination des grandeurs physiques d'une bouffee de plasma par l'analyse de signaux diamagnetiques. 1. partie: modele d'expansion de bouffee. 2. partie: confrontation des resultats experimentaux et du modele d'expansion de la bouffee de plasma

    Energy Technology Data Exchange (ETDEWEB)

    Jacquinot, J; Leloup, Ch; Waelbroeck, F; Poffe, J P [Commissariat a l' Energie Atomique, Fontenay-aux-Roses (France). Centre d' Etudes Nucleaires

    1964-07-01

    The flow of a dense plasma puff, along the axis of a uniform magnetic field is examined, assuming the following hypotheses: the axial distribution of the line density can be described at any time by a gaussian function whose characteristic parameter is independent of the distance from the axis of the system; the {beta} ratio is less than 0,6. An approximate solution of the magnetohydrodynamics equations is obtained. The evolution of the characteristic properties of the plasma (local velocity, temperature and density) can be calculated from a set of equations involving 5 plasma parameters. A method leading to the determination of these parameters is described. It uses 5 informations picked up from the diamagnetic signals induced by the plasma into a set of 4 compensated magnetic loops. (authors) [French] L'ecoulement d'une bouffee dense de plasma le long des lignes de force d'un champ magnetique uniforme est etudie en faisant les hypotheses suivantes : la distribution axiale de la densite lineique est, a chaque instant, une gaussienne dont le pa