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Sample records for embryonic morphogen nodal

  1. Embryonic Morphogen Nodal Is Associated with Progression and Poor Prognosis of Hepatocellular Carcinoma

    PubMed Central

    Jia, Wei-Dong; Xu, Ge-Liang; Ma, Jin-Liang; Ren, Yun; Chen, Hao; Sun, Si-Nan; Huang, Mei; Li, Jian-Sheng

    2014-01-01

    Background Nodal, a TGF-β-related embryonic morphogen, is involved in multiple biologic processes. However, the expression of Nodal in hepatocellular carcinoma (HCC) and its correlation with tumor angiogenesis, epithelial-mesenchymal transition, and prognosis is unclear. Methods We used real-time PCR and Western blotting to investigate Nodal expression in 6 HCC cell lines and 1 normal liver cell line, 16 pairs of tumor and corresponding paracarcinomatous tissues from HCC patients. Immunohistochemistry was performed to examine Nodal expression in HCC and corresponding paracarcinomatous tissues from 96 patients. CD34 and Vimentin were only examined in HCC tissues of patients mentioned above. Nodal gene was silenced by shRNA in MHCC97H and HCCLM3 cell lines, and cell migration and invasion were detected. Statistical analyses were applied to evaluate the prognostic value and associations of Nodal expression with clinical parameters. Results Nodal expression was detected in HCC cell lines with high metastatic potential alone. Nodal expression is up-regulated in HCC tissues compared with paracarcinomatous and normal liver tissues. Nodal protein was expressed in 70 of the 96 (72.9%) HCC tumors, and was associated with vascular invasion (P = 0.000), status of metastasis (P = 0.004), AFP (P = 0.049), ICGR15 (indocyanine green retention rate at 15 min) (P = 0.010) and tumor size (P = 0.000). High Nodal expression was positively correlated with high MVD (microvessal density) (P = 0.006), but not with Vimentin expression (P = 0.053). Significantly fewer migrated and invaded cells were seen in shRNA group compared with blank group and negative control group (P<0.05). High Nodal expression was found to be an independent factor for predicting overall survival of HCC. Conclusions Our study demonstrated that Nodal expression is associated with aggressive characteristics of HCC. Its aberrant expression may be a predictive factor of unfavorable prognosis

  2. Extracellular interactions and ligand degradation shape the nodal morphogen gradient

    PubMed Central

    Wang, Yin; Wang, Xi; Wohland, Thorsten; Sampath, Karuna

    2016-01-01

    The correct distribution and activity of secreted signaling proteins called morphogens is required for many developmental processes. Nodal morphogens play critical roles in embryonic axis formation in many organisms. Models proposed to generate the Nodal gradient include diffusivity, ligand processing, and a temporal activation window. But how the Nodal morphogen gradient forms in vivo remains unclear. Here, we have measured in vivo for the first time, the binding affinity of Nodal ligands to their major cell surface receptor, Acvr2b, and to the Nodal inhibitor, Lefty, by fluorescence cross-correlation spectroscopy. We examined the diffusion coefficient of Nodal ligands and Lefty inhibitors in live zebrafish embryos by fluorescence correlation spectroscopy. We also investigated the contribution of ligand degradation to the Nodal gradient. We show that ligand clearance via degradation shapes the Nodal gradient and correlates with its signaling range. By computational simulations of gradient formation, we demonstrate that diffusivity, extra-cellular interactions, and selective ligand destruction collectively shape the Nodal morphogen gradient. DOI: http://dx.doi.org/10.7554/eLife.13879.001 PMID:27101364

  3. Embryonic pattern scaling achieved by oppositely directed morphogen gradients.

    PubMed

    McHale, Peter; Rappel, Wouter-Jan; Levine, Herbert

    2006-06-01

    Morphogens are proteins, often produced in a localized region, whose concentrations spatially demarcate regions of differing gene expression in developing embryos. The boundaries of gene expression are typically sharp and the genes can be viewed as abruptly switching from on to off or vice versa upon crossing the boundary. To ensure the viability of the organism these boundaries must be set at certain fractional positions within the corresponding developing field. Remarkably this can be done with high precision despite the fact that the size of the developing field itself can vary widely from embryo to embryo. How this scaling is accomplished is unknown but it is clear that a single morphogen gradient is insufficient. Here we show how a pair of morphogens A and B, produced at opposite ends of a one-dimensional developing field, can solve the pattern-scaling problem. In the most promising scenario the morphogens interact via an effective annihilation reaction A + B --> slashed circle and the switch occurs according to the absolute concentration of A or B. We define a scaling criterion and show that morphogens coupled in this way can set embryonic markers across the entire developing field in proportion to the field size. This scaling occurs at developing-field sizes of a few times the morphogen decay length. The scaling criterion is not met if instead the gradients couple combinatorially such that downstream genes are regulated by the ratio A/B of the morphogen concentrations. PMID:16829697

  4. Response to Nodal morphogen gradient is determined by the kinetics of target gene induction

    PubMed Central

    Dubrulle, Julien; Jordan, Benjamin M; Akhmetova, Laila; Farrell, Jeffrey A; Kim, Seok-Hyung; Solnica-Krezel, Lilianna; Schier, Alexander F

    2015-01-01

    Morphogen gradients expose cells to different signal concentrations and induce target genes with different ranges of expression. To determine how the Nodal morphogen gradient induces distinct gene expression patterns during zebrafish embryogenesis, we measured the activation dynamics of the signal transducer Smad2 and the expression kinetics of long- and short-range target genes. We found that threshold models based on ligand concentration are insufficient to predict the response of target genes. Instead, morphogen interpretation is shaped by the kinetics of target gene induction: the higher the rate of transcription and the earlier the onset of induction, the greater the spatial range of expression. Thus, the timing and magnitude of target gene expression can be used to modulate the range of expression and diversify the response to morphogen gradients. DOI: http://dx.doi.org/10.7554/eLife.05042.001 PMID:25869585

  5. A Mechanochemical Model for Embryonic Pattern Formation: Coupling Tissue Mechanics and Morphogen Expression

    PubMed Central

    Mercker, Moritz; Hartmann, Dirk; Marciniak-Czochra, Anna

    2013-01-01

    Motivated by recent experimental findings, we propose a novel mechanism of embryonic pattern formation based on coupling of tissue curvature with diffusive signaling by a chemical factor. We derive a new mathematical model using energy minimization approach and show that the model generates a variety of morphogen and curvature patterns agreeing with experimentally observed structures. The mechanism proposed transcends the classical Turing concept which requires interactions between two morphogens with a significantly different diffusivity. Our studies show how biomechanical forces may replace the elusive long-range inhibitor and lead to formation of stable spatially heterogeneous structures without existence of chemical prepatterns. We propose new experimental approaches to decisively test our central hypothesis that tissue curvature and morphogen expression are coupled in a positive feedback loop. PMID:24376555

  6. Human Cerberus Prevents Nodal-Receptor Binding, Inhibits Nodal Signaling, and Suppresses Nodal-Mediated Phenotypes

    PubMed Central

    Aykul, Senem; Ni, Wendi; Mutatu, Washington; Martinez-Hackert, Erik

    2015-01-01

    The Transforming Growth Factor-ß (TGFß) family ligand Nodal is an essential embryonic morphogen that is associated with progression of breast and other cancers. It has therefore been suggested that Nodal inhibitors could be used to treat breast cancers where Nodal plays a defined role. As secreted antagonists, such as Cerberus, tightly regulate Nodal signaling during embryonic development, we undertook to produce human Cerberus, characterize its biochemical activities, and determine its effect on human breast cancer cells. Using quantitative methods, we investigated the mechanism of Nodal signaling, we evaluated binding of human Cerberus to Nodal and other TGFß family ligands, and we characterized the mechanism of Nodal inhibition by Cerberus. Using cancer cell assays, we examined the ability of Cerberus to suppress aggressive breast cancer cell phenotypes. We found that human Cerberus binds Nodal with high affinity and specificity, blocks binding of Nodal to its signaling partners, and inhibits Nodal signaling. Moreover, we showed that Cerberus profoundly suppresses migration, invasion, and colony forming ability of Nodal expressing and Nodal supplemented breast cancer cells. Taken together, our studies provide mechanistic insights into Nodal signaling and Nodal inhibition with Cerberus and highlight the potential value of Cerberus as anti-Nodal therapeutic. PMID:25603319

  7. The Role of Regulated mRNA Stability in Establishing Bicoid Morphogen Gradient in Drosophila Embryonic Development

    PubMed Central

    Liu, Wei; Niranjan, Mahesan

    2011-01-01

    The Bicoid morphogen is amongst the earliest triggers of differential spatial pattern of gene expression and subsequent cell fate determination in the embryonic development of Drosophila. This maternally deposited morphogen is thought to diffuse in the embryo, establishing a concentration gradient which is sensed by downstream genes. In most model based analyses of this process, the translation of the bicoid mRNA is thought to take place at a fixed rate from the anterior pole of the embryo and a supply of the resulting protein at a constant rate is assumed. Is this process of morphogen generation a passive one as assumed in the modelling literature so far, or would available data support an alternate hypothesis that the stability of the mRNA is regulated by active processes? We introduce a model in which the stability of the maternal mRNA is regulated by being held constant for a length of time, followed by rapid degradation. With this more realistic model of the source, we have analysed three computational models of spatial morphogen propagation along the anterior-posterior axis: (a) passive diffusion modelled as a deterministic differential equation, (b) diffusion enhanced by a cytoplasmic flow term; and (c) diffusion modelled by stochastic simulation of the corresponding chemical reactions. Parameter estimation on these models by matching to publicly available data on spatio-temporal Bicoid profiles suggests strong support for regulated stability over either a constant supply rate or one where the maternal mRNA is permitted to degrade in a passive manner. PMID:21949782

  8. Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts.

    PubMed

    Sarkar, Prasenjit; Randall, Shan M; Collier, Timothy S; Nero, Anthony; Russell, Teal A; Muddiman, David C; Rao, Balaji M

    2015-04-01

    Human embryonic stem cells (hESCs) have been routinely treated with bone morphogenetic protein and/or inhibitors of activin/nodal signaling to obtain cells that express trophoblast markers. Trophoblasts can terminally differentiate to either extravillous trophoblasts or syncytiotrophoblasts. The signaling pathways that govern the terminal fate of these trophoblasts are not understood. We show that activin/nodal signaling switches the terminal fate of these hESC-derived trophoblasts. Inhibition of activin/nodal signaling leads to formation of extravillous trophoblast, whereas loss of activin/nodal inhibition leads to the formation of syncytiotrophoblasts. Also, the ability of hESCs to form bona fide trophoblasts has been intensely debated. We have examined hESC-derived trophoblasts in the light of stringent criteria that were proposed recently, such as hypomethylation of the ELF5-2b promoter region and down-regulation of HLA class I antigens. We report that trophoblasts that possess these properties can indeed be obtained from hESCs. PMID:25670856

  9. Activin/Nodal Signaling Switches the Terminal Fate of Human Embryonic Stem Cell-derived Trophoblasts*

    PubMed Central

    Sarkar, Prasenjit; Randall, Shan M.; Collier, Timothy S.; Nero, Anthony; Russell, Teal A.; Muddiman, David C.; Rao, Balaji M.

    2015-01-01

    Human embryonic stem cells (hESCs) have been routinely treated with bone morphogenetic protein and/or inhibitors of activin/nodal signaling to obtain cells that express trophoblast markers. Trophoblasts can terminally differentiate to either extravillous trophoblasts or syncytiotrophoblasts. The signaling pathways that govern the terminal fate of these trophoblasts are not understood. We show that activin/nodal signaling switches the terminal fate of these hESC-derived trophoblasts. Inhibition of activin/nodal signaling leads to formation of extravillous trophoblast, whereas loss of activin/nodal inhibition leads to the formation of syncytiotrophoblasts. Also, the ability of hESCs to form bona fide trophoblasts has been intensely debated. We have examined hESC-derived trophoblasts in the light of stringent criteria that were proposed recently, such as hypomethylation of the ELF5-2b promoter region and down-regulation of HLA class I antigens. We report that trophoblasts that possess these properties can indeed be obtained from hESCs. PMID:25670856

  10. Plasticity underlies tumor progression: role of Nodal signaling.

    PubMed

    Bodenstine, Thomas M; Chandler, Grace S; Seftor, Richard E B; Seftor, Elisabeth A; Hendrix, Mary J C

    2016-03-01

    The transforming growth factor beta (TGFβ) superfamily member Nodal is an established regulator of early embryonic development, with primary roles in endoderm induction, left-right asymmetry, and primitive streak formation. Nodal signals through TGFβ family receptors at the plasma membrane and induces signaling cascades leading to diverse transcriptional regulation. While conceptually simple, the regulation of Nodal and its molecular effects are profoundly complex and context dependent. Pioneering work by developmental biologists has characterized the signaling pathways, regulatory components, and provided detailed insight into the mechanisms by which Nodal mediates changes at the cellular and organismal levels. Nodal is also an important factor in maintaining pluripotency of embryonic stem cells through regulation of core transcriptional programs. Collectively, this work has led to an appreciation for Nodal as a powerful morphogen capable of orchestrating multiple cellular phenotypes. Although Nodal is not active in most adult tissues, its reexpression and signaling have been linked to multiple types of human cancer, and Nodal has emerged as a driver of tumor growth and cellular plasticity. In vitro and in vivo experimental evidence has demonstrated that inhibition of Nodal signaling reduces cancer cell aggressive characteristics, while clinical data have established associations with Nodal expression and patient outcomes. As a result, there is great interest in the potential targeting of Nodal activity in a therapeutic setting for cancer patients that may provide new avenues for suppressing tumor growth and metastasis. In this review, we evaluate our current understanding of the complexities of Nodal function in cancer and highlight recent experimental evidence that sheds light on the therapeutic potential of its inhibition. PMID:26951550

  11. BMP Inhibition in Seminomas Initiates Acquisition of Pluripotency via NODAL Signaling Resulting in Reprogramming to an Embryonal Carcinoma

    PubMed Central

    Nettersheim, Daniel; Jostes, Sina; Sharma, Rakesh; Schneider, Simon; Hofmann, Andrea; Ferreira, Humberto J.; Hoffmann, Per; Kristiansen, Glen; Esteller, Manel B.; Schorle, Hubert

    2015-01-01

    Type II germ cell cancers (GCC) can be subdivided into seminomas and non-seminomas. Seminomas are similar to carcinoma in situ (CIS) cells, the common precursor of type II GCCs, with regard to epigenetics and expression, while embryonal carcinomas (EC) are totipotent and differentiate into teratomas, yolk-sac tumors and choriocarcinomas. GCCs can present as seminomas with a non-seminoma component, raising the question if a CIS gives rise to seminomas and ECs at the same time or whether seminomas can be reprogrammed to ECs. In this study, we utilized the seminoma cell line TCam-2 that acquires an EC-like status after xenografting into the murine flank as a model for a seminoma to EC transition and screened for factors initiating and driving this process. Analysis of expression and DNA methylation dynamics during transition of TCam-2 revealed that many pluripotency- and reprogramming-associated genes were upregulated while seminoma-markers were downregulated. Changes in expression level of 53 genes inversely correlated to changes in DNA methylation. Interestingly, after xenotransplantation 6 genes (GDF3, NODAL, DNMT3B, DPPA3, GAL, AK3L1) were rapidly induced, followed by demethylation of their genomic loci, suggesting that these 6 genes are poised for expression driving the reprogramming. We demonstrate that inhibition of BMP signaling is the initial event in reprogramming, resulting in activation of the pluripotency-associated genes and NODAL signaling. We propose that reprogramming of seminomas to ECs is a multi-step process. Initially, the microenvironment causes inhibition of BMP signaling, leading to induction of NODAL signaling. During a maturation phase, a fast acting NODAL loop stimulates its own activity and temporarily inhibits BMP signaling. During the stabilization phase, a slow acting NODAL loop, involving WNTs re-establishes BMP signaling and the pluripotency circuitry. In parallel, DNMT3B-driven de novo methylation silences seminoma-associated genes

  12. Disrupting Foxh1-Groucho Interaction Reveals Robustness of Nodal-Based Embryonic Patterning

    PubMed Central

    Halstead, Angela M.; Wright, Christopher V. E.

    2016-01-01

    The winged-helix transcription factor Foxh1 is an essential regulator of Nodal signaling during the key developmental processes of gastrulation, anterior-posterior (A-P) patterning, and the derivation of left-right (L-R) asymmetry. Current models have Foxh1 bound to phospho-Smad2/3 (pSmad2/3) as a central transcriptional activator for genes targeted by Nodal signaling including Nodal itself, the feedback inhibitor Lefty2, and the positive transcriptional effector Pitx2. However, the conserved Engrailed homology-1 (EH1) motif present in Foxh1 suggests that modulated interaction with Groucho (Grg) co-repressors would allow Foxh1 to function as a transcriptional switch, toggling between transcriptional on and off states via pSmad2-Grg protein-switching, to ensure the properly timed initiation and suppression, and/or amplitude, of expression of Nodal and its target genes. We minimally mutated the Foxh1 EH1 motif, creating a novel Foxh1mEH1 allele to test directly the contribution of Foxh1-Grg–mediated repression on the transient, dynamic pattern of Nodal signaling in mice. All aspects of Nodal and its target gene expression in Foxh1mEH1/mEH1 embryos were equivalent to wild type. A-P patterning and organ situs in homozygous embryos and adult mice were also unaffected. The finding that Foxh1-Grg–mediated repression is not essential for Nodal expression during mouse embryogenesis suggests that other regulators compensate for the loss of repressive regulatory input that is mediated by Grg interactions. We suggest that the pervasive inductive properties of Nodal signaling exist within the context of a strongly buffered regulatory system that contributes to resilience and accuracy of its dynamic expression pattern. PMID:25511461

  13. Interaction of morphogens with geometry

    NASA Astrophysics Data System (ADS)

    Cummings, F. W.

    2005-09-01

    Morphogen patterns are viewed as being affected by epithelial sheet geometry in early development. As the total area of the (closed) sheet changes, the changing geometry acts back in turn to change the morphogen pattern. A number of constraints are given on the functional form of the Gauss and Mean curvatures, considered as functions of the morphogen concentrations and their derivatives. It is shown that the constraints are sufficient to motivate a convincing dependence of the two curvatures on the morphogen concentrations.

  14. Nodal expression in triple-negative breast cancer: Cellular effects of its inhibition following doxorubicin treatment.

    PubMed

    Bodenstine, Thomas M; Chandler, Grace S; Reed, David W; Margaryan, Naira V; Gilgur, Alina; Atkinson, Janis; Ahmed, Nida; Hyser, Matthew; Seftor, Elisabeth A; Strizzi, Luigi; Hendrix, Mary J C

    2016-05-01

    Triple-negative breast cancer (TNBC) represents an aggressive cancer subtype characterized by the lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The independence of TNBC from these growth promoting factors eliminates the efficacy of therapies which specifically target them, and limits TNBC patients to traditional systemic neo/adjuvant chemotherapy. To better understand the growth advantage of TNBC - in the absence of ER, PR and HER2, we focused on the embryonic morphogen Nodal (associated with the cancer stem cell phenotype), which is re-expressed in aggressive breast cancers. Most notably, our previous data demonstrated that inhibition of Nodal signaling in breast cancer cells reduces their tumorigenic capacity. Furthermore, inhibiting Nodal in other cancers has resulted in improved effects of chemotherapy, although the mechanisms for this remain unknown. Thus, we hypothesized that targeting Nodal in TNBC cells in combination with conventional chemotherapy may improve efficacy and represent a potential new strategy. Our preliminary data demonstrate that Nodal is highly expressed in TNBC when compared to invasive hormone receptor positive samples. Treatment of Nodal expressing TNBC cell lines with a neutralizing anti-Nodal antibody reduces the viability of cells that had previously survived treatment with the anthracycline doxorubicin. We show that inhibiting Nodal may alter response mechanisms employed by cancer cells undergoing DNA damage. These data suggest that development of therapies which target Nodal in TNBC may lead to additional treatment options in conjunction with chemotherapy regimens - by altering signaling pathways critical to cellular survival. PMID:27007464

  15. Nodal Promotes Functional Luteolysis via Down-Regulation of Progesterone and Prostaglandins E2 and Promotion of PGF2α Synthetic Pathways in Mare Corpus Luteum.

    PubMed

    Galvão, António; Skarzynski, Dariusz; Ferreira-Dias, Graça

    2016-02-01

    In the present work, we investigated the role of Nodal, an embryonic morphogen from the TGFβ superfamily in corpus luteum (CL) secretory activity using cells isolated from equine CL as a model. Expression pattern of Nodal and its receptors activin receptor A type IIB (ACVR2B), activin receptor-like kinase (Alk)-7, and Alk4, as well as the Nodal physiological role, demonstrate the involvement of this pathway in functional luteolysis. Nodal and its receptors were immune localized in small and large luteal cells and endothelial cells, except ACVR2B, which was not detected in the endothelium. Nodal mRNA in situ hybridization confirmed its transcription in steroidogenic and endothelial cells. Expression analysis of the aforementioned factors evidenced that Nodal and Alk7 proteins peaked at the mid-CL (P < .01), the time of luteolysis initiation, whereas Alk4 and ACVR2B proteins increased from mid- to late CL (P < .05). The Nodal treatment of luteal cells decreased progesterone and prostaglandin (PG) E2 concentrations in culture media (P < .05) as well as mRNA and protein of secretory enzymes steroidogenic acute regulatory protein, cholesterol side-chain cleavage enzyme, cytosolic PGE2 synthase, and microsomal PGE2 synthase-1 (P < .05). Conversely, PGF2α secretion and gene expression of PG-endoperoxidase synthase 2 and PGF2α synthase were increased after Nodal treatment (P < .05). Mid-CL cells cultured with PGF2α had increased Nodal protein expression (P < .05) and phosphorylated mothers against decapentaplegic-3 phosphorylation (P < .05). Finally, the supportive interaction between Nodal and PGF2α on luteolysis was shown to its greatest extent because both factors together more significantly inhibited progesterone (P < .05) and promoted PGF2α (P < .05) synthesis than Nodal or PGF2α alone. Our results neatly pinpoint the sites of action of the Nodal signaling pathway toward functional luteolysis in the mare. PMID:26653568

  16. Cytonemes and the dispersion of morphogens

    PubMed Central

    Kornberg, Thomas B.

    2014-01-01

    Filopodia are cellular protrusions that have been implicated in many types of mechanosensory activities. Morphogens are signaling proteins that regulate the patterned development of embryos and tissues. Both have long histories that date to the beginnings of cell and developmental biology in the early 20th century, but recent findings tie specialized filopodia called cytonemes to morphogen movement and morphogen signaling. This review explores the conceptual and experimental background for a model of paracrine signaling in which the exchange of morphogens between cells is directed to sites where cytonemes directly link cells that produce morphogens to cells that receive and respond to them. PMID:25186102

  17. Quantitative multivariate analysis of dynamic multicellular morphogenic trajectories.

    PubMed

    White, Douglas E; Sylvester, Jonathan B; Levario, Thomas J; Lu, Hang; Streelman, J Todd; McDevitt, Todd C; Kemp, Melissa L

    2015-07-01

    Interrogating fundamental cell biology principles that govern tissue morphogenesis is critical to better understanding of developmental biology and engineering novel multicellular systems. Recently, functional micro-tissues derived from pluripotent embryonic stem cell (ESC) aggregates have provided novel platforms for experimental investigation; however elucidating the factors directing emergent spatial phenotypic patterns remains a significant challenge. Computational modelling techniques offer a unique complementary approach to probe mechanisms regulating morphogenic processes and provide a wealth of spatio-temporal data, but quantitative analysis of simulations and comparison to experimental data is extremely difficult. Quantitative descriptions of spatial phenomena across multiple systems and scales would enable unprecedented comparisons of computational simulations with experimental systems, thereby leveraging the inherent power of computational methods to interrogate the mechanisms governing emergent properties of multicellular biology. To address these challenges, we developed a portable pattern recognition pipeline consisting of: the conversion of cellular images into networks, extraction of novel features via network analysis, and generation of morphogenic trajectories. This novel methodology enabled the quantitative description of morphogenic pattern trajectories that could be compared across diverse systems: computational modelling of multicellular structures, differentiation of stem cell aggregates, and gastrulation of cichlid fish. Moreover, this method identified novel spatio-temporal features associated with different stages of embryo gastrulation, and elucidated a complex paracrine mechanism capable of explaining spatiotemporal pattern kinetic differences in ESC aggregates of different sizes. PMID:26095427

  18. Keeping a lid on nodal: transcriptional and translational repression of nodal signalling

    PubMed Central

    Robertson, Elizabeth J.

    2016-01-01

    Nodal is an evolutionarily conserved member of the transforming growth factor-β (TGF-β) superfamily of secreted signalling factors. Nodal factors are known to play key roles in embryonic development and asymmetry in a variety of organisms ranging from hydra and sea urchins to fish, mice and humans. In addition to embryonic patterning, Nodal signalling is required for maintenance of human embryonic stem cell pluripotency and mis-regulated Nodal signalling has been found associated with tumour metastases. Therefore, precise and timely regulation of this pathway is essential. Here, we discuss recent evidence from sea urchins, frogs, fish, mice and humans that show a role for transcriptional and translational repression of Nodal signalling during early development. PMID:26791244

  19. Multiple roles of Activin/Nodal, bone morphogenetic protein, fibroblast growth factor and Wnt/β-catenin signalling in the anterior neural patterning of adherent human embryonic stem cell cultures

    PubMed Central

    Lupo, Giuseppe; Novorol, Claire; Smith, Joseph R.; Vallier, Ludovic; Miranda, Elena; Alexander, Morgan; Biagioni, Stefano; Pedersen, Roger A.; Harris, William A.

    2013-01-01

    Several studies have successfully produced a variety of neural cell types from human embryonic stem cells (hESCs), but there has been limited systematic analysis of how different regional identities are established using well-defined differentiation conditions. We have used adherent, chemically defined cultures to analyse the roles of Activin/Nodal, bone morphogenetic protein (BMP), fibroblast growth factor (FGF) and Wnt/β-catenin signalling in neural induction, anteroposterior patterning and eye field specification in hESCs. We show that either BMP inhibition or activation of FGF signalling is required for effective neural induction, but these two pathways have distinct outcomes on rostrocaudal patterning. While BMP inhibition leads to specification of forebrain/midbrain positional identities, FGF-dependent neural induction is associated with strong posteriorization towards hindbrain/spinal cord fates. We also demonstrate that Wnt/β-catenin signalling is activated during neural induction and promotes acquisition of neural fates posterior to forebrain. Therefore, inhibition of this pathway is needed for efficient forebrain specification. Finally, we provide evidence that the levels of Activin/Nodal and BMP signalling have a marked influence on further forebrain patterning and that constitutive inhibition of these pathways represses expression of eye field genes. These results show that the key mechanisms controlling neural patterning in model vertebrate species are preserved in adherent, chemically defined hESC cultures and reveal new insights into the signals regulating eye field specification. PMID:23576785

  20. Multiple roles of Activin/Nodal, bone morphogenetic protein, fibroblast growth factor and Wnt/β-catenin signalling in the anterior neural patterning of adherent human embryonic stem cell cultures.

    PubMed

    Lupo, Giuseppe; Novorol, Claire; Smith, Joseph R; Vallier, Ludovic; Miranda, Elena; Alexander, Morgan; Biagioni, Stefano; Pedersen, Roger A; Harris, William A

    2013-04-01

    Several studies have successfully produced a variety of neural cell types from human embryonic stem cells (hESCs), but there has been limited systematic analysis of how different regional identities are established using well-defined differentiation conditions. We have used adherent, chemically defined cultures to analyse the roles of Activin/Nodal, bone morphogenetic protein (BMP), fibroblast growth factor (FGF) and Wnt/β-catenin signalling in neural induction, anteroposterior patterning and eye field specification in hESCs. We show that either BMP inhibition or activation of FGF signalling is required for effective neural induction, but these two pathways have distinct outcomes on rostrocaudal patterning. While BMP inhibition leads to specification of forebrain/midbrain positional identities, FGF-dependent neural induction is associated with strong posteriorization towards hindbrain/spinal cord fates. We also demonstrate that Wnt/β-catenin signalling is activated during neural induction and promotes acquisition of neural fates posterior to forebrain. Therefore, inhibition of this pathway is needed for efficient forebrain specification. Finally, we provide evidence that the levels of Activin/Nodal and BMP signalling have a marked influence on further forebrain patterning and that constitutive inhibition of these pathways represses expression of eye field genes. These results show that the key mechanisms controlling neural patterning in model vertebrate species are preserved in adherent, chemically defined hESC cultures and reveal new insights into the signals regulating eye field specification. PMID:23576785

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-10-26

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

  3. Positive modulator of bone morphogenic protein-2

    DOEpatents

    Zamora, Paul O.; Pena, Louis A.; Lin, Xinhua; Takahashi, Kazuyuki

    2009-01-27

    Compounds of the present invention of formula I and formula II are disclosed in the specification and wherein the compounds are modulators of Bone Morphogenic Protein activity. Compounds are synthetic peptides having a non-growth factor heparin binding region, a linker, and sequences that bind specifically to a receptor for Bone Morphogenic Protein. Uses of compounds of the present invention in the treatment of bone lesions, degenerative joint disease and to enhance bone formation are disclosed.

  4. Fundamental origins and limits for scaling a maternal morphogen gradient

    PubMed Central

    He, Feng; Wei, Chuanxian; Wu, Honggang; Cheung, David; Jiao, Renjie; Ma, Jun

    2015-01-01

    Tissue expansion and patterning are integral to development, but it is unknown quantitatively how a mother accumulates molecular resources to invest in the future of instructing robust embryonic patterning. Here we develop a model, Tissue Expansion-Modulated Maternal Morphogen Scaling (TEM3S), to study scaled anterior-posterior patterning in Drosophila embryos. Using both ovaries and embryos, we measure a core quantity of the model, the scaling power of the Bicoid (Bcd) morphogen gradient’s amplitude nA. We also evaluate directly model-derived predictions about Bcd gradient and patterning properties. Our results show that scaling of the Bcd gradient in the embryo originates from, and is constrained fundamentally by, a dynamic relationship between maternal tissue expansion and bcd gene copy number expansion in the ovary. This delicate connection between the two transitioning stages of a life cycle, stemming from a finite value of nA ~ 3, underscores a key feature of developmental systems depicted by TEM3S. PMID:25809405

  5. Activin/Nodal signaling and NANOG orchestrate human embryonic stem cell fate decisions by controlling the H3K4me3 chromatin mark

    PubMed Central

    Bertero, Alessandro; Madrigal, Pedro; Galli, Antonella; Hubner, Nina C.; Moreno, Inmaculada; Burks, Deborah; Brown, Stephanie; Pedersen, Roger A.; Gaffney, Daniel; Mendjan, Sasha; Pauklin, Siim

    2015-01-01

    Stem cells can self-renew and differentiate into multiple cell types. These characteristics are maintained by the combination of specific signaling pathways and transcription factors that cooperate to establish a unique epigenetic state. Despite the broad interest of these mechanisms, the precise molecular controls by which extracellular signals organize epigenetic marks to confer multipotency remain to be uncovered. Here, we use human embryonic stem cells (hESCs) to show that the Activin–SMAD2/3 signaling pathway cooperates with the core pluripotency factor NANOG to recruit the DPY30-COMPASS histone modifiers onto key developmental genes. Functional studies demonstrate the importance of these interactions for correct histone 3 Lys4 trimethylation and also self-renewal and differentiation. Finally, genetic studies in mice show that Dpy30 is also necessary to maintain pluripotency in the pregastrulation embryo, thereby confirming the existence of similar regulations in vivo during early embryonic development. Our results reveal the mechanisms by which extracellular factors coordinate chromatin status and cell fate decisions in hESCs. PMID:25805847

  6. Activin/nodal signaling and NANOG orchestrate human embryonic stem cell fate decisions by controlling the H3K4me3 chromatin mark.

    PubMed

    Bertero, Alessandro; Madrigal, Pedro; Galli, Antonella; Hubner, Nina C; Moreno, Inmaculada; Burks, Deborah; Brown, Stephanie; Pedersen, Roger A; Gaffney, Daniel; Mendjan, Sasha; Pauklin, Siim; Vallier, Ludovic

    2015-04-01

    Stem cells can self-renew and differentiate into multiple cell types. These characteristics are maintained by the combination of specific signaling pathways and transcription factors that cooperate to establish a unique epigenetic state. Despite the broad interest of these mechanisms, the precise molecular controls by which extracellular signals organize epigenetic marks to confer multipotency remain to be uncovered. Here, we use human embryonic stem cells (hESCs) to show that the Activin-SMAD2/3 signaling pathway cooperates with the core pluripotency factor NANOG to recruit the DPY30-COMPASS histone modifiers onto key developmental genes. Functional studies demonstrate the importance of these interactions for correct histone 3 Lys4 trimethylation and also self-renewal and differentiation. Finally, genetic studies in mice show that Dpy30 is also necessary to maintain pluripotency in the pregastrulation embryo, thereby confirming the existence of similar regulations in vivo during early embryonic development. Our results reveal the mechanisms by which extracellular factors coordinate chromatin status and cell fate decisions in hESCs. PMID:25805847

  7. Mathematical embryology: the fluid mechanics of nodal cilia

    NASA Astrophysics Data System (ADS)

    Smith, D. J.; Smith, A. A.; Blake, J. R.

    2011-07-01

    Left-right symmetry breaking is critical to vertebrate embryonic development; in many species this process begins with cilia-driven flow in a structure termed the `node'. Primary `whirling' cilia, tilted towards the posterior, transport morphogen-containing vesicles towards the left, initiating left-right asymmetric development. We review recent theoretical models based on the point-force stokeslet and point-torque rotlet singularities, explaining how rotation and surface-tilt produce directional flow. Analysis of image singularity systems enforcing the no-slip condition shows how tilted rotation produces a far-field `stresslet' directional flow, and how time-dependent point-force and time-independent point-torque models are in this respect equivalent. Associated slender body theory analysis is reviewed; this approach enables efficient and accurate simulation of three-dimensional time-dependent flow, time-dependence being essential in predicting features of the flow such as chaotic advection, which have subsequently been determined experimentally. A new model for the nodal flow utilising the regularized stokeslet method is developed, to model the effect of the overlying Reichert's membrane. Velocity fields and particle paths within the enclosed domain are computed and compared with the flow profiles predicted by previous `membrane-less' models. Computations confirm that the presence of the membrane produces flow-reversal in the upper region, but no continuous region of reverse flow close to the epithelium. The stresslet far-field is no longer evident in the membrane model, due to the depth of the cavity being of similar magnitude to the cilium length. Simulations predict that vesicles released within one cilium length of the epithelium are generally transported to the left via a `loopy drift' motion, sometimes involving highly unpredictable detours around leftward cilia [truncated

  8. An essential role for maternal control of Nodal signaling

    PubMed Central

    Kumari, Pooja; Gilligan, Patrick C; Lim, Shimin; Tran, Long Duc; Winkler, Sylke; Philp, Robin; Sampath, Karuna

    2013-01-01

    Growth factor signaling is essential for pattern formation, growth, differentiation, and maintenance of stem cell pluripotency. Nodal-related signaling factors are required for axis formation and germ layer specification from sea urchins to mammals. Maternal transcripts of the zebrafish Nodal factor, Squint (Sqt), are localized to future embryonic dorsal. The mechanisms by which maternal sqt/nodal RNA is localized and regulated have been unclear. Here, we show that maternal control of Nodal signaling via the conserved Y box-binding protein 1 (Ybx1) is essential. We identified Ybx1 via a proteomic screen. Ybx1 recognizes the 3’ untranslated region (UTR) of sqt RNA and prevents premature translation and Sqt/Nodal signaling. Maternal-effect mutations in zebrafish ybx1 lead to deregulated Nodal signaling, gastrulation failure, and embryonic lethality. Implanted Nodal-coated beads phenocopy ybx1 mutant defects. Thus, Ybx1 prevents ectopic Nodal activity, revealing a new paradigm in the regulation of Nodal signaling, which is likely to be conserved. DOI: http://dx.doi.org/10.7554/eLife.00683.001 PMID:24040511

  9. Studies of morphogens: keep calm and carry on

    PubMed Central

    Stathopoulos, Angelike; Iber, Dagmar

    2013-01-01

    Morphogens are signaling factors that direct cell fate and tissue development at a distance from their source, and various modes of transport and interpretation have been suggested for morphogens. The recent EMBO Workshop on ‘Morphogen gradients’, which took place in Oxford, UK in June 2013, centered on the formation and interpretation of such morphogen gradients during development. This meeting allowed an exchange of views in light of recent results. Here, we provide a brief overview of the talks, organized in relation to several major themes of discussion at the meeting: (1) morphogen gradient formation; (2) morphogen gradient interpretation; (3) signaling networks and feedback in morphogenesis; (4) emergence of patterns; (5) scaling of patterns; (6) the control of growth; and (7) new techniques in the field. PMID:24086076

  10. Multi-lineage MSC Differentiation via Engineered Morphogen Fields

    PubMed Central

    Arany, P.R.; Huang, G.X.; Gadish, O.; Feliz, J.; Weaver, J.C.; Kim, J.; Yuen, W.W.; Mooney, D.J.

    2014-01-01

    Tissue loss due to oral diseases requires the healing and regeneration of tissues of multiple lineages. While stem cells are native to oral tissues, a current major limitation to regeneration is the ability to direct their lineage-specific differentiation. This work utilizes polymeric scaffold systems with spatiotemporally controlled morphogen cues to develop precise morphogen fields to direct mesenchymal stem cell differentiation. First, a simple three-layer scaffold design was developed that presented two spatially segregated, lineage-specific cues (Dentinogenic TGF-β1 and Osteogenic BMP4). However, this system resulted in diffuse morphogen fields, as assessed by the in vitro imaging of cell-signaling pathways triggered by the morphogens. Mathematical modeling was then exploited, in combination with incorporation of specific inhibitors (neutralizing antibodies or a small molecule kinase inhibitor) into each morphogen in an opposing spatial pattern as the respective morphogen, to design a five-layer scaffold that was predicted to yield distinct, spatially segregated zones of morphogen signaling. To validate this system, undifferentiated MSCs were uniformly seeded in these scaffold systems, and distinct mineralized tissue differentiation were noted within these morphogen zones. Finally, to demonstrate temporal control over morphogen signaling, latent TGF-β1 was incorporated into one region of a concentric scaffold design, and laser treatment was used to activate the morphogen on-demand and to induce dentin differentiation solely within that specific spatial zone. This study demonstrates a significant advance in scaffold design to generate precise morphogen fields that can be used to develop in situ models to explore tissue differentiation and may ultimately be useful in engineering multi-lineage tissues in clinical dentistry. PMID:25143513

  11. Patterning the cerebral cortex: traveling with morphogens.

    PubMed

    Borello, Ugo; Pierani, Alessandra

    2010-08-01

    The neocortex represents the brain structure that has been subjected to a major expansion in its relative size during the course of mammalian evolution. An exquisite coordination of appropriate growth of competent territories along multiple axes and their spatial patterning is required for regionalization of the cortical primordium and the formation of functional areas. The achievement of such a highly complex architecture relies on a precise orchestration of the proliferation of progenitors, onset of neurogenesis, spatio-temporal generation of distinct cell types and control of their migration. We will review recent work on alternative molecular mechanisms that, via the migration of signaling cells/structures, participate in coordinating growth and spatial patterning in the developing cerebral cortex. By integrating temporal and spatial parameters as well as absolute levels of signaling this novel strategy might represent a general mechanism for long-range patterning in large structures, in addition to the passive diffusion of morphogens. PMID:20542680

  12. Spatiotemporal Analysis of Different Mechanisms for Interpreting Morphogen Gradients

    PubMed Central

    Richards, David M.; Saunders, Timothy E.

    2015-01-01

    During development, multicellular organisms must accurately control both temporal and spatial aspects of tissue patterning. This is often achieved using morphogens, signaling molecules that form spatially varying concentrations and so encode positional information. Typical analysis of morphogens assumes that spatial information is decoded in steady state by measuring the value of the morphogen concentration. However, recent experimental work suggests that both pre-steady-state readout and measurement of spatial and temporal derivatives of the morphogen concentration can play important roles in defining boundaries. Here, we undertake a detailed theoretical and numerical study of the accuracy of patterning—both in space and time—in models where readout is provided not by the morphogen concentration but by its spatial and temporal derivatives. In both cases we find that accurate patterning can be achieved, with sometimes even smaller errors than directly reading the morphogen concentration. We further demonstrate that such models provide other potential benefits to the system, such as the ability to switch on and off gene response with a high degree of spatiotemporal accuracy. Finally, we discuss how such derivatives might be calculated biologically and examine these models in relation to Sonic Hedgehog signaling in the vertebrate central nervous system. We show that, when coupled to a downstream transcriptional network, pre-steady-state measurement of the temporal change in the Shh morphogen is a plausible mechanism for determining precise gene boundaries in both space and time. PMID:25902445

  13. Morphogenic Peptides in Regeneration of Load Bearing Tissues.

    PubMed

    Moeinzadeh, Seyedsina; Jabbari, Esmaiel

    2015-01-01

    Morphogenic proteins due to their short half-life require high doses of growth factors in regeneration of load bearing tissues which leads to undesirable side effects. These side effects include bone overgrowth, tumor formation and immune reaction. An alternative approach to reduce undesirable side effects of proteins in regenerative medicine is to use morphogenic peptides derived from the active domains of morphogenic proteins or soluble and insoluble components of the extracellular matrix of mineralized load bearing tissues to induce differentiation of progenitor cells, mineralization, maturation and bone formation. In that regard, many peptides with osteogenic activity have been discovered. These include peptides derived from bone morphogenic proteins (BMPs), those based on interaction with integrin and heparin-binding receptors, collagen derived peptides, peptides derived from other soluble ECM proteins such as bone sialoprotein and enamel matrix proteins, and those peptides derived from vasculoinductive and neuro-inductive proteins. Although these peptides show significant osteogenic activity in vitro and increase mineralization and bone formation in animal models, they are not widely used in clinical orthopedic applications as an alternative to morphogenic proteins. This is partly due to the limited availability of data on structure and function of morphogenic peptides in physiological medium, particularly in tissue engineered scaffolds. Due to their amphiphilic nature, peptides spontaneously self-assemble and aggregate into micellar structures in physiological medium. Aggregation alters the sequence of amino acids in morphogenic peptides that interact with cell surface receptors thus affecting osteogenic activity of the peptide. Aggregation and micelle formation can dramatically reduce the active concentration of morphogenic peptides with many-fold increase in peptide concentration in physiological medium. Other factors that affect bioactivity are the non

  14. The Role of Feedback in the Formation of Morphogen Territories

    PubMed Central

    Syed, Adeela; Theisen, Heidi; Lukacsovich, Tamas; Naghibi, Mehrangiz; Marsh, Lawrence J.; Wan, Fred; Nie, Qing

    2009-01-01

    In this paper, we consider a mathematical model for the formation of spatial morphogen territories of two key morphogens: Wingless (Wg) and Decapentaplegic (DPP), involved in leg development of Drosophila. We define a gene regulatory network (GRN) that utilizes auto-activation and cross inhibition (modeled by Hill equations) to establish and maintain stable boundaries of gene expression. By computational analysis we find that in the presence of a general activator, neither auto-activation, nor cross inhibition alone are sufficient to maintain stable sharp boundaries of morphogen production in the leg disc. The minimal requirements for a self-organizing system are a coupled system of two morphogens in-which the auto-activation and cross-inhibition have Hill coefficients strictly greater than one. In addition, the GRN modeled here describes the regenerative responses to genetic manipulations of positional identity in the leg disc. PMID:18613734

  15. Chlorpyrifos and chlorpyrifos-oxon inhibit axonal growth by interfering with the morphogenic activity of acetylcholinesterase

    SciTech Connect

    Yang Dongren; Howard, Angela; Bruun, Donald; Ajua-Alemanj, Mispa; Pickart, Cecile; Lein, Pamela J.

    2008-04-01

    A primary role of acetylcholinesterase (AChE) is regulation of cholinergic neurotransmission by hydrolysis of synaptic acetylcholine. In the developing nervous system, however, AChE also functions as a morphogenic factor to promote axonal growth. This raises the question of whether organophosphorus pesticides (OPs) that are known to selectively bind to and inactivate the enzymatic function of AChE also interfere with its morphogenic function to perturb axonogenesis. To test this hypothesis, we exposed primary cultures of sensory neurons derived from embryonic rat dorsal root ganglia (DRG) to chlorpyrifos (CPF) or its oxon metabolite (CPFO). Both OPs significantly decreased axonal length at concentrations that had no effect on cell viability, protein synthesis or the enzymatic activity of AChE. Comparative analyses of the effects of CPF and CPFO on axonal growth in DRG neurons cultured from AChE nullizygous (AChE{sup -/-}) versus wild type (AChE{sup +/+}) mice indicated that while these OPs inhibited axonal growth in AChE{sup +/+} DRG neurons, they had no effect on axonal growth in AChE{sup -/-} DRG neurons. However, transfection of AChE{sup -/-} DRG neurons with cDNA encoding full-length AChE restored the wild type response to the axon inhibitory effects of OPs. These data indicate that inhibition of axonal growth by OPs requires AChE, but the mechanism involves inhibition of the morphogenic rather than enzymatic activity of AChE. These findings suggest a novel mechanism for explaining not only the functional deficits observed in children and animals following developmental exposure to OPs, but also the increased vulnerability of the developing nervous system to OPs.

  16. Chlorpyrifos and Chlorpyrifos-Oxon Inhibit Axonal Growth by Interfering with the Morphogenic Activity of Acetylcholinesterase

    PubMed Central

    Yang, Dongren; Howard, Angela; Bruun, Donald; Ajua-Alemanj, Mispa; Pickart, Cecile; Lein, Pamela J.

    2008-01-01

    A primary role of acetylcholinesterase (AChE) is regulation of cholinergic neurotransmission by hydrolysis of synaptic acetylcholine. In the developing nervous system, however, AChE also functions as a morphogenic factor to promote axonal growth. This raises the question of whether organophosphorus pesticides (OPs) that are known to selectively bind to and inactivate the enzymatic function of AChE also interfere with its morphogenic function to perturb axonogenesis. To test this hypothesis, we exposed primary cultures of sensory neurons derived from embryonic rat dorsal root ganglia (DRG) to chlorpyrifos (CPF) or its oxon metabolite (CPFO). Both OPs significantly decreased axonal length at concentrations that had no effect on cell viability, protein synthesis or the enzymatic activity of AChE. Comparative analyses of the effects of CPF and CPFO on axonal growth in DRG neurons cultured from AChE nullizygous (AChE−/−) versus wildtype (AChE+/+) mice indicated that while these OPs inhibited axonal growth in AChE+/+ DRG neurons, they had no effect on axonal growth in AChE−/− DRG neurons. However, transfection of AChE−/− DRG neurons with cDNA encoding full-length AChE restored the wildtype response to the axon inhibitory effects of OPs. These data indicate that inhibition of axonal growth by OPs requires AChE, but the mechanism involves inhibition of the morphogenic rather than enzymatic activity of AChE. These findings suggest a novel mechanism for explaining not only the functional deficits observed in children and animals following developmental exposure to OPs, but also the increased vulnerability of the developing nervous system to OPs. PMID:18076960

  17. Regeneration of Articular Cartilage Surface: Morphogens, Cells, and Extracellular Matrix Scaffolds.

    PubMed

    Sakata, Ryosuke; Iwakura, Takashi; Reddi, A Hari

    2015-10-01

    The articular cartilage is a well-organized tissue for smooth and friction-free joint movement for locomotion in animals and humans. Adult articular cartilage has a very low self-regeneration capacity due to its avascular nature. The regeneration of articular cartilage surface is critical to prevent the progression to osteoarthritis (OA). Although various joint resurfacing procedures in experimental articular cartilage defects have been developed, no standardized clinical protocol has yet been established. The three critical ingredients for tissue regeneration are morphogens and growth factors, cells, and scaffolds. The concepts based on the regeneration triad have been extensively investigated in animal models. However, these studies in animal models have demonstrated variable results and outcomes. An optimal animal model must precisely mimic and model the sequence of events in articular cartilage regeneration in human. In this article, the progress and remaining challenges in articular cartilage regeneration in animal models are reviewed. The role of individual morphogens and growth factors in cartilage regeneration has been investigated. In normal articular cartilage homeostasis, morphogens and growth factors function sequentially in tissue regeneration. Mesenchymal stem cell-based repair of articular cartilage defects, performed with or without various growth factors and scaffolds, has been widely attempted in animal models. Stem cells, including embryonic and adult stem cells and induced pluripotent stem cells, have also been reported as attractive cell sources for articular cartilage surface regeneration. Several studies with regard to scaffolds have been advanced, including recent investigations based on nanomaterials, functional mechanocompatible scaffolds, multilayered scaffolds, and extracellular matrix scaffolds for articular cartilage surface regeneration. Continuous refinement of animal models in chondral and osteochondral defects provide opportunities

  18. Read-Out of Dynamic Morphogen Gradients on Growing Domains

    PubMed Central

    Fried, Patrick; Iber, Dagmar

    2015-01-01

    Quantitative data from the Drosophila wing imaginal disc reveals that the amplitude of the Decapentaplegic (Dpp) morphogen gradient increases continuously. It is an open question how cells can determine their relative position within a domain based on a continuously increasing gradient. Here we show that pre-steady state diffusion-based dispersal of morphogens results in a zone within the growing domain where the concentration remains constant over the patterning period. The position of the zone that is predicted based on quantitative data for the Dpp morphogen corresponds to where the Dpp-dependent gene expression boundaries of spalt (sal) and daughters against dpp (dad) emerge. The model also suggests that genes that are scaling and are expressed at lateral positions are either under the control of a different read-out mechanism or under the control of a different morphogen. The patterning mechanism explains the extraordinary robustness that is observed for variations in Dpp production, and offers an explanation for the dual role of Dpp in controlling patterning and growth. Pre-steady-state dynamics are pervasive in morphogen-controlled systems, thus making this a probable general mechanism for the scaled read-out of morphogen gradients in growing developmental systems. PMID:26599604

  19. Nodal-mediated epigenesis requires dynamin-mediated endocytosis

    PubMed Central

    Ertl, Robin P.; Robertson, Anthony J.; Saunders, Diane; Coffman, James A.

    2011-01-01

    Nodal proteins are diffusible morphogens that drive pattern formation via short-range feedback activation coupled to long-range Lefty-mediated inhibition. In the sea urchin embryo, specification of the secondary (oral-aboral) axis occurs via zygotic expression of nodal, which is localized to the prospective oral ectoderm at early blastula stage. In mid-blastula stage embryos treated with low micromolar nickel or zinc, nodal expression expands progressively beyond the confines of this localized domain to encompass the entire equatorial circumference of the embryo, producing radialized embryos lacking an oral-aboral axis. RNAseq analysis of embryos treated with nickel, zinc or cadmium (which does not radialize embryos) showed that several genes involved in endocytosis were similarly perturbed by nickel and zinc but not cadmium. Inhibiting dynamin, a GTPase required for receptor-mediated endocytosis, phenocopies the effects of nickel and zinc, suggesting that dynamin-mediated endocytosis is required as a sink to limit the range of Nodal signaling. PMID:21337468

  20. Elsevier Trophoblast Research Award lecture: The multifaceted role of Nodal signaling during mammalian reproduction.

    PubMed

    Park, C B; Dufort, D

    2011-03-01

    Nodal, a secreted signaling protein in the transforming growth factor-beta (TGF-β) superfamily, has established roles in vertebrate development. However, components of the Nodal signaling pathway are also expressed at the maternal-fetal interface and have been implicated in many processes of mammalian reproduction. Emerging evidence indicates that Nodal and its extracellular inhibitor Lefty are expressed in the uterus and complex interactions between the two proteins mediate menstruation, decidualization and embryo implantation. Furthermore, several studies have shown that Nodal from both fetal and maternal sources may regulate trophoblast cell fate and facilitate placentation as both embryonic and uterine-specific Nodal knockout mouse strains exhibit disrupted placenta morphology. Here we review the established and prospective roles of Nodal signaling in facilitating successful pregnancy, including recent evidence supporting a potential link to parturition and preterm birth. PMID:21195476

  1. Development of morphogen gradient: The role of dimension and discreteness

    SciTech Connect

    Teimouri, Hamid; Kolomeisky, Anatoly B.

    2014-02-28

    The fundamental processes of biological development are governed by multiple signaling molecules that create non-uniform concentration profiles known as morphogen gradients. It is widely believed that the establishment of morphogen gradients is a result of complex processes that involve diffusion and degradation of locally produced signaling molecules. We developed a multi-dimensional discrete-state stochastic approach for investigating the corresponding reaction-diffusion models. It provided a full analytical description for stationary profiles and for important dynamic properties such as local accumulation times, variances, and mean first-passage times. The role of discreteness in developing of morphogen gradients is analyzed by comparing with available continuum descriptions. It is found that the continuum models prediction about multiple time scales near the source region in two-dimensional and three-dimensional systems is not supported in our analysis. Using ideas that view the degradation process as an effective potential, the effect of dimensionality on establishment of morphogen gradients is also discussed. In addition, we investigated how these reaction-diffusion processes are modified with changing the size of the source region.

  2. Morphogengineering roots: comparing mechanisms of morphogen gradient formation

    PubMed Central

    2012-01-01

    Background In developmental biology, there has been a recent focus on the robustness of morphogen gradients as possible providers of positional information. It was shown that functional morphogen gradients present strong biophysical constraints and lack of robustness to noise. Here we explore how the details of the mechanism which underlies the generation of a morphogen gradient can influence those properties. Results We contrast three gradient-generating mechanisms, (i) a source-decay mechanism; and (ii) a unidirectional transport mechanism; and (iii) a so-called reflux-loop mechanism. Focusing on the dynamics of the phytohormone auxin in the root, we show that only the reflux-loop mechanism can generate a gradient that would be adequate to supply functional positional information for the Arabidopsis root, for biophysically reasonable kinetic parameters. Conclusions We argue that traits that differ in spatial and temporal time-scales can impose complex selective pressures on the mechanism of morphogen gradient formation used for the development of the particular organism. PMID:22583698

  3. Transforming Growth Factor {beta} Can Stimulate Smad1 Phosphorylation Independently of Bone Morphogenic Protein Receptors.

    PubMed

    Wrighton, Katharine H; Lin, Xia; Yu, Paul B; Feng, Xin-Hua

    2009-04-10

    Transforming growth factor-beta (TGFbeta) superfamily ligands control a diverse set of cellular processes by activating type I and type II serine-threonine receptor kinases. Canonical TGFbeta signaling is mediated via the TbetaRI/ALK5 type I receptor that phosphorylates Smad2 and Smad3 in their SXS motif to facilitate their activation and subsequent role in transcriptional regulation. Canonical bone morphogenic protein (BMP) signaling is mediated via the ALK1/2/3/6 type I receptors that phosphorylate Smad1, Smad5, and Smad8 in their SXS motif. However, studies in endothelial cells have shown that TGFbeta can also lead to the phosphorylation of Smad1, dependent on ALK1 receptor activity. Here we present data showing that TGFbeta can significantly induce Smad1 phosphorylation in several non-endothelial cell lineages. Additionally, by using chemical inhibitors specific for the TGFbeta/activin/nodal (ALK4/5/7) and BMP (ALK1/2/3/6) type I receptors, we show that in some cell types TGFbeta induces Smad1 phosphorylation independently of the BMP type I receptors. Thus, TGFbeta-mediated Smad1 phosphorylation appears to occur via different receptor complexes in a cell type-specific manner. PMID:19224917

  4. Morphogenic role for acetylcholinesterase in axonal outgrowth during neural development.

    PubMed Central

    Bigbee, J W; Sharma, K V; Gupta, J J; Dupree, J L

    1999-01-01

    Acetylcholinesterase (AChE) is the enzyme that hydrolyzes the neurotransmitter acetylcholine at cholinergic synapses and neuromuscular junctions. However, results from our laboratory and others indicate that AChE has an extrasynaptic, noncholinergic role during neural development. This article is a review of our findings demonstrating the morphogenic role of AChE, using a neuronal cell culture model. We also discuss how these data suggest that AChE has a cell adhesive function during neural development. These results could have additional significance as AChE is the target enzyme of agricultural organophosphate and carbamate pesticides as well as the commonly used household organophosphate chlorpyrifos (Dursban). Prenatal exposure to these agents could have adverse effects on neural development by interfering with the morphogenic function of AChE. Images Figure 1 Figure 2 Figure 4 Figure 5 Figure 6 Figure 7 PMID:10229710

  5. Nodal Promotes Glioblastoma Cell Growth

    PubMed Central

    De Silva, Tanya; Ye, Gang; Liang, Yao-Yun; Fu, Guodong; Xu, Guoxiong; Peng, Chun

    2012-01-01

    Nodal is a member of the transforming growth factor-β (TGF-β) superfamily that plays critical roles during embryogenesis. Recent studies in ovarian, breast, prostate, and skin cancer cells suggest that Nodal also regulates cell proliferation, apoptosis, and invasion in cancer cells. However, it appears to exert both tumor-suppressing and tumor-promoting effects, depending on the cell type. To further understand the role of Nodal in tumorigenesis, we examined the effect of Nodal in glioblastoma cell growth and spheroid formation using U87 cell line. Treatment of U87 with recombinant Nodal significantly increased U87 cell growth. In U87 cells stably transfected with the plasmid encoding Nodal, Smad2 phosphorylation was strongly induced and cell growth was significantly enhanced. Overexpression of Nodal also resulted in tight spheroid formation. On the other hand, the cells stably transfected with Nodal siRNA formed loose spheroids. Nodal is known to signal through activin receptor-like kinase 4 (ALK4) and ALK7 and the Smad2/3 pathway. To determine which receptor and Smad mediate the growth promoting effect of Nodal, we transfected siRNAs targeting ALK4, ALK7, Smad2, or Smad3 into Nodal-overexpressing cells and observed that cell growth was significantly inhibited by ALK4, ALK7, and Smad3 siRNAs. Taken together, these findings suggest that Nodal may have tumor-promoting effects on glioblastoma cells and these effects are mediated by ALK4, ALK7, and Smad3. PMID:22645523

  6. ProNodal acts via FGFR3 to govern duration of Shh expression in the prechordal mesoderm.

    PubMed

    Ellis, Pamela S; Burbridge, Sarah; Soubes, Sandrine; Ohyama, Kyoji; Ben-Haim, Nadav; Chen, Canhe; Dale, Kim; Shen, Michael M; Constam, Daniel; Placzek, Marysia

    2015-11-15

    The secreted glycoprotein sonic hedgehog (Shh) is expressed in the prechordal mesoderm, where it plays a crucial role in induction and patterning of the ventral forebrain. Currently little is known about how Shh is regulated in prechordal tissue. Here we show that in the embryonic chick, Shh is expressed transiently in prechordal mesoderm, and is governed by unprocessed Nodal. Exposure of prechordal mesoderm microcultures to Nodal-conditioned medium, the Nodal inhibitor CerS, or to an ALK4/5/7 inhibitor reveals that Nodal is required to maintain both Shh and Gsc expression, but whereas Gsc is largely maintained through canonical signalling, Nodal signals through a non-canonical route to maintain Shh. Further, Shh expression can be maintained by a recombinant Nodal cleavage mutant, proNodal, but not by purified mature Nodal. A number of lines of evidence suggest that proNodal acts via FGFR3. ProNodal and FGFR3 co-immunoprecipitate and proNodal increases FGFR3 tyrosine phosphorylation. In microcultures, soluble FGFR3 abolishes Shh without affecting Gsc expression. Further, prechordal mesoderm cells in which Fgfr3 expression is reduced by Fgfr3 siRNA fail to bind to proNodal. Finally, targeted electroporation of Fgfr3 siRNA to prechordal mesoderm in vivo results in premature Shh downregulation without affecting Gsc. We report an inverse correlation between proNodal-FGFR3 signalling and pSmad1/5/8, and show that proNodal-FGFR3 signalling antagonises BMP-mediated pSmad1/5/8 signalling, which is poised to downregulate Shh. Our studies suggest that proNodal/FGFR3 signalling governs Shh duration by repressing canonical BMP signalling, and that local BMPs rapidly silence Shh once endogenous Nodal-FGFR3 signalling is downregulated. PMID:26417042

  7. ProNodal acts via FGFR3 to govern duration of Shh expression in the prechordal mesoderm

    PubMed Central

    Ellis, Pamela S.; Burbridge, Sarah; Soubes, Sandrine; Ohyama, Kyoji; Ben-Haim, Nadav; Chen, Canhe; Dale, Kim; Shen, Michael M.; Constam, Daniel; Placzek, Marysia

    2015-01-01

    The secreted glycoprotein sonic hedgehog (Shh) is expressed in the prechordal mesoderm, where it plays a crucial role in induction and patterning of the ventral forebrain. Currently little is known about how Shh is regulated in prechordal tissue. Here we show that in the embryonic chick, Shh is expressed transiently in prechordal mesoderm, and is governed by unprocessed Nodal. Exposure of prechordal mesoderm microcultures to Nodal-conditioned medium, the Nodal inhibitor CerS, or to an ALK4/5/7 inhibitor reveals that Nodal is required to maintain both Shh and Gsc expression, but whereas Gsc is largely maintained through canonical signalling, Nodal signals through a non-canonical route to maintain Shh. Further, Shh expression can be maintained by a recombinant Nodal cleavage mutant, proNodal, but not by purified mature Nodal. A number of lines of evidence suggest that proNodal acts via FGFR3. ProNodal and FGFR3 co-immunoprecipitate and proNodal increases FGFR3 tyrosine phosphorylation. In microcultures, soluble FGFR3 abolishes Shh without affecting Gsc expression. Further, prechordal mesoderm cells in which Fgfr3 expression is reduced by Fgfr3 siRNA fail to bind to proNodal. Finally, targeted electroporation of Fgfr3 siRNA to prechordal mesoderm in vivo results in premature Shh downregulation without affecting Gsc. We report an inverse correlation between proNodal-FGFR3 signalling and pSmad1/5/8, and show that proNodal-FGFR3 signalling antagonises BMP-mediated pSmad1/5/8 signalling, which is poised to downregulate Shh. Our studies suggest that proNodal/FGFR3 signalling governs Shh duration by repressing canonical BMP signalling, and that local BMPs rapidly silence Shh once endogenous Nodal-FGFR3 signalling is downregulated. PMID:26417042

  8. Nodal promotes invasive phenotypes via a Mitogen Activated Protein Kinase-dependent pathway

    PubMed Central

    Quail, DF; Zhang, G; Findlay, SD; Hess, DA; Postovit, LM

    2016-01-01

    The progression of cancer from localized to invasive disease is requisite for metastasis, and is often characterized by epithelial-to-mesenchymal transition (EMT) and alterations in cellular adhesion and migration. Studies have shown that this transition is associated with an up-regulation of embryonic stem cell-associated genes, resulting in a dedifferentiated phenotype and poor patient prognosis. Nodal is an embryonic factor that plays a critical role in promoting early invasive events during development. Nodal is silenced as stem cells differentiate; however, it re-emerges in adult life during placentation and mammary gland development, and is aberrantly expressed in many cancers. Here, we show that Nodal over-expression, in poorly-invasive breast cancer and choriocarcinoma cells, causes increased invasion and migration in vitro. Furthermore, we show that Nodal over-expression in these epithelial cancer types induces an EMT-like event concomitant with the internalization of E-Cadherin. This ability of Nodal to promote cellular invasion and EMT-like phenomena is dependent upon the phosphorylation of ERK1/2. Since Nodal normally signals through SMADs, these findings lend insight into an alternative pathway that is hijacked by this protein in cancer. To evaluate the clinical implications of our results, we show that Nodal inhibition reduces liver tumor burden in a model of spontaneous breast cancer metastasis in vivo, and that Nodal loss-of-function in aggressive breast cancer lines results in a decrease in invasive phenotypes. Our results demonstrate that Nodal is involved in promoting invasion in multiple cellular contexts, and that Nodal inhibition may be useful as a therapeutic target for patients with progressive disease. PMID:23334323

  9. Quantifying stretch and secretion in the embryonic lung: Implications for morphogenesis.

    PubMed

    George, Uduak Z; Bokka, Kishore K; Warburton, David; Lubkin, Sharon R

    2015-11-01

    Branching in the embryonic lung is controlled by a variety of morphogens. Mechanics is also believed to play a significant role in lung branching. The relative roles and interactions of these two broad factors are challenging to determine. We considered three hypotheses for explaining why tracheal occlusion triples branching with no overall increase in size. Both hypotheses are based on tracheal occlusion blocking the exit of secretions. (H1) Increased lumen pressure stretches tissues; stretch receptors at shoulders of growing tips increase local rate of branching. (H2) Blocking exit of secretions blocks advective transport of morphogens, leading to (H2a) increased overall concentration of morphogens or (H2b) increased flux of morphogens at specific locations. We constructed and analyzed computational models of tissue stretch and solute transport in a 3D lung geometry. Observed tissue stresses and stretches were predominantly in locations unrelated to subsequent branch locations, suggesting that tissue stretch (H1) is not the mechanism of enhancement of branching. Morphogen concentration in the mesenchyme (H2a) increased with tracheal occlusion, consistent with previously reported results. Morphogen flux at the epithelial surface (H2b) completely changed its distribution pattern when the trachea was occluded, tripling the number of locations at which it was elevated. Our results are consistent with the hypothesis that tracheal occlusion blocks outflow of secretions, leading to a higher number of high-flux locations at branching tips, in turn leading to a large increase in number of branching locations. PMID:26189687

  10. Topological semimetals and nodal superconductors

    NASA Astrophysics Data System (ADS)

    Chang, Po-Yao

    Besides topological band insulators, which have a full bulk gap, there are also gapless phases of matter that belong to the broad class of topological materials, such as topological semimetals and nodal superconductors. We systematically study these gapless topological phases described by the Bloch and Bogoliubov-de Gennes Hamiltonians. We discuss a generalized bulk-boundary correspondence, which relates the topological properties in the bulk of gapless topological phases and the protected zero-energy states at the boundary. We study examples of gapless topological phases, focusing in particular on nodal superconductors, such as nodal noncentrosymmetric superconductors (NCSs). We compute the surface density of states of nodal NCSs and interpret experimental measurements of surface states. In addition, we investigate Majorana vortex-bound states in both nodal and fully gapped NCSs using numerical and analytical methods. We show that different topological properties of the bulk Bogoliubov-quasiparticle wave functions reflect themselves in different types of zero-energy vortex-bound states. In particular, in the case of NCSs with tetragonal point-group symmetry, we find that the stability of these Majorana zero modes is guaranteed by a combination of reflection, time-reversal, and particle-hole symmetries. Finally, by using K-theory arguments and a dimensional reduction procedure from higher-dimensional topological insulators and superconductors, we derive a classification of topologically stable Fermi surfaces in semimetals and nodal lines in superconductors.

  11. Activin/Nodal signalling before implantation: setting the stage for embryo patterning

    PubMed Central

    Papanayotou, Costis; Collignon, Jérôme

    2014-01-01

    Activins and Nodal are members of the transforming growth factor beta (TGF-β) family of growth factors. Their Smad2/3-dependent signalling pathway is well known for its implication in the patterning of the embryo after implantation. Although this pathway is active early on at preimplantation stages, embryonic phenotypes for loss-of-function mutations of prominent components of the pathway are not detected before implantation. It is only fairly recently that an understanding of the role of the Activin/Nodal signalling pathway at these stages has started to emerge, notably from studies detailing how it controls the expression of target genes in embryonic stem cells. We review here what is currently known of the TGF-β-related ligands that determine the activity of Activin/Nodal signalling at preimplantation stages, and recent advances in the elucidation of the Smad2/3-dependent mechanisms underlying developmental progression. PMID:25349448

  12. Role of morphogens in neural crest cell determination.

    PubMed

    Jones, Natalie C; Trainor, Paul A

    2005-09-15

    The neural crest is a transient, migratory cell population found in all vertebrate embryos that generate a diverse range of cell and tissue derivatives including, but not limited, to the neurons and glia of the peripheral nervous system, smooth muscle, connective tissue, melanocytes, craniofacial cartilage, and bone. Over the past few years, many studies have provided tremendous insights into understanding the mechanisms regulating the induction and migration of neural crest cell development. This review highlights the surprising and perhaps unexpected roles for morphogens in these distinct processes. A comparison of studies performed in several different vertebrates emphasizes the requirement for coordination between multiple signaling pathways in the induction and migration of neural crest cells in the developing embryo. PMID:16041760

  13. Theoretical analysis of degradation mechanisms in the formation of morphogen gradients

    NASA Astrophysics Data System (ADS)

    Bozorgui, Behnaz; Teimouri, Hamid; Kolomeisky, Anatoly B.

    2015-07-01

    Fundamental biological processes of development of tissues and organs in multicellular organisms are governed by various signaling molecules, which are called morphogens. It is known that spatial and temporal variations in the concentration profiles of signaling molecules, which are frequently referred as morphogen gradients, lead to a cell differentiation via activating specific genes in a concentration-dependent manner. It is widely accepted that the establishment of the morphogen gradients involves multiple biochemical reactions and diffusion processes. One of the critical elements in the formation of morphogen gradients is a degradation of signaling molecules. We develop a new theoretical approach that provides a comprehensive description of the degradation mechanisms. It is based on the idea that the degradation works as an effective potential that drives the signaling molecules away from the source region. Utilizing the method of first-passage processes, the dynamics of the formation of morphogen gradients for various degradation mechanisms is explicitly evaluated. It is found that linear degradation processes lead to a dynamic behavior specified by times to form the morphogen gradients that depend linearly on the distance from the source. This is because the effective potential due to the degradation is quite strong. At the same time, nonlinear degradation mechanisms yield a quadratic scaling in the morphogen gradients formation times since the effective potentials are much weaker. Physical-chemical explanations of these phenomena are presented.

  14. S6K is a morphogenic protein with a mechanism involving Filamin-A phosphorylation and phosphatidic acid binding

    PubMed Central

    Henkels, Karen M.; Mallets, Elizabeth R.; Dennis, Patrick B.; Gomez-Cambronero, Julian

    2015-01-01

    Change of cell shape in vivo plays many roles that are central to life itself, such as embryonic development, inflammation, wound healing, and pathologic processes such as cancer metastasis. Nonetheless, the spatiotemporal mechanisms that control the concerted regulation of cell shape remain understudied. Here, we show that ribosomal S6K, which is normally considered a protein involved in protein translation, is a morphogenic protein. Its presence in cells alters the overall organization of the cell surface and cell circularity [(4π × area)/(perimeter)2] from 0.47 ± 0.06 units in mock-treated cells to 0.09 ± 0.03 units in S6K-overexpressing macrophages causing stellation and arborization of cell shape. This effect was partially reversed in cells expressing a kinase-inactive S6K mutant and was fully reversed in cells silenced with small interference RNA. Equally important is that S6K is itself regulated by phospholipids, specifically phosphatidic acid, whereby 300 nM 1,2-dioleoyl-sn-glycero-3-phosphate (DOPA), but not the control 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), binds directly to S6K and causes an ∼2.9-fold increase in S6K catalytic activity. This was followed by an increase in Filamin A (FLNA) functionality as measured by phospho-FLNA (S2152) expression and by a subsequent elevation of actin nucleation. This reliance of S6K on phosphatidic acid (PA), a curvature-inducing phospholipid, explained the extra-large perimeter of cells that overexpressed S6K. Furthermore, the diversity of the response to S6K in several unrelated cell types (fibroblasts, leukocytes, and invasive cancer cells) that we report here indicates the existence of an underlying common mechanism in mammalian cells. This new signaling set, PA-S6K-FLNA-actin, sheds light for the first time into the morphogenic pathway of cytoskeletal structures that are crucial for adhesion and cell locomotion during inflammation and metastasis.—Henkels, K. M., Mallets, E. R., Dennis, P. B

  15. Systems control of BMP morphogen flow in vertebrate embryos

    PubMed Central

    Plouhinec, Jean-Louis; Zakin, Lise; De Robertis, Edward M.

    2011-01-01

    Embryonic morphogenetic programs coordinate cell behavior to ensure robust pattern formation. Having identified components of those programs by molecular genetics, developmental biology is now borrowing concepts and tools from systems biology to decode their regulatory logic. Dorsal-ventral (D-V) patterning of the frog gastrula by Bone Morphogenetic Proteins (BMPs) is one of the best studied examples of a self-regulating embryonic patterning system. Embryological analyses and mathematical modeling are revealing that the BMP activity gradient is maintained by a directed flow of BMP ligands towards the ventral side. Pattern robustness is ensured through feedback control of the levels of extracellular BMP pathway modulators that adjust the flow to the dimensions of the embryonic field. PMID:21937218

  16. Effects of Bone Morphogenic Proteins on Engineered Cartilage

    NASA Technical Reports Server (NTRS)

    Gooch, Keith, J.; Blunk, Torsten; Courter, Donald L.; Sieminski, Alisha; Vunjak-Novakovic, Gordana; Freed, Lisa E.

    2007-01-01

    A report describes experiments on the effects of bone morphogenic proteins (BMPs) on engineered cartilage grown in vitro. In the experiments, bovine calf articular chondrocytes were seeded onto biodegradable polyglycolic acid scaffolds and cultured in, variously, a control medium or a medium supplemented with BMP-2, BMP-12, or BMP-13 in various concentrations. Under all conditions investigated, cell-polymer constructs cultivated for 4 weeks macroscopically and histologically resembled native cartilage. At a concentration of 100 ng/mL, BMP-2, BMP-12, or BMP-13 caused (1) total masses of the constructs to exceed those of the controls by 121, 80, or 62 percent, respectively; (2) weight percentages of glycosaminoglycans in the constructs to increase by 27, 18, or 15, respectively; and (3) total collagen contents of the constructs to decrease to 63, 89, or 83 percent of the control values, respectively. BMP-2, but not BMP-12 or BMP-13, promoted chondrocyte hypertrophy. These observations were interpreted as suggesting that the three BMPs increase the growth rates and modulate the compositions of engineered cartilage. It was also concluded that in vitro engineered cartilage is a suitable system for studying effects of BMPs on chondrogenesis in a well-defined environment.

  17. Bone morphogenic protein-4 expression in vascular lesions of calciphylaxis.

    PubMed

    Griethe, Wanja; Schmitt, Roland; Jurgensen, Jan Steffen; Bachmann, Sebastian; Eckardt, Kai-Uwe; Schindler, Ralf

    2003-01-01

    Calciphylaxis is characterized by an extensive media-calcification of cutaneous and subcutaneous arterioles and capillaries. Recent studies have provided evidence that vascular calcification is a process with similarities to bone metabolism. Bone morphogenic protein-4 (BMP-4) is physiologically involved in bone development and repair. The presence of BMP-4 in atherosclerosis and in sclerotic heart valves led us to suggest that BMP-4 is also involved in calciphylaxis. A 47-year-old male patient developed end-stage renal failure due to chronic glomerulonephritis. He has had two kidney transplants with an immunosuppressive regimen consisting of cyclosporine A and steroids. He was admitted to our hospital because of an increase in serum creatinine (Cr) and he subsequently developed progressive dermal ulcerations. A skin biopsy led to the diagnosis of calciphylaxis. Immunohistochemistry for BMP-4 of a skin specimen from our patient showed strong cytoplasmic immunoreactivity of intradermal cells with clear spatial association to arterioles and hair follicles. Whereas there are identified inhibitors and promoters of vascular calcification, the presence of BMP-4 has not been demonstrated in calcific uremic arteriolopathy. In contrast to atherosclerosis, BMP-4 in calciphylaxis cannot be found in vascular media, but in intradermal cells at the border of arterioles and hair follicles. Therefore, in calciphylaxis BMP-4 can play the role of a cytokine, a growth factor or a media-calcification promoter. PMID:14733421

  18. Temporal control of self-organized pattern formation without morphogen gradients in bacteria

    PubMed Central

    Payne, Stephen; Li, Bochong; Cao, Yangxiaolu; Schaeffer, David; Ryser, Marc D; You, Lingchong

    2013-01-01

    Diverse mechanisms have been proposed to explain biological pattern formation. Regardless of their specific molecular interactions, the majority of these mechanisms require morphogen gradients as the spatial cue, which are either predefined or generated as a part of the patterning process. However, using Escherichia coli programmed by a synthetic gene circuit, we demonstrate here the generation of robust, self-organized ring patterns of gene expression in the absence of an apparent morphogen gradient. Instead of being a spatial cue, the morphogen serves as a timing cue to trigger the formation and maintenance of the ring patterns. The timing mechanism enables the system to sense the domain size of the environment and generate patterns that scale accordingly. Our work defines a novel mechanism of pattern formation that has implications for understanding natural developmental processes. PMID:24104480

  19. A New Stabilized Nodal Integration Approach

    SciTech Connect

    Puso, M; Zywicz, E; Chen, J S

    2006-02-08

    A new stabilized nodal integration scheme is proposed and implemented. In this work, focus is on the natural neighbor meshless interpolation schemes. The approach is a modification of the stabilized conforming nodal integration (SCNI) scheme and is shown to perform well in several benchmark problems.

  20. Embryonic hematopoiesis.

    PubMed

    Golub, Rachel; Cumano, Ana

    2013-12-01

    Blood cells are continually produced from a pool of progenitors that derive from hematopoietic stem cells (HSCs). In vertebrates, the hematopoietic system develops from two distinct waves or generation of precursors. The first wave occurs in the yolk sac, in mammals or equivalent embryonic structure, and produces nucleated primitive erythrocytes that provide the embryo with the first oxygen transporter and are, therefore, essential for the viability of the embryo. The yolk sac also produces myeloid cells that migrate to the central nervous system and to the skin to form the microglia and skin specific macrophages, the Langerhans cells. The second wave occurs in the dorsal aorta and produces multipotential hematopoietic progenitors. These cells are generated once in the lifetime from mesoderm derivatives closely related to endothelial cells, during a short period of embryonic development. Newly generated cells do not reconstitute the hematopoietic compartment of conventional recipients; therefore, they are designated as immature or pre-HSCs. They undergo maturation into adult HSCs in the aorta or in the fetal liver accompanied by the expression of MHC class I, CD45, CD150, Sca-1 and the absence of CD48. Differentiation of HSCs first occurs in the fetal liver, giving rise to mature blood cells. HSCs also expand in the fetal liver, and in a short time period (four days in the mouse embryo), they increase over 40-fold. HSCs and progenitor cells exit the fetal liver and colonize the spleen, where differentiation to the myeloid lineage and particular lymphoid subsets is favored. PMID:24041595

  1. An ultrastructural study of sinuatrial node cells in the embryonic rat heart.

    PubMed Central

    Domenech-Mateu, J M; Boya-Vegué, J

    1975-01-01

    Sinuatrial nodal tissue, obtained from rat embryos of 15, 16 and 17 days, was examined with the electron microscope. Embryonic nodal cells were generally similar to adult cells except that (1) they showed thick prolongations of the cytoplasm which insinuated themselves between neighbouring cells; (2) they possessed osmiophilic granules with a predeliction for the region of the Golgi complex; (3) they exhibited a lesser and variable degree of pinocytosis. Images Fig. 1 Fig. 2 Fig. 3 PMID:1133091

  2. Heterogeneous treatment in the variational nodal method

    SciTech Connect

    Fanning, T.H.; Palmiotti, G.

    1995-06-01

    The variational nodal transport method is reduced to its diffusion form and generalized for the treatment of heterogeneous nodes while maintaining nodal balances. Adapting variational methods to heterogeneous nodes requires the ability to integrate over a node with discontinuous cross sections. In this work, integrals are evaluated using composite gaussian quadrature rules, which permit accurate integration while minimizing computing time. Allowing structure within a nodal solution scheme avoids some of the necessity of cross section homogenization, and more accurately defines the intra-nodal flux shape. Ideally, any desired heterogeneity can be constructed within the node; but in reality, the finite set of basis functions limits the practical resolution to which fine detail can be defined within the node. Preliminary comparison tests show that the heterogeneous variational nodal method provides satisfactory results even if some improvements are needed for very difficult, configurations.

  3. Symmetry Breaking in a Model for Nodal Cilia

    NASA Astrophysics Data System (ADS)

    Brokaw, Charles J.

    2005-03-01

    Nodal cilia are very short cilia found in the embryonic node on the ventral surface of early mammalian embryos. They create a right to left fluid flow that is responsible for determining the normal asymmetry of the internal organs of the mammalian body. To do this, the distal end of the cilium must circle in a counterclockwise sense. Computer simulations with 3-dimensional models of flagella allow examination of 3-dimensional movements such as those of nodal cilia. 3-dimensional circling motions of short cilia can be achieved with velocity controlled models, in which dynein activity is regulated by sliding velocity. If dyneins on one outer doublet are controlled by the sliding velocity experienced by that doublet, the system is symmetric, and the 3-dimensional models can show either clockwise or counterclockwise circling. My computer simulations have examined two possible symmetry breaking mechanisms: 1) dyneins on doublet N are regulated by a mixture of the sliding velocities experienced by doublets N and N+1 (numbered in a clockwise direction, looking from the base). or 2) symmetry is broken by an off-axis force that produces a right-handed twist of the axoneme, consistent with observations that some dyneins can rotate their substrate microtubules in a clockwise direction.

  4. Stepwise renal lineage differentiation of mouse embryonic stem cells tracing in vivo development

    SciTech Connect

    Nishikawa, Masaki; Yanagawa, Naomi; Kojima, Nobuhiko; Yuri, Shunsuke; Hauser, Peter V.; Jo, Oak D.; Yanagawa, Norimoto

    2012-01-13

    Highlights: Black-Right-Pointing-Pointer We induced renal lineages from mESCs by following the in vivo developmental cues. Black-Right-Pointing-Pointer We induced nephrogenic intermediate mesoderm by stepwise addition of factors. Black-Right-Pointing-Pointer We induced two types of renal progenitor cells by reciprocal conditioned media. Black-Right-Pointing-Pointer We propose the potential role of CD24 for the enrichment of renal lineage cells. -- Abstract: The in vitro derivation of renal lineage progenitor cells is essential for renal cell therapy and regeneration. Despite extensive studies in the past, a protocol for renal lineage induction from embryonic stem cells remains unestablished. In this study, we aimed to induce renal lineages from mouse embryonic stem cells (mESC) by following in vivo developmental stages, i.e., the induction of mesoderm (Stage I), intermediate mesoderm (Stage II) and renal lineages (Stage III). For stage I induction, in accordance with known signaling pathways involved in mesoderm development in vivo, i.e., Nodal, bone morphogenic proteins (BMPs) and Wnt, we found that the sequential addition of three factors, i.e., Activin-A (A), a surrogate for Nodal signaling, during days 0-2, A plus BMP-4 (4) during days 2-4, and A4 plus lithium (L), a surrogate for Wnt signaling, during days 4-6, was most effective to induce the mesodermal marker, Brachyury. For stage II induction, the addition of retinoic acid (R) in the continuous presence of A4L during days 6-8 was most effective to induce nephrogenic intermediate mesodermal markers, such as Pax2 and Lim1. Under this condition, more than 30% of cells were stained positive for Pax2, and there was a concomitant decrease in the expression of non-mesodermal markers. For stage III induction, in resemblance to the reciprocal induction between ureteric bud (UB) and metanephric mesenchyme (MM) during kidney development, we found that the exposure to conditioned media derived from UB and MM cells was

  5. Cells change their sensitivity to an EGF morphogen gradient to control EGF-induced gene expression

    PubMed Central

    van Zon, Jeroen Sebastiaan; Kienle, Simone; Huelsz-Prince, Guizela; Barkoulas, Michalis; van Oudenaarden, Alexander

    2015-01-01

    How cells in developing organisms interpret the quantitative information contained in morphogen gradients is an open question. Here we address this question using a novel integrative approach that combines quantitative measurements of morphogen-induced gene expression at single-mRNA resolution with mathematical modelling of the induction process. We focus on the induction of Notch ligands by the LIN-3/EGF morphogen gradient during vulva induction in Caenorhabditis elegans. We show that LIN-3/EGF-induced Notch ligand expression is highly dynamic, exhibiting an abrupt transition from low to high expression. Similar transitions in Notch ligand expression are observed in two highly divergent wild C. elegans isolates. Mathematical modelling and experiments show that this transition is driven by a dynamic increase in the sensitivity of the induced cells to external LIN-3/EGF. Furthermore, this increase in sensitivity is independent of the presence of LIN-3/EGF. Our integrative approach might be useful to study induction by morphogen gradients in other systems. PMID:25958991

  6. Rapid differential transport of Nodal and Lefty on sulfated proteoglycan-rich extracellular matrix regulates left-right asymmetry in Xenopus

    PubMed Central

    Marjoram, Lindsay; Wright, Christopher

    2011-01-01

    The spatiotemporally dynamic distribution of instructive ligands within embryonic tissue, and their feedback antagonists, including inherent stabilities and rates of clearance, are affected by interactions with cell surfaces or extracellular matrix (ECM). Nodal (here, Xnr1 or Nodal1 in Xenopus) and Lefty interact in a cross-regulatory relationship in mesendoderm induction, and are the conserved instructors of left-right (LR) asymmetry in early somitogenesis stage embryos. By expressing Xnr1 and Lefty proproteins that produce mature functional epitope-tagged ligands in vivo, we found that ECM is a principal surface of Nodal and Lefty accumulation. We detected Lefty moving faster than Nodal, with evidence that intact sulfated proteoglycans in the ECM facilitate the remarkable long distance movement of Nodal. We propose that Nodal autoregulation substantially aided by rapid ligand transport underlies the anteriorward shift of Nodal expression in the left LPM (lateral plate mesoderm), and speculate that the higher levels of chondroitin-sulfate proteoglycan (CSPG) in more mature anterior regions provide directional transport cues. Immunodetection and biochemical analysis showed transfer of Lefty from left LPM to right LPM, providing direct evidence that left-side-derived Lefty is a significant influence in ensuring the continued suppression of right-sided expression of Nodal, maintaining unilateral expression of this conserved determinant of asymmetry. PMID:21205792

  7. Encoding of temporal signals by the TGF-β pathway and implications for embryonic patterning

    PubMed Central

    Sorre, Benoit; Warmflash, Aryeh; Brivanlou, Ali H.; Siggia, Eric D.

    2014-01-01

    Summary Genetics and biochemistry have defined the components and wiring of the signaling pathways that pattern the embryo. Among them, the TGF-β pathway has the potential to behave as a morphogen: invitro experiments have clearly established that it can dictate cell fate in a concentration dependent manner. How morphogens convey positional information in a developing embryo, where signal levels are changing with time, is less understood. Using integrated microfluidic cell culture and time-lapse microscopy, we demonstrate here that the speed of ligand presentation has a key and previously unexpected influence on TGF-β signaling outcomes. The response to a TGF-β concentration step is transient and adaptive, slowly increasing the ligand concentration diminishes the response and well-spaced pulses of ligand combine additively resulting in greater pathway output than with constant stimulation. Our results suggest that in an embryonic context, the speed of change of ligand concentration is an instructive signal for patterning. PMID:25065773

  8. Optical conductivity of nodal metals

    NASA Astrophysics Data System (ADS)

    Homes, C. C.; Gu, G. D.; Tu, J. J.; Li, J.; Akrap, A.

    2014-03-01

    Fermi liquid theory is remarkably successful in describing the transport and optical properties of metals; at frequencies higher than the scattering rate, the optical conductivity adopts the well-known power law behavior σ1(ω) ~ω-2 . We have observed an unusual non-Fermi liquid response σ1(ω) ~ω - 1 +/- 0 . 2 in the ground states of several quasi two-dimensional cuprate (optimally doped Bi2Sr2CaCu2O8+δ, optimally and underdoped YBa2Cu3O7-δ) and iron-based materials (AFe2As2, A = Ba, Ca) which undergo electronic or magnetic phase transitions resulting in dramatically reduced or nodal Fermi surfaces. The identification of an inverse (or fractional) power-law behavior in the residual optical conductivity now permits the removal of this contribution, revealing the direct transitions across the gap and allowing the nature of the electron-boson coupling to be probed. The non-Fermi liquid behavior in these systems may be the result of a common Fermi surface topology of Dirac cone-like features in the electronic dispersion. Supported by the DOE under Contract No. DE-AC02-98CH10886.

  9. Optical conductivity of nodal metals

    PubMed Central

    Homes, C. C.; Tu, J. J.; Li, J.; Gu, G. D.; Akrap, A.

    2013-01-01

    Fermi liquid theory is remarkably successful in describing the transport and optical properties of metals; at frequencies higher than the scattering rate, the optical conductivity adopts the well-known power law behavior σ1(ω) ∝ ω−2. We have observed an unusual non-Fermi liquid response σ1(ω) ∝ ω−1±0.2 in the ground states of several cuprate and iron-based materials which undergo electronic or magnetic phase transitions resulting in dramatically reduced or nodal Fermi surfaces. The identification of an inverse (or fractional) power-law behavior in the residual optical conductivity now permits the removal of this contribution, revealing the direct transitions across the gap and allowing the nature of the electron-boson coupling to be probed. The non-Fermi liquid behavior in these systems may be the result of a common Fermi surface topology of Dirac cone-like features in the electronic dispersion. PMID:24336241

  10. Nodal network generator for CAVE3

    NASA Technical Reports Server (NTRS)

    Palmieri, J. V.; Rathjen, K. A.

    1982-01-01

    A new extension of CAVE3 code was developed that automates the creation of a finite difference math model in digital form ready for input to the CAVE3 code. The new software, Nodal Network Generator, is broken into two segments. One segment generates the model geometry using a Tektronix Tablet Digitizer and the other generates the actual finite difference model and allows for graphic verification using Tektronix 4014 Graphic Scope. Use of the Nodal Network Generator is described.

  11. Coordinate Nodal and BMP inhibition directs Baf60c-dependent cardiomyocyte commitment

    PubMed Central

    Cai, Wenqing; Albini, Sonia; Wei, Ke; Willems, Erik; Guzzo, Rosa M.; Tsuda, Masanao; Giordani, Lorenzo; Spiering, Sean; Kurian, Leo; Yeo, Gene W.; Puri, Pier Lorenzo; Mercola, Mark

    2013-01-01

    A critical but molecularly uncharacterized step in heart formation and regeneration is the process that commits progenitor cells to differentiate into cardiomyocytes. Here, we show that the endoderm-derived dual Nodal/bone morphogenetic protein (BMP) antagonist Cerberus-1 (Cer1) in embryonic stem cell cultures orchestrates two signaling pathways that direct the SWI/SNF chromatin remodeling complex to cardiomyogenic loci in multipotent (KDR/Flk1+) progenitors, activating lineage-specific transcription. Transient inhibition of Nodal by Cer1 induces Brahma-associated factor 60c (Baf60c), one of three Baf60 variants (a, b, and c) that are mutually exclusively assembled into SWI/SNF. Blocking Nodal and BMP also induces lineage-specific transcription factors Gata4 and Tbx5, which interact with Baf60c. siRNA to Cer1, Baf60c, or the catalytic SWI/SNF subunit Brg1 prevented the developmental opening of chromatin surrounding the Nkx2.5 early cardiac enhancer and cardiomyocyte differentiation. Overexpression of Baf60c fully rescued these deficits, positioning Baf60c and SWI/SNF function downstream from Cer1. Thus, antagonism of Nodal and BMP coordinates induction of the myogenic Baf60c variant and interacting transcription factors to program the developmental opening of cardiomyocyte-specific loci in chromatin. This is the first demonstration that cues from the progenitor cell environment direct the subunit variant composition of SWI/SNF to remodel the transcriptional landscape for lineage-specific differentiation. PMID:24186978

  12. Nodal signalling determines biradial asymmetry in Hydra.

    PubMed

    Watanabe, Hiroshi; Schmidt, Heiko A; Kuhn, Anne; Höger, Stefanie K; Kocagöz, Yigit; Laumann-Lipp, Nico; Ozbek, Suat; Holstein, Thomas W

    2014-11-01

    In bilaterians, three orthogonal body axes define the animal form, with distinct anterior-posterior, dorsal-ventral and left-right asymmetries. The key signalling factors are Wnt family proteins for the anterior-posterior axis, Bmp family proteins for the dorsal-ventral axis and Nodal for the left-right axis. Cnidarians, the sister group to bilaterians, are characterized by one oral-aboral body axis, which exhibits a distinct biradiality of unknown molecular nature. Here we analysed the biradial growth pattern in the radially symmetrical cnidarian polyp Hydra, and we report evidence of Nodal in a pre-bilaterian clade. We identified a Nodal-related gene (Ndr) in Hydra magnipapillata, and this gene is essential for setting up an axial asymmetry along the main body axis. This asymmetry defines a lateral signalling centre, inducing a new body axis of a budding polyp orthogonal to the mother polyp's axis. Ndr is expressed exclusively in the lateral bud anlage and induces Pitx, which encodes an evolutionarily conserved transcription factor that functions downstream of Nodal. Reminiscent of its function in vertebrates, Nodal acts downstream of β-Catenin signalling. Our data support an evolutionary scenario in which a 'core-signalling cassette' consisting of β-Catenin, Nodal and Pitx pre-dated the cnidarian-bilaterian split. We presume that this cassette was co-opted for various modes of axial patterning: for example, for lateral branching in cnidarians and left-right patterning in bilaterians. PMID:25156256

  13. EMBRYO DEVELOPMENT. BMP gradients: A paradigm for morphogen-mediated developmental patterning.

    PubMed

    Bier, Ethan; De Robertis, Edward M

    2015-06-26

    Bone morphogenetic proteins (BMPs) act in dose-dependent fashion to regulate cell fate choices in a myriad of developmental contexts. In early vertebrate and invertebrate embryos, BMPs and their antagonists establish epidermal versus central nervous system domains. In this highly conserved system, BMP antagonists mediate the neural-inductive activities proposed by Hans Spemann and Hilde Mangold nearly a century ago. BMPs distributed in gradients subsequently function as morphogens to subdivide the three germ layers into distinct territories and act to organize body axes, regulate growth, maintain stem cell niches, or signal inductively across germ layers. In this Review, we summarize the variety of mechanisms that contribute to generating reliable developmental responses to BMP gradients and other morphogen systems. PMID:26113727

  14. A System of Repressor Gradients Spatially Organizes the Boundaries of “Morphogen-dependent” Target Genes

    PubMed Central

    Chen, Hongtao; Xu, Zhe; Mei, Constance; Yu, Danyang; Small, Stephen

    2012-01-01

    Summary The homeodomain (HD) protein Bicoid (Bcd) is thought to function as a gradient morphogen that positions boundaries of target genes via threshold-dependent activation mechanisms. Here we analyze 66 Bcd-dependent regulatory elements, and show that their boundaries are positioned primarily by repressive gradients that antagonize Bcd-mediated activation. A major repressor is the pair-rule protein Runt, which is expressed in an opposing gradient, and is necessary and sufficient for limiting Bcd-dependent activation. Evidence is presented that Runt functions with the maternal repressor Capicua and the gap protein Kruppel as the principal components of a repression system that correctly orders boundaries throughout the anterior half of the embryo. These results put conceptual limits on the Bcd morphogen hypothesis, and demonstrate how the Bcd gradient functions within the gene network that patterns the embryo. PMID:22541432

  15. SoxB1-driven transcriptional network underlies neural-specific interpretation of morphogen signals.

    PubMed

    Oosterveen, Tony; Kurdija, Sanja; Ensterö, Mats; Uhde, Christopher W; Bergsland, Maria; Sandberg, Magnus; Sandberg, Rickard; Muhr, Jonas; Ericson, Johan

    2013-04-30

    The reiterative deployment of a small cadre of morphogen signals underlies patterning and growth of most tissues during embyogenesis, but how such inductive events result in tissue-specific responses remains poorly understood. By characterizing cis-regulatory modules (CRMs) associated with genes regulated by Sonic hedgehog (Shh), retinoids, or bone morphogenetic proteins in the CNS, we provide evidence that the neural-specific interpretation of morphogen signaling reflects a direct integration of these pathways with SoxB1 proteins at the CRM level. Moreover, expression of SoxB1 proteins in the limb bud confers on mesodermal cells the potential to activate neural-specific target genes upon Shh, retinoid, or bone morphogenetic protein signaling, and the collocation of binding sites for SoxB1 and morphogen-mediatory transcription factors in CRMs faithfully predicts neural-specific gene activity. Thus, an unexpectedly simple transcriptional paradigm appears to conceptually explain the neural-specific interpretation of pleiotropic signaling during vertebrate development. Importantly, genes induced in a SoxB1-dependent manner appear to constitute repressive gene regulatory networks that are directly interlinked at the CRM level to constrain the regional expression of patterning genes. Accordingly, not only does the topology of SoxB1-driven gene regulatory networks provide a tissue-specific mode of gene activation, but it also determines the spatial expression pattern of target genes within the developing neural tube. PMID:23589857

  16. Tomoregulin-1 (TMEFF1) inhibits nodal signaling through direct binding to the nodal coreceptor Cripto

    PubMed Central

    Harms, Paul W.; Chang, Chenbei

    2003-01-01

    Transforming growth factor β (TGF-β) signals regulate multiple processes during development and in adult. We recently showed that tomoregulin-1 (TMEFF1), a transmembrane protein, selectively inhibits nodal but not activin in early Xenopus embryos. Here we report that TMEFF1 binds to the nodal coreceptor Cripto, but does not associate with either nodal or the type I ALK (activin receptor-like kinase) 4 receptor in coimmunoprecipitation assays. The inhibition of the nodal signaling by TMEFF1 in Xenopus ectodermal explants is rescued with wild-type but not mutant forms of Cripto. Furthermore, we show that the Cripto-FRL1-Cryptic (CFC) domain in Cripto, which is essential for its binding to ALK4, is also important for its interaction with TMEFF1. Our results demonstrate for the first time that nodal signaling can be regulated by a novel mechanism of blocking the Cripto coreceptor. PMID:14563676

  17. Nodal Quasiparticle in Pseudogapped Colossal Magnetoresistive Manganites

    SciTech Connect

    Mannella, N.

    2010-06-02

    A characteristic feature of the copper oxide high-temperature superconductors is the dichotomy between the electronic excitations along the nodal (diagonal) and antinodal (parallel to the Cu-O bonds) directions in momentum space, generally assumed to be linked to the d-wave symmetry of the superconducting state. Angle-resolved photoemission measurements in the superconducting state have revealed a quasiparticle spectrum with a d-wave gap structure that exhibits a maximum along the antinodal direction and vanishes along the nodal direction. Subsequent measurements have shown that, at low doping levels, this gap structure persists even in the high-temperature metallic state, although the nodal points of the superconducting state spread out in finite Fermi arcs. This is the so-called pseudogap phase, and it has been assumed that it is closely linked to the superconducting state, either by assigning it to fluctuating superconductivity or by invoking orders which are natural competitors of d-wave superconductors. Here we report experimental evidence that a very similar pseudogap state with a nodal-antinodal dichotomous character exists in a system that is markedly different from a superconductor: the ferromagnetic metallic groundstate of the colossal magnetoresistive bilayer manganite La{sub 1.2}Sr{sub 1.8}Mn{sub 2}O{sub 7}. Our findings therefore cast doubt on the assumption that the pseudogap state in the copper oxides and the nodal-antinodal dichotomy are hallmarks of the superconductivity state.

  18. Nodal analysis of two-phase instabilities

    SciTech Connect

    Lahey, R.T. Jr.; Garea, V.P.

    1995-10-01

    Nodal models having moving nodal boundaries have been developed for the analysis of two-phase flow instabilities in a boiling channel. The first model, which was based on a Galerkin method for the discretization, has been found to be accurate in the prediction of the onset of instabilities as well as the frequency of oscillations. This model however, had some problems with the prediction of chaotic phenomena and did not allow for flow reversal in the channel. A second nodal model, based on a finite difference approach, has been found to perform better for the prediction of non-linear response and it also allows for flow reversal. Both models are numerically more efficient than the existing fixed grid models for instabilities analysis.

  19. A lymph nodal capillary-cavernous hemangioma.

    PubMed

    Dellachà, A; Fulcheri, E; Campisi, C

    1999-09-01

    A capillary-cavernous hemangioma in an obturator lymph node was found incidentally in a 64 year-old woman who had undergone unilateral salpingo-oophorectomy and lymphadenectomy for an ovarian neoplasm. Vascular tumors of lymph nodes are briefly reviewed including eight previously described nodal capillary-cavernous hemangiomas. The association with other splanchnic hemangiomas is pointed out and the likelihood that the lesion is a hamartoma rather than a true neoplasm is addressed. Despite its rarity, this entity needs to be recognized by lymphologists who image lymph nodes by lymphangiography as well as by lymph nodal pathologists. PMID:10494525

  20. Compactin enhances osteogenesis in murine embryonic stem cells.

    PubMed

    Phillips, B W; Belmonte, N; Vernochet, C; Ailhaud, G; Dani, C

    2001-06-01

    Embryonic stem (ES) cells have the capacity to differentiate into various cell types in vitro. In this study, we show that retinoic acid is important for the commitment of ES cells into osteoblasts. Culturing retinoic acid treated ES cells in the presence of the osteogenic supplements ascorbic acid and beta-glycerophosphate resulted in the expression of several osteoblast marker genes, osteocalcin, alkaline phosphatase, and osteopontin. However, there was only a slight amount of mineralized matrix secretion. Addition of bone morphogenic protein-2 or compactin, a drug of the statin family of HMG-CoA reductase inhibitors, resulted in a greatly enhanced formation of bone nodules. Compactin did not modify the expression of osteogenic markers, but at the late stage of differentiation promoted an increase in BMP-2 expression. These results establish ES-cell derived osteogenesis as an effective model system to study the molecular mechanisms by which the statin compactin promotes osteoblastic differentiation and bone nodule formation. PMID:11394905

  1. Nodal·Gdf1 Heterodimers with Bound Prodomains Enable Serum-independent Nodal Signaling and Endoderm Differentiation

    PubMed Central

    Fuerer, Christophe; Nostro, M. Cristina; Constam, Daniel B.

    2014-01-01

    The TGFβ family member Nodal is central to control pluripotent stem cell fate, but its use as a stem cell differentiation factor is limited by low specific activity. During development, Nodal depends on growth and differentiation factor (Gdf)-1 and on the shared co-receptor Cryptic to specify visceral left-right axis asymmetry. We therefore asked whether the functionality of Nodal can be augmented by Gdf1. Because Nodal and Gdf1 coimmunoprecipitate each other, they were predicted to form heterodimers, possibly to facilitate diffusion or to increase the affinity for signaling receptors. Here, we report that Gdf1 suppresses an unexpected dependence of Nodal on serum proteins and that it is critically required for non-autonomous signaling in cells expressing Cryptic. Nodal, Gdf1, and their cleaved propeptides copurified as a heterodimeric low molecular weight complex that stimulated Activin receptor (Acvr) signaling far more potently than Nodal alone. Although heterodimerization with Gdf1 did not increase binding of Nodal to Fc fusions of co-receptors or Acvr extracellular domains, it was essential for soluble Acvr2 to inhibit Nodal signaling. This implies that Gdf1 potentiates Nodal activity by stabilizing a low molecular weight fraction that is susceptible to neutralization by soluble Acvr2. Finally, in differentiating human ES cells, endodermal markers were more efficiently induced by Nodal·Gdf1 than by Nodal, suggesting that Nodal·Gdf1 is an attractive new reagent to direct stem cell differentiation. PMID:24798330

  2. Combination of Controllably Released Platelet Rich Plasma Alginate Beads and Bone Morphogenic Protein-2 Gene-Modified Mesenchymal Stem Cells for Bone Regeneration

    PubMed Central

    Fernandes, Gabriela; Wang, Changdong; Yuan, Xue; Liu, Zunpeng; Dziak, Rosemary; Yang, Shuying

    2016-01-01

    Background Platelet rich plasma (PRP) consists of platelet derived growth factor (PDGF) and Transforming growth factor-beta (TGF-β) that increase cell proliferation of mesenchymal stem cells (MSCs), whereas, bone morphogenic Protein-2 (BMP2) promotes osteogenic differentiation of MSCs. However, the high degradation rate of fibrin leads to the dissociation of cytokines even before the process of bone regeneration has begun. Hence, for the first time, we studied the combined effect of sustained released PRP from alginate beads on BMP2 modified MSCs osteogenic differentiation in vitro and of sustained PRP alone on a fracture defect model ex vivo as well as its effect on the calvarial suture closure. Methods After optimizing the concentration of alginate for the microspheres, the osteogenic and mineralization effect of PRP and BMP2 in combinations on MSCs was studied. A self-setting alginate hydrogel carrying PRP was tested on a femur defect model ex-vivo. The effect of PRP was studied on the closure of the embryonic (E15) mouse calvaria sutures ex vivo. Results Increase of PRP concentration promoted cellular proliferation of MSCs. 2.5%–10% of PRP displayed gradually increased ALP activity on the cells in a dose dependent manner. Sustained release PRP and BMP2 demonstrated a significantly higher ALP and mineralization activity (p<0.05). The radiographs of alginate hydrogel with PRP treated bone demonstrated a nearly complete healing of the fracture and the histological sections of the embryonic calvaria revealed that PRP leads to suture fusion. Conclusions Sustained release of PRP along with BMP2 gene modified MSCs can significantly promote bone regeneration. PMID:26745613

  3. Network and Nodal Accessibility Teaching Exercise.

    ERIC Educational Resources Information Center

    Wheeler, James O.

    1988-01-01

    Presents an exercise, for use in college-level economic geography courses, which teaches the concept of nodal and network accessibility with an application to manufacturing locations. Intended to guide students to think spatially and to generalize from numeric data, this out-of-class activity teaches students to discover results, to do simple…

  4. Fucoidan Promotes Early Step of Cardiac Differentiation from Human Embryonic Stem Cells and Long-Term Maintenance of Beating Areas

    PubMed Central

    Hamidi, Sofiane; Letourneur, Didier; Aid-Launais, Rachida; Di Stefano, Antonio; Vainchenker, William; Norol, Françoise

    2014-01-01

    Somatic stem cells require specific niches and three-dimensional scaffolds provide ways to mimic this microenvironment. Here, we studied a scaffold based on Fucoidan, a sulfated polysaccharide known to influence morphogen gradients during embryonic development, to support human embryonic stem cells (hESCs) differentiation toward the cardiac lineage. A macroporous (pore 200 μm) Fucoidan scaffold was selected to support hESCs attachment and proliferation. Using a protocol based on the cardiogenic morphogen bone morphogenic protein 2 (BMP2) and transforming growth factor (TGFβ) followed by tumor necrosis factor (TNFα), an effector of cardiopoietic priming, we examined the cardiac differentiation in the scaffold compared to culture dishes and embryoid bodies (EBs). At day 8, Fucoidan scaffolds supported a significantly higher expression of the 3 genes encoding for transcription factors marking the early step of embryonic cardiac differentiation NKX2.5 (p<0.05), MEF2C (p<0.01), and GATA4 (p<0.01), confirmed by flow cytometry analysis for MEF2C and NKX2.5. The ability of Fucoidan scaffolds to locally concentrate and slowly release TGFβ and TNFα was confirmed by Luminex technology. We also found that Fucoidan scaffolds supported the late stage of embryonic cardiac differentiation marked by a significantly higher atrial natriuretic factor (ANF) expression (p<0.001), although only rare beating areas were observed. We postulated that absence of mechanical stress in the soft hydrogel impaired sarcomere formation, as confirmed by molecular analysis of the cardiac muscle myosin MYH6 and immunohistological staining of sarcomeric α-actinin. Nevertheless, Fucoidan scaffolds contributed to the development of thin filaments connecting beating areas through promotion of smooth muscle cells, thus enabling maintenance of beating areas for up to 6 months. In conclusion, Fucoidan scaffolds appear as a very promising biomaterial to control cardiac differentiation from hESCs that

  5. The structure and morphogenic changes of antennae of Matsucoccus matsumurae (Hemiptera: Coccoidea: Matsucoccidae) in different instars.

    PubMed

    Wang, Xu; Xie, Yingping; Zhang, Yanfeng; Liu, Weimin; Wu, Jun

    2016-05-01

    To better understand the functioning and morphogenic changes of the antennae of Matsucoccus matsumurae (Kuwana) in different instars, the antennae are examined using light microscopy, scanning and transmission electron microscopy. The results show that the antennae of M. matsumurae display three different styles in morphology and sensillar distribution in different instars. The antennae of first instar nymphs are relatively simple, including one campaniform sensillum (Ca), four smooth aporous trichoid sensilla (SAt), two intersegmental sensilla (Ins), two coeloconic sensilla (Co), three multiporous pegs (Mp) and four uniporous pegs (Up). The antennae of adult females and third instar male nymphs both possess similar antennae, and exhibit seven types of sensilla. Adult female antennae have in total 82-108 sensilla, including 9-16 Böhm's bristle (Bb), 3-7 Ca, 50-75 SAt, 0-3 Ins, 3-10 Co, 8 Mp and 5 Up, whereas third instar male nymph antennae possess approximately 62-79 sensilla. Adult male antennae are the most developed, possessing 259-312 sensilla, including 7-15 Bb, 2-5 Ca, 7-11 grooved aporous trichoid sensilla, 4-9 SAt, 0-3 Ins, 2-7 Co, 23-29 knobbed seta sensilla, 179-230 multiporous trichoid sensilla and 8 Mp. Based on these results, the main functions and morphogenic changes of antennae M. matsumurae in different instars are discussed. PMID:26849968

  6. Distance measurements via the morphogen gradient of Bicoid in Drosophila embryos

    PubMed Central

    2010-01-01

    Background Patterning along the anterior-posterior (A-P) axis in Drosophila embryos is instructed by the morphogen gradient of Bicoid (Bcd). Despite extensive studies of this morphogen, how embryo geometry may affect gradient formation and target responses has not been investigated experimentally. Results In this report, we systematically compare the Bcd gradient profiles and its target expression patterns on the dorsal and ventral sides of the embryo. Our results support a hypothesis that proper distance measurement and the encoded positional information of the Bcd gradient are along the perimeter of the embryo. Our results also reveal that the dorsal and ventral sides of the embryo have a fundamentally similar relationship between Bcd and its target Hunchback (Hb), suggesting that Hb expression properties on the two sides of the embryo can be directly traced to Bcd gradient properties. Our 3-D simulation studies show that a curvature difference between the two sides of an embryo is sufficient to generate Bcd gradient properties that are consistent with experimental observations. Conclusions The findings described in this report provide a first quantitative, experimental evaluation of embryo geometry on Bcd gradient formation and target responses. They demonstrate that the physical features of an embryo, such as its shape, are integral to how pattern is formed. PMID:20678215

  7. Nodal and Lefty signaling regulates the growth of pancreatic cells

    PubMed Central

    Zhang, You-Qing; Sterling, Lori; Stotland, Aleksandr; Hua, Hong; Kritzik, Marcie; Sarvetnick, Nora

    2014-01-01

    Nodal and its antagonist, Lefty, are important mediators specifying the laterality of the organs during embryogenesis. Nodal signals through activin receptors in the presence of its co-receptor, Cripto. In the present study, we investigated the possible roles of Nodal and Lefty signaling during islet development and regeneration. We found that both Nodal and Lefty are expressed in the pancreas during embryogenesis and islet regeneration. In vitro studies demonstrated that Nodal inhibits, whereas Lefty enhances, the proliferation of a pancreatic cell line. In addition, we showed that Lefty-1 activates MAPK and Akt phosphorylation in these cells. In vivo blockade of endogenous Lefty using neutralizing Lefty-1 monoclonal antibody results in a significantly decreased proliferation of duct epithelial cells during islet regeneration. This is the first study to decipher the expression and function of Nodal and Lefty in pancreatic growth. Importantly, our results highlight a novel function of Nodal-Lefty signaling in the regulation of expansion of pancreatic cells. PMID:18393305

  8. Nodal resonance in a strong standing wave

    NASA Astrophysics Data System (ADS)

    Fernández C., David J.; Mielnik, Bogdan

    1990-06-01

    The motion of charged particles in a standing electromagnetic wave is considered. For amplitudes that are not too high, the wave causes an effect of attraction of particles to the nodal points, resembling the channeling effect reported by Salomon, Dalibard, Aspect, Metcalf, and Cohen-Tannoudji [Phys. Rev. Lett. 59, 1659 (1987)] consistent with the ``high-frequency potential'' of Kapitza [Zh. Eksp. Teor. Fiz. 21, 588 (1951)]. For high-field intensities, however, the nodal points undergo a qualitative metamorphosis, converting themselves from particle attractors into resonant centers. Some chaotic phenomena arise and the description of the oscillating field in terms of an ``effective potential'' becomes inappropriate. The question of a correct Floquet Hamiltonian that could describe the standing wave within this amplitude and frequency regime is open.

  9. Morphogenetic Implications of Peristalsis-Driven Fluid Flow in the Embryonic Lung

    PubMed Central

    Bokka, Kishore K.; Jesudason, Edwin C.; Lozoya, Oswaldo A.; Guilak, Farshid; Warburton, David; Lubkin, Sharon R.

    2015-01-01

    Epithelial organs are almost universally secretory. The lung secretes mucus of extremely variable consistency. In the early prenatal period, the secretions are of largely unknown composition, consistency, and flow rates. In addition to net outflow from secretion, the embryonic lung exhibits transient reversing flows from peristalsis. Airway peristalsis (AP) begins as soon as the smooth muscle forms, and persists until birth. Since the prenatal lung is liquid-filled, smooth muscle action can transport fluid far from the immediately adjacent tissues. The sensation of internal fluid flows has been shown to have potent morphogenetic effects, as has the transport of morphogens. We hypothesize that these effects play an important role in lung morphogenesis. To test these hypotheses in a quantitative framework, we analyzed the fluid-structure interactions between embryonic tissues and lumen fluid resulting from peristaltic waves that partially occlude the airway. We found that if the airway is closed, fluid transport is minimal; by contrast, if the trachea is open, shear rates can be very high, particularly at the stenosis. We performed a parametric analysis of flow characteristics' dependence on tissue stiffnesses, smooth muscle force, geometry, and fluid viscosity, and found that most of these relationships are governed by simple ratios. We measured the viscosity of prenatal lung fluid with passive bead microrheology. This paper reports the first measurements of the viscosity of embryonic lung lumen fluid. In the range tested, lumen fluid can be considered Newtonian, with a viscosity of 0.016 ± 0.008 Pa-s. We analyzed the interaction between the internal flows and diffusion and conclude that AP has a strong effect on flow sensing away from the tip and on transport of morphogens. These effects may be the intermediate mechanisms for the enhancement of branching seen in occluded embryonic lungs. PMID:26147967

  10. Isolation of bovine corneal keratan sulfate and its growth factor and morphogen binding.

    PubMed

    Weyers, Amanda; Yang, Bo; Solakyildirim, Kemal; Yee, Vienna; Li, Lingyun; Zhang, Fuming; Linhardt, Robert J

    2013-05-01

    Keratan sulfate (KS) is an important glycosaminoglycan that is found in cartilage, reproductive tissues, and neural tissues. Corneal KS glycosaminoglycan is found N-linked to lumican, keratocan and mimecan proteoglycans, and has been widely studied by investigators interested in corneal development and diseases. Recently, the availability of corneal KS has become severely limited, owing to restrictions on the shipment of bovine central nervous system byproducts across international borders in an effort to prevent additional cases of mad cow disease. We report a simple method for the purification of multi-milligram quantities of bovine corneal KS, and characterize its structural properties. We also examined its protein-binding properties, and discovered that corneal KS bound with high affinity to fibroblast growth factor-2 and sonic hedgehog, a growth factor and a morphogen involved in corneal development and healing. PMID:23402351

  11. Systems analysis of the role of bone morphogenic protein 4 in endothelial inflammation.

    PubMed

    Yin, Weiwei; Jo, Hanjoong; Voit, Eberhard O

    2010-02-01

    Shear stress is an important factor in the onset and progression of atherosclerosis. High and unidirectional laminar stress is seen as protective, while low and oscillatory shear stress is considered pro-inflammatory and pro-atherogenic. The mechanosensitive response of endothelial cells is governed by a complex system of genes, proteins, and signals that operate at distinctly different time scales. We propose a dynamic mathematical model that quantitatively describes this mechanosensing system and permits novel insights into its functioning. The model, the first of its kind, is constructed within the guidelines of Biochemical Systems Theory and accounts for different time scales by means of approximated delays. Parameter values are obtained directly from biochemical observations in an ad hoc fashion. The model reflects most documented observations well and leads to a number of predictions and novel hypotheses. In particular, it demonstrates the crucial role of Bone Morphogenic Protein 4 and p47(phox)-dependent NADPH oxidases in endothelial inflammation. PMID:19851868

  12. Biomaterial delivery of morphogens to mimic the natural healing cascade in bone

    PubMed Central

    Mehta, Manav; Schmidt-Bleek, Katharina; Duda, Georg N; Mooney, David J

    2012-01-01

    Complications in treatment of large bone defects using bone grafting still remain. Our understanding of the endogenous bone regeneration cascade has inspired the exploration of a wide variety of growth factors (GFs) in an effort to mimic the natural signaling that controls bone healing. Biomaterial-based delivery of single exogenous GFs has shown therapeutic efficacy, and this likely relates to its ability to recruit and promote replication of cells involved in tissue development and the healing process. However, as the natural bone healing cascade involves the action of multiple factors, each acting in a specific spatiotemporal pattern, strategies aiming to mimic the critical aspects of this process will likely benefit from the usage of multiple therapeutic agents. This article reviews the current status of approaches to deliver single GFs, as well as ongoing efforts to develop sophisticated delivery platforms to deliver multiple lineage-directing morphogens (multiple GFs) during bone healing. PMID:22626978

  13. The Formation of the Bicoid Morphogen Gradient Requires Protein Movement from Anteriorly Localized mRNA

    PubMed Central

    Kneeland, Thomas B.; Wieschaus, Eric F.; Gregor, Thomas

    2011-01-01

    The Bicoid morphogen gradient directs the patterning of cell fates along the anterior-posterior axis of the syncytial Drosophila embryo and serves as a paradigm of morphogen-mediated patterning. The simplest models of gradient formation rely on constant protein synthesis and diffusion from anteriorly localized source mRNA, coupled with uniform protein degradation. However, currently such models cannot account for all known gradient characteristics. Recent work has proposed that bicoid mRNA spatial distribution is sufficient to produce the observed protein gradient, minimizing the role of protein transport. Here, we adapt a novel method of fluorescent in situ hybridization to quantify the global spatio-temporal dynamics of bicoid mRNA particles. We determine that >90% of all bicoid mRNA is continuously present within the anterior 20% of the embryo. bicoid mRNA distribution along the body axis remains nearly unchanged despite dynamic mRNA translocation from the embryo core to the cortex. To evaluate the impact of mRNA distribution on protein gradient dynamics, we provide detailed quantitative measurements of nuclear Bicoid levels during the formation of the protein gradient. We find that gradient establishment begins 45 minutes after fertilization and that the gradient requires about 50 minutes to reach peak levels. In numerical simulations of gradient formation, we find that incorporating the actual bicoid mRNA distribution yields a closer prediction of the observed protein dynamics compared to modeling protein production from a point source at the anterior pole. We conclude that the spatial distribution of bicoid mRNA contributes to, but cannot account for, protein gradient formation, and therefore that protein movement, either active or passive, is required for gradient formation. PMID:21390295

  14. Self-construction of supramolecular polyrotaxane films by an electrotriggered morphogen-driven process.

    PubMed

    Rydzek, Gaulthier; Garnier, Tony; Schaaf, Pierre; Voegel, Jean-Claude; Senger, Bernard; Frisch, Benoît; Haikel, Youssef; Petit, Corinne; Schlatter, Guy; Jierry, Loïc; Boulmedais, Fouzia

    2013-08-27

    The design of films using a one-pot process has recently attracted increasing interest in the field of polymer thin film formation. Herein we describe the preparation of one-pot supramolecular polyrotaxane (PRX) films using the morphogen-driven self-construction process. This one-pot buildup strategy where the film growth is triggered by the electrochemical formation and diffusion of a catalyst in close vicinity of the substrate has recently been introduced by our group. A one-pot mixture was used that contained (i) poly(acrylic acid) (PAA) functionalized by azide groups grafted on the polymer chain through oligo(ethylene glycol) (EG) arms, leading to PAA-EG13-N3, (ii) cyclodextrins (α and β CD), as macrocycles that can be threaded along EG arms, (iii) alkyne-functionalized stoppers (ferrocene or adamantane), to cap the PRX assembly by click chemistry, and (iv) copper sulfate. The one-pot mixture solution was brought into contact with a gold electrode. Cu(I), the morphogen, was generated electrochemically from Cu(II) at the electrode/one-pot solution interface. This electrotriggered click reaction leads to the capping of polypseudorotaxane yielding to PRXs. The PRXs can self-assemble through lateral supramolecular interactions to form aggregates and ensure the cohesion of the film. The film buildup was investigated using different types of CD and alkyne functionalized stoppers. Supramolecular PRX aggregates were characterized by X-ray diffraction measurements. The film topographies were imaged by atomic force microscopy. The influence of the concentration in CD and the presence of a competitor were studied as well. The stability of the resulting film was tested in contact with 8 M urea and during the electrochemical oxidation of ferrocene. PMID:23895332

  15. Small renal tumor with lymph nodal enlargement: A histopathological surprise

    PubMed Central

    Thottathil, Mujeeburahiman; Verma, Ashish; D’souza, Nischith; Khan, Altaf

    2016-01-01

    Renal cancer with lymph nodal mass on the investigation is clinically suggestive of an advanced tumor. Small renal cancers are not commonly associated with lymph nodal metastasis. Association of renal cell carcinoma with renal tuberculosis (TB) in the same kidney is also rare. We report here a case of small renal cancer with multiple hilar and paraaortic lymph nodes who underwent radical nephrectomy, and histopathology report showed renal and lymph nodal TB too. PMID:27453671

  16. Phonon analogue of topological nodal semimetals

    NASA Astrophysics Data System (ADS)

    Po, Hoi Chun; Bahri, Yasaman; Vishwanath, Ashvin

    2015-03-01

    Recently, Kane and Lubensky proposed a mapping between bosonic phonon problems on isostatic lattices to chiral fermion systems based on factorization of the dynamical matrix [Nat. Phys. 10, 39 (2014)]. The existence of topologically protected zero modes in such mechanical problems is related to their presence in the fermionic system and is dictated by a local index theorem. Here we adopt the proposed mapping to construct a two-dimensional mechanical analogue of a fermionic topological nodal semimetal that hosts a robust bulk node in its linearized phonon spectrum. Such topologically protected soft modes with tunable wavevector may be useful in designing mechanical structures with fault-tolerant properties.

  17. The AN neutron transport by nodal diffusion

    SciTech Connect

    Barbarino, A.; Tomatis, D.

    2013-07-01

    The two group diffusion model combined to a nodal approach in space is the preferred scheme for the industrial simulation of nuclear water reactors. The main selling point is the speed of computation, allowing a large number of parametric studies. Anyway, the drawbacks of the underlying diffusion equation may arise with highly heterogeneous interfaces, often encountered in modern UO{sub 2} and MO{sub x} fuel loading patterns, and boron less controlled systems. This paper aims at showing how the simplified AN transport model, equivalent to the well known SPN, can be implemented in standard diffusion codes with minor modifications. Some numerical results are illustrated. (authors)

  18. Zero-energy bound states in a nodal topological lattice

    NASA Astrophysics Data System (ADS)

    Lee, Soo-Yong; Han, Jung Hoon

    2015-06-01

    A nodal topological lattice is a form of magnetic crystal with topologically nontrivial spin texture, which further exhibits a periodic array of nodes with vanishing magnetization. An electronic structure for conduction electrons strongly Hund coupled to such a nodal topological lattice is examined. Our analysis shows that each node attracts two localized states which form narrow bands through internode hybridization within the mid-gap region. Nodal bands carry a Chern number under suitable perturbations, suggesting their potential role in the topological Hall effect. Enhancement of the density of states near zero energy observable in a tunneling experiment will provide a signature of the formation of a nodal topological lattice.

  19. Stem cell-derived nodal-like cardiomyocytes as a novel pharmacologic tool: insights from sinoatrial node development and function.

    PubMed

    Barbuti, Andrea; Robinson, Richard B

    2015-01-01

    Since the first reports on the isolation and differentiation of stem cells, and in particular since the early success in driving these cells down a cardiac lineage, there has been interest in the potential of such preparations in cardiac regenerative therapy. Much of the focus of such research has been on improving mechanical function after myocardial infarction; however, electrophysiologic studies of these preparations have revealed a heterogeneous mix of action potential characteristics, including some described as "pacemaker" or "nodal-like," which in turn led to interest in the therapeutic potential of these preparations in the treatment of rhythm disorders; several proof-of-concept studies have used these cells to create a biologic alternative to electronic pacemakers. Further, there are additional potential applications of a preparation of pacemaker cells derived from stem cells, for example, in high-throughput screens of new chronotropic agents. All such applications require reasonably efficient methods for selecting or enriching the "nodal-like" cells, however, which in turn depends on first defining what constitutes a nodal-like cell since not all pacemaking cells are necessarily of nodal lineage. This review discusses the current state of the field in terms of characterizing sinoatrial-like cardiomyocytes derived from embryonic and induced pluripotent stem cells, markers that might be appropriate based on the current knowledge of the gene program leading to sinoatrial node development, what functional characteristics might be expected and desired based on studies of the sinoatrial node, and recent efforts at enrichment and selection of nodal-like cells. PMID:25733770

  20. Market redesign and technology upgrade: a nodal implementation

    SciTech Connect

    Isemonger, Alan G.

    2009-10-15

    The California ISO and its market participants collectively cut over to a new nodal-based market on April 1, largely without incident and 11 years to the day from the initial startup in 1998. Thus far, the new nodal framework has proven robust, and the inevitable design and implementation issues that have emerged since cutover have been manageable. (author)

  1. Dynamics of Drosophila embryonic patterning network perturbed in space and time using microfluidics

    PubMed Central

    Lucchetta, Elena M.; Lee, Ji Hwan; Fu, Lydia A.; Patel, Nipam H.; Ismagilov, Rustem F.

    2009-01-01

    Biochemical networks are perturbed both by fluctuations in environmental conditions and genetic variation. These perturbations must be compensated for, especially when they occur during embryonic pattern formation. Complex chemical reaction networks displaying spatiotemporal dynamics have been controlled and understood by perturbing their environment in space and time1–3. Here, we apply this approach using microfluidics to investigate the robust network in Drosophila melanogaster that compensates for variation in the Bicoid morphogen gradient. We show that the compensation system can counteract the effects of extremely unnatural environmental conditions—a temperature step—in which the anterior and posterior halves of the embryo are developing at different temperatures and thus at different rates. Embryonic patterning was normal under this condition, suggesting that a simple reciprocal gradient system is not the mechanism of compensation. Time-specific reversals of the temperature step narrowed down the critical period for compensation to between 65 and 100 min after onset of embryonic development. The microfluidic technology used here may prove useful to future studies, as it allows spatial and temporal regulation of embryonic development. PMID:15858575

  2. Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction.

    PubMed

    Minuth, Will W; Denk, Lucia

    2016-01-01

    Formation of a nephron depends on reciprocal signaling of different morphogens between epithelial and mesenchymal cells within the renal stem/progenitor cell niche. Previously, it has been surmised that a close proximity exists between both involved cell types and that morphogens are transported between them by diffusion. However, actual morphological data illustrate that mesenchymal and epithelial stem/progenitor cell bodies are separated by a striking interface. Special fixation of specimens by glutaraldehyde (GA) solution including cupromeronic blue, ruthenium red, or tannic acid for electron microscopy depicts that the interface is not void but filled in extended areas by textured extracellular matrix. Surprisingly, projections of mesenchymal cells cross the interface to contact epithelial cells. At those sites the plasma membranes of a mesenchymal and an epithelial cell are connected via tunneling nanotubes. Regarding detected morphological features in combination with involved morphogens, their transport cannot longer be explained solely by diffusion. Instead, it has to be sorted according to biophysical properties of morphogens and to detected environment. Thus, the new working hypothesis is that morphogens with good solubility such as glial cell line-derived neurotrophic factor (GDNF) or fibroblast growth factors (FGFs) are transported by diffusion. Morphogens with minor solubility such as bone morphogenetic proteins (BMPs) are secreted and stored for delivery on demand in illustrated extracellular matrix. In contrast, morphogens with poor solubility such as Wnts are transported in mesenchymal cell projections along the plasma membrane or via illustrated tunneling nanotubes. However, the presence of an intercellular route between mesenchymal and epithelial stem/progenitor cells by tunneling nanotubes also makes it possible that all morphogens are transported this way. PMID:26862472

  3. Special Morphological Features at the Interface of the Renal Stem/Progenitor Cell Niche Force to Reinvestigate Transport of Morphogens During Nephron Induction

    PubMed Central

    Minuth, Will W.; Denk, Lucia

    2016-01-01

    Abstract Formation of a nephron depends on reciprocal signaling of different morphogens between epithelial and mesenchymal cells within the renal stem/progenitor cell niche. Previously, it has been surmised that a close proximity exists between both involved cell types and that morphogens are transported between them by diffusion. However, actual morphological data illustrate that mesenchymal and epithelial stem/progenitor cell bodies are separated by a striking interface. Special fixation of specimens by glutaraldehyde (GA) solution including cupromeronic blue, ruthenium red, or tannic acid for electron microscopy depicts that the interface is not void but filled in extended areas by textured extracellular matrix. Surprisingly, projections of mesenchymal cells cross the interface to contact epithelial cells. At those sites the plasma membranes of a mesenchymal and an epithelial cell are connected via tunneling nanotubes. Regarding detected morphological features in combination with involved morphogens, their transport cannot longer be explained solely by diffusion. Instead, it has to be sorted according to biophysical properties of morphogens and to detected environment. Thus, the new working hypothesis is that morphogens with good solubility such as glial cell line-derived neurotrophic factor (GDNF) or fibroblast growth factors (FGFs) are transported by diffusion. Morphogens with minor solubility such as bone morphogenetic proteins (BMPs) are secreted and stored for delivery on demand in illustrated extracellular matrix. In contrast, morphogens with poor solubility such as Wnts are transported in mesenchymal cell projections along the plasma membrane or via illustrated tunneling nanotubes. However, the presence of an intercellular route between mesenchymal and epithelial stem/progenitor cells by tunneling nanotubes also makes it possible that all morphogens are transported this way. PMID:26862472

  4. Modeling digits. Digit patterning is controlled by a Bmp-Sox9-Wnt Turing network modulated by morphogen gradients.

    PubMed

    Raspopovic, J; Marcon, L; Russo, L; Sharpe, J

    2014-08-01

    During limb development, digits emerge from the undifferentiated mesenchymal tissue that constitutes the limb bud. It has been proposed that this process is controlled by a self-organizing Turing mechanism, whereby diffusible molecules interact to produce a periodic pattern of digital and interdigital fates. However, the identities of the molecules remain unknown. By combining experiments and modeling, we reveal evidence that a Turing network implemented by Bmp, Sox9, and Wnt drives digit specification. We develop a realistic two-dimensional simulation of digit patterning and show that this network, when modulated by morphogen gradients, recapitulates the expression patterns of Sox9 in the wild type and in perturbation experiments. Our systems biology approach reveals how a combination of growth, morphogen gradients, and a self-organizing Turing network can achieve robust and reproducible pattern formation. PMID:25082703

  5. Radar response from vegetation with nodal structure

    NASA Technical Reports Server (NTRS)

    Blanchard, B. J.; Oneill, P. E.

    1984-01-01

    Radar images from the SEASAT synthetic aperture radar (SAR) produced unusually high returns from corn and sorghum fields, which seem to indicate a correlation between nodal separation in the stalk and the wavelength of the radar. These images also show no difference in return from standing or harvested corn. Further investigation using images from the Shuttle Imaging Radar (SIR-A) substantiated these observations and showed a degradation of the high return with time after harvest. From portions of corn and sweet sorghum stalks that were sampled to measure stalk water content, it was determined that near and after maturity the water becomes more concentrated in the stalk nodes. The stalk then becomes a linear sequence of alternating dielectrics as opposed to a long slender cylinder with uniform dielectric properties.

  6. Nodal aberration theory applied to freeform surfaces

    NASA Astrophysics Data System (ADS)

    Fuerschbach, Kyle; Rolland, Jannick P.; Thompson, Kevin P.

    2014-12-01

    When new three-dimensional packages are developed for imaging optical systems, the rotational symmetry of the optical system is often broken, changing its imaging behavior and making the optical performance worse. A method to restore the performance is to use freeform optical surfaces that compensate directly the aberrations introduced from tilting and decentering the optical surfaces. In order to effectively optimize the shape of a freeform surface to restore optical functionality, it is helpful to understand the aberration effect the surface may induce. Using nodal aberration theory the aberration fields induced by a freeform surface in an optical system are explored. These theoretical predications are experimentally validated with the design and implementation of an aberration generating telescope.

  7. Experience with advanced nodal codes at YAEC

    SciTech Connect

    Cacciapouti, R.J.

    1990-01-01

    Yankee Atomic Electric Company (YAEC) has been performing reload licensing analysis since 1969. The basic pressurized water reactor (PWR) methodology involves the use of LEOPARD for cross-section generation, PDQ for radial power distributions and integral control rod worth, and SIMULATE for axial power distributions and differential control rod worth. In 1980, YAEC began performing reload licensing analysis for the Vermont Yankee boiling water reactor (BWR). The basic BWR methodology involves the use of CASMO for cross-section generation and SIMULATE for three-dimensional power distributions. In 1986, YAEC began investigating the use of CASMO-3 for cross-section generation and the advanced nodal code SIMULATE-3 for power distribution analysis. Based on the evaluation, the CASMO-3/SIMULATE-3 methodology satisfied all requirements. After careful consideration, the cost of implementing the new methodology is expected to be offset by reduced computing costs, improved engineering productivity, and fuel-cycle performance gains.

  8. Millennium recurrence interval of morphogenic earthquakes on the Qingchuan fault, northeastern segment of the Longmen Shan Thrust Belt, China

    NASA Astrophysics Data System (ADS)

    Lin, Aiming; Yan, Bing; Rao, Gang

    2016-04-01

    The 2008 M w 7.9 Wenchuan produced a ˜285-300-km-long coseismic surface rupture zone, including a 60-km-long segment along the Qingchuan fault, the northeastern segment of the Longmen Shan Thrust Belt (LSTB), Sichuan Basin, central China. Field investigations, trench excavations, and radiocarbon dating results reveal that (i) the Qingchuan fault is currently active as a seismogenic fault, along which four morphogenic earthquakes including the 2008 Wenchuan earthquake occurred in the past ca. 3500 years, suggesting an average millennium recurrence interval of morphogenic earthquakes in the late Holocene; (ii) the most recent event prior to the 2008 Wenchuan earthquake took place in the period between AD 1400 and AD 1100; (iii) the penultimate paleoseismic event occurred in the period around 2000 years BP in the Han Dynasty (206 BC-AD 220); (iv) the third paleoseismic event occurred in the period between 900 and 1800 BC; and (v) at least three seismic faulting events occurred in the early Holocene. The present results are comparable with those inferred in the central and southwestern segments of the LSTB within which the Wenchuan magnitude earthquakes occurred in a millennium recurrence interval, that are in contrast with previous estimates of 2000-10,000 years for the recurrence interval of morphogenic earthquakes within the LSTB and thereby necessitating substantial modifications to existing seismic hazard models for the densely populated region at the Sichuan region.

  9. miRNA-mediated feedback inhibition of JAK/STAT morphogen signalling establishes a cell fate threshold.

    PubMed

    Yoon, Wan Hee; Meinhardt, Hans; Montell, Denise J

    2011-09-01

    Patterns of cell fates generated by morphogens are critically important for normal development; however, the mechanisms by which graded morphogen signals are converted into all-or-none cell fate responses are incompletely understood. In the Drosophila ovary, high and sustained levels of the secreted morphogen Unpaired (Upd) specify the migratory border-cell population by activating the signal transducer and activator of transcription (STAT). A lower or transient level of STAT activity specifies a non-migratory population of follicle cells. Here we identify miR-279 as a component of a feedback pathway that further dampens the response in cells with low levels of JAK/STAT activity. miR-279 directly repressed STAT, and loss of miR-279 mimicked STAT gain-of-function or loss of Apontic (Apt), a known feedback inhibitor of STAT. Apt was essential for miR-279 expression in non-migratory follicle cells, whereas another STAT target, Ken and Barbie (Ken), downregulated miR-279 in border cells. Mathematical modelling and simulations of this regulatory circuit including miR-279, Apt and Ken supported key roles for miR-279 and Apt in generating threshold responses to the Upd gradient. PMID:21857668

  10. The Wingless morphogen gradient is established by the cooperative action of Frizzled and Heparan Sulfate Proteoglycan receptors.

    PubMed

    Baeg, Gyeong-Hun; Selva, Erica M; Goodman, Robyn M; Dasgupta, Ramanuj; Perrimon, Norbert

    2004-12-01

    We have examined the respective contribution of Heparan Sulfate Proteoglycans (HSPGs) and Frizzled (Fz) proteins in the establishment of the Wingless (Wg) morphogen gradient. From the analysis of mutant clones of sulfateless/N-deacetylase-sulphotransferase in the wing imaginal disc, we find that lack of Heparan Sulfate (HS) causes a dramatic reduction of both extracellular and intracellular Wg in receiving cells. Our studies, together with others [Kirkpatrick, C.A., Dimitroff, B.D., Rawson, J.M., Selleck, S.B., 2004. Spatial regulation of Wingless morphogen distribution and signalling by Dally-like protein. Dev. Cell (in press)], reveals that the Glypican molecule Dally-like Protein (Dlp) is associated with both negative and positive roles in Wg short- and long-range signaling, respectively. In addition, analyses of the two Fz proteins indicate that the Fz and DFz2 receptors, in addition to transducing the signal, modulate the slope of the Wg gradient by regulating the amount of extracellular Wg. Taken together, our analysis illustrates how the coordinated activities of HSPGs and Fz/DFz2 shape the Wg morphogen gradient. PMID:15531366

  11. A BMP-FGF Morphogen Toggle Switch Drives the Ultrasensitive Expression of Multiple Genes in the Developing Forebrain

    PubMed Central

    Currle, D. Spencer; Fung, Ernest S.; Hayes, Wayne B.; Lander, Arthur D.; Monuki, Edwin S.

    2014-01-01

    Borders are important as they demarcate developing tissue into distinct functional units. A key challenge is the discovery of mechanisms that can convert morphogen gradients into tissue borders. While mechanisms that produce ultrasensitive cellular responses provide a solution, how extracellular morphogens drive such mechanisms remains poorly understood. Here, we show how Bone Morphogenetic Protein (BMP) and Fibroblast Growth Factor (FGF) pathways interact to generate ultrasensitivity and borders in the dorsal telencephalon. BMP and FGF signaling manipulations in explants produced border defects suggestive of cross inhibition within single cells, which was confirmed in dissociated cultures. Using mathematical modeling, we designed experiments that ruled out alternative cross inhibition mechanisms and identified a cross-inhibitory positive feedback (CIPF) mechanism, or “toggle switch”, which acts upstream of transcriptional targets in dorsal telencephalic cells. CIPF explained several cellular phenomena important for border formation such as threshold tuning, ultrasensitivity, and hysteresis. CIPF explicitly links graded morphogen signaling in the telencephalon to switch-like cellular responses and has the ability to form multiple borders and scale pattern to size. These benefits may apply to other developmental systems. PMID:24550718

  12. A BMP-FGF morphogen toggle switch drives the ultrasensitive expression of multiple genes in the developing forebrain.

    PubMed

    Srinivasan, Shyam; Hu, Jia Sheng; Currle, D Spencer; Fung, Ernest S; Hayes, Wayne B; Lander, Arthur D; Monuki, Edwin S

    2014-02-01

    Borders are important as they demarcate developing tissue into distinct functional units. A key challenge is the discovery of mechanisms that can convert morphogen gradients into tissue borders. While mechanisms that produce ultrasensitive cellular responses provide a solution, how extracellular morphogens drive such mechanisms remains poorly understood. Here, we show how Bone Morphogenetic Protein (BMP) and Fibroblast Growth Factor (FGF) pathways interact to generate ultrasensitivity and borders in the dorsal telencephalon. BMP and FGF signaling manipulations in explants produced border defects suggestive of cross inhibition within single cells, which was confirmed in dissociated cultures. Using mathematical modeling, we designed experiments that ruled out alternative cross inhibition mechanisms and identified a cross-inhibitory positive feedback (CIPF) mechanism, or "toggle switch", which acts upstream of transcriptional targets in dorsal telencephalic cells. CIPF explained several cellular phenomena important for border formation such as threshold tuning, ultrasensitivity, and hysteresis. CIPF explicitly links graded morphogen signaling in the telencephalon to switch-like cellular responses and has the ability to form multiple borders and scale pattern to size. These benefits may apply to other developmental systems. PMID:24550718

  13. Loop-Nodal and Point-Nodal Semimetals in Three-Dimensional Honeycomb Lattices

    NASA Astrophysics Data System (ADS)

    Ezawa, Motohiko

    2016-03-01

    A honeycomb structure has a natural extension to three dimensions. Simple examples are hyperhoneycomb and stripy-honeycomb lattices, which are realized in β -Li2IrO3 and γ -Li2IrO3 , respectively. We propose a wide class of three-dimensional (3D) honeycomb lattices which are loop-nodal semimetals. Their edge states have intriguing properties similar to the two-dimensional honeycomb lattice in spite of a dimensional difference. Partial flat bands emerge at the zigzag or bearded edge of the 3D honeycomb lattice, whose boundary is given by the Fermi loop in the bulk spectrum. On the other hand, perfect flat bands emerge in the zigzag-bearded edge or when the anisotropy is large. The loop-nodal structure is destroyed once staggered potential or antiferromagnetic order is introduced. All these 3D honeycomb lattices become strong topological insulators with the inclusion of the spin-orbit interaction (SOI). Furthermore, point-nodal semimetals may be realized in the presence of both antiferromagnetic order and the SOI. We construct the effective four-band theory with the SOI to understand the physics near the Fermi level, based upon which the density of states and the dc conductivity are calculated.

  14. Loop-Nodal and Point-Nodal Semimetals in Three-Dimensional Honeycomb Lattices.

    PubMed

    Ezawa, Motohiko

    2016-03-25

    A honeycomb structure has a natural extension to three dimensions. Simple examples are hyperhoneycomb and stripy-honeycomb lattices, which are realized in β-Li_{2}IrO_{3} and γ-Li_{2}IrO_{3}, respectively. We propose a wide class of three-dimensional (3D) honeycomb lattices which are loop-nodal semimetals. Their edge states have intriguing properties similar to the two-dimensional honeycomb lattice in spite of a dimensional difference. Partial flat bands emerge at the zigzag or bearded edge of the 3D honeycomb lattice, whose boundary is given by the Fermi loop in the bulk spectrum. On the other hand, perfect flat bands emerge in the zigzag-bearded edge or when the anisotropy is large. The loop-nodal structure is destroyed once staggered potential or antiferromagnetic order is introduced. All these 3D honeycomb lattices become strong topological insulators with the inclusion of the spin-orbit interaction (SOI). Furthermore, point-nodal semimetals may be realized in the presence of both antiferromagnetic order and the SOI. We construct the effective four-band theory with the SOI to understand the physics near the Fermi level, based upon which the density of states and the dc conductivity are calculated. PMID:27058097

  15. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress stimulates an inflammatory response

    NASA Technical Reports Server (NTRS)

    Sorescu, George P.; Sykes, Michelle; Weiss, Daiana; Platt, Manu O.; Saha, Aniket; Hwang, Jinah; Boyd, Nolan; Boo, Yong C.; Vega, J. David; Taylor, W. Robert; Jo, Hanjoong

    2003-01-01

    Atherosclerosis is now viewed as an inflammatory disease occurring preferentially in arterial regions exposed to disturbed flow conditions, including oscillatory shear stress (OS), in branched arteries. In contrast, the arterial regions exposed to laminar shear (LS) are relatively lesion-free. The mechanisms underlying the opposite effects of OS and LS on the inflammatory and atherogenic processes are not clearly understood. Here, through DNA microarrays, protein expression, and functional studies, we identify bone morphogenic protein 4 (BMP4) as a mechanosensitive and pro-inflammatory gene product. Exposing endothelial cells to OS increased BMP4 protein expression, whereas LS decreased it. In addition, we found BMP4 expression only in the selective patches of endothelial cells overlying foam cell lesions in human coronary arteries. The same endothelial patches also expressed higher levels of intercellular cell adhesion molecule-1 (ICAM-1) protein compared with those of non-diseased areas. Functionally, we show that OS and BMP4 induced ICAM-1 expression and monocyte adhesion by a NFkappaB-dependent mechanism. We suggest that BMP4 is a mechanosensitive, inflammatory factor playing a critical role in early steps of atherogenesis in the lesion-prone areas.

  16. High glucose and palmitate increases bone morphogenic protein 4 expression in human endothelial cells

    PubMed Central

    Hong, Oak-Kee; Yoo, Soon-Jib; Son, Jang-Won; Kim, Mee-Kyoung; Baek, Ki-Hyun; Song, Ki-Ho; Cha, Bong-Yun; Jo, Hanjoong

    2016-01-01

    Here, we investigated whether hyperglycemia and/or free fatty acids (palmitate, PAL) aff ect the expression level of bone morphogenic protein 4 (BMP4), a proatherogenic marker, in endothelial cells and the potential role of BMP4 in diabetic vascular complications. To measure BMP4 expression, human umbilical vein endothelial cells (HUVECs) were exposed to high glucose concentrations and/or PAL for 24 or 72 h, and the effects of these treatments on the expression levels of adhesion molecules and reactive oxygen species (ROS) were examined. BMP4 loss-of-function status was achieved via transfection of a BMP4-specific siRNA. High glucose levels increased BMP4 expression in HUVECs in a dose-dependent manner. PAL potentiated such expression. The levels of adhesion molecules and ROS production increased upon treatment with high glucose and/or PAL, but this eff ect was negated when BMP4 was knocked down via siRNA. Signaling of BMP4, a proinflammatory and pro-atherogenic cytokine marker, was increased by hyperglycemia and PAL. BMP4 induced the expression of infl ammatory adhesion molecules and ROS production. Our work suggests that BMP4 plays a role in atherogenesis induced by high glucose levels and/or PAL. PMID:26937213

  17. The bone morphogenic protein inhibitor, noggin, reduces glycemia and vascular inflammation in db/db mice.

    PubMed

    Koga, Mitsuhisa; Engberding, Niels; Dikalova, Anna E; Chang, Kyung Hwa; Seidel-Rogol, Bonnie; Long, James S; Lassègue, Bernard; Jo, Hanjoong; Griendling, Kathy K

    2013-09-01

    Vascular diseases frequently accompany diabetes mellitus. Based on the current understanding of atherosclerosis as an inflammatory disorder of the vascular wall, it has been speculated that diabetes may accelerate atherosclerosis by inducing a proinflammatory milieu in the vasculature. ANG II and bone morphogenic proteins (BMPs) have been implicated in vascular inflammation. We evaluated the effect of angiotensin receptor blockade by valsartan and BMP inhibition by noggin on markers of vascular inflammation in a mouse model of diabetes. Noggin had no effect on blood pressure but decreased serum glucose levels, whereas valsartan significantly decreased blood pressure, but not serum glucose. Both inhibitors reduced reactive oxygen species production in the aorta. Additionally, noggin and valsartan diminish gene transcription and protein expression of various inflammatory molecules in the vascular wall. These observations indicate that although both inhibitors block superoxide production and have similar effects on inflammatory gene expression, glycemia and blood pressure may represent a secondary target differentially affected by noggin and valsartan. Our data clearly identify the BMP pathway as a potentially potent therapeutic target in diabetic inflammatory vascular disease. PMID:23812391

  18. Morphogen-based simulation model of ray growth and joint patterning during fin development and regeneration.

    PubMed

    Rolland-Lagan, Anne-Gaëlle; Paquette, Mathieu; Tweedle, Valerie; Akimenko, Marie-Andrée

    2012-03-01

    The fact that some organisms are able to regenerate organs of the correct shape and size following amputation is particularly fascinating, but the mechanism by which this occurs remains poorly understood. The zebrafish (Danio rerio) caudal fin has emerged as a model system for the study of bone development and regeneration. The fin comprises 16 to 18 bony rays, each containing multiple joints along its proximodistal axis that give rise to segments. Experimental observations on fin ray growth, regeneration and joint formation have been described, but no unified theory has yet been put forward to explain how growth and joint patterns are controlled. We present a model for the control of fin ray growth during development and regeneration, integrated with a model for joint pattern formation, which is in agreement with published, as well as new, experimental data. We propose that fin ray growth and joint patterning are coordinated through the interaction of three morphogens. When the model is extended to incorporate multiple rays across the fin, it also accounts for how the caudal fin acquires its shape during development, and regains its correct size and shape following amputation. PMID:22318227

  19. [MORPHOMETRIC AND HISTOCHEMICAL CHARACTERISTICS OF THE THYROID GLAND AFTER ADMINISTRATION OF HYDRA PEPTIDE MORPHOGEN].

    PubMed

    Kulayeva, V V; Bykov, V L

    2016-01-01

    The effect of Hydra peptide morphogen (HPM) on quantitative histochemical and morphometric parameters of the thyroid gland (TG) was studied. The experiments were conducted on 40 outbred albino male mice weighing 20-25 g, which were injected intraperitoneally with HPM at the dose of 100 μg/kg of body weight per day for 5 days. Relative volumes occupied by the epithelium (E), including its follicular (E(f)), interfollicular (E(i)) components, and colloid (C) were determined using stereological method on TG transverse sections. E(f)/E(i) and E/C ratios were calculated as the indices of follicular organization and TG activity, respectively. Mitotic activity of thyrocytes was also evaluated. The enzymes, characterizing the metabolic activity of thyrocytes: NADH-diaphorase, succinate- and lactate dehydrogenases were demonstrated on cryostat sections of material, frozen in liquid nitrogen and their activity was assessed cytophotometrically. The results demonstrated that HPM administration lead to a significant increase in relative volume of thyroid epithelium with a concomitant reduction of the volume of the colloid. E(f)/E(i) ratio was not significantly different from that in the control. HPM also induced a significant increase of thyrocyte proliferation rate and of the activity of enzymes studied. Collectively, the quantitative histoenzymological and morphometric data obtained indicate the stimulating effect of HPM on TG functional activity and thyrocyte proliferation. PMID:27487666

  20. Morphogenic regulator EFG1 affects the drug susceptibilities of pathogenic Candida albicans.

    PubMed

    Prasad, Tulika; Hameed, Saif; Manoharlal, Raman; Biswas, Sudipta; Mukhopadhyay, Chinmay K; Goswami, Shyamal K; Prasad, Rajendra

    2010-08-01

    This study shows that the morphogenic regulator EFG1 level affects the drug susceptibilities of Candida albicans when grown on solid growth media. The Deltaefg1 mutant showed sensitivity particularly to those drugs that target ergosterol or its metabolism. Efg1p disruption showed a gene-dosage effect on drug susceptibilities and resulted in enhanced susceptibility to drugs in the homozygous mutant as compared with the wild type, heterozygous and revertant strains. The enhanced sensitivity to drugs was independent of the status of ATP-binding cassette and MFS multidrug efflux pumps of C. albicans. The Deltaefg1 mutant displayed increased membrane fluidity that coincided with the downregulation of ERG11 and upregulation of OLE1 and ERG3, leading to enhanced passive diffusion of drugs. Interestingly, Deltaefg1 mutant cells displayed enhanced levels of endogenous ROS levels. Notably, the higher levels of ROS in the Deltaefg1 mutant could be reversed by the addition of antioxidants. However, the restoration of ROS levels did not reverse the drug sensitivities of the Deltaefg1 mutant. Taken together, we, for the first time, establish a new role to EFG1 in affecting the drug susceptibilities of C. albicans cells, independent of ROS and known drug efflux mechanisms. PMID:20491944

  1. The bone morphogenic protein inhibitor, noggin, reduces glycemia and vascular inflammation in db/db mice

    PubMed Central

    Koga, Mitsuhisa; Engberding, Niels; Dikalova, Anna E.; Chang, Kyung Hwa; Seidel-Rogol, Bonnie; Long, James S.; Lassègue, Bernard; Jo, Hanjoong

    2013-01-01

    Vascular diseases frequently accompany diabetes mellitus. Based on the current understanding of atherosclerosis as an inflammatory disorder of the vascular wall, it has been speculated that diabetes may accelerate atherosclerosis by inducing a proinflammatory milieu in the vasculature. ANG II and bone morphogenic proteins (BMPs) have been implicated in vascular inflammation. We evaluated the effect of angiotensin receptor blockade by valsartan and BMP inhibition by noggin on markers of vascular inflammation in a mouse model of diabetes. Noggin had no effect on blood pressure but decreased serum glucose levels, whereas valsartan significantly decreased blood pressure, but not serum glucose. Both inhibitors reduced reactive oxygen species production in the aorta. Additionally, noggin and valsartan diminish gene transcription and protein expression of various inflammatory molecules in the vascular wall. These observations indicate that although both inhibitors block superoxide production and have similar effects on inflammatory gene expression, glycemia and blood pressure may represent a secondary target differentially affected by noggin and valsartan. Our data clearly identify the BMP pathway as a potentially potent therapeutic target in diabetic inflammatory vascular disease. PMID:23812391

  2. Anamnestic risk factor questionnaire as reliable diagnostic instrument for osteoporosis (reduced bone morphogenic density)

    PubMed Central

    2011-01-01

    Background Osteoporosis is a major health problem worldwide, and is included in the WHO list of the top 10 major diseases. However, it is often undiagnosed until the first fracture occurs, due to inadequate patient education and lack of insurance coverage for screening tests. Anamnestic risk factors like positive family anamnesis or early menopause are assumed to correlate with reduced BMD. Methods In our study of 78 patients with metaphyseal long bone fractures, we searched for a correlation between anamnestic risk factors, bone specific laboratory values, and the bone morphogenic density (BMD). Each indicator was examined as a possible diagnostic instrument for osteoporosis. The secondary aim of this study was to demonstrate the high prevalence of osteoporosis in patients with metaphyseal fractures. Results 76.9% of our fracture patients had decreased bone density and 43.6% showed manifest osteoporosis in DXA (densitometry) measurements. Our questionnaire, identifying anamnestic risk factors, correlated highly significantly (p = 0.01) with reduced BMD, whereas seven bone-specific laboratory values (p = 0.046) correlated significantly. Conclusions Anamnestic risk factors correlate with pathological BMD. The medical questionnaire used in this study would therefore function as a cost-effective primary diagnostic instrument for identification of osteoporosis patients. PMID:21849030

  3. Morphogenic Protein RodZ Interacts with Sporulation Specific SpoIIE in Bacillus subtilis

    PubMed Central

    Muchová, Katarína; Chromiková, Zuzana; Bradshaw, Niels; Wilkinson, Anthony J.

    2016-01-01

    The first landmark in sporulation of Bacillus subtilis is the formation of an asymmetric septum followed by selective activation of the transcription factor σF in the resulting smaller cell. How the morphological transformations that occur during sporulation are coupled to cell-specific activation of transcription is largely unknown. The membrane protein SpoIIE is a constituent of the asymmetric sporulation septum and is a crucial determinant of σF activation. Here we report that the morphogenic protein, RodZ, which is essential for cell shape determination, is additionally required for asymmetric septum formation and sporulation. In cells depleted of RodZ, formation of asymmetric septa is disturbed and σF activation is perturbed. During sporulation, we found that SpoIIE recruits RodZ to the asymmetric septum. Moreover, we detected a direct interaction between SpoIIE and RodZ in vitro and in vivo, indicating that SpoIIE-RodZ may form a complex to coordinate asymmetric septum formation and σF activation. We propose that RodZ could provide a link between the cell shape machinery and the coordinated morphological and developmental transitions required to form a resistant spore. PMID:27415800

  4. [Morpho-functional characteristics of the lingual epithelium after administration of hydra peptide morphogen].

    PubMed

    Kulaeva, V V; Bykov, V L

    2007-01-01

    Using histological, morphometric and quantitative histoenzymological methods, the changes of lingual epithelium were studied in 40 outbred albino mice after 5 intraperitoneal injections of 100 micrograms of hydra peptide morphogen (HPM) per 1 kg of body weight. Administration of HPM was found to increase the total thickness of epithelial layer on the dorsal tongue surface in the interpapillary regions, while in the area of filiform papillae these changes were not significant. On the ventral tongue surface HPM induced a marked increase of total thickness of the epithelial layer as compared to that in control animals. Mitotic activity was increased in the epithelium covering the ventral surface and in the interpapillary regions on the dorsal tongue surface. Histoenzymologic study which involved the demonstration of NADH-diaphorase, succinate- and lactate-dehydrogenase (LDH) activities, followed by a cytophotometric evaluation of enzyme activity, has shown a stimulatory effect of HPM on the activity of all the enzymes studied, which was most pronounced in respect to LDH and was maximally expressed on the dorsal tongue surface. These findings collectively suggest that HPM exerts a stimulatory effect on proliferation activity and metabolism of lingual epithelium, which is differentially expressed in its variuoe topographical zones. PMID:17722572

  5. NODAL — The second life of the accelerator control language

    NASA Astrophysics Data System (ADS)

    Cuisinier, G.; Perriollat, F.; Ribeiro, P.; Kagarmanov, A.; Kovaltsov, V.

    1994-12-01

    NODAL has been a popular interpreter language for accelerator controls since the beginning of the 1970s. NODAL has been rewritten in the C language to be easily portable to the different computer platforms which are in use in accelerator controls. The paper describes the major features of this new version of NODAL, the major software packages which are available through this implementation, the platforms on which it is currently running, and some relevant performances. The experience gained during the rejuvenation project of the CERN accelerator control systems is presented. The benefit of this is discussed, in particular in a view of the prevailing strong constraints in personnel and money resources.

  6. Optimal Hedge for Nodal Price Risk using FTR

    NASA Astrophysics Data System (ADS)

    Tanaka, Hiroaki; Makino, Michiko; Ichida, Yoshio; Akiyoshi, Masanori

    As the deregulation of electric business proceeds, each company needs to construct a risk hedging system. So far many companies have not been taking much care of this suffciently. In this paper, we address the nodal price hedge issue. Most companies have risks for the nodal prices which tend to be highly volatile. There's almost no doubt that such a company actually needs hedge products to make profits stable. We suggest the usage of FTR for this purpose. First, we briefly note the mechanisms of nodal price in PJM market and FTR, and suggest the mathematical formulations. Then we show some numerical examples and discuss our findings.

  7. Tunable Weyl Points in Periodically Driven Nodal Line Semimetals.

    PubMed

    Yan, Zhongbo; Wang, Zhong

    2016-08-19

    Weyl semimetals and nodal line semimetals are characterized by linear band touching at zero-dimensional points and one-dimensional lines, respectively. We predict that a circularly polarized light drives nodal line semimetals into Weyl semimetals. The Floquet Weyl points thus obtained are tunable by the incident light, which enables investigations of them in a highly controllable manner. The transition from nodal line semimetals to Weyl semimetals is accompanied by the emergence of a large and tunable anomalous Hall conductivity. Our predictions are experimentally testable by transport measurement in film samples or by pump-probe angle-resolved photoemission spectroscopy. PMID:27588882

  8. Morphogen Electrochemically Triggered Self-Construction of Polymeric Films Based on Mussel-Inspired Chemistry.

    PubMed

    Maerten, Clément; Garnier, Tony; Lupattelli, Paolo; Chau, Nguyet Trang Thanh; Schaaf, Pierre; Jierry, Loïc; Boulmedais, Fouzia

    2015-12-15

    Inspired by the strong chemical adhesion mechanism of mussels, we designed a catechol-based electrochemically triggered self-assembly of films based on ethylene glycol molecules bearing catechol groups on both sides and denoted as bis-catechol molecules. These molecules play the role of morphogens and, in contrast to previously investigated systems, they are also one of the constituents, after reaction, of the film. Unable to interact together, commercially available poly(allylamine hydrochloride) (PAH) chains and bis-catechol molecules are mixed in an aqueous solution and brought in contact with an electrode. By application of defined potential cycles, bis-catechol molecules undergo oxidation leading to molecules bearing "reactive" quinone groups which diffuse toward the solution. In this active state, the quinones react with amino groups of PAH through Michael addition and Schiff's base condensation reaction. The application of cyclic voltammetry (CV) between 0 and 500 mV (vs Ag/AgCl, scan rate of 50 mV/s) of a PAH/bis-catechol solution results in a fast self-construction of a film that reaches a thickness of 40 nm after 60 min. The films present a spiky structure which is attributed to the use of bis-functionalized molecules as one component of the films. XPS measurements show the presence of both PAH and bis-catechol cross-linked together in a covalent way. We show that the amine/catechol ratio is an important parameter which governs the film buildup. For a given amine/catechol ratio, it does exist an optimum CV scan rate leading to a maximum of the film thickness as a function of the scan rate. PMID:26575431

  9. Curcumin Inhibits Prostate Cancer Bone Metastasis by Up-Regulating Bone Morphogenic Protein-7 in Vivo

    PubMed Central

    Dorai, Thambi; Diouri, Janane; O'Shea, Orla; Doty, Stephen B.

    2014-01-01

    A number of studies have focused on the beneficial properties of Curcumin (diferuloyl methane, used in South Asian cuisine and traditional medicine) such as the chemoprevention of cancer. Recent studies have also indicated that this material has significant benefits for the treatment of cancer and is currently undergoing several clinical trials. We have been interested in the application of this compound as a therapeutic agent for advanced prostate cancer, particularly the skeletal complications in this malignancy. Our earlier work indicated that this compound could inhibit the osteomimetic properties which occur in castration resistant prostate cancer cells, by interfering with the common denominators between these cancer cells and the bone cells in the metastatic tumor microenvironment, namely the osteoblasts and the osteoclast. We predicted that curcumin could break the vicious cycle of reciprocal stimulation that results in uncontrolled osteolysis in the bony matrix. In this work, we have evaluated the potential of this compound in inhibiting the bone metastasis of hormone refractory prostate cancer cells in an established animal model. Our results strongly suggest that curcumin modulates the TGF-β signaling that occurs due to bone matrix degradation by up-regulating the metastasis inhibitory bone morphogenic protein-7 (BMP- 7). This enhancement of BMP-7 in the context of TGF-βin the tumor microenvironment is shown to enhance the mesenchymal-to-epithelial transition. Most importantly, we show that as a result of BMP-7 up-regulation, a novel brown/beige adipogenic differentiation program is also up-regu- lated which plays a role in the inhibition of bone metastasis. Our results suggest that curcumin may subvert the TGF-βsignaling to an alternative adipogenic differentiation program in addition to the previously established interference with the osteomimetic properties, thus inhibiting the bone metastatic processes in a chemopreventive as well as therapeutic

  10. Curcumin Inhibits Prostate Cancer Bone Metastasis by Up-Regulating Bone Morphogenic Protein-7 in Vivo.

    PubMed

    Dorai, Thambi; Diouri, Janane; O'Shea, Orla; Doty, Stephen B

    2014-04-01

    A number of studies have focused on the beneficial properties of Curcumin (diferuloyl methane, used in South Asian cuisine and traditional medicine) such as the chemoprevention of cancer. Recent studies have also indicated that this material has significant benefits for the treatment of cancer and is currently undergoing several clinical trials. We have been interested in the application of this compound as a therapeutic agent for advanced prostate cancer, particularly the skeletal complications in this malignancy. Our earlier work indicated that this compound could inhibit the osteomimetic properties which occur in castration resistant prostate cancer cells, by interfering with the common denominators between these cancer cells and the bone cells in the metastatic tumor microenvironment, namely the osteoblasts and the osteoclast. We predicted that curcumin could break the vicious cycle of reciprocal stimulation that results in uncontrolled osteolysis in the bony matrix. In this work, we have evaluated the potential of this compound in inhibiting the bone metastasis of hormone refractory prostate cancer cells in an established animal model. Our results strongly suggest that curcumin modulates the TGF-β signaling that occurs due to bone matrix degradation by up-regulating the metastasis inhibitory bone morphogenic protein-7 (BMP- 7). This enhancement of BMP-7 in the context of TGF-βin the tumor microenvironment is shown to enhance the mesenchymal-to-epithelial transition. Most importantly, we show that as a result of BMP-7 up-regulation, a novel brown/beige adipogenic differentiation program is also up-regu- lated which plays a role in the inhibition of bone metastasis. Our results suggest that curcumin may subvert the TGF-βsignaling to an alternative adipogenic differentiation program in addition to the previously established interference with the osteomimetic properties, thus inhibiting the bone metastatic processes in a chemopreventive as well as therapeutic

  11. Public awareness of the bone morphogenic protein controversy: Evidence from news publications

    PubMed Central

    Drazin, Doniel; Shweikeh, Faris; Wieshofer, Erich; Kim, Terrence T.; Johnson, J. Patrick

    2014-01-01

    Background: Use of recombinant human bone morphogenic protein-2 (rhBMP-2) in spinal fusion has seen a tremendous increase. Public awareness of rhBMP-2 and its complications has not been assessed. The authors studied published news media articles to analyze information provided to the public on this bone graft substitute. Methods: We utilized the academic database, LexisNexis, to locate newspaper articles published between January 2001 and July 2013. All articles were coded by a coder and reviewed by the principal investigator. Results: The search identified 87 national and 99 local newspaper articles. Complications mentioned in national newspapers included cancer (24%), retrograde ejaculation (24%), and abnormal bone growth (14%). Local newspapers cited cancer (14%), inflammation (14%), and retrograde ejaculation (9.2%) most frequently. Fifty national (59%) and 35 local (54%) articles had no mention of complications. Sources of evidence cited by articles were (in order of frequency): Governmental agencies, medical research or published studies, healthcare personnel or patients, and companies or corporations. Conclusions: Only a small percentage of newspaper articles presented potential complications. Despite lack of clear scientific causal relationship between rhBMP-2 and cancer, this risk was disproportionately reported. Additionally, many did not cite scientific sources. Lack of reliable information available to the public reiterates the role of physicians in discussing risks and benefits BMP use in spinal surgery, assuring that patients are making informed decisions. Future news media articles should present risks in an impartial and evidence-based manner. Collaboration between advocacy groups, medical institutions, and media outlets would be beneficial in achieving this goal. PMID:25593772

  12. Present Status of GNF New Nodal Simulator

    SciTech Connect

    Iwamoto, T.; Tamitani, M.; Moore, B.

    2001-06-17

    This paper presents core simulator consolidation work done at Global Nuclear Fuel (GNF). The unified simulator needs to supercede the capabilities of past simulator packages from the original GNF partners: GE, Hitachi, and Toshiba. At the same time, an effort is being made to produce a simulation package that will be a state-of-the-art analysis tool when released, in terms of the physics solution methodology and functionality. The core simulator will be capable and qualified for (a) high-energy cycles in the U.S. markets, (b) mixed-oxide (MOX) introduction in Japan, and (c) high-power density plants in Europe, etc. The unification of the lattice physics code is also in progress based on a transport model with collision probability methods. The AETNA core simulator is built upon the PANAC11 software base. The goal is to essentially replace the 1.5-energy-group model with a higher-order multigroup nonlinear nodal solution capable of the required modeling fidelity, while keeping highly automated library generation as well as functionality. All required interfaces to PANAC11 will be preserved, which minimizes the impact on users and process automation. Preliminary results show statistical accuracy improvement over the 1.5-group model.

  13. Classification, Electrophysiological Features and Therapy of Atrioventricular Nodal Reentrant Tachycardia

    PubMed Central

    Josephson, Mark E

    2016-01-01

    Atrioventricular nodal reentrant tachycardia (AVNRT) should be classified as typical or atypical. The term ‘fast-slow AVNRT’ is rather misleading. Retrograde atrial activation during tachycardia should not be relied upon as a diagnostic criterion. Both typical and atypical atrioventricular nodal reentrant tachycardia are compatible with varying retrograde atrial activation patterns. Attempts at establishing the presence of a ‘lower common pathway’ are probably of no practical significance. When the diagnosis of AVNRT is established, ablation should be only directed towards the anatomic position of the slow pathway. If right septal attempts are unsuccessful, the left septal side should be tried. Ablation targeting earliest atrial activation sites during typical atrioventricular nodal reentrant tachycardia or the fast pathway in general for any kind of typical or atypical atrioventricular nodal reentrant tachycardia, are not justified. In this review we discuss current concepts about the tachycardia circuit, electrophysiologic diagnosis, and ablation of this arrhythmia.

  14. Nodal analysis for reactor kinetics and stability. [PWR; BWR

    SciTech Connect

    Park, J.K.; Becker, M.; Park, G.C.

    1983-07-01

    General space kinetics models have been developed for more accurate stability analysis utilizing nodal analysis, a commonly used technique for analyzing power distributions in large power reactors. Kinetics parameters for use in these kinetics models have been properly derived by utilizing self-consistent nodal data and power distributions. The procedure employed in the nodal code SIMULATE has been utilized for power distribution, since that methodology is general and includes various commonly used nodal methods as special cases. Cross sections are correlated as functions of void fraction and exposure. A computer program investigating thermo-hydrodynamic stability, NUFREQ has been modified to accommodate general spatial kinetics models with an improved thermal-hydraulics model. Stability analyses have been performed for density wave oscillations for a representative operating BWR system. Spatial coupling effects on the stability margins were found to be significant.

  15. BEACON: An application of nodal methods for operational support

    SciTech Connect

    Boyd, W.A.; Nguyen, T.Q. )

    1992-01-01

    A practical application of nodal methods is on-line plant operational support. However, to enable plant personnel to take full advantage of a nodal model to support plant operations, (a) a core nodal model must always be up to date with the current core history and conditions, (b) the nodal methods must be fast enough to allow numerous core calculations to be performed in minutes to support engineering decisions, and (c) the system must be easily accessible to engineering personnel at the reactor, their offices, or any other location considered appropriate. A core operational support package developed by Westinghouse called BEACON (best estimate analysis of core operations - nuclear) has been installed at several plants. Results from these plants and numerous in-core flux maps analyzed have demonstrated the accuracy of the model and the effectiveness of the methodology

  16. Bilinear nodal transport method in weighted diamond difference form

    SciTech Connect

    Azmy, Y.Y.

    1987-01-01

    Nodal methods have been developed and implemented for the numerical solution of the discrete ordinates neutron transport equation. Numerical testing of these methods and comparison of their results to those obtained by conventional methods have established the high accuracy of nodal methods. Furthermore, it has been suggested that the linear-linear approximation is the most computationally efficient, practical nodal approximation. Indeed, this claim has been substantiated by comparing the accuracy in the solution, and the CPU time required to achieve convergence to that solution by several nodal approximations, as well as the diamond difference scheme. Two types of linear-linear nodal methods have been developed in the literature: analytic linear-linear (NLL) methods, in which the transverse-leakage terms are derived analytically, and approximate linear-linear (PLL) methods, in which these terms are approximated. In spite of their higher accuracy, NLL methods result in very complicated discrete-variable equations that exhibit a high degree of coupling, thus requiring special solution algorithms. On the other hand, the sacrificed accuracy in PLL methods is compensated for by the simple discrete-variable equations and diamond-difference-like solution algorithm. In this paper the authors outline the development of an NLL nodal method, the bilinear method, which can be written in a weighted diamond difference form with one spatial weight per dimension that is analytically derived rather than preassigned in an ad hoc fashion.

  17. Stochastic Cell Fate Progression in Embryonic Stem Cells

    NASA Astrophysics Data System (ADS)

    Zou, Ling-Nan; Doyle, Adele; Jang, Sumin; Ramanathan, Sharad

    2013-03-01

    Studies on the directed differentiation of embryonic stem (ES) cells suggest that some early developmental decisions may be stochastic in nature. To identify the sources of this stochasticity, we analyzed the heterogeneous expression of key transcription factors in single ES cells as they adopt distinct germ layer fates. We find that under sufficiently stringent signaling conditions, the choice of lineage is unambiguous. ES cells flow into differentiated fates via diverging paths, defined by sequences of transitional states that exhibit characteristic co-expression of multiple transcription factors. These transitional states have distinct responses to morphogenic stimuli; by sequential exposure to multiple signaling conditions, ES cells are steered towards specific fates. However, the rate at which cells travel down a developmental path is stochastic: cells exposed to the same signaling condition for the same amount of time can populate different states along the same path. The heterogeneity of cell states seen in our experiments therefore does not reflect the stochastic selection of germ layer fates, but the stochastic rate of progression along a chosen developmental path. Supported in part by the Jane Coffin Childs Fund

  18. Critical Timing without a Timer for Embryonic Development.

    PubMed

    Tufcea, Daniel E; François, Paul

    2015-10-20

    Timing of embryonic development is precisely controlled, but the mechanisms underlying biological timers are still unclear. Here, a validated model for timing under control of Sonic Hedgehog is revisited and generalized to an arbitrary number of genes. The developmental dynamics where a temporal sequence of gene expression recapitulates a steady-state spatial pattern can be realized through a simple network close to criticality, controlled by the duration of exposure to a morphogen. Criticality simultaneously accounts for many observed biological properties, such as timing, multistability, and canalization of genetic expression. This process can be parsimoniously generalized in many dimensions with a minimum number of genes, all repressing each other with asymmetrical strengths, which also explains sequential activation of different fates. Separation of timescales allows for a simple analytical interpretation. Finally, it is shown that even in the presence of noise, coupling between cells preserves criticality and robust patterning. The model offers a simple theoretical framework for the study of emergent developmental timers. PMID:26488664

  19. Organoids and the genetically encoded self‐assembly of embryonic stem cells

    PubMed Central

    Baillie‐Johnson, Peter

    2015-01-01

    Understanding the mechanisms of early embryonic patterning and the timely allocation of specific cells to embryonic regions and fates as well as their development into tissues and organs, is a fundamental problem in Developmental Biology. The classical explanation for this process had been built around the notion of positional information. Accordingly the programmed appearance of sources of Morphogens at localized positions within a field of cells directs their differentiation. Recently, the development of organs and tissues from unpatterned and initially identical stem cells (adult and embryonic) has challenged the need for positional information and even the integrity of the embryo, for pattern formation. Here we review the emerging area of organoid biology from the perspective of Developmental Biology. We argue that the events underlying the development of these systems are not purely linked to “self‐organization,” as often suggested, but rather to a process of genetically encoded self‐assembly where genetic programs encode and control the emergence of biological structures. PMID:26666846

  20. Chordin forms a self-organizing morphogen gradient in the extracellular space between ectoderm and mesoderm in the Xenopus embryo

    PubMed Central

    Plouhinec, Jean-Louis; Zakin, Lise; Moriyama, Yuki; De Robertis, Edward M.

    2013-01-01

    The vertebrate body plan follows stereotypical dorsal–ventral (D-V) tissue differentiation controlled by bone morphogenetic proteins (BMPs) and secreted BMP antagonists, such as Chordin. The three germ layers—ectoderm, mesoderm, and endoderm—are affected coordinately by the Chordin–BMP morphogen system. However, extracellular morphogen gradients of endogenous proteins have not been directly visualized in vertebrate embryos to date. In this study, we improved immunolocalization methods in Xenopus embryos and analyzed the distribution of endogenous Chordin using a specific antibody. Chordin protein secreted by the dorsal Spemann organizer was found to diffuse along a narrow region that separates the ectoderm from the anterior endoderm and mesoderm. This Fibronectin-rich extracellular matrix is called “Brachet’s cleft” in the Xenopus gastrula and is present in all vertebrate embryos. Chordin protein formed a smooth gradient that encircled the embryo, reaching the ventral-most Brachet cleft. Depletion with morpholino oligos showed that this extracellular gradient was regulated by the Chordin protease Tolloid and its inhibitor Sizzled. The Chordin gradient, as well as the BMP signaling gradient, was self-regulating and, importantly, was able to rescale in dorsal half-embryos. Transplantation of Spemann organizer tissue showed that Chordin diffused over long distances along this signaling highway between the ectoderm and mesoderm. Chordin protein must reach very high concentrations in this narrow region. We suggest that as ectoderm and mesoderm undergo morphogenetic movements during gastrulation, cells in both germ layers read their positional information coordinately from a single morphogen gradient located in Brachet’s cleft. PMID:24284174

  1. Miz1 Is Required for Early Embryonic Development during Gastrulation

    PubMed Central

    Adhikary, Sovana; Peukert, Karen; Karsunky, Holger; Beuger, Vincent; Lutz, Werner; Elsässer, Hans-Peter; Möröy, Tarik; Eilers, Martin

    2003-01-01

    Miz1 is a member of the POZ domain/zinc finger transcription factor family. In vivo, Miz1 forms a complex with the Myc oncoprotein and recruits Myc to core promoter elements. Myc represses transcription through Miz1 binding sites. We now show that the Miz1 gene is ubiquitously expressed during mouse embryogenesis. In order to elucidate the physiological function of Miz1, we have deleted the mouse Miz1 gene by homologous recombination. Miz1+/− mice are indistinguishable from wild-type animals; in contrast, Miz1−/− embryos are not viable. They are severely retarded in early embryonic development and do not undergo normal gastrulation. Expression of Goosecoid and Brachyury is detectable in Miz1−/− embryos, suggesting that Miz1 is not required for signal transduction by Nodal. Expression of p21Cip1, a target gene of Miz1 is unaltered; in contrast, expression of p57Kip2, another target gene of Miz1 is absent in Miz1−/− embryos. Miz1−/− embryos succumb to massive apoptosis of ectodermal cells around day 7.5 of embryonic development. Our results show that Miz1 is required for early embryonic development during gastrulation. PMID:14560010

  2. Gravity and embryonic development

    NASA Technical Reports Server (NTRS)

    Young, R. S.

    1976-01-01

    The relationship between the developing embryo (both plant and animal) and a gravitational field has long been contemplated. The difficulty in designing critical experiments on the surface of the earth because of its background of 1 g, has been an obstacle to a resolution of the problem. Biological responses to gravity (particularly in plants) are obvious in many cases; however, the influence of gravity as an environmental input to the developing embryo is not as obvious and has proven to be extremely difficult to define. In spite of this, over the years numerous attempts have been made using a variety of embryonic materials to come to grips with the role of gravity in development. Three research tools are available: the centrifuge, the clinostat, and the orbiting spacecraft. Experimental results are now available from all three sources. Some tenuous conclusions are drawn, and an attempt at a unifying theory of gravitational influence on embryonic development is made.

  3. Intraosseous Delivery of Bone Morphogenic Protein-2 Using a Self-Assembling Peptide Hydrogel.

    PubMed

    Phipps, Matthew C; Monte, Felipe; Mehta, Manav; Kim, Harry K W

    2016-07-11

    Osteonecrosis of the femoral head (ONFH) is a debilitating hip disorder, which often produces a permanent femoral head deformity and osteoarthritis. The local delivery of biological agents capable of stimulating bone healing offer potential new treatment options for patients with ONFH. Previous studies from our laboratory have shown that a local intraosseous infusion of bone morphogenic protein-2 (BMP-2) was effective in stimulating new bone formation in a piglet model of ischemic ONFH. However, infusion of BMP-2 solution was associated with unwanted dissemination of BMP-2 out of the femoral head and produced heterotopic ossification in the hip capsule. Injectable hydrogels offer a potential method to control the dissemination of biological molecules in vivo. In the present study, we evaluated the potential of a peptide-based, self-assembling hydrogel called RADA16 to transition from a solution to a gel following infusion into the femoral head, thereby preventing backflow, as well as its potential use as a delivery vehicle for BMP-2. Cadaver pig femoral heads were used to study the backflow and the distribution of RADA16 following an intraosseous infusion. Microcomputed tomography analysis following the infusion of RADA16 mixed with a radiocontrast agent revealed a significant decrease in the amount of back flow of radiocontrast agent down the needle track compared to the soluble infusion of radiocontrast without RADA16. Furthermore, RADA16 mixed with radiocontrast agent showed good distribution within the femoral head. In addition, in vitro experiments revealed that higher concentrations of RADA16 decreased the rate of BMP-2 dissemination out of the hydrogel. The BMP-2 that was released from RADA16 maintains its biological activity, inducing the phosphorylation of SMAD1/5/8 in pig primary bone marrow stromal cells. Lastly, pig primary bone marrow stromal cells showed significantly increased in vitro proliferation on RADA16 hydrogels over 1 week compared to tissue

  4. Noggin enhances dopamine neuron production from human embryonic stem cells and improves behavioral outcome after transplantation into Parkinsonian rats.

    PubMed

    Chiba, Shunmei; Lee, Young Mook; Zhou, Wenbo; Freed, Curt R

    2008-11-01

    Symptoms of Parkinson's disease have been improved by transplantation of fetal dopamine neurons recovered from aborted fetal tissue, but tissue recovery is difficult. Human embryonic stem cells may provide unlimited cells for transplantation if they can be converted to dopamine neurons and survive transplantation into brain. We have found that the bone morphogenic protein antagonist Noggin increased the number of dopamine neurons generated in vitro from human and mouse embryonic stem cells differentiated on mouse PA6 stromal cells. Noggin effects were seen with either early (for mouse, days 0-7, and for human, days 0-9) or continuous treatment. After transplant into cyclosporin-immunosuppressed rats, human dopamine neurons improved apomorphine circling in direct relation to the number of surviving dopamine neurons, which was fivefold greater after Noggin treatment than with control human embryonic stem cell transplants differentiated only on PA6 cells. We conclude that Noggin promotes dopamine neuron differentiation and survival from human and mouse embryonic stem cells. Disclosure of potential conflicts of interest is found at the end of this article. PMID:18772316

  5. The interplay of matrix metalloproteinases, morphogens and growth factors is necessary for branching of mammary epithelial cells

    SciTech Connect

    Simian, M.; Harail, Y.; Navre, M.; Werb, Z.; Lochter, A.; Bissell, M.J.

    2002-03-06

    The mammary gland develops its adult form by a process referred to as branching morphogenesis. Many factors have been reported to affect this process. We have used cultured primary mammary epithelial organoids and mammary epithelial cell lines in three-dimensional collagen gels to elucidate which growth factors, matrix metalloproteinases (MMPs) and mammary morphogens interact in branching morphogenesis. Branching stimulated by stromal fibroblasts, epidermal growth factor, fibroblast growth factor 7, fibroblast growth factor 2 and hepatocyte growth factor was strongly reduced by inhibitors of MMPs, indicating the requirement of MMPs for three-dimensional growth involved in morphogenesis. Recombinant stromelysin 1/MMP-3 alone was sufficient to drive branching in the absence of growth factors in the organoids. Plasmin also stimulated branching; however, plasmin-dependent branching was abolished by both inhibitors of plasmin and MMPs, suggesting that plasmin activates MMPs. To differentiate between signals for proliferation and morphogenesis, we used a cloned mammary epithelial cell line that lacks epimorphin, an essential mammary morphogen. Both epimorphin and MMPs were required for morphogenesis, but neither was required for epithelial cell proliferation. These results provide direct evidence for a critical role of MMPs in branching in mammary epithelium and suggest that, in addition to epimorphin, MMP activity is a minimum requirement for branching morphogenesis in the mammary gland.

  6. Nodal signaling promotes a tumorigenic phenotype in human breast cancer.

    PubMed

    Kirsammer, Gina; Strizzi, Luigi; Margaryan, Naira V; Gilgur, Alina; Hyser, Matthew; Atkinson, Janis; Kirschmann, Dawn A; Seftor, Elisabeth A; Hendrix, Mary J C

    2014-12-01

    The Ras-ERK pathway is deregulated in approximately a third of human cancers, particularly those of epithelial origin. In aggressive, triple-negative, basal-like breast cancers, most tumors display increased MEK and ERK phosphorylation and exhibit a gene expression profile characteristic of Kras or EGFR mutant tumors; however, Ras family genetic mutations are uncommon in triple-negative breast cancer and EGFR mutations account for only a subset of these tumors. Therefore, the upstream events that activate MAPK signaling and promote tumor aggression in triple-negative breast cancers remain poorly defined. We have previously shown that a secreted TGF-β family signaling ligand, Nodal, is expressed in breast cancer in correlation with disease progression. Here we highlight key findings demonstrating that Nodal is required in aggressive human breast cancer cells to activate ERK signaling and downstream tumorigenic phenotypes both in vitro and in vivo. Experimental knockdown of Nodal signaling downregulates ERK activity, resulting in loss of c-myc, upregulation of p27, G1 cell cycle arrest, increased apoptosis and decreased tumorigenicity. The data suggest that ERK activation by Nodal signaling regulates c-myc and p27 proteins post-translationally and that this cascade is essential for aggressive breast tumor behavior in vivo. As the MAPK pathway is an important target for treating triple-negative breast cancers, upstream Nodal signaling may represent a promising target for breast cancer diagnosis and combined therapies aimed at blocking ERK pathway activation. PMID:25073112

  7. Nodal signaling promotes a tumorigenic phenotype in human breast cancer

    PubMed Central

    Kirsammer, Gina; Strizzi, Luigi; Margaryan, Naira V.; Gilgur, Alina; Hyser, Matthew; Atkinson, Janis; Kirschmann, Dawn A.; Seftor, Elisabeth A.; Hendrix, Mary J.C.

    2014-01-01

    The Ras-ERK pathway is deregulated in approximately a third of human cancers, particularly those of epithelial origin. In aggressive, triple-negative, basal-like breast cancers, most tumors display increased MEK and ERK phosphorylation and exhibit a gene expression profile characteristic of Kras or EGFR mutant tumors; however, Ras family genetic mutations are uncommon in triple-negative breast cancer and EGFR mutations account for only a subset of these tumors. Therefore, the upstream events that activate MAPK signaling and promote tumor aggression in triple-negative breast cancers remain poorly defined. We have previously shown that a secreted TGF-β family signaling ligand, Nodal, is expressed in breast cancer in correlation with disease progression. Here we highlight key findings demonstrating that Nodal is required in aggressive human breast cancer cells to activate ERK signaling and downstream tumorigenic phenotypes both in vitro and in vivo. Experimental knockdown of Nodal signaling downregulates ERK activity, resulting in loss of c-myc, upregulation of p27, G1 cell cycle arrest, increased apoptosis and decreased tumorigenicity. The data suggest that ERK activation by Nodal signaling regulates c-myc and p27 proteins post-translationally and that this cascade is essential for aggressive breast tumor behavior in vivo. As the MAPK pathway is an important target for treating triple-negative breast cancers, upstream Nodal signaling may represent a promising target for breast cancer diagnosis and combined therapies aimed at blocking ERK pathway activation. PMID:25073112

  8. Magnesium and Embryonic Development

    PubMed Central

    Komiya, Yuko; Su, Li-Ting; Chen, Hsiang-Chin; Habas, Raymond; Runnels, Loren W.

    2014-01-01

    Important for energy metabolism, neurotransmission, bone stability, and other cellular functions, Mg2+ has well-established and undisputedly critical roles in adult tissues. Its contributions to early embryonic development are less clearly understood. For decades it has been known that gestational Mg2+ deficiency in rodents produces teratogenic effects. More recent studies have linked deficiency in this vital cation to birth defects in humans, including spina bifida, a neural fold closure defect in humans that occurs at an average rate of 1 per 1000 pregnancies. The first suggestion that Mg2+ may be playing a more specific role in early development arose from studies of the TRPM7 and TRPM6 ion channels. TRPM7 and TRPM6 are divalent-selective ion channels in possession of their own kinase domains that have been implicated in the control of Mg2+ homeostasis in vertebrates. Disruption of the functions of these ion channels in mice as well as in frogs interferes with gastrulation, a pivotal process during early embryonic development that executes the emergence of the body plan and closure of the neural tube. Surprisingly, gastrulation defects produced by depletion of TRPM7 can be prevented by Mg2+ supplementation, indicating an essential role for Mg2+ in gastrulation and neural fold closure. The aim of this review is to summarize the data emerging from molecular genetic, biochemical and electrophysiological studies of TRPM6 and TRPM7 and provide a model of how Mg2+, through these unique channel-kinases, may be impacting early embryonic development. PMID:24721994

  9. A computational study of nodal-based tetrahedral element behavior.

    SciTech Connect

    Gullerud, Arne S.

    2010-09-01

    This report explores the behavior of nodal-based tetrahedral elements on six sample problems, and compares their solution to that of a corresponding hexahedral mesh. The problems demonstrate that while certain aspects of the solution field for the nodal-based tetrahedrons provide good quality results, the pressure field tends to be of poor quality. Results appear to be strongly affected by the connectivity of the tetrahedral elements. Simulations that rely on the pressure field, such as those which use material models that are dependent on the pressure (e.g. equation-of-state models), can generate erroneous results. Remeshing can also be strongly affected by these issues. The nodal-based test elements as they currently stand need to be used with caution to ensure that their numerical deficiencies do not adversely affect critical values of interest.

  10. Super-nodal methods for space-time kinetics

    NASA Astrophysics Data System (ADS)

    Mertyurek, Ugur

    The purpose of this research has been to develop an advanced Super-Nodal method to reduce the run time of 3-D core neutronics models, such as in the NESTLE reactor core simulator and FORMOSA nuclear fuel management optimization codes. Computational performance of the neutronics model is increased by reducing the number of spatial nodes used in the core modeling. However, as the number of spatial nodes decreases, the error in the solution increases. The Super-Nodal method reduces the error associated with the use of coarse nodes in the analyses by providing a new set of cross sections and ADFs (Assembly Discontinuity Factors) for the new nodalization. These so called homogenization parameters are obtained by employing consistent collapsing technique. During this research a new type of singularity, namely "fundamental mode singularity", is addressed in the ANM (Analytical Nodal Method) solution. The "Coordinate Shifting" approach is developed as a method to address this singularity. Also, the "Buckling Shifting" approach is developed as an alternative and more accurate method to address the zero buckling singularity, which is a more common and well known singularity problem in the ANM solution. In the course of addressing the treatment of these singularities, an effort was made to provide better and more robust results from the Super-Nodal method by developing several new methods for determining the transverse leakage and collapsed diffusion coefficient, which generally are the two main approximations in the ANM methodology. Unfortunately, the proposed new transverse leakage and diffusion coefficient approximations failed to provide a consistent improvement to the current methodology. However, improvement in the Super-Nodal solution is achieved by updating the homogenization parameters at several time points during a transient. The update is achieved by employing a refinement technique similar to pin-power reconstruction. A simple error analysis based on the relative

  11. A transient, quadratic nodal method for triangular-Z geometry

    SciTech Connect

    DeLorey, T.F.

    1993-06-01

    Many systematically-derived nodal methods have been developed for Cartesian geometry due to the extensive interest in Light Water Reactors. These methods typically model the transverse-integrated flux as either an analytic or low order polynomial function of position within the node. Recently, quadratic nodal methods have been developed for R-Z and hexagonal geometry. A static and transient quadratic nodal method is developed for triangular-Z geometry. This development is particularly challenging because the quadratic expansion in each node must be performed between the node faces and the triangular points. As a consequence, in the 2-D plane, the flux and current at the points of the triangles must be treated. Quadratic nodal equations are solved using a non-linear iteration scheme, which utilizes the corrected, mesh-centered finite difference equations, and forces these equations to match the quadratic equations by computing discontinuity factors during the solution. Transient nodal equations are solved using the improved quasi-static method, which has been shown to be a very efficient solution method for transient problems. Several static problems are used to compare the quadratic nodal method to the Coarse Mesh Finite Difference (CMFD) method. The quadratic method is shown to give more accurate node-averaged fluxes. However, it appears that the method has difficulty predicting node leakages near reactor boundaries and severe material interfaces. The consequence is that the eigenvalue may be poorly predicted for certain reactor configurations. The transient methods are tested using a simple analytic test problem, a heterogeneous heavy water reactor benchmark problem, and three thermal hydraulic test problems. Results indicate that the transient methods have been implemented correctly.

  12. Chiral Spin-Orbital Liquids with Nodal Lines

    NASA Astrophysics Data System (ADS)

    Natori, W. M. H.; Andrade, E. C.; Miranda, E.; Pereira, R. G.

    2016-07-01

    Strongly correlated materials with strong spin-orbit coupling hold promise for realizing topological phases with fractionalized excitations. Here, we propose a chiral spin-orbital liquid as a stable phase of a realistic model for heavy-element double perovskites. This spin liquid state has Majorana fermion excitations with a gapless spectrum characterized by nodal lines along the edges of the Brillouin zone. We show that the nodal lines are topological defects of a non-Abelian Berry connection and that the system exhibits dispersing surface states. We discuss some experimental signatures of this state and compare them with properties of the spin liquid candidate Ba2YMoO6.

  13. Long period nodal motion of sun synchronous orbits

    NASA Technical Reports Server (NTRS)

    Duck, K. I.

    1975-01-01

    An approximative model is formulated for assessing these perturbations that significantly affect long term modal motion of sun synchronous orbits. Computer simulations with several independent computer programs consider zonal and tesseral gravitational harmonics, third body gravitational disturbances induced by the sun and the moon, and atmospheric drag. A pendulum model consisting of evenzonal harmonics through order 4 and solar gravity dominated nodal motion approximation. This pendulum motion results from solar gravity inducing an inclination oscillation which couples into the nodal precession induced by the earth's oblateness. The pendulum model correlated well with simulations observed flight data.

  14. Comparison between submucosal (extra-nodal) and nodal non-Hodgkin's lymphoma (NHL) in the oral and maxillofacial region.

    PubMed

    Shindoh, M; Takami, T; Arisue, M; Yamashita, T; Saito, T; Kohgo, T; Notani, K; Totsuka, Y; Amemiya, A

    1997-07-01

    Fifty-two cases of non-Hodgkin's lymphoma (NHL) in the oral and maxillofacial region, comprising 31 submucosal (extra-nodal) and 21 cervical node NHLs, were investigated. The patients' ages ranged from 5 to 86 years, with a bimodal age distribution among young people below 12 years of age (average 8 years) and in those aged 30 years or older (average 60.3 years). The male-to-female gender difference ratio was 1.3:1. Patients presented with swelling as the major symptom. Histologically, diffuse, large cell malignant lymphoma was the most frequent type and 67.9% of lymphomas were of intermediate malignancy as defined by the Working Formulation for Clinical Usage. All submucosal lymphomas showed diffuse proliferation patterns, although follicular proliferation was identified in 5 of the 21 nodal lymphomas. Immunohistochemistry showed that the B-cell type was predominant, especially in nodal lymphomas. PMID:9234189

  15. A transient, Hex-Z nodal code corrected by discontinuity factors. Volume 1: The transient nodal code; Final report

    SciTech Connect

    Shatilla, Y.A.M.; Henry, A.F.

    1993-12-31

    This document constitutes Volume 1 of the Final Report of a three-year study supported by the special Research Grant Program for Nuclear Energy Research set up by the US Department of Energy. The original motivation for the work was to provide a fast and accurate computer program for the analysis of transients in heavy water or graphite-moderated reactors being considered as candidates for the New Production Reactor. Thus, part of the funding was by way of pass-through money from the Savannah River Laboratory. With this intent in mind, a three-dimensional (Hex-Z), general-energy-group transient, nodal code was created, programmed, and tested. In order to improve accuracy, correction terms, called {open_quotes}discontinuity factors,{close_quotes} were incorporated into the nodal equations. Ideal values of these factors force the nodal equations to provide node-integrated reaction rates and leakage rates across nodal surfaces that match exactly those edited from a more exact reference calculation. Since the exact reference solution is needed to compute the ideal discontinuity factors, the fact that they result in exact nodal equations would be of little practical interest were it not that approximate discontinuity factors, found at a greatly reduced cost, often yield very accurate results. For example, for light-water reactors, discontinuity factors found from two-dimensional, fine-mesh, multigroup transport solutions for two-dimensional cuts of a fuel assembly provide very accurate predictions of three-dimensional, full-core power distributions. The present document (volume 1) deals primarily with the specification, programming and testing of the three-dimensional, Hex-Z computer program. The program solves both the static (eigenvalue) and transient, general-energy-group, nodal equations corrected by user-supplied discontinuity factors.

  16. Effect of Embryonic Cerebrospinal Fluid on Proliferation and Differentiation of Neuroprogenitor Cells

    PubMed Central

    Yari, Siamak; Parivar, Kazem; Nabiuni, Mohammad; Keramatipour, Mohammad

    2013-01-01

    Objective: Embryonic cerebrospinal fluid (e-CSF) has an important role in development of embryonic and adult brain. Proteomic analysis suggests that this fluid has many morphogenes and cytokines that alter in time and space throughout embryonic life. The aim of this study was to evaluate the developmental effect of embryonic CSF on proliferation and differentiation of neuroprogenitor cells in different gestational age. Materials and Methods: In this In this experimental study, we examined the role of e- CSF on proliferation and differentiation of neuroprogenitor cells using neurosphere culture method. Neurospheres size analysis and MTT assay were used to assess cell proliferation after four days in vitro. Glial differentiation study was carried out by immunocytochemistry. Neurospheres size and percentage of glial fibrialy acidic protein (GFAP) positive cells were measured by image analyzer (image J). The data were analyzed by one-way ANOVA, followed by the Tukey’s post hoc test. Data were expressed as mean ± SEM, and differences were considered significant when p<0.05, 0.01 and 0.001. Results: Viability and proliferation of neuro progenitor cells in cultures conditioned with E16 CSF and E18 CSF were significantly increased compare to control group. A dramatic decrease in percentage of GFAP-positive cells was found following the application of CSF from E16 and E18 embryos, but not E20 CSF. Conclusion: Our data suggest that, e-CSF altered proliferation and differentiation of neuro progenitor cells in age dependent manner. E16 and E18 CSF enhanced proliferation and viability of neuro progenitor cells, and inhibited differentiation to glial fate in comparison with control group. PMID:23700558

  17. PoroTomo Subtask 6.3 Nodal Seismometers Metadata

    DOE Data Explorer

    Lesley Parker

    2016-03-28

    Metadata for the nodal seismometer array deployed at the POROTOMO's Natural Laboratory in Brady Hot Spring, Nevada during the March 2016 testing. Metadata includes location and timing for each instrument as well as file lists of data to be uploaded in a separate submission.

  18. Bud emergence and shoot growth from mature citrus nodal segments

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bud emergence and shoot growth from adult phase citrus nodal cultures were studied using Citrus mitis (calamondin), Citrus paradisi (grapefruit), and Citrus sinensis (sweet orange). The effects of 6-benzylaminopurine (BA), indole 3-acetic acid (IAA), and citrus type on shoot quality and growth fro...

  19. Nodal Structure and the Partitioning of Equivalence Classes

    ERIC Educational Resources Information Center

    Fields, Lanny; Watanabe-Rose, Mari

    2008-01-01

    By definition, all of the stimuli in an equivalence class have to be functionally interchangeable with each other. The present experiment, however, demonstrated that this was not the case when using post-class-formation dual-option response transfer tests. With college students, two 4-node 6-member equivalence classes with nodal structures of…

  20. 47 CFR 101.503 - Digital Electronic Message Service Nodal Stations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 47 Telecommunication 5 2010-10-01 2010-10-01 false Digital Electronic Message Service Nodal... AND SPECIAL RADIO SERVICES FIXED MICROWAVE SERVICES 24 GHz Service and Digital Electronic Message Service § 101.503 Digital Electronic Message Service Nodal Stations. 10.6 GHz DEMS Nodal Stations may...

  1. 47 CFR 101.503 - Digital Electronic Message Service Nodal Stations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 47 Telecommunication 5 2011-10-01 2011-10-01 false Digital Electronic Message Service Nodal... AND SPECIAL RADIO SERVICES FIXED MICROWAVE SERVICES 24 GHz Service and Digital Electronic Message Service § 101.503 Digital Electronic Message Service Nodal Stations. 10.6 GHz DEMS Nodal Stations may...

  2. Wave pinning and spatial patterning in a mathematical model of Antivin/Lefty-Nodal signalling.

    PubMed

    Middleton, A M; King, J R; Loose, M

    2013-12-01

    Nodal signals are key regulators of mesoderm and endoderm development in vertebrate embryos. It has been observed experimentally that in Xenopus embryos the spatial range of Nodal signals is restricted by the signal Antivin (also known as Lefty). Nodal signals can activate both Nodal and Antivin, whereas Antivin is thought to antagonise Nodal by binding either directly to it or to its receptor. In this paper we develop a mathematical model of this signalling network in a line of cells. We consider the heterodimer and receptor-mediated inhibition mechanisms separately and find that, in both cases, the restriction by Antivin to the range of Nodal signals corresponds to wave pinning in the model. Our analysis indicates that, provided Antivin diffuses faster than Nodal, either mechanism can robustly account for the experimental data. We argue that, in the case of Xenopus development, it is wave pinning, rather than Turing-type patterning, that is underlying Nodal-Antivin dynamics. This leads to several experimentally testable predictions, which are discussed. Furthermore, for heterodimer-mediated inhibition to prevent waves of Nodal expression from propagating, the Nodal-Antivin complex must be turned over, and diffusivity of the complex must be negligible. In the absence of molecular mechanisms regulating these, we suggest that Antivin restricts Nodal signals via receptor-mediated, and not heterodimer-mediated, inhibition. PMID:23070212

  3. Intra and Interfraction Mediastinal Nodal Region Motion: Implications for Internal Target Volume Expansions

    SciTech Connect

    Thomas, Jonathan G.; Kashani, Rojano; Balter, James M.; Tatro, Daniel; Kong, F.-M.; Pan, Charlie C.

    2009-07-01

    The purpose of this study was to determine the intra and interfraction motion of mediastinal lymph node regions. Ten patients with nonsmall-cell lung cancer underwent controlled inhale and exhale computed tomography (CT) scans during two sessions (40 total datasets) and mediastinal nodal stations 1-8 were outlined. Corresponding CT scans from different sessions were registered to remove setup error and, in this reference frame, the centroid of each nodal station was compared for right-left (RL), anterior-posterior (AP), and superior-inferior (SI) displacement. In addition, an anisotropic volume expansion encompassing the change of the nodal region margins in all directions was used. Intrafraction displacement was determined by comparing same session inhale-exhale scans. Interfraction reproducibility of nodal regions was determined by comparing the same respiratory phase scans between two sessions. Intrafraction displacement of centroid varied between nodal stations. All nodal regions moved posteriorly and superiorly with exhalation, and inferior nodal stations showed the most motion. Based on anisotropic expansion, nodal regions expanded mostly in the RL direction from inhale to exhale. The interpatient variations in intrafraction displacement were large compared with the displacements themselves. Moreover, there was substantial interfractional displacement ({approx}5 mm). Mediastinal lymph node regions clearly move during breathing. In addition, deformation of nodal regions between inhale and exhale occurs. The degree of motion and deformation varies by station and by individual. This study indicates the potential advantage of characterizing individualized nodal region motion to safely maximize conformality of mediastinal nodal targets.

  4. MicroRNA-127 Promotes Mesendoderm Differentiation of Mouse Embryonic Stem Cells by Targeting Left-Right Determination Factor 2.

    PubMed

    Ma, Haixia; Lin, Yu; Zhao, Zhen-Ao; Lu, Xukun; Yu, Yang; Zhang, Xiaoxin; Wang, Qiang; Li, Lei

    2016-06-01

    Specification of the three germ layers is a fundamental process and is essential for the establishment of organ rudiments. Multiple genetic and epigenetic factors regulate this dynamic process; however, the function of specific microRNAs in germ layer differentiation remains unknown. In this study, we established that microRNA-127 (miR-127) is related to germ layer specification via microRNA array analysis of isolated three germ layers of E7.5 mouse embryos and was verified through differentiation of mouse embryonic stem cells. miR-127 is highly expressed in endoderm and primitive streak. Overexpression of miR-127 increases and inhibition of miR-127 decreases the expression of mesendoderm markers. We further show that miR-127 promotes mesendoderm differentiation through the nodal pathway, a determinative signaling pathway in early embryogenesis. Using luciferase reporter assay, left-right determination factor 2 (Lefty2), an antagonist of nodal, is identified to be a novel target of miR-127. Furthermore, the role of miR-127 in mesendoderm differentiation is attenuated by Lefty2 overexpression. Altogether, our results indicate that miR-127 accelerates mesendoderm differentiation of mouse embryonic stem cells through nodal signaling by targeting Lefty2. PMID:27072135

  5. Off-diagonal Jacobian support for Nodal BCs

    SciTech Connect

    Peterson, John W.; Andrs, David; Gaston, Derek R.; Permann, Cody J.; Slaughter, Andrew E.

    2015-01-01

    In this brief note, we describe the implementation of o-diagonal Jacobian computations for nodal boundary conditions in the Multiphysics Object Oriented Simulation Environment (MOOSE) [1] framework. There are presently a number of applications [2{5] based on the MOOSE framework that solve complicated physical systems of partial dierential equations whose boundary conditions are often highly nonlinear. Accurately computing the on- and o-diagonal Jacobian and preconditioner entries associated to these constraints is crucial for enabling ecient numerical solvers in these applications. Two key ingredients are required for properly specifying the Jacobian contributions of nonlinear nodal boundary conditions in MOOSE and nite element codes in general: 1. The ability to zero out entire Jacobian matrix rows after \

  6. Long-range Coulomb interaction in nodal-ring semimetals

    NASA Astrophysics Data System (ADS)

    Huh, Yejin; Moon, Eun-Gook; Kim, Yong Baek

    2016-01-01

    Recently there have been several proposals of materials predicted to be nodal-ring semimetals, where zero energy excitations are characterized by a nodal ring in the momentum space. This class of materials falls between the Dirac-like semimetals and the more conventional Fermi-surface systems. As a step towards understanding this unconventional system, we explore the effects of the long-range Coulomb interaction. Due to the vanishing density of states at the Fermi level, Coulomb interaction is only partially screened and remains long-ranged. Through renormalization group and large-Nf computations, we have identified a nontrivial interacting fixed point. The screened Coulomb interaction at the interacting fixed point is an irrelevant perturbation, allowing controlled perturbative evaluations of physical properties of quasiparticles. We discuss unique experimental consequences of such quasiparticles: acoustic wave propagation, anisotropic dc conductivity, and renormalized phonon dispersion as well as energy dependence of quasiparticle lifetime.

  7. Nodal failure index approach to groundwater remediation design

    USGS Publications Warehouse

    Lee, J.; Reeves, H.W.; Dowding, C.H.

    2008-01-01

    Computer simulations often are used to design and to optimize groundwater remediation systems. We present a new computationally efficient approach that calculates the reliability of remedial design at every location in a model domain with a single simulation. The estimated reliability and other model information are used to select a best remedial option for given site conditions, conceptual model, and available data. To evaluate design performance, we introduce the nodal failure index (NFI) to determine the number of nodal locations at which the probability of success is below the design requirement. The strength of the NFI approach is that selected areas of interest can be specified for analysis and the best remedial design determined for this target region. An example application of the NFI approach using a hypothetical model shows how the spatial distribution of reliability can be used for a decision support system in groundwater remediation design. ?? 2008 ASCE.

  8. Anomalous contagion and renormalization in networks with nodal mobility

    NASA Astrophysics Data System (ADS)

    Manrique, Pedro D.; Qi, Hong; Zheng, Minzhang; Xu, Chen; Hui, Pak Ming; Johnson, Neil F.

    2016-07-01

    A common occurrence in everyday human activity is where people join, leave and possibly rejoin clusters of other individuals —whether this be online (e.g. social media communities) or in real space (e.g. popular meeting places such as cafes). In the steady state, the resulting interaction network would appear static over time if the identities of the nodes are ignored. Here we show that even in this static steady-state limit, a non-zero nodal mobility leads to a diverse set of outbreak profiles that is dramatically different from known forms, and yet matches well with recent real-world social outbreaks. We show how this complication of nodal mobility can be renormalized away for a particular class of networks.

  9. Concomitant nodal involvement by Langerhans cell histiocytosis and Hodgkin's lymphoma.

    PubMed

    Geurten, Claire; Thiry, Albert; Jamblin, Paul; Demarche, Martine; Hoyoux, Claire

    2015-12-01

    A 10-year-old girl with a family history of Hodgkin's lymphoma presented with a 2 month history of cervical lymphadenopathy and weight loss. Biopsy indicated concomitant nodal involvement by Langerhans cell histiocytosis and Hodgkin's lymphoma. Such an association is rare, especially so in children, but is not an isolated phenomenon, thereby prompting the question of whether Langerhans cell histiocytosis is a reactive or a neoplastic process. PMID:26556799

  10. NODAL PATHWAY GENES ARE DOWNREGULATED IN FACIAL ASYMMETRY

    PubMed Central

    Nicot, Romain; Hottenstein, Molly; Raoul, Gwenael; Ferri, Joel; Horton, Michael; Tobias, John W.; Barton, Elisabeth; Gelé, Patrick; Sciote, James J.

    2014-01-01

    Purpose Facial asymmetry is a common comorbid condition in patients with jaw deformation malocclusion. Heritability of malocclusion is advancing rapidly, but very little is known regarding genetic contributions to asymmetry. This study identifies differences in expression of key asymmetry-producing genes which are down regulated in facial asymmetry patients. Material and Methods Masseter muscle samples were collected during BSSO orthognathic surgery to correct skeletal-based malocclusion. Patients were classified as Class II or III and open or deep bite malocclusion with or without facial asymmetry. Muscle samples were analyzed for gene expression differences on Affymetrix HT2.0 microarray global expression chips. Results Overall gene expression was different for asymmetric patients compared to other malocclusion classifications by principal component analysis (P<0.05). We identified differences in the nodal signaling pathway (NSP) which promotes development of mesoderm and endoderm and left-right patterning during embryogenesis. Nodal and Lefty expression was 1.39–1.84 fold greater (P<3.41×10−5) whereas integral membrane Nodal-modulators Nomo1,2,3 were −5.63 to −5.81 (P<3.05×10−4) less in asymmetry subjects. Fold differences among intracellular pathway members were negative in the range of −7.02 to −2.47 (P<0.003). Finally Pitx2, a upstream effector of Nodal known to influence the size of type II skeletal muscle fibers was also significantly decreased in facial asymmetry (P<0.05). Conclusions When facial asymmetry is part of skeletal malocclusion there are decreases of NSP genes in masseter muscle. This data suggests that the NSP is down regulated to help promote development of asymmetry. Pitx2 expression differences also contributed to both skeletal and muscle development in this condition. PMID:25364968

  11. Nodal Basin Recurrence After Sentinel Lymph Node Biopsy for Melanoma

    PubMed Central

    Kretschmer, Lutz; Bertsch, Hans Peter; Zapf, Antonia; Mitteldorf, Christina; Satzger, Imke; Thoms, Kai-Martin; Völker, Bernward; Schön, Michael Peter; Gutzmer, Ralf; Starz, Hans

    2015-01-01

    Abstract The objective of this study was to analyze different types of nodal basin recurrence after sentinel lymph node biopsy (SLNB) for melanoma. Patients and Methods: Kaplan–Meier estimates and the Cox proportional hazards model were used to study 2653 patients from 3 German melanoma centers retrospectively. The estimated 5-year negative predictive value of SLNB was 96.4%. The estimated false-negative (FN) rates after 1, 2, 3, 5, and 10 years were 2.5%, 4.6%, 6.4%, 8.7%, and 12.6%, respectively. Independent factors associated with false negativity were older age, fewer SLNs excised, and head or neck location of the primary tumor. Compared with SLN-positive patients, the FNs had a significantly lower survival. In SLN-positive patients undergoing completion lymphadenectomy (CLND), the 5-year nodal basin recurrence rate was 18.3%. The recurrence rates for axilla, groin, and neck were 17.2%, 15.5%, and 44.1%, respectively. Significant factors predicting local relapse after CLND were older age, head, or neck location of the primary tumor, ulceration, deeper penetration of the metastasis into the SLN, tumor-positive CLND, and >2 lymph node metastases. All kinds of nodal relapse were associated with a higher prevalence of in-transit metastases. The FN rate after SLNB steadily increases over the observation period and should, therefore, be estimated by the Kaplan–Meier method. False-negativity is associated with fewer SLNs excised. The beneficial effect of CLND on nodal basin disease control varies considerably across different risk groups. This should be kept in mind about SLN-positive patients when individual decisions on prophylactic CLND are taken. PMID:26356697

  12. Nodal equivalence theory for hexagonal geometry, thermal reactor analysis

    SciTech Connect

    Zika, M.; Downar, T. )

    1992-01-01

    An important aspect of advanced nodal methods is the determination of equivalent few-group parameters for the relatively large homogenized regions used in the nodal flux solution. The theoretical foundation for light water reactor (LWR) assembly homogenization methods has been clearly established, and during the last several years, its successes have secured its position in the stable of dependable LWR analysis methods. Groupwise discontinuity factors that correct for assembly homogenization errors are routinely generated along with the group constants during lattice physics analysis. During the last several years, there has been interest in applying equivalence theory to other reactor types and other geometries. A notable effort has been the work at Argonne National Laboratory to incorporate nodal equivalence theory (NET) for hexagonal lattices into the nodal diffusion option of the DIF3D code. This work was originally intended to improve the neutronics methods used for the analysis of the Experimental Breeder Reactor II (EBR-II), and Ref. 4 discusses the success of that application. More recently, however, attempts were made to apply NET to advanced, thermal reactor designs such as the modular high-temperature gas reactor (MHTGR) and the new production heavy water reactor (NPR/HWR). The same methods that were successful for EBR-II have encountered problems for these reactors. Our preliminary analysis indicates that the sharp global flux gradients in these cores requires large discontinuity factors (greater than 4 or 5) to reproduce the reference solution. This disrupts the convergence of the iterative methods used to solve for the node-wise flux moments and partial currents. Several attempts to remedy the problem have been made over the last few years, including bounding the discontinuity factors and providing improved initial guesses for the flux solution, but nothing has been satisfactory.

  13. LSST Telescope Alignment Plan Based on Nodal Aberration Theory

    NASA Astrophysics Data System (ADS)

    Sebag, J.; Gressler, W.; Schmid, T.; Rolland, J. P.; Thompson, K. P.

    2012-04-01

    The optical alignment of the Large Synoptic Survey Telescope (LSST) is potentially challenging, due to its fast three-mirror optical design and its large 3.5° field of view (FOV). It is highly advantageous to align the three-mirror optical system prior to the integration of the complex science camera on the telescope, which corrects the FOV via three refractive elements and includes the operational wavefront sensors. A telescope alignment method based on nodal aberration theory (NAT) is presented here to address this challenge. Without the science camera installed on the telescope, the on-axis imaging performance of the telescope is diffraction-limited, but the field of view is not corrected. The nodal properties of the three-mirror telescope design have been analyzed and an alignment approach has been developed using the intrinsically linear nodal behavior, which is linked via sensitivities to the misalignment parameters. Since mirror figure errors will exist in any real application, a methodology to introduce primary-mirror figure errors into the analysis has been developed and is also presented.

  14. Upper bound shakedown analysis with the nodal natural element method

    NASA Astrophysics Data System (ADS)

    Zhou, Shutao; Liu, Yinghua; Wang, Dongdong; Wang, Kai; Yu, Suyuan

    2014-11-01

    In this paper, a novel numerical solution procedure is developed for the upper bound shakedown analysis of elastic-perfectly plastic structures. The nodal natural element method (nodal-NEM) combines the advantages of the NEM and the stabilized conforming nodal integration scheme, and is used to discretize the established mathematical programming formulation of upper bound shakedown analysis based on Koiter's theorem. In this formulation, the displacement field is approximated by using the Sibson interpolation and the difficulty caused by the time integration is solved by König's technique. Meanwhile, the nonlinear and non-differentiable characteristic of objective function is overcome by distinguishing non-plastic areas from plastic areas and modifying associated constraint conditions and goal function at each iteration step. Finally, the objective function subjected to several equality constraints is linearized and the upper bound shakedown load multiplier is obtained. This direct iterative process can ensure the shakedown load to monotonically converge to the upper bound of true solution. Several typical numerical examples confirm the efficiency and accuracy of the proposed method.

  15. Topological Phase Transitions in Line-nodal Superconductors

    NASA Astrophysics Data System (ADS)

    Cho, Gil Young; Han, Sangeun; Moon, Eun-Gook

    Fathoming interplay between symmetry and topology of many-electron wave-functions deepens our understanding in quantum nature of many particle systems. Topology often protects zero-energy excitation, and in a certain class, symmetry is intrinsically tied to the topological protection. Namely, unless symmetry is broken, topological nature is intact. We study one specific case of such class, symmetry-protected line-nodal superconductors in three spatial dimensions (3d). Mismatch between phase spaces of order parameter fluctuation and line-nodal fermion excitation induces an exotic universality class in a drastic contrast to one of the conventional ϕ4 theory in 3d. Hyper-scaling violation and relativistic dynamic scaling with unusually large quantum critical region are main characteristics, and their implication in experiments is discussed. For example, continuous phase transition out of line-nodal superconductors has a linear phase boundary in a temperature-tuning parameter phase-diagram. This work was supported by the Brain Korea 21 PLUS Project of Korea Government and KAIST start-up funding.

  16. A nodal domain theorem for integrable billiards in two dimensions

    SciTech Connect

    Samajdar, Rhine; Jain, Sudhir R.

    2014-12-15

    Eigenfunctions of integrable planar billiards are studied — in particular, the number of nodal domains, ν of the eigenfunctions with Dirichlet boundary conditions are considered. The billiards for which the time-independent Schrödinger equation (Helmholtz equation) is separable admit trivial expressions for the number of domains. Here, we discover that for all separable and non-separable integrable billiards, ν satisfies certain difference equations. This has been possible because the eigenfunctions can be classified in families labelled by the same value of mmodkn, given a particular k, for a set of quantum numbers, m,n. Further, we observe that the patterns in a family are similar and the algebraic representation of the geometrical nodal patterns is found. Instances of this representation are explained in detail to understand the beauty of the patterns. This paper therefore presents a mathematical connection between integrable systems and difference equations. - Highlights: • We find that the number of nodal domains of eigenfunctions of integrable, planar billiards satisfy a class of difference equations. • The eigenfunctions labelled by quantum numbers (m,n) can be classified in terms of mmodkn. • A theorem is presented, realising algebraic representations of geometrical patterns exhibited by the domains. • This work presents a connection between integrable systems and difference equations.

  17. Anomalous scaling of the penetration depth in nodal superconductors

    NASA Astrophysics Data System (ADS)

    She, Jian-Huang; Lawler, Michael J.; Kim, Eun-Ah

    2015-07-01

    Recent findings of anomalous superlinear scaling of low-temperature (T ) penetration depth (PD) in several nodal superconductors near putative quantum critical points suggest that the low-temperature PD can be a useful probe of quantum critical fluctuations in a superconductor. On the other hand, cuprates, which are poster child nodal superconductors, have not shown any such anomalous scaling of PD, despite growing evidence of quantum critical points (QCP). Then it is natural to ask when and how can quantum critical fluctuations cause anomalous scaling of PD? Carrying out the renormalization group calculation for the problem of two-dimensional superconductors with point nodes, we show that quantum critical fluctuations associated with a point group symmetry reduction result in nonuniversal logarithmic corrections to the T dependence of the PD. The resulting apparent power law depends on the bare velocity anisotropy ratio. We then compare our results to data sets from two distinct nodal superconductors: YBa2Cu3O6.95 and CeCoIn5. Considering all symmetry-lowering possibilities of the point group of interest, C4 v, we find our results to be remarkably consistent with YBa2Cu3O6.95 being near a vertical nematic QCP and CeCoIn5 being near a diagonal nematic QCP. Our results motivate a search for diagonal nematic fluctuations in CeCoIn5.

  18. Sequential injection immunoassay for human bone morphogenic protein-7 using an immunoreactor immobilized with anti-human bone morphogenic protein-7 antibody--CdSe/ZnS quantum dot conjugates.

    PubMed

    Kim, Chun-Kwang; Duong, Hong Dinh; Rhee, Jong Il

    2013-07-01

    The detection of human bone morphogenic protein-7 (BMP-7) was achieved using a sequential injection immunoassay (SIIA) system. The SIIA system is based on the binding between BMP-7 and anti-human BMP-7 (AbBMP7)-CdSe/ZnS quantum dot (QD) conjugates immobilized onto a glass disk or an optical fiber, using fluorescence detection at excitation and emission wavelengths of 470 nm and 580 nm, respectively. The AbBMP7-QD conjugates were prepared by conjugating anti-human BMP-7 antibody (AbBMP7) to hydrophilic CdSe/ZnS core/shell quantum dots (QDs). The SIIA system was fully automated using software written in the LabVIEW™ development environment. The analytical performance of the SIIA system was characterized with a number of variables such as carrier flow rate and elution buffer. Under partially optimized operating conditions, the SIIA system had a linear calibration graph at up to 10.0 ng mL(-1) BMP-7 (R(2)≥0.975) and a sample frequency of two samples per hour. The SIIA system with an optical fiber immunosensor was used to detect and quantify BMP-7 in spiked real samples obtained from a biological process with recoveries in the range of 95-102%. PMID:23790295

  19. Modulation of ornithine decarboxylase activity in the normal and regenerating rat liver by various doses of the peptide morphogen of Hydra

    SciTech Connect

    Yarygin, K.N.; Kazimirskii, A.N.; Kositskii, G.I.; Rubina, A.Yu.; Vinogradov, V.A.; Pylaev, A.S.

    1986-11-01

    In this investigation, changes in ornithine decarboxylase (ODC) activity were studied in the normal and regenerating liver of rats receiving injections of various doses of Hydra peptide morphogen (HPM). Activity of ODC was determined by a radioisotope method based on liberation of /sup 14/CO/sub 2/ from L-(1-/sup 14/C)-ornithine. The results indicate in the author's opinion that HPM may have a role in the regulation of anabolic processes and, in particular, of regenerative processes in mammals.

  20. Mechanotransduction in Embryonic Vascular Development

    PubMed Central

    Roman, Beth L.; Pekkan, Kerem

    2015-01-01

    A plethora of biochemical signals provides spatial and temporal cues that carefully orchestrate the complex process of vertebrate embryonic development. The embryonic vasculature develops not only in the context of these biochemical cues, but also in the context of the biomechanical forces imparted by blood flow. In the mature vasculature, different blood flow regimes induce distinct genetic programs, and significant progress has been made toward understanding how these forces are perceived by endothelial cells and transduced into biochemical signals. However, it cannot be assumed that paradigms that govern the mature vasculature are pertinent to the developing embryonic vasculature. The embryonic vasculature can respond to the mechanical forces of blood flow, and these responses are critical in vascular remodeling, certain aspects of sprouting angiogenesis, and maintenance of arterial-venous identity. Here, we review data regarding mechanistic aspects of endothelial cell mechanotransduction, with a focus on the response to shear stress, and elaborate upon the multifarious effects of shear stress on the embryonic vasculature. In addition, we discuss emerging predictive vascular growth models and highlight the prospect of combining signaling pathway information with computational modeling. We assert that correlation of precise measurements of hemodynamic parameters with effects on endothelial cell gene expression and cell behavior is required for fully understanding how blood flow-induced loading governs normal vascular development and shapes congenital cardiovascular abnormalities. PMID:22744845

  1. The morphogen Decapentaplegic employs a two-tier mechanism to activate target retinal determining genes during ectopic eye formation in Drosophila.

    PubMed

    Aggarwal, Poonam; Gera, Jayati; Mandal, Lolitika; Mandal, Sudip

    2016-01-01

    Understanding the role of morphogen in activating its target genes, otherwise epigenetically repressed, during change in cell fate specification is a very fascinating yet relatively unexplored domain. Our in vivo loss-of-function genetic analyses reveal that specifically during ectopic eye formation, the morphogen Decapentaplegic (Dpp), in conjunction with the canonical signaling responsible for transcriptional activation of retinal determining (RD) genes, triggers another signaling cascade. Involving dTak1 and JNK, this pathway down-regulates the expression of polycomb group of genes to do away with their repressive role on RD genes. Upon genetic inactivation of members of this newly identified pathway, the canonical Dpp signaling fails to trigger RD gene expression beyond a threshold, critical for ectopic photoreceptor differentiation. Moreover, the drop in ectopic RD gene expression and subsequent reduction in ectopic photoreceptor differentiation resulting from inactivation of dTak1 can be rescued by down-regulating the expression of polycomb group of genes. Our results unravel an otherwise unknown role of morphogen in coordinating simultaneous transcriptional activation and de-repression of target genes implicating its importance in cellular plasticity. PMID:27270790

  2. The morphogen Decapentaplegic employs a two-tier mechanism to activate target retinal determining genes during ectopic eye formation in Drosophila

    PubMed Central

    Aggarwal, Poonam; Gera, Jayati; Mandal, Lolitika; Mandal, Sudip

    2016-01-01

    Understanding the role of morphogen in activating its target genes, otherwise epigenetically repressed, during change in cell fate specification is a very fascinating yet relatively unexplored domain. Our in vivo loss-of-function genetic analyses reveal that specifically during ectopic eye formation, the morphogen Decapentaplegic (Dpp), in conjunction with the canonical signaling responsible for transcriptional activation of retinal determining (RD) genes, triggers another signaling cascade. Involving dTak1 and JNK, this pathway down-regulates the expression of polycomb group of genes to do away with their repressive role on RD genes. Upon genetic inactivation of members of this newly identified pathway, the canonical Dpp signaling fails to trigger RD gene expression beyond a threshold, critical for ectopic photoreceptor differentiation. Moreover, the drop in ectopic RD gene expression and subsequent reduction in ectopic photoreceptor differentiation resulting from inactivation of dTak1 can be rescued by down-regulating the expression of polycomb group of genes. Our results unravel an otherwise unknown role of morphogen in coordinating simultaneous transcriptional activation and de-repression of target genes implicating its importance in cellular plasticity. PMID:27270790

  3. Bone regeneration using hyaluronic acid-based hydrogel with bone morphogenic protein-2 and human mesenchymal stem cells.

    PubMed

    Kim, Jungju; Kim, In Sook; Cho, Tae Hyung; Lee, Kyu Back; Hwang, Soon Jung; Tae, Giyoong; Noh, Insup; Lee, Sang Hoon; Park, Yongdoo; Sun, Kyung

    2007-04-01

    Acrylated hyaluronic acid (HA) was used as a scaffold for bone morphogenic protein-2 (BMP-2) and human mesenchymal stem cells (hMSCs) for rat calvarial defect regeneration. HA was acrylated by two-step reactions: (1) introduction of an amine group using adipic acid dihydrazide (ADH); (2) acrylation by N-acryloxysuccinimide. Tetrathiolated poly(ethylene) glycol (PEG-SH(4)) was used as a cross-linker by a Michael-type addition reaction and the hydrogel was formed within 10min under physiological conditions. This hydrogel is degraded completely by 100U/ml hyaluronidase in vitro. hMSCs and/or BMP-2 was added during gelation. Cellular viability in vitro was increased up to 55% in the hydrogels with BMP-2 compared with the control. For in vivo calvarial defect regeneration, five different samples (i.e., control, hydrogel, hydrogel with BMP-2, hydrogel with MSCs, and hydrogel with BMP-2 and MSCs) were implanted for 4 weeks. The histological results demonstrated that the hydrogels with BMP-2 and MSCs had the highest expression of osteocalcin and mature bone formation with vascular markers, such as CD31 and vascular endothelial growth factors, compared with the other samples. This study demonstrated that HA base hydrogel can be used for cell and growth factor carriers for tissue regeneration. PMID:17208295

  4. The Immunologic Properties of Bone Morphogenic Protein Receptor IB Positive Subpopulation before and after Osteogenic Differentiation in Mouse Dermis

    PubMed Central

    Wang, Tao; Xu, Hua; Zhang, Yi; Dong, Jia-Sheng

    2016-01-01

    We have previously reported that human dermal bone morphogenic protein receptor (BMPR) IB positive subpopulation had a high osteogenic differentiation potential and may be a promising cell source for allogeneic bone tissue engineering. In this study, the immunologic properties of dermal BMPR-IB+ subpopulation before and after osteogenic differentiation were reported. The results confirmed that dermal BMPR-IB+ cells possessed a similar osteogenic differentiation potential with bone marrow mesenchymal stromal cells in a mouse model. Furthermore, the expression of immune rejection-related surface antigens such as major histocompatibility class II and co-stimulatory proteins (CD40, CD80, and CD86) were absent on dermal BMPRIB+ cells. Dermal BMPRIB+ cells elicited no proliferation of allogeneic splenocytes and suppressed the proliferation of stimulated immune cells. Interestingly, osteogenic differentiation in vitro had no adverse effect on the immunological features of these cells. Most importantly, inducible NO synthase (iNOS) was involved in immunoregulatory effects by undifferentiated BMPRIB+ fibroblasts, whereas indoleamine 2,3-dioxygenase (IDO) activity was related to mediating immunomodulatory function by osteogenic differentiated BMPRIB+ fibroblasts. In conclusion, dermal BMPRIB+ cells have a low immunogenicity and possess immunosuppressive capacity before and after osteogenic differentiation in vitro, which would facilitate the allotransplantation in the future. However, mechanisms mediating immunoregulatory property between undifferentiated and osteogenic differentiated BMPRIB+ fibroblasts may be different and need further investigation. PMID:27552226

  5. Human type II receptor for bone morphogenic proteins (BMPs): extension of the two-kinase receptor model to the BMPs.

    PubMed Central

    Liu, F; Ventura, F; Doody, J; Massagué, J

    1995-01-01

    Bone morphogenic proteins (BMPs) are universal regulators of animal development. We report the identification and cloning of the BMP type II receptor (BMPR-II), a missing component of this receptor system in vertebrates. BMPR-II is a transmembrane serine/threonine kinase that binds BMP-2 and BMP-7 in association with multiple type I receptors, including BMPR-IA/Brk1, BMPR-IB, and ActR-I, which is also an activin type I receptor. Cloning of BMPR-II resulted from a strong interaction of its cytoplasmic domain with diverse transforming growth factor beta family type I receptor cytoplasmic domains in a yeast two-hybrid system. In mammalian cells, however, the interaction of BMPR-II is restricted to BMP type I receptors and is ligand dependent. BMPR-II binds BMP-2 and -7 on its own, but binding is enhanced by coexpression of type I BMP receptors. BMP-2 and BMP-7 can induce a transcriptional response when added to cells coexpressing ActR-I and BMPR-II but not to cells expressing either receptor alone. The kinase activity of both receptors is essential for signaling. Thus, despite their ability to bind to type I and II receptors receptors separately, BMPs appear to require the cooperation of these two receptors for optimal binding and for signal transduction. The combinatorial nature of these receptors and their capacity to crosstalk with the activin receptor system may underlie the multifunctional nature of their ligands. PMID:7791754

  6. The Immunologic Properties of Bone Morphogenic Protein Receptor IB Positive Subpopulation before and after Osteogenic Differentiation in Mouse Dermis.

    PubMed

    He, Jin-Guang; Wang, Ting-Liang; Wang, Tao; Xu, Hua; Zhang, Yi; Dong, Jia-Sheng

    2016-01-01

    We have previously reported that human dermal bone morphogenic protein receptor (BMPR) IB positive subpopulation had a high osteogenic differentiation potential and may be a promising cell source for allogeneic bone tissue engineering. In this study, the immunologic properties of dermal BMPR-IB+ subpopulation before and after osteogenic differentiation were reported. The results confirmed that dermal BMPR-IB+ cells possessed a similar osteogenic differentiation potential with bone marrow mesenchymal stromal cells in a mouse model. Furthermore, the expression of immune rejection-related surface antigens such as major histocompatibility class II and co-stimulatory proteins (CD40, CD80, and CD86) were absent on dermal BMPRIB+ cells. Dermal BMPRIB+ cells elicited no proliferation of allogeneic splenocytes and suppressed the proliferation of stimulated immune cells. Interestingly, osteogenic differentiation in vitro had no adverse effect on the immunological features of these cells. Most importantly, inducible NO synthase (iNOS) was involved in immunoregulatory effects by undifferentiated BMPRIB+ fibroblasts, whereas indoleamine 2,3-dioxygenase (IDO) activity was related to mediating immunomodulatory function by osteogenic differentiated BMPRIB+ fibroblasts. In conclusion, dermal BMPRIB+ cells have a low immunogenicity and possess immunosuppressive capacity before and after osteogenic differentiation in vitro, which would facilitate the allotransplantation in the future. However, mechanisms mediating immunoregulatory property between undifferentiated and osteogenic differentiated BMPRIB+ fibroblasts may be different and need further investigation. PMID:27552226

  7. Response of millet and sorghum to a varying water supply around the primary and nodal roots

    PubMed Central

    Rostamza, M.; Richards, R. A.; Watt, M.

    2013-01-01

    Background and Aims Cereals have two root systems. The primary system originates from the embryo when the seed germinates and can support the plant until it produces grain. The nodal system can emerge from stem nodes throughout the plant's life; its value for yield is unclear and depends on the environment. The aim of this study was to test the role of nodal roots of sorghum and millet in plant growth in response to variation in soil moisture. Sorghum and millet were chosen as both are adapted to dry conditions. Methods Sorghum and millet were grown in a split-pot system that allowed the primary and nodal roots to be watered separately. Key Results When primary and nodal roots were watered (12 % soil water content; SWC), millet nodal roots were seven times longer than those of sorghum and six times longer than millet plants in dry treatments, mainly from an 8-fold increase in branch root length. When soil was allowed to dry in both compartments, millet nodal roots responded and grew 20 % longer branch roots than in the well-watered control. Sorghum nodal roots were unchanged. When only primary roots received water, nodal roots of both species emerged and elongated into extremely dry soil (0·6–1·5 % SWC), possibly with phloem-delivered water from the primary roots in the moist inner pot. Nodal roots were thick, short, branchless and vertical, indicating a tropism that was more pronounced in millet. Total nodal root length increased in both species when the dry soil was covered with plastic, suggesting that stubble retention or leaf mulching could facilitate nodal roots reaching deeper moist layers in dry climates. Greater nodal root length in millet than in sorghum was associated with increased shoot biomass, water uptake and water use efficiency (shoot mass per water). Millet had a more plastic response than sorghum to moisture around the nodal roots due to (1) faster growth and progression through ontogeny for earlier nodal root branch length and (2

  8. Differential diffusivity of Nodal and Lefty underlies a reaction-diffusion patterning system

    PubMed Central

    Müller, Patrick; Rogers, Katherine W.; Jordan, Ben M.; Lee, Joon S.; Robson, Drew; Ramanathan, Sharad; Schier, Alexander F.

    2012-01-01

    Biological systems involving short-range activators and long-range inhibitors can generate complex patterns. Reaction-diffusion models postulate that differences in signaling range are caused by differential diffusivity of inhibitor and activator. Other models suggest that differential clearance underlies different signaling ranges. To test these models, we measured the biophysical properties of the Nodal/Lefty activator/inhibitor system during zebrafish embryogenesis. Analysis of Nodal and Lefty gradients reveals that Nodals have a shorter range than Lefty proteins. Pulse-labelinganalysis indicates that Nodals and Leftys have similar clearance kinetics, whereas fluorescence recovery assays reveal that Leftys have a higher effective diffusion coefficient than Nodals. These results indicate that differential diffusivity is the major determinant of the differences in Nodal/Lefty range and provide biophysical support for reaction-diffusion models of activator/inhibitor-mediated patterning. PMID:22499809

  9. Approximate Schur complement preconditioning of the lowest order nodal discretizations

    SciTech Connect

    Moulton, J.D.; Ascher, U.M.; Morel, J.E.

    1996-12-31

    Particular classes of nodal methods and mixed hybrid finite element methods lead to equivalent, robust and accurate discretizations of 2nd order elliptic PDEs. However, widespread popularity of these discretizations has been hindered by the awkward linear systems which result. The present work exploits this awkwardness, which provides a natural partitioning of the linear system, by defining two optimal preconditioners based on approximate Schur complements. Central to the optimal performance of these preconditioners is their sparsity structure which is compatible with Dendy`s black box multigrid code.

  10. Evaluation of the use of nodal methods for MTR neutronic analysis

    SciTech Connect

    Reitsma, F.; Mueller, E.Z.

    1997-08-01

    Although modern nodal methods are used extensively in the nuclear power industry, their use for research reactor analysis has been very limited. The suitability of nodal methods for material testing reactor analysis is investigated with the emphasis on the modelling of the core region (fuel assemblies). The nodal approach`s performance is compared with that of the traditional finite-difference fine mesh approach. The advantages of using nodal methods coupled with integrated cross section generation systems are highlighted, especially with respect to data preparation, simplicity of use and the possibility of performing a great variety of reactor calculations subject to strict time limitations such as are required for the RERTR program.

  11. Nodal systems with maximal domain of exactness for Gaussian quadrature formulas

    NASA Astrophysics Data System (ADS)

    Berriochoa, E.; Cachafeiro, A.

    2008-03-01

    The aim of this work is to study quadrature formulas for measures on the complex plane. The novelty of our contribution is to consider the exactness on subspaces of polynomials on the variables z and . Using this approach we characterize, in a unified way, the classical nodal systems for measures on the real line and the nodal systems for measures on the unit circle, which are based on para-orthogonal polynomials. We also characterize the nodal systems on the unit circle, which are not based on para-orthogonal polynomials (only for the case of nodal systems with 1 or 2 points).

  12. Nodal line optimization and its application to violin top plate design

    NASA Astrophysics Data System (ADS)

    Yu, Yonggyun; Jang, In Gwun; Kim, In Kyum; Kwak, Byung Man

    2010-10-01

    In the literature, most problems of structural vibration have been formulated to adjust a specific natural frequency: for example, to maximize the first natural frequency. In musical instruments like a violin; however, mode shapes are equally important because they are related to sound quality in the way that natural frequencies are related to the octave. The shapes of nodal lines, which represent the natural mode shapes, are generally known to have a unique feature for good violins. Among the few studies on mode shape optimization, one typical study addresses the optimization of nodal point location for reducing vibration in a one-dimensional beam structure. However, nodal line optimization, which is required in violin plate design, has not yet been considered. In this paper, the central idea of controlling the shape of the nodal lines is proposed and then applied to violin top plate design. Finite element model for a violin top plate was constructed using shell elements. Then, optimization was performed to minimize the square sum of the displacement of selected nodes located along the target nodal lines by varying the thicknesses of the top plate. We conducted nodal line optimization for the second and the fifth modes together at the same time, and the results showed that the nodal lines obtained match well with the target nodal lines. The information on plate thickness distribution from nodal line optimization would be valuable for tailored trimming of a violin top plate for the given performances.

  13. Translational significance of Nodal, Cripto-1 and Notch4 in adult nevi

    PubMed Central

    Strizzi, Luigi; Margaryan, Naira V.; Gerami, Pedram; Haghighat, Zahra; Harms, Paul W.; Madonna, Gabriele; Botti, Gerardo; Ascierto, Paolo A.; Hendrix, Mary J.C.

    2016-01-01

    The TGF-β associated growth factor Nodal is highly expressed in aggressive metastatic melanoma. Determining the risk for melanomagenesis from Nodal expression in nevi prior to the development of melanoma may be useful for both the screening and prevention of melanoma. Tissue sections of human adult nevi with or without a history of melanoma were stained by immunohistochemistry (IHC) for Nodal, the Nodal co-receptor Cripto-1, and Notch4, which have previously been shown to be associated with Nodal expression in melanoma. The degree of Nodal, Cripto-1 and Notch4 staining was scored and correlated with available clinical data. Median IHC scores for Nodal, Cripto-1 and Notch4 expression were significantly higher in nevi removed from patients who eventually developed melanoma compared with nevi from patients with no history of melanoma. In addition, the degree of Nodal expression in nevi from patients who eventually developed melanoma correlated significantly with the Breslow depth of the melanoma. Expression of Nodal and components of its signaling pathway in nevi may represent a biomarker for selecting a unique subset of patients requiring increased surveillance for screening and prevention of melanoma.

  14. Bone morphogenic protein-2 regulates the myogenic differentiation of PMVECs in CBDL rat serum-induced pulmonary microvascular remodeling.

    PubMed

    Liu, Chang; Chen, Lin; Zeng, Jing; Cui, Jian; Ning, Jiao-Nin; Wang, Guan-Song; Belguise, Karine; Wang, Xiaobo; Qian, Gui-Sheng; Lu, Kai-Zhi; Yi, Bin

    2015-08-01

    Hepatopulmonary syndrome (HPS) is characterized by an arterial oxygenation defect induced by intrapulmonary vasodilation (IPVD) that increases morbidity and mortality. In our previous study, it was determined that both the proliferation and the myogenic differentiation of pulmonary microvascular endothelial cells (PMVECs) play a key role in the development of IPVD. However, the molecular mechanism underlying the relationship between IPVD and the myogenic differentiation of PMVECs remains unknown. Additionally, it has been shown that bone morphogenic protein-2 (BMP2), via the control of protein expression, may regulate cell differentiation including cardiomyocyte differentiation, neuronal differentiation and odontoblastic differentiation. In this study, we observed that common bile duct ligation (CBDL)-rat serum induced the upregulation of the expression of several myogenic proteins (SM-α-actin, calponin, SM-MHC) and enhanced the expression levels of BMP2 mRNA and protein in PMVECs. We also observed that both the expression levels of Smad1/5 and the activation of phosphorylated Smad1/5 were significantly elevated in PMVECs following exposure to CBDL-rat serum, which was accompanied by the down-regulation of Smurf1. The blockage of the BMP2/Smad signaling pathway with Noggin inhibited the myogenic differentiation of PMVECs, a process that was associated with relatively low expression levels of both SM-α-actin and calponin in the setting of CBDL-rat serum exposure, although SM-MHC expression was not affected. These findings suggested that the BMP2/Smad signaling pathway is involved in the myogenic differentiation of the PMVECs. In conclusion, our data highlight the pivotal role of BMP2 in the CBDL-rat serum-induced myogenic differentiation of PMVECs via the activation of both Smad1 and Smad5 and the down-regulation of Smurf1, which may represent a potential therapy for HPS-induced pulmonary vascular remodeling. PMID:26071935

  15. The Role of Hepatocyte Hemojuvelin in the Regulation of Bone Morphogenic Protein-6 and Hepcidin Expression in Vivo*

    PubMed Central

    Zhang, An-Sheng; Gao, Junwei; Koeberl, Dwight D.; Enns, Caroline A.

    2010-01-01

    Both hemojuvelin (HJV) and bone morphogenic protein-6 (BMP6) are essential for hepcidin expression. Hepcidin is the key peptide hormone in iron homeostasis, and is secreted predominantly by hepatocytes. HJV expression is detected in hepatocytes, as well as in skeletal and heart muscle. HJV binds BMP6 and increases hepcidin expression presumably by acting as a BMP co-receptor. We characterized the role of hepatocyte HJV in the regulation of BMP6 and hepcidin expression. In HJV-null (Hjv−/−) mice that have severe iron overload and marked suppression of hepcidin expression, we detected 4-fold higher hepatic BMP6 mRNA than in wild-type counterparts. These results indicate that Hjv−/− mice do not lack BMP6. Furthermore, iron depletion in Hjv−/− mice decreased hepatic BMP6 mRNA. Expression of HJV in hepatocytes of Hjv−/− mice using an AAV2/8 vector, increased hepatic hepcidin mRNA by 65-fold and phosphorylated Smad1/5/8 in the liver by about 2.5-fold. However, no significant change in BMP6 mRNA was detected in either the liver or the small intestine of these animals. Our results revealed a close correlation of hepatic BMP6 mRNA expression with hepatic iron-loading. Together, our data indicate that the regulation of hepatic BMP6 expression by iron is independent of HJV, and that expression of HJV in hepatocytes plays an essential role in hepcidin expression by potentiating the BMP6-mediated signaling. PMID:20363739

  16. The role of hepatocyte hemojuvelin in the regulation of bone morphogenic protein-6 and hepcidin expression in vivo.

    PubMed

    Zhang, An-Sheng; Gao, Junwei; Koeberl, Dwight D; Enns, Caroline A

    2010-05-28

    Both hemojuvelin (HJV) and bone morphogenic protein-6 (BMP6) are essential for hepcidin expression. Hepcidin is the key peptide hormone in iron homeostasis, and is secreted predominantly by hepatocytes. HJV expression is detected in hepatocytes, as well as in skeletal and heart muscle. HJV binds BMP6 and increases hepcidin expression presumably by acting as a BMP co-receptor. We characterized the role of hepatocyte HJV in the regulation of BMP6 and hepcidin expression. In HJV-null (Hjv(-/-)) mice that have severe iron overload and marked suppression of hepcidin expression, we detected 4-fold higher hepatic BMP6 mRNA than in wild-type counterparts. These results indicate that Hjv(-/-) mice do not lack BMP6. Furthermore, iron depletion in Hjv(-/-) mice decreased hepatic BMP6 mRNA. Expression of HJV in hepatocytes of Hjv(-/-) mice using an AAV2/8 vector, increased hepatic hepcidin mRNA by 65-fold and phosphorylated Smad1/5/8 in the liver by about 2.5-fold. However, no significant change in BMP6 mRNA was detected in either the liver or the small intestine of these animals. Our results revealed a close correlation of hepatic BMP6 mRNA expression with hepatic iron-loading. Together, our data indicate that the regulation of hepatic BMP6 expression by iron is independent of HJV, and that expression of HJV in hepatocytes plays an essential role in hepcidin expression by potentiating the BMP6-mediated signaling. PMID:20363739

  17. A Biphasic Calcium Sulphate/Hydroxyapatite Carrier Containing Bone Morphogenic Protein-2 and Zoledronic Acid Generates Bone.

    PubMed

    Raina, Deepak Bushan; Isaksson, Hanna; Hettwer, Werner; Kumar, Ashok; Lidgren, Lars; Tägil, Magnus

    2016-01-01

    In orthopedic surgery, large amount of diseased or injured bone routinely needs to be replaced. Autografts are mainly used but their availability is limited. Commercially available bone substitutes allow bone ingrowth but lack the capacity to induce bone formation. Thus, off-the-shelf osteoinductive bone substitutes that can replace bone grafts are required. We tested the carrier properties of a biphasic, calcium sulphate and hydroxyapatite ceramic material, containing a combination of recombinant human bone morphogenic protein-2 (rhBMP-2) to induce bone, and zoledronic acid (ZA) to delay early resorption. In-vitro, the biphasic material released 90% of rhBMP-2 and 10% of ZA in the first week. No major changes were found in the surface structure using scanning electron microscopy (SEM) or in the mechanical properties after adding rhBMP-2 or ZA. In-vivo bone formation was studied in an abdominal muscle pouch model in rats (n = 6/group). The mineralized volume was significantly higher when the biphasic material was combined with both rhBMP-2 and ZA (21.4 ± 5.5 mm(3)) as compared to rhBMP-2 alone (10.9 ± 2.1 mm(3)) when analyzed using micro computed tomography (μ-CT) (p < 0.01). In the clinical setting, the biphasic material combined with both rhBMP-2 and ZA can potentially regenerate large volumes of bone. PMID:27189411

  18. The stationary-phase morphogene bolA from Escherichia coli is induced by stress during early stages of growth.

    PubMed

    Santos, J M; Freire, P; Vicente, M; Arraiano, C M

    1999-05-01

    The Escherichia coli morphogene bolA causes round morphology when overexpressed. The expression of bolA is mainly regulated by a sigmas-dependent gearbox promoter bolA1p. Such regulation results in increased relative levels of expression at slow growth rates, as seen with those attained at the onset of stationary phase. We demonstrate that bolA1p is also induced during early logarithmic growth in response to several forms of stress, and that this induction can be partially sigmas independent. Sudden carbon starvation results in a 17-fold increase in mRNA levels derived from bolA1p 1 h after stress imposition. Increased osmolarity results in a more than 20-fold increase after the same period. Considerable increases in bolA1p mRNA levels were also detected as a result of heat shock, acidic stress and oxidative stress, which has been shown to inhibit sigmas translation. The orders of magnitude of bolA1p induction in log phase due to sudden starvation, osmotic shock and oxidative stress surpass the levels reached in stationary phase. Under sudden carbon starvation and osmotic shock, the cells changed their morphology, resembling those cells in which bolA is overexpressed in stationary phase. Increased expression and morphological changes due to sudden carbon starvation and osmotic shock still occur when sigmaS is not present in a rpoS- background. The results show that expression of bolA is not confined to stationary phase, but it can also play an important role in general stress response. We propose that bolA1p stress induction overrides the normal regulation imposed by growth rate, which is strictly the result of sigmaS-directed transcription. PMID:10361282

  19. A Biphasic Calcium Sulphate/Hydroxyapatite Carrier Containing Bone Morphogenic Protein-2 and Zoledronic Acid Generates Bone

    PubMed Central

    Raina, Deepak Bushan; Isaksson, Hanna; Hettwer, Werner; Kumar, Ashok; Lidgren, Lars; Tägil, Magnus

    2016-01-01

    In orthopedic surgery, large amount of diseased or injured bone routinely needs to be replaced. Autografts are mainly used but their availability is limited. Commercially available bone substitutes allow bone ingrowth but lack the capacity to induce bone formation. Thus, off-the-shelf osteoinductive bone substitutes that can replace bone grafts are required. We tested the carrier properties of a biphasic, calcium sulphate and hydroxyapatite ceramic material, containing a combination of recombinant human bone morphogenic protein-2 (rhBMP-2) to induce bone, and zoledronic acid (ZA) to delay early resorption. In-vitro, the biphasic material released 90% of rhBMP-2 and 10% of ZA in the first week. No major changes were found in the surface structure using scanning electron microscopy (SEM) or in the mechanical properties after adding rhBMP-2 or ZA. In-vivo bone formation was studied in an abdominal muscle pouch model in rats (n = 6/group). The mineralized volume was significantly higher when the biphasic material was combined with both rhBMP-2 and ZA (21.4 ± 5.5 mm3) as compared to rhBMP-2 alone (10.9 ± 2.1 mm3) when analyzed using micro computed tomography (μ-CT) (p < 0.01). In the clinical setting, the biphasic material combined with both rhBMP-2 and ZA can potentially regenerate large volumes of bone. PMID:27189411

  20. Nodal Diffusion Burnable Poison Treatment for Prismatic Reactor Cores

    SciTech Connect

    A. M. Ougouag; R. M. Ferrer

    2010-10-01

    The prismatic block version of the High Temperature Reactor (HTR) considered as a candidate Very High Temperature Reactor (VHTR)design may use burnable poison pins in locations at some corners of the fuel blocks (i.e., assembly equivalent structures). The presence of any highly absorbing materials, such as these burnable poisons, within fuel blocks for hexagonal geometry, graphite-moderated High Temperature Reactors (HTRs) causes a local inter-block flux depression that most nodal diffusion-based method have failed to properly model or otherwise represent. The location of these burnable poisons near vertices results in an asymmetry in the morphology of the assemblies (or blocks). Hence the resulting inadequacy of traditional homogenization methods, as these “spread” the actually local effect of the burnable poisons throughout the assembly. Furthermore, the actual effect of the burnable poison is primarily local with influence in its immediate vicinity, which happens to include a small region within the same assembly as well as similar regions in the adjacent assemblies. Traditional homogenization methods miss this artifact entirely. This paper presents a novel method for treating the local effect of the burnable poison explicitly in the context of a modern nodal method.

  1. Amyloid precursor protein at node of Ranvier modulates nodal formation.

    PubMed

    Xu, De-En; Zhang, Wen-Min; Yang, Zara Zhuyun; Zhu, Hong-Mei; Yan, Ke; Li, Shao; Bagnard, Dominique; Dawe, Gavin S; Ma, Quan-Hong; Xiao, Zhi-Cheng

    2014-01-01

    Amyloid precursor protein (APP), commonly associated with Alzheimer disease, is upregulated and distributes evenly along the injured axons, and therefore, also known as a marker of demyelinating axonal injury and axonal degeneration. However, the physiological distribution and function of APP along myelinated axons was unknown. We report that APP aggregates at nodes of Ranvier (NOR) in the myelinated central nervous system (CNS) axons but not in the peripheral nervous system (PNS). At CNS NORs, APP expression co-localizes with tenascin-R and is flanked by juxtaparanodal potassium channel expression demonstrating that APP localized to NOR. In APP-knockout (KO) mice, nodal length is significantly increased, while sodium channels are still clustered at NORs. Moreover, APP KO and APP-overexpressing transgenic (APP TG) mice exhibited a decreased and an increased thickness of myelin in spinal cords, respectively, although the changes are limited in comparison to their littermate WT mice. The thickness of myelin in APP KO sciatic nerve also increased in comparison to that in WT mice. Our observations indicate that APP acts as a novel component at CNS NORs, modulating nodal formation and has minor effects in promoting myelination. PMID:25482638

  2. Why the embryo still matters: CSF and the neuroepithelium as interdependent regulators of embryonic brain growth, morphogenesis and histiogenesis.

    PubMed

    Gato, Angel; Desmond, Mary E

    2009-03-15

    The key focus of this review is that both the neuroepithelium and embryonic cerebrospinal fluid (CSF) work in an integrated way to promote embryonic brain growth, morphogenesis and histiogenesis. The CSF generates pressure and also contains many biologically powerful trophic factors; both play key roles in early brain development. Accumulation of fluid via an osmotic gradient creates pressure that promotes rapid expansion of the early brain in a developmental regulated way, since the rates of growth differ between the vesicles and for different species. The neuroepithelium and ventricles both contribute to this growth but by different and coordinated mechanisms. The neuroepithelium grows primarily by cell proliferation and at the same time the ventricle expands via hydrostatic pressure generated by active transport of Na(+) and transport or secretion of proteins and proteoglycans that create an osmotic gradient which contribute to the accumulation of fluid inside the sealed brain cavity. Recent evidence shows that the CSF regulates relevant aspects of neuroepithelial behavior such as cell survival, replication and neurogenesis by means of growth factors and morphogens. Here we try to highlight that early brain development requires the coordinated interplay of the CSF contained in the brain cavity with the surrounding neuroepithelium. The information presented is essential in order to understand the earliest phases of brain development and also how neuronal precursor behavior is regulated. PMID:19154733

  3. All-trans retinol and retinol-binding protein from embryonic cerebrospinal fluid exhibit dynamic behaviour during early central nervous system development.

    PubMed

    Parada, Carolina; Gato, Angel; Bueno, David

    2008-06-11

    Embryonic cerebrospinal fluid (E-CSF) is involved in the regulation of survival, proliferation and neurogenesis of neuroectodermal progenitor cells, as well as in the control of mesencephalic gene expression in collaboration with the isthmic organizer. Recently, we showed the presence of retinol-binding protein (RBP) within the E-CSF proteome. RBP is an all-trans retinol carrier, a molecule that can be metabolized into retinoic acid, a morphogen involved in central nervous system (CNS) morphogenesis and patterning. Here we demonstrate the presence of all-trans retinol within the E-CSF and analyse the dynamics of RBP and all-trans retinol within this fluid, as well as the expression of retinoic acid-synthesizing enzymes during early CNS development. Our results suggest a relationship between the dynamics of these molecules and the early events of CNS patterning. PMID:18520998

  4. Distal end of the atrioventricular nodal artery predicts the risk of atrioventricular block during slow pathway catheter ablation of atrioventricular nodal re-entrant tachycardia

    PubMed Central

    Lin, J; Huang, S; Lai, L; Lin, L; Chen, J; Tseng, Y; Lien, W

    2000-01-01

    OBJECTIVE—To search for a reliable anatomical landmark within Koch's triangle to predict the risk of atrioventricular (AV) block during radiofrequency slow pathway catheter ablation of AV nodal re-entrant tachycardia (AVNRT).
PATIENTS AND METHODS—To test the hypothesis that the distal end of the AV nodal artery represents the anatomical location of the AV node, and thus could be a useful landmark for predicting the risk of AV block, 128 consecutive patients with AVNRT receiving slow pathway catheter ablation were prospectively studied in two phases. In phase I (77 patients), angiographic demonstration of the AV nodal artery and its ending was performed at the end of the ablation procedure, whereas in the subsequent phase II study (51 patients), the angiography was performed immediately before catheter ablation to assess the value of identifying this new landmark in reducing the risk of AV block. Multiple electrophysiologic and anatomical parameters were analysed. The former included the atrial activation sequence between the His bundle recording site (HBE) and the coronary sinus orifice or the catheter ablation site, either during AVNRT or during sinus rhythm. The latter included the spatial distances between the distal end of the AV nodal artery and the HBE and the final catheter ablation site, and the distance between the HBE and the tricuspid border at the coronary sinus orifice floor.
RESULTS—In phase I, nine of the 77 patients had complications of transient (seven patients) or permanent (two patients) complete AV block during stepwise, anatomy guided slow pathway catheter ablation. These nine patients had a wider distance between the HBE and the distal end of the AV nodal artery, and a closer approximation of the catheter ablation site to the distal end of the AV nodal artery, which independently predicted the risk of AV block. In contrast, none of the available electrophysiologic parameters were shown to be reliable. When the distance between

  5. Directed Differentiation of Dopaminergic Neuronal Subtypes from Human Embryonic Stem Cells

    PubMed Central

    Yan, Yiping; Yang, Dali; Zarnowska, Ewa D.; Du, Zhongwei; Werbel, Brian; Valliere, Chuck; Pearce, Robert A.; Thomson, James A.; Zhang, Su-Chun

    2009-01-01

    How dopamine (DA) neuronal subtypes are specified remains unknown. In this study we show a robust generation of functional DA neurons from human embryonic stem cells (hESCs) through a specific sequence of application of fibroblast growth factor 8 (FGF8) and sonic hedgehog (SHH). Treatment of hESC-derived Sox1+ neuroepithelial cells with FGF8 and SHH resulted in production of tyrosine hydroxylase (TH)–positive neurons that were mostly bipolar cells, coexpression with γ-aminobutyric acid, and lack of midbrain marker engrailed 1 (En1) expression. However, FGF8 treatment of precursor cells before Sox1 expression led to the generation of a similar proportion of TH+ neurons characteristic of midbrain projection DA neurons with large cell bodies and complex processes and coexpression of En1. This suggests that one mechanism of generating neuronal subtypes is temporal availability of morphogens to a specific group of precursors. The in vitro–generated DA neurons were electrophysiologically active and released DA in an activity-dependent manner. They may thus provide a renewable source of functional human DA neurons for drug screening and development of sustainable therapeutics for disorders affecting the DA system. PMID:15917474

  6. Generation of anterior foregut endoderm from human embryonic and induced pluripotent stem cells

    PubMed Central

    Green, Michael D; Chen, Antonia; Nostro, Maria-Cristina; d'Souza, Sunita L; Schaniel, Christoph; Lemischka, Ihor R; Gouon-Evans, Valerie; Keller, Gordon; Snoeck, Hans-Willem

    2016-01-01

    Directed differentiation of human embryonic stem (hES) cells and human induced pluripotent stem (hiPS) cells captures in vivo developmental pathways for specifying lineages in vitro, thus avoiding perturbation of the genome with exogenous genetic material. Thus far, derivation of endodermal lineages has focused predominantly on hepatocytes, pancreatic endocrine cells and intestinal cells1–5. The ability to differentiate pluripotent cells into anterior foregut endoderm (AFE) derivatives would expand their utility for cell therapy and basic research to tissues important for immune function, such as the thymus; for metabolism, such as thyroid and parathyroid; and for respiratory function, such as trachea and lung. We find that dual inhibition of transforming growth factor (TGF)-β and bone morphogenic protein (BMP) signaling after specification of definitive endoderm from pluripotent cells results in a highly enriched AFE population that is competent to be patterned along dorsoventral and anteroposterior axes. These findings provide an approach for the generation of AFE derivatives. PMID:21358635

  7. Embryonic development during chronic acceleration

    NASA Technical Reports Server (NTRS)

    Smith, A. H.; Abbott, U. K.

    1982-01-01

    Experiments carried out on chicken eggs indicate that the embryo is affected during very early development, especially over the first four days, and during hatching. In the first four days, the brain develops as well as the anlage for all other organs. In addition, the heart commences to function and the extraembryonic membranes that compartmentalize the egg contents form. The latter require an appreciable extension and folding of tissue which may be disrupted by the mechanical load. Observations of embryonic abnormalities that occur during chronic acceleration suggest an inhibition of development of the axial skeleton, which is rarely seen otherwise, a general retardation of embryonic growth, and circulatory problems. The final stages of development (after 18 days) involve the uptake of fluids, the transition to aerial respiration, and the reorientation of the embryo into a normal hatching position. At 4 G mortality is very high during this period, with a majority of embryos failing to reorient into the normal hatching position.

  8. Embryonic Heart Progenitors and Cardiogenesis

    PubMed Central

    Brade, Thomas; Pane, Luna S.; Moretti, Alessandra; Chien, Kenneth R.; Laugwitz, Karl-Ludwig

    2013-01-01

    The mammalian heart is a highly specialized organ, comprised of many different cell types arising from distinct embryonic progenitor populations during cardiogenesis. Three precursor populations have been identified to contribute to different myocytic and nonmyocytic cell lineages of the heart: cardiogenic mesoderm cells (CMC), the proepicardium (PE), and cardiac neural crest cells (CNCCs). This review will focus on molecular cues necessary for proper induction, expansion, and lineage-specific differentiation of these progenitor populations during cardiac development in vivo. Moreover, we will briefly discuss how the knowledge gained on embryonic heart progenitor biology can be used to develop novel therapeutic strategies for the management of congenital heart disease as well as for improvement of cardiac function in ischemic heart disease. PMID:24086063

  9. Prepatterning and patterning of the thalamus along embryonic development of Xenopus laevis

    PubMed Central

    Bandín, Sandra; Morona, Ruth; González, Agustín

    2015-01-01

    Previous developmental studies of the thalamus (alar part of the diencephalic prosomere p2) have defined the molecular basis for the acquisition of the thalamic competence (preparttening), the subsequent formation of the secondary organizer in the zona limitans intrathalamica, and the early specification of two anteroposterior domains (rostral and caudal progenitor domains) in response to inducing activities and that are shared in birds and mammals. In the present study we have analyzed the embryonic development of the thalamus in the anuran Xenopus laevis to determine conserved or specific features in the amphibian diencephalon. From early embryonic stages to the beginning of the larval period, the expression patterns of 22 markers were analyzed by means of combined In situ hybridization (ISH) and immunohistochemical techniques. The early genoarchitecture observed in the diencephalon allowed us to discern the boundaries of the thalamus with the prethalamus, pretectum, and epithalamus. Common molecular features were observed in the thalamic prepatterning among vertebrates in which Wnt3a, Fez, Pax6 and Xiro1 expression were of particular importance in Xenopus. The formation of the zona limitans intrathalamica was observed, as in other vertebrates, by the progressive expression of Shh. The largely conserved expressions of Nkx2.2 in the rostral thalamic domain vs. Gbx2 and Ngn2 (among others) in the caudal domain strongly suggest the role of Shh as morphogen in the amphibian thalamus. All these data showed that the molecular characteristics observed during preparttening and patterning in the thalamus of the anuran Xenopus (anamniote) share many features with those described during thalamic development in amniotes (common patterns in tetrapods) but also with zebrafish, strengthening the idea of a basic organization of this diencephalic region across vertebrates. PMID:26321920

  10. Wnt/Axin1/β-Catenin Signaling Regulates Asymmetric Nodal Activation, Elaboration, and Concordance of CNS Asymmetries

    PubMed Central

    Carl, Matthias; Bianco, Isaac H.; Bajoghli, Baubak; Aghaallaei, Narges; Czerny, Thomas; Wilson, Stephen W.

    2007-01-01

    Summary Nodal activity in the left lateral plate mesoderm (LPM) is required to activate left-sided Nodal signaling in the epithalamic region of the zebrafish forebrain. Epithalamic Nodal signaling subsequently determines the laterality of neuroanatomical asymmetries. We show that overactivation of Wnt/Axin1/β-catenin signaling during late gastrulation leads to bilateral epithalamic expression of Nodal pathway genes independently of LPM Nodal signaling. This is consistent with a model whereby epithalamic Nodal signaling is normally bilaterally repressed, with Nodal signaling from the LPM unilaterally alleviating repression. We suggest that Wnt signaling regulates the establishment of the bilateral repression. We identify a second role for the Wnt pathway in the left/right regulation of LPM Nodal pathway gene expression, and finally, we show that at later stages Axin1 is required for the elaboration of concordant neuroanatomical asymmetries. PMID:17678853

  11. Less may be more: nodal treatment in neck positive head neck cancer patients.

    PubMed

    Studer, Gabriela; Huber, Gerhard F; Holz, Edna; Glanzmann, Christoph

    2016-06-01

    Ongoing debates about the need and extent of planned neck dissection (PND), and required nodal radiation doses volumes lead to this evaluation. Aim was to assess nodal control after definitive intensity modulated radiation therapy (IMRT ± systemic therapy) followed by PND in our head neck cancer cohort with advanced nodal disease. Between 01/2005 and 12/2013, 99 squamous cell cancer HNC patients with pre-therapeutic nodal metastasis ≥3 cm were treated with definitive IMRT followed by PND. In addition, outcome in 103 patients with nodal relapse after IMRT and observation only (no-PND cohort) were analyzed. Prior to PND, PET-CT, fine needle aspirations, ultrasound and palpation were assessed regarding its predictive value. Patterns of nodal relapse were assessed in patients with isolated neck failure after definitive IMRT alone. 70/99 (70 %) PND specimens showed histopathological complete response (hCR), which translated into statistically significantly superior survival compared with partial response (hPR) with 4-year overall survival, disease specific survival and nodal control rates of 90/83/96 vs 67/60/78 % (p = 0.002/0.001/0.003). 1/99 patient developed isolated subsequent nodal disease. 64/2147 removed nodes contained viable tumor (3 %). Predictive information of the performed diagnostic investigations was not reliable. 17/70 hCR patients showed true negative findings in available three to four investigations (0/29 hPR). 27/103 no-PND patients developed isolated neck disease (26 %) with successful salvage in 21/24 [88 %, or 21/27 (78 %)]. Nearly all failures occurred in the prior nodal gross tumor volume area. A more restrictive approach regarding PND and/or nodal IMRT dose-volumes may be justified. PMID:25920604

  12. Nodal weighting factor method for ex-core fast neutron fluence evaluation

    SciTech Connect

    Chiang, R. T.

    2012-07-01

    The nodal weighting factor method is developed for evaluating ex-core fast neutron flux in a nuclear reactor by utilizing adjoint neutron flux, a fictitious unit detector cross section for neutron energy above 1 or 0.1 MeV, the unit fission source, and relative assembly nodal powers. The method determines each nodal weighting factor for ex-core neutron fast flux evaluation by solving the steady-state adjoint neutron transport equation with a fictitious unit detector cross section for neutron energy above 1 or 0.1 MeV as the adjoint source, by integrating the unit fission source with a typical fission spectrum to the solved adjoint flux over all energies, all angles and given nodal volume, and by dividing it with the sum of all nodal weighting factors, which is a normalization factor. Then, the fast neutron flux can be obtained by summing the various relative nodal powers times the corresponding nodal weighting factors of the adjacent significantly contributed peripheral assembly nodes and times a proper fast neutron attenuation coefficient over an operating period. A generic set of nodal weighting factors can be used to evaluate neutron fluence at the same location for similar core design and fuel cycles, but the set of nodal weighting factors needs to be re-calibrated for a transition-fuel-cycle. This newly developed nodal weighting factor method should be a useful and simplified tool for evaluating fast neutron fluence at selected locations of interest in ex-core components of contemporary nuclear power reactors. (authors)

  13. Contemporary Management of Recurrent Nodal Disease in Differentiated Thyroid Carcinoma.

    PubMed

    Na'ara, Shorook; Amit, Moran; Fridman, Eran; Gil, Ziv

    2016-01-01

    Differentiated thyroid carcinoma (DTC) comprises over 90% of thyroid tumors and includes papillary and follicular carcinomas. Patients with DTC have an excellent prognosis, with a 10-year survival rate of over 90%. However, the risk of recurrent tumor ranges between 5% and 30% within 10 years of the initial diagnosis. Cervical lymph node disease accounts for the majority of recurrences and in most cases is detected during follow-up by ultrasound or elevated levels of serum thyroglobulin. Recurrent disease is accompanied by increased morbidity. The mainstay of treatment of nodal recurrence is surgical management. We provide an overview of the literature addressing surgical management of recurrent or persistent lymph node disease in patients with DTC. PMID:26886954

  14. Contemporary Management of Recurrent Nodal Disease in Differentiated Thyroid Carcinoma

    PubMed Central

    Na’ara, Shorook; Amit, Moran; Fridman, Eran; Gil, Ziv

    2016-01-01

    Differentiated thyroid carcinoma (DTC) comprises over 90% of thyroid tumors and includes papillary and follicular carcinomas. Patients with DTC have an excellent prognosis, with a 10-year survival rate of over 90%. However, the risk of recurrent tumor ranges between 5% and 30% within 10 years of the initial diagnosis. Cervical lymph node disease accounts for the majority of recurrences and in most cases is detected during follow-up by ultrasound or elevated levels of serum thyroglobulin. Recurrent disease is accompanied by increased morbidity. The mainstay of treatment of nodal recurrence is surgical management. We provide an overview of the literature addressing surgical management of recurrent or persistent lymph node disease in patients with DTC. PMID:26886954

  15. Typical nodal calcifications in the maxillofacial region: a case report

    PubMed Central

    Wu, Guomin; Sun, Xiumei; Ni, Shilei; Zhang, Zhimin

    2014-01-01

    Multiple nodal calcifications in the maxillofacial region are very rare. This case report described a 49-year-old female patient diagnosed with calcified lymph nodes due to chronic inflammation of the lymphatic nodes, including the parotid lymphatic nodes, the posterior auricular lymphatic nodes and submandibular lymphatic nodes in the right maxillofacial region. In clinical practice, we conducted ultrasonography, three-dimensional reconstruction of CT and sialography make a preliminary diagnosis. Then we took surgery, while removing the calcified blocks within the lymphatic node and cleaning the wound cavity. After surgery, we used anti-inflammatory therapy for one week. Six months follow-up indicated no evidence of other calcified lymph nodes infection. PMID:25356188

  16. Space-angle approximations in the variational nodal method.

    SciTech Connect

    Lewis, E. E.; Palmiotti, G.; Taiwo, T.

    1999-03-12

    The variational nodal method is formulated such that the angular and spatial approximations maybe examined separately. Spherical harmonic, simplified spherical harmonic, and discrete ordinate approximations are coupled to the primal hybrid finite element treatment of the spatial variables. Within this framework, two classes of spatial trial functions are presented: (1) orthogonal polynomials for the treatment of homogeneous nodes and (2) bilinear finite subelement trial functions for the treatment of fuel assembly sized nodes in which fuel-pin cell cross sections are represented explicitly. Polynomial and subelement trial functions are applied to benchmark water-reactor problems containing MOX fuel using spherical harmonic and simplified spherical harmonic approximations. The resulting accuracy and computing costs are compared.

  17. CAISO flicks switch on nodal scheme and lights stay on

    SciTech Connect

    2009-06-15

    In 2000-01, two years after introducing a competitive wholesale power auction in California - with a separate day-ahead zonal market operated by the California Power Exchange and a zonal market for ancillary services and balancing energy operated by the California Independent System Operator (CAISO) - the California market collapsed from exorbitant prices, flagrant gaming, and abuse of market power. Nine years later, CAISO introduced a nodal pricing auction for the wholesale market in April, replacing the zonal scheme, which was among many causes of the original market's demise. With nearly 3,000 nodes on the network, high prices in one region do not affect prices everywhere on the system. After investing some $200 million to upgrade the software, countless delays, and 18 months of market simulation and testing, the new auction was introduced and nothing unusual happened.

  18. Bone morphogenic protein-2 regulates the myogenic differentiation of PMVECs in CBDL rat serum-induced pulmonary microvascular remodeling

    SciTech Connect

    Liu, Chang; Chen, Lin; Zeng, Jing; Cui, Jian; Ning, Jiao-nin; Wang, Guan-song; Belguise, Karine; Wang, Xiaobo; Qian, Gui-sheng; Lu, Kai-zhi; Yi, Bin

    2015-08-01

    Hepatopulmonary syndrome (HPS) is characterized by an arterial oxygenation defect induced by intrapulmonary vasodilation (IPVD) that increases morbidity and mortality. In our previous study, it was determined that both the proliferation and the myogenic differentiation of pulmonary microvascular endothelial cells (PMVECs) play a key role in the development of IPVD. However, the molecular mechanism underlying the relationship between IPVD and the myogenic differentiation of PMVECs remains unknown. Additionally, it has been shown that bone morphogenic protein-2 (BMP2), via the control of protein expression, may regulate cell differentiation including cardiomyocyte differentiation, neuronal differentiation and odontoblastic differentiation. In this study, we observed that common bile duct ligation (CBDL)-rat serum induced the upregulation of the expression of several myogenic proteins (SM-α-actin, calponin, SM-MHC) and enhanced the expression levels of BMP2 mRNA and protein in PMVECs. We also observed that both the expression levels of Smad1/5 and the activation of phosphorylated Smad1/5 were significantly elevated in PMVECs following exposure to CBDL-rat serum, which was accompanied by the down-regulation of Smurf1. The blockage of the BMP2/Smad signaling pathway with Noggin inhibited the myogenic differentiation of PMVECs, a process that was associated with relatively low expression levels of both SM-α-actin and calponin in the setting of CBDL-rat serum exposure, although SM-MHC expression was not affected. These findings suggested that the BMP2/Smad signaling pathway is involved in the myogenic differentiation of the PMVECs. In conclusion, our data highlight the pivotal role of BMP2 in the CBDL-rat serum-induced myogenic differentiation of PMVECs via the activation of both Smad1 and Smad5 and the down-regulation of Smurf1, which may represent a potential therapy for HPS-induced pulmonary vascular remodeling. - Highlights: • CBDL-rat serum promotes the myogenic

  19. Granulin epithelin precursor: a bone morphogenic protein 2-inducible growth factor that activates Erk1/2 signaling and JunB transcription factor in chondrogenesis

    PubMed Central

    Feng, Jian Q.; Guo, Feng-Jin; Jiang, Bai-Chun; Zhang, Yan; Frenkel, Sally; Wang, Da-Wei; Tang, Wei; Xie, Yixia; Liu, Chuan-Ju

    2010-01-01

    Granulin epithelin precursor (GEP) has been implicated in development, tissue regeneration, tumorigenesis, and inflammation. Herein we report that GEP stimulates chondrocyte differentiation from mesenchymal stem cells in vitro and endochondral ossification ex vivo, and GEP-knockdown mice display skeleton defects. Similar to bone morphogenic protein (BMP) 2, application of the recombinant GEP accelerates rabbit cartilage repair in vivo. GEP is a key downstream molecule of BMP2, and it is required for BMP2-mediated chondrocyte differentiation. We also show that GEP activates chondrocyte differentiation through Erk1/2 signaling and that JunB transcription factor is one of key downstream molecules of GEP in chondrocyte differentiation. Collectively, these findings reveal a novel critical role of GEP growth factor in chondrocyte differentiation and the molecular events both in vivo and in vitro.—Feng, J. Q., Guo, F.-J., Jiang, B.-C., Zhang, Y., Frenkel, S., Wang, D.-W., Tang, W., Xie, Y., Liu, C.-J. Granulin epithelin precursor: a bone morphogenic protein 2-inducible growth factor that activates Erk1/2 signaling and JunB transcription factor in chondrogenesis. PMID:20124436

  20. Culture and Manipulation of Embryonic Cells

    PubMed Central

    Edgar, Lois G.; Goldstein, Bob

    2012-01-01

    The direct manipulation of embryonic cells is an important tool for addressing key questions in cell and developmental biology. C. elegans is relatively unique among genetic model systems in being amenable to manipulation of embryonic cells. Embryonic cell manipulation has allowed the identification of cell interactions by direct means, and it has been an important technique for dissecting mechanisms by which cell fates are specified, cell divisions are oriented, and morphogenesis is accomplished. Here, we present detailed methods for isolating, manipulating and culturing embryonic cells of C. elegans. PMID:22226523

  1. Drumhead surface states and topological nodal-line fermions in TlTaSe2

    NASA Astrophysics Data System (ADS)

    Bian, Guang; Chang, Tay-Rong; Zheng, Hao; Velury, Saavanth; Xu, Su-Yang; Neupert, Titus; Chiu, Ching-Kai; Huang, Shin-Ming; Sanchez, Daniel S.; Belopolski, Ilya; Alidoust, Nasser; Chen, Peng-Jen; Chang, Guoqing; Bansil, Arun; Jeng, Horng-Tay; Lin, Hsin; Hasan, M. Zahid

    2016-03-01

    A topological nodal-line semimetal is a state of matter with one-dimensional bulk nodal lines and two-dimensional so-called drumhead surface bands. Based on first-principles calculations and an effective k .p model, we theoretically propose the existence of topological nodal-line fermions in the ternary transition-metal chalcogenide TlTaSe2. The noncentrosymmetric structure and strong spin-orbit coupling give rise to spinful nodal-line bulk states which are protected by a mirror reflection symmetry of this compound. This is remarkably distinguished from other proposed nodal-line semimetals such as Cu3NPb (Zn) in which the nodal line exists only in the limit of vanishing spin-orbit coupling and thus is not as robust. In addition, we show that the drumhead surface states in TlTaSe2, which are associated with the topological nodal lines, exhibit an unconventional chiral spin texture and an exotic Lifshitz transition as a consequence of the linkage among multiple drumhead surface-state pockets.

  2. Xantivin suppresses the activity of EGF-CFC genes to regulate nodal signaling.

    PubMed

    Tanegashima, Kousuke; Haramoto, Yoshikazu; Yokota, Chika; Takahashi, Shuji; Asashima, Makoto

    2004-06-01

    Lefty, antivin and related genes act in a feedback inhibition mechanism for nodal signaling at a number of stages of vertebrate embryogenesis. To analyze the function of the feedback inhibitor of nodal signaling, Xantivin in Xenopus embryos, we designed a morpholino antisense oligonucleotide (XatvMO) for this gene. XatvMO caused the expansion of mesodermal tissue and head defects. XatvMO-injected gastrulae showed up-regulated expression of the mesodermal markers Xbra, Xwnt8, Xnot, and Chordin, suggesting expansion of the trunk-tail organizer. As expected, depletion of Xantivin also up-regulated nodal signaling as confirmed by the enhanced ectopic expression of Xantivin mRNA, a known target gene of nodal signaling. Furthermore, we investigated the relationship between Xantivin and the EGF-CFC gene FRL-1, which is a component of the nodal receptor. In animal cap assays, FRL-1 could not induce expression of nodal-responsive genes, but could up-regulate expression of these genes when FRL-1 was coinjected with a low dose of Xnr1; coinjection of Xantivin suppressed this up-regulation by FRL-1. We also found that Xantivin can rescue the caudalized phenotype induced by overexpression of FRL-1. Co-immunoprecipitation assays showed that Xantivin interacted with the EGF-CFC proteins, FRL-1 and cripto. Taken together, these results suggest that Xantivin opposes the activity of EGF-CFC genes and thereby antagonizes nodal signaling. PMID:15300508

  3. Cripto is essential to capture mouse epiblast stem cell and human embryonic stem cell pluripotency.

    PubMed

    Fiorenzano, Alessandro; Pascale, Emilia; D'Aniello, Cristina; Acampora, Dario; Bassalert, Cecilia; Russo, Francesco; Andolfi, Gennaro; Biffoni, Mauro; Francescangeli, Federica; Zeuner, Ann; Angelini, Claudia; Chazaud, Claire; Patriarca, Eduardo J; Fico, Annalisa; Minchiotti, Gabriella

    2016-01-01

    Known molecular determinants of developmental plasticity are mainly transcription factors, while the extrinsic regulation of this process has been largely unexplored. Here we identify Cripto as one of the earliest epiblast markers and a key extracellular determinant of the naive and primed pluripotent states. We demonstrate that Cripto sustains mouse embryonic stem cell (ESC) self-renewal by modulating Wnt/β-catenin, whereas it maintains mouse epiblast stem cell (EpiSC) and human ESC pluripotency through Nodal/Smad2. Moreover, we provide unprecedented evidence that Cripto controls the metabolic reprogramming in ESCs to EpiSC transition. Remarkably, Cripto deficiency attenuates ESC lineage restriction in vitro and in vivo, and permits ESC transdifferentiation into trophectoderm lineage, suggesting that Cripto has earlier functions than previously recognized. All together, our studies provide novel insights into the current model of mammalian pluripotency and contribute to the understanding of the extrinsic regulation of the first cell lineage decision in the embryo. PMID:27586544

  4. Occult Nodal Disease Prevalence and Distribution in Recurrent Laryngeal Cancer Requiring Salvage Laryngectomy

    PubMed Central

    Birkeland, Andrew C.; Rosko, Andrew J.; Issa, Mohamad R.; Shuman, Andrew G.; Prince, Mark E.; Wolf, Gregory T.; Bradford, Carol R.; McHugh, Jonathan B.; Brenner, J. Chad; Spector, Matthew E.

    2016-01-01

    Objectives The indications for neck dissection concurrent with salvage laryngectomy in the clinically N0 setting remain unclear. Our goals were to determine the prevalence of occult nodal disease, analyze nodal disease distribution patterns, and identify predictors of occult nodal disease in a salvage laryngectomy cohort. Study Design Case series with planned data collection. Setting Tertiary academic center. Subjects Patients with persistent or recurrent laryngeal squamous cell carcinoma after radiation/chemoradiation failure undergoing salvage laryngectomy with neck dissection. Methods We analyzed a single-institution retrospective case series of patients between 1997–2014 and identified those who had clinically N0 necks (n = 203). Clinical and pathologic data, including nodal prevalence and distribution were collected, and statistical analyses were performed. Results Overall, cN0 necks had histologically positive occult nodes in 17% (n=35) of cases. Univariate predictors of occult nodal positivity included recurrent T4 stage (34% T4 vs. 12% non-T4; p=0.0003), and supraglottic subsite (28% supraglottic vs. 10% non-supraglottic; p=0.0006). Histologically positive nodes associated with supraglottic primaries were most frequently positive in ipsilateral level II and III (17% and 16%). Positive nodes for glottic SCC were most frequently positive in the ipsilateral and contralateral paratracheal nodes (11% and 9%). Conclusion Histologically positive occult nodes are identified in 17% of cN0 patients undergoing salvage laryngectomy with neck dissection. Occult nodal disease varies in frequency and distribution based upon tumor subsite. Predictors of high (>20%) occult nodal positivity include T4 tumors and supraglottic subsite. In glottic SCCs, the most frequent sites of occult nodal disease are the paratracheal nodal basins. PMID:26884365

  5. Nodal signaling is required for closure of the anterior neural tube in zebrafish

    PubMed Central

    Aquilina-Beck, Allisan; Ilagan, Kristine; Liu, Qin; Liang, Jennifer O

    2007-01-01

    Background Nodals are secreted signaling proteins with many roles in vertebrate development. Here, we identify a new role for Nodal signaling in regulating closure of the rostral neural tube of zebrafish. Results We find that the neural tube in the presumptive forebrain fails to close in zebrafish Nodal signaling mutants. For instance, the cells that will give rise to the pineal organ fail to move from the lateral edges of the neural plate to the midline of the diencephalon. The open neural tube in Nodal signaling mutants may be due in part to reduced function of N-cadherin, a cell adhesion molecule expressed in the neural tube and required for neural tube closure. N-cadherin expression and localization to the membrane are reduced in fish that lack Nodal signaling. Further, N-cadherin mutants and morphants have a pineal phenotype similar to that of mutants with deficiencies in the Nodal pathway. Overexpression of an activated form of the TGFβ Type I receptor Taram-A (Taram-A*) cell autonomously rescues mesendoderm formation in fish with a severe decrease in Nodal signaling. We find that overexpression of Taram-A* also corrects their open neural tube defect. This suggests that, as in mammals, the mesoderm and endoderm have an important role in regulating closure of the anterior neural tube of zebrafish. Conclusion This work helps establish a role for Nodal signals in neurulation, and suggests that defects in Nodal signaling could underlie human neural tube defects such as exencephaly, a fatal condition characterized by an open neural tube in the anterior brain. PMID:17996054

  6. The accuracy of preoperative axillary nodal staging in primary breast cancer by ultrasound is modified by nodal metastatic load and tumor biology.

    PubMed

    Dihge, Looket; Grabau, Dorthe A; Rasmussen, Rogvi W; Bendahl, Pär-Ola; Rydén, Lisa

    2016-08-01

    Background The outcome of axillary ultrasound (AUS) with fine-needle aspiration biopsy (FNAB) in the diagnostic work-up of primary breast cancer has an impact on therapy decisions. We hypothesize that the accuracy of AUS is modified by nodal metastatic burden and clinico-pathological characteristics. Material and methods The performance of AUS and AUS-guided FNAB for predicting nodal metastases was assessed in a prospective breast cancer cohort subjected for surgery during 2009-2012. Predictors of accuracy were included in multivariate analysis. Results AUS had a sensitivity of 23% and a specificity of 95%, while AUS-guided FNAB obtained 73% and 100%, respectively. AUS-FNAB exclusively detected macro-metastases (median four metastases) and identified patients with more extensive nodal metastatic burden in comparison with sentinel node biopsy. The accuracy of AUS was affected by metastatic size (OR 1.11), obesity (OR 2.46), histological grade (OR 4.43), and HER2-status (OR 3.66); metastatic size and histological grade were significant in the multivariate analysis. Conclusions The clinical utility of AUS in low-risk breast cancer deserves further evaluation as the accuracy decreased with a low nodal metastatic burden. The diagnostic performance is modified by tumor and clinical characteristics. Patients with nodal disease detected by AUS-FNAB represent a group for whom neoadjuvant therapy should be considered. PMID:27050668

  7. Simulation of turbulent flows using nodal integral method

    NASA Astrophysics Data System (ADS)

    Singh, Suneet

    Nodal methods are the backbone of the production codes for neutron-diffusion and transport equations. Despite their high accuracy, use of these methods for simulation of fluid flow is relatively new. Recently, a modified nodal integral method (MNIM) has been developed for simulation of laminar flows. In view of its high accuracy and efficiency, extension of this method for the simulation of turbulent flows is a logical step forward. In this dissertation, MNIM is extended in two ways to simulate incompressible turbulent flows---a new MNIM is developed for the 2D k-epsilon equations; and 3D, parallel MNIM is developed for direct numerical simulations. Both developments are validated, and test problems are solved. In this dissertation, a new nodal numerical scheme is developed to solve the k-epsilon equations to simulate turbulent flows. The MNIM developed earlier for laminar flow equations is modified to incorporate eddy viscosity approximation and coupled with the above mentioned schemes for the k and epsilon equations, to complete the implementation of the numerical scheme for the k-epsilon model. The scheme developed is validated by comparing the results obtained by the developed method with the results available in the literature obtained using direct numerical simulations (DNS). The results of current simulations match reasonably well with the DNS results. The discrepancies in the results are mainly due to the limitations of the k-epsilon model rather than the deficiency in the developed MNIM. A parallel version of the MNIM is needed to enhance its capability, in order to carry out DNS of the turbulent flows. The parallelization of the scheme, however, presents some unique challenges as dependencies of the discrete variables are different from those that exist in other schemes (for example in finite volume based schemes). Hence, a parallel MNIM (PMNIM) is developed and implemented into a computer code with communication strategies based on the above mentioned

  8. Virus isolation and propagation in embryonating eggs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The embryonating egg is one of the most versatile, easy to work with, and widely used host systems for the isolation and propagation of avian viruses. The embryonating chicken egg (ECE) is the most commonly available system that is both specific pathogen free and supports the replication of viruses...

  9. Topological nodal Cooper pairing in doped Weyl metals

    NASA Astrophysics Data System (ADS)

    Li, Yi; Haldane, F. D. M.

    We generalize the concept of Berry connection of the single-electron band structure to the two-particle Cooper pair states between two Fermi surfaces with opposite Chern numbers. Because of underlying Fermi surface topology, the pairing Berry phase acquires non-trivial monopole structure. Consequently, pairing gap functions have the topologically-protected nodal structure as vortices in the momentum space with the total vorticity solely determined by the monopole charge qp. The pairing nodes behave as the Weyl-Majorana points of the Bogoliubov-de Gennes pairing Hamiltonian. Their relation with the connection patterns of the surface modes from theWeyl band structure and the Majorana surface modes inside the pairing gap is also discussed. Under the approximation of spherical Fermi surfaces, the pairing symmetry are represented by monopole harmonic functions. The lowest possible pairing channel carries angular momentum number j =|qp|, and the corresponding gap functions are holomorphic or anti-holomorphic functions on Fermi surfaces. F.D.M.H. acknowledges the support from MRSEC NSF-DMR-1420541 and the W. M. Keck Foundation.

  10. Micropropagation of Calophyllum brasiliense (Cambess.) from nodal segments.

    PubMed

    Silveira, S S; Cordeiro-Silva, R; Degenhardt-Goldbach, J; Quoirin, M

    2016-05-01

    Micropropagation of Calophyllum brasiliense Cambess. (Clusiaceae) is a way to overcome difficulties in achieving large-scale plant production, given the recalcitrant nature of the seeds, irregular fructification and absence of natural vegetative propagation of the species. Cultures were established using nodal segments 2 cm in length, obtained from 1-2 year old seedlings, maintained in a greenhouse. Mercury chloride and Plant Preservative Mixture™ were used in the surface sterilizing stage, better results being achieved with Plant Preservative Mixture™ incorporation in culture medium, at any concentration. Polyvinylpyrrolidone, activated charcoal, cysteine, ascorbic acid or citric acid were added to the culture medium to avoid oxidation. After 30 days of culture, polyvinylpirrolidone and ascorbic acid gave better results, eliminating oxidation in most explants. For shoot multiplication, benzylaminopurine was used in concentrations of 4.4 and 8.8 µM in Woody Plant Medium, resulting in an average of 4.43 and 4.68 shoots per explant, respectively, after 90 days. Indole-3-butyric acid and α-naphthalene acetic acid were used to induce root formation, reaching a maximum rooting rate of 24% with 20µM α-naphthalene acetic acid. For acclimatization. the rooted plants were transferred to Plantmax® substrate and cultured in a greenhouse, reaching 79% of survival after 30 days and 60% after one year. PMID:27143061

  11. Relation between finite element methods and nodal methods in transport theory

    SciTech Connect

    Walters, W.F.

    1985-01-01

    This paper examines the relationship between nodal methods and finite-element methods for solving the discrete-ordinates form of the transport equation in x-y geometry. Specifically, we will examine the relation of three finite-element schemes to the linear-linear (LL) and linear-nodal (LN) nodal schemes. The three finite-element schemes are the linear-continuous-diamond-difference (DD) scheme, the linear-discontinuous (LD) scheme, and the quadratic-discontinuous (QD) scheme. A brief derivation of the (LL) and (LN) nodal schemes is given in the third section of this paper. The approximations that cause the LL scheme to reduce to the DD, LD, and QD schemes are then indicated. An extremely simple method of deriving the finite-element schemes is then introduced.

  12. Topological Nodal-Line Superfluid in Spin-Orbit Coupled Cold Atomic Systems

    NASA Astrophysics Data System (ADS)

    He, Wen-Yu; Xu, Dong-Hui; Zhou, Tong; Law, K. T.; Hong Kong University of Science; Technology Collaboration

    Topological nodal line superconductivity or superfluidity is a fascinating topological gapless phase which hosts bulk Weyl ring degeneracy in the quasiparticle excitation spectrum and supports Majorana zero bound modes with a large density of states at the edge. In this work, based on the experimental realized 1D spin orbit coupling, we show the emergence of topological nodal line superfluid phase in Fermionic atoms trapped in 3D cubic optical lattice when the s wave pairing field is introduced through Feshbach resonance between the two atomic hyperfine spin states. The nodal line degeneracy is further found to evolve into Weyl nodes once another component of spin orbit coupling field enters to break the chiral symmetry. The momentum resolved radio frequency spectroscopy is suggested to manifest the topological nodal line superfluid phase.

  13. Dose-dependent Nodal/Smad signals pattern the early mouse embryo.

    PubMed

    Robertson, Elizabeth J

    2014-08-01

    Nodal signals in the early post-implantation stage embryo are essential to establish initial proximal-distal (P-D) polarity and generate the final anterior-posterior (A-P) body axis. Nodal signaling in the epiblast results in the phosphorylation of Smad2 in the overlying visceral endoderm necessary to induce the AVE, in part via Smad2-dependent activation of the T-box gene Eomesodermin. Slightly later following mesoderm induction a continuum of dose-dependent Nodal signaling during the process of gastrulation underlies specification of mesodermal and definitive endoderm progenitors. Dynamic Nodal expression during the critical 72 h time window immediately following implantation, accomplished by a series of feed-back and feed-forward mechanisms serves to provide key positional cues required for establishment of the body plan and controls cell fate decisions in the early mammalian embryo. PMID:24704361

  14. ANOVA-HDMR structure of the higher order nodal diffusion solution

    SciTech Connect

    Bokov, P. M.; Prinsloo, R. H.; Tomasevic, D. I.

    2013-07-01

    Nodal diffusion methods still represent a standard in global reactor calculations, but employ some ad-hoc approximations (such as the quadratic leakage approximation) which limit their accuracy in cases where reference quality solutions are sought. In this work we solve the nodal diffusion equations utilizing the so-called higher-order nodal methods to generate reference quality solutions and to decompose the obtained solutions via a technique known as High Dimensional Model Representation (HDMR). This representation and associated decomposition of the solution provides a new formulation of the transverse leakage term. The HDMR structure is investigated via the technique of Analysis of Variance (ANOVA), which indicates why the existing class of transversely-integrated nodal methods prove to be so successful. Furthermore, the analysis leads to a potential solution method for generating reference quality solutions at a much reduced calculational cost, by applying the ANOVA technique to the full higher order solution. (authors)

  15. Effects of a novel Nodal-targeting monoclonal antibody in melanoma

    PubMed Central

    Margaryan, Naira V.; Focà, Annalia; Sanguigno, Luca; Bodenstine, Thomas M.; Chandler, Grace S.; Reed, David W.; Gilgur, Alina; Seftor, Elisabeth A.; Seftor, Richard E.B.; Khalkhali-Ellis, Zhila; Leonardi, Antonio; Ruvo, Menotti; Hendrix, Mary J.C.

    2015-01-01

    Nodal is highly expressed in various human malignancies, thus supporting the rationale for exploring Nodal as a therapeutic target. Here, we describe the effects of a novel monoclonal antibody (mAb), 3D1, raised against human Nodal. In vitro treatment of C8161 human melanoma cells with 3D1 mAb shows reductions in anchorage-independent growth and vasculogenic network formation. 3D1 treated cells also show decreases of Nodal and downstream signaling molecules, P-Smad2 and P-ERK and of P-H3 and CyclinB1, with an increase in p27. Similar effects were previously reported in human breast cancer cells where Nodal expression was generally down-regulated; following 3D1 mAb treatment, both Nodal and P-H3 levels are reduced. Noteworthy is the reduced growth of human melanoma xenografts in Nude mice treated with 3D1 mAb, where immunostaining of representative tumor sections show diminished P-Smad2 expression. Similar effects both in vitro and in vivo were observed in 3D1 treated A375SM melanoma cells harboring the active BRAF(V600E) mutation compared to treatments with IgG control or a BRAF inhibitor, dabrafenib. Finally, we describe a 3D1-based ELISA for the detection of Nodal in serum samples from cancer patients. These data suggest the potential of 3D1 mAb for selecting and targeting Nodal expressing cancers. PMID:26460952

  16. Nodal signaling in Xenopus gastrulae is cell-autonomous and patterned by beta-catenin.

    PubMed

    Hashimoto-Partyka, Minako K; Yuge, Masahiro; Cho, Ken W Y

    2003-01-01

    The classical three-signal model of amphibian mesoderm induction and more recent modifications together propose that an activin-like signaling activity is uniformly distributed across the vegetal half of the Xenopus blastula and that this activity contributes to mesoderm induction. In support of this, we have previously shown that the activin-response element (DE) of the goosecoid promoter is uniformly activated across the vegetal half of midgastrula-stage embryos. Here, we further examine the nature of this activity by measuring DE activation by endogenous signals over time. We find that the spatiotemporal pattern of DE activation is much more dynamic than was previously appreciated and also conclude that DE(6X)Luc activity reflects endogenous nodal signaling in the embryo. Using both the DE(6X)Luc construct and endogenous Xbra and Xgsc expression as read-outs for nodal activity, and the cleavage-mutant version of Xnr2 (CmXnr2) to regionally suppress endogenous nodal activity, we demonstrate that nodal signals act cell-autonomously in Xenopus gastrulae. Nodal-expressing cells are unable to rescue either reporter gene activation or target gene expression in distant nodal-deficient cells, suggesting that nodals function at short range in this context. Finally, we show that DE activation by endogenous signals occurs in the absence of dorsal beta-catenin-mediated signaling, but that the timing of dorsal initiation is altered. We conclude that nodal signals in Xenopus gastrulae function cell autonomously at short ranges and that the spatiotemporal pattern of this signaling along the dorsoventral axis is regulated by maternal Wnt-like signaling. PMID:12490202

  17. Undifferentiated Embryonal Sarcoma of Liver

    PubMed Central

    Kallam, Avyakta; Krishnamurthy, Jairam; Kozel, Jessica

    2015-01-01

    Undifferentiated embryonal sarcoma of the liver (UESL) is a rare malignant hepatic tumor. A 47 year old male presented with symptoms of sour taste in his mouth, occasional nausea, indigestion and 15-pound weight loss over two months. He had an unremarkable upper gastrointestinal endoscopy. Imaging showed a large liver mass in the left hepatic lobe that was resected and then reported as UESL. He went on to develop lung metastases and was initially treated with doxorubicin and ifosfamide followed by switching of therapy to gemcitabine and docetaxel due to progression of disease. He had a good response after two cycles and went on to receive four more cycles, achieving stable disease. We can therefore conclude that the combination of gemcitabine and docetaxel is a potential therapeutic option for patients with UESL. PMID:26788276

  18. Infrared inhibition of embryonic hearts

    NASA Astrophysics Data System (ADS)

    Wang, Yves T.; Rollins, Andrew M.; Jenkins, Michael W.

    2016-06-01

    Infrared control is a new technique that uses pulsed infrared lasers to thermally alter electrical activity. Originally developed for nerves, we have applied this technology to embryonic hearts using a quail model, previously demonstrating infrared stimulation and, here, infrared inhibition. Infrared inhibition enables repeatable and reversible block, stopping cardiac contractions for several seconds. Normal beating resumes after the laser is turned off. The block can be spatially specific, affecting propagation on the ventricle or initiation on the atrium. Optical mapping showed that the block affects action potentials and not just calcium or contraction. Increased resting intracellular calcium was observed after a 30-s exposure to the inhibition laser, which likely resulted in reduced mechanical function. Further optimization of the laser illumination should reduce potential damage. Stopping cardiac contractions by disrupting electrical activity with infrared inhibition has the potential to be a powerful tool for studying the developing heart.

  19. Undifferentiated Embryonal Sarcoma of Liver.

    PubMed

    Kallam, Avyakta; Krishnamurthy, Jairam; Kozel, Jessica; Shonka, Nicole

    2015-12-29

    Undifferentiated embryonal sarcoma of the liver (UESL) is a rare malignant hepatic tumor. A 47 year old male presented with symptoms of sour taste in his mouth, occasional nausea, indigestion and 15-pound weight loss over two months. He had an unremarkable upper gastrointestinal endoscopy. Imaging showed a large liver mass in the left hepatic lobe that was resected and then reported as UESL. He went on to develop lung metastases and was initially treated with doxorubicin and ifosfamide followed by switching of therapy to gemcitabine and docetaxel due to progression of disease. He had a good response after two cycles and went on to receive four more cycles, achieving stable disease. We can therefore conclude that the combination of gemcitabine and docetaxel is a potential therapeutic option for patients with UESL. PMID:26788276

  20. Developmental angiogenesis: quail embryonic vasculature.

    PubMed

    Poole, T J; Coffin, J D

    1988-03-01

    We have examined the segregation and early morphogenesis of the embryonic vasculature by using a monoclonal antibody for immunofluorescence and by scanning electron microscopy. This antibody labels the presumptive endothelial cells (PECs) as they segregate from mesoderm. Similar embryos prepared for SEM revealed finer details of how these segregated cells interact to form the rudiments of the major blood vessels. Here we concentrate on the development of the dorsal aortae and the posterior cardinal veins. The dorsal aortae form from single PECs which segregate from the lateral mesoderm and aggregate into a loose cord ventral to the somites. These cells become more closely associated and a lumen forms. The posterior cardinal veins form from a loose plexus of cells segregated from the lateral mesoderm on its dorsal surface. These cells become intimately associated with the Wolffian ducts. PMID:3285464

  1. Solution and Study of the Two-Dimensional Nodal Neutron Transport Equation

    SciTech Connect

    Panta Pazos, Ruben; Biasotto Hauser, Eliete; Tullio de Vilhena, Marco

    2002-07-01

    In the last decade Vilhena and coworkers reported an analytical solution to the two-dimensional nodal discrete-ordinates approximations of the neutron transport equation in a convex domain. The key feature of these works was the application of the combined collocation method of the angular variable and nodal approach in the spatial variables. By nodal approach we mean the transverse integration of the SN equations. This procedure leads to a set of one-dimensional S{sub N} equations for the average angular fluxes in the variables x and y. These equations were solved by the old version of the LTS{sub N} method, which consists in the application of the Laplace transform to the set of nodal S{sub N} equations and solution of the resulting linear system by symbolic computation. It is important to recall that this procedure allow us to increase N the order of S{sub N} up to 16. To overcome this drawback we step forward performing a spectral painstaking analysis of the nodal S{sub N} equations for N up to 16 and we begin the convergence of the S{sub N} nodal equations defining an error for the angular flux and estimating the error in terms of the truncation error of the quadrature approximations of the integral term. Furthermore, we compare numerical results of this approach with those of other techniques used to solve the two-dimensional discrete approximations of the neutron transport equation. (authors)

  2. The Apelin receptor enhances Nodal/TGFβ signaling to ensure proper cardiac development

    PubMed Central

    Deshwar, Ashish R; Chng, Serene C; Ho, Lena; Reversade, Bruno; Scott, Ian C

    2016-01-01

    The Apelin receptor (Aplnr) is essential for heart development, controlling the early migration of cardiac progenitors. Here we demonstrate that in zebrafish Aplnr modulates Nodal/TGFβ signaling, a key pathway essential for mesendoderm induction and migration. Loss of Aplnr function leads to a reduction in Nodal target gene expression whereas activation of Aplnr by a non-peptide agonist increases the expression of these same targets. Furthermore, loss of Aplnr results in a delay in the expression of the cardiogenic transcription factors mespaa/ab. Elevating Nodal levels in aplnra/b morphant and double mutant embryos is sufficient to rescue cardiac differentiation defects. We demonstrate that loss of Aplnr attenuates the activity of a point source of Nodal ligands Squint and Cyclops in a non-cell autonomous manner. Our results favour a model in which Aplnr is required to fine-tune Nodal output, acting as a specific rheostat for the Nodal/TGFβ pathway during the earliest stages of cardiogenesis. DOI: http://dx.doi.org/10.7554/eLife.13758.001 PMID:27077952

  3. Final Report, NERI Project: ''An Innovative Reactor Analysis Methodology Based on a Quasidiffusion Nodal Core Model''

    SciTech Connect

    Dmitriy Y. Anistratov; Marvin L. Adams; Todd S. Palmer; Kord S. Smith; Kevin Clarno; Hikaru Hiruta; Razvan Nes

    2003-08-04

    OAK (B204) Final Report, NERI Project: ''An Innovative Reactor Analysis Methodology Based on a Quasidiffusion Nodal Core Model'' The present generation of reactor analysis methods uses few-group nodal diffusion approximations to calculate full-core eigenvalues and power distributions. The cross sections, diffusion coefficients, and discontinuity factors (collectively called ''group constants'') in the nodal diffusion equations are parameterized as functions of many variables, ranging from the obvious (temperature, boron concentration, etc.) to the more obscure (spectral index, moderator temperature history, etc.). These group constants, and their variations as functions of the many variables, are calculated by assembly-level transport codes. The current methodology has two main weaknesses that this project addressed. The first weakness is the diffusion approximation in the full-core calculation; this can be significantly inaccurate at interfaces between different assemblies. This project used the nodal diffusion framework to implement nodal quasidiffusion equations, which can capture transport effects to an arbitrary degree of accuracy. The second weakness is in the parameterization of the group constants; current models do not always perform well, especially at interfaces between unlike assemblies. The project developed a theoretical foundation for parameterization and homogenization models and used that theory to devise improved models. The new models were extended to tabulate information that the nodal quasidiffusion equations can use to capture transport effects in full-core calculations.

  4. A quasi-static polynomial nodal method for nuclear reactor analysis

    SciTech Connect

    Gehin, J.C.

    1992-09-01

    Modern nodal methods are currently available which can accurately and efficiently solve the static and transient neutron diffusion equations. Most of the methods, however, are limited to two energy groups for practical application. The objective of this research is the development of a static and transient, multidimensional nodal method which allows more than two energy groups and uses a non-linear iterative method for efficient solution of the nodal equations. For both the static and transient methods, finite-difference equations which are corrected by the use of discontinuity factors are derived. The discontinuity factors are computed from a polynomial nodal method using a non-linear iteration technique. The polynomial nodal method is based upon a quartic approximation and utilizes a quadratic transverse-leakage approximation. The solution of the time-dependent equations is performed by the use of a quasi-static method in which the node-averaged fluxes are factored into shape and amplitude functions. The application of the quasi-static polynomial method to several benchmark problems demonstrates that the accuracy is consistent with that of other nodal methods. The use of the quasi-static method is shown to substantially reduce the computation time over the traditional fully-implicit time-integration method. Problems involving thermal-hydraulic feedback are accurately, and efficiently, solved by performing several reactivity/thermal-hydraulic updates per shape calculation.

  5. 28. Embryonic and adult stem cell therapy.

    PubMed

    Henningson, Carl T; Stanislaus, Marisha A; Gewirtz, Alan M

    2003-02-01

    Stem cells are characterized by the ability to remain undifferentiated and to self-renew. Embryonic stem cells derived from blastocysts are pluripotent (able to differentiate into many cell types). Adult stem cells, which were traditionally thought to be monopotent multipotent, or tissue restricted, have recently also been shown to have pluripotent properties. Adult bone marrow stem cells have been shown to be capable of differentiating into skeletal muscle, brain microglia and astroglia, and hepatocytes. Stem cell lines derived from both embryonic stem and embryonic germ cells (from the embryonic gonadal ridge) are pluripotent and capable of self-renewal for long periods. Therefore embryonic stem and germ cells have been widely investigated for their potential to cure diseases by repairing or replacing damaged cells and tissues. Studies in animal models have shown that transplantation of fetal, embryonic stem, or embryonic germ cells may be able to treat some chronic diseases. In this review, we highlight recent developments in the use of stem cells as therapeutic agents for three such diseases: Diabetes, Parkinson disease, and congestive heart failure. We also discuss the potential use of stem cells as gene therapy delivery cells and the scientific and ethical issues that arise with the use of human stem cells. PMID:12592319

  6. TGF-β promotes glioma cell growth via activating Nodal expression through Smad and ERK1/2 pathways

    SciTech Connect

    Sun, Jing; Liu, Su-zhi; Lin, Yan; Cao, Xiao-pan; Liu, Jia-ming

    2014-01-17

    Highlights: •TGF-β promoted Nodal expression in glioma cells. •TGF-β promoted Nodal expression via activating Smad and ERK1/2 pathways. •TGF-β promotes glioma cell growth via activating Nodal expression. -- Abstract: While there were certain studies focusing on the mechanism of TGF-β promoting the growth of glioma cells, the present work revealed another novel mechanism that TGF-β may promote glioma cell growth via enhancing Nodal expression. Our results showed that Nodal expression was significantly upregulated in glioma cells when TGF-β was added, whereas the TGF-β-induced Nodal expression was evidently inhibited by transfection Smad2 or Smad3 siRNAs, and the suppression was especially significant when the Smad3 was downregulated. Another, the attenuation of TGF-β-induced Nodal expression was observed with blockade of the ERK1/2 pathway also. Further detection of the proliferation, apoptosis, and invasion of glioma cells indicated that Nodal overexpression promoted the proliferation and invasion of tumor cells and inhibited their apoptosis, resembling the effect of TGF-β addition. Downregulation of Nodal expression via transfection Nodal-specific siRNA in the presence of TGF-β weakened the promoting effect of the latter on glioma cells growth, and transfecting Nodal siRNA alone in the absence of exogenous TGF-β more profoundly inhibited the growth of glioma cells. These results demonstrated that while both TGF-β and Nodal promoted glioma cells growth, the former might exert such effect by enhancing Nodal expression, which may form a new target for glioma therapy.

  7. Cluster analysis of contaminated sediment data: nodal analysis.

    PubMed

    Hartwell, S Ian; Claflin, Larry W

    2005-07-01

    The objective of the present study was to explore the use of multivariate statistical methods as a means to discern relationships between contaminants and biological and/or toxicological effects in a representative data set from the National Status and Trends (NS&T) Program. Data from the National Oceanic and Atmospheric Administration, NS&T Program's Bioeffects Survey of Delaware Bay, USA, were examined using various univariate and multivariate statistical techniques, including cluster analysis. Each approach identified consistent patterns and relationships between the three types of triad data. The analyses also identified factors that bias the interpretation of the data, primarily the presence of rare and unique species and the dependence of species distributions on physical parameters. Sites and species were clustered with the unweighted pair-group method using arithmetic averages clustering with the Jaccard coefficient that clustered species and sites into mutually consistent groupings. Pearson product moment correlation coefficients, normalized for salinity, also were clustered. The most informative analysis, termed nodal analysis, was the intersection of species cluster analysis with site cluster analysis. This technique produced a visual representation of species association patterns among site clusters. Site characteristics, such as salinity and grain size, not contaminant concentrations, appeared to be the primary factors determining species distributions. This suggests the sediment-quality triad needs to use physical parameters as a distinct leg from chemical concentrations to improve sediment-quality assessments in large bodies of water. Because the Delaware Bay system has confounded gradients of contaminants and physical parameters, analyses were repeated with data from northern Chesapeake Bay, USA, with similar results. PMID:16050601

  8. Regulation of expression driven by human immunodeficiency virus type 1 and human T-cell leukemia virus type I long terminal repeats in pluripotential human embryonic cells

    SciTech Connect

    Maio, J.; Brown, F.L. )

    1988-04-01

    Human pluripotential embryonic teratocarcinoma cells differentially expressed gene activity controlled by the human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type I (HTLV-I) long terminal repeats (LTRs) when differentiation was induced by the morphogen all-trans retinoic acid. The alterations occurred after commitment and before the appearance of the multiple cell types characteristic of these pluripotential cells. After commitment, gene activity controlled by the HIV-1 LTR markedly increased, whereas that controlled by the HTLV-I LTR decreased. Steady-state mRNA levels and nuclear run-on transcription indicated that the increased HIV-1-directed activity during differentiation occurred posttranscriptionally, whereas the decreased HTLV-I activity was at the transcriptional level. Phorbol esters did not cause commitment but strongly enhanced expression by both viral LTRs at the transcriptional level. Differentiating cells gradually lost the ability to respond to phorbol ester stimulation. Experiments with a deletion mutant of the HIV-1 LTR suggested that this was due to imposition of negative regulation during differentiation that was not reversed by phorbol ester induction. Cycloheximide, with or without phorbol ester, slightly stimulated HIV-1-directed activity at the transcriptional level and massively increased the amounts of steady-state mRNA by posttranscriptional superinduction. It appeared, however, that new nuclear protein synthesis was required for maximal transcriptional stimulation by phorbol esters. Thus, changing cellular regulatory mechanisms influenced human retrovirus expression during human embryonic cell differentiation.

  9. Role of microglia in embryonic neurogenesis

    PubMed Central

    Tong, Chih Kong

    2016-01-01

    Microglia begin colonizing the developing brain as early as embryonic day 9, prior to the emergence of neurons and other glia. Their ontogeny is also distinct from other central nervous system cells, as they derive from yolk sac hematopoietic progenitors and not neural progenitors. In this review, we feature these unique characteristics of microglia and assess the spatiotemporal similarities between microglia colonization of the central nervous system and embryonic neurogenesis. We also infer to existing evidence for microglia function from embryonic through to postnatal neurodevelopment to postulate roles for microglia in neurogenesis. PMID:27555616

  10. Measuring time during early embryonic development.

    PubMed

    Ferree, Patrick L; Deneke, Victoria E; Di Talia, Stefano

    2016-07-01

    In most metazoans, embryonic development is orchestrated by a precise series of cellular behaviors. Understanding how such events are regulated to achieve a stereotypical temporal progression is a fundamental problem in developmental biology. In this review, we argue that studying the regulation of the cell cycle in early embryonic development will reveal novel principles of how embryos accurately measure time. We will discuss the strategies that have emerged from studying early development of Drosophila embryos. By comparing the development of flies to that of other metazoans, we will highlight both conserved and alternative mechanisms to generate precision during embryonic development. PMID:26994526