Mechanism of IRSp53 inhibition and combinatorial activation by Cdc42 and downstream effectors.

Science.gov (United States)

Kast, David J; Yang, Changsong; Disanza, Andrea; Boczkowska, Malgorzata; Madasu, Yadaiah; Scita, Giorgio; Svitkina, Tatyana; Dominguez, Roberto

2014-04-01

The Rho family GTPase effector IRSp53 has essential roles in filopodia formation and neuronal development, but its regulatory mechanism is poorly understood. IRSp53 contains a membrane-binding BAR domain followed by an unconventional CRIB motif that overlaps with a proline-rich region (CRIB-PR) and an SH3 domain that recruits actin cytoskeleton effectors. Using a fluorescence reporter assay, we show that human IRSp53 adopts a closed inactive conformation that opens synergistically with the binding of human Cdc42 to the CRIB-PR and effector proteins, such as the tumor-promoting factor Eps8, to the SH3 domain. The crystal structure of Cdc42 bound to the CRIB-PR reveals a new mode of effector binding to Rho family GTPases. Structure-inspired mutations disrupt autoinhibition and Cdc42 binding in vitro and decouple Cdc42- and IRSp53-dependent filopodia formation in cells. The data support a combinatorial mechanism of IRSp53 activation.

Rac1 and Cdc42 are regulators of HRasV12-transformation and angiogenic factors in human fibroblasts

International Nuclear Information System (INIS)

Appledorn, Daniel M; Dao, Kim-Hien T; O'Reilly, Sandra; Maher, Veronica M; McCormick, J Justin

2010-01-01

The activities of Rac1 and Cdc42 are essential for HRas-induced transformation of rodent fibroblasts. What is more, expression of constitutively activated mutants of Rac1 and/or Cdc42 is sufficient for their malignant transformation. The role for these two Rho GTPases in HRas-mediated transformation of human fibroblasts has not been studied. Here we evaluated the contribution of Rac1 and Cdc42 to maintaining HRas-induced transformation of human fibroblasts, and determined the ability of constitutively activated mutants of Rac1 or Cdc42 to induce malignant transformation of a human fibroblast cell strain. Under the control of a tetracycline regulatable promoter, dominant negative mutants of Rac1 and Cdc42 were expressed in a human HRas-transformed, tumor derived fibroblast cell line. These cells were used to determine the roles of Rac1 and/or Cdc42 proteins in maintaining HRas-induced transformed phenotypes. Similarly, constitutively active mutants were expressed in a non-transformed human fibroblast cell strain to evaluate their potential to induce malignant transformation. Affymetrix GeneChip arrays were used for transcriptome analyses, and observed expression differences were subsequently validated using protein assays. Expression of dominant negative Rac1 and/or Cdc42 significantly altered transformed phenotypes of HRas malignantly transformed human fibroblasts. In contrast, expression of constitutively active mutants of Rac1 or Cdc42 was not sufficient to induce malignant transformation. Microarray analysis revealed that the expression of 29 genes was dependent on Rac1 and Cdc42, many of which are known to play a role in cancer. The dependence of two such genes, uPA and VEGF was further validated in both normoxic and hypoxic conditions. The results presented here indicate that expression of both Rac1 and Cdc42 is necessary for maintaining several transformed phenotypes in oncogenic HRas transformed human cells, including their ability to form tumors in athymic

Rac1 and Cdc42 are regulators of HRasV12-transformation and angiogenic factors in human fibroblasts

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Dao Kim-Hien T

2010-01-01

Full Text Available Abstract Background The activities of Rac1 and Cdc42 are essential for HRas-induced transformation of rodent fibroblasts. What is more, expression of constitutively activated mutants of Rac1 and/or Cdc42 is sufficient for their malignant transformation. The role for these two Rho GTPases in HRas-mediated transformation of human fibroblasts has not been studied. Here we evaluated the contribution of Rac1 and Cdc42 to maintaining HRas-induced transformation of human fibroblasts, and determined the ability of constitutively activated mutants of Rac1 or Cdc42 to induce malignant transformation of a human fibroblast cell strain. Methods Under the control of a tetracycline regulatable promoter, dominant negative mutants of Rac1 and Cdc42 were expressed in a human HRas-transformed, tumor derived fibroblast cell line. These cells were used to determine the roles of Rac1 and/or Cdc42 proteins in maintaining HRas-induced transformed phenotypes. Similarly, constitutively active mutants were expressed in a non-transformed human fibroblast cell strain to evaluate their potential to induce malignant transformation. Affymetrix GeneChip arrays were used for transcriptome analyses, and observed expression differences were subsequently validated using protein assays. Results Expression of dominant negative Rac1 and/or Cdc42 significantly altered transformed phenotypes of HRas malignantly transformed human fibroblasts. In contrast, expression of constitutively active mutants of Rac1 or Cdc42 was not sufficient to induce malignant transformation. Microarray analysis revealed that the expression of 29 genes was dependent on Rac1 and Cdc42, many of which are known to play a role in cancer. The dependence of two such genes, uPA and VEGF was further validated in both normoxic and hypoxic conditions. Conclusion(s The results presented here indicate that expression of both Rac1 and Cdc42 is necessary for maintaining several transformed phenotypes in oncogenic HRas

A crucial role for CDC42 in senescence-associated inflammation and atherosclerosis.

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Takashi K Ito

Full Text Available Risk factors for atherosclerosis accelerate the senescence of vascular endothelial cells and promote atherogenesis by inducing vascular inflammation. A hallmark of endothelial senescence is the persistent up-regulation of pro-inflammatory genes. We identified CDC42 signaling as a mediator of chronic inflammation associated with endothelial senescence. Inhibition of CDC42 or NF-κB signaling attenuated the sustained up-regulation of pro-inflammatory genes in senescent human endothelial cells. Endothelium-specific activation of the p53/p21 pathway, a key mediator of senescence, also resulted in up-regulation of pro-inflammatory molecules in mice, which was reversed by Cdc42 deletion in endothelial cells. Likewise, endothelial-specific deletion of Cdc42 significantly attenuated chronic inflammation and plaque formation in atherosclerotic mice. While inhibition of NF-κB suppressed the pro-inflammatory responses in acute inflammation, the influence of Cdc42 deletion was less marked. Knockdown of cdc-42 significantly down-regulated pro-inflammatory gene expression and restored the shortened lifespan to normal in mutant worms with enhanced inflammation. These findings indicate that the CDC42 pathway is critically involved in senescence-associated inflammation and could be a therapeutic target for chronic inflammation in patients with age-related diseases without compromising host defenses.

Rac1 and Cdc42 GTPases regulate shear stress-driven β-catenin signaling in osteoblasts

International Nuclear Information System (INIS)

Wan, Qiaoqiao; Cho, Eunhye; Yokota, Hiroki; Na, Sungsoo

2013-01-01

Highlights: •Shear stress increased TCF/LEF activity and stimulated β-catenin nuclear localization. •Rac1, Cdc42, and RhoA displayed distinct dynamic activity patterns under flow. •Rac1 and Cdc42, but not RhoA, regulate shear stress-driven TCF/LEF activation. •Cytoskeleton did not significantly affect shear stress-induced TCF/LEF activation. -- Abstract: Beta-catenin-dependent TCF/LEF (T-cell factor/lymphocyte enhancing factor) is known to be mechanosensitive and an important regulator for promoting bone formation. However, the functional connection between TCF/LEF activity and Rho family GTPases is not well understood in osteoblasts. Herein we investigated the molecular mechanisms underlying oscillatory shear stress-induced TCF/LEF activity in MC3T3-E1 osteoblast cells using live cell imaging. We employed fluorescence resonance energy transfer (FRET)-based and green fluorescent protein (GFP)-based biosensors, which allowed us to monitor signal transduction in living cells in real time. Oscillatory (1 Hz) shear stress (10 dynes/cm 2 ) increased TCF/LEF activity and stimulated translocation of β-catenin to the nucleus with the distinct activity patterns of Rac1 and Cdc42. The shear stress-induced TCF/LEF activity was blocked by the inhibition of Rac1 and Cdc42 with their dominant negative mutants or selective drugs, but not by a dominant negative mutant of RhoA. In contrast, constitutively active Rac1 and Cdc42 mutants caused a significant enhancement of TCF/LEF activity. Moreover, activation of Rac1 and Cdc42 increased the basal level of TCF/LEF activity, while their inhibition decreased the basal level. Interestingly, disruption of cytoskeletal structures or inhibition of myosin activity did not significantly affect shear stress-induced TCF/LEF activity. Although Rac1 is reported to be involved in β-catenin in cancer cells, the involvement of Cdc42 in β-catenin signaling in osteoblasts has not been identified. Our findings in this study demonstrate

Rac1 and Cdc42 GTPases regulate shear stress-driven β-catenin signaling in osteoblasts

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Wan, Qiaoqiao; Cho, Eunhye [Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202 (United States); Yokota, Hiroki [Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202 (United States); Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202 (United States); Na, Sungsoo, E-mail: sungna@iupui.edu [Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202 (United States)

2013-04-19

Highlights: •Shear stress increased TCF/LEF activity and stimulated β-catenin nuclear localization. •Rac1, Cdc42, and RhoA displayed distinct dynamic activity patterns under flow. •Rac1 and Cdc42, but not RhoA, regulate shear stress-driven TCF/LEF activation. •Cytoskeleton did not significantly affect shear stress-induced TCF/LEF activation. -- Abstract: Beta-catenin-dependent TCF/LEF (T-cell factor/lymphocyte enhancing factor) is known to be mechanosensitive and an important regulator for promoting bone formation. However, the functional connection between TCF/LEF activity and Rho family GTPases is not well understood in osteoblasts. Herein we investigated the molecular mechanisms underlying oscillatory shear stress-induced TCF/LEF activity in MC3T3-E1 osteoblast cells using live cell imaging. We employed fluorescence resonance energy transfer (FRET)-based and green fluorescent protein (GFP)-based biosensors, which allowed us to monitor signal transduction in living cells in real time. Oscillatory (1 Hz) shear stress (10 dynes/cm{sup 2}) increased TCF/LEF activity and stimulated translocation of β-catenin to the nucleus with the distinct activity patterns of Rac1 and Cdc42. The shear stress-induced TCF/LEF activity was blocked by the inhibition of Rac1 and Cdc42 with their dominant negative mutants or selective drugs, but not by a dominant negative mutant of RhoA. In contrast, constitutively active Rac1 and Cdc42 mutants caused a significant enhancement of TCF/LEF activity. Moreover, activation of Rac1 and Cdc42 increased the basal level of TCF/LEF activity, while their inhibition decreased the basal level. Interestingly, disruption of cytoskeletal structures or inhibition of myosin activity did not significantly affect shear stress-induced TCF/LEF activity. Although Rac1 is reported to be involved in β-catenin in cancer cells, the involvement of Cdc42 in β-catenin signaling in osteoblasts has not been identified. Our findings in this study demonstrate

Cdc42 and Tks5: a minimal and universal molecular signature for functional invadosomes.

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Di Martino, Julie; Paysan, Lisa; Gest, Caroline; Lagrée, Valérie; Juin, Amélie; Saltel, Frédéric; Moreau, Violaine

2014-01-01

Invadosomes are actin-based structures involved in extracellular-matrix degradation. Invadosomes, either known as podosomes or invadopodia, are found in an increasing number of cell types. Moreover, their overall organization and molecular composition may vary from one cell type to the other. Some are constitutive such as podosomes in hematopoietic cells whereas others are inducible. However, they share the same feature, their ability to interact and to degrade the extracellular matrix. Based on the literature and our own experiments, the aim of this study was to establish a minimal molecular definition of active invadosomes. We first highlighted that Cdc42 is the key RhoGTPase involved in invadosome formation in all described models. Using different cellular models, such as NIH-3T3, HeLa, and endothelial cells, we demonstrated that overexpression of an active form of Cdc42 is sufficient to form invadosome actin cores. Therefore, active Cdc42 must be considered not only as an inducer of filopodia, but also as an inducer of invadosomes. Depending on the expression level of Tks5, these Cdc42-dependent actin cores were endowed or not with a proteolytic activity. In fact, Tks5 overexpression rescued this activity in Tks5 low expressing cells. We thus described the adaptor protein Tks5 as a major actor of the invadosome degradation function. Surprisingly, we found that Src kinases are not always required for invadosome formation and function. These data suggest that even if Src family members are the principal kinases involved in the majority of invadosomes, it cannot be considered as a common element for all invadosome structures. We thus define a minimal and universal molecular signature of invadosome that includes Cdc42 activity and Tks5 presence in order to drive the actin machinery and the proteolytic activity of these invasive structures.

Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury

DEFF Research Database (Denmark)

Blattner, Simone M; Hodgin, Jeffrey B; Nishio, Masashi

2013-01-01

-specific deletion of Rac1 prevented foot process effacement. In a long-term model of chronic hypertensive glomerular damage, however, loss of Rac1 led to an exacerbation of albuminuria and glomerulosclerosis. In contrast, mice with podocyte-specific deletion of Cdc42 had severe proteinuria, podocyte foot process...... effacement, and glomerulosclerosis beginning as early as 10 days of age. In addition, slit diaphragm proteins nephrin and podocin were redistributed, and cofilin was dephosphorylated. Cdc42 is necessary for the maintenance of podocyte structure and function, but Rac1 is entirely dispensable in physiological...... steady state. However, Rac1 has either beneficial or deleterious effects depending on the context of podocyte impairment. Thus, our study highlights the divergent roles of Rac1 and Cdc42 function in podocyte maintenance and injury.Kidney International advance online publication, 15 May 2013; doi:10...

Different roles of the small GTPases Rac1, Cdc42, and RhoG in CALEB/NGC-induced dendritic tree complexity.

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Schulz, Jana; Franke, Kristin; Frick, Manfred; Schumacher, Stefan

2016-10-01

Rho GTPases play prominent roles in the regulation of cytoskeletal reorganization. Many aspects have been elaborated concerning the individual functions of Rho GTPases in distinct signaling pathways leading to cytoskeletal rearrangements. However, major questions have yet to be answered regarding the integration and the signaling hierarchy of different Rho GTPases in regulating the cytoskeleton in fundamental physiological events like neuronal process differentiation. Here, we investigate the roles of the small GTPases Rac1, Cdc42, and RhoG in defining dendritic tree complexity stimulated by the transmembrane epidermal growth factor family member CALEB/NGC. Combining gain-of-function and loss-of-function analysis in primary hippocampal neurons, we find that Rac1 is essential for CALEB/NGC-mediated dendritic branching. Cdc42 reduces the complexity of dendritic trees. Interestingly, we identify the palmitoylated isoform of Cdc42 to adversely affect dendritic outgrowth and dendritic branching, whereas the prenylated Cdc42 isoform does not. In contrast to Rac1, CALEB/NGC and Cdc42 are not directly interconnected in regulating dendritic tree complexity. Unlike Rac1, the Rac1-related GTPase RhoG reduces the complexity of dendritic trees by acting upstream of CALEB/NGC. Mechanistically, CALEB/NGC activates Rac1, and RhoG reduces the amount of CALEB/NGC that is located at the right site for Rac1 activation at the cell membrane. Thus, Rac1, Cdc42, and RhoG perform very specific and non-redundant functions at different levels of hierarchy in regulating dendritic tree complexity induced by CALEB/NGC. Rho GTPases play a prominent role in dendritic branching. CALEB/NGC is a transmembrane member of the epidermal growth factor (EGF) family that mediates dendritic branching, dependent on Rac1. CALEB/NGC stimulates Rac1 activity. RhoG inhibits CALEB/NGC-mediated dendritic branching by decreasing the amount of CALEB/NGC at the plasma membrane. Palmitoylated, but not prenylated form

miR-330 regulates the proliferation of colorectal cancer cells by targeting Cdc42

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Li, Yuefeng [The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001 (China); Zhu, Xiaolan; Xu, Wenlin [The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001 (China); Wang, Dongqing [The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001 (China); Yan, Jinchuan, E-mail: jiangdalyf2009@126.com [The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001 (China)

2013-02-15

Highlights: ► miR-330 was inversely correlated with Cdc42 in colorectal cancer cells. ► Elevated miR-330 suppressed cell proliferation in vivo and in vitro. ► Elevated miR-330 mimicked the effect of Cdc42 knockdown. ► Restoration of Cdc42 could partially attenuate the effects of miR-330. -- Abstract: MicroRNAs are small non-coding RNA molecules that play important roles in the multistep process of colorectal carcinoma (CRC) development. However, the miRNA–mRNA regulatory network is far from being fully understood. The objective of this study was to investigate the expression and the biological roles of miR-330 in colorectal cancer cells. Cdc42, one of the best characterized members of the Rho GTPase family, was found to be up-regulated in several types of human tumors including CRC and has been implicated in cancer initiation and progression. In the present study, we identified miR-330, as a potential regulator of Cdc42, was found to be inversely correlated with Cdc42 expression in colorectal cancer cell lines. Ectopic expression of miR-330 down-regulated Cdc42 expression at both protein and mRNA level, mimicked the effect of Cdc42 knockdown in inhibiting proliferation, inducing G1 cell cycle arrest and apoptosis of the colorectal cancer cells, whereas restoration of Cdc42 could partially attenuate the effects of miR-330. In addition, elevated expression of miR-330 could suppress the immediate downstream effectors of Cdc42 and inhibit the growth of colorectal cancer cells in vivo. To sum up, our results establish a role of miR-330 in negatively regulating Cdc42 expression and colorectal cancer cell proliferation. They suggest that manipulating the expression level of Cdc42 by miR-330 has the potential to influence colorectal cancer progression.

miR-330 regulates the proliferation of colorectal cancer cells by targeting Cdc42

International Nuclear Information System (INIS)

Li, Yuefeng; Zhu, Xiaolan; Xu, Wenlin; Wang, Dongqing; Yan, Jinchuan

2013-01-01

Highlights: ► miR-330 was inversely correlated with Cdc42 in colorectal cancer cells. ► Elevated miR-330 suppressed cell proliferation in vivo and in vitro. ► Elevated miR-330 mimicked the effect of Cdc42 knockdown. ► Restoration of Cdc42 could partially attenuate the effects of miR-330. -- Abstract: MicroRNAs are small non-coding RNA molecules that play important roles in the multistep process of colorectal carcinoma (CRC) development. However, the miRNA–mRNA regulatory network is far from being fully understood. The objective of this study was to investigate the expression and the biological roles of miR-330 in colorectal cancer cells. Cdc42, one of the best characterized members of the Rho GTPase family, was found to be up-regulated in several types of human tumors including CRC and has been implicated in cancer initiation and progression. In the present study, we identified miR-330, as a potential regulator of Cdc42, was found to be inversely correlated with Cdc42 expression in colorectal cancer cell lines. Ectopic expression of miR-330 down-regulated Cdc42 expression at both protein and mRNA level, mimicked the effect of Cdc42 knockdown in inhibiting proliferation, inducing G1 cell cycle arrest and apoptosis of the colorectal cancer cells, whereas restoration of Cdc42 could partially attenuate the effects of miR-330. In addition, elevated expression of miR-330 could suppress the immediate downstream effectors of Cdc42 and inhibit the growth of colorectal cancer cells in vivo. To sum up, our results establish a role of miR-330 in negatively regulating Cdc42 expression and colorectal cancer cell proliferation. They suggest that manipulating the expression level of Cdc42 by miR-330 has the potential to influence colorectal cancer progression

Cdc42 regulates epithelial cell polarity and cytoskeletal function during kidney tubule development

DEFF Research Database (Denmark)

Elias, Bertha C; Das, Amrita; Parekh, Diptiben V

2015-01-01

The Rho GTPase Cdc42 regulates key signaling pathways required for multiple cell functions, including maintenance of shape, polarity, proliferation, migration, differentiation and morphogenesis. Although previous studies have shown that Cdc42 is required for proper epithelial development and main......The Rho GTPase Cdc42 regulates key signaling pathways required for multiple cell functions, including maintenance of shape, polarity, proliferation, migration, differentiation and morphogenesis. Although previous studies have shown that Cdc42 is required for proper epithelial development...

Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes.

Science.gov (United States)

Martinelli, Simone; Krumbach, Oliver H F; Pantaleoni, Francesca; Coppola, Simona; Amin, Ehsan; Pannone, Luca; Nouri, Kazem; Farina, Luciapia; Dvorsky, Radovan; Lepri, Francesca; Buchholzer, Marcel; Konopatzki, Raphael; Walsh, Laurence; Payne, Katelyn; Pierpont, Mary Ella; Vergano, Samantha Schrier; Langley, Katherine G; Larsen, Douglas; Farwell, Kelly D; Tang, Sha; Mroske, Cameron; Gallotta, Ivan; Di Schiavi, Elia; Della Monica, Matteo; Lugli, Licia; Rossi, Cesare; Seri, Marco; Cocchi, Guido; Henderson, Lindsay; Baskin, Berivan; Alders, Mariëlle; Mendoza-Londono, Roberto; Dupuis, Lucie; Nickerson, Deborah A; Chong, Jessica X; Meeks, Naomi; Brown, Kathleen; Causey, Tahnee; Cho, Megan T; Demuth, Stephanie; Digilio, Maria Cristina; Gelb, Bruce D; Bamshad, Michael J; Zenker, Martin; Ahmadian, Mohammad Reza; Hennekam, Raoul C; Tartaglia, Marco; Mirzaa, Ghayda M

2018-01-17

Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in vitro, and in vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Hepatocyte-specific deletion of Cdc42 results in delayed liver regeneration after partial hepatectomy in mice

DEFF Research Database (Denmark)

Yuan, Haixin; Zhang, Hong; Wu, Xunwei

2009-01-01

Cdc42, a member of the Rho guanosine triphosphatase (GTPase) family, plays important roles in the regulation of the cytoskeleton, cell proliferation, cell polarity, and cellular transport, but little is known about its specific function in mammalian liver. We investigated the function of Cdc42...... in regulating liver regeneration. Using a mouse model with liver-specific knockout of Cdc42 (Cdc42LK), we studied liver regeneration after partial hepatectomy. Histological analysis, immunostaining, and western blot analysis were performed to characterize Cdc42LK livers and to explore the role of Cdc42 in liver...... regeneration. In control mouse livers, Cdc42 became activated between 3 and 24 hours after partial hepatectomy. Loss of Cdc42 led to a significant delay of liver recovery after partial hepatectomy, which was associated with reduced and delayed DNA synthesis indicated by 5-bromo-2'-deoxyuridine staining...

Binding of Cdc42 to phospholipase D1 is important in neurite outgrowth of neural stem cells

International Nuclear Information System (INIS)

Yoon, Mee-Sup; Cho, Chan Ho; Lee, Ki Sung; Han, Joong-Soo

2006-01-01

We previously demonstrated that phospholipase D (PLD) expression and PLD activity are upregulated during neuronal differentiation. In the present study, employing neural stem cells from the brain cortex of E14 rat embryos, we investigated the role of Rho family GTPases in PLD activation and in neurite outgrowth of neural stem cells during differentiation. As neuronal differentiation progressed, the expression levels of Cdc42 and RhoA increased. Furthermore, Cdc42 and PLD1 were mainly localized in neurite, whereas RhoA was localized in cytosol. Co-immunoprecipitation revealed that Cdc42 was bound to PLD1 during differentiation, whereas RhoA was associated with PLD1 during both proliferation and differentiation. These results indicate that the association between Cdc42 and PLD1 is related to neuronal differentiation. To examine the effect of Cdc42 on PLD activation and neurite outgrowth, we transfected dominant negative Cdc42 (Cdc42N17) and constitutively active Cdc42 (Cdc42V12) into neural stem cells, respectively. Overexpression of Cdc42N17 decreased both PLD activity and neurite outgrowth, whereas co-transfection with Cdc42N17 and PLD1 restored them. On the other hand, Cdc42V12 increased both PLD activity and neurite outgrowth, suggesting that active state of Cdc42 is important in upregulation of PLD activity which is responsible for the increase of neurite outgrowth

Cdc42 is crucial for the establishment of epithelial polarity during early mammalian development

DEFF Research Database (Denmark)

Wu, Xunwei; Li, Shaohua; Chrostek-Grashoff, Anna

2007-01-01

To study the role of Cdc42 in the establishment of epithelial polarity during mammalian development, we generated murine Cdc42-null embryonic stem cells and analyzed peri-implantation development using embryoid bodies (EBs). Mutant EBs developed endoderm and underlying basement membrane, but exhi......To study the role of Cdc42 in the establishment of epithelial polarity during mammalian development, we generated murine Cdc42-null embryonic stem cells and analyzed peri-implantation development using embryoid bodies (EBs). Mutant EBs developed endoderm and underlying basement membrane...

Gene targeting implicates Cdc42 GTPase in GPVI and non-GPVI mediated platelet filopodia formation, secretion and aggregation.

Directory of Open Access Journals (Sweden)

Huzoor Akbar

Full Text Available Cdc42 and Rac1, members of the Rho family of small GTPases, play critical roles in actin cytoskeleton regulation. We have shown previously that Rac1 is involved in regulation of platelet secretion and aggregation. However, the role of Cdc42 in platelet activation remains controversial. This study was undertaken to better understand the role of Cdc42 in platelet activation.We utilized the Mx-cre;Cdc42(lox/lox inducible mice with transient Cdc42 deletion to investigate the involvement of Cdc42 in platelet function. The Cdc42-deficient mice exhibited a significantly reduced platelet count than the matching Cdc42(+/+ mice. Platelets isolated from Cdc42(-/-, as compared to Cdc42(+/+, mice exhibited (a diminished phosphorylation of PAK1/2, an effector molecule of Cdc42, (b inhibition of filopodia formation on immobilized CRP or fibrinogen, (c inhibition of CRP- or thrombin-induced secretion of ATP and release of P-selectin, (d inhibition of CRP, collagen or thrombin induced platelet aggregation, and (e minimal phosphorylation of Akt upon stimulation with CRP or thrombin. The bleeding times were significantly prolonged in Cdc42(-/- mice compared with Cdc42(+/+ mice.Our data demonstrate that Cdc42 is required for platelet filopodia formation, secretion and aggregation and therefore plays a critical role in platelet mediated hemostasis and thrombosis.

Cooperation of Rho family proteins Rac1 and Cdc42 in cartilage development and calcified tissue formation.

Science.gov (United States)

Ikehata, Mikiko; Yamada, Atsushi; Fujita, Koji; Yoshida, Yuko; Kato, Tadashi; Sakashita, Akiko; Ogata, Hiroaki; Iijima, Takehiko; Kuroda, Masahiko; Chikazu, Daichi; Kamijo, Ryutaro

2018-04-20

Rac1 and Cdc42, Rho family low molecular weight G proteins, are intracellular signaling factors that transmit various information from outside to inside cells. Primarily, they are known to control various biological activities mediated by actin cytoskeleton reorganization, such as cell proliferation, differentiation, and apoptosis. In order to investigate the functions of Rac1 and Cdc42 in bone formation, we prepared cartilage-specific double conditional knockout mice, Rac1 fl/fl ; Cdc42 fl/fl ; Col2-Cre (Rac1: Cdc42 dcKO mice), which died just after birth, similar to Cdc42 fl/fl ; Col2-Cre mice (Cdc42 cKO mice). Our findings showed that the long tubule bone in Rac1: Cdc42 dcKO mice was shorter than that in Rac1 fl/fl ; Col2-Cre mice (Rac1 cKO mice) and Cdc42 cKO mice. Abnormal skeleton formation was also observed and disordered columnar formation in the growth plate of the Rac1: Cdc42 dcKO mice was more severe as compared to the Rac1 cKO and Cdc42 cKO mice. Together, these results suggest that Rac1 and Cdc42 have cooperating roles in regulation of bone development. Copyright © 2018 Elsevier Inc. All rights reserved.

Essential roles of Cdc42 and MAPK in cadmium-induced apoptosis in Litopenaeus vannamei

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Peng, Ting; Wang, Wei-Na, E-mail: weina63@aliyun.com; Gu, Mei-Mei; Xie, Chen-Ying; Xiao, Yu-Chao; Liu, Yuan; Wang, Lei

2015-06-15

Highlights: • Cd{sup 2+} induces Cdc42 and MAPKs pathway related gene of Litopenaeus vannamei up-regulation. • Reduction of THC, increase of ROS production and apoptotic cell rate were observed when the shrimps exposure to Cd{sup 2+}. • DsRNA-suppression of LvCdc42 and MAPKs during Cd{sup 2+} stress reduces the ROS production and apoptosis. • We conclude that LvCdc42 and MAPKs play key roles in Cd{sup 2+} stress responses of shrimps. - Abstract: Cadmium, one of the most toxic heavy metals in aquatic environments, has severe effects on marine invertebrates and fishes. The MAPK signaling pathway plays a vital role in stress responses of animals. The mitogen-activated protein kinase (MAPK) signaling pathway plays a vital role in animals’ stress responses, including mediation of apoptosis induced by the Rho GTPase Cdc42. However, there is limited knowledge about its function in shrimps, although disorders exacerbated by environmental stresses (including heavy metal pollution) have caused serious mortality in commercially cultured shrimps. Thus, we probed roles of Cdc42 in Litopenaeus vannamei shrimps (LvCdc42) during cadmium exposure by inhibiting its expression using dsRNA-mediated RNA interference. The treatment successfully reduced expression levels of MAPKs (including p38, JNK, and ERK). Cadmium exposure induced significant increases in expression levels of LvCdc42 and MAPKs, accompanied by reductions in total hemocyte counts (THC) and increases in apoptotic hemocyte ratios and ROS production. However, all of these responses were much weaker in LvCdc42-suppressed shrimps, in which mortality rates were higher than in controls. Our results suggest that the MAPK pathway plays a vital role in shrimps’ responses to Cd{sup 2+}. They also indicate that LvCdc42 in shrimps participates in its regulation, and thus plays key roles in ROS production, regulation of apoptosis and associated stress responses.

Essential roles of Cdc42 and MAPK in cadmium-induced apoptosis in Litopenaeus vannamei

International Nuclear Information System (INIS)

Peng, Ting; Wang, Wei-Na; Gu, Mei-Mei; Xie, Chen-Ying; Xiao, Yu-Chao; Liu, Yuan; Wang, Lei

2015-01-01

Highlights: • Cd 2+ induces Cdc42 and MAPKs pathway related gene of Litopenaeus vannamei up-regulation. • Reduction of THC, increase of ROS production and apoptotic cell rate were observed when the shrimps exposure to Cd 2+ . • DsRNA-suppression of LvCdc42 and MAPKs during Cd 2+ stress reduces the ROS production and apoptosis. • We conclude that LvCdc42 and MAPKs play key roles in Cd 2+ stress responses of shrimps. - Abstract: Cadmium, one of the most toxic heavy metals in aquatic environments, has severe effects on marine invertebrates and fishes. The MAPK signaling pathway plays a vital role in stress responses of animals. The mitogen-activated protein kinase (MAPK) signaling pathway plays a vital role in animals’ stress responses, including mediation of apoptosis induced by the Rho GTPase Cdc42. However, there is limited knowledge about its function in shrimps, although disorders exacerbated by environmental stresses (including heavy metal pollution) have caused serious mortality in commercially cultured shrimps. Thus, we probed roles of Cdc42 in Litopenaeus vannamei shrimps (LvCdc42) during cadmium exposure by inhibiting its expression using dsRNA-mediated RNA interference. The treatment successfully reduced expression levels of MAPKs (including p38, JNK, and ERK). Cadmium exposure induced significant increases in expression levels of LvCdc42 and MAPKs, accompanied by reductions in total hemocyte counts (THC) and increases in apoptotic hemocyte ratios and ROS production. However, all of these responses were much weaker in LvCdc42-suppressed shrimps, in which mortality rates were higher than in controls. Our results suggest that the MAPK pathway plays a vital role in shrimps’ responses to Cd 2+ . They also indicate that LvCdc42 in shrimps participates in its regulation, and thus plays key roles in ROS production, regulation of apoptosis and associated stress responses

Cdc42 controls primary mesenchyme cell morphogenesis in the sea urchin embryo.

Science.gov (United States)

Sepúlveda-Ramírez, Silvia P; Toledo-Jacobo, Leslie; Henson, John H; Shuster, Charles B

2018-05-15

In the sea urchin embryo, gastrulation is characterized by the ingression and directed cell migration of primary mesenchyme cells (PMCs), as well as the primary invagination and convergent extension of the endomesoderm. Like all cell shape changes, individual and collective cell motility is orchestrated by Rho family GTPases and their modulation of the actomyosin cytoskeleton. And while endomesoderm specification has been intensively studied in echinoids, much less is known about the proximate regulators driving cell motility. Toward these ends, we employed anti-sense morpholinos, mutant alleles and pharmacological inhibitors to assess the role of Cdc42 during sea urchin gastrulation. While inhibition of Cdc42 expression or activity had only mild effects on PMC ingression, PMC migration, alignment and skeletogenesis were disrupted in the absence of Cdc42, as well as elongation of the archenteron. PMC migration and patterning of the larval skeleton relies on the extension of filopodia, and Cdc42 was required for filopodia in vivo as well as in cultured PMCs. Lastly, filopodial extension required both Arp2/3 and formin actin-nucleating factors, supporting models of filopodial nucleation observed in other systems. Together, these results suggest that Cdc42 plays essential roles during PMC cell motility and organogenesis. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Estrogen and Resveratrol Regulate Rac and Cdc42 Signaling to the Actin Cytoskeleton of Metastatic Breast Cancer Cells

Directory of Open Access Journals (Sweden)

Nicolas G. Azios

2007-02-01

Full Text Available Estrogen and structurally related molecules play critical roles in breast cancer. We reported that resveratrol (50 µM, an estrogen-like phytosterol from grapes, acts in an antiestrogenic manner in breast cancer cells to reduce cell migration and to induce a global and sustained extension of actin structures called filopodia. Herein, we report that resveratrol-induced filopodia formation is time-dependent and concentration-dependent. In contrast to resveratrol at 50 µM, resveratrol at 5 µM acts in a manner similar to estrogen by increasing lamellipodia, as well as cell migration and invasion. Because Rho GTPases regulate the extension of actin structures, we investigated a role for Rac and Cdc42 in estrogen and resveratrol signaling. Our results demonstrate that 50 µM resveratrol decreases Rac and Cdc42 activity, whereas estrogen and 5 µM resveratrol increase Rac activity in breast cancer cells. MDA-MB-231 cells expressing dominant-negative Cdc42 or dominantnegative Rac retain filopodia response to 50 µM resveratrol. Lamellipodia response to 5 µM resveratrol, estrogen, or epidermal growth factor is inhibited in cells expressing dominant-negative Rac, indicating that Rac regulates estrogen and resveratrol (5 µM signaling to the actin cytoskeleton. These results indicate that signaling to the actin cytoskeleton by low and high concentrations of resveratrol may be differentially regulated by Rac and Cdc42.

The small GTPase Cdc42 modulates the number of exocytosis-competent dense-core vesicles in PC12 cells

Energy Technology Data Exchange (ETDEWEB)

Sato, Mai [Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro, Tokyo 153-8902 (Japan); Kitaguchi, Tetsuya [Cell Signaling Group, Waseda Bioscience Research Institute in Singapore (WABOIS), Waseda University, 11 Biopolis Way, 05-01/02 Helios, Singapore 138667 (Singapore); Numano, Rika [The Electronics-Inspired Interdisciplinary Research Institute (EIIRIS), Toyohashi University of Technology, 1-1 Hibarigaoka, Tennpaku-cho, Toyohashi, Aichi 441-8580 (Japan); Ikematsu, Kazuya [Forensic Pathology and Science, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan); Kakeyama, Masaki [Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-0033 (Japan); Murata, Masayuki; Sato, Ken [Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro, Tokyo 153-8902 (Japan); Tsuboi, Takashi, E-mail: takatsuboi@bio.c.u-tokyo.ac.jp [Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro, Tokyo 153-8902 (Japan)

2012-04-06

Highlights: Black-Right-Pointing-Pointer Regulation of exocytosis by Rho GTPase Cdc42. Black-Right-Pointing-Pointer Cdc42 increases the number of fusion events from newly recruited vesicles. Black-Right-Pointing-Pointer Cdc42 increases the number of exocytosis-competent dense-core vesicles. -- Abstract: Although the small GTPase Rho family Cdc42 has been shown to facilitate exocytosis through increasing the amount of hormones released, the precise mechanisms regulating the quantity of hormones released on exocytosis are not well understood. Here we show by live cell imaging analysis under TIRF microscope and immunocytochemical analysis under confocal microscope that Cdc42 modulated the number of fusion events and the number of dense-core vesicles produced in the cells. Overexpression of a wild-type or constitutively-active form of Cdc42 strongly facilitated high-KCl-induced exocytosis from the newly recruited plasma membrane vesicles in PC12 cells. By contrast, a dominant-negative form of Cdc42 inhibited exocytosis from both the newly recruited and previously docked plasma membrane vesicles. The number of intracellular dense-core vesicles was increased by the overexpression of both a wild-type and constitutively-active form of Cdc42. Consistently, activation of Cdc42 by overexpression of Tuba, a Golgi-associated guanine nucleotide exchange factor for Cdc42 increased the number of intracellular dense-core vesicles, whereas inhibition of Cdc42 by overexpression of the Cdc42/Rac interactive binding domain of neuronal Wiskott-Aldrich syndrome protein decreased the number of them. These findings suggest that Cdc42 facilitates exocytosis by modulating both the number of exocytosis-competent dense-core vesicles and the production of dense-core vesicles in PC12 cells.

The small GTPase Cdc42 modulates the number of exocytosis-competent dense-core vesicles in PC12 cells

International Nuclear Information System (INIS)

Sato, Mai; Kitaguchi, Tetsuya; Numano, Rika; Ikematsu, Kazuya; Kakeyama, Masaki; Murata, Masayuki; Sato, Ken; Tsuboi, Takashi

2012-01-01

Highlights: ► Regulation of exocytosis by Rho GTPase Cdc42. ► Cdc42 increases the number of fusion events from newly recruited vesicles. ► Cdc42 increases the number of exocytosis-competent dense-core vesicles. -- Abstract: Although the small GTPase Rho family Cdc42 has been shown to facilitate exocytosis through increasing the amount of hormones released, the precise mechanisms regulating the quantity of hormones released on exocytosis are not well understood. Here we show by live cell imaging analysis under TIRF microscope and immunocytochemical analysis under confocal microscope that Cdc42 modulated the number of fusion events and the number of dense-core vesicles produced in the cells. Overexpression of a wild-type or constitutively-active form of Cdc42 strongly facilitated high-KCl-induced exocytosis from the newly recruited plasma membrane vesicles in PC12 cells. By contrast, a dominant-negative form of Cdc42 inhibited exocytosis from both the newly recruited and previously docked plasma membrane vesicles. The number of intracellular dense-core vesicles was increased by the overexpression of both a wild-type and constitutively-active form of Cdc42. Consistently, activation of Cdc42 by overexpression of Tuba, a Golgi-associated guanine nucleotide exchange factor for Cdc42 increased the number of intracellular dense-core vesicles, whereas inhibition of Cdc42 by overexpression of the Cdc42/Rac interactive binding domain of neuronal Wiskott–Aldrich syndrome protein decreased the number of them. These findings suggest that Cdc42 facilitates exocytosis by modulating both the number of exocytosis-competent dense-core vesicles and the production of dense-core vesicles in PC12 cells.

Cdc42-dependent structural development of auditory supporting cells is required for wound healing at adulthood

DEFF Research Database (Denmark)

Anttonen, Tommi; Kirjavainen, Anna; Belevich, Ilya

2012-01-01

of a basolateral membrane protein in the apical domain were observed. These defects and changes in aPKCλ/ι expression suggested that apical polarization is impaired. Following a lesion at adulthood, supporting cells with Cdc42 loss-induced maturational defects collapsed and failed to remodel F-actin belts...

Novel Activities of Select NSAID R-Enantiomers against Rac1 and Cdc42 GTPases.

Directory of Open Access Journals (Sweden)

Tudor I Oprea

Full Text Available Rho family GTPases (including Rac, Rho and Cdc42 collectively control cell proliferation, adhesion and migration and are of interest as functional therapeutic targets in numerous epithelial cancers. Based on high throughput screening of the Prestwick Chemical Library® and cheminformatics we identified the R-enantiomers of two approved drugs (naproxen and ketorolac as inhibitors of Rac1 and Cdc42. The corresponding S-enantiomers are considered the active component in racemic drug formulations, acting as non-steroidal anti-inflammatory drugs (NSAIDs with selective activity against cyclooxygenases. Here, we show that the S-enantiomers of naproxen and ketorolac are inactive against the GTPases. Additionally, more than twenty other NSAIDs lacked inhibitory action against the GTPases, establishing the selectivity of the two identified NSAIDs. R-naproxen was first identified as a lead compound and tested in parallel with its S-enantiomer and the non-chiral 6-methoxy-naphthalene acetic acid (active metabolite of nabumetone, another NSAID as a structural series. Cheminformatics-based substructure analyses-using the rotationally constrained carboxylate in R-naproxen-led to identification of racemic [R/S] ketorolac as a suitable FDA-approved candidate. Cell based measurement of GTPase activity (in animal and human cell lines demonstrated that the R-enantiomers specifically inhibit epidermal growth factor stimulated Rac1 and Cdc42 activation. The GTPase inhibitory effects of the R-enantiomers in cells largely mimic those of established Rac1 (NSC23766 and Cdc42 (CID2950007/ML141 specific inhibitors. Docking predicts that rotational constraints position the carboxylate moieties of the R-enantiomers to preferentially coordinate the magnesium ion, thereby destabilizing nucleotide binding to Rac1 and Cdc42. The S-enantiomers can be docked but are less favorably positioned in proximity to the magnesium. R-naproxen and R-ketorolac have potential for rapid

Frequent alterations of SLIT2–ROBO1–CDC42 signalling pathway ...

Indian Academy of Sciences (India)

breast cancer; alterations of SLIT2–ROBO1 signalling; active CDC42; ... proportion of four subtypes were tested for molecular alterations of SLIT2, ... reduced expression of phospho Serine-71 CDC42 predicted poor survival of BC patients.

Frequent alterations of SLIT2–ROBO1–CDC42 signalling pathway ...

Indian Academy of Sciences (India)

2016-09-07

Sep 7, 2016 ... Keywords. breast cancer; alterations of SLIT2–ROBO1 signalling; active CDC42; pSer71-CDC42 . Journal of ... have already been studied in head and neck squamous cell ...... lung, oral, cervical, breast, kidney (Dallol et al.

AERO2S - SUBSONIC AERODYNAMIC ANALYSIS OF WINGS WITH LEADING- AND TRAILING-EDGE FLAPS IN COMBINATION WITH CANARD OR HORIZONTAL TAIL SURFACES (IBM PC VERSION)

Science.gov (United States)

Carlson, H. W.

1994-01-01

This code was developed to aid design engineers in the selection and evaluation of aerodynamically efficient wing-canard and wing-horizontal-tail configurations that may employ simple hinged-flap systems. Rapid estimates of the longitudinal aerodynamic characteristics of conceptual airplane lifting surface arrangements are provided. The method is particularly well suited to configurations which, because of high speed flight requirements, must employ thin wings with highly swept leading edges. The code is applicable to wings with either sharp or rounded leading edges. The code provides theoretical pressure distributions over the wing, the canard or horizontal tail, and the deflected flap surfaces as well as estimates of the wing lift, drag, and pitching moments which account for attainable leading edge thrust and leading edge separation vortex forces. The wing planform information is specified by a series of leading edge and trailing edge breakpoints for a right hand wing panel. Up to 21 pairs of coordinates may be used to describe both the leading edge and the trailing edge. The code has been written to accommodate 2000 right hand panel elements, but can easily be modified to accommodate a larger or smaller number of elements depending on the capacity of the target computer platform. The code provides solutions for wing surfaces composed of all possible combinations of leading edge and trailing edge flap settings provided by the original deflection multipliers and by the flap deflection multipliers. Up to 25 pairs of leading edge and trailing edge flap deflection schedules may thus be treated simultaneously. The code also provides for an improved accounting of hinge-line singularities in determination of wing forces and moments. To determine lifting surface perturbation velocity distributions, the code provides for a maximum of 70 iterations. The program is constructed so that successive runs may be made with a given code entry. To make additional runs, it is

Cdc42 regulates cofilin during the establishment of neuronal polarity

DEFF Research Database (Denmark)

Garvalov, Boyan K; Flynn, Kevin C; Neukirchen, Dorothee

2007-01-01

suppressed ability to form axons both in vivo and in culture. This was accompanied by disrupted cytoskeletal organization, enlargement of the growth cones, and inhibition of filopodial dynamics. Axon formation in the knock-out neurons was rescued by manipulation of the actin cytoskeleton, indicating...... that the effects of Cdc42 ablation are exerted through modulation of actin dynamics. In addition, the knock-outs showed a specific increase in the phosphorylation (inactivation) of the Cdc42 effector cofilin. Furthermore, the active, nonphosphorylated form of cofilin was enriched in the axonal growth cones of wild...

The signaling pathway of Campylobacter jejuni-induced Cdc42 activation: Role of fibronectin, integrin beta1, tyrosine kinases and guanine exchange factor Vav2

LENUS (Irish Health Repository)

Krause-Gruszczynska, Malgorzata

2011-12-28

Abstract Background Host cell invasion by the foodborne pathogen Campylobacter jejuni is considered as one of the primary reasons of gut tissue damage, however, mechanisms and key factors involved in this process are widely unclear. It was reported that small Rho GTPases, including Cdc42, are activated and play a role during invasion, but the involved signaling cascades remained unknown. Here we utilised knockout cell lines derived from fibronectin-\\/-, integrin-beta1-\\/-, focal adhesion kinase (FAK)-\\/- and Src\\/Yes\\/Fyn-\\/- deficient mice, and wild-type control cells, to investigate C. jejuni-induced mechanisms leading to Cdc42 activation and bacterial uptake. Results Using high-resolution scanning electron microscopy, GTPase pulldowns, G-Lisa and gentamicin protection assays we found that each studied host factor is necessary for induction of Cdc42-GTP and efficient invasion. Interestingly, filopodia formation and associated membrane dynamics linked to invasion were only seen during infection of wild-type but not in knockout cells. Infection of cells stably expressing integrin-beta1 variants with well-known defects in fibronectin fibril formation or FAK signaling also exhibited severe deficiencies in Cdc42 activation and bacterial invasion. We further demonstrated that infection of wild-type cells induces increasing amounts of phosphorylated FAK and growth factor receptors (EGFR and PDGFR) during the course of infection, correlating with accumulating Cdc42-GTP levels and C. jejuni invasion over time. In studies using pharmacological inhibitors, silencing RNA (siRNA) and dominant-negative expression constructs, EGFR, PDGFR and PI3-kinase appeared to represent other crucial components upstream of Cdc42 and invasion. siRNA and the use of Vav1\\/2-\\/- knockout cells further showed that the guanine exchange factor Vav2 is required for Cdc42 activation and maximal bacterial invasion. Overexpression of certain mutant constructs indicated that Vav2 is a linker

Cdc42 is crucial for the maturation of primordial cell junctions in keratinocytes independent of Rac1

DEFF Research Database (Denmark)

Du, Dan; Pedersen, Esben; Wang, Zhipeng

2008-01-01

Cell-cell contacts are crucial for the integrity of all tissues. Contrasting reports have been published about the role of Cdc42 in epithelial cell-cell contacts in vitro. In keratinocytes, it was suggested that Rac1 and not Cdc42 is crucial for the formation of mature epithelial junctions, based...... on dominant negative inhibition experiments. Deletion of the Cdc42 gene in keratinocytes in vivo slowly impaired the maintenance of cell-cell contacts by an increased degradation of beta-catenin. Whether Cdc42 is required for the formation of mature junctions was not tested. We show now that Cdc42-deficient...... immortalized and primary keratinocytes form only punctate primordial cell contacts in vitro, which cannot mature into belt-like junctions. This defect was independent of enhanced degradation of beta-catenin, but correlated to an impaired activation and localization of aPKCzeta in the Cdc42-null keratinocytes...

Cdc42-dependent leading edge coordination is essential for interstitial dendritic cell migration

DEFF Research Database (Denmark)

Lammermann, Tim; Renkawitz, Jorg; Wu, Xunwei

2009-01-01

Mature dendritic cells (DCs) moving from the skin to the lymph node are a prototypic example of rapidly migrating amoeboid leukocytes. Interstitial DC migration is directionally guided by chemokines, but independent of specific adhesive interactions with the tissue as well as pericellular proteol...

The Cdc42 guanine nucleotide exchange factor FGD6 coordinates cell polarity and endosomal membrane recycling in osteoclasts.

Science.gov (United States)

Steenblock, Charlotte; Heckel, Tobias; Czupalla, Cornelia; Espírito Santo, Ana Isabel; Niehage, Christian; Sztacho, Martin; Hoflack, Bernard

2014-06-27

The initial step of bone digestion is the adhesion of osteoclasts onto bone surfaces and the assembly of podosomal belts that segregate the bone-facing ruffled membrane from other membrane domains. During bone digestion, membrane components of the ruffled border also need to be recycled after macropinocytosis of digested bone materials. How osteoclast polarity and membrane recycling are coordinated remains unknown. Here, we show that the Cdc42-guanine nucleotide exchange factor FGD6 coordinates these events through its Src-dependent interaction with different actin-based protein networks. At the plasma membrane, FGD6 couples cell adhesion and actin dynamics by regulating podosome formation through the assembly of complexes comprising the Cdc42-interactor IQGAP1, the Rho GTPase-activating protein ARHGAP10, and the integrin interactors Talin-1/2 or Filamin A. On endosomes and transcytotic vesicles, FGD6 regulates retromer-dependent membrane recycling through its interaction with the actin nucleation-promoting factor WASH. These results provide a mechanism by which a single Cdc42-exchange factor controlling different actin-based processes coordinates cell adhesion, cell polarity, and membrane recycling during bone degradation. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

The Rho GTPase Cdc42 regulates hair cell planar polarity and cellular patterning in the developing cochlea

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Anna Kirjavainen

2015-03-01

Full Text Available Hair cells of the organ of Corti (OC of the cochlea exhibit distinct planar polarity, both at the tissue and cellular level. Planar polarity at tissue level is manifested as uniform orientation of the hair cell stereociliary bundles. Hair cell intrinsic polarity is defined as structural hair bundle asymmetry; positioning of the kinocilium/basal body complex at the vertex of the V-shaped bundle. Consistent with strong apical polarity, the hair cell apex displays prominent actin and microtubule cytoskeletons. The Rho GTPase Cdc42 regulates cytoskeletal dynamics and polarization of various cell types, and, thus, serves as a candidate regulator of hair cell polarity. We have here induced Cdc42 inactivation in the late-embryonic OC. We show the role of Cdc42 in the establishment of planar polarity of hair cells and in cellular patterning. Abnormal planar polarity was displayed as disturbances in hair bundle orientation and morphology and in kinocilium/basal body positioning. These defects were accompanied by a disorganized cell-surface microtubule network. Atypical protein kinase C (aPKC, a putative Cdc42 effector, colocalized with Cdc42 at the hair cell apex, and aPKC expression was altered upon Cdc42 depletion. Our data suggest that Cdc42 together with aPKC is part of the machinery establishing hair cell planar polarity and that Cdc42 acts on polarity through the cell-surface microtubule network. The data also suggest that defects in apical polarization are influenced by disturbed cellular patterning in the OC. In addition, our data demonstrates that Cdc42 is required for stereociliogenesis in the immature cochlea.

Cdc42 is a key regulator of B cell differentiation and is required for antiviral humoral immunity

DEFF Research Database (Denmark)

Burbage, Marianne; Keppler, Selina J; Gasparrini, Francesca

2015-01-01

The small Rho GTPase Cdc42, known to interact with Wiskott-Aldrich syndrome (WAS) protein, is an important regulator of actin remodeling. Here, we show that genetic ablation of Cdc42 exclusively in the B cell lineage is sufficient to render mice unable to mount antibody responses. Indeed Cdc42-de...

The small G-proteins Rac1 and Cdc42 are essential for myoblast fusion in the mouse

DEFF Research Database (Denmark)

Vasyutina, Elena; Martarelli, Benedetta; Brakebusch, Cord

2009-01-01

Rac1 and Cdc42 are small G-proteins that regulate actin dynamics and affect plasma membrane protrusion and vesicle traffic. We used conditional mutagenesis in mice to demonstrate that Rac1 and Cdc42 are essential for myoblast fusion in vivo and in vitro. The deficit in fusion of Rac1 or Cdc42 mut...... genetic analysis demonstrates thus that the function of Rac in myoblast fusion is evolutionarily conserved from insects to mammals and that Cdc42, a molecule hitherto not implicated in myoblast fusion, is essential for the fusion of murine myoblasts....

The signaling pathway of Campylobacter jejuni-induced Cdc42 activation: Role of fibronectin, integrin beta1, tyrosine kinases and guanine exchange factor Vav2

Directory of Open Access Journals (Sweden)

Krause-Gruszczynska Malgorzata

2011-12-01

Full Text Available Abstract Background Host cell invasion by the foodborne pathogen Campylobacter jejuni is considered as one of the primary reasons of gut tissue damage, however, mechanisms and key factors involved in this process are widely unclear. It was reported that small Rho GTPases, including Cdc42, are activated and play a role during invasion, but the involved signaling cascades remained unknown. Here we utilised knockout cell lines derived from fibronectin-/-, integrin-beta1-/-, focal adhesion kinase (FAK-/- and Src/Yes/Fyn-/- deficient mice, and wild-type control cells, to investigate C. jejuni-induced mechanisms leading to Cdc42 activation and bacterial uptake. Results Using high-resolution scanning electron microscopy, GTPase pulldowns, G-Lisa and gentamicin protection assays we found that each studied host factor is necessary for induction of Cdc42-GTP and efficient invasion. Interestingly, filopodia formation and associated membrane dynamics linked to invasion were only seen during infection of wild-type but not in knockout cells. Infection of cells stably expressing integrin-beta1 variants with well-known defects in fibronectin fibril formation or FAK signaling also exhibited severe deficiencies in Cdc42 activation and bacterial invasion. We further demonstrated that infection of wild-type cells induces increasing amounts of phosphorylated FAK and growth factor receptors (EGFR and PDGFR during the course of infection, correlating with accumulating Cdc42-GTP levels and C. jejuni invasion over time. In studies using pharmacological inhibitors, silencing RNA (siRNA and dominant-negative expression constructs, EGFR, PDGFR and PI3-kinase appeared to represent other crucial components upstream of Cdc42 and invasion. siRNA and the use of Vav1/2-/- knockout cells further showed that the guanine exchange factor Vav2 is required for Cdc42 activation and maximal bacterial invasion. Overexpression of certain mutant constructs indicated that Vav2 is a linker

RhoA, Rac1 and Cdc42 differentially regulate aSMA and collagen I expression in mesenchymal stem cells.

Science.gov (United States)

Ge, Jianfeng; Burnier, Laurent; Adamopoulou, Maria; Kwa, Mei Qi; Schaks, Matthias; Rottner, Klemens; Brakebusch, Cord

2018-04-26

Mesenchymal stem cells (MSC) are suggested to be important progenitors of myofibroblasts in fibrosis. To understand the role of Rho GTPase signaling in TGFβ-induced myofibroblast differentiation of MSC, we generated a novel MSC line and descendants of it lacking functional Rho GTPases and Rho GTPase signaling components. Unexpectedly, our data revealed that Rho GTPase signaling is required for TGFβ-induced expression of αSMA, but not of collagen I α1 (col1a1). While loss of RhoA and Cdc42 reduced αSMA expression, ablation of the Rac1 gene had the opposite effect. Although actin polymerization and MRTFa were crucial for TGFβ-induced αSMA expression, neither Arp2/3 dependent actin polymerization nor cofilin dependent severing and depolymerization of F-actin were required. Instead, F-actin levels were dependent on cell contraction and TGFβ-induced actin polymerisation correlated with increased cell contraction mediated by RhoA and Cdc42. Finally, we observed impaired collagen I secretion in MSC lacking RhoA or Cdc42. These data give novel molecular insights into the role of Rho GTPases in TGFβ signaling and have implications for our understanding of MSC function in fibrosis. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Cdc45 (cell division cycle protein 45) guards the gate of the Eukaryote Replisome helicase stabilizing leading strand engagement

Science.gov (United States)

Petojevic, Tatjana; Pesavento, James J.; Costa, Alessandro; Liang, Jingdan; Wang, Zhijun; Berger, James M.; Botchan, Michael R.

2015-01-01

DNA replication licensing is now understood to be the pathway that leads to the assembly of double hexamers of minichromosome maintenance (Mcm2–7) at origin sites. Cell division control protein 45 (Cdc45) and GINS proteins activate the latent Mcm2–7 helicase by inducing allosteric changes through binding, forming a Cdc45/Mcm2-7/GINS (CMG) complex that is competent to unwind duplex DNA. The CMG has an active gate between subunits Mcm2 and Mcm5 that opens and closes in response to nucleotide binding. The consequences of inappropriate Mcm2/5 gate actuation and the role of a side channel formed between GINS/Cdc45 and the outer edge of the Mcm2–7 ring for unwinding have remained unexplored. Here we uncover a novel function for Cdc45. Cross-linking studies trace the path of the DNA with the CMG complex at a fork junction between duplex and single strands with the bound CMG in an open or closed gate conformation. In the closed state, the lagging strand does not pass through the side channel, but in the open state, the leading strand surprisingly interacts with Cdc45. Mutations in the recombination protein J fold of Cdc45 that ablate this interaction diminish helicase activity. These data indicate that Cdc45 serves as a shield to guard against occasional slippage of the leading strand from the core channel. PMID:25561522

Leucine-rich repeat kinase-1 regulates osteoclast function by modulating RAC1/Cdc42 Small GTPase phosphorylation and activation.

Science.gov (United States)

Zeng, Canjun; Goodluck, Helen; Qin, Xuezhong; Liu, Bo; Mohan, Subburaman; Xing, Weirong

2016-10-01

Leucine-rich repeat kinase-1 (Lrrk1) consists of ankyrin repeats (ANK), leucine-rich repeats (LRR), a GTPase-like domain of Roc (ROC), a COR domain, a serine/threonine kinase domain (KD), and WD40 repeats (WD40). Previous studies have revealed that knockout (KO) of Lrrk1 in mice causes severe osteopetrosis, and a human mutation of Lrrk1 leads to osteosclerotic metaphysial dysplasia. The molecular mechanism by which Lrrk1 regulates osteoclast function is unknown. In this study, we generated a series of Lrrk1 mutants and evaluated their ability to rescue defective bone resorption in Lrrk1-deficient osteoclasts by use of pit formation assays. Overexpression of Lrrk1 or LRR-truncated Lrrk1, but not ANK-truncated Lrrk1, WD40-truncated Lrrk1, Lrrk1-KD, or K651A mutant Lrrk1, rescued bone resorption function of Lrrk1 KO osteoclasts. We next examined whether RAC1/Cdc42 small GTPases are direct substrates of Lrrk1 in osteoclasts. Western blot and pull-down assays revealed that Lrrk1 deficiency in osteoclasts resulted in reduced phosphorylation and activation of RAC1/Cdc42. In vitro kinase assays confirmed that recombinant Lrrk1 phosphorylated RAC1-GST protein, and immunoprecipitation showed that the interaction of Lrrk1 with RAC1 occurred within 10 min after RANKL treatment. Overexpression of constitutively active Q61L RAC1 partially rescued the resorptive function of Lrrk1-deficient osteoclasts. Furthermore, lack of Lrrk1 in osteoclasts led to reduced autophosphorylation of p21 protein-activated kinase-1 at Ser 144 , catalyzed by RAC1/Cdc42 binding and activation. Our data indicate that Lrrk1 regulates osteoclast function by directly modulating phosphorylation and activation of small GTPase RAC1/Cdc42 and that its function depends on ANK, ROC, WD40, and kinase domains. Copyright © 2016 the American Physiological Society.

Coordination by Cdc42 of Actin, Contractility, and Adhesion for Melanoblast Movement in Mouse Skin

DEFF Research Database (Denmark)

Woodham, Emma F; Paul, Nikki R; Tyrrell, Benjamin

2017-01-01

traverse the dermis to reach the epidermis of the skin and hair follicles. We previously established that Rac1 signals via Scar/WAVE and Arp2/3 to effect pseudopod extension and migration of melanoblasts in skin. Here we show that RhoA is redundant in the melanocyte lineage but that Cdc42 coordinates...... multiple motility systems independent of Rac1. Similar to Rac1 knockouts, Cdc42 null mice displayed a severe loss of pigmentation, and melanoblasts showed cell-cycle progression, migration, and cytokinesis defects. However, unlike Rac1 knockouts, Cdc42 null melanoblasts were elongated and displayed large...... null cells lacked the ability to polarize their Golgi and coordinate motility systems for efficient movement. Loss of Cdc42 de-coupled three main systems: actin assembly via the formin FMNL2 and Arp2/3, active myosin-II localization, and integrin-based adhesion dynamics....

Unraveling the molecular mechanism of interactions of the Rho GTPases Cdc42 and Rac1 with the scaffolding protein IQGAP2.

Science.gov (United States)

Ozdemir, E Sila; Jang, Hyunbum; Gursoy, Attila; Keskin, Ozlem; Li, Zhigang; Sacks, David B; Nussinov, Ruth

2018-03-09

IQ motif-containing GTPase-activating proteins (IQGAPs) are scaffolding proteins playing central roles in cell-cell adhesion, polarity, and motility. The Rho GTPases Cdc42 and Rac1, in their GTP-bound active forms, interact with all three human IQGAPs. The IQGAP-Cdc42 interaction promotes metastasis by enhancing actin polymerization. However, despite their high sequence identity, Cdc42 and Rac1 differ in their interactions with IQGAP. Two Cdc42 molecules can bind to the Ex-domain and the RasGAP site of the GTPase-activating protein (GAP)-related domain (GRD) of IQGAP and promote IQGAP dimerization. Only one Rac1 molecule might bind to the RasGAP site of GRD and may not facilitate the dimerization, and the exact mechanism of Cdc42 and Rac1 binding to IQGAP is unclear. Using all-atom molecular dynamics simulations, site-directed mutagenesis, and Western blotting, we unraveled the detailed mechanisms of Cdc42 and Rac1 interactions with IQGAP2. We observed that Cdc42 binding to the Ex-domain of GRD of IQGAP2 (GRD2) releases the Ex-domain at the C-terminal region of GRD2, facilitating IQGAP2 dimerization. Cdc42 binding to the Ex-domain promoted allosteric changes in the RasGAP site, providing a binding site for the second Cdc42 in the RasGAP site. Of note, the Cdc42 "insert loop" was important for the interaction of the first Cdc42 with the Ex-domain. By contrast, differences in Rac1 insert-loop sequence and structure precluded its interaction with the Ex-domain. Rac1 could bind only to the RasGAP site of apo-GRD2 and could not facilitate IQGAP2 dimerization. Our detailed mechanistic insights help decipher how Cdc42 can stimulate actin polymerization in metastasis.

Cdc42 expression in keratinocytes is required for the maintenance of the basement membrane in skin

DEFF Research Database (Denmark)

Wu, Xunwei; Quondamatteo, Fabio; Brakebusch, Cord

2006-01-01

, structure and number of hemidesomosomes were not significantly changed in the Cdc42 mutant skin compared with the control mice and no blister formation was observed in mutant skin. These data indicate that Cdc42 in keratinocytes is important for maintenance of the basement membrane of skin....... process, which requires directed secretion, deposition and organization of basement membrane components at the basal side of epithelial cells. In the current study, we analyzed the maintenance of skin basement membrane in mice with a keratinocyte-restricted deletion of the Cdc42 gene. In the absence...

Continuous cell injury promotes hepatic tumorigenesis in cdc42-deficient mouse liver

DEFF Research Database (Denmark)

van Hengel, Jolanda; D'Hooge, Petra; Hooghe, Bart

2008-01-01

be required for liver function. METHODS: Mice in which Cdc42 was ablated in hepatocytes and bile duct cells were generated by Cre-loxP technology. Livers were examined by histologic, immunohistochemical, ultrastructural, and serum analysis to define the effect of loss of Cdc42 on liver structure. RESULTS...... of 2 months, the canaliculi between hepatocytes were greatly enlarged, although the tight junctions flanking the canaliculi appeared normal. Regular liver plates were absent. E-cadherin expression pattern and gap junction localization were distorted. Analysis of serum samples indicated cholestasis...

Involvement of the Cdc42 pathway in CFTR post-translational turnover and in its plasma membrane stability in airway epithelial cells.

Directory of Open Access Journals (Sweden)

Romain Ferru-Clément

Full Text Available Cystic fibrosis transmembrane conductance regulator (CFTR is a chloride channel that is expressed on the apical plasma membrane (PM of epithelial cells. The most common deleterious allele encodes a trafficking-defective mutant protein undergoing endoplasmic reticulum-associated degradation (ERAD and presenting lower PM stability. In this study, we investigated the involvement of the Cdc42 pathway in CFTR turnover and trafficking in a human bronchiolar epithelial cell line (CFBE41o- expressing wild-type CFTR. Cdc42 is a small GTPase of the Rho family that fulfils numerous cell functions, one of which is endocytosis and recycling process via actin cytoskeleton remodelling. When we treated cells with chemical inhibitors such as ML141 against Cdc42 and wiskostatin against the downstream effector N-WASP, we observed that CFTR channel activity was inhibited, in correlation with a decrease in CFTR amount at the cell surface and an increase in dynamin-dependent CFTR endocytosis. Anchoring of CFTR to the cortical cytoskeleton was then presumably impaired by actin disorganization. When we performed siRNA-mediated depletion of Cdc42, actin polymerization was not impacted, but we observed actin-independent consequences upon CFTR. Total and PM CFTR amounts were increased, resulting in greater activation of CFTR. Pulse-chase experiments showed that while CFTR degradation was slowed, CFTR maturation through the Golgi apparatus remained unaffected. In addition, we observed increased stability of CFTR in PM and reduction of its endocytosis. This study highlights the involvement of the Cdc42 pathway at several levels of CFTR biogenesis and trafficking: (i Cdc42 is implicated in the first steps of CFTR biosynthesis and processing; (ii it contributes to the stability of CFTR in PM via its anchoring to cortical actin; (iii it promotes CFTR endocytosis and presumably its sorting toward lysosomal degradation.

Microgravity simulation activates Cdc42 via Rap1GDS1 to promote vascular branch morphogenesis during vasculogenesis

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Shouli Wang

2017-12-01

Full Text Available Gravity plays an important role in normal tissue maintenance. The ability of stem cells to repair tissue loss in space through regeneration and differentiation remains largely unknown. To investigate the impact of microgravity on blood vessel formation from pluripotent stem cells, we employed the embryoid body (EB model for vasculogenesis and simulated microgravity by clinorotation. We first differentiated mouse embryonic stem cells into cystic EBs containing two germ layers and then analyzed vessel formation under clinorotation. We observed that endothelial cell differentiation was slightly reduced under clinorotation, whereas vascular branch morphogenesis was markedly enhanced. EB-derived endothelial cells migrated faster, displayed multiple cellular processes, and had higher Cdc42 and Rac1 activity when subjected to clinorotation. Genetic analysis and rescue experiments demonstrated that Cdc42 but not Rac1 is required for microgravity-induced vascular branch morphogenesis. Furthermore, affinity pull-down assay and mass spectrometry identified Rap1GDS1 to be a Cdc42 guanine nucleotide exchange factor, which was upregulated by clinorotation. shRNA-mediated knockdown of Rap1GDS1 selectively suppressed Cdc42 activation and inhibited both baseline and microgravity-induced vasculogenesis. This was rescued by ectopic expression of constitutively active Cdc42. Taken together, these results support the notion that simulated microgravity activates Cdc42 via Rap1GDS1 to promote vascular branch morphogenesis.

Genetic deletion of cdc42 reveals a crucial role for astrocyte recruitment to the injury site in vitro and in vivo

DEFF Research Database (Denmark)

Robel, Stefanie; Bardehle, Sophia; Lepier, Alexandra

2011-01-01

signals, the small RhoGTPase Cdc42, selectively in mouse astrocytes in vitro and in vivo. We used an in vitro scratch assay as a minimal wounding model and found that astrocytes lacking Cdc42 (Cdc42Δ) were still able to form protrusions, although in a nonoriented way. Consequently, they failed to migrate...... in a directed manner toward the scratch. When animals were injured in vivo through a stab wound, Cdc42Δ astrocytes developed protrusions properly oriented toward the lesion, but the number of astrocytes recruited to the lesion site was significantly reduced. Surprisingly, however, lesions in Cdc42Δ animals...

Cdc42/N-WASP signaling links actin dynamics to pancreatic β cell delamination and differentiation

Science.gov (United States)

Kesavan, Gokul; Lieven, Oliver; Mamidi, Anant; Öhlin, Zarah Löf; Johansson, Jenny Kristina; Li, Wan-Chun; Lommel, Silvia; Greiner, Thomas Uwe; Semb, Henrik

2014-01-01

Delamination plays a pivotal role during normal development and cancer. Previous work has demonstrated that delamination and epithelial cell movement within the plane of an epithelium are associated with a change in cellular phenotype. However, how this positional change is linked to differentiation remains unknown. Using the developing mouse pancreas as a model system, we show that β cell delamination and differentiation are two independent events, which are controlled by Cdc42/N-WASP signaling. Specifically, we show that expression of constitutively active Cdc42 in β cells inhibits β cell delamination and differentiation. These processes are normally associated with junctional actin and cell-cell junction disassembly and the expression of fate-determining transcription factors, such as Isl1 and MafA. Mechanistically, we demonstrate that genetic ablation of N-WASP in β cells expressing constitutively active Cdc42 partially restores both delamination and β cell differentiation. These findings elucidate how junctional actin dynamics via Cdc42/N-WASP signaling cell-autonomously control not only epithelial delamination but also cell differentiation during mammalian organogenesis. PMID:24449844

Rsr1 Focuses Cdc42 Activity at Hyphal Tips and Promotes Maintenance of Hyphal Development in Candida albicans

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Pulver, Rebecca; Heisel, Timothy; Gonia, Sara; Robins, Robert; Norton, Jennifer; Haynes, Paula

2013-01-01

The extremely elongated morphology of fungal hyphae is dependent on the cell's ability to assemble and maintain polarized growth machinery over multiple cell cycles. The different morphologies of the fungus Candida albicans make it an excellent model organism in which to study the spatiotemporal requirements for constitutive polarized growth and the generation of different cell shapes. In C. albicans, deletion of the landmark protein Rsr1 causes defects in morphogenesis that are not predicted from study of the orthologous protein in the related yeast Saccharomyces cerevisiae, thus suggesting that Rsr1 has expanded functions during polarized growth in C. albicans. Here, we show that Rsr1 activity localizes to hyphal tips by the differential localization of the Rsr1 GTPase-activating protein (GAP), Bud2, and guanine nucleotide exchange factor (GEF), Bud5. In addition, we find that Rsr1 is needed to maintain the focused localization of hyphal polarity structures and proteins, including Bem1, a marker of the active GTP-bound form of the Rho GTPase, Cdc42. Further, our results indicate that tip-localized Cdc42 clusters are associated with the cell's ability to express a hyphal transcriptional program and that the ability to generate a focused Cdc42 cluster in early hyphae (germ tubes) is needed to maintain hyphal morphogenesis over time. We propose that in C. albicans, Rsr1 “fine-tunes” the distribution of Cdc42 activity and that self-organizing (Rsr1-independent) mechanisms of polarized growth are not sufficient to generate narrow cell shapes or to provide feedback to the transcriptional program during hyphal morphogenesis. PMID:23223038

Cdc42 is not essential for filopodium formation, directed migration, cell polarization, and mitosis in fibroblastoid cells

DEFF Research Database (Denmark)

Czuchra, Aleksandra; Wu, Xunwei; Meyer, Hannelore

2005-01-01

of Cdc42 did not affect filopodium or lamellipodium formation and had no significant influence on the speed of directed migration nor on mitosis. Cdc42-deficient cells displayed a more elongated cell shape and had a reduced area. Furthermore, directionality during migration and reorientation of the Golgi...

Insights into Cdc13 Dependent Telomere Length Regulation

Energy Technology Data Exchange (ETDEWEB)

M Mason; E Skordalakes

2011-12-31

Cdc13 is a single stranded telomere binding protein that specifically localizes to the telomere ends of budding yeasts and is essential for cell viability. It caps the ends of chromosomes thus preventing chromosome end-to-end fusions and exonucleolytic degradation, events that could lead to genomic instability and senescence, the hallmark of aging. Cdc13 is also involved in telomere length regulation by recruiting or preventing access of telomerase to the telomeric overhang. Recruitment of telomerase to the telomeres for G-strand extension is required for continuous cell division, while preventing its access to the telomeres through capping the chromosome ends prevents mitotic events that could lead to cell immortality, the hall mark of carcinogenesis. Cdc13 and its putative homologues human CTC1 and POT1 are therefore key to many biological processes directly associated with life extension and cancer prevention and can be viewed as an ideal target for cancer and age related therapies.

Stage-specific functions of the small Rho GTPases Cdc42 and Rac1 for adult hippocampal neurogenesis

DEFF Research Database (Denmark)

Vadodaria, Krishna C; Brakebusch, Cord; Suter, Ueli

2013-01-01

The molecular mechanisms underlying the generation, maturation, and integration of new granule cells generated throughout life in the mammalian hippocampus remain poorly understood. Small Rho GTPases, such as Cdc42 and Rac1, have been implicated previously in neural stem/progenitor cell (NSPC......) proliferation and neuronal maturation during embryonic development. Here we used conditional genetic deletion and virus-based loss-of-function approaches to identify temporally distinct functions for Cdc42 and Rac1 in adult hippocampal neurogenesis. We found that Cdc42 is involved in mouse NSPC proliferation......, initial dendritic development, and dendritic spine maturation. In contrast, Rac1 is dispensable for early steps of neuronal development but is important for late steps of dendritic growth and spine maturation. These results establish cell-autonomous and stage-specific functions for the small Rho GTPases...

Topology optimization of compliant adaptive wing leading edge with composite materials

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Tong Xinxing

2014-12-01

Full Text Available An approach for designing the compliant adaptive wing leading edge with composite material is proposed based on the topology optimization. Firstly, an equivalent constitutive relationship of laminated glass fiber reinforced epoxy composite plates has been built based on the symmetric laminated plate theory. Then, an optimization objective function of compliant adaptive wing leading edge was used to minimize the least square error (LSE between deformed curve and desired aerodynamics shape. After that, the topology structures of wing leading edge of different glass fiber ply-orientations were obtained by using the solid isotropic material with penalization (SIMP model and sensitivity filtering technique. The desired aerodynamics shape of compliant adaptive wing leading edge was obtained based on the proposed approach. The topology structures of wing leading edge depend on the glass fiber ply-orientation. Finally, the corresponding morphing experiment of compliant wing leading edge with composite materials was implemented, which verified the morphing capability of topology structure and illustrated the feasibility for designing compliant wing leading edge. The present paper lays the basis of ply-orientation optimization for compliant adaptive wing leading edge in unmanned aerial vehicle (UAV field.

A hot-spot mutation in CDC42 (p.Tyr64Cys) and novel phenotypes in the third patient with Takenouchi-Kosaki syndrome.

Science.gov (United States)

Motokawa, Midori; Watanabe, Satoshi; Nakatomi, Akiko; Kondoh, Tatsuro; Matsumoto, Tadashi; Morifuji, Kanako; Sawada, Hirotake; Nishimura, Toyoki; Nunoi, Hiroyuki; Yoshiura, Koh-Ichiro; Moriuchi, Hiroyuki; Dateki, Sumito

2018-03-01

Takenouchi-Kosaki syndrome (TKS) is a congenital malformation syndrome characterized by severe developmental delay, macrothrombocytopenia, camptodactyly, sensorineural hearing loss, and dysmorphic facial features. Recently, a heterozygous de novo mutation (p.Tyr64Cys) in the CDC42 gene, which encodes a key small GTP-binding protein of the Rho-subfamily, was identified in two unrelated patients with TKS. We herein report a third patient with TKS who had the same heterozygous CDC42 mutation. The phenotype of the patient was very similar to those of the two previously reported patients with TKS; however, she also demonstrated novel clinical manifestations, such as congenital hypothyroidism and immunological disturbance. Thus, despite the heterozygous mutation of CDC42 (p.Tyr64Cys) likely being a hot-spot mutation for TKS, its phenotype may be variable. Further studies and the accumulation of patients with CDC42 mutations are needed to clarify the phenotype in patients with TKS and the pathophysiological roles of the CDC42 mutation.

Inhibition of Cdc42 and Rac1 activities in pheochromocytoma, the adrenal medulla tumor.

Science.gov (United States)

Croisé, Pauline; Brunaud, Laurent; Tóth, Petra; Gasman, Stéphane; Ory, Stéphane

2017-04-03

Altered Rho GTPase signaling has been linked to many types of cancer. As many small G proteins, Rho GTPases cycle between an active and inactive state thanks to specific regulators that catalyze exchange of GDP into GTP (Rho-GEF) or hydrolysis of GTP into GDP (Rho-GAP). Recent studies have shown that alteration takes place either at the level of Rho proteins themselves (expression levels, point mutations) or at the level of their regulators, mostly RhoGEFs and RhoGAPs. Most reports describe Rho GTPases gain of function that may participate to the tumorigenesis processes. In contrast, we have recently reported that decreased activities of Cdc42 and Rac1 as well as decreased expression of 2 Rho-GEFs, FARP1 and ARHGEF1, correlate with pheochromocytomas, a tumor developing in the medulla of the adrenal gland (Croisé et al., Endocrine Related Cancer, 2016). Here we highlight the major evidence and further study the correlation between Rho GTPases activities and expression levels of ARHGEF1 and FARP1. Finally we also discuss how the decrease of Cdc42 and Rac1 activities may help human pheochromocytomas to develop and comment the possible relationship between FARP1, ARHGEF1 and the 2 Rho GTPases Cdc42 and Rac1 in tumorigenesis.

Daphnetin inhibits invasion and migration of LM8 murine osteosarcoma cells by decreasing RhoA and Cdc42 expression

Energy Technology Data Exchange (ETDEWEB)

Fukuda, Hiroki [Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto (Japan); Nakamura, Seikou [Department of Pharmacognosy, Kyoto Pharmaceutical University, Kyoto (Japan); Chisaki, Yugo [Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto (Japan); Takada, Tetsuya [Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto (Japan); Toda, Yuki [Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Kyoto (Japan); Murata, Hiroaki [Department of Orthopedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto (Japan); Department of Orthopedic Surgery, Matsushita Memorial Hospital, Osaka (Japan); Itoh, Kazuyuki [Department of Biology, Osaka Medical Center of Cancer and Cardiovascular Diseases, Osaka (Japan); Yano, Yoshitaka [Education and Research Center for Clinical Pharmacy, Kyoto Pharmaceutical University, Kyoto (Japan); Takata, Kazuyuki [Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto (Japan); Ashihara, Eishi, E-mail: ash@mb.kyoto-phu.ac.jp [Department of Clinical and Translational Physiology, Kyoto Pharmaceutical University, Kyoto (Japan)

2016-02-26

Daphnetin, 7,8-dihydroxycoumarin, present in main constituents of Daphne odora var. marginatai, has multiple pharmacological activities including anti-proliferative effects in cancer cells. In this study, using a Transwell system, we showed that daphnetin inhibited invasion and migration of highly metastatic murine osteosarcoma LM8 cells in a dose-dependent manner. Following treatment by daphnetin, cells that penetrated the Transwell membrane were rounder than non-treated cells. Immunofluorescence analysis revealed that daphnetin decreased the numbers of intracellular stress fibers and filopodia. Moreover, daphnetin treatment dramatically decreased the expression levels of RhoA and Cdc42. In summary, the dihydroxycoumarin derivative daphnetin inhibits the invasion and migration of LM8 cells, and therefore represents a promising agent for use against metastatic cancer. - Highlights: • Daphnetin, a coumarin-derivative, inhibited invasion and migration of LM8 cells. • Stress fibers and filopodia were decreased by daphnetin treatment. • Daphnetin decreased RhoA and Cdc42 protein expression.

Daphnetin inhibits invasion and migration of LM8 murine osteosarcoma cells by decreasing RhoA and Cdc42 expression

International Nuclear Information System (INIS)

Fukuda, Hiroki; Nakamura, Seikou; Chisaki, Yugo; Takada, Tetsuya; Toda, Yuki; Murata, Hiroaki; Itoh, Kazuyuki; Yano, Yoshitaka; Takata, Kazuyuki; Ashihara, Eishi

2016-01-01

Daphnetin, 7,8-dihydroxycoumarin, present in main constituents of Daphne odora var. marginatai, has multiple pharmacological activities including anti-proliferative effects in cancer cells. In this study, using a Transwell system, we showed that daphnetin inhibited invasion and migration of highly metastatic murine osteosarcoma LM8 cells in a dose-dependent manner. Following treatment by daphnetin, cells that penetrated the Transwell membrane were rounder than non-treated cells. Immunofluorescence analysis revealed that daphnetin decreased the numbers of intracellular stress fibers and filopodia. Moreover, daphnetin treatment dramatically decreased the expression levels of RhoA and Cdc42. In summary, the dihydroxycoumarin derivative daphnetin inhibits the invasion and migration of LM8 cells, and therefore represents a promising agent for use against metastatic cancer. - Highlights: • Daphnetin, a coumarin-derivative, inhibited invasion and migration of LM8 cells. • Stress fibers and filopodia were decreased by daphnetin treatment. • Daphnetin decreased RhoA and Cdc42 protein expression.

RIT1 controls actin dynamics via complex formation with RAC1/CDC42 and PAK1.

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Uta Meyer Zum Büschenfelde

2018-05-01

Full Text Available RIT1 belongs to the RAS family of small GTPases. Germline and somatic RIT1 mutations have been identified in Noonan syndrome (NS and cancer, respectively. By using heterologous expression systems and purified recombinant proteins, we identified the p21-activated kinase 1 (PAK1 as novel direct effector of RIT1. We found RIT1 also to directly interact with the RHO GTPases CDC42 and RAC1, both of which are crucial regulators of actin dynamics upstream of PAK1. These interactions are independent of the guanine nucleotide bound to RIT1. Disease-causing RIT1 mutations enhance protein-protein interaction between RIT1 and PAK1, CDC42 or RAC1 and uncouple complex formation from serum and growth factors. We show that the RIT1-PAK1 complex regulates cytoskeletal rearrangements as expression of wild-type RIT1 and its mutant forms resulted in dissolution of stress fibers and reduction of mature paxillin-containing focal adhesions in COS7 cells. This effect was prevented by co-expression of RIT1 with dominant-negative CDC42 or RAC1 and kinase-dead PAK1. By using a transwell migration assay, we show that RIT1 wildtype and the disease-associated variants enhance cell motility. Our work demonstrates a new function for RIT1 in controlling actin dynamics via acting in a signaling module containing PAK1 and RAC1/CDC42, and highlights defects in cell adhesion and migration as possible disease mechanism underlying NS.

RIT1 controls actin dynamics via complex formation with RAC1/CDC42 and PAK1.

Science.gov (United States)

Meyer Zum Büschenfelde, Uta; Brandenstein, Laura Isabel; von Elsner, Leonie; Flato, Kristina; Holling, Tess; Zenker, Martin; Rosenberger, Georg; Kutsche, Kerstin

2018-05-01

RIT1 belongs to the RAS family of small GTPases. Germline and somatic RIT1 mutations have been identified in Noonan syndrome (NS) and cancer, respectively. By using heterologous expression systems and purified recombinant proteins, we identified the p21-activated kinase 1 (PAK1) as novel direct effector of RIT1. We found RIT1 also to directly interact with the RHO GTPases CDC42 and RAC1, both of which are crucial regulators of actin dynamics upstream of PAK1. These interactions are independent of the guanine nucleotide bound to RIT1. Disease-causing RIT1 mutations enhance protein-protein interaction between RIT1 and PAK1, CDC42 or RAC1 and uncouple complex formation from serum and growth factors. We show that the RIT1-PAK1 complex regulates cytoskeletal rearrangements as expression of wild-type RIT1 and its mutant forms resulted in dissolution of stress fibers and reduction of mature paxillin-containing focal adhesions in COS7 cells. This effect was prevented by co-expression of RIT1 with dominant-negative CDC42 or RAC1 and kinase-dead PAK1. By using a transwell migration assay, we show that RIT1 wildtype and the disease-associated variants enhance cell motility. Our work demonstrates a new function for RIT1 in controlling actin dynamics via acting in a signaling module containing PAK1 and RAC1/CDC42, and highlights defects in cell adhesion and migration as possible disease mechanism underlying NS.

Membrane tension controls adhesion positioning at the leading edge of cells.

Science.gov (United States)

Pontes, Bruno; Monzo, Pascale; Gole, Laurent; Le Roux, Anabel-Lise; Kosmalska, Anita Joanna; Tam, Zhi Yang; Luo, Weiwei; Kan, Sophie; Viasnoff, Virgile; Roca-Cusachs, Pere; Tucker-Kellogg, Lisa; Gauthier, Nils C

2017-09-04

Cell migration is dependent on adhesion dynamics and actin cytoskeleton remodeling at the leading edge. These events may be physically constrained by the plasma membrane. Here, we show that the mechanical signal produced by an increase in plasma membrane tension triggers the positioning of new rows of adhesions at the leading edge. During protrusion, as membrane tension increases, velocity slows, and the lamellipodium buckles upward in a myosin II-independent manner. The buckling occurs between the front of the lamellipodium, where nascent adhesions are positioned in rows, and the base of the lamellipodium, where a vinculin-dependent clutch couples actin to previously positioned adhesions. As membrane tension decreases, protrusion resumes and buckling disappears, until the next cycle. We propose that the mechanical signal of membrane tension exerts upstream control in mechanotransduction by periodically compressing and relaxing the lamellipodium, leading to the positioning of adhesions at the leading edge of cells. © 2017 Pontes et al.

Caveolin-1 and CDC42 mediated endocytosis of silica-coated iron oxide nanoparticles in HeLa cells

Directory of Open Access Journals (Sweden)

Nils Bohmer

2015-01-01

Full Text Available Nanomedicine is a rapidly growing field in nanotechnology, which has great potential in the development of new therapies for numerous diseases. For example iron oxide nanoparticles are in clinical use already in the thermotherapy of brain cancer. Although it has been shown, that tumor cells take up these particles in vitro, little is known about the internalization routes. Understanding of the underlying uptake mechanisms would be very useful for faster and precise development of nanoparticles for clinical applications. This study aims at the identification of key proteins, which are crucial for the active uptake of iron oxide nanoparticles by HeLa cells (human cervical cancer as a model cell line. Cells were transfected with specific siRNAs against Caveolin-1, Dynamin 2, Flotillin-1, Clathrin, PIP5Kα and CDC42. Knockdown of Caveolin-1 reduces endocytosis of superparamagnetic iron oxide nanoparticles (SPIONs and silica-coated iron oxide nanoparticles (SCIONs between 23 and 41%, depending on the surface characteristics of the nanoparticles and the experimental design. Knockdown of CDC42 showed a 46% decrease of the internalization of PEGylated SPIONs within 24 h incubation time. Knockdown of Dynamin 2, Flotillin-1, Clathrin and PIP5Kα caused no or only minor effects. Hence endocytosis in HeLa cells of iron oxide nanoparticles, used in this study, is mainly mediated by Caveolin-1 and CDC42. It is shown here for the first time, which proteins of the endocytotic pathway mediate the endocytosis of silica-coated iron oxide nanoparticles in HeLa cells in vitro. In future studies more experiments should be carried out with different cell lines and other well-defined nanoparticle species to elucidate possible general principles.

Moveable Leading Edge Device for a Wing

Science.gov (United States)

Pitt, Dale M. (Inventor); Eckstein, Nicholas Stephen (Inventor)

2013-01-01

A method and apparatus for managing a flight control surface system. A leading edge section on a wing of an aircraft is extended into a deployed position. A deformable section connects the leading edge section to a trailing section. The deformable section changes from a deformed shape to an original shape when the leading edge section is moved into the deployed position. The leading edge section on the wing is moved from the deployed position to an undeployed position. The deformable section changes to the deformed shape inside of the wing.

Modulation of leading edge vorticity and aerodynamic forces in flexible flapping wings.

Science.gov (United States)

Zhao, Liang; Deng, Xinyan; Sane, Sanjay P

2011-09-01

In diverse biological flight systems, the leading edge vortex has been implicated as a flow feature of key importance in the generation of flight forces. Unlike fixed wings, flapping wings can translate at higher angles of attack without stalling because their leading edge vorticity is more stable than the corresponding fixed wing case. Hence, the leading edge vorticity has often been suggested as the primary determinant of the high forces generated by flapping wings. To test this hypothesis, it is necessary to modulate the size and strength of the leading edge vorticity independently of the gross kinematics while simultaneously monitoring the forces generated by the wing. In a recent study, we observed that forces generated by wings with flexible trailing margins showed a direct dependence on the flexural stiffness of the wing. Based on that study, we hypothesized that trailing edge flexion directly influences leading edge vorticity, and thereby the magnitude of aerodynamic forces on the flexible flapping wings. To test this hypothesis, we visualized the flows on wings of varying flexural stiffness using a custom 2D digital particle image velocimetry system, while simultaneously monitoring the magnitude of the aerodynamic forces. Our data show that as flexion decreases, the magnitude of the leading edge vorticity increases and enhances aerodynamic forces, thus confirming that the leading edge vortex is indeed a key feature for aerodynamic force generation in flapping flight. The data shown here thus support the hypothesis that camber influences instantaneous aerodynamic forces through modulation of the leading edge vorticity.

Leading-edge vortex lifts swifts.

Science.gov (United States)

Videler, J J; Stamhuis, E J; Povel, G D E

2004-12-10

The current understanding of how birds fly must be revised, because birds use their hand-wings in an unconventional way to generate lift and drag. Physical models of a common swift wing in gliding posture with a 60 degrees sweep of the sharp hand-wing leading edge were tested in a water tunnel. Interactions with the flow were measured quantitatively with digital particle image velocimetry at Reynolds numbers realistic for the gliding flight of a swift between 3750 and 37,500. The results show that gliding swifts can generate stable leading-edge vortices at small (5 degrees to 10 degrees) angles of attack. We suggest that the flow around the arm-wings of most birds can remain conventionally attached, whereas the swept-back hand-wings generate lift with leading-edge vortices.

Defective homing is associated with altered Cdc42 activity in cells from patients with Fanconi anemia group A

Science.gov (United States)

Zhang, Xiaoling; Shang, Xun; Guo, Fukun; Murphy, Kim; Kirby, Michelle; Kelly, Patrick; Reeves, Lilith; Smith, Franklin O.; Williams, David A.

2008-01-01

Previous studies showed that Fanconi anemia (FA) murine stem cells have defective reconstitution after bone marrow (BM) transplantation. The mechanism underlying this defect is not known. Here, we report defective homing of FA patient BM progenitors transplanted into mouse models. Using cells from patients carrying mutations in FA complementation group A (FA-A), we show that when transplanted into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) recipient mice, FA-A BM cells exhibited impaired homing activity. FA-A cells also showed defects in both cell-cell and cell-matrix adhesion. Complementation of FA-A deficiency by reexpression of FANCA readily restored adhesion of FA-A cells. A significant decrease in the activity of the Rho GTPase Cdc42 was found associated with these defective functions in patient-derived cells, and expression of a constitutively active Cdc42 mutant was able to rescue the adhesion defect of FA-A cells. These results provide the first evidence that FA proteins influence human BM progenitor homing and adhesion via the small GTPase Cdc42-regulated signaling pathway. PMID:18565850

SU-F-T-675: Down-Regulating the Expression of Cdc42 and Inhibition of Migration of A549 with Combined Treatment of Ionizing Radiation and Sevoflurane

International Nuclear Information System (INIS)

Feng, Y; Feng, J; Huang, Z

2016-01-01

Purpose: Cdc42 is involved in cell transformation, proliferation, invasion and metastasis of human cancer cells. Cdc42 overexpression has been reported in several types of cancers. This study investigated the combined treatment effects of ionizing radiation and sevoflurane on down-regulating Cdc42 expression and suppressing migration of human adenocarcinoma cell line A549. Methods: Samples of A549 cells with Cdc42 overexpression were created and Cdc42 expression was determined by Western blotting. Increase of migration speed by Cdc42-HA overexpression was confirmed with an initial in-vitro scratch assay. The cells grown in culture media were separated into 2 groups of 6 samples: one for the control and the other was treated with 4% sevoflurane for 5hrs prior to a single-fraction radiation of 4Gy using a 6MV beam. Cell migration speeds of the 2 groups were measured with an initial in-vitro scratch assay. The scratch was created with a pipette tip immediately after treatment and images at 4 post-treatment time points (0h, 3h, 6h, 12h) were acquired. The distance between the two separated sides at 0h was used as reference and subsequent changes of the distance over time was defined as the cell migration speed. Image processing and measurement were performed with an in-house software. The experiment was repeated three times independently to evaluate the repeatability and reliability. Statistical analysis was performed with SPSS 19.0. Results: Western blotting showed the treatment down-regulated Cdc42 overexpression. Quantitative analysis and two-tailed t-test showed that cell migration speed of the treated group was higher than the control group at all time points after treatment (p < 0.02). Conclusion: Combined treatment of 6MV photon and sevoflurane can cause the effects of down-regulating Cdc42 overexpression and decrease of migration speed of A549 cells which provides potential of clinical benefit for the cancer therapy. More investigation is needed to further

SU-F-T-675: Down-Regulating the Expression of Cdc42 and Inhibition of Migration of A549 with Combined Treatment of Ionizing Radiation and Sevoflurane

Energy Technology Data Exchange (ETDEWEB)

Feng, Y [East Carolina University, Greenville, NC (United States); Feng, J [Tianjin University, Tianjin (China); Huang, Z [East Carolina University, Greenville, NC (United States)

2016-06-15

Purpose: Cdc42 is involved in cell transformation, proliferation, invasion and metastasis of human cancer cells. Cdc42 overexpression has been reported in several types of cancers. This study investigated the combined treatment effects of ionizing radiation and sevoflurane on down-regulating Cdc42 expression and suppressing migration of human adenocarcinoma cell line A549. Methods: Samples of A549 cells with Cdc42 overexpression were created and Cdc42 expression was determined by Western blotting. Increase of migration speed by Cdc42-HA overexpression was confirmed with an initial in-vitro scratch assay. The cells grown in culture media were separated into 2 groups of 6 samples: one for the control and the other was treated with 4% sevoflurane for 5hrs prior to a single-fraction radiation of 4Gy using a 6MV beam. Cell migration speeds of the 2 groups were measured with an initial in-vitro scratch assay. The scratch was created with a pipette tip immediately after treatment and images at 4 post-treatment time points (0h, 3h, 6h, 12h) were acquired. The distance between the two separated sides at 0h was used as reference and subsequent changes of the distance over time was defined as the cell migration speed. Image processing and measurement were performed with an in-house software. The experiment was repeated three times independently to evaluate the repeatability and reliability. Statistical analysis was performed with SPSS 19.0. Results: Western blotting showed the treatment down-regulated Cdc42 overexpression. Quantitative analysis and two-tailed t-test showed that cell migration speed of the treated group was higher than the control group at all time points after treatment (p < 0.02). Conclusion: Combined treatment of 6MV photon and sevoflurane can cause the effects of down-regulating Cdc42 overexpression and decrease of migration speed of A549 cells which provides potential of clinical benefit for the cancer therapy. More investigation is needed to further

FMNL2 and -3 regulate Golgi architecture and anterograde transport downstream of Cdc42

DEFF Research Database (Denmark)

Kage, Frieda; Steffen, Anika; Ellinger, Adolf

2017-01-01

The Rho-family small GTPase Cdc42 localizes at plasma membrane and Golgi complex and aside from protrusion and migration operates in vesicle trafficking, endo- and exocytosis as well as establishment and/or maintenance of cell polarity. The formin family members FMNL2 and -3 are actin assembly fa...

Dynamic Stall Characteristics of Drooped Leading Edge Airfoils

Science.gov (United States)

Sankar, Lakshmi N.; Sahin, Mehmet; Gopal, Naveen

2000-01-01

Helicopters in high-speed forward flight usually experience large regions of dynamic stall over the retreating side of the rotor disk. The rapid variations in the lift and pitching moments associated with the stall process can result in vibratory loads, and can cause fatigue and failure of pitch links. In some instances, the large time lag between the aerodynamic forces and the blade motion can trigger stall flutter. A number of techniques for the alleviation of dynamic stall have been proposed and studied by researchers. Passive and active control techniques have both been explored. Passive techniques include the use of high solidity rotors that reduce the lift coefficients of individual blades, leading edge slots and leading edge slats. Active control techniques include steady and unsteady blowing, and dynamically deformable leading edge (DDLE) airfoils. Considerable amount of experimental and numerical data has been collected on the effectiveness of these concepts. One concept that has not received as much attention is the drooped-leading edge airfoil idea. It has been observed in wind tunnel studies and flight tests that drooped leading edge airfoils can have a milder dynamic stall, with a significantly milder load hysteresis. Drooped leading edge airfoils may not, however, be suitable at other conditions, e.g. in hover, or in transonic flow. Work needs to be done on the analysis and design of drooped leading edge airfoils for efficient operation in a variety of flight regimes (hover, dynamic stall, and transonic flow). One concept that is worthy of investigation is the dynamically drooping airfoil, where the leading edge shape is changed roughly once-per-rev to mitigate the dynamic stall.

Symmetric airfoil geometry effects on leading edge noise.

Science.gov (United States)

Gill, James; Zhang, X; Joseph, P

2013-10-01

Computational aeroacoustic methods are applied to the modeling of noise due to interactions between gusts and the leading edge of real symmetric airfoils. Single frequency harmonic gusts are interacted with various airfoil geometries at zero angle of attack. The effects of airfoil thickness and leading edge radius on noise are investigated systematically and independently for the first time, at higher frequencies than previously used in computational methods. Increases in both leading edge radius and thickness are found to reduce the predicted noise. This noise reduction effect becomes greater with increasing frequency and Mach number. The dominant noise reduction mechanism for airfoils with real geometry is found to be related to the leading edge stagnation region. It is shown that accurate leading edge noise predictions can be made when assuming an inviscid meanflow, but that it is not valid to assume a uniform meanflow. Analytic flat plate predictions are found to over-predict the noise due to a NACA 0002 airfoil by up to 3 dB at high frequencies. The accuracy of analytic flat plate solutions can be expected to decrease with increasing airfoil thickness, leading edge radius, gust frequency, and Mach number.

Leading-edge flow criticality as a governing factor in leading-edge vortex initiation in unsteady airfoil flows

Science.gov (United States)

Ramesh, Kiran; Granlund, Kenneth; Ol, Michael V.; Gopalarathnam, Ashok; Edwards, Jack R.

2018-04-01

A leading-edge suction parameter (LESP) that is derived from potential flow theory as a measure of suction at the airfoil leading edge is used to study initiation of leading-edge vortex (LEV) formation in this article. The LESP hypothesis is presented, which states that LEV formation in unsteady flows for specified airfoil shape and Reynolds number occurs at a critical constant value of LESP, regardless of motion kinematics. This hypothesis is tested and validated against a large set of data from CFD and experimental studies of flows with LEV formation. The hypothesis is seen to hold except in cases with slow-rate kinematics which evince significant trailing-edge separation (which refers here to separation leading to reversed flow on the aft portion of the upper surface), thereby establishing the envelope of validity. The implication is that the critical LESP value for an airfoil-Reynolds number combination may be calibrated using CFD or experiment for just one motion and then employed to predict LEV initiation for any other (fast-rate) motion. It is also shown that the LESP concept may be used in an inverse mode to generate motion kinematics that would either prevent LEV formation or trigger the same as per aerodynamic requirements.

Cdc42 and Rac1 signaling are both required for and act synergistically in the correct formation of myelin sheaths in the CNS

DEFF Research Database (Denmark)

Thurnherr, Tina; Benninger, Yves; Wu, Xunwei

2006-01-01

. This was characterized by the extraordinary enlargement of the inner tongue of the oligodendrocyte process and concomitant formation of a myelin outfolding as a result of abnormal accumulation of cytoplasm in this region. Ablation of Rac1 also resulted in the abnormal accumulation of cytoplasm in the inner tongue...... of the oligodendrocyte process, and we provide genetic evidence that rac1 synergizes with cdc42 in a gene dosage-dependent way to regulate myelination....

Protein Tyrosine Phosphatase-PEST and β8 Integrin Regulate Spatiotemporal Patterns of RhoGDI1 Activation in Migrating Cells

Science.gov (United States)

Lee, Hye Shin; Cheerathodi, Mujeeburahiman; Chaki, Sankar P.; Reyes, Steve B.; Zheng, Yanhua; Lu, Zhimin; Paidassi, Helena; DerMardirossian, Celine; Lacy-Hulbert, Adam; Rivera, Gonzalo M.

2015-01-01

Directional cell motility is essential for normal development and physiology, although how motile cells spatiotemporally activate signaling events remains largely unknown. Here, we have characterized an adhesion and signaling unit comprised of protein tyrosine phosphatase (PTP)-PEST and the extracellular matrix (ECM) adhesion receptor β8 integrin that plays essential roles in directional cell motility. β8 integrin and PTP-PEST form protein complexes at the leading edge of migrating cells and balance patterns of Rac1 and Cdc42 signaling by controlling the subcellular localization and phosphorylation status of Rho GDP dissociation inhibitor 1 (RhoGDI1). Translocation of Src-phosphorylated RhoGDI1 to the cell's leading edge promotes local activation of Rac1 and Cdc42, whereas dephosphorylation of RhoGDI1 by integrin-bound PTP-PEST promotes RhoGDI1 release from the membrane and sequestration of inactive Rac1/Cdc42 in the cytoplasm. Collectively, these data reveal a finely tuned regulatory mechanism for controlling signaling events at the leading edge of directionally migrating cells. PMID:25666508

Activated Cdc42 kinase regulates Dock localization in male germ cells during Drosophila spermatogenesis.

Science.gov (United States)

Abdallah, Abbas M; Zhou, Xin; Kim, Christine; Shah, Kushani K; Hogden, Christopher; Schoenherr, Jessica A; Clemens, James C; Chang, Henry C

2013-06-15

Deregulation of the non-receptor tyrosine kinase ACK1 (Activated Cdc42-associated kinase) correlates with poor prognosis in cancers and has been implicated in promoting metastasis. To further understand its in vivo function, we have characterized the developmental defects of a null mutation in Drosophila Ack, which bears a high degree of sequence similarity to mammalian ACK1 but lacks a CRIB domain. We show that Ack, while not essential for viability, is critical for sperm formation. This function depends on Ack tyrosine kinase activity and is required cell autonomously in differentiating male germ cells at or after the spermatocyte stage. Ack associates predominantly with endocytic clathrin sites in spermatocytes, but disruption of Ack function has no apparent effect on clathrin localization and receptor-mediated internalization of Boss (Bride of sevenless) protein in eye discs. Instead, Ack is required for the subcellular distribution of Dock (dreadlocks), the Drosophila homolog of the SH2- and SH3-containing adaptor protein Nck. Moreover, Dock forms a complex with Ack, and the localization of Dock in male germ cells depends on its SH2 domain. Together, our results suggest that Ack-dependent tyrosine phosphorylation recruits Dock to promote sperm differentiation. Copyright © 2013 Elsevier Inc. All rights reserved.

Turbine Airfoil Leading Edge Film Cooling Bibliography: 1972–1998

Directory of Open Access Journals (Sweden)

D. M. Kercher

2000-01-01

Full Text Available Film cooling for turbine airfoil leading edges has been a common practice for at least 35 years as turbine inlet gas temperatures and pressures have continually increased along with cooling air temperatures for higher engine cycle efficiency. With substantial engine cycle performance improvements from higher gas temperatures, it has become increasingly necessary to film cool nozzle and rotor blade leading edges since external heat transfer coefficients and thus heat load are the highest in this airfoil region. Optimum cooling air requirements in this harsh environment has prompted a significant number of film cooling investigations and analytical studies reported over the past 25 years from academia, industry and government agencies. Substantial progress has been made in understanding the complex nature of leading edge film cooling from airfoil cascades, simulated airfoil leading edges and environment. This bibliography is a report of the open-literature references available which provide information on the complex aero–thermo interaction of leading edge gaseous film cooling with mainstream flow. From much of this investigative information has come successful operational leading edge film cooling design systems capable of sustaining airfoil leading edge durability in very hostile turbine environments.

Primary angle closure glaucoma (PACG) susceptibility gene PLEKHA7 encodes a novel Rac1/Cdc42 GAP that modulates cell migration and blood-aqueous barrier function.

Science.gov (United States)

Lee, Mei-Chin; Shei, William; Chan, Anita S; Chua, Boon-Tin; Goh, Shuang-Ru; Chong, Yaan-Fun; Hilmy, Maryam H; Nongpiur, Monisha E; Baskaran, Mani; Khor, Chiea-Chuen; Aung, Tin; Hunziker, Walter; Vithana, Eranga N

2017-10-15

PLEKHA7, a gene recently associated with primary angle closure glaucoma (PACG), encodes an apical junctional protein expressed in components of the blood aqueous barrier (BAB). We found that PLEKHA7 is down-regulated in lens epithelial cells and in iris tissue of PACG patients. PLEKHA7 expression also correlated with the C risk allele of the sentinel SNP rs11024102 with the risk allele carrier groups having significantly reduced PLEKHA7 levels compared to non-risk allele carriers. Silencing of PLEKHA7 in human immortalized non-pigmented ciliary epithelium (h-iNPCE) and primary trabecular meshwork cells, which are intimately linked to BAB and aqueous humor outflow respectively, affected actin cytoskeleton organization. PLEKHA7 specifically interacts with GTP-bound Rac1 and Cdc42, but not RhoA, and the activation status of the two small GTPases is linked to PLEKHA7 expression levels. PLEKHA7 stimulates Rac1 and Cdc42 GTP hydrolysis, without affecting nucleotide exchange, identifying PLEKHA7 as a novel Rac1/Cdc42 GAP. Consistent with the regulatory role of Rac1 and Cdc42 in maintaining the tight junction permeability, silencing of PLEKHA7 compromises the paracellular barrier between h-iNPCE cells. Thus, downregulation of PLEKHA7 in PACG may affect BAB integrity and aqueous humor outflow via its Rac1/Cdc42 GAP activity, thereby contributing to disease etiology. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Chronophin coordinates cell leading edge dynamics by controlling active cofilin levels

Science.gov (United States)

Delorme-Walker, Violaine; Seo, Ji-Yeon; Gohla, Antje; Fowler, Bruce; Bohl, Ben; DerMardirossian, Céline

2015-01-01

Cofilin, a critical player of actin dynamics, is spatially and temporally regulated to control the direction and force of membrane extension required for cell locomotion. In carcinoma cells, although the signaling pathways regulating cofilin activity to control cell direction have been established, the molecular machinery required to generate the force of the protrusion remains unclear. We show that the cofilin phosphatase chronophin (CIN) spatiotemporally regulates cofilin activity at the cell edge to generate persistent membrane extension. We show that CIN translocates to the leading edge in a PI3-kinase–, Rac1-, and cofilin-dependent manner after EGF stimulation to activate cofilin, promotes actin free barbed end formation, accelerates actin turnover, and enhances membrane protrusion. In addition, we establish that CIN is crucial for the balance of protrusion/retraction events during cell migration. Thus, CIN coordinates the leading edge dynamics by controlling active cofilin levels to promote MTLn3 cell protrusion. PMID:26324884

Plexin-B2 negatively regulates macrophage motility, Rac, and Cdc42 activation.

Directory of Open Access Journals (Sweden)

Kelly E Roney

Full Text Available Plexins are cell surface receptors widely studied in the nervous system, where they mediate migration and morphogenesis though the Rho family of small GTPases. More recently, plexins have been implicated in immune processes including cell-cell interaction, immune activation, migration, and cytokine production. Plexin-B2 facilitates ligand induced cell guidance and migration in the nervous system, and induces cytoskeletal changes in overexpression assays through RhoGTPase. The function of Plexin-B2 in the immune system is unknown. This report shows that Plexin-B2 is highly expressed on cells of the innate immune system in the mouse, including macrophages, conventional dendritic cells, and plasmacytoid dendritic cells. However, Plexin-B2 does not appear to regulate the production of proinflammatory cytokines, phagocytosis of a variety of targets, or directional migration towards chemoattractants or extracellular matrix in mouse macrophages. Instead, Plxnb2(-/- macrophages have greater cellular motility than wild type in the unstimulated state that is accompanied by more active, GTP-bound Rac and Cdc42. Additionally, Plxnb2(-/- macrophages demonstrate faster in vitro wound closure activity. Studies have shown that a closely related family member, Plexin-B1, binds to active Rac and sequesters it from downstream signaling. The interaction of Plexin-B2 with Rac has only been previously confirmed in yeast and bacterial overexpression assays. The data presented here show that Plexin-B2 functions in mouse macrophages as a negative regulator of the GTPases Rac and Cdc42 and as a negative regulator of basal cell motility and wound healing.

Ang II-AT2R increases mesenchymal stem cell migration by signaling through the FAK and RhoA/Cdc42 pathways in vitro.

Science.gov (United States)

Xu, Xiu-Ping; He, Hong-Li; Hu, Shu-Ling; Han, Ji-Bin; Huang, Li-Li; Xu, Jing-Yuan; Xie, Jian-Feng; Liu, Ai-Ran; Yang, Yi; Qiu, Hai-Bo

2017-07-12

Mesenchymal stem cells (MSCs) migrate via the bloodstream to sites of injury and are possibly attracted by inflammatory factors. As a proinflammatory mediator, angiotensin II (Ang II) reportedly enhances the migration of various cell types by signaling via the Ang II receptor in vitro. However, few studies have focused on the effects of Ang II on MSC migration and the underlying mechanisms. Human bone marrow MSCs migration was measured using wound healing and Boyden chamber migration assays after treatments with different concentrations of Ang II, an AT1R antagonist (Losartan), and/or an AT2R antagonist (PD-123319). To exclude the effect of proliferation on MSC migration, we measured MSC proliferation after stimulation with the same concentration of Ang II. Additionally, we employed the focal adhesion kinase (FAK) inhibitor PF-573228, RhoA inhibitor C3 transferase, Rac1 inhibitor NSC23766, or Cdc42 inhibitor ML141 to investigate the role of cell adhesion proteins and the Rho-GTPase protein family (RhoA, Rac1, and Cdc42) in Ang II-mediated MSC migration. Cell adhesion proteins (FAK, Talin, and Vinculin) were detected by western blot analysis. The Rho-GTPase family protein activities were assessed by G-LISA and F-actin levels, which reflect actin cytoskeletal organization, were detected by using immunofluorescence. Human bone marrow MSCs constitutively expressed AT1R and AT2R. Additionally, Ang II increased MSC migration in an AT2R-dependent manner. Notably, Ang II-enhanced migration was not mediated by Ang II-mediated cell proliferation. Interestingly, Ang II-enhanced migration was mediated by FAK activation, which was critical for the formation of focal contacts, as evidenced by increased Talin and Vinculin expression. Moreover, RhoA and Cdc42 were activated by FAK to increase cytoskeletal organization, thus promoting cell contraction. Furthermore, FAK, Talin, and Vinculin activation and F-actin reorganization in response to Ang II were prevented by PD-123319 but

A mechanism of leading-edge protrusion in the absence of Arp2/3 complex.

Science.gov (United States)

Suraneni, Praveen; Fogelson, Ben; Rubinstein, Boris; Noguera, Philippe; Volkmann, Niels; Hanein, Dorit; Mogilner, Alex; Li, Rong

2015-03-01

Cells employ protrusive leading edges to navigate and promote their migration in diverse physiological environments. Classical models of leading-edge protrusion rely on a treadmilling dendritic actin network that undergoes continuous assembly nucleated by the Arp2/3 complex, forming ruffling lamellipodia. Recent work demonstrated, however, that, in the absence of the Arp2/3 complex, fibroblast cells adopt a leading edge with filopodia-like protrusions (FLPs) and maintain an ability to move, albeit with altered responses to different environmental signals. We show that formin-family actin nucleators are required for the extension of FLPs but are insufficient to produce a continuous leading edge in fibroblasts lacking Arp2/3 complex. Myosin II is concentrated in arc-like regions of the leading edge in between FLPs, and its activity is required for coordinated advancement of these regions with formin-generated FLPs. We propose that actomyosin contraction acting against membrane tension advances the web of arcs between FLPs. Predictions of this model are verified experimentally. The dependence of myosin II in leading-edge advancement helps explain the previously reported defect in directional movement in the Arpc3-null fibroblasts. We provide further evidence that this defect is cell autonomous during chemotaxis. © 2015 Suraneni et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Development of Advanced High Lift Leading Edge Technology for Laminar Flow Wings

Science.gov (United States)

Bright, Michelle M.; Korntheuer, Andrea; Komadina, Steve; Lin, John C.

2013-01-01

This paper describes the Advanced High Lift Leading Edge (AHLLE) task performed by Northrop Grumman Systems Corporation, Aerospace Systems (NGAS) for the NASA Subsonic Fixed Wing project in an effort to develop enabling high-lift technology for laminar flow wings. Based on a known laminar cruise airfoil that incorporated an NGAS-developed integrated slot design, this effort involved using Computational Fluid Dynamics (CFD) analysis and quality function deployment (QFD) analysis on several leading edge concepts, and subsequently down-selected to two blown leading-edge concepts for testing. A 7-foot-span AHLLE airfoil model was designed and fabricated at NGAS and then tested at the NGAS 7 x 10 Low Speed Wind Tunnel in Hawthorne, CA. The model configurations tested included: baseline, deflected trailing edge, blown deflected trailing edge, blown leading edge, morphed leading edge, and blown/morphed leading edge. A successful demonstration of high lift leading edge technology was achieved, and the target goals for improved lift were exceeded by 30% with a maximum section lift coefficient (Cl) of 5.2. Maximum incremental section lift coefficients ( Cl) of 3.5 and 3.1 were achieved for a blown drooped (morphed) leading edge concept and a non-drooped leading edge blowing concept, respectively. The most effective AHLLE design yielded an estimated 94% lift improvement over the conventional high lift Krueger flap configurations while providing laminar flow capability on the cruise configuration.

Cell cycle- and cell growth-regulated proteolysis of mammalian CDC6 is dependent on APC-CDH1

DEFF Research Database (Denmark)

Petersen, B O; Wagener, C; Marinoni, F

2000-01-01

is targeted for ubiquitin-mediated proteolysis by the anaphase promoting complex (APC)/cyclosome in G(1). A combination of point mutations in the destruction box and KEN-box motifs in CDC6 stabilizes the protein in G(1) and in quiescent cells. Furthermore, APC, in association with CDH1, ubiquitinates CDC6...... in vitro, and both APC and CDH1 are required and limiting for CDC6 proteolysis in vivo. Although a stable mutant of CDC6 is biologically active, overexpression of this mutant or wild-type CDC6 is not sufficient to induce multiple rounds of DNA replication in the same cell cycle. The APC-CDH1-dependent...

Wing Leading Edge Concepts for Noise Reduction

Science.gov (United States)

Shmilovich, Arvin; Yadlin, Yoram; Pitera, David M.

2010-01-01

This study focuses on the development of wing leading edge concepts for noise reduction during high-lift operations, without compromising landing stall speeds, stall characteristics or cruise performance. High-lift geometries, which can be obtained by conventional mechanical systems or morphing structures have been considered. A systematic aerodynamic analysis procedure was used to arrive at several promising configurations. The aerodynamic design of new wing leading edge shapes is obtained from a robust Computational Fluid Dynamics procedure. Acoustic benefits are qualitatively established through the evaluation of the computed flow fields.

Method for a Leading Edge Slat on a Wing of an Aircraft

Science.gov (United States)

Pitt, Dale M. (Inventor); Eckstein, Nicholas Stephen (Inventor)

2016-01-01

A method for managing a flight control surface system. A leading edge device is moved on a leading edge from an undeployed position to a deployed position. The leading edge device has an outer surface, an inner surface, and a deformable fairing attached to the leading edge device such that the deformable fairing covers at least a portion of the inner surface. The deformable fairing changes from a deformed shape to an original shape when the leading edge device is moved to the deployed position. The leading edge device is then moved from the deployed position to the undeployed position, wherein the deformable fairing changes from the original shape to the deformed shape.

Redundant and nonredundant roles for Cdc42 and Rac1 in lymphomas developed in NPM-ALK transgenic mice

DEFF Research Database (Denmark)

Choudhari, Ramesh; Minero, Valerio Giacomo; Menotti, Matteo

2016-01-01

Increasing evidence suggests that Rho family GTPases could have a critical role in the biology of T-cell lymphoma. In ALK-rearranged anaplastic large cell lymphoma (ALCL), a specific subtype of T-cell lymphoma, the Rho family GTPases Cdc42 and Rac1 are activated by the ALK oncogenic activity. In ...

Flow over 50º Delta Wings with Different Leading-Edge Radii

NARCIS (Netherlands)

Verhaagen, N.G.

2011-01-01

The experimental study focuses on the effects of the leading-edge radius on the flow over 50º swept delta wing models. Three models were tested, one model has a sharp leading edge and two other have a semi-circular leading edge of different radius. The vortical flow on and off the surface of the

Cdc20 mediates D-box-dependent degradation of Sp100

International Nuclear Information System (INIS)

Wang, Ran; Li, Ke-min; Zhou, Cai-hong; Xue, Jing-lun; Ji, Chao-neng; Chen, Jin-zhong

2011-01-01

Highlights: ► Cdc20 is a co-activator of APC/C complex. ► Cdc20 recruits Sp100 and mediates its degradation. ► The D-box of Sp100 is required for Cdc20-mediated degradation. ► Sp100 expresses consistently at both the mRNA and protein levels in cell cycle. -- Abstract: Cdc20 is a co-activator of the anaphase-promoting complex/cyclosome (APC/C complex), which recruits substrates at particular phases of the cell cycle and mediates their degradation. Sp100 is a PML-NB scaffold protein, which localizes to nuclear particles during interphase and disperses from them during mitosis, participates in viral resistance, transcriptional regulation, and apoptosis. However, its metabolism during the cell cycle has not yet been fully characterized. We found a putative D-box in Sp100 using the Eukaryotic Linear Motif (ELM) predictor database. The putative D-box of Sp100 was verified by mutational analysis. Overexpression of Cdc20 resulted in decreased levels of both endogenous Sp100 protein and overexpressed Sp100 mRNA in HEK 293 cells. Only an overexpressed D-box deletion mutant of Sp100 accumulated in HEK293 cells that also overexpressed Cdc20. Cdc20 knockdown by cdc20 specific siRNA resulted in increased Sp100 protein levels in cells. Furthermore, we discovered that the Cdc20 mediated degradation of Sp100 is diminished by the proteasome inhibitor MG132, which suggests that the ubiquitination pathway is involved in this process. However, unlike the other Cdc20 substrates, which display oscillating protein levels, the level of Sp100 protein remains constant throughout the cell cycle. Additionally, both overexpression and knockdown of endogenous Sp100 had no effect on the cell cycle. Our results suggested that sp100 is a novel substrate of Cdc20 and it is degraded by the ubiquitination pathway. The intact D-box of Sp100 was necessary for this process. These findings expand our knowledge of both Sp100 and Cdc20 as well as their role in ubiquitination.

What is the critical height of leading edge roughness for aerodynamics?

DEFF Research Database (Denmark)

Bak, Christian; Gaunaa, Mac; Olsen, Anders Smærup

2016-01-01

-C2-18 and at three different Reynolds numbers with two different leading edge roughness tape heights. Firstly, an analysis of the momentum thickness as function of Reynolds number was carried out based on the boundary layer theory by Thwaites. Secondly, the wind tunnel measurements combined......In this paper the critical leading edge roughness height is analyzed in two cases: 1) leading edge roughness influencing the lift-drag ratio and 2) leading edge roughness influencing the maximum lift. The analysis was based on wind tunnel measurements on the airfoils NACA0015, Risoe-B1-18 and Risoe...

Leading-Edge Vortex lifts swifts

NARCIS (Netherlands)

Videler, JJ; Stamhuis, EJ; Povel, GDE

2004-01-01

The current understanding of how birds fly must be revised, because birds use their hand-wings in an unconventional way to generate lift and drag. Physical models of a common swift wing in gliding posture with a 60degrees sweep of the sharp hand-wing leading edge were tested in a water tunnel.

The leading-edge vortex of yacht sails

Science.gov (United States)

Arredondo-Galeana, Abel; Viola, Ignazio Maria

2017-11-01

We experimentally show, for the first time, that a stable Leading-Edge Vortex (LEV) can be formed on an asymmetric spinnaker, which is a high-lift sail used by yachts to sail downwind. We tested a 3D printed rigid sail in a water flume at a chord-based Reynolds number of ca. 104. We found that on the leeward side of the sail (the suction side), the flow separates at the leading edge reattaching further downstream and forming a stable LEV. The LEV grows in diameter from the root to the tip of the sail, where it merges with the tip vortex. We detected the LEV using the γ criterion, and we verified its stability over time. The lift contribution provided by the LEV was computed solving a complex potential model of each sail section. This analysis indicated that the LEV provides a substantial contribution to the total sail's lift. These findings suggest that the maximum lift of low-aspect-ratio wings with a sharp leading edge, such as spinnakers, can be enhanced by promoting a stable LEV. This work was funded by the Consejo Nacional de Ciencia y Tecnologia (CONACYT).

Structural Health Monitoring Analysis for the Orbiter Wing Leading Edge

Science.gov (United States)

Yap, Keng C.

2010-01-01

This viewgraph presentation reviews Structural Health Monitoring Analysis for the Orbiter Wing Leading Edge. The Wing Leading Edge Impact Detection System (WLE IDS) and the Impact Analysis Process are also described to monitor WLE debris threats. The contents include: 1) Risk Management via SHM; 2) Hardware Overview; 3) Instrumentation; 4) Sensor Configuration; 5) Debris Hazard Monitoring; 6) Ascent Response Summary; 7) Response Signal; 8) Distribution of Flight Indications; 9) Probabilistic Risk Analysis (PRA); 10) Model Correlation; 11) Impact Tests; 12) Wing Leading Edge Modeling; 13) Ascent Debris PRA Results; and 14) MM/OD PRA Results.

Defective tubulin organization and proplatelet formation in murine megakaryocytes lacking Rac1 and Cdc42

DEFF Research Database (Denmark)

Pleines, Irina; Dütting, Sebastian; Cherpokova, Deya

2013-01-01

Blood platelets are anuclear cell fragments that are essential for blood clotting. Platelets are produced by bone marrow megakaryocytes (MKs), which extend protrusions, or so-called proplatelets, into bone marrow sinusoids. Proplatelet formation requires a profound reorganization of the MK actin...... normally in vivo but displayed highly abnormal morphology and uncontrolled fragmentation. Consistently, a lack of Rac1/Cdc42 virtually abrogated proplatelet formation in vitro. Strikingly, this phenotype was associated with severely defective tubulin organization, whereas actin assembly and structure were...

Cdc20 mediates D-box-dependent degradation of Sp100

Energy Technology Data Exchange (ETDEWEB)

Wang, Ran; Li, Ke-min; Zhou, Cai-hong; Xue, Jing-lun [State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai (China); Ji, Chao-neng, E-mail: Chnji@fudan.edu.cn [State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai (China); Chen, Jin-zhong, E-mail: kingbellchen@fudan.edu.cn [State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai (China)

2011-12-02

Highlights: Black-Right-Pointing-Pointer Cdc20 is a co-activator of APC/C complex. Black-Right-Pointing-Pointer Cdc20 recruits Sp100 and mediates its degradation. Black-Right-Pointing-Pointer The D-box of Sp100 is required for Cdc20-mediated degradation. Black-Right-Pointing-Pointer Sp100 expresses consistently at both the mRNA and protein levels in cell cycle. -- Abstract: Cdc20 is a co-activator of the anaphase-promoting complex/cyclosome (APC/C complex), which recruits substrates at particular phases of the cell cycle and mediates their degradation. Sp100 is a PML-NB scaffold protein, which localizes to nuclear particles during interphase and disperses from them during mitosis, participates in viral resistance, transcriptional regulation, and apoptosis. However, its metabolism during the cell cycle has not yet been fully characterized. We found a putative D-box in Sp100 using the Eukaryotic Linear Motif (ELM) predictor database. The putative D-box of Sp100 was verified by mutational analysis. Overexpression of Cdc20 resulted in decreased levels of both endogenous Sp100 protein and overexpressed Sp100 mRNA in HEK 293 cells. Only an overexpressed D-box deletion mutant of Sp100 accumulated in HEK293 cells that also overexpressed Cdc20. Cdc20 knockdown by cdc20 specific siRNA resulted in increased Sp100 protein levels in cells. Furthermore, we discovered that the Cdc20 mediated degradation of Sp100 is diminished by the proteasome inhibitor MG132, which suggests that the ubiquitination pathway is involved in this process. However, unlike the other Cdc20 substrates, which display oscillating protein levels, the level of Sp100 protein remains constant throughout the cell cycle. Additionally, both overexpression and knockdown of endogenous Sp100 had no effect on the cell cycle. Our results suggested that sp100 is a novel substrate of Cdc20 and it is degraded by the ubiquitination pathway. The intact D-box of Sp100 was necessary for this process. These findings expand

An Elongated Leading Edge Facilitates Rotation Flap Closure: In Vivo Demonstration.

Science.gov (United States)

Lichon, Vanessa; Barbosa, Naiara; Gomez, Doug; Goldman, Glenn

2016-01-01

Variation in the design of a rotation flap may affect wound closure tension. Lengthening the leading edge of a rotation flap has been a method of reducing the tension of closure in the primary motion. An in vitro study negating this tenant has been published. The authors set out to design an in vivo experiment to determine if lengthening the leading edge of a rotation flap has the effect of reducing closure tension in the primary motion of the repair. An animal study approved by Institutional Animal Care and Use Committee was undertaken in a pig model. A tension-measuring apparatus was designed using Teflon-coated wires and digital tensiometers. Rotation flaps of a standard design and with elongated leading edges were incised on the flanks of pigs under general anesthesia. Flap closure tensions were measured at points along the leading edge of the flap and in the secondary motion. Elongating the leading edge of a flap led to a statistically significant reduction in closure tension in the primary motion of the flap and at the flap tip. The secondary motion closure tensions were essentially unaffected. The authors confirm that elongating the leading edge of a standard rotation flap will reduce closure tension in the primary flap motion.

Leading-edge vortex shedding from rotating wings

Energy Technology Data Exchange (ETDEWEB)

Kolomenskiy, Dmitry [Centre de Recherches Mathématiques (CRM), Department of Mathematics and Statistics, McGill University, 805 Sherbrooke W., Montreal, QC H3A 0B9 (Canada); Elimelech, Yossef [Faculty of Aerospace Engineering, Technion-Israel Institute of Technology, Haifa 32000 (Israel); Schneider, Kai, E-mail: dkolom@gmail.com [M2P2–CNRS, Université d' Aix-Marseille, 39, rue Frédéric Joliot-Curie, F-13453 Marseille Cedex 13 (France)

2014-06-01

This paper presents a numerical investigation of the leading-edge vortices generated by rotating triangular wings at Reynolds number Re = 250. A series of three-dimensional numerical simulations have been carried out using a Fourier pseudo-spectral method with volume penalization. The transition from stable attachment of the leading-edge vortex to periodic vortex shedding is explored, as a function of the wing aspect ratio and the angle of attack. It is found that, in a stable configuration, the spanwise flow in the recirculation bubble past the wing is due to the centrifugal force, incompressibility and viscous stresses. For the flow outside of the bubble, an inviscid model of spanwise flow is presented. (papers)

Quantification of local morphodynamics and local GTPase activity by edge evolution tracking.

Directory of Open Access Journals (Sweden)

Yuki Tsukada

2008-11-01

Full Text Available Advances in time-lapse fluorescence microscopy have enabled us to directly observe dynamic cellular phenomena. Although the techniques themselves have promoted the understanding of dynamic cellular functions, the vast number of images acquired has generated a need for automated processing tools to extract statistical information. A problem underlying the analysis of time-lapse cell images is the lack of rigorous methods to extract morphodynamic properties. Here, we propose an algorithm called edge evolution tracking (EET to quantify the relationship between local morphological changes and local fluorescence intensities around a cell edge using time-lapse microscopy images. This algorithm enables us to trace the local edge extension and contraction by defining subdivided edges and their corresponding positions in successive frames. Thus, this algorithm enables the investigation of cross-correlations between local morphological changes and local intensity of fluorescent signals by considering the time shifts. By applying EET to fluorescence resonance energy transfer images of the Rho-family GTPases Rac1, Cdc42, and RhoA, we examined the cross-correlation between the local area difference and GTPase activity. The calculated correlations changed with time-shifts as expected, but surprisingly, the peak of the correlation coefficients appeared with a 6-8 min time shift of morphological changes and preceded the Rac1 or Cdc42 activities. Our method enables the quantification of the dynamics of local morphological change and local protein activity and statistical investigation of the relationship between them by considering time shifts in the relationship. Thus, this algorithm extends the value of time-lapse imaging data to better understand dynamics of cellular function.

Cdc42 and phosphoinositide 3-kinase drive Rac-mediated actin polymerization downstream of c-Met in distinct and common pathways

DEFF Research Database (Denmark)

Bosse, Tanja; Ehinger, Julia; Czuchra, Aleksandra

2007-01-01

-WASP. Instead, actin polymerization was driven by Arp2/3 complex activation through the WAVE complex downstream of Rac. Together, our data establish an intricate signaling network comprising as key molecules Cdc42 and PI3-kinase, which converge on Rac-mediated actin reorganization essential for Listeria...

On the study of wavy leading-edge vanes to achieve low fan interaction noise

Science.gov (United States)

Tong, Fan; Qiao, Weiyang; Xu, Kunbo; Wang, Liangfeng; Chen, Weijie; Wang, Xunnian

2018-04-01

The application of wavy leading-edge vanes to reduce a single-stage axial fan noise is numerically studied. The aerodynamic and acoustic performance of the fan is numerically investigated using a hybrid unsteady Reynolds averaged Navier-Stokes (URANS)/acoustic analogy method (Goldstein equations). First, the hybrid URANS/Goldstein method is developed and successfully validated against experiment results. Next, numerical simulations are performed to investigate the noise reduction effects of the wavy leading-edge vanes. The aerodynamic and acoustic performance is assessed for a fan with vanes equipped with two different wavy leading-edge profiles and compared with the performance of conventional straight leading-edge vanes. Results indicate that a fan with wavy leading-edge vanes produces lower interaction noise than the baseline fan without a significant loss in aerodynamic performance. In fact, it is demonstrated that wavy leading-edge vanes have the potential to lead to both aerodynamic and acoustic improvements. The two different wavy leading-edge profiles are shown to successfully reduce the fan tone sound power level by 1.2 dB and 4.3 dB, respectively. Fan efficiency is also improved by about 1% with one of the tested wavy leading-edge profiles. Large eddy simulation (LES) is also performed for a simplified fan stage model to assess the effects of wavy leading-edge vanes on the broadband fan noise. Results indicate that the overall sound power level of a fan can be reduced by about 4 dB with the larger wavy leading-edge profile. Finally, the noise reduction mechanisms are investigated and analysed. It is found that the wavy leading-edge profiles can induce significant streamwise vorticity around the leading-edge protuberances and reduce pressure fluctuations (especially at locations of wavy leading-edge hills) and unsteady forces on the stator vanes. The underlying mechanism of the reduced pressure fluctuations is also discussed by examining the magnitude

Isolation of a cdc28 mutation that abrogates the dependence of S ...

Indian Academy of Sciences (India)

We have isolated a mutation in the budding yeast Saccharomyces cerevisisae CDC28 gene that allows cdc13 cells, carrying damaged DNA, to continue with the cell division cycle. While cdc13 mutant cells are arrested as large-budded cells at the nonpermissive temperature 37°C, the cdc13 cdc28 double mutant culture ...

Regulated degradation of the APC coactivator Cdc20

Directory of Open Access Journals (Sweden)

Robbins Jonathan A

2010-09-01

Full Text Available Abstract Background Cdc20 is a highly conserved activator of the anaphase-promoting complex (APC, promoting cell-cycle-regulated ubiquitination and proteolysis of a number of critical cell-cycle-regulatory targets including securin and mitotic cyclins. APC-Cdc20 activity is tightly regulated, and this regulation is likely important for accurate cell cycle control. One significant component of Cdc20 regulation is thought to be Cdc20 proteolysis. However, published literature suggests different mechanisms and requirements for Cdc20 proteolysis. The degree to which Cdc20 proteolysis is cell-cycle regulated, the dependence of Cdc20 proteolysis on Cdc20 destruction boxes (recognition sequences for APC-mediated ubiqutination, either by Cdc20 or by the related Cdh1 APC activator, and the need for APC itself for Cdc20 proteolysis all have been disputed to varying extents. In animals, Cdc20 proteolysis is thought to be mediated by Cdh1, contributing an intrinsic order of APC activation by Cdc20 and then by Cdh1. One report suggests a Cdh1 requirement for Cdc20 proteolysis in budding yeast; this idea has not been tested further. Results We characterized Cdc20 proteolysis using Cdc20 expressed from its endogenous locus; previous studies generally employed strongly overexpressed Cdc20, which can cause significant artifacts. We analyzed Cdc20 proteolysis with or without mutations in previously identified destruction box sequences, using varying methods of cell cycle synchronization, and in the presence or absence of Cdh1. Cdc20 instability is only partially dependent on destruction boxes. A much stronger dependence on Cdh1 for Cdc20 proteolysis was observed, but Cdh1-independent proteolysis was also clearly observed. Cdc20 proteolysis independent of both destruction boxes and Cdh1 was especially detectable around the G1/S transition; Cdh1-dependent proteolysis was most notable in late mitosis and G1. Conclusions Cdc20 proteolysis is under complex control

Mechanisms of collective cell movement lacking a leading or free front edge in vivo.

Science.gov (United States)

Uechi, Hiroyuki; Kuranaga, Erina

2017-08-01

Collective cell movement is one of the strategies for achieving the complex shapes of tissues and organs. In this process, multiple cells within a group held together by cell-cell adhesion acquire mobility and move together in the same direction. In some well-studied models of collective cell movement, the mobility depends strongly on traction generated at the leading edge by cells located at the front. However, recent advances in live-imaging techniques have led to the discovery of other types of collective cell movement lacking a leading edge or even a free edge at the front, in a diverse array of morphological events, including tubule elongation, epithelial sheet extension, and tissue rotation. We herein review some of the developmental events that are organized by collective cell movement and attempt to elucidate the underlying cellular and molecular mechanisms, which include membrane protrusions, guidance cues, cell intercalation, and planer cell polarity, or chirality pathways.

Characterization of cyclin-dependent kinases and Cdc2/Cdc28 kinase subunits in Trichomonas vaginalis.

Science.gov (United States)

Amador, Erick; López-Pacheco, Karla; Morales, Nataly; Coria, Roberto; López-Villaseñor, Imelda

2017-04-01

Cyclin-dependent kinases (CDKs) have important roles in regulating key checkpoints between stages of the cell cycle. Their activity is tightly regulated through a variety of mechanisms, including through binding with cyclin proteins and the Cdc2/Cdc28 kinase subunit (CKS), and their phosphorylation at specific amino acids. Studies of the components involved in cell cycle control in parasitic protozoa are limited. Trichomonas vaginalis is the causative agent of trichomoniasis in humans and is therefore important in public health; however, some of the basic biological processes used by this organism have not been defined. Here, we characterized proteins potentially involved in cell cycle regulation in T. vaginalis. Three genes encoding protein kinases were identified in the T. vaginalis genome, and the corresponding recombinant proteins (TvCRK1, TvCRK2, TvCRK5) were studied. These proteins displayed similar sequence features to CDKs. Two genes encoding CKSs were also identified, and the corresponding recombinant proteins were found to interact with TvCRK1 and TvCRK2 by a yeast two-hybrid system. One putative cyclin B protein from T. vaginalis was found to bind to and activate the kinase activities of TvCRK1 and TvCRK5, but not TvCRK2. This work is the first characterization of proteins involved in cell cycle control in T. vaginalis.

Method and Apparatus for a Leading Edge Slat on a Wing of an Aircraft

Science.gov (United States)

Pitt, Dale M. (Inventor); Eckstein, Nicholas Stephen (Inventor)

2013-01-01

A method and apparatus for managing a flight control surface system. A leading edge device is moved on a leading edge from an undeployed position to a deployed position. The leading edge device has an outer surface, an inner surface, and a deformable fairing attached to the leading edge device such that the deformable fairing covers at least a portion of the inner surface. The deformable fairing changes from a deformed shape to an original shape when the leading edge device is moved to the deployed position. The leading edge device is then moved from the deployed position to the undeployed position, wherein the deformable fairing changes from the original shape to the deformed shape.

Numerical investigation of mist/air impingement cooling on ribbed blade leading-edge surface.

Science.gov (United States)

Bian, Qingfei; Wang, Jin; Chen, Yi-Tung; Wang, Qiuwang; Zeng, Min

2017-12-01

The working gas turbine blades are exposed to the environment of high temperature, especially in the leading-edge region. The mist/air two-phase impingement cooling has been adopted to enhance the heat transfer on blade surfaces and investigate the leading-edge cooling effectiveness. An Euler-Lagrange particle tracking method is used to simulate the two-phase impingement cooling on the blade leading-edge. The mesh dependency test has been carried out and the numerical method is validated based on the available experimental data of mist/air cooling with jet impingement on a concave surface. The cooling effectiveness on three target surfaces is investigated, including the smooth and the ribbed surface with convex/concave columnar ribs. The results show that the cooling effectiveness of the mist/air two-phase flow is better than that of the single-phase flow. When the ribbed surfaces are used, the heat transfer enhancement is significant, the surface cooling effectiveness becomes higher and the convex ribbed surface presents a better performance. With the enhancement of the surface heat transfer, the pressure drop in the impingement zone increases, but the incremental factor of the flow friction is smaller than that of the heat transfer enhancement. Copyright © 2017 Elsevier Ltd. All rights reserved.

Impact of Leading-Edge Orientation and Shape on Performance of Compressor Blades

National Research Council Canada - National Science Library

Powell, Jonathan D

2005-01-01

This thesis presents a Computation Fluid Dynamics (CFD) analysis of the aerodynamic performance of circular and elliptical leading edges of compressor blades, with a range of leading edge droop angles...

Two closely related Rho GTPases, Cdc42 and RacA, of the en-dophytic fungus Epichloë festucae have contrasting roles for ROS production and symbiotic infection synchronized with the host plant.

Science.gov (United States)

Kayano, Yuka; Tanaka, Aiko; Takemoto, Daigo

2018-01-01

Epichloë festucae is an endophytic fungus which systemically colonizes temperate grasses to establish symbiotic associations. Maintaining symptomless infection is a key requirement for endophytes, a feature that distinguishes them from pathogenic fungi. While pathogenic fungi extend their hyphae by tip growth, hyphae of E. festucae systemically colonize the intercellular space of expanding host leaves via a unique mechanism of hyphal intercalary growth. This study reports that two homologous Rho GTPases, Cdc42 and RacA, have distinctive roles in the regulation of E. festucae growth in planta. Here we highlight the vital role of Cdc42 for intercalary hyphal growth, as well as involvement of RacA in regulation of hyphal network formation, and demonstrate the consequences of mutations in these genes on plant tissue infection. Functions of Cdc42 and RacA are mediated via interactions with BemA and NoxR respectively, which are expected components of the ROS producing NOX complex. Symbiotic defects found in the racA mutant were rescued by introduction of a Cdc42 with key amino acids substitutions crucial for RacA function, highlighting the significance of the specific interactions of these GTPases with BemA and NoxR for their functional differentiation in symbiotic infection.

The leading-edge vortex of swift-wing shaped delta wings

Science.gov (United States)

Muir, Rowan; Arredondo-Galeana, Abel; Viola, Ignazio Maria

2017-11-01

Recent investigations on the aerodynamics of natural fliers have illuminated the significance of the Leading-Edge Vortex (LEV) for lift generation in a variety of flight conditions. In this investigation, a model non-slender delta shaped wing with a sharp leading-edge is tested at low Reynolds Number, along with a delta wing of the same design, but with a modified trailing edge inspired by the wing of a common swift Apus apus. The effect of the tapering swift wing on LEV development and stability is compared with the flow structure over the un-modified delta wing model through particle image velocimetry. For the first time, a leading-edge vortex system consisting of a dual or triple LEV is recorded on a swift-wing shaped delta wing, where such a system is found across all tested conditions. It is shown that the spanwise location of LEV breakdown is governed by the local chord rather than Reynolds Number or angle of attack. These findings suggest that the trailing-edge geometry of the swift wing alone does not prevent the common swift from generating an LEV system comparable with that of a delta shaped wing. This work received funding from the Engineering and Physical Sciences Research Council [EP/M506515/1] and the Consejo Nacional de Ciencia y Tecnología (CONACYT).

Superior Reproducibility of the Leading to Leading Edge and Inner to Inner Edge Methods in the Ultrasound Assessment of Maximum Abdominal Aortic Diameter

DEFF Research Database (Denmark)

Borgbjerg, Jens; Bøgsted, Martin; Lindholt, Jes S

2018-01-01

Objectives: Controversy exists regarding optimal caliper placement in ultrasound assessment of maximum abdominal aortic diameter. This study aimed primarily to determine reproducibility of caliper placement in relation to the aortic wall with the three principal methods: leading to leading edge...

Hypersonic Engine Leading Edge Experiments in a High Heat Flux, Supersonic Flow Environment

Science.gov (United States)

Gladden, Herbert J.; Melis, Matthew E.

1994-01-01

A major concern in advancing the state-of-the-art technologies for hypersonic vehicles is the development of an aeropropulsion system capable of withstanding the sustained high thermal loads expected during hypersonic flight. Three aerothermal load related concerns are the boundary layer transition from laminar to turbulent flow, articulating panel seals in high temperature environments, and strut (or cowl) leading edges with shock-on-shock interactions. A multidisciplinary approach is required to address these technical concerns. A hydrogen/oxygen rocket engine heat source has been developed at the NASA Lewis Research Center as one element in a series of facilities at national laboratories designed to experimentally evaluate the heat transfer and structural response of the strut (or cowl) leading edge. A recent experimental program conducted in this facility is discussed and related to cooling technology capability. The specific objective of the experiment discussed is to evaluate the erosion and oxidation characteristics of a coating on a cowl leading edge (or strut leading edge) in a supersonic, high heat flux environment. Heat transfer analyses of a similar leading edge concept cooled with gaseous hydrogen is included to demonstrate the complexity of the problem resulting from plastic deformation of the structures. Macro-photographic data from a coated leading edge model show progressive degradation over several thermal cycles at aerothermal conditions representative of high Mach number flight.

Role of TGF-beta1-independent changes in protein neosynthesis, p38alphaMAPK, and cdc42 in hydrogen peroxide-induced senescence-like morphogenesis

DEFF Research Database (Denmark)

Chrétien, Aline; Dierick, Jean-François; Delaive, Edouard

2008-01-01

for p38(MAPK) activation, in turn triggering phosphorylation of L-caldesmon and HSP27. Cdc42 was also shown to be mainly responsible for the increase in TGF-beta1 mRNA level observed at 24 h after treatment with H(2)O(2) and onward. This study further clarified the mechanisms of senescence......The role of TGF-beta1 in hydrogen peroxide-induced senescence-like morphogenesis has been described. The aim of this work was to investigate whether TGF-beta1-independent changes in protein synthesis are involved in this morphogenesis and to study possible mechanisms occurring earlier than TGF-beta......1 overexpression. Among the multiple TGF-beta1-independent changes in protein neosynthesis, followed or not by posttranslational modifications, identified by proteomic analysis herein, those of ezrin, L-caldesmon, and HSP27 were particularly studied. Rho-GTPase cdc42 was shown to be responsible...

On the effect of leading edge blowing on circulation control airfoil aerodynamics

Science.gov (United States)

Mclachlan, B. G.

1987-01-01

In the present context the term circulation control is used to denote a method of lift generation that utilizes tangential jet blowing over the upper surface of a rounded trailing edge airfoil to determine the location of the boundary layer separation points, thus setting an effective Kutta condition. At present little information exists on the flow structure generated by circulation control airfoils under leading edge blowing. Consequently, no theoretical methods exist to predict airfoil performance under such conditions. An experimental study of the flow field generated by a two dimensional circulation control airfoil under steady leading and trailing edge blowing was undertaken. The objective was to fundamentally understand the overall flow structure generated and its relation to airfoil performance. Flow visualization was performed to define the overall flow field structure. Measurements of the airfoil forces were also made to provide a correlation of the observed flow field structure to airfoil performance. Preliminary results are presented, specifically on the effect on the flow field structure of leading edge blowing, alone and in conjunction with trailing edge blowing.

Effect of leading-edge geometry on boundary-layer receptivity to freestream sound

Science.gov (United States)

Lin, Nay; Reed, Helen L.; Saric, W. S.

1991-01-01

The receptivity to freestream sound of the laminar boundary layer over a semi-infinite flat plate with an elliptic leading edge is simulated numerically. The incompressible flow past the flat plate is computed by solving the full Navier-Stokes equations in general curvilinear coordinates. A finite-difference method which is second-order accurate in space and time is used. Spatial and temporal developments of the Tollmien-Schlichting wave in the boundary layer, due to small-amplitude time-harmonic oscillations of the freestream velocity that closely simulate a sound wave travelling parallel to the plate, are observed. The effect of leading-edge curvature is studied by varying the aspect ratio of the ellipse. The boundary layer over the flat plate with a sharper leading edge is found to be less receptive. The relative contribution of the discontinuity in curvature at the ellipse-flat-plate juncture to receptivity is investigated by smoothing the juncture with a polynomial. Continuous curvature leads to less receptivity. A new geometry of the leading edge, a modified super ellipse, which provides continuous curvature at the juncture with the flat plate, is used to study the effect of continuous curvature and inherent pressure gradient on receptivity.

Fundamental aerodynamic characteristics of delta wings with leading-edge vortex flows

Science.gov (United States)

Wood, R. M.; Miller, D. S.

1985-01-01

An investigation of the aerodynamics of sharp leading-edge delta wings at supersonic speeds has been conducted. The supporting experimental data for this investigation were taken from published force, pressure, and flow-visualization data in which the Mach number normal to the wing leading edge is always less than 1.0. The individual upper- and lower-surface nonlinear characteristics for uncambered delta wings are determined and presented in three charts. The upper-surface data show that both the normal-force coefficient and minimum pressure coefficient increase nonlinearly with a decreasing slope with increasing angle of attack. The lower-surface normal-force coefficient was shown to be independent of Mach number and to increase nonlinearly, with an increasing slope, with increasing angle of attack. These charts are then used to define a wing-design space for sharp leading-edge delta wings.

The leading-edge vortex of swift wing-shaped delta wings.

Science.gov (United States)

Muir, Rowan Eveline; Arredondo-Galeana, Abel; Viola, Ignazio Maria

2017-08-01

Recent investigations on the aerodynamics of natural fliers have illuminated the significance of the leading-edge vortex (LEV) for lift generation in a variety of flight conditions. A well-documented example of an LEV is that generated by aircraft with highly swept, delta-shaped wings. While the wing aerodynamics of a manoeuvring aircraft, a bird gliding and a bird in flapping flight vary significantly, it is believed that this existing knowledge can serve to add understanding to the complex aerodynamics of natural fliers. In this investigation, a model non-slender delta-shaped wing with a sharp leading edge is tested at low Reynolds number, along with a delta wing of the same design, but with a modified trailing edge inspired by the wing of a common swift Apus apus . The effect of the tapering swift wing on LEV development and stability is compared with the flow structure over the unmodified delta wing model through particle image velocimetry. For the first time, a leading-edge vortex system consisting of a dual or triple LEV is recorded on a swift wing-shaped delta wing, where such a system is found across all tested conditions. It is shown that the spanwise location of LEV breakdown is governed by the local chord rather than Reynolds number or angle of attack. These findings suggest that the trailing-edge geometry of the swift wing alone does not prevent the common swift from generating an LEV system comparable with that of a delta-shaped wing.

Turbine Airfoil With CMC Leading-Edge Concept Tested Under Simulated Gas Turbine Conditions

Science.gov (United States)

Robinson, R. Craig; Hatton, Kenneth S.

2000-01-01

Silicon-based ceramics have been proposed as component materials for gas turbine engine hot-sections. When the Navy s Harrier fighter experienced engine (Pegasus F402) failure because of leading-edge durability problems on the second-stage high-pressure turbine vane, the Office of Naval Research came to the NASA Glenn Research Center at Lewis Field for test support in evaluating a concept for eliminating the vane-edge degradation. The High Pressure Burner Rig (HPBR) was selected for testing since it could provide temperature, pressure, velocity, and combustion gas compositions that closely simulate the engine environment. The study focused on equipping the stationary metal airfoil (Pegasus F402) with a ceramic matrix composite (CMC) leading-edge insert and evaluating the feasibility and benefits of such a configuration. The test exposed the component, with and without the CMC insert, to the harsh engine environment in an unloaded condition, with cooling to provide temperature relief to the metal blade underneath. The insert was made using an AlliedSignal Composites, Inc., enhanced HiNicalon (Nippon Carbon Co. LTD., Yokohama, Japan) fiber-reinforced silicon carbide composite (SiC/SiC CMC) material fabricated via chemical vapor infiltration. This insert was 45-mils thick and occupied a recessed area in the leading edge and shroud of the vane. It was designed to be free floating with an end cap design. The HPBR tests provided a comparative evaluation of the temperature response and leading-edge durability and included cycling the airfoils between simulated idle, lift, and cruise flight conditions. In addition, the airfoils were aircooled, uniquely instrumented, and exposed to the exact set of internal and external conditions, which included gas temperatures in excess of 1370 C (2500 F). In addition to documenting the temperature response of the metal vane for comparison with the CMC, a demonstration of improved leading-edge durability was a primary goal. First, the

Application of a Beamforming Technique to the Measurement of Airfoil Leading Edge Noise

Directory of Open Access Journals (Sweden)

Thomas Geyer

2012-01-01

Full Text Available The present paper describes the use of microphone array technology and beamforming algorithms for the measurement and analysis of noise generated by the interaction of a turbulent flow with the leading edge of an airfoil. Experiments were performed using a setup in an aeroacoustic wind tunnel, where the turbulent inflow is provided by different grids. In order to exactly localize the aeroacoustic noise sources and, moreover, to separate airfoil leading edge noise from grid-generated noise, the selected deconvolution beamforming algorithm is extended to be used on a fully three-dimensional source region. The result of this extended beamforming are three-dimensional mappings of noise source locations. Besides acoustic measurements, the investigation of airfoil leading edge noise requires the measurement of parameters describing the incident turbulence, such as the intensity and a characteristic length scale or time scale. The method used for the determination of these parameters in the present study is explained in detail. To demonstrate the applicability of the extended beamforming algorithm and the experimental setup as a whole, the noise generated at the leading edge of airfoils made of porous materials was measured and compared to that generated at the leading edge of a common nonporous airfoil.

The Gcn2 Regulator Yih1 Interacts with the Cyclin Dependent Kinase Cdc28 and Promotes Cell Cycle Progression through G2/M in Budding Yeast.

Directory of Open Access Journals (Sweden)

Richard C Silva

Full Text Available The Saccharomyces cerevisiae protein Yih1, when overexpressed, inhibits the eIF2 alpha kinase Gcn2 by competing for Gcn1 binding. However, deletion of YIH1 has no detectable effect on Gcn2 activity, suggesting that Yih1 is not a general inhibitor of Gcn2, and has no phenotypic defect identified so far. Thus, its physiological role is largely unknown. Here, we show that Yih1 is involved in the cell cycle. Yeast lacking Yih1 displays morphological patterns and DNA content indicative of a delay in the G2/M phases of the cell cycle, and this phenotype is independent of Gcn1 and Gcn2. Accordingly, the levels of phosphorylated eIF2α, which show a cell cycle-dependent fluctuation, are not altered in cells devoid of Yih1. We present several lines of evidence indicating that Yih1 is in a complex with Cdc28. Yih1 pulls down endogenous Cdc28 in vivo and this interaction is enhanced when Cdc28 is active, suggesting that Yih1 modulates the function of Cdc28 in specific stages of the cell cycle. We also demonstrate, by Bimolecular Fluorescence Complementation, that endogenous Yih1 and Cdc28 interact with each other, confirming Yih1 as a bona fide Cdc28 binding partner. Amino acid substitutions within helix H2 of the RWD domain of Yih1 enhance Yih1-Cdc28 association. Overexpression of this mutant, but not of wild type Yih1, leads to a phenotype similar to that of YIH1 deletion, supporting the view that Yih1 is involved through Cdc28 in the regulation of the cell cycle. We further show that IMPACT, the mammalian homologue of Yih1, interacts with CDK1, the mammalian counterpart of Cdc28, indicating that the involvement with the cell cycle is conserved. Together, these data provide insights into the cellular function of Yih1/IMPACT, and provide the basis for future studies on the role of this protein in the cell cycle.

Measuring leading placental edge to internal cervical os: Transabdominal versus transvaginal approach

DEFF Research Database (Denmark)

Westerway, Susan Campbell; Hyett, Jon; Henning Pedersen, Lars

2017-01-01

We aimed to compare the value of transabdominal (TA) and transvaginal (TV) approaches for assessing the risk of a low-lying placenta. This involved a comparison of TA and TV measurements between the leading placental edge and the internal cervical os. We also assessed the intra-/interobserver var......We aimed to compare the value of transabdominal (TA) and transvaginal (TV) approaches for assessing the risk of a low-lying placenta. This involved a comparison of TA and TV measurements between the leading placental edge and the internal cervical os. We also assessed the intra......-/interobserver variation for these measurements and the efficacy of TA measures in screening for a low placenta. Methodology Transabdominal and TV measurements of the leading placental edge to the internal cervical os were performed on 369 consecutive pregnancies of 16–41 weeks' gestation. The difference (TA-TV) from...... the area under the receiver operator characteristics (ROC) curve. Intra-/interobserver variations were also calculated. Results Of the pregnancies, 278 had a leading placental edge that was visible with the TV approach. Differences (TA-TV) ranged from −50 mm to +57 mm. Bland-Altman plot shows that TA...

Cdc25A localisation and shuttling: characterisation of sequences mediating nuclear export and import

International Nuclear Information System (INIS)

Kaellstroem, Helena; Lindqvist, Arne; Pospisil, Vitek; Lundgren, Andreas; Karlsson Rosenthal, Christina

2005-01-01

The Cdc25 phosphatases play crucial roles in cell cycle progression by removing inhibitory phosphates from tyrosine and threonine residues of cyclin-dependent kinases. Cdc25A is an important regulator of the G1/S transition but functions also in the mitotic phase of the human cell cycle. In this paper, we investigate the sub-cellular localisation of exogenously expressed Cdc25A. We show that YFP-Cdc25A is localised both in the nucleus and the cytoplasm of HeLa cells and untransformed fibroblasts. Cell fusion assays and fluorescence loss in photobleaching (FLIP) assays reveal that the localisation is dynamic and the protein shuttles between the nucleus and the cytoplasm. We demonstrate that nuclear export of Cdc25A is partly mediated by an N-terminal nuclear export sequence (NES), in a manner not sensitive to the Exportin 1-inhibitor leptomycin B. A nuclear localisation signal (NLS) is also characterised, mutation of which leads to cytoplasmic localisation of Cdc25A. Our results imply that the Cdc25A phosphatase may interact with substrates and regulators both in the nucleus and the cytoplasm

Molecular cloning of the gene for the human placental GTP-binding protein Gp (G25K): Identification of this GTP-binding protein as the human homolog of the yeast cell-division-cycle protein CDC42

International Nuclear Information System (INIS)

Shinjo, K.; Koland, J.G.; Hart, M.J.; Narasimhan, V.; Cerione, R.A.; Johnson, D.I.; Evans, T.

1990-01-01

The authors have isolated cDNA clones from a human placental library that code for a low molecular weight GTP-binding protein originally designated G p (also called G25K). This identification is based on comparisons with the available peptide sequences for the purified human G p protein and the use of two highly specific anti-peptide antibodies. The predicted amino acid sequence of the protein is very similar to those of various members of the ras superfamily of low molecular weight GTP-binding proteins, including the N-, Ki-, and Ha-ras proteins (30-35% identical), the rho proteins and the rac proteins. The highest degree of sequence identity (80%) is found with the Saccharomyces cerevisiae cell division-cycle protein CDC42. The human placental gene, which they designate CDC42Hs, complements the cdc42-1 mutation in S. cerevisiae, which suggests that this GTP-binding protein is the human homolog of the yeast protein

Aerodynamic robustness in owl-inspired leading-edge serrations: a computational wind-gust model.

Science.gov (United States)

Rao, Chen; Liu, Hao

2018-06-08

Owls are a master to achieve silent flight in gliding and flapping flights under natural turbulent environments owing to their unique wing morphologies. While the leading-edge serrations are recently revealed, as a passive flow control micro-device, to play a crucial role in aerodynamic force production and sound suppression [25], the characteristics of wind-gust rejection associated with leading-edge serrations remain unclear. Here we address a large-eddy simulation (LES)-based study of aerodynamic robustness in owl-inspired leading-edge serrations, which is conducted with clean and serrated wing models through mimicking wind-gusts under a longitudinal fluctuation in free-stream inflow and a lateral fluctuation in pitch angle over a broad range of angles of attack (AoAs) over 0° ≤ Φ ≤ 20°. Our results show that the leading-edge serration-based passive flow control mechanisms associated with laminar-turbulent transition work effectively under fluctuated inflow and wing pitch, indicating that the leading-edge serrations are of potential gust fluctuation rejection or robustness in aerodynamic performance. Moreover, it is revealed that the tradeoff between turbulent flow control (i.e., aero-acoustic suppression) and force production in the serrated model holds independently to the wind-gust environments: poor at lower AoAs but capable of achieving equivalent aerodynamic performance at higher AoAs > 15o compared to the clean model. Our results reveal that the owl-inspired leading-edge serrations can be a robust micro-device for aero-acoustic control coping with unsteady and complex wind environments in biomimetic rotor designs for various fluid machineries. © 2018 IOP Publishing Ltd.

A high-performance, low-cost, leading edge discriminator

Indian Academy of Sciences (India)

Abstract. A high-performance, low-cost, leading edge discriminator has been designed with a timing performance comparable to state-of-the-art, commercially available discrim- inators. A timing error of 16 ps is achieved under ideal operating conditions. Under more realistic operating conditions the discriminator displays a ...

Functions of mammalian Cdc7 kinase in initiation/monitoring of DNA replication and development

Energy Technology Data Exchange (ETDEWEB)

Kim, Jung Min; Yamada, Masayuki; Masai, Hisao

2003-11-27

Cdc7 kinase plays an essential role in firing of replication origins by phosphorylating components of the replication complexes. Cdc7 kinase has also been implicated in S phase checkpoint signaling downstream of the ATR and Chk1 kinases. Inactivation of Cdc7 in yeast results in arrest of cell growth with 1C DNA content after completion of the ongoing DNA replication. In contrast, conditional inactivation of Cdc7 in undifferentiated mouse embryonic stem (ES) cells leads to growth arrest with rapid cessation of DNA synthesis, suggesting requirement of Cdc7 functions for continuation of ongoing DNA synthesis. Furthermore, loss of Cdc7 function induces recombinational repair (nuclear Rad51 foci) and G2/M checkpoint responses (inhibition of Cdc2 kinase). Eventually, p53 becomes highly activated and the cells undergo massive p53-dependent apoptosis. Thus, defective origin activation in mammalian cells can generate DNA replication checkpoint signals. Efficient removal of those cells in which replication has been perturbed, through cell death, may be beneficial to maintain the highest level of genetic integrity in totipotent stem cells. Partial, rather than total, loss of Cdc7 kinase expression results in retarded growth at both cellular and whole body levels, with especially profound impairment of germ cell development.

Functions of mammalian Cdc7 kinase in initiation/monitoring of DNA replication and development

International Nuclear Information System (INIS)

Kim, Jung Min; Yamada, Masayuki; Masai, Hisao

2003-01-01

Cdc7 kinase plays an essential role in firing of replication origins by phosphorylating components of the replication complexes. Cdc7 kinase has also been implicated in S phase checkpoint signaling downstream of the ATR and Chk1 kinases. Inactivation of Cdc7 in yeast results in arrest of cell growth with 1C DNA content after completion of the ongoing DNA replication. In contrast, conditional inactivation of Cdc7 in undifferentiated mouse embryonic stem (ES) cells leads to growth arrest with rapid cessation of DNA synthesis, suggesting requirement of Cdc7 functions for continuation of ongoing DNA synthesis. Furthermore, loss of Cdc7 function induces recombinational repair (nuclear Rad51 foci) and G2/M checkpoint responses (inhibition of Cdc2 kinase). Eventually, p53 becomes highly activated and the cells undergo massive p53-dependent apoptosis. Thus, defective origin activation in mammalian cells can generate DNA replication checkpoint signals. Efficient removal of those cells in which replication has been perturbed, through cell death, may be beneficial to maintain the highest level of genetic integrity in totipotent stem cells. Partial, rather than total, loss of Cdc7 kinase expression results in retarded growth at both cellular and whole body levels, with especially profound impairment of germ cell development

Model for adhesion clutch explains biphasic relationship between actin flow and traction at the cell leading edge

Science.gov (United States)

Craig, Erin M.; Stricker, Jonathan; Gardel, Margaret L.; Mogilner, Alex

2015-01-01

Cell motility relies on the continuous reorganization of a dynamic actin-myosin-adhesion network at the leading edge of the cell, in order to generate protrusion at the leading edge and traction between the cell and its external environment. We analyze experimentally measured spatial distributions of actin flow, traction force, myosin density, and adhesion density in control and pharmacologically perturbed epithelial cells in order to develop a mechanical model of the actin-adhesion-myosin self-organization at the leading edge. A model in which the F-actin network is treated as a viscous gel, and adhesion clutch engagement is strengthened by myosin but weakened by actin flow, can explain the measured molecular distributions and correctly predict the spatial distributions of the actin flow and traction stress. We test the model by comparing its predictions with measurements of the actin flow and traction stress in cells with fast and slow actin polymerization rates. The model predicts how the location of the lamellipodium-lamellum boundary depends on the actin viscosity and adhesion strength. The model further predicts that the location of the lamellipodium-lamellum boundary is not very sensitive to the level of myosin contraction. PMID:25969948

Cell cycle-dependent mobility of Cdc45 determined in vivo by fluorescence correlation spectroscopy.

Directory of Open Access Journals (Sweden)

Ronan Broderick

Full Text Available Eukaryotic DNA replication is a dynamic process requiring the co-operation of specific replication proteins. We measured the mobility of eGFP-Cdc45 by Fluorescence Correlation Spectroscopy (FCS in vivo in asynchronous cells and in cells synchronized at the G1/S transition and during S phase. Our data show that eGFP-Cdc45 mobility is faster in G1/S transition compared to S phase suggesting that Cdc45 is part of larger protein complex formed in S phase. Furthermore, the size of complexes containing Cdc45 was estimated in asynchronous, G1/S and S phase-synchronized cells using gel filtration chromatography; these findings complemented the in vivo FCS data. Analysis of the mobility of eGFP-Cdc45 and the size of complexes containing Cdc45 and eGFP-Cdc45 after UVC-mediated DNA damage revealed no significant changes in diffusion rates and complex sizes using FCS and gel filtration chromatography analyses. This suggests that after UV-damage, Cdc45 is still present in a large multi-protein complex and that its mobility within living cells is consistently similar following UVC-mediated DNA damage.

Role of AtCDC48 & the AtCDC48 Regulatory Protein Family, PUX, in Plant Cell Morphogenesis

Energy Technology Data Exchange (ETDEWEB)

Bednarek, Sebastian, Y.

2009-11-08

The long-term objective of this work is to understand the molecular events and mechanisms involved in secretory membrane trafficking and organelle biogenesis, which are crucial for normal plant growth and development. Our studies have suggested a vital role for the cytosolic chaperone Cdc48p/p97 during cytokinesis and cell expansion which are highly dependent upon secretory membrane trafficking. Localization studies have shown that the plant Cdc48p/p97, AtCDC48, and the Arabidopsis ortholog of the ER- and Golgi-associated SNARE, syntaxin 5, (referred to as SYP31) are targeted to the division plane during cytokinesis. In addition, AtCDC48 and SYP31 were shown to interact in vitro and in vivo. To characterize further the function of AtCDC48 and SYP31 we have utilized affinity chromatography and MALDI-MS to identify several plant-specific proteins that interact with SYP31 and/or modulate the activity of AtCDC48 including two UBX (i.e. ubiquitin-like) domain containing proteins, PUX1 and PUX2 (Proteins containing UBX domain). These proteins define a plant protein family consisting of 15 uncharacterized members that we postulate interact with AtCDC48. Biochemical studies have demonstrated that PUX2 is a novel membrane adapter for AtCDC48 that mediates AtCDC48/SYP31 interaction and is likely to control AtCDC48-dependent membrane fusion. In contrast, PUX1 negatively regulates AtCDC48 by inhibiting its ATPase activity and by promoting the disassembly of the active hexamer. These findings provide the first evidence that the assembly and disassembly of the CDC48/p97complex is actually a dynamic process. This new unexpected level of regulation for CDC48/p97 was demonstrated to be critical in vivo as pux1 loss-of-function mutants grow faster than wild-type plants. These studies suggest a role for AtCDC48 in plant cell cycle progression including cytokinesis and/or cell expansion. The proposed studies are designed to: 1) characterize further the localization and function of AtCDC

Modification of the NACA 632-415 leading edge for better aerodynamic performance

DEFF Research Database (Denmark)

Bak, C.; Fuglsang, P.

2002-01-01

Double stall causes more than one power level when stall-regulated wind turbines operate in stall. This involves significant uncertainty on power production and loads. To avoid double stall, a new leading edge was designed for the NACA 632-415 airfoil, an airfoil that is often used in the tip...... region of wind turbines. A numerical optimization tool incorporating XFOIL was used with a special formulation for the airfoil leading edge shape. The EllipSys2D CFD code was used to analyze the modified airfoil. In theory and in wind tunnel tests, the modified airfoil showed smooth and stable stall...... stall and aerodynamic damping characteristics for the modified airfoil and the NACA 632-415 airfoil were the same. The modified airfoil with leading edge roughness in general had better characteristics compared with the NACA 632-415 airfoil. ©2002 ASME...

Ablative overlays for Space Shuttle leading edge ascent heat protection

Science.gov (United States)

Strauss, E. L.

1975-01-01

Ablative overlays were evaluated via a plasma-arc simulation of the ascent pulse on the leading edge of the Space Shuttle Orbiter. Overlay concepts included corkboard, polyisocyanurate foam, low-density Teflon, epoxy, and subliming salts. Their densities ranged from 4.9 to 81 lb per cu ft, and the thicknesses varied from 0.107 to 0.330 in. Swept-leading-edge models were fabricated from 30-lb per cu ft silicone-based ablators. The overlays were bonded to maintain the surface temperature of the base ablator below 500 F during ascent. Foams provided minimum-weight overlays, and subliming salts provided minimum-thickness overlays. Teflon left the most uniform surface after ascent heating.

Twin lead ballistic conductor based on nanoribbon edge transport

Science.gov (United States)

Konôpka, Martin; Dieška, Peter

2018-03-01

If a device like a graphene nanoribbon (GNR) has all its four corners attached to electric current leads, the device becomes a quantum junction through which two electrical circuits can interact. We study such system theoretically for stationary currents. The 4-point energy-dependent conductance matrix of the nanostructure and the classical resistors in the circuits are parameters of the model. The two bias voltages in the circuits are the control variables of the studied system while the electrochemical potentials at the device's terminals are non-trivially dependent on the voltages. For the special case of the linear-response regime analytical formulae for the operation of the coupled quantum-classical device are derived and applied. For higher bias voltages numerical solutions are obtained. The effects of non-equilibrium Fermi levels are captured using a recursive algorithm in which self-consistency between the electrochemical potentials and the currents is reached within few iterations. The developed approach allows to study scenarios ranging from independent circuits to strongly coupled ones. For the chosen model of the GNR with highly conductive zigzag edges we determine the regime in which the single device carries two almost independent currents.

Interplay between phosphoinositide lipids and calcium signals at the leading edge of chemotaxing ameboid cells☆

Science.gov (United States)

Falke, Joseph J.; Ziemba, Brian P.

2014-01-01

The chemotactic migration of eukaryotic ameboid cells up concentration gradients is among the most advanced forms of cellular behavior. Chemotaxis is controlled by a complex network of signaling proteins bound to specific lipids on the cytoplasmic surface of the plasma membrane at the front of the cell, or the leading edge. The central lipid players in this leading edge signaling pathway include the phosphoinositides PI(4,5)P2 (PIP2) and PI(3,4,5)P3 (PIP3), both of which play multiple roles. The products of PI(4,5)P2 hydrolysis, diacylglycerol (DAG) and Ins(1,4,5)P3 (IP3), are also implicated as important players. Together, these leading edge phosphoinositides and their degradation products, in concert with a local Ca2+ signal, control the recruitment and activities of many peripheral membrane proteins that are crucial to the leading edge signaling network. The present critical review summarizes the current molecular understanding of chemotactic signaling at the leading edge, including newly discovered roles of phosphoinositide lipids and Ca2+, while highlighting key questions for future research. PMID:24451847

Moderate variations in CDC25B protein levels modulate the response to DNA damaging agents

International Nuclear Information System (INIS)

Aressy, B.; Bugler, B.; Valette, A.; Ducommun, B.; Biard, D.

2008-01-01

CDC25B, one of the three members of the CDC25 dual-specificity phosphatase family, plays a critical role in the control of the cell cycle and in the checkpoint response to DNA damage. CDC25B is responsible for the initial dephosphorylation and activation of the cyclin-dependent kinases, thus initiating the train of events leading to entry into mitosis. The critical role played by CDC25B is illustrated by the fact that it is specifically required for checkpoint recovery and that unscheduled accumulation of CDC25B is responsible for illegitimate entry into mitosis. Here, we report that in p53 colon carcinoma cells, a moderate increase in the CDC25B level is sufficient to impair the DNA damage checkpoint, to increase spontaneous mutagenesis, and to sensitize cells to ionising radiation and genotoxic agents. Using a tumour cell spheroid assay as an alternative to animal studies, we demonstrate that the level of CDC25B expression modulates growth inhibition and apoptotic death. Since CDC25B overexpression has been observed in a significant number of human cancers, including colon carcinoma, and is often associated with high grade tumours and poor prognosis, our work suggests that the expression level of CDC25B might be a potential key parameter of the cellular response to cancer therapy. (authors)

Effects of Leading Edge Defect on the Aerodynamic and Flow Characteristics of an S809 Airfoil.

Science.gov (United States)

Wang, Yan; Zheng, Xiaojing; Hu, Ruifeng; Wang, Ping

Unexpected performance degradation occurs in wind turbine blades due to leading edge defect when suffering from continuous impacts with rain drops, hails, insects, or solid particles during its operation life. To assess this issue, this paper numerically investigates the steady and dynamic stall characteristics of an S809 airfoil with various leading edge defects. More leading edge defect sizes and much closer to practical parameters are investigated in the paper. Numerical computation is conducted using the SST k-ω turbulence model, and the method has been validated by comparison with existed published data. In order to ensure the calculation convergence, the residuals for the continuity equation are set to be less than 10-7 and 10-6 in steady state and dynamic stall cases. The simulations are conducted with the software ANSYS Fluent 13.0. It is found that the characteristics of aerodynamic coefficients and flow fields are sensitive to leading edge defect both in steady and dynamic conditions. For airfoils with the defect thickness of 6%tc, leading edge defect has a relative small influence on the aerodynamics of S809 airfoil. For other investigated defect thicknesses, leading edge defect has much greater influence on the flow field structures, pressure coefficients and aerodynamic characteristics of airfoil at relative small defect lengths. For example, the lift coefficients decrease and drag coefficients increase sharply after the appearance of leading edge defect. However, the aerodynamic characteristics could reach a constant value when the defect length is large enough. The flow field, pressure coefficient distribution and aerodynamic coefficients do not change a lot when the defect lengths reach to 0.5%c,1%c, 2%c and 3%c with defect thicknesses of 6%tc, 12%tc,18%tc and 25%tc, respectively. In addition, the results also show that the critical defect length/thickness ratio is 0.5, beyond which the aerodynamic characteristics nearly remain unchanged. In

Ubiquitination of Cdc20 by the APC occurs through an intramolecular mechanism

Science.gov (United States)

Foe, Ian T.; Foster, Scott A.; Cheung, Stephanie K.; DeLuca, Steven Z.; Morgan, David O.; Toczyski, David P.

2012-01-01

SUMMARY Background Cells control progression through late mitosis by regulating Cdc20 and Cdh1, the two mitotic activators of the Anaphase Promoting Complex (APC). The control of Cdc20 protein levels during the cell cycle is not well understood. Results Here, we demonstrate that Cdc20 is degraded in budding yeast by multiple APC-dependent mechanisms. We find that the majority of Cdc20 turnover does not involve a second activator molecule, but instead depends on in cis Cdc20 autoubiquitination while it is bound to its activator-binding site on the APC core. Unlike in trans ubiquitination of Cdc20 substrates, the APC ubiquitinates Cdc20 independent of APC activation by Cdc20’s C-box. Cdc20 turnover by this intramolecular mechanism is cell cycle-regulated, contributing to the decline in Cdc20 levels that occurs after anaphase. Interestingly, high substrate levels in vitro significantly reduce Cdc20 autoubiquitination. Conclusion We show here that Cdc20 fluctuates through the cell cycle via a distinct form of APC-mediated ubiquitination. This in cis autoubiquitination may preferentially occur in early anaphase, following depletion of Cdc20 substrates. This suggests that distinct mechanisms are able to target Cdc20 for ubiquitination at different points during the cell cycle. PMID:22079111

Leading-Edge Flow Sensing for Aerodynamic Parameter Estimation

Science.gov (United States)

Saini, Aditya

The identification of inflow air data quantities such as airspeed, angle of attack, and local lift coefficient on various sections of a wing or rotor blade provides the capability for load monitoring, aerodynamic diagnostics, and control on devices ranging from air vehicles to wind turbines. Real-time measurement of aerodynamic parameters during flight provides the ability to enhance aircraft operating capabilities while preventing dangerous stall situations. This thesis presents a novel Leading-Edge Flow Sensing (LEFS) algorithm for the determination of the air -data parameters using discrete surface pressures measured at a few ports in the vicinity of the leading edge of a wing or blade section. The approach approximates the leading-edge region of the airfoil as a parabola and uses pressure distribution from the exact potential-ow solution for the parabola to _t the pressures measured from the ports. Pressures sensed at five discrete locations near the leading edge of an airfoil are given as input to the algorithm to solve the model using a simple nonlinear regression. The algorithm directly computes the inflow velocity, the stagnation-point location, section angle of attack and lift coefficient. The performance of the algorithm is assessed using computational and experimental data in the literature for airfoils under different ow conditions. The results show good correlation between the actual and predicted aerodynamic quantities within the pre-stall regime, even for a rotating blade section. Sensing the deviation of the aerodynamic behavior from the linear regime requires additional information on the location of ow separation on the airfoil surface. Bio-inspired artificial hair sensors were explored as a part of the current research for stall detection. The response of such artificial micro-structures can identify critical ow characteristics, which relate directly to the stall behavior. The response of the microfences was recorded via an optical microscope for

Interplay between phosphoinositide lipids and calcium signals at the leading edge of chemotaxing ameboid cells.

Science.gov (United States)

Falke, Joseph J; Ziemba, Brian P

2014-09-01

The chemotactic migration of eukaryotic ameboid cells up concentration gradients is among the most advanced forms of cellular behavior. Chemotaxis is controlled by a complex network of signaling proteins bound to specific lipids on the cytoplasmic surface of the plasma membrane at the front of the cell, or the leading edge. The central lipid players in this leading edge signaling pathway include the phosphoinositides PI(4,5)P2 (PIP2) and PI(3,4,5)P3 (PIP3), both of which play multiple roles. The products of PI(4,5)P2 hydrolysis, diacylglycerol (DAG) and Ins(1,4,5)P3 (IP3), are also implicated as important players. Together, these leading edge phosphoinositides and their degradation products, in concert with a local Ca(2+) signal, control the recruitment and activities of many peripheral membrane proteins that are crucial to the leading edge signaling network. The present critical review summarizes the current molecular understanding of chemotactic signaling at the leading edge, including newly discovered roles of phosphoinositide lipids and Ca(2+), while highlighting key questions for future research. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Leading-Edge Velocities and Lifted Methane Jet Flame Stability

Directory of Open Access Journals (Sweden)

W. Wang

2010-01-01

Full Text Available Current interest exists in understanding reaction-zone dynamics and mechanisms with respect to how they counterpropagate against incoming reactants. Images of flame position and flow-field morphology are presented from flame chemiluminescence and particle image velocimetry (PIV measurements. In the present study, PIV experiments were carried out to measure the methane jet lifted-flame flow-field velocities in the vicinity of the flame leading edge. Specifically, velocity fields within the high-temperature zone were examined in detail, which complements previous studies, whose prime focus is the flow-field upstream of the high-temperature boundary. PIV data is used not only to determine the velocities, but, along with chemiluminescence images, to also indicate the approximate location of the reaction zone (further supported by/through the leading-edge flame velocity distributions. The velocity results indirectly support the concept that the flame is anchored primarily through the mechanism of partially premixed flame propagation.

Potential environmental effects of the leading edge hydrokinetic energy technology.

Science.gov (United States)

2017-05-01

The Volpe Center evaluated potential environmental challenges and benefits of the ARPA-E funded research project, Marine Hydrokinetic Energy Harvesting Using Cyber-Physical Systems, led by Brown University. The Leading Edge research team develo...

Control of leading edge vortex breakdown by blowing

Science.gov (United States)

Visser, K. D.; Iwanski, K. P.; Nelson, R. C.; Ng, T. T.

1988-01-01

An investigation into the effects of using a jet of air to control the vortex breakdown position on a 70 degree delta wing is presented. The specific objectives focused on optimizing the blowing positions in terms of maximum lift increments obtained for minimum blowing rates. The tests were conducted at chord Reynolds numbers of 150,000, 200,000, and 250,000 at angles of incidence of 30 and 35 degrees. Visualization and force data is presented to show the effect of the jet on the wing aerodynamic characteristics. The results indicate a jet position located at and aligned parallel to the leading edge to be the optimum. Nearness to the apex and tangency to the upper surface were also crucial factors. The influence of the jet on the leading edge vortex structure was examined using laser Doppler anemometry. Velocity surveys through the vortex showed that at high blowing rates the parallel velocity in the outer swirling region of the vortex increased and the normal velocity decreased. This resulted in a decrease in the swirling angle in the outer region. The peak core velocity was reduced and the vortex breakdown was delayed.

Stage-specific control of neural crest stem cell proliferation by the small rho GTPases Cdc42 and Rac1

DEFF Research Database (Denmark)

Fuchs, Sebastian; Herzog, Dominik; Sumara, Grzegorz

2009-01-01

-renewal and proliferation of later stage, but not early migratory NCSCs. This stage-specific requirement for small Rho GTPases is due to changes in NCSCs that, during development, acquire responsiveness to mitogenic EGF acting upstream of both Cdc42 and Rac1. Thus, our data reveal distinct mechanisms for growth control......The neural crest (NC) generates a variety of neural and non-neural tissues during vertebrate development. Both migratory NC cells and their target structures contain cells with stem cell features. Here we show that these populations of neural crest-derived stem cells (NCSCs) are differentially...

Probabilistic Structural Health Monitoring of the Orbiter Wing Leading Edge

Science.gov (United States)

Yap, Keng C.; Macias, Jesus; Kaouk, Mohamed; Gafka, Tammy L.; Kerr, Justin H.

2011-01-01

A structural health monitoring (SHM) system can contribute to the risk management of a structure operating under hazardous conditions. An example is the Wing Leading Edge Impact Detection System (WLEIDS) that monitors the debris hazards to the Space Shuttle Orbiter s Reinforced Carbon-Carbon (RCC) panels. Since Return-to-Flight (RTF) after the Columbia accident, WLEIDS was developed and subsequently deployed on board the Orbiter to detect ascent and on-orbit debris impacts, so as to support the assessment of wing leading edge structural integrity prior to Orbiter re-entry. As SHM is inherently an inverse problem, the analyses involved, including those performed for WLEIDS, tend to be associated with significant uncertainty. The use of probabilistic approaches to handle the uncertainty has resulted in the successful implementation of many development and application milestones.

The non-receptor tyrosine kinase Lyn controls neutrophil adhesion by recruiting the CrkL–C3G complex and activating Rap1 at the leading edge

Science.gov (United States)

He, Yuan; Kapoor, Ashish; Cook, Sara; Liu, Shubai; Xiang, Yang; Rao, Christopher V.; Kenis, Paul J. A.; Wang, Fei

2011-01-01

Establishing new adhesions at the extended leading edges of motile cells is essential for stable polarity and persistent motility. Despite recent identification of signaling pathways that mediate polarity and chemotaxis in neutrophils, little is known about molecular mechanisms governing cell–extracellular-matrix (ECM) adhesion in these highly polarized and rapidly migrating cells. Here, we describe a signaling pathway in neutrophils that is essential for localized integrin activation, leading edge attachment and persistent migration during chemotaxis. This pathway depends upon Gi-protein-mediated activation and leading edge recruitment of Lyn, a non-receptor tyrosine kinase belonging to the Src kinase family. We identified the small GTPase Rap1 as a major downstream effector of Lyn to regulate neutrophil adhesion during chemotaxis. Depletion of Lyn in neutrophil-like HL-60 cells prevented chemoattractant-induced Rap1 activation at the leading edge of the cell, whereas ectopic expression of Rap1 largely rescued the defects induced by Lyn depletion. Furthermore, Lyn controls spatial activation of Rap1 by recruiting the CrkL–C3G protein complex to the leading edge. Together, these results provide novel mechanistic insights into the poorly understood signaling network that controls leading edge adhesion during chemotaxis of neutrophils, and possibly other amoeboid cells. PMID:21628423

Effects of Leading Edge Defect on the Aerodynamic and Flow Characteristics of an S809 Airfoil.

Directory of Open Access Journals (Sweden)

Yan Wang

Full Text Available Unexpected performance degradation occurs in wind turbine blades due to leading edge defect when suffering from continuous impacts with rain drops, hails, insects, or solid particles during its operation life. To assess this issue, this paper numerically investigates the steady and dynamic stall characteristics of an S809 airfoil with various leading edge defects. More leading edge defect sizes and much closer to practical parameters are investigated in the paper.Numerical computation is conducted using the SST k-ω turbulence model, and the method has been validated by comparison with existed published data. In order to ensure the calculation convergence, the residuals for the continuity equation are set to be less than 10-7 and 10-6 in steady state and dynamic stall cases. The simulations are conducted with the software ANSYS Fluent 13.0.It is found that the characteristics of aerodynamic coefficients and flow fields are sensitive to leading edge defect both in steady and dynamic conditions. For airfoils with the defect thickness of 6%tc, leading edge defect has a relative small influence on the aerodynamics of S809 airfoil. For other investigated defect thicknesses, leading edge defect has much greater influence on the flow field structures, pressure coefficients and aerodynamic characteristics of airfoil at relative small defect lengths. For example, the lift coefficients decrease and drag coefficients increase sharply after the appearance of leading edge defect. However, the aerodynamic characteristics could reach a constant value when the defect length is large enough. The flow field, pressure coefficient distribution and aerodynamic coefficients do not change a lot when the defect lengths reach to 0.5%c,1%c, 2%c and 3%c with defect thicknesses of 6%tc, 12%tc,18%tc and 25%tc, respectively. In addition, the results also show that the critical defect length/thickness ratio is 0.5, beyond which the aerodynamic characteristics nearly remain

Design & fabrication of two seated aircraft with an advanced rotating leading edge wing

Science.gov (United States)

Al Ahmari, Saeed Abdullah Saeed

The title of this thesis is "Design & Fabrication of two Seated Aircraft with an Advanced Rotating Leading Edge Wing", this gives almost a good description of the work has been done. In this research, the moving surface boundary-layer control (MSBC) concept was investigated and implemented. An experimental model was constructed and tested in wind tunnel to determine the aerodynamic characteristics using the leading edge moving surface of modified semi-symmetric airfoil NACA1214. The moving surface is provided by a high speed rotating cylinder, which replaces the leading edge of the airfoil. The angle of attack, the cylinder surfaces velocity ratio Uc/U, and the flap deflection angle effects on the lift and drag coefficients and the stall angle of attack were investigated. This new technology was applied to a 2-seat light-sport aircraft that is designed and built in the Aerospace Engineering Department at KFUPM. The project team is led by the aerospace department chairman Dr. Ahmed Z. AL-Garni and Dr. Wael G. Abdelrahman and includes graduate and under graduate student. The wing was modified to include a rotating cylinder along the leading edge of the flap portion. This produced very promising results such as the increase of the maximum lift coefficient at Uc/U=3 by 82% when flaps up and 111% when flaps down at 40° and stall was delayed by 8degrees in both cases. The laboratory results also showed that the effective range of the leading-edge rotating cylinder is at low angles of attack which reduce the need for higher angles of attack for STOL aircraft.

Effect of guide wall on jet impingement cooling in blade leading edge channel

International Nuclear Information System (INIS)

Zhao, Qing-Yang; Chung, Heeyoon; Choi, Seok Min; Cho, Hyung Hee

2016-01-01

The characteristics of fluid flow and heat transfer, which are affected by the guide wall in a jet impinged leading edge channel, have been investigated numerically using three-dimensional Reynolds-averaged Navier-Stokes analysis via the shear stress transport turbulence model and gamma theta transitional turbulence model. A constant wall heat flux condition has been applied to the leading edge surface. The jet-to-surface distance is constant, which is three times that of the jet diameter. The arrangement of the guide wall near the jet hole is set as a variable. Results presented in this study include the Nusselt number contour, velocity vector, streamline with velocity, and local Nusselt number distribution along the central line on the leading edge surface. The average Nusselt number and average pressure loss between jet nozzle and channel exit are calculated to assess the thermal performance. The application of the guide wall is aimed at improving heat transfer uniformity on the leading edge surface. Results indicated that the streamwise guide wall ensures the vertical jet impingement flow intensity and prevents the flow after impingement to reflux into jet flow. Thus, a combined rectangular guide wall benefits the average heat transfer, thermal performance and heat transfer distribution uniformity

Periodic and aperiodic flow patterns around an airfoil with leading-edge protuberances

Science.gov (United States)

Cai, Chang; Zuo, Zhigang; Maeda, Takao; Kamada, Yasunari; Li, Qing'an; Shimamoto, Kensei; Liu, Shuhong

2017-11-01

Recently leading-edge protuberances have attracted great attention as a passive method for separation control. In this paper, the effect of multiple leading-edge protuberances on the performance of a two-dimensional airfoil is investigated through experimental measurement of aerodynamic forces, surface tuft visualization, and numerical simulation. In contrast to the sharp stall of the baseline airfoil with large hysteresis effect during AOA (angle of attack) increasing and decreasing, the stall process of the modified airfoil with leading-edge protuberances is gentle and stable. Flow visualization revealed that the flow past each protuberance is periodic and symmetric at small AOAs. Streamwise vortices are generated on the shoulders of the protuberance, leading to a larger separation around the valley sections and a longer attachment along the peak sections. When some critical AOA is exceeded, aperiodic and asymmetric flow patterns occur on the protuberances at different spanwise positions, with leading-edge separation on some of the valley sections and non-stalled condition elsewhere. A combined mechanism, involving both the compartmentalization effect of the slender momentum-enhanced attached flows on the protuberance peaks and the downwash effect of the local stalled region with low circulation, is proposed to explain the generation of the aperiodic flow patterns. The influence of the number of protuberances is also investigated, which shows similar aperiodic flow patterns. The distance between the neighboring local stalled valley sections is found to be in the range of 4-7 times the protuberance wavelength. According to the proposed mechanism, it is speculated that the distance between the neighboring local stalled valley sections is inclined to increase with a smaller protuberance amplitude or at a larger AOA.

SiC/SiC Leading Edge Turbine Airfoil Tested Under Simulated Gas Turbine Conditions

Science.gov (United States)

Robinson, R. Craig; Hatton, Kenneth S.

1999-01-01

Silicon-based ceramics have been proposed as component materials for use in gas turbine engine hot-sections. A high pressure burner rig was used to expose both a baseline metal airfoil and ceramic matrix composite leading edge airfoil to typical gas turbine conditions to comparatively evaluate the material response at high temperatures. To eliminate many of the concerns related to an entirely ceramic, rotating airfoil, this study has focused on equipping a stationary metal airfoil with a ceramic leading edge insert to demonstrate the feasibility and benefits of such a configuration. Here, the idea was to allow the SiC/SiC composite to be integrated as the airfoil's leading edge, operating in a "free-floating" or unrestrained manner. and provide temperature relief to the metal blade underneath. The test included cycling the airfoils between simulated idle, lift, and cruise flight conditions. In addition, the airfoils were air-cooled, uniquely instrumented, and exposed to the same internal and external conditions, which included gas temperatures in excess of 1370 C (2500 F). Results show the leading edge insert remained structurally intact after 200 simulated flight cycles with only a slightly oxidized surface. The instrumentation clearly suggested a significant reduction (approximately 600 F) in internal metal temperatures as a result of the ceramic leading edge. The object of this testing was to validate the design and analysis done by Materials Research and Design of Rosemont, PA and to determine the feasibility of this design for the intended application.

Cooling Strategies for Vane Leading Edges in a Syngas Environment Including Effects of Deposition and Turbulence

Energy Technology Data Exchange (ETDEWEB)

Ames, Forrest [Univ. of North Dakota, Grand Forks, ND (United States); Bons, Jeffrey [Univ. of North Dakota, Grand Forks, ND (United States)

2014-09-30

The Department of Energy has goals to move land based gas turbine systems to alternate fuels including coal derived synthetic gas and hydrogen. Coal is the most abundant energy resource in the US and in the world and it is economically advantageous to develop power systems which can use coal. Integrated gasification combined cycles are (IGCC) expected to allow the clean use of coal derived fuels while improving the ability to capture and sequester carbon dioxide. These cycles will need to maintain or increase turbine entry temperatures to develop competitive efficiencies. The use of coal derived syngas introduces a range of potential contaminants into the hot section of the gas turbine including sulfur, iron, calcium, and various alkali metals. Depending on the effectiveness of the gas clean up processes, there exists significant likelihood that the remaining materials will become molten in the combustion process and potentially deposit on downstream turbine surfaces. Past evidence suggests that deposition will be a strong function of increasing temperature. Currently, even with the best gas cleanup processes a small level of particulate matter in the syngas is expected. Consequently, particulate deposition is expected to be an important consideration in the design of turbine components. The leading edge region of first stage vanes most often have higher deposition rates than other areas due to strong fluid acceleration and streamline curvature in the vicinity of the surface. This region remains one of the most difficult areas in a turbine nozzle to cool due to high inlet temperatures and only a small pressure ratio for cooling. The leading edge of a vane often has relatively high heat transfer coefficients and is often cooled using showerhead film cooling arrays. The throat of the first stage nozzle is another area where deposition potentially has a strongly adverse effect on turbine performance as this region meters the turbine inlet flow. Based on roughness

Analytical model and stability analysis of the leading edge spar of a passively morphing ornithopter wing.

Science.gov (United States)

Wissa, Aimy; Calogero, Joseph; Wereley, Norman; Hubbard, James E; Frecker, Mary

2015-10-26

This paper presents the stability analysis of the leading edge spar of a flapping wing unmanned air vehicle with a compliant spine inserted in it. The compliant spine is a mechanism that was designed to be flexible during the upstroke and stiff during the downstroke. Inserting a variable stiffness mechanism into the leading edge spar affects its structural stability. The model for the spar-spine system was formulated in terms of the well-known Mathieu's equation, in which the compliant spine was modeled as a torsional spring with a sinusoidal stiffness function. Experimental data was used to validate the model and results show agreement within 11%. The structural stability of the leading edge spar-spine system was determined analytically and graphically using a phase plane plot and Strutt diagrams. Lastly, a torsional viscous damper was added to the leading edge spar-spine model to investigate the effect of damping on stability. Results show that for the un-damped case, the leading edge spar-spine response was stable and bounded; however, there were areas of instability that appear for a range of spine upstroke and downstroke stiffnesses. Results also show that there exist a damping ratio between 0.2 and 0.5, for which the leading edge spar-spine system was stable for all values of spine upstroke and downstroke stiffnesses.

Vasoactive intestinal peptide-induced neurite remodeling in human neuroblastoma SH-SY5Y cells implicates the Cdc42 GTPase and is independent of Ras-ERK pathway

International Nuclear Information System (INIS)

Alleaume, Celine; Eychene, Alain; Harnois, Thomas; Bourmeyster, Nicolas; Constantin, Bruno; Caigneaux, Evelyne; Muller, Jean-Marc; Philippe, Michel

2004-01-01

Vasoactive intestinal peptide (VIP) is known to regulate proliferation or differentiation in normal and tumoral cells. SH-SY5Y is a differentiated cell subclone derived from the SK-N-SH human neuroblastoma cell line and possess all the components for an autocrine action of VIP. In the present study, we investigated the morphological changes and intracellular signaling pathways occurring upon VIP treatment of SH-SY5Y cells. VIP induced an early remodeling of cell projections: a branched neurite network spread out and prominent varicosities developed along neurites. Although activated by VIP, the Ras/ERK pathway was not required for the remodeling process. In contrast, pull-down experiments revealed a strong Cdc42 activation by VIP while expression of a dominant-negative Cdc42 prevented the VIP-induced neurite changes, suggesting an important role for this small GTPase in the process. These data provide the first evidence for a regulation of the activity of Rho family GTPases by VIP and bring new insights in the signaling pathways implicated in neurite remodeling process induced by VIP in neuroblastoma cells

Shuttle Wing Leading Edge Root Cause NDE Team Findings and Implementation of Quantitative Flash Infrared Thermography

Science.gov (United States)

Burke, Eric R.

2009-01-01

Comparison metrics can be established to reliably and repeatedly establish the health of the joggle region of the Orbiter Wing Leading Edge reinforced carbon carbon (RCC) panels. Using these metrics can greatly reduced the man hours needed to perform, wing leading edge scanning for service induced damage. These time savings have allowed for more thorough inspections to be preformed in the necessary areas with out affecting orbiter flow schedule. Using specialized local inspections allows for a larger margin of safety by allowing for more complete characterizations of panel defects. The presence of the t-seal during thermographic inspection can have adverse masking affects on ability properly characterize defects that exist in the joggle region of the RCC panels. This masking affect dictates the final specialized inspection should be preformed with the t-seal removed. Removal of the t-seal and use of the higher magnification optics has lead to the most effective and repeatable inspection method for characterizing and tracking defects in the wing leading edge. Through this study some inadequacies in the main health monitoring system for the orbiter wing leading edge have been identified and corrected. The use of metrics and local specialized inspection have lead to a greatly increased reliability and repeatable inspection of the shuttle wing leading edge.

Cervical Length & Leading Placental Edge to Internal OS Measurements - TA vs TV

DEFF Research Database (Denmark)

Westerway, Sue Campbell; Pedersen, Lars Henning; Hyett, Jon

Brief Description of the Purpose of the Study: To compare cervical length/leading placental edge from the internal cervical os measurements obtained by both transabdominal (TA) and transvaginal (TV) approach and to assess intra / inter-observer variation for these measurements. Methods: Cross...... sectional study of 374 consecutive pregnancies with gestation 12 weeks to term. The cervical length was estimated as the distance from internal to external os, and the placenta / cervix distance as the leading placental edge to internal cervical os. Bland-Altman plots were used to evaluate the two methods....... Importance of the Conclusions: TA estimates of cervix and placental edge position did not reflect the estimates obtained by TV assessment. As both measures are important markers of pregnancy outcome and management, the transabdominal method in the present form is insuffi- cient in clinical management....

Development flight tests of JetStar LFC leading-edge flight test experiment

Science.gov (United States)

Fisher, David F.; Fischer, Michael C.

1987-01-01

The overall objective of the flight tests on the JetStar aircraft was to demonstrate the effectiveness and reliability of laminar flow control under representative flight conditions. One specific objective was to obtain laminar flow on the JetStar leading-edge test articles for the design and off-design conditions. Another specific objective was to obtain operational experience on a Laminar Flow Control (LFC) leading-edge system in a simulated airline service. This included operational experience with cleaning requirements, the effect of clogging, possible foreign object damage, erosion, and the effects of ice particle and cloud encounters. Results are summarized.

50 CFR 300.42 - Findings leading to removal from fishing area.

Science.gov (United States)

2010-10-01

... 50 Wildlife and Fisheries 7 2010-10-01 2010-10-01 false Findings leading to removal from fishing area. 300.42 Section 300.42 Wildlife and Fisheries INTERNATIONAL FISHING AND RELATED ACTIVITIES INTERNATIONAL FISHERIES REGULATIONS South Pacific Tuna Fisheries § 300.42 Findings leading to removal from...

Owl-inspired leading-edge serrations play a crucial role in aerodynamic force production and sound suppression.

Science.gov (United States)

Rao, Chen; Ikeda, Teruaki; Nakata, Toshiyuki; Liu, Hao

2017-07-04

Owls are widely known for silent flight, achieving remarkably low noise gliding and flapping flights owing to their unique wing morphologies, which are normally characterized by leading-edge serrations, trailing-edge fringes and velvet-like surfaces. How these morphological features affect aerodynamic force production and sound suppression or noise reduction, however, is still not well known. Here we address an integrated study of owl-inspired single feather wing models with and without leading-edge serrations by combining large-eddy simulations (LES) with particle-image velocimetry (PIV) and force measurements in a low-speed wind tunnel. With velocity and pressure spectra analysis, we demonstrate that leading-edge serrations can passively control the laminar-turbulent transition over the upper wing surface, i.e. the suction surface at all angles of attack (0°    15° where owl wings often reach in flight. Our results indicate that the owl-inspired leading-edge serrations may be a useful device for aero-acoustic control in biomimetic rotor designs for wind turbines, aircrafts, multi-rotor drones as well as other fluid machinery.

Simulated big sagebrush regeneration supports predicted changes at the trailing and leading edges of distribution shifts

Science.gov (United States)

Schlaepfer, Daniel R.; Taylor, Kyle A.; Pennington, Victoria E.; Nelson, Kellen N.; Martin, Trace E.; Rottler, Caitlin M.; Lauenroth, William K.; Bradford, John B.

2015-01-01

Many semi-arid plant communities in western North America are dominated by big sagebrush. These ecosystems are being reduced in extent and quality due to economic development, invasive species, and climate change. These pervasive modifications have generated concern about the long-term viability of sagebrush habitat and sagebrush-obligate wildlife species (notably greater sage-grouse), highlighting the need for better understanding of the future big sagebrush distribution, particularly at the species' range margins. These leading and trailing edges of potential climate-driven sagebrush distribution shifts are likely to be areas most sensitive to climate change. We used a process-based regeneration model for big sagebrush, which simulates potential germination and seedling survival in response to climatic and edaphic conditions and tested expectations about current and future regeneration responses at trailing and leading edges that were previously identified using traditional species distribution models. Our results confirmed expectations of increased probability of regeneration at the leading edge and decreased probability of regeneration at the trailing edge below current levels. Our simulations indicated that soil water dynamics at the leading edge became more similar to the typical seasonal ecohydrological conditions observed within the current range of big sagebrush ecosystems. At the trailing edge, an increased winter and spring dryness represented a departure from conditions typically supportive of big sagebrush. Our results highlighted that minimum and maximum daily temperatures as well as soil water recharge and summer dry periods are important constraints for big sagebrush regeneration. Overall, our results confirmed previous predictions, i.e., we see consistent changes in areas identified as trailing and leading edges; however, we also identified potential local refugia within the trailing edge, mostly at sites at higher elevation. Decreasing

Flexible Plug Repair for Shuttle Wing Leading Edge

Science.gov (United States)

Camarda, Charles J.; Sikora, Joseph; Smith, Russel; Rivers, H.; Scotti, Stephen J.; Fuller, Alan M.; Klacka, Robert; Reinders, Martin; Schwind, Francis; Sullivan, Brian;

Rotational accelerations stabilize leading edge vortices on revolving fly wings

NARCIS (Netherlands)

Lentink, D.; Dickinson, M.H.

2009-01-01

The aerodynamic performance of hovering insects is largely explained by the presence of a stably attached leading edge vortex (LEV) on top of their wings. Although LEVs have been visualized on real, physically modeled, and simulated insects, the physical mechanisms responsible for their stability

Ufd1-Npl4 Recruit Cdc48 for Disassembly of Ubiquitylated CMG Helicase at the End of Chromosome Replication

Directory of Open Access Journals (Sweden)

Marija Maric

2017-03-01

Full Text Available Disassembly of the Cdc45-MCM-GINS (CMG DNA helicase is the key regulated step during DNA replication termination in eukaryotes, involving ubiquitylation of the Mcm7 helicase subunit, leading to a disassembly process that requires the Cdc48 “segregase”. Here, we employ a screen to identify partners of budding yeast Cdc48 that are important for disassembly of ubiquitylated CMG helicase at the end of chromosome replication. We demonstrate that the ubiquitin-binding Ufd1-Npl4 complex recruits Cdc48 to ubiquitylated CMG. Ubiquitylation of CMG in yeast cell extracts is dependent upon lysine 29 of Mcm7, which is the only detectable site of ubiquitylation both in vitro and in vivo (though in vivo other sites can be modified when K29 is mutated. Mutation of K29 abrogates in vitro recruitment of Ufd1-Npl4-Cdc48 to the CMG helicase, supporting a model whereby Ufd1-Npl4 recruits Cdc48 to ubiquitylated CMG at the end of chromosome replication, thereby driving the disassembly reaction.

Study on measurement of leading and trailing edges of blades based on optical scanning system

Science.gov (United States)

Chao, Bi; Liu, Hongguang; Bao, Longxiang; Li, Di

2017-10-01

In the field of aeronautics, the geometry and dimensional accuracy of the blade edges has a large influence on the aerodynamic performance of aero engine. Therefore, a non-contact optical scanning system is established to realize the measurement of leading and trailing edges of blades in a rapid, precise and efficient manner in the paper. Based on the mechanical framework of a traditional CMM, the system is equipped with a specified sensing device as the scanning probe, which is made up by two new-style laser scanning sensors installed at a certain angle to each other by a holder. In the measuring procedure, the geometric dimensions of the measured blade edges on every contour plane are determined by the contour information on five transversals at the leading or trailing edges, which can be used to determine the machining allowance of the blades. In order to verify the effectiveness and practicality of the system set up, a precision forging blade after grinded is adopted as the measured object and its leading and trailing edges are measured by the system respectively. In the experiment, the thickness of blade edges on three contour planes is measured by the optical scanning system several times. As the experiment results show, the repeatability accuracy of the system can meet its design requirements and the inspecting demands of the blade edges. As a result, the optical scanning system could serve as a component of the intelligent manufacturing system of blades to improve the machining quality of the blade edges.

An analytically-based method for predicting the noise generated by the interaction between turbulence and a serrated leading edge

Science.gov (United States)

Mathews, J. R.; Peake, N.

2018-05-01

This paper considers the interaction of turbulence with a serrated leading edge. We investigate the noise produced by an aerofoil moving through a turbulent perturbation to uniform flow by considering the scattered pressure from the leading edge. We model the aerofoil as an infinite half plane with a leading edge serration, and develop an analytical model using a Green's function based upon the work of Howe. This allows us to consider both deterministic eddies and synthetic turbulence interacting with the leading edge. We show that it is possible to reduce the noise by using a serrated leading edge compared with a straight edge, but the optimal noise-reducing choice of serration is hard to predict due to the complex interaction. We also consider the effect of angle of attack, and find that in general the serrations are less effective at higher angles of attack.

Social networks: Evolving graphs with memory dependent edges

Science.gov (United States)

Grindrod, Peter; Parsons, Mark

2011-10-01

The plethora of digital communication technologies, and their mass take up, has resulted in a wealth of interest in social network data collection and analysis in recent years. Within many such networks the interactions are transient: thus those networks evolve over time. In this paper we introduce a class of models for such networks using evolving graphs with memory dependent edges, which may appear and disappear according to their recent history. We consider time discrete and time continuous variants of the model. We consider the long term asymptotic behaviour as a function of parameters controlling the memory dependence. In particular we show that such networks may continue evolving forever, or else may quench and become static (containing immortal and/or extinct edges). This depends on the existence or otherwise of certain infinite products and series involving age dependent model parameters. We show how to differentiate between the alternatives based on a finite set of observations. To test these ideas we show how model parameters may be calibrated based on limited samples of time dependent data, and we apply these concepts to three real networks: summary data on mobile phone use from a developing region; online social-business network data from China; and disaggregated mobile phone communications data from a reality mining experiment in the US. In each case we show that there is evidence for memory dependent dynamics, such as that embodied within the class of models proposed here.

Thermostructural applications of heat pipes for cooling leading edges of high-speed aerospace vehicles

Science.gov (United States)

Camarda, Charles J.; Glass, David E.

1992-01-01

Heat pipes have been considered for use on wing leading edge for over 20 years. Early concepts envisioned metal heat pipes cooling a metallic leading edge. Several superalloy/sodium heat pipes were fabricated and successfully tested for wing leading edge cooling. Results of radiant heat and aerothermal testing indicate the feasibility of using heat pipes to cool the stagnation region of shuttle-type space transportation systems. The test model withstood a total seven radiant heating tests, eight aerothermal tests, and twenty-seven supplemental radiant heating tests. Cold-wall heating rates ranged from 21 to 57 Btu/sq ft-s and maximum operating temperatures ranged from 1090 to 1520 F. Follow-on studies investigated the application of heat pipes to cool the stagnation regions of single-stage-to-orbit and advanced shuttle vehicles. Results of those studies indicate that a 'D-shaped' structural design can reduce the mass of the heat-pipe concept by over 44 percent compared to a circular heat-pipe geometry. Simple analytical models for heat-pipe startup from the frozen state (working fluid initially frozen) were adequate to approximate transient, startup, and steady-state heat-pipe performance. Improvement in analysis methods has resulted in the development of a finite-element analysis technique to predict heat-pipe startup from the frozen state. However, current requirements of light-weight design and reliability suggest that metallic heat pipes embedded in a refractory composite material should be used. This concept is the concept presently being evaluated for NASP. A refractory-composite/heat-pipe-cooled wing leading edge is currently being considered for the National Aero-Space Plane (NASP). This concept uses high-temperature refractory-metal/lithium heat pipes embedded within a refractory-composite structure and is significantly lighter than an actively cooled wing leading edge because it eliminates the need for active cooling during ascent and descent. Since the

Piezoelectric ceramic (PZT) modulates axonal guidance growth of rat cortical neurons via RhoA, Rac1, and Cdc42 pathways.

Science.gov (United States)

Wen, Jianqiang; Liu, Meili

2014-03-01

Electrical stimulation is critical for axonal connection, which can stimulate axonal migration and deformation to promote axonal growth in the nervous system. Netrin-1, an axonal guidance cue, can also promote axonal guidance growth, but the molecular mechanism of axonal guidance growth under indirect electric stimulation is still unknown. We investigated the molecular mechanism of axonal guidance growth under piezoelectric ceramic lead zirconate titanate (PZT) stimulation in the primary cultured cortical neurons. PZT induced marked axonal elongation. Moreover, PZT activated the excitatory postsynaptic currents (EPSCs) by increasing the frequency and amplitude of EPSCs of the cortical neurons in patch clamp assay. PZT downregulated the expression of Netrin-1 and its receptor Deleted in Colorectal Cancer (DCC). Rho GTPase signaling is involved in interactions of Netrin-1 and DCC. PZT activated RhoA. Dramatic decrease of Cdc42 and Rac1 was also observed after PZT treatment. RhoA inhibitor Clostridium botulinum C3 exoenzyme (C3-Exo) prevented the PZT-induced downregulation of Netrin-1 and DCC. We suggest that PZT can promote axonal guidance growth by downregulation of Netrin-1 and DCC to mediate axonal repulsive responses via the Rho GTPase signaling pathway. Obviously, piezoelectric materials may provide a new approach for axonal recovery and be beneficial for clinical therapy in the future.

Case Studies of Leading Edge Small Urban High Schools. Relevance Strategic Designs: 4. Boston Arts Academy

Science.gov (United States)

Shields, Regis Anne; Ireland, Nicole; City, Elizabeth; Derderian, Julie; Miles, Karen Hawley

2008-01-01

This report is one of nine detailed case studies of small urban high schools that served as the foundation for the Education Resource Strategies (ERS) report "Strategic Designs: Lessons from Leading Edge Small Urban High Schools." These nine schools were dubbed "Leading Edge Schools" because they stand apart from other high…

Case Studies of Leading Edge Small Urban High Schools. Relevance Strategic Designs: 6. Perspectives Charter School

Science.gov (United States)

Shields, Regis Anne; Ireland, Nicole; City, Elizabeth; Derderian, Julie; Miles, Karen Hawley

2008-01-01

This report is one of nine detailed case studies of small urban high schools that served as the foundation for the Education Resource Strategies (ERS) report "Strategic Designs: Lessons from Leading Edge Small Urban High Schools." These nine schools were dubbed "Leading Edge Schools" because they stand apart from other high…

Case Studies of Leading Edge Small Urban High Schools. Relevance Strategic Designs: 7. TechBoston Academy

Science.gov (United States)

Shields, Regis Anne; Ireland, Nicole; City, Elizabeth; Derderian, Julie; Miles, Karen Hawley

2008-01-01

This report is one of nine detailed case studies of small urban high schools that served as the foundation for the Education Resource Strategies (ERS) report "Strategic Designs: Lessons from Leading Edge Small Urban High Schools." These nine schools were dubbed "Leading Edge Schools" because they stand apart from other high…

Cdc7 kinase - a new target for drug development.

Science.gov (United States)

Swords, Ronan; Mahalingam, Devalingam; O'Dwyer, Michael; Santocanale, Corrado; Kelly, Kevin; Carew, Jennifer; Giles, Francis

2010-01-01

The cell division cycle 7 (Cdc7) is a serine threonine kinase that is of critical importance in the regulation of normal cell cycle progression. Cdc7 kinase is highly conserved during evolution and much has been learned about its biological roles in humans through the study of lower eukaryotes, particularly yeasts. Two important regulator proteins, Dbf4 and Drf1, bind to and modulate the kinase activity of human Cdc7 which phosphorylates several sites on Mcm2 (minichromosome maintenance protein 2), one of the six subunits of the replicative DNA helicase needed for duplication of the genome. Through regulation of both DNA synthesis and DNA damage response, both key functions in the survival of tumour cells, Cdc7 becomes an attractive target for pharmacological inhibition. There are much data available on the pre-clinical anti-cancer effects of Cdc7 depletion and although there are no available Cdc7 inhibitors in clinical trials as yet, several lead compounds are being optimised for this purpose. In this review, we will address the current status of Cdc7 as an important target for new drug development.

CDC Climat - 2011 Sustainable Development Report

International Nuclear Information System (INIS)

2012-08-01

CDC Climat is the Caisse des Depots (CDC) subsidiary that is dedicated to combating climate change. Its activities aim to support the transition towards a low resource and low greenhouse gas emission (GHG) economy, through services that are cutting-edge, pro table, and in line with CDC's public policy goals. Through its corporate purpose, CDC Climat embodies the CDC's commitments in the sustainable development field. CDC Climat supports the implementation of public GHG emission reduction policies, primarily through emission trading schemes at the European and international level. Since it was founded in 2010, and throughout 2011, its strategic priorities have consisted in: - developing a long-term policy for investing in carbon credits generated by environmental initiatives, as part of the project mechanisms set up by the Kyoto Protocol, and used in the European Emission Trading Scheme; - supporting the development of its investments in carbon finance operators, like BlueNext, the European carbon exchange, for instance; - broadening the scope of its research into climate economics, which is supported by CDC and available to everyone, in order to serve the public and private players concerned. Its teams have supported French and European governments, international organisations and the United Nations, and various NGOs in their work and thinking on the future of tools for combating climate change. They have specifically contributed reports based on their research and operational feedback. When it was founded, CDC Climat was closely linked to public policies aimed at combating climate change via allowance and carbon trading mechanisms. The difficulties encountered by international negotiations, together with the effects of the economic and financial downturn in Europe, have resulted in a very pronounced fall in the price of carbon assets on these markets since the summer of 2011, with no prospect of recovery for several years. This environment is calling some of the

SCF^{Cyclin F}-dependent degradation of CDC6 suppresses DNA re-replication

DEFF Research Database (Denmark)

Walter, David; Hoffmann, Saskia; Komseli, Eirini-Stavroula

2016-01-01

interact through defined sequence motifs that promote CDC6 ubiquitylation and degradation. Absence of Cyclin F or expression of a stable mutant of CDC6 promotes re-replication and genome instability in cells lacking the CDT1 inhibitor Geminin. Together, our work reveals a novel SCF(Cyclin F...

Atom-Dependent Edge-Enhanced Second-Harmonic Generation on MoS2 Monolayers.

Science.gov (United States)

Lin, Kuang-I; Ho, Yen-Hung; Liu, Shu-Bai; Ciou, Jian-Jhih; Huang, Bo-Ting; Chen, Christopher; Chang, Han-Ching; Tu, Chien-Liang; Chen, Chang-Hsiao

2018-02-14

Edge morphology and lattice orientation of single-crystal molybdenum disulfide (MoS 2 ) monolayers, a transition metal dichalcogenide (TMD), possessing a triangular shape with different edges grown by chemical vapor deposition are characterized by atomic force microscopy and transmission electron microscopy. Multiphoton laser scanning microscopy is utilized to study one-dimensional atomic edges of MoS 2 monolayers with localized midgap electronic states, which result in greatly enhanced optical second-harmonic generation (SHG). Microscopic S-zigzag edge and S-Mo Klein edge (bare Mo atoms protruding from a S-zigzag edge) terminations and the edge-atom dependent resonance energies can therefore be deduced based on SHG images. Theoretical calculations based on density functional theory clearly explain the lower energy of the S-zigzag edge states compared to the corresponding S-Mo Klein edge states. Characterization of the atomic-scale variation of edge-enhanced SHG is a step forward in this full-optical and high-yield technique of atomic-layer TMDs.

Cdc42 and Rab8a are critical for intestinal stem cell division, survival, and differentiation in mice

DEFF Research Database (Denmark)

Sakamori, Ryotaro; Das, Soumyashree; Yu, Shiyan

2012-01-01

The constant self renewal and differentiation of adult intestinal stem cells maintains a functional intestinal mucosa for a lifetime. However, the molecular mechanisms that regulate intestinal stem cell division and epithelial homeostasis are largely undefined. We report here that the small GTPases...... reminiscent of human microvillus inclusion disease (MVID), a devastating congenital intestinal disorder that results in severe nutrient deprivation. Further analysis revealed that Cdc42-deficient stem cells had cell division defects, reduced capacity for clonal expansion and differentiation into Paneth cells...... suggest that defects of the stem cell niche can cause MVID. This hypothesis represents a conceptual departure from the conventional view of this disease, which has focused on the affected enterocytes, and suggests stem cell-based approaches could be beneficial to infants with this often lethal condition....

Rac1-dependent recruitment of PAK2 to G 2 phase centrosomes and their roles in the regulation of mitotic entry

DEFF Research Database (Denmark)

May, Martin; Schelle, Ilona; Brakebusch, Cord Herbert

2014-01-01

-GTPases Rac/Cdc42. In this study, Rac1 (but not RhoA or Cdc42) is presented to associate with the centrosomes from early G 2 phase until prometaphase in a cell cycle-dependent fashion, as evidenced by western blot analysis of prepared centrosomes and by immunolabeling. PAK associates with the G 2/M......-phase centrosomes in a Rac1-dependent fashion. Furthermore, specific inhibition of Rac1 by C. difficile toxinB-catalyzed glucosylation or by knockout results in inhibited activation of PAK1/2, Aurora A, and the CyclinB/Cdk1 complex in late G 2 phase/prophase and delayed mitotic entry. Inhibition of PAK activation...

DNA replication initiator Cdc6 also regulates ribosomal DNA transcription initiation.

Science.gov (United States)

Huang, Shijiao; Xu, Xiaowei; Wang, Guopeng; Lu, Guoliang; Xie, Wenbing; Tao, Wei; Zhang, Hongyin; Jiang, Qing; Zhang, Chuanmao

2016-04-01

RNA-polymerase-I-dependent ribosomal DNA (rDNA) transcription is fundamental to rRNA processing, ribosome assembly and protein synthesis. However, how this process is initiated during the cell cycle is not fully understood. By performing a proteomic analysis of transcription factors that bind RNA polymerase I during rDNA transcription initiation, we identified that the DNA replication initiator Cdc6 interacts with RNA polymerase I and its co-factors, and promotes rDNA transcription in G1 phase in an ATPase-activity-dependent manner. We further showed that Cdc6 is targeted to the nucleolus during late mitosis and G1 phase in a manner that is dependent on B23 (also known as nucleophosmin, NPM1), and preferentially binds to the rDNA promoter through its ATP-binding domain. Overexpression of Cdc6 increases rDNA transcription, whereas knockdown of Cdc6 results in a decreased association of both RNA polymerase I and the RNA polymerase I transcription factor RRN3 with rDNA, and a reduction of rDNA transcription. Furthermore, depletion of Cdc6 impairs the interaction between RRN3 and RNA polymerase I. Taken together, our data demonstrate that Cdc6 also serves as a regulator of rDNA transcription initiation, and indicate a mechanism by which initiation of rDNA transcription and DNA replication can be coordinated in cells. © 2016. Published by The Company of Biologists Ltd.

Plasma current dependence of the edge pedestal height in JET ELM-free H-modes

International Nuclear Information System (INIS)

Nave, M.F.F; Lomas, P.; Gowers, C.; Guo, H.; Hawkes, N.; Huysmans, G.T.A.; Jones, T.; Parail, V.V.; Rimini, F.; Schunke, B.

2000-01-01

Some models for the suppression of turbulence in the L to H transition, suggest that the width of the H-mode edge barrier is either proportional or is of the order of the thermal or the fast-ion poloidal Larmor radius. This would require that the width of the edge barrier should depend on the plasma current. This dependence has been clearly verified at JET in experiments designed to control the edge MHD stability of ELM-free hot-ion H-mode plasmas. The effects of isotopic mass and the applicability of several edge barrier models to the hot-ion H-mode plasmas were analysed in (Guo H Y et al 2000 Edge transport barrier in JET hot-ion H-modes Nucl. Fusion 40 69) using a large database containing both deuterium-only and deuterium-tritium plasmas. This database has now been enlarged to include discharges from a plasma shape scan, allowing one to study the dependence of the pedestal height on the edge shear. In addition, the range of plasma currents was extended up to 6 MA. It is shown that the edge data are best described by a model where the edge barrier width is determined by the fast ions weighted towards the components with largest poloidal Larmor radii. However, it is not possible to conclusively eliminate the thermal ion model. (author)

The human homolog of S. cerevisiae CDC27, CDC27 Hs, is encoded by a highly conserved intronless gene present in multiple copies in the human genome

Energy Technology Data Exchange (ETDEWEB)

Devor, E.J.; Dill-Devor, R.M. [Univ. of Iowa College of Medicine, Iowa City (United States)

1994-09-01

We have obtained a number of unique sequences via PCR amplification of human genomic DNA using degenerate primers under low stringency (42{degrees}C). One of these, an 853 bp product, has been identified as a partial genomic sequence of the human homolog of the S. cerevisiae CDC27 gene, CDC27Hs (GenBank No. U00001). This gene, reported by Turgendreich et al. is also designated EST00556 from Adams et al. We have undertaken a more detailed examination of our sequence, MCP34N, and have found that: 1. the genomic sequence is nearly identical to CDC27Hs over its entire 853 bp length; 2. an MCP34N-specific PCR assay of several non-human primate species reveals amplification products in chimpanzee and gorilla genomes having greater than 90% sequence identity with CDC27Hs; and 3. an MCP34N-specific PCR assay of the BIOS hybrid cell line panel gives a discordancy pattern suggesting multiple loci. Based upon these data, we present the following initial characterization: 1. the complete MCP34N sequence identity with CDC27Hs indicates that the latter is encoded by an intronless gene; 2. CDC27Hs is highly conserved among higher primates; and 3. CDC27Hs is present in multiple copies in the human genome. These characteristics, taken together with those initially reported for CDC27Hs, suggest that this is an old gene that carries out an important but, as yet, unknown function in the human brain.

Using solution- and solid-state S K-edge X-ray absorption spectroscopy with density functional theory to evaluate M-S bonding for MS4(2-) (M = Cr, Mo, W) dianions.

Science.gov (United States)

Olson, Angela C; Keith, Jason M; Batista, Enrique R; Boland, Kevin S; Daly, Scott R; Kozimor, Stosh A; MacInnes, Molly M; Martin, Richard L; Scott, Brian L

2014-12-14

Herein, we have evaluated relative changes in M-S electronic structure and orbital mixing in Group 6 MS4(2-) dianions using solid- and solution-phase S K-edge X-ray absorption spectroscopy (XAS; M = Mo, W), as well as density functional theory (DFT; M = Cr, Mo, W) and time-dependent density functional theory (TDDFT) calculations. To facilitate comparison with solution measurements (conducted in acetonitrile), theoretical models included gas-phase calculations as well as those that incorporated an acetonitrile dielectric, the latter of which provided better agreement with experiment. Two pre-edge features arising from S 1s → e* and t electron excitations were observed in the S K-edge XAS spectra and were reasonably assigned as (1)A1 → (1)T2 transitions. For MoS4(2-), both solution-phase pre-edge peak intensities were consistent with results from the solid-state spectra. For WS4(2-), solution- and solid-state pre-edge peak intensities for transitions involving e* were equivalent, while transitions involving the t orbitals were less intense in solution. Experimental and computational results have been presented in comparison to recent analyses of MO4(2-) dianions, which allowed M-S and M-O orbital mixing to be evaluated as the principle quantum number (n) for the metal valence d orbitals increased (3d, 4d, 5d). Overall, the M-E (E = O, S) analyses revealed distinct trends in orbital mixing. For example, as the Group 6 triad was descended, e* (π*) orbital mixing remained constant in the M-S bonds, but increased appreciably for M-O interactions. For the t orbitals (σ* + π*), mixing decreased slightly for M-S bonding and increased only slightly for the M-O interactions. These results suggested that the metal and ligand valence orbital energies and radial extensions delicately influenced the orbital compositions for isoelectronic ME4(2-) (E = O, S) dianions.

Exploratory study of the effects of wing-leading-edge modifications on the stall/spin behavior of a light general aviation airplane

Science.gov (United States)

1979-01-01

Configurations with full-span and segmented leading-edge flaps and full-span and segmented leading-edge droop were tested. Studies were conducted with wind-tunnel models, with an outdoor radio-controlled model, and with a full-scale airplane. Results show that wing-leading-edge modifications can produce large effects on stall/spin characteristics, particularly on spin resistance. One outboard wing-leading-edge modification tested significantly improved lateral stability at stall, spin resistance, and developed spin characteristics.

Plasma current dependence of the edge pedestal height in JET ELM-free H-modes

International Nuclear Information System (INIS)

Nave, M.; Lomas, P.; Gowers, C.

2000-01-01

Models for the suppression of turbulence in the L to H transition, suggest that the width of the H-mode edge barrier is either proportional or is of the order of the ion poloidal Larmor radius. This would require that the width of the edge barrier should depend on the plasma current. This dependence has been clearly verified at JET in experiments designed to control the edge MHD stability of ELM-free hot-ion H-mode plasmas. The effects of isotopic mass and the applicability of several edge barrier models to the hot-ion H-mode plasmas were analysed in using a large database containing both Deuterium-only (DD) and Deuterium-Tritium (DT) plasmas. This database has now been enlarged to include discharges from a plasma shape scan, allowing to study the dependence of the pedestal height on the edge shear. In addition the range of plasma currents was extended up to 6 MA. It is shown that the edge data is best described by a model where the edge barrier width is determined by the fast ions weighted towards the components with largest poloidal Larmor radii. However, it is not possible to eliminate conclusively the thermal ion model. (author)

42 CFR 435.510 - Determination of dependency.

Science.gov (United States)

2010-10-01

... 42 Public Health 4 2010-10-01 2010-10-01 false Determination of dependency. 435.510 Section 435... ISLANDS, AND AMERICAN SAMOA Categorical Requirements for Eligibility Dependency § 435.510 Determination of dependency. For families with dependent children who are not receiving AFDC, the agency must use the...

Case Studies of Leading Edge Small Urban High Schools. Relevance Strategic Designs: 8. High Tech High School

Science.gov (United States)

Shields, Regis Anne; Ireland, Nicole; City, Elizabeth; Derderian, Julie; Miles, Karen Hawley

2008-01-01

This report is one of nine detailed case studies of small urban high schools that served as the foundation for the Education Resource Strategies (ERS) report "Strategic Designs: Lessons from Leading Edge Small Urban High Schools." These nine schools were dubbed "Leading Edge Schools" because they stand apart from other high…

Case Studies of Leading Edge Small Urban High Schools. Personalization Strategic Designs: 9. MetWest High School

Science.gov (United States)

Shields, Regis Anne; Ireland, Nicole; City, Elizabeth; Derderian, Julie; Miles, Karen Hawley

2008-01-01

This report is one of nine detailed case studies of small urban high schools that served as the foundation for the Education Resource Strategies (ERS) report "Strategic Designs: Lessons from Leading Edge Small Urban High Schools." These nine schools were dubbed "Leading Edge Schools" because they stand apart from other high…

Insect Residue Contamination on Wing Leading Edge Surfaces: A Materials Investigation for Mitigation

Science.gov (United States)

Lorenzi, Tyler M.; Wohl, Christopher J.; Penner, Ronald K.; Smith, Joseph G.; Siochi, Emilie J.

2011-01-01

Flight tests have shown that residue from insect strikes on aircraft wing leading edge surfaces may induce localized transition of laminar to turbulent flow. The highest density of insect populations have been observed between ground level and 153 m during light winds (2.6 -- 5.1 m/s), high humidity, and temperatures from 21 -- 29 C. At a critical residue height, dependent on the airfoil and Reynolds number, boundary layer transition from laminar to turbulent results in increased drag and fuel consumption. Although this represents a minimal increase in fuel burn for conventional transport aircraft, future aircraft designs will rely on maintaining laminar flow across a larger portion of wing surfaces to reduce fuel burn during cruise. Thus, insect residue adhesion mitigation is most critical during takeoff and initial climb to maintain laminar flow in fuel-efficient aircraft configurations. Several exterior treatments investigated to mitigate insect residue buildup (e.g., paper, scrapers, surfactants, flexible surfaces) have shown potential; however, implementation has proven to be impractical. Current research is focused on evaluation of wing leading edge surface coatings that may reduce insect residue adhesion. Initial work under NASA's Environmentally Responsible Aviation Program focused on evaluation of several commercially available products (commercial off-the-shelf, COTS), polymers, and substituted alkoxy silanes that were applied to aluminum (Al) substrates. Surface energies of these coatings were determined from contact angle data and were correlated to residual insect excrescence on coated aluminum substrates using a custom-built "bug gun." Quantification of insect excrescence surface coverage was evaluated by a series of digital photographic image processing techniques.

A fence barrier method of leading edge cell capture for explorative biochemical research.

Science.gov (United States)

Wager, Lucas J; Murray, Rachael Z; Thompson, Erik W; Leavesley, David I

2017-09-03

The scratch or wound-healing assay is used ubiquitously for investigating re-epithelialisation and has already revealed the importance of cells comprising the leading edge of healing epithelial wounds. However it is currently limited to studying the effect of known biochemical agents on the tissue of choice. Here we present an adaptation that extends the utility of this model to encompass the collection of cells from the leading edge of migrating epithelial sheets making available explorative biochemical analyses. The method is scalable and does not require expensive apparatus, making it suitable for large and small laboratories alike. We detail the application of our method and exemplify proof of principle data derived from primary human keratinocyte cultures.

A Reduced-Complexity Investigation of Blunt Leading-Edge Separation Motivated by UCAV Aerodynamics

Science.gov (United States)

Luckring, James M.; Boelens, Okko J.

2015-01-01

A reduced complexity investigation for blunt-leading-edge vortical separation has been undertaken. The overall approach is to design the fundamental work in such a way so that it relates to the aerodynamics of a more complex Uninhabited Combat Air Vehicle (UCAV) concept known as SACCON. Some of the challenges associated with both the vehicle-class aerodynamics and the fundamental vortical flows are reviewed, and principles from a hierarchical complexity approach are used to relate flow fundamentals to system-level interests. The work is part of roughly 6-year research program on blunt-leading-edge separation pertinent to UCAVs, and was conducted under the NATO Science and Technology Organization, Applied Vehicle Technology panel.

SIMS chemical analysis of extended impacts on the leading and trailing edges of LDEF experiment AO187-2

Science.gov (United States)

Amari, S.; Foote, J.; Swan, P.; Walker, R. M.; Zinner, E.; Lange, G.

1993-01-01

Numerous 'extended impacts' found in both leading and trailing edge capture cells were successfully analyzed for the chemical composition of projectile residues by secondary ion mass spectrometry (SIMS). Most data were obtained from the trailing edge cells where 45 of 58 impacts were classified as 'probably natural' and the remainder as 'possibly man-made debris.' This is in striking contrast to leading edge cells where 9 of 11 impacts so far measured are definitely classified as orbital debris. Although all the leading edge cells had lost their plastic entrance foils during flight, the rate of foil failure was similar to that of the trailing edge cells, 10 percent of which were recovered intact. Ultraviolet embrittlement is suspected as the major cause of failure on both leading and trailing edges. The major impediment to the accurate determination of projectile chemistry is the fractionation of volatile and refractory elements in the hypervelocity impact and redeposition processes. This effect had been noted in a simulation experiment but is more pronounced in the LDEF capture cells, probably due to the higher average velocities of the space impacts. Surface contamination of the pure Ge surfaces with a substance rich in Si, but also containing Mg and Al, provides an additional problem for the accurate determination of impactor chemistry. The effect is variable, being much larger on surfaces that were exposed to space than in those cells that remained intact. Future work will concentrate on the analyses of more leading edge impacts and the development of new SIMS techniques for the measurement of elemental abundances in extended impacts.

Test and Analysis Correlation of Form Impact onto Space Shuttle Wing Leading Edge RCC Panel 8

Science.gov (United States)

Fasanella, Edwin L.; Lyle, Karen H.; Gabrys, Jonathan; Melis, Matthew; Carney, Kelly

2004-01-01

Soon after the Columbia Accident Investigation Board (CAIB) began their study of the space shuttle Columbia accident, "physics-based" analyses using LS-DYNA were applied to characterize the expected damage to the Reinforced Carbon-Carbon (RCC) leading edge from high-speed foam impacts. Forensic evidence quickly led CAIB investigators to concentrate on the left wing leading edge RCC panels. This paper will concentrate on the test of the left-wing RCC panel 8 conducted at Southwest Research Institute (SwRI) and the correlation with an LS-DYNA analysis. The successful correlation of the LS-DYNA model has resulted in the use of LS-DYNA as a predictive tool for characterizing the threshold of damage for impacts of various debris such as foam, ice, and ablators onto the RCC leading edge for shuttle return-to-flight.

Numerical investigation of rarefaction effects in the vicinity of a sharp leading edge

Science.gov (United States)

Pan, Shaowu; Gao, Zhenxun; Lee, Chunhian

2014-12-01

This paper presents a study of rarefaction effect on hypersonic flow over a sharp leading edge. Both continuum approach and kinetic method: a widely spread commercial Computational Fluid Dynamics-Navior-Stokes-Fourier (CFD-NSF) software - Fluent together with a direct simulation Monte Carlo (DSMC) code developed by the authors are employed for simulation of transition regime with Knudsen number ranging from 0.005 to 0.2. It is found that Fluent can predict the wall fluxes in the case of hypersonic argon flow over the sharp leading edge for the lowest Kn case (Kn = 0.005) in current paper while for other cases it also has a good agreement with DSMC except at the location near the sharp leading edge. Among all of the wall fluxes, it is found that coefficient of pressure is the most sensitive to rarefaction while heat transfer is the least one. A parameter based on translational nonequilibrium and a cut-off value of 0.34 is proposed for continuum breakdown in this paper. The structure of entropy and velocity profile in boundary layer is analyzed. Also, it is found that the ratio of heat transfer coefficient to skin friction coefficient remains uniform along the surface for the four cases in this paper.

Edge energies and shapes of nanoprecipitates.

Energy Technology Data Exchange (ETDEWEB)

Hamilton, John C.

2006-01-01

In this report we present a model to explain the size-dependent shapes of lead nano-precipitates in aluminum. Size-dependent shape transitions, frequently observed at nanolength scales, are commonly attributed to edge energy effects. This report resolves an ambiguity in the definition and calculation of edge energies and presents an atomistic calculation of edge energies for free clusters. We also present a theory for size-dependent shapes of Pb nanoprecipitates in Al, introducing the concept of ''magic-shapes'' defined as precipitate shapes having near zero elastic strains when inserted into similarly shaped voids in the Al matrix. An algorithm for constructing a complete set of magic-shapes is presented. The experimental observations are explained by elastic strain energies and interfacial energies; edge energies play a negligible role. We replicate the experimental observations by selecting precipitates having magic-shapes and interfacial energies less than a cutoff value.

CDC Vital Signs–Cancer and Obesity

Centers for Disease Control (CDC) Podcasts

2017-10-04

This podcast is based on the October 2017 CDC Vital Signs report. Obesity is a leading cancer risk factor. Unfortunately, two out of three U.S. adults weigh more than recommended. Find out what can be done to help people get to and keep a healthy weight.  Created: 10/4/2017 by Centers for Disease Control and Prevention (CDC).   Date Released: 10/4/2017.

Reduced innate immunity of Cuban Treefrogs at leading edge of range expansion.

Science.gov (United States)

Goetz, Scott M; Romagosa, Christina M; Appel, Arthur G; Guyer, Craig; Mendonça, Mary T

2017-12-01

During geographic range expansion, populations of non-indigenous species at the invasion front may benefit from directing resources away from immune defense. To test this hypothesis, we investigated the strength of two innate immune components in populations of invasive Cuban Treefrogs (Osteopilus septentrionalis) in a long-colonized area (core region) and at the invasion front (leading-edge region). First, we compared the region-specific metabolic response of frogs injected with an endotoxin that induces systemic inflammation (lipopolysaccharide, LPS) to sham-injected control frogs pooled from both regions. Males and females were analyzed independently because we detected a sex-related difference in mass-independent metabolism of control frogs, with males exhibiting a significantly higher metabolic rate (F 1, 21  = 29.02, P leading-edge populations, there was no significant difference in the metabolic rate of LPS-injected and control frogs (males, P  = 0.195; females, P  = 0.132). Second, we directly compared bacterial killing ability of frog blood plasma between regions. Bactericidal ability of plasma was significantly greater in frogs from the core region in comparison with those at the leading edge (F 1, 26   = 28.67, P < 0.001). For both immune components that we examined, populations from the core exhibited stronger immune responses. Our findings support hypotheses predicting an inverse relationship between immunity and range expansion. © 2018 Wiley Periodicals, Inc.

Edge-defect induced spin-dependent Seebeck effect and spin figure of merit in graphene nanoribbons.

Science.gov (United States)

Liu, Qing-Bo; Wu, Dan-Dan; Fu, Hua-Hua

2017-10-11

By using the first-principle calculations combined with the non-equilibrium Green's function approach, we have studied spin caloritronic properties of graphene nanoribbons (GNRs) with different edge defects. The theoretical results show that the edge-defected GNRs with sawtooth shapes can exhibit spin-dependent currents with opposite flowing directions by applying temperature gradients, indicating the occurrence of the spin-dependent Seebeck effect (SDSE). The edge defects bring about two opposite effects on the thermal spin currents: the enhancement of the symmetry of thermal spin-dependent currents, which contributes to the realization of pure thermal spin currents, and the decreasing of the spin thermoelectric conversion efficiency of the devices. It is fortunate that applying a gate voltage is an efficient route to optimize these two opposite spin thermoelectric properties towards realistic device applications. Moreover, due to the existence of spin-splitting band gaps, the edge-defected GNRs can be designed as spin-dependent Seebeck diodes and rectifiers, indicating that the edge-defected GNRs are potential candidates for room-temperature spin caloritronic devices.

42 CFR 436.510 - Determination of dependency.

Science.gov (United States)

2010-10-01

... 42 Public Health 4 2010-10-01 2010-10-01 false Determination of dependency. 436.510 Section 436.510 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES... Requirements for Medicaid Eligibility Dependency § 436.510 Determination of dependency. For families with...

CDC Vital Signs-Cancer and Obesity

Centers for Disease Control (CDC) Podcasts

This podcast is based on the October 2017 CDC Vital Signs report. Obesity is a leading cancer risk factor. Unfortunately, two out of three U.S. adults weigh more than recommended. Find out what can be done to help people get to and keep a healthy weight.

Aerodynamic improvement of a delta wing in combination with leading edge flaps

Directory of Open Access Journals (Sweden)

Tadateru Ishide

2017-11-01

Full Text Available Recently, various studies of micro air vehicle (MAV and unmanned air vehicle (UAV have been reported from wide range points of view. The aim of this study is to research the aerodynamic improvement of delta wing in low Reynold’s number region to develop an applicative these air vehicle. As an attractive tool in delta wing, leading edge flap (LEF is employed to directly modify the strength and structure of vortices originating from the separation point along the leading edge. Various configurations of LEF such as drooping apex flap and upward deflected flap are used in combination to enhance the aerodynamic characteristics in the delta wing. The fluid force measurement by six component load cell and particle image velocimetry (PIV analysis are performed as the experimental method. The relations between the aerodynamic superiority and the vortex behavior around the models are demonstrated.

Case Studies of Leading Edge Small Urban High Schools. Core Academic Strategic Designs: 3. University Park Campus School

Science.gov (United States)

Shields, Regis Anne; Ireland, Nicole; City, Elizabeth; Derderian, Julie; Miles, Karen Hawley

2008-01-01

This report is one of nine detailed case studies of small urban high schools that served as the foundation for the Education Resource Strategies (ERS) report "Strategic Designs: Lessons from Leading Edge Small Urban High Schools." These nine schools were dubbed "Leading Edge Schools" because they stand apart from other high…

ATR-Chk1-APC/C-dependent stabilization of Cdc7-ASK (Dbf4) kinase is required for DNA lesion bypass under replication stress

DEFF Research Database (Denmark)

Yamada, M.; Watanabe, K.; Mistrik, M.

2013-01-01

replication. Stalled DNA replication evoked stabilization of the Cdc7-ASK (Dbf4) complex in a manner dependent on ATR-Chk1-mediated checkpoint signaling and its interplay with the anaphase-promoting complex/cyclosomeCdh1 (APC/C) ubiquitin ligase. Mechanistically, Chk1 kinase inactivates APC/C through...... degradation of Cdh1 upon replication block, thereby stabilizing APC/C substrates, including Cdc7-ASK (Dbf4). Furthermore, motif C of ASK (Dbf4) interacts with the N-terminal region of RAD18 ubiquitin ligase, and this interaction is required for chromatin binding of RAD18. Impaired interaction of ASK (Dbf4...

Leading edge analysis of transcriptomic changes during pseudorabies virus infection.

Science.gov (United States)

Fleming, Damarius S; Miller, Laura C

2016-12-01

Eight RNA samples taken from the tracheobronchial lymph nodes (TBLN) of pigs that were either infected or non-infected with a feral isolate of porcine pseudorabies virus (PRV) were used to investigate changes in gene expression related to the pathogen. The RNA was processed into fastq files for each library prior to being analyzed using Illumina Digital Gene Expression Tag Profiling sequences (DGETP) which were used as the downstream measure of differential expression. Analyzed tags consisted of 21 base pair sequences taken from time points 1, 3, 6, and 14 days' post infection (dpi) that generated 1,927,547 unique tag sequences. Tag sequences were analyzed for differential transcript expression and gene set enrichment analysis (GSEA) to uncover transcriptomic changes related to PRV pathology progression. In conjunction with the DGETP and GSEA, the study also incorporated use of leading edge analysis to help link the TBLN transcriptome data to clinical progression of PRV at each of the sampled time points. The purpose of this manuscript is to provide useful background on applying the leading edge analysis to GSEA and expression data to help identify genes considered to be of high biological interest. The data in the form of fastq files has been uploaded to the NCBI Gene Expression Omnibus (GEO) (GSE74473) database.

Polo kinase Cdc5 is a central regulator of meiosis I

Science.gov (United States)

Attner, Michelle A.; Miller, Matthew P.; Ee, Ly-sha; Elkin, Sheryl K.; Amon, Angelika

2013-01-01

During meiosis, two consecutive rounds of chromosome segregation yield four haploid gametes from one diploid cell. The Polo kinase Cdc5 is required for meiotic progression, but how Cdc5 coordinates multiple cell-cycle events during meiosis I is not understood. Here we show that CDC5-dependent phosphorylation of Rec8, a subunit of the cohesin complex that links sister chromatids, is required for efficient cohesin removal from chromosome arms, which is a prerequisite for meiosis I chromosome segregation. CDC5 also establishes conditions for centromeric cohesin removal during meiosis II by promoting the degradation of Spo13, a protein that protects centromeric cohesin during meiosis I. Despite CDC5’s central role in meiosis I, the protein kinase is dispensable during meiosis II and does not even phosphorylate its meiosis I targets during the second meiotic division. We conclude that Cdc5 has evolved into a master regulator of the unique meiosis I chromosome segregation pattern. PMID:23918381

Fission yeast cdc24(+) encodes a novel replication factor required for chromosome integrity.

Science.gov (United States)

Gould, K L; Burns, C G; Feoktistova, A; Hu, C P; Pasion, S G; Forsburg, S L

1998-07-01

A mutation within the Schizosaccharomyces pombe cdc24(+) gene was identified previously in a screen for cell division cycle mutants and the cdc24(+) gene was determined to be essential for S phase in this yeast. We have isolated the cdc24(+) gene by complementation of a new temperature-sensitive allele of the gene, cdc24-G1. The DNA sequence predicts the presence of an open reading frame punctuated by six introns which encodes a pioneer protein of 58 kD. A cdc24 null mutant was generated by homologous recombination. Haploid cells lacking cdc24(+) are inviable, indicating that cdc24(+) is an essential gene. The transcript of cdc24(+) is present at constant levels throughout the cell cycle. Cells lacking cdc24(+) function show a checkpoint-dependent arrest with a 2N DNA content, indicating a block late in S phase. Arrest is accompanied by a rapid loss of viability and chromosome breakage. An S. pombe homolog of the replicative DNA helicase DNA2 of S. cerevisiae suppresses cdc24. These results suggest that Cdc24p plays a role in the progression of normal DNA replication and is required to maintain genomic integrity.

Molecular Mechanism of Substrate Processing by the Cdc48 ATPase Complex.

Science.gov (United States)

Bodnar, Nicholas O; Rapoport, Tom A

2017-05-04

The Cdc48 ATPase and its cofactors Ufd1/Npl4 (UN) extract polyubiquitinated proteins from membranes or macromolecular complexes, but how they perform these functions is unclear. Cdc48 consists of an N-terminal domain that binds UN and two stacked hexameric ATPase rings (D1 and D2) surrounding a central pore. Here, we use purified components to elucidate how the Cdc48 complex processes substrates. After interaction of the polyubiquitin chain with UN, ATP hydrolysis by the D2 ring moves the polypeptide completely through the double ring, generating a pulling force on the substrate and causing its unfolding. ATP hydrolysis by the D1 ring is important for subsequent substrate release from the Cdc48 complex. This release requires cooperation of Cdc48 with a deubiquitinase, which trims polyubiquitin to an oligoubiquitin chain that is then also translocated through the pore. Together, these results lead to a new paradigm for the function of Cdc48 and its mammalian ortholog p97/VCP. Copyright © 2017 Elsevier Inc. All rights reserved.

Cell cycle sibling rivalry: Cdc2 vs. Cdk2.

Science.gov (United States)

Kaldis, Philipp; Aleem, Eiman

2005-11-01

It has been long believed that the cyclin-dependent kinase 2 (Cdk2) binds to cyclin E or cyclin A and exclusively promotes the G1/S phase transition and that Cdc2/cyclin B complexes play a major role in mitosis. We now provide evidence that Cdc2 binds to cyclin E (in addition to cyclin A and B) and is able to promote the G1/S transition. This new concept indicates that both Cdk2 and/or Cdc2 can drive cells through G1/S phase in parallel. In this review we discuss the classic cell cycle model and how results from knockout mice provide new evidence that refute this model. We focus on the roles of Cdc2 and p27 in regulating the mammalian cell cycle and propose a new model for cell cycle regulation that accommodates these novel findings.

Methodology for heat flux investigation on leading edges using infrared thermography

Czech Academy of Sciences Publication Activity Database

Corre, Y.; Gardarein, J.-L.; Dejarnac, Renaud; Gaspar, J.; Gunn, J. P.; Aumeunier, M.-H.; Courtois, X.; Missirlian, M.; Rigollet, F.

2017-01-01

Roč. 57, č. 1 (2017), č. článku 016009. ISSN 0029-5515 Institutional support: RVO:61389021 Keywords : IR thermography * leading edge * heat flux * limiter Subject RIV: BL - Plasma and Gas Discharge Physics OBOR OECD: Fluids and plasma physics (including surface physics) Impact factor: 3.307, year: 2016 http://iopscience.iop.org/article/10.1088/0029-5515/57/1/016009/meta

Overexpression of CDC25B, CDC25C and phospho-CDC25C (Ser216 in vulvar squamous cell carcinomas are associated with malignant features and aggressive cancer phenotypes

Directory of Open Access Journals (Sweden)

Flørenes Vivi

2010-05-01

Full Text Available Abstract Background CDC25 phosphatases are important regulators of the cell cycle. Their abnormal expression detected in a number of tumors implies that their dysregulation is involved in malignant transformation. However, the role of CDC25s in vulvar cancer is still unknown. To shed light on their roles in the pathogenesis and to clarify their prognostic values, expression of CDC25A, CDC25B and CDC25C in a large series of vulvar squamous cell carcinomas were examined. Methods Expression of CDC25A, CDC25B, CDC25C and phosphorylated (phospho-CDC25C (Ser216 were examined in 300 vulvar carcinomas using immunohistochemistry. Western blot analysis was utilized to demonstrate CDC25s expression in vulvar cancer cell lines. Kinase and phosphatase assays were performed to exclude cross reactivity among CDC25s isoform antibodies. Results High nuclear CDC25A and CDC25B expression were observed in 51% and 16% of the vulvar carcinomas, respectively, whereas high cytoplasmic CDC25C expression was seen in 63% of the cases. In cytoplasm, nucleus and cytoplasm/nucleus high phospho-CDC25C (Ser216 expression was identified in 50%, 70% and 77% of the carcinomas, respectively. High expression of CDC25s correlated significantly with malignant features, including poor differentiation and infiltration of vessel for CDC25B, high FIGO stage, presence of lymph node metastases, large tumor diameter, poor differentiation for CDC25C and high FIGO stage, large tumor diameter, deep invasion and poor differentiation for phospho-CDC25C (Ser216. In univariate analysis, high expression of phospho-CDC25C (Ser216 was correlated with poor disease-specific survival (p = 0.04. However, such an association was annulled in multivariate analysis. Conclusions Our results suggest that CDC25C and phospho-CDC25C (Ser216 play a crucial role and CDC25B a minor role in the pathogenesis and/or progression of vulvar carcinomas. CDC25B, CDC25C and phospho-CDC25C (Ser216 were associated with

Overexpression of CDC25B, CDC25C and phospho-CDC25C (Ser216) in vulvar squamous cell carcinomas are associated with malignant features and aggressive cancer phenotypes

International Nuclear Information System (INIS)

Wang, Zhihui; Trope, Claes G; Flørenes, Vivi Ann; Suo, Zhenhe; Nesland, Jahn M; Holm, Ruth

2010-01-01

CDC25 phosphatases are important regulators of the cell cycle. Their abnormal expression detected in a number of tumors implies that their dysregulation is involved in malignant transformation. However, the role of CDC25s in vulvar cancer is still unknown. To shed light on their roles in the pathogenesis and to clarify their prognostic values, expression of CDC25A, CDC25B and CDC25C in a large series of vulvar squamous cell carcinomas were examined. Expression of CDC25A, CDC25B, CDC25C and phosphorylated (phospho)-CDC25C (Ser216) were examined in 300 vulvar carcinomas using immunohistochemistry. Western blot analysis was utilized to demonstrate CDC25s expression in vulvar cancer cell lines. Kinase and phosphatase assays were performed to exclude cross reactivity among CDC25s isoform antibodies. High nuclear CDC25A and CDC25B expression were observed in 51% and 16% of the vulvar carcinomas, respectively, whereas high cytoplasmic CDC25C expression was seen in 63% of the cases. In cytoplasm, nucleus and cytoplasm/nucleus high phospho-CDC25C (Ser216) expression was identified in 50%, 70% and 77% of the carcinomas, respectively. High expression of CDC25s correlated significantly with malignant features, including poor differentiation and infiltration of vessel for CDC25B, high FIGO stage, presence of lymph node metastases, large tumor diameter, poor differentiation for CDC25C and high FIGO stage, large tumor diameter, deep invasion and poor differentiation for phospho-CDC25C (Ser216). In univariate analysis, high expression of phospho-CDC25C (Ser216) was correlated with poor disease-specific survival (p = 0.04). However, such an association was annulled in multivariate analysis. Our results suggest that CDC25C and phospho-CDC25C (Ser216) play a crucial role and CDC25B a minor role in the pathogenesis and/or progression of vulvar carcinomas. CDC25B, CDC25C and phospho-CDC25C (Ser216) were associated with malignant features and aggressive cancer phenotypes. However, the

Blastomyces dermatitidis septins CDC3, CDC10, and CDC12 impact the morphology of yeast and hyphae, but are not required for the phase transition.

Science.gov (United States)

Marty, Amber J; Gauthier, Gregory M

2013-01-01

Blastomyces dermatitidis, the etiologic agent of blastomycosis, belongs to a group of thermally dimorphic fungi that change between mold (22°C) and yeast (37°C) in response to temperature. The contribution of structural proteins such as septins to this phase transition in these fungi remains poorly understood. Septins are GTPases that serve as a scaffold for proteins involved with cytokinesis, cell polarity, and cell morphology. In this study, we use a GFP sentinel RNA interference system to investigate the impact of CDC3, CDC10, CDC12, and ASPE on the morphology and phase transition of B. dermatitidis. Targeting CDC3, CDC10, and CDC12 by RNA interference resulted in yeast with aberrant morphology at 37°C with defects in cytokinesis. Downshifting the temperature to 22°C promoted the conversion to the mold phase, but did not abrogate the morphologic defects. CDC3, CDC10, and CDC12 knockdown strains grew as mold with curved, thickened hyphae. Knocking down ASPE transcript did not alter morphology of yeast at 37°C or mold at 22°C. Following an increase in temperature from 22°C to 37°C, all septin knockdown strains were able to revert to yeast. In conclusion, CDC3, CDC10, and CDC12 septin- encoding genes are required for proper morphology of yeast and hyphae, but are dispensable for the phase transition.

cdc-25.4, a Caenorhabditis elegans Ortholog of cdc25, Is Required for Male Mating Behavior

Directory of Open Access Journals (Sweden)

Sangmi Oh

2016-12-01

Full Text Available Cell division cycle 25 (cdc25 is an evolutionarily conserved phosphatase that promotes cell cycle progression. Among the four cdc25 orthologs in Caenorhabditis elegans, we found that cdc-25.4 mutant males failed to produce outcrossed progeny. This was not caused by defects in sperm development, but by defects in male mating behavior. The cdc-25.4 mutant males showed various defects during male mating, including contact response, backing, turning, and vulva location. Aberrant turning behavior was the most prominent defect in the cdc-25.4 mutant males. We also found that cdc-25.4 is expressed in many neuronal cells throughout development. The turning defect in cdc-25.4 mutant males was recovered by cdc-25.4 transgenic expression in neuronal cells, suggesting that cdc-25.4 functions in neurons for male mating. However, the neuronal morphology of cdc-25.4 mutant males appeared to be normal, as examined with several neuronal markers. Also, RNAi depletion of wee-1.3, a C. elegans ortholog of Wee1/Myt1 kinase, failed to suppress the mating defects of cdc-25.4 mutant males. These findings suggest that, for successful male mating, cdc-25.4 does not target cell cycles that are required for neuronal differentiation and development. Rather, cdc-25.4 likely regulates noncanonical substrates in neuronal cells.

Dependence of the red edge of the RR Lyrae gap on helium abundance

International Nuclear Information System (INIS)

Deupree, R.G.

1976-01-01

Calculations have been performed to determine the position of the red edge of the RR Lyrae gap with the chemical compositions (X,Z) = (0.7, 0.001) and (0.8, 0.001). The calculations are composed of the time integration of the conservation equations of mass, momentum, and energy in two spatial dimensions. The calculations allow time-dependent convection to be followed without either arbitrary assumptions regarding time dependence or the application of any theory of convection. The primary assumptions are the restriction to two spatial dimensions and that an ''eddy viscosity'' is employed to mimic the process of turbulent cascade and the conversion of convective kinetic energy into heat. The ability of time dependent convection to stabilize pulsation is shown, and the process by which this is achieved is discussed. The time dependence of convection is found to play a crucial role in the stabilization process. The dependence of the position of the red edge on helium abundance is examined. The results indicate that the color difference between the red and blue edges is a sensitive indicator of helium abundance. Comparison is made with certain globular cluster color differences which indicate that the helium abundance is close to 0.3 by weight

Leading edge analysis of transcriptomic changes during pseudorabies virus infection

Directory of Open Access Journals (Sweden)

Damarius S. Fleming

2016-12-01

Full Text Available Eight RNA samples taken from the tracheobronchial lymph nodes (TBLN of pigs that were either infected or non-infected with a feral isolate of porcine pseudorabies virus (PRV were used to investigate changes in gene expression related to the pathogen. The RNA was processed into fastq files for each library prior to being analyzed using Illumina Digital Gene Expression Tag Profiling sequences (DGETP which were used as the downstream measure of differential expression. Analyzed tags consisted of 21 base pair sequences taken from time points 1, 3, 6, and 14 days' post infection (dpi that generated 1,927,547 unique tag sequences. Tag sequences were analyzed for differential transcript expression and gene set enrichment analysis (GSEA to uncover transcriptomic changes related to PRV pathology progression. In conjunction with the DGETP and GSEA, the study also incorporated use of leading edge analysis to help link the TBLN transcriptome data to clinical progression of PRV at each of the sampled time points. The purpose of this manuscript is to provide useful background on applying the leading edge analysis to GSEA and expression data to help identify genes considered to be of high biological interest. The data in the form of fastq files has been uploaded to the NCBI Gene Expression Omnibus (GEO (GSE74473 database.

Case Studies of Leading Edge Small Urban High Schools. Relevance Strategic Designs: 5. Life Academy of Health and Bioscience

Science.gov (United States)

Shields, Regis Anne; Ireland, Nicole; City, Elizabeth; Derderian, Julie; Miles, Karen Hawley

2008-01-01

This report is one of nine detailed case studies of small urban high schools that served as the foundation for the Education Resource Strategies (ERS) report "Strategic Designs: Lessons from Leading Edge Small Urban High Schools." These nine schools were dubbed "Leading Edge Schools" because they stand apart from other high…

Case Studies of Leading Edge Small Urban High Schools. Core Academic Strategic Designs: 1. Academy of the Pacific Rim

Science.gov (United States)

Shields, Regis Anne; Ireland, Nicole; City, Elizabeth; Derderian, Julie; Miles, Karen Hawley

2008-01-01

This report is one of nine detailed case studies of small urban high schools that served as the foundation for the Education Resource Strategies (ERS) report "Strategic Designs: Lessons from Leading Edge Small Urban High Schools." These nine schools were dubbed "Leading Edge Schools" because they stand apart from other high…

Case Studies of Leading Edge Small Urban High Schools. Core Academic Strategic Designs: 2. Noble Street Charter High School

Science.gov (United States)

Shields, Regis Anne; Ireland, Nicole; City, Elizabeth; Derderian, Julie; Miles, Karen Hawley

2008-01-01

This report is one of nine detailed case studies of small urban high schools that served as the foundation for the Education Resource Strategies (ERS) report "Strategic Designs: Lessons from Leading Edge Small Urban High Schools." These nine schools were dubbed "Leading Edge Schools" because they stand apart from other high…

MDA-9/Syntenin (SDCBP) modulates small GTPases RhoA and Cdc42 via transforming growth factor β1 to enhance epithelial-mesenchymal transition in breast cancer.

Science.gov (United States)

Menezes, Mitchell E; Shen, Xue-Ning; Das, Swadesh K; Emdad, Luni; Sarkar, Devanand; Fisher, Paul B

2016-12-06

Epithelial-mesenchymal transition (EMT) is one of the decisive steps regulating cancer invasion and metastasis. However, the molecular mechanisms underlying this transition require further clarification. MDA-9/syntenin (SDCBP) expression is elevated in breast cancer patient samples as well as cultured breast cancer cells. Silencing expression of MDA-9 in mesenchymal metastatic breast cancer cells triggered a change in cell morphology in both 2D- and 3D-cultures to a more epithelial-like phenotype, along with changes in EMT markers, cytoskeletal rearrangement and decreased invasion. Conversely, over expressing MDA-9 in epithelial non-metastatic breast cancer cells instigated a change in morphology to a more mesenchymal phenotype with corresponding changes in EMT markers, cytoskeletal rearrangement and an increase in invasion. We also found that MDA-9 upregulated active levels of known modulators of EMT, the small GTPases RhoA and Cdc42, via TGFβ1. Reintroducing TGFβ1 in MDA-9 silenced cells restored active RhoA and cdc42 levels, modulated cytoskeletal rearrangement and increased invasion. We further determined that MDA-9 interacts with TGFβ1 via its PDZ1 domain. Finally, in vivo studies demonstrated that silencing the expression of MDA-9 resulted in decreased lung metastasis and TGFβ1 re-expression partially restored lung metastases. Our findings provide evidence for the relevance of MDA-9 in mediating EMT in breast cancer and support the potential of MDA-9 as a therapeutic target against metastatic disease.

Morphological Variations of Leading-Edge Serrations in Owls (Strigiformes.

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Matthias Weger

Full Text Available Owls have developed serrations, comb-like structures, along the leading edge of their wings. Serrations were investigated from a morphological and a mechanical point of view, but were not yet quantitatively compared for different species. Such a comparative investigation of serrations from species of different sizes and activity patterns may provide new information about the function of the serrations.Serrations on complete wings and on tenth primary remiges of seven owl species were investigated. Small, middle-sized, and large owl species were investigated as well as species being more active during the day and owls being more active during the night. Serrations occurred at the outer parts of the wings, predominantly at tenth primary remiges, but also on further wing feathers in most species. Serration tips were oriented away from the feather rachis so that they faced into the air stream during flight. The serrations of nocturnal owl species were higher developed as demonstrated by a larger inclination angle (the angle between the base of the barb and the rachis, a larger tip displacement angle (the angle between the tip of the serration and the base of the serration and a longer length. Putting the measured data into a clustering algorithm yielded dendrograms that suggested a strong influence of activity pattern, but only a weak influence of size on the development of the serrations.Serrations are supposed to be involved in noise reduction during flight and also depend on the aerodynamic properties that in turn depend on body size. Since especially nocturnal owls have to rely on hearing during prey capture, the more pronounced serrations of nocturnal species lend further support to the notion that serrations have an important function in noise reduction. The differences in shape of the serrations investigated indicate that a silent flight requires well-developed serrations.

Morphological Variations of Leading-Edge Serrations in Owls (Strigiformes)

Science.gov (United States)

Weger, Matthias; Wagner, Hermann

2016-01-01

Background Owls have developed serrations, comb-like structures, along the leading edge of their wings. Serrations were investigated from a morphological and a mechanical point of view, but were not yet quantitatively compared for different species. Such a comparative investigation of serrations from species of different sizes and activity patterns may provide new information about the function of the serrations. Results Serrations on complete wings and on tenth primary remiges of seven owl species were investigated. Small, middle-sized, and large owl species were investigated as well as species being more active during the day and owls being more active during the night. Serrations occurred at the outer parts of the wings, predominantly at tenth primary remiges, but also on further wing feathers in most species. Serration tips were oriented away from the feather rachis so that they faced into the air stream during flight. The serrations of nocturnal owl species were higher developed as demonstrated by a larger inclination angle (the angle between the base of the barb and the rachis), a larger tip displacement angle (the angle between the tip of the serration and the base of the serration) and a longer length. Putting the measured data into a clustering algorithm yielded dendrograms that suggested a strong influence of activity pattern, but only a weak influence of size on the development of the serrations. Conclusions Serrations are supposed to be involved in noise reduction during flight and also depend on the aerodynamic properties that in turn depend on body size. Since especially nocturnal owls have to rely on hearing during prey capture, the more pronounced serrations of nocturnal species lend further support to the notion that serrations have an important function in noise reduction. The differences in shape of the serrations investigated indicate that a silent flight requires well-developed serrations. PMID:26934104

The reduction of leading- and trailing-edge of high-voltage steep pulse in plasma immersion ion implantation

International Nuclear Information System (INIS)

Zhu Zongtao; Gui Gang; Wang Zhijian; Gong Chunzhi; Yang Shiqin; Tian Xiubo

2010-01-01

During plasma immersion ion implantation (PIII) processes, due to the capacitance effect of the coaxial cable and plasma load, the output voltage pulse of high-voltage modulator possesses a longer leading- and trailing-edge time. The leading- and trailing-edge of the high voltage (HV) pulse have a critical effect on the ion-energy uniformity, depth and dose distribution during PIII processes. In this work, a tetrode was used as a hard tube to switch the DC high voltage, and a HV pulse modulator with a maximum pulse voltage of 40 kV was built successfully. The effect of the trailing-edge time on the implantation uniformity was simulated by one-dimension PIC method. The potential on the control grids of the tetrode was optimized to obtain a HV pulse with a short rise time. In our system, 200 V potential on grid one is utilized and the leading-edge time of pulse can be as small as 1 μs. The IGBTs in series was utilized to release the remnant charges reserved in the equivalent capacitance of the plasma load and coaxial cable. Thus the trailing-edge time of the HV pulse could be reduced. The effect of the driver signals with different delay time and the absorption parameters of each IGBTs were simulated by PSPICE software to optimize the design the electric circuit. (authors)

Turbulence Amplification with Incidence at the Leading Edge of a Compressor Cascade

Directory of Open Access Journals (Sweden)

Garth V. Hobson

1999-01-01

Full Text Available Detailed measurements, with a two-component laser-Doppler velocimeter and a thermal anemometer were made near the suction surface leading edge of controlled-diffusion airfoils in cascade. The Reynolds number was near 700,000, Mach number equal to 0.25, and freestream turbulence was at 1.5% ahead of the cascade.

Superior Reproducibility of the Leading to Leading Edge and Inner to Inner Edge Methods in the Ultrasound Assessment of Maximum Abdominal Aortic Diameter.

Science.gov (United States)

Borgbjerg, Jens; Bøgsted, Martin; Lindholt, Jes S; Behr-Rasmussen, Carsten; Hørlyck, Arne; Frøkjær, Jens B

2018-02-01

Controversy exists regarding optimal caliper placement in ultrasound assessment of maximum abdominal aortic diameter. This study aimed primarily to determine reproducibility of caliper placement in relation to the aortic wall with the three principal methods: leading to leading edge (LTL), inner to inner edge (ITI), and outer to outer edge (OTO). The secondary aim was to assess the mean difference between the OTO, ITI, and LTL diameters and estimate the impact of using either of these methods on abdominal aortic aneurysm (AAA) prevalence in a screening program. Radiologists (n=18) assessed the maximum antero-posterior abdominal aortic diameter by completing repeated caliper placements with the OTO, LTL, and ITI methods on 50 still abdominal aortic images obtained from an AAA screening program. Inter-observer reproducibility was calculated as the limit of agreement with the mean (LoA), which represents expected deviation of a single observer from the mean of all observers. Intra-observer reproducibility was assessed averaging the LoA for each observer with their repeated measurements. Based on data from an AAA screening trial and the estimated mean differences between the three principal methods, AAA prevalence was estimated using each of the methods. The inter-observer LoA of the OTO, ITI, and LTL was 2.6, 1.9, and 1.9 mm, whereas the intra-observer LoA was 2.0, 1.6, and 1.5 mm, respectively. Mean differences of 5.0 mm were found between OTO and ITI measurements, 2.6 mm between OTO and LTL measurements, and 2.4 mm between LTL and ITI measurements. The prevalence of AAA almost doubled using OTO instead of ITI, while the difference between ITI and LTL was minor (3.3% vs. 4.0% AAA). The study shows superior reproducibility of LTL and ITI compared with the OTO method of caliper placement in ultrasound determination of maximum abdominal aortic diameter, and the choice of caliper placement method significantly affects the prevalence of AAAs in screening programs

20 CFR 219.42 - When evidence of child's dependency is required.

Science.gov (United States)

2010-04-01

... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false When evidence of child's dependency is required. 219.42 Section 219.42 Employees' Benefits RAILROAD RETIREMENT BOARD REGULATIONS UNDER THE... child's dependency is required. Evidence of a child's dependency on the employee is required when— (a...

A high-yield co-expression system for the purification of an intact drs2p-cdc50p lipid flippase complex, critically dependent on and stabilized by phosphatidylinositol-4-phosphate

DEFF Research Database (Denmark)

Azouaoui, Hassina; Montigny, Cédric; Ash, Miriam-Rose

2014-01-01

, the Drs2p-Cdc50p complex. After recovery of yeast membranes expressing both proteins, efficient purification was achieved in a single step by affinity chromatography on streptavidin beads, yielding ∼1-2 mg purified Drs2p-Cdc50p complex per liter of culture. Importantly, the procedure enabled us to recover...... was critically dependent on the simultaneous presence of PI4P and PS. We also identified a prominent role for PI4P in stabilization of the Drs2p-Cdc50p complex towards temperature- or C12E8-induced irreversible inactivation. These results indicate that the Drs2p-Cdc50p complex remains functional after affinity...... purification and that PI4P as a cofactor tightly controls its stability and catalytic activity. This work offers appealing perspectives for detailed structural and functional characterization of the Drs2p-Cdc50p lipid transport mechanism....

A PKC-MARCKS-PI3K regulatory module links Ca2+ and PIP3 signals at the leading edge of polarized macrophages.

Directory of Open Access Journals (Sweden)

Brian P Ziemba

Full Text Available The leukocyte chemosensory pathway detects attractant gradients and directs cell migration to sites of inflammation, infection, tissue damage, and carcinogenesis. Previous studies have revealed that local Ca2+ and PIP3 signals at the leading edge of polarized leukocytes play central roles in positive feedback loop essential to cell polarization and chemotaxis. These prior studies showed that stimulation of the leading edge Ca2+ signal can strongly activate PI3K, thereby triggering a larger PIP3 signal, but did not elucidate the mechanistic link between Ca2+ and PIP3 signaling. A hypothesis explaining this link emerged, postulating that Ca2+-activated PKC displaces the MARCKS protein from plasma membrane PIP2, thereby releasing sequestered PIP2 to serve as the target and substrate lipid of PI3K in PIP3 production. In vitro single molecule studies of the reconstituted pathway on lipid bilayers demonstrated the feasibility of this PKC-MARCKS-PI3K regulatory module linking Ca2+ and PIP3 signals in the reconstituted system. The present study tests the model predictions in live macrophages by quantifying the effects of: (a two pathway activators-PDGF and ATP that stimulate chemoreceptors and Ca2+ influx, respectively; and (b three pathway inhibitors-wortmannin, EGTA, and Go6976 that inhibit PI3K, Ca2+ influx, and PKC, respectively; on (c four leading edge activity sensors-AKT-PH-mRFP, CKAR, MARCKSp-mRFP, and leading edge area that report on PIP3 density, PKC activity, MARCKS membrane binding, and leading edge expansion/contraction, respectively. The results provide additional evidence that PKC and PI3K are both essential elements of the leading edge positive feedback loop, and strongly support the existence of a PKC-MARCKS-PI3K regulatory module linking the leading edge Ca2+ and PIP3 signals. As predicted, activators stimulate leading edge PKC activity, displacement of MARCKS from the leading edge membrane and increased leading edge PIP3 levels, while

A PKC-MARCKS-PI3K regulatory module links Ca2+ and PIP3 signals at the leading edge of polarized macrophages.

Science.gov (United States)

Ziemba, Brian P; Falke, Joseph J

2018-01-01

The leukocyte chemosensory pathway detects attractant gradients and directs cell migration to sites of inflammation, infection, tissue damage, and carcinogenesis. Previous studies have revealed that local Ca2+ and PIP3 signals at the leading edge of polarized leukocytes play central roles in positive feedback loop essential to cell polarization and chemotaxis. These prior studies showed that stimulation of the leading edge Ca2+ signal can strongly activate PI3K, thereby triggering a larger PIP3 signal, but did not elucidate the mechanistic link between Ca2+ and PIP3 signaling. A hypothesis explaining this link emerged, postulating that Ca2+-activated PKC displaces the MARCKS protein from plasma membrane PIP2, thereby releasing sequestered PIP2 to serve as the target and substrate lipid of PI3K in PIP3 production. In vitro single molecule studies of the reconstituted pathway on lipid bilayers demonstrated the feasibility of this PKC-MARCKS-PI3K regulatory module linking Ca2+ and PIP3 signals in the reconstituted system. The present study tests the model predictions in live macrophages by quantifying the effects of: (a) two pathway activators-PDGF and ATP that stimulate chemoreceptors and Ca2+ influx, respectively; and (b) three pathway inhibitors-wortmannin, EGTA, and Go6976 that inhibit PI3K, Ca2+ influx, and PKC, respectively; on (c) four leading edge activity sensors-AKT-PH-mRFP, CKAR, MARCKSp-mRFP, and leading edge area that report on PIP3 density, PKC activity, MARCKS membrane binding, and leading edge expansion/contraction, respectively. The results provide additional evidence that PKC and PI3K are both essential elements of the leading edge positive feedback loop, and strongly support the existence of a PKC-MARCKS-PI3K regulatory module linking the leading edge Ca2+ and PIP3 signals. As predicted, activators stimulate leading edge PKC activity, displacement of MARCKS from the leading edge membrane and increased leading edge PIP3 levels, while inhibitors

CDC Vital Signs-Hispanic Health

Centers for Disease Control (CDC) Podcasts

This podcast is based on the May 2015 CDC Vital Signs report. About one in six people living in the U.S. are Hispanic. The two leading causes of death in this group are heart disease and cancer, accounting for two out of five deaths. Unfortunately, many Hispanics face considerable barriers to getting high quality health care, including language and low income. Learn what can be done to reduce the barriers.

Leading edge erosion of coated wind turbine blades: Review of coating life models

NARCIS (Netherlands)

Slot, H.M.; Gelinck, E.R.M.; Rentrop, A.; van der Heide, Emile

2015-01-01

Erosion of the leading edge of wind turbine blades by droplet impingement wear, reduces blade aerodynamic efficiency and power output. Eventually, it compromises the integrity of blade surfaces. Elastomeric coatings are currently used for erosion resistance, yet the life of such coatings cannot be

The influence of airfoil kinematics on the formation of leading-edge vortices in bio-inspired flight

Energy Technology Data Exchange (ETDEWEB)

Rival, David; Prangemeier, Tim; Tropea, Cameron [Technische Universitaet Darmstadt (Germany). Institute of Fluid Mechanics and Aerodynamics

2009-05-15

The formation process of leading-edge vortices has been investigated experimentally using Particle Image Velocimetry. Various airfoil kinematics have been tested, including asymmetric and peak-shifted plunging motions, and are evaluated for Re = 30,000 and a reduced frequency range of 0.2{<=}k{<=}0.33. By measuring the growth in the leading-edge vortex during the dynamic-stall process, the vortex pinch-off process is examined based on the concept of an optimal vortex formation time. The various kinematics are then evaluated with respect to their associated vortex strength, timing and convection into the wake. (orig.)

An empirically-based model for the lift coefficients of twisted airfoils with leading-edge tubercles

Science.gov (United States)

Ni, Zao; Su, Tsung-chow; Dhanak, Manhar

2018-04-01

Experimental data for untwisted airfoils are utilized to propose a model for predicting the lift coefficients of twisted airfoils with leading-edge tubercles. The effectiveness of the empirical model is verified through comparison with results of a corresponding computational fluid-dynamic (CFD) study. The CFD study is carried out for both twisted and untwisted airfoils with tubercles, the latter shown to compare well with available experimental data. Lift coefficients of twisted airfoils predicted from the proposed empirically-based model match well with the corresponding coefficients determined using the verified CFD study. Flow details obtained from the latter provide better insight into the underlying mechanism and behavior at stall of twisted airfoils with leading edge tubercles.

Experimental investigation of wavy leading edges on rod-aerofoil interaction noise

Science.gov (United States)

Chen, Weijie; Qiao, Weiyang; Tong, Fan; Wang, Liangfeng; Wang, Xunnian

2018-05-01

Experimental studies are performed to investigate the effect of wavy leading edges on rod-aerofoil interaction noise in an open-jet anechoic wind tunnel. NACA 0012 aerofoils with straight and wavy leading edges (denoted by SLE and WLE, respectively) are embedded in the wake of a circular rod. The WLEs are in the form of sinusoidal profiles of amplitude, A, and wavelength, W. Parametric studies of the amplitude and wavelength characteristics are conducted to understand the effect of WLEs on noise reduction. It is observed that the sound power reduction level is sensitive to both the amplitude and wavelength of the WLEs. The WLE with the largest amplitude and smallest wavelength can achieve the most considerable noise reduction effect of up to 4 dB. The influences of rod diameter, d, and free-stream velocity, U0, on the noise reduction effect of the WLEs are also investigated. In addition, a parametric study of the influence of separating rod-aerofoil distance on the acoustic radiation of the SLE case and on the sound power reduction level of the WLE cases is performed. It is found that a critical spacing exists where the acoustic radiation and noise reduction can be divided into two different "modes".

Leading-Edge Noise Prediction of General Airfoil Profiles with Spanwise-Varying Inflow Conditions

NARCIS (Netherlands)

Miotto, Renato Fuzaro; Wolf, William Roberto; De Santana, Leandro Dantas

2018-01-01

This paper presents a study of the leading-edge noise radiated by an airfoil undergoing a turbulent inflow. The noise prediction of generic airfoil profiles subjected to spanwise-varying inflow conditions is performed with the support of Amiet’s theory and the inverse strip technique. In the

Leading-Edge Noise Prediction of General Airfoil Profiles with Spanwise-Varying Inflow Conditions

NARCIS (Netherlands)

Miotto, Renato Fuzaro; Wolf, William Roberto; De Santana, Leandro Dantas

This paper presents a study of the leading-edge noise radiated by an airfoil undergoing a turbulent inflow. The noise prediction of generic airfoil profiles subjected to spanwise-varying inflow conditions is performed with the support of Amiet’s theory and the inverse strip technique. In the

Rapid and dynamic arginylation of the leading edge β-actin is required for cell migration.

Science.gov (United States)

Pavlyk, Iuliia; Leu, Nicolae A; Vedula, Pavan; Kurosaka, Satoshi; Kashina, Anna

2018-04-01

β-actin plays key roles in cell migration. Our previous work demonstrated that β-actin in migratory non-muscle cells is N-terminally arginylated and that this arginylation is required for normal lamellipodia extension. Here, we examined the function of β-actin arginylation in cell migration. We found that arginylated β-actin is concentrated at the leading edge of lamellipodia and that this enrichment is abolished after serum starvation as well as in contact-inhibited cells in confluent cultures, suggesting that arginylated β-actin at the cell leading edge is coupled to active migration. Arginylated actin levels exhibit dynamic changes in response to cell stimuli, lowered after serum starvation and dramatically elevating within minutes after cell stimulation by readdition of serum or lysophosphatidic acid. These dynamic changes require active translation and are not seen in confluent contact-inhibited cell cultures. Microinjection of arginylated actin antibodies into cells severely and specifically inhibits their migration rates. Together, these data strongly suggest that arginylation of β-actin is a tightly regulated dynamic process that occurs at the leading edge of locomoting cells in response to stimuli and is integral to the signaling network that regulates cell migration. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

CDC Disease Detective Camp

Centers for Disease Control (CDC) Podcasts

2010-08-02

The CDC Disease Detective Camp gives rising high school juniors and seniors exposure to key aspects of the CDC, including basic epidemiology, infectious and chronic disease tracking, public health law, and outbreak investigations. The camp also helps students explore careers in public health.  Created: 8/2/2010 by Centers for Disease Control and Prevention (CDC).   Date Released: 8/2/2010.

Direct Numerical Simulation of an Airfoil with Sand Grain Roughness on the Leading Edge

Science.gov (United States)

Ribeiro, Andre F. P.; Casalino, Damiano; Fares, Ehab; Choudhari, Meelan

2016-01-01

As part of a computational study of acoustic radiation due to the passage of turbulent boundary layer eddies over the trailing edge of an airfoil, the Lattice-Boltzmann method is used to perform direct numerical simulations of compressible, low Mach number flow past an NACA 0012 airfoil at zero degrees angle of attack. The chord Reynolds number of approximately 0.657 million models one of the test conditions from a previous experiment by Brooks, Pope, and Marcolini at NASA Langley Research Center. A unique feature of these simulations involves direct modeling of the sand grain roughness on the leading edge, which was used in the abovementioned experiment to trip the boundary layer to fully turbulent flow. This report documents the findings of preliminary, proof-of-concept simulations based on a narrow spanwise domain and a limited time interval. The inclusion of fully-resolved leading edge roughness in this simulation leads to significantly earlier transition than that in the absence of any roughness. The simulation data is used in conjunction with both the Ffowcs Williams-Hawkings acoustic analogy and a semi-analytical model by Roger and Moreau to predict the farfield noise. The encouraging agreement between the computed noise spectrum and that measured in the experiment indicates the potential payoff from a full-fledged numerical investigation based on the current approach. Analysis of the computed data is used to identify the required improvements to the preliminary simulations described herein.

Fission Yeast Apc15 Stabilizes MCC-Cdc20-APC/C Complexes, Ensuring Efficient Cdc20 Ubiquitination and Checkpoint Arrest.

Science.gov (United States)

May, Karen M; Paldi, Flora; Hardwick, Kevin G

2017-04-24

During mitosis, cells must segregate the replicated copies of their genome to their daughter cells with extremely high fidelity. Segregation errors lead to an abnormal chromosome number (aneuploidy), which typically results in disease or cell death [1]. Chromosome segregation and anaphase onset are initiated through the action of the multi-subunit E3 ubiquitin ligase known as the anaphase-promoting complex or cyclosome (APC/C [2]). The APC/C is inhibited by the spindle checkpoint in the presence of kinetochore attachment defects [3, 4]. Here we demonstrate that two non-essential APC/C subunits (Apc14 and Apc15) regulate association of spindle checkpoint proteins, in the form of the mitotic checkpoint complex (MCC), with the APC/C. apc14Δ mutants display increased MCC association with the APC/C and are unable to silence the checkpoint efficiently. Conversely, apc15Δ mutants display reduced association between the MCC and APC/C, are defective in poly-ubiquitination of Cdc20, and are checkpoint defective. In vitro reconstitution studies have shown that human MCC-APC/C can contain two molecules of Cdc20 [5-7]. Using a yeast strain expressing two Cdc20 genes with different epitope tags, we show by co-immunoprecipitation that this is true in vivo. MCC binding to the second molecule of Cdc20 is mediated via the C-terminal KEN box in Mad3. Somewhat surprisingly, complexes containing both molecules of Cdc20 accumulate in apc15Δ cells, and the implications of this observation are discussed. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

A Time-Walk Correction Method for PET Detectors Based on Leading Edge Discriminators.

Science.gov (United States)

Du, Junwei; Schmall, Jeffrey P; Judenhofer, Martin S; Di, Kun; Yang, Yongfeng; Cherry, Simon R

2017-09-01

The leading edge timing pick-off technique is the simplest timing extraction method for PET detectors. Due to the inherent time-walk of the leading edge technique, corrections should be made to improve timing resolution, especially for time-of-flight PET. Time-walk correction can be done by utilizing the relationship between the threshold crossing time and the event energy on an event by event basis. In this paper, a time-walk correction method is proposed and evaluated using timing information from two identical detectors both using leading edge discriminators. This differs from other techniques that use an external dedicated reference detector, such as a fast PMT-based detector using constant fraction techniques to pick-off timing information. In our proposed method, one detector was used as reference detector to correct the time-walk of the other detector. Time-walk in the reference detector was minimized by using events within a small energy window (508.5 - 513.5 keV). To validate this method, a coincidence detector pair was assembled using two SensL MicroFB SiPMs and two 2.5 mm × 2.5 mm × 20 mm polished LYSO crystals. Coincidence timing resolutions using different time pick-off techniques were obtained at a bias voltage of 27.5 V and a fixed temperature of 20 °C. The coincidence timing resolution without time-walk correction were 389.0 ± 12.0 ps (425 -650 keV energy window) and 670.2 ± 16.2 ps (250-750 keV energy window). The timing resolution with time-walk correction improved to 367.3 ± 0.5 ps (425 - 650 keV) and 413.7 ± 0.9 ps (250 - 750 keV). For comparison, timing resolutions were 442.8 ± 12.8 ps (425 - 650 keV) and 476.0 ± 13.0 ps (250 - 750 keV) using constant fraction techniques, and 367.3 ± 0.4 ps (425 - 650 keV) and 413.4 ± 0.9 ps (250 - 750 keV) using a reference detector based on the constant fraction technique. These results show that the proposed leading edge based time-walk correction method works well. Timing resolution obtained

CDC73 intragenic deletion in familial primary hyperparathyroidism associated with parathyroid carcinoma.

Science.gov (United States)

Korpi-Hyövälti, Eeva; Cranston, Treena; Ryhänen, Eeva; Arola, Johanna; Aittomäki, Kristiina; Sane, Timo; Thakker, Rajesh V; Schalin-Jäntti, Camilla

2014-09-01

CDC73 mutations frequently underlie the hyperparathyroidism-jaw tumor syndrome, familial isolated hyperparathyroidism (FIHP), and parathyroid carcinoma. It has also been suggested that CDC73 deletion analysis should be performed in those patients without CDC73 mutations. To investigate for CDC73 deletion in a family with FIHP previously reported not to have CDC73 mutations. Eleven members (six affected with primary hyperparathyroidism and five unaffected) were ascertained from the family, and multiplex ligation-dependent probe amplification was performed to detect CDC73 deletion using leukocyte DNA. A previously unreported deletion of CDC73 involving exons 1-10 was detected in five affected members and two unaffected members who were 26 and 39 years of age. Two affected members had parathyroid carcinomas at the ages of 18 and 32 years, and they had Ki-67 proliferation indices of 5 and 14.5% and did not express parafibromin, encoded by CDC73. Primary hyperparathyroidism in the other affected members was due to adenomas and atypical adenomas, and none had jaw tumors. Two affected members had thoracic aortic aneurysms, which in one member occurred with parathyroid carcinoma and renal cysts. A previously unreported intragenic deletion of exons 1 to 10 of CDC73 was detected in a three-generation family with FIHP, due to adenomas, atypical adenomas, and parathyroid carcinomas. In addition, two affected males had thoracic aortic aneurysms, which may represent another associated clinical feature of this disorder.

Amplitude-dependent topological edge states in nonlinear phononic lattices

Science.gov (United States)

Pal, Raj Kumar; Vila, Javier; Leamy, Michael; Ruzzene, Massimo

2018-03-01

This work investigates the effect of nonlinearities on topologically protected edge states in one- and two-dimensional phononic lattices. We first show that localized modes arise at the interface between two spring-mass chains that are inverted copies of each other. Explicit expressions derived for the frequencies of the localized modes guide the study of the effect of cubic nonlinearities on the resonant characteristics of the interface, which are shown to be described by a Duffing-like equation. Nonlinearities produce amplitude-dependent frequency shifts, which in the case of a softening nonlinearity cause the localized mode to migrate to the bulk spectrum. The case of a hexagonal lattice implementing a phononic analog of a crystal exhibiting the quantum spin Hall effect is also investigated in the presence of weakly nonlinear cubic springs. An asymptotic analysis provides estimates of the amplitude dependence of the localized modes, while numerical simulations illustrate how the lattice response transitions from bulk-to-edge mode-dominated by varying the excitation amplitude. In contrast with the interface mode of the first example studies, this occurs both for hardening and softening springs. The results of this study provide a theoretical framework for the investigation of nonlinear effects that induce and control topologically protected wave modes through nonlinear interactions and amplitude tuning.

Next-generation science information network for leading-edge applications

International Nuclear Information System (INIS)

Urushidani, S.; Matsukata, J.

2008-01-01

High-speed networks are definitely essential tools for leading-edge applications in many research areas, including nuclear fusion research. This paper describes a number of advanced features in the Japanese next-generation science information network, called SINET3, and gives researchers clues on the uses of advanced high-speed network for their applications. The network services have four categories, multiple layer transfer, enriched virtual private network, enhanced quality-of-service, and bandwidth on demand services, and comprise a versatile service platform. The paper also describes the network architecture and advanced networking capabilities that enable economical service accommodation and flexible network resource assignment as well as effective use of Japan's first 40-Gbps lines

Next-generation science information network for leading-edge applications

Energy Technology Data Exchange (ETDEWEB)

Urushidani, S. [National Institute of Informatics, 2-1-2 Hitotsubashi Chiyoda-ku, Tokyo 101-8430 (Japan)], E-mail: urushi@nii.ac.jp; Matsukata, J. [National Institute of Informatics, 2-1-2 Hitotsubashi Chiyoda-ku, Tokyo 101-8430 (Japan)

2008-04-15

High-speed networks are definitely essential tools for leading-edge applications in many research areas, including nuclear fusion research. This paper describes a number of advanced features in the Japanese next-generation science information network, called SINET3, and gives researchers clues on the uses of advanced high-speed network for their applications. The network services have four categories, multiple layer transfer, enriched virtual private network, enhanced quality-of-service, and bandwidth on demand services, and comprise a versatile service platform. The paper also describes the network architecture and advanced networking capabilities that enable economical service accommodation and flexible network resource assignment as well as effective use of Japan's first 40-Gbps lines.

Low-Speed Wind-Tunnel Investigation of Blowing Boundary-Layer Control on Leading- and Trailing-Edge Flaps of a Large-Scale, Low-Aspect-Ratio, 45 Swept-wing Airplane Configuration

Science.gov (United States)

Maki, Ralph L.

1959-01-01

Blowing boundary-layer control was applied to the leading- and trailing-edge flaps of a 45 deg sweptback-wing complete model in a full-scale low-speed wind-tunnel study. The principal purpose of the study was to determine the effects of leading-edge flap deflection and boundary-layer control on maximum lift and longitudinal stability. Leading-edge flap deflection alone was sufficient to maintain static longitudinal stability without trailing-edge flaps. However, leading-edge flap blowing was required to maintain longitudinal stability by delaying leading-edge flow separation when trailing-edge flaps were deflected either with or without blowing. Partial-span leading-edge flaps deflected 60 deg with moderate blowing gave the major increase in maximum lift, although higher deflection and additional blowing gave some further increase. Inboard of 0.4 semispan leading-edge flap deflection could be reduced to 40 deg and/or blowing could be omitted with only small loss in maximum lift. Trailing-edge flap lift increments were increased by boundary-layer control for deflections greater than 45 deg. Maximum lift was not increased with deflected trailing-edge flaps with blowing.

Rotational accelerations stabilize leading edge vortices on revolving fly wings.

Science.gov (United States)

Lentink, David; Dickinson, Michael H

2009-08-01

The aerodynamic performance of hovering insects is largely explained by the presence of a stably attached leading edge vortex (LEV) on top of their wings. Although LEVs have been visualized on real, physically modeled, and simulated insects, the physical mechanisms responsible for their stability are poorly understood. To gain fundamental insight into LEV stability on flapping fly wings we expressed the Navier-Stokes equations in a rotating frame of reference attached to the wing's surface. Using these equations we show that LEV dynamics on flapping wings are governed by three terms: angular, centripetal and Coriolis acceleration. Our analysis for hovering conditions shows that angular acceleration is proportional to the inverse of dimensionless stroke amplitude, whereas Coriolis and centripetal acceleration are proportional to the inverse of the Rossby number. Using a dynamically scaled robot model of a flapping fruit fly wing to systematically vary these dimensionless numbers, we determined which of the three accelerations mediate LEV stability. Our force measurements and flow visualizations indicate that the LEV is stabilized by the ;quasi-steady' centripetal and Coriolis accelerations that are present at low Rossby number and result from the propeller-like sweep of the wing. In contrast, the unsteady angular acceleration that results from the back and forth motion of a flapping wing does not appear to play a role in the stable attachment of the LEV. Angular acceleration is, however, critical for LEV integrity as we found it can mediate LEV spiral bursting, a high Reynolds number effect. Our analysis and experiments further suggest that the mechanism responsible for LEV stability is not dependent on Reynolds number, at least over the range most relevant for insect flight (100wind turbines at much higher Reynolds numbers suggest that even large flying animals could potentially exploit LEV-based force augmentation during slow hovering flight, take-offs or landing

Structural characteristics of the shock-induced boundary layer separation extended to the leading edge

Science.gov (United States)

Tao, Y.; Liu, W. D.; Fan, X. Q.; Zhao, Y. L.

2017-07-01

For a better understanding of the local unstart of supersonic/hypersonic inlet, a series of experiments has been conducted to investigate the shock-induced boundary layer separation extended to the leading edge. Using the nanoparticle-based planar laser scattering, we recorded the fine structures of these interactions under different conditions and paid more attention to their structural characteristics. According to their features, these interactions could be divided into four types. Specifically, Type A wave pattern is similar to the classic shock wave/turbulent boundary layer interaction, and Type B wave configuration consists of an overall Mach reflection above the large scale separation bubble. Due to the gradual decrease in the size of the separation bubble, the separation bubble was replaced by several vortices (Type C wave pattern). Besides, for Type D wave configuration which exists in the local unstart inlet, there appears to be some flow spillage around the leading edge.

Redox-dependent spatially resolved electrochemistry at graphene and graphite step edges.

Science.gov (United States)

Güell, Aleix G; Cuharuc, Anatolii S; Kim, Yang-Rae; Zhang, Guohui; Tan, Sze-yin; Ebejer, Neil; Unwin, Patrick R

2015-04-28

The electrochemical (EC) behavior of mechanically exfoliated graphene and highly oriented pyrolytic graphite (HOPG) is studied at high spatial resolution in aqueous solutions using Ru(NH3)6(3+/2+) as a redox probe whose standard potential sits close to the intrinsic Fermi level of graphene and graphite. When scanning electrochemical cell microscopy (SECCM) data are coupled with that from complementary techniques (AFM, micro-Raman) applied to the same sample area, different time-dependent EC activity between the basal planes and step edges is revealed. In contrast, other redox couples (ferrocene derivatives) whose potential is further removed from the intrinsic Fermi level of graphene and graphite show uniform and high activity (close to diffusion-control). Macroscopic voltammetric measurements in different environments reveal that the time-dependent behavior after HOPG cleavage, peculiar to Ru(NH3)6(3+/2+), is not associated particularly with any surface contaminants but is reasonably attributed to the spontaneous delamination of the HOPG with time to create partially coupled graphene layers, further supported by conductive AFM measurements. This process has a major impact on the density of states of graphene and graphite edges, particularly at the intrinsic Fermi level to which Ru(NH3)6(3+/2+) is most sensitive. Through the use of an improved voltammetric mode of SECCM, we produce movies of potential-resolved and spatially resolved HOPG activity, revealing how enhanced activity at step edges is a subtle effect for Ru(NH3)6(3+/2+). These latter studies allow us to propose a microscopic model to interpret the EC response of graphene (basal plane and edges) and aged HOPG considering the nontrivial electronic band structure.

Fabrication of lithium/C-103 alloy heat pipes for sharp leading edge cooling

Science.gov (United States)

Ai, Bangcheng; Chen, Siyuan; Yu, Jijun; Lu, Qin; Han, Hantao; Hu, Longfei

2018-05-01

In this study, lithium/C-103 alloys heat pipes are proposed for sharp leading edge cooling. Three models of lithium/C-103 alloy heat pipes were fabricated. And their startup properties were tested by radiant heat tests and aerothermal tests. It is found that the startup temperature of lithium heat pipe was about 860 °C. At 1000 °C radiant heat tests, the operating temperature of lithium/C-103 alloy heat pipe is lower than 860 °C. Thus, startup failure occurs. At 1100 °C radiant heat tests and aerothermal tests, the operating temperature of lithium/C-103 alloy heat pipe is higher than 860 °C, and the heat pipe starts up successfully. The startup of lithium/C-103 alloy heat pipe decreases the leading edge temperature effectively, which endows itself good ablation resistance. After radiant heat tests and aerothermal tests, all the heat pipe models are severely oxidized because of the C-103 poor oxidation resistance. Therefore, protective coatings are required for further applications of lithium/C-103 alloy heat pipes.

Space Shuttle Orbiter Wing-Leading-Edge Panel Thermo-Mechanical Analysis for Entry Conditions

Science.gov (United States)

Knight, Norman F., Jr.; Song, Kyongchan; Raju, Ivatury S.

2010-01-01

Linear elastic, thermo-mechanical stress analyses of the Space Shuttle Orbiter wing-leading-edge panels is presented for entry heating conditions. The wing-leading-edge panels are made from reinforced carbon-carbon and serve as a part of the overall thermal protection system. Three-dimensional finite element models are described for three configurations: integrated configuration, an independent single-panel configuration, and a local lower-apex joggle segment. Entry temperature conditions are imposed and the through-the-thickness response is examined. From the integrated model, it was concluded that individual panels can be analyzed independently since minimal interaction between adjacent components occurred. From the independent single-panel model, it was concluded that increased through-the-thickness stress levels developed all along the chord of a panel s slip-side joggle region, and hence isolated local joggle sections will exhibit the same trend. From the local joggle models, it was concluded that two-dimensional plane-strain models can be used to study the influence of subsurface defects along the slip-side joggle region of these panels.

Two Functionally Distinct Sources of Actin Monomers Supply the Leading Edge of Lamellipodia

Science.gov (United States)

Vitriol, Eric A.; McMillen, Laura M.; Kapustina, Maryna; Gomez, Shawn M.; Vavylonis, Dimitrios; Zheng, James Q.

2015-01-01

Summary Lamellipodia, the sheet-like protrusions of motile cells, consist of networks of actin filaments (F-actin) regulated by the ordered assembly from and disassembly into actin monomers (G-actin). Traditionally, G-actin is thought to exist as a homogeneous pool. Here, we show that there are two functionally and molecularly distinct sources of G-actin that supply lamellipodial actin networks. G-actin originating from the cytosolic pool requires the monomer binding protein thymosin β4 (Tβ4) for optimal leading edge localization, is targeted to formins, and is responsible for creating an elevated G/F-actin ratio that promotes membrane protrusion. The second source of G-actin comes from recycled lamellipodia F-actin. Recycling occurs independently of Tβ4 and appears to regulate lamellipodia homeostasis. Tβ4-bound G-actin specifically localizes to the leading edge because it doesn’t interact with Arp2/3-mediated polymerization sites found throughout the lamellipodia. These findings demonstrate that actin networks can be constructed from multiple sources of monomers with discrete spatiotemporal functions. PMID:25865895

Strategic role of the ubiquitin-dependent segregase p97 (VCP or Cdc48) in DNA replication.

Science.gov (United States)

Ramadan, Kristijan; Halder, Swagata; Wiseman, Katherine; Vaz, Bruno

2017-02-01

Genome amplification (DNA synthesis) is one of the most demanding cellular processes in all proliferative cells. The DNA replication machinery (also known as the replisome) orchestrates genome amplification during S-phase of the cell cycle. Genetic material is particularly vulnerable to various events that can challenge the replisome during its assembly, activation (firing), progression (elongation) and disassembly from chromatin (termination). Any disturbance of the replisome leads to stalling of the DNA replication fork and firing of dormant replication origins, a process known as DNA replication stress. DNA replication stress is considered to be one of the main causes of sporadic cancers and other pathologies related to tissue degeneration and ageing. The mechanisms of replisome assembly and elongation during DNA synthesis are well understood. However, once DNA synthesis is complete, the process of replisome disassembly, and its removal from chromatin, remains unclear. In recent years, a growing body of evidence has alluded to a central role in replisome regulation for the ubiquitin-dependent protein segregase p97, also known as valosin-containing protein (VCP) in metazoans and Cdc48 in lower eukaryotes. By orchestrating the spatiotemporal turnover of the replisome, p97 plays an essential role in DNA replication. In this review, we will summarise our current knowledge about how p97 controls the replisome from replication initiation, to elongation and finally termination. We will also further examine the more recent findings concerning the role of p97 and how mutations in p97 cofactors, also known as adaptors, cause DNA replication stress induced genomic instability that leads to cancer and accelerated ageing. To our knowledge, this is the first comprehensive review concerning the mechanisms involved in the regulation of DNA replication by p97.

Unsteady behavior of leading-edge vortex and diffuser stall in a centrifugal compressor with vaned diffuser

Science.gov (United States)

Fujisawa, Nobumichi; Hara, Shotaro; Ohta, Yutaka

2016-02-01

The characteristics of a rotating stall of an impeller and diffuser and the evolution of a vortex generated at the diffuser leading-edge (i.e., the leading-edge vortex (LEV)) in a centrifugal compressor were investigated by experiments and numerical analysis. The results of the experiments revealed that both the impeller and diffuser rotating stalls occurred at 55 and 25 Hz during off-design flow operation. For both, stall cells existed only on the shroud side of the flow passages, which is very close to the source location of the LEV. According to the CFD results, the LEV is made up of multiple vortices. The LEV is a combination of a separated vortex near the leading- edge and a longitudinal vortex generated by the extended tip-leakage flow from the impeller. Therefore, the LEV is generated by the accumulation of vorticity caused by the velocity gradient of the impeller discharge flow. In partial-flow operation, the spanwise extent and the position of the LEV origin are temporarily transmuted. The LEV develops with a drop in the velocity in the diffuser passage and forms a significant blockage within the diffuser passage. Therefore, the LEV may be regarded as being one of the causes of a diffuser stall in a centrifugal compressor.

Chlamydia - CDC Fact Sheet

Science.gov (United States)

... Archive STDs Home Page Bacterial Vaginosis (BV) Chlamydia Gonorrhea Genital Herpes Hepatitis HIV/AIDS & STDs Human Papillomavirus ( ... sheet Pelvic Inflammatory Disease (PID) – CDC fact sheet Gonorrhea – CDC fact sheet STDs Home Page Bacterial Vaginosis ( ...

Optically Unraveling the Edge Chirality-Dependent Band Structure and Plasmon Damping in Graphene Edges.

Science.gov (United States)

Duan, Jiahua; Chen, Runkun; Cheng, Yuan; Yang, Tianzhong; Zhai, Feng; Dai, Qing; Chen, Jianing

2018-05-01

The nontrivial topological origin and pseudospinorial character of electron wavefunctions make edge states possess unusual electronic properties. Twenty years ago, the tight-binding model calculation predicted that zigzag termination of 2D sheets of carbon atoms have peculiar edge states, which show potential application in spintronics and modern information technologies. Although scanning probe microscopy is employed to capture this phenomenon, the experimental demonstration of its optical response remains challenging. Here, the propagating graphene plasmon provides an edge-selective polaritonic probe to directly detect and control the electronic edge state at ambient condition. Compared with armchair, the edge-band structure in the bandgap gives rise to additional optical absorption and strongly absorbed rim at zigzag edge. Furthermore, the optical conductivity is reconstructed and the anisotropic plasmon damping in graphene systems is revealed. The reported approach paves the way for detecting edge-specific phenomena in other van der Waals materials and topological insulators. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Streamwise counter-rotating vortices generated by triangular leading edge pattern in flat plate boundary layer

KAUST Repository

Hasheminejad, S. M.; Mitsudharmadi, Hatsari; Winoto, S. H.; Lua, K. B.; Low, H. T.

2016-01-01

A series of flow visualizations were conducted to qualitatively study the development of streamwise counter-rotating vortices over a flat plate induced by triangular patterns at the leading edge of a flat plate. The experiments were carried out

Overexpression of CDC25B, CDC25C and phospho-CDC25C (Ser216) in vulvar squamous cell carcinomas are associated with malignant features and aggressive cancer phenotypes

OpenAIRE

Wang, Zhihui; Trope, Claes G; Fl?renes, Vivi Ann; Suo, Zhenhe; Nesland, Jahn M; Holm, Ruth

2010-01-01

Background CDC25 phosphatases are important regulators of the cell cycle. Their abnormal expression detected in a number of tumors implies that their dysregulation is involved in malignant transformation. However, the role of CDC25s in vulvar cancer is still unknown. To shed light on their roles in the pathogenesis and to clarify their prognostic values, expression of CDC25A, CDC25B and CDC25C in a large series of vulvar squamous cell carcinomas were examined. ...

Materials, Manufacturing, and Test Development of a Composite Fan Blade Leading Edge Subcomponent for Improved Impact Resistance

Science.gov (United States)

Miller, Sandi G.; Handschuh, Katherine; Sinnott, Matthew J.; Kohlman, Lee W.; Roberts, Gary D.; Martin, Richard E.; Ruggeri, Charles R.; Pereira, J. Michael

2015-01-01

Application of polymer matrix composite materials for jet engine fan blades is becoming attractive as an alternative to metallic blades; particularly for large engines where significant weight savings are recognized on moving to a composite structure. However, the weight benefit of the composite is offset by a reduction of aerodynamic efficiency resulting from a necessary increase in blade thickness; relative to the titanium blades. Blade dimensions are largely driven by resistance to damage on bird strike. Further development of the composite material is necessary to allow composite blade designs to approximate the dimensions of a metallic fan blade. The reduction in thickness over the state of the art composite blades is expected to translate into structural weight reduction, improved aerodynamic efficiency, and therefore reduced fuel consumption. This paper presents test article design, subcomponent blade leading edge fabrication, test method development, and initial results from ballistic impact of a gelatin projectile on the leading edge of composite fan blades. The simplified test article geometry was developed to realistically simulate a blade leading edge while decreasing fabrication complexity. Impact data is presented on baseline composite blades and toughened blades; where a considerable improvement to impact resistance was recorded.

Leading edge effect in laminar boundary layer excitation by sound

International Nuclear Information System (INIS)

Leehey, P.; Shapiro, P.

1980-01-01

Essentially plane pure tone sound waves were directed downstream over a heavily damped smooth flat plate installed in a low turbulence (0.04%) subsonic wind tunnel. Laminar boundary layer disturbance growth rates were measured with and without sound excitation and compared with numerical results from spatial stability theory. The data indicate that the sound field and Tollmien-Schlichting (T-S) waves coexist with comparable amplitudes when the latter are damped; moreover, the response is linear. Higher early growth rates occur for excitation by sound than by stream turbulence. Theoretical considerations indicate that the boundary layer is receptive to sound excitation primarily at the test plate leading edge. (orig.)

Caffeine stabilizes Cdc25 independently of Rad3 in S chizosaccharomyces pombe contributing to checkpoint override

Science.gov (United States)

Alao, John P; Sjölander, Johanna J; Baar, Juliane; Özbaki-Yagan, Nejla; Kakoschky, Bianca; Sunnerhagen, Per

2014-01-01

Cdc25 is required for Cdc2 dephosphorylation and is thus essential for cell cycle progression. Checkpoint activation requires dual inhibition of Cdc25 and Cdc2 in a Rad3-dependent manner. Caffeine is believed to override activation of the replication and DNA damage checkpoints by inhibiting Rad3-related proteins in both S chizosaccharomyces pombe and mammalian cells. In this study, we have investigated the impact of caffeine on Cdc25 stability, cell cycle progression and checkpoint override. Caffeine induced Cdc25 accumulation in S . pombe independently of Rad3. Caffeine delayed cell cycle progression under normal conditions but advanced mitosis in cells treated with replication inhibitors and DNA-damaging agents. In the absence of Cdc25, caffeine inhibited cell cycle progression even in the presence of hydroxyurea or phleomycin. Caffeine induces Cdc25 accumulation in S . pombe by suppressing its degradation independently of Rad3. The induction of Cdc25 accumulation was not associated with accelerated progression through mitosis, but rather with delayed progression through cytokinesis. Caffeine-induced Cdc25 accumulation appears to underlie its ability to override cell cycle checkpoints. The impact of Cdc25 accumulation on cell cycle progression is attenuated by Srk1 and Mad2. Together our findings suggest that caffeine overrides checkpoint enforcement by inducing the inappropriate nuclear localization of Cdc25. PMID:24666325

CDC Disease Detective Camp

Centers for Disease Control (CDC) Podcasts

The CDC Disease Detective Camp gives rising high school juniors and seniors exposure to key aspects of the CDC, including basic epidemiology, infectious and chronic disease tracking, public health law, and outbreak investigations. The camp also helps students explore careers in public health.

Properties on the edge: graphene edge energies, edge stresses, edge warping, and the Wulff shape of graphene flakes

International Nuclear Information System (INIS)

Branicio, Paulo S; Jhon, Mark H; Gan, Chee Kwan; Srolovitz, David J

2011-01-01

It has been shown that the broken bonds of an unreconstructed graphene edge generate compressive edge stresses leading to edge warping. Here, we investigate edge energies and edge stresses of graphene nanoribbons with arbitrary orientations from armchair to zigzag, considering both flat and warped edge shapes in the presence and absence of hydrogen. We use the second generation reactive empirical bond order potential to calculate the edge energies and stresses for clean and hydrogenated edges. Using these energies, we perform a Wulff construction to determine the equilibrium shapes of flat graphene flakes as a function of hydrogen chemical potential. While edge stresses for clean, flat edges are compressive, they become tensile if allowed to warp. Conversely, we find that edge energies change little (∼1%) with edge warping. Hydrogenation of the edges virtually eliminates both the edge energy and edge stresses. For warped edges an approximately linear relationship is found between amplitudes and wavelengths. The equilibrium shape of a graphene flake is determined by the value of the hydrogen chemical potential. For very small (and large) values of it the flakes have a nearly hexagonal (dodecagon) shape with zigzag oriented edges, while for intermediate values graphene flakes are found with complex shapes

Characterization of Unsteady Flow Structures Near Leading-Edge Slat. Part 1; PIV Measurements

Science.gov (United States)

Jenkins, Luther N.; Khorrami, Mehdi R.; Choudhari, Meelan

2004-01-01

A comprehensive computational and experimental study has been performed at the NASA Langley Research Center as part of the Quiet Aircraft Technology (QAT) Program to investigate the unsteady flow near a leading-edge slat of a two-dimensional, high-lift system. This paper focuses on the experimental effort conducted in the NASA Langley Basic Aerodynamics Research Tunnel (BART) where Particle Image Velocimetry (PIV) data was acquired in the slat cove and at the slat trailing edge of a three-element, high-lift model at 4, 6, and 8 degrees angle of attack and a freestream Mach Number of 0.17. Instantaneous velocities obtained from PIV images are used to obtain mean and fluctuating components of velocity and vorticity. The data show the recirculation in the cove, reattachment of the shear layer on the slat lower surface, and discrete vortical structures within the shear layer emanating from the slat cusp and slat trailing edge. Detailed measurements are used to examine the shear layer formation at the slat cusp, vortex shedding at the slat trailing edge, and convection of vortical structures through the slat gap. Selected results are discussed and compared with unsteady, Reynolds-Averaged Navier-Stokes (URANS) computations for the same configuration in a companion paper by Khorrami, Choudhari, and Jenkins (2004). The experimental dataset provides essential flow-field information for the validation of near-field inputs to noise prediction tools.

42 CFR 61.9 - Payments: Stipends; dependency allowances; travel allowances.

Science.gov (United States)

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Payments: Stipends; dependency allowances; travel... FELLOWSHIPS, INTERNSHIPS, TRAINING FELLOWSHIPS Regular Fellowships § 61.9 Payments: Stipends; dependency allowances; travel allowances. Payments for stipends, dependency allowances, and the travel allowances...

Assignment of C1q-binding HLA antibodies as unacceptable HLA antigens avoids positive CDC-crossmatches prior to transplantation of deceased donor organs.

Science.gov (United States)

Juhl, David; Marget, Matthias; Hallensleben, Michael; Görg, Siegfried; Ziemann, Malte

2017-03-01

Soon, a virtual crossmatch shall replace the complement-dependent cytotoxicity (CDC) allocation crossmatch in the Eurotransplant region. To prevent positive CDC-crossmatches in the recipient centre, careful definition of unacceptable antigens is necessary. For highly sensitized patients, this is difficult by CDC alone. Assignment of all antibodies detected by sensitive assays, however, could prevent organ allocation. To assess the usefulness of the Luminex C1q-assay to prevent positive CDC-crossmatches, all CDC-crossmatches performed prior to deceased kidney transplantation in a 16-month-period were reviewed. Sera causing positive crossmatches were investigated by the C1q-assay. 31 out of 1432 crossmatches (2.2%) were positive. Sera involved in 26 positive crossmatches were available. C1q-binding donor-specific antibodies were detected in 19 sera (73.1%). The other sera were from recipients without any HLA antibodies detectable by CDC or common solid phase assays. Three patients had known Non-HLA antibodies causing positive CDC-results. Four crossmatches were only weak positive. Therefore, avoidance of donors with HLA antigens against whom C1q-binding antibodies were detected would have prevented all positive crossmatches due to HLA antibodies. Provided that all HLA specificities against which antibodies are detected by the Luminex C1q-assay are considered as unacceptable antigens, CDC-crossmatches prior to transplantation might safely be omitted in many patients. They should be maintained in highly immunized patients, however, for whom assignment of all C1q-positive antibodies as unacceptable antigens could lead to a significant delay or even prevention of transplantation. Copyright © 2017 Elsevier B.V. All rights reserved.

Method and System for Weakening Shock Wave Strength at Leading Edge Surfaces of Vehicle in Supersonic Atmospheric Flight

Science.gov (United States)

Daso, Endwell O. (Inventor); Pritchett, Victor E., II (Inventor); Wang, Ten-See (Inventor); Farr, Rebecca Ann (Inventor); Auslender, Aaron Howard (Inventor); Blankson, Isaiah M. (Inventor); Plotkin, Kenneth J. (Inventor)

2015-01-01

A method and system are provided to weaken shock wave strength at leading edge surfaces of a vehicle in atmospheric flight. One or more flight-related attribute sensed along a vehicle's outer mold line are used to control the injection of a non-heated, non-plasma-producing gas into a local external flowfield of the vehicle from at least one leading-edge surface location along the vehicle's outer mold line. Pressure and/or mass flow rate of the gas so-injected is adjusted in order to cause a Rankine-Hugoniot Jump Condition along the vehicle's outer mold line to be violated.

Managed aquifer recharge: rediscovering nature as a leading edge technology.

Science.gov (United States)

Dillon, P; Toze, S; Page, D; Vanderzalm, J; Bekele, E; Sidhu, J; Rinck-Pfeiffer, S

2010-01-01

Use of Managed Aquifer Recharge (MAR) has rapidly increased in Australia, USA, and Europe in recent years as an efficient means of recycling stormwater or treated sewage effluent for non-potable and indirect potable reuse in urban and rural areas. Yet aquifers have been relied on knowingly for water storage and unwittingly for water treatment for millennia. Hence if 'leading edge' is defined as 'the foremost part of a trend; a vanguard', it would be misleading to claim managed aquifer recharge as a leading edge technology. However it has taken a significant investment in scientific research in recent years to demonstrate the effectiveness of aquifers as sustainable treatment systems to enable managed aquifer recharge to be recognised along side engineered treatment systems in water recycling. It is a 'cross-over' technology that is applicable to water and wastewater treatment and makes use of passive low energy processes to spectacularly reduce the energy requirements for water supply. It is robust within limits, has low cost, is suitable from village to city scale supplies, and offers as yet almost untapped opportunities for producing safe drinking water supplies where they do not yet exist. It will have an increasingly valued role in securing water supplies to sustain cities affected by climate change and population growth. However it is not a universal panacea and relies on the presence of suitable aquifers and sources of water together with effective governance to ensure human health and environment protection and water resources planning and management. This paper describes managed aquifer recharge, illustrates its use in Australia, outlining economics, guidelines and policies, and presents some of the knowledge about aquifer treatment processes that are revealing the latent value of aquifers as urban water infrastructure and provide a driver to improving our understanding of urban hydrogeology.

Parallel Algorithms for Switching Edges in Heterogeneous Graphs.

Science.gov (United States)

Bhuiyan, Hasanuzzaman; Khan, Maleq; Chen, Jiangzhuo; Marathe, Madhav

2017-06-01

An edge switch is an operation on a graph (or network) where two edges are selected randomly and one of their end vertices are swapped with each other. Edge switch operations have important applications in graph theory and network analysis, such as in generating random networks with a given degree sequence, modeling and analyzing dynamic networks, and in studying various dynamic phenomena over a network. The recent growth of real-world networks motivates the need for efficient parallel algorithms. The dependencies among successive edge switch operations and the requirement to keep the graph simple (i.e., no self-loops or parallel edges) as the edges are switched lead to significant challenges in designing a parallel algorithm. Addressing these challenges requires complex synchronization and communication among the processors leading to difficulties in achieving a good speedup by parallelization. In this paper, we present distributed memory parallel algorithms for switching edges in massive networks. These algorithms provide good speedup and scale well to a large number of processors. A harmonic mean speedup of 73.25 is achieved on eight different networks with 1024 processors. One of the steps in our edge switch algorithms requires the computation of multinomial random variables in parallel. This paper presents the first non-trivial parallel algorithm for the problem, achieving a speedup of 925 using 1024 processors.

CDC Vital Signs-Hispanic Health

Centers for Disease Control (CDC) Podcasts

2015-05-05

This podcast is based on the May 2015 CDC Vital Signs report. About one in six people living in the U.S. are Hispanic. The two leading causes of death in this group are heart disease and cancer, accounting for two out of five deaths. Unfortunately, many Hispanics face considerable barriers to getting high quality health care, including language and low income. Learn what can be done to reduce the barriers.  Created: 5/5/2015 by Office of Minority Health & Health Equity (OMHHE).   Date Released: 5/5/2015.

Are quantum spin Hall edge modes more resilient to disorder, sample geometry and inelastic scattering than quantum Hall edge modes?

Science.gov (United States)

Mani, Arjun; Benjamin, Colin

2016-04-13

On the surface of 2D topological insulators, 1D quantum spin Hall (QSH) edge modes occur with Dirac-like dispersion. Unlike quantum Hall (QH) edge modes, which occur at high magnetic fields in 2D electron gases, the occurrence of QSH edge modes is due to spin-orbit scattering in the bulk of the material. These QSH edge modes are spin-dependent, and chiral-opposite spins move in opposing directions. Electronic spin has a larger decoherence and relaxation time than charge. In view of this, it is expected that QSH edge modes will be more robust to disorder and inelastic scattering than QH edge modes, which are charge-dependent and spin-unpolarized. However, we notice no such advantage accrues in QSH edge modes when subjected to the same degree of contact disorder and/or inelastic scattering in similar setups as QH edge modes. In fact we observe that QSH edge modes are more susceptible to inelastic scattering and contact disorder than QH edge modes. Furthermore, while a single disordered contact has no effect on QH edge modes, it leads to a finite charge Hall current in the case of QSH edge modes, and thus a vanishing of the pure QSH effect. For more than a single disordered contact while QH states continue to remain immune to disorder, QSH edge modes become more susceptible--the Hall resistance for the QSH effect changes sign with increasing disorder. In the case of many disordered contacts with inelastic scattering included, while quantization of Hall edge modes holds, for QSH edge modes a finite charge Hall current still flows. For QSH edge modes in the inelastic scattering regime we distinguish between two cases: with spin-flip and without spin-flip scattering. Finally, while asymmetry in sample geometry can have a deleterious effect in the QSH case, it has no impact in the QH case.

Are quantum spin Hall edge modes more resilient to disorder, sample geometry and inelastic scattering than quantum Hall edge modes?

International Nuclear Information System (INIS)

Mani, Arjun; Benjamin, Colin

2016-01-01

On the surface of 2D topological insulators, 1D quantum spin Hall (QSH) edge modes occur with Dirac-like dispersion. Unlike quantum Hall (QH) edge modes, which occur at high magnetic fields in 2D electron gases, the occurrence of QSH edge modes is due to spin–orbit scattering in the bulk of the material. These QSH edge modes are spin-dependent, and chiral-opposite spins move in opposing directions. Electronic spin has a larger decoherence and relaxation time than charge. In view of this, it is expected that QSH edge modes will be more robust to disorder and inelastic scattering than QH edge modes, which are charge-dependent and spin-unpolarized. However, we notice no such advantage accrues in QSH edge modes when subjected to the same degree of contact disorder and/or inelastic scattering in similar setups as QH edge modes. In fact we observe that QSH edge modes are more susceptible to inelastic scattering and contact disorder than QH edge modes. Furthermore, while a single disordered contact has no effect on QH edge modes, it leads to a finite charge Hall current in the case of QSH edge modes, and thus a vanishing of the pure QSH effect. For more than a single disordered contact while QH states continue to remain immune to disorder, QSH edge modes become more susceptible—the Hall resistance for the QSH effect changes sign with increasing disorder. In the case of many disordered contacts with inelastic scattering included, while quantization of Hall edge modes holds, for QSH edge modes a finite charge Hall current still flows. For QSH edge modes in the inelastic scattering regime we distinguish between two cases: with spin-flip and without spin-flip scattering. Finally, while asymmetry in sample geometry can have a deleterious effect in the QSH case, it has no impact in the QH case. (paper)

NUMERICAL AND EXPERIMENTAL INVESTIGATION ON THE FLUTTER OF CANTILEVERED PLATES WITH FREE LEADING EDGE IN AXIAL FLOW

Directory of Open Access Journals (Sweden)

I. P. G. SOPAN RAHTIKA

2017-10-01

Full Text Available This paper reports the results of the numerical and experimental investigation on the flutter of cantilevered thin flat plates with free leading edge in axial flow. Three methods of in-vacuo modal analyses of the plates are presented and compared in this paper, namely the finite element modal analysis using ANSYS STUDENT Modal, the analytical beam model, and the experimental modal analysis. In this study, the numerical Fluid Structure Interaction was performed using the ANSYS STUDENT Structural Transient Analysis and ANSYS STUDENT CFX to obtain the system response in the time domain. Furthermore, the experimental investigation was conducted in the smooth flow of a wind tunnel to observe the flutter speeds of the plates and their vibration characteristics. The plates’ vibration behaviors were mapped on the normalized air speed. The normalized air speed can be divided into four speed zones based on the experimental plates’ vibration characteristics. A new finding observed during the experiments is the presence of intermittent vibration behavior that is unique to the free leading edge configuration and has not been reported by other researchers in the earlier references of the clamped leading edge configuration. The potential application of this Fluid Structure Interaction configuration to wind harvesting is inquired.

Diabetes: What's Your Type? (A Cup of Health with CDC)

Centers for Disease Control (CDC) Podcasts

Diabetes is a common chronic disease and the seventh leading cause of death in the U.S. The CDC estimates that about 30 million people in the United States have diabetes. In this podcast, Dr. Stephen Benoit discusses the importance of managing diabetes.

Diabetes: What's Your Type? (A Minute of Health with CDC)

Centers for Disease Control (CDC) Podcasts

Diabetes is a common chronic disease and the seventh leading cause of death in the U.S. The CDC estimates that about 30 million people in the United States have diabetes. In this podcast, Dr. Stephen Benoit discusses the importance of managing diabetes.

α-Crystallin localizes to the leading edges of migrating lens epithelial cells

International Nuclear Information System (INIS)

Maddala, Rupalatha; Vasantha Rao, P.

2005-01-01

α-crystallin (αA and αB) is a major lens protein, which belongs to the small heat-shock family of proteins and binds to various cytoskeletal proteins including actin, vimentin and desmin. In this study, we investigated the cellular localization of αA and αB-crystallins in migrating epithelial cells isolated from porcine lens. Immunofluorescence localization and confocal imaging of αB-crystallin in confluent and in migrating subconfluent cell cultures revealed a distinct pattern of subcellular distribution. While αB-crystallin localization was predominantly cytoplasmic in confluent cultures, it was strongly localized to the leading edges of cell membrane or the lamellipodia in migrating cells. In accordance with this pattern, we found abundant levels of αB-crystallin in membrane fractions compared to cytosolic and nuclear fractions in migrating lens epithelial cells. αA-crystallin, which has 60% sequence identity to αB-crystallin, also exhibited a distribution profile localizing to the leading edge of the cell membrane in migrating lens epithelial cells. Localization of αB-crystallin to the lamellipodia appears to be dependent on phosphorylation of residue serine-59. An inhibitor of p38 MAP kinase (SB202190), but not the ERK kinase inhibitor PD98059, was found to diminish localization of αB-crystallin to the lamellipodia, and this effect was found to be associated with reduced levels of Serine-59 phosphorylated αB-crystallin in SB202190-treated migrating lens epithelial cells. αB-crystallin localization to the lamellipodia was also altered by the treatment with RGD (Arg-Ala-Asp) peptide, dominant negative N17 Rac1 GTPase, cytochalasin D and Src kinase inhibitor (PP2), but not by the Rho kinase inhibitor Y-27632 or the myosin II inhibitor, blebbistatin. Additionally, in migrating lens epithelial cells, αB-crystallin exhibited a clear co-localization with the actin meshwork, β-catenin, WAVE-1, a promoter of actin nucleation, Abi-2, a component of WAVE

The Cytokinin Requirement for Cell Division in Cultured Nicotiana plumbaginifolia Cells Can Be Satisfied by Yeast Cdc25 Protein Tyrosine Phosphatase. Implications for Mechanisms of Cytokinin Response and Plant Development

Science.gov (United States)

Zhang, Kerong; Diederich, Ludger; John, Peter C.L.

2005-01-01

Cultured cells of Nicotiana plumbaginifolia, when deprived of exogenous cytokinin, arrest in G2 phase prior to mitosis and then contain cyclin-dependent protein kinase (CDK) that is inactive because phosphorylated on tyrosine (Tyr). The action of cytokinin in stimulating the activation of CDK by removal of inhibitory phosphorylation from Tyr is not a secondary downstream consequence of other hormone actions but is the key primary effect of the hormone in its stimulation of cell proliferation, since cytokinin could be replaced by expression of cdc25, which encodes the main Cdc2 (CDK)-Tyr dephosphorylating enzyme of yeast (Saccharomyces cerevisiae). The cdc25 gene, under control of a steroid-inducible promoter, induced a rise in cdc25 mRNA, accumulation of p67Cdc25 protein, and increase in Cdc25 phosphatase activity that was measured in vitro with Tyr-phosphorylated Cdc2 as substrate. Cdc25 phosphatase activity peaked during mitotic prophase at the time CDK activation was most rapid. Mitosis that was induced by cytokinin also involved increase in endogenous plant CDK Tyr phosphatase activity during prophase, therefore indicating that this is a normal part of plant mitosis. These results suggest a biochemical mechanism for several previously described transgene phenotypes in whole plants and suggest that a primary signal from cytokinin leading to progression through mitosis is the activation of CDK by dephosphorylation of Tyr. PMID:15618425

The cytokinin requirement for cell division in cultured Nicotiana plumbaginifolia cells can be satisfied by yeast Cdc25 protein tyrosine phosphatase: implications for mechanisms of cytokinin response and plant development.

Science.gov (United States)

Zhang, Kerong; Diederich, Ludger; John, Peter C L

2005-01-01

Cultured cells of Nicotiana plumbaginifolia, when deprived of exogenous cytokinin, arrest in G2 phase prior to mitosis and then contain cyclin-dependent protein kinase (CDK) that is inactive because phosphorylated on tyrosine (Tyr). The action of cytokinin in stimulating the activation of CDK by removal of inhibitory phosphorylation from Tyr is not a secondary downstream consequence of other hormone actions but is the key primary effect of the hormone in its stimulation of cell proliferation, since cytokinin could be replaced by expression of cdc25, which encodes the main Cdc2 (CDK)-Tyr dephosphorylating enzyme of yeast (Saccharomyces cerevisiae). The cdc25 gene, under control of a steroid-inducible promoter, induced a rise in cdc25 mRNA, accumulation of p67(Cdc25) protein, and increase in Cdc25 phosphatase activity that was measured in vitro with Tyr-phosphorylated Cdc2 as substrate. Cdc25 phosphatase activity peaked during mitotic prophase at the time CDK activation was most rapid. Mitosis that was induced by cytokinin also involved increase in endogenous plant CDK Tyr phosphatase activity during prophase, therefore indicating that this is a normal part of plant mitosis. These results suggest a biochemical mechanism for several previously described transgene phenotypes in whole plants and suggest that a primary signal from cytokinin leading to progression through mitosis is the activation of CDK by dephosphorylation of Tyr.

April 28, 2015 CDC Ebola Response Update

Centers for Disease Control (CDC) Podcasts

In any disease outbreak, misinformation, a lack of understanding, and fear can lead to unfortunate side effects, like stigma. Stigma presents a challenge for communities during a time when they need to be strong to fight the disease. In this podcast, Molly Gaines-McCollom, CDC Health Communication Specialist, discusses the impact of stigma in the current Ebola outbreak and why it’s so important to fight it.

The Leading Edge of Early Childhood Education: Linking Science to Policy for a New Generation

Science.gov (United States)

Lesaux, Nonie K., Ed.; Jones, Stephanie M., Ed.

2016-01-01

"The Leading Edge of Early Childhood Education" aims to support the effort to simultaneously scale up and improve the quality of early childhood education by bringing together relevant insights from emerging research to provide guidance for this critical, fledgling field. It reflects the growing recognition that early childhood…

Dynamics of edge currents in a linearly quenched Haldane model

Science.gov (United States)

Mardanya, Sougata; Bhattacharya, Utso; Agarwal, Amit; Dutta, Amit

2018-03-01

In a finite-time quantum quench of the Haldane model, the Chern number determining the topology of the bulk remains invariant, as long as the dynamics is unitary. Nonetheless, the corresponding boundary attribute, the edge current, displays interesting dynamics. For the case of sudden and adiabatic quenches the postquench edge current is solely determined by the initial and the final Hamiltonians, respectively. However for a finite-time (τ ) linear quench in a Haldane nanoribbon, we show that the evolution of the edge current from the sudden to the adiabatic limit is not monotonic in τ and has a turning point at a characteristic time scale τ =τ0 . For small τ , the excited states lead to a huge unidirectional surge in the edge current of both edges. On the other hand, in the limit of large τ , the edge current saturates to its expected equilibrium ground-state value. This competition between the two limits lead to the observed nonmonotonic behavior. Interestingly, τ0 seems to depend only on the Semenoff mass and the Haldane flux. A similar dynamics for the edge current is also expected in other systems with topological phases.

Mechanisms of leading edge protrusion in interstitial migration

Science.gov (United States)

Wilson, Kerry; Lewalle, Alexandre; Fritzsche, Marco; Thorogate, Richard; Duke, Tom; Charras, Guillaume

2013-01-01

While the molecular and biophysical mechanisms underlying cell protrusion on two-dimensional substrates are well understood, our knowledge of the actin structures driving protrusion in three-dimensional environments is poor, despite relevance to inflammation, development and cancer. Here we report that, during chemotactic migration through microchannels with 5 μm × 5 μm cross-sections, HL60 neutrophil-like cells assemble an actin-rich slab filling the whole channel cross-section at their front. This leading edge comprises two distinct F-actin networks: an adherent network that polymerizes perpendicular to cell-wall interfaces and a ‘free’ network that grows from the free membrane at the cell front. Each network is polymerized by a distinct nucleator and, due to their geometrical arrangement, the networks interact mechanically. On the basis of our experimental data, we propose that, during interstitial migration, medial growth of the adherent network compresses the free network preventing its retrograde movement and enabling new polymerization to be converted into forward protrusion. PMID:24305616

The FAK–Arp2/3 interaction promotes leading edge advance and haptosensing by coupling nascent adhesions to lamellipodia actin

Science.gov (United States)

Swaminathan, Vinay; Fischer, R. S.; Waterman, Clare M.

2016-01-01

Cell migration is initiated in response to biochemical or physical cues in the environment that promote actin-mediated lamellipodial protrusion followed by the formation of nascent integrin adhesions (NAs) within the protrusion to drive leading edge advance. Although FAK is known to be required for cell migration through effects on focal adhesions, its role in NA formation and lamellipodial dynamics is unclear. Live-cell microscopy of FAK−/− cells with expression of phosphorylation deficient or a FERM-domain mutant deficient in Arp2/3 binding revealed a requirement for FAK in promoting the dense formation, transient stabilization, and timely turnover of NA within lamellipodia to couple actin-driven protrusion to adhesion and advance of the leading edge. Phosphorylation on Y397 of FAK promotes dense NA formation but is dispensable for transient NA stabilization and leading edge advance. In contrast, transient NA stabilization and advance of the cell edge requires FAK–Arp2/3 interaction, which promotes Arp2/3 localization to NA and reduces FAK activity. Haptosensing of extracellular matrix (ECM) concentration during migration requires the interaction between FAK and Arp2/3, whereas FAK phosphorylation modulates mechanosensing of ECM stiffness during spreading. Taken together, our results show that mechanistically separable functions of FAK in NA are required for cells to distinguish distinct properties of their environment during migration. PMID:26842895

On the effects of leading edge vortex generators on an OA209 airfoil

OpenAIRE

Heine, Benjamin; Mulleners, Karen; Gardner, Anthony; Mai, Holger

2009-01-01

Leading edge vortex generators have been found to significantly increase the aerodynamic performance of an airfoil under dynamic stall conditions. However, the principle of operation of these devices is still unclear. Therefore static wind and water tunnel experiments as well as CFD simulations have been conducted on a rotary aircraft wing profile OA209. A POD analysis applied to the vector fields generated by PIV measurements showed that the vortex generators break larger flow structures...

Cdc6 is a rate-limiting factor for proliferative capacity during HL60 cell differentiation

International Nuclear Information System (INIS)

Barkley, Laura R.; Hong, Hye Kyung; Kingsbury, Sarah R.; James, Michelle; Stoeber, Kai; Williams, Gareth H.

2007-01-01

The DNA replication (or origin) licensing pathway represents a critical step in cell proliferation control downstream of growth signalling pathways. Repression of origin licensing through down-regulation of the MCM licensing factors (Mcm2-7) is emerging as a ubiquitous route for lowering proliferative capacity as metazoan cells exit the cell division cycle into quiescent, terminally differentiated and senescent 'out-of-cycle' states. Using the HL60 monocyte/macrophage differentiation model system and a cell-free DNA replication assay, we have undertaken direct biochemical investigations of the coupling of origin licensing to the differentiation process. Our data show that down-regulation of the MCM loading factor Cdc6 acts as a molecular switch that triggers loss of proliferative capacity during early engagement of the somatic differentiation programme. Consequently, addition of recombinant Cdc6 protein to in vitro replication reactions restores DNA replication competence in nuclei prepared from differentiating cells. Differentiating HL60 cells over-expressing either wild-type Cdc6 or a CDK phosphorylation-resistant Cdc6 mutant protein (Cdc6A4) exhibit an extended period of cell proliferation compared to mock-infected cells. Notably, differentiating HL60 cells over-expressing the Cdc6A4 mutant fail to down-regulate Cdc6 protein levels, suggesting that CDK phosphorylation of Cdc6 is linked to its down-regulation during differentiation and the concomitant decrease in cell proliferation. In this experimental model, Cdc6 therefore plays a key role in the sequential molecular events leading to repression of origin licensing and loss of proliferative capacity during execution of the differentiation programme

PIV Study on Flow around Leading-Edge Slat of 30P30N Airfoil

Science.gov (United States)

Ando, Ryosuke; Onishi, Yusaku; Sakakibara, Jun

2017-11-01

We measured flow velocity distribution around leading-edge slat using PIV. Simultaneously, noise measurement using microphone was also performed. A leading-edge slat and main wing model having a chord length of 160 mm was placed in the tunnel with free stream velocity of about 26m/s and chord Reynolds number of 2.8 x 105. Angle of attack was changed from 4 degrees to 10 degrees at two degree intervals. In this experiment, we investigated the relationship between the unsteady flow condition and the noise. At 4 degrees in the angle of attack, vortices shedding from the slat cusp were moved to the downstream. At 6 degrees or more, flow velocity distributions show that vortices were reattached on the slat lower surface and the flow in the slat cove recirculated. In FFT analysis of noise measurement, at 6 degrees in the angle of attack, there were some peaks on low frequency area and dominant peak on high frequency area was found. At 8 degrees or more, there were also some peaks on low frequency area. But dominant peak on high frequency area disappeared.

Strain-Dependent Edge Structures in MoS2 Layers.

Science.gov (United States)

Tinoco, Miguel; Maduro, Luigi; Masaki, Mukai; Okunishi, Eiji; Conesa-Boj, Sonia

2017-11-08

Edge structures are low-dimensional defects unavoidable in layered materials of the transition metal dichalcogenides (TMD) family. Among the various types of such structures, the armchair (AC) and zigzag (ZZ) edge types are the most common. It has been predicted that the presence of intrinsic strain localized along these edges structures can have direct implications for the customization of their electronic properties. However, pinning down the relation between local structure and electronic properties at these edges is challenging. Here, we quantify the local strain field that arises at the edges of MoS 2 flakes by combining aberration-corrected transmission electron microscopy (TEM) with the geometrical-phase analysis (GPA) method. We also provide further insight on the possible effects of such edge strain on the resulting electronic behavior by means of electron energy loss spectroscopy (EELS) measurements. Our results reveal that the two-dominant edge structures, ZZ and AC, induce the formation of different amounts of localized strain fields. We also show that by varying the free edge curvature from concave to convex, compressive strain turns into tensile strain. These results pave the way toward the customization of edge structures in MoS 2 , which can be used to engineer the properties of layered materials and thus contribute to the optimization of the next generation of atomic-scale electronic devices built upon them.

Crystal structure of the karyopherin Kap121p bound to the extreme C-terminus of the protein phosphatase Cdc14p

Energy Technology Data Exchange (ETDEWEB)

Kobayashi, Junya [Division of Biological Science, Graduate School of Science, Nagoya University (Japan); Hirano, Hidemi [Division of Biological Science, Graduate School of Science, Nagoya University (Japan); Structural Biology Research Center, Graduate School of Science, Nagoya University (Japan); Matsuura, Yoshiyuki, E-mail: matsuura.yoshiyuki@d.mbox.nagoya-u.ac.jp [Division of Biological Science, Graduate School of Science, Nagoya University (Japan); Structural Biology Research Center, Graduate School of Science, Nagoya University (Japan)

2015-07-31

In Saccharomyces cerevisiae, the protein phosphatase Cdc14p is an antagonist of mitotic cyclin-dependent kinases and is a key regulator of late mitotic events such as chromosome segregation, spindle disassembly and cytokinesis. The activity of Cdc14p is controlled by cell-cycle dependent changes in its association with its competitive inhibitor Net1p (also known as Cfi1p) in the nucleolus. For most of the cell cycle up to metaphase, Cdc14p is sequestered in the nucleolus in an inactive state. During anaphase, Cdc14p is released from Net1p, spreads into the nucleus and cytoplasm, and dephosphorylates key mitotic targets. Although regulated nucleocytoplasmic shuttling of Cdc14p has been suggested to be important for exit from mitosis, the mechanism underlying Cdc14p nuclear trafficking remains poorly understood. Here we show that the C-terminal region (residues 517–551) of Cdc14p can function as a nuclear localization signal (NLS) in vivo and also binds to Kap121p (also known as Pse1p), an essential nuclear import carrier in yeast, in a Gsp1p-GTP-dependent manner in vitro. Moreover we report a crystal structure, at 2.4 Å resolution, of Kap121p bound to the C-terminal region of Cdc14p. The structure and structure-based mutational analyses suggest that either the last five residues at the extreme C-terminus of Cdc14p (residues 547–551; Gly-Ser-Ile-Lys-Lys) or adjacent residues with similar sequence (residues 540–544; Gly-Gly-Ile-Arg-Lys) can bind to the NLS-binding site of Kap121p, with two residues (Ile in the middle and Lys at the end of the five residues) of Cdc14p making key contributions to the binding specificity. Based on comparison with other structures of Kap121p-ligand complexes, we propose “IK-NLS” as an appropriate term to refer to the Kap121p-specific NLS. - Highlights: • The C-terminus of Cdc14p binds to Kap121p in a Gsp1p-GTP-dependent manner. • The crystal structure of Kap121p-Cdc14p complex is determined. • The structure reveals how

Crystal structure of the karyopherin Kap121p bound to the extreme C-terminus of the protein phosphatase Cdc14p

International Nuclear Information System (INIS)

Kobayashi, Junya; Hirano, Hidemi; Matsuura, Yoshiyuki

2015-01-01

In Saccharomyces cerevisiae, the protein phosphatase Cdc14p is an antagonist of mitotic cyclin-dependent kinases and is a key regulator of late mitotic events such as chromosome segregation, spindle disassembly and cytokinesis. The activity of Cdc14p is controlled by cell-cycle dependent changes in its association with its competitive inhibitor Net1p (also known as Cfi1p) in the nucleolus. For most of the cell cycle up to metaphase, Cdc14p is sequestered in the nucleolus in an inactive state. During anaphase, Cdc14p is released from Net1p, spreads into the nucleus and cytoplasm, and dephosphorylates key mitotic targets. Although regulated nucleocytoplasmic shuttling of Cdc14p has been suggested to be important for exit from mitosis, the mechanism underlying Cdc14p nuclear trafficking remains poorly understood. Here we show that the C-terminal region (residues 517–551) of Cdc14p can function as a nuclear localization signal (NLS) in vivo and also binds to Kap121p (also known as Pse1p), an essential nuclear import carrier in yeast, in a Gsp1p-GTP-dependent manner in vitro. Moreover we report a crystal structure, at 2.4 Å resolution, of Kap121p bound to the C-terminal region of Cdc14p. The structure and structure-based mutational analyses suggest that either the last five residues at the extreme C-terminus of Cdc14p (residues 547–551; Gly-Ser-Ile-Lys-Lys) or adjacent residues with similar sequence (residues 540–544; Gly-Gly-Ile-Arg-Lys) can bind to the NLS-binding site of Kap121p, with two residues (Ile in the middle and Lys at the end of the five residues) of Cdc14p making key contributions to the binding specificity. Based on comparison with other structures of Kap121p-ligand complexes, we propose “IK-NLS” as an appropriate term to refer to the Kap121p-specific NLS. - Highlights: • The C-terminus of Cdc14p binds to Kap121p in a Gsp1p-GTP-dependent manner. • The crystal structure of Kap121p-Cdc14p complex is determined. • The structure reveals how

Flight test operations using an F-106B research airplane modified with a wing leading-edge vortex flap

Science.gov (United States)

Dicarlo, Daniel J.; Brown, Philip W.; Hallissy, James B.

1992-01-01

Flight tests of an F-106B aircraft equipped with a leading-edge vortex flap, which represented the culmination of a research effort to examine the effectiveness of the flap, were conducted at the NASA Langley Research Center. The purpose of the flight tests was to establish a data base on the use of a wing leading-edge vortex flap as a means to validate the design and analysis methods associated with the development of such a vortical flow-control concept. The overall experiment included: refinements of the design codes for vortex flaps; numerous wind tunnel entries to aid in verifying design codes and determining basic aerodynamic characteristics; design and fabrication of the flaps, structural modifications to the wing tip and leading edges of the test aircraft; development and installation of an aircraft research instrumentation system, including wing and flap surface pressure measurements and selected structural loads measurements; ground-based simulation to assess flying qualities; and finally, flight testing. This paper reviews the operational aspects associated with the flight experiment, which includes a description of modifications to the research airplane, the overall flight test procedures, and problems encountered. Selected research results are also presented to illustrate the accomplishments of the research effort.

Myosin X is recruited to nascent focal adhesions at the leading edge and induces multi-cycle filopodial elongation.

Science.gov (United States)

He, Kangmin; Sakai, Tsuyoshi; Tsukasaki, Yoshikazu; Watanabe, Tomonobu M; Ikebe, Mitsuo

2017-10-20

Filopodia protrude from the leading edge of cells and play important roles in cell motility. Here we report the mechanism of myosin X (encoded by Myo10)-induced multi-cycle filopodia extension. We found that actin, Arp2/3, vinculin and integrin-β first accumulated at the cell's leading edge. Myosin X was then gathered at these sites, gradually clustered by lateral movement, and subsequently initiated filopodia formation. During filopodia extension, we found the translocation of Arp2/3 and integrin-β along filopodia. Arp2/3 and integrin-β then became localized at the tip of filopodia, from where myosin X initiated the second extension of filopodia with a change in extension direction, thus producing long filopodia. Elimination of integrin-β, Arp2/3 and vinculin by siRNA significantly attenuated the myosin-X-induced long filopodia formation. We propose the following mechanism. Myosin X accumulates at nascent focal adhesions at the cell's leading edge, where myosin X promotes actin convergence to create the base of filopodia. Then myosin X moves to the filopodia tip and attracts integrin-β and Arp2/3 for further actin nucleation. The tip-located myosin X then initiates the second cycle of filopodia elongation to produce the long filopodia.

Development of Streamwise Counter-Rotating Vortices in Flat Plate Boundary Layer Pre-set by Leading Edge Patterns

KAUST Repository

Hasheminejad, S.M.; Mitsudharmadi, Hatsari; Winoto, S.H.; Low, H.T.; Lua, K.B.

2017-01-01

Development of streamwise counter-rotating vortices induced by leading edge patterns with different pattern shape is investigated using hot-wire anemometry in the boundary layer of a flat plate. A triangular, sinusoidal and notched patterns

Numerical Simulation and Experiment of a Lifting Body with Leading-Edge Rotating Cylinder

OpenAIRE

A. Badarudin; C. S. Oon; S. N. Kazi; N. Nik-Ghazali; Y. J. Lee; W. T. Chong

2013-01-01

An experimental and simulation flight test has been carried out to evaluate the longitudinal gliding characteristics of a lifting body with blunted half-cone geometry. The novelty here is the lifting body's pitch control mechanism, which consists of a pair of leading-edge rotating cylinders. Flight simulation uses aerodynamic data from computational fluid dynamics supported by wind-tunnel test. Flight test consists of releasing an aluminum lifting body model from a moving vehicle at the appro...

Sequencing Analysis of Mutant Allele $cdc$28-$srm$ of Protein Kinase CDC28 and Molecular Dynamics Study of Glycine-Rich Loop in Wild-Type and Mutant Allele G16S of CDK2 as Model

CERN Document Server

Koltovaya, N A; Kholmurodov, Kh T; Kretov, D A

2005-01-01

The central role that cyclin-dependent kinases play in the timing of cell division and the high incidence of genetic alteration of CDKs or deregulation of CDK inhibitors in a number of cancers make CDC28 of the yeast \\textit{Saccharomyces cerevisiae }very attractive model for studies of mechanisms of CDK regulation. Earlier it was found that certain gene mutations including \\textit{cdc28-srm} affect cell cycle progression, maintenance of different genetic structures and increase cell sensitivity to ionizing radiation. A~\\textit{cdc28-srm} mutation is not temperature-sensitive mutation and differs from the known \\textit{cdc28-ts }mutations because it has the evident phenotypic manifestations at 30 $^{\\circ}$C. Sequencing analysis of \\textit{cdc28-srm} revealed a single nucleotide substitution G20S. This is a third glycine in a conserved sequence GxGxxG in the G-rich loop positioned opposite the activation T-loop. Despite its demonstrated importance, the role of the G-loop has remained unclear. The crystal stru...

42 CFR 61.8 - Benefits: Stipends; dependency allowances; travel allowances; vacation.

Science.gov (United States)

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Benefits: Stipends; dependency allowances; travel...; dependency allowances; travel allowances; vacation. Individuals awarded regular fellowships shall be entitled...) Stipend. (b) Dependency allowances. (c) When authorized in advance, separate allowances for travel. Such...

A high-yield co-expression system for the purification of an intact drs2p-cdc50p lipid flippase complex, critically dependent on and stabilized by phosphatidylinositol-4-phosphate

DEFF Research Database (Denmark)

Azouaoui, Hassina; Montigny, Cédric; Ash, Miriam-Rose

2014-01-01

P-type ATPases from the P4 subfamily (P4-ATPases) are energy-dependent transporters, which are thought to establish lipid asymmetry in eukaryotic cell membranes. Together with their Cdc50 accessory subunits, P4-ATPases couple ATP hydrolysis to lipid transport from the exoplasmic to the cytoplasmic...... leaflet of plasma membranes, late Golgi membranes, and endosomes. To gain insights into the structure and function of these important membrane pumps, robust protocols for expression and purification are required. In this report, we present a procedure for high-yield co-expression of a yeast flippase......, the Drs2p-Cdc50p complex. After recovery of yeast membranes expressing both proteins, efficient purification was achieved in a single step by affinity chromatography on streptavidin beads, yielding ∼1-2 mg purified Drs2p-Cdc50p complex per liter of culture. Importantly, the procedure enabled us to recover...

Enhanced CDC of B cell chronic lymphocytic leukemia cells mediated by rituximab combined with a novel anti-complement factor H antibody.

Directory of Open Access Journals (Sweden)

Mark T Winkler

Full Text Available Rituximab therapy for B cell chronic lymphocytic leukemia (B-CLL has met with mixed success. Among several factors to which resistance can be attributed is failure to activate complement dependent cytotoxicity (CDC due to protective complement regulatory proteins, including the soluble regulator complement factor H (CFH. We hypothesized that rituximab killing of non-responsive B-CLL cells could be augmented by a novel human monoclonal antibody against CFH. The B cells from 11 patients with B-CLL were tested ex vivo in CDC assays with combinations of CFH monoclonal antibody, rituximab, and a negative control antibody. CDC of rituximab non-responsive malignant B cells from CLL patients could in some cases be augmented by the CFH monoclonal antibody. Antibody-mediated cytotoxicity of cells was dependent upon functional complement. In one case where B-CLL cells were refractory to CDC by the combination of rituximab plus CFH monoclonal antibody, additionally neutralizing the membrane complement regulatory protein CD59 allowed CDC to occur. Inhibiting CDC regulatory proteins such as CFH holds promise for overcoming resistance to rituximab therapy in B-CLL.

Cdc20 control of cell fate during prolonged mitotic arrest

DEFF Research Database (Denmark)

Nilsson, Jakob

2011-01-01

The fate of cells arrested in mitosis by antimitotic compounds is complex but is influenced by competition between pathways promoting cell death and pathways promoting mitotic exit. As components of both of these pathways are regulated by Cdc20-dependent degradation, I hypothesize that variations...

Jaridonin-induced G2/M phase arrest in human esophageal cancer cells is caused by reactive oxygen species-dependent Cdc2-tyr15 phosphorylation via ATM–Chk1/2–Cdc25C pathway

Energy Technology Data Exchange (ETDEWEB)

Ma, Yong-Cheng [Clinical Pharmacology Laboratory, Henan Province People' s Hospital, No. 7, Wei Wu Road, Zhengzhou, Henan (China); Su, Nan [Department of Quality Detection and Management, Henan University of Animal Husbandry and Economy, Zhengzhou, Henan (China); Shi, Xiao-Jing; Zhao, Wen; Ke, Yu [School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Science Avenue, Zhengzhou, Henan (China); Zi, Xiaolin [Department of Urology, University of California, Irvine, Orange, CA (United States); Department of Pharmacology, University of California, Irvine, Orange, CA (United States); Department of Pharmaceutical Sciences, University of California, Irvine, Orange, CA (United States); Zhao, Ning-Min; Qin, Yu-Hua; Zhao, Hong-Wei [Clinical Pharmacology Laboratory, Henan Province People' s Hospital, No. 7, Wei Wu Road, Zhengzhou, Henan (China); Liu, Hong-Min, E-mail: liuhm@zzu.edu.cn [School of Pharmaceutical Sciences, Zhengzhou University, No. 100, Science Avenue, Zhengzhou, Henan (China)

2015-01-15

Jaridonin, a novel diterpenoid from Isodon rubescens, has been shown previously to inhibit proliferation of esophageal squamous cancer cells (ESCC) through G2/M phase cell cycle arrest. However, the involved mechanism is not fully understood. In this study, we found that the cell cycle arrest by Jaridonin was associated with the increased expression of phosphorylation of ATM at Ser1981 and Cdc2 at Tyr15. Jaridonin also resulted in enhanced phosphorylation of Cdc25C via the activation of checkpoint kinases Chk1 and Chk2, as well as in increased phospho-H2A.X (Ser139), which is known to be phosphorylated by ATM in response to DNA damage. Furthermore, Jaridonin-mediated alterations in cell cycle arrest were significantly attenuated in the presence of NAC, implicating the involvement of ROS in Jaridonin's effects. On the other hand, addition of ATM inhibitors reversed Jaridonin-related activation of ATM and Chk1/2 as well as phosphorylation of Cdc25C, Cdc2 and H2A.X and G2/M phase arrest. In conclusion, these findings identified that Jaridonin-induced cell cycle arrest in human esophageal cancer cells is associated with ROS-mediated activation of ATM–Chk1/2–Cdc25C pathway. - Highlights: • Jaridonin induced G2/M phase arrest through induction of redox imbalance. • Jaridonin increased the level of ROS through depleting glutathione in cell. • ATM–Chk1/2–Cdc25C were involved in Jaridonin-induced cell cycle arrest. • Jaridonin selectively inhibited cancer cell viability and cell cycle progression.

CDC Vital Signs–Native Americans With Diabetes

Centers for Disease Control (CDC) Podcasts

This podcast is based on the January 2017 CDC Vital Signs report. Diabetes is the leading cause of kidney failure and Native Americans have a greater chance of having diabetes than any other racial group in the U.S. Learn how to manage your diabetes to delay or prevent kidney failure.

Active control of noise amplification in the flow over a square leading-edge flat plate utilizing DBD plasma actuator

Science.gov (United States)

Yadong, HUANG; Benmou, ZHOU

2018-05-01

Perturbation is generally considered as the flow noise, and its energy can gain transient growth in the separation bubble. The amplified perturbations may cause unstable Kelvin–Helmohltz vortices which induce the three-dimensional transition. Active control of noise amplification via dielectric barrier discharge plasma actuator in the flow over a square leading-edge flat plate is numerically studied. The actuator is installed near the plate leading-edge where the separation bubble is formed. The maximum energy amplification of perturbations is positively correlated with the separation bubble scale which decreases with the increasing control parameters. As the magnitude of noise amplification is reduced, the laminar-turbulent transition is successfully suppressed.

42 CFR 34.2 - Definitions.

Science.gov (United States)

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Definitions. 34.2 Section 34.2 Public Health PUBLIC... OF ALIENS § 34.2 Definitions. As used in this part, terms shall have the following meanings: (a) CDC... International Health Regulations (http://www.who.int/csr/ihr/en/), as adopted by the Fifty-Eighth World Health...

An experimental investigation of the shear-layer and acoustic sources produced by a leading edge slat

Science.gov (United States)

Wilkins, Stephen; Richard, Patrick; Hall, Joseph; Turbulence; Flow Noise Laboratory Team

2013-11-01

Leading edge slats are a common addition to airfoils as part of a high lift configuration employed during take-off and landing; the unsteady flow caused by these slats is a major contributor to the overal airframe noise. As the next generation of aircraft seeks to reduce these noise concerns, a better understanding of the sources of aeroacoustic noise generation is sought. Particle Image Velocimetry (PIV) and simultaneous multipoint measurements of the unsteady surface pressure are used herein to investigate the unsteady flow around a leading edge slat coupled with an airfoil for several different configurations and a range of Reynolds numbers (Re = 156 , 000 to Re = 1 . 2 million based on the wing chord). Shear-layer development off the slat cusp and the related unsteady vortex structures are examined in detail to better establish and understand the mechanisms responsible for the generation of aeroacoustic slat noise. The authors are grateful for the support provided by GARDN.

Morphological Analysis of CDC2 and Glycogen Synthase Kinase 3β Phosphorylation as Markers of G2 → M Transition in Glioma

Directory of Open Access Journals (Sweden)

José Javier Otero

2011-01-01

Full Text Available G2 → M transition is a strategic target for glioma chemotherapy. Key players in G2 → M transition include CDC2 and glycogen synthase kinase 3β (GSK3β, which are highly regulated by posttranslational phosphorylation. This report is a morphological analysis of CDC2 and GSK3β phosphorylation using immunohistochemistry in gliomas with different biological properties. GBM showed a 2.8-fold and 5.6-fold increase in number of cells positive for pThr161CDC2 and a 4.2- and 6.9-fold increase in number of cells positive for pTyr15CDC2 relative to oligodendroglioma and ependymoma, respectively. Elevated labeling for inhibited phospho-CDC2 (pTyr15CDC correlates with elevated levels of phosphorylated glycogen synthase kinase 3β (GSK3β. 71% of the GBM cases showed intermediate to high intensity staining for pSer9SGK3β 53% of oligodendroglioma, and 73% of ependymoma showed low intensity staining. CDC2 gene amplification correlates with increased survival in glioblastoma multiforme (GBM and astrocytoma WHO grades II-III, but not in oligodendroglioma WHO grades II-III.

13 CFR 120.851 - CDC ethical requirements.

Science.gov (United States)

2010-01-01

... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false CDC ethical requirements. 120.851... Company Loan Program (504) Other Cdc Requirements § 120.851 CDC ethical requirements. CDCs and their Associates must act ethically and exhibit good character. They must meet all of the ethical requirements of...

Event review: How Interesting Archaeology Is! - Captivating and Leading-Edge Student Research

Directory of Open Access Journals (Sweden)

Atsushi Uemine

2015-03-01

Full Text Available Kyoto City Archaeological Museum situated in Kansai region, the central part of Honshu Island, Japan, has held special exhibitions in collaboration with external organizations every year since 2011. From 2011 to 2013, several universities and even a high school have participated projects, and in 2014, the Kansai Archaeological Association for Students (KAAS played an important role as partner, producing the exhibit “ここまでわかる！考古学―学生が魅せる最先端” (“How Interesting Archaeology Is! - Captivating and Leading-Edge Student Research”.

Driver or passenger effects of augmented c-Myc and Cdc20 in gliomagenesis.

Science.gov (United States)

Ji, Ping; Zhou, Xinhui; Liu, Qun; Fuller, Gregory N; Phillips, Lynette M; Zhang, Wei

2016-04-26

Cdc20 and c-Myc are commonly overexpressed in a broad spectrum of cancers, including glioblastoma (GBM). Despite this clear association, whether c-Myc and Cdc20 overexpression is a driver or passenger event in gliomagenesis remains unclear. Both c-Myc and Cdc20 induced the proliferation of primary glial progenitor cells. c-Myc also promoted the formation of soft agar anchorage-independent colonies. In the RCAS/Ntv-a glia-specific transgenic mouse model, c-Myc increased the GBM incidence from 19.1% to 47.4% by 12 weeks of age when combined with kRas and Akt3 in Ntv-a INK4a-ARF (also known as CDKN2A)-null mice. In contrast, Cdc20 decreased the GBM incidence from 19.1% to 9.1%. Moreover, cell differentiation was modulated by c-Myc in kRas/Akt3-induced GBM on the basis of Nestin/GFAP expression (glial progenitor cell differentiation), while Cdc20 had no effect on primary glial progenitor cell differentiation. We used glial progenitor cells from Ntv-a newborn mice to evaluate the role of c-Myc and Cdc20 in the proliferation and transformation of GBM in vitro and in vivo. We further determined whether c-Myc and Cdc20 have a driver or passenger role in GBM development using kRas/Akt3 signals in a RCAS/Ntv-a mouse model. These results suggest that the driver or passenger of oncogene signaling is dependent on cellular status. c-Myc is a driver when combined with kRas/Akt3 oncogenic signals in gliomagenesis, whereas Cdc20 overexpression is a passenger. Inhibition of cell differentiation of c-Myc may be a target for anti-glioma therapy.

Multiple Scattering Approach to Polarization Dependence of F K-Edge XANES Spectra for Highly Oriented Polytetrafluoroethylene (PTFE) Thin Film

International Nuclear Information System (INIS)

Nagamatsu, S.; Ono, M.; Kera, S.; Okudaira, K. K.; Fujikawa, T.; Ueno, N.

2007-01-01

The polarization dependence of F K-edge X-ray absorption near edge structure (XANES) spectra of highly-oriented thin-film of polytetrafluoroethylene (PTFE) has been analyzed by using multiple scattering theory. The spectra show clear polarization dependence due to the highly-oriented structure. The multiple scattering calculations reflects a local structure around an absorbing atom. The calculated results obtained by considering intermolecular-interactions are in good agreement with the observed polarization-dependence. We have also analyzed structural models of the radiation damaged PTFE films

Effects of Alternate Leading Edge Cutback on the Space Shuttle Main Engine Low Pressure Fuel Pump

Science.gov (United States)

Mulder, Andrew; Skelley, Stephen

2016-01-01

A higher order cavitation oscillation observed in the SSME low pressure fuel pump has been eliminated in water flow testing of a modified subscale replica of the inducer. The low pressure pump was modified by removing the outboard sections of two opposing blades of the four-bladed inducer, blending the "cutback" regions into the blades at the leading edge and tip, and removing material on the suction sides to decrease the exposed leading edge thickness. The leading edge tips of the cutback blades were moved approximately 25 degrees from their previous locations, thereby increasing one blade to blade spacing, decreasing the second, while simultaneously moving the cutback tips downstream. The test was conducted in MSFC's inducer test loop at scaled operating conditions in degassed and filtered water. In addition to eliminating HOC across the entire scaled operating regime, rotating cavitation was suppressed while the range of both alternate blade and asymmetric cavitation were increased. These latter phenomena, and more significantly, the shifts between these cavitation modes also resulted in significant changes to the head coefficient at low cavitation numbers. Reverse flow was detected at a slightly larger flow coefficient with the cutback inducer and suction capability was reduced by approximately 1 velocity head at and above approximately 90% of the reference flow coefficient. These performance changes along with more intense reverse flow are consistent with poor flow area management and increased incidence in the cutback region. Although the test demonstrated that the inducer modification was successful at eliminating the higher order cavitation across the entire scaled operating regime, different, previously unobserved, cavitation oscillations were introduced and significant performance penalties were imposed.

Experimental Surface Pressure Data Obtained on 65 deg Delta Wing Across Reynolds Number and Mach Number Ranges. Volume 2; Small-Radius Leading Edge

Science.gov (United States)

Chu, Julio; Luckring, James M.

1996-01-01

An experimental wind tunnel test of a 65 deg. delta wing model with interchangeable leading edges was conducted in the Langley National Transonic Facility (NTF). The objective was to investigate the effects of Reynolds and Mach numbers on slender-wing leading-edge vortex flows with four values of wing leading-edge bluntness. Experimentally obtained pressure data are presented without analysis in tabulated and graphical formats across a Reynolds number range of 6 x 10(exp 6) to 84 x 10(exp 6) at a Mach number of 0.85 and across a Mach number range of 0.4 to 0.9 at Reynolds numbers of 6 x 10(exp 6) and 60 x 10(exp 6). Normal-force and pitching-moment coefficient plots for these Reynolds number and Mach number ranges are also presented.

Fracture Mechanics Analyses of the Slip-Side Joggle Regions of Wing-Leading-Edge Panels

Science.gov (United States)

Raju, Ivatury S.; Knight, Norman F., Jr.; Song, Kyongchan; Phillips, Dawn R.

2011-01-01

The Space Shuttle wing-leading edge consists of panels that are made of reinforced carbon-carbon. Coating spallation was observed near the slip-side region of the panels that experience extreme heating. To understand this phenomenon, a root-cause investigation was conducted. As part of that investigation, fracture mechanics analyses of the slip-side joggle regions of the hot panels were conducted. This paper presents an overview of the fracture mechanics analyses.

Effect of flow obstacles with various leading and trailing edges on critical heat flux

International Nuclear Information System (INIS)

Pioro, I.L.; Groeneveld, D.C.; Groeneveld, D.C.; Cheng, S.C.; Antoshko, Y.V.

2001-01-01

A joint investigation has been performed by the University of Ottawa and Chalk River Laboratories that examined the effect of the shape of the leading and trailing edges of the turbulence enhancing devices ('flow obstacles') on critical heat flux (CHF). The objective of this study was to gain a better overall understanding of the limit of CHF improvement for various obstacle designs and the impact of flow conditions on the improvements. (author)

Effects of free-stream turbulence intensity and blowing ratio on film cooling of turbine blade leading edge

International Nuclear Information System (INIS)

Kim, S. M.; Kim, Youn J.; Cho, H. H.

2001-01-01

We used a cylindrical model which simulates turbine blade leading edge to investigate the effects of free-stream turbulence intensity and blowing ratio on film cooling of turbine blade leading edge. Tests are carried out in a low-speed wind tunnel on a cylindrical model with three rows of injection holes. Mainstream Reynolds number based on the cylinder diameter was 7.1x10 4 . Two types of turbulence grid are used to increase a free-stream turbulence intensity. The effect of coolant blowing ratio was studied for various blowing ratios. For each blowing ratios, wall temperatures around the surface of the test model are measured by thermocouples installed inside the model. Results show that blowing ratios have small effect on spanwise-averaged film effectiveness at high free-stream turbulence intensity. However, an increase in free-stream turbulence intensity enhances significantly spanwise-averaged film effectiveness at low blowing ratio

Effects of V-shaped edge defect and H-saturation on spin-dependent electronic transport of zigzag MoS2 nanoribbons

International Nuclear Information System (INIS)

Li, Xin-Mei; Long, Meng-Qiu; Cui, Li-Ling; Xiao, Jin; Zhang, Xiao-Jiao; Zhang, Dan; Xu, Hui

2014-01-01

Based on nonequilibrium Green's function in combination with density functional theory calculations, the spin-dependent electronic transport properties of one-dimensional zigzag molybdenum disulfide (MoS 2 ) nanoribbons with V-shaped defect and H-saturation on the edges have been studied. Our results show that the spin-polarized transport properties can be found in all the considered zigzag MoS 2 nanoribbons systems. The edge defects, especially the V-shaped defect on the Mo edge, and H-saturation on the edges can suppress the electronic transport of the systems. Also, the spin-filtering and negative differential resistance behaviors can be observed obviously. The mechanisms are proposed for these phenomena. - Highlights: • The spin-dependent electronic transport of zigzag MoS 2 nanoribbons. • The effects of V-shaped edge defect and H-saturation. • The effects of spin-filter and negative differential resistance can be observed

Shear flows at the tokamak edge and their interaction with edge-localized modes

International Nuclear Information System (INIS)

Aydemir, A. Y.

2007-01-01

Shear flows in the scrape-off layer (SOL) and the edge pedestal region of tokamaks are shown to arise naturally out of transport processes in a magnetohydrodynamic model. In quasi-steady-state conditions, collisional resistivity coupled with a simple bootstrap current model necessarily leads to poloidal and toroidal flows, mainly localized to the edge and SOL. The role of these flows in the grad-B drift direction dependence of the power threshold for the L (low) to H (high) transition, and their effect on core rotation, are discussed. Theoretical predictions based on symmetries of the underlying equations, coupled with computational results, are found to be in agreement with observations in Alcator C-Mod [Phys. Plasmas 12, 056111 (2005)]. The effects of these self-consistent flows on linear peeling/ballooning modes and their nonlinear consequences are also examined

New approach to the suction force at the leading edge of a profile with zero thickness

NARCIS (Netherlands)

Sparenberg, JA; de Jager, EM

2004-01-01

This paper considers the suction force at the leading edge of a profile with zero thickness in an incompressible and inviscid fluid flow. The theory is linear, and the approach to the suction force is from the innerside of the profile. It is shown that the suction force can be considered as an

CDC Vital Signs–Cancer and Tobacco Use

Centers for Disease Control (CDC) Podcasts

2016-11-10

This podcast is based on the November 2016 CDC Vital Signs report. There is a long list of cancers linked to tobacco use, the leading preventable cause of cancer and cancer deaths. Learn more here.  Created: 11/10/2016 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 11/10/2016.

CDC 7600 Module

CERN Multimedia

1970-01-01

The CDC 7600 has been created by Seymour Cray. It was designed to be compatible with the 6600, which allows for a substantial increase in performance. Furthermore the rise of new technologies has enabled this performance by reducing the minor cycle clock period from 100 ns to 27.5 ns (4 time faster). A very large machine, the 7600 had over 120 miles of hand-wired interconnections. It was the most powerful computer of its time. However, this speed caused a ground-loop problem causing intermittent faults, and eventually requiring all modules to be fitted with sheathed rubber bands. The CDC 7600 was replaced in 1983 by CRAY-1A.

Multiple domains of fission yeast Cdc19p (MCM2) are required for its association with the core MCM complex.

Science.gov (United States)

Sherman, D A; Pasion, S G; Forsburg, S L

1998-07-01

The members of the MCM protein family are essential eukaryotic DNA replication factors that form a six-member protein complex. In this study, we use antibodies to four MCM proteins to investigate the structure of and requirements for the formation of fission yeast MCM complexes in vivo, with particular regard to Cdc19p (MCM2). Gel filtration analysis shows that the MCM protein complexes are unstable and can be broken down to subcomplexes. Using coimmunoprecipitation, we find that Mis5p (MCM6) and Cdc21p (MCM4) are tightly associated with one another in a core complex with which Cdc19p loosely associates. Assembly of Cdc19p with the core depends upon Cdc21p. Interestingly, there is no obvious change in Cdc19p-containing MCM complexes through the cell cycle. Using a panel of Cdc19p mutants, we find that multiple domains of Cdc19p are required for MCM binding. These studies indicate that MCM complexes in fission yeast have distinct substructures, which may be relevant for function.

42 CFR 137.305 - May Self-Governance Tribes act as lead, cooperating, or joint lead agencies for environmental...

Science.gov (United States)

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false May Self-Governance Tribes act as lead, cooperating... HEALTH AND HUMAN SERVICES TRIBAL SELF-GOVERNANCE Construction Nepa Process § 137.305 May Self-Governance...-Governance Tribes assuming Federal environmental responsibilities for construction projects under section 509...

Scheme and scale dependences of leading electroweak corrections

International Nuclear Information System (INIS)

Kniehl, B.A.; Sirlin, A.

1996-01-01

The scheme and scale dependences of leading M t -dependent contributions to Δρ, Δr, and τ, which arise because of the truncation of the perturbative series, are investigated by comparing expressions in the on-shell and MS schemes of renormalization, and studying their scale variations. Starting from the conventional on-shell formulae, we find rather large scheme and scale dependences. We then propose a simple, physically motivated modification of the conventional expressions and show that it leads to a sharp reduction in the scheme and scale dependences. Implications for electroweak physics are discussed. (orig.)

Numerical Prediction of the Impact of Non-Uniform Leading Edge Coatings On the Aerodynamic Performance of Compressor Airfoils

National Research Council Canada - National Science Library

Elmstrom, Michael

2004-01-01

A computational fluid dynamic (CFD) investigation is presented that provides predictions of the aerodynamic impact of uniform and non-uniform coatings applied to the leading edge of a compressor airfoil in a cascade. Using a NACA 65(12...

Fracture Mechanics Analyses of the Slip-Side Joggle Regions of Wing-Leading Edge Panels

Science.gov (United States)

Raju, Ivatury S.; Knight, Norman F., Jr.; Song, Kyongchan; Phillips, Dawn R.

2010-01-01

The Space Shuttle Orbiter wing comprises of 22 leading edge panels on each side of the wing. These panels are part of the thermal protection system that protects the Orbiter wings from extreme heating that take place on the reentry in to the earth atmosphere. On some panels that experience extreme heating, liberation of silicon carbon (SiC) coating was observed on the slip side regions of the panels. Global structural and local fracture mechanics analyses were performed on these panels as a part of the root cause investigation of this coating liberation anomaly. The wing-leading-edge reinforced carbon-carbon (RCC) panels, Panel 9, T-seal 10, and Panel 10, are shown in Figure 1 and the progression of the stress analysis models is presented in Figure 2. The global structural analyses showed minimal interaction between adjacent panels and the T-seal that bridges the gap between the panels. A bounding uniform temperature is applied to a representative panel and the resulting stress distribution is examined. For this loading condition, the interlaminar normal stresses showed negligible variation in the chord direction and increased values in the vicinity of the slip-side joggle shoulder. As such, a representative span wise slice on the panel can be taken and the cross section can be analyzed using plane strain analysis.

Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression.

Science.gov (United States)

Chauhan, Neha; Visram, Myriam; Cristobal-Sarramian, Alvaro; Sarkleti, Florian; Kohlwein, Sepp D

2015-03-10

Cell growth and division requires the precise duplication of cellular DNA content but also of membranes and organelles. Knowledge about the cell-cycle-dependent regulation of membrane and storage lipid homeostasis is only rudimentary. Previous work from our laboratory has shown that the breakdown of triacylglycerols (TGs) is regulated in a cell-cycle-dependent manner, by activation of the Tgl4 lipase by the major cyclin-dependent kinase Cdc28. The lipases Tgl3 and Tgl4 are required for efficient cell-cycle progression during the G1/S (Gap1/replication phase) transition, at the onset of bud formation, and their absence leads to a cell-cycle delay. We now show that defective lipolysis activates the Swe1 morphogenesis checkpoint kinase that halts cell-cycle progression by phosphorylation of Cdc28 at tyrosine residue 19. Saturated long-chain fatty acids and phytosphingosine supplementation rescue the cell-cycle delay in the Tgl3/Tgl4 lipase-deficient strain, suggesting that Swe1 activity responds to imbalanced sphingolipid metabolism, in the absence of TG degradation. We propose a model by which TG-derived sphingolipids are required to activate the protein phosphatase 2A (PP2A(Cdc55)) to attenuate Swe1 phosphorylation and its inhibitory effect on Cdc28 at the G1/S transition of the cell cycle.

Cdc20 is critical for meiosis I and fertility of female mice.

Directory of Open Access Journals (Sweden)

Fang Jin

2010-09-01

Full Text Available Chromosome missegregation in germ cells is an important cause of unexplained infertility, miscarriages, and congenital birth defects in humans. However, the molecular defects that lead to production of aneuploid gametes are largely unknown. Cdc20, the activating subunit of the anaphase-promoting complex/cyclosome (APC/C, initiates sister-chromatid separation by ordering the destruction of two key anaphase inhibitors, cyclin B1 and securin, at the transition from metaphase to anaphase. The physiological significance and full repertoire of functions of mammalian Cdc20 are unclear at present, mainly because of the essential nature of this protein in cell cycle progression. To bypass this problem we generated hypomorphic mice that express low amounts of Cdc20. These mice are healthy and have a normal lifespan, but females produce either no or very few offspring, despite normal folliculogenesis and fertilization rates. When mated with wild-type males, hypomorphic females yield nearly normal numbers of fertilized eggs, but as these embryos develop, they become malformed and rarely reach the blastocyst stage. In exploring the underlying mechanism, we uncover that the vast majority of these embryos have abnormal chromosome numbers, primarily due to chromosome lagging and chromosome misalignment during meiosis I in the oocyte. Furthermore, cyclin B1, cyclin A2, and securin are inefficiently degraded in metaphase I; and anaphase I onset is markedly delayed. These results demonstrate that the physiologically effective threshold level of Cdc20 is high for female meiosis I and identify Cdc20 hypomorphism as a mechanism for chromosome missegregation and formation of aneuploid gametes.

Is Your Child Safe from Lead Poisoning?

Centers for Disease Control (CDC) Podcasts

In this podcast, Dr. Mary Jean Brown, chief of CDC's Lead Poisoning and Prevention Program, discusses the importance of testing children for lead poisoning, who should be tested, and what parents can do to prevent lead poisoning.

CDC28, NETI, and HFII are required for checkpoints in Saccharomyces cerevisiae

International Nuclear Information System (INIS)

Koltovaya, N.A.; Kadyshevskaya, E.Yu.; Roshina, M.P.; Devin, A.B.

2009-01-01

The involvement of SRM genes selected as genes affecting genetic stability and radiosensitivity in a cell cycle arrest under the action of damaging agents was studied. It was shown that the srm5/cdc28-srm, srm8/netI-srm, and srmI2/hfiI-srm mutations prevent checkpoint activation by DNA damage, particularly the G 0 /S (srm5, srm8), G 1 /S (srm5, srm8, srm12), S (srm8, srm12) and S/G 2 (srm5) checkpoints. It seems that in budding yeast the CDC28, HFII/ADAI, and NETI genes mediate cellular response induced by DNA damage with checkpoint control. The well-known checkpoint-genes RAD9, RAD17, RAD24, and RAD53, and the genes CDC28, and NETI have been found to belong to one epistasis group named RAD9-group as regards cell sensitivity to γ radiation. An analysis of the radiosensitivity of double mutants has revealed that the mutation cdc-28-srm is hypostatic to each of mutations rad9Δ, and rad24Δ, and additive to rad17Δ. The mutation netI-srm is hypostatic to the mutations rad9Δ but additive to rad17Δ, rad24Δ, and rad53. The mutation hfiI-srm has an additive effect in compound with the mutations rad24Δ and rad9Δ. So, investigations of epistatic interactions have demonstrated a branched RAD9-dependent pathway. The analyzed genes can also participate in a minor mechanism involved in determining cell radiation sensitivity independently of the mentioned RAD9-dependent pathway

A Unit-Problem Investigation of Blunt Leading-Edge Separation Motivated by AVT-161 SACCON Research

Science.gov (United States)

Luckring, James M.; Boelens, Okko J.

2011-01-01

A research effort has been initiated to examine in more detail some of the challenging flow fields discovered from analysis of the SACCON configuration aerodynamics. This particular effort is oriented toward a diamond wing investigation specifically designed to isolate blunt leading-edge separation phenomena relevant to the SACCON investigations of the present workshop. The approach taken to design this new effort is reviewed along with the current status of the program.

Mechanisms controlling the temporal degradation of Nek2A and Kif18A by the APC/C-Cdc20 complex

DEFF Research Database (Denmark)

Sedgwick, G.G.; Hayward, D.G.; Nilsson, J.

2013-01-01

The Anaphase Promoting Complex/Cyclosome (APC/C) in complex with its co-activator Cdc20 is responsible for targeting proteins for ubiquitin-mediated degradation during mitosis. The activity of APC/C-Cdc20 is inhibited during prometaphase by the Spindle Assembly Checkpoint (SAC) yet certain...... substrates escape this inhibition. Nek2A degradation during prometaphase depends on direct binding of Nek2A to the APC/C via a C-terminal MR dipeptide but whether this motif alone is sufficient is not clear. Here, we identify Kif18A as a novel APC/C-Cdc20 substrate and show that Kif18A degradation depends...... by the APC/C. Nek2A and the mitotic checkpoint complex (MCC) have an overlap in APC/C subunit requirements for binding and we propose that Nek2A binds with high affinity to apo-APC/C and is degraded by the pool of Cdc20 that avoids inhibition by the SAC....

Edge-functionalization of armchair graphene nanoribbons with pentagonal-hexagonal edge structures.

Science.gov (United States)

Ryou, Junga; Park, Jinwoo; Kim, Gunn; Hong, Suklyun

2017-06-21

Using density functional theory calculations, we have studied the edge-functionalization of armchair graphene nanoribbons (AGNRs) with pentagonal-hexagonal edge structures. While the AGNRs with pentagonal-hexagonal edge structures (labeled (5,6)-AGNRs) are metallic, the edge-functionalized (5,6)-AGNRs with substitutional atoms opens a band gap. We find that the band structures of edge-functionalized (5,6)-N-AGNRs by substitution resemble those of defect-free (N-1)-AGNR at the Γ point, whereas those at the X point show the original ones of the defect-free N-AGNR. The overall electronic structures of edge-functionalized (5,6)-AGNRs depend on the number of electrons, supplied by substitutional atoms, at the edges of functionalized (5,6)-AGNRs.

Problems with the random number generator RANF implemented on the CDC cyber 205

Science.gov (United States)

Kalle, Claus; Wansleben, Stephan

1984-10-01

We show that using RANF may lead to wrong results when lattice models are simulated by Monte Carlo methods. We present a shift-register sequence random number generator which generates two random numbers per cycle on a two pipe CDC Cyber 205.

CDC Health Disparities and Inequalities Report--U.S. 2013

Science.gov (United States)

... Women's Health Health Literacy Health Equity CDC Health Disparities & Inequalities Report (CHDIR) Recommend on Facebook Tweet Share ... 2011 Report More Information CDC Releases Second Health Disparities & Inequalities Report - United States, 2013 CDC and its ...

Conjugate calculation of a film-cooled blade for improvement of the leading edge cooling configuration

Directory of Open Access Journals (Sweden)

Norbert Moritz

2013-03-01

Full Text Available Great efforts are still put into the design process of advanced film-cooling configurations. In particular, the vanes and blades of turbine front stages have to be cooled extensively for a safe operation. The conjugate calculation technique is used for the three-dimensional thermal load prediction of a film-cooled test blade of a modern gas turbine. Thus, it becomes possible to take into account the interaction of internal flows, external flow, and heat transfer without the prescription of heat transfer coefficients. The focus of the investigation is laid on the leading edge part of the blade. The numerical model consists of all internal flow passages and cooling hole rows at the leading edge. Furthermore, the radial gap flow is also part of the model. The comparison with thermal pyrometer measurements shows that with respect to regions with high thermal load a qualitatively and quantitatively good agreement of the conjugate results and the measurements can be found. In particular, the region in the vicinity of the mid-span section is exposed to a higher thermal load, which requires further improvement of the cooling arrangement. Altogether the achieved results demonstrate that the conjugate calculation technique is applicable for reasonable prediction of three-dimensional thermal load of complex cooling configurations for blades.

Roughness Effects on the Formation of a Leading Edge Vortex

Science.gov (United States)

Elliott, Cassidy; Lang, Amy; Wahidi, Redha; Wilroy, Jacob

2016-11-01

Microscopic scales cover the wings of Monarch butterflies, creating a patterned surface. This patterning is an important natural flow control mechanism that is thought to delay the growth of the leading edge vortex (LEV) produced by the flapping motion of a wing. The increased skin friction caused by the scales leads to a weaker LEV being shed into the butterfly's wake, lessening drag and increasing flight efficiency. To test this theory, a plate of random roughness was designed in SolidWorks and printed on the Objet 30 Pro 3D printer. A 2x3x5 cubic foot tow tank was used to test the rough plate at Reynold's numbers of 1500, 3000, and 6000 (velocities of 8, 16, and 32 mm/s) at an angle of attack of 45 degrees. Particle Image Velocimetry (PIV) captured images of the LEV generated by the plate when towed upwards through the particle-seeded flow. Codes written in MatLab were used to automatically track and determine the strength of the LEV. Circulation values for the randomly-rough plate were then compared to the same values generated in a previous experiment that used a smooth plate and a grooved plate to determine the effect of the patterning on vortex development. Funding provided by NSF REU site Grant EEC 1358991 and CBET 1628600.

An edge pedestal model

International Nuclear Information System (INIS)

Stacev, W.M.

2001-01-01

A new model for calculation of the gradient scale lengths in the edge pedestal region and of the edge transport barrier width in H-mode tokamak plasmas will be described. Model problem calculations which demonstrate the promise of this model for predicting experimental pedestal properties will be discussed. The density and Prague gradient scale lengths (L) in the edge are calculated from the particle and ion and electron energy radial transport equations, making use of (presumed) known particle and energy fluxes flowing across the edge transport barrier from the core into the SOL and of edge transport coefficients. The average values of the particle and heat fluxes in the edge transport barrier are calculated in terms of the fluxes crossing into the SOL and the atomic physics reaction rates (ionisation, charge-exchange, elastic scattering, impurity radiation) in the edge by integrating the respective transport equations from the pedestal to the separatrix. An important implication of this model is that the pedestal gradient scale lengths depend not just on local pedestal platers properties but also on particle and energy fluxes from the core plasma and on recycling neutral fluxes that penetrate into the plasma edge, both of which in turn depend on the pedestal properties. The MHD edge pressure gradient constraint α≤ α C is used to determine the pressure width of the edge transport barrier, Δ TB = Δ TB (α c ). Three different models for the MHD edge pressure gradient constraint have been investigated: (1) nominal ideal ballooning mode theory, (2) ballooning mode theory taking into account the edge geometry and shear to access He second stability region; and pedestal β-limit theory when the ballooning modes are stabilised by diamagnetic effects. A series of calculations have been made for a DIII-D model problem. The calculated gradient scale lengths and edge transport barrier widths are of the magnitude of values observed experimentally, and certain trends

Origin of long lifetime of band-edge charge carriers in organic-inorganic lead iodide perovskites.

Science.gov (United States)

Chen, Tianran; Chen, Wei-Liang; Foley, Benjamin J; Lee, Jooseop; Ruff, Jacob P C; Ko, J Y Peter; Brown, Craig M; Harriger, Leland W; Zhang, Depei; Park, Changwon; Yoon, Mina; Chang, Yu-Ming; Choi, Joshua J; Lee, Seung-Hun

2017-07-18

Long carrier lifetime is what makes hybrid organic-inorganic perovskites high-performance photovoltaic materials. Several microscopic mechanisms behind the unusually long carrier lifetime have been proposed, such as formation of large polarons, Rashba effect, ferroelectric domains, and photon recycling. Here, we show that the screening of band-edge charge carriers by rotation of organic cation molecules can be a major contribution to the prolonged carrier lifetime. Our results reveal that the band-edge carrier lifetime increases when the system enters from a phase with lower rotational entropy to another phase with higher entropy. These results imply that the recombination of the photoexcited electrons and holes is suppressed by the screening, leading to the formation of polarons and thereby extending the lifetime. Thus, searching for organic-inorganic perovskites with high rotational entropy over a wide range of temperature may be a key to achieve superior solar cell performance.

START-GAP3/DLC3 is a GAP for RhoA and Cdc42 and is localized in focal adhesions regulating cell morphology

International Nuclear Information System (INIS)

Kawai, Katsuhisa; Kiyota, Minoru; Seike, Junichi; Deki, Yuko; Yagisawa, Hitoshi

2007-01-01

In the human genome there are three genes encoding RhoGAPs that contain the START (steroidogenic acute regulatory protein (StAR)-related lipid transfer)-domain. START-GAP3/DLC3 is a tumor suppressor gene similar to two other human START-GAPs known as DLC1 or DLC2. Although expression of START-GAP3/DLC3 inhibits the proliferation of cancer cells, its molecular function is not well understood. In this study we carried out biochemical characterization of START-GAP3/DLC3, and explored the effects of its expression on cell morphology and intracellular localization. We found that START-GAP3/DLC3 serves as a stimulator of PLCδ1 and as a GAP for both RhoA and Cdc42 in vitro. Moreover, we found that the GAP activity is responsible for morphological changes. The intracellular localization of endogenous START-GAP3/DLC3 was explored by immunocytochemistry and was revealed in focal adhesions. These results indicate that START-GAP3/DLC3 has characteristics similar to other START-GAPs and the START-GAP family seems to share common characteristics

Androgen receptor (AR) promotes clear cell renal cell carcinoma (ccRCC) migration and invasion via altering the circHIAT1/miR-195-5p/29a-3p/29c-3p/CDC42 signals.

Science.gov (United States)

Wang, Kefeng; Sun, Yin; Tao, Wei; Fei, Xiang; Chang, Chawnshang

2017-05-28

Increasing evidence has demonstrated that the androgen receptor (AR) plays important roles to promote the metastasis of clear cell renal cell carcinoma (ccRCC). The detailed mechanisms, especially how AR functions via altering the circular RNAs (circRNAs) remain unclear. Here we identified a new circRNA (named as circHIAT1) whose expression was lower in ccRCCs than adjacent normal tissues. Targeting AR could suppress ccRCC cell progression via increasing circHIAT1 expression. ChIP assay and luciferase assay demonstrated that AR suppressed circHIAT1 expression via regulating its host gene, Hippocampus Abundant Transcript 1 (HIAT1) expression at the transcriptional level. The consequences of AR-suppressed circHIAT1 resulted in deregulating miR-195-5p/29a-3p/29c-3p expressions, which increased CDC42 expression to enhance ccRCC cell migration and invasion. Increasing this newly identified signal via circHIAT1 suppressed AR-enhanced ccRCC cell migration and invasion. Together, these results suggested that circHIAT1 functioned as a metastatic inhibitor to suppress AR-enhanced ccRCC cell migration and invasion. Targeting this newly identified AR-circHIAT1-mediated miR-195-5p/29a-3p/29c-3p/CDC42 signals may help us develop potential new therapies to better suppress ccRCC metastasis. Copyright © 2017 Elsevier B.V. All rights reserved.

CDC WONDER: Births

Data.gov (United States)

U.S. Department of Health & Human Services — The Births (Natality) online databases in CDC WONDER report birth rates, fertility rates and counts of live births occurring within the United States to U.S....

Decreased uv mutagenesis in cdc8, a DNA replication mutant of Saccharomyces cerevisiae

International Nuclear Information System (INIS)

Prakash, L.; Hinkle, D.; Prakash, S.

1978-01-01

A DNA replication mutant of yeast, cdc8, was found to decrease uv-induced reversion of lys2-1, arg4-17, tryl and ural. This effect was observed with all three alleles of cdc8 tested. Survival curves obtained following uv irradiation in cdc8 rad double mutants show that cdc8 is epistatic to rad6, as well as to rad1; cdc8 rad51 double mutants seem to be more sensitive than the single mutants. Since uv-induced reversion in cdc8 rad1 and cdc8 rad51 double mutants is like that of the cdc8 single mutants, we conclude that CDC8 plays a direct role in error-prone repair. To test whether CDC8 codes for a DNA polymerase, we have purified both DNA polymerase I and DNA polymerase II from cdc8 and CDC+ cells. The purified DNA polymerases from cdc8 were no more heat labile than those from CDC+, suggesting that CDC8 is not a structural gene for either enzyme

Depolarization-stimulated 42K+ efflux in rat aorta is calcium- and cellular volume-dependent

International Nuclear Information System (INIS)

Magliola, L.; Jones, A.W.

1987-01-01

The purpose of this study was to investigate the factors controlling membrane permeability to potassium of smooth muscle cells from rat aorta stimulated by depolarization. The increase 42 K+ efflux (change in the rate constant) induced by depolarization (application of high concentrations of potassium chloride) was inhibited significantly by the calcium antagonists diltiazem and nisoldipine. Parallel inhibitory effects on contraction were observed. Diltiazem also inhibited potassium-stimulated 36 Cl- efflux. The addition of 25-150 mM KCl to normal physiologic solution stimulated 42 K+ efflux in a concentration-dependent manner. Diltiazem suppressed potassium-stimulated 42 K+ efflux approximately 90% at 25 mM KCl and approximately 40% at 150 mM KCl. The ability of nisoldipine to inhibit 42 K+ efflux also diminished as the potassium chloride concentration was elevated. The component of efflux that was resistant to calcium antagonists probably resulted from a decrease in the electrochemical gradient for potassium. Cellular water did not change during potassium addition. Substitution of 80 and 150 mM KCl for sodium chloride produced cellular swelling and enhanced potassium-stimulated 42 K+ efflux compared with potassium chloride addition. The addition of sucrose to prevent cellular swelling reduced efflux response to potassium substitution toward that of potassium addition. A hypoosmolar physiologic solution produced an increase in the 42 K+ efflux and a contracture that were both prevented by the addition of sucrose. We concluded that the depolarization-mediated 42 K+ efflux has three components: one is calcium dependent; a second is dependent on cellular volume; and a third is resistant to inhibition by calcium antagonists

"Partners in Science": A Model Cooperative Program Introducing High School Teachers and Students to Leading-Edge Pharmaceutical Science

Science.gov (United States)

Woska, Joseph R., Jr.; Collins, Danielle M.; Canney, Brian J.; Arcario, Erin L.; Reilly, Patricia L.

2005-01-01

"Partners in Science" is a cooperative program between Boehringer Ingelheim Pharmaceuticals, Inc. and area high schools in the community surrounding our Connecticut campus. It is a two-phase program that introduces high school students and teachers to the world of drug discovery and leading-edge pharmaceutical research. Phase 1 involves…

Power deposition on misaligned edges in COMPASS

Directory of Open Access Journals (Sweden)

R. Dejarnac

2017-08-01

Full Text Available If the decision is made not to apply a toroidal chamfer to tungsten monoblocks at ITER divertor vertical targets, exposed leading edges will arise as a result of assembly tolerances between adjacent plasma-facing components. Then, the advantage of glancing magnetic field angles for spreading plasma heat flux on top surfaces is lost at the misaligned edges with an interaction occurring at near normal incidence, which can drive melting for the expected inter-ELM heat fluxes. A dedicated experiment has been performed on the COMPASS tokamak to thoroughly study power deposition on misaligned edges using inner-wall limited discharges on a special graphite tile presenting gaps and leading edges directly viewed by a high resolution infra-red camera. The parallel power flux deducted from the unperturbed measurement far from the gap is fully consistent with the observed temperature increase at the leading edge, respecting the power balance. All the power flowing into the gap is deposited at the leading edge and no mitigation factor is required to explain the thermal response. Particle-in-cell simulations show that the ion Larmor smoothing effect is weak and that the power deposition on misaligned edges is well described by the optical approximation because of an electron dominated regime associated with non-ambipolar parallel current flow.

Small polaron conduction in lead modified lanthanum ferrite ceramics

Energy Technology Data Exchange (ETDEWEB)

Bhargav, K.K.; Ram, S.; Majumder, S.B., E-mail: subhasish@matsc.iitkgp.ernet.in

2015-07-25

Highlights: • La{sub 0.8}Pb{sub 0.2}FeO{sub 3} (ε{sub r} ∼ 30,000) shows higher dielectric constant than LaFeO{sub 3} (∼14,000). • Lower A-site dopant content, the dielectric maxima shift to higher temperature. • The frequency dependence of ε{sub r} and tan δ vs. temperature exhibit CDC like behavior. • R{sub g} and R{sub gb} of Pb modified LaFeO{sub 3} follow small polaron hopping conduction model. - Abstract: In the present work we have illustrated the physics of the electrical characteristics of nanocrystalline La{sub 1−x}Pb{sub x}FeO{sub 3,} (0 ⩽ x ⩽ 0.2) powder prepared using auto-combustion synthesis. The effect of lead doping on the dielectric, impedance and ac conductivity characteristics of lanthanum ferrite has systematically been investigated. The synthesized powders were phase pure and crystallized into centro-symmetric Pnma space group. As compared to pure LaFeO{sub 3} ceramics (dielectric constant ∼ 14,000), the dielectric constant is grossly increased (∼30,000) in Pb doped LaFeO{sub 3}. The temperature dependence of dielectric constant of 10.0 at.% Pb doped LaFeO{sub 3} exhibits dielectric maxima similar to that observed in ferroelectric ceramics with non-centrosymmetric point group. For La{sub 0.8}Pb{sub 0.2}FeO{sub 3} ceramics, the frequency dependence of the dielectric constant and loss tangent at various temperatures (300–450 K) exhibit typical colossal dielectric constant (CDC) like behavior. From the impedance spectroscopy we have estimated the grain and grain boundary resistance and capacitance of Pb doped LaFeO{sub 3} that follow a small polaron hopping conduction model. Long range movement of the charge carriers govern the CDC behavior.

Distinct pools of cdc25C are phosphorylated on specific TP sites and differentially localized in human mitotic cells.

Directory of Open Access Journals (Sweden)

Celine Franckhauser

Full Text Available BACKGROUND: The dual specificity phosphatase cdc25C was the first human cdc25 family member found to be essential in the activation of cdk1/cyclin B1 that takes place at the entry into mitosis. Human cdc25C is phosphorylated on Proline-dependent SP and TP sites when it becomes active at mitosis and the prevalent model is that this phosphorylation/activation of cdc25C would be part of an amplification loop with cdk1/cyclin B1. METHODOLOGY/PRINCIPAL FINDINGS: Using highly specific antibodies directed against cdc25C phospho-epitopes, pT67 and pT130, we show here that these two phospho-forms of cdc25C represent distinct pools with differential localization during human mitosis. Phosphorylation on T67 occurs from prophase and the cdc25C-pT67 phospho-isoform closely localizes with condensed chromosomes throughout mitosis. The phospho-T130 form of cdc25C arises in late G2 and associates predominantly with centrosomes from prophase to anaphase B where it colocalizes with Plk1. As shown by immunoprecipitation of each isoform, these two phospho-forms are not simultaneously phosphorylated on the other mitotic TP sites or associated with one another. Phospho-T67 cdc25C co-precipitates with MPM2-reactive proteins while pT130-cdc25C is associated with Plk1. Interaction and colocalization of phosphoT130-cdc25C with Plk1 demonstrate in living cells, that the sequence around pT130 acts as a true Polo Box Domain (PBD binding site as previously identified from in vitro peptide screening studies. Overexpression of non-phosphorylatable alanine mutant forms for each isoform, but not wild type cdc25C, strongly impairs mitotic progression showing the functional requirement for each site-specific phosphorylation of cdc25C at mitosis. CONCLUSIONS/SIGNIFICANCE: These results show for the first time that in human mitosis, distinct phospho-isoforms of cdc25C exist with different localizations and interacting partners, thus implying that the long-standing model of a cdc25C

Numerical simulation of flow characteristics behind the aerodynamic performances on an airfoil with leading edge protuberances

Directory of Open Access Journals (Sweden)

Ming Zhao

2017-01-01

Full Text Available This article presents a numerical investigation of the effects of leading-edge protuberances on airfoil stall and post-stall performance. An improved delayed detached eddy simulation (IDDES method was adopted. As a result, to clarify the effects of ‘bi-periodic’ phenomenon around stall region, it was found that the flow separation at troughs was the main inducement of aerodynamic lift degradation within pre-stall regime and the flow pattern where vortices diverged was predominant. It was also found that the variations in flow patterns led to the gentle stall process. Furthermore, to study the statistical characteristics of unsteady vortex shedding, corresponding spectrum characteristics were also analyzed from another perspective, suggesting that the vortex shedding frequency was higher where vortices converged. Eventually, the improved performances of tubercled airfoil within post-stall regime could be attributed to the strong streamwise vortices generated by the leading-edge protuberances. Deploying the methods of vortex dynamics, the generation and evolution of the streamwise vortices were depicted. It turned out that the primary and secondary vortices were induced by spanwise pressure gradient at airfoil surface; meanwhile, vortex stretching played a key role in primary vortex evolution, which initially enhanced the strength of vortices corresponding to the acceleration of streamwise velocity.

Edge instabilities of topological superconductors

Energy Technology Data Exchange (ETDEWEB)

Hofmann, Johannes S. [Institut fuer Theoretische Physik und Astrophysik, Universitaet Wuerzburg (Germany); Max-Planck-Institut fuer Festkoerperforschung, Stuttgart (Germany); Assaad, Fakher F. [Institut fuer Theoretische Physik und Astrophysik, Universitaet Wuerzburg (Germany); Schnyder, Andreas P. [Max-Planck-Institut fuer Festkoerperforschung, Stuttgart (Germany)

2016-07-01

Nodal topological superconductors display zero-energy Majorana flat bands at generic edges. The flatness of these edge bands, which is protected by time-reversal and translation symmetry, gives rise to an extensive ground state degeneracy and a diverging density of states. Therefore, even arbitrarily weak interactions lead to an instability of the flat-band edge states towards time-reversal and translation-symmetry broken phases, which lift the ground-state degeneracy. Here, we employ Monte Carlo simulations combined with mean-field considerations to examine the instabilities of the flat-band edge states of d{sub xy}-wave superconductors. We find that attractive interactions induce a complex s-wave pairing instability together with a density wave instability. Repulsive interactions, on the other hand, lead to ferromagnetism mixed with spin-triplet pairing at the edge. We discuss the implications of our findings for experiments on cuprate high-temperature superconductors.

Transport Mechanisms Governing initial Leading-Edge Vortex Development on a Pitching Wing

Science.gov (United States)

Wabick, Kevin; Berdon, Randall; Buchholz, James; Johnson, Kyle; Thurow, Brian

2017-11-01

The formation and evolution of Leading Edge Vortices (LEVs) are ubiquitous in natural fliers and maneuvering wings, and have a profound impact on aerodynamic loads. The formation of an LEV is experimentally investigated on a pitching flat-plate wing of aspect-ratio 2, and dimensionless pitch rates of k = Ωc / 2 U of 0.1, 0.2, and 0.5, at a Reynolds number of 104. The sources and sinks of vorticity that contribute to the growth and evolution of the LEV are investigated at spanwise regions of interest, and their relative balance is compared to other wing kinematics, and the case of a two-dimensional pitching wing. This work is supported by the Air Force Office of Scientific Research (Grant Number FA9550-16-1-0107, Dr. Douglas Smith, program manager).

CDC Vital Signs–Native Americans With Diabetes

Centers for Disease Control (CDC) Podcasts

2017-01-10

This podcast is based on the January 2017 CDC Vital Signs report. Diabetes is the leading cause of kidney failure and Native Americans have a greater chance of having diabetes than any other racial group in the U.S. Learn how to manage your diabetes to delay or prevent kidney failure.  Created: 1/10/2017 by National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP).   Date Released: 1/10/2017.

Temperature dependent evolution of the local electronic structure of atmospheric plasma treated carbon nanotubes: Near edge x-ray absorption fine structure study

International Nuclear Information System (INIS)

Roy, S. S.; Papakonstantinou, P.; Okpalugo, T. I. T.; Murphy, H.

2006-01-01

Near edge x-ray absorption fine structure (NEXAFS) spectroscopy has been employed to obtain the temperature dependent evolution of the electronic structure of acid treated carbon nanotubes, which were further modified by dielectric barrier discharge plasma processing in an ammonia atmosphere. The NEXAFS studies were performed from room temperature up to 900 deg. C. The presence of oxygen and nitrogen containing functional groups was observed in C K edge, N K edge, and O K edge NEXAFS spectra of the multiwalled carbon nanotubes. The N K edge spectra revealed three types of π* features, the source of which was decisively identified by their temperature dependent evolution. It was established that these features are attributed to pyridinelike, NO, and graphitelike structures, respectively. The O K edge indicated that both carbonyl (C=O), π*(CO), and ether C-O-C, σ*(CO), functionalities were present. Upon heating in a vacuum to 900 deg. C the π*(CO) resonances disappeared while the σ*(CO) resonances were still present confirming their higher thermal stability. Heating did not produce a significant change in the π* feature of the C K edge spectrum indicating that the tabular structure of the nanotubes is essentially preserved following the thermal decomposition of the functional groups on the nanotube surface

Temperature dependence of the soft-x-ray emission edges of simple metals

International Nuclear Information System (INIS)

Tagle, J.A.; Arakawa, E.T.; Callcott, T.A.

1980-01-01

The widths and energy positions of the M/sub 2,3/-emission edge of potassium, K-emission edge of beryllium, and L/sub 2,3/-emission edges of aluminum and magnesium have been measured for temperatures between 80 and 600 0 K. All band edges broaden (ΔGAMMA) and shift in energy (ΔE) with increasing temperatures for these materials. Similar results were reported earlier for the Li K-emission edge and Na L/sub 2,3/ edge. Lattice-relaxation processes and the phonon core-hole interaction are the dominant mechanisms affecting the core-level widths and the experimentally observed edge widths. The edge shifts are found to be proportional to the thermal expansion of the lattice, and are discussed in terms of the electron energy-level shifts which occur as the lattice dilates

AMELIA CESTOL Test: Acoustic Characteristics of Circulation Control Wing with Leading- and Trailing-Edge Slot Blowing

Science.gov (United States)

Horne, William C.; Burnside, Nathan J.

2013-01-01

The AMELIA Cruise-Efficient Short Take-off and Landing (CESTOL) configuration concept was developed to meet future requirements of reduced field length, noise, and fuel burn by researchers at Cal Poly, San Luis Obispo and Georgia Tech Research Institute under sponsorship by the NASA Fundamental Aeronautics Program (FAP), Subsonic Fixed Wing Project. The novel configuration includes leading- and trailing-edge circulation control wing (CCW), over-wing podded turbine propulsion simulation (TPS). Extensive aerodynamic measurements of forces, surfaces pressures, and wing surface skin friction measurements were recently measured over a wide range of test conditions in the Arnold Engineering Development Center(AEDC) National Full-Scale Aerodynamics Complex (NFAC) 40- by 80-Ft Wind Tunnel. Acoustic measurements of the model were also acquired for each configuration with 7 fixed microphones on a line under the left wing, and with a 48-element, 40-inch diameter phased microphone array under the right wing. This presentation will discuss acoustic characteristics of the CCW system for a variety of tunnel speeds (0 to 120 kts), model configurations (leading edge(LE) and/or trailing-edge(TE) slot blowing, and orientations (incidence and yaw) based on acoustic measurements acquired concurrently with the aerodynamic measurements. The flow coefficient, Cmu= mVSLOT/qSW varied from 0 to 0.88 at 40 kts, and from 0 to 0.15 at 120 kts. Here m is the slot mass flow rate, VSLOT is the slot exit velocity, q is dynamic pressure, and SW is wing surface area. Directivities at selected 1/3 octave bands will be compared with comparable measurements of a 2-D wing at GTRI, as will as microphone array near-field measurements of the right wing at maximum flow rate. The presentation will include discussion of acoustic sensor calibrations as well as characterization of the wind tunnel background noise environment.

Infective endocarditis following transcatheter edge-to-edge mitral valve repair: A systematic review.

Science.gov (United States)

Asmarats, Lluis; Rodriguez-Gabella, Tania; Chamandi, Chekrallah; Bernier, Mathieu; Beaudoin, Jonathan; O'Connor, Kim; Dumont, Eric; Dagenais, François; Paradis, Jean-Michel; Rodés-Cabau, Josep

2018-05-10

To assess the clinical characteristics, management, and outcomes of patients diagnosed with infective endocarditis (IE) after edge-to-edge mitral valve repair with the MitraClip device. Transcatheter edge-to-edge mitral valve repair has emerged as an alternative to surgery in high-risk patients. However, few data exist on IE following transcatheter mitral procedures. Four electronic databases (PubMed, Google Scholar, Embase, and Cochrane Library) were searched for original published studies on IE after edge-to-edge transcatheter mitral valve repair from 2003 to 2017. A total of 10 publications describing 12 patients with definitive IE (median age 76 years, 55% men) were found. The mean logistic EuroSCORE/EuroSCORE II were 41% and 45%, respectively. The IE episode occurred early (within 12 months post-procedure) in nine patients (75%; within the first month in five patients). Staphylococcus aureus was the most frequent (60%) causal microorganism, and severe mitral regurgitation was present in all cases but one. Surgical mitral valve replacement (SMVR) was performed in most (67%) patients, and the mortality associated with the IE episode was high (42%). IE following transcatheter edge-to-edge mitral valve repair is a rare but life-threatening complication, usually necessitating SMVR despite the high-risk profile of the patients. These results highlight the importance of adequate preventive measures and a prompt diagnosis and treatment of this serious complication. © 2018 Wiley Periodicals, Inc.

Roughness Effects on the Formation of a Leading Edge Vortex

Science.gov (United States)

Elliott, Cassidy; Lang, Amy; Wahidi, Redha; Wilroy, Jacob

2017-11-01

Microscopic scales cover the wings of Monarch butterflies, creating a patterned surface that acts as a natural energy capture mechanism. This patterning is thought to delay the growth of the leading edge vortex (LEV) produced by the flapping motion of a wing. Increased skin friction caused by the scales leads to a weaker LEV being shed into the butterfly's wake, lessening drag and increasing flight efficiency. To test how this roughness effects LEV formation, a plate of random roughness was designed in SolidWorks and printed on the Objet 30 Pro 3D printer. A 2x3x5 cubic foot tow tank was used to test the rough plate at Reynold's numbers of 1500, 3000, and 6000 (velocities of 8, 16, and 32 mm/s) at an angle of attack of 45 degrees. Images were captured of the LEV generated when the plate was towed upwards through the particle-seeded flow. These images were used to determine the XY velocity of the particles using a technique called Digital Particle Image Velocimetry (DPIV). Codes written in MATLAB were used to track and measure the strength of the LEV. Circulation values for the randomly-rough plate were then compared to the same values generated in a previous experiment that used a smooth plate and a grooved plate to determine the effect of the patterning on vortex development. Funding for this research project was provided by the National Science Foundation under the Research Experience for Undergraduates (REU) program (REU Supplement CBET 1628600 under CBET 1335848).

Dielectric response and pyroelectric properties of lead-free ferroelectric Ba3(VO42

Directory of Open Access Journals (Sweden)

Biswajit Pati

2015-03-01

Full Text Available The current paper presents results of dielectric response, pyroelectric behavior and conductivity study of lead-free ferroelectric barium orthovanadate (Ba3(VO42 or Ba3V2O8 ceramic, for a wide range of temperature and frequency. An X-ray diffraction study suggests the formation of a single-phase compound in trigonal crystal system. The SEM micrograph of gold-coated pellet sample shows well-defined and homogeneous morphology. Detailed studies of dielectric parameters (εr and tan δ of the compound as a function of temperature and frequency reveal their independence over a wide range of temperature and frequency. The nature of Polarization versus electric field (P–E hysteresis loop of Ba3V2O8 at room temperature suggests its ferroelectric nature. The temperature dependence of pyroelectric coefficient and figure of merits of the sample support its dielectric response. The nature of variation of dc conductivity with temperature confirms the Arrhenius and negative temperature coefficient of resistance (NTCR behavior of the material.

Center edge angle measurement for hip preservation surgery: technique and caveats.

Science.gov (United States)

Anderson, Lucas A; Gililland, Jeremy; Pelt, Christopher; Linford, Samuel; Stoddard, Gregory J; Peters, Christopher L

2011-01-01

Anterior and lateral center edge angles have traditionally been used to determine acetabular coverage, and thereby strongly influence the decision to perform acetabular reorientation versus osteochondroplasty in patients with dysplasia and/or femoroacetabular impingement. We propose templating the center of the contained articular femoral head in aspherical hips to provide reliable assessment of acetabular coverage. Digital radiographs of 30 patients with various combinations of femoral and acetabular morphologies were evaluated using 2 methods to identify the anterior center edge angle and lateral center edge angle. The control method used an estimated femoral head center for angle apex. The study technique determined the center of the femoral head by templating the congruent aspect of the femoral head contained by the acetabulum while ignoring the increasing lateral and anterior radius associated with cam deformities. Four readers measured lateral center edge angles on anteroposterior radiographs and anterior center edge angles on false-profile radiographs. Two reads were performed by each reader using both the estimated and the templated methods for a total of 4 reads. Interobserver reliability using the proposed method compared to the standard was much improved for anterior center edge angles (intraclass correlation coefficient of 0.76 vs 0.55) as well as with lateral center edge angles (ICC of 0.80 vs 0.42). Decreased correlation was most commonly associated with abnormal sourcil morphology, posterior wall deficiency combined with calcified labra, and os acetabuli. Including the anterolateral cam deformity in identifying the center of the femoral head for measuring center edge angles leads to an underestimation of acetabular coverage, which may negatively affect hip preservation surgical decision making. Copyright 2011, SLACK Incorporated.

MHD forced and free convection boundary layer flow near the leading edge

International Nuclear Information System (INIS)

Hossain, M.A.; Ahmed, M.

1988-07-01

Magnetohydrodynamic forced and free convection flow of an electrically conducting viscous incompressible fluid past a vertical flat plate with uniform heat flux in the presence of a magnetic field acting normal to the plate that moves with the fluid has been studied near the leading edge of the plate. The coupled non-linear equations are solved by the method of superposition for the values of the Prandtl number ranges from 0.01 to 10.0. The velocity and the temperature profiles are presented graphically and the values of the wall shear-stress as well as the heat transfer rate are presented in tabular form showing the effect of the buoyancy force and the applied magnetic field. To show the accuracy of the present method some typical values are compared with the available one. (author). 17 refs, 3 figs, 2 tabs

The human ubiquitin-conjugating enzyme Cdc34 controls cellular proliferation through regulation of p27Kip1 protein levels

International Nuclear Information System (INIS)

Butz, Nicole; Ruetz, Stephan; Natt, Francois; Hall, Jonathan; Weiler, Jan; Mestan, Juergen; Ducarre, Monique; Grossenbacher, Rita; Hauser, Patrick; Kempf, Dominique; Hofmann, Francesco

2005-01-01

Ubiquitin-mediated degradation of the cyclin-dependent kinase inhibitor p27 Kip1 was shown to be required for the activation of key cyclin-dependent kinases, thereby triggering the onset of DNA replication and cell cycle progression. Although the SCF Skp2 ubiquitin ligase has been reported to mediate p27 Kip1 degradation, the nature of the human ubiquitin-conjugating enzyme involved in this process has not yet been determined at the cellular level. Here, we show that antisense oligonucleotides targeting the human ubiquitin-conjugating enzyme Cdc34 downregulate its expression, inhibit the degradation of p27 Kip1 , and prevent cellular proliferation. Elevation of p27 Kip1 protein level is found to be the sole requirement for the inhibition of cellular proliferation induced upon downregulation of Cdc34. Indeed, reducing the expression of p27 Kip1 with a specific antisense oligonucleotide is sufficient to reverse the anti-proliferative phenotype elicited by the Cdc34 antisense. Furthermore, downregulation of Cdc34 is found to specifically increase the abundance of the SCF Skp2 ubiquitin ligase substrate p27 Kip1 , but has no concomitant effect on the level of IkBα and β-catenin, which are known substrates of a closely related SCF ligase

The G2/M DNA damage checkpoint inhibits mitosis through Tyr15 phosphorylation of p34cdc2 in Aspergillus nidulans.

Science.gov (United States)

Ye, X S; Fincher, R R; Tang, A; Osmani, S A

1997-01-02

It is possible to cause G2 arrest in Aspergillus nidulans by inactivating either p34cdc2 or NIMA. We therefore investigated the negative control of these two mitosis-promoting kinases after DNA damage. DNA damage caused rapid Tyr15 phosphorylation of p34cdc2 and transient cell cycle arrest but had little effect on the activity of NIMA. Dividing cells deficient in Tyr15 phosphorylation of p34cdc2 were sensitive to both MMS and UV irradiation and entered lethal premature mitosis with damaged DNA. However, non-dividing quiescent conidiospores of the Tyr15 mutant strain were not sensitive to DNA damage. The UV and MMS sensitivity of cells unable to tyrosine phosphorylate p34cdc2 is therefore caused by defects in DNA damage checkpoint regulation over mitosis. Both the nimA5 and nimT23 temperature-sensitive mutations cause an arrest in G2 at 42 degrees C. Addition of MMS to nimT23 G2-arrested cells caused a marked delay in their entry into mitosis upon downshift to 32 degrees C and this delay was correlated with a long delay in the dephosphorylation and activation of p34cdc2. Addition of MMS to nimA5 G2-arrested cells caused inactivation of the H1 kinase activity of p34cdc2 due to an increase in its Tyr15 phosphorylation level and delayed entry into mitosis upon return to 32 degrees C. However, if Tyr15 phosphorylation of p34cdc2 was prevented then its H1 kinase activity was not inactivated upon MMS addition to nimA5 G2-arrested cells and they rapidly progressed into a lethal mitosis upon release to 32 degrees C. Thus, Tyr15 phosphorylation of p34cdc2 in G2 arrests initiation of mitosis after DNA damage in A. nidulans.

STEADI: CDC's approach to make older adult fall prevention part of every primary care practice.

Science.gov (United States)

Sarmiento, Kelly; Lee, Robin

2017-12-01

Primary care providers play a critical role in protecting older adult patients from one of the biggest threats to their health and independence-falls. A fall among an older adult patient cannot only be fatal or cause a devastating injury, but can also lead to problems that can effect a patient's overall quality of life. In response, the Centers for Disease Control and Prevention (CDC) developed the STEADI initiative to give health care providers the tools they need to help reduce their older adult patient's risk of a fall. CDC's STEADI resources have been distributed widely and include practical materials and tools for health care providers and their patients that are designed to be integrated into every primary care practice. As the population ages, the need for fall prevention efforts, such as CDC's STEADI, will become increasingly critical to safeguard the health of Americans. STEADI's electronic health records (EHRs), online trainings, assessment tools, and patient education materials are available at no-cost and can be downloaded online at www.cdc.gov/STEADI. Health care providers should look for opportunities to integrate STEADI materials into their practice, using a team-based approach, to help protect their older patients. Published by Elsevier Ltd.

Nek2A destruction marks APC/C activation at the prophase-to-prometaphase transition by spindle-checkpoint-restricted Cdc20.

Science.gov (United States)

Boekhout, Michiel; Wolthuis, Rob

2015-04-15

Nek2 isoform A (Nek2A) is a presumed substrate of the anaphase-promoting complex/cyclosome containing Cdc20 (APC/C(Cdc20)). Nek2A, like cyclin A, is degraded in mitosis while the spindle checkpoint is active. Cyclin A prevents spindle checkpoint proteins from binding to Cdc20 and is recruited to the APC/C in prometaphase. We found that Nek2A and cyclin A avoid being stabilized by the spindle checkpoint in different ways. First, enhancing mitotic checkpoint complex (MCC) formation by nocodazole treatment inhibited the degradation of geminin and cyclin A, whereas Nek2A disappeared at a normal rate. Second, depleting Cdc20 effectively stabilized cyclin A but not Nek2A. Nevertheless, Nek2A destruction crucially depended on Cdc20 binding to the APC/C. Third, in contrast to cyclin A, Nek2A was recruited to the APC/C before the start of mitosis. Interestingly, the spindle checkpoint very effectively stabilized an APC/C-binding mutant of Nek2A, which required the Nek2A KEN box. Apparently, in cells, the spindle checkpoint primarily prevents Cdc20 from binding destruction motifs. Nek2A disappearance marks the prophase-to-prometaphase transition, when Cdc20, regardless of the spindle checkpoint, activates the APC/C. However, Mad2 depletion accelerated Nek2A destruction, showing that spindle checkpoint release further increases APC/C(Cdc20) catalytic activity. © 2015. Published by The Company of Biologists Ltd.

CDC Kerala 1: Organization of clinical child development services (1987-2013).

Science.gov (United States)

Nair, M K C; George, Babu; Nair, G S Harikumaran; Bhaskaran, Deepa; Leena, M L; Russell, Paul Swamidhas Sudhakar

2014-12-01

The main objective of establishing the Child Development Centre (CDC), Kerala for piloting comprehensive child adolescent development program in India, has been to understand the conceptualization, design and scaling up of a pro-active positive child development initiative, easily replicable all over India. The process of establishing the Child Development Centre (CDC) Kerala for research, clinical services, training and community extension services over the last 25 y, has been as follows; Step 1: Conceptualization--The life cycle approach to child development; Step 2: Research basis--CDC model early stimulation is effective; Step 3: Development and validation of seven simple developmental screening tools; Step 4: CDC Diagnostic services--Ultrasonology and genetic, and metabolic laboratory; Step 5: Developing seven intervention packages; Step 6: Training--Post graduate diploma in clinical child development; Step 7: CDC Clinic Services--seven major ones; Step 8: CDC Community Services--Child development referral units; Step 9: Community service delivery models--Childhood disability and for adolescent care counselling projects; Step 10: National capacity building--Four child development related courses. CDC Kerala follow-up and clinic services are offered till 18 y of age and premarital counselling till 24 y of age as shown in "CDC Kerala Clinic Services Flow Chart" and 74,291 children have availed CDC clinic services in the last 10 y. CDC Kerala is the first model for comprehensive child adolescent development services using a lifecycle approach in the Government sector and hence declared as the collaborative centre for Rashtriya Bal Swasthya Karyakram (RBSK), in Kerala.

Myosin II activity is required for functional leading-edge cells and closure of epidermal sheets in fish skin ex vivo.

Science.gov (United States)

Morita, Toshiyuki; Tsuchiya, Akiko; Sugimoto, Masazumi

2011-09-01

Re-epithelialization in skin wound healing is a process in which epidermal sheets grow and close the wound. Although the actin-myosin system is thought to have a pivotal role in re-epithelialization, its role is not clear. In fish skin, re-epithelialization occurs around 500 μm/h and is 50 times faster than in mammalian skin. We had previously reported that leading-edge cells of the epidermal outgrowth have both polarized large lamellipodia and "purse string"-like actin filament cables in the scale-skin culture system of medaka fish, Oryzias latipes (Cell Tissue Res, 2007). The actin purse-string (APS) is a supracellular contractile machinery in which adherens junctions (AJs) link intracellular myosin II-including actin cables between neighboring cells. In this study, we developed a modified "face-to-face" scale-skin culture system as an ex vivo model to study epidermal wound healing, and examined the role of the actin-myosin system in the rapid re-epithelialization using a myosin II ATPase inhibitor, blebbistatin. A low level of blebbistatin suppressed the formation of APS and induced the dissociation of keratocytes from the leading edge without attenuating the growth of the epidermal sheet or the migration rate of solitary keratocytes. AJs in the superficial layer showed no obvious changes elicited by blebbistatin. However, two epidermal sheets without APSs did not make a closure with each other, which was confirmed by inhibiting the connecting AJs between the superficial layers. These results suggest that myosin II activity is required for functional leading-edge cells and for epidermal closure.

MRG15 activates the cdc2 promoter via histone acetylation in human cells

International Nuclear Information System (INIS)

Pena, AndreAna N.; Tominaga, Kaoru; Pereira-Smith, Olivia M.

2011-01-01

Chromatin remodeling is required for transcriptional activation and repression. MRG15 (MORF4L1), a chromatin modulator, is a highly conserved protein and is present in complexes containing histone acetyltransferases (HATs) as well as histone deacetylases (HDACs). Loss of expression of MRG15 in mice and Drosophila results in embryonic lethality and fibroblast and neural stem/progenitor cells cultured from Mrg15 null mouse embryos exhibit marked proliferative defects when compared with wild type cells. To determine the role of MRG15 in cell cycle progression we performed chromatin immunoprecipitation with an antibody to MRG15 on normal human fibroblasts as they entered the cell cycle from a quiescent state, and analyzed various cell cycle gene promoters. The results demonstrated a 3-fold increase in MRG15 occupancy at the cdc2 promoter during S phase of the cell cycle and a concomitant increase in acetylated histone H4. H4 lysine 12 was acetylated at 24 h post-serum stimulation while there was no change in acetylation of lysine 16. HDAC1 and 2 were decreased at this promoter during cell cycle progression. Over-expression of MRG15 in HeLa cells activated a cdc2 promoter-reporter construct in a dose-dependent manner, whereas knockdown of MRG15 resulted in decreased promoter activity. In order to implicate HAT activity, we treated cells with the HAT inhibitor anacardic acid and determined that HAT inhibition results in loss of expression of cdc2 mRNA. Further, chromatin immunoprecipitation with Tip60 localizes the protein to the same 110 bp stretch of the cdc2 promoter pulled down by MRG15. Additionally, we determined that cotransfection of MRG15 with the known associated HAT Tip60 had a cooperative effect in activating the cdc2 promoter. These results suggest that MRG15 is acting in a HAT complex involving Tip60 to modify chromatin via acetylation of histone H4 at the cdc2 promoter to activate transcription.

MRG15 activates the cdc2 promoter via histone acetylation in human cells

Energy Technology Data Exchange (ETDEWEB)

Pena, AndreAna N., E-mail: andreana.pena@gmail.com [Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX (United States); Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, TX (United States); Tominaga, Kaoru; Pereira-Smith, Olivia M. [Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX (United States); Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, TX (United States)

2011-07-01

Chromatin remodeling is required for transcriptional activation and repression. MRG15 (MORF4L1), a chromatin modulator, is a highly conserved protein and is present in complexes containing histone acetyltransferases (HATs) as well as histone deacetylases (HDACs). Loss of expression of MRG15 in mice and Drosophila results in embryonic lethality and fibroblast and neural stem/progenitor cells cultured from Mrg15 null mouse embryos exhibit marked proliferative defects when compared with wild type cells. To determine the role of MRG15 in cell cycle progression we performed chromatin immunoprecipitation with an antibody to MRG15 on normal human fibroblasts as they entered the cell cycle from a quiescent state, and analyzed various cell cycle gene promoters. The results demonstrated a 3-fold increase in MRG15 occupancy at the cdc2 promoter during S phase of the cell cycle and a concomitant increase in acetylated histone H4. H4 lysine 12 was acetylated at 24 h post-serum stimulation while there was no change in acetylation of lysine 16. HDAC1 and 2 were decreased at this promoter during cell cycle progression. Over-expression of MRG15 in HeLa cells activated a cdc2 promoter-reporter construct in a dose-dependent manner, whereas knockdown of MRG15 resulted in decreased promoter activity. In order to implicate HAT activity, we treated cells with the HAT inhibitor anacardic acid and determined that HAT inhibition results in loss of expression of cdc2 mRNA. Further, chromatin immunoprecipitation with Tip60 localizes the protein to the same 110 bp stretch of the cdc2 promoter pulled down by MRG15. Additionally, we determined that cotransfection of MRG15 with the known associated HAT Tip60 had a cooperative effect in activating the cdc2 promoter. These results suggest that MRG15 is acting in a HAT complex involving Tip60 to modify chromatin via acetylation of histone H4 at the cdc2 promoter to activate transcription.

CDC Child Growth Charts

Data.gov (United States)

U.S. Department of Health & Human Services — CDC child growth charts consist of a series of percentile curves that illustrate the distribution of selected body measurements in U.S. children. Pediatric growth...

MiR-27a Promotes Hemin-Induced Erythroid Differentiation of K562 Cells by Targeting CDC25B

Directory of Open Access Journals (Sweden)

Dongsheng Wang

2018-03-01

Full Text Available Background/Aims: MicroRNAs (miRNAs play a crucial role in erythropoiesis. MiR-23a∼27a∼24-2 clusters have been proven to take part in erythropoiesis via some proteins. CDC25B (cell division control Cdc2 phosphostase B is also the target of mir-27a; whether it regulates erythropoiesis and its mechanism are unknown. Methods: To evaluate the potential role of miR-27a during erythroid differentiation, we performed miR-27a gain- and loss-of-function experiments on hemin-induced K562 cells. We detected miR-27a expression after hemin stimulation at different time points. At the same time, the γ-globin gene also was measured via real-time PCR. According to the results of the chips, we screened the target protein of miR-27a through a dual-luciferase reporter assay and identified it via Western blot analyses. To evaluate the function of CDC25B, benzidine staining and flow cytometry were employed to detect the cell differentiation and cell cycle. Results: We found that miR-27a promotes hemin-induced erythroid differentiation of human K562 cells by targeting cell division cycle 25 B (CDC25B. Overexpression of miR-27a promotes the differentiation of hemin-induced K562 cells, as demonstrated by γ-globin overexpression. The inhibition of miR-27a expression suppresses erythroid differentiation, thus leading to a reduction in the γ-globin gene. CDC25B was identified as a new target of miR-27a during erythroid differentiation. Overexpression of miR-27a led to decreased CDC25B expression after hemin treatment, and CDC25B was up-regulated when miR-27a expression was inhibited. Moreover, the inhibition of CDC25B affected erythroid differentiation, as assessed by γ-globin expression. Conclusion: This study is the first report of the interaction between miR-27a and CDC25B, and it improves the understanding of miRNA functions during erythroid differentiation.

The effect of butterfly-scale inspired patterning on leading-edge vortex growth

Science.gov (United States)

Wilroy, Jacob Aaron

Leading edge vortices (LEVs) are important for generating thrust and lift in flapping flight, and the surface patterning (scales) on butterfly wings is hypothesized to play a role in the vortex formation of the LEV. To simplify this complex flow problem, an experiment was designed to focus on the alteration of 2-D vortex development with a variation in surface patterning. Specifically, the secondary vorticity generated by the LEV interacting at the patterned surface was studied, as well as the subsequent effect on the LEV's growth rate and peak circulation. For this experiment, rapid-prototyped grooves based on the scale geometry of the Monarch butterfly (Danaus plexippus) were created using additive manufacturing and were attached to a flat plate with a chordwise orientation, thus increasing plate surface area. The vortex generated by the grooved plate was then compared to a smooth plate case in an experiment where the plate translated vertically through a 2 x 3 x 5 cubic foot tow tank. The plate was impulsively started in quiescent water and flow fields at Rec = 1416, 2833, and 5667 are examined using Digital Particle Image Velocimetry (DPIV). The maximum vortex formation number is 2.8 and is based on the flat plate travel length and chord length. Flow fields from each case show the generation of a secondary vortex whose interaction with the shear layer and LEV caused different behaviors depending upon the surface type. The vortex development process varied for each Reynolds number and it was found that for the lowest Reynolds number case a significant difference does not exist between surface types, however, for the other two cases the grooves affected the secondary vortex's behavior and the LEV's ability to grow at a rate similar to the smooth plate case.

Is Your Child Safe from Lead Poisoning?

Centers for Disease Control (CDC) Podcasts

2008-10-02

In this podcast, Dr. Mary Jean Brown, chief of CDC's Lead Poisoning and Prevention Program, discusses the importance of testing children for lead poisoning, who should be tested, and what parents can do to prevent lead poisoning.  Created: 10/2/2008 by National Center for Environmental Health (NCEH).   Date Released: 10/2/2008.

CDC Best Practices for Comprehensive Tobacco Control Programs - 2007

Data.gov (United States)

U.S. Department of Health & Human Services — Centers for Disease Control and Prevention (CDC). Best Practices for Comprehensive Tobacco Control Programs. Funding. CDC's Best Practices for Comprehensive Tobacco...

CDC Best Practices for Comprehensive Tobacco Control Programs - 2014

Data.gov (United States)

U.S. Department of Health & Human Services — Centers for Disease Control and Prevention (CDC). Best Practices for Comprehensive Tobacco Control Programs. Funding. CDC's Best Practices for Comprehensive Tobacco...

The Hsk1(Cdc7) Replication Kinase Regulates Origin Efficiency

OpenAIRE

Patel, Prasanta K.; Kommajosyula, Naveen; Rosebrock, Adam; Bensimon, Aaron; Leatherwood, Janet; Bechhoefer, John; Rhind, Nicholas

2008-01-01

Origins of DNA replication are generally inefficient, with most firing in fewer than half of cell cycles. However, neither the mechanism nor the importance of the regulation of origin efficiency is clear. In fission yeast, origin firing is stochastic, leading us to hypothesize that origin inefficiency and stochasticity are the result of a diffusible, rate-limiting activator. We show that the Hsk1-Dfp1 replication kinase (the fission yeast Cdc7-Dbf4 homologue) plays such a role. Increasing or ...

Cdc45-induced loading of human RPA onto single-stranded DNA.

Science.gov (United States)

Szambowska, Anna; Tessmer, Ingrid; Prus, Piotr; Schlott, Bernhard; Pospiech, Helmut; Grosse, Frank

2017-04-07

Cell division cycle protein 45 (Cdc45) is an essential component of the eukaryotic replicative DNA helicase. We found that human Cdc45 forms a complex with the single-stranded DNA (ssDNA) binding protein RPA. Moreover, it actively loads RPA onto nascent ssDNA. Pull-down assays and surface plasmon resonance studies revealed that Cdc45-bound RPA complexed with ssDNA in the 8-10 nucleotide binding mode, but dissociated when RPA covered a 30-mer. Real-time analysis of RPA-ssDNA binding demonstrated that Cdc45 catalytically loaded RPA onto ssDNA. This placement reaction required physical contacts of Cdc45 with the RPA70A subdomain. Our results imply that Cdc45 controlled stabilization of the 8-nt RPA binding mode, the subsequent RPA transition into 30-mer mode and facilitated an ordered binding to ssDNA. We propose that a Cdc45-mediated loading guarantees a seamless deposition of RPA on newly emerging ssDNA at the nascent replication fork. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

An experimental analysis of critical factors involved in the breakdown process of leading edge vortex flows. Ph.D. Thesis

Science.gov (United States)

Visser, Kenneth D.

1991-01-01

Experimental crosswire measurements of the flowfield above a 70 and 75 degree flat plate delta wing were performed at a Reynolds number of 250,000. Survey grids were taken normal to the platform at a series of chordwise locations for angles of attack of 20 and 30 degrees. Axial and azimuthal vorticity distributions were derived from the velocity fields. The dependence of circulation on distance from the vortex core as well as on chordwise location was examined. The effects of nondimensionalization in comparison with other experimental data was made. The circulation distribution scales with the local semispan and grows approximately linearly in the chordwise direction. For regions of the flow outside of the vortex subcore, the circulation at any chordwise station was observed to vary logarithmically with distance from the vortex axis. The circulation was also found to increase linearly with angle of incidence at a given chordwise station. A reduction in the local circulation about the vortex axis occurred at breakdown. The spanwise distribution of axial vorticity was severely altered through the breakdown region and the spanwise distribution of axial vorticity present appeared to reach a maximum immediately preceding breakdown. The local concentration of axial vorticity about the vortex axis was reduced while the magnitude of the azimuthal vorticity decreased throughout the breakdown zone. The axial vorticity components with a negative sense, found in the secondary vortex, remained unaffected by changes in wing sweep or angle of attack, in direct contrast to the positive components. The inclusion of the local wing geometry into a previously derived correlation parameter indicated that the circulation of growing leading edge vortex flows were similar at corresponding radii from the vortex axis. It was concluded that the flow over a delta wing, upstream of the breakdown regions and away from the apex and trailing edge regions, is conical. In addition, the dominating

Transcatheter Treatment of Tricuspid Regurgitation Using Edge-to-Edge Repair: Procedural Results, Clinical Implications and Predictors for Success.

Science.gov (United States)

Lurz, Philipp; Besler, Christian; Noack, Thilo; Forner, Anna Flo; Bevilacqua, Carmine; Seeburger, Joerg; Rommel, Karl-Philipp; Blazek, Stephan; Hartung, Philipp; Zimmer, Marion; Mohr, Friedrich; Schuler, Gerhard; Linke, Axel; Ender, Joerg; Thiele, Holger

2018-04-10

To analyze the feasibility, safety and effectiveness of Tricuspid valve (TV) repair using the MitraClip system in patients at high surgical risk. Forty-two elderly high-risk patients (76.8±7.3 years, EuroScore II 8.1±5.7) with isolated TR or combined TR and mitral regurgitation (MR) underwent edge-to-edge repair of the TV (n=11) or combined edge-to-edge repair of the TV and mitral valve (n=31). Procedural details, success rate, impact on TR severity and predictors for success at 30 day follow-up were analyzed. Successful edge-to-edge repair of TR was achieved in 35/42 patients (83%, 68 clips in total, 94% in the anteroseptal commissure, 6% in the posteroseptal commissure). In 5 patients, grasping of the leaflets was impossible and two patients had no decrease in TR after clipping. In those with procedural success, clipping of the TV led to a reduction in effective regurgitant orifice area by -62,5 % (from 0.8±0.4 to 0.3±0.2 cm2; pEdge-to-edge repair of the TV is feasible with promising reduction in TR, which could result in clinical improvement.

The effect of DNA replication on mutation of the Saccharomyces cerevisiae CDC8 gene.

Science.gov (United States)

Zaborowska, D; Zuk, J

1990-04-01

Incubation in YPD medium under permissive conditions when DNA replication is going on, strongly stimulates the induction of cdc+ colonies of UV-irradiated cells of yeast strains HB23 (cdc8-1/cdc8-3), HB26 (cdc8-3/cdc8-3) and HB7 (cdc8-1/cdc8-1). Inhibition of DNA replication by hydroxyurea, araCMP, cycloheximide or caffeine or else by incubation in phosphate buffer pH 7.0, abolishes this stimulation. Thus the replication of DNA is strongly correlated with the high induction of cdc+ colonies by UV irradiation. It is postulated that these UV-induced cdc+ colonies arise as the result infidelity in DNA replication.

Magnetic field dependence of electronic properties of MoS2 quantum dots with different edges

Science.gov (United States)

Chen, Qiao; Li, L. L.; Peeters, F. M.

2018-02-01

Using the tight-binding approach, we investigate the energy spectrum of square, triangular, and hexagonal MoS2 quantum dots (QDs) in the presence of a perpendicular magnetic field. Novel edge states emerge in MoS2 QDs, which are distributed over the whole edge which we call ring states. The ring states are robust in the presence of spin-orbit coupling (SOC). The corresponding energy levels of the ring states oscillate as a function of the perpendicular magnetic field which are related to Aharonov-Bohm oscillations. Oscillations in the magnetic field dependence of the energy levels and the peaks in the magneto-optical spectrum emerge (disappear) as the ring states are formed (collapsed). The period and the amplitude of the oscillation decrease with the size of the MoS2 QDs.

Edge passivation induced single-edge ferromagnetism of zigzag MoS_2 nanoribbons

International Nuclear Information System (INIS)

Wang, Rui; Sun, Hui; Ma, Ben; Hu, Jingguo; Pan, Jing

2017-01-01

We performed density functional theory study on electronic structure, magnetic properties and stability of zigzag MoS_2 nanoribbons (ZMoS_2NRs) with and without oxygen (O) passivation. The bare ZMoS_2NRs are magnetic metal with ferromagnetic edge states, edge passivation decreases their magnetism because of the decrease of edge unsaturated electrons. Obviously, the electronic structure and magnetic properties of ZMoS_2NRs greatly depend on edge states. When both edges are passivated by O atoms, ZMoS_2NRs are nonmagnetic metals. When either edge is passivated by O atoms, the systems exhibit single-edge ferromagnetism and magnetism concentrates on the non-passivated edge. Edge passivation can not only tune the magnetism of ZMoS_2NRs, but also enhance their stability by eliminating dangling bonds. These interesting findings on ZMoS_2NRs may open the possibility of their application in nanodevices and spintronics. - Highlights: • Edge passivation for tuning magnetism of zigzag MoS_2 nanoribbons (ZMoS_2NRs) is proposed. • Edge passivation can tune ZMoS_2NRs from nonmagnetic metal to ferromagnetic metal. • When either edge is passivated, the systems exhibit single-edge ferromagnetic states. • These findings may inspire great interest in the community of ZMoS_2NRs and motivate numerous experimental researches.