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Sample records for chin-1 regulate cdc-42

  1. 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...

  2. 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.

  3. 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

  4. Cdc42 regulates cofilin during the establishment of neuronal polarity

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    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...

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

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    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...

  6. Synapse Formation in Monosynaptic Sensory–Motor Connections Is Regulated by Presynaptic Rho GTPase Cdc42

    Science.gov (United States)

    Imai, Fumiyasu; Ladle, David R.; Leslie, Jennifer R.; Duan, Xin; Rizvi, Tilat A.; Ciraolo, Georgianne M.; Zheng, Yi

    2016-01-01

    Spinal reflex circuit development requires the precise regulation of axon trajectories, synaptic specificity, and synapse formation. Of these three crucial steps, the molecular mechanisms underlying synapse formation between group Ia proprioceptive sensory neurons and motor neurons is the least understood. Here, we show that the Rho GTPase Cdc42 controls synapse formation in monosynaptic sensory–motor connections in presynaptic, but not postsynaptic, neurons. In mice lacking Cdc42 in presynaptic sensory neurons, proprioceptive sensory axons appropriately reach the ventral spinal cord, but significantly fewer synapses are formed with motor neurons compared with wild-type mice. Concordantly, electrophysiological analyses show diminished EPSP amplitudes in monosynaptic sensory–motor circuits in these mutants. Temporally targeted deletion of Cdc42 in sensory neurons after sensory–motor circuit establishment reveals that Cdc42 does not affect synaptic transmission. Furthermore, addition of the synaptic organizers, neuroligins, induces presynaptic differentiation of wild-type, but not Cdc42-deficient, proprioceptive sensory neurons in vitro. Together, our findings demonstrate that Cdc42 in presynaptic neurons is required for synapse formation in monosynaptic sensory–motor circuits. SIGNIFICANCE STATEMENT Group Ia proprioceptive sensory neurons form direct synapses with motor neurons, but the molecular mechanisms underlying synapse formation in these monosynaptic sensory–motor connections are unknown. We show that deleting Cdc42 in sensory neurons does not affect proprioceptive sensory axon targeting because axons reach the ventral spinal cord appropriately, but these neurons form significantly fewer presynaptic terminals on motor neurons. Electrophysiological analysis further shows that EPSPs are decreased in these mice. Finally, we demonstrate that Cdc42 is involved in neuroligin-dependent presynaptic differentiation of proprioceptive sensory neurons in vitro

  7. 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.

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

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    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.

  9. 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

  10. 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

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

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    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.

  12. 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...

  13. 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.

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

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    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.

  15. 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

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

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    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

  17. 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

  18. 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

  19. Cdc42-dependent actin dynamics controls maturation and secretory activity of dendritic cells

    DEFF Research Database (Denmark)

    Schulz, Anna M; Stutte, Susanne; Hogl, Sebastian

    2015-01-01

    Cell division cycle 42 (Cdc42) is a member of the Rho guanosine triphosphatase family and has pivotal functions in actin organization, cell migration, and proliferation. To further study the molecular mechanisms of dendritic cell (DC) regulation by Cdc42, we used Cdc42-deficient DCs. Cdc42 defici...

  20. 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.

  1. 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...

  2. Cdc42 controls progenitor cell differentiation and beta-catenin turnover in skin

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    Wu, Xunwei; Quondamatteo, Fabio; Lefever, Tine

    2006-01-01

    for differentiation of skin progenitor cells into HF lineage and that it regulates the turnover of beta-catenin. In the absence of Cdc42, degradation of beta-catenin was increased corresponding to a decreased phosphorylation of GSK3beta at Ser 9 and an increased phosphorylation of axin, which is known to be required...... for binding of beta-catenin to the degradation machinery. Cdc42-mediated regulation of beta-catenin turnover was completely dependent on PKCzeta, which associated with Cdc42, Par6, and Par3. These data suggest that Cdc42 regulation of beta-catenin turnover is important for terminal differentiation of HF...

  3. 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.

  4. 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.

  5. Rho GTPase protein Cdc42 is critical for postnatal cartilage development

    International Nuclear Information System (INIS)

    Nagahama, Ryo; Yamada, Atsushi; Tanaka, Junichi; Aizawa, Ryo; Suzuki, Dai; Kassai, Hidetoshi; Yamamoto, Matsuo; Mishima, Kenji; Aiba, Atsu; Maki, Koutaro; Kamijo, Ryutaro

    2016-01-01

    Cdc42, a small Rho GTPase family member, has been shown to regulate multiple cellular functions in vitro, including actin cytoskeletal reorganization, cell migration, proliferation, and gene expression. However, its tissue-specific roles in vivo remain largely unknown, especially in postnatal cartilage development, as cartilage-specific Cdc42 inactivated mice die within a few days after birth. In this study, we investigated the physiological functions of Cdc42 during cartilage development after birth using tamoxifen-induced cartilage-specific inactivated Cdc42 conditional knockout (Cdc42 "f"l"/"f"l; Col2-CreERT) mice, which were generated by crossing Cdc42 flox mice (Cdc42 "f"l"/"f"l) with tamoxifen-induced type II collagen (Col2) Cre transgenic mice using a Cre/loxP system. The gross morphology of the Cdc42 cKO mice was shorter limbs and body, as well as reduced body weight as compared with the controls. In addition, severe defects were found in growth plate chondrocytes of the long bones, characterized by a shorter proliferating zone (PZ), wider hypertrophic zone (HZ), and loss of columnar organization of proliferating chondrocytes, resulting in delayed endochondral bone formation associated with abnormal bone growth. Our findings demonstrate the importance of Cdc42 for cartilage development during both embryonic and postnatal stages. - Highlights: • Tamoxifen-induced cartilage specific inactivated Cdc42 mutant mice were generated. • Cdc42 mutant mice were shorter limbs and body. • Severe defects were found in growth plate chondrocytes.

  6. Rho GTPase protein Cdc42 is critical for postnatal cartilage development

    Energy Technology Data Exchange (ETDEWEB)

    Nagahama, Ryo [Department of Biochemistry, School of Dentistry, Showa University, Tokyo (Japan); Department of Orthodontics, School of Dentistry, Showa University, Tokyo (Japan); Yamada, Atsushi, E-mail: yamadaa@dent.showa-u.ac.jp [Department of Biochemistry, School of Dentistry, Showa University, Tokyo (Japan); Tanaka, Junichi [Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo (Japan); Aizawa, Ryo [Department of Periodontology, School of Dentistry, Showa University, Tokyo (Japan); Suzuki, Dai [Department of Biochemistry, School of Dentistry, Showa University, Tokyo (Japan); Kassai, Hidetoshi [Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo (Japan); Yamamoto, Matsuo [Department of Periodontology, School of Dentistry, Showa University, Tokyo (Japan); Mishima, Kenji [Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Tokyo (Japan); Aiba, Atsu [Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo (Japan); Maki, Koutaro [Department of Orthodontics, School of Dentistry, Showa University, Tokyo (Japan); Kamijo, Ryutaro [Department of Biochemistry, School of Dentistry, Showa University, Tokyo (Japan)

    2016-02-19

    Cdc42, a small Rho GTPase family member, has been shown to regulate multiple cellular functions in vitro, including actin cytoskeletal reorganization, cell migration, proliferation, and gene expression. However, its tissue-specific roles in vivo remain largely unknown, especially in postnatal cartilage development, as cartilage-specific Cdc42 inactivated mice die within a few days after birth. In this study, we investigated the physiological functions of Cdc42 during cartilage development after birth using tamoxifen-induced cartilage-specific inactivated Cdc42 conditional knockout (Cdc42 {sup fl/fl}; Col2-CreERT) mice, which were generated by crossing Cdc42 flox mice (Cdc42 {sup fl/fl}) with tamoxifen-induced type II collagen (Col2) Cre transgenic mice using a Cre/loxP system. The gross morphology of the Cdc42 cKO mice was shorter limbs and body, as well as reduced body weight as compared with the controls. In addition, severe defects were found in growth plate chondrocytes of the long bones, characterized by a shorter proliferating zone (PZ), wider hypertrophic zone (HZ), and loss of columnar organization of proliferating chondrocytes, resulting in delayed endochondral bone formation associated with abnormal bone growth. Our findings demonstrate the importance of Cdc42 for cartilage development during both embryonic and postnatal stages. - Highlights: • Tamoxifen-induced cartilage specific inactivated Cdc42 mutant mice were generated. • Cdc42 mutant mice were shorter limbs and body. • Severe defects were found in growth plate chondrocytes.

  7. Interaction of the Small GTPase Cdc42 with Arginine Kinase Restricts White Spot Syndrome Virus in Shrimp.

    Science.gov (United States)

    Xu, Ji-Dong; Jiang, Hai-Shan; Wei, Tian-Di; Zhang, Ke-Yi; Wang, Xian-Wei; Zhao, Xiao-Fan; Wang, Jin-Xing

    2017-03-01

    Many types of small GTPases are widely expressed in eukaryotes and have different functions. As a crucial member of the Rho GTPase family, Cdc42 serves a number of functions, such as regulating cell growth, migration, and cell movement. Several RNA viruses employ Cdc42-hijacking tactics in their target cell entry processes. However, the function of Cdc42 in shrimp antiviral immunity is not clear. In this study, we identified a Cdc42 protein in the kuruma shrimp ( Marsupenaeus japonicus ) and named it Mj Cdc42. Mj Cdc42 was upregulated in shrimp challenged by white spot syndrome virus (WSSV). The knockdown of Mj Cdc42 and injection of Cdc42 inhibitors increased the proliferation of WSSV. Further experiments determined that Mj Cdc42 interacted with an arginine kinase ( Mj AK). By analyzing the binding activity and enzyme activity of Mj AK and its mutant, Δ Mj AK, we found that Mj AK could enhance the replication of WSSV in shrimp. Mj AK interacted with the envelope protein VP26 of WSSV. An inhibitor of AK activity, quercetin, could impair the function of Mj AK in WSSV replication. Further study demonstrated that the binding of Mj Cdc42 and Mj AK depends on Cys 271 of Mj AK and suppresses the WSSV replication-promoting effect of Mj AK. By interacting with the active site of Mj AK and suppressing its enzyme activity, Mj Cdc42 inhibits WSSV replication in shrimp. Our results demonstrate a new function of Cdc42 in the cellular defense against viral infection in addition to the regulation of actin and phagocytosis, which has been reported in previous studies. IMPORTANCE The interaction of Cdc42 with arginine kinase plays a crucial role in the host defense against WSSV infection. This study identifies a new mechanism of Cdc42 in innate immunity and enriches the knowledge of the antiviral innate immunity of invertebrates. Copyright © 2017 American Society for Microbiology.

  8. Phosphatidylserine and GTPase activation control Cdc42 nanoclustering to counter dissipative diffusion.

    Science.gov (United States)

    Sartorel, Elodie; Ünlü, Caner; Jose, Mini; Massoni-Laporte, Aurélie; Meca, Julien; Sibarita, Jean-Baptiste; McCusker, Derek

    2018-04-18

    The anisotropic organization of plasma membrane constituents is indicative of mechanisms that drive the membrane away from equilibrium. However, defining these mechanisms is challenging due to the short spatio-temporal scales at which diffusion operates. Here, we use high-density single protein tracking combined with photoactivation localization microscopy (sptPALM) to monitor Cdc42 in budding yeast, a system in which Cdc42 exhibits anisotropic organization. Cdc42 exhibited reduced mobility at the cell pole, where it was organized in nanoclusters. The Cdc42 nanoclusters were larger at the cell pole than those observed elsewhere in the cell. These features were exacerbated in cells expressing Cdc42-GTP, and were dependent on the scaffold Bem1, which contributed to the range of mobility and nanocluster size exhibited by Cdc42. The lipid environment, in particular phosphatidylserine levels, also played a role in regulating Cdc42 nanoclustering. These studies reveal how the mobility of a Rho GTPase is controlled to counter the depletive effects of diffusion, thus stabilizing Cdc42 on the plasma membrane and sustaining cell polarity. Movie S1 Movie S1 sptPALM imaging of live yeast expressing Pil1-mEOS expressed at the genomic locus. Pil1-mEOS was simultaneously photo-converted with a 405 nm laser and imaged with a 561 nm laser using HiLo illumination. Images were acquired at 20 ms intervals, of which 300 frames are shown at 7 frames per second.

  9. 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.

  10. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  12. 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

  13. 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

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  15. Cdc42-mediated tubulogenesis controls cell specification

    DEFF Research Database (Denmark)

    Kesavan, Gokul; Sand, Fredrik Wolfhagen; Greiner, Thomas Uwe

    2009-01-01

    Understanding how cells polarize and coordinate tubulogenesis during organ formation is a central question in biology. Tubulogenesis often coincides with cell-lineage specification during organ development. Hence, an elementary question is whether these two processes are independently controlled......, or whether proper cell specification depends on formation of tubes. To address these fundamental questions, we have studied the functional role of Cdc42 in pancreatic tubulogenesis. We present evidence that Cdc42 is essential for tube formation, specifically for initiating microlumen formation and later...... for maintaining apical cell polarity. Finally, we show that Cdc42 controls cell specification non-cell-autonomously by providing the correct microenvironment for proper control of cell-fate choices of multipotent progenitors. For a video summary of this article, see the PaperFlick file with the Supplemental Data...

  16. 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....

  17. Essential and distinct roles for cdc42 and rac1 in the regulation of Schwann cell biology during peripheral nervous system development

    DEFF Research Database (Denmark)

    Benninger, Yves; Thurnherr, Tina; Pereira, Jorge A

    2007-01-01

    During peripheral nervous system (PNS) myelination, Schwann cells must interpret extracellular cues to sense their environment and regulate their intrinsic developmental program accordingly. The pathways and mechanisms involved in this process are only partially understood. We use tissue-specific......During peripheral nervous system (PNS) myelination, Schwann cells must interpret extracellular cues to sense their environment and regulate their intrinsic developmental program accordingly. The pathways and mechanisms involved in this process are only partially understood. We use tissue...

  18. 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.

  19. Cdc42 promotes host defenses against fatal infection

    DEFF Research Database (Denmark)

    Lee, Keunwook; Boyd, Kelli L; Parekh, Diptiben V

    2013-01-01

    attempted to specifically delete it in these cells by crossing the Cdc42(fl/fl) mouse with a FSP-1 cre mouse, which is thought to mediate recombination exclusively in fibroblasts. Surprisingly, the FSP-1cre;Cdc42(fl/fl) mice died at 3 weeks of age due to overwhelming suppurative upper airway infections...... showed that in addition to fibroblasts, the FSP-1 cre deleted Cdc42 very efficiently in all leukocytes. Thus, by using this non-specific cre mouse we inadvertently demonstrated the importance of Cdc42 in host protection from lethal infections and suggest a critical role for this small GTPase in innate...

  20. Cdc42 and RhoA reveal different spatio-temporal dynamics upon local stimulation with Semaphorin-3A

    Directory of Open Access Journals (Sweden)

    Federico eIseppon

    2015-08-01

    Full Text Available Small RhoGTPases, such as Cdc42 and RhoA, are key players in integrating external cues and intracellular signaling pathways that regulate growth cone (GC motility. Indeed, Cdc42 is involved in actin polymerization and filopodia formation, whereas RhoA induces GC collapse and neurite retraction through actomyosin contraction. In this study we employed Förster Resonance Energy Transfer (FRET microscopy to study the spatio-temporal dynamics of Cdc42 and RhoA in GCs in response to local Semaphorin-3A stimulation obtained with lipid vesicles filled with Semaphorin-3A and positioned near the selected GC using optical tweezers. We found that Cdc42 and RhoA were activated at the leading edge of NG108-15 neuroblastoma cells during spontaneous cycles of protrusion and retraction, respectively. The release of Semaphorin-3A brought to a progressive activation of RhoA within 30 seconds from the stimulus in the central region of the GC that collapsed and retracted. In contrast, the same stimulation evoked waves of Cdc42 activation propagating away from the stimulated region. A more localized stimulation obtained with Sema3A coated beads placed on the GC, led to Cdc42 active waves that propagated in a retrograde manner with a mean period of 70 seconds, and followed by GC retraction. Therefore, Semaphorin-3A activates both Cdc42 and RhoA with a complex and different spatial-temporal dynamics.

  1. A New Genetically Encoded Single-Chain Biosensor for Cdc42 Based on FRET, Useful for Live-Cell Imaging

    Science.gov (United States)

    Cox, Dianne; Hodgson, Louis

    2014-01-01

    Cdc42 is critical in a myriad of cellular morphogenic processes, requiring precisely regulated activation dynamics to affect specific cellular events. To facilitate direct observations of Cdc42 activation in live cells, we developed and validated a new biosensor of Cdc42 activation. The biosensor is genetically encoded, of single-chain design and capable of correctly localizing to membrane compartments as well as interacting with its upstream regulators including the guanine nucleotide dissociation inhibitor. We characterized this new biosensor in motile mouse embryonic fibroblasts and observed robust activation dynamics at leading edge protrusions, similar to those previously observed for endogenous Cdc42 using the organic dye-based biosensor system. We then extended our validations and observations of Cdc42 activity to macrophages, and show that this new biosensor is able to detect differential activation patterns during phagocytosis and cytokine stimulation. Furthermore, we observe for the first time, a highly transient and localized activation of Cdc42 during podosome formation in macrophages, which was previously hypothesized but never directly visualized. PMID:24798463

  2. 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.

  3. Prominin-2 expression increases protrusions, decreases caveolae and inhibits Cdc42 dependent fluid phase endocytosis

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Raman Deep, E-mail: Takhter.Ramandeep@mayo.edu; Schroeder, Andreas S.; Scheffer, Luana; Holicky, Eileen L.; Wheatley, Christine L.; Marks, David L., E-mail: Marks.david@mayo.edu; Pagano, Richard E.

    2013-05-10

    localize to lipid rafts and recruit cholesterol into protrusions and away from caveolae, leading to increased phosphorylation of caveolin-1, which inhibits Cdc42-dependent endocytosis. This study provides a new insight for the role for prominins in the regulation of PM lipid organization.

  4. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. 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.

  7. 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.

  8. Loss of Cdc42 leads to defects in synaptic plasticity and remote memory recall.

    Science.gov (United States)

    Kim, Il Hwan; Wang, Hong; Soderling, Scott H; Yasuda, Ryohei

    2014-07-08

    Cdc42 is a signaling protein important for reorganization of actin cytoskeleton and morphogenesis of cells. However, the functional role of Cdc42 in synaptic plasticity and in behaviors such as learning and memory are not well understood. Here we report that postnatal forebrain deletion of Cdc42 leads to deficits in synaptic plasticity and in remote memory recall using conditional knockout of Cdc42. We found that deletion of Cdc42 impaired LTP in the Schaffer collateral synapses and postsynaptic structural plasticity of dendritic spines in CA1 pyramidal neurons in the hippocampus. Additionally, loss of Cdc42 did not affect memory acquisition, but instead significantly impaired remote memory recall. Together these results indicate that the postnatal functions of Cdc42 may be crucial for the synaptic plasticity in hippocampal neurons, which contribute to the capacity for remote memory recall.

  9. 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.

  10. 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...

  11. 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.

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

    Science.gov (United States)

    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

  13. 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

  14. Podocyte-specific loss of cdc42 leads to congenital nephropathy

    DEFF Research Database (Denmark)

    Scott, Rizaldy P; Hawley, Steve P; Ruston, Julie

    2012-01-01

    in the absence of Cdc42, indicating a disruption of the slit diaphragm. Kidneys from Rac1- and RhoA-mutant mice, however, had normal glomerular morphology and intact foot processes. A nephrin clustering assay suggested that Cdc42 deficiency, but not Rac1 or RhoA deficiency, impairs the polymerization of actin...

  15. 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.

  16. Multiple alterations of platelet functions dominated by increased secretion in mice lacking Cdc42 in platelets

    DEFF Research Database (Denmark)

    Pleines, Irina; Eckly, Anita; Elvers, Margitta

    2010-01-01

    formation and exocytosis in various cell types, but its exact function in platelets is not established. Here, we show that the megakaryocyte/platelet-specific loss of Cdc42 leads to mild thrombocytopenia and a small increase in platelet size in mice. Unexpectedly, Cdc42-deficient platelets were able to form...

  17. 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.

  18. 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

  19. 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...

  20. 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....

  1. 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...

  2. 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....

  3. 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...

  4. 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...

  5. 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

  6. 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.

  7. 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...

  8. 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...

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

    Science.gov (United States)

    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.

  10. A TOCA/CDC-42/PAR/WAVE functional module required for retrograde endocytic recycling

    Science.gov (United States)

    Bai, Zhiyong; Grant, Barth D.

    2015-01-01

    Endosome-to-Golgi transport is required for the function of many key membrane proteins and lipids, including signaling receptors, small-molecule transporters, and adhesion proteins. The retromer complex is well-known for its role in cargo sorting and vesicle budding from early endosomes, in most cases leading to cargo fusion with the trans-Golgi network (TGN). Transport from recycling endosomes to the TGN has also been reported, but much less is understood about the molecules that mediate this transport step. Here we provide evidence that the F-BAR domain proteins TOCA-1 and TOCA-2 (Transducer of Cdc42 dependent actin assembly), the small GTPase CDC-42 (Cell division control protein 42), associated polarity proteins PAR-6 (Partitioning defective 6) and PKC-3/atypical protein kinase C, and the WAVE actin nucleation complex mediate the transport of MIG-14/Wls and TGN-38/TGN38 cargo proteins from the recycling endosome to the TGN in Caenorhabditis elegans. Our results indicate that CDC-42, the TOCA proteins, and the WAVE component WVE-1 are enriched on RME-1–positive recycling endosomes in the intestine, unlike retromer components that act on early endosomes. Furthermore, we find that retrograde cargo TGN-38 is trapped in early endosomes after depletion of SNX-3 (a retromer component) but is mainly trapped in recycling endosomes after depletion of CDC-42, indicating that the CDC-42–associated complex functions after retromer in a distinct organelle. Thus, we identify a group of interacting proteins that mediate retrograde recycling, and link these proteins to a poorly understood trafficking step, recycling endosome-to-Golgi transport. We also provide evidence for the physiological importance of this pathway in WNT signaling. PMID:25775511

  11. 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....

  12. 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.

  13. 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...

  14. 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...

  15. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  17. 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

    not Losartan, indicating that FAK activation and F-actin reorganization were downstream of AT2R. These data indicate that Ang II-AT2R regulates human bone marrow MSC migration by signaling through the FAK and RhoA/Cdc42 pathways. This study provides insights into the mechanisms by which MSCs home to injury sites and will enable the rational design of targeted therapies to improve MSC engraftment.

  18. The structure of FMNL2-Cdc42 yields insights into the mechanism of lamellipodia and filopodia formation

    Science.gov (United States)

    Kühn, Sonja; Erdmann, Constanze; Kage, Frieda; Block, Jennifer; Schwenkmezger, Lisa; Steffen, Anika; Rottner, Klemens; Geyer, Matthias

    2015-05-01

    Formins are actin polymerization factors that elongate unbranched actin filaments at the barbed end. Rho family GTPases activate Diaphanous-related formins through the relief of an autoregulatory interaction. The crystal structures of the N-terminal domains of human FMNL1 and FMNL2 in complex with active Cdc42 show that Cdc42 mediates contacts with all five armadillo repeats of the formin with specific interactions formed by the Rho-GTPase insert helix. Mutation of three residues within Rac1 results in a gain-of-function mutation for FMNL2 binding and reconstitution of the Cdc42 phenotype in vivo. Dimerization of FMNL1 through a parallel coiled coil segment leads to formation of an umbrella-shaped structure that--together with Cdc42--spans more than 15 nm in diameter. The two interacting FMNL-Cdc42 heterodimers expose six membrane interaction motifs on a convex protein surface, the assembly of which may facilitate actin filament elongation at the leading edge of lamellipodia and filopodia.

  19. 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.

  20. 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.

  1. 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...

  2. 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 ...

  3. 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.

  4. 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.

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

    Science.gov (United States)

    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

  6. 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

  7. 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

  8. 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.

  9. 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...

  10. 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

  11. 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.

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

    DEFF Research Database (Denmark)

    Bosse, Tanja; Ehinger, Julia; Czuchra, Aleksandra

    2007-01-01

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

  13. 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...

  14. Suppression of chemotaxis by SSeCKS via scaffolding of phosphoinositol phosphates and the recruitment of the Cdc42 GEF, Frabin, to the leading edge.

    Science.gov (United States)

    Ko, Hyun-Kyung; Guo, Li-wu; Su, Bing; Gao, Lingqiu; Gelman, Irwin H

    2014-01-01

    Chemotaxis is controlled by interactions between receptors, Rho-family GTPases, phosphatidylinositol 3-kinases, and cytoskeleton remodeling proteins. We investigated how the metastasis suppressor, SSeCKS, attenuates chemotaxis. Chemotaxis activity inversely correlated with SSeCKS levels in mouse embryo fibroblasts (MEF), DU145 and MDA-MB-231 cancer cells. SSeCKS loss induced chemotactic velocity and linear directionality, correlating with replacement of leading edge lamellipodia with fascin-enriched filopodia-like extensions, the formation of thickened longitudinal F-actin stress fibers reaching to filopodial tips, relative enrichments at the leading edge of phosphatidylinositol (3,4,5)P3 (PIP3), Akt, PKC-ζ, Cdc42-GTP and active Src (SrcpoY416), and a loss of Rac1. Leading edge lamellipodia and chemotaxis inhibition in SSeCKS-null MEF could be restored by full-length SSeCKS or SSeCKS deleted of its Src-binding domain (ΔSrc), but not by SSeCKS deleted of its three MARCKS (myristylated alanine-rich C kinase substrate) polybasic domains (ΔPBD), which bind PIP2 and PIP3. The enrichment of activated Cdc42 in SSeCKS-null leading edge filopodia correlated with recruitment of the Cdc42-specific guanine nucleotide exchange factor, Frabin, likely recruited via multiple PIP2/3-binding domains. Frabin knockdown in SSeCKS-null MEF restores leading edge lamellipodia and chemotaxis inhibition. However, SSeCKS failed to co-immunoprecipitate with Rac1, Cdc42 or Frabin. Consistent with the notion that chemotaxis is controlled by SSeCKS-PIP (vs. -Src) scaffolding activity, constitutively-active phosphatidylinositol 3-kinase could override the ability of the Src inhibitor, SKI-606, to suppress chemotaxis and filopodial enrichment of Frabin in SSeCKS-null MEF. Our data suggest a role for SSeCKS in controlling Rac1 vs. Cdc42-induced cellular dynamics at the leading chemotactic edge through the scaffolding of phospholipids and signal mediators, and through the reorganization of the

  15. 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.

  16. 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.

  17. Involvement of Chromatin Remodeling Genes and the Rho GTPases RhoB and CDC42 in Ovarian Clear Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Nicolai Skovbjerg Arildsen

    2017-05-01

    Full Text Available ObjectiveOvarian clear cell carcinomas (OCCCs constitute a rare ovarian cancer subtype with distinct clinical features, but may nonetheless be difficult to distinguish morphologically from other subtypes. There is limited knowledge of genetic events driving OCCC tumorigenesis beyond ARID1A, which is reportedly mutated in 30–50% of OCCCs. We aimed to further characterize OCCCs by combined global transcriptional profiling and targeted deep sequencing of a panel of well-established cancer genes. Increased knowledge of OCCC-specific genetic aberrations may help in guiding development of targeted treatments and ultimately improve patient outcome.MethodsGene expression profiling of formalin-fixed, paraffin-embedded (FFPE tissue from a cohort of the major ovarian cancer subtypes (cohort 1; n = 67 was performed using whole-genome cDNA-mediated Annealing, Selection, extension and Ligation (WG-DASL bead arrays, followed by pathway, gene module score, and gene ontology analyses, respectively. A second FFPE cohort of 10 primary OCCCs was analyzed by targeted DNA sequencing of a panel of 60 cancer-related genes (cohort 2. Non-synonymous and non-sense variants affecting single-nucleotide variations and insertions or deletions were further analyzed. A tissue microarray of 43 OCCCs (cohort 3 was used for validation by immunohistochemistry and chromogenic in situ hybridization.ResultsGene expression analyses revealed a distinct OCCC profile compared to other histological subtypes, with, e.g., ERBB2, TFAP2A, and genes related to cytoskeletal actin regulation being overexpressed in OCCC. ERBB2 was, however, not overexpressed on the protein level and ERBB2 amplification was rare in the validation cohort. Targeted deep sequencing revealed non-synonymous variants or insertions/deletions in 11/60 cancer-related genes. Genes involved in chromatin remodeling, including ARID1A, SPOP, and KMT2D were frequently mutated across OCCC tumors.ConclusionOCCCs appear

  18. 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

  19. Differential gene expression analysis of tubule forming and non-tubule forming endothelial cells: CDC42GAP as a counter-regulator in tubule formation

    NARCIS (Netherlands)

    Engelse, M.A.; Laurens, N.; Verloop, R.E.; Koolwijk, P.; Hinsbergh, V.W.M. van

    2008-01-01

    The formation of new tubular structures from a quiescent endothelial lining is one of the hallmarks of sprouting angiogenesis. This process can be mimicked in vitro by inducing capillary-like tubular structures in a three-dimensional (3D) fibrin matrix. We aimed to analyze the differential mRNA

  20. Novel derivative of Paeonol, Paeononlsilatie sodium, alleviates behavioral damage and hippocampal dendritic injury in Alzheimer's disease concurrent with cofilin1/phosphorylated-cofilin1 and RAC1/CDC42 alterations in rats.

    Directory of Open Access Journals (Sweden)

    Fei Han

    Full Text Available Alzheimer's disease (AD is a typical hippocampal amnesia and the most common senile dementia. Many studies suggest that cognitive impairments are more closely correlated with synaptic loss than the burden of amyloid deposits in AD progression. To date, there is no effective treatment for this disease. Paeonol has been widely employed in traditional Chinese medicine. This compound improves learning behavior in an animal model; however, the mechanism remains unclear. In this study, Paeononlsilatie sodium (Pa, a derivative of Paeonol, attenuated D-galactose (D-gal and AlCl3-induced behavioral damages in rats based on evaluations of the open field test (OFT, elevated plus maze test (EPMT, and Morris water maze test (MWMT. Pa increased the dendritic complexity and the density of dendritic spines. Correlation analysis indicated that morphological changes in neuronal dendrites are closely correlated with behavioral changes. Pa treatment reduced the production of Aβ, affected the phosphorylation and redistribution of cofilin1 and inhibited rod-like formation in hippocampal neurons. The induction of D-gal and AlCl3 promoted the expression of RAC1/CDC42 expression; however, the tendency of gene expression was inhibited by pretreatment with Pa. Taken together, our results suggest that Pa may represent a novel therapeutic agent for the improvement of cognitive and emotional behaviors and dendritic morphology in an AD animal model.

  1. Disruption of the Cdc42/Par6/aPKC or Dlg/Scrib/Lgl Polarity Complex Promotes Epithelial Proliferation via Overlapping Mechanisms.

    Science.gov (United States)

    Schimizzi, Gregory V; Maher, Meghan T; Loza, Andrew J; Longmore, Gregory D

    2016-01-01

    The establishment and maintenance of apical-basal polarity is a defining characteristic and essential feature of functioning epithelia. Apical-basal polarity (ABP) proteins are also tumor suppressors that are targeted for disruption by oncogenic viruses and are commonly mutated in human carcinomas. Disruption of these ABP proteins is an early event in cancer development that results in increased proliferation and epithelial disorganization through means not fully characterized. Using the proliferating Drosophila melanogaster wing disc epithelium, we demonstrate that disruption of the junctional vs. basal polarity complexes results in increased epithelial proliferation via distinct downstream signaling pathways. Disruption of the basal polarity complex results in JNK-dependent proliferation, while disruption of the junctional complex primarily results in p38-dependent proliferation. Surprisingly, the Rho-Rok-Myosin contractility apparatus appears to play opposite roles in the regulation of the proliferative phenotype based on which polarity complex is disrupted. In contrast, non-autonomous Tumor Necrosis Factor (TNF) signaling appears to suppress the proliferation that results from apical-basal polarity disruption, regardless of which complex is disrupted. Finally we demonstrate that disruption of the junctional polarity complex activates JNK via the Rho-Rok-Myosin contractility apparatus independent of the cortical actin regulator, Moesin.

  2. Rho Kinase (ROCK) collaborates with Pak to Regulate Actin Polymerization and Contraction in Airway Smooth Muscle.

    Science.gov (United States)

    Zhang, Wenwu; Bhetwal, Bhupal P; Gunst, Susan J

    2018-05-10

    The mechanisms by which Rho kinase (ROCK) regulates airway smooth muscle contraction were determined in tracheal smooth muscle tissues. ROCK may mediate smooth muscle contraction by inhibiting myosin regulatory light chain (RLC) phosphatase. ROCK can also regulate F-actin dynamics during cell migration, and actin polymerization is critical for airway smooth muscle contraction. Our results show that ROCK does not regulate airway smooth muscle contraction by inhibiting myosin RLC phosphatase or by stimulating myosin RLC phosphorylation. We find that ROCK regulates airway smooth muscle contraction by activating the serine-threonine kinase Pak, which mediates the activation of Cdc42 and Neuronal-Wiskott-Aldrich Syndrome protein (N-WASp). N-WASP transmits signals from cdc42 to the Arp2/3 complex for the nucleation of actin filaments. These results demonstrate a novel molecular function for ROCK in the regulation of Pak and cdc42 activation that is critical for the processes of actin polymerization and contractility in airway smooth muscle. Rho kinase (ROCK), a RhoA GTPase effector, can regulate the contraction of airway and other smooth muscle tissues. In some tissues, ROCK can inhibit myosin regulatory light chain (RLC) phosphatase, which increases the phosphorylation of myosin RLC and promotes smooth muscle contraction. ROCK can also regulate cell motility and migration by affecting F-actin dynamics. Actin polymerization is stimulated by contractile agonists in airway smooth muscle tissues and is required for contractile tension development in addition to myosin RLC phosphorylation. We investigated the mechanisms by which ROCK regulates the contractility of tracheal smooth muscle tissues by expressing a kinase inactive mutant of ROCK, ROCK-K121G, in the tissues or by treating them with the ROCK inhibitor, H-1152P. Our results show no role for ROCK in the regulation of non-muscle or smooth muscle myosin RLC phosphorylation during contractile stimulation in this tissue

  3. An extracellular-matrix-specific GEF-GAP interaction regulates Rho GTPase crosstalk for 3D collagen migration.

    Science.gov (United States)

    Kutys, Matthew L; Yamada, Kenneth M

    2014-09-01

    Rho-family GTPases govern distinct types of cell migration on different extracellular matrix proteins in tissue culture or three-dimensional (3D) matrices. We searched for mechanisms selectively regulating 3D cell migration in different matrix environments and discovered a form of Cdc42-RhoA crosstalk governing cell migration through a specific pair of GTPase activator and inhibitor molecules. We first identified βPix, a guanine nucleotide exchange factor (GEF), as a specific regulator of migration in 3D collagen using an affinity-precipitation-based GEF screen. Knockdown of βPix specifically blocks cell migration in fibrillar collagen microenvironments, leading to hyperactive cellular protrusion accompanied by increased collagen matrix contraction. Live FRET imaging and RNAi knockdown linked this βPix knockdown phenotype to loss of polarized Cdc42 but not Rac1 activity, accompanied by enhanced, de-localized RhoA activity. Mechanistically, collagen phospho-regulates βPix, leading to its association with srGAP1, a GTPase-activating protein (GAP), needed to suppress RhoA activity. Our results reveal a matrix-specific pathway controlling migration involving a GEF-GAP interaction of βPix with srGAP1 that is critical for maintaining suppressive crosstalk between Cdc42 and RhoA during 3D collagen migration.

  4. The protection of acetylcholinesterase inhibitor on β-amyloid-induced injury of neurite outgrowth via regulating axon guidance related genes expression in neuronal cells

    OpenAIRE

    Shen, Jiao-Ning; Wang, Deng-Shun; Wang, Rui

    2012-01-01

    Cognitive deficits in AD correlate with progressive synaptic dysfunction and loss. The Rho family of small GTPases, including Rho, Rac, and Cdc42, has a central role in cellular motility and cytokinesis. Acetylcholinesterase inhibitor has been found to protect cells against a broad range of reagents-induced injuries. Present studies examined if the effect of HupA on neurite outgrowth in Aβ-treated neuronal cells executed via regulating Rho-GTPase mediated axon guidance relative gene expressio...

  5. Cloning and differential expression analyses of Cdc42 from sheep

    Directory of Open Access Journals (Sweden)

    Yang Yong-Jie

    2018-03-01

    Full Text Available Introduction: Serological diagnosis of brucellosis is still a great challenge due to the infeasibility of discriminating infected animals from vaccinated ones, so it is necessary to search for diagnostic biomarkers for differential diagnosis of brucellosis.

  6. The protection of acetylcholinesterase inhibitor on β-amyloid-induced injury of neurite outgrowth via regulating axon guidance related genes expression in neuronal cells

    Science.gov (United States)

    Shen, Jiao-Ning; Wang, Deng-Shun; Wang, Rui

    2012-01-01

    Cognitive deficits in AD correlate with progressive synaptic dysfunction and loss. The Rho family of small GTPases, including Rho, Rac, and Cdc42, has a central role in cellular motility and cytokinesis. Acetylcholinesterase inhibitor has been found to protect cells against a broad range of reagents-induced injuries. Present studies examined if the effect of HupA on neurite outgrowth in Aβ-treated neuronal cells executed via regulating Rho-GTPase mediated axon guidance relative gene expression. Affymetrix cDNA microarray assay followed by real-time RT-PCR and Western Blotting analysis were used to elucidate and analyze the signaling pathway involved in Aβ and HupA’s effects. The effects of Aβ and HupA on the neurite outgrowth were further confirmed via immunofluorescence staining. Aβ up-regulated the mRNA expressions of NFAT5, LIMK1, EPHA1, NTN4 and RAC2 markedly in SH-SY5Y cells. Co-incubation of Aβ and HupA reversed or decreased the changes of NFAT5, NTN4, RAC2, CDC42 and SEMA4F. HupA treated alone increased NFAT5, LIMK1, NTN4 significantly. Following qRT-PCR validation showed that the correlation of the gene expression ratio between microarray and qRT-PCR is significant. Western blot result showed that the change of CDC42 protein is consistent with the mRNA level while RAC2 is not. The morphological results confirmed that HupA improved, or partly reversed, the Aβ-induced damage of neurite outgrowth. The protective effect of HupA from Aβ induced morphological injury might be correlative to, at least partially, regulating the network of neurite outgrowth related genes. PMID:23119107

  7. The protection of acetylcholinesterase inhibitor on β-amyloid-induced the injury of neurite outgrowth via regulating axon guidance related genes expression in neuronal cells.

    Science.gov (United States)

    Shen, Jiao-Ning; Wang, Deng-Shun; Wang, Rui

    2012-01-01

    Cognitive deficits in AD correlate with progressive synaptic dysfunction and loss. The Rho family of small GTPases, including Rho, Rac, and Cdc42, has a central role in cellular motility and cytokinesis. Acetylcholinesterase inhibitor has been found to protect cells against a broad range of reagents-induced injuries. Present studies examined if the effect of HupA on neurite outgrowth in Aβ-treated neuronal cells executed via regulating Rho-GTPase mediated axon guidance relative gene expression. Affymetrix cDNA microarray assay followed by real-time RT-PCR and Western Blotting analysis were used to elucidate and analyze the signaling pathway involved in Aβ and HupA's effects. The effects of Aβ and HupA on the neurite outgrowth were further confirmed via immunofluorescence staining. Aβ up-regulated the mRNA expressions of NFAT5, LIMK1, EPHA1, NTN4 and RAC2 markedly in SH-SY5Y cells. Co-incubation of Aβ and HupA reversed or decreased the changes of NFAT5, NTN4, RAC2, CDC42 and SEMA4F. HupA treated alone increased NFAT5, LIMK1, NTN4 significantly. Following qRT-PCR validation showed that the correlation of the gene expression ratio between microarray and qRT-PCR is significant. Western blot result showed that the change of CDC42 protein is consistent with the mRNA level while RAC2 is not. The morphological results confirmed that HupA improved, or partly reversed, the Aβ-induced damage of neurite outgrowth. The protective effect of HupA from Aβ induced morphological injury might be correlative to, at least partially, regulating the network of neurite outgrowth related genes.

  8. Cytoskeletal Regulation by AUTS2 in Neuronal Migration and Neuritogenesis

    Directory of Open Access Journals (Sweden)

    Kei Hori

    2014-12-01

    Full Text Available Mutations in the Autism susceptibility candidate 2 gene (AUTS2, whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development. Immunohistochemistry and fractionation studies show that AUTS2 localizes not only in nuclei, but also in the cytoplasm, including in the growth cones in the developing brain. AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These findings suggest that cytoplasmic AUTS2 acts as a regulator of Rho family GTPases to contribute to brain development and give insight into the pathology of human psychiatric disorders with AUTS2 mutations.

  9. Expression of CD44 3′-untranslated region regulates endogenous microRNA functions in tumorigenesis and angiogenesis

    Science.gov (United States)

    Jeyapalan, Zina; Deng, Zhaoqun; Shatseva, Tatiana; Fang, Ling; He, Chengyan; Yang, Burton B.

    2011-01-01

    The non-coding 3′-untranslated region (UTR) plays an important role in the regulation of microRNA (miRNA) functions, since it can bind and inactivate multiple miRNAs. Here, we show the 3′-UTR of CD44 is able to antagonize cytoplasmic miRNAs, and result in the increased translation of CD44 and downstream target mRNA, CDC42. A series of cell function assays in the human breast cancer cell line, MT-1, have shown that the CD44 3′-UTR inhibits proliferation, colony formation and tumor growth. Furthermore, it modulated endothelial cell activities, favored angiogenesis, induced tumor cell apoptosis and increased sensitivity to Docetaxel. These results are due to the interaction of the CD44 3′-UTR with multiple miRNAs. Computational algorithms have predicted three miRNAs, miR-216a, miR-330 and miR-608, can bind to both the CD44 and CDC42 3′-UTRs. This was confirmed with luciferase assays, western blotting and immunohistochemical staining and correlated with a series of siRNA assays. Thus, the non-coding CD44 3′-UTR serves as a competitor for miRNA binding and subsequently inactivates miRNA functions, by freeing the target mRNAs from being repressed. PMID:21149267

  10. Expression of CD44 3'-untranslated region regulates endogenous microRNA functions in tumorigenesis and angiogenesis.

    Science.gov (United States)

    Jeyapalan, Zina; Deng, Zhaoqun; Shatseva, Tatiana; Fang, Ling; He, Chengyan; Yang, Burton B

    2011-04-01

    The non-coding 3'-untranslated region (UTR) plays an important role in the regulation of microRNA (miRNA) functions, since it can bind and inactivate multiple miRNAs. Here, we show the 3'-UTR of CD44 is able to antagonize cytoplasmic miRNAs, and result in the increased translation of CD44 and downstream target mRNA, CDC42. A series of cell function assays in the human breast cancer cell line, MT-1, have shown that the CD44 3'-UTR inhibits proliferation, colony formation and tumor growth. Furthermore, it modulated endothelial cell activities, favored angiogenesis, induced tumor cell apoptosis and increased sensitivity to Docetaxel. These results are due to the interaction of the CD44 3'-UTR with multiple miRNAs. Computational algorithms have predicted three miRNAs, miR-216a, miR-330 and miR-608, can bind to both the CD44 and CDC42 3'-UTRs. This was confirmed with luciferase assays, western blotting and immunohistochemical staining and correlated with a series of siRNA assays. Thus, the non-coding CD44 3'-UTR serves as a competitor for miRNA binding and subsequently inactivates miRNA functions, by freeing the target mRNAs from being repressed.

  11. Optimal experimental design in an epidermal growth factor receptor signalling and down-regulation model.

    Science.gov (United States)

    Casey, F P; Baird, D; Feng, Q; Gutenkunst, R N; Waterfall, J J; Myers, C R; Brown, K S; Cerione, R A; Sethna, J P

    2007-05-01

    We apply the methods of optimal experimental design to a differential equation model for epidermal growth factor receptor signalling, trafficking and down-regulation. The model incorporates the role of a recently discovered protein complex made up of the E3 ubiquitin ligase, Cbl, the guanine exchange factor (GEF), Cool-1 (beta -Pix) and the Rho family G protein Cdc42. The complex has been suggested to be important in disrupting receptor down-regulation. We demonstrate that the model interactions can accurately reproduce the experimental observations, that they can be used to make predictions with accompanying uncertainties, and that we can apply ideas of optimal experimental design to suggest new experiments that reduce the uncertainty on unmeasurable components of the system.

  12. Regulation

    International Nuclear Information System (INIS)

    Ballereau, P.

    1999-01-01

    The different regulations relative to nuclear energy since the first of January 1999 are given here. Two points deserve to be noticed: the decree of the third august 1999 authorizing the national Agency for the radioactive waste management to install and exploit on the commune of Bures (Meuse) an underground laboratory destined to study the deep geological formations where could be stored the radioactive waste. The second point is about the uranium residues and the waste notion. The judgment of the administrative tribunal of Limoges ( 9. july 1998) forbidding the exploitation of a storage installation of depleted uranium considered as final waste and qualifying it as an industrial waste storage facility has been annulled bu the Court of Appeal. It stipulated that, according to the law number 75663 of the 15. july 1965, no criteria below can be applied to depleted uranium: production residue (possibility of an ulterior enrichment), abandonment of a personal property or simple intention to do it ( future use aimed in the authorization request made in the Prefecture). This judgment has devoted the primacy of the waste notion on this one of final waste. (N.C.)

  13. Co-ordinate regulation of distinct host cell signalling pathways by multifunctional enteropathogenic Escherichia coli effector molecules.

    Science.gov (United States)

    Kenny, Brendan; Ellis, Sarah; Leard, Alan D; Warawa, Jonathan; Mellor, Harry; Jepson, Mark A

    2002-05-01

    Enteropathogenic Escherichia coli (EPEC) is a major cause of paediatric diarrhoea and a model for the family of attaching and effacing (A/E) pathogens. A/E pathogens encode a type III secretion system to transfer effector proteins into host cells. The EPEC Tir effector protein acts as a receptor for the bacterial surface protein intimin and is involved in the formation of Cdc42-independent, actin-rich pedestal structures beneath the adhered bacteria. In this paper, we demonstrate that EPEC binding to HeLa cells also induces Tir-independent, cytoskeletal rearrangement evidenced by the early, transient formation of filopodia-like structures at sites of infection. Filopodia formation is dependent on expression of the EPEC Map effector molecule - a protein that targets mitochondria and induces their dysfunction. We show that Map-induced filopodia formation is independent of mitochondrial targeting and is abolished by cellular expression of the Cdc42 inhibitory WASP-CRIB domain, demonstrating that Map has at least two distinct functions in host cells. The transient nature of the filopodia is related to an ability of EPEC to downregulate Map-induced cell signalling that, like pedestal formation, was dependent on both Tir and intimin proteins. The ability of Tir to downregulate filopodia was impaired by disrupting a putative GTPase-activating protein (GAP) motif, suggesting that Tir may possess such a function, with its interaction with intimin triggering this activity. Furthermore, we also found that Map-induced cell signalling inhibits pedestal formation, revealing that the cellular effects of Tir and Map must be co-ordinately regulated during infection. Possible implications of the multifunctional nature of EPEC effector molecules in pathogenesis are discussed.

  14. 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...

  15. Rho-family GTPase Cdc42 controls migration of Langerhans cells in vivo

    DEFF Research Database (Denmark)

    Luckashenak, Nancy; Wähe, Anna; Breit, Katharina

    2013-01-01

    Epidermal Langerhans cells (LCs) of the skin represent the prototype migratory dendritic cell (DC) subtype. In the skin, they take up Ag, migrate to the draining lymph nodes, and contribute to Ag transport and immunity. Different depletion models for LCs have revealed contrasting roles and contri...

  16. A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis

    DEFF Research Database (Denmark)

    Dütting, Sebastian; Gaits-Iacovoni, Frederique; Stegner, David

    2017-01-01

    Blood platelets are produced by large bone marrow (BM) precursor cells, megakaryocytes (MKs), which extend cytoplasmic protrusions (proplatelets) into BM sinusoids. The molecular cues that control MK polarization towards sinusoids and limit transendothelial crossing to proplatelets remain unknown...

  17. DNA topoisomerase IIβ stimulates neurite outgrowth in neural differentiated human mesenchymal stem cells through regulation of Rho-GTPases (RhoA/Rock2 pathway) and Nurr1 expression.

    Science.gov (United States)

    Zaim, Merve; Isik, Sevim

    2018-04-25

    DNA topoisomerase IIβ (topo IIβ) is known to regulate neural differentiation by inducing the neuronal genes responsible for critical neural differentiation events such as neurite outgrowth and axon guidance. However, the pathways of axon growth controlled by topo IIβ have not been clarified yet. Microarray results of our previous study have shown that topo IIβ silencing in neural differentiated primary human mesenchymal stem cells (hMSCs) significantly alters the expression pattern of genes involved in neural polarity, axonal growth, and guidance, including Rho-GTPases. This study aims to further analyze the regulatory role of topo IIβ on the process of axon growth via regulation of Rho-GTPases. For this purpose, topo IIβ was silenced in neurally differentiated hMSCs. Cells lost their morphology because of topo IIβ deficiency, becoming enlarged and flattened. Additionally, a reduction in both neural differentiation efficiency and neurite length, upregulation in RhoA and Rock2, downregulation in Cdc42 gene expression were detected. On the other hand, cells were transfected with topo IIβ gene to elucidate the possible neuroprotective effect of topo IIβ overexpression on neural-induced hMSCs. Topo IIβ overexpression prompted all the cells to exhibit neural cell morphology as characterized by longer neurites. RhoA and Rock2 expressions were downregulated, whereas Cdc42 expression was upregulated. Nurr1 expression level correlated with topo IIβ in both topo IIβ-overexpressed and -silenced cells. Furthermore, differential translocation of Rho-GTPases was detected by immunostaining in response to topo IIβ. Our results suggest that topo IIβ deficiency could give rise to neurodegeneration through dysregulation of Rho-GTPases. However, further in-vivo research is needed to demonstrate if re-regulation of Rho GTPases by topo IIβ overexpression could be a neuroprotective treatment in the case of neurodegenerative diseases.

  18. Ornithine decarboxylase and extracellular polyamines regulate microvascular sprouting and actin cytoskeleton dynamics in endothelial cells

    International Nuclear Information System (INIS)

    Kucharzewska, Paulina; Welch, Johanna E.; Svensson, Katrin J.; Belting, Mattias

    2010-01-01

    The polyamines are essential for cancer cell proliferation during tumorigenesis. Targeted inhibition of ornithine decarboxylase (ODC), i.e. a key enzyme of polyamine biosynthesis, by α-difluoromethylornithine (DFMO) has shown anti-neoplastic activity in various experimental models. This activity has mainly been attributed to the anti-proliferative effect of DFMO in cancer cells. Here, we provide evidence that unperturbed ODC activity is a requirement for proper microvessel sprouting ex vivo as well as the migration of primary human endothelial cells. DFMO-mediated ODC inhibition was reversed by extracellular polyamine supplementation, showing that anti-angiogenic effects of DFMO were specifically related to polyamine levels. ODC inhibition was associated with an abnormal morphology of the actin cytoskeleton during cell spreading and migration. Moreover, our data suggest that de-regulated actin cytoskeleton dynamics in DFMO treated endothelial cells may be related to constitutive activation of the small GTPase CDC42, i.e. a well-known regulator of cell motility and actin cytoskeleton remodeling. These insights into the potential role of polyamines in angiogenesis should stimulate further studies testing the combined anti-tumor effect of polyamine inhibition and established anti-angiogenic therapies in vivo.

  19. RAGE, receptor of advanced glycation endoproducts, negatively regulates chondrocytes differentiation.

    Directory of Open Access Journals (Sweden)

    Tatsuya Kosaka

    Full Text Available RAGE, receptor for advanced glycation endoproducts (AGE, has been characterized as an activator of osteoclastgenesis. However, whether RAGE directly regulates chondrocyte proliferation and differentiation is unclear. Here, we show that RAGE has an inhibitory role in chondrocyte differentiation. RAGE expression was observed in chondrocytes from the prehypertrophic to hypertrophic regions. In cultured cells, overexpression of RAGE or dominant-negative-RAGE (DN-RAGE demonstrated that RAGE inhibited cartilaginous matrix production, while DN-RAGE promoted production. Additionally, RAGE regulated Ihh and Col10a1 negatively but upregulated PTHrP receptor. Ihh promoter analysis and real-time PCR analysis suggested that downregulation of Cdxs was the key for RAGE-induced inhibition of chondrocyte differentiation. Overexpression of the NF-κB inhibitor I-κB-SR inhibited RAGE-induced NF-κB activation, but did not influence inhibition of cartilaginous matrix production by RAGE. The inhibitory action of RAGE was restored by the Rho family GTPases inhibitor Toxin B. Furthermore, inhibitory action on Ihh, Col10a1 and Cdxs was reproduced by constitutively active forms, L63RhoA, L61Rac, and L61Cdc42, but not by I-κB-SR. Cdx1 induced Ihh and Col10a1 expressions and directly interacted with Ihh promoter. Retinoic acid (RA partially rescued the inhibitory action of RAGE. These data combined suggests that RAGE negatively regulates chondrocyte differentiation at the prehypertrophic stage by modulating NF-κB-independent and Rho family GTPases-dependent mechanisms.

  20. Tyrosine Phosphorylation of Rac1: A Role in Regulation of Cell Spreading

    Science.gov (United States)

    Chang, Fumin; Lemmon, Christopher; Lietha, Daniel; Eck, Michael; Romer, Lewis

    2011-01-01

    Rac1 influences a multiplicity of vital cellular- and tissue-level control functions, making it an important candidate for targeted therapeutics. The activity of the Rho family member Cdc42 has been shown to be modulated by tyrosine phosphorylation at position 64. We therefore investigated consequences of the point mutations Y64F and Y64D in Rac1. Both mutations altered cell spreading from baseline in the settings of wild type, constitutively active, or dominant negative Rac1 expression, and were accompanied by differences in Rac1 targeting to focal adhesions. Rac1-Y64F displayed increased GTP-binding, increased association with βPIX, and reduced binding with RhoGDI as compared with wild type Rac1. Rac1-Y64D had less binding to PAK than Rac1-WT or Rac1-64F. In vitro assays demonstrated that Y64 in Rac1 is a target for FAK and Src. Taken together, these data suggest a mechanism for the regulation of Rac1 activity by non-receptor tyrosine kinases, with consequences for membrane extension. PMID:22163037

  1. Next-generation sequencing analysis of gene regulation in the rat model of retinopathy of prematurity.

    Science.gov (United States)

    Griffith, Rachel M; Li, Hu; Zhang, Nan; Favazza, Tara L; Fulton, Anne B; Hansen, Ronald M; Akula, James D

    2013-08-01

    The purpose of this study was to identify the genes, biochemical signaling pathways, and biological themes involved in the pathogenesis of retinopathy of prematurity (ROP). Next-generation sequencing (NGS) was performed on the RNA transcriptome of rats with the Penn et al. (Pediatr Res 36:724-731, 1994) oxygen-induced retinopathy model of ROP at the height of vascular abnormality, postnatal day (P) 19, and normalized to age-matched, room-air-reared littermate controls. Eight custom-developed pathways with potential relevance to known ROP sequelae were evaluated for significant regulation in ROP: The three major Wnt signaling pathways, canonical, planar cell polarity (PCP), and Wnt/Ca(2+); two signaling pathways mediated by the Rho GTPases RhoA and Cdc42, which are, respectively, thought to intersect with canonical and non-canonical Wnt signaling; nitric oxide signaling pathways mediated by two nitric oxide synthase (NOS) enzymes, neuronal (nNOS) and endothelial (eNOS); and the retinoic acid (RA) signaling pathway. Regulation of other biological pathways and themes was detected by gene ontology using the Kyoto Encyclopedia of Genes and Genomes and the NIH's Database for Annotation, Visualization, and Integrated Discovery's GO terms databases. Canonical Wnt signaling was found to be regulated, but the non-canonical PCP and Wnt/Ca(2+) pathways were not. Nitric oxide signaling, as measured by the activation of nNOS and eNOS, was also regulated, as was RA signaling. Biological themes related to protein translation (ribosomes), neural signaling, inflammation and immunity, cell cycle, and cell death were (among others) highly regulated in ROP rats. These several genes and pathways identified by NGS might provide novel targets for intervention in ROP.

  2. Next Generation Sequencing Analysis of Gene Regulation in the Rat Model of Retinopathy of Prematurity

    Science.gov (United States)

    Griffith, Rachel M.; Li, Hu; Zhang, Nan; Favazza, Tara L.; Fulton, Anne B.; Hansen, Ronald M.; Akula, James D.

    2013-01-01

    Purpose To identify the genes, biochemical signaling pathways and biological themes involved in the pathogenesis of retinopathy of prematurity (ROP). Methods Next-generation sequencing (NGS) was performed on the RNA transcriptome of rats with the Penn et al. (1994) oxygen-induced retinopathy (OIR) model of ROP at the height of vascular abnormality, postnatal day (P) 19, and normalized to age-matched, room-air-reared littermate controls. Eight custom developed pathways with potential relevance to known ROP sequelae were evaluated for significant regulation in ROP: The three major Wnt signaling pathways, canonical, planar cell polarity (PCP), and Wnt/Ca2+, two signaling pathways mediated by the Rho GTPases RhoA and Cdc42, which are respectively thought to intersect with canonical and noncanonical Wnt signaling, nitric oxide signaling pathways mediated by two nitrox oxide synthase (NOS) enzymes, neuronal (nNOS) and endothelial (eNOS), and the retinoic acid (RA) signaling pathway. Regulation of other biological pathways and themes were detected by gene ontology using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and the NIH's Database for Annotation, Visualization and Integrated Discovery (DAVID)'s GO terms databases. Results Canonical Wnt signaling was found to be regulated, but the non-canonical PCP and Wnt/Ca2+ pathways were not. Nitric oxide (NO) signaling, as measured by the activation of nNOS eNOS, was also regulated, as was RA signaling. Biological themes related to protein translation (ribosomes), neural signaling, inflammation and immunity, cell cycle and cell death, were (among others) highly regulated in ROP rats. Conclusions These several genes and pathways identified by NGS might provide novel targets for intervention in ROP. PMID:23775346

  3. GIT1/βPIX signaling proteins and PAK1 kinase regulate microtubule nucleation.

    Science.gov (United States)

    Černohorská, Markéta; Sulimenko, Vadym; Hájková, Zuzana; Sulimenko, Tetyana; Sládková, Vladimíra; Vinopal, Stanislav; Dráberová, Eduarda; Dráber, Pavel

    2016-06-01

    Microtubule nucleation from γ-tubulin complexes, located at the centrosome, is an essential step in the formation of the microtubule cytoskeleton. However, the signaling mechanisms that regulate microtubule nucleation in interphase cells are largely unknown. In this study, we report that γ-tubulin is in complexes containing G protein-coupled receptor kinase-interacting protein 1 (GIT1), p21-activated kinase interacting exchange factor (βPIX), and p21 protein (Cdc42/Rac)-activated kinase 1 (PAK1) in various cell lines. Immunofluorescence microscopy revealed association of GIT1, βPIX and activated PAK1 with centrosomes. Microtubule regrowth experiments showed that depletion of βPIX stimulated microtubule nucleation, while depletion of GIT1 or PAK1 resulted in decreased nucleation in the interphase cells. These data were confirmed for GIT1 and βPIX by phenotypic rescue experiments, and counting of new microtubules emanating from centrosomes during the microtubule regrowth. The importance of PAK1 for microtubule nucleation was corroborated by the inhibition of its kinase activity with IPA-3 inhibitor. GIT1 with PAK1 thus represent positive regulators, and βPIX is a negative regulator of microtubule nucleation from the interphase centrosomes. The regulatory roles of GIT1, βPIX and PAK1 in microtubule nucleation correlated with recruitment of γ-tubulin to the centrosome. Furthermore, in vitro kinase assays showed that GIT1 and βPIX, but not γ-tubulin, serve as substrates for PAK1. Finally, direct interaction of γ-tubulin with the C-terminal domain of βPIX and the N-terminal domain of GIT1, which targets this protein to the centrosome, was determined by pull-down experiments. We propose that GIT1/βPIX signaling proteins with PAK1 kinase represent a novel regulatory mechanism of microtubule nucleation in interphase cells. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Sprouty regulates cell migration by inhibiting the activation of Rac1 GTPase

    International Nuclear Information System (INIS)

    Poppleton, Helen M.; Edwin, Francis; Jaggar, Laura; Ray, Ramesh; Johnson, Leonard R.; Patel, Tarun B.

    2004-01-01

    Sprouty (SPRY) protein negatively modulates fibroblast growth factor and epidermal growth factor actions. We showed that human SPRY2 inhibits cell growth and migration in response to serum and several growth factors. Using rat intestinal epithelial (IEC-6) cells, we investigated the involvement of the Rho family of GTPases, RhoA, Rac1, and cdc42 in SPRY2-mediated inhibition of cell migration and proliferation. The ability of TAT-tagged SPRY2 to inhibit proliferation and migration of IEC-6 cells transfected with constitutively active mutants of RhoA(G14V), Rac1(G12V), and cdc42 (F28L) was determined. Constitutively active RhoA(G14V), Rac1(G12V), or cdc42(F28L) did not protect cells from the anti-proliferative actions of TAT-SPRY2. The ability of TAT-hSPRY2 to inhibit migration was not altered by of RhoA(G14V) and cdc42(F28L). However, Rac1(G12V) obliterated the ability of SPRY2 to inhibit cell autonomous or serum-induced migration. Also, the activation of endogenous Rac1 was attenuated by TAT-SPRY2. Thus, SPRY2 mediates its anti-migratory actions by inhibiting Rac1 activation

  5. The Rac-RhoGDI complex and the structural basis for the regulation of Rho proteins by RhoGDI

    DEFF Research Database (Denmark)

    Scheffzek, K; Stephan, I; Jensen, Ole Nørregaard

    2000-01-01

    Rho family-specific guanine nucleotide dissociation inhibitors (RhoGDIs) decrease the rate of nucleotide dissociation and release Rho proteins such as RhoA, Rac and Cdc42 from membranes, forming tight complexes that shuttle between cytosol and membrane compartments. We have solved the crystal...

  6. Endocytic crosstalk: cavins, caveolins, and caveolae regulate clathrin-independent endocytosis.

    Directory of Open Access Journals (Sweden)

    Natasha Chaudhary

    2014-04-01

    Full Text Available Several studies have suggested crosstalk between different clathrin-independent endocytic pathways. However, the molecular mechanisms and functional relevance of these interactions are unclear. Caveolins and cavins are crucial components of caveolae, specialized microdomains that also constitute an endocytic route. Here we show that specific caveolar proteins are independently acting negative regulators of clathrin-independent endocytosis. Cavin-1 and Cavin-3, but not Cavin-2 or Cavin-4, are potent inhibitors of the clathrin-independent carriers/GPI-AP enriched early endosomal compartment (CLIC/GEEC endocytic pathway, in a process independent of caveola formation. Caveolin-1 (CAV1 and CAV3 also inhibit the CLIC/GEEC pathway upon over-expression. Expression of caveolar protein leads to reduction in formation of early CLIC/GEEC carriers, as detected by quantitative electron microscopy analysis. Furthermore, the CLIC/GEEC pathway is upregulated in cells lacking CAV1/Cavin-1 or with reduced expression of Cavin-1 and Cavin-3. Inhibition by caveolins can be mimicked by the isolated caveolin scaffolding domain and is associated with perturbed diffusion of lipid microdomain components, as revealed by fluorescence recovery after photobleaching (FRAP studies. In the absence of cavins (and caveolae CAV1 is itself endocytosed preferentially through the CLIC/GEEC pathway, but the pathway loses polarization and sorting attributes with consequences for membrane dynamics and endocytic polarization in migrating cells and adult muscle tissue. We also found that noncaveolar Cavin-1 can act as a modulator for the activity of the key regulator of the CLIC/GEEC pathway, Cdc42. This work provides new insights into the regulation of noncaveolar clathrin-independent endocytosis by specific caveolar proteins, illustrating multiple levels of crosstalk between these pathways. We show for the first time a role for specific cavins in regulating the CLIC/GEEC pathway, provide

  7. The small GTPase RhoH is an atypical regulator of haematopoietic cells

    Directory of Open Access Journals (Sweden)

    Kubatzky Katharina F

    2008-09-01

    Full Text Available Abstract Rho GTPases are a distinct subfamily of the superfamily of Ras GTPases. The best-characterised members are RhoA, Rac and Cdc42 that regulate many diverse actions such as actin cytoskeleton reorganisation, adhesion, motility as well as cell proliferation, differentiation and gene transcription. Among the 20 members of that family, only Rac2 and RhoH show an expression restricted to the haematopoietic lineage. RhoH was first discovered in 1995 as a fusion transcript with the transcriptional repressor LAZ3/BCL6. It was therefore initially named translation three four (TTF but later on renamed RhoH due to its close relationship to the Ras/Rho family of GTPases. Since then, RhoH has been implicated in human cancer as the gene is subject to somatic hypermutation and by the detection of RHOH as a translocation partner for LAZ3/BCL6 or other genes in human lymphomas. Underexpression of RhoH is found in hairy cell leukaemia and acute myeloid leukaemia. Some of the amino acids that are crucial for GTPase activity are mutated in RhoH so that the protein is a GTPase-deficient, so-called atypical Rho GTPase. Therefore other mechanisms of regulating RhoH activity have been described. These include regulation at the mRNA level and tyrosine phosphorylation of the protein's unique ITAM-like motif. The C-terminal CaaX box of RhoH is mainly a target for farnesyl-transferase but can also be modified by geranylgeranyl-transferase. Isoprenylation of RhoH and changes in subcellular localisation may be an additional factor to fine-tune signalling. Little is currently known about its signalling, regulation or interaction partners. Recent studies have shown that RhoH negatively influences the proliferation and homing of murine haematopoietic progenitor cells, presumably by acting as an antagonist for Rac1. In leukocytes, RhoH is needed to keep the cells in a resting, non-adhesive state, but the exact mechanism has yet to be elucidated. RhoH has also been

  8. Regulating the Regulator

    Energy Technology Data Exchange (ETDEWEB)

    1992-08-26

    The article reports on a challenge to the UK electricity regulator to defend his record by the Coalition for Fair Electricity Regulation (COFFER). The challenge centres on whether the obligation for the regional electric companies (REC) to purchase power from the cheapest source is being enforced. This is related to the wider issue of whether the REC's support of combined-cycle gas turbine (CCGT) is economic. COFFER considers that uneconomic gas-fired power plants are being allowed to displace economic coal-fired stations. Aspects discussed include the background to the dispute and the costs of CCGT and coal fired power generation. 1 fig., 1 tab.

  9. Dynamin1 is a novel target for IRSp53 protein and works with mammalian enabled (Mena) protein and Eps8 to regulate filopodial dynamics.

    Science.gov (United States)

    Chou, Ai Mei; Sem, Kai Ping; Wright, Graham Daniel; Sudhaharan, Thankiah; Ahmed, Sohail

    2014-08-29

    Filopodia are dynamic actin-based structures that play roles in processes such as cell migration, wound healing, and axonal guidance. Cdc42 induces filopodial formation through IRSp53, an Inverse-Bin-Amphiphysins-Rvs (I-BAR) domain protein. Previous work from a number of laboratories has shown that IRSp53 generates filopodia by coupling membrane protrusion with actin dynamics through its Src homology 3 domain binding partners. Here, we show that dynamin1 (Dyn1), the large guanosine triphosphatase, is an interacting partner of IRSp53 through pulldown and Förster resonance energy transfer analysis, and we explore its role in filopodial formation. In neuroblastoma cells, Dyn1 localizes to filopodia, associated tip complexes, and the leading edge just behind the anti-capping protein mammalian enabled (Mena). Dyn1 knockdown reduces filopodial formation, which can be rescued by overexpressing wild-type Dyn1 but not the GTPase mutant Dyn1-K44A and the loss-of-function actin binding domain mutant Dyn1-K/E. Interestingly, dynasore, an inhibitor of Dyn GTPase, also reduced filopodial number and increased their lifetime. Using rapid time-lapse total internal reflection fluorescence microscopy, we show that Dyn1 and Mena localize to filopodia only during initiation and assembly. Dyn1 actin binding domain mutant inhibits filopodial formation, suggesting a role in actin elongation. In contrast, Eps8, an actin capping protein, is seen most strongly at filopodial tips during disassembly. Taken together, the results suggest IRSp53 partners with Dyn1, Mena, and Eps8 to regulate filopodial dynamics. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Market, Regulation, Market, Regulation

    DEFF Research Database (Denmark)

    Frankel, Christian; Galland, Jean-Pierre

    2015-01-01

    barriers to trade in Europe, realized the free movement of products by organizing progressively several orders of markets and regulation. Based on historical and institutional documents, on technical publications, and on interviews, this article relates how the European Commission and the Member States had......This paper focuses on the European Regulatory system which was settled both for opening the Single Market for products and ensuring the consumers' safety. It claims that the New Approach and Standardization, and the Global Approach to conformity assessment, which suppressed the last technical...... alternatively recourse to markets and to regulations, at the three main levels of the New Approach Directives implementation. The article focuses also more specifically on the Medical Devices sector, not only because this New Approach sector has long been controversial in Europe, and has recently been concerned...

  11. Specific deletion of Cdc42 does not affect meiotic spindle organization/migration and homologous chromosome segregation but disrupts polarity establishment and cytokinesis in mouse oocytes

    DEFF Research Database (Denmark)

    Wang, Zhen-Bo; Jiang, Zong-Zhe; Zhang, Qing-Hua

    2013-01-01

    Mammalian oocyte maturation is distinguished by highly asymmetric meiotic divisions during which a haploid female gamete is produced and almost all the cytoplasm is maintained in the egg for embryo development. Actin-dependent meiosis I spindle positioning to the cortex induces the formation...

  12. Radiation regulation

    International Nuclear Information System (INIS)

    Braithwaite, J.; Grabosky, P.

    1985-01-01

    The five main areas of radiation regulation considered are radiation exposure in the mining of uranium and other minerals, exposure in the use of uranium in nuclear reactors, risks in the transport of radioactive materials and hazards associated with the disposal of used materials. In Australia these problems are regulated by mines departments, the Australian Atomic Energy Commission and radiation control branches in state health departments. Each of these instutional areas of regulation is examined

  13. 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...

  14. Regulative environmental policy. Regulative Umweltpolitik

    Energy Technology Data Exchange (ETDEWEB)

    Goerlitz, A; Voigt, R [Universitaet der Bundeswehr Muenchen, Neubiberg (Germany, F.R.). Fakultaet fuer Sozialwissenschaften; eds.

    1991-01-01

    Regulative policy means those governmental attempts to steer the course of things which can fall back on a certain repertoire of instruments for actions in order to warrant the causal and temporal connection between the making available and the employment of means. The fact that environmental protection needs regulative policy is substantiated by the thesis that the market has failed; consequently only government can manage the public goods 'environment' in a suitable way, and it is a matter of fact that environmental protection at present is operated preferably via regulative policy. The problems of regulative enviromental policy are manifold. Its implementation often miscarries because of limited administrative resources on the one hand - making sufficient control impossible for instance -, and because of poor quality regulative instruments on the other hand. One way out would be to increase the efficiency of regulative policy by sophisticating judicial techniques. Other ways out point to the executing level and aim at improving implementation strategies or are concerned with post-regulative law. The latter refers to a new legal quality which demonstrates itself already in corporatistical crisis regulation or in induction programs such as pollution limits. A final way out favours deregulation strategies which includes the introduction of environmental levies or the allocation of environmental licences. An interdisciplinary discourse is to find out what would happen if these ways were taken. Pointers to solutions from varying scientific disciplines resulting from this discourse are to be found in this volume. (orig./HSCH).

  15. 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

  16. NORM regulations

    Energy Technology Data Exchange (ETDEWEB)

    Gray, P. [ed.

    1997-02-01

    The author reviews the question of regulation for naturally occuring radioactive material (NORM), and the factors that have made this a more prominent concern today. Past practices have been very relaxed, and have often involved very poor records, the involvment of contractors, and the disposition of contaminated equipment back into commercial service. The rationale behind the establishment of regulations is to provide worker protection, to exempt low risk materials, to aid in scrap recycling, to provide direction for remediation and to examine disposal options. The author reviews existing regulations at federal and state levels, impending legislation, and touches on the issue of site remediation and potential liabilities affecting the release of sites contaminated by NORM.

  17. Fisheries regulation

    DEFF Research Database (Denmark)

    Jensen, Frank; Frost, Hans Staby; Abildtrup, Jens

    2017-01-01

    Economists normally claim that a stock externality arises within fisheries because each individual fisherman does not take the effect on stock size into account when making harvest decisions. Due to the stock externality, it is commonly argued that fisheries regulation is necessary, but regulatory...... decisions are complicated by a tremendous amount of uncertainty and asymmetric information. This paper provides an overview of selected parts of the literature on the regulation of fisheries under uncertainty and asymmetric information, and possible areas for future research are identified. Specifically...

  18. French regulations

    International Nuclear Information System (INIS)

    Ballereau, P.

    1998-01-01

    In this issue are given the new French regulations relative to radiation protection of temporary personnel, the licensing to release gaseous and liquid wastes and the licensing granted to thirty two laboratories using beta and gamma decay radioisotopes. (N.C.)

  19. Group I Paks Promote Skeletal Myoblast Differentiation In Vivo and In Vitro

    DEFF Research Database (Denmark)

    Joseph, Giselle A; Lu, Min; Radu, Maria

    2017-01-01

    fusion in Drosophila We report that both Pak1 and Pak2 are activated during mammalian myoblast differentiation. One pathway of activation is initiated by N-cadherin ligation and involves the cadherin coreceptor Cdo with its downstream effector, Cdc42. Individual genetic deletion of Pak1 and Pak2 in mice....... Furthermore, primary myoblasts lacking Pak1 and Pak2 display delayed expression of myogenic differentiation markers and myotube formation. These results identify Pak1 and Pak2 as redundant regulators of myoblast differentiation in vitro and in vivo and as components of the promyogenic Ncad/Cdo/Cdc42 signaling...

  20. Regulating Internalities

    OpenAIRE

    Sunstein, Cass Robert; Allcott, Hunt

    2015-01-01

    This paper offers a framework for regulating internalities. Using a simple economic model, we provide four principles for designing and evaluating behaviorally-motivated policy. We then outline rules for determining which contexts reliably reflect true preferences and discuss empirical strategies for measuring internalities. As a case study, we focus on energy efficiency policy, including Corporate Average Fuel Economy (CAFE) standards and appliance and lighting energy efficiency standards.

  1. Competition between bank regulators

    OpenAIRE

    Schindler, Dirk; Eggert, Wolfgang

    2004-01-01

    This paper examines competition between bank regulators in open economies. We use a model where credit demand of firms is endogenous and show any tendency for downward competition in regulation policy is limited by the effect of regulation on profits of nonfinancial firms. Moreover, perfect mobility on loans and deposit markets fully eliminates the incentives of regulators to set bank regulation at ine±cient low levels.

  2. Regulating through leverage: Civil regulation in China

    NARCIS (Netherlands)

    Fürst, K.

    2016-01-01

    The overarching goal of this study is to examine the efforts of Chinese NGOs to prevent and/or control industrial pollution risks and then use the findings of this research to study the nature of civil regulation in, and beyond, China’s authoritarian setting. It first argues that 'regulation through

  3. Atomic Energy Control Regulations

    International Nuclear Information System (INIS)

    1992-01-01

    This is the consolidated text of the Atomic Energy Control Regulations of 17 March 1960, with amendments to 27 August 1992. The Regulations cover the licensing of nuclear facilities, radiation sources, including uranium mining, radiation protection questions, etc. (NEA)

  4. Environmental regulation and competitiveness

    NARCIS (Netherlands)

    Mulatu, A.; Florax, R.J.G.M.; Withagen, C.A.A.M.

    2001-01-01

    The potential relationship between domestic environmental regulation and international competitiveness has evoked various speculations. The common neoclassical train of thought is that strict environmental regulation is detrimental to the competitiveness of industry, and that it induces phenomena

  5. Ocean Dumping Control Regulations

    International Nuclear Information System (INIS)

    1978-01-01

    These Regulations were made further to the Ocean Dumping Control Act which provides for restrictions in dumping operations. The Regulations contain model applications for permits to dump or load a series of materials. (NEA)

  6. Regulation of Genetic Tests

    Science.gov (United States)

    ... for Genomics Research Intellectual Property Issues in Genetics Archive Online Bioethics Resources Privacy in Genomics Regulation of ... are not regulated, meaning that they go to market without any independent analysis to verify the claims ...

  7. Trout Stream Special Regulations

    Data.gov (United States)

    Minnesota Department of Natural Resources — This layer shows Minnesota trout streams that have a special regulation as described in the 2006 Minnesota Fishing Regulations. Road crossings were determined using...

  8. Culture and emotion regulation.

    Science.gov (United States)

    Ford, Brett Q; Mauss, Iris B

    2015-06-01

    While anthropological research has long emphasized cultural differences in whether emotions are viewed as beneficial versus harmful, psychological science has only recently begun to systematically examine those differences and their implications for emotion regulation and well-being. Underscoring the pervasive role of culture in people's emotions, we summarize research that has examined links between culture, emotion regulation, and well-being. Specifically, we focus on two questions. First, how does culture lead individuals to regulate their emotions? And second, how does culture modulate the link between emotion regulation and well-being? We finish by suggesting directions for future research to advance the study of culture and emotion regulation.

  9. Radiation Control Regulation 1993

    International Nuclear Information System (INIS)

    1993-01-01

    This Regulation (No. 434-1993) was made in pursuance of the Radiation Control Act 1990 and replaces the Active Substances Regulations 1959 repealed by the Act. It entered into force on 1 September 1993. The Regulation specifies that the technical radiation protection definitions have the same meaning as in the 1990 recommendations. The Regulation provides for the licensing of persons to use radioactive substances and radiation apparatus. It prescribes activities which may only be carried out by an accredited radiation expert and regulates the use of radiation apparatus and radioactive substances as well as the disposal and transport of radiation apparatus and radioactive substances. (NEA)

  10. Load regulating expansion fixture

    International Nuclear Information System (INIS)

    Wagner, L.M.; Strum, M.J.

    1998-01-01

    A free standing self contained device for bonding ultra thin metallic films, such as 0.001 inch beryllium foils is disclosed. The device will regulate to a predetermined load for solid state bonding when heated to a bonding temperature. The device includes a load regulating feature, whereby the expansion stresses generated for bonding are regulated and self adjusting. The load regulator comprises a pair of friction isolators with a plurality of annealed copper members located there between. The device, with the load regulator, will adjust to and maintain a stress level needed to successfully and economically complete a leak tight bond without damaging thin foils or other delicate components. 1 fig

  11. Volume regulation in epithelia

    DEFF Research Database (Denmark)

    Larsen, Erik Hviid; Hoffmann, Else Kay

    2016-01-01

    to amphibian skin and mammalian cortical collecting tubule of low and intermediate osmotic permeability. Crosstalk between entrance and exit mechanisms interferes with volume regulation both at aniso-osmotic and iso-osmotic volume perturbations. It has been proposed that cell volume regulation is an intrinsic...... regulation are cloned. The volume-regulated anion channel (VRAC) exhibiting specific electrophysiological characteristics seems exclusive to serve cell volume regulation. This is contrary to K+ channels as well as cotransporters and exchange mechanisms that may serve both transepithelial transport and cell...... volume regulation. In the same cell, these functions may be maintained by different ion pathways that are separately regulated. RVD is often preceded by increase in cytosolic free Ca2+, probably via influx through TRP channels, but Ca2+ release from intracellular stores has also been observed. Cell...

  12. Voltage regulator for generator

    Energy Technology Data Exchange (ETDEWEB)

    Naoi, K

    1989-01-17

    It is an object of this invention to provide a voltage regulator for a generator charging a battery, wherein even if the ambient temperature at the voltage regulator rises abnormally high, possible thermal breakage of the semiconductor elements constituting the voltage regulator can be avoided. A feature of this invention is that the semiconductor elements can be protected from thermal breakage, even at an abnormal ambient temperature rise at the voltage regulator for the battery charging generator, by controlling a maximum conduction ratio of a power transistor in the voltage regulator in accordance with the temperature at the voltage regulator. This is achieved through a switching device connected in series to the field coil of the generator and adapted to be controlled in accordance with an output voltage of the generator and the ambient temperature at the voltage regulator. 6 figs.

  13. TOWARD MORE EFFECTIVE REGULATION

    Energy Technology Data Exchange (ETDEWEB)

    J. GRAF

    2000-06-01

    This paper proposes a model relationship between the operator engaged in a hazardous activity, the regulator of that activity, and the general public. The roles and responsibilities of each entity are described in a way that allows effective communication flow. The role of the regulator is developed using the steam boiler as an example of a hazard subject to regulation; however, the model applies to any regulated activity. In this model the safety analyst has the extremely important role of communicating sometimes difficult technical information to the regulator in a way that the regulator can provide credible assurance to the general public as to the adequacy of the control of the hazardous activity. The conclusion asserts that acceptance of the model, understanding of the roles and responsibilities and definition of who communicates what information to whom will mitigate frustration on the part of each of the three entities.

  14. The development of regulations

    International Nuclear Information System (INIS)

    Slokan Dusic, D.; Levstek, M.F.; Stritar, A.

    2003-01-01

    In October 2002, The Act on Protection Against Ionising Radiation and Nuclear Safety which regulates all aspects of protection against ionising radiation and nuclear safety entered into force in Slovenia. The Slovenian government and its responsible ministries shall issue several governmental and ministerial regulations to support the above - mentioned act. The Slovenian Nuclear Safety Administration (SNSA) which acts within the Ministry of the Environment, Spatial Planing and Energy takes an active part in drafting the regulations which are defined in the act. Due to a very comprehensive and pretentious task, that is to be completed in a relatively short period of time, taking into consideration the involvement of stakeholders and all competent ministries, the SNSA within the Quality Management System developed a special procedure that insures the systematic approach to the preparation of regulations. The article will briefly represent the process that: defines the preparation, development, harmonisation, review, approval and issue of regulations and uniforms the format of developed regulations. (author)

  15. Regulating hedge funds.

    OpenAIRE

    Daníelsson, J.; Zigrand, JP.

    2007-01-01

    Due to the ever-increasing amounts under management and their unregulated and opaque nature, hedge funds have emerged as a key concern for policymakers. While until now, hedge funds have been left essentially unregulated, we are seeing increasing calls for regulation for both microprudential and macroprudential reasons. In our view, most calls for the regulation of hedge funds are based on a misperception of the effectiveness of financial regulations, perhaps coupled with a lack of understand...

  16. Regulating household financial advice

    Directory of Open Access Journals (Sweden)

    Benjamin F. Cummings

    2012-08-01

    Full Text Available This paper reviews economic theory related to investment advice. This theory explains 1 why financial advisors need to be carefully regulated for the benefit of both the investment advice industry and for consumers, 2 why principles-based regulation (e.g., a fiduciary standard is more efficient than rules-based regulation, 3 why dual regulation of financial professionals providing investment or insurance advice is inefficient and inequitable policy, and 4 why the application of a universal and uniform fiduciary standard will be difficult to implement.

  17. The regulation of hunting

    DEFF Research Database (Denmark)

    Abildtrup, Jens; Jensen, Frank

    Within hunting, wildlife populations are estimated to be too high in many countries which is assumed to be due to the market failure, that each hunter harvests too little compared to what the regulator wants. This may be due to the existing regulation which, among other things, requires knowledge...... by an individual, variable tax rate. The variable tax rate is, among other things, based on the difference in marginal value of the population between the hunter and the regulator. The paper shows that the population tax/subsidy secures a first-best optimum. Thus, the population tax is a good alternative...... to the existing regulation....

  18. Nuclear safety and regulation

    International Nuclear Information System (INIS)

    Kim, Hho Jung

    2000-03-01

    This book contains 12 chapters, which are atom and radiation, nuclear reactor and kinds of nuclear power plant, safeguard actuation system and stability evaluation for rock foundation of nuclear power plant, nuclear safety and principle, safety analysis and classification of incident, probabilistic safety assessment and major incident, nuclear safety regulation, system of nuclear safety regulation, main function and subject of safety regulation in nuclear facilities, regulation of fuel cycle and a nuclear dump site, protection of radiation and, safety supervision and, safety supervision and measurement of environmental radioactivity.

  19. Peak regulation right

    International Nuclear Information System (INIS)

    Gao, Z. |; Ren, Z.; Li, Z.; Zhu, R.

    2005-01-01

    A peak regulation right concept and corresponding transaction mechanism for an electricity market was presented. The market was based on a power pool and independent system operator (ISO) model. Peak regulation right (PRR) was defined as a downward regulation capacity purchase option which allowed PRR owners to buy certain quantities of peak regulation capacity (PRC) at a specific price during a specified period from suppliers. The PRR owner also had the right to decide whether or not they would buy PRC from suppliers. It was the power pool's responsibility to provide competitive and fair peak regulation trading markets to participants. The introduction of PRR allowed for unit capacity regulation. The PRR and PRC were rated by the supplier, and transactions proceeded through a bidding process. PRR suppliers obtained profits by selling PRR and PRC, and obtained downward regulation fees regardless of whether purchases are made. It was concluded that the peak regulation mechanism reduced the total cost of the generating system and increased the social surplus. 6 refs., 1 tab., 3 figs

  20. Soft Regulators, though judges

    NARCIS (Netherlands)

    de Geest, G.G.A.; Dari Mattiacci, G.

    Judges have a tendency to be more demanding than regulators. In the United States, a majority of the courts has adopted the rule that the unexcused violation of a statutory standard is negligence per se. However, the converse does not hold: compliance with regulation does not relieve the injurer of

  1. Mortgage market regulation: Europe

    NARCIS (Netherlands)

    Aalbers, M.B.; Smith, S.J.

    2012-01-01

    Despite several European Union (EU) initiatives, there is only limited pan-European mortgage market regulation. The EU strategy can be characterised as one of parallel liberalisation and consolidation. This article highlights the key differences in regulation among European mortgage markets.

  2. Regulation as Rhetoric

    DEFF Research Database (Denmark)

    Boll, Karen; Györy, Csaba

    This paper analyses the way regulatory agencies strategically use public ‘rhetoric’ and ‘management of appearance’ to strengthen their regulation. It reports a comparative study of the Securities and Exchange Commission (SEC) which is the US federal securities regulator and the Danish Tax...... and Customs Administration (SKAT) which is the national tax regulator in Denmark. SEC operates in a US context where the agency fights to get trust, while SKAT operates in a context where high trust in public agencies is a basic condition. We argue, however, that despite the radically different institutional...... engage reflectively in image promotion which serves two purposes: establishing and maintaining legitimacy in a particular social and political environment and producing compliance. Further, we argue that this regulation is a form of ‘post-bureaucratic’ regulation in which compliance is achieved...

  3. Reconceptualizing Civil Regulation

    DEFF Research Database (Denmark)

    Galang, Roberto Martin; Castello, Itziar

    2011-01-01

    This article re-conceptualizes the notion of civil regulation, through an analysis of 775 projects by firms located in 21 Asian countries, wherein we map the state of civil regulation initiatives in the region. We challenge two established assumptions in the Corporate Social Responsibility litera....... Finally, we argue that, in Asia, governments act as a structuration mechanism which challenges the current understanding of CSR.......This article re-conceptualizes the notion of civil regulation, through an analysis of 775 projects by firms located in 21 Asian countries, wherein we map the state of civil regulation initiatives in the region. We challenge two established assumptions in the Corporate Social Responsibility...... and environmental standards; but also that local, small and medium companies play a key role in the development of Asian civil regulation. We call this second finding the “CSR importation trap”. Our findings are supported by evidence on the limitations in the interchangeable properties of business and governments...

  4. Risk-informed regulation

    International Nuclear Information System (INIS)

    Hoffman, D.R.

    2003-01-01

    In assessing safety for nuclear facilities, regulators have traditionally used a deterministic approach. New techniques for assessing nuclear or radiological risks make it possible for regulators to incorporate risk insights into their regulations. By 'risk-informing' the regulatory processes, independent bodies tasked with protecting the health and safety of the public can focus on those design and operational issues most important to safety. Such an approach is a move away from prescriptive regulations that were based on conservative engineering judgments toward regulations focused on issues that contribute significantly to safety. Despite the availability of probabilistic risk assessment (PRA) tools, organisations often struggle with how to best use this capability. Most international regulations are still based largely on deterministic analyses that were developed without the benefit of quantitative or measurable estimates of risk. PRA considers issues of risk in a more comprehensive manner by examining a wider spectrum of initiating events and their frequency, and considers the likelihood of events in a rigorous and comprehensive manner. In some countries, nuclear regulators are actively moving toward increasing the use of risk insights in a variety of strategic arenas, including risk-informed technical specifications (operating limits and conditions), in-service inspection and testing, programs, and assessment and enforcement actions. A risk-informed approach enhances the traditional deterministic approach by explicitly considering a broader range of safety challenges, focusing resources on the basis of risk significance, considering a broader range of counter measures to mitigate challenges, and explicitly identifying and quantifying uncertainties in analyses. (author)

  5. Epigenetic Regulation of Adipokines

    Directory of Open Access Journals (Sweden)

    Tho X. Pham

    2017-08-01

    Full Text Available Adipose tissue expansion in obesity leads to changes in the expression of adipokines, adipocyte-specific hormones that can regulate whole body energy metabolism. Epigenetic regulation of gene expression is a mechanism by which cells can alter gene expression through the modifications of DNA and histones. Epigenetic mechanisms, such as DNA methylation and histone modifications, are intimately tied to energy metabolism due to their dependence on metabolic intermediates such as S-adenosylmethionine and acetyl-CoA. Altered expression of adipokines in obesity may be due to epigenetic changes. The goal of this review is to highlight current knowledge of epigenetic regulation of adipokines.

  6. The power of regulation

    International Nuclear Information System (INIS)

    Lewis, M.G.

    1995-01-01

    Slides accompanying a presentation at The Power of Change Conference in Vancouver, BC in April 1995 about regulations affecting the power industry were presented. Issues addressed included customer choice, incentive regulation changes (price-caps, revenue sharing and pricing flexibility), the reactions of Canadian industry to regulatory changes, and anticipated reactions of the financial markets to changes in regulations. The potential effects of competition and changes that will create competition were discussed. The level of readiness of Canadian financial, ownership and regulatory bodies was discussed. The needs and expectations of investors from a new regulatory regime were quesstimated. Possible alternatives to the present regulatory framework were suggested

  7. Electrical installations and regulations

    CERN Document Server

    Whitfield, J F

    1966-01-01

    Electrical Installations and Regulations focuses on the regulations that apply to electrical installations and the reasons for them. Topics covered range from electrical science to alternating and direct current supplies, as well as equipment for providing protection against excess current. Cables, wiring systems, and final subcircuits are also considered, along with earthing, discharge lighting, and testing and inspection.Comprised of 12 chapters, this book begins with an overview of electrical installation work, traits of a good electrician, and the regulations governing installations. The r

  8. Legislation and regulation

    International Nuclear Information System (INIS)

    1998-01-01

    This document presents the fulfilling of the Brazilian obligations under the Convention on Nuclear Safety. The Chapter 3 of the document contains some details about the Brazilian legislation and regulation, the nuclear and environmental licensing, and emergency preparedness legislation

  9. Benchmarking and Regulation

    DEFF Research Database (Denmark)

    Agrell, Per J.; Bogetoft, Peter

    . The application of benchmarking in regulation, however, requires specific steps in terms of data validation, model specification and outlier detection that are not systematically documented in open publications, leading to discussions about regulatory stability and economic feasibility of these techniques...

  10. Legislation and regulation

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-09-01

    This document presents the fulfilling of the Brazilian obligations under the Convention on Nuclear Safety. The Chapter 3 of the document contains some details about the Brazilian legislation and regulation, the nuclear and environmental licensing, and emergency preparedness legislation.

  11. The regulation of appetite

    OpenAIRE

    Druce, M; Bloom, S R

    2006-01-01

    The worsening global obesity epidemic, particularly the increase in childhood obesity, has prompted research into the mechanisms of appetite regulation. Complex pathways modulate energy balance, involving appetite centres in the hypothalamus and brain stem, and hormonal signals of energy status released by the gut and by the periphery. Better understanding of appetite regulation improves understanding of the aetiology of obesity. Manipulation of this homoeostatic system offers potentially use...

  12. Corruption, Institutions and Regulation

    OpenAIRE

    Michael Breen; Robert Gillanders

    2011-01-01

    We analyze the effects of corruption and institutional quality on the quality of business regulation. Our key findings indicate that corruption negatively aspects the quality of regulation and that general institutional quality is insignificant once corruption is controlled for. These findings hold over a number of specifications which include additional exogenous historical and geographic controls. The findings imply that policy-makers should focus on curbing corruption to improve regulat...

  13. Regulating deregulated energy markets

    International Nuclear Information System (INIS)

    Jackson, M.

    2002-01-01

    The North American gas and electricity markets are fast evolving, and regulators are currently faced with a host of issues such as market-based rates, unbundling, stranded costs, open access, and incentive regulation are surfacing as a result of deregulation. The regulatory environment in Ontario was reviewed by the author. Deregulated markets rule, from commodities to gas and electricity. Additionally, there is an evolution of traditional utility regulation. A look at deregulated markets revealed that there are regulations on boundary conditions on the deregulated market. Under the Ontario Energy Board (OEB), all generators, transmitters, distributors, and retailers of electricity must be licensed. The standard supply service (SSS) offered by electricity distributors and system gas which is still being sold by natural gas distributors continues to be regulated by OEB. One issue that was addressed was separation for revenues and costs of the utility's purchase and sale of gas business, at least for accounting purposes. The next issue discussed was cost of system gas and SSS, followed by timely signals and prudent incurred costs. Historical benefits were reviewed, such as historical commitments to low-cost electricity. Pooling transportation costs, transmission pricing continued, market-based rates, unbundling, stranded costs, open access, incentive regulation/ performance based regulation (PBR) were all discussed. Price cap on PBR, both partial and comprehensive were looked at. A requirement to review guidelines on cost of capital and an application to extend blanket approval provisions for gas storage were discussed, as they are amongst some of the challenges of the future. Other challenges include revised rules and practice and procedure; practice directions for cost awards, appeals, and other functions; confidentiality guidelines; and refinements to the role of and approaches to alternative dispute resolution. The future role of regulators was examined in light

  14. Interpersonal emotion regulation.

    Science.gov (United States)

    Zaki, Jamil; Williams, W Craig

    2013-10-01

    Contemporary emotion regulation research emphasizes intrapersonal processes such as cognitive reappraisal and expressive suppression, but people experiencing affect commonly choose not to go it alone. Instead, individuals often turn to others for help in shaping their affective lives. How and under what circumstances does such interpersonal regulation modulate emotional experience? Although scientists have examined allied phenomena such as social sharing, empathy, social support, and prosocial behavior for decades, there have been surprisingly few attempts to integrate these data into a single conceptual framework of interpersonal regulation. Here we propose such a framework. We first map a "space" differentiating classes of interpersonal regulation according to whether an individual uses an interpersonal regulatory episode to alter their own or another person's emotion. We then identify 2 types of processes--response-dependent and response-independent--that could support interpersonal regulation. This framework classifies an array of processes through which interpersonal contact fulfills regulatory goals. More broadly, it organizes diffuse, heretofore independent data on "pieces" of interpersonal regulation, and identifies growth points for this young and exciting research domain.

  15. Federal Aviation Regulations - National Aviation Regulations of Russia

    Science.gov (United States)

    Chernykh, O.; Bakiiev, M.

    2018-03-01

    Chinese Aerospace Engineering is currently developing cooperation with Russia on a wide-body airplane project that has directed the work towards better understanding of Russian airworthiness management system. The paper introduces national Aviation regulations of Russia, presents a comparison of them with worldwide recognized regulations, and highlights typical differences. They have been found to be: two general types of regulations used in Russia (Aviation Regulations and Federal Aviation Regulations), non-unified structure of regulations on Aircraft Operation management, various separate agencies responsible for regulation issuance instead of one national aviation authority, typical confusions in references. The paper also gives a list of effective Russian Regulations of both types.

  16. Nuclear regulation in transition

    International Nuclear Information System (INIS)

    Tomain, J.P.

    1986-01-01

    The current state of nuclear regulations in the USA is examined. Since Three Mile Island the regulation of the nuclear power industry has been undergoing a noticeable transition. It will be argued here that the transition is characterized by two indicia. First, the primary focus of state and federal regulators has been on the financial aspects of the industry: this is best seen in the context of decisions allocating the costs of nuclear plant cancellations. Second, decisionmaking power has been decentralized: although the regulatory history of nuclear power demonstrates the tradition of centralized decisionmaking power (i.e., formerly the primary decisionmaking body was the Atomic Energy Commission), now States share decisionmaking power with the Nuclear Regulatory Commission. In Section 1 a brief legislative history of nuclear regulation is presented to establish the assertion that nuclear regulation, both de jure and de facto, was centralized. Next, Section 2 canvasses recent United States Supreme Court opinions regarding nuclear regulation. The Court frequently acts as policymaker through the consequences of its opinions, if not by its intent. In the area of nuclear policymaking, the Court has paid allegiance recently both to the tradition of centralization and to the movement toward decentralization. This dualism is reflected in other federal court decisions as well which will be briefly mentioned. Continuing the analysis of Federal regulation, Section 3 examines the current reform efforts of the NRC. Section 4 presents an examination of State responses to nuclear plant cancellations. In this section, State administrative agency and court decisions will be examined and recent State legislation will be discussed. (author)

  17. Nuclear regulation in transition

    Energy Technology Data Exchange (ETDEWEB)

    Tomain, J.P. (Cincinnati Univ., OH, US. Coll. of Law)

    1986-01-01

    The current state of nuclear regulations in the USA is examined. Since Three Mile Island the regulation of the nuclear power industry has been undergoing a noticeable transition. It will be argued here that the transition is characterized by two indicia. First, the primary focus of state and federal regulators has been on the financial aspects of the industry: this is best seen in the context of decisions allocating the costs of nuclear plant cancellations. Second, decisionmaking power has been decentralized: although the regulatory history of nuclear power demonstrates the tradition of centralized decisionmaking power (i.e., formerly the primary decisionmaking body was the Atomic Energy Commission), now States share decisionmaking power with the Nuclear Regulatory Commission. In Section 1 a brief legislative history of nuclear regulation is presented to establish the assertion that nuclear regulation, both de jure and de facto, was centralized. Next, Section 2 canvasses recent United States Supreme Court opinions regarding nuclear regulation. The Court frequently acts as policymaker through the consequences of its opinions, if not by its intent. In the area of nuclear policymaking, the Court has paid allegiance recently both to the tradition of centralization and to the movement toward decentralization. This dualism is reflected in other federal court decisions as well which will be briefly mentioned. Continuing the analysis of Federal regulation, Section 3 examines the current reform efforts of the NRC. Section 4 presents an examination of State responses to nuclear plant cancellations. In this section, State administrative agency and court decisions will be examined and recent State legislation will be discussed.

  18. To regulate or not to regulate?

    Energy Technology Data Exchange (ETDEWEB)

    Mason, G.; Wrixon, A. [IAEA, Vienna (Austria)

    2006-07-01

    Full text of publication follows: In Hamlet famous soliloquy to be or not to be, he wrestles with the perennial human problem of choosing the right course of action in difficult circumstances. In recent years, we have witnessed a cast of thousands playing out a long-running scene that seems to echo Hamlet dilemma on a rather more prosaic level. When is it necessary to apply regulations to the control of exposure to ionizing radiation and when is regulatory control not warranted? This seemingly straightforward question has brought out the philosopher, ethician, lawyer, pragmatist, orator in simple radiation protection folk and has led to passionate debate on numerous occasions. This paper attempts an answer based on a review of recent developments. For deciding when to apply regulatory controls, several concepts have evolved over time, including exemption of practices and sources, exclusion of exposures and clearance of materials. These have different origins, purposes and characteristics. Exemption and clearance have often been associated with triviality of risk, while exclusion has been related to un-amenability of control. For each concept, criteria have been developed to assist the regulator in reaching a decision, but there has much disputation over numerical values. This paper briefly reviews and analyses recent developments and attempts to clarify the problem from first principles. The conclusion is that the underlying issue in each case is to determine when regulatory controls become unwarranted: that is, when the societal resources expended in applying them and complying with them would be disproportionate to any benefit they might bring. This is a natural extension of the principle of optimization of protection to the regulatory control of protection, in the context of exposure to radiation at very low levels. It also reflects common expectations of good governance: wise management of finite societal resources and avoidance of unwarranted controls on

  19. To regulate or not to regulate?

    International Nuclear Information System (INIS)

    Mason, G.; Wrixon, A.

    2006-01-01

    Full text of publication follows: In Hamlet famous soliloquy to be or not to be, he wrestles with the perennial human problem of choosing the right course of action in difficult circumstances. In recent years, we have witnessed a cast of thousands playing out a long-running scene that seems to echo Hamlet dilemma on a rather more prosaic level. When is it necessary to apply regulations to the control of exposure to ionizing radiation and when is regulatory control not warranted? This seemingly straightforward question has brought out the philosopher, ethician, lawyer, pragmatist, orator in simple radiation protection folk and has led to passionate debate on numerous occasions. This paper attempts an answer based on a review of recent developments. For deciding when to apply regulatory controls, several concepts have evolved over time, including exemption of practices and sources, exclusion of exposures and clearance of materials. These have different origins, purposes and characteristics. Exemption and clearance have often been associated with triviality of risk, while exclusion has been related to un-amenability of control. For each concept, criteria have been developed to assist the regulator in reaching a decision, but there has much disputation over numerical values. This paper briefly reviews and analyses recent developments and attempts to clarify the problem from first principles. The conclusion is that the underlying issue in each case is to determine when regulatory controls become unwarranted: that is, when the societal resources expended in applying them and complying with them would be disproportionate to any benefit they might bring. This is a natural extension of the principle of optimization of protection to the regulatory control of protection, in the context of exposure to radiation at very low levels. It also reflects common expectations of good governance: wise management of finite societal resources and avoidance of unwarranted controls on

  20. The Effect of Z-Ligustilide on the Mobility of Human Glioblastoma T98G Cells.

    Directory of Open Access Journals (Sweden)

    Jun Yin

    Full Text Available Z-ligustilide (LIG, an essential oil extract from Radix Angelica sinensis, has broad pharmaceutical applications in treating cardio-vascular diseases and ischemic brain injury. Recently, LIG has been connected to Glioblastoma multiforme (GBM because of its structural similarity to 3-n-alkyphthalide (NBP, which is specifically cytotoxic to GBM cells. Hence, we investigated LIG's effect on GBM T98G cells. The study shows that LIG can significantly reduce T98G cells' migration in a dose-dependent manner. Furthermore, the attenuation of cellular mobility can be linked to the activity of the Rho GTPases (RhoA, Rac1 and Cdc42, the three critical molecular switches governing cytoskeleton remodeling; thus, regulating cell migration. LIG significantly reduces the expression of RhoA and affects in a milder manner the expression of Cdc42 and Rac1.

  1. Molecular characterization of a novel RhoGAP, RRC-1 of the nematode Caenorhabditis elegans

    International Nuclear Information System (INIS)

    Delawary, Mina; Nakazawa, Takanobu; Tezuka, Tohru; Sawa, Mariko; Iino, Yuichi; Takenawa, Tadaomi; Yamamoto, Tadashi

    2007-01-01

    The GTPase-activating proteins for Rho family GTPases (RhoGAP) transduce diverse intracellular signals by negatively regulating Rho family GTPase-mediated pathways. In this study, we have cloned and characterized a novel RhoGAP for Rac1 and Cdc42, termed RRC-1, from Caenorhabditis elegans. RRC-1 was highly homologous to mammalian p250GAP and promoted GTP hydrolysis of Rac1 and Cdc42 in cells. The rrc-1 mRNA was expressed in all life stages. Using an RRC-1::GFP fusion protein, we found that RRC-1 was localized to the coelomocytes, excretory cell, GLR cells, and uterine-seam cell in adult worms. These data contribute toward understanding the roles of Rho family GTPases in C. elegans

  2. Staff rules and regulations

    CERN Multimedia

    HR Department

    2007-01-01

    The 11th edition of the Staff Rules and Regulations, dated 1 January 2007, adopted by the Council and the Finance Committee in December 2006, is currently being distributed to departmental secretariats. The Staff Rules and Regulations, together with a summary of the main modifications made, will be available, as from next week, on the Human Resources Department's intranet site: http://cern.ch/hr-web/internal/admin_services/rules/default.asp The main changes made to the Staff Rules and Regulations stem from the five-yearly review of employment conditions of members of the personnel. The changes notably relate to: the categories of members of the personnel (e.g. removal of the local staff category); the careers structure and the merit recognition system; the non-residence, installation and re-installation allowances; the definition of family, family allowances and family-related leave; recognition of partnerships; education fees. The administrative circulars, some of which are being revised following the ...

  3. Deciphering Transcriptional Regulation

    DEFF Research Database (Denmark)

    Valen, Eivind

    The myriad of cells in the human body are all made from the same blueprint: the human genome. At the heart of this diversity lies the concept of gene regulation, the process in which it is decided which genes are used where and when. Genes do not function as on/off buttons, but more like a volume...... mostly near the start of the gene known as the promoter. This region contains patterns scattered in the DNA that the TFs can recognize and bind to. Such binding can prompt the assembly of the pre-initiation complex which ultimately leads to transcription of the gene. In order to achieve the regulation...... on what characterizes a hippocampus promoter. Pairing CAGE with TF binding site prediction we identi¿ed a likely key regulator of hippocampus. Finally, we developed a method for CAGE exploration. While the DeepCAGE library characterized a full 1.4 million transcription initiation events it did not capture...

  4. Radiation emitting devices regulations

    International Nuclear Information System (INIS)

    1970-01-01

    The Radiation Emitting Devices Regulations are the regulations referred to in the Radiation Emitting Devices Act and relate to the operation of devices. They include standards of design and construction, standards of functioning, warning symbol specifications in addition to information relating to the seizure and detention of machines failing to comply with the regulations. The radiation emitting devices consist of the following: television receivers, extra-oral dental x-ray equipment, microwave ovens, baggage inspection x-ray devices, demonstration--type gas discharge devices, photofluorographic x-ray equipment, laser scanners, demonstration lasers, low energy electron microscopes, high intensity mercury vapour discharge lamps, sunlamps, diagnostic x-ray equipment, ultrasound therapy devices, x-ray diffraction equipment, cabinet x-ray equipment and therapeutic x-ray equipment

  5. Natural Gas Regulation

    International Nuclear Information System (INIS)

    1995-01-01

    The regulation of Natural Gas. Natural gas Regulation clarifies and consolidates the legal and institutional framework for development of the industry through six principal elements: 1) Establishment of a vision of the industry. 2) Development of regulatory objectives. 3) Determination of relationships among industry participants. 4) Clear specification of the role of PEMEX in the industry. 5) Definition of the functions of the Regulatory authority. 6) Creation of a transition regime. In parallel with the development of the substantive legal framework, the law of the Comision Reguladora de Energia (CRE) was also enacted by Congress in October 1995 to strength the institutional framework and implement the legal changes. This law defines the CRE as an agency of the Energy Ministry with technical, operational, and budgetary autonomy, and responsibility for implementing natural gas industry regulation. (Author)

  6. Volume Regulated Channels

    DEFF Research Database (Denmark)

    Klausen, Thomas Kjær

    of volume perturbations evolution have developed system of channels and transporters to tightly control volume homeostasis. In the past decades evidence has been mounting, that the importance of these volume regulated channels and transporters are not restricted to the defense of cellular volume...... but are also essential for a number of physiological processes such as proliferation, controlled cell death, migration and endocrinology. The thesis have been focusing on two Channels, namely the swelling activated Cl- channel (ICl, swell) and the transient receptor potential Vanilloid (TRPV4) channel. I: Cl......- serves a multitude of functions in the mammalian cell, regulating the membrane potential (Em), cell volume, protein activity and the driving force for facilitated transporters giving Cl- and Cl- channels a major potential of regulating cellular function. These functions include control of the cell cycle...

  7. QUANTITATIVE ANALYSIS OF FLUX REGULATION THROUGH HIERARCHICAL REGULATION ANALYSIS

    NARCIS (Netherlands)

    van Eunen, Karen; Rossell, Sergio; Bouwman, Jildau; Westerhoff, Hans V.; Bakker, Barbara M.; Jameson, D; Verma, M; Westerhoff, HV

    2011-01-01

    Regulation analysis is a methodology that quantifies to what extent a change in the flux through a metabolic pathway is regulated by either gene expression or metabolism. Two extensions to regulation analysis were developed over the past years: (i) the regulation of V(max) can be dissected into the

  8. Quantitative analysis of flux regulation through hierarchical regulation analysis

    NARCIS (Netherlands)

    Eunen, K. van; Rossell, S.; Bouwman, J.; Westerhoff, H.V.; Bakker, B.M.

    2011-01-01

    Regulation analysis is a methodology that quantifies to what extent a change in the flux through a metabolic pathway is regulated by either gene expression or metabolism. Two extensions to regulation analysis were developed over the past years: (i) the regulation of Vmax can be dissected into the

  9. The Impact of Regulating Social Science Research with Biomedical Regulations

    Science.gov (United States)

    Durosinmi, Brenda Braxton

    2011-01-01

    The Impact of Regulating Social Science Research with Biomedical Regulations Since 1974 Federal regulations have governed the use of human subjects in biomedical and social science research. The regulations are known as the Federal Policy for the Protection of Human Subjects, and often referred to as the "Common Rule" because 18 Federal…

  10. Public regulators and CSR

    DEFF Research Database (Denmark)

    Buhmann, Karin

    2016-01-01

    The social licence to operate (SLO) concept is little developed in the academic literature so far. Deployment of the term was made by the United National (UN) Guiding Principles on Business and Human Rights and the UN ‘Protect, Respect and Remedy’ Framework, which apply SLO as an argument...... for responsible business conduct, connecting to social expectations and bridging to public regulation. This UN guidance has had a significant bearing on how public regulators seek to influence business conduct beyond Human Rights to broader Corporate Social Responsibility (CSR) concerns. Drawing on examples...

  11. Collaborative Tax Regulation

    DEFF Research Database (Denmark)

    Boll, Karen

    2016-01-01

    This article shows a new form of regulation within a tax administration where tax administrators abate tax evasion by nudging and motivating consumers to only purchase services from tax compliant businesses. This indirectly closes or forces tax evading businesses to change their practices, because...... stakeholders, i.e. the consumers, in the regulatory craft. The study is based on a qualitative methodology and draws on a unique case of regulation in the cleaning sector. This sector is at high risk of tax evasion and human exploitation of vulnerable workers operating in the informal economy. The article has...

  12. Public regulators and CSR

    DEFF Research Database (Denmark)

    Buhmann, Karin

    2016-01-01

    of such public regulatory governance, this article explores and explains developments towards a juridification of CSR entailing efforts by public regulators to reach beyond jurisdictional and territorial limitations of conventional public law to address adverse effects of transnational economic activity. Through...... analysis of an expansion of law into the normative framing of what constitutes responsible business conduct, we demonstrate a process of juridification entailing a legal framing of social expectations of companies, a proliferation of law into the field of business ethics, and an increased regulation by law...

  13. Nuclear regulations and environment

    International Nuclear Information System (INIS)

    Oliveira, Antonio A.

    2001-01-01

    After an historical overview of the nuclear regulation system in Argentina a description is made of the country's Nuclear Regulatory Authority (ARN) and of its regulation and control functions. Its organic structure is also outlined. A detailed report is given of the environmental monitoring activities in the sites of the operating Argentine nuclear power plants as well as those of the nuclear research centres. A special reference is made of the monitoring of the relevant uranium mining districts in Argentina. The radon determination in houses of several regions of the country is also mentioned

  14. Nuclear regulation and safety

    International Nuclear Information System (INIS)

    Hendrie, J.M.

    1982-01-01

    Nuclear regulation and safety are discussed from the standpoint of a hypothetical country that is in the process of introducing a nuclear power industry and setting up a regulatory system. The national policy is assumed to be in favor of nuclear power. The regulators will have responsibility for economic, reliable electric production as well as for safety. Reactor safety is divided into three parts: shut it down, keep it covered, take out the afterheat. Emergency plans also have to be provided. Ways of keeping the core covered with water are discussed

  15. Regulated underground storage tanks

    International Nuclear Information System (INIS)

    1992-06-01

    This guidance package is designed to assist DOE Field operations by providing thorough guidance on the underground storage tank (UST) regulations. [40 CFR 280]. The guidance uses tables, flowcharts, and checklists to provide a ''roadmap'' for DOE staff who are responsible for supervising UST operations. This package is tailored to address the issues facing DOE facilities. DOE staff should use this guidance as: An overview of the regulations for UST installation and operation; a comprehensive step-by-step guidance for the process of owning and operating an UST, from installation to closure; and a quick, ready-reference guide for any specific topic concerning UST ownership or operation

  16. Ketamine and international regulations.

    Science.gov (United States)

    Liao, Yanhui; Tang, Yi-Lang; Hao, Wei

    2017-09-01

    Ketamine is an anesthetic commonly used in low-income countries and has recently been shown to be effective for treatment-resistant depression. However, the illicit manufacturing, trafficking, and nonmedical use of ketamine are increasing globally, and its illicit use poses major public health challenges in many countries. To review the nonmedical use of ketamine in selected countries and its regulatory control. We conducted a review of literature identified from searches of the China National Knowledge Infrastructure (CNKI) (1979-2016) and PubMed databases, supplemented by additional references identified by the authors. Special attention was given to the regulation of ketamine. Illicit manufacturing, trafficking, and use of ketamine appear to have begun on a large scale in several Asian nations, and it has subsequently spread to other regions. Regulations governing availability of ketamine vary across countries, but there is a clear trend toward tighter regulations. As nonmedical use of ketamine and its harmful consequences have worsened globally, stricter controls are necessary. Appropriate regulation of ketamine is important for international efforts to control ketamine's cross-border trafficking and its nonmedical use.

  17. Federal Gasoline Regulations

    Science.gov (United States)

    The Clean Air Act requires EPA to regulate fuels and fuel additives for use in mobile sources if such fuel, fuel additive or any emission products causes or contributes to air or water pollution that may endanger the public health or welfare.

  18. Emotion regulation during isolation

    Czech Academy of Sciences Publication Activity Database

    Poláčková Šolcová, Iva; Šolcová, Iva

    2012-01-01

    Roč. 47, Suppl. 1 (2012) ISSN 0020-7594. [International Congress of Psychology /30./. 22.07.2012-27.07.2012, Cape Town] R&D Projects: GA ČR(CZ) GAP407/11/2226 Institutional support: RVO:68081740 Keywords : emotion regulation * isolation * Mars500 Subject RIV: AN - Psychology

  19. Legislation and regulation

    International Nuclear Information System (INIS)

    2001-01-01

    This document presents the fulfilling of the Brazilian obligations under the Convention on Nuclear Safety. The Chapter 3 of the document contains some details about the Brazilian legislation and regulation, the legislative and regulatory framework, regulatory body and responsibility of the license holder

  20. Legislation and regulation

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2001-09-01

    This document presents the fulfilling of the Brazilian obligations under the Convention on Nuclear Safety. The Chapter 3 of the document contains some details about the Brazilian legislation and regulation, the legislative and regulatory framework, regulatory body and responsibility of the license holder.

  1. Regulations in radiation protection

    International Nuclear Information System (INIS)

    1986-01-01

    On the occasion of the twenty fifth anniversary of the Dutch Society for Radiation Protection, a symposium was held about Regulations in Radiation Protection. The program consisted of six contributions of which four are included in this publication. The posters presented are published in NVS-nieuws, 1985, vol. 11(5). (G.J.P.)

  2. Nuclear safety regulations

    International Nuclear Information System (INIS)

    1998-01-01

    The Departmental Rules and The Safety Guides were issued by the NNSA in 1998. The NNSA performed the activities of propagation and implementation of nuclear safety regulations at QTNPP in order to improve the nuclear safety culture of operating organization and construct and contract organizations

  3. Regulation under Uncertainty

    DEFF Research Database (Denmark)

    Sabel, Charles; Herrigel, Gary; Hull Kristensen, Peer

    2017-01-01

    generation of the implicated components or installations are updated accordingly. In this essay we develop these arguments and look closely at changes in the Norwegian offshore oil and gas industry and its regulator, the Petroleum Safety Authority to better understand the coevolution of vertically...

  4. Nondissipative optimum charge regulator

    Science.gov (United States)

    Rosen, R.; Vitebsky, J. N.

    1970-01-01

    Optimum charge regulator provides constant level charge/discharge control of storage batteries. Basic power transfer and control is performed by solar panel coupled to battery through power switching circuit. Optimum controller senses battery current and modifies duty cycle of switching circuit to maximize current available to battery.

  5. Vehicle recycling regulations

    DEFF Research Database (Denmark)

    Smink, Carla

    2007-01-01

    The number of end-of-life vehicles (ELVs) in the EU is increasing continously. Around 75 percent of an ELV are recyclable metals. The forecast growth in the number of ELVs calls for regulation that aims to minimise the environmental impact of a car. Using Denmark as an example, this article...

  6. Regulating nuclear fuel waste

    International Nuclear Information System (INIS)

    1995-01-01

    When Parliament passed the Atomic Energy Control Act in 1946, it erected the framework for nuclear safety in Canada. Under the Act, the government created the Atomic Energy Control Board and gave it the authority to make and enforce regulations governing every aspect of nuclear power production and use in this country. The Act gives the Control Board the flexibility to amend its regulations to adapt to changes in technology, health and safety standards, co-operative agreements with provincial agencies and policy regarding trade in nuclear materials. This flexibility has allowed the Control Board to successfully regulate the nuclear industry for more than 40 years. Its mission statement 'to ensure that the use of nuclear energy in Canada does not pose undue risk to health, safety, security and the environment' concisely states the Control Board's primary objective. The Atomic Energy Control Board regulates all aspects of nuclear energy in Canada to ensure there is no undue risk to health, safety, security or the environment. It does this through a multi-stage licensing process

  7. Metabolic regulation of yeast

    Science.gov (United States)

    Fiechter, A.

    1982-12-01

    Metabolic regulation which is based on endogeneous and exogeneous process variables which may act constantly or time dependently on the living cell is discussed. The observed phenomena of the regulation are the result of physical, chemical, and biological parameters. These parameters are identified. Ethanol is accumulated as an intermediate product and the synthesis of biomass is reduced. This regulatory effect of glucose is used for the aerobic production of ethanol. Very high production rates are thereby obtained. Understanding of the regulation mechanism of the glucose effect has improved. In addition to catabolite repression, several other mechanisms of enzyme regulation have been described, that are mostly governed by exogeneous factors. Glucose also affects the control of respiration in a third class of yeasts which are unable to make use of ethanol as a substrate for growth. This is due to the lack of any anaplerotic activity. As a consequence, diauxic growth behavior is reduced to a one-stage growth with a drastically reduced cell yield. The pulse chemostat technique, a systematic approach for medium design is developed and medium supplements that are essential for metabolic control are identified.

  8. Voltage regulating circuit

    NARCIS (Netherlands)

    2005-01-01

    A voltage regulating circuit comprising a rectifier (2) for receiving an AC voltage (Vmains) and for generating a rectified AC voltage (vrec), and a capacitor (3) connected in parallel with said rectified AC voltage for providing a DC voltage (VDC) over a load (5), characterized by a unidirectional

  9. Maintenance and regulations

    International Nuclear Information System (INIS)

    Noel, R.

    1984-01-01

    Description of the main regulations concerning the processes tied with maintenance and in service supervision of the pressure vessels in classical or nuclear power plants or of their accessories (essentially in order to fix the time-table of the hydraulic test procedures and the inspection chronology [fr

  10. Allosteric Regulation of Proteins

    Indian Academy of Sciences (India)

    ... Lecture Workshops · Refresher Courses · Symposia · Live Streaming. Home; Journals; Resonance – Journal of Science Education; Volume 22; Issue 1. Allosteric Regulation of Proteins: A Historical Perspective on the Development of Concepts and Techniques. General Article Volume 22 Issue 1 January 2017 pp 37-50 ...

  11. Optimal Regulation of Lumpy Investments

    NARCIS (Netherlands)

    Zwart, G.; Broer, D.P.

    2012-01-01

    When a monopolist has discretion over the timing of infrastructure investments, regulation of post-investment prices interferes with incentivizing socially optimal investment timing. In a model of regulated lumpy investment under uncertainty, we study regulation when the regulator can condition

  12. Markets, religion, regulation

    DEFF Research Database (Denmark)

    Fischer, Johan

    2016-01-01

    Most recent scholarship on moral economies or religious markets argues for the compatibility of economies/markets and religious practices in particular national or regional contexts. However, over the last couple of decades or so religious markets have entered a new phase characterized by new forms...... of regulation, certification and standardization on a global scale. Building on research on global kosher (a Hebrew term meaning “fit” or “proper”), halal (an Arabic word that literally means “permissible” or “lawful”) and Hindu vegetarianism this paper argues that these economies or markets to a large extent...... are conditioned by and themselves condition forms of transnational governmentality, that is, new and often overlapping practices of government and grassroots politics. I explore religious economies and markets at three interrelated levels of the social scale: state and non-state regulation, the marketplace...

  13. Environmental considerations and regulations

    International Nuclear Information System (INIS)

    Blanco, R.E.

    1976-01-01

    Methods used to control the radiological impact of the nuclear fuel cycle are described. This control is exercised through the application of a series of federal laws and regulations that are used as the basis for licensing nuclear facilities. The control is exercised more directly by the use of radwaste treatment equipment at the nuclear facilities to limit the release of radioactive materials. Federal laws and regulations are summarized and their applications in licensing actions are discussed. Radiological doses from materials released from licensed facilities are compared with doses from natural background. A series of cost/benefit engineering surveys are being made to determine the cost and effectiveness of radwaste systems for decreasing the release of radioactive materials from model fuel cycle facilities and to determine the benefits in terms of reduction in dose commitment to individuals and populations in surrounding areas

  14. Transients: The regulator's view

    International Nuclear Information System (INIS)

    Sheron, B.W.; Speis, T.P.

    1984-01-01

    This chapter attempts to clarify the basis for the regulator's concerns for transient events. Transients are defined as both anticipated operational occurrences and postulated accidents. Recent operational experience, supplemented by improved probabilistic risk analysis methods, has demonstrated that non-LOCA transient events can be significant contributors to overall risk. Topics considered include lessons learned from events and issues, the regulations governing plant transients, multiple failures, different failure frequencies, operator errors, and public pressure. It is concluded that the formation of Owners Groups and Regulatory Response Groups within the owners groups are positive signs of the industry's concern for safety and responsible dealing with the issues affecting both the US NRC and the industry

  15. The regulator's perspective

    International Nuclear Information System (INIS)

    Norrby, S.

    1997-01-01

    Recommendations on general safety objectives and good practices related to radioactive waste management are given by international organisations such as the OECD/NEA and the IAEA. Moreover, international conventions and other supranational legal instruments, such as EU directives, lay down requirements on the safe management of radioactive waste. The implementer of the system for waste management and disposal and the regulator will have different roles. The responsibility for the management and disposal of radioactive waste is with the implementer, who has taken over that responsibility from the generator of the waste. The regulator's responsibility is to define safety and radiation protection requirements, to issue guidance on safety assessment methodology and documentation, to review the implementer's safety assessments as a basis for licensing of waste management and disposal activities and facilities and to inspect and review construction and operation of nuclear facilities to ensure compliance with licensing conditions. (R.P.)

  16. Probiotics and Appetite Regulation

    DEFF Research Database (Denmark)

    Bjerg, Anne Toksvig

    resistance and blood lipid profile among others. Probiotics which are health promoting bacteria can potentially be used to affect the GM and thereby change metabolic outcomes of the host. Animal studies have shown associations between intake of probiotics and appetite regulation, but currently no human...... studies have investigated this effect. Supplementation with different probiotic strains have been shown to have an effect on blood lipid profiles in both animals and humans and the mechanisms behind have been studied in vitro and in rodents. The aim of the present thesis was to examine in an ex vivo...... intestine, in an animal study and in two human studies the effect of the probiotic bacteria Lactobacillus paracasei subsp. paracasei L. casei W8 (W8) on appetite regulation, blood lipids and blood fatty acids. In addition, it was investigated if W8 had an effect on the fecal microbiota of the human...

  17. Regulation of Meiotic Recombination

    Energy Technology Data Exchange (ETDEWEB)

    Gregory p. Copenhaver

    2011-11-09

    Meiotic recombination results in the heritable rearrangement of DNA, primarily through reciprocal exchange between homologous chromosome or gene conversion. In plants these events are critical for ensuring proper chromosome segregation, facilitating DNA repair and providing a basis for genetic diversity. Understanding this fundamental biological mechanism will directly facilitate trait mapping, conventional plant breeding, and development of genetic engineering techniques that will help support the responsible production and conversion of renewable resources for fuels, chemicals, and the conservation of energy (1-3). Substantial progress has been made in understanding the basal recombination machinery, much of which is conserved in organisms as diverse as yeast, plants and mammals (4, 5). Significantly less is known about the factors that regulate how often and where that basal machinery acts on higher eukaryotic chromosomes. One important mechanism for regulating the frequency and distribution of meiotic recombination is crossover interference - or the ability of one recombination event to influence nearby events. The MUS81 gene is thought to play an important role in regulating the influence of interference on crossing over. The immediate goals of this project are to use reverse genetics to identify mutants in two putative MUS81 homologs in the model plant Arabidopsis thaliana, characterize those mutants and initiate a novel forward genetic screen for additional regulators of meiotic recombination. The long-term goal of the project is to understand how meiotic recombination is regulated in higher eukaryotes with an emphasis on the molecular basis of crossover interference. The ability to monitor recombination in all four meiotic products (tetrad analysis) has been a powerful tool in the arsenal of yeast geneticists. Previously, the qrt mutant of Arabidopsis, which causes the four pollen products of male meiosis to remain attached, was developed as a facile system

  18. German seismic regulations

    International Nuclear Information System (INIS)

    Danisch, Ruediger

    2002-01-01

    Rules and regulations for seismic design in Germany cover the following: seismic design of conventional buildings; and seismic design of nuclear facilities. Safety criteria for NPPs, accident guidelines, and guidelines for PWRs as well as safety standards are cited. Safety standards concerned with NPPs seismic design include basic principles, soil analysis, design of building structures, design of mechanical and electrical components, seismic instrumentation, and measures to be undertaken after the earthquake

  19. Regulation and the Marketplace

    OpenAIRE

    Shyam Sunder; Michael Maier; Karim Jamal

    2004-01-01

    Under what conditions is government regulation better at protecting market participants than private, evolving, market-driven protections? An intriguing answer to that question emerges if we examine a relatively unregulated area of market participant protection: e-commerce privacy. In the United States, the privacy of participants engaged in e-commerce is largely unregulated by government; instead, many commercial websites contract with third parties to establish privacy protection codes and ...

  20. The regulation of hunting

    DEFF Research Database (Denmark)

    Abildtrup, Jens; Jensen, Frank

    2014-01-01

    This paper examines a tax/subsidy on hunters based on game population. The tax/subsidy is the difference between actual and optimal population multiplied by an individual, variable tax rate. The tax rate is, among other things, based on the difference between the marginal value of the game popula...... population to the hunter and the regulator and differences in user costs of the population. The paper shows that the population tax/subsidy secures a first-best optimum....

  1. Human telomerase activity regulation

    OpenAIRE

    Wojtyla, Aneta; Gladych, Marta; Rubis, Blazej

    2010-01-01

    Telomerase has been recognized as a relevant factor distinguishing cancer cells from normal cells. Thus, it has become a very promising target for anticancer therapy. The cell proliferative potential can be limited by replication end problem, due to telomeres shortening, which is overcome in cancer cells by telomerase activity or by alternative telomeres lengthening (ALT) mechanism. However, this multisubunit enzymatic complex can be regulated at various levels, including expression control b...

  2. Improving CS regulations.

    Energy Technology Data Exchange (ETDEWEB)

    Nesse, R.J.; Scheer, R.M.; Marasco, A.L.; Furey, R.

    1980-10-01

    President Carter issued Executive Order 12044 (3/28/78) that required all Federal agencies to distinguish between significant and insignificant regulations, and to determine whether a regulation will result in major impacts. This study gathered information on the impact of the order and the guidelines on the Office of Conservation and Solar Energy (CS) regulatory practices, investigated problems encountered by the CS staff when implementing the order and guidelines, and recommended solutions to resolve these problems. Major tasks accomplished and discussed are: (1) legislation, Executive Orders, and DOE Memoranda concerning Federal administrative procedures relevant to the development and analysis of regulations within CS reviewed; (2) relevant DOE Orders and Memoranda analyzed and key DOE and CS staff interviewed in order to accurately describe the current CS regulatory process; (3) DOE staff from the Office of the General Counsel, the Office of Policy and Evaluation, the Office of the Environment, and the Office of the Secretary interviewed to explore issues and problems encountered with current CS regulatory practices; (4) the regulatory processes at five other Federal agencies reviewed in order to see how other agencies have approached the regulatory process, dealt with specific regulatory problems, and responded to the Executive Order; and (5) based on the results of the preceding four tasks, recommendations for potential solutions to the CS regulatory problems developed. (MCW)

  3. Staff rules and regulations

    CERN Multimedia

    HR Department

    2007-01-01

    The 11th edition of the Staff Rules and Regulations, dated 1 January 2007, adopted by the Council and the Finance Committee in December 2006, is currently being distributed to departmental secretariats. The Staff Rules and Regulations, together with a summary of the main modifications made, will be available, as from next week, on the Human Resources Department's intranet site: http://cern.ch/hr-web/internal/admin_services/rules/default.asp The main changes made to the Staff Rules and Regulations stem from the five-yearly review of employment conditions of members of the personnel. The changes notably relate to: the categories of members of the personnel (e.g. removal of the local staff category); the careers structure and the merit recognition system; the non-residence, installation and re-installation allowances; the definition of family, family allowances and family-related leave; recognition of partnerships; education fees. The administrative circulars, some of which are being revised following the m...

  4. Whither tobacco product regulation?

    Science.gov (United States)

    McNeill, Ann; Hammond, David; Gartner, Coral

    2012-03-01

    Despite decades of industry innovation and regulatory efforts, the harmfulness of conventional cigarettes has not changed. There are several pitfalls in this area, including the long time lag before health impacts of product regulatory changes become apparent, the danger of consumers deriving false reassurance of lesser harm in the interim period, the lack of relevant expertise and the lack of an internationally agreed and evidence-based strategic approach. Articles 9 and 10 of the Framework Convention on Tobacco Control provide the potential for such a global strategy, and knowledge and research has increased significantly over recent years. However, there are huge opportunity costs in implementing product disclosure and regulatory strategies: most national regulators have very limited human and financial resources, which should be focused on other evidence-based tobacco control interventions. We believe therefore that it is now time to abandon the notion of safe or safer cigarettes while moving consumers towards cleaner nicotine products as soon as possible. In parallel to this, we recommend a number of other strategies be implemented including: reducing the appeal of all tobacco products, forbidding new tobacco products or brand variants being marketed without evidence of reduced harm, appeal or addictiveness, and developing a tobacco industry resourced, but industry independent, Framework Convention on Tobacco Control global repository to assist national regulators in understanding and regulating the products on their markets.

  5. Nuclear Safety Regulations

    International Nuclear Information System (INIS)

    Novosel, N.; Prah, M.

    2008-01-01

    Beside new Ordinance on the control of nuclear material and special equipment ('Official Gazette' No. 15/08), from 2006 State Office for Nuclear Safety (SONS) adopted Ordinance on performing nuclear activities ('Official Gazette' No. 74/06) and Ordinance on special requirements which expert organizations must fulfil in order to perform certain activities in the field of nuclear safety ('Official Gazette' No. 74/06), based on Nuclear Safety Act ('Official Gazette' No. 173/03). The Ordinance on performing nuclear activities regulates the procedure of notification of the intent to perform nuclear activities, submitting the application for the issue of a licence to perform nuclear activities, and the procedure for issuing decisions on granting a licence to perform a nuclear activity. The Ordinance also regulates the content of the forms for notification of the intent to perform nuclear activities, as well as of the application for the issue of a licence to perform the nuclear activity and the method of keeping the register of nuclear activities. According to the Nuclear Safety Act, nuclear activities are the production, processing, use, storage, disposal, transport, import, export, possession or other handling of nuclear material or specified equipment. The Ordinance on special requirements which expert organizations must fulfil in order to perform certain activities in the field of nuclear safety regulates these mentioned conditions, whereas compliance is established by a decision passed by the SONS. Special requirements which expert organizations must fulfil in order to perform certain activities in the field of nuclear safety are organizational, technical, technological conditions and established system of quality assurance. In 2007, State Office for Nuclear Safety finalized the text of new Ordinance on conditions for nuclear safety and protection with regard to the siting, design, construction, use and decommissioning of a facility in which a nuclear activity is

  6. New Nuclear Safety Regulations

    International Nuclear Information System (INIS)

    Novosel, N.; Prah, M.; Cizmek, A.

    2008-01-01

    Beside new Ordinance on the control of nuclear material and special equipment (Official Gazette No. 15/08), from 2006 State Office for Nuclear Safety (SONS) adopted Ordinance on performing nuclear activities (Official Gazette No. 74/06) and Ordinance on special conditions for individual activities to be performed by expert organizations which perform activities in the area of nuclear safety (Official Gazette No. 74/06), based on Nuclear Safety Act (Official Gazette No. 173/03). The Ordinance on performing nuclear activities regulates the procedure of announcing the intention to perform nuclear activity, submitting an application for the issue of a license to perform nuclear activity, and the procedure for adoption a decision on issuing a nuclear activity license. The Ordinance also regulates the contents of the application form for the announcement of the intention to perform nuclear activity, as well as of the application for the issue of a nuclear activity license and the method of keeping a nuclear activity register. The Ordinance on special conditions for individual activities to be performed by expert organizations which perform activities in the area of nuclear safety regulates these mentioned conditions, whereas compliance is established by a decision passed by the SONS. Special conditions for individual activities to be performed by expert organizations which perform activities in the area of nuclear safety are organizational, technical, technological conditions and established system of quality assurance. In 2007, SONS finalized the text of new Ordinance on nuclear safety and protection conditions for location, design, construction, operation and decommissioning of facility in which nuclear activity is performed. This Ordinance regulates nuclear safety and protection conditions for location, design, construction, operation and decommissioning of facility in which nuclear activity is performed. This Ordinance defines facilities in which nuclear activity is

  7. The international radioactive transportation regulations: A model for national regulations

    International Nuclear Information System (INIS)

    Pope, R.B.; Rawl, R.R.

    1990-06-01

    The International Atomic Energy Agency's (IAEA) Regulations for the Safe Transport of Radioactive Material, Safety Series No. 6 (herein after denoted as the ''International Regulations'') serve as the model for the regulations for individual countries and international modal organizations controlling the packaging and transportation of radioactive materials. The purpose of this paper is to outline the background and history of the International Regulations, the general principles behind the requirements of the International Regulations, the structure and general contents of the latest edition of the International Regulations, and the roles of various international bodies in the development and implementation of the International Regulations and the current status of regulatory and supportive document development at both the international and domestic level. This review will provide a basis for users and potential users to better understand the source and application of the International Regulations. 1 tab

  8. RhoG protein regulates platelet granule secretion and thrombus formation in mice.

    Science.gov (United States)

    Goggs, Robert; Harper, Matthew T; Pope, Robert J; Savage, Joshua S; Williams, Christopher M; Mundell, Stuart J; Heesom, Kate J; Bass, Mark; Mellor, Harry; Poole, Alastair W

    2013-11-22

    Rho GTPases such as Rac, RhoA, and Cdc42 are vital for normal platelet function, but the role of RhoG in platelets has not been studied. In other cells, RhoG orchestrates processes integral to platelet function, including actin cytoskeletal rearrangement and membrane trafficking. We therefore hypothesized that RhoG would play a critical role in platelets. Here, we show that RhoG is expressed in human and mouse platelets and is activated by both collagen-related peptide (CRP) and thrombin stimulation. We used RhoG(-/-) mice to study the function of RhoG in platelets. Integrin activation and aggregation were reduced in RhoG(-/-) platelets stimulated by CRP, but responses to thrombin were normal. The central defect in RhoG(-/-) platelets was reduced secretion from α-granules, dense granules, and lysosomes following CRP stimulation. The integrin activation and aggregation defects could be rescued by ADP co-stimulation, indicating that they are a consequence of diminished dense granule secretion. Defective dense granule secretion in RhoG(-/-) platelets limited recruitment of additional platelets to growing thrombi in flowing blood in vitro and translated into reduced thrombus formation in vivo. Interestingly, tail bleeding times were normal in RhoG(-/-) mice, suggesting that the functions of RhoG in platelets are particularly relevant to thrombotic disorders.

  9. BAG3 regulates formation of the SNARE complex and insulin secretion

    Science.gov (United States)

    Iorio, V; Festa, M; Rosati, A; Hahne, M; Tiberti, C; Capunzo, M; De Laurenzi, V; Turco, M C

    2015-01-01

    Insulin release in response to glucose stimulation requires exocytosis of insulin-containing granules. Glucose stimulation of beta cells leads to focal adhesion kinase (FAK) phosphorylation, which acts on the Rho family proteins (Rho, Rac and Cdc42) that direct F-actin remodeling. This process requires docking and fusion of secretory vesicles to the release sites at the plasma membrane and is a complex mechanism that is mediated by SNAREs. This transiently disrupts the F-actin barrier and allows the redistribution of the insulin-containing granules to more peripheral regions of the β cell, hence facilitating insulin secretion. In this manuscript, we show for the first time that BAG3 plays an important role in this process. We show that BAG3 downregulation results in increased insulin secretion in response to glucose stimulation and in disruption of the F-actin network. Moreover, we show that BAG3 binds to SNAP-25 and syntaxin-1, two components of the t-SNARE complex preventing the interaction between SNAP-25 and syntaxin-1. Upon glucose stimulation BAG3 is phosphorylated by FAK and dissociates from SNAP-25 allowing the formation of the SNARE complex, destabilization of the F-actin network and insulin release. PMID:25766323

  10. Regulations for ionizing radiation protection

    International Nuclear Information System (INIS)

    1999-01-01

    General regulations and principles of radiation protection and safety are presented. In addition, the regulations for licensing and occupational and medical exposure as well as for safe transport of radioactive materials and wastes are given

  11. [Regulation of terpene metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, R.

    1992-01-01

    This report describes accomplishments over the past year on understanding of terpene synthesis in mint plants and sage. Specifically reported are the fractionation of 4-S-limonene synthetase, the enzyme responsible for the first committed step to monoterpene synthesis, along with isolation of the corresponding RNA and DNA cloning of its gene; the localization of the enzyme within the oil glands, regulation of transcription and translation of the synthetase, the pathway to camphor biosynthesis,a nd studies on the early stages and branch points of the isoprenoid pathway.

  12. Wiring regulations in brief

    CERN Document Server

    Tricker, Ray

    2012-01-01

    Tired of trawling through the Wiring Regs?Perplexed by Part P?Confused by cables, conductors and circuits?Then look no further! This handy guide provides an on-the-job reference source for Electricians, Designers, Service Engineers, Inspectors, Builders, Students, DIY enthusiastsTopic-based chapters link areas of working practice - such as cables, installations, testing and inspection, special locations - with the specifics of the Regulations themselves. This allows quick and easy identification of the official requirements relating to the situati

  13. Regulated functions and integrability

    Directory of Open Access Journals (Sweden)

    Ján Gunčaga

    2009-04-01

    Full Text Available Properties of functions defined on a bounded closed interval, weaker than continuity, have been considered by many mathematicians. Functions having both sides limits at each point are called regulated and were considered by J. Dieudonné [2], D. Fraňková [3] and others (see for example S. Banach [1], S. Saks [8]. The main class of functions we deal with consists of piece-wise constant ones. These functions play a fundamental role in the integration theory which had been developed by Igor Kluvanek (see Š. Tkacik [9]. We present an outline of this theory.

  14. Nanomaterials: Regulation and Risk Assessment

    DEFF Research Database (Denmark)

    Hansen, Steffen Foss; Grieger, Khara Deanne; Baun, Anders

    2013-01-01

    , the Water Framework Directive, pharmaceuticals regulation, and the Novel Foods Regulation. Current regulation of nanomaterials entail three overall challenges: 1) limitations in regard to terminology and definitions of key terms such as a “substance,” “novel food,” etc.; 2) safety assessment requirements...

  15. Nuclear regulation - the Canadian approach

    International Nuclear Information System (INIS)

    Jennekens, J.

    1981-09-01

    Although the Atomic Energy Control Board was established 35 years ago the basic philosophy of nuclear regulation in Canada and the underlying principles of the regulatory process remain essentially unchanged. This paper outlines the Canadian approach to nuclear regulation and explains in practical terms how the principles of regulation are applied. (author)

  16. The Regulation of Street Foods

    DEFF Research Database (Denmark)

    Forkour, John Boulard; Samuelsen, Helle; Yeboah, Eric Henry

    2017-01-01

    the challenges and negotiating strategies of regulators of street-vended foods in Ghana and analyses the implication for their relationship with street food vendors. The paper reveals that regulators operate in a context of limited resources, leading to a general feeling of neglect. In coping, regulators adopt...

  17. A novel micromechanical flow regulator

    NARCIS (Netherlands)

    van Toor, M.W.; van Toor, M.W.; Lammerink, Theodorus S.J.; Gardeniers, Johannes G.E.; Elwenspoek, Michael Curt; Monsma, D.J.

    1996-01-01

    A new concept for a micromechanical flow regulator is presented. Regulation of the flow is achieved using variation of channel length instead of channel diameter. Several design concepts together with their application in fluidic systems are presented. A regulator for biomedical use, as a part of a

  18. Regulations and Procedures Manual

    Energy Technology Data Exchange (ETDEWEB)

    Young, Lydia J. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2011-07-25

    The purpose of the Regulations and Procedures Manual (RPM) is to provide LBNL personnel with a reference to University and Lawrence Berkeley National Laboratory (LBNL or Laboratory) policies and regulations by outlining normal practices and answering most policy questions that arise in the day-to-day operations of Laboratory organizations. Much of the information in this manual has been condensed from detail provided in LBNL procedure manuals, Department of Energy (DOE) directives, and Contract DE-AC02-05CH11231. This manual is not intended, however, to replace any of those documents. RPM sections on personnel apply only to employees who are not represented by unions. Personnel policies pertaining to employees represented by unions may be found in their labor agreements. Questions concerning policy interpretation should be directed to the LBNL organization responsible for the particular policy. A link to the Managers Responsible for RPM Sections is available on the RPM home page. If it is not clear which organization is responsible for a policy, please contact Requirements Manager Lydia Young or the RPM Editor.

  19. Regulations and Procedures Manual

    Energy Technology Data Exchange (ETDEWEB)

    Young, Lydia [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2010-09-30

    The purpose of the Regulations and Procedures Manual (RPM) is to provide Laboratory personnel with a reference to University and Lawrence Berkeley National Laboratory policies and regulations by outlining the normal practices and answering most policy questions that arise in the day-to-day operations of Laboratory departments. Much of the information in this manual has been condensed from detail provided in Laboratory procedure manuals, Department of Energy (DOE) directives, and Contract DE-AC02-05CH11231. This manual is not intended, however, to replace any of those documents. The sections on personnel apply only to employees who are not represented by unions. Personnel policies pertaining to employees represented by unions may be found in their labor agreements. Questions concerning policy interpretation should be directed to the department responsible for the particular policy. A link to the Managers Responsible for RPM Sections is available on the RPM home page. If it is not clear which department should be called, please contact the Associate Laboratory Director of Operations.

  20. Strategisk compliance og regulering

    DEFF Research Database (Denmark)

    Kühn Pedersen, Mogens

    2016-01-01

    Denne artikel introducerer strategisk compliance og påpeger dens samspil med klassiske og nyere former for reguleringer i digital værdiskabelse. Konteksten er den digitale økonomi, som vokser frem imellem den materielle økonomis bærepiller: Virksomheder og markeder, men består af en helt ny...... materialitet, som er det digitale univers og dets modsvarighed i nye krav til compliance. Den nye materialitet stiller nye krav, hvad angår digitale processer og transaktioner. Klassisk regulering, som aktører ikke selv kan ændre, støder på egenregulering, hvor aktørerne selv opsætter regler for at skabe...... digital værdi. Dette kalder på strategisk compliance. Med digitalisering er strategisk compliance sat på dagsordnen i reguleringsdebatten. Vi hævder, at regulering og egenregulering kan komme til at virke komplementært i det post-industrielle, digitaliserede samfund....

  1. [Regulation of terpene metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, R.

    1991-01-01

    During the last grant period, we have completed studies on the key pathways of monoterpene biosynthesis and catabolism in sage and peppermint, and have, by several lines of evidence, deciphered the rate-limiting step of each pathway. We have at least partially purified and characterized the relevant enzymes of each pathway. We have made a strong case, based on analytical, in vivo, and in vitro studies, that terpene accumulation depends upon the balance between biosynthesis and catabolism, and provided supporting evidence that these processes are developmentally-regulated and very closely associated with senescence of the oil glands. Oil gland ontogeny has been characterized at the ultrastructural level. We have exploited foliar-applied bioregulators to delay gland senescence, and have developed tissue explant and cell culture systems to study several elusive aspects of catabolism. We have isolated pure gland cell clusters and localized monoterpene biosynthesis and catabolism within these structures, and have used these preparations as starting materials for the purification to homogeneity of target regulatory'' enzymes. We have thus developed the necessary background knowledge, based on a firm understanding of enzymology, as well as the necessary experimental tools for studying the regulation of monoterpene metabolism at the molecular level. Furthermore, we are now in a position to extend our systematic approach to other terpenoid classes (C[sub 15]-C[sub 30]) produced by oil glands.

  2. Circadian rhythms regulate amelogenesis.

    Science.gov (United States)

    Zheng, Li; Seon, Yoon Ji; Mourão, Marcio A; Schnell, Santiago; Kim, Doohak; Harada, Hidemitsu; Papagerakis, Silvana; Papagerakis, Petros

    2013-07-01

    Ameloblasts, the cells responsible for making enamel, modify their morphological features in response to specialized functions necessary for synchronized ameloblast differentiation and enamel formation. Secretory and maturation ameloblasts are characterized by the expression of stage-specific genes which follows strictly controlled repetitive patterns. Circadian rhythms are recognized as key regulators of the development and diseases of many tissues including bone. Our aim was to gain novel insights on the role of clock genes in enamel formation and to explore the potential links between circadian rhythms and amelogenesis. Our data shows definitive evidence that the main clock genes (Bmal1, Clock, Per1 and Per2) oscillate in ameloblasts at regular circadian (24 h) intervals both at RNA and protein levels. This study also reveals that the two markers of ameloblast differentiation i.e. amelogenin (Amelx; a marker of secretory stage ameloblasts) and kallikrein-related peptidase 4 (Klk4, a marker of maturation stage ameloblasts) are downstream targets of clock genes. Both, Amelx and Klk4 show 24h oscillatory expression patterns and their expression levels are up-regulated after Bmal1 over-expression in HAT-7 ameloblast cells. Taken together, these data suggest that both the secretory and the maturation stages of amelogenesis might be under circadian control. Changes in clock gene expression patterns might result in significant alterations of enamel apposition and mineralization. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Regulation of ATM induction

    International Nuclear Information System (INIS)

    Clarke, R.A.; Fang, Z.M.; Kearsley, J.H.; Lee, C.S.; Sarris, M.; De Murrell, D.

    2000-01-01

    Full text: ATM, the tumour suppressor protein mutated in ataxia-telangiectasia, is of pivotal importance in controlling the cells primary response to ionising radiation (IR) induced DNA damage. Mutations in ATM which reduce the level of the ATM protein and/or compromise ATM functions are known to give rise to radiosensitivity and defective cell cycle checkpoint control. In response to DNA damage ATM kinase is rapidly activated and initiates downstream signalling to cell cycle control molecules including p53. To investigate additional mechanisms of ATM control we have employed ATM antisense expression in cultured cells, western analyses and immunohistochemistry in situ. We report that ATM can be up-regulated up to 10-fold following exposure to low levels of ionising radiation. ATM radiation-induction was radiation dose dependent while the rapidity of the response indicates a post translational pathway. The concurrent time frames for the radiation-induction of ATM levels and the activation of ATM kinase activity appear to be complimentary in boosting ATM's protective response to IR induced DNA damage, especially in ATM 'low expressing' systems. We also provide the first report of ATM misregulation in 2 cancer patients, indicating that ATM is not only radio-protective but has possible implications in cancer, particularly breast cancer. These results have particular importance in defining the regulation of the ATM protein as an: adaptive radio-response; radio-prognostic market in tumours and normal tissue, and breast cancer marker

  4. Is self-regulation possible

    International Nuclear Information System (INIS)

    Barkenbus, J.N.

    1983-01-01

    The Nuclear Regulatory Commission's increasingly prescriptive regulation of the nuclear industry can have deleterious effects, perhaps the most serious being the shift in responsibility for safety from the utility to the NRC. Several factors account for this type of regulation including the nature and structure of the nuclear industry, public opinion and bureaucratic incentives, and the nature of the technology itself. The opportunities to create heightened industry self-regulation (performance-based regulation) deserve further examination. The key to self-regulation is to structure incentives so that it is clearly within the nuclear utilities' interests to build and operate nuclear power facilities in the safest manner possible. 27 references

  5. Regulation as delegation

    Directory of Open Access Journals (Sweden)

    Oren Bar-Gill

    2016-03-01

    Full Text Available Objective to consider the conception of reverse delegation when the government acts a principal and an individual ndash an agent from the point of view of behavioral PrincipalAgent Theory. Methods statistical method sociological polling. Results In diverse areas ndash from retirement savings to consumer credit to prescription drug use to fuel economy and energy efficiency rules to tobacco consumption to food and beverage consumption ndash government makes decisions for us or endeavors to help us make better decisions thus serving as our agent. From the point of view of PrincipalAgent Theory and behavioral PrincipalAgent Theory a great deal of modern regulation can be helpfully evaluated as a hypothetical delegation. Shifting from personal decisions to public goods problems the authors view the idea of reverse delegation with the government as principal and the individuals as agents. They show that the essence of delegation changes depending on the context. The article describes conditions under which various approaches will make sense. Scientific novelty the paper is devoted to the foreign experience of regulation through delegation by the example of a country with developed market economy the USA. It shows the prospects of such approach in solving both the public and the private tasks. Application of PrincipalAgent Theory and behavioral PrincipalAgent Theory is viewed to distinguish between such types of hypothetical delegation as information default rules incentives precommitments mandates and prohibitions. The article considers the benefits and costs of delegation and circumstances in which one or another approach makes sense. Practical significance PrincipalAgent Theory is widely used in economics and political science and can serve as a convenient tool to consider the optimal scale and essence of the assistance rendered to us by the government as our agent. The paper is of interest for the Russian legal science as the institution of

  6. Current environmental regulations

    International Nuclear Information System (INIS)

    Martz, M.K.

    1985-01-01

    An overview of the Federal environmental statutes and implementation regulations is provided, including the National Environmental Policy Act, the Clean Air Act, the Clean Water Act, the Safe Drinking Water Act, the Resource Conservation and Recovery Act, the Comprehensive Environmental Response, Compensation, and Liability Act, the Toxic Substances Control Act, the Federal Insecticide, Fungicide, and Rodenticide Act, and the Endangered Species Act. Recent developments which may have a direct impact on waste repository siting and management activities include: final promulgation of National Emission Standards for hazardous Air Pollutants for radionuclides, the DOE-EPA memorandum of understanding which brings mixed radioactive and chemical waste under the requirements of RCRA, and the proposed designation of additional sole source aquifers

  7. Meat and Appetite Regulation

    DEFF Research Database (Denmark)

    Kehlet, Ursula Nana

    effects of new formulations of pork products. Different strategies can be applied to potentially enhance the satiating properties of pork. Processed meat products such as meatballs can serve as a matrix for the addition of fiber ingredients. Based on their high protein and fiber contents, high......-fibre meatballs could provide a dual mechanistic action that would lead to greater satiety. For whole muscles, cooking is known to induce structural, physical and chemical changes of the meat proteins, which in turn may affect protein digestibility and potentially affect satiety. The overall aim of this Ph......D thesis was to investigate the effects of fiber addition to meatballs and the effects of cooking methods of pork on appetite regulation. The PhD thesis is based on three human meal test studies and one analytical study related to the characteristics of fiber meat products. In paper I, the objective...

  8. From research to regulations

    International Nuclear Information System (INIS)

    Flury-Herard, A.

    2000-01-01

    from the beginning of nuclear energy utilization, the necessity arose to take into account the knowledge progress in order to give the best scientific base possible to the regulation protecting workers and the public against the potentially injurious effects of ionizing radiations. These next years, the experts should make their benefit of numerous new results with the conjunction of ultra precise experimental irradiation techniques and to global approach of the genome. The United Nations scientific committee on effect of atomic radiation (U.N.S.C.E.A.R.) plays an essential part in the analysis and the synthesis of the most recent researches to evaluate more precisely, these effects, especially for low radiations doses. (N.C.)

  9. Higher regulators, algebraic

    CERN Document Server

    Bloch, Spencer J

    2000-01-01

    This book is the long-awaited publication of the famous Irvine lectures. Delivered in 1978 at the University of California at Irvine, these lectures turned out to be an entry point to several intimately-connected new branches of arithmetic algebraic geometry, such as regulators and special values of L-functions of algebraic varieties, explicit formulas for them in terms of polylogarithms, the theory of algebraic cycles, and eventually the general theory of mixed motives which unifies and underlies all of the above (and much more). In the 20 years since, the importance of Bloch's lectures has not diminished. A lucky group of people working in the above areas had the good fortune to possess a copy of old typewritten notes of these lectures. Now everyone can have their own copy of this classic work.

  10. NRC's license renewal regulations

    International Nuclear Information System (INIS)

    Akstulewicz, Francis

    1991-01-01

    In order to provide for the continuity of the current generation of nuclear power plant operating licenses and at the same time ensure the health and safety of the public, and the quality of the environment, the US Nuclear Regulatory Commission (NRC) established a goal of developing and issuing regulations and regulatory guidance for license renewal in the early 1990s. This paper will discuss some of those activities underway to achieve this goal. More specifically, this paper will discuss the Commission's regulatory philosophy for license renewal and the two major license renewal rule makings currently underway. The first is the development of a new Part 54 to address procedural and technical requirements for license renewal; the second is a revision to existing Part 51 to exclude environmental issues and impacts from consideration during the license renewal process. (author)

  11. NCAM regulates cell motility

    DEFF Research Database (Denmark)

    Prag, Søren; Lepekhin, Eugene A; Kolkova, Kateryna

    2002-01-01

    Cell migration is required during development of the nervous system. The regulatory mechanisms for this process, however, are poorly elucidated. We show here that expression of or exposure to the neural cell adhesion molecule (NCAM) strongly affected the motile behaviour of glioma cells...... independently of homophilic NCAM interactions. Expression of the transmembrane 140 kDa isoform of NCAM (NCAM-140) caused a significant reduction in cellular motility, probably through interference with factors regulating cellular attachment, as NCAM-140-expressing cells exhibited a decreased attachment...... to a fibronectin substratum compared with NCAM-negative cells. Ectopic expression of the cytoplasmic part of NCAM-140 also inhibited cell motility, presumably via the non-receptor tyrosine kinase p59(fyn) with which NCAM-140 interacts. Furthermore, we showed that the extracellular part of NCAM acted as a paracrine...

  12. [Regulation of terpene metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Croteau, R.

    1989-11-09

    Terpenoid oils, resins, and waxes from plants are important renewable resources. The objective of this project is to understand the regulation of terpenoid metabolism using the monoterpenes (C[sub 10]) as a model. The pathways of monoterpene biosynthesis and catabolism have been established, and the relevant enzymes characterized. Developmental studies relating enzyme levels to terpene accumulation within the oil gland sites of synthesis, and work with bioregulators, indicate that monoterpene production is controlled by terpene cyclases, the enzymes catalyzing the first step of the monoterpene pathway. As the leaf oil glands mature, cyclase levels decline and monoterpene biosynthesis ceases. Yield then decreases as the monoterpenes undergo catabolism by a process involving conversion to a glycoside and transport from the leaf glands to the root. At this site, the terpenoid is oxidatively degraded to acetate that is recycled into other lipid metabolites. During the transition from terpene biosynthesis to catabolism, the oil glands undergo dramatic ultrastructural modification. Degradation of the producing cells results in mixing of previously compartmentized monoterpenes with the catabolic enzymes, ultimately leading to yield decline. This regulatory model is being applied to the formation of other terpenoid classes (C[sub 15] C[sub 20], C[sub 30], C[sub 40]) within the oil glands. Preliminary investigations on the formation of sesquiterpenes (C[sub 15]) suggest that the corresponding cyclases may play a lesser role in determining yield of these products, but that compartmentation effects are important. From these studies, a comprehensive scheme for the regulation of terpene metabolism is being constructed. Results from this project wail have important consequences for the yield and composition of terpenoid natural products that can be made available for industrial exploitation.

  13. Branded prescription drug fee. Final regulations, temporary regulations, and removal of temporary regulations.

    Science.gov (United States)

    2014-07-28

    This document contains final regulations that provide guidance on the annual fee imposed on covered entities engaged in the business of manufacturing or importing branded prescription drugs. This fee was enacted by section 9008 of the Patient Protection and Affordable Care Act, as amended by section 1404 of the Health Care and Education Reconciliation Act of 2010. This document also withdraws the Branded Prescription Drug Fee temporary regulations and contains new temporary regulations regarding the definition of controlled group that apply beginning on January 1, 2015. The final regulations and the new temporary regulations affect persons engaged in the business of manufacturing or importing certain branded prescription drugs. The text of the temporary regulations in this document also serves as the text of proposed regulations set forth in a notice of proposed rulemaking (REG-123286-14) on this subject in the Proposed Rules section in this issue of the Federal Register.

  14. Regulation of the power sector

    CERN Document Server

    2013-01-01

    Regulation of the Power Sector is a unified, consistent and comprehensive treatment of the theories and practicalities of regulation in modern power-supply systems. The need for generation to occur at the time of use occasioned by the impracticality of large-scale electricity storage coupled with constant and often unpredictable changes in demand make electricity-supply systems large, dynamic and complex and their regulation a daunting task. Conceptually arranged in four parts, this book addresses both traditional regulatory frameworks and also liberalized and re-regulated environments. First, an introduction gives a full characterization of power supply including engineering, economic and regulatory viewpoints. The second part presents the fundamentals of regulation and the third looks at the regulation of particular components of the power sector in detail. Advanced topics and subjects still open or subject to dispute form the content of the fourth part. In a sector where regulatory design is the key driver...

  15. Age discrimination: the new Regulations

    OpenAIRE

    Sprack, John

    2006-01-01

    A summary of the principal changes introduced by the Employment Equality (Age) Regulations 2006 as they came into effect in England and Wales. Extracts from the Regulations follow the commentary. Article by John Sprack (Barrister, part-time Chairman of Employment Tribunals and author of Tottel's Guide to the Age Discrimination Regulations 2006) published in Amicus Curiae – Journal of the Society for Advanced Legal Studies at the Institute of Advanced Legal Studies. The Journal is produced by ...

  16. Regulations for RA reactor operation

    International Nuclear Information System (INIS)

    1980-09-01

    Regulations for RA reactor operation are written in accordance with the legal regulations defined by the Law about radiation protection and related legal acts, as well as technical standards according to the IAEA recommendations. The contents of this book include: fundamental data about the reactor; legal regulations for reactor operation; organizational scheme for reactor operation; general and detailed instructions for operation, behaviour in the reactor building, performing experiments; operating rules for operation under steady state and accidental conditions [sr

  17. Banking regulation and market making

    OpenAIRE

    Cimon, David A.; Garriott, Corey

    2017-01-01

    We present a model of market makers subject to recent banking regulations: liquidity and capital constraints in the style of Basel III and a position limit in the style of the Volcker Rule. Regulation causes market makers to reduce their intermediation by refusing principal positions. However, it can improve the bid-ask spread because it induces new market makers to enter. Since market makers intermediate less, asset prices exhibit a liquidity premium. Costs of regulation can be assessed by m...

  18. Financial Private Regulation and Enforcement

    OpenAIRE

    MILLER, Geoffrey

    2011-01-01

    This paper has been delivered within the context of the research project "Transnational Private Regulatory Regimes: Constitutional foundations and governance design". This paper considers the topic of private regulation and enforcement for internationally active financial services firms. The paper documents the following types of regulation and enforcement that involve significant private input: house rules, contracts, internal compliance, management-based regulation, private standard-sett...

  19. Thermal flow regulator of refrigerant

    International Nuclear Information System (INIS)

    Dubinskij, S.I.; Savchenko, A.G.; Suplin, V.Z.

    1988-01-01

    A thermal flow regulator of refrigerant for helium flow-type temperature-controlled cryostats based on controlling the channel hydraulic resistance due to variation of the flow density and viscosity during liquid helium transformation into the gaseous state. Behind the regulator both two-phase flow and a heated gas can be produced. The regulator resolution is (7-15)x10 -4 l/mW of liquid helium

  20. Electricity regulation and economic growth

    OpenAIRE

    Costa, M. Teresa (Maria Teresa), 1951-; Garcia-Quevedo, Jose; Trujillo-Baute, Elisa

    2018-01-01

    The main objective of this paper is to analyse the effect of electricity regulation on economic growth. Although the relationship between electricity consumption and economic growth has been extensively analysed in the empirical literature, this framework has not been used to estimate the effect of electricity regulation on economic growth. Understanding this effect is essential for the assessment of regulatory policy. Specifically, we assess the effects of two major areas of regulation, rene...

  1. Epigenetic regulation in obesity.

    Science.gov (United States)

    Drummond, Elaine M; Gibney, Eileen R

    2013-07-01

    Research suggests that 65% of variation in obesity is genetic. However, much of the known genetic associations have little known function and their effect size small, thus the gene-environment interaction, including epigenetic influences on gene expression, is suggested to be an important factor in the susceptibilty to obesity. This review will explore the potential of epigenetic markers to influence expression of genes associated with obesity. Epigenetic changes in utero are known to have direct implications on the phenotype of the offspring. More recently work has focused on how such epigenetic changes continue to regulate risk of obesity from infancy through to adulthood. Work has shown that, for example, hypomethylation of the MC4 gene causes an increase in expression, and has a direct impact on appetite and intake, and thus influences risk of obesity. Similar influences are also seen in other aspects of obesity including inflammation and adiposity. Maternal diet during foetal development has many epigenetic implications, which affect the offspring's risk factors for obesity during childhood and adulthood, and even in subsequent generations. Genes associated with risk of obesity, are susceptible to epigenetic mutations, which have subsequent effects on disease mechanisms, such as appetite and impaired glucose and insulin tolerance.

  2. Challenges in Regulating Ageing

    International Nuclear Information System (INIS)

    Tiippana, P.

    2016-01-01

    Finland has recent experience in regulating design, construction, commissioning and operation of nuclear facilities. Also decommissioning is topical as the research reactor will enter a decommissioning phase in the near future. From regulator’s point of view, the paper discusses potential challenges related to ageing management at the Finnish nuclear facilities throughout their lifetime. Based on the experience the most important decisions to ensure adequate provisions against adverse effects of various ageing phenomena and mechanisms are made much earlier than operation starts, namely during design, construction and manufacturing of systems, structures and components (SSC). Early consideration of ageing management resulting in good engineering including ageing-proof manufacturing and construction practices is of particular importance for new reactors. Elongated design lifetime of new reactors underlines the need of all available means to minimize progress of ageing beforehand and to create prerequisites for well-established condition monitoring and maintenance up to decommissioning. Furthermore, continuous research and development in order to understand various types of ageing and to detect degradation before SSC’s failure is expected as soon as a facility has been put in service. All these activities have to be supported by proper information and knowledge management in each phase of the facility’s life span. (author)

  3. [Ghrelin: beyond hunger regulation].

    Science.gov (United States)

    Milke García, Maria del Pilar

    2005-01-01

    Man ingests food to mitigate hunger (mediated by physiological and biochemical signals), satisfy appetite (subjective sensation) and because of psychosocial reasons. Satiation biomarkers (stop feeding) are gastric distention and hormones (CCK, GLP-1) and satiety biomarkers (induce feeding) are food-induced thermogenesis, body temperature, glycaemia and also hormones (insulin, leptin and ghrelin). Oxidative metabolism/body composition, tryptophan/serotonin and proinflammatory cytokines are also implicated on hunger physiology. At the present time, ghrelin is the only known circulating orexigenic with potential on hunger/body weight regulation. It is a neuropeptide (endogenous ligand for the GH secretagogue) recently isolated from the oxyntic mucosa and synthesized mainly in the stomach. Its blood concentration depends on diet, hyperglucemia and adiposity/leptin. It is secreted 1-2 hours preprandially and its concentration decreases drastically during the postprandium. Ghrelin acts on the lateral hypothalamus and theoretically inhibits proinflammatory cytokine secretion and antagonizes leptin. Ghrelin physiologically increases food intake and stimulates adipogenesis, gastrointestinal motility and gastric acid secretion, and has other hormonal and cardiovascular functions. Ghrelin blood concentration is reduced in massive obesity, non-alcoholic steatohepatitis, polycystic ovary syndrome, acromegaly, hypogonadism, ageing, short bowel syndrome and rheumatoid arthritis; and increased in primary or secondary anorexia, starvation, chronic liver disease and celiac disease. Cerebral and peritoneal ghrelin administration (rats) and systemic administration (rats and healthy volunteers, cancer patients or patients on peritoneal dialysis) promotes food consumption and increases adiposity, of utmost importance in the treatment of patients with anorexia.

  4. Regulating the sharing economy

    Directory of Open Access Journals (Sweden)

    Kristofer Erickson

    2016-06-01

    Full Text Available In this introductory essay, we explore definitions of the ‘sharing economy’, a concept indicating both social (relational, communitarian and economic (allocative, profit-seeking aspects which appear to be in tension. We suggest combining the social and economic logics of the sharing economy to focus on the central features of network enabled, aggregated membership in a pool of offers and demands (for goods, services, creative expressions. This definition of the sharing economy distinguishes it from other related peer-to-peer and collaborative forms of production. Understanding the social and economic motivations for and implications of participating in the sharing economy is important to its regulation. Each of the papers in this special issue contributes to knowledge by linking the social and economic aspects of sharing economy practices to regulatory norms and mechanisms. We conclude this essay by suggesting future research to further clarify and render intelligible the sharing economy, not as a contradiction in terms but as an empirically observable realm of socio-economic activity.

  5. Between regulation and independence

    International Nuclear Information System (INIS)

    Ladoucette, Ph. de

    2007-01-01

    This article stresses, first, on the differences between electricity and gas in terms of storability and place of production before introducing the gas sector and its reorganization and re-structuration in the framework of energy markets deregulation. Then, it presents the actions carried out by the commission of energy regulation (CRE) intended to improve the operation of the gas market: improvement of transparency, incitation to invest in transportation infrastructures, organisation of the downstream market and development of regional gas markets. Since July 1, 2007, the opening of gas market is juridically and technically complete. The role of CRE is also to inform the consumers and to warrant a non-discriminatory access to infrastructures in a context of sound competition. On this point, the new situation is satisfactory but improvements are needed to increase the offer. The future objectives of CRE is to maintain a climate favorable to investments, to implement stable and efficient conditions of access to infrastructures and, finally, to regularly work at the European scale for the building up of a domestic gas market synonymous of security of supplies, sustainable development and competitiveness. (J.S.)

  6. Power-MOSFET Voltage Regulator

    Science.gov (United States)

    Miller, W. N.; Gray, O. E.

    1982-01-01

    Ninety-six parallel MOSFET devices with two-stage feedback circuit form a high-current dc voltage regulator that also acts as fully-on solid-state switch when fuel-cell out-put falls below regulated voltage. Ripple voltage is less than 20 mV, transient recovery time is less than 50 ms. Parallel MOSFET's act as high-current dc regulator and switch. Regulator can be used wherever large direct currents must be controlled. Can be applied to inverters, industrial furnaces photovoltaic solar generators, dc motors, and electric autos.

  7. Personality and Emotion Regulation Strategies

    Directory of Open Access Journals (Sweden)

    Esti Hayu Purnamaningsih

    2017-01-01

    Full Text Available The emotions has many important functions in our life such as in relation of interpersonal communication, and health. In interpersonal communicative function aimed to signal to other information about internal state. Emotions manifests in specific cognitive, behavioural, and physiological reactions, thus closely related to health. There is wide variety of ways for individuals to regulate their emotion. In this regard, there are two kinds of emotion regulation strategy; first Antecedent-focused emotion regulation consisting of situation selection, situation modification, attentional deployment, cognitive change and second, Response-focused emotion regulation consisting of suppression. The purpose of this research is to investigate personality factors relate with emotion regulation strategies. 339 students from Faculty of Psychology, Universitas Gadjah Mada were participating in this study and given The Big Five Personality Factors (Ramdhani, 2012, adaptation, and the modified version of the Emotion Regulation Scale was used, Emotion Regulation Questionnaire (John & Gross, 2004 which measure personality and emotion regulation respectively. Using multiple regression analysis, the study indicated that personality predicts emotion regulation strategies.

  8. Utility regulation and competition policy

    International Nuclear Information System (INIS)

    Robinson, Colin

    2002-03-01

    Contents: 1. The New Electricity Trading Arrangements in England and Wales: A Review - David Currie, 2. A Critique of Rail Regulation - Dieter Helm, 3. Moving to a Competitive Market in Water - Colin Robinson, 4. The New Gas Trading Arrangements - George Yarrow, 5. A Review of Privatization and Regulation Experience in Britain - Irwin M. Stelzer, 6. Converging Communications: Implications for Regulation - Mark Armstrong, 7. Opening European Electricity and Gas Markets - Graham Shuttleworth, 8. Concurrency or Convergence? Competition and Regulation Under the Competition Act 1998 - Tom Sharpe QC, 9. Ten Years of European Merger Control - Paul Seabright. (Author)

  9. Drinking Water Contaminants -- Standards and Regulations

    Science.gov (United States)

    ... and Research Centers Contact Us Share Drinking Water Contaminants – Standards and Regulations EPA identifies contaminants to regulate ... other partners to implement these SDWA provisions. Regulated Contaminants National Primary Drinking Water Regulations (NPDWRs) - table of ...

  10. Choosing to regulate: does choice enhance craving regulation?

    Science.gov (United States)

    Mobasser, Arian; Zeithamova, Dagmar; Pfeifer, Jennifer H

    2018-01-01

    Abstract Goal-directed behavior and lifelong well-being often depend on the ability to control appetitive motivations, such as cravings. Cognitive reappraisal is an effective way to modulate emotional states, including cravings, but is often studied under explicit instruction to regulate. Despite the strong prediction from Self-Determination Theory that choice should enhance task engagement and regulation success, little is known empirically about whether and how regulation is different when participants choose (vs are told) to exert control. To investigate how choice affects neural activity and regulation success, participants reappraised their responses to images of personally-craved foods while undergoing functional neuroimaging. Participants were either instructed to view or reappraise (‘no-choice’) or chose freely to view or reappraise (‘yes-choice’). Choice increased activity in the frontoparietal control network. We expected this activity would be associated with increased task engagement, resulting in better regulation success. However, contrary to this prediction, choice slightly reduced regulation success. Follow-up multivariate functional neuroimaging analyses indicated that choice likely disrupted allocation of limited cognitive resources during reappraisal. While unexpected, these results highlight the importance of studying upstream processes such as regulation choice, as they may affect the ability to regulate cravings and other emotional states. PMID:29462475

  11. Post-translational regulation enables robust p53 regulation.

    Science.gov (United States)

    Shin, Yong-Jun; Chen, Kai-Yuan; Sayed, Ali H; Hencey, Brandon; Shen, Xiling

    2013-08-30

    The tumor suppressor protein p53 plays important roles in DNA damage repair, cell cycle arrest and apoptosis. Due to its critical functions, the level of p53 is tightly regulated by a negative feedback mechanism to increase its tolerance towards fluctuations and disturbances. Interestingly, the p53 level is controlled by post-translational regulation rather than transcriptional regulation in this feedback mechanism. We analyzed the dynamics of this feedback to understand whether post-translational regulation provides any advantages over transcriptional regulation in regard to disturbance rejection. When a disturbance happens, even though negative feedback reduces the steady-state error, it can cause a system to become less stable and transiently overshoots, which may erroneously trigger downstream reactions. Therefore, the system needs to balance the trade-off between steady-state and transient errors. Feedback control and adaptive estimation theories revealed that post-translational regulation achieves a better trade-off than transcriptional regulation, contributing to a more steady level of p53 under the influence of noise and disturbances. Furthermore, post-translational regulation enables cells to respond more promptly to stress conditions with consistent amplitude. However, for better disturbance rejection, the p53- Mdm2 negative feedback has to pay a price of higher stochastic noise. Our analyses suggest that the p53-Mdm2 feedback favors regulatory mechanisms that provide the optimal trade-offs for dynamic control.

  12. ORF Alignment: NC_003284 [GENIUS II[Archive

    Lifescience Database Archive (English)

    Full Text Available Kinase, colocalized with Rac1/CED-10 and CDC-42 at ... hypodermal cell boundaries during embryo elong...ation., ... colocalized with Rac1/CED-10 and CDC-42 at hypodermal ... cell boundaries during e

  13. Constructing regulation and regulating for energy efficient construction

    Energy Technology Data Exchange (ETDEWEB)

    Shove, Elizabeth [Lancaster University (United Kingdom). Centre for the Study of Environmental Change

    1998-07-01

    This project considers the process of formulating energy-related building regulation in the light of the revisions to Part L (Conservation of Fuel and Power) of the Building Regulations for England and Wales. Details are given of the main objectives of the research, namely, the examination of the roles of the UK government, local government and pressure groups in shaping energy efficiency standards, the impacts of environmental regulations, the limits of energy-related regulation, environmental regulation of the building sector, and the features of energy related building control. This control is compared with current practice in other European countries. The methodology of the project involving the review of governmental documents and interviews is described. (UK)

  14. Regulation of electricity prices?

    International Nuclear Information System (INIS)

    Mihok, P.

    2006-01-01

    In this paper author deals with the regulation of electricity prices in the Slovak Republic. Author contests the social policy of the government through doped prices of electricity. Two thirds of electricity is generated in nuclear power plants in Slovakia. Hence, it is necessary to focus on the solution of problem of nuclear waste. In 2004 Ministry of Economy stated, that the deficit in nuclear fund, from which the country have to fully cover the costs of liquidation and final disposal of nuclear waste, is estimated in the amount of around 89 billion Slovak crowns (≅ 3.7 billion $). From it, so called historical deficit, which originated because of late foundation of fund, represents officially 15 billion Slovak crowns (≅ 0.62 billion $). In Slovakia exists the real risk, that by maintenance of present state by creation and draw of the fund, it will be possible to ensure only 39 per cent of financial sources necessary for full financial handling of the back part of nuclear energetic. Even though the Ministry of Economy in connection with privatisation of Slovenske elektrarne designed to decrease the transfers of operators of nuclear power plants into nuclear fund. In 2006 the Parliament decreased by the law the level of gains of the fund from sale of nuclear electricity (the second from two components of the gains of the fund) from 6.8 to 5.95 per cent from annual revenues. So the tax of forced reduction of the price of nuclear electricity will be represented by loading of the further generations

  15. Deceptive Business Practices: Federal Regulations.

    Science.gov (United States)

    Rohrer, Daniel Morgan

    Federal regulations to prevent deceptive advertising seek to balance the advertiser's freedom of speech with protection of the consumer. This paper discusses what the Federal Trade Commission (FTC) has done to regulate advertising and evaluates the adequacy of its controls. The commission uses cease-and-desist orders, affirmative disclosure,…

  16. The evolution of nuclear regulation

    International Nuclear Information System (INIS)

    Martin, A.

    1997-01-01

    The already not so young history of nuclear regulations shows patterns and specific causes that have characterized and influenced its own evolution as well as the industry itself. Today's regulation is facing relevant challenges with potential significant effects. The quest for higher regulatory efficiency brings up the increasing need to base future actions on firmly established strategies. (Author) 7 refs

  17. Gravity and body mass regulation

    Science.gov (United States)

    Warren, L. E.; Horwitz, B. A.; Fuller, C. A.

    1997-01-01

    The effects of altered gravity on body mass, food intake, energy expenditure, and body composition are examined. Metabolic adjustments are reviewed in maintenance of energy balance, neural regulation, and humoral regulation are discussed. Experiments with rats indicate that genetically obese rats respond differently to hypergravity than lean rats.

  18. Forhastet regulering af de store

    DEFF Research Database (Denmark)

    Thomsen, Steen

    2013-01-01

    Christiansborg gennemfører sandsynligvis en markant skærpet regulering af de store finansielle virksomheder. Det vil virke kontraktivt og medvirke til erhvervslivets kredittørke.......Christiansborg gennemfører sandsynligvis en markant skærpet regulering af de store finansielle virksomheder. Det vil virke kontraktivt og medvirke til erhvervslivets kredittørke....

  19. The Organization of Regulated Production

    DEFF Research Database (Denmark)

    Jansen, Jos; Jeon, Doh-Shin; Menicucci, Domenico

    2008-01-01

    We analyze the choice between vertical separation (VS) and vertical integration (VI) when two regulated firms produce complementary inputs with correlated costs and are protected by ex post break-even constraints. First, in the absence of collusion the regulator prefers VI (VS) for negative...

  20. Environmental regulation and international trade

    NARCIS (Netherlands)

    Mulatu, A.; Florax, R.J.G.M.; Withagen, C.A.A.M.

    2004-01-01

    We empirically investigate the responsiveness of international trade to the stringency of environmental regulation. Stringent environmental regulation may impair the export competitiveness of ´dirty´ domestic industries, and as a result, ´pollution havens´ emerge in countries where environmental

  1. Regulating Pornography: A Public Dilemma.

    Science.gov (United States)

    Thompson, Margaret E.; And Others

    1990-01-01

    Examines attitudes toward sex and pornography by means of a telephone survey of Dane County, Wisconsin, adults. Describes survey questions about sexual attitudes, perceived effects of pornography, and pornography regulation. Concludes that adults who feel more strongly that pornography has negative effects are more opposed to its regulation. (SG)

  2. RNA-guided transcriptional regulation

    Science.gov (United States)

    Church, George M.; Mali, Prashant G.; Esvelt, Kevin M.

    2016-02-23

    Methods of modulating expression of a target nucleic acid in a cell are provided including introducing into the cell a first foreign nucleic acid encoding one or more RNAs complementary to DNA, wherein the DNA includes the target nucleic acid, introducing into the cell a second foreign nucleic acid encoding a nuclease-null Cas9 protein that binds to the DNA and is guided by the one or more RNAs, introducing into the cell a third foreign nucleic acid encoding a transcriptional regulator protein or domain, wherein the one or more RNAs, the nuclease-null Cas9 protein, and the transcriptional regulator protein or domain are expressed, wherein the one or more RNAs, the nuclease-null Cas9 protein and the transcriptional regulator protein or domain co-localize to the DNA and wherein the transcriptional regulator protein or domain regulates expression of the target nucleic acid.

  3. REGULATION OF NATIONAL QUALIFICATIONS SYSTEMS

    Directory of Open Access Journals (Sweden)

    Anna A. Muravyeva

    2014-01-01

    Full Text Available The paper looks into the diverse aspects of qualifications system regulation, designed for balancing the supply and demand in the labor and educational service markets. Both the objects and mechanisms of such regulation are described. Special attention is given to institutions, involved in regulation of qualifications, and their jurisdiction. Another emphasis is on the industry-related regulation of qualifications which proved to be effective both on the national and European level. Such structures were first established on the national levels to regulate the qualifications and ensure their comparability and compatibility, given the economic globalization and growing labor and academic mobility. The author points out the role of the ministries of education and labor in maintaining a steady qualifications system, and outlines the positive experience of Great Britain using the industry councils for continuing development of qualifications system.

  4. Regulation of gas infrastructure expansion

    International Nuclear Information System (INIS)

    De Joode, J.

    2012-01-01

    The topic of this dissertation is the regulation of gas infrastructure expansion in the European Union (EU). While the gas market has been liberalised, the gas infrastructure has largely remained in the regulated domain. However, not necessarily all gas infrastructure facilities - such as gas storage facilities, LNG import terminals and certain gas transmission pipelines - need to be regulated, as there may be scope for competition. In practice, the choice of regulation of gas infrastructure expansion varies among different types of gas infrastructure facilities and across EU Member States. Based on a review of economic literature and on a series of in-depth case studies, this study explains these differences in choices of regulation from differences in policy objectives, differences in local circumstances and differences in the intrinsic characteristics of the infrastructure projects. An important conclusion is that there is potential for a larger role for competition in gas infrastructure expansion.

  5. Designing Next Generation Telecom Regulation

    DEFF Research Database (Denmark)

    Henten, Anders; Samarajiva, Rohan

    – ICT convergence regulation and multisector utility regulation. Whatever structure of next generation telecom regulation is adopted, all countries will need to pay much greater attention to the need for increased coordination of policy directions and regulatory activities both across the industries......Continuously expanding applications of information and communication technologies (ICT) are transforming local, national, regional and international economies into network economies, the foundation for information societies. They are being built upon expanded and upgraded national telecom networks...... to creating an environment to foster a massive expansion in the coverage and capabilities of the information infrastructure networks, with national telecom regulators as the key implementers of the policies of reform. The first phase of reform has focused on industry specific telecom policy and regulation...

  6. Regulation of GMOs in China.

    Science.gov (United States)

    Liu, Yinliang

    2008-12-01

    Genetically modified organisms (GMOs) are created by biotechnology to serve people with much benefit while may impose risks to ecological environment and human health and therefore need careful regulation. During the past two decades, GMOs have been well developed in China and so has their corresponding regulation. This paper reviews and comments the multiple aspects of mainly the agricultural GMOs, including their safety assessment, control measures, trade activities, import, labels, and GM food, which have been prescribed by the corresponding laws, regulations and administrative measures. It is held that till present a framework for regulation of agricultural GMOs and GM food has been established basically in China, while a more comprehensive system for regulation of all kinds of GMOs and all kinds of related activities is still needed at present and in the future.

  7. PPARγ regulates exocrine pancreas lipase.

    Science.gov (United States)

    Danino, Hila; Naor, Ronny Peri-; Fogel, Chen; Ben-Harosh, Yael; Kadir, Rotem; Salem, Hagit; Birk, Ruth

    2016-12-01

    Pancreatic lipase (triacylglycerol lipase EC 3.1.1.3) is an essential enzyme in hydrolysis of dietary fat. Dietary fat, especially polyunsaturated fatty acids (PUFA), regulate pancreatic lipase (PNLIP); however, the molecular mechanism underlying this regulation is mostly unknown. As PUFA are known to regulate expression of proliferator-activated receptor gamma (PPARγ), and as we identified in-silico putative PPARγ binding sites within the putative PNLIP promoter sequence, we hypothesized that PUFA regulation of PNLIP might be mediated by PPARγ. We used in silico bioinformatics tools, reporter luciferase assay, PPARγ agonists and antagonists, PPARγ overexpression in exocrine pancreas AR42J and primary cells to study PPARγ regulation of PNLIP. Using in silico bioinformatics tools we mapped PPARγ binding sites (PPRE) to the putative promoter region of PNLIP. Reporter luciferase assay in AR42J rat exocrine pancreas acinar cells transfected with various constructs of the putative PNLIP promoter showed that PNLIP transcription is significantly enhanced by PPARγ dose-dependently, reaching maximal levels with multi PPRE sites. This effect was significantly augmented in the presence of PPARγ agonists and reduced by PPARγ antagonists or mutagenesis abrogating PPRE sites. Over-expression of PPARγ significantly elevated PNLIP transcript and protein levels in AR42J cells and in primary pancreas cells. Moreover, PNLIP expression was up-regulated by PPARγ agonists (pioglitazone and 15dPGJ2) and significantly down-regulated by PPARγ antagonists in non-transfected rat exocrine pancreas AR42J cell line cells. PPARγ transcriptionally regulates PNLIP gene expression. This transcript regulation resolves part of the missing link between dietary PUFA direct regulation of PNLIP. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. The regulator's view

    International Nuclear Information System (INIS)

    Sendin, P.

    2004-01-01

    Spanish experience holds a relatively important position in the field of the decommissioning of nuclear and radioactive facilities. Nuclear facilities are subject to a system of prior authorization by the competent authorities before they come into service and to subsequent regulation and control during their operating life. Nuclear and radioactive facilities that stop operating, for technical or financial reasons or because they are compelled to, remain subject to this regulatory control system as long as the competent authorities consider that their residual radioactivity represents a potential source of radiological hazard to the individuals affected or entails an unacceptable environmental risk. The decommissioning of nuclear facilities is contemplated in Spain a further or an additional step of their life cycle in which, in principle, the whole regulatory framework in force during the previous stages - sitting, construction, commissioning, operation, etc. - remains applicable. The term decommissioning is used to delineate the final stage of the life of a definitely non-operational facility and also to introduce a new licensing regime and a new regulatory control scheme. In the regulatory context, the decommissioning of a facility is understood as a set of administrative and technical actions and processes whose purpose, once a facility has been withdrawn from service, is to release it from regulatory control and so to relieve the former licensee of its previous responsibilities relating to the facility's safety. With the increasing age of nuclear and radioactive facilities in service, and as the number of facilities reaching the end of their operating life rises, the administrative process required in order to decommissioning them safely has become a real challenge in all countries, especially in those like Spain with an old nuclear power programme. Let me first give you a quick overview of the Spanish regulatory decommissioning framework. Then I will try to

  9. Regulating chemicals: law, science, and the unbearable burdens of regulation.

    Science.gov (United States)

    Silbergeld, Ellen K; Mandrioli, Daniele; Cranor, Carl F

    2015-03-18

    The challenges of regulating industrial chemicals remain unresolved in the United States. The Toxic Substances Control Act (TSCA) of 1976 was the first legislation to extend coverage to the regulation of industrial chemicals, both existing and newly registered. However, decisions related to both law and science that were made in passing this law inevitably rendered it ineffectual. Attempts to fix these shortcomings have not been successful. In light of the European Union's passage of innovative principles and requirements for chemical regulation, it is no longer possible to deny the opportunity and need for reform in US law and practice.

  10. Ionising radiation: a guide to the Regulations

    International Nuclear Information System (INIS)

    Hughes, Donald.

    1986-01-01

    The author explains the basic requirements on health and safety personnel in relation to the Ionising Radiations Regulations 1985. The outline paper is presented under the following headings: Dose assessment, Interpretation and general regulations 1-5, Dose limitation regulations 6 and 7, Regulation of work - regulations 8-12, Dosimetry and medical surveillance - regulations 13-17, summary of records to be kept, entry to controlled areas, Control of radioactive substances -regulations 18-23, Monitoring of radiation regulation 24, Assessments and notifications - regulations 25-31, Safety of articles and equipment - regulations 32-34, Other guidance. (U.K.)

  11. Regulated electricity retailing in Chile

    Energy Technology Data Exchange (ETDEWEB)

    Galetovic, Alexander, E-mail: alexander@galetovic.cl [Facultad de Ciencias Economicas y Empresariales, Universidad de los Andes, Santiago, Chile. Av. San Carlos de Apoquindo 2200, Las Condes, Santiago (Chile); Munoz, Cristian M., E-mail: cmunozm@aes.com [AES Gener and Departamento de Ingenieria Electrica, Universidad Catolica de Chile (Chile)

    2011-10-15

    While some countries have unbundled distribution and retailing, skeptics argue that the physical attributes of electricity make retailers redundant. Instead, it is claimed that passive pass through of wholesale prices plus regulated charges for transmission and distribution suffice for customers to benefit from competitive generation markets. We review the Chilean experience with regulated retailing and pass through of wholesale prices. We argue that when energy wholesale prices are volatile and prices are stabilized, distortions emerge. Regulated retailers gain little by mitigating or correcting them. On the contrary, sometimes price distortions increase their profits. We estimate the cost of three distortions that neither regulated retailers nor the regulator have shown any interest in correcting. - Highlights: > We review Chile's experience with regulated electricity retailing. > Distortions emerge when energy wholesale prices are volatile and prices stabilized. > Regulated retailers gain little by mitigating or correcting distortions. > Sometimes price distortions increase retailers' profits. > We estimate the cost of three distortions, which retailers have not corrected.

  12. Regulated electricity retailing in Chile

    International Nuclear Information System (INIS)

    Galetovic, Alexander; Munoz, Cristian M.

    2011-01-01

    While some countries have unbundled distribution and retailing, skeptics argue that the physical attributes of electricity make retailers redundant. Instead, it is claimed that passive pass through of wholesale prices plus regulated charges for transmission and distribution suffice for customers to benefit from competitive generation markets. We review the Chilean experience with regulated retailing and pass through of wholesale prices. We argue that when energy wholesale prices are volatile and prices are stabilized, distortions emerge. Regulated retailers gain little by mitigating or correcting them. On the contrary, sometimes price distortions increase their profits. We estimate the cost of three distortions that neither regulated retailers nor the regulator have shown any interest in correcting. - Highlights: → We review Chile's experience with regulated electricity retailing. → Distortions emerge when energy wholesale prices are volatile and prices stabilized. → Regulated retailers gain little by mitigating or correcting distortions. → Sometimes price distortions increase retailers' profits. → We estimate the cost of three distortions, which retailers have not corrected.

  13. Grandfather regulations, new source bias, and state air toxics regulations

    International Nuclear Information System (INIS)

    Levinson, Arik

    1999-01-01

    This paper uses plant-level data from the Census of Manufactures and the variation in toxic air pollution regulations across states to measure the effects of laws that are more stringent for new sources of pollution than for existing sources (so-called 'grandfather' regulations). Of particular interest is the resulting 'new source bias' and its effects on capital vintage and investment. Two industries are examined: commercial printing, which has a local product market; and paint manufacturing, which has a more national market. In general, there seem to be no statistically significant differences in capital vintage or investment between plants in states that grandfather new sources of pollution, plants in states that have no air toxics regulations, and plants in states that regulate both new and existing sources

  14. Hygienic regulation of ionizing radiations

    International Nuclear Information System (INIS)

    Saurov, M.M.

    1984-01-01

    Modern state of the problem on hygienic regulation of ionizing radiations is considered. Concepts and principles of the regulation based on risk concept are presented according to ICRP 26 and 27. Two types of risk are designated: ''absolute'' and ''relative'' ones. The concept of acceptable risk on the basis of cost - benefit ratio is substantiated. Special attention is paid to the principle of accounting the complex of health signs, when determining radiation hazard. To determine the level of permissible risk and permissible dose to population the concept of ''inadmissibility of s-tatistically significant risk'' has been developed. Standards, regulating population doses in the USSR, which are valid nowadays, are considered

  15. Introduction to international radio regulations

    Energy Technology Data Exchange (ETDEWEB)

    Radicella, S M [Abdus Salam International Centre for Theoretical Physics, Trieste (Italy)

    2003-12-15

    These lecture notes contain an overview of basic problems of the International Radio Regulations. Access to the existing information infrastructure, and to that of the future Information Society, depends critically on radio, especially in poor, remote and sparsely populated regions with under-developed telecommunication infrastructure. How the spectrum of radio frequencies is regulated has profound impact on the society, its security, prosperity, and culture. The radio regulations represent a very important framework for an adequate use of radio and should be known by all of those working in the field.

  16. Introduction to international radio regulations

    International Nuclear Information System (INIS)

    Radicella, S.M.

    2003-01-01

    These lecture notes contain an overview of basic problems of the International Radio Regulations. Access to the existing information infrastructure, and to that of the future Information Society, depends critically on radio, especially in poor, remote and sparsely populated regions with under-developed telecommunication infrastructure. How the spectrum of radio frequencies is regulated has profound impact on the society, its security, prosperity, and culture. The radio regulations represent a very important framework for an adequate use of radio and should be known by all of those working in the field

  17. Nanometrology - challenges for health regulation

    Directory of Open Access Journals (Sweden)

    Jailton Carreteiro Damasceno

    2013-11-01

    Full Text Available The relationship between metrology, nanotechnology and nanoscience and sanitary regulation is discussed from the point of view of its importance and the interrelationship between the themes for the development of products and services involving nanotech-nology. The discussion involves the main techniques for measuring dimensional, chemical and biological properties of materials, and presents some of the challenges for the future. Issues such as processes of standardization and regulation in Europe, U.S. and Brazil are also addressed, providing an overview of how these processes are related to sanitary regulation.

  18. Designing Next Generation Telecom Regulation

    DEFF Research Database (Denmark)

    Henten, Anders; Samarajiva, Rohan; Melody, William H.

    2003-01-01

    This article critically examines the multiple rationales for telecom, IT, media convergence regulation, on the one hand, and multisector utility regulation, on the other, and the practical questions of implementation they pose, with a view to contributing to informed policy and regulatory decisions...... to the regulatory process such as scarcity of regulatory resources and safeguards for regulatory independence, are examined. It is concluded that ICT and media convergence issues are primarily about improving the efficiency of market economies, and how changes in regulation can facilitate this process. Multi...

  19. Molecular Regulation of Histamine Synthesis

    Directory of Open Access Journals (Sweden)

    Hua Huang

    2018-06-01

    Full Text Available Histamine is a critical mediator of IgE/mast cell-mediated anaphylaxis, a neurotransmitter and a regulator of gastric acid secretion. Histamine is a monoamine synthesized from the amino acid histidine through a reaction catalyzed by the enzyme histidine decarboxylase (HDC, which removes carboxyl group from histidine. Despite the importance of histamine, transcriptional regulation of HDC gene expression in mammals is still poorly understood. In this review, we focus on discussing advances in the understanding of molecular regulation of mammalian histamine synthesis.

  20. Towards trust in regulation. Moving to a public value regulation

    Energy Technology Data Exchange (ETDEWEB)

    Mitchell, Catherine; Woodman, Bridget [Energy Policy Group, University of Exeter Cornwall Campus, Treliever Road, Penryn, TR10 9EZ (United Kingdom)

    2010-06-15

    The UK Government has committed itself to reducing its carbon dioxide emissions. The challenge of successfully achieving a transition to a sustainable energy system, in the context of the UK's largely privately owned energy industry, rests on the ability of policy makers to encourage and enable the necessary changes or innovation at all levels of the energy system. This paper argues that the UK's current, dominant political paradigm or framework (the regulatory state paradigm (RSP)) and within it, the role of the economic regulator, Ofgem acts as a fundamental block to this challenge. The current economic regulatory system is based on trust in the market, or on predicted (albeit theoretical) known outcomes. To expand our regulatory system to one which can deliver a sustainable energy system requires innovation in a certain direction (as opposed to any innovation). That is the antithesis of the current process of regulation. Trust is required that Ofgem, the economic regulator, will develop rules and incentives which deliver an agreed sustainable energy goal, which is 'trusted' to be the 'right' goal. This requires Ofgem moving away from ex-ante regulation to a type of regulation where all costs, benefits and outcomes cannot be known beforehand and where they cannot necessarily be quantifiable. This has, very provisionally, been called Public Value Regulation (PVR). (author)

  1. Attachment and Dyadic Regulation Processes.

    Science.gov (United States)

    Overall, Nickola C; Simpson, Jeffry A

    2015-02-01

    Insecurely attached people have relatively unhappy and unstable romantic relationships, but the quality of their relationships depends on how their partners regulate them. Some partners find ways to regulate the emotional and behavioral reactions of insecurely attached individuals, which promotes greater relationship satisfaction and security. We discuss attachment theory and interdependence dilemmas, and then explain how and why certain responses by partners assuage the cardinal concerns of insecure individuals in key interdependent situations. We then review recent studies illustrating how partners can successfully regulate the reactions of anxiously and avoidantly attached individuals, yielding more constructive interactions. We finish by considering how these regulation processes can create a more secure dyadic environment, which helps to improve relationships and attachment security across time.

  2. Network Regulation and Support Schemes

    DEFF Research Database (Denmark)

    Ropenus, Stephanie; Schröder, Sascha Thorsten; Jacobsen, Henrik

    2009-01-01

    -in tariffs to market-based quota systems, and network regulation approaches, comprising rate-of-return and incentive regulation. National regulation and the vertical structure of the electricity sector shape the incentives of market agents, notably of distributed generators and network operators......At present, there exists no explicit European policy framework on distributed generation. Various Directives encompass distributed generation; inherently, their implementation is to the discretion of the Member States. The latter have adopted different kinds of support schemes, ranging from feed....... This article seeks to investigate the interactions between the policy dimensions of support schemes and network regulation and how they affect the deployment of distributed generation. Firstly, a conceptual analysis examines how the incentives of the different market agents are affected. In particular...

  3. Electronic Code of Federal Regulations

    Data.gov (United States)

    National Archives and Records Administration — The Electronic Code of Federal Regulations (e-CFR) is the codification of the general and permanent rules published in the Federal Register by the executive...

  4. Comparison of some European regulations

    Energy Technology Data Exchange (ETDEWEB)

    Argyriadis, K [Germanisher Lloyd, Hamburg (Germany)

    1996-09-01

    Fatigue calculations are an essential part in certification of a wind turbine. Manufacturers have to fulfill recommendations of several different regulations throughout Europe with the result that the design has often to be altered to satisfy them. In general three national (D/GL, NL, DK), and two international (GL, IEC) regulations are in use, with the IEC standard getting more importance with wind energy deploying to more in regions with no yet clearly defined national standards (India, Spain). The Germanischer Lloyd made calculations for wind turbines they are certifying and in one case we compared the resulting damages for different regulations and classes on a 600 kW, three bladed, stall regulated wind turbine. (EG) 18 refs.

  5. How should Bitcoin be regulated ?

    OpenAIRE

    SHCHERBAK, Sergii

    2014-01-01

    The lack of clarity about Bitcoin’s legal framework has meant that none of the regulators across the EU have yet achieved sufficient clarity in the legal treatment of Bitcoin and its stakeholders. This uncertainty poses a number of substantial risks to Bitcoin stakeholders and creates challenges for regulatory authorities. Therefore, there is a need for a clear strategy for Bitcoin’s regulation aiming to ensure the maximum possible balance between the interests of Bitcoin stakeholders longing...

  6. Money Laundering and its Regulation

    OpenAIRE

    Alberto E. Chong; Florencio López-de-Silanes

    2007-01-01

    The recent wave of terrorist attacks has increased the attention paid to money laundering activities. Using several methodologies, this paper investigates empirically the determinants of money laundering and its regulation in over 80 countries by assembling a cross-country dataset on proxies for money laundering and the prevalence of feeding activities. The paper additionally constructs specific money laundering regulation indices based on available information on laws and their mechanisms of...

  7. The Legal Regulation of Cybersecurity

    OpenAIRE

    Darius Štitilis

    2013-01-01

    Cybercrime has become a global phenomenon, which is causing more harm to individual citizens, organizations, society and the state. Most countries in the world compare cybercrime with offences such as terrorism and drug trafficking due to its risks and profitability. Cybersecurity is the central category to fight cybercrime in cyberspace. Therefore, the strategic legal regulation of cybersecurity is one of the most relevant problems in EU, including Lithuania. So far cybersecurity legal regul...

  8. Regulation on control systems tests

    International Nuclear Information System (INIS)

    Grau, J.; Navarro, J.M.

    1978-01-01

    Requirements under regulation applicable to the testing of control systems and controlled equipments in the case of USA nuclear projects are examined. They are reviewed, in particular, the following standards and criteria: 10 Code of Federal Regulations 50, Appendix A, General Design Criteria 20 and 21; IEEE Standards 279 and 308; IEEE Standard 338; US Regulatory Guides 1.22 and 1.118.(J.E.de C.)

  9. Liquidity regulation and bank behavior

    OpenAIRE

    Bonner, C.

    2014-01-01

    In response to the 2007-08 financial crisis, the Basel Committee on Banking Supervision proposed two liquidity standards to reinforce banks’ resilience to liquidity risks. The purpose of this thesis is to analyze the impact of liquidity regulation on bank behavior. The first of four main chapters analyzes the development of global liquidity standards, their objectives as well as their interaction with capital standards. The analysis suggests that regulating capital is associated with declinin...

  10. Civilsamfundets ABC: R for Regulering

    DEFF Research Database (Denmark)

    Meyer, Gitte; Lund, Anker Brink

    2016-01-01

    Hvad er civilsamfundet? Anker Brink Lund og Gitte Meyer fra CBS Center for Civil Society Studies gennemgår civilsamfundet bogstav for bogstav. Vi er nået til R for Regulering.......Hvad er civilsamfundet? Anker Brink Lund og Gitte Meyer fra CBS Center for Civil Society Studies gennemgår civilsamfundet bogstav for bogstav. Vi er nået til R for Regulering....

  11. 7 CFR 987.48 - Container regulation.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 8 2010-01-01 2010-01-01 false Container regulation. 987.48 Section 987.48... IN RIVERSIDE COUNTY, CALIFORNIA Order Regulating Handling Container Regulation § 987.48 Container regulation. Whenever the Committee deems it advisable to establish a container regulation for any variety of...

  12. Two new pollution regulations introduced

    International Nuclear Information System (INIS)

    Anon.

    2000-01-01

    A newly proposed regulation in Ontario will require the mandatory tracking of 358 airborne pollutants by the electricity sector as well as by other large industrial facilities such as iron and steel manufacturers and petroleum refiners. If passed, the regulation would make Ontario the first jurisdiction in the world to require monitoring and reporting of a full suite of major greenhouse gases, including smog and acid-rain causing emissions. The proposed regulation also provides for immediate public access to any reported information. Ontario residents can comment on the proposed regulation through the Environmental Bill of Rights registry. A new, more severe hazardous waste regulation will also take effect on March 31, 2001, whereby testing for 88 contaminants will be done according to a new standard called the Toxicity Characteristic Leaching Procedure (TCLP). This new regulation also introduces a new 'derived from' rule which requires that a listed hazardous waste keep its classification until it can be demonstrated otherwise. Ontario's list of hazardous wastes has been updated to include 129 new chemicals and industrial processes. The Ontario Ministry has also adopted the Canada-wide Standards for Particulate Matter and Ozone, as well as the Canada-wide Standards for mercury emissions from base metal smelters as well as from incineration of sewage sludge and municipal, medical, hazardous waste

  13. Erk5 inhibits endothelial migration via KLF2-dependent down-regulation of PAK1.

    Science.gov (United States)

    Komaravolu, Ravi K; Adam, Christian; Moonen, Jan-Renier A J; Harmsen, Martin C; Goebeler, Matthias; Schmidt, Marc

    2015-01-01

    The MEK5/Erk5 pathway mediates beneficial effects of laminar flow, a major physiological factor preventing vascular dysfunction. Forced Erk5 activation induces a protective phenotype in endothelial cell (EC) that is associated with a dramatically decreased migration capacity of those cells. Transcriptional profiling identified the Krüppel-like transcription factors KLF2 and KLF4 as central mediators of Erk5-dependent gene expression. However, their downstream role regarding migration is unclear and relevant secondary effectors remain elusive. Here, we further investigated the mechanism underlying Erk5-dependent migration arrest in ECs. Our experiments reveal KLF2-dependent loss of the pro-migratory Rac/Cdc42 mediator, p21-activated kinase 1 (PAK1), as an important mechanism of Erk5-induced migration inhibition. We show that endothelial Erk5 activation by expression of a constitutively active MEK5 mutant, by statin treatment, or by application of laminar shear stress strongly decreased PAK1 mRNA and protein expression. Knockdown of KLF2 but not of KLF4 prevented Erk5-mediated PAK1 mRNA inhibition, revealing KLF2 as a novel PAK1 repressor in ECs. Importantly, both PAK1 re-expression and KLF2 knockdown restored the migration capacity of Erk5-activated ECs underscoring their functional relevance downstream of Erk5. Our data provide first evidence for existence of a previously unknown Erk5/KLF2/PAK1 axis, which may limit undesired cell migration in unperturbed endothelium and lower its sensitivity for migratory cues that promote vascular diseases including atherosclerosis. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

  14. Regulation Development for Drinking Water Contaminants

    Science.gov (United States)

    To explain what process and information underlies regulations including how the Safe Drinking Water Act applies to regulation development i.e. how does the drinking water law translate into regulations.

  15. To Regulate or Not to Regulate? Views on Electronic Cigarette Regulations and Beliefs about the Reasons for and against Regulation.

    Directory of Open Access Journals (Sweden)

    Ashley Sanders-Jackson

    Full Text Available Policies designed to restrict marketing, access to, and public use of electronic cigarettes (e-cigarettes are increasingly under debate in various jurisdictions in the US. Little is known about public perceptions of these policies and factors that predict their support or opposition.Using a sample of US adults from Amazon Mechanical Turk in May 2015, this paper identifies beliefs about the benefits and costs of regulating e-cigarettes and identifies which of these beliefs predict support for e-cigarette restricting policies.A higher proportion of respondents agreed with 8 different reasons to regulate e-cigarettes (48.5% to 83.3% agreement versus 7 reasons not to regulate e-cigarettes (11.5% to 18.9%. The majority of participants agreed with 7 out of 8 reasons for regulation. When all reasons to regulate or not were included in a final multivariable model, beliefs about protecting people from secondhand vapor and protecting youth from trying e-cigarettes significantly predicted stronger support for e-cigarette restricting policies, whereas concern about government intrusion into individual choices was associated with reduced support.This research identifies key beliefs that may underlie public support or opposition to policies designed to regulate the marketing and use of e-cigarettes. Advocates on both sides of the issue may find this research valuable in developing strategic campaigns related to the issue.Specific beliefs of potential benefits and costs of e-cigarette regulation (protecting youth, preventing exposure to secondhand vapor, and government intrusion into individual choices may be effectively deployed by policy makers or health advocates in communicating with the public.

  16. To Regulate or Not to Regulate? Views on Electronic Cigarette Regulations and Beliefs about the Reasons for and against Regulation.

    Science.gov (United States)

    Sanders-Jackson, Ashley; Tan, Andy S L; Bigman, Cabral A; Mello, Susan; Niederdeppe, Jeff

    2016-01-01

    Policies designed to restrict marketing, access to, and public use of electronic cigarettes (e-cigarettes) are increasingly under debate in various jurisdictions in the US. Little is known about public perceptions of these policies and factors that predict their support or opposition. Using a sample of US adults from Amazon Mechanical Turk in May 2015, this paper identifies beliefs about the benefits and costs of regulating e-cigarettes and identifies which of these beliefs predict support for e-cigarette restricting policies. A higher proportion of respondents agreed with 8 different reasons to regulate e-cigarettes (48.5% to 83.3% agreement) versus 7 reasons not to regulate e-cigarettes (11.5% to 18.9%). The majority of participants agreed with 7 out of 8 reasons for regulation. When all reasons to regulate or not were included in a final multivariable model, beliefs about protecting people from secondhand vapor and protecting youth from trying e-cigarettes significantly predicted stronger support for e-cigarette restricting policies, whereas concern about government intrusion into individual choices was associated with reduced support. This research identifies key beliefs that may underlie public support or opposition to policies designed to regulate the marketing and use of e-cigarettes. Advocates on both sides of the issue may find this research valuable in developing strategic campaigns related to the issue. Specific beliefs of potential benefits and costs of e-cigarette regulation (protecting youth, preventing exposure to secondhand vapor, and government intrusion into individual choices) may be effectively deployed by policy makers or health advocates in communicating with the public.

  17. Balancing Public and Private Regulation

    Directory of Open Access Journals (Sweden)

    Martijn Scheltema

    2016-01-01

    Full Text Available Voluntary Sustainability Standards (VSS might develop into a viable alternative to public regulation. However, it turns on the (regulatory circumstances whether that holds true in practice. If public regulation on CSR topics is lacking, governments are unable to agree upon certain topics on a global level or diverging public regulation exists, VSS can be helpful to set global standards. Obviously, private standards will especially be helpful if they are commensurate with local public legislation (and e.g. treaties and/or are accepted by local governments. If one neglects this, numerous domestic structures might exist that frustrate VSS. Furthermore, governments have to remain vigilant as to whether these private regimes do not result in market disruption, consumer detriment or hamper trade. VSS might also compete with public arrangements which might limit the uptake of VSS. However, if public regulation exists VSS might be a viable alternative if compliance with not too compelling public norms by market participants is rather poor and the public policymaker is aiming to incentivize the better performing part of the market to embark on higher standards and thus only desires to regulate the less performing part of the market. However, of paramount importance is the effectiveness of VSS in order to be a viable alternative to public regulation. The effectiveness of VSS should be assessed using an integrated multi-disciplinary (comparative approach entailing legal, impact-assessment, legitimacy, governance and behavioural aspects. Only effective VSS in the aforementioned sense are a true alternative to public regulation.Beyond that, the legal perspective in connection with (the effectiveness of VSS is discussed, featuring FSC and UTZ Certified as an example. It is important from this perspective that VSS have a clear and sufficiently selective objective and sufficiently specific norms, are regularly evaluated, entail ‘conflict of law rules’ and

  18. Re-Framing Biotechnology Regulation.

    Science.gov (United States)

    Peck, Alison

    Biotechnology is about to spill the banks of federal regulation. New genetic engineering techniques like CRISPR-Cas9 promise revolutionary breakthroughs in medicine, agriculture, and public health—but those techniques would not be regulated under the terms of the Coordinated Framework for Regulation of Biotechnology. This revolutionary moment in biotechnology offers an opportunity to correct the flaws in the framework, which was hastily patched together at the advent of the technology. The framework has never captured all relevant technologies, has never satisfied the public that risk is being effectively managed, and has never been accessible to small companies and publicly-funded labs that increasingly are positioned to make radical, life-saving innovations. This Article offers a proposal for new legislation that would reshape biotechnology regulation to better meet these goals. Key reforms include tying regulation to risk rather than technology category; consolidating agency review; capturing distinct regulatory expertise through inter-agency consultations; creating a clearinghouse to help guide applicants and disseminate information; setting up more comprehensive monitoring of environmental effects; and providing federal leadership to fill key data gaps and address socio-economic impacts.

  19. Progress toward risk informed regulation

    International Nuclear Information System (INIS)

    Rogers, K.C.

    1997-01-01

    For the last several years, the NRC, with encouragement from the industry, has been moving in the direction of risk informed regulation. This is consistent with the regulatory principle of efficiency, formally adopted by the Nuclear Regulatory Commission in 1991, which requires that regulatory activities be consistent with the degree of risk reduction they achieve. Probabilistic risk analysis has become the tool of choice for selecting the best of several alternatives. Closely related to risk informed regulation is the development of performance based rules. Such rules focus on the end result to be achieved. They do not specify the process, but instead establish the goals to be reached and how the achievement of those goals is to be judged. The inspection and enforcement activity is based on whether or not the goals have been met. The author goes on to offer comments on the history of the development of this process and its probable development in the future. He also addresses some issues which must be resolved or at least acknowledged. The success of risk informed regulation ultimately depends on having sufficiently reliable data to allow quantification of regulatory alternatives in terms of relative risk. Perhaps the area of human reliability and organizational performance has the greatest potential for improvement in reactor safety. The ability to model human performance is significantly less developed that the ability to model mechanical or electrical systems. The move toward risk informed, performance based regulation provides an unusual, perhaps unique, opportunity to establish a more rational, more effective basis for regulation

  20. Regulation of Autophagy by Kinases

    International Nuclear Information System (INIS)

    Sridharan, Savitha; Jain, Kirti; Basu, Alakananda

    2011-01-01

    Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, including cancer. Therapeutic exploitation of this process requires a clear understanding of its regulation. Although the core molecular components involved in the execution of autophagy are well studied there is limited information on how cellular signaling pathways, particularly kinases, regulate this complex process. Protein kinases are integral to the autophagy process. Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR. Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process. This review focuses on the regulation of autophagy by several kinases with particular emphasis on serine/threonine protein kinases such as mTOR, AMP-activated protein kinase, Akt, mitogen-activated protein kinase (ERK, p38 and JNK) and protein kinase C that are often deregulated in cancer and are important therapeutic targets

  1. Regulation of Autophagy by Kinases

    Energy Technology Data Exchange (ETDEWEB)

    Sridharan, Savitha; Jain, Kirti; Basu, Alakananda, E-mail: alakananda.basu@unthsc.edu [Department of Molecular Biology and Immunology, Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, TX 76107 (United States)

    2011-06-09

    Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, including cancer. Therapeutic exploitation of this process requires a clear understanding of its regulation. Although the core molecular components involved in the execution of autophagy are well studied there is limited information on how cellular signaling pathways, particularly kinases, regulate this complex process. Protein kinases are integral to the autophagy process. Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR. Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process. This review focuses on the regulation of autophagy by several kinases with particular emphasis on serine/threonine protein kinases such as mTOR, AMP-activated protein kinase, Akt, mitogen-activated protein kinase (ERK, p38 and JNK) and protein kinase C that are often deregulated in cancer and are important therapeutic targets.

  2. Regulation of Autophagy by Kinases

    Science.gov (United States)

    Sridharan, Savitha; Jain, Kirti; Basu, Alakananda

    2011-01-01

    Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, including cancer. Therapeutic exploitation of this process requires a clear understanding of its regulation. Although the core molecular components involved in the execution of autophagy are well studied there is limited information on how cellular signaling pathways, particularly kinases, regulate this complex process. Protein kinases are integral to the autophagy process. Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR. Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process. This review focuses on the regulation of autophagy by several kinases with particular emphasis on serine/threonine protein kinases such as mTOR, AMP-activated protein kinase, Akt, mitogen-activated protein kinase (ERK, p38 and JNK) and protein kinase C that are often deregulated in cancer and are important therapeutic targets. PMID:24212825

  3. Regulation of Autophagy by Kinases

    Directory of Open Access Journals (Sweden)

    Savitha Sridharan

    2011-06-01

    Full Text Available Autophagy is a process of self-degradation that maintains cellular viability during periods of metabolic stress. Although autophagy is considered a survival mechanism when faced with cellular stress, extensive autophagy can also lead to cell death. Aberrations in autophagy are associated with several diseases, including cancer. Therapeutic exploitation of this process requires a clear understanding of its regulation. Although the core molecular components involved in the execution of autophagy are well studied there is limited information on how cellular signaling pathways, particularly kinases, regulate this complex process. Protein kinases are integral to the autophagy process. Atg1, the first autophagy-related protein identified, is a serine/threonine kinase and it is regulated by another serine/threonine kinase mTOR. Emerging studies suggest the participation of many different kinases in regulating various components/steps of this catabolic process. This review focuses on the regulation of autophagy by several kinases with particular emphasis on serine/threonine protein kinases such as mTOR, AMP-activated kinase, Akt, mitogen-activated protein kinase (ERK, p38 and JNK and protein kinase C that are often deregulated in cancer and are important therapeutic targets.

  4. Cosmetic Regulations: A Comparative Study.

    Science.gov (United States)

    Suhag, Jyoti; Dureja, Harish

    2015-01-01

    The regulatory framework, compliance requirement, efficacy, safety, and marketing of cosmetic products are considered the most important factors for growth of the cosmetic industry. There are different regulatory bodies across the globe that have their own insights for regulation; moreover, governments such as the United States, European Union, and Japan follow a stringent regulatory framework, whereas cosmetics are not so much strictly regulated in countries such as India, Brazil, and China. The alignment of a regulatory framework will play a significant role in the removal of barriers to trade, growth of market at an international level, innovation in the development and presentation of new products, and most importantly safety and efficacy of the marketed products. The present contribution gives insight into the important cosmetic regulations in areas of premarket approval, ingredient control, and labeling and warnings, with a special focus on the cosmetic regulatory environments in the United States, European Union, Japan, and India. Most importantly, the authors highlight the dark side of cosmetics associated with allergic reactions and even skin cancer. The importance of cosmetic regulations has been highlighted by dint of which the society can be healthier, accomplished by more stringent and harmonized regulations.

  5. 7 CFR 301.89-5 - Movement of regulated articles from regulated areas.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 5 2010-01-01 2010-01-01 false Movement of regulated articles from regulated areas. 301.89-5 Section 301.89-5 Agriculture Regulations of the Department of Agriculture (Continued) ANIMAL... § 301.89-5 Movement of regulated articles from regulated areas. (a) Any regulated article may be moved...

  6. BRAF and RAS oncogenes regulate Rho GTPase pathways to mediate migration and invasion properties in human colon cancer cells: a comparative study

    Directory of Open Access Journals (Sweden)

    Shirasawa Senji

    2011-09-01

    Full Text Available Abstract Background Colorectal cancer is a common disease that involves genetic alterations, such as inactivation of tumour suppressor genes and activation of oncogenes. Among them are RAS and BRAF mutations, which rarely coexist in the same tumour. Individual members of the Rho (Ras homology GTPases contribute with distinct roles in tumour cell morphology, invasion and metastasis. The aim of this study is to dissect cell migration and invasion pathways that are utilised by BRAFV600E as compared to KRASG12V and HRASG12V oncoproteins. In particular, the role of RhoA (Ras homolog gene family, member A, Rac1 (Ras-related C3 botulinum toxin substrate 1 and Cdc42 (cell division cycle 42 in cancer progression induced by each of the three oncogenes is described. Methods Colon adenocarcinoma cells with endogenous as well as ectopically expressed or silenced oncogenic mutations of BRAFV600E, KRASG12V and HRASG12V were employed. Signalling pathways and Rho GTPases were inhibited with specific kinase inhibitors and siRNAs. Cell motility and invasion properties were correlated with cytoskeletal properties and Rho GTPase activities. Results Evidence presented here indicate that BRAFV600E significantly induces cell migration and invasion properties in vitro in colon cancer cells, at least in part through activation of RhoA GTPase. The relationship established between BRAFV600E and RhoA activation is mediated by the MEK-ERK pathway. In parallel, KRASG12V enhances the ability of colon adenocarcinoma cells Caco-2 to migrate and invade through filopodia formation and PI3K-dependent Cdc42 activation. Ultimately increased cell migration and invasion, mediated by Rac1, along with the mesenchymal morphology obtained through the Epithelial-Mesenchymal Transition (EMT were the main characteristics rendered by HRASG12V in Caco-2 cells. Moreover, BRAF and KRAS oncogenes are shown to cooperate with the TGFβ-1 pathway to provide cells with additional transforming

  7. Decisions to regulate genotoxic substances

    Energy Technology Data Exchange (ETDEWEB)

    Bengtsson, G

    1988-07-01

    Decisions to regulate genotoxic substances involve trade-offs between various incomparable factors such as risks to human health and other environmental risks, public perceptions, costs and uncertainties. Two different approaches towards these trade-offs are discussed. In one approach, all relevant factors are defined and trade-offs are considered using a general and very elaborate analysis. Cost-benefit analysis is an exponent of this approach. An illustration is given for the regulation of transboundary releases of radioactive materials. The other approach considers what is politically feasible for the time being and seeks a decision with much room for later corrections. Incrementalism is a philosophy in this vein. It is illustrated by reference to the regulation of transboundary air pollution. Weaknesses and strengths of the two approaches are discussed. (author)

  8. Digital Convergence and Content Regulation

    Directory of Open Access Journals (Sweden)

    Michael John Starks

    2014-12-01

    Full Text Available Broadcasting, Press and Internet journalism systems of distribution are converging: the same infrastructure can deliver all three historically separate services. Reception devices mirror this: the Connected TV, the tablet and the smart phone overlap in their functionality. Service overlaps are evident too, with broadcasters providing online and on-demand services and newspapers developing electronic versions. Does this mean that media regulation policies must converge too?My argument is that they should, though only where historically different communications are now fulfilling a similar function, e.g. broadcaster online services and electronic versions of newspapers. Convergence requires a degree of harmonisation and, to this end, I advocate a review of UK broadcasting's 'due impartiality' requirement and of the UK's application of the public service concept. I also argue for independent self-regulation (rather than state-based regulation of non-public-service broadcasting journalism.

  9. Environmental Regulation and International Trade

    Energy Technology Data Exchange (ETDEWEB)

    Mulatu, A. [London School of Economics, London (United Kingdom); Florax, R.J.G.M.; Withagen, C.A. [Faculty of Economics and Business Administration, Vrije Universiteit, Amsterdam (Netherlands)

    2004-07-01

    We empirically investigate the responsiveness of international trade to the stringency of environmental regulation. Stringent environmental regulation may impair the export competitiveness of 'dirty' domestic industries, and as a result, 'pollution havens' emerge in countries where environmental regulation is 'over-lax.' We examine the impact of pollution abatement and control costs on net exports in order to grasp this phenomenon. Theoretically, our analysis is related to a general equilibrium model of trade and pollution nesting the pollution haven motive for trade with the factor endowment motive. We analyze data on two-digit ISIC manufacturing industries during the period 1977-1992 in Germany, the Netherlands and the US, and show that trade patterns in 'dirty' commodities are jointly determined by relative factor endowments and environmental stringency differentials.

  10. Decisions to regulate genotoxic substances

    International Nuclear Information System (INIS)

    Bengtsson, G.

    1988-01-01

    Decisions to regulate genotoxic substances involve trade-offs between various incomparable factors such as risks to human health and other environmental risks, public perceptions, costs and uncertainties. Two different approaches towards these trade-offs are discussed. In one approach, all relevant factors are defined and trade-offs are considered using a general and very elaborate analysis. Cost-benefit analysis is an exponent of this approach. An illustration is given for the regulation of transboundary releases of radioactive materials. The other approach considers what is politically feasible for the time being and seeks a decision with much room for later corrections. Incrementalism is a philosophy in this vein. It is illustrated by reference to the regulation of transboundary air pollution. Weaknesses and strengths of the two approaches are discussed. (author)

  11. Guidelines on Building Regulations 2008

    DEFF Research Database (Denmark)

    Thse guidelines clarify and intepret the provisions of the Building Regulations of 2008 (BR08). The Guidelines, which match BR08 in terms of organisation into Parts, are accompanied by the full text of the regulations and the explanatory notes issued by the Danish Enterprise and Construction...... Authority. The Guidelines refer the reader to sources such as relevant standards, instructions and other background material which provides more detailed information. The Guidelines cover the same ground as BR08, including building control regulations, layout, fitting out, structures, fire safety, indoor...... climate, energy consumotion and services. The Guidelines are aimed at all professionals involved in building projects, particularly building design consultants, contractors and municipal application officers....

  12. Regulation of beta cell replication

    DEFF Research Database (Denmark)

    Lee, Ying C; Nielsen, Jens Høiriis

    2008-01-01

    Beta cell mass, at any given time, is governed by cell differentiation, neogenesis, increased or decreased cell size (cell hypertrophy or atrophy), cell death (apoptosis), and beta cell proliferation. Nutrients, hormones and growth factors coupled with their signalling intermediates have been...... suggested to play a role in beta cell mass regulation. In addition, genetic mouse model studies have indicated that cyclins and cyclin-dependent kinases that determine cell cycle progression are involved in beta cell replication, and more recently, menin in association with cyclin-dependent kinase...... inhibitors has been demonstrated to be important in beta cell growth. In this review, we consider and highlight some aspects of cell cycle regulation in relation to beta cell replication. The role of cell cycle regulation in beta cell replication is mostly from studies in rodent models, but whether...

  13. Retooling for new environmental regulations

    International Nuclear Information System (INIS)

    Levy, W.W.

    1997-01-01

    The petroleum industry is subject to regulations which require better management of emissions. This presentation discussed those regulations that dealt specifically with gasoline and diesel fuels and how they impact on vehicle emissions. The review showed that since 1975 the average fuel economy and improvements in tailpipe emissions for a light duty vehicle has increased significantly. Nitrogen oxide emissions were reduced by 94 per cent, carbon monoxide emissions were reduced by 96 per cent, and hydrocarbon emissions from tailpipes were reduced by 98 per cent. The phase-out of lead in fuel formulations, the controversy over the octane enhancing fuel additive MMT and a major study underway investigating the reduction of sulphur in gasoline, were also discussed. Future developments in regulations are likely to include capture of vapour emissions, mandatory inspection and maintenance programs, remote sensing of tailpipe emissions, and scrapping of old high emitting vehicles.5 figs

  14. Planned and proposed pipeline regulations

    International Nuclear Information System (INIS)

    De Leon, C.

    1992-01-01

    The Research and Special Programs Administration administers the Natural Gas Pipeline Safety Act of 1968 (NGPSA) and the Hazardous Liquid Pipeline Safety Act of 1979 (HLPSA). The RSPA issues and enforces design, construction, operation and maintenance regulations for natural gas pipelines and hazardous liquid pipelines. This paper discusses a number of proposed and pending safety regulations and legislative initiatives currently being considered by the RSPA and the US Congress. Some new regulations have been enacted. The next few years will see a great deal of regulatory activity regarding natural gas and hazardous liquid pipelines, much of it resulting from legislative requirements. The office of Pipeline Safety is currently conducting a study to streamline its operations. This study is analyzing the office's business, social and technical operations with the goal of improving overall efficiency, effectiveness, productivity and job satisfaction to meet the challenges of the future

  15. Air pollution control regulation. [Japan

    Energy Technology Data Exchange (ETDEWEB)

    Sogabe, K

    1975-05-01

    The Basic Law for Environmental Pollution Control is reviewed. The fundamental ideology of pollution control, range of pollution control, environmental standards, and national policy concerning pollution control are discussed. The content of the Air Pollution Control Law is summarized. The purpose of the Air Pollution Control Law, a list of substances regulated by the law, the type of facilities regulated by the law, control standards, type of control means, and emission standards for flue gas (sulfur oxides, particulate matters, and toxic substances) are described. The environmental standard for each pollutant and the target date for achieving the environmental standard are also given. The list of cities where the 7-rank K value control regulation for SOx is enforced is given. The procedure for registration in compliance with the law is also described.

  16. Assessing self-regulation strategies

    DEFF Research Database (Denmark)

    de Vet, Emely; de Ridder, Denise T. D.; Stok, Marijn

    2014-01-01

    intake and background characteristics. In study 3, the TESQ-E was administered twice within four weeks to evaluate test-retest reliability (n = 140). Study 4 was a cross-sectional survey (n = 93) that assessed the TESQ-E and related psychological constructs (e.g., motivation, autonomy, self-control). All...... general self-regulation and motivation measures. Conclusions: The TESQ-E provides a reliable and valid measure to assess six theory-based self-regulation strategies that adolescents may use to ensure their healthy eating....

  17. Supersymmetric regulators and supercurrent anomalies

    International Nuclear Information System (INIS)

    Majumdar, P.; Poggio, E.C.; Schnitzer, H.J.

    1980-01-01

    The supercurrent anomalies of the supercurrent deltasub(μ) of the supersymmetric Yang-Mills theory in Wess-Zumino gauge are computed using the supersymmetric dimensional regulator of Siegel. It is shown that γsub(μ)deltasup(μ) = 0 and deltasub(μ)deltasup(μ) unequal 0 in agreement with an earlier calculation based on the Adler-Rosenberg method. The problem of exhibiting the chiral anomaly and a regulator for local supersymmetry suggests that the interpretation of dimensional reduction in component language is incomplete. (orig.)

  18. Introduction to international radio regulations

    Energy Technology Data Exchange (ETDEWEB)

    Struzak, R

    2003-12-15

    These notes introduce the ITU Radio Regulations and related UN and WTO agreements that specify how terrestrial and satellite radio should be used in all countries over the planet. Access to the existing information infrastructure, and to that of the future Information Society, depends critically on these regulations. The paper also discusses few problems related to the use of the radio frequencies and satellite orbits. The notes are extracted from a book under preparation, in which these issues are discussed in more detail. (author)

  19. Introduction to international radio regulations

    International Nuclear Information System (INIS)

    Struzak, R.

    2003-01-01

    These notes introduce the ITU Radio Regulations and related UN and WTO agreements that specify how terrestrial and satellite radio should be used in all countries over the planet. Access to the existing information infrastructure, and to that of the future Information Society, depends critically on these regulations. The paper also discusses few problems related to the use of the radio frequencies and satellite orbits. The notes are extracted from a book under preparation, in which these issues are discussed in more detail. (author)

  20. Government regulation of gambling business

    Directory of Open Access Journals (Sweden)

    Stepasyuk S.A.

    2017-05-01

    Full Text Available the article deals with the problems of modern gambling business in the Russian Federation, political and legal, civil and economic aspects of state politics development in the field of activities regulation. The Federal Law regulating the activity of gambling business has been analyzed. The author has offered some developments of gambling business in the Russian Federation in order to increase the revenues to the budgets of the regions; to increase the attractiveness of the Russian resorts; to create more job opportunities and to eradicate unemployment.

  1. Gas distribution regulations (Nova Scotia)

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-11-03

    A consolidation of Nova Scotia`s gas distribution regulations made under subsection 42(1) of the Gas Distribution Act S.N.S. 1997, c4 - O.I.C. 1998-576 (November 10, 1998), N.S. Reg. 86/98 are presented. The consolidation is issued for reference purposes only, and while it has no official sanction, it is considered useful in providing an interpretation of the regulation, explaining franchise evaluation, the granting of franchises, and exemptions from application requirements. 1 tab.

  2. Explaining (Missing) Regulator Paradigm Shifts

    DEFF Research Database (Denmark)

    Wigger, Angela; Buch-Hansen, Hubert

    2014-01-01

    The global financial and economic crisis has prompted some scholars to suggest that a fundamental regulatory shift away from neoliberalism will take place – both in general and in the field of EU competition regulation. This paper shows that so far no radical break with the neoliberal type...... regulation after the crisis in the 1970s, the paper argues that the preconditions for a fundamental shift in this issue area are not present this time around. Several reasons account for this: the current crisis has been construed by economic and political elites as a crisis within and not of neoliberal...

  3. Minsky and dynamic macroprudential regulation

    Directory of Open Access Journals (Sweden)

    Jan Kregel

    2014-06-01

    Full Text Available In the context of current debates about the proper form of prudential regulation and proposals for the imposition of liquidity and capital ratios, the paper examines Hyman Minsky’s work as a consultant to government agencies exploring financial regulatory reform in the 1960s. As the author explains, this often-overlooked early work, a precursor to Minsky’s “financial instability hypothesis”, serves as yet another useful guide to explaining why regulation and supervision in the lead-up to the 2008 financial crisis were flawed, and why the approach to reregulation after the crisis has been incomplete.

  4. Development of waste management regulations

    International Nuclear Information System (INIS)

    Elnour, E.G.

    2012-04-01

    Radioactive wastes are generated during nuclear fuel cycle operation, production and application of radioisotope in medicine, industry, research, and agriculture, and as a by product of natural resource exploitation, which includes mining and processing of ores. To ensure the protection of human health and the environment from the hazard of these wastes, a planned integrated radioactive waste management practice should be applied. The purpose of this study is to develop regulations for radioactive waste management for low and intermediate radioactive level waste (LILW), and other purpose of regulations is to establish requirements with which all organizations must comply in Sudan from LILW in particular disused/spent sources, not including radioactive waste for milling and mining practices. The national regulations regarding the radioactive waste management, should prescribe the allocation of responsibilities and roles of the Country, the regulatory body, user/owner, waste management organization, including regulations on transport packaging of waste and applied a quality assurance programme, to ensure that radioactive waste management is done safely and securely. (author)

  5. Regulating and Combating Underground Banking

    NARCIS (Netherlands)

    Borgers, M.J.

    2009-01-01

    In combating and regulating underground banking, a choice can be made of roughly two models, the risk model and the assimilation model. The risk model comes down to a complete prohibition of underground banking combined with an active investigation and prosecution policy. In the assimilation model,

  6. Transcriptional regulation of hepatic lipogenesis.

    Science.gov (United States)

    Wang, Yuhui; Viscarra, Jose; Kim, Sun-Joong; Sul, Hei Sook

    2015-11-01

    Fatty acid and fat synthesis in the liver is a highly regulated metabolic pathway that is important for very low-density lipoprotein (VLDL) production and thus energy distribution to other tissues. Having common features at their promoter regions, lipogenic genes are coordinately regulated at the transcriptional level. Transcription factors, such as upstream stimulatory factors (USFs), sterol regulatory element-binding protein 1C (SREBP1C), liver X receptors (LXRs) and carbohydrate-responsive element-binding protein (ChREBP) have crucial roles in this process. Recently, insights have been gained into the signalling pathways that regulate these transcription factors. After feeding, high blood glucose and insulin levels activate lipogenic genes through several pathways, including the DNA-dependent protein kinase (DNA-PK), atypical protein kinase C (aPKC) and AKT-mTOR pathways. These pathways control the post-translational modifications of transcription factors and co-regulators, such as phosphorylation, acetylation or ubiquitylation, that affect their function, stability and/or localization. Dysregulation of lipogenesis can contribute to hepatosteatosis, which is associated with obesity and insulin resistance.

  7. Technical regulation of nondestructive inspection

    International Nuclear Information System (INIS)

    1995-01-01

    It starts with the explanation of definition of nondestructive inspection and qualifications for a inspection. It lists the technical regulations of nondestructive inspections which are radiographic testing, ultrasonic flaw detecting test, liquid penetrant test, magnetic particle inspection, eddy current test visual inspection and leakage test.

  8. Immune regulation by microbiome metabolites.

    Science.gov (United States)

    Kim, Chang H

    2018-03-22

    Commensal microbes and the host immune system have been co-evolved for mutual regulation. Microbes regulate the host immune system, in part, by producing metabolites. A mounting body of evidence indicates that diverse microbial metabolites profoundly regulate the immune system via host receptors and other target molecules. Immune cells express metabolite-specific receptors such as P2X 7 , GPR41, GPR43, GPR109A, aryl hydrocarbon receptor precursor (AhR), pregnane X receptor (PXR), farnesoid X receptor (FXR), TGR5 and other molecular targets. Microbial metabolites and their receptors form an extensive array of signals to respond to changes in nutrition, health and immunological status. As a consequence, microbial metabolite signals contribute to nutrient harvest from diet, and regulate host metabolism and the immune system. Importantly, microbial metabolites bidirectionally function to promote both tolerance and immunity to effectively fight infection without developing inflammatory diseases. In pathogenic conditions, adverse effects of microbial metabolites have been observed as well. Key immune-regulatory functions of the metabolites, generated from carbohydrates, proteins and bile acids, are reviewed in this article. © 2018 John Wiley & Sons Ltd.

  9. Deceptive Business Practices: State Regulations.

    Science.gov (United States)

    Rohrer, Daniel Morgan

    Although much has been done at the federal level to control deceptive advertising practices, many states have no criminal laws designed to regulate advertising, and several states recently repealed such laws. This paper examines states' efforts to balance the advertiser's freedom of speech with the consumer's need for information about products by…

  10. Lasp-1 regulates podosome function.

    Directory of Open Access Journals (Sweden)

    Miriam Stölting

    Full Text Available Eukaryotic cells form a variety of adhesive structures to connect with their environment and to regulate cell motility. In contrast to classical focal adhesions, podosomes, highly dynamic structures of different cell types, are actively engaged in matrix remodelling and degradation. Podosomes are composed of an actin-rich core region surrounded by a ring-like structure containing signalling molecules, motor proteins as well as cytoskeleton-associated proteins. Lasp-1 is a ubiquitously expressed, actin-binding protein that is known to regulate cytoskeleton architecture and cell migration. This multidomain protein is predominantely present at focal adhesions, however, a second pool of Lasp-1 molecules is also found at lamellipodia and vesicle-like microdomains in the cytosol.In this report, we show that Lasp-1 is a novel component and regulator of podosomes. Immunofluorescence studies reveal a localization of Lasp-1 in the podosome ring structure, where it colocalizes with zyxin and vinculin. Life cell imaging experiments demonstrate that Lasp-1 is recruited in early steps of podosome assembly. A siRNA-mediated Lasp-1 knockdown in human macrophages affects podosome dynamics as well as their matrix degradation capacity. In summary, our data indicate that Lasp-1 is a novel component of podosomes and is involved in the regulation of podosomal function.

  11. Entry: direct control or regulation?

    NARCIS (Netherlands)

    Perotti, E.; Vorage, M.

    2009-01-01

    We model a setting in which citizens form coalitions to seek preferential entry to a given market. The lower entry the higher firm profits and political contributions, but the lower social welfare. Politicians choose to either control entry directly and be illegally bribed, or regulate entry using a

  12. Hard work in soft regulation

    DEFF Research Database (Denmark)

    Hohnen, Pernille; Hasle, Peter; Helbo Jespersen, Anne

    Certified occupational health and safety management (OHSM) systems have become a global instrument in the regulation of work environment. However, their actual impact on occupational health and safety – in particular on ‘softer’ psychosocial areas of the working environment – has been questioned...

  13. Epigenetic regulation of macrophage function

    NARCIS (Netherlands)

    Hoeksema, M.A.

    2016-01-01

    Atherosclerosis is a lipid-driven chronic inflammatory disorder with a key role for macrophages in all disease stages. Macrophages are involved as scavengers of lipids, regulate inflammation, attract other immune cells and contribute to the resolution of inflammation, fibrosis and plaque stability.

  14. Incentives and regulation in banking

    NARCIS (Netherlands)

    Martynova, N.

    2015-01-01

    The financial crisis of 2007-2008 has unveiled the hidden flaws in the regulatory framework of the financial sector. The rules of the game established by regulators were not stringent enough and provided bankers with wrong incentives to gamble with depositors’ money. There are two major challenges

  15. Wave Dragon Buoyancy Regulation Study

    DEFF Research Database (Denmark)

    Jakobsen, Jens; Kofoed, Jens Peter

    Wave Dragon is a wave energy converter, which was deployed offshore at Nissum Bredning in Denmark in 2003. The experience gained from operating Wave Dragon during 2003 and 2004 has shown that the buoyancy regulation system can be improved in a number of ways. This study describes the current...

  16. Some regulation aspects in dismantling

    International Nuclear Information System (INIS)

    Niel, J.C.

    1993-01-01

    In the French regulation framework, operations linked to dismantling are controlled by an overall technical and legislative system applied to all the different stages of the facility (commissioning, etc.). Government control on facilities under dismantling is aimed at dismantling operation safety and security, and dismantling waste processing in order to ensure public and environmental protection

  17. Compliance with air quality regulations

    International Nuclear Information System (INIS)

    Steen, D.V.; Tackett, D.L.

    1990-01-01

    Due to the probable passage of Clean Air Act Amendments in 1990, electric utilities throughout the United States are faced with numerous choices to comply with the new acid rain regulations, expected in 1991. The choice of a compliance plan is not a simple task. Every compliance option will be costly. At Ohio Edison, deliberations are quite naturally influenced by past compliance with air quality regulations. This paper discusses compliance with air quality regulations in the 1970's, clean coal technologies and advanced scrubbers, and compliance with air quality regulations in 1995 - 2000. The choice of a compliance strategy for many utilities will involve serving customer loads through some combination of scrubbers, clean coal technologies, fuel switching, fuel blending, redispatch of units, and emissions trading. Whatever the final choice, it must be economic while providing sufficient flexibility to accommodate the critical uncertainties of load growth, state regulatory treatment, markets for emission allowances, advancements in control technologies, additional federal requirements for air emissions, equipment outages and fuel supply disruptions.s

  18. Transport regulation for radioactive materials

    International Nuclear Information System (INIS)

    Ha Vinh Phuong.

    1986-01-01

    Taking into account the specific dangers associated with the transport of radioactive materials (contamination, irradiation, heat, criticality), IAEA regulations concerning technical specifications and administrative procedures to ward off these dangers are presented. The international agreements related to the land transport, maritime transport and air transport of radioactive materials are also briefly reviewed

  19. Liquidity regulation and bank behavior

    NARCIS (Netherlands)

    Bonner, C.

    2014-01-01

    In response to the 2007-08 financial crisis, the Basel Committee on Banking Supervision proposed two liquidity standards to reinforce banks’ resilience to liquidity risks. The purpose of this thesis is to analyze the impact of liquidity regulation on bank behavior. The first of four main chapters

  20. Capital regulation and tail risk

    NARCIS (Netherlands)

    Perotti, E.; Ratnovski, L.; Vlahu, R.

    2011-01-01

    The paper studies risk mitigation associated with capital regulation, in a context when banks may choose tail risk assets. We show that this undermines the traditional result that higher capital reduces excess risk-taking driven by limited liability. When capital raising is costly, poorly

  1. Capital regulation and tail risk

    NARCIS (Netherlands)

    Perotti, E.; Ratnovski, L.; Vlahu, R.

    2011-01-01

    The paper studies risk mitigation associated with capital regulation, in a context where banks may choose tail risk assets. We show that this undermines the traditional result that higher capital reduces excess risk taking driven by limited liability. Moreover, higher capital may have an unintended

  2. The New Brussels I Regulation

    DEFF Research Database (Denmark)

    Arnt Nielsen, Peter

    2013-01-01

    The most important amendments to the Brussels I Regulation adopted on 12 December 2012 are presented and discussed. The amendments concern: 1) arbitration, 2) external situations, 3) choice-of-court agreements, and 4) abolition of exequatur. Compared to the Commission's ambitions, only modest...

  3. 7 CFR 3.87 - Agency regulations.

    Science.gov (United States)

    2010-01-01

    ... 7 Agriculture 1 2010-01-01 2010-01-01 false Agency regulations. 3.87 Section 3.87 Agriculture Office of the Secretary of Agriculture DEBT MANAGEMENT Federal Salary Offset § 3.87 Agency regulations. USDA agencies may issue regulations or policies not inconsistent with OPM regulations (5 CFR part 550...

  4. 76 FR 62630 - Information Security Regulations

    Science.gov (United States)

    2011-10-11

    ... CENTRAL INTELLIGENCE AGENCY 32 CFR Part 1902 Information Security Regulations AGENCY: Central... information security regulations which have become outdated. The Executive Order upon which the regulations... CFR Part 1902 Information security regulations. PART 1902 [REMOVED AND RESERVED] Sec. 1902.13 [Removed...

  5. The Legal Regulation of Cybersecurity

    Directory of Open Access Journals (Sweden)

    Darius Štitilis

    2013-08-01

    Full Text Available Cybercrime has become a global phenomenon, which is causing more harm to individual citizens, organizations, society and the state. Most countries in the world compare cybercrime with offences such as terrorism and drug trafficking due to its risks and profitability. Cybersecurity is the central category to fight cybercrime in cyberspace. Therefore, the strategic legal regulation of cybersecurity is one of the most relevant problems in EU, including Lithuania. So far cybersecurity legal regulation analysis in scientific literature has been rather limited. The European Commission, together with the High Representative of the Union for Foreign Affairs and Security Policy, has published a cybersecurity strategy alongside a Commission proposed directive on network and information security (NIS. The cybersecurity strategy – “An Open, Safe and Secure Cyberspace” - represents the EU’s comprehensive vision on how best to prevent and respond to cyber disruptions and attacks. The purpose of its is to further European values of freedom and democracy and ensure the digital economy can safely grow. Specific actions are aimed at enhancing cyber resilience of information systems, reducing cybercrime and strengthening EU international cyber-security policy and cyber defence. The main goal of the paper is to analyze and compare the EU cybersecurity strategy and experience of several foreign countries with the strategic legal regulation of cybersecurity in Lithuania. The article consists of four parts. The first part dealt with the EU cybersecurity strategy. The second part of the article examines the comparative aspect of foreign cybersecurity strategic legal regulation. The third part deals with attempts in Lithuania to draft cybersecurity law and the holistic approach of cybersecurity legal regulation. The fourth part examines Lithuanian cybersecurity strategy and comments on the main probleas related with the strategy. Several different approaches

  6. Self-regulation in securities markets

    OpenAIRE

    Carson, John

    2011-01-01

    This paper canvasses the trends in self-regulation and the role of self-regulation in securities markets in different parts of the world. The paper also describes the conditions in which self-regulation might be an effective element of securities markets regulation, particularly in emerging markets. Use of self-regulation and self-regulatory organizations is often recommended in emerging m...

  7. Connections or conflicts between nuclear regulations and other regulations

    International Nuclear Information System (INIS)

    Shapar, H.K.

    1976-01-01

    The potential for conflicts between nuclear and other regulations stems in large part from overlapping jurisdictional lines which reflect not only the basic governmental structure but the political realities as well. A completely logical pattern - with a clear differentiation of responsibilities assigned to the various departments and agencies involved - is assuredly a worthy goal, but one not often, if ever, achieved. Fortunately, innovative means for obviating or mitigating the conflicts can be and have been found. (Auth) [fr

  8. Targeted genome regulation via synthetic programmable transcriptional regulators

    KAUST Repository

    Piatek, Agnieszka Anna

    2016-04-19

    Regulation of gene transcription controls cellular functions and coordinates responses to developmental, physiological and environmental cues. Precise and efficient molecular tools are needed to characterize the functions of single and multiple genes in linear and interacting pathways in a native context. Modular DNA-binding domains from zinc fingers (ZFs) and transcriptional activator-like proteins (TALE) are amenable to bioengineering to bind DNA target sequences of interest. As a result, ZF and TALE proteins were used to develop synthetic programmable transcription factors. However, these systems are limited by the requirement to re-engineer proteins for each new target sequence. The clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR associated 9 (Cas9) genome editing tool was recently repurposed for targeted transcriptional regulation by inactivation of the nuclease activity of Cas9. Due to the facile engineering, simplicity, precision and amenability to library construction, the CRISPR/Cas9 system is poised to revolutionize the functional genomics field across diverse eukaryotic species. In this review, we discuss the development of synthetic customizable transcriptional regulators and provide insights into their current and potential applications, with special emphasis on plant systems, in characterization of gene functions, elucidation of molecular mechanisms and their biotechnological applications. © 2016 Informa UK Limited, trading as Taylor & Francis Group

  9. Regulating danger on the highways: hours of service regulations.

    Science.gov (United States)

    Mansfield, Daniel; Kryger, Meir

    2015-12-01

    Current hours of service regulations governing commercial truck drivers in place in the United States, Canada, Australia, and the European Union are summarized and compared to facilitate the assessment of the effectiveness of such provisions in preventing fatigue and drowsiness among truck drivers. Current hours of service provisions governing commercial truck drivers were derived from governmental sources. The commercial truck driver hours of service provisions in the United States, Canada, and the European Union permit drivers to work 14 hours and those of Australia permit drivers to work 12 hours a day on a regular basis. The regulations do not state what a driver may do with time off. They are consistent with a driver being able to drive after 24 hours without sleep. They do not take into account circadian rhythm by linking driving or rest to time of day. Current hours of service regulations governing commercial truck drivers leave gaps--permitting drivers to work long hours on a regular basis, permitting driving after no sleep for 24 hours, and failing to take into account the importance of circadian rhythm, endangering the public safety and the truck drivers themselves. Copyright © 2015 National Sleep Foundation. Published by Elsevier Inc. All rights reserved.

  10. Incentive regulation of nuclear power plants by state regulators

    International Nuclear Information System (INIS)

    Martin, R.L.; Baker, K.; Olson, J.

    1991-02-01

    The Nuclear Regulatory Commission (NRC) monitors incentive programs established by state regulators in order to obtain current information and to consider the potential safety effects of the incentive programs as applied to nuclear units. The current report is an update of NUREG/CR-5509, Incentive Regulation of Nuclear Power Plants by State Public Utility Commissions, published in December 1989. The information in this report was obtained from interviews conducted with each state regulator and each utility with a minimum entitlement of 10%. The agreements, orders, and settlements from which each incentive program was implemented were reviewed as required. The interviews and supporting documentation form the basis for the individual state reports describing the structure and financial impact of each incentive program. The programs currently in effect represent the adoption of an existing nuclear performance incentive program proposal and one new program. In addition, since 1989 a number of nuclear units have been included in one existing program; while one program was discontinued and another one concluded. 6 refs., 27 tabs

  11. Study on the Regulating Performance of Sliding Regulation-Valve

    Science.gov (United States)

    Hu, Wei; Peng, Xiaoyong; Zhang, Yuan; Zheng, Yulan; Zhu, Fangyao

    2018-01-01

    Using a proven reliable method of CFD to study the regulating performance of a sliding regulation valve with a conical spool and rugby body. The numerical simulation results indicate that no matter where the spool is located, the flow field always has a vortex at the center of the valve body; When the spool is at the origin, the vortex and resistance coefficient of the valve are the minimum; When the spool moves from the origin to the right (the opening of the valve becomes smaller) to reach a certain position later, vortex currents also begin to appear around the tube wall behind the orifice. In addition, the vortex increases as the throttling port decreases whereas the resistance coefficient of the valve ascends slowly with the increase of the deviation of the spool and the rise in series; This type of regulating valve has S type (slow at both ends, sensitive at the center) flow characteristics at the stroke, and is not affected by the size of Re.

  12. ErbB2-Driven Breast Cancer Cell Invasion Depends on a Complex Signaling Network Activating Myeloid Zinc Finger-1-Dependent Cathepsin B Expression

    DEFF Research Database (Denmark)

    Rafn, Bo; Nielsen, Christian Thomas Friberg; Andersen, Sofie Hagel

    2012-01-01

    Aberrant ErbB2 receptor tyrosine kinase activation in breast cancer is strongly linked to an invasive disease. The molecular basis of ErbB2-driven invasion is largely unknown. We show that cysteine cathepsins B and L are elevated in ErbB2 positive primary human breast cancer and function...... as effectors of ErbB2-induced invasion in vitro. We identify Cdc42-binding protein kinase beta, extracellular regulated kinase 2, p21-activated protein kinase 4, and protein kinase C alpha as essential mediators of ErbB2-induced cysteine cathepsin expression and breast cancer cell invasiveness. The identified...

  13. Dealing with duplicate regulations and conflicting jurisdictions

    International Nuclear Information System (INIS)

    Aamodt, P.L.

    1991-01-01

    There are a number of situations where mixed wastes are regulated by dual regulations and regulators. This presentation attempts to show where such duplication exists and how it evolved historically through legislative actions. The presentation includes a discussion of strategies that have been used to deal with the problems that result from duplicate regulations and jurisdictional conflicts. The RCRA and AEA regulations are really more similar than dissimilar. There are significant issues that must be worked through with the regulators. It is most important to work with your regulators early in process. The following are suggestions for dealing with the regulators. (1) Know the regulations in advance of discussions. (2) Begin dialogue with the regulator(s) as early as possible and get to know the people you will be dealing with -- and let them know you. (3) Explain the technical/regulatory issues/problems that you face at your facility in sufficient detail that they are clearly understood, and work with the regulator(s) to reasonably address them in the language/requirements of the permit. (4) Always attempt to comply with the regulations first before going in with a variance request -- document your efforts, and be honest with your assessment of issues. (5) Don't be adversarial -- remember that the regulator has the same objectives as you do. 1 tab

  14. Frontiers of environmental regulation: environmental management systems: a regulator`s perspective

    Energy Technology Data Exchange (ETDEWEB)

    Stone, M.J. [South Australian Dept. of Mines and Energy, Adelaide, SA (Australia)

    1996-12-31

    Leading edge companies throughout the world have embraced management systems to achieve optimal sustainable performance in the ever changing business environment of the 1990s. Given that the natural environment and environmental performance have become major issues affecting organizations, the need for integrating environmental management with all the other components of an organization`s overall management approach is now widely recognized. This paper is organized in five parts. The first explores recently released environmental standards, the interim environmental management systems (EMS) general guidelines standard AS/NZS ISO 14004 (Int) and identifies how this has dealt with the regulator/community/company interface. The second identifies company requirements for addressing environmental issues. The third, considers regulatory theory to identify current requirements for an effective regulatory system and how this can interface with a company`s EMS. These form the basis in the fourth section for identifying some opportunities which occur at the company/ regulator interface. The fifth and final section draws a number of conclusions about the current frontiers of environmental regulation. The coincidence of the requirements of a regulatory framework with the areas of interface between what is referred to in the draft International Standard for EMS as `Interested Parties`, the regulators and community, are identified. (author). 1 tab., 2 figs., 20 refs.

  15. 75 FR 10997 - Cuban Assets Control Regulations; Sudanese Sanctions Regulations; Iranian Transactions Regulations

    Science.gov (United States)

    2010-03-10

    ... specific license, or otherwise exempt, the exportation of such services and software from the United States... services and software. Paragraph (c) of each of these two sections provides that specific licenses may be... Iranian Transactions Regulations to authorize the exportation of certain services and software incident to...

  16. Information, Interests, and Environmental Regulation

    DEFF Research Database (Denmark)

    Winter, Søren; May, Peter J.

    2002-01-01

    This study contributes to the understanding of informational approaches to bringing about compliance with environmental regulations with particular attention to differences in the influence of information provided by different information sources. Based on theorizing from a combination of informa......This study contributes to the understanding of informational approaches to bringing about compliance with environmental regulations with particular attention to differences in the influence of information provided by different information sources. Based on theorizing from a combination...... of information processing and interest group literatures, we develop hypotheses about regulatees' reliance upon and the influence of different sources of information. We test these hypotheses for Danish farmers’ compliance with agro-environmental rules. Our findings show that information plays a role in bringing...

  17. Ligand-regulated peptide aptamers.

    Science.gov (United States)

    Miller, Russell A

    2009-01-01

    The peptide aptamer approach employs high-throughput selection to identify members of a randomized peptide library displayed from a scaffold protein by virtue of their interaction with a target molecule. Extending this approach, we have developed a peptide aptamer scaffold protein that can impart small-molecule control over the aptamer-target interaction. This ligand-regulated peptide (LiRP) scaffold, consisting of the protein domains FKBP12, FRB, and GST, binds to the cell-permeable small-molecule rapamycin and the binding of this molecule can prevent the interaction of the randomizable linker region connecting FKBP12 with FRB. Here we present a detailed protocol for the creation of a peptide aptamer plasmid library, selection of peptide aptamers using the LiRP scaffold in a yeast two-hybrid system, and the screening of those peptide aptamers for a ligand-regulated interaction.

  18. Electric Power Regulation in Mexico

    Energy Technology Data Exchange (ETDEWEB)

    Landa, J V [Universidad Nacional Autonoma de Mexico, Mexico City (Mexico)

    1994-12-31

    The history of the electrical power sector in Mexico, the prominent role that government plays in the generation, transformation, distribution and supply of electrical power, and the implications of the North American Free Trade Agreement (NAFTA) for this sector were summarized. The slow pace of the Mexican electricity sector in achieving cost efficiency through pricing policy was criticized, and the issue of regulation versus deregulation of the electricity sector was examined in the context of NAFTA, emphasizing the contradiction between the idea of international trade and a highly regulated industry. Revisions of the original constitutional article to exclude electrical power generation from governmental control and to allow market mechanisms and competition to lower costs and increase efficiency was recommended.It was considered a pre-condition to a stable balance between competition and energy efficient environmentally friendly practices.

  19. Decentralized method for utility regulation

    Energy Technology Data Exchange (ETDEWEB)

    Loeb, M. (North Carolina State Univ., Raleigh); Magat, W.A.

    1979-10-01

    A new institutional arrangement for regulating utilities is suggested that minimizes the costs of natural monopolies. A mixture of regulation and franchising, the plan draws on the advantages of each and eliminates many of the problems. The proposal allows utilities to set their own price on the basis of demand and marginal-cost projections. Subsidies are provided by the regulatory agency if there is a consumer surplus. The system encourages the utility to select a competitive price and to produce only the amount of service needed. Operating efficiency is encouraged by rewarding cost reductions and discouraging cost overstatement at the rate review. The regulatory agency would not need to take action to bring price and marginal costs into equality. The franchise sale can be made by competitive bidding, in which the bidders would capitalize part or all of the subsidy or the regulatory agency could recover the subsidy in a lump-sum tax on the utility.

  20. Regulating health: transcending disciplinary boundaries.

    Science.gov (United States)

    Seddon, Toby

    2013-03-01

    Health and health care problems can be addressed from multiple disciplinary perspectives. This raises challenges for how to do cross-disciplinary scholarship in ways that are still robust, rigorous and coherent. This paper sets out one particular approach to cross-cutting research--regulation--which has proved extremely fertile for scholars working in diverse fields, from coal mine safety to tax compliance. The first part of the paper considers how regulatory ideas might be applied to health and health care research in general. The second part goes on to sketch out how a regulation perspective on one specific area, illicit drug policy, can open up new directions for research. In conclusion, a future research agenda is outlined for regulatory scholarship on health and health care.

  1. Culture, emotion regulation, and adjustment.

    Science.gov (United States)

    Matsumoto, David; Yoo, Seung Hee; Nakagawa, Sanae

    2008-06-01

    This article reports differences across 23 countries on 2 processes of emotion regulation--reappraisal and suppression. Cultural dimensions were correlated with country means on both and the relationship between them. Cultures that emphasized the maintenance of social order--that is, those that were long-term oriented and valued embeddedness and hierarchy--tended to have higher scores on suppression, and reappraisal and suppression tended to be positively correlated. In contrast, cultures that minimized the maintenance of social order and valued individual Affective Autonomy and Egalitarianism tended to have lower scores on Suppression, and Reappraisal and Suppression tended to be negatively correlated. Moreover, country-level emotion regulation was significantly correlated with country-level indices of both positive and negative adjustment. (PsycINFO Database Record (c) 2008 APA, all rights reserved).

  2. Public regulation of nuclear plants

    International Nuclear Information System (INIS)

    Burtheret, M.; Cormis, de

    1980-01-01

    The construction and operation of nuclear plants are subject to a complex system of governmental administration. The authors list the various governmental authorisations and rules applicable to these plants. In the first part, they describe the national regulations which relate specifically to nuclear plants, and emphasize the provisions which are intended to ensure the safety of the installations and the protection of the public against ionizing radiation. However, while the safety of nuclear plants is a major concern of the authorities, other interests are also protected. This is accomplished by various laws or regulations which apply to nuclear plants as well as other industrial installations. The duties which these texts, and the administrative practice based thereon, impose on Electricite de France are covered in the second part [fr

  3. Epigenetic microRNA Regulation

    DEFF Research Database (Denmark)

    Wiklund, Erik Digman

    2011-01-01

    MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) that negatively regulate gene expression post-transcriptionally by binding to complementary sequences in the 3’UTR of target mRNAs in the cytoplasm. However, recent evidence suggests that certain miRNAs are enriched in the nucleus, and their t......MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) that negatively regulate gene expression post-transcriptionally by binding to complementary sequences in the 3’UTR of target mRNAs in the cytoplasm. However, recent evidence suggests that certain miRNAs are enriched in the nucleus...

  4. Molecular Mechanisms of Appetite Regulation

    Directory of Open Access Journals (Sweden)

    Ji Hee Yu

    2012-12-01

    Full Text Available The prevalence of obesity has been rapidly increasing worldwide over the last several decades and has become a major health problem in developed countries. The brain, especially the hypothalamus, plays a key role in the control of food intake by sensing metabolic signals from peripheral organs and modulating feeding behaviors. To accomplish these important roles, the hypothalamus communicates with other brain areas such as the brainstem and reward-related limbic pathways. The adipocyte-derived hormone leptin and pancreatic β-cell-derived insulin inform adiposity to the hypothalamus. Gut hormones such as cholecystokinin, peptide YY, pancreatic polypeptide, glucagon-like peptide 1, and oxyntomodulin transfer satiety signals to the brain and ghrelin relays hunger signals. The endocannabinoid system and nutrients are also involved in the physiological regulation of food intake. In this article, we briefly review physiological mechanisms of appetite regulation.

  5. Regulating Power from Supermarket Refrigeration

    DEFF Research Database (Denmark)

    O'Connell, Niamh; Madsen, Henrik; Pinson, Pierre

    2014-01-01

    the Danfoss refrigeration test centre. The complexities of modelling demand response are demonstrated through simulation. Simulations are conducted by placing the identified model in a direct-control demand response architecture, with power reference tracking using model predictive control. The energylimited......This paper presents an analysis of the demand response capabilities of a supermarket refrigeration system, with a particular focus on the suitability for participation in the regulating power market. An ARMAX model of a supermarket refrigeration system is identified using experimental data from...... nature of demand response from refrigeration is identified as the key consideration when considering participation in the regulating power market. It is demonstrated that by restricting the operating regions of the supermarket refrigeration system, a simple relationship can be found between the available...

  6. Epigenetic regulation of photoperiodic flowering

    OpenAIRE

    Takeno, Kiyotoshi

    2010-01-01

    The cytidine analogue 5-azacytidine, which causes DNA demethylation, induced flowering in the non-vernalization-requiring plants Perilla frutescens var. crispa, Silene armeria and Pharbitis nil (synonym Ipomoea nil) under non-inductive photoperiodic conditions, suggesting that the expression of photoperiodic flowering-related genes is regulated epigenetically by DNA methylation. The flowering state induced by DNA demethylation was not heritable. Changes in the genome-wide methylation state we...

  7. Insurance: Accounting, Regulation, Actuarial Science

    OpenAIRE

    Alain Tosetti; Thomas Behar; Michel Fromenteau; Stéphane Ménart

    2001-01-01

    We shall be examining the following topics: (i) basic frameworks for accounting and for statutory insurance rules; and (ii) actuarial principles of insurance; for both life and nonlife (i.e. casualty and property) insurance.Section 1 introduces insurance terminology, regarding what an operation must include in order to be an insurance operation (the legal, statistical, financial or economic aspects), and introduces the accounting and regulation frameworks and the two actuarial models of insur...

  8. Radiation Safety (Qualifications) Regulations 1980

    International Nuclear Information System (INIS)

    1980-01-01

    These Regulations, promulgated pursuant to the provisions of the Radiation Safety Act, 1975-1979, require persons engaged in activities involving radiation to pass a radiation safety examination or to possess an approved qualification in radiation. The National Health and Medical Research Council is authorised to exempt persons from compliance with these requirements or, conversely, to impose such requirements on persons other than those designated. (NEA) [fr

  9. Illiquidity, insolvency, and banking regulation

    OpenAIRE

    Cao, Jin

    2010-01-01

    This paper provides a compact framework for banking regulation analysis in the presence of uncertainty between systemic liquidity and solvency shocks. Extending the work by Cao & Illing (2009a, b), it is shown that systemic liquidity shortage arises endogenously as part of the inferior mixed strategy equilibrium. The paper compares dierent traditional regulatory policies which intend to fix the ineciencies, and argues that the co-existence of illiquidity and insolvency problems adds extra ...

  10. Radioactive waste management and regulation

    International Nuclear Information System (INIS)

    Willrich, M.

    1976-12-01

    The following conclusions are reached: (1) safe management of post-fission radioactive waste is already a present necessity and an irreversible long-term commitment; (2) basic goals of U.S. radioactive waste policy are unclear; (3) the existing organization for radioactive waste management is likely to be unworkable if left unchanged; and (4) the existing framework for radioactive waste regulation is likely to be ineffective if left unchanged

  11. Regulators of Tfh cell differentiation

    Directory of Open Access Journals (Sweden)

    Gajendra Motiram Jogdand

    2016-11-01

    Full Text Available The follicular helper T (Tfh cells help is critical for activation of B cells, antibody class switching and germinal center formation. The Tfh cells are characterized by the expression of CXCR5, ICOS, PD-1, Bcl-6, and IL-21. They are involved in clearing infections and are adversely linked with autoimmune diseases and also have a role in viral replication as well as clearance. Tfh cells are generated from naïve CD4 T cells with sequential steps involving cytokine signaling (IL-21, IL-6, IL-12, activin A, migration and positioning in the germinal center by CXCR5, surface receptors (ICOS/ICOSL, SAP/SLAM as well as transcription factor (Bcl-6, c-Maf, STAT3 signaling and repressor miR155. On the other hand Tfh generation is negatively regulated at specific steps of Tfh generation by specific cytokine (IL-2, IL-7, surface receptor (PD-1, CTLA-4, transcription factors Blimp-1, STAT5, T-bet, KLF-2 signaling and repressor miR 146a. Interestingly, miR 17-92 and FOXO1 acts as a positive as well as a negative regulator of Tfh differentiation depending on the time of expression and disease specificity. Tfh cells are also generated from the conversion of other effector T cells as exemplified by Th1 cells converting into Tfh during viral infection. The mechanistic details of effector T cells conversion into Tfh are yet to be clear. To manipulate Tfh cells for therapeutic implication and or for effective vaccination strategies, it is important to know positive and negative regulators of Tfh generation. Hence, in this review we have highlighted and interlinked molecular signaling from cytokines, surface receptors, transcription factors, ubiquitin Ligase and miRNA as positive and negative regulators for Tfh differentiation.

  12. Regulation of eucaryotic gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Brent, R.; Ptashne, M.S

    1989-05-23

    This patent describes a method of regulating the expression of a gene in a eucaryotic cell. The method consists of: providing in the eucaryotic cell, a peptide, derived from or substantially similar to a peptide of a procaryotic cell able to bind to DNA upstream from or within the gene, the amount of the peptide being sufficient to bind to the gene and thereby control expression of the gene.

  13. On self regulation and laughter

    DEFF Research Database (Denmark)

    Buhl, Mie

      Abstract: The paper addresses the new premises for being a professional in the increasing virtual reality of universities. The new premises are being exemplified with the expansion of the professional duties of the university scholar to extend beyond merely acting as a disseminator of knowledge...... that video streaming increases self regulation and laughter. The discussions are based on empirical material in relation to both video streamed teaching sessions and online discussions....

  14. Self-regulation: the need to succeed

    International Nuclear Information System (INIS)

    Sorenson, G.C.

    1985-01-01

    The nuclear industry has long complained that it is over-regulated. Others - including the regulator - are now beginning to accept this complaint and acknowledge that perhaps the industry is over regulated and something should be done to provide relief. It is clear that regulation will not simply go away. The industry is perceived by some as one that cannot be trusted and must be closely regulated or serious health and safety consequences will result. Headlines claiming coverup of design deficiencies, allegations concerning construction problems, cheating on exams, mismanagement, intimidation of QA/QC personnel, etc., do little to dispel these concerns for the layman. This paper looks at two areas that must be considered in attempting to decrease the amount of regulator-imposed activities and increase self-regulation: 1) establish greater trust and confidence in the industry's ability to do a good job and be responsible for self-regulation; and 2) establish industry initiatives to regulate itself

  15. Circadian Regulation of Glutamate Transporters

    Directory of Open Access Journals (Sweden)

    Donají Chi-Castañeda

    2018-06-01

    Full Text Available L-glutamate is the major excitatory amino acid in the mammalian central nervous system (CNS. This neurotransmitter is essential for higher brain functions such as learning, cognition and memory. A tight regulation of extra-synaptic glutamate levels is needed to prevent a neurotoxic insult. Glutamate removal from the synaptic cleft is carried out by a family of sodium-dependent high-affinity transporters, collectively known as excitatory amino acid transporters. Dysfunction of glutamate transporters is generally involved in acute neuronal injury and neurodegenerative diseases, so characterizing and understanding the mechanisms that lead to the development of these disorders is an important goal in the design of novel treatments for the neurodegenerative diseases. Increasing evidence indicates glutamate transporters are controlled by the circadian system in direct and indirect manners, so in this contribution we focus on the mechanisms of circadian regulation (transcriptional, translational, post-translational and post-transcriptional regulation of glutamate transport in neuronal and glial cells, and their consequence in brain function.

  16. Redox regulation of plant development.

    Science.gov (United States)

    Considine, Michael J; Foyer, Christine H

    2014-09-20

    We provide a conceptual framework for the interactions between the cellular redox signaling hub and the phytohormone signaling network that controls plant growth and development to maximize plant productivity under stress-free situations, while limiting growth and altering development on exposure to stress. Enhanced cellular oxidation plays a key role in the regulation of plant growth and stress responses. Oxidative signals or cycles of oxidation and reduction are crucial for the alleviation of dormancy and quiescence, activating the cell cycle and triggering genetic and epigenetic control that underpin growth and differentiation responses to changing environmental conditions. The redox signaling hub interfaces directly with the phytohormone network in the synergistic control of growth and its modulation in response to environmental stress, but a few components have been identified. Accumulating evidence points to a complex interplay of phytohormone and redox controls that operate at multiple levels. For simplicity, we focus here on redox-dependent processes that control root growth and development and bud burst. The multiple roles of reactive oxygen species in the control of plant growth and development have been identified, but increasing emphasis should now be placed on the functions of redox-regulated proteins, along with the central roles of reductants such as NAD(P)H, thioredoxins, glutathione, glutaredoxins, peroxiredoxins, ascorbate, and reduced ferredoxin in the regulation of the genetic and epigenetic factors that modulate the growth and vigor of crop plants, particularly within an agricultural context.

  17. Neuroendocrine Regulation of Maternal Behavior

    Science.gov (United States)

    Bridges, Robert S.

    2015-01-01

    The expression of maternal behavior in mammals is regulated by the developmental and experiential events over a female’s lifetime. In this review the relationships between the endocrine and neural systems that play key roles in these developmental and experiential that affect both the establishment and maintenance of maternal care are presented. The involvement of the hormones estrogen, progesterone, and lactogens are discussed in the context of ligand, receptor, and gene activity in rodents and to a lesser extent in higher mammals. The roles of neuroendocrine factors, including oxytocin, vasopressin, classical neurotransmitters, and other neural gene products that regulate aspects of maternal care are set forth, and the interactions of hormones with central nervous system mediators of maternal behavior are discussed. The impact of prior developmental factors, including epigenetic events, and maternal experience on subsequent maternal care are assessed over the course of the female’s lifespan. It is proposed that common neuroendocrine mechanisms underlie the regulation of maternal care in mammals. PMID:25500107

  18. Hate crimes and normative regulation

    Directory of Open Access Journals (Sweden)

    Kovačević Milica

    2011-01-01

    Full Text Available This paper is primarily devoted to issues related to the normative regulation of hate crimes, with special reference to the regulations of the Republic of Serbia, which are indirectly related to this matter. This kind of crimes are characterized by prejudices that perpetrators have towards injured parties, as members of certain, mostly, minority groups, due to which many hate crimes could be also called crimes of prejudice. In comparative law there are two different basic directions when it comes to regulating hate crimes: separation of hate crimes in a separate category on the one hand, and punishment of perpetrators of criminal acts with the detriment of minority groups through the usual charges of a given criminal justice system, on the other. The author finds that, regardless of the formal response forms, real life suggests that hate crimes can be essentially suppressed only by promoting values such as equality, respect for diversity and tolerance, and by continuous education of public about the danger of hate crimes.

  19. NRC - regulator of nuclear safety

    International Nuclear Information System (INIS)

    1997-01-01

    The U.S. Nuclear Regulatory Commission (NRC) was formed in 1975 to regulate the various commercial and institutional uses of nuclear energy, including nuclear power plants. The agency succeeded the Atomic Energy Commission, which previously had responsibility for both developing and regulating nuclear activities. Federal research and development work for all energy sources, as well as nuclear weapons production, is now conducted by the U.S. Department of Energy. Under its responsibility to protect public health and safety, the NRC has three principal regulatory functions: (1) establish standards and regulations, (2) issue licenses for nuclear facilities and users of nuclear materials, and (3) inspect facilities and users of nuclear materials to ensure compliance with the requirements. These regulatory functions relate to both nuclear power plants and to other uses of nuclear materials - like nuclear medicine programs at hospitals, academic activities at educational institutions, research work, and such industrial applications as gauges and testing equipment. The NRC places a high priority on keeping the public informed of its work. The agency recognizes the interest of citizens in what it does through such activities as maintaining public document rooms across the country and holding public hearings, public meetings in local areas, and discussions with individuals and organizations

  20. Regulation of cell wall biosynthesis.

    Science.gov (United States)

    Zhong, Ruiqin; Ye, Zheng-Hua

    2007-12-01

    Plant cell walls differ in their amount and composition among various cell types and even in different microdomains of the wall of a given cell. Plants must have evolved regulatory mechanisms controlling biosynthesis, targeted secretion, and assembly of wall components to achieve the heterogeneity in cell walls. A number of factors, including hormones, the cytoskeleton, glycosylphosphatidylinositol-anchored proteins, phosphoinositides, and sugar nucleotide supply, have been implicated in the regulation of cell wall biosynthesis or deposition. In the past two years, there have been important discoveries in transcriptional regulation of secondary wall biosynthesis. Several transcription factors in the NAC and MYB families have been shown to be the key switches for activation of secondary wall biosynthesis. These studies suggest a transcriptional network comprised of a hierarchy of transcription factors is involved in regulating secondary wall biosynthesis. Further investigation and integration of the regulatory players participating in the making of cell walls will certainly lead to our understanding of how wall amounts and composition are controlled in a given cell type. This may eventually allow custom design of plant cell walls on the basis of our needs.

  1. Rethinking regulations for disposal criticality

    International Nuclear Information System (INIS)

    Scott, M.; Doering, T.

    1997-01-01

    This paper provides the basis for the position that the current U.S. Nuclear Regulatory Commission (NRC) criticality regulation is in need of revision to address problems in implementing it for the postclosure period in a geologic high-level waste repository. The authors believe that the applicant for such a facility should be able to demonstrate that postulated postclosure criticality events will not cause unacceptable risk of deleterious effects on public health and safety. In addition, the applicant should be expected to take practical and feasible measures to reduce the probability of a criticality occurring, even if (as expected) the consequences of such a criticality for repository performance and public health and safety would be negligible. This approach, while recognizing the probabilistic nature of analyses of events and conditions in the distant future, is also arguably consistent with the defense in depth concept that has been successfully applied to nuclear reactor regulation. The authors believe regulations for postclosure criticality control should support this dual approach, rather than require a deterministic prohibition of criticality as does the current rule. The existing rule seems appropriate for the preclosure period, as long as it is clearly specified to apply only to that period

  2. Deregulation, a challenge for regulators

    International Nuclear Information System (INIS)

    Alonso, Augustin

    2001-01-01

    Deregulation and competitiveness in the electricity market invites the plant owner/operator to reduce operating cost with a potential reduction in maintenance, degradation of investment in safety, reduction of operating staff and a downgrading in research and development. On the other side, deregulation and competitiveness brings the social and industrial benefit of reducing the electricity cost. Regulatory organisations have to watch that the safety level of the plant does not go beyond the established level, while recognising the benefits of the new situation; therefore they have the moral responsibility of regulating nuclear energy effectively and efficiently and in eliminating unnecessary regulatory burdens. Regulation has evolved with time and in accordance with the knowledge gained from research and the analysis of operating experience. The knowledge gained has made it possible to follow the path of other modern advanced technologies, where risk is quantified and the system approved when the risk becomes lower than an accepted level. The regulatory use of this advanced tool is being now developed by the most advanced regulatory organisations, under the name of risk informed regulation, where the reference level is the expected frequency of core damage. Deregulation and competitiveness will not change the basis of the already well established procedure to verify compliance. Nevertheless, the contents of Safety Analysis Reports and other regulatory documents, such as Technical Specifications for Operation, offer room for improvement in the sense of being more to the roots of the matter and becoming more efficient tools in the verification process. The contents of these documents have been evolving along the time and they have become unnecessary voluminous and rather burdensome. Much work has been done to improve the efficiency of regulatory inspections by concentrating on basic aspects. As a partial application of the already mentioned risk-informed regulation

  3. Regulation, control, tele-management; Regulation, commande, telegestion

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2001-07-01

    In 1998, the French public authorities have started an ambitious energy mastery policy under the auspices of the Agency of environment and energy mastery (Ademe). One aspect of this policy concerns the R and D, industrial development and applications of automation and computerized control to the energy systems of buildings. This RCT 2000 seminar takes stock of the recent advances in this domain 7 years after the previous RCT issue. The first day of the seminar was devoted to new developments in regulation and control (ergonomics aspects, lighting systems, air conditioning in accommodations, solar systems etc..). Stress was put on the revolution expected with the introduction of domestic computer applications and Internet. This first day ended with a precise status of the standardization and future regulatory aspects. The second day was dealing with tele-management and technical management systems for buildings with an analysis of the impact of Internet and of the sensors and actuators capacity in information processing. The consequences and new requirements of the thermal regulation 2000 and the factors of success of a new start-up of the tele-management market in local authorities and social accommodations were analyzed too. (J.S.)

  4. Feedback regulation between autophagy and PKA.

    Science.gov (United States)

    Torres-Quiroz, Francisco; Filteau, Marie; Landry, Christian R

    2015-01-01

    Protein kinase A (PKA) controls diverse cellular processes and homeostasis in eukaryotic cells. Many processes and substrates of PKA have been described and among them are direct regulators of autophagy. The mechanisms of PKA regulation and how they relate to autophagy remain to be fully understood. We constructed a reporter of PKA activity in yeast to identify genes affecting PKA regulation. The assay systematically measures relative protein-protein interactions between the regulatory and catalytic subunits of the PKA complex in a systematic set of genetic backgrounds. The candidate PKA regulators we identified span multiple processes and molecular functions (autophagy, methionine biosynthesis, TORC signaling, protein acetylation, and DNA repair), which themselves include processes regulated by PKA. These observations suggest the presence of many feedback loops acting through this key regulator. Many of the candidate regulators include genes involved in autophagy, suggesting that not only does PKA regulate autophagy but that autophagy also sends signals back to PKA.

  5. 77 FR 4885 - Patent Compensation Board Regulations

    Science.gov (United States)

    2012-02-01

    ... existing regulations and the promulgation of new regulations, section 3(a) of E.O.12988, ``Civil Justice... constitutional and statutory authority supporting any action that would limit the policymaking discretion of the...

  6. The financial regulations of the Agency

    International Nuclear Information System (INIS)

    2000-01-01

    On 8 June 1999, the Board of Governors adopted certain amendments to the IAEA Financial Regulations to take effect from 1 January 2002. A consolidated text of the Financial Regulations, as revised, will be issued in 2001

  7. New regulation of radioactive materials transport

    International Nuclear Information System (INIS)

    Grenier, M.

    1993-01-01

    In this text we give the modifications bringed to the French regulation to take into account the IAEA recommendations of 1990 and the regulations of the European agreements RID and ADR. 3 figs., 6 refs

  8. 75 FR 10567 - Commerce Acquisition Regulation (CAR)

    Science.gov (United States)

    2010-03-08

    ... regulations, Federal acquisition regulations, Government procurement, Government contracts, Procurement, Reporting and recordkeeping requirements. 48 CFR Part 1302 Definitions, Government procurement, Terms. 48 CFR Part 1303 Antitrust, Conflict of interests, Ethical conduct, Government procurement, Reporting and...

  9. Emotion regulation strategies in Patients with schizophrenia

    NARCIS (Netherlands)

    van der Meer, Lisette; van't Wout, Mascha; Aleman, Andre

    2009-01-01

    Schizophrenia patients might experience difficulties in applying two widely used emotion regulation strategies, reappraisal and suppression. We investigated the relationships among emotion regulation strategies, alexithymia (i.e. inability to identify and verbalize feelings) and the role of

  10. A Consumer Protection Model for Regulating Lawyers.

    Science.gov (United States)

    Chalfie, Deborah M.

    1992-01-01

    Describes and critiques the "discipline model" of lawyer regulation from a consumer point of view and outlines an alternative model for regulating lawyers that is grounded in consumer protection principles. (JOW)

  11. Working without limits – reconsidering regulation

    DEFF Research Database (Denmark)

    Jensen, Per Langå

    2001-01-01

    In the light ofthe development of industry and working conditions present challenges to regulation is presented.......In the light ofthe development of industry and working conditions present challenges to regulation is presented....

  12. Contract & agency labour: beyond self-regulation?

    OpenAIRE

    Cotton, Elizabeth

    2010-01-01

    A paper about the regulation of contract labour. Academic and legal aspects as well as case studies of global union federation work to organise and regulate contract labour in Thailand, Pakistan, Colombia, South Korea and at international level.

  13. Securities regulation and implicit penalties

    Directory of Open Access Journals (Sweden)

    Donghua Chen

    2011-06-01

    Full Text Available The extant literature offers extensive support for the significant role played by institutions in financial markets, but implicit regulation and monitoring have yet to be examined. This study fills this void in the literature by employing unique Chinese datasets to explore the implicit regulation and penalties imposed by the Chinese government in regulating the initial public offering (IPO market. Of particular interest are the economic consequences of underwriting IPO deals for client firms that violate regulatory rules in China’s capital market. We provide evidence to show that the associated underwriters’ reputations are impaired and their market share declines. We further explore whether such negative consequences result from a market disciplinary mechanism or a penalty imposed by the government. To analyze the possibility of a market disciplinary mechanism at work, we investigate (1 the market reaction to other client firms whose IPO deals were underwritten by underwriters associated with a violation at the time the violation was publicly disclosed and (2 the under-pricing of IPO deals undertaken by these underwriters after such disclosure. To analyze whether the government imposes an implicit penalty, we examine the application processing time for future IPO deals underwritten by the associated underwriters and find it to be significantly longer than for IPO deals underwritten by other underwriters. Overall, there is little evidence to suggest that the market penalizes underwriters for the rule-violating behavior of their client firms in China. Instead, the Chinese government implicitly penalizes them by imposing more stringent criteria on and lengthening the processing time of the IPO deals they subsequently underwrite.

  14. Regulation of radioactive waste management

    International Nuclear Information System (INIS)

    2002-01-01

    This bulletin contains information about activities of the Nuclear Regulatory Authority of the Slovak Republic (UJD). In this leaflet the regulation of radioactive waste management of the UJD are presented. Radioactive waste (RAW) is the gaseous, liquid or solid material that contains or is contaminated with radionuclides at concentrations or activities greater than clearance levels and for which no use is foreseen. The classification of radioactive waste on the basis of type and activity level is: - transition waste; - short lived low and intermediate level waste (LlLW-SL); - long lived low and intermediate level waste (LlLW-LL); - high level waste. Waste management (in accordance with Act 130/98 Coll.) involves collection, sorting, treatment, conditioning, transport and disposal of radioactive waste originated by nuclear facilities and conditioning, transport to repository and disposal of other radioactive waste (originated during medical, research and industrial use of radioactive sources). The final goal of radioactive waste management is RAW isolation using a system of engineered and natural barriers to protect population and environment. Nuclear Regulatory Authority of the Slovak Republic regulates radioactive waste management in accordance with Act 130/98 Coll. Inspectors regularly inspect and evaluate how the requirements for nuclear safety at nuclear facilities are fulfilled. On the basis of safety documentation evaluation, UJD issued permission for operation of four radioactive waste management facilities. Nuclear facility 'Technologies for treatment and conditioning contains bituminization plants and Bohunice conditioning centre with sorting, fragmentation, evaporation, incineration, supercompaction and cementation. Final product is waste package (Fibre reinforced container with solidified waste) acceptable for near surface repository in Mochovce. Republic repository in Mochovce is built for disposal of short lived low and intermediate level waste. Next

  15. Regulated polyploidy in halophilic archaea.

    Directory of Open Access Journals (Sweden)

    Sebastian Breuert

    Full Text Available Polyploidy is common in higher eukaryotes, especially in plants, but it is generally assumed that most prokaryotes contain a single copy of a circular chromosome and are therefore monoploid. We have used two independent methods to determine the genome copy number in halophilic archaea, 1 cell lysis in agarose blocks and Southern blot analysis, and 2 Real-Time quantitative PCR. Fast growing H. salinarum cells contain on average about 25 copies of the chromosome in exponential phase, and their ploidy is downregulated to 15 copies in early stationary phase. The chromosome copy number is identical in cultures with a twofold lower growth rate, in contrast to the results reported for several other prokaryotic species. Of three additional replicons of H. salinarum, two have a low copy number that is not growth-phase regulated, while one replicon even shows a higher degree of growth phase-dependent regulation than the main replicon. The genome copy number of H. volcanii is similarly high during exponential phase (on average 18 copies/cell, and it is also downregulated (to 10 copies as the cells enter stationary phase. The variation of genome copy numbers in the population was addressed by fluorescence microscopy and by FACS analysis. These methods allowed us to verify the growth phase-dependent regulation of ploidy in H. salinarum, and they revealed that there is a wide variation in genome copy numbers in individual cells that is much larger in exponential than in stationary phase. Our results indicate that polyploidy might be more widespread in archaea (or even prokaryotes in general than previously assumed. Moreover, the presence of so many genome copies in a prokaryote raises questions about the evolutionary significance of this strategy.

  16. Autonomic Regulation of Splanchnic Circulation

    Directory of Open Access Journals (Sweden)

    Kathleen A Fraser

    1991-01-01

    Full Text Available The role of the autonomic nervous system in circulatory regulation of the splanchnic organs (stomach, small intestine, colon, liver, pancreas and spleen is reviewed. In general, the sympathetic nervous system is primarily involved in vasoconstriction, while the parasympathetic contributes to vasodilation. Vasoconstriction in the splanchnic circulation appears to be mediated by alpha-2 receptors and vasodilation by activation of primary afferent nerves with subsequent release of vasodilatory peptides, or by stimulation of beta-adrenergic receptors. As well, an important function of the autonomic nervous system is to provide a mechanism by which splanchnic vascular reserve can be mobilized during stress to maintain overall cardiovascular homeostasis.

  17. Regulation on radioactive waste management

    International Nuclear Information System (INIS)

    1999-01-01

    A national calculator control system for the metropolitan radioactive waste banks was developed in 1999. The NNSA reviewed by the regulations the feasibility of some rectification projects for uranium ore decommissioning and conducted field inspections on waste treating systems and radioactive waste banks at the 821 plant. The NNSA realized in 1999 the calculator control for the disposal sites of low and medium radioactive waste. 3 routine inspections were organized on the reinforced concrete structures for disposal units and their pouring of concrete at waste disposal site and specific requirements were put forth

  18. Pricing regulations in Great Britain

    International Nuclear Information System (INIS)

    Cicoletti, G.

    1993-01-01

    This paper briefly describes the structure and functions of Great Britain's essential electric power regulatory authority institutionalized by the 1989 British Electricity Act, i.e., the Office of Electricity Regulation, OFFER, and the responsibilities and tasks of the head of OFFER -the Director General of Electricity Supply (DGES). In particular, with regard to the latter, the paper describes how the DGES works together with regional electricity commissions to ensure the respect, by the various utilities, of consumer price caps and compliance with overall quality of service standards, as well as, to oversee 'pooling' activities by producers and distributors

  19. Pricing regulations in Great Britain

    International Nuclear Information System (INIS)

    Cicoletti, G.

    1993-01-01

    This paper briefly describes the structure and functions of Great Britain's essential electric power regulatory authority institutionalized by the 1989 British Electricity Act, i.e., the Office of Electricity Regulation, OFFER, and the responsibilities and tasks of the head of OFFER - the Director General of Electricity Supply (DGES). In particular, with regard to the latter, the paper describes how the DGES works together with regional electricity commissions to ensure the respect, by the various utilities, of consumer price caps and compliance with overall quality of service standards, as well as, to oversee 'pooling' activities by producers and distributors

  20. Gene regulation by growth factors

    International Nuclear Information System (INIS)

    Metz, R.; Gorham, J.; Siegfried, Z.; Leonard, D.; Gizang-Ginsberg, E.; Thompson, M.A.; Lawe, D.; Kouzarides, T.; Vosatka, R.; MacGregor, D.; Jamal, S.; Greenberg, M.E.; Ziff, E.B.

    1988-01-01

    To coordinate the proliferation and differentiation of diverse cell types, cells of higher eukaryotes communicate through the release of growth factors. These peptides interact with specific transmembrane receptors of other cells and thereby generate intracellular messengers. The many changes in cellular physiology and activity that can be induced by growth factors imply that growth factor-induced signals can reach the nucleus and control gene activity. Moreover, current evidence also suggests that unregulated signaling along such pathways can induce aberrant proliferation and the formation of tumors. This paper reviews investigations of growth factor regulation of gene expression conducted by the authors' laboratory

  1. QB1 - Stochastic Gene Regulation

    Energy Technology Data Exchange (ETDEWEB)

    Munsky, Brian [Los Alamos National Laboratory

    2012-07-23

    Summaries of this presentation are: (1) Stochastic fluctuations or 'noise' is present in the cell - Random motion and competition between reactants, Low copy, quantization of reactants, Upstream processes; (2) Fluctuations may be very important - Cell-to-cell variability, Cell fate decisions (switches), Signal amplification or damping, stochastic resonances; and (3) Some tools are available to mode these - Kinetic Monte Carlo simulations (SSA and variants), Moment approximation methods, Finite State Projection. We will see how modeling these reactions can tell us more about the underlying processes of gene regulation.

  2. International aspect of waste regulations

    International Nuclear Information System (INIS)

    Nercy, B. de.

    1981-01-01

    The international agreements respecting the immersion of waste in the sea, the transportation of radioactive waste and the civil liability of the operators are examined. The specialized international organizations (IAEA, NEA, EEC) have, for many years now, been making a significant effort to bring together and unify the technical rules and legal standards. Finally, an endeavour is made to single out the broad lines of the foreign regulations relating to the long term control of radioactive waste which is beginning to come to light in various countries [fr

  3. Nuclear safety: risks and regulation

    International Nuclear Information System (INIS)

    Wood, W.C.

    1983-01-01

    Taking a fresh look at nuclear safety regulations, this study finds that the mandate and organization of the Nuclear Regulatory Commission (NRC) militate against its making sound decisions. The author criticizes failures to make hard decisions on societal risk, to clarify responsibility, and to implement cost-effective safety measures. Among his recommendations are reorganization of the NRC under a single authoritative administrator, separation of technical issues from social ones, and reform of the Price-Anderson Act. The author concludes that the worst eventuality would be to continue the current state of indecision. 161 references, 6 figures, 4 tables

  4. Power electronics converters and regulators

    CERN Document Server

    Dokić, Branko L

    2015-01-01

    This book is the result of the extensive experience the authors gained through their year-long occupation at the Faculty of Electrical Engineering at the University of Banja Luka. Starting at the fundamental basics of electrical engineering, the book guides the reader into this field and covers all the relevant types of converters and regulators. Understanding is enhanced by the given examples, exercises and solutions. Thus this book can be used as a textbook for students, for self-study or as a reference book for professionals.

  5. Model of accounting regulation in Lithuania

    OpenAIRE

    Rudžionienė, Kristina; Gipienė, Gailutė

    2008-01-01

    This paper analyses the regulation of accounting system in Lithuania. There are different approaches to accounting regulation. For example, the "free market" approach is against any regulation; it says that each process in the market will be in equilibrium itself. Mostly it is clear that regulation is important and useful, especially in financial accounting. It makes information in financial reports understandable and comparable in one country or different countries. There are three theories ...

  6. Analysis of the Portuguese building regulation system

    OpenAIRE

    Costa Branco De Oliveira Pedro, J.A.; Meijer, F.M.; Visscher, H.J.

    2008-01-01

    The Portuguese building regulation system has undergone significant changes in the last 20 years. Almost all building regulations presently in force were approved during that period. Some of those building regulations resulted from the transposition of European Directives. Other building regulations were changed due to improvements in the scientific knowledge. The changes in the building control system were mainly driven by an adaptation to more pressing circumstances of practice. The lack...

  7. Regulating a Monopoly Offering Priority Service

    OpenAIRE

    Matsukawa, Isamu

    2006-01-01

    This paper investigates the effects of alternative forms of regulation on the market penetration and capacity, which are determined by a profit-maximizing monopolist providing priority service to consumers. For continuous priority service, a minimum reliability standard, price cap and rate of return regulation lead to larger capacity than in the absence of regulation. A minimum reliability standard reduces the market penetration while price cap and rate of return regulation increase it. T...

  8. Regulations and instructions; Propisi i uputstva

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1960-07-01

    Regulations and instructions for operating the RA reactor consist of the following chapters: general regulations with the fundamental RA reactor characteristics, operating regulations and instructions for the personnel on duty, regulations for accidental conditions, training program for the staff of the Laboratory for reactor operation. Propisi i uputstva za rad reaktora RA sadrze sledeca poglavlja: opsti deo sa kratkim opisom karakteristika reaktora RA, propisi za rad dezurnog osoblja, propisi za slucaj udesa, program obuke osoblja Laboratorije za eksploataciju reaktora RA.

  9. Market reaction to bank liquidity regulation

    OpenAIRE

    Bruno, Brunella; Onali, Enrico; Schaeck, Klaus

    2018-01-01

    We measure market reactions to announcements concerning liquidity regulation, a key innovation in the Basel framework. Our initial results show that liquidity regulation attracts negative abnormal returns. However, the price responses are less pronounced when coinciding announcements concerning capital regulation are backed out, suggesting that markets do not consider liquidity regulation to be binding. Bank- and country-specific characteristics also matter. Liquid balance sheets and high cha...

  10. Emotional Intelligence of Self Regulated Learners

    Science.gov (United States)

    Rathore, Ami

    2018-01-01

    The study was conducted on self regulated learners of senior secondary school. The main objectives of the study were to find out significant dimensions of emotional intelligence held by self regulated learners. To compare the emotional intelligence dimensions of self regulated learners, in terms of subject and gender. To find out the relationship…

  11. 50 CFR 216.86 - Local regulations.

    Science.gov (United States)

    2010-10-01

    ... Pribilof Islands Administration § 216.86 Local regulations. Local regulations will be published from time... 50 Wildlife and Fisheries 7 2010-10-01 2010-10-01 false Local regulations. 216.86 Section 216.86 Wildlife and Fisheries NATIONAL MARINE FISHERIES SERVICE, NATIONAL OCEANIC AND ATMOSPHERIC ADMINISTRATION...

  12. Good Practice Standards – a Regulation Tool

    DEFF Research Database (Denmark)

    Sørensen, Marie Jull

    2013-01-01

    The purpose of this article is to identify the considerations weighed in regulation with good practice standards. In this article, potential due process problems with regulation via legal standards are identified and compared to other considerations, which this regulation technique meets....

  13. The financial regulations of the Agency

    International Nuclear Information System (INIS)

    1994-01-01

    On 14 September 1994, the Board of Governors approved revised Financial Regulations of the Agency, with implementation of these Regulations beginning 1 January 1995. The Financial Regulations, as revised, are reproduced in this document for the information of all Member States

  14. Understanding Regulation of Metabolism through Feasibility Analysis

    NARCIS (Netherlands)

    Nikerel, I.E.; Berkhout, J.; Hu, F.; Teusink, B.; Reinders, M.J.T.; De Ridder, D.

    2012-01-01

    Understanding cellular regulation of metabolism is a major challenge in systems biology. Thus far, the main assumption was that enzyme levels are key regulators in metabolic networks. However, regulation analysis recently showed that metabolism is rarely controlled via enzyme levels only, but

  15. Business Models and Regulation | Distributed Generation Interconnection

    Science.gov (United States)

    Collaborative | NREL Business Models and Regulation Business Models and Regulation Subscribe to new business models and approaches. The growing role of distributed resources in the electricity system is leading to a shift in business models and regulation for electric utilities. These

  16. The theory of regulation : a review article

    NARCIS (Netherlands)

    Uche, C.U.

    2001-01-01

    This paper examines the various theoretical issues in regulation with a view to enhancing understanding of the regulation arena. Special emphasis has been placed on the banking industry. The paper shows how regulation serves different purposes for different interest groups on different occasions. It

  17. Identification of let-7-regulated oncofetal genes

    DEFF Research Database (Denmark)

    Boyerinas, Benjamin; Park, Sun-Mi; Shomron, Noam

    2008-01-01

    -regulated at the end of embryonic development. Let-7 is often down-regulated early during cancer development, suggesting that let-7-regulated oncofetal genes (LOG) may become reexpressed in cancer cells. Using comparative bioinformatics, we have identified 12 conserved LOGs that include HMGA2 and IMP-1/CRD-BP. IMP-1...

  18. No. 434 - Radiation Control Regulation 1993

    International Nuclear Information System (INIS)

    1993-01-01

    This Regulation, made under the Radiation Control Act 1990, replaces the Radioactive Substances Regulation 1959, repealed by the 1990 Act. It deals with licensing of the use of radioactive substances and radiation apparatus, regulates their use, disposal and transport. It also provides for radiation monitoring and emergency planning. (NEA)

  19. Definitional Issues in Emotion Regulation Research

    Science.gov (United States)

    Bridges, Lisa J.; Denham, Susanne A.; Ganiban, Jody M.

    2004-01-01

    Operational definitions of emotion regulation are frequently unclear, as are links between emotion regulation measures and underlying theoretical constructs. This is of concern because measurement decisions can have both intentional and unintentional implications for underlying conceptualizations of emotion regulation. This report examines the…

  20. 78 FR 15869 - Repeal of Disclosure Regulations

    Science.gov (United States)

    2013-03-13

    ...) with respect to the entities regulated by OFHEO and by the Finance Board. The regulations being repealed govern public financial disclosures made by the entities with respect to certain federal... Government to regulate and oversee the Federal National Mortgage Association, the Federal Home Loan Mortgage...

  1. 76 FR 79529 - Community Reinvestment Act Regulations

    Science.gov (United States)

    2011-12-22

    ... ``agencies'') are amending their Community Reinvestment Act (CRA) regulations to adjust the asset-size... ``intermediate small savings association.'' As required by the CRA regulations, the adjustment to the threshold... Description of the Joint Final Rule The agencies' CRA regulations establish CRA performance standards for...

  2. 25 CFR 275.4 - Implementing regulations.

    Science.gov (United States)

    2010-04-01

    ... 25 Indians 1 2010-04-01 2010-04-01 false Implementing regulations. 275.4 Section 275.4 Indians BUREAU OF INDIAN AFFAIRS, DEPARTMENT OF THE INTERIOR INDIAN SELF-DETERMINATION AND EDUCATION ASSISTANCE ACT PROGRAM STAFFING § 275.4 Implementing regulations. Regulations to implement section 105 of the Act...

  3. Self-Regulation in Online Learning

    Science.gov (United States)

    Cho, Moon-Heum; Shen, Demei

    2013-01-01

    The purpose of this study was to examine the role of goal orientation and academic self-efficacy in student achievement mediated by effort regulation, metacognitive regulation, and interaction regulation in an online course. The results show that intrinsic goal orientation and academic self-efficacy predicted students' metacognitive…

  4. 76 FR 9988 - Improving EPA Regulations

    Science.gov (United States)

    2011-02-23

    ... suggestions do you have for how the Agency could change the regulations to be more flexible? 6. Benefits and... public input on the design of a plan to use for periodic retrospective review of its regulations. DATES... At this time, EPA seeks help in designing the plan it will use for periodic review of regulations...

  5. Self-regulation through Goal Setting

    DEFF Research Database (Denmark)

    Koch, Alexander; Nafziger, Julia

    self-control problems. We show how goals permit self-regulation, but also that they are painful self-disciplining devices. Greater self-control problems therefore lead to stronger self-regulation through goals only up to a certain point. For severely present-biased preferences, the required goal...... for self-regulation is too painful and the individual rather gives up....

  6. [Consideration of Mobile Medical Device Regulation].

    Science.gov (United States)

    Peng, Liang; Yang, Pengfei; He, Weigang

    2015-07-01

    The regulation of mobile medical devices is one of the hot topics in the industry now. The definition, regulation scope and requirements, potential risks of mobile medical devices were analyzed and discussed based on mobile computing techniques and the FDA guidance of mobile medical applications. The regulation work of mobile medical devices in China needs to adopt the risk-based method.

  7. Reducing Ripple In A Switching Voltage Regulator

    Science.gov (United States)

    Paulkovich, John; Rodriguez, G. Ernest

    1994-01-01

    Ripple voltage in output of switching voltage regulator reduced substantially by simple additional circuitry adding little to overall weight and size of regulator. Heretofore, additional filtering circuitry needed to obtain comparable reductions in ripple typically as large and heavy as original regulator. Current opposing ripple current injected into filter capacitor.

  8. NRC regulation of DOE facilities

    International Nuclear Information System (INIS)

    Buhl, A.R.; Edgar, G.; Silverman, D.; Murley, T.

    1997-01-01

    The US Department of Energy (DOE), its contractors, and the Nuclear Regulatory Commission (NRC) are in for major changes if the DOE follows through on its intentions announced December 20, 1996. The DOE is seeking legislation to establish the NRC as the regulatory agency with jurisdiction over nuclear health, safety, and security at a wide range of DOE facilities. At this stage, it appears that as many as 200 (though not all) DOE facilities would be affected. On March 28, 1997, the NRC officially endorsed taking over the responsibility for regulatory oversight of DOE nuclear facilities as the DOE had proposed, contingent upon adequate funding, staffing resources, and a clear delineation of NRC authority. This article first contrasts the ways in which the NRC and the DOE carry out their basic regulatory functions. Next, it describes the NRC's current authority over DOE facilities and the status of the DOE's initiative to expand that authority. Then, it discusses the basic changes and impacts that can be expected in the regulation of DOE facilities. The article next describes key lessons learned from the recent transition of the GDPs from DOE oversight to NRC regulation and the major regulatory issues that arose in that transition. Finally, some general strategies are suggested for resolving issues likely to arise as the NRC assumes regulatory authority over DOE facilities

  9. New technologies to meet regulations

    International Nuclear Information System (INIS)

    Frank, C.; Harmon, L.

    1991-01-01

    The US Department of Energy's (DOE's) Office of Environmental Restoration and Waste Management has set the ambitious goal of having all of its facilities cleaned up and in compliance with applicable environmental laws and regulations by the year 2019. This goal is ambitious both because of the magnitude of the effort required and because, in many cases, the means for attaining the goal do not now exist. The DOE's strategy for reaching its goal is based on applied research and development, education, and cooperation with regulators. The Office of Technology Development (OTD) within the Office of Environmental Restoration and Waste Management has instituted a program to assess the magnitude of the cleanup effort and to evaluate the potential technologies to be used. The OTD has program responsibility for providing new and more effective technologies for meeting DOE's goal for compliance and cleanup. Included are research and development of new technologies; demonstration, testing, and evaluation of technologies developed elsewhere; transportation; and educational programs to produce the scientists and engineers needed to maintain the momentum of research, development, demonstration, testing, and evaluation (RDDT and E) until the job is complete

  10. [Drug regulation: theory and practice].

    Science.gov (United States)

    Zara Yahni, C; Segú Tolsa, L; Font Pous, M; Rovira, J

    1998-01-01

    Regulation of drugs from the public administration is an activity which is produced in different countries independently from the sanitary model they own. In the field of public financing of drugs there have been several measures to improve the efficiency of their use. However, the analysis of the impact of these measures is complex and this may justify the shortage of objectivable results, especially at long term. The objective of this study is to perform a systematic review of such measures due to the need to have information about the different alternatives before making a decision. The introduction of an isolated measure is in many cases compensated by other changes in other regulating or aiding fields which suggests the creation of an integral strategy which affects different fields (supply/demand of drugs and prescribers). It seems necessary to suggest a social debate taking as a basis the scientific information available at the moment and promote the taking of decisions which lead to a rational use of the available pharmacological resources.

  11. Strategic regulation of gas transport

    International Nuclear Information System (INIS)

    Nese, Gjermund; Straume, Odd Rune

    2005-01-01

    The basis of the article has been the steadily increasing focus particularly from EU, on increased competition in the natural gas markets. This could influence the profit distribution between the gas producing and consuming counties which is an important problem situation for Norway as a gas producer. The gas market value chain consist of three parts (production, transport and distribution). How the countries may use strategic regulation of the transport tariff for the transport and distribution systems in order to move as much as possible of the total profit to the part of the value chain in control is studied. The focus has been on how increased competition influences the incentives of the authorities through low or high transport tariff and to what extent increased competition influences the welfare level in the producer and consumer counties when strategic regulations of the transport occur. The analysis is based on a theoretical model developed in 2005. Some central mechanisms related to the natural gas market are mapped and Norway may counteract some negative effects of liberalisation of the European gas market through strategic adaptation of the transport tariff to the Norwegian gas transport systems

  12. Corticostriatal Regulation of Acute Pain

    Directory of Open Access Journals (Sweden)

    Erik Martinez

    2017-05-01

    Full Text Available The mechanisms for acute pain regulation in the brain are not well understood. The prefrontal cortex (PFC provides top-down control of emotional processes, and it projects to the nucleus accumbens (NAc. This corticostriatal projection forms an important regulatory pathway within the brain’s reward system. Recently, this projection has been suggested to control both sensory and affective phenotypes specifically associated with chronic pain. As this projection is also known to play a role in the transition from acute to chronic pain, we hypothesized that this corticostriatal circuit can also exert a modulatory function in the acute pain state. Here, we used optogenetics to specifically target the projection from the PFC to the NAc. We tested sensory pain behaviors with Hargreaves’ test and mechanical allodynia, and aversive pain behaviors with conditioned place preference (CPP test. We found that the activation of this corticostriatal circuit gave rise to bilateral relief from peripheral nociceptive inputs. Activation of this circuit also provided important control for the aversive response to transient noxious stimulations. Hence, our results support a novel role for corticostriatal circuitry in acute pain regulation.

  13. Substation Reactive Power Regulation Strategy

    Science.gov (United States)

    Zhang, Junfeng; Zhang, Chunwang; Ma, Daqing

    2018-01-01

    With the increasing requirements on the power supply quality and reliability of distribution network, voltage and reactive power regulation of substations has become one of the indispensable ways to ensure voltage quality and reactive power balance and to improve the economy and reliability of distribution network. Therefore, it is a general concern of the current power workers and operators that what kind of flexible and effective control method should be used to adjust the on-load tap-changer (OLTC) transformer and shunt compensation capacitor in a substation to achieve reactive power balance in situ, improve voltage pass rate, increase power factor and reduce active power loss. In this paper, based on the traditional nine-zone diagram and combining with the characteristics of substation, a fuzzy variable-center nine-zone diagram control method is proposed and used to make a comprehensive regulation of substation voltage and reactive power. Through the calculation and simulation of the example, this method is proved to have satisfactorily reconciled the contradiction between reactive power and voltage in real-time control and achieved the basic goal of real-time control of the substation, providing a reference value to the practical application of the substation real-time control method.

  14. ARF1 recruits RAC1 to leading edge in neutrophil chemotaxis.

    Science.gov (United States)

    Mazaki, Yuichi; Onodera, Yasuhito; Higashi, Tsunehito; Horinouchi, Takahiro; Oikawa, Tsukasa; Sabe, Hisataka

    2017-10-02

    The small GTPase ARF1 mediates membrane trafficking mostly from the Golgi, and is essential for the G protein-coupled receptor (GPCR)-mediated chemotaxis of neutrophils. In this process, ARF1 is activated by the guanine nucleotide exchanger GBF1, and is inactivated by the GTPase-activating protein GIT2. Neutrophils generate the Gβγ-PAK1-αPIX-GIT2 linear complex during GPCR-induced chemotaxis, in which αPIX activates RAC1/CDC42, which then employs PAK1. However, it has remained unclear as to why GIT2 is included in this complex. We investigated the association between ARF1 and RAC1/CDC42 during the fMLP-stimulated chemotaxis of HL60 cells. We found that the silencing of GBF1 significantly impaired the recruitment of RAC1 to the leading edges, but not PAK1, αPIX, RAC2, or CDC42. A significant population of RAC1 colocalized with ARF1 at the leading edges in stimulated cells, whereas fMLP activated both ARF1 and ARF5. Consistently, the silencing of ARF1, but not ARF5, impaired the recruitment of RAC1, whereas the silencing of RAC1 did not affect the recruitment of ARF1 to the leading edges. Our results indicated that the activation of ARF1 triggers the plasma membrane recruitment of RAC1 in GPCR-mediated chemotaxis, which is essential for cortical actin remodeling. Thus, membrane remodeling at the leading edges appears to precede actin remodeling in chemotaxis. Together with the fact that GIT2, which inactivates ARF1, is an integral component of the machinery activating RAC1, we proposed a model in which the ARF1-RAC1 linkage enables the regulation of ARF1 by repetitive on/off cycles during GPCR-mediated neutrophil chemotaxis.

  15. PTEN phosphatase-independent maintenance of glandular morphology in a predictive colorectal cancer model system.

    Science.gov (United States)

    Jagan, Ishaan C; Deevi, Ravi K; Fatehullah, Aliya; Topley, Rebecca; Eves, Joshua; Stevenson, Michael; Loughrey, Maurice; Arthur, Kenneth; Campbell, Frederick Charles

    2013-11-01

    Organotypic models may provide mechanistic insight into colorectal cancer (CRC) morphology. Three-dimensional (3D) colorectal gland formation is regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN) coupling of cell division cycle 42 (cdc42) to atypical protein kinase C (aPKC). This study investigated PTEN phosphatase-dependent and phosphatase-independent morphogenic functions in 3D models and assessed translational relevance in human studies. Isogenic PTEN-expressing or PTEN-deficient 3D colorectal cultures were used. In translational studies, apical aPKC activity readout was assessed against apical membrane (AM) orientation and gland morphology in 3D models and human CRC. We found that catalytically active or inactive PTEN constructs containing an intact C2 domain enhanced cdc42 activity, whereas mutants of the C2 domain calcium binding region 3 membrane-binding loop (M-CBR3) were ineffective. The isolated PTEN C2 domain (C2) accumulated in membrane fractions, but C2 M-CBR3 remained in cytosol. Transfection of C2 but not C2 M-CBR3 rescued defective AM orientation and 3D morphogenesis of PTEN-deficient Caco-2 cultures. The signal intensity of apical phospho-aPKC correlated with that of Na(+)/H(+) exchanger regulatory factor-1 (NHERF-1) in the 3D model. Apical NHERF-1 intensity thus provided readout of apical aPKC activity and associated with glandular morphology in the model system and human colon. Low apical NHERF-1 intensity in CRC associated with disruption of glandular architecture, high cancer grade, and metastatic dissemination. We conclude that the membrane-binding function of the catalytically inert PTEN C2 domain influences cdc42/aPKC-dependent AM dynamics and gland formation in a highly relevant 3D CRC morphogenesis model system.

  16. PTEN Phosphatase-Independent Maintenance of Glandular Morphology in a Predictive Colorectal Cancer Model System

    Directory of Open Access Journals (Sweden)

    Ishaan C. Jagan

    2013-11-01

    Full Text Available Organotypic models may provide mechanistic insight into colorectal cancer (CRC morphology. Three-dimensional (3D colorectal gland formation is regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN coupling of cell division cycle 42 (cdc42 to atypical protein kinase C (aPKC. This study investigated PTEN phosphatase-dependent and phosphatase-independent morphogenic functions in 3D models and assessed translational relevance in human studies. Isogenic PTEN-expressing or PTEN-deficient 3D colorectal cultures were used. In translational studies, apical aPKC activity readout was assessed against apical membrane (AM orientation and gland morphology in 3D models and human CRC. We found that catalytically active or inactive PTEN constructs containing an intact C2 domain enhanced cdc42 activity, whereas mutants of the C2 domain calcium binding region 3 membrane-binding loop (M-CBR3 were ineffective. The isolated PTEN C2 domain (C2 accumulated in membrane fractions, but C2 M-CBR3 remained in cytosol. Transfection of C2 but not C2 M-CBR3 rescued defective AM orientation and 3D morphogenesis of PTEN-deficient Caco-2 cultures. The signal intensity of apical phospho-aPKC correlated with that of Na+/H+ exchanger regulatory factor-1 (NHERF-1 in the 3D model. Apical NHERF-1 intensity thus provided readout of apical aPKC activity and associated with glandular morphology in the model system and human colon. Low apical NHERF-1 intensity in CRC associated with disruption of glandular architecture, high cancer grade, and metastatic dissemination. We conclude that the membrane-binding function of the catalytically inert PTEN C2 domain influences cdc42/aPKC-dependent AM dynamics and gland formation in a highly relevant 3D CRC morphogenesis model system.

  17. Transcriptional regulation by Ferric Uptake Regulator (Fur) in pathogenic bacteria.

    Science.gov (United States)

    Troxell, Bryan; Hassan, Hosni M

    2013-01-01

    In the ancient anaerobic environment, ferrous iron (Fe(2+)) was one of the first metal cofactors. Oxygenation of the ancient world challenged bacteria to acquire the insoluble ferric iron (Fe(3+)) and later to defend against reactive oxygen species (ROS) generated by the Fenton chemistry. To acquire Fe(3+), bacteria produce low-molecular weight compounds, known as siderophores, which have extremely high affinity for Fe(3+). However, during infection the host restricts iron from pathogens by producing iron- and siderophore-chelating proteins, by exporting iron from intracellular pathogen-containing compartments, and by limiting absorption of dietary iron. Ferric Uptake Regulator (Fur) is a transcription factor which utilizes Fe(2+) as a corepressor and represses siderophore synthesis in pathogens. Fur, directly or indirectly, controls expression of enzymes that protect against ROS damage. Thus, the challenges of iron homeostasis and defense against ROS are addressed via Fur. Although the role of Fur as a repressor is well-documented, emerging evidence demonstrates that Fur can function as an activator. Fur activation can occur through three distinct mechanisms (1) indirectly via small RNAs, (2) binding at cis regulatory elements that enhance recruitment of the RNA polymerase holoenzyme (RNAP), and (3) functioning as an antirepressor by removing or blocking DNA binding of a repressor of transcription. In addition, Fur homologs control defense against peroxide stress (PerR) and control uptake of other metals such as zinc (Zur) and manganese (Mur) in pathogenic bacteria. Fur family members are important for virulence within bacterial pathogens since mutants of fur, perR, or zur exhibit reduced virulence within numerous animal and plant models of infection. This review focuses on the breadth of Fur regulation in pathogenic bacteria.

  18. The undertow of de-regulation : re-regulation

    International Nuclear Information System (INIS)

    Bradford, J.A.

    2003-01-01

    Alberta, Ontario and New Brunswick each initiated steps to deregulate their electric power industries in order to remain competitive with lower electricity rates in certain American states where the industry was also moving towards deregulation. This paper considers how the original sweep of deregulation policy goals succumbed to electricity re regulation policies. The decision by British Columbia to re-examine its deregulation plans in light of the experience in Canada's 3 other province's was also examined. The paper describes the electric power industry from 1900 to 1960s, before the deregulation wave hit the industry and then proceeds to the 1970s which was marked by the oil embargo. The 1980s saw a new era of policy shifts towards deregulation and privatization activity which was intended to introduce competition into regulated industries. Technological advances were taking place in the electricity sector, improving the viability of small gas turbines and making cogeneration possible. In the 1990s, Alberta was the first Canadian province to introduce competition to its electricity industry in an effort to remain competitive with neighbouring U.S. jurisdictions. By the 1990s Ontario's vertically integrated electricity industry was in trouble and recommendations were made to dissolve Ontario's Hydro One monopoly, particularly in power generation. In 1999, New Brunswick restructured its electricity industry to remain competitive with New England's electricity industry. The paper describes the gradual pull back from deregulation by all three provinces and the measures taken to impose price controls. Both industry and consumers paid a price for major policy changes. Complete competition in New Brunswick never materialized. It was suggested that controlled competition will likely move the electricity industry in the future. 40 refs

  19. Corruption and optimal regulation under common agency

    Directory of Open Access Journals (Sweden)

    Pedro Hemsley

    2016-05-01

    Full Text Available I show that it is optimal to separate non-benevolent regulators when regulated projects are large. Separation prevents regulators from coordinating to appropriate all of the agent's informational rent when they know the type of the latter; therefore, there is a trade-off between saving on informational rent and efficiency, since the game between the regulators induced by separation causes further distortions when compared to the allocation under one regulator. When the informational rent at stake is large due to the size of the project, separation is the optimal institutional answer.

  20. Public and private regulation of reproductive technologies.

    Science.gov (United States)

    Byk, C

    1995-01-01

    Human reproduction is interrelated with privacy. However, in most countries where new reproductive technologies are used public regulations have been passed to provide a legal framework for such technologies. This interference in private life can be justified by the need to control medical intervention in the human reproductive process. But in order to find a balance between public regulations and other social regulations, this article analyses the impact private regulation may have on issues raised by reproductive technologies. It also addresses the issue of the influence of private bodies on the drafting of public regulations.

  1. Phosphorylation regulates SIRT1 function.

    Directory of Open Access Journals (Sweden)

    Tsutomu Sasaki

    Full Text Available BACKGROUND: SIR2 is an NAD(+-dependent deacetylase [1]-[3] implicated in the regulation of lifespan in species as diverse as yeast [4], worms [5], and flies [6]. We previously reported that the level of SIRT1, the mammalian homologue of SIR2 [7], [8], is coupled to the level of mitotic activity in cells both in vitro and in vivo[9]. Cells from long-lived mice maintained SIRT1 levels of young mice in tissues that undergo continuous cell replacement by proliferating stem cells. Changes in SIRT1 protein level were not associated with changes in mRNA level, suggesting that SIRT1 could be regulated post-transcriptionally. However, other than a recent report on sumoylation [10] and identification of SIRT1 as a nuclear phospho-protein by mass spectrometry [11], post-translational modifications of this important protein have not been reported. METHODOLOGY/PRINCIPAL FINDINGS: We identified 13 residues in SIRT1 that are phosphorylated in vivo using mass spectrometry. Dephosphorylation by phosphatases in vitro resulted in decreased NAD(+-dependent deacetylase activity. We identified cyclinB/Cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates SIRT1. Mutation of two residues phosphorylated by Cyclin B/Cdk1 (threonine 530 and serine 540 disturbs normal cell cycle progression and fails to rescue proliferation defects in SIRT1-deficient cells [12], [13]. CONCLUSIONS/SIGNIFICANCE: Pharmacological manipulation of SIRT1 activity is currently being tested as a means of extending lifespan in mammals. Treatment of obese mice with resveratrol, a pharmacological activator of SIRT1, modestly but significantly improved longevity and, perhaps more importantly, offered some protection against the development of type 2 diabetes mellitus and metabolic syndrome [14]-[16]. Understanding the endogenous mechanisms that regulate the level and activity of SIRT1, therefore, has obvious relevance to human health and disease. Our results identify

  2. 75 FR 75904 - Global Terrorism Sanctions Regulations; Terrorism Sanctions Regulations; Foreign Terrorist...

    Science.gov (United States)

    2010-12-07

    ... Terrorism Sanctions Regulations; Terrorism Sanctions Regulations; Foreign Terrorist Organizations Sanctions... Foreign Assets Control (``OFAC'') of the U.S. Department of the Treasury is amending the Global Terrorism Sanctions Regulations (``GTSR'') and the Terrorism Sanctions Regulations (``TSR'') to expand the scope of...

  3. Private regulation in EU better regulation : Past performance and future promises

    NARCIS (Netherlands)

    Verbruggen, Paul

    The promotion of private regulation is frequently part of better regulation programmes. Also the Better Regulation programme of the European Union (EU) initiated in 2002 advocated forms of private regulation as important means to improve EU law-making activities. However, for various reasons the

  4. 78 FR 31551 - Federal Acquisition Regulation; Submission for OMB Review; Commerce Patent Regulations

    Science.gov (United States)

    2013-05-24

    ...; Submission for OMB Review; Commerce Patent Regulations AGENCIES: Department of Defense (DOD), General... collection requirement concerning Department of Commerce patent regulations. A notice was published in...- 0095, Commerce Patent Regulations, by any of the following methods: Regulations.gov : http://www...

  5. The challenge of legitimizing spatially differentiated regulation

    DEFF Research Database (Denmark)

    Thorsøe, Martin Hvarregaard; Graversgaard, Morten; Noe, Egon

    2017-01-01

    Differentiating regulation is a promising approach to agri-environmental regulation that may potentially reduce the environmental impact of agriculture at the lowest possible costs for the farmers and society, but also possesses a number of challenges. In this article, we explore the challenges...... to the legitimacy of agri-environmental regulation that occurs when the regulatory regime changes from general regulation to differentiated regulation. The analysis is based on a case study of the implementation of the Buffer zone act in Denmark – a regulation that prevents agricultural production in a 10 (later 9......) meter fringe around selected waterbodies. We distinguish between two different ways of legitimizing: Producing knowledge and participation. We conclude that to harvest some of the obvious benefits of differentiated regulation a number of challenges must be resolved, 1) ensuring legitimacy...

  6. Fire safety regulations and licensing

    International Nuclear Information System (INIS)

    Berg, H.P.

    1998-01-01

    Experience of the past tow decades of nuclear power plant operation and results obtained from modern analytical techniques confirm that fires may be a real threat to nuclear safety and should receive adequate attention from the design phase throughout the life of the plant. Fire events, in particular influence significantly plant safety due to the fact that fires have the potential to simultaneously damage components of redundant safety-related equipment. Hence, the importance of fire protection for the overall safety of a nuclear power plant has to be reflected by the fire safety regulations and to be checked during the licensing process of a plant as well as during the continuous supervision of the operating plant

  7. SOCIAL BONDING: REGULATION BY NEUROPEPTIDES

    Directory of Open Access Journals (Sweden)

    Claudia eLieberwirth

    2014-06-01

    Full Text Available Affiliative social relationships (e.g., among spouses, family members, and friends play an essential role in human society. These relationships affect psychological, physiological, and behavioral functions. As positive and enduring bonds are critical for the overall well-being of humans, it is not surprising that considerable effort has been made to study the neurobiological mechanisms that underlie social bonding behaviors. The present review details the involvement of the nonapeptides, oxytocin (OT and arginine vasopressin (AVP, in the regulation of social bonding in mammals including humans. In particular, we will discuss the role of OT and AVP in the formation of social bonds between partners of a mating pair as well as between parents and their offspring. Furthermore, the role of OT and AVP in the formation of interpersonal bonding involving trust is also discussed.

  8. Hard work in soft regulation

    DEFF Research Database (Denmark)

    Hohnen, Pernille; Hasle, Peter; Helbo Jespersen, Anne

    2014-01-01

    Certified occupational health and safety management (OHSM) systems have become a global instrument in the regulation of work environment (Frick and Wren 2000; Gallagher et al. 2001, Rocha 2010; Robson et al 2007). However, their actual impact on occupational health and safety – in particular...... on ‘softer’ psychosocial areas of the working environment – has been questioned (Hohnen & Hasle 2011; Walters and Frick 2000; Hasle & Zwetsloot 2011). This has resulted in recent British attempts to develop new publically available guidelines (PAS 1010) to be used together with OHSAS 18001 focusing...... specifically on psychosocial risk management attempting to guide and control not only management systems and related procedures but also the concrete work domain in which psychosocial risks are produced, experienced and monitored (Leka 2011). Based on an analysis of OHSAS 18001 and PAS 1010 the present paper...

  9. Neuroepigenetic Regulation of Pathogenic Memories.

    Science.gov (United States)

    Sillivan, Stephanie E; Vaissière, Thomas; Miller, Courtney A

    2015-01-01

    Our unique collection of memories determines our individuality and shapes our future interactions with the world. Remarkable advances into the neurobiological basis of memory have identified key epigenetic mechanisms that support the stability of memory. Various forms of epigenetic regulation at the levels of DNA methylation, histone modification, and non-coding RNAs (ncRNAs) can modulate transcriptional and translational events required for memory processes. By changing the cellular profile in the brain's emotional, reward, and memory circuits, these epigenetic modifications have also been linked to perseverant, pathogenic memories. In this review, we will delve into the relevance of epigenetic dysregulation to pathogenic memory mechanisms by focusing on two neuropsychiatric disorders perpetuated by aberrant memory associations: substance use disorder (SUD) and post-traumatic stress disorder (PTSD). As our understanding improves, neuroepigenetic mechanisms may someday be harnessed to develop novel therapeutic targets for the treatment of these chronic, relapsing disorders.

  10. Neuroepigenetic regulation of pathogenic memories

    Directory of Open Access Journals (Sweden)

    Stephanie E. Sillivan

    2015-01-01

    Full Text Available Our unique collection of memories determines our individuality and shapes our future interactions with the world. Remarkable advances into the neurobiological basis of memory have identified key epigenetic mechanisms that support the stability of memory. Various forms of epigenetic regulation at the levels of DNA methylation, histone modification, and noncoding RNAs can modulate transcriptional and translational events required for memory processes. By changing the cellular profile in the brain’s emotional, reward, and memory circuits, these epigenetic modifications have also been linked to perseverant, pathogenic memories. In this review, we will delve into the relevance of epigenetic dysregulation to pathogenic memory mechanisms by focusing on 2 neuropsychiatric disorders perpetuated by aberrant memory associations: substance use disorder and post-traumatic stress disorder. As our understanding improves, neuroepigenetic mechanisms may someday be harnessed to develop novel therapeutic targets for the treatment of these chronic, relapsing disorders.

  11. Epigenetic regulation of female puberty.

    Science.gov (United States)

    Lomniczi, Alejandro; Wright, Hollis; Ojeda, Sergio R

    2015-01-01

    Substantial progress has been made in recent years toward deciphering the molecular and genetic underpinnings of the pubertal process. The availability of powerful new methods to interrogate the human genome has led to the identification of genes that are essential for puberty to occur. Evidence has also emerged suggesting that the initiation of puberty requires the coordinated activity of gene sets organized into functional networks. At a cellular level, it is currently thought that loss of transsynaptic inhibition, accompanied by an increase in excitatory inputs, results in the pubertal activation of GnRH release. This concept notwithstanding, a mechanism of epigenetic repression targeting genes required for the pubertal activation of GnRH neurons was recently identified as a core component of the molecular machinery underlying the central restraint of puberty. In this chapter we will discuss the potential contribution of various mechanisms of epigenetic regulation to the hypothalamic control of female puberty. Copyright © 2014 Elsevier Inc. All rights reserved.

  12. Cell swelling and volume regulation

    DEFF Research Database (Denmark)

    Hoffmann, Else Kay

    1992-01-01

    The extracellular space in the brain is typically 20% of the tissue volume and is reduced to at least half its size under conditions of neural insult. Whether there is a minimum size to the extracellular space was discussed. A general model for cell volume regulation was presented, followed...... by a discussion on how many of the generally involved mechanisms are identified in neural cells and (or) in astrocytes. There seems to be clear evidence suggesting that parallel K+ and Cl- channels mediate regulatory volume decrease in primary cultures of astrocytes, and a stretch-activated cation channel has...... been reported. The role of the different channels was discussed. A taurine leak pathway is clearly activated after cell swelling both in astrocytes and in neurones. The relations between the effect of glutamate and cell swelling were discussed. Discussion on the clearance of potassium from...

  13. Cyberspace regulation: cesurist and traditionalists

    Directory of Open Access Journals (Sweden)

    Lino Santos

    2015-05-01

    Full Text Available In the amazing Code and Other Laws of Cyberspace, Professor L. Lessig writes "that something fundamental has changed" with cyberspace with regard to the state's ability to enforce the law. On the one hand, the structure and characteristics of cyberspace pose some difficulties related to jurisdiction and the choice of applicable law. On the other, it raises questions about the very concept of sovereignty as we know it. This paper examines the arguments of those who advocate a regulation of cyberspace on the edges of state sovereignty or within a new concept of sovereignty and capacity to enforce the law, and the arguments of those who reject this exceptional treatment of cyberspace.

  14. Large-scale river regulation

    International Nuclear Information System (INIS)

    Petts, G.

    1994-01-01

    Recent concern over human impacts on the environment has tended to focus on climatic change, desertification, destruction of tropical rain forests, and pollution. Yet large-scale water projects such as dams, reservoirs, and inter-basin transfers are among the most dramatic and extensive ways in which our environment has been, and continues to be, transformed by human action. Water running to the sea is perceived as a lost resource, floods are viewed as major hazards, and wetlands are seen as wastelands. River regulation, involving the redistribution of water in time and space, is a key concept in socio-economic development. To achieve water and food security, to develop drylands, and to prevent desertification and drought are primary aims for many countries. A second key concept is ecological sustainability. Yet the ecology of rivers and their floodplains is dependent on the natural hydrological regime, and its related biochemical and geomorphological dynamics. (Author)

  15. Implementing CITES regulations for timber.

    Science.gov (United States)

    Blundell, Arthur G

    2007-03-01

    Foresters are currently confronted with a new challenge. For the first time a commonly traded timber species has been listed on the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). At the 12th Conference of the Parties in November 2002, countries voted 68 to 30 to place the premier timber species of Latin America, big-leaf mahogany (Swietenia macrophylla King [Meliaceae]), on CITES Appendix II. Under Appendix II regulations, trade in mahogany requires that exporting countries verify that each shipment was legally obtained and that its harvest was non-detrimental to the survival of the species. Unfortunately, implementation has been weak, in part because countries have yet to develop a common, pragmatic, cost-effective system to make the legal and non-detriment findings. This paper recommends what such a system might include.

  16. Redox Regulation of Mitochondrial Function

    Science.gov (United States)

    Handy, Diane E.

    2012-01-01

    Abstract Redox-dependent processes influence most cellular functions, such as differentiation, proliferation, and apoptosis. Mitochondria are at the center of these processes, as mitochondria both generate reactive oxygen species (ROS) that drive redox-sensitive events and respond to ROS-mediated changes in the cellular redox state. In this review, we examine the regulation of cellular ROS, their modes of production and removal, and the redox-sensitive targets that are modified by their flux. In particular, we focus on the actions of redox-sensitive targets that alter mitochondrial function and the role of these redox modifications on metabolism, mitochondrial biogenesis, receptor-mediated signaling, and apoptotic pathways. We also consider the role of mitochondria in modulating these pathways, and discuss how redox-dependent events may contribute to pathobiology by altering mitochondrial function. Antioxid. Redox Signal. 16, 1323–1367. PMID:22146081

  17. Histaminergic regulation of prolactin secretion

    DEFF Research Database (Denmark)

    Knigge, U P

    1990-01-01

    Histamine (HA), which acts as a neurotransmitter in the central nervous system, participates in the neuroendocrine regulation of prolactin (PRL) secretion. HA has a predominant stimulatory effect which is mediated via H2-receptors following central administration and via H1-receptors following...... systemic infusion of the amine. In addition, HA seems to exert a minor inhibitory effect on PRL secretion, an effect unmasked only during blockade of the receptor mediating the stimulatory effect. Following central administration the inhibitory effect is mediated via H1-receptors, while following systemic...... administration this effect is mediated via H2-receptors. In accordance with these findings, the H2-receptor antagonist cimetidine (CIM) has an inhibitory (following central administration) or stimulatory (following systemic administration) effect on PRL secretion. However, high doses of CIM possess an additional...

  18. Environmental regulation and technological innovation

    Energy Technology Data Exchange (ETDEWEB)

    Farrell, A.E. [Carnegie Mellon Electricity Industry Center, Pittsburg, PA (United States)

    2002-07-01

    Government policies are a major factor in the determination of structural conditions of competition. The innovative activity comprises the following: invention, adoption, and diffusion. Invention involves research and development activities such as patenting, research and development budgets. The adoption phase is concerned with deployment. As for the diffusion phase, it involves commercialization, and scale-economies. The process of introducing new technologies that are adopted by small numbers of customers in a niche market was explained. Once costs are lowered through experience gained in designing, manufacturing and servicing the new technology, mew applications generally lead to larger markets. Environmental technologies have no early adopters, implying that governments have an important role to play. However, commercial processes are not normally as well known to government as it is to the private sector. The electoral cycle also interferes with long term research and development efforts for technological clusters. A look at sulphur dioxide control at United States power plants illustrated the problem. The author then explained the reasons behind low allowance prices. Low-sulphur western coal was rendered economic in large areas of the United States by rail deregulation. Electricity restructuring was also a factor. The author indicated that binding government regulation must come before adoption and diffusion of emission controls. A summary of recent research was provided, in which the author stated that no single policy instrument was likely to properly stimulate innovative activity. In those cases where both supply and demand are stimulated by government, the technological innovation is greatest. Stringent regulations induce innovation, as do greater flexibility and greater regulatory certainty. Knowledge transfer within the industry is vital. 8 refs., 3 figs.

  19. Microbial Regulation in Gorgonian Corals

    Directory of Open Access Journals (Sweden)

    Laura D. Mydlarz

    2012-06-01

    Full Text Available Gorgonian corals possess many novel natural products that could potentially mediate coral-bacterial interactions. Since many bacteria use quorum sensing (QS signals to facilitate colonization of host organisms, regulation of prokaryotic cell-to-cell communication may represent an important bacterial control mechanism. In the present study, we examined extracts of twelve species of Caribbean gorgonian corals, for mechanisms that regulate microbial colonization, such as antibacterial activity and QS regulatory activity. Ethanol extracts of gorgonians collected from Puerto Rico and the Florida Keys showed a range of both antibacterial and QS activities using a specific Pseudomonas aeruginosa QS reporter, sensitive to long chain AHLs and a short chain N-acylhomoserine lactones (AHL biosensor, Chromobacterium violaceium. Overall, the gorgonian corals had higher antimicrobial activity against non-marine strains when compared to marine strains. Pseudopterogorgia americana, Pseusopterogorgia acerosa, and Pseudoplexuara flexuosa had the highest QS inhibitory effect. Interestingly, Pseudoplexuara porosa extracts stimulated QS activity with a striking 17-fold increase in signal. The stimulation of QS by P. porosa or other elements of the holobiont may encourage colonization or recruitment of specific microbial species. Overall, these results suggest the presence of novel stimulatory QS, inhibitory QS and bactericidal compounds in gorgonian corals. A better understanding of these compounds may reveal insight into coral-microbial ecology and whether a therapeutic potential exists.

  20. Conformational Regulation of the Essential Epigenetic Regulator UHRF1

    KAUST Repository

    Pantoja Angles, Aaron

    2018-05-01

    UHRF1 is an essential epigenetic regulator implicated in the maintenance of DNA methylation. While its functional state has been suggested to be allosterically regulated by phosphatidylinositol 5-phosphate and dependent on purification conditions and tags coupled to the protein, the expression system might have a broader impact on UHRF1s interaction properties. We hypothesized that the translation kinetics defined by the expression host has an impact on the folding process of the protein, which ultimately affects its structure and function. To test this idea, the cDNA of UHRF1 was recoded in order to generate optimized and harmonized sequences that were expected to alter the overall translation speed. Both proteins were expressed in Escherichia coli BL21-DE3 and their interaction profiles with H3K9me3 and unmodified H3 peptides were determined by microscale thermophoresis assays. The dissociation constants were compared by ttests in order to evaluate a possible change in the interaction properties of the optimized and harmonized proteins, compared to non-optimized UHRF1 expressed in E. coli BL21-DE3. While no difference was found for the interaction of optimized UHRF1 with the H3K9me3 peptide, a significant difference was found for its interaction with the unmodified H3 peptide. Moreover, both the interactions of harmonized UHRF1 with H3K9me3 and unmodified H3 peptides were determined to change. For this reason, we concluded that translation kinetics dependent on the expression system impacts the functional state of UHRF1. To further study this phenomenon, we expressed the consensus sequence of UHRF1 in Escherichia coli BL21-Codon Plus-(DE3)-RIL, a bacterial strain that is enriched with arginine, isoleucine, and leucine tRNA isoacceptors. Differences in its interaction profile with histone peptides were found when compared with UHRF1 expressed in Escherichia coli BL21-DE3. Since the major difference between these strains is the abundance of tRNAs, we obtained

  1. Global approaches to regulating electronic cigarettes

    Science.gov (United States)

    Kennedy, Ryan David; Awopegba, Ayodeji; De León, Elaine; Cohen, Joanna E

    2017-01-01

    Objectives Classify and describe the policy approaches used by countries to regulate e-cigarettes. Methods National policies regulating e-cigarettes were identified by (1) conducting web searches on Ministry of Health websites, and (2) broad web searches. The mechanisms used to regulate e-cigarettes were classified as new/amended laws, or existing laws. The policy domains identified include restrictions or prohibitions on product: sale, manufacturing, importation, distribution, use, product design including e-liquid ingredients, advertising/promotion/sponsorship, trademarks, and regulation requiring: taxation, health warning labels and child-safety standards. The classification of the policy was reviewed by a country expert. Results The search identified 68 countries that regulate e-cigarettes: 22 countries regulate e-cigarettes using existing regulations; 25 countries enacted new policies to regulate e-cigarettes; 7 countries made amendments to existing legislation; 14 countries use a combination of new/amended and existing regulation. Common policies include a minimum-age-of-purchase, indoor-use (vape-free public places) bans and marketing restrictions. Few countries are applying a tax to e-cigarettes. Conclusions A range of regulatory approaches are being applied to e-cigarettes globally; many countries regulate e-cigarettes using legislation not written for e-cigarettes. PMID:27903958

  2. HIPPA privacy regulations: practical information for physicians.

    Science.gov (United States)

    McMahon, E B; Lee-Huber, T

    2001-07-01

    After much debate and controversy, the Bush administration announced on April 12, 2001, that it would implement the Health Insurance Portability and Accountability Act (HIPAA) privacy regulations issued by the Clinton administration in December of 2000. The privacy regulations became effective on April 14, 2001. Although the regulations are considered final, the Secretary of the Department of Health and Human Services has the power to modify the regulations at any time during the first year of implementation. These regulations affect how a patient's health information is used and disclosed, as well as how patients are informed of their privacy rights. As "covered entities," physicians have until April 14, 2003, to comply fully with the HIPAA privacy regulations, which are more than 1,500 pages in length. This article presents a basic overview of the new and complex regulations and highlights practical information about physicians' compliance with the regulations. However, this summary of the HIPAA privacy regulations should not be construed as legal advice or an opinion on specific situations. Please consult an attorney concerning your compliance with HIPAA and the regulations promulgated thereunder.

  3. Environmental regulations and their effects on the nuclear regulator

    International Nuclear Information System (INIS)

    McManus, J.G.

    1994-01-01

    Environmental regulations are discussed from the point of view of the Canadian Atomic Energy Control Board (AECB). The AECB's mission includes the environment, namely 'to ensure that the use of nuclear energy in Canada does not pose any undue risk to health, safety, security or the environment'. The regulatory process was governed by the Atomic Energy Control Act, which at the time of the conference was outdated and due for replacement by a new version, and by the Environmental Assessment and Review Process Guidelines Order, which was due to be replaced by the Canadian Environmental Assessment Act, still not in force at the time of the conference. Through court decisions, the Guidelines Order had effectively acquired statutory authority. Public hearings and review can result in some considerable delay to the approval of a project, yet the AECB has no choice but to ensure that the requirements of the Guidelines Order are fulfilled. Collaboration between the federal and provincial governments is very evident in Saskatchewan. Of six mining projects being considered by the AECB, five were being reviewed by a joint federal provincial panel. For the future, it was hoped that the new Atomic Energy Control Act would increase fines and the powers of inspectors, require financial guarantees for decommissioning, regularize cooperation with the provinces, and empower the AECB to hold hearings that could effectively substitute for those prescribed by the Canadian Environmental Assessment Act

  4. Erratic Black Hole Regulates Itself

    Science.gov (United States)

    2009-03-01

    New results from NASA's Chandra X-ray Observatory have made a major advance in explaining how a special class of black holes may shut off the high-speed jets they produce. These results suggest that these black holes have a mechanism for regulating the rate at which they grow. Black holes come in many sizes: the supermassive ones, including those in quasars, which weigh in at millions to billions of times the mass of the Sun, and the much smaller stellar-mass black holes which have measured masses in the range of about 7 to 25 times the Sun's mass. Some stellar-mass black holes launch powerful jets of particles and radiation, like seen in quasars, and are called "micro-quasars". The new study looks at a famous micro-quasar in our own Galaxy, and regions close to its event horizon, or point of no return. This system, GRS 1915+105 (GRS 1915 for short), contains a black hole about 14 times the mass of the Sun that is feeding off material from a nearby companion star. As the material swirls toward the black hole, an accretion disk forms. This system shows remarkably unpredictable and complicated variability ranging from timescales of seconds to months, including 14 different patterns of variation. These variations are caused by a poorly understood connection between the disk and the radio jet seen in GRS 1915. Chandra, with its spectrograph, has observed GRS 1915 eleven times since its launch in 1999. These studies reveal that the jet in GRS 1915 may be periodically choked off when a hot wind, seen in X-rays, is driven off the accretion disk around the black hole. The wind is believed to shut down the jet by depriving it of matter that would have otherwise fueled it. Conversely, once the wind dies down, the jet can re-emerge. "We think the jet and wind around this black hole are in a sort of tug of war," said Joseph Neilsen, Harvard graduate student and lead author of the paper appearing in the journal Nature. "Sometimes one is winning and then, for reasons we don

  5. Regulation at nuclear fuel cycle

    International Nuclear Information System (INIS)

    2002-01-01

    This bulletin contains information about activities of the Nuclear Regulatory Authority of the Slovak Republic (UJD). In this leaflet the role of the UJD in regulation at nuclear fuel cycle is presented. The Nuclear Fuel Cycle (NFC) is a complex of activities linked with production of nuclear fuel for nuclear reactors as a source of energy used for production of electricity and heat, and of activities linked with spent nuclear fuel handling. Activities linked with nuclear fuel (NF) production, known as the Front-End of Nuclear Fuel Cycle, include (production of nuclear fuel from uranium as the most frequently used element). After discharging spent nuclear fuel (SNF) from nuclear reactor the activities follow linked with its storage, reprocessing and disposal known as the Back-End of Nuclear Fuel Cycle. Individual activity, which penetrates throughout the NFC, is transport of nuclear materials various forms during NF production and transport of NF and SNF. Nuclear reactors are installed in the Slovak Republic only in commercial nuclear power plants and the NFC is of the open type is imported from abroad and SNF is long-term supposed without reprocessing. The main mission of the area of NFC is supervision over: - assurance of nuclear safety throughout all NFC activities; - observance of provisions of the Treaty on Non-Proliferation of Nuclear Weapons during nuclear material handling; with an aim to prevent leakage of radioactive substances into environment (including deliberated danage of NFC sensitive facilities and misuse of nuclear materials to production of nuclear weapons. The UJD carries out this mission through: - assessment of safety documentation submitted by operators of nuclear installations at which nuclear material, NF and SNF is handled; - inspections concentrated on assurance of compliance of real conditions in NFC, i.e. storage and transport of NF and SNF; storage, transport and disposal of wastes from processing of SNF; with assumptions of the safety

  6. Synthetic risks, risk potency, and carcinogen regulation.

    Science.gov (United States)

    Viscusi, W K; Hakes, J K

    1998-01-01

    This article analyzes a comprehensive sample of over 350 chemicals tested for carcinogenicity to assess the determinants of the probability of regulation. Controlling for differences in the risk potency and noncancer risks, synthetic chemicals have a significantly higher probability of regulation overall: this is due to the greater likelihood of U.S. Food and Drug Administration (FDA) regulation. Measures of risk potency increase the probability of regulation by the U.S. Environmental Protection Agency (EPA), have a somewhat weaker positive effect on regulation by the U.S. Occupational Safety and Health Administration (OSHA), and decrease the likelihood of regulation by the FDA. The overall regulatory pattern is one in which the FDA targets synthetic chemicals and chemicals that pose relatively minor cancer risk. The EPA particularly performed more sensibly than many critics have suggested.

  7. Endogenous vs. exogenous regulations in the commons

    DEFF Research Database (Denmark)

    Abatayo, Anna Lou; Lynham, John

    2016-01-01

    It is widely believed that there is strong experimental evidence to support the idea that exogenously imposed regulations crowd out the intrinsic motivations of common pool resource (CPR) users to refrain from over-harvesting. We introduce a novel experimental design that attempts to disentangle...... potential confounds in previous experiments. A key feature of our experimental design is to have the exact same regulations chosen endogenously as those that are imposed exogenously. When we compare the same regulations chosen endogenously to those externally imposed, we observe no differences in extraction...... endogenous regulations with communication and exogenous regulations without communication. Our results suggest that externally imposed regulations do not crowd out intrinsic motivations in the lab and they confirm that communication facilitates cooperation to reduce extraction....

  8. Cap and trade offsets regulation - consultation paper

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2010-07-01

    Due to increasing concerns about the environment, British Columbia has committed to reducing its 2007 greenhouse gas emissions levels by 33% in 2020 and 80% in 2050. To reach those objectives, emissions trading and offset regulations are being developed by the Climate Action Secretariat. The aim of this document is to present a first draft of the regulations to the various stakeholders, including First Nations and the general public, together with the proposed offset eligibility criteria and related process, and to get their feedback. This document is itself part of the 5-phase process of developing the regulations. Following the 45 days during which comments on the proposed regulation were sought, the climate action secretariat will complete legal drafting of the regulations, drawing on help from this stakeholder input, and the regulation will subsequently be implemented. An accompanying response form was attached to this consultation paper.

  9. The regulations of the Nuclear Technology Committee

    International Nuclear Information System (INIS)

    Schwarzer, W.

    1984-01-01

    The work of the Nuclear Technology Committee (NTC) is characterised by the key words 'safety related regulations' and 'nuclear technology'. The rationalisation effect desired from regulations and the not unlimited number of experts qualified for working out regulations, make it necessary to establish priorities. The NTC has almost exclusively worked out regulations for nuclear powerstations and mainly for light water reactors. The program defined at present seems to cover the most important areas. Future developments can be foreseen in the execution of the part of the program not yet concluded, the maintenance of the regulations and, depending on the development of nuclear technology, the greater inclusion of the HTR and possibly the expansion of the regulations to fast breeder reactors and plant of the fuel circuit. (orig./HSCH) [de

  10. Self-regulation in the mining industry

    DEFF Research Database (Denmark)

    Sinding, Knud; Peck, Philip

    2013-01-01

    Many industries have established their own systems for self-regulation. They often do so when companies involved in the industry operate in countries where financial, technical, environmental and social regulation is weak and when the industry is challenged by legitimacy issues related to behaviour...... in one of these areas. One industry that has progressed unevenly down the road of self-regulation in these areas is mining. Developing self-regulation for mines and mining companies involves difficult questions of scope, rules, membership, assessment criteria and performance evaluation. While self-regulation...... may bring benefits to members, they are likely to take a long time coming; but when they do arrive they may be substantial. Using a range of theoretical and empirical results from research on self-regulation, performance rating and corporate strategy, this paper analyses the strategic and operational...

  11. Recent changes in federal PCB regulations

    International Nuclear Information System (INIS)

    Ewing, H.

    1995-01-01

    An overview of the federal regulations dealing with PCBs, the draft PCB Transformer Decontamination Standards and Protocols, and the Practice of Ballast Splitting was given. Answers were provided to practical questions concerning the regulations, specifically, responsibility for storage, labelling requirements, waste export regulations, treatment and destruction standards, transformer decontamination, decontamination standards, and the practice of ballast splitting into PCB and non-PCB materials. Details of sampling procedures and sample handling were also described

  12. Global approaches to regulating electronic cigarettes

    OpenAIRE

    Kennedy, Ryan David; Awopegba, Ayodeji; De Le?n, Elaine; Cohen, Joanna E

    2016-01-01

    Objectives Classify and describe the policy approaches used by countries to regulate e-cigarettes. Methods National policies regulating e-cigarettes were identified by (1) conducting web searches on Ministry of Health websites, and (2) broad web searches. The mechanisms used to regulate e-cigarettes were classified as new/amended laws, or existing laws. The policy domains identified include restrictions or prohibitions on product: sale, manufacturing, importation, distribution, use, product d...

  13. Circuit Regulates Speed Of dc Motor

    Science.gov (United States)

    Weaver, Charles; Padden, Robin; Brown, Floyd A., Jr.

    1990-01-01

    Driving circuit regulates speed of small dc permanent-magnet motor in tape recorder. Two nested feedback loops maintain speed within 1 percent of constant value. Inner loop provides coarse regulation, while outer loop removes most of variation in speed that remains in the presence of regulation by the inner loop. Compares speed of motor with commanded speed and adjusts current supplied to motor accordingly.

  14. New storm water regulations impact industry

    International Nuclear Information System (INIS)

    Gemar, C.

    1991-01-01

    In November 1990, new Environmental Protection Agency (EPA) regulations aimed at governing the discharge of storm water from industrial facilities became effective. Because some industrial runoff contains toxics and other pollutants, the EPA considers storm water a major source of water contamination. The new regulations will have a profound impact on the National Pollutant Discharge Elimination System (NPDES) permit requirements for industry. This paper summarizes the new storm water regulations, focusing on the requirements for industrial facilities. It also presents suggestions for compliance

  15. The staff regulations of the Agency

    International Nuclear Information System (INIS)

    2002-01-01

    Following the first comprehensive review of the Provisional Staff Regulations conducted by the Secretariat, the Board of Governors approved on 12 June 2002 amendments to the Provisional Staff Regulations including the removal of the attribute 'provisional' from their title. The revised Staff Regulations of the Agency are set forth in this document for the information of all Members of the Agency. There is a subject index at the end of the document

  16. Medical devices regulations, standards and practices

    CERN Document Server

    Ramakrishna, Seeram; Wang, Charlene

    2015-01-01

    Medical Devices and Regulations: Standards and Practices will shed light on the importance of regulations and standards among all stakeholders, bioengineering designers, biomaterial scientists and researchers to enable development of future medical devices. Based on the authors' practical experience, this book provides a concise, practical guide on key issues and processes in developing new medical devices to meet international regulatory requirements and standards. Provides readers with a global perspective on medical device regulationsConcise and comprehensive information on how to desig

  17. Legal regulation of treatment of wild animals

    OpenAIRE

    Kolečkářová, Eliška

    2014-01-01

    The diploma thesis deals with the legal regulation of the treatment with wild animals. It compares different terms used in legal regulation of protection of animals. It specified differences between concept of an animal in private law and public law. The diploma thesis is focused on possibilities of gaining ownership to the wild animals, proving origin of animals bred in human care. It concerns with legal regulation of treatment with handicap animals. The diploma thesis analyzes preparation a...

  18. Radioactive waste management and regulation

    International Nuclear Information System (INIS)

    Willrich, M.; Lester, R.K.; Greenberg, S.C.; Mitchell, H.C.; Walker, D.A.

    1977-01-01

    Purpose of this book is to assist in developing public policy and institutions for the safe management of radioactive waste, currently and long term. Both high-level waste and low-level waste containing transuranium elements are covered. The following conclusions are drawn: the safe management of post-fission radioactive waste is already a present necessity and an irreversible long-term commitment; the basic goals of U.S. radioactive waste policy are unclear; the existing organization for radioactive waste management is likely to be unworkable if left unchanged; and the existing framework for radioactive waste regulation is likely to be ineffective if left unchanged. The following recommendations are made: a national Radioactive Waste Authority should be established as a federally chartered public corporation; with NRC as the primary agency, a comprehensive regulatory framework should be established to assure the safety of all radioactive waste management operations under U.S. jurisdiction or control; ERDA should continue to have primary government responsibility for R and D and demonstration of radioactive waste technology; and the U.S. government should propose that an international Radioactive Waste Commission be established under the IAEA

  19. Regulation of pulpal blood flow

    International Nuclear Information System (INIS)

    Kim, S.

    1985-01-01

    The regulation of blood flow of the dental pulp was investigated in dogs and rats anesthetized with sodium pentobarbital. Pulpal blood flow was altered by variations of local and systemic hemodynamics. Macrocirculatory blood flow (ml/min/100 g) in the dental pulp was measured with both the 133 Xe washout and the 15-microns radioisotope-labeled microsphere injection methods on the canine teeth of dogs, to provide a comparison of the two methods in the same tooth. Microcirculatory studies were conducted in the rat incisor tooth with microscopic determination of the vascular pattern, RBC velocity, and intravascular volumetric flow distribution. Pulpal resistance vessels have alpha- and beta-adrenergic receptors. Activation of alpha-receptors by intra-arterial injection of norepinephrine (NE) caused both a reduction in macrocirculatory Qp in dogs and decreases in arteriolar and venular diameters and intravascular volumetric flow (Qi) in rats. These responses were blocked by the alpha-antagonist PBZ. Activation of beta-receptors by intra-arterial injection of isoproterenal (ISO) caused a paradoxical reduction of Qp in dogs. In rats, ISO caused a transient increase in arteriolar Qi followed by a flow reduction; arteriolar dilation was accompanied by venular constriction. These macrocirculatory and microcirculatory responses to ISO were blocked by the alpha-antagonist propranolol

  20. Kyoto : implications for utility regulation

    International Nuclear Information System (INIS)

    Dunsky, P.

    2003-01-01

    The author provided a historical perspective of energy use and the role of carbon in the western hemisphere by displaying a series of graphs showing carbon intensity of energy, carbon emissions from energy, and the long path to green power. The 1990s represented a decade of progress. Almost three times as much wind capacity as nuclear capacity was added worldwide in 2001. The main challenge for the 21st century will be to bring under-developed countries into the fold while perpetuating the economic and human progress of the twentieth century. It was emphasized that environmental damage caused by utilities must be reversed. The contemporary context for the Kyoto Protocol was reviewed. Canada's commitment under the Kyoto Protocol is to reduce greenhouse gas emissions by 6 per cent below 1990 levels. The challenge for utility regulators to meet this commitment was examined. The costs are not entirely excessive. Some of the regulatory issues were discussed, namely revising a broad rate making framework, cost recovery and others. The Kyoto compliance plan was also reviewed with reference to internal options, external options, identification of regulatory barriers, and consideration of greenhouse gas credit markets. figs