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Sample records for constitutively activated alk2

  1. Mouse smad8 phosphorylation downstream of BMP receptors ALK-2, ALK-3, and ALK-6 induces its association with Smad4 and transcriptional activity.

    Science.gov (United States)

    Kawai, S; Faucheu, C; Gallea, S; Spinella-Jaegle, S; Atfi, A; Baron, R; Roman, S R

    2000-05-19

    Smads are intracellular signaling mediators for TGF-beta superfamily. Smad1 and Smad5 are activated by BMP receptors. Here, we have cloned mouse Smad8 and functionally characterized its ability to transduce signals from BMP receptors. Constitutively active BMP type I receptors, ALK-3 and ALK-6, as well as ALK-2, were phosphorylated Smad8 and induced Smad8 interaction with Smad4. Nuclear translocation of Smad8 was stimulated by constitutively active BMP type I receptors. In contrast, constitutively active TGF-beta type I receptor, ALK-5, did not exhibit any action on Smad8. Smad8 and Smad4 cooperatively induced the promoter of Xvent2, a homeobox gene that responds specifically to BMP signaling. Dominant-negative Smad8 was shown to inhibit the increase of alkaline phosphatase activity induced by BMP-2 on pluripotent mesenchymal C3H10T1/2 and myoblastic C2C12 cell lines. The presence of Smad8 mRNA in mouse calvaria cells and osteoblasts suggests a role of Smad8 in the osteoblast differentiation and maturation. Copyright 2000 Academic Press.

  2. Secreted Stress-Induced Phosphoprotein 1 Activates the ALK2-SMAD Signaling Pathways and Promotes Cell Proliferation of Ovarian Cancer Cells

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    Chia-Lung Tsai

    2012-08-01

    Full Text Available Stress-induced phosphoprotein 1 (STIP1, a cochaperone that organizes other chaperones, heat shock proteins (HSPs, was recently shown to be secreted by human ovarian cancer cells. In neuronal tissues, binding to prion protein was required for STIP1 to activate the ERK (extracellular-regulated MAP kinase signaling pathways. However, we report that STIP1 binding to a bone morphogenetic protein (BMP receptor, ALK2 (activin A receptor, type II-like kinase 2, was necessary and sufficient to stimulate proliferation of ovarian cancer cells. The binding of STIP1 to ALK2 activated the SMAD signaling pathway, leading to transcriptional activation of ID3 (inhibitor of DNA binding 3, promoting cell proliferation. In conclusion, ovarian-cancer-tissue-secreted STIP1 stimulates cancer cell proliferation by binding to ALK2 and activating the SMAD-ID3 signaling pathways. Although animal studies are needed to confirm these mechanisms in vivo, our results may pave the way for developing novel therapeutic strategies for ovarian cancer.

  3. BMP type I receptor ALK2 is required for angiotensin II-induced cardiac hypertrophy

    Science.gov (United States)

    Spagnolli, Ester; Ernande, Laura; Thoonen, Robrecht; Kolodziej, Starsha A.; Leyton, Patricio A.; Cheng, Juan; Tainsh, Robert E. T.; Mayeur, Claire; Rhee, David K.; Wu, Mei. X.; Scherrer-Crosbie, Marielle; Buys, Emmanuel S.; Zapol, Warren M.; Bloch, Kenneth D.; Bloch, Donald B.

    2016-01-01

    Bone morphogenetic protein (BMP) signaling contributes to the development of cardiac hypertrophy. However, the identity of the BMP type I receptor involved in cardiac hypertrophy and the underlying molecular mechanisms are poorly understood. By using quantitative PCR and immunoblotting, we demonstrated that BMP signaling increased during phenylephrine-induced hypertrophy in cultured neonatal rat cardiomyocytes (NRCs), as evidenced by increased phosphorylation of Smads 1 and 5 and induction of Id1 gene expression. Inhibition of BMP signaling with LDN193189 or noggin, and silencing of Smad 1 or 4 using small interfering RNA diminished the ability of phenylephrine to induce hypertrophy in NRCs. Conversely, activation of BMP signaling with BMP2 or BMP4 induced hypertrophy in NRCs. Luciferase reporter assay further showed that BMP2 or BMP4 treatment of NRCs repressed atrogin-1 gene expression concomitant with an increase in calcineurin protein levels and enhanced activity of nuclear factor of activated T cells, providing a mechanism by which BMP signaling contributes to cardiac hypertrophy. In a model of cardiac hypertrophy, C57BL/6 mice treated with angiotensin II (A2) had increased BMP signaling in the left ventricle. Treatment with LDN193189 attenuated A2-induced cardiac hypertrophy and collagen deposition in left ventricles. Cardiomyocyte-specific deletion of BMP type I receptor ALK2 (activin-like kinase 2), but not ALK1 or ALK3, inhibited BMP signaling and mitigated A2-induced cardiac hypertrophy and left ventricular fibrosis in mice. The results suggest that BMP signaling upregulates the calcineurin/nuclear factor of activated T cell pathway via BMP type I receptor ALK2, contributing to cardiac hypertrophy and fibrosis. PMID:26873969

  4. CONSTITUTIONALISM

    African Journals Online (AJOL)

    eliasn

    1 Hilaire Barnett, Constitutional and Administrative Law 5 (London: Cavendish ... 3(2) Mizan Law Rev. NOTES ON CONSTITUTIONALISM. 359 independent judiciary, respect for individual rights and the right to self- determination as essential ..... “Our principle is the party commands the gun, and the gun must never be.

  5. Fibrodysplasia ossificans progressiva-related activated activin-like kinase signaling enhances osteoclast formation during heterotopic ossification in muscle tissues.

    Science.gov (United States)

    Yano, Masato; Kawao, Naoyuki; Okumoto, Katsumi; Tamura, Yukinori; Okada, Kiyotaka; Kaji, Hiroshi

    2014-06-13

    Fibrodysplasia ossificans progressiva is characterized by extensive ossification within muscle tissues, and its molecular pathogenesis is responsible for the constitutively activating mutation (R206H) of the bone morphogenetic protein type 1 receptor, activin-like kinase 2 (ALK2). In this study, we investigated the effects of implanting ALK2 (R206H)-transfected myoblastic C2C12 cells into nude mice on osteoclast formation during heterotopic ossification in muscle and subcutaneous tissues. The implantation of ALK2 (R206H)-transfected C2C12 cells with BMP-2 in nude mice induced robust heterotopic ossification with an increase in the formation of osteoclasts in muscle tissues but not in subcutaneous tissues. The implantation of ALK2 (R206H)-transfected C2C12 cells in muscle induced heterotopic ossification more effectively than that of empty vector-transfected cells. A co-culture of ALK2 (R206H)-transfected C2C12 cells as well as the conditioned medium from ALK2 (R206H)-transfected C2C12 cells enhanced osteoclast formation in Raw264.7 cells more effectively than those with empty vector-transfected cells. The transfection of ALK2 (R206H) into C2C12 cells elevated the expression of transforming growth factor (TGF)-β, whereas the inhibition of TGF-β signaling suppressed the enhanced formation of osteoclasts in the co-culture with ALK2 (R206H)-transfected C2C12 cells and their conditioned medium. In conclusion, this study demonstrated that the causal mutation transfection of fibrodysplasia ossificans progressiva in myoblasts enhanced the formation of osteoclasts from its precursor through TGF-β in muscle tissues. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Common mutations in ALK2/ACVR1, a multi-faceted receptor, have roles in distinct pediatric musculoskeletal and neural orphan disorders.

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    Pacifici, Maurizio; Shore, Eileen M

    2016-02-01

    Activin receptor-like kinase-2 (ALK2), the product of ACVR1, is a member of the type I bone morphogenetic protein (BMP) receptor family. ALK2 exerts key and non-redundant roles in numerous developmental processes, including the specification, growth and morphogenesis of endochondral skeletal elements. There is also strong evidence that BMP signaling plays important roles in determination, differentiation and function of neural cells and tissues. Here we focus on the intriguing discovery that common activating mutations in ALK2 occur in Fibrodysplasia Ossificans Progressiva (FOP) and Diffuse Intrinsic Pontine Gliomas (DIPGs), distinct pediatric disorders of significant severity that are associated with premature death. Pathogenesis and treatment remain elusive for both. We consider recent studies on the nature of the ACVR1 mutations, possible modes of action and targets, and plausible therapeutic measures. Comparisons of the diverse - but genetically interrelated - pathologies of FOP and DIPG will continue to be of major mutual benefit with broad biomedical and clinical relevance. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Biological effects of rAAV-caAlk2 coating on structural allograft healing

    DEFF Research Database (Denmark)

    Koefoed, Mette; Ito, Hiromu; Gromov, Kirill

    2005-01-01

    Structural bone allografts often fracture due to their lack of osteogenic and remodeling potential. To overcome these limitations, we utilized allografts coated with recombinant adeno-associated virus (rAAV) that mediate in vivo gene transfer. Using beta-galactosidase as a reporter gene, we show...... that 4-mm murine femoral allografts coated with rAAV-LacZ are capable of transducing adjacent inflammatory cells and osteoblasts in the fracture callus following transplantation. While this LacZ vector had no effect on allograft healing, bone morphogenetic protein signals delivered via rAAV-caAlk2...... coating induced endochondral bone formation directly on the cortical surface of the allograft by day 14. By day 28 there was evidence of remodeling of the new woven bone and massive osteoclastic resorption of the cortical surface of the rAAV-caAlk2-coated allografts only. Micro-CT analysis of r...

  8. Constitutively activated ERK sensitizes cancer cells to doxorubicin ...

    Indian Academy of Sciences (India)

    2017-02-03

    Feb 3, 2017 ... Constitutively activated ERK sensitizes cancer cells to doxorubicin: Involvement of p53-EGFR-ERK pathway. RATNA KUMARI. 1,†. , SURBHI CHOUHAN. 1,†. , SNAHLATA SINGH. 1,†. , RISHI RAJ CHHIPA. 2. ,. AMRENDRA KUMAR AJAY. 3 and MANOJ KUMAR BHAT*. National Centre for Cell Science, ...

  9. Constitutive Activation of Raf-1 Induces Glioma Formation in Mice

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    Yelena Lyustikman

    2008-05-01

    Full Text Available In human glioblastoma multiforme (GBM, RAS activity is upregulated in the majority of the tumors. Furthermore, the levels of phospho-mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK, a downstream effector of RAS, are also increased. In mice, activated KRas cooperates with the loss of INK4a-ARF locus or with activated Akt to induce gliomas, confirming an important role for this pathway in glioma biology. However, to correctly target therapies against the RAS signaling pathway, it is necessary to identify the effectors that contribute to RAS-mediated gliomagenesis. In this study, we investigated the contribution of RAF signaling in glioma oncogenesis. We find that the levels of RAF-1 and BRAF proteins and RAF kinase activity are increased in human GBM samples. We confirm the importance of this finding by demonstrating a causal role for a constitutively active Raf-1 mutant in glioma formation in mice. Specifically, we find that activated Raf-1 cooperates with Arf loss or Akt activation to generate gliomas similar to activated KRas under the same conditions. Our study suggests that the oncogenic effect of KRas in glioma formation may be transduced at least in part through Raf signaling and that therapeutic targeting of this pathway may be beneficial in glioma treatment.

  10. New constitutive latex osmotin-like proteins lacking antifungal activity.

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    Freitas, Cleverson D T; Silva, Maria Z R; Bruno-Moreno, Frederico; Monteiro-Moreira, Ana C O; Moreira, Renato A; Ramos, Márcio V

    2015-11-01

    Proteins that share similar primary sequences to the protein originally described in salt-stressed tobacco cells have been named osmotins. So far, only two osmotin-like proteins were purified and characterized of latex fluids. Osmotin from Carica papaya latex is an inducible protein lacking antifungal activity, whereas the Calotropis procera latex osmotin is a constitutive antifungal protein. To get additional insights into this subject, we investigated osmotins in latex fluids of five species. Two potential osmotin-like proteins in Cryptostegia grandiflora and Plumeria rubra latex were detected by immunological cross-reactivity with polyclonal antibodies produced against the C. procera latex osmotin (CpOsm) by ELISA, Dot Blot and Western Blot assays. Osmotin-like proteins were not detected in the latex of Thevetia peruviana, Himatanthus drasticus and healthy Carica papaya fruits. Later, the two new osmotin-like proteins were purified through immunoaffinity chromatography with anti-CpOsm immobilized antibodies. Worth noting the chromatographic efficiency allowed for the purification of the osmotin-like protein belonging to H. drasticus latex, which was not detectable by immunoassays. The identification of the purified proteins was confirmed after MS/MS analyses of their tryptic digests. It is concluded that the constitutive osmotin-like proteins reported here share structural similarities to CpOsm. However, unlike CpOsm, they did not exhibit antifungal activity against Fusarium solani and Colletotrichum gloeosporioides. These results suggest that osmotins of different latex sources may be involved in distinct physiological or defensive events. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  11. CONSTITUTIVE ACTIVITY OF TRP CHANNELS: METHODS FOR MEASURING THE ACTIVITY AND ITS OUTCOME

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    Lev, Shaya; Minke, Baruch

    2011-01-01

    TRP channels participate in many cellular processes including cell death. These channels mediate these effects mainly by changing the cellular concentration of Ca2+, a prominent cellular second messenger. Measuring the current-voltage relationship and state of activation of TRP channels is of utmost importance for evaluating their contribution to a cellular process within a spatial and temporal context. The study of TRP channels and characterization of their mode of activation will benefit and progress our understanding of each channel’s role in specific cellular mechanisms. Many TRP channels exhibit constitutive activity, which is mostly observed in cell based expression systems. This constitutive activity can lead, in many cases, to cellular degeneration, which can be readily observed morphologically and by biochemical assays. This chapter describes in brief, different modes of TRP channel activity and their current voltage relationships. The chapter outlines methods for visualizing this activity and methods to correlate between TRP channel activity and cell death, and it illustrates mechanisms that prevent cell death in spite of constitutive activity. Finally, it describes methods for qualitatively and quantitatively measuring the accompanied cellular degeneration. PMID:21036252

  12. Transgenic mice expressing constitutive active MAPKAPK5 display gender-dependent differences in exploration and activity

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    Moens Ugo

    2007-11-01

    Full Text Available Abstract Background The mitogen-activated protein kinases, MAPKs for short, constitute cascades of signalling pathways involved in the regulation of several cellular processes that include cell proliferation, differentiation and motility. They also intervene in neurological processes like fear conditioning and memory. Since little remains known about the MAPK-Activated Protein Kinase, MAPKAPK5, we constructed the first MAPKAPK knockin mouse model, using a constitutive active variant of MAPKAPK5 and analyzed the resulting mice for changes in anxiety-related behaviour. Methods We performed primary SHIRPA observations during background breeding into the C57BL/6 background and assessed the behaviour of the background-bred animals on the elevated plus maze and in the light-dark test. Our results were analyzed using Chi-square tests and homo- and heteroscedatic T-tests. Results Female transgenic mice displayed increased amounts of head dips and open arm time on the maze, compared to littermate controls. In addition, they also explored further into the open arm on the elevated plus maze and were less active in the closed arm compared to littermate controls. Male transgenic mice displayed no differences in anxiety, but their locomotor activity increased compared to non-transgenic littermates. Conclusion Our results revealed anxiety-related traits and locomotor differences between transgenic mice expressing constitutive active MAPKAPK5 and control littermates.

  13. Morphine withdrawal enhances constitutive μ-opioid receptor activity in the ventral tegmental area

    NARCIS (Netherlands)

    Meye, F.J.; van Zessen, R.; Smidt, M.P.; Adan, R.A.H.; Ramakers, G.M.J.

    2012-01-01

    μ-opioid receptors (MORs) in the ventral tegmental area (VTA) are pivotally involved in addictive behavior. While MORs are typically activated by opioids, they can also become constitutively active in the absence of any agonist. In the current study, we present evidence that MOR constitutive

  14. Nutrition, activity behavior and body constitution in primary school children

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    F Carandente

    2009-12-01

    Full Text Available Child and adolescent obesity currently affects at least 10-25�0of the paediatric population in most developed countries. The BMI value is one of the most appropriate method of defining obesity and has a strong association with body fatness and health risk. Two main environmental factors, nutrition and physical activity, could influence paediatric obesity development. This paper studies the relationship between sedentariness, snack and soft drink intake and overweight or obesity in children. 1194 primary school children (age 8-10 participated in the study. For all the subjects we measured the anthropometric data to calculate the BMI. The overweight and obesity prevalence was estimated using age-specific BMI cutoffs. A questionaire was also submitted to all the children by a single interviewer to obtain data about: a Weekly Physical Activity, b Weekly Sedentary Activity, c Alimentary Style. Spearman rank correlation and the Student’s t-test were used. The data demonstrated that 23.2�0of the children is overweight and the 4.8�0obese. BMI is inversely correlated to the physical activity, while there is positive correlation between BMI and number of double portions. Statistically significant positive correlation is present among eating snacks and hours of sedentariness, while there is a negative correlation between physical activity and TV hours. Physical activity in the childhood could be an important tool to prevent obesity development and adult-onset chronic diseases. It is important to encourage an active lifestyle in order to reduce sedentariness.

  15. Constitutively activated ERK sensitizes cancer cells to doxorubicin ...

    Indian Academy of Sciences (India)

    The tumour suppressor gene p53 is mutated in approximately 50% of the human cancers. p53 is involved in genotoxicstress-induced cellular responses. The role of EGFR and ERK in DNA-damage-induced apoptosis is well known. Weinvestigated the involvement of activation of ERK signalling as a consequence of ...

  16. Common structural basis for constitutive activity of the ghrelin receptor family

    DEFF Research Database (Denmark)

    Holst, Birgitte; Holliday, Nicholas D; Bach, Anders

    2004-01-01

    Three members of the ghrelin receptor family were characterized in parallel: the ghrelin receptor, the neurotensin receptor 2 and the orphan receptor GPR39. In transiently transfected COS-7 and human embryonic kidney 293 cells, all three receptors displayed a high degree of ligand......-independent signaling activity. The structurally homologous motilin receptor served as a constitutively silent control; upon agonist stimulation, however, it signaled with a similar efficacy to the three related receptors. The constitutive activity of the ghrelin receptor and of neurotensin receptor 2 through the G...... demonstrated that the epitope-tagged ghrelin receptor was constitutively internalized but could be trapped at the cell surface by an inverse agonist, whereas GPR39 remained at the cell surface. Mutational analysis showed that the constitutive activity of both the ghrelin receptor and GPR39 could systematically...

  17. Phosphorylated Nuclear Receptor CAR Forms a Homodimer To Repress Its Constitutive Activity for Ligand Activation.

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    Shizu, Ryota; Osabe, Makoto; Perera, Lalith; Moore, Rick; Sueyoshi, Tatsuya; Negishi, Masahiko

    2017-05-15

    The nuclear receptor CAR (NR1I3) regulates hepatic drug and energy metabolism as well as cell fate. Its activation can be a critical factor in drug-induced toxicity and the development of diseases, including diabetes and tumors. CAR inactivates its constitutive activity by phosphorylation at threonine 38. Utilizing receptor for protein kinase 1 (RACK1) as the regulatory subunit, protein phosphatase 2A (PP2A) dephosphorylates threonine 38 to activate CAR. Here we demonstrate that CAR undergoes homodimer-monomer conversion to regulate this dephosphorylation. By coexpression of two differently tagged CAR proteins in Huh-7 cells, mouse primary hepatocytes, and mouse livers, coimmunoprecipitation and two-dimensional gel electrophoresis revealed that CAR can form a homodimer in a configuration in which the PP2A/RACK1 binding site is buried within its dimer interface. Epidermal growth factor (EGF) was found to stimulate CAR homodimerization, thus constraining CAR in its inactive form. The agonistic ligand CITCO binds directly to the CAR homodimer and dissociates phosphorylated CAR into its monomers, exposing the PP2A/RACK1 binding site for dephosphorylation. Phenobarbital, which is not a CAR ligand, binds the EGF receptor, reversing the EGF signal to monomerize CAR for its indirect activation. Thus, the homodimer-monomer conversion is the underlying molecular mechanism that regulates CAR activation, by placing phosphorylated threonine 38 as the common target for both direct and indirect activation of CAR. Copyright © 2017 American Society for Microbiology.

  18. Tax-Independent Constitutive IκB Kinase Activation in Adult T-Cell Leukemia Cells

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    Noriko Hironaka

    2004-05-01

    Full Text Available Adult T-cell leukemia (ATL is a fatal T-cell malignancy that arises long after infection with human T-cell leukemia virus type I (HTLV-I. We reported previously that nuclear factor-κB (NF-κB was constitutively activated in ATL cells, although expression of the viral proteins was barely detectable, including Tax, which was known to persistently activate NF-κB. Here we demonstrate that ATL cells that do not express detectable Tax protein exhibit constitutive IKB kinase (IKK activity. Transfection studies revealed that a dominant-negative form of IKK1, not of IKK2 or NF-κB essential modulator (NEMO, suppressed constitutive NF-κB activity in ATL cells. This IKK activity was accompanied by elevated expression of p52, suggesting that the recently described noncanonical pathway of NF-κB activation operates in ATL cells. We finally show that specific inhibition of NF-κB by a super-repressor form of IκBα (SR-IκBα in HTLV-Iinfected T cells results in cell death regardless of Tax expression, providing definitive evidence of an essential role for NF-κB in the survival of ATL cells. In conclusion, the IKK complex is constitutively activated in ATL cells through a cellular mechanism distinct from that of Tax-mediated IKK activation. Further elucidation of this cellular mechanism should contribute to establishing a rationale for treatment of ATL.

  19. Assessment of constitutive activity and internalization of GPR54 (KISS1-R).

    Science.gov (United States)

    Pampillo, Macarena; Babwah, Andy V

    2010-01-01

    The kisspeptin/GPR54 signaling system positively regulates GnRH secretion, thereby acting as an important regulator of the hypothalamic-pituitary-gonadal axis. It also negatively regulates tumor metastases and placental trophoblast invasion. GPR54 is a G(q/11)-coupled GPCR and activation by kisspeptin stimulates PIP(2) hydrolysis and inositol phosphate (IP) formation, Ca(2+) mobilization, arachidonic acid release, and ERK1/2 and p38 MAP kinase phosphorylation. Recently, we reported that GPR54 displays constitutive activity and internalization in the heterologous human embryonic kidney 293 cell system. Given the physiological and clinical importance of GPR54 as well as other GPCRs, we present assays for measuring constitutive receptor internalization and activity. Specifically, we describe the use of immunofluorescence coupled to confocal imaging, flow cytometry and indirect receptor radiolabeling to measure constitutive receptor internalization, and IP turnover in intact cells to measure constitutive activity. While we use the FLAG-tagged GPR54 molecule as an example to describe these assays, the assays can be applied to a wide range of GPCRs. Copyright © 2010 Elsevier Inc. All rights reserved.

  20. beta-agonist-induced constitutive beta(2)-adrenergic receptor activity in bovine tracheal smooth muscle

    NARCIS (Netherlands)

    de Vries, B; Meurs, H; Roffel, AF; Elzinga, CRS; Hoiting, BH; de Vries, MML; Zaagsma, J

    2000-01-01

    1 According to the two state receptor model, the beta (2)-adrenergic receptor (beta (2)-AR) isomerizes between an inactive state and a constitutively active state, which couples to the stimulatory G-protein in the absence of agonist. In bovine tracheal smooth muscle (BTSM), we investigated the

  1. Constitutive and inducible hydroxylase activities involved in the degradation of naphthalene by Cunninghamella elegans.

    Science.gov (United States)

    Faber, B W; Schonewille, A B; van Gorcom, R F; Duine, J A

    2001-05-01

    The non-ligninolytic fungus Cunninghamella elegans was investigated for its ability to produce naphthalene hydroxylase (NAH) and naphthol hydroxylase (NOH) activities under various conditions. When the organism was cultivated on a rich growth medium, the mycelia exhibited significant constitutive NAH activity in the late exponential growth phase, but not in the early-exponential-growth-phase. On incubating the early-exponential-growth-phase mycelia with naphthalene, NAH activity was increased five-fold; however, this increase did not occur in the presence of the protein synthesis inhibitor cycloheximide. Since incubation of the late-phase mycelia with naphthalene did not lead to a higher degradation rate of naphthalene, mycelia in this physiological state have apparently lost the ability to induce synthesis of the enzyme exhibiting NAH activity. This is not due to an overall inability to perform de novo protein synthesis, since NOH activity, non-constitutive at all growth phases, could be induced by incubating late-phase mycelia with naphthalene. Whether inducible and constitutive NAH activity originate from one and the same enzyme remains to be elucidated. It is suggested that naphthalene oxidizing enzyme(s) may also oxidize pyrene, but not anthracene or benzo[a]pyrene, although the latter are degradable by C. elegans.

  2. Constitutive integrin activation on tumor cells contributes to progression of leptomeningeal metastases1

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    Brandsma, Dieta; Ulfman, Laurien; Reijneveld, Jaap C.; Bracke, Madelon; Taphoorn, Martin J.B.; Zwaginga, Jaap Jan; Gebbink, Martijn F.B.; de Boer, Hetty; Koenderman, Leo; Voest, Emile E.

    2006-01-01

    Leptomeningeal metastases are a serious neurological complication in cancer patients and associated with a dismal prognosis. Tumor cells that enter the subarachnoid space adhere to the leptomeninges and form tumor deposits. It is largely unknown which adhesion molecules mediate tumor cell adhesion to leptomeninges. We studied the role of integrin expression and activation in the progression of leptomeningeal metastases. For this study, we used a mouse acute lymphocytic leukemic cell line that was grown in suspension (L1210-S cell line) to develop an adherent L1210 cell line (L1210-A) by selectively culturing the few adherent cells in the cell culture. β1, β2, and β3 integrins were in a constitutively high active state on L1210-A cells and in a low, but inducible, active state on L1210-S cells. Expression levels of these integrins were comparable in the two cell lines. Static adhesion levels of L1210-A cells on a leptomeningeal cell layer were significantly higher than those of L1210-S cells. All mice that were injected intrathecally with L1210-A cells died rapidly of leptomeningeal leukemia. In contrast, 45% long-term survival was seen after intrathecal injection of mice with L1210-S cells. Our data indicate that constitutive integrin activation on leukemic cells promotes progression of leptomeningeal leukemia by increased tumor cell adhesion to the leptomeninges. We argue that an aberrantly regulated inside-out signaling pathway underlies constitutive integrin activation on the adherent leukemic cell population. PMID:16533879

  3. Adverse Effects of Osteocytic Constitutive Activation of ß-Catenin on Bone Strength and Bone Growth.

    Science.gov (United States)

    Chen, Sixu; Feng, Jianquan; Bao, Quanwei; Li, Ang; Zhang, Bo; Shen, Yue; Zhao, Yufeng; Guo, Qingshan; Jing, Junjun; Lin, Shuxian; Zong, Zhaowen

    2015-07-01

    The activation of the canonical Wnt/β-catenin signaling pathway in both mesenchymal stem cells and osteoblasts has been demonstrated to increase bone mass, showing promise for the treatment of low bone volume conditions such as osteoporosis. However, the possible side effects of manipulating this pathway have not been fully addressed. Previously, we reported that the constitutive activation of ß-catenin in osteoblasts impaired vertebral linear growth. In the present study, β-catenin was constitutively activated in osteocytes by crossing Catnb+/lox(exon 3) mice with dentin matrix protein 1(DMP1)-Cre transgenic mice, and the effects of this activation on bone mass, bone growth and bone strength were then observed. DMP1-Cre was found to be predominantly expressed in osteocytes, with weak expression in a small portion of osteoblasts and growth plate chondrocytes. After the activation, the cancellous bone mass was dramatically increased, almost filling the entire bone marrow cavity in long bones. However, bone strength decreased significantly. Thinner and more porous cortical bone along with impaired mineralization were responsible for the decrease in bone strength. Furthermore, the mice showed shorter stature with impaired linear growth of the long bones. Moreover, the concentration of serum phosphate decreased significantly after the activation of ß-catenin, and a high inorganic phosphate (Pi) diet could partially rescue the phenotype of decreased mineralization level and impaired linear growth. Taken together, the constitutive activation of β-catenin in osteocytes may increase cancellous bone mass; however, the activation also had adverse effects on bone strength and bone growth. These adverse effects should be addressed before the adoption of any therapeutic clinical application involving adjustment of the Wnt/β-catenin signaling pathway. © 2015 American Society for Bone and Mineral Research.

  4. Constitutive activity and ligand-dependent activation of the nuclear receptor CAR-insights from molecular dynamics simulations.

    Science.gov (United States)

    Windshügel, Björn; Poso, Antti

    2011-01-01

    The constitutive androstane receptor (CAR) possesses, unlike most other nuclear receptors, a pronounced basal activity in vitro whose structural basis is still not fully understood. Using comparative molecular dynamics simulations of CAR X-ray crystal structures, we evaluated the molecular basis for constitutive activity and ligand-dependent receptor activation. Our results suggest that a combination of van der Waals interactions and hydrogen bonds is required to maintain the activation helix in the active conformation also in absence of a ligand. Furthermore, we identified conformational rearrangements within the ligand-binding pocket upon agonist binding and an influence of CAR inducers pregnanedione and CITCO on the helical conformation of the activation helix. Based on the results a model for ligand-dependent CAR activation is suggested. Copyright © 2011 John Wiley & Sons, Ltd.

  5. Constitutive Expression of Functionally Active Protease-Activated Receptors 1 and 2 in Human Conjunctival Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Timothy J. Nickel

    2006-01-01

    epithelial cells as in vitro model. We performed RT-PCR and immunofluorescence analyses to determine the expression of PAR1 and PAR2, and monitored the production of IL-6 after activating HCECs with PAR1 activating agents (thrombin or TFLLRN or PAR2 activating agents (tryptase, trypsin, or SLIGKV. The results show that HCECs constitutively express PAR1 and PAR2 mRNA and proteins, and produce significant amounts of IL-6 when incubated with specific PAR-activating enzymes or agonist peptides. Thrombin- and tryptase-induced HCEC activation was blocked by PAR1 and PAR2 neutralizing antibodies, respectively, and by specific enzyme inhibitors. The constitutive expression of PAR1 and PAR2, and their activation by thrombin and tryptase, respectively, may have important implications in ocular inflammation.

  6. Interaction Between Familial Transmission and a Constitutively Active Immune System Shapes Gut Microbiota in Drosophila melanogaster

    Science.gov (United States)

    Mistry, Rupal; Kounatidis, Ilias; Ligoxygakis, Petros

    2017-01-01

    Resident gut bacteria are constantly influencing the immune system, yet the role of the immune system in shaping microbiota composition during an organism’s life span has remained unclear. Experiments in mice have been inconclusive due to differences in husbandry schemes that led to conflicting results. We used Drosophila as a genetically tractable system with a simpler gut bacterial population structure streamlined genetic backgrounds and established cross schemes to address this issue. We found that, depending on their genetic background, young flies had microbiota of different diversities that converged with age to the same Acetobacteraceae-dominated pattern in healthy flies. This pattern was accelerated in immune-compromised flies with higher bacterial load and gut cell death. Nevertheless, immune-compromised flies resembled their genetic background, indicating that familial transmission was the main force regulating gut microbiota. In contrast, flies with a constitutively active immune system had microbiota readily distinguishable from their genetic background with the introduction and establishment of previously undetectable bacterial families. This indicated the influence of immunity over familial transmission. Moreover, hyperactive immunity and increased enterocyte death resulted in the highest bacterial load observed starting from early adulthood. Cohousing experiments showed that the microenvironment also played an important role in the structure of the microbiota where flies with constitutive immunity defined the gut microbiota of their cohabitants. Our data show that, in Drosophila, constitutively active immunity shapes the structure and density of gut microbiota. PMID:28413160

  7. Importance of constitutive activity and arrestin-independent mechanisms for intracellular trafficking of the ghrelin receptor

    DEFF Research Database (Denmark)

    Holliday, Nicholas D; Holst, Birgitte; Rodionova, Elena A

    2007-01-01

    The ghrelin receptor (GhrelinR) and its related orphan GPR39 each display constitutive signaling, but only GhrelinRs undergo basal internalization. Here we investigate these differences by considering the roles of the C tail receptor domains for constitutive internalization and activity....... Furthermore the interaction between phosphorylated receptors and beta-arrestin adaptor proteins has been examined. Replacement of the FLAG-tagged GhrelinR C tail with the equivalent GPR39 domain (GhR-39 chimera) preserved G(q) signaling. However in contrast to the GhrelinR, GhR-39 receptors exhibited no basal...... and substantially decreased agonist-induced internalization in transiently transfected HEK293 cells. Internalized GhrelinR and GhR-39 were predominantly localized to recycling compartments, identified with transferrin and the monomeric G proteins Rab5 and Rab11. Both the inverse agonist [d-Arg(1), d-Phe(5), d-Trp(7...

  8. Prevalence of bortezomib-resistant constitutive NF-kappaB activity in mantle cell lymphoma

    Directory of Open Access Journals (Sweden)

    Kahl Brad S

    2008-05-01

    Full Text Available Abstract Background The proteasome inhibitor bortezomib can inhibit activation of the transcription factor NF-κB, a mechanism implicated in its anti-neoplastic effects observed in mantle cell lymphoma (MCL. However, NF-κB can be activated through many distinct mechanisms, including proteasome independent pathways. While MCL cells have been shown to harbor constitutive NF-κB activity, what fraction of this activity in primary MCL samples is sensitive or resistant to inhibition by bortezomib remains unclear. Results Proteasome activity in the EBV-negative MCL cell lines Jeko-1 and Rec-1 is inhibited by greater than 80% after exposure to 20 nM bortezomib for 4 hours. This treatment decreased NF-κB activity in Jeko-1 cells, but failed to do so in Rec-1 cells when assessed by electrophoretic mobility shift assay (EMSA. Concurrently, Rec-1 cells were more resistant to the cytotoxic effects of bortezomib than Jeko-1 cells. Consistent with a proteasome inhibitor resistant pathway of activation described in mouse B-lymphoma cells (WEHI231 and a breast carcinoma cell line (MDA-MB-468, the bortezomib-resistant NF-κB activity in Rec-1 cells is inhibited by calcium chelators, calmodulin inhibitors, and perillyl alcohol, a monoterpene capable of blocking L-type calcium channels. Importantly, the combination of perillyl alcohol and bortezomib is synergistic in eliciting Rec-1 cell cytotoxicity. The relevance of these results is illuminated by the additional finding that a considerable fraction of primary MCL samples (8 out of 10 displayed bortezomib-resistant constitutive NF-κB activity. Conclusion Our findings show that bortezomib-resistant NF-κB activity is frequently observed in MCL samples and suggest that this activity may be relevant to MCL biology as well as serve as a potential therapeutic target.

  9. Growth hormone (GH)-independent dimerization of GH receptor by a leucine zipper results in constitutive activation

    DEFF Research Database (Denmark)

    Behncken, S N; Billestrup, Nils; Brown, R

    2000-01-01

    and cytoplasmic domains of the GHR in the absence of the extracellular domain can lead to the constitutive activation of known GH signaling end points, supporting the view that proximity of Janus kinase 2 (JAK2) kinases is the essential element in signaling. Such constitutively active GH receptors may have...

  10. Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses.

    Science.gov (United States)

    Jiang, Lin; Campagne, Cécile; Sundström, Elisabeth; Sousa, Pedro; Imran, Saima; Seltenhammer, Monika; Pielberg, Gerli; Olsson, Mats J; Egidy, Giorgia; Andersson, Leif; Golovko, Anna

    2014-11-21

    Constitutive activation of the ERK pathway, occurring in the vast majority of melanocytic neoplasms, has a pivotal role in melanoma development. Different mechanisms underlie this activation in different tumour settings. The Grey phenotype in horses, caused by a 4.6 kb duplication in intron 6 of Syntaxin 17 (STX17), is associated with a very high incidence of cutaneous melanoma, but the molecular mechanism behind the melanomagenesis remains unknown. Here, we investigated the involvement of the ERK pathway in melanoma development in Grey horses. Grey horse melanoma tumours, cell lines and normal skin melanocytes were analyzed with help of indirect immunofluorescence and immunoblotting for the expression of phospho-ERK1/2 in comparison to that in non-grey horse and human counterparts. The mutational status of BRAF, RAS, GNAQ, GNA11 and KIT genes in Grey horse melanomas was determined by direct sequencing. The effect of RAS, RAF and PI3K/AKT pathways on the activation of the ERK signaling in Grey horse melanoma cells was investigated with help of specific inhibitors and immunoblotting. Individual roles of RAF and RAS kinases on the ERK activation were examined using si-RNA based approach and immunoblotting. We found that the ERK pathway is constitutively activated in Grey horse melanoma tumours and cell lines in the absence of somatic activating mutations in BRAF, RAS, GNAQ, GNA11 and KIT genes or alterations in the expression of the main components of the pathway. The pathway is mitogenic and is mediated by BRAF, CRAF and KRAS kinases. Importantly, we found high activation of the ERK pathway also in epidermal melanocytes, suggesting a general predisposition to melanomagenesis in these horses. These findings demonstrate that the presence of the intronic 4.6 kb duplication in STX17 is strongly associated with constitutive activation of the ERK pathway in melanocytic cells in Grey horses in the absence of somatic mutations commonly linked to the activation of this

  11. Evidence for constitutively-active adenosine receptors at mammalian motor nerve endings

    OpenAIRE

    Searl, Timothy J; Silinsky, Eugene M

    2012-01-01

    A study was made to determine if constitutively active adenosine receptors are present at mouse motor nerve endings. In preparations blocked by low Ca2+ / high Mg2+ solution, 8-cyclopentyl-1,3,dipropylxanthine (CPX, 10–100 nM), which has been reported to be both an A1 adenosine receptor antagonist and inverse agonist, produced a dose-dependent increase in the number of acetylcholine quanta released by a nerve impulse. Adenosine deaminase, which degrades ambient adenosine into its inactive con...

  12. Constitutively active endothelial Notch4 causes lung arteriovenous shunts in mice

    Science.gov (United States)

    Jelin, Eric B.; Ng, Jennifer; Wu, Jianfeng; Carlson, Timothy R.; Wu, Xiaoqing; Looney, Mark R.; Wang, Rong A.

    2010-01-01

    Lung arteriovenous (AV) shunts or malformations cause significant morbidity and mortality in several distinct clinical syndromes. For most patients with lung AV shunts, there is still no optimal treatment. The underlying molecular and cellular etiology for lung AV shunts remains elusive, and currently described animal models have insufficiently addressed this problem. Using a tetracycline-repressible system, we expressed constitutively active Notch4 (Notch4*) specifically in the endothelium of adult mice. More than 90% of mice developed lung hemorrhages and respiratory insufficiency and died by 6–7 wk after gene expression began. Vascular casting and fluorescent microsphere analysis showed evidence of lung AV shunts in affected mice. Cessation of Notch4* expression reversed these pathophysiological effects. Assessment of the vascular morphology revealed enlarged, tortuous vessels in the lungs that resembled arteriovenous malformations. By using whole lung organ culture, we demonstrated the effects of constitutively active Notch4 on the lung vasculature to be a primary lung phenomenon. Together, our results indicate the importance of Notch signaling in maintaining the lung vasculature and offer a new, reliable model with which to study the pathobiology of lung arteriovenous shunts and malformations. PMID:19933399

  13. Constitutive Activity of the Human TRPML2 Channel Induces Cell Degeneration*

    Science.gov (United States)

    Lev, Shaya; Zeevi, David A.; Frumkin, Ayala; Offen-Glasner, Vered; Bach, Gideon; Minke, Baruch

    2010-01-01

    The mucolipin (TRPML) ion channel proteins represent a distinct subfamily of channel proteins within the transient receptor potential (TRP) superfamily of cation channels. Mucolipin 1, 2, and 3 (TRPML1, -2, and -3, respectively) are channel proteins that share high sequence homology with each other and homology in the transmembrane domain with other TRPs. Mutations in the TRPML1 protein are implicated in mucolipidosis type IV, whereas mutations in TRPML3 are found in the varitint-waddler mouse. The properties of the wild type TRPML2 channel are not well known. Here we show functional expression of the wild type human TRPML2 channel (h-TRPML2). The channel is functional at the plasma membrane and characterized by a significant inward rectification similar to other constitutively active TRPML mutant isoforms. The h-TRPML2 channel displays nonselective cation permeability, which is Ca2+-permeable and inhibited by low extracytosolic pH but not Ca2+ regulated. In addition, constitutively active h-TRPML2 leads to cell death by causing Ca2+ overload. Furthermore, we demonstrate by functional mutation analysis that h-TRPML2 shares similar characteristics and structural similarities with other TRPML channels that regulate the channel in a similar manner. Hence, in addition to overall structure, all three TRPML channels also share common modes of regulation. PMID:19940139

  14. Conditional expression of constitutively active estrogen receptor {alpha} in chondrocytes impairs longitudinal bone growth in mice

    Energy Technology Data Exchange (ETDEWEB)

    Ikeda, Kazuhiro [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Tsukui, Tohru [Experimental Animal Laboratory, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Imazawa, Yukiko; Horie-Inoue, Kuniko [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Inoue, Satoshi, E-mail: INOUE-GER@h.u-tokyo.ac.jp [Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama (Japan); Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan); Department of Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo (Japan)

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer Conditional transgenic mice expressing constitutively active estrogen receptor {alpha} (caER{alpha}) in chondrocytes were developed. Black-Right-Pointing-Pointer Expression of caER{alpha} in chondrocytes impaired longitudinal bone growth in mice. Black-Right-Pointing-Pointer caER{alpha} affects chondrocyte proliferation and differentiation. Black-Right-Pointing-Pointer This mouse model is useful for understanding the physiological role of ER{alpha}in vivo. -- Abstract: Estrogen plays important roles in the regulation of chondrocyte proliferation and differentiation, which are essential steps for longitudinal bone growth; however, the mechanisms of estrogen action on chondrocytes have not been fully elucidated. In the present study, we generated conditional transgenic mice, designated as caER{alpha}{sup ColII}, expressing constitutively active mutant estrogen receptor (ER) {alpha} in chondrocytes, using the chondrocyte-specific type II collagen promoter-driven Cre transgenic mice. caER{alpha}{sup ColII} mice showed retardation in longitudinal growth, with short bone lengths. BrdU labeling showed reduced proliferation of hypertrophic chondrocytes in the proliferating layer of the growth plate of tibia in caER{alpha}{sup ColII} mice. In situ hybridization analysis of type X collagen revealed that the maturation of hypertrophic chondrocytes was impaired in caER{alpha}{sup ColII} mice. These results suggest that ER{alpha} is a critical regulator of chondrocyte proliferation and maturation during skeletal development, mediating longitudinal bone growth in vivo.

  15. Retinoblastoma pathway defects show differential ability to activate the constitutive DNA damage response in human tumorigenesis

    DEFF Research Database (Denmark)

    Tort, F.; Bartkova, J.; Sehested, M.

    2006-01-01

    activation. Here, we show that, in a series of human colorectal adenomas, those with deregulation of cyclin D1 and/or p16(Ink4a) showed little evidence of constitutive DNA damage response (DDR), contrary to cyclin E-overexpressing higher-grade cases. These observations were consistent with diverse cell...... culture models with differential defects of retinoblastoma pathway components, as overexpression of cyclin D1 or lack of p16(Ink4a), either alone or combined, did not elicit detectable DDR. In contrast, inactivation of pRb, the key component of the pathway, activated the DDR in cultured human or mouse...... cells, analogous to elevated cyclin E. These results highlight differential effect of diverse oncogenic events on driving the 'cancer cell cycles' and their ability to deregulate the replication-driving CDK2 kinase and to alarm the DDR as a potential anticancer barrier in accordance...

  16. Dimerization by a cytokine receptor is necessary for constitutive activation of JAK2V617F.

    Science.gov (United States)

    Lu, Xiaohui; Huang, Lily Jun-Shen; Lodish, Harvey F

    2008-02-29

    The majority of the BCR-ABL-negative myeloproliferative disorders express the mutant JAK2, JAK2V617F. Previously we showed that constitutive activation of this oncogenic JAK2 mutant in Ba/F3 or 32D cells requires coexpression of a cognate homodimeric cytokine receptor, such as the EpoR. However, overexpression of JAK2V617F in Ba/F3 cells renders them cytokine-independent for growth in the absence of an exogenous cytokine receptor. Here, we demonstrated that JAK2V617F domains required for receptor association are essential for cytokine-independent growth by overexpressed JAK2V617F, suggesting JAK2V617F is binding to an unknown endogenous cytokine receptor(s) for its activation. We further showed that disruption of EpoR dimerization by coexpressing a truncated EpoR disrupted JAK2V617F-mediated transformation, indicating that EpoR dimerization plays an essential role in the activation of JAK2V617F. Interestingly, coexpression of JAK2V617F with EpoR mutants that retain JAK2 binding but are defective in mediating Epo-dependent JAK2 activation due to mutations in a conserved juxtamembrane motif does lead to cytokine-independent activation of JAK2V617F. Overall, these findings confirm that JAK2V617F requires binding to a dimerized cytokine receptor for its activation, and that the key EpoR juxtamembrane regulatory motif essential for Epo-dependent JAK2 activation is not essential for the activation of JAK2V617F. The structure of the activated JAK2V617F is thus likely to be different from that of the activated wild-type JAK2, raising the possibility of developing a specifically targeted therapy for myeloproliferative disorders.

  17. Constitutive cellulase production from glucose using the recombinant Trichoderma reesei strain overexpressing an artificial transcription activator.

    Science.gov (United States)

    Zhang, Xiaoyue; Li, Yonghao; Zhao, Xinqing; Bai, Fengwu

    2017-01-01

    The high cost of cellulase production presents biggest challenge in biomass deconstruction. Cellulase production by Trichoderma reesei using low cost carbon source is of great interest. In this study, an artificial transcription activator containing the Cre1 binding domain linked to the Xyr1 effector and binding domains was designed and constitutively overexpressed in T. reesei RUT C30. The recombinant strain T. reesei zxy-2 displayed constitutive cellulase production using glucose as a sole carbon source, and the production titer was 12.75-fold of that observed with T. reesei RUT C30 in shake flask culture. Moreover, FPase and xylanase titers of 2.63 and 108.72IU/mL, respectively, were achieved using glucose as sole carbon source within 48h in a 7-L fermenter by batch fermentation using T. reesei zxy-2. The crude enzyme obtained was used to hydrolyze alkali pretreated corn stover, and a high glucose yield of 99.18% was achieved. Copyright © 2016. Published by Elsevier Ltd.

  18. Characterization of the anisotropic mechanical behaviour of colonic tissues: experimental activity and constitutive formulation.

    Science.gov (United States)

    Carniel, E L; Gramigna, V; Fontanella, C G; Frigo, A; Stefanini, C; Rubini, A; Natali, A N

    2014-05-01

    The aim was to investigate the biomechanical behaviour of colonic tissues by a coupled experimental and numerical approach. The wall of the colon is composed of different tissue layers. Within each layer, different fibre families are distributed according to specific spatial orientations, which lead to a strongly anisotropic configuration. Accounting for the complex histology of the tissues, mechanical tests must be planned and designed to evaluate the behaviour of the colonic wall in different directions. Uni-axial tensile tests were performed on tissue specimens from 15 fresh pig colons, accounting for six different loading directions (five specimens for each loading direction). The next step of the investigation was to define an appropriate constitutive framework and develop a procedure for identification of the constitutive parameters. A specific hyperelastic formulation was developed that accounted for the multilayered conformation of the colonic wall and the fibre-reinforced configuration of the tissues. The parameters were identified by inverse analyses of the mechanical tests. The comparison of model results with experimental data, together with the evaluation of satisfaction of material thermomechanics principles, confirmed the reliability of the analysis developed. This work forms the basis for more comprehensive activities that aim to provide computational tools for the interpretation of surgical procedures that involve the gastrointestinal tract, considering the specific biomedical devices adopted. © 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.

  19. Identification of chemical modulators of the constitutive activated receptor (CAR) in a gene expression compendium

    Science.gov (United States)

    Oshida, Keiyu; Vasani, Naresh; Jones, Carlton; Moore, Tanya; Hester, Susan; Nesnow, Stephen; Auerbach, Scott; Geter, David R.; Aleksunes, Lauren M.; Thomas, Russell S.; Applegate, Dawn; Klaassen, Curtis D.; Corton, J. Christopher

    2015-01-01

    The nuclear receptor family member constitutive activated receptor (CAR) is activated by structurally diverse drugs and environmentally-relevant chemicals leading to transcriptional regulation of genes involved in xenobiotic metabolism and transport. Chronic activation of CAR increases liver cancer incidence in rodents, whereas suppression of CAR can lead to steatosis and insulin insensitivity. Here, analytical methods were developed to screen for chemical treatments in a gene expression compendium that lead to alteration of CAR activity. A gene expression biomarker signature of 83 CAR-dependent genes was identified using microarray profiles from the livers of wild-type and CAR-null mice after exposure to three structurally-diverse CAR activators (CITCO, phenobarbital, TCPOBOP). A rank-based algorithm (Running Fisher’s algorithm (p-value ≤ 10-4)) was used to evaluate the similarity between the CAR biomarker signature and a test set of 28 and 32 comparisons positive or negative, respectively, for CAR activation; the test resulted in a balanced accuracy of 97%. The biomarker signature was used to identify chemicals that activate or suppress CAR in an annotated mouse liver/primary hepatocyte gene expression database of ~1850 comparisons. CAR was activated by 1) activators of the aryl hydrocarbon receptor (AhR) in wild-type but not AhR-null mice, 2) pregnane X receptor (PXR) activators in wild-type and to lesser extents in PXR-null mice, and 3) activators of PPARα in wild-type and PPARα-null mice. CAR was consistently activated by five conazole fungicides and four perfluorinated compounds. Comparison of effects in wild-type and CAR-null mice showed that the fungicide propiconazole increased liver weight and hepatocyte proliferation in a CAR-dependent manner, whereas the perfluorinated compound perfluorooctanoic acid (PFOA) increased these endpoints in a CAR-independent manner. A number of compounds suppressed CAR coincident with increases in markers of

  20. Modulation of constitutive activity and signaling bias of the ghrelin receptor by conformational constraint in the second extracellular loop

    DEFF Research Database (Denmark)

    Mokrosinski, Jacek; Frimurer, Thomas M; Sivertsen, Bjoern

    2012-01-01

    Based on a rare, natural Glu for Ala204(C+6) variant located six residues after the conserved Cys residue in extracellular loop 2 (ECL2b) associated with selective elimination of the high constitutive signaling of the ghrelin receptor, this loop was subjected to a detailed structure functional....... Moreover, the constitutive activity of the receptor was inhibited by Zn(2+) binding in an engineered metal-ion site stabilizing an a-helical conformation of this loop segment. It is concluded that the high constitutive activity of the ghrelin receptor is dependent upon flexibility in the C-terminal segment...

  1. Constitutive Models

    DEFF Research Database (Denmark)

    Sales-Cruz, Mauricio; Piccolo, Chiara; Heitzig, Martina

    2011-01-01

    This chapter presents various types of constitutive models and their applications. There are 3 aspects dealt with in this chapter, namely: creation and solution of property models, the application of parameter estimation and finally application examples of constitutive models. A systematic...... procedure is introduced for the analysis and solution of property models. Models that capture and represent the temperature dependent behaviour of physical properties are introduced, as well as equation of state models (EOS) such as the SRK EOS. Modelling of liquid phase activity coefficients are also...... covered, illustrating several models such as the Wilson equation and NRTL equation, along with their solution strategies. A section shows how to use experimental data to regress the property model parameters using a least squares approach. A full model analysis is applied in each example that discusses...

  2. CINPA1 Is an Inhibitor of Constitutive Androstane Receptor That Does Not Activate Pregnane X Receptor

    Science.gov (United States)

    Cherian, Milu T; Lin, Wenwei; Wu, Jing

    2015-01-01

    Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic sensors that enhance the detoxification and elimination of xenobiotics and endobiotics by modulating the expression of genes encoding drug-metabolizing enzymes and transporters. Elevated levels of drug-metabolizing enzymes and efflux transporters, resulting from CAR activation in various cancers, promote the elimination of chemotherapeutic agents, leading to reduced therapeutic effectiveness and acquired drug resistance. CAR inhibitors, in combination with existing chemotherapeutics, could therefore be used to attenuate multidrug resistance in cancers. Interestingly, all previously reported CAR inverse-agonists are also activators of PXR, rendering them mechanistically counterproductive in tissues where both these xenobiotic receptors are present and active. We used a directed high-throughput screening approach, followed by subsequent mechanistic studies, to identify novel, potent, and specific small-molecule CAR inhibitors that do not activate PXR. We describe here one such inhibitor, CINPA1 (CAR inhibitor not PXR activator 1), capable of reducing CAR-mediated transcription with an IC50 of ∼70 nM. CINPA1 1) is a specific xenobiotic receptor inhibitor and has no cytotoxic effects up to 30 µM; 2) inhibits CAR-mediated gene expression in primary human hepatocytes, where CAR is endogenously expressed; 3) does not alter the protein levels or subcellular localization of CAR; 4) increases corepressor and reduces coactivator interaction with the CAR ligand-binding domain in mammalian two-hybrid assays; and 5) disrupts CAR binding to the promoter regions of target genes in chromatin immunoprecipitation assays. CINPA1 could be used as a novel molecular tool for understanding CAR function. PMID:25762023

  3. CINPA1 is an inhibitor of constitutive androstane receptor that does not activate pregnane X receptor.

    Science.gov (United States)

    Cherian, Milu T; Lin, Wenwei; Wu, Jing; Chen, Taosheng

    2015-05-01

    Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic sensors that enhance the detoxification and elimination of xenobiotics and endobiotics by modulating the expression of genes encoding drug-metabolizing enzymes and transporters. Elevated levels of drug-metabolizing enzymes and efflux transporters, resulting from CAR activation in various cancers, promote the elimination of chemotherapeutic agents, leading to reduced therapeutic effectiveness and acquired drug resistance. CAR inhibitors, in combination with existing chemotherapeutics, could therefore be used to attenuate multidrug resistance in cancers. Interestingly, all previously reported CAR inverse-agonists are also activators of PXR, rendering them mechanistically counterproductive in tissues where both these xenobiotic receptors are present and active. We used a directed high-throughput screening approach, followed by subsequent mechanistic studies, to identify novel, potent, and specific small-molecule CAR inhibitors that do not activate PXR. We describe here one such inhibitor, CINPA1 (CAR inhibitor not PXR activator 1), capable of reducing CAR-mediated transcription with an IC50 of ∼70 nM. CINPA1 1) is a specific xenobiotic receptor inhibitor and has no cytotoxic effects up to 30 µM; 2) inhibits CAR-mediated gene expression in primary human hepatocytes, where CAR is endogenously expressed; 3) does not alter the protein levels or subcellular localization of CAR; 4) increases corepressor and reduces coactivator interaction with the CAR ligand-binding domain in mammalian two-hybrid assays; and 5) disrupts CAR binding to the promoter regions of target genes in chromatin immunoprecipitation assays. CINPA1 could be used as a novel molecular tool for understanding CAR function. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

  4. Structure-activity correlations for illicit amphetamines using ANN and constitutional descriptors.

    Science.gov (United States)

    Gosav, S; Praisler, M; Dorohoi, D O; Popa, G

    2006-12-15

    The goal of this study was to develop an expert system capable to identify the potential biological activity of new substances having a molecular structure similar to illicit amphetamines. For this purpose we have designed two types of artificial neural network (ANN) systems, which have been trained to classify amphetamines according to their toxicological activity (stimulant amphetamines or hallucinogenic amphetamines) and distinguish them from nonamphetamines. Such a system is essential for testing new molecular structures for epidemiological, clinical, and forensic purposes. The first type of artificial neural network is a "spectral" neural network, which has as input variables the most important 100 absorption intensities from a total of 260 measured for each normalized infrared spectrum 10cm(-1) apart. The spectral data consists of a database built with the GC-FT-IR spectra of the most popular drugs of abuse (mainly central stimulants, hallucinogens, sympathomimetic amines, narcotics and other potent analgesics), precursors and derivatized counterparts. All samples were also characterized by their constitutional descriptors (CDs). For each sample, a number of 45 CDs were computed and introduced as input variables for a second type of ANN, which uses a structural database. The efficiency of this "structural" artificial neural network (CD-ANN) has been improved by optimizing the training set and increasing the number of input variables (CDs). A comparative analysis of the spectral and the structural networks is presented.

  5. Evodia alkaloids suppress gluconeogenesis and lipogenesis by activating the constitutive androstane receptor.

    Science.gov (United States)

    Yu, Lushan; Wang, Zhangting; Huang, Minmin; Li, Yingying; Zeng, Kui; Lei, Jinxiu; Hu, Haihong; Chen, Baian; Lu, Jing; Xie, Wen; Zeng, Su

    2016-09-01

    The constitutive androstane receptor (CAR) is a key sensor in xenobiotic detoxification and endobiotic metabolism. Increasing evidence suggests that CAR also plays a role in energy metabolism by suppressing the hepatic gluconeogenesis and lipogenesis. In this study, we investigated the effects of two evodia alkaloids, rutaecarpine (Rut) and evodiamine (Evo), on gluconeogenesis and lipogenesis through their activation of the human CAR (hCAR). We found that both Rut and Evo exhibited anti-lipogenic and anti-gluconeogenic effects in the hyperlipidemic HepG2 cells. Both compounds can potently activate hCAR, and treatment of cells with hCAR antagonists reversed the anti-lipogenic and anti-gluconeogenic effects of Rut and Evo. The anti-gluconeogenic effect of Rut and Evo was due to the CAR-mediated inhibition of the recruitment of forkhead box O1 (FoxO1) and hepatocyte nuclear factor 4α (HNF4α) onto the phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) gene promoters. In vivo, we showed that treatment of mice with Rut improved glucose tolerance in a CAR-dependent manner. Our results suggest that the evodia alkaloids Rut and Evo may have a therapeutic potential for the treatment of hyperglycemia and type 2 diabetes. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Phenobarbital and Insulin Reciprocate Activation of the Nuclear Receptor Constitutive Androstane Receptor through the Insulin Receptor.

    Science.gov (United States)

    Yasujima, Tomoya; Saito, Kosuke; Moore, Rick; Negishi, Masahiko

    2016-05-01

    Phenobarbital (PB) antagonized insulin to inactivate the insulin receptor and attenuated the insulin receptor downstream protein kinase B (AKT)-forkhead box protein O1 and extracellular signal-regulated kinase 1/2 signals in mouse primary hepatocytes and HepG2 cells. Hepatic AKT began dephosphorylation in an early stage of PB treatment, and blood glucose levels transiently increased in both wild-type and constitutive androstane receptor (CAR) knockout (KO) mice. On the other hand, blood glucose levels increased in wild-type mice, but not KO mice, in later stages of PB treatment. As a result, PB, acting as an insulin receptor antagonist, elicited CAR-independent increases and CAR-dependent decreases of blood glucose levels at these different stages of treatment, respectively. Reciprocally, insulin activation of the insulin receptor repressed CAR activation and induction of its target CYP2B6 gene in HepG2 cells. Thus, PB and insulin cross-talk through the insulin receptor to regulate glucose and drug metabolism reciprocally. Copyright © 2016 by U.S. Government work not protected by U.S. copyright.

  7. Functional characterization of a constitutively active kinase variant of Arabidopsis phototropin 1.

    Science.gov (United States)

    Petersen, Jan; Inoue, Shin-Ichiro; Kelly, Sharon M; Sullivan, Stuart; Kinoshita, Toshinori; Christie, John M

    2017-08-18

    Phototropins (phots) are plasma membrane-associated serine/threonine kinases that coordinate a range of processes linked to optimizing photosynthetic efficiency in plants. These photoreceptors contain two light-, oxygen-, or voltage-sensing (LOV) domains within their N terminus, with each binding one molecule of flavin mononucleotide as a UV/blue light-absorbing chromophore. Although phots contain two LOV domains, light-induced activation of the C-terminal kinase domain and subsequent receptor autophosphorylation is controlled primarily by the A'α-LOV2-Jα photosensory module. Mutations that disrupt interactions between the LOV2 core and its flanking helical segments can uncouple this mode of light regulation. However, the impact of these mutations on phot function in Arabidopsis has not been explored. Here we report that histidine substitution of Arg-472 located within the A'α-helix of Arabidopsis phot1 constitutively activates phot1 kinase activity in vitro without affecting LOV2 photochemistry. Expression analysis of phot1 R472H in the phot-deficient mutant confirmed that it is autophosphorylated in darkness in vivo but unable to initiate phot1 signaling in the absence of light. Instead, we found that phot1 R472H is poorly functional under low-light conditions but can restore phototropism, chloroplast accumulation, stomatal opening, and leaf positioning and expansion at higher light intensities. Our findings suggest that Arabidopsis can adapt to the elevated phosphorylation status of the phot1 R472H mutant in part by reducing its stability, whereas the activity of the mutant under high-light conditions can be attributed to additional increases in LOV2-mediated photoreceptor autophosphorylation. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Constitutive NF-κB activation and tumor-growth promotion by Romo1-mediated reactive oxygen species production

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Jin Sil; Lee, Sora; Yoo, Young Do, E-mail: ydy1130@korea.ac.kr

    2014-08-08

    Highlights: • Romo1 expression is required for constitutive nuclear DNA-binding activity of NF-κB. • Romo1 depletion suppresses tumor growth in vivo. • Romo1 presents a potential therapeutic target for diseases. - Abstract: Deregulation of nuclear factor-κB (NF-κB) and related pathways contribute to tumor cell proliferation and invasion. Mechanisms for constitutive NF-κB activation are not fully explained; however, the underlying defects appear to generate and maintain pro-oxidative conditions. In hepatocellular carcinoma (HCC) tissues, up-regulation of reactive oxygen species modulator 1 (Romo1) correlates positively with tumor size. In the present study, we showed that Romo1 expression is required to maintain constitutive nuclear DNA-binding activity of NF-κB and transcriptional activity through constitutive IκBα phosphorylation. Overexpression of Romo1 promoted p65 nuclear translocation and DNA-binding activity. We also show that Romo1 depletion suppressed anchorage-independent colony formation by HCC cells and suppressed tumor growth in vivo. Based on these findings, Romo1 may be a principal regulatory factor in the maintenance of constitutive NF-κB activation in tumor cells. In the interest of anti-proliferative treatments for cancer, Romo1 may also present a productive target for drug development.

  9. Constitutive activation of the midgut response to Bacillus thuringiensis in Bt-resistant Spodoptera exigua.

    Directory of Open Access Journals (Sweden)

    Patricia Hernández-Martínez

    Full Text Available Bacillus thuringiensis is the most effective microbial control agent for controlling numerous species from different insect orders. The main threat for the long term use of B. thuringiensis in pest control is the ability of insects to develop resistance. Thus, the identification of insect genes involved in conferring resistance is of paramount importance. A colony of Spodoptera exigua (Lepidoptera: Noctuidae was selected for 15 years in the laboratory for resistance to Xentari™, a B. thuringiensis-based insecticide, reaching a final resistance level of greater than 1,000-fold. Around 600 midgut ESTs were analyzed by DNA-macroarray in order to find differences in midgut gene expression between susceptible and resistant insects. Among the differentially expressed genes, repat and arylphorin were identified and their increased expression was correlated with B. thuringiensis resistance. We also found overlap among genes that were constitutively over-expressed in resistant insects with genes that were up-regulated in susceptible insects after exposure to Xentari™, suggesting a permanent activation of the response to Xentari™ in resistant insects. Increased aminopeptidase activity in the lumen of resistant insects in the absence of exposure to Xentari™ corroborated the hypothesis of permanent activation of response genes. Increase in midgut proliferation has been proposed as a mechanism of response to pathogens in the adult from several insect species. Analysis of S. exigua larvae revealed that midgut proliferation was neither increased in resistant insects nor induced by exposure of susceptible larvae to Xentari™, suggesting that mechanisms other than midgut proliferation are involved in the response to B. thuringiensis by S. exigua larvae.

  10. Pyrene is a Novel Constitutive Androstane Receptor (CAR) Activator and Causes Hepatotoxicity by CAR.

    Science.gov (United States)

    Zhang, Xiao-Jie; Shi, Zhe; Lyv, Jing-Xi; He, Xuyan; Englert, Neal A; Zhang, Shu-Yun

    2015-10-01

    Polycyclic aromatic hydrocarbons (PAHs) are a class of ubiquitous persistent environmental pollutants which are primarily formed from the incomplete combustion of organic materials. Many potential sources of human exposure to PAHs exist, including daily exposures from the ambient environment or occupational settings. PAHs have been found to cause harmful effects on human health. Here, we evaluated the adverse effects of pyrene, a common PAH, on the liver. The present study demonstrates that pyrene is able to activate mouse constitutive androstane receptor (CAR). CAR protein, as measured by Western blot analysis, was observed to translocate into the nucleus from the cytoplasm in mouse liver after exposure to pyrene. Utilizing CAR null mice, we identified that CAR mediates pyrene-induced hepatotoxicity. Increased relative liver weight, hepatocellular hypertrophy, and elevated serum alanine aminotransferase levels were found in wild-type but not CAR null mice after orally administered pyrene. We further show that pyrene induced the expression of mouse liver metabolism enzymes including CYP2B10, CYP3A11, GSTm1, GSTm3, and SULT1A1, and caused hepatic glutathione depletion in wild-type but not CAR null mice. Moreover, by luciferase reporter assay and quantitative real-time PCR analysis, pyrene was found to be a potential inducer of CYP2B6 expression via activation of human CAR in HepG2 cells and human primary hepatocytes. Our observations suggest that pyrene is a novel CAR activator and that CAR is essential for mediating pyrene-induced liver injury. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. Selective elimination of high constitutive activity or chemokine binding in the human herpesvirus 8 encoded seven transmembrane oncogene ORF74

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Kledal, T N; Holst, Peter Johannes

    2000-01-01

    Open reading frame 74 (ORF74) encoded by human herpesvirus 8 is a highly constitutively active seven transmembrane (7TM) receptor stimulated by angiogenic chemokines, e.g. growth-related oncogene-alpha, and inhibited by angiostatic chemokines e.g. interferon-gamma-inducible protein. Transgenic mice...... either agonist or inverse agonist modulation as well as high constitutive activity of the virally encoded oncogene ORF74 and that these mutant forms presumably can be used in transgenic animals to identify the molecular mechanism of its transforming activity....

  12. Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension.

    Science.gov (United States)

    Nawa, Nobutoshi; Ishida, Hidekazu; Katsuragi, Shinichi; Baden, Hiroki; Takahashi, Kunihiko; Higeno, Ryota; Torigoe, Fumiko; Mihara, Seiko; Narita, Jun; Miura, Kohji; Nakamura, Kazufumi; Kogaki, Shigetoyo; Ozono, Keiichi

    2016-01-01

    We recently found a constitutively active mutant of natriuretic peptide receptor 2 (caNPR2; V883M), which synthesizes larger amounts of cyclic guanosine monophosphate (cGMP) intracellularly without any ligand stimulation than existing drugs. The aim of this study was to investigate the therapeutic effects of gene transduction using caNPR2 for pulmonary arterial hypertension (PAH). In vitro gene transduction into human pulmonary arterial smooth muscle cells using Sendai virus (SeV) vectors carrying caNPR2 induced 10,000-fold increases in the synthesis of cGMP without ligand stimulation, and the proliferation of caNPR2-expressing cells was significantly attenuated. The PAH model rats generated by hypoxia and the administration of SU5416 were then treated with SeV vectors through a direct injection into the left pulmonary artery. Right ventricular systolic pressure was significantly decreased 2 weeks after the treatment, while systemic blood pressure remained unchanged. Histological analyses revealed that the medial wall thickness and occlusion rate of pulmonary arterioles were significantly improved in caNPR2-treated lungs. Neither the systemic integration of virus vectors nor side effects were observed. The massive stimulation of cGMP synthesis by gene therapy with caNPR2 was safe and effective in a PAH rat model and, thus, has potential as a novel therapy for patients with severe progressive PAH.

  13. Molecular pharmacological phenotyping of EBI2. An orphan seven-transmembrane receptor with constitutive activity

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M; Benned-Jensen, Tau; Holst, Peter J

    2006-01-01

    Epstein-Barr virus (EBV)-induced receptor 2 (EBI2) is an orphan seven-transmembrane (7TM) receptor originally identified as the most up-regulated gene (>200-fold) in EBV-infected cells. Here we show that EBI2 signals with constitutive activity through Galpha(i) as determined by a receptor......2, showed similar expression and signaling through Galpha(i) as full-length EBI2. By using a 32P-labeled EBI2 probe we found a very high expression in lymphoid tissue (spleen and lymph node) and peripheral blood mononuclear cells and a high expression in lung tissue. Real-time PCR of EBV......-infected cells showed high expression of EBI2 during latent and lytic infection, in contrast to the EBV-encoded 7TM receptor BILF1, which was induced during lytic infection. EBI2 clustered with the orphan GPR18 by alignment analysis as well as by close proximity in the chromosomal region 13q32.3. Based...

  14. Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension

    Directory of Open Access Journals (Sweden)

    Nobutoshi Nawa

    2016-01-01

    Full Text Available We recently found a constitutively active mutant of natriuretic peptide receptor 2 (caNPR2; V883M, which synthesizes larger amounts of cyclic guanosine monophosphate (cGMP intracellularly without any ligand stimulation than existing drugs. The aim of this study was to investigate the therapeutic effects of gene transduction using caNPR2 for pulmonary arterial hypertension (PAH. In vitro gene transduction into human pulmonary arterial smooth muscle cells using Sendai virus (SeV vectors carrying caNPR2 induced 10,000-fold increases in the synthesis of cGMP without ligand stimulation, and the proliferation of caNPR2-expressing cells was significantly attenuated. The PAH model rats generated by hypoxia and the administration of SU5416 were then treated with SeV vectors through a direct injection into the left pulmonary artery. Right ventricular systolic pressure was significantly decreased 2 weeks after the treatment, while systemic blood pressure remained unchanged. Histological analyses revealed that the medial wall thickness and occlusion rate of pulmonary arterioles were significantly improved in caNPR2-treated lungs. Neither the systemic integration of virus vectors nor side effects were observed. The massive stimulation of cGMP synthesis by gene therapy with caNPR2 was safe and effective in a PAH rat model and, thus, has potential as a novel therapy for patients with severe progressive PAH.

  15. Tax-Independent Constitutive IκB Kinase Activation in Adult T-Cell Leukemia Cells1

    Science.gov (United States)

    Hironaka, Noriko; Mochida, Kanako; Mori, Naoki; Maeda, Michiyuki; Yamamoto, Naoki; Yamaoka, Shoji

    2004-01-01

    Abstract Adult T-cell leukemia (ATL) is a fatal T-cell malignancy that arises long after infection with human T-cell leukemia virus type I (HTLV-I). We reported previously that nuclear factor-κB (NF-κB) was constitutively activated in ATL cells, although expression of the viral proteins was barely detectable, including Tax, which was known to persistently activate NF-κB. Here we demonstrate that ATL cells that do not express detectable Tax protein exhibit constitutive IκB kinase (IKK) activity. Transfection studies revealed that a dominant-negative form of IKK1, and not of IKK2 or NF-κB essential modulator (NEMO), suppressed constitutive NFκB activity in ATL cells. This IKK activity was accompanied by elevated expression of p52, suggesting that the recently described noncanonical pathway of NF-κB activation operates in ATL cells. We finally show that specific inhibition of NF-κB by a super-repressor form of IκBα (SR-IκBα) in HTLV-I-infected T cells results in cell death regardless of Tax expression, providing definitive evidence of an essential role for NF-κB in the survival of ATL cells. In conclusion, the IKK complex is constitutively activated in ATL cells through a cellular mechanism distinct from that of Tax-mediated IKK activation. Further elucidation of this cellular mechanism should contribute to establishing a rationale for treatment of ATL. PMID:15153339

  16. Constitutive activation of Nrf2 induces a stable reductive state in the mouse myocardium

    Directory of Open Access Journals (Sweden)

    Gobinath Shanmugam

    2017-08-01

    Full Text Available Redox homeostasis regulates key cellular signaling pathways in both physiology and pathology. The cell's antioxidant response provides a defense against oxidative stress and establishes a redox tone permissive for cell signaling. The molecular regulation of the well-known Keap1/Nrf2 system acts as sensor responding to changes in redox homeostasis and is poorly studied in the heart. Importantly, it is not yet known whether Nrf2 alone can serve as a master regulator of cellular redox homeostasis without compensation of the transcriptional regulation of antioxidant response element (ARE genes through alternate mechanisms. Here, we addressed this question using cardiac-specific transgenic expression at two different levels of constitutively active nuclear erythroid related factor 2 (caNrf2 functioning independently of Keap1. The caNrf2 mice showed augmentation of glutathione (GSH, the key regulator of the cellular thiol redox state. The Trans-AM assay for Nrf2-binding to the antioxidant response element (ARE showed a dose-dependent increase associated with upregulation of several major antioxidant genes and proteins. This was accompanied by a significant decrease in dihydroethidium staining and malondialdehyde (MDA in the caNrf2-TG mice myocardium. Interestingly, caNrf2 gene-dosage dependent redox changes were noted resulting in generation of a multi-stage model of pro-reductive and reductive conditions in the myocardium of TG-low and TG-high mice, respectively. These data clearly show that Nrf2 levels alone are capable of serving as the master regulator of the ARE. These models provide an important platform to investigate the impact of the Nrf2 system independent of the need to regulate the activity of Keap1 and the consequent exposure to pro-oxidants or electrophiles, which have numerous off-target effects.

  17. Constitutive activation of BMP signalling abrogates experimental metastasis of OVCA429 cells via reduced cell adhesion

    Directory of Open Access Journals (Sweden)

    Shepherd Trevor G

    2010-02-01

    Full Text Available Abstract Background Activation of bone morphogenetic protein (BMP4 signalling in human ovarian cancer cells induces a number of phenotypic changes in vitro, including altered cell morphology, adhesion, motility and invasion, relative to normal human ovarian surface epithelial cells. From these in vitro analyses, we had hypothesized that active BMP signalling promotes the metastatic potential of ovarian cancer. Methods To test this directly, we engineered OVCA429 human ovarian cancer cells possessing doxycycline-inducible expression of a constitutively-active mutant BMP receptor, ALK3QD, and administered these cells to immunocompromised mice. Further characterization was performed in vitro to address the role of activated BMP signalling on the EOC phenotype, with particular emphasis on epithelial-mesenchymal transition (EMT and cell adhesion. Results Unexpectedly, doxycycline-induced ALK3QD expression in OVCA429 cells reduced tumour implantation on peritoneal surfaces and ascites formation when xenografted into immunocompromised mice by intraperitoneal injection. To determine the potential mechanisms controlling this in vivo observation, we followed with several cell culture experiments. Doxycycline-induced ALK3QD expression enhanced the refractile, spindle-shaped morphology of cultured OVCA429 cells eliciting an EMT-like response. Using in vitro wound healing assays, we observed that ALK3QD-expressing cells migrated with long, cytoplasmic projections extending into the wound space. The phenotypic alterations of ALK3QD-expressing cells correlated with changes in specific gene expression patterns of EMT, including increased Snail and Slug and reduced E-cadherin mRNA expression. In addition, ALK3QD signalling reduced β1- and β3-integrin expression, critical molecules involved in ovarian cancer cell adhesion. The combination of reduced E-cadherin and β-integrin expression correlates directly with the reduced EOC cell cohesion in spheroids and

  18. Constitutional changes and the dilemmas of constitutionalism

    OpenAIRE

    Bačić, Arsen

    2009-01-01

    The need to develop constitutional mechanisms whose aim is to resolve fundamental relations in society demands the widest possible inclusion of all of society’s active participants in the discussion on the need to adopt or revise the Constitution. The opening of every new round of constitutional changes is of great importance because it always unlocks certain new and important questions. The answers to those questions should be offered by state authority (policy) and civil society including s...

  19. Constitutive activation of Flt3 and STAT5A enhances self-renewal and alters differentiation of hematopoietic stem cells

    NARCIS (Netherlands)

    Moore, Malcolm A. S.; Dorn, David C.; Schuringa, Jan Jacob; Chung, Ki Young; Morrone, Giovanni

    Objective. To model human leukemogenesis by transduction of human hematopoietic stem cells (HSC) with genes associated with leukemia and expressed in leukemic stem cells. Methods. Constitutive activation of Flt3 (Flt3-ITD) has been reported in 25 to 30% of patients with acute myeloid leukemia (AML).

  20. Constitutively active IRF7/IRF3 fusion protein completely protects swine against Foot-and-Mouth Disease

    Science.gov (United States)

    Foot-and-mouth disease (FMD) remains one of the most devastating livestock diseases around the world. Several serotype specific vaccine formulations exist but require about 5-7 days to induce protective immunity. Our previous studies have shown that a constitutively active fusion protein of porcine ...

  1. Agonists and inverse agonists for the herpesvirus 8-encoded constitutively active seven-transmembrane oncogene product, ORF-74

    DEFF Research Database (Denmark)

    Rosenkilde, M M; Kledal, T N; Bräuner-Osborne, Hans

    1999-01-01

    A number of CXC chemokines competed with similar, nanomolar affinity against 125I-interleukin-8 (IL-8) binding to ORF-74, a constitutively active seven-transmembrane receptor encoded by human herpesvirus 8. However, in competition against 125I-labeled growth-related oncogene (GRO)-alpha, the ORF-74...

  2. Constitutive activation of a slowly migrating isoform of Stat3 in mycosis fungoides: tyrphostin AG490 inhibits Stat3 activation and growth of mycosis fungoides tumor cell lines

    DEFF Research Database (Denmark)

    Nielsen, M; Kaltoft, K; Nordahl, M

    1997-01-01

    Mycosis fungoides (MF) is a low-grade cutaneous T cell lymphoma of unknown etiology. In this report, the Jak/Stat (Janus kinase/signal transducer and activator of transcription) signaling pathway was investigated in tumor cell lines established from skin biopsy specimens from a patient with MF....... Jaks link cytokine receptors to Stats, and abnormal Jak/Stat signaling has been observed in some hemopoietic cancers. In MF tumor cells, a slowly migrating isoform of Stat3, Stat3(sm), was found to be constitutively activated, i.e., (i) Stat3(sm) was constitutively phosphorylated on tyrosine residues...... specific. Thus, neither the fast migrating isoform of Stat3 (Stat3(fm)) nor other Stats (Stat1, Stat2, and Stat4 through Stat6) were constitutively activated. The Jak kinase inhibitor, tyrphostin AG490, blocked the constitutive activation of Stat3(sm) and inhibited spontaneous as well as interleukin 2...

  3. Authoritarian Constitutionalism

    OpenAIRE

    Tushnet, Mark V.

    2015-01-01

    Legal scholars and political theorists interested in constitutionalism as a normative concept tend to dichotomize the subject. There is liberal constitutionalism of the sort familiar in the modern West, with core commitments to human rights and self-governance implemented by means of varying institutional devices, and there is authoritarianism, rejecting human rights entirely and governed by unconstrained power-holders. This Article explores the possibility of forms of constitutionalism other...

  4. Constitutive β-catenin activation in osteoblasts impairs terminal osteoblast differentiation and bone quality

    Energy Technology Data Exchange (ETDEWEB)

    Bao, Quanwei; Chen, Sixu; Qin, Hao [State Key Laboratory of Trauma, Burn and Combined injury, Department of Trauma Surgery, Daping Hospital, Third Military Medical University, ChongQing 400042 (China); Feng, Jianquan [Department of Biomedical Sciences, Baylor College of Dentistry, Texas A& M Health Science Center, Dallas, TX 75246 (United States); Liu, Huayu; Liu, Daocheng; Li, Ang; Shen, Yue; Zhong, Xiaozheng; Li, Junfeng [State Key Laboratory of Trauma, Burn and Combined injury, Department of Trauma Surgery, Daping Hospital, Third Military Medical University, ChongQing 400042 (China); Zong, Zhaowen, E-mail: zongzhaowen@sina.cn [State Key Laboratory of Trauma, Burn and Combined injury, Department of Trauma Surgery, Daping Hospital, Third Military Medical University, ChongQing 400042 (China)

    2017-01-01

    Accumulating evidence suggests that Wnt/β-catenin signaling plays a central role in controlling bone mass. We previously reported that constitutive activation of β-catenin (CA-β-catenin) in osteoblasts potentially has side effects on the bone growth and bone remodeling process, although it could increase bone mass. The present study aimed to observe the effects of osteoblastic CA-β-catenin on bone quality and to investigate possible mechanisms of these effects. It was found that CA-β-catenin mice exhibited lower mineralization levels and disorganized collagen in long bones as confirmed by von Kossa staining and sirius red staining, respectively. Also, bone strength decreased significantly in CA-β-catenin mice. Then the effect of CA-β-catenin on biological functions of osteoblasts were investigated and it was found that the expression levels of osteocalcin, a marker for the late differentiation of osteoblasts, decreased in CA-β-catenin mice, while the expression levels of osterix and alkaline phosphatase, two markers for the early differentiation of osteoblasts, increased in CA-β-catenin mice. Furthermore, higher proliferation rate were revealed in osteoblasts that were isolated from CA-β-catenin mice. The Real-time PCR and western blot examination found that the expression level of c-myc and cyclin D1, two G1 progression-related molecules, increased in osteoblasts that were isolated from the CA-β-catenin mice, and the expression levels of CDK14 and cyclin Y, two mitotic-related molecules that can accelerate cells entering into S and G2/M phases, increased in osteoblasts that were isolated from the CA-β-catenin mice. In summary, osteoblastic CA-β-catenin kept osteoblasts in high proliferative state and impaired the terminal osteoblast differentiation, and this led to changed bone structure and decreased bone strength. - Highlights: • Wnt/β-catenin signaling plays a central role in controlling bone mass. • CA-β-catenin has side effects on the bone

  5. Constitutive activation of the thyroid-stimulating hormone receptor (TSHR by mutating Ile691 in the cytoplasmic tail segment.

    Directory of Open Access Journals (Sweden)

    Zheng Liu

    Full Text Available BACKGROUND: Autosomal dominant non-autoimmune hyperthyroidism (ADNAH is a rare genetic disorder of the endocrine system. Molecular genetic studies in ADNAH have revealed heterozygous germline mutations in the TSHR. To data, mutations leading to an increase in the constitutive activation of the TSHR have been described in the transmembrane segments, exoloops and cytoplasmic loop of TSHR. These mutations result in constitutive activation of the G(αs/cAMP or G(αq/11/inositol phosphate (IP pathways, which stimulate thyroid hormone production and thyroid proliferation. METHODOLOGY/PRINCIPAL FINDINGS: In a previous study, we reported a new TSHR mutation located in the C-terminal domain of TSHR, which results in a substitution of the conserved Ile(691 for Phe. In this study, to address the question of whether the I691F mutated receptor could be responsible for G(αs/cAMP or G(αq/11/IP constitutive activity, wild-type and TSHR mutants were expressed in COS-7 cells to determine cAMP constitutive activity and IP formation. Compared to the cell surface with expression of the A623V mutated receptor as positive control, the I691F mutated receptor showed a slight increase of cAMP accumulation. Furthermore, I691F resulted in constitutive activation of the G(αq/11/IP signaling pathway. CONCLUSIONS/SIGNIFICANCE: Our results indicate that Ile(691 not only contributes to keeping TSHR inactive in the G(αs/cAMP pathways but also in the G(αq/11/IP cascade.

  6. High constitutive activity of a virus-encoded seven transmembrane receptor in the absence of the conserved DRY motif (Asp-Arg-Tyr) in transmembrane helix 3

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M; Kledal, Thomas N; Schwartz, Thue W

    2005-01-01

    of activated T cells. Coexpression of the ORF74-EHV2 receptor with the promiscuous G protein Gqi4myr supported the constitutive Gi activation as determined by inositol phosphate turnover and CREB activation. The constitutive activity was inhibited by nonpeptide inverse agonists with micromolar potencies...

  7. Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas

    DEFF Research Database (Denmark)

    Bartkova, J; Hamerlik, P; Stockhausen, Marie

    2010-01-01

    , initially limiting cell proliferation (low Ki-67 index) and selecting for mutations of p53 and likely other genes that allow escape (higher Ki-67 index) from the checkpoint and facilitate tumor progression. Overall, these results support the potential role of the DDR machinery as a barrier to gliomagenesis......Malignant gliomas, the deadliest of brain neoplasms, show rampant genetic instability and resistance to genotoxic therapies, implicating potentially aberrant DNA damage response (DDR) in glioma pathogenesis and treatment failure. Here, we report on gross, aberrant constitutive activation of DNA...... that the DDR machinery is constitutively activated in gliomas, as documented by phosphorylated histone H2AX (gammaH2AX), activation of the ATM-Chk2-p53 pathway, 53BP1 foci and other markers. Oxidative DNA damage (8-oxoguanine) was high in some GBM cell lines and many GBM tumors, while it was low in normal...

  8. Constitutively active Notch1 converts cranial neural crest-derived frontonasal mesenchyme to perivascular cells in vivo

    Directory of Open Access Journals (Sweden)

    Sophie R. Miller

    2017-03-01

    Full Text Available Perivascular/mural cells originate from either the mesoderm or the cranial neural crest. Regardless of their origin, Notch signalling is necessary for their formation. Furthermore, in both chicken and mouse, constitutive Notch1 activation (via expression of the Notch1 intracellular domain is sufficient in vivo to convert trunk mesoderm-derived somite cells to perivascular cells, at the expense of skeletal muscle. In experiments originally designed to investigate the effect of premature Notch1 activation on the development of neural crest-derived olfactory ensheathing glial cells (OECs, we used in ovo electroporation to insert a tetracycline-inducible NotchΔE construct (encoding a constitutively active mutant of mouse Notch1 into the genome of chicken cranial neural crest cell precursors, and activated NotchΔE expression by doxycycline injection at embryonic day 4. NotchΔE-targeted cells formed perivascular cells within the frontonasal mesenchyme, and expressed a perivascular marker on the olfactory nerve. Hence, constitutively activating Notch1 is sufficient in vivo to drive not only somite cells, but also neural crest-derived frontonasal mesenchyme and perhaps developing OECs, to a perivascular cell fate. These results also highlight the plasticity of neural crest-derived mesenchyme and glia.

  9. Recombinant Nox4 cytosolic domain produced by a cell or cell-free base systems exhibits constitutive diaphorase activity

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, Minh Vu Chuong, E-mail: mvchuong@yahoo.fr [GREPI AGIM FRE 3405 CNRS-UJF, Universite Joseph Fourier, Grenoble (France); Zhang, Leilei [GREPI AGIM FRE 3405 CNRS-UJF, Universite Joseph Fourier, Grenoble (France); Lhomme, Stanislas; Mouz, Nicolas [PX' Therapeutics, MINATEC/Batiment de Haute Technologie, Grenoble (France); Lenormand, Jean-Luc [HumProTher Laboratory, TheReX/TIMC-IMAG UMR 5525 CNRS UJF, Universite Joseph Fourier, UFR de Medecine, Domaine de la Merci, 38706 La Tronche (France); Lardy, Bernard; Morel, Francoise [GREPI AGIM FRE 3405 CNRS-UJF, Universite Joseph Fourier, Grenoble (France)

    2012-03-16

    Highlights: Black-Right-Pointing-Pointer A comparison of two bacterial cell and cell-free protein expression systems is presented. Black-Right-Pointing-Pointer Soluble and active truncated Nox4 proteins are produced. Black-Right-Pointing-Pointer Nox4 has a constitutive diaphorase activity which is independent of cytosolic factors. Black-Right-Pointing-Pointer Isoform Nox4B is unable to initiate the first electronic transfer step. Black-Right-Pointing-Pointer Findings contribute to the understanding of the mechanism of Nox4 oxidase activity. -- Abstract: The membrane protein NADPH (nicotinamide adenine dinucleotide phosphate) oxidase Nox4 constitutively generates reactive oxygen species differing from other NADPH oxidases activity, particularly in Nox2 which needs a stimulus to be active. Although the precise mechanism of production of reactive oxygen species by Nox2 is well characterized, the electronic transfer throughout Nox4 remains unclear. Our study aims to investigate the initial electronic transfer step (diaphorase activity) of the cytosolic tail of Nox4. For this purpose, we developed two different approaches to produce soluble and active truncated Nox4 proteins. We synthesized soluble recombinant proteins either by in vitro translation or by bacteria induction. While proteins obtained by bacteria induction demonstrate an activity of 4.4 {+-} 1.7 nmol/min/nmol when measured against iodonitro tetrazolium chloride and 20.5 {+-} 2.8 nmol/min/nmol with cytochrome c, the soluble proteins produced by cell-free expression system exhibit a diaphorase activity with a turn-over of 26 {+-} 2.6 nmol/min/nmol when measured against iodonitro tetrazolium chloride and 48 {+-} 20.2 nmol/min/nmol with cytochrome c. Furthermore, the activity of the soluble proteins is constitutive and does not need any stimulus. We also show that the cytosolic tail of the isoform Nox4B lacking the first NADPH binding site is unable to demonstrate any diaphorase activity pointing out the

  10. CONSTITUTION AND CONSTITUTIONALISM CONTEMPORARY ISSUE

    Directory of Open Access Journals (Sweden)

    Marius ANDREESCU

    2017-05-01

    Full Text Available In a democratic society, the judicial legitimacy of the state and its power, of its institutions, but also the social and political grounds are generated and determined by the Constitution, defined as expressively as possible as being: “The fundamental political and judicial settlement of a people” (I. Deleanu. The supremacy of the Constitution has as main effect the conformity of the entire system of law with the constitutional norms. Guaranteeing the compliance with this principle, essential for the state of law, is first of all an attribution of the Constitutional Court, but also an obligation of the legislative power to receive, through the adopted normative acts, in content and in form, the constitutional norms. Altering the fundamental law of a state represents a political and judicial act extremely complex with major meanings and implications for the socio-political and national systems, but also for each individual. This is why such measure should be very well justified, to answer certain socio-political and legal needs well shaped and mainly to match the principles and rules specific to a democratic constitutional and state system, by insuring its stability and functionality. These are a few aspects of the Romanian contemporary constitutionalism that this study shall critically analyse in order to differentiate between the constitutional ideal and reality.

  11. Lack of in vitro constitutive activity for four previously reported TSH receptor mutations identified in patients with nonautoimmune hyperthyroidism and hot thyroid carcinomas

    OpenAIRE

    Paschke, Ralf; Jaeschke, Holger; Mueller, Sandra; Eszlinger, Markus

    2010-01-01

    Abstract Objective: Constitutively activating mutations of the TSHR are the major cause for nonautoimmune hyperthyroidism. Re-examination of constitutive activity previously determined in CHO cell lines recently demonstrated the caveats for the in vitro determination of constitutive TSHR activity, which leads to false positive conclusions regarding the molecular origin of hyperthyroidism or hot thyroid carcinomas. Design: Mutations L677V and T620I identified in hot thyroid carc...

  12. Molecular determinants for the high constitutive activity of the human histamine H4 receptor: functional studies on orthologues and mutants.

    Science.gov (United States)

    Wifling, D; Löffel, K; Nordemann, U; Strasser, A; Bernhardt, G; Dove, S; Seifert, R; Buschauer, A

    2015-02-01

    Some histamine H4 receptor ligands act as inverse agonists at the human H4 receptor (hH4 R), a receptor with exceptionally high constitutive activity, but as neutral antagonists or partial agonists at the constitutively inactive mouse H4 receptor (mH4 R) and rat H4 receptor (rH4 R). To study molecular determinants of constitutive activity, H4 receptor reciprocal mutants were constructed: single mutants: hH4 R-F169V, mH4 R-V171F, hH4 R-S179A, hH4 R-S179M; double mutants: hH4 R-F169V+S179A, hH4 R-F169V+S179M and mH4 R-V171F+M181S. Site-directed mutagenesis with pVL1392 plasmids containing hH4 or mH4 receptors were performed. Wild-type or mutant receptors were co-expressed with Gαi2 and Gβ1 γ2 in Sf9 cells. Membranes were studied in saturation and competition binding assays ([(3) H]-histamine), and in functional [(35) S]-GTPγS assays with inverse, partial and full agonists of the hH4 receptor. Constitutive activity decreased from the hH4 receptor via the hH4 R-F169V mutant to the hH4 R-F169V+S179A and hH4 R-F169V+S179M double mutants. F169 alone or in concert with S179 plays a major role in stabilizing a ligand-free active state of the hH4 receptor. Partial inverse hH4 receptor agonists like JNJ7777120 behaved as neutral antagonists or partial agonists at species orthologues with lower or no constitutive activity. Some partial and full hH4 receptor agonists showed decreased maximal effects and potencies at hH4 R-F169V and double mutants. However, the mutation of S179 in the hH4 receptor to M as in mH4 receptor or A as in rH4 receptor did not significantly reduce constitutive activity. F169 and S179 are key amino acids for the high constitutive activity of hH4 receptors and may also be of relevance for other constitutively active GPCRs. This article is part of a themed issue on Histamine Pharmacology Update published in volume 170 issue 1. To view the other articles in this issue visit http://onlinelibrary.wiley.com/doi/10.1111/bph.2013.170.issue-1/issuetoc.

  13. SR Proteins Induce Alternative Exon Skipping through Their Activities on the Flanking Constitutive Exons▿

    Science.gov (United States)

    Han, Joonhee; Ding, Jian-Hua; Byeon, Cheol W.; Kim, Jee H.; Hertel, Klemens J.; Jeong, Sunjoo; Fu, Xiang-Dong

    2011-01-01

    SR proteins are well known to promote exon inclusion in regulated splicing through exonic splicing enhancers. SR proteins have also been reported to cause exon skipping, but little is known about the mechanism. We previously characterized SRSF1 (SF2/ASF)-dependent exon skipping of the CaMKIIδ gene during heart remodeling. By using mouse embryo fibroblasts derived from conditional SR protein knockout mice, we now show that SR protein-induced exon skipping depends on their prevalent actions on a flanking constitutive exon and requires collaboration of more than one SR protein. These findings, coupled with other established rules for SR proteins, provide a theoretical framework to understand the complex effect of SR protein-regulated splicing in mammalian cells. We further demonstrate that heart-specific CaMKIIδ splicing can be reconstituted in fibroblasts by downregulating SR proteins and upregulating a RBFOX protein and that SR protein overexpression impairs regulated CaMKIIδ splicing and neuronal differentiation in P19 cells, illustrating that SR protein-dependent exon skipping may constitute a key strategy for synergism with other splicing regulators in establishing tissue-specific alternative splicing critical for cell differentiation programs. PMID:21135118

  14. SR proteins induce alternative exon skipping through their activities on the flanking constitutive exons.

    Science.gov (United States)

    Han, Joonhee; Ding, Jian-Hua; Byeon, Cheol W; Kim, Jee H; Hertel, Klemens J; Jeong, Sunjoo; Fu, Xiang-Dong

    2011-02-01

    SR proteins are well known to promote exon inclusion in regulated splicing through exonic splicing enhancers. SR proteins have also been reported to cause exon skipping, but little is known about the mechanism. We previously characterized SRSF1 (SF2/ASF)-dependent exon skipping of the CaMKIIδ gene during heart remodeling. By using mouse embryo fibroblasts derived from conditional SR protein knockout mice, we now show that SR protein-induced exon skipping depends on their prevalent actions on a flanking constitutive exon and requires collaboration of more than one SR protein. These findings, coupled with other established rules for SR proteins, provide a theoretical framework to understand the complex effect of SR protein-regulated splicing in mammalian cells. We further demonstrate that heart-specific CaMKIIδ splicing can be reconstituted in fibroblasts by downregulating SR proteins and upregulating a RBFOX protein and that SR protein overexpression impairs regulated CaMKIIδ splicing and neuronal differentiation in P19 cells, illustrating that SR protein-dependent exon skipping may constitute a key strategy for synergism with other splicing regulators in establishing tissue-specific alternative splicing critical for cell differentiation programs.

  15. Constitutive activation of a CC-NB-LRR protein alters morphogenesis through the cytokinin pathway in Arabidopsis.

    Science.gov (United States)

    Igari, Kadunari; Endo, Sachiko; Hibara, Ken-ichiro; Aida, Mitsuhiro; Sakakibara, Hitoshi; Kawasaki, Tsutomu; Tasaka, Masao

    2008-07-01

    Possible links between plant defense responses and morphogenesis have been postulated, but their molecular nature remains unknown. Here, we introduce the Arabidopsis semi-dominant mutant uni-1D with morphological defects. UNI encodes a coiled-coil nucleotide-binding leucine-rich-repeat protein that belongs to the disease resistance (R) protein family involved in pathogen recognition. The uni-1D mutation causes the constitutive activation of the protein, which is stabilized by the RAR1 function in a similar way as in other R proteins. The uni-1D mutation induces the upregulation of the Pathogenesis-related gene via the accumulation of salicylic acid, and evokes some of the morphological defects through the accumulation of cytokinin. The rin4 knock-down mutation, which causes the constitutive activation of two R proteins, RPS2 and RPM1, induces an upregulation of cytokinin-responsive genes and morphological defects similar to the uni-1D mutation, indicating that the constitutive activation of some R proteins alters morphogenesis through the cytokinin pathway. From these data, we propose that the modification of the cytokinin pathway might be involved in some R protein-mediated responses.

  16. Constitutive Cdk2 activity promotes aneuploidy while altering the spindle assembly and tetraploidy checkpoints

    DEFF Research Database (Denmark)

    Jahn, Stephan C; Corsino, Patrick E; Davis, Bradley J

    2013-01-01

    The cell has many mechanisms for protecting the integrity of its genome. These mechanisms are often weakened or absent in many cancers, leading to high rates of chromosomal instability in tumors. Control of the cell cycle is crucial for the function of these checkpoints, and is frequently lost...... instability. Expression of these complexes in the MCF10A cell line leads to retinoblastoma protein (Rb) hyperphosphorylation, a subsequent increase in proliferation rate, and increased expression of the spindle assembly checkpoint protein Mad2. This results in a strengthening of the spindle assembly...... checkpoint and renders cells more sensitive to the spindle poison paclitaxel. Constitutive Rb phosphorylation also causes a weakening of the p53-dependent tetraploidy checkpoint. Cells with overactive Cdk2 fail to arrest after mitotic slippage in the presence of paclitaxel or cytokinesis failure during...

  17. Interaction Between Familial Transmission and a Constitutively Active Immune System Shapes Gut Microbiota inDrosophila melanogaster.

    Science.gov (United States)

    Mistry, Rupal; Kounatidis, Ilias; Ligoxygakis, Petros

    2017-06-01

    Resident gut bacteria are constantly influencing the immune system, yet the role of the immune system in shaping microbiota composition during an organism's life span has remained unclear. Experiments in mice have been inconclusive due to differences in husbandry schemes that led to conflicting results. We used Drosophila as a genetically tractable system with a simpler gut bacterial population structure streamlined genetic backgrounds and established cross schemes to address this issue. We found that, depending on their genetic background, young flies had microbiota of different diversities that converged with age to the same Acetobacteraceae-dominated pattern in healthy flies. This pattern was accelerated in immune-compromised flies with higher bacterial load and gut cell death. Nevertheless, immune-compromised flies resembled their genetic background, indicating that familial transmission was the main force regulating gut microbiota. In contrast, flies with a constitutively active immune system had microbiota readily distinguishable from their genetic background with the introduction and establishment of previously undetectable bacterial families. This indicated the influence of immunity over familial transmission. Moreover, hyperactive immunity and increased enterocyte death resulted in the highest bacterial load observed starting from early adulthood. Cohousing experiments showed that the microenvironment also played an important role in the structure of the microbiota where flies with constitutive immunity defined the gut microbiota of their cohabitants. Our data show that, in Drosophila , constitutively active immunity shapes the structure and density of gut microbiota. Copyright © 2017 Mistry et al.

  18. Activation of host constitutive immune defence by an intestinal trypanosome parasite of bumble bees.

    Science.gov (United States)

    Brown, M J F; Moret, Y; Schmid-Hempel, P

    2003-03-01

    Many parasites, including important species that affect humans and livestock, must survive the harsh environment of insect guts to complete their life-cycle. Hence, understanding how insects protect themselves against such parasites has immediate practical implications. Previously, such protection has been thought to consist mainly of mechanical structures and the action of lectins. However, recently it has become apparent that gut infections may interact with the host immune system in more complex ways. Here, using bumble bees, Bombus terrestris and their non-invasive gut trypanosome, Crithidia bombi, as a model system we investigated the effects of parasitic infection, host resources and the duration of infections on the host immune system. We found that infection doubled standing levels of immune defence in the haemolymph (the constitutive pro-phenoloxidase system), which is used as a first, general defence against parasites. However, physical separation of the parasite from the haemolymph suggests the presence of a messenger system between the gut and the genes that control the pro-phenoloxidase system. Surprisingly, we found no direct effect of host resource-stress or duration of the infection on the immune system. Our results suggest a novel and tactical response of insects to gut infections, demonstrating the complexity of such host-parasite systems.

  19. Structural motifs of importance for the constitutive activity of the orphan 7TM receptor EBI2: analysis of receptor activation in the absence of an agonist

    DEFF Research Database (Denmark)

    Benned-Jensen, Tau; Rosenkilde, Mette M

    2008-01-01

    of these molecular mechanisms for EBI2 activation is important from a drug development point of view, in that it may facilitate the rational design and development of small-molecule inverse agonists against EBI2 of putative importance as antiviral- or immune modulatory therapy.......The Epstein-Barr induced receptor 2 (EBI2) is a lymphocyte-expressed orphan seven transmembrane-spanning (7TM) receptor that signals constitutively through Galphai, as shown, for instance by guanosine 5'-O-(3-thio)triphosphate incorporation. Two regions of importance for the constitutive activity...

  20. Investigations on organic fungicides; V. Chemical constitution and fungistatic activity of aliphatic bisdithiocarbamates and isothiocyanates

    NARCIS (Netherlands)

    Klöpping, H.L.; Kerk, G.J.M. van der

    1951-01-01

    In this paper, the investigations on the relations of structure to antifungal activity of sulphur compounds described in the previous publication of this series are extended to bisdithiocarbamates and isothiocyanates. The most active sulphur fungicide described in the literature so far, disodium

  1. Constitutively active Arabidopsis MAP Kinase 3 triggers defense responses involving salicylic acid and SUMM2 resistance protein

    KAUST Repository

    Genot, Baptiste

    2017-04-12

    Mitogen-activated protein kinases (MAPKs) are important regulators of plant immunity. Most of the knowledge about the function of these pathways is derived from loss-of-function approaches. Using a gain-of-function approach, we investigated the responses controlled by a constitutively active (CA) MPK3 in Arabidopsis thaliana. CA-MPK3 plants are dwarfed and display a massive de-repression of defense genes associated with spontaneous cell death as well as accumulation of reactive oxygen species (ROS), phytoalexins and the stress-related hormones ethylene and salicylic acid (SA). Remarkably CA-MPK3/sid2 and CA-MPK3/ein2-50 lines which are impaired in SA synthesis and ethylene signaling, respectively, retain most of the CA-MPK3-associated phenotypes, indicating that constitutive activity of MPK3 can bypass SA and ethylene signaling to activate defense responses. A comparative analysis of the molecular phenotypes of CA-MPK3 and mpk4 autoimmunity suggested convergence between the MPK3 and MPK4-guarding modules. In support of this model, CA-MPK3 crosses with summ1 and summ2, two known suppressors of mpk4, resulted in a partial reversion of the CA-MPK3 phenotypes. Overall, our data unravel a novel mechanism by which the MAPK signaling network contributes to a robust defense response system.

  2. A constitutively active G-protein-coupled receptor causes mating self-compatibility in the mushroom Coprinus.

    Science.gov (United States)

    Olesnicky, N S; Brown, A J; Dowell, S J; Casselton, L A

    1999-01-01

    In the mushroom Coprinus cinereus, the multiallelic B mating type genes are predicted to encode a large family of seven-transmembrane domain receptors and CaaX-modified pheromones. We have shown that a single amino acid change Q229P in transmembrane domain VI of one receptor confers a self-compatible mating phenotype. Using a heterologous yeast assay, we have demonstrated that this C.cinereus pheromone receptor is a G-protein-coupled receptor and that the Q229P mutation is constitutively activating. A C.cinereus pheromone precursor was processed to an active species specifically in yeast MATa cells and activated the co-expressed wild-type receptor. Yeast cells expressing the wild-type receptor were used to test the activity of synthetic peptides, enabling us to predict the structure of the mature C.cinereus pheromone and to show that the Q229P mutation does not compromise normal receptor function. PMID:10329622

  3. Specific inhibition of transcriptional activity of the constitutive androstane receptor (CAR) by the splicing factor SF3a3.

    Science.gov (United States)

    Yun, Hye Jin; Kwon, Jungsun; Seol, Wongi

    2008-10-01

    The constitutive androstane receptor (CAR) is a member of the nuclear receptor superfamily and plays an important role in the degradation of xenobiotics in the liver. Using yeast two-hybrid screening, we identified SF3a3, a 60-kDa subunit of the splicing factor 3a complex, as a specific CAR-interacting protein. We further confirmed their interaction by both co-immunoprecipitation and GST pull-down assay. Functional studies showed that overexpression of SF3a3 inhibited the reporter activity driven by a promoter containing CAR binding sequences by up to 50%, whereas reduced expression of SF3a3 activated the same reporter activity by approximately three-fold. The inhibitory function of SF3a3 is independent of the presence of TCPOBOP, a CAR ligand. These data suggest that SF3a3 functions as a co-repressor of CAR transcriptional activity, in addition to its canonical function.

  4. The role of constitutive nitric-oxide synthase in ultraviolet B light-induced nuclear factor κB activity.

    Science.gov (United States)

    Tong, Lingying; Wu, Shiyong

    2014-09-19

    NF-κB is a transcription factor involved in many signaling pathways that also plays an important role in UV-induced skin tumorigenesis. UV radiation can activate NF-κB, but the detailed mechanism remains unclear. In this study, we provided evidence that the activation of constitutive nitric-oxide synthase plays a role in regulation of IκB reduction and NF-κB activation in human keratinocyte HaCaT cells in early phase (within 6 h) post-UVB. Treating the cells with l-NAME, a selective inhibitor of constitutive nitric-oxide synthase (cNOS), can partially reverse the IκB reduction and inhibit the DNA binding activity as well as nuclear translocation of NF-κB after UVB radiation. A luciferase reporter assay indicates that UVB-induced NF-κB activation is totally diminished in cNOS null cells. The cNOS-mediated reduction of IκB is likely due to the imbalance of nitric oxide/peroxynitrite because treating the cells with lower (50 μm), but not higher (100-500 μm), concentration of S-nitroso-N-acetylpenicillamine (SNAP) can reverse the effect of l-NAME in partial restore IκB level post-UVB. Our data also showed that NF-κB activity was required for maintaining a stable IκB kinase α subunit (IKKα) level because treating the cells with NF-κB or cNOS inhibitors could reduce IKKα level upon UVB radiation. In addition, our data demonstrated that although NF-κB protects cells from UVB-induced death, its pro-survival activity was likely neutralized by the pro-death activity of peroxynitrite after UVB radiation. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. Antigen-Specific Monoclonal Antibodies Isolated from B Cells Expressing Constitutively Active STAT5

    NARCIS (Netherlands)

    Scheeren, F.A.; van Geelen, C.M.M.; Yasuda, E.; Spits, H.; Beaumont, T.

    2011-01-01

    Background: Fully human monoclonal antibodies directed against specific pathogens have a high therapeutic potential, but are difficult to generate. Methodology/Principal Findings: Memory B cells were immortalized by expressing an inducible active mutant of the transcription factor Signal Transducer

  6. Constitutive activity of the cannabinoid CB1 receptor regulates the function of co-expressed Mu opioid receptors.

    Science.gov (United States)

    Canals, Meritxell; Milligan, Graeme

    2008-04-25

    The human mu opioid receptor was expressed stably in Flp-In T-REx HEK293 cells. Occupancy by the agonist DAMGO (Tyr-d-Ala-Gly-N-methyl-Phe-Gly-ol) resulted in phosphorylation of the ERK1/2 MAP kinases, which was blocked by the opioid antagonist naloxone but not the cannabinoid CB1 receptor inverse agonist SR141716A. Expression of the human cannabinoid CB1 receptor in these cells from the inducible Flp-In T-REx locus did not alter expression levels of the mu opioid receptor. This allowed the cannabinoid CB1 agonist WIN55212-2 to stimulate ERK1/2 phosphorylation but resulted in a large reduction in the capacity of DAMGO to activate these kinases. Although lacking affinity for the mu opioid receptor, co-addition of SR141716A caused recovery of the effectiveness of DAMGO. In contrast co-addition of the CB1 receptor neutral antagonist O-2050 did not. Induction of the CB1 receptor also resulted in an increase of basal [(35)S]guanosine 5'-3-O-(thio)triphosphate (GTPgammaS) binding and thereby a greatly reduced capacity of DAMGO to further stimulate [(35)S]GTPgammaS binding. CB1 inverse agonists attenuated basal [(35)S]GTPgammaS binding and restored the capacity of DAMGO to stimulate. Flp-In T-REx HEK293 cells were generated, which express the human mu opioid receptor constitutively and harbor a modified D163N cannabinoid CB1 receptor that lacks constitutive activity. Induction of expression of the modified cannabinoid CB1 receptor did not limit DAMGO-mediated ERK1/2 MAP kinase phosphorylation and did not allow SR141716A to enhance the function of DAMGO. These data indicate that it is the constitutive activity inherent in the cannabinoid CB1 receptor that reduces the capacity of co-expressed mu opioid receptor to function.

  7. Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors.

    Science.gov (United States)

    Zhao, Yuechao; Laws, Mary J; Guillen, Valeria Sanabria; Ziegler, Yvonne; Min, Jian; Sharma, Abhishek; Kim, Sung Hoon; Chu, David; Park, Ben Ho; Oesterreich, Steffi; Mao, Chengjian; Shapiro, David J; Nettles, Kendall W; Katzenellenbogen, John A; Katzenellenbogen, Benita S

    2017-10-15

    Many estrogen receptor α (ERα)-positive breast cancers develop resistance to endocrine therapy via mutation of ERs whose constitutive activation is associated with shorter patient survival. Because there is now a clinical need for new antiestrogens (AE) against these mutant ERs, we describe here our development and characterization of three chemically novel AEs that effectively suppress proliferation of breast cancer cells and tumors. Our AEs are effective against wild-type and Y537S and D538G ERs, the two most commonly occurring constitutively active ERs. The three new AEs suppressed proliferation and estrogen target gene expression in WT and mutant ER-containing cells and were more effective in D538G than in Y537S cells and tumors. Compared with WT ER, mutants exhibited approximately 10- to 20-fold lower binding affinity for AE and a reduced ability to be blocked in coactivator interaction, likely contributing to their relative resistance to inhibition by AE. Comparisons between mutant ER-containing MCF7 and T47D cells revealed that AE responses were compound, cell-type, and ERα-mutant dependent. These new ligands have favorable pharmacokinetic properties and effectively suppressed growth of WT and mutant ER-expressing tumor xenografts in NOD/SCID-γ mice after oral or subcutaneous administration; D538G tumors were more potently inhibited by AE than Y537S tumors. These studies highlight the differential responsiveness of the mutant ERs to different AEs and make clear the value of having a toolkit of AEs for treatment of endocrine therapy-resistant tumors driven by different constitutively active ERs. Cancer Res; 77(20); 5602-13. ©2017 AACR. ©2017 American Association for Cancer Research.

  8. Constitutive activation of CaMKKα signaling is sufficient but not necessary for mTORC1 activation and growth in mouse skeletal muscle.

    Science.gov (United States)

    Ferey, Jeremie L A; Brault, Jeffrey J; Smith, Cheryl A S; Witczak, Carol A

    2014-10-15

    Skeletal muscle loading/overload stimulates the Ca²⁺-activated, serine/threonine kinase Ca²⁺/calmodulin-dependent protein kinase kinase-α (CaMKKα); yet to date, no studies have examined whether CaMKKα regulates muscle growth. The purpose of this study was to determine if constitutive activation of CaMKKα signaling could stimulate muscle growth and if so whether CaMKKα is essential for this process. CaMKKα signaling was selectively activated in mouse muscle via expression of a constitutively active form of CaMKKα using in vivo electroporation. After 2 wk, constitutively active CaMKKα expression increased muscle weight (~10%) and protein content (~10%), demonstrating that activation of CaMKKα signaling can stimulate muscle growth. To determine if active CaMKKα expression stimulated muscle growth via increased mammalian target of rapamycin complex 1 (mTORC1) signaling and protein synthesis, [³H]phenylalanine incorporation into proteins was assessed with or without the mTORC1 inhibitor rapamycin. Constitutively active CaMKKα increased protein synthesis ~60%, and this increase was prevented by rapamycin, demonstrating a critical role for mTORC1 in this process. To determine if CaMKKα is essential for growth, muscles from CaMKKα knockout mice were stimulated to hypertrophy via unilateral ablation of synergist muscles (overload). Surprisingly, compared with wild-type mice, muscles from CaMKKα knockout mice exhibited greater growth (~15%) and phosphorylation of the mTORC1 substrate 70-kDa ribosomal protein S6 kinase (Thr³⁸⁹; ~50%), demonstrating that CaMKKα is not essential for overload-induced mTORC1 activation or muscle growth. Collectively, these results demonstrate that activation of CaMKKα signaling is sufficient but not necessary for activation of mTORC1 signaling and growth in mouse skeletal muscle. Copyright © 2014 the American Physiological Society.

  9. UBL/BAG-domain co-chaperones cause cellular stress upon overexpression through constitutive activation of Hsf1

    DEFF Research Database (Denmark)

    Poulsen, Esben Guldahl; Kampmeyer, Caroline; Kriegenburg, Franziska

    2017-01-01

    As a result of exposure to stress conditions, mutations, or defects during synthesis, cellular proteins are prone to misfold. To cope with such partially denatured proteins, cells mount a regulated transcriptional response involving the Hsf1 transcription factor, which drives the synthesis......, binds Bag101 and Bag102 and key residues in the Hsp70 ATPase domains, required for interaction with Bag101 and Bag102, were identified. In humans, BAG-1 overexpression is typically observed in cancers. Overexpression of bag101 and bag102 in fission yeast leads to a strong growth defect caused......, leading to constitutive Hsf1 activation and growth defects....

  10. Spontaneous interleukin-5 production in cutaneous T-cell lymphoma lines is mediated by constitutively activated Stat3

    DEFF Research Database (Denmark)

    Nielsen, Mette; Nissen, Mogens H; Gerwien, Jens

    2002-01-01

    Mycosis fungoides is a low-grade cutaneous T-cell lymphoma (CTCL) of unknown etiology. In advanced stages of CTCL, a shift in cytokine profile from T(H)1 to T(H)2 is observed, which coincides with eosinophilia, high levels of immunoglobulin E, and increased susceptibility to bacterial infections......, constitutively activated Stat3 is found to mediate a spontaneous IL-5 production and regulate IL-13 production in CTCL cell lines, pointing toward a new role of Stat3 in malignant transformation....

  11. Constitutive activation of the DNA damage response pathway as a novel therapeutic target in diffuse large B-cell lymphoma

    Science.gov (United States)

    Derenzini, Enrico; Agostinelli, Claudio; Imbrogno, Enrica; Iacobucci, Ilaria; Casadei, Beatrice; Brighenti, Elisa; Righi, Simona; Fuligni, Fabio; Di Rorà, Andrea Ghelli Luserna; Ferrari, Anna; Martinelli, Giovanni; Pileri, Stefano; Zinzani, Pier Luigi

    2015-01-01

    The recent finding that MYC-driven cancers are sensitive to inhibition of the DNA damage response (DDR) pathway, prompted us to investigate the role of DDR pathway as therapeutic target in diffuse large B-cell lymphoma (DLBCL), which frequently overexpresses the MYC oncogene. In a preliminary immunohistochemical study conducted on 99 consecutive DLBCL patients, we found that about half of DLBCLs showed constitutive expression of the phosphorylated forms of checkpoint kinases (CHK) and CDC25c, markers of DDR activation, and of phosphorylated histone H2AX (γH2AX), marker of DNA damage and genomic instability. Constitutive γH2AX expression correlated with c-MYC levels and DDR activation, and defined a subset of tumors characterised by poor outcome. Next, we used the CHK inhibitor PF-0477736 as a tool to investigate whether the inhibition of the DDR pathway might represent a novel therapeutic approach in DLBCL. Submicromolar concentrations of PF-0477736 hindered proliferation in DLBCL cell lines with activated DDR pathway. These results were fully recapitulated with a different CHK inhibitor (AZD-7762). Inhibition of checkpoint kinases induced rapid DNA damage accumulation and apoptosis in DLBCL cell lines and primary cells. These data suggest that pharmacologic inhibition of DDR through targeting of CHK kinases may represent a novel therapeutic strategy in DLBCL. PMID:25544753

  12. Subclinical Nonautoimmune Hyperthyroidism in a Family Segregates with a Thyrotropin Receptor Mutation with Weakly Increased Constitutive Activity

    Science.gov (United States)

    Chen, Chun-Rong; Higashiyama, Takuya; Mizutori-Sasai, Yumiko; Ito, Mitsuru; Kubota, Sumihisa; Amino, Nobuyuki; Miyauchi, Akira; Rapoport, Basil

    2010-01-01

    Background Subclinical hyperthyroidism is usually associated with Graves' disease or toxic nodular goiter. Here we report a family with hereditary subclinical hyperthyroidism caused by a constitutively activating germline mutation of the thyrotropin receptor (TSHR) gene. Methods The proband was a 64-year-old Japanese woman who presented with a thyroid nodule and was found to be euthyroid with a suppressed serum TSH. The nodule was not hot. Although antibodies to thyroid peroxidase and thyroglobulin antibodies were present, TSHR antibodies were not detected by TSH-binding inhibition or by bioassay. Two of her middle-aged sons, but not her daughter, also had subclinical hyperthyroidism without TSHR antibodies. Without therapy, the clinical condition of the affected individuals remained unchanged over 3 years without development of overt hyperthyroidism. Results A novel heterozygous TSHR point mutation causing a glutamic acid to lysine substitution at codon 575 (E575K) in the second extracellular loop was detected in the three family members with subclinical hyperthyroidism, but was absent in her one daughter with normal thyroid function. In vitro functional studies of the E575K TSHR mutation demonstrated a weak, but significant, increase in constitutive activation of the cAMP pathway. Conclusion Although hereditary nonautoimmune overt hyperthyroidism is very rare, TSHR activating mutations as a cause of subclinical hyperthyroidism may be more common and should be considered in the differential diagnosis, especially if familial. PMID:20929407

  13. Constitutive Activity of the Arabidopsis MAP Kinase 3 Confers Resistance to Pseudomonas syringae and Drives Robust Immune Responses

    KAUST Repository

    Lang, Julien

    2017-08-02

    Mitogen Activated Protein Kinases (MAPKs) are known to be important mediators of plant responses to biotic and abiotic stresses. In a recent report, we enlarged the understanding of the Arabidopsis thaliana MPK3 functions showing that the expression of a constitutively active (CA) form of the protein led to auto-immune phenotypes. CA-MPK3 plants are dwarf and display defense responses that are characterized by the accumulation of salicylic acid and phytoalexins as well as by the upregulation of several defense genes. Consistently with these data, we present here results demonstrating that, compared to wild type controls, CA-MPK3 plants are more resistant to the hemibiotrophic pathogen Pseudomonas syringae DC3000. Based on our previous work, we also discuss the mechanisms of robust plant immunity controlled by sustained MPK3 activity, focusing especially on the roles of disease resistance proteins.

  14. Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas

    DEFF Research Database (Denmark)

    Bartkova, J; Hamerlik, P; Stockhausen, Marie

    2010-01-01

    that the DDR machinery is constitutively activated in gliomas, as documented by phosphorylated histone H2AX (gammaH2AX), activation of the ATM-Chk2-p53 pathway, 53BP1 foci and other markers. Oxidative DNA damage (8-oxoguanine) was high in some GBM cell lines and many GBM tumors, while it was low in normal......-oxygen culture conditions and in clinical specimens of both low- and high-grade tumors. The observed global checkpoint signaling, in contrast to only focal areas of overabundant p53 (indicative of p53 mutation) in grade II astrocytomas, are consistent with DDR activation being an early event in gliomagenesis......, initially limiting cell proliferation (low Ki-67 index) and selecting for mutations of p53 and likely other genes that allow escape (higher Ki-67 index) from the checkpoint and facilitate tumor progression. Overall, these results support the potential role of the DDR machinery as a barrier to gliomagenesis...

  15. Constitutive activity of the A2A adenosine receptor and compartmentalised cyclic AMP signalling fine-tune noradrenaline release.

    Science.gov (United States)

    Ibrisimovic, Edin; Drobny, Helmut; Yang, Qiong; Höfer, Thomas; Boehm, Stefan; Nanoff, Christian; Schicker, Klaus

    2012-12-01

    Neuroblastoma SH-SY5Y (SH) cells endogenously express A(2A) adenosine receptors and can be differentiated into a sympathetic neuronal phenotype, capable of depolarisation-dependent noradrenaline release. Using differentiated SH culture, we here explored the link between A(2A)-receptor signalling and neurotransmitter release. In response to the receptor agonist CGS21680, the cells produced cyclic AMP (cAMP), and when depolarised, they released increased amounts of noradrenaline. An A(2A)-receptor antagonist, XAC, as well as an inhibitor of cAMP-dependent protein kinase A (PKA), H89, depressed agonist-dependent release. In the presence of XAC or H89, noradrenaline release was found to be below basal values. This suggested that release facilitation also owes to constitutive receptor activity. We demonstrate that even in the absence of an agonist, the native A(2A)-receptor stimulated cAMP production, leading to the activation of PKA and enhanced noradrenaline release. Ancillary, non-cAMP-dependent effects of the receptor (i.e. phosphorylation of CREB, of Rabphilin3A) were refractory to constitutive activation. PKA-dependent facilitation of noradrenaline release was recapitulated with membrane-permeable 8-Br-cAMP; in addition to facilitation, 8-Br-cAMP caused marked inhibition of release, an effect not observed upon receptor activation. Inhibition by receptor-independent cAMP was likely due to suppression of voltage-dependent calcium current (VDCC) and increased activity of Src-family kinases. Receptor-mediated release facilitation was reproduced in the presence of tetrodotoxin (blocking action potentials); hence, the signalling occurred at the active zone comprising release sites. Our findings thus support (1) presynaptic localisation of the A(2A)-receptor and (2) suggest that compartmentalised pathways transmit cAMP signalling in order to facilitate depolarisation-dependent neurotransmitter release.

  16. Rho A and the Rho kinase pathway regulate fibroblast contraction: Enhanced contraction in constitutively active Rho A fibroblast cells

    Energy Technology Data Exchange (ETDEWEB)

    Nobe, Koji, E-mail: kojinobe@pharm.showa-u.ac.jp [Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, Tokyo (Japan); Nobe, Hiromi [Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, Tokyo (Japan); Department of Physical Therapy, Bunkyo-Gakuin University (Japan); Yoshida, Hiroko [Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, Tokyo (Japan); Kolodney, Michael S. [Dermatology Division, Department of Medicine, UCLA, Los Angeles, CA (United States); Paul, Richard J. [Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, OH (United States); Honda, Kazuo [Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, Tokyo (Japan)

    2010-08-20

    Research highlights: {yields} Mechanisms of fibroblast cell contraction in collagen matrix. {yields} Assessed an isometric force development using 3D-reconstituted-fibroblast fiber. {yields} Constitutively active Rho A induced the over-contraction of fibroblast cells. {yields} Rho A and Rho kinase pathway has a central role in fibroblast cell contraction. -- Abstract: Fibroblast cells play a central role in the proliferation phase of wound healing processes, contributing to force development. The intracellular signaling pathways regulating this non-muscle contraction are only partially understood. To study the relations between Rho A and contractile responses, constitutively active Rho A (CA-Rho A) fibroblast cells were reconstituted into fibers and the effects of calf serum (CS) on isometric force were studied. CS-induced force in CA-Rho A fibroblast fibers was twice as large as that in wild type (NIH 3T3) fibroblast fibers. During this response, the translocation of Rho A from the cytosol to the membrane was detected by Rho A activity assays and Western blot analysis. Pre-treatment with a Rho specific inhibitor (C3-exoenzyme) suppressed translocation as well as contraction. These results indicate that Rho A activation is essential for fibroblast contraction. The Rho kinase inhibitor ( (Y27632)) inhibited both NIH 3T3 and CA-Rho A fibroblast fiber contractions. Activation of Rho A is thus directly coupled with Rho kinase activity. We conclude that the translocation of Rho A from the cytosol to the membrane and the Rho kinase pathway can regulate wound healing processes mediated by fibroblast contraction.

  17. Conservation laws and constitutive equations for an electro-active polymer

    OpenAIRE

    Tixier, Mireille; Pouget, Joël

    2017-01-01

    Ionic electro-active polymer (Nafion for example) can be used as sensor or actuator. To this end, a thin film of the water-saturated material is sandwiched between two electrodes. Water saturation causes a quasi-complete dissociation of the polymer and the release of small cations. The application of an electric field across the thickness results in the bending of the strip. Conversely, a voltage can be detected between the two electrodes when the strip is bent. This phenomenon involves multi...

  18. Micromechanical analysis of constitutive properties of active piezoelectric structural fiber (PSF) composites

    Science.gov (United States)

    Ng, Kenny; Dai, Qingli

    2011-04-01

    Recent studies showed that the active piezoelectric structural fiber (PSF) composites may achieve significant and simultaneous improvements in sensing/actuating, stiffness, fracture toughness and vibration damping. These characteristics can be very important in the application of civil, mechanical and aerospace structures. The PSF is fabricated by coating the piezoceramic onto the silicon carbide core fiber with electrophoretic deposition (EPD) process to overcome the fragile nature of the monolithic piezoelectric materials. The PSF composite laminates are made of longitudinally poled PSFs that are unidirectionally deployed in the polymer binding matrix. The PSF laminate transducer has electrical inputs/outputs that are delivered through a separate etched interdigital electrode layer. This study analyzed the electromechanical properties with the generalized dilute scheme for active PSF composite laminate by considering multiinclusions. The well-known Mori-Tanaka approach was used to evaluate the concentration tensor in the multi-inclusion micromechanics model. To accurately predict the transverse properties, the extended role of mixtures were applied by considering the inclusions' geometry and shape. The micromechanical finite element modeling was also conducted with representative volume element (RVE) to compare with the micromechanics analysis on the electromechanical properties. The micromechanics analysis and finite element micromechanical modeling were conducted with varied fiber geometry dimensions and volume fractions. These comparison studies indicate the combined micromechanics models with the generalized dilute scheme can effectively predict the electro-elastic properties of multi-inclusion PSF composites.

  19. At High Levels, Constitutively Activated STAT3 Induces Apoptosis of Chronic Lymphocytic Leukemia Cells.

    Science.gov (United States)

    Rozovski, Uri; Harris, David M; Li, Ping; Liu, Zhiming; Wu, Ji Yuan; Grgurevic, Srdana; Faderl, Stefan; Ferrajoli, Alessandra; Wierda, William G; Martinez, Matthew; Verstovsek, Srdan; Keating, Michael J; Estrov, Zeev

    2016-05-15

    In chronic lymphocytic leukemia (CLL), the increment in PBLs is slower than the expected increment calculated from the cells' proliferation rate, suggesting that cellular proliferation and apoptosis are concurrent. Exploring this phenomenon, we found overexpression of caspase-3, higher cleaved poly (ADP-ribose) polymerase levels (p < 0.007), and a higher apoptosis rate in cells from patients with high counts compared with cells from patients with low counts. Although we previously found that STAT3 protects CLL cells from apoptosis, STAT3 levels were significantly higher in cells from patients with high counts than in cells from patients with low counts. Furthermore, overexpression of STAT3 did not protect the cells. Rather, it upregulated caspase-3 and induced apoptosis. Remarkably, putative STAT3 binding sites were identified in the caspase-3 promoter, and a luciferase assay, chromatin immunoprecipitation, and an EMSA revealed that STAT3 activated caspase-3 However, caspase-3 levels increased only when STAT3 levels were sufficiently high. Using chromatin immunoprecipitation and EMSA, we found that STAT3 binds with low affinity to the caspase-3 promoter, suggesting that at high levels, STAT3 activates proapoptotic mechanisms and induces apoptosis in CLL cells. Copyright © 2016 by The American Association of Immunologists, Inc.

  20. Livers with constitutive mTORC1 activity resist steatosis independent of feedback suppression of Akt.

    Directory of Open Access Journals (Sweden)

    Heidi L Kenerson

    Full Text Available Insulin resistance is an important contributing factor in non-alcoholic fatty liver disease. AKT and mTORC1 are key components of the insulin pathway, and play a role in promoting de novo lipogenesis. However, mTORC1 hyperactivity per se does not induce steatosis in mouse livers, but instead, protects against high-fat diet induced steatosis. Here, we investigate the in vivo mechanism of steatosis-resistance secondary to mTORC1 activation, with emphasis on the role of S6K1-mediated feedback inhibition of AKT. Mice with single or double deletion of Tsc1 and/or S6k1 in a liver-specific or whole-body manner were generated to study glucose and hepatic lipid metabolism between the ages of 6-14 weeks. Following 8 weeks of high-fat diet, the Tsc1-/-;S6k1-/- mice had lower body weights but higher liver TG levels compared to that of the Tsc1-/- mice. However, the loss of S6k1 did not relieve feedback inhibition of Akt activity in the Tsc1-/- livers. To overcome Akt suppression, Pten was deleted in Tsc1-/- livers, and the resultant mice showed improved glucose tolerance compared with the Tsc1-/- mice. However, liver TG levels were significantly reduced in the Tsc1-/-;Pten-/- mice compared to the Pten-/- mice, which was restored with rapamycin. We found no correlation between liver TG and serum NEFA levels. Expression of lipogenic genes (Srebp1c, Fasn were elevated in the Tsc1-/-;Pten-/- livers, but this was counter-balanced by an up-regulation of Cpt1a involved in fatty acid oxidation and the anti-oxidant protein, Nrf2. In summary, our in vivo models showed that mTORC1-induced resistance to steatosis was dependent on S6K1 activity, but not secondary to AKT suppression. These findings confirm that AKT and mTORC1 have opposing effects on hepatic lipid metabolism in vivo.

  1. Triclocarban mediates induction of xenobiotic metabolism through activation of the constitutive androstane receptor and the estrogen receptor alpha.

    Directory of Open Access Journals (Sweden)

    Mei-Fei Yueh

    Full Text Available Triclocarban (3,4,4'-trichlorocarbanilide, TCC is used as a broad-based antimicrobial agent that is commonly added to personal hygiene products. Because of its extensive use in the health care industry and resistance to degradation in sewage treatment processes, TCC has become a significant waste product that is found in numerous environmental compartments where humans and wildlife can be exposed. While TCC has been linked to a range of health and environmental effects, few studies have been conducted linking exposure to TCC and induction of xenobiotic metabolism through regulation by environmental sensors such as the nuclear xenobiotic receptors (XenoRs. To identify the ability of TCC to activate xenobiotic sensors, we monitored XenoR activities in response to TCC treatment using luciferase-based reporter assays. Among the XenoRs in the reporter screening assay, TCC promotes both constitutive androstane receptor (CAR and estrogen receptor alpha (ERα activities. TCC treatment to hUGT1 mice resulted in induction of the UGT1A genes in liver. This induction was dependent upon the constitutive active/androstane receptor (CAR because no induction occurred in hUGT1Car(-/- mice. Induction of the UGT1A genes by TCC corresponded with induction of Cyp2b10, another CAR target gene. TCC was demonstrated to be a phenobarbital-like activator of CAR in receptor-based assays. While it has been suggested that TCC be classified as an endocrine disruptor, it activates ERα leading to induction of Cyp1b1 in female ovaries as well as in promoter activity. Activation of ERα by TCC in receptor-based assays also promotes induction of human CYP2B6. These observations demonstrate that TCC activates nuclear xenobiotic receptors CAR and ERα both in vivo and in vitro and might have the potential to alter normal physiological homeostasis. Activation of these xenobiotic-sensing receptors amplifies gene expression profiles that might represent a mechanistic base for

  2. Triclocarban Mediates Induction of Xenobiotic Metabolism through Activation of the Constitutive Androstane Receptor and the Estrogen Receptor Alpha

    Science.gov (United States)

    Yueh, Mei-Fei; Li, Tao; Evans, Ronald M.; Hammock, Bruce; Tukey, Robert H.

    2012-01-01

    Triclocarban (3,4,4′-trichlorocarbanilide, TCC) is used as a broad-based antimicrobial agent that is commonly added to personal hygiene products. Because of its extensive use in the health care industry and resistance to degradation in sewage treatment processes, TCC has become a significant waste product that is found in numerous environmental compartments where humans and wildlife can be exposed. While TCC has been linked to a range of health and environmental effects, few studies have been conducted linking exposure to TCC and induction of xenobiotic metabolism through regulation by environmental sensors such as the nuclear xenobiotic receptors (XenoRs). To identify the ability of TCC to activate xenobiotic sensors, we monitored XenoR activities in response to TCC treatment using luciferase-based reporter assays. Among the XenoRs in the reporter screening assay, TCC promotes both constitutive androstane receptor (CAR) and estrogen receptor alpha (ERα) activities. TCC treatment to hUGT1 mice resulted in induction of the UGT1A genes in liver. This induction was dependent upon the constitutive active/androstane receptor (CAR) because no induction occurred in hUGT1Car−/− mice. Induction of the UGT1A genes by TCC corresponded with induction of Cyp2b10, another CAR target gene. TCC was demonstrated to be a phenobarbital-like activator of CAR in receptor-based assays. While it has been suggested that TCC be classified as an endocrine disruptor, it activates ERα leading to induction of Cyp1b1 in female ovaries as well as in promoter activity. Activation of ERα by TCC in receptor-based assays also promotes induction of human CYP2B6. These observations demonstrate that TCC activates nuclear xenobiotic receptors CAR and ERα both in vivo and in vitro and might have the potential to alter normal physiological homeostasis. Activation of these xenobiotic-sensing receptors amplifies gene expression profiles that might represent a mechanistic base for potential human

  3. Constitutive spectral EEG peaks in the gamma range: suppressed by sleep, reduced by mental activity and resistant to sensory stimulation

    Directory of Open Access Journals (Sweden)

    Tyler Samuel Grummett

    2014-11-01

    Full Text Available Objective: In a systematic study of gamma activity in neuro-psychiatric disease, we unexpectedly observed distinctive, apparently persistent, electroencephalogram (EEG spectral peaks in the gamma range (25-100 Hz. Our objective, therefore, was to examine the incidence, distribution and some of the characteristics of these peaks.Methods: High sample-rate, 128-channel, EEG was recorded in 603 volunteers (510 with neuropsychiatric disorders, 93 controls, whilst performing cognitive tasks, and converted to power spectra. Peaks of spectral power, including in the gamma range, were determined algorithmically for all electrodes. To determine if peaks were stable, 24-hour ambulatory recordings were obtained from 16 subjects with peaks. In 10 subjects, steady-state responses to stimuli at peak frequency were compared with off-peak-frequency stimulation to determine if peaks were a feature of underlying network resonances and peaks were evaluated with easy and hard versions of oddball tasks to determine if peaks might be influenced by mental effort.Results: 57 % of subjects exhibited peaks > 2 dB above trough power at or above 25 Hz. Larger peaks (> 5 dB were present in 13 % of subjects. Peaks were distributed widely over the scalp, more frequent centrally. Peaks were present through the day and were suppressed by slow-wave-sleep. Steady-state responses were the same with on- or off-peak sensory stimulation. In contrast, mental effort resulted in reductions in power and frequency of gamma peaks, although the suppression did not correlate with level of effort.Conclusions: Gamma EEG can be expressed constitutively as concentrations of power in narrow or wide frequency bands that play an, as yet, unknown role in cognitive activity.Significance: These findings expand the described range of rhythmic EEG phenomena. In particular, in addition to evoked, induced and sustained gamma band activity, gamma activity can be present constitutively in spectral peaks.

  4. Constitutively activated NLRP3 inflammasome causes inflammation and abnormal skeletal development in mice.

    Directory of Open Access Journals (Sweden)

    Sheri L Bonar

    Full Text Available The NLRP3 inflammasome complex is responsible for maturation of the pro-inflammatory cytokine, IL-1β. Mutations in NLRP3 are responsible for the cryopyrinopathies, a spectrum of conditions including neonatal-onset multisystem inflammatory disease (NOMID. While excessive production of IL-1β and systemic inflammation are common to all cryopyrinopathy disorders, skeletal abnormalities, prominently in the knees, and low bone mass are unique features of patients with NOMID. To gain insights into the mechanisms underlying skeletal abnormalities in NOMID, we generated knock-in mice globally expressing the D301N NLRP3 mutation (ortholog of D303N in human NLRP3. NOMID mice exhibit neutrophilia in blood and many tissues, including knee joints, and high levels of serum inflammatory mediators. They also exhibit growth retardation and severe postnatal osteopenia stemming at least in part from abnormally accelerated bone resorption, attended by increased osteoclastogenesis. Histologic analysis of knee joints revealed abnormal growth plates, with loss of chondrocytes and growth arrest in the central region of the epiphyses. Most strikingly, a tissue "spike" was observed in the mid-region of the growth plate in the long bones of all NOMID mice that may be the precursor to more severe deformations analogous to those observed in NOMID patients. These findings provide direct evidence linking a NOMID-associated NLRP3-activating mutation to abnormalities of postnatal skeletal growth and bone remodeling.

  5. CsTFL1, a constitutive local repressor of flowering, modulates floral initiation by antagonising florigen complex activity in chrysanthemum.

    Science.gov (United States)

    Higuchi, Yohei; Hisamatsu, Tamotsu

    2015-08-01

    Chrysanthemums require repeated cycles of short-day (SD) photoperiod for successful anthesis, but their vegetative state is strictly maintained under long-day (LD) or night-break (NB) conditions. We have previously demonstrated that photoperiodic flowering of a wild diploid chrysanthemum (Chrysanthemum seticuspe f. boreale) is controlled by a pair of systemic floral regulators, florigen (CsFTL3) and anti-florigen (CsAFT), produced in the leaves. Here, we report the functional characterisation of a local floral regulator, CsTFL1, a chrysanthemum orthologue of TERMINAL FLOWER 1 gene in Arabidopsis. Constitutive expression of CsTFL1 in C. seticuspe (CsTFL1-ox) resulted in extremely late flowering under SD and prevented up-regulation of floral meristem identity genes in shoot tips and leaves. Bimolecular fluorescence complementation assay showed that both CsTFL1 and CsFTL3 interacted with CsFDL1, a bZIP transcription factor FD homologue, in the nucleus. The transient gene expression assay indicated that CsTFL1 suppresses flowering by directly antagonising the flower inductive activity of the CsFTL3-CsFDL1 complex. Our results suggest that strict maintenance of vegetative state under non-inductive photoperiod is achieved by the coordinated action of both the systemic floral inhibitor and local floral inhibitor CsTFL1, which is constitutively expressed in shoot tips. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  6. The E92K Melanocortin 1 Receptor Mutant Induces cAMP Production and Arrestin Recruitment but Not ERK Activity Indicating Biased Constitutive Signaling

    Science.gov (United States)

    Benned-Jensen, Tau; Mokrosinski, Jacek; Rosenkilde, Mette M.

    2011-01-01

    Background The melanocortin 1 receptor (MC1R) constitutes a key regulator of melanism. Consequently, many naturally-occurring MC1R mutations are associated with a change in color. An example is the Glu-to-Lys substitution found at position II:20/2.60 in the top of transmembrane helix II which has been identified in melanic mice and several other species. This mutation induces a pronounced increase in MC1R constitutive activity suggesting a link between constitutive activity and melanism which is corroborated by the attenuation of α-melanocyte stimulating hormone (αMSH) induced activation. However, the mechanism by which the mutation induces constitutive activity is currently not known. Methodology/Principal Findings Here we characterize the constitutive activity, cell surface expression and internalization of the mouse mutant, Mc1r E92K. As previously reported, only positively charged residues at position II:20/2.60 induced an increase in constitutive activity as measured by cAMP accumulation and CREB activation. Furthermore, the mutation induced a constitutive recruitment of β-arrestin. This phenomenon is only observed in MC1R, however, as the equivalent mutations in MC2-5R had no effect on receptor signaling. Interestingly, the mutation did not induce constitutive ERK1/2 phosphorylation or increase the internalization rate indicating the constitutive activity to be biased. Finally, to identify regions of importance for the increased constitutive activity of Mc1r E92K, we employed a chimeric approach and identified G102 and L110 in the extracellular loop 1 to be selectively important for the constitutive activity as this, but not αMSH-mediated activation, was abolished upon Ala substitution. Conclusions/Significance It is concluded that the E92K mutation induces an active conformation distinct from that induced by αMSH and that the extracellular loop 1 is involved in maintaining this conformational state. In turn, the results suggest that in MC1R, which lacks

  7. Constitutive arginine-dependent nitric oxide synthase activity in different organs of pea seedlings during plant development.

    Science.gov (United States)

    Corpas, Francisco J; Barroso, Juan B; Carreras, Alfonso; Valderrama, Raquel; Palma, José M; León, Ana M; Sandalio, Luisa M; del Río, Luis A

    2006-07-01

    Nitric oxide (NO) is an important signalling molecule in different animal and plant physiological processes. Little is known about its biological function in plants and on the enzymatic source or site of NO production during plant development. The endogenous NO production from L-arginine (NO synthase activity) was analyzed in leaves, stems and roots during plant development, using pea seedlings as a model. NOS activity was analyzed using a novel chemiluminescence-based assay which is more sensitive and specific than previous methods used in plant tissues. In parallel, NO accumulation was analyzed by confocal laser scanning microscopy using as fluorescent probes either DAF-2 DA or DAF-FM DA. A strong increase in NOS activity was detected in stems after 11 days growth, coinciding with the maximum stem elongation. The arginine-dependent NOS activity was constitutive and sensitive to aminoguanidine, a well-known irreversible inhibitor of animal NOS, and this NOS activity was differentially modulated depending on the plant organ and seedling developmental stage. In all tissues studied, NO was localized mainly in the vascular tissue (xylem) and epidermal cells and in root hairs. These loci of NO generation and accumulation suggest novel functions for NO in these cell types.

  8. Functional characterization of human RSK4, a new 90-kDa ribosomal S6 kinase, reveals constitutive activation in most cell types

    DEFF Research Database (Denmark)

    Dümmler, Bettina A; Hauge, Camilla; Silber, Joachim

    2005-01-01

    characterization of a predicted new human RSK homologue, RSK4. We showed that RSK4 is a predominantly cytosolic protein with very low expression and several characteristics of the RSK family kinases, including the presence of two functional kinase domains and a C-terminal docking site for ERK. Surprisingly......, however, in all cell types analyzed, endogenous RSK4 was maximally (constitutively) activated under serum-starved conditions where other RSKs are inactive due to their requirement for growth factor stimulation. Constitutive activation appeared to result from constitutive phosphorylation of Ser232, Ser372...

  9. MicroRNA-122 down-regulation is involved in phenobarbital-mediated activation of the constitutive androstane receptor.

    Directory of Open Access Journals (Sweden)

    Ryota Shizu

    Full Text Available Constitutive androstane receptor (CAR is a nuclear receptor that regulates the transcription of target genes, including CYP2B and 3A. Phenobarbital activates CAR, at least in part, in an AMP-activated protein kinase (AMPK-dependent manner. However, the precise mechanisms underlying phenobarbital activation of AMPK are still unclear. In the present study, it was demonstrated that phenobarbital administration to mice decreases hepatic miR-122, a liver-enriched microRNA involved in both hepatic differentiation and function. The time-course change in the phenobarbital-mediated down-regulation of miR-122 was inversely correlated with AMPK activation. Phenobarbital decreased primary miR-122 to approximately 25% of the basal level as early as 1 h and suppressed transactivity of mir-122 promoter in HuH-7 cells, suggesting that the down-regulation occurred at the transcriptional level. AMPK activation by metformin or 5-aminoimidazole-4-carboxamide 1-β-D-ribonucleoside had no evident effect on miR-122 levels. An inhibitory RNA specific for miR-122 increased activated AMPK and CAR-mediated trancactivation of the phenobarbital-responsive enhancer module in HepG2 cells. Conversely, the reporter activity induced by the ectopic CAR was almost completely suppressed by co-transfection with the miR-122 mimic RNA. GFP-tagged CAR was expressed in the cytoplasm in addition to the nucleus in the majority of HuH-7 cells in which miR-122 was highly expressed. Co-transfection of the mimic or the inhibitor RNA for miR-122 further increased or decreased, respectively, the number of cells that expressed GFP-CAR in the cytoplasm. Taken together, these results suggest that phenobarbital-mediated down-regulation of miR-122 is an early and important event in the AMPK-dependent CAR activation and transactivation of its target genes.

  10. MicroRNA-122 down-regulation is involved in phenobarbital-mediated activation of the constitutive androstane receptor.

    Science.gov (United States)

    Shizu, Ryota; Shindo, Sawako; Yoshida, Takemi; Numazawa, Satoshi

    2012-01-01

    Constitutive androstane receptor (CAR) is a nuclear receptor that regulates the transcription of target genes, including CYP2B and 3A. Phenobarbital activates CAR, at least in part, in an AMP-activated protein kinase (AMPK)-dependent manner. However, the precise mechanisms underlying phenobarbital activation of AMPK are still unclear. In the present study, it was demonstrated that phenobarbital administration to mice decreases hepatic miR-122, a liver-enriched microRNA involved in both hepatic differentiation and function. The time-course change in the phenobarbital-mediated down-regulation of miR-122 was inversely correlated with AMPK activation. Phenobarbital decreased primary miR-122 to approximately 25% of the basal level as early as 1 h and suppressed transactivity of mir-122 promoter in HuH-7 cells, suggesting that the down-regulation occurred at the transcriptional level. AMPK activation by metformin or 5-aminoimidazole-4-carboxamide 1-β-D-ribonucleoside had no evident effect on miR-122 levels. An inhibitory RNA specific for miR-122 increased activated AMPK and CAR-mediated trancactivation of the phenobarbital-responsive enhancer module in HepG2 cells. Conversely, the reporter activity induced by the ectopic CAR was almost completely suppressed by co-transfection with the miR-122 mimic RNA. GFP-tagged CAR was expressed in the cytoplasm in addition to the nucleus in the majority of HuH-7 cells in which miR-122 was highly expressed. Co-transfection of the mimic or the inhibitor RNA for miR-122 further increased or decreased, respectively, the number of cells that expressed GFP-CAR in the cytoplasm. Taken together, these results suggest that phenobarbital-mediated down-regulation of miR-122 is an early and important event in the AMPK-dependent CAR activation and transactivation of its target genes.

  11. G-protein coupled receptor 83 (GPR83 signaling determined by constitutive and zinc(II-induced activity.

    Directory of Open Access Journals (Sweden)

    Anne Müller

    Full Text Available The G-protein coupled receptor 83 (GPR83 is an orphan G-protein coupled receptor for which the natural ligand(s and signaling pathway(s remain to be identified. Previous studies suggest a role of GPR83 in the regulation of thermogenesis and the control of circulating adiponectin. The aim of this study was to gain insights into the molecular underpinnings underlying GPR83 signaling. In particular, we aimed to assess the underlying G-protein activated signaling pathway of GPR83 and how this pathway is affected by mutational activation and zinc(II challenge. Finally, we assessed the capacity of GPR83 for homodimerization. Our results show for the first time that mouse (m GPR83 has high basal Gq/11 activity without affecting Gi or Gs signaling. Furthermore, we found that, under physiological conditions, zinc(II (but not calcium(II and magnesium(II potently activates mGPR83, thus identifying zinc(II as an endogenous molecule with agonistic capability to activate mGPR83. In line with the observation that zinc(II-ions activate mGPR83, we identified a cluster of ion-binding sensitive amino acids (e.g. His145, His204, Cys207, Glu217 in an activation sensitive receptor region of mGPR83. The occurrence of a constitutive activating mutant and a zinc(II-binding residue at the N-terminal part corroborate the importance of this region in mGPR83 signal regulation. Finally, our results indicate that mGPR83 forms homodimers, which extend the current knowledge and molecular facets of GPR83 signaling.

  12. Constitutive Activation of the Fission Yeast Pheromone-Responsive Pathway Induces Ectopic Meiosis and Reveals Ste11 as a Mitogen-Activated Protein Kinase Target

    DEFF Research Database (Denmark)

    Kjærulff, Søren; Lautrup-Larsen, I.; Truelsen, S.

    2005-01-01

    In the fission yeast Schizosaccharomyces pombe, meiosis normally takes place in diploid zygotes resulting from conjugation of haploid cells. In the present study, we report that the expression of a constitutively activated version of the pheromone-responsive mitogen-activated protein kinase kinase...... kinase (MAP3K) Byr2 can induce ectopic meiosis directly in haploid cells. We find that the Ste11 transcription factor becomes constitutively expressed in these cells and that the expression of pheromone-responsive genes no longer depends on nitrogen starvation. Epistasis analysis revealed...... found that haploid meiosis was dramatically reduced when Ste11 was mutated to mimic phosphorylation by Pat1. The mutation of two putative MAPK sites in Ste11 also dramatically reduced the level of haploid meiosis, suggesting that Ste11 is a direct target of Spk1. Supporting this, we show that Spk1 can...

  13. Identification and Characterization of CINPA1 Metabolites Facilitates Structure-Activity Studies of the Constitutive Androstane Receptor

    Science.gov (United States)

    Cherian, Milu T.; Yang, Lei; Chai, Sergio C.; Lin, Wenwei

    2016-01-01

    The constitutive androstane receptor (CAR) regulates the expression of genes involved in drug metabolism and other processes. A specific inhibitor of CAR is critical for modulating constitutive CAR activity. We recently described a specific small-molecule inhibitor of CAR, CINPA1 (ethyl (5-(diethylglycyl)-10,11-dihydro-5H-dibenzo[b,f]azepin-3-yl)carbamate), which is capable of reducing CAR-mediated transcription by changing the coregulator recruitment pattern and reducing CAR occupancy at the promoter regions of its target genes. In this study, we showed that CINPA1 is converted to two main metabolites in human liver microsomes. By using cell-based reporter gene and biochemical coregulator recruitment assays, we showed that although metabolite 1 was very weak in inhibiting CAR function and disrupting CAR-coactivator interaction, metabolite 2 was inactive in this regard. Docking studies using the CAR ligand-binding domain structure showed that although CINPA1 and metabolite 1 can bind in the CAR ligand-binding pocket, metabolite 2 may be incapable of the molecular interactions required for binding. These results indicate that the metabolites of CINPA1 may not interfere with the action of CINPA1. We also used in vitro enzyme assays to identify the cytochrome P450 enzymes responsible for metabolizing CINPA1 in human liver microsomes and showed that CINPA1 was first converted to metabolite 1 by CYP3A4 and then further metabolized by CYP2D6 to metabolite 2. Identification and characterization of the metabolites of CINPA1 enabled structure-activity relationship studies of this family of small molecules and provided information to guide in vivo pharmacological studies. PMID:27519550

  14. A physiological role of AMP-activated protein kinase in phenobarbital-mediated constitutive androstane receptor activation and CYP2B induction

    OpenAIRE

    Shindo, Sawako; NUMAZAWA Satoshi; Yoshida, Takemi

    2007-01-01

    CAR (constitutive androstane receptor) is a nuclear receptor that regulates the transcription of target genes, including CYP (cytochrome P450) 2B and 3A. The transactivation by CAR is regulated by its subcellular localization; however, the mechanism that governs nuclear translocation has yet to be clarified. It has been reported recently that AMPK (AMP-activated protein kinase) is involved in phenobarbital-mediated CYP2B induction in a particular culture system. We therefore investigated in v...

  15. Vestigialization of an allosteric switch: genetic and structural mechanisms for the evolution of constitutive activity in a steroid hormone receptor.

    Directory of Open Access Journals (Sweden)

    Jamie T Bridgham

    2014-01-01

    Full Text Available An important goal in molecular evolution is to understand the genetic and physical mechanisms by which protein functions evolve and, in turn, to characterize how a protein's physical architecture influences its evolution. Here we dissect the mechanisms for an evolutionary shift in function in the mollusk ortholog of the steroid hormone receptors (SRs, a family of biologically essential transcription factors. In vertebrates, the activity of SRs allosterically depends on binding a hormonal ligand; in mollusks, however, the SR ortholog (called ER, because of high sequence similarity to vertebrate estrogen receptors activates transcription in the absence of ligand and does not respond to steroid hormones. To understand how this shift in regulation evolved, we combined evolutionary, structural, and functional analyses. We first determined the X-ray crystal structure of the ER of the Pacific oyster Crassostrea gigas (CgER, and found that its ligand pocket is filled with bulky residues that prevent ligand occupancy. To understand the genetic basis for the evolution of mollusk ERs' unique functions, we resurrected an ancient SR progenitor and characterized the effect of historical amino acid replacements on its functions. We found that reintroducing just two ancient replacements from the lineage leading to mollusk ERs recapitulates the evolution of full constitutive activity and the loss of ligand activation. These substitutions stabilize interactions among key helices, causing the allosteric switch to become "stuck" in the active conformation and making activation independent of ligand binding. Subsequent changes filled the ligand pocket without further affecting activity; by degrading the allosteric switch, these substitutions vestigialized elements of the protein's architecture required for ligand regulation and made reversal to the ancestral function more complex. These findings show how the physical architecture of allostery enabled a few large

  16. Overexpression and Constitutive Activation of FLT3 Induces STAT5 Activation in Primary Acute Myeloid Leukemia Blast Cells

    National Research Council Canada - National Science Library

    Karsten Spiekermann; Ksenia Bagrintseva; Ruth Schwab; Karin Schmieja; Wolfgang Hiddemann

    2003-01-01

    ...) of FLT3 represent the most frequent genetic alterations in acute myeloid leukemia (AML). However, the functional role of active FLT3 mutants in primary AML blast cells is not well characterized...

  17. Inhibition of constitutively activated Stat3 correlates with altered Bcl-2/Bax expression and induction of apoptosis in mycosis fungoides tumor cells

    DEFF Research Database (Denmark)

    Nielsen, M; Kaestel, C G; Eriksen, K W

    1999-01-01

    in malignant transformation. In a previous study, we found constitutively tyrosine phosphorylated Stat3 in mycosis fungoides tumor cells. Here, we show that the Jak kinase inhibitor, Ag490, inhibits the constitutive binding of Stat3 to an oligonucleotide representing the Stat-binding sequence from the ICAM......The Jak/Stat signaling pathway transmits signals from many cytokine and growth factor receptors to target genes in the nucleus. Constitutive activation of Stat3 has recently been observed in many tumor cells and dysregulation of the Stat signaling pathway has been proposed to be implicated...

  18. Activation of the constitutive androstane receptor inhibits gluconeogenesis without affecting lipogenesis or fatty acid synthesis in human hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Lynch, Caitlin; Pan, Yongmei; Li, Linhao [Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201 (United States); Heyward, Scott; Moeller, Timothy [Bioreclamation In Vitro Technologies, Baltimore, MD 21227 (United States); Swaan, Peter W. [Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201 (United States); Wang, Hongbing, E-mail: hwang@rx.umaryland.edu [Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201 (United States)

    2014-08-15

    Objective: Accumulating evidence suggests that activation of mouse constitutive androstane receptor (mCAR) alleviates type 2 diabetes and obesity by inhibiting hepatic gluconeogenesis, lipogenesis, and fatty acid synthesis. However, the role of human (h) CAR in energy metabolism is largely unknown. The present study aims to investigate the effects of selective hCAR activators on hepatic energy metabolism in human primary hepatocytes (HPH). Methods: Ligand-based structure–activity models were used for virtual screening of the Specs database ( (www.specs.net)) followed by biological validation in cell-based luciferase assays. The effects of two novel hCAR activators (UM104 and UM145) on hepatic energy metabolism were evaluated in HPH. Results: Real-time PCR and Western blotting analyses reveal that activation of hCAR by UM104 and UM145 significantly repressed the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, two pivotal gluconeogenic enzymes, while exerting negligible effects on the expression of genes associated with lipogenesis and fatty acid synthesis. Functional experiments show that UM104 and UM145 markedly inhibit hepatic synthesis of glucose but not triglycerides in HPH. In contrast, activation of mCAR by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, a selective mCAR activator, repressed the expression of genes associated with gluconeogenesis, lipogenesis, and fatty acid synthesis in mouse primary hepatocytes, which were consistent with previous observations in mouse model in vivo. Conclusion: Our findings uncover an important species difference between hCAR and mCAR in hepatic energy metabolism, where hCAR selectively inhibits gluconeogenesis without suppressing fatty acid synthesis. Implications: Such species selectivity should be considered when exploring CAR as a potential therapeutic target for metabolic disorders. - Highlights: • Novel hCAR activators were identified by computational and biological approaches. • The role

  19. Desensitization of menthol-activated cold receptors in lower extremities during local cooling in young women with a cold constitution.

    Science.gov (United States)

    Yamazaki, Fumio; Sone, Ryoko

    2017-03-01

    To test the hypothesis that topical menthol-induced reactivity of cold sensation and cutaneous vasoconstriction to local cooling is augmented in individuals with a cold constitution, we examined thermal sensation and cutaneous vasoconstrictor responses at menthol-treated and untreated sites in the legs during local skin cooling in young women complaining of chilliness (C group) and young women with no complaint as a normal control group (N group). During local skin cooling, the sensitivity to cold sensation was greater in the C group than in the N group. The application of menthol enhanced the cold sensation at a low temperature in the N group, but not in the C group. Cutaneous vasoconstrictor responses to local skin cooling were not altered by menthol treatment in either of the two groups. These findings suggest the desensitization of menthol-activated cold receptors in the legs of C group subjects, and a minor role of cold receptor activity in cutaneous vasoconstrictor response to local cooling.

  20. Chronic lung injury by constitutive expression of activation-induced cytidine deaminase leads to focal mucous cell metaplasia and cancer.

    Science.gov (United States)

    Kitamura, Jiro; Uemura, Munehiro; Kurozumi, Mafumi; Sonobe, Makoto; Manabe, Toshiaki; Hiai, Hiroshi; Date, Hiroshi; Kinoshita, Kazuo

    2015-01-01

    Activation-induced cytidine deaminase (AID) is an enzyme required for antibody diversification, and it causes DNA mutations and strand breaks. Constitutive AID expression in mice invariably caused lung lesions morphologically similar to human atypical adenomatous hyperplasia (AAH), which can be a precursor of bronchioloalveolar carcinoma. Similar to AAH, mouse AAH-like lesion (MALL) exhibited signs of alveolar differentiation, judging from the expression of alveolar type II (AT2) cell marker surfactant protein C (SP-C). However, electron microscopy indicated that MALL, which possessed certain features of a mucous cell, is distinct from an AAH or AT2 cell. Although MALL developed in all individuals within 30 weeks after birth, lung tumors occurred in only 10%; this suggests that the vast majority of MALLs fail to grow into visible tumors. MALL expressed several recently described markers of lung alveolar regeneration such as p63, keratin 5, keratin 14, leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5), and Lgr6. Increased cell death was observed in the lungs of AID transgenic mice compared with wild-type mice. Based on these observations, we speculate that MALL is a regenerating tissue compensating for cellular loss caused by AID cytotoxicity. AID expression in such regenerating tissue should predispose cells to malignant transformation via its mutagenic activity.

  1. The nuclear immune receptor RPS4 is required for RRS1SLH1-dependent constitutive defense activation in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Kee Hoon Sohn

    2014-10-01

    Full Text Available Plant nucleotide-binding leucine-rich repeat (NB-LRR disease resistance (R proteins recognize specific "avirulent" pathogen effectors and activate immune responses. NB-LRR proteins structurally and functionally resemble mammalian Nod-like receptors (NLRs. How NB-LRR and NLR proteins activate defense is poorly understood. The divergently transcribed Arabidopsis R genes, RPS4 (resistance to Pseudomonas syringae 4 and RRS1 (resistance to Ralstonia solanacearum 1, function together to confer recognition of Pseudomonas AvrRps4 and Ralstonia PopP2. RRS1 is the only known recessive NB-LRR R gene and encodes a WRKY DNA binding domain, prompting suggestions that it acts downstream of RPS4 for transcriptional activation of defense genes. We define here the early RRS1-dependent transcriptional changes upon delivery of PopP2 via Pseudomonas type III secretion. The Arabidopsis slh1 (sensitive to low humidity 1 mutant encodes an RRS1 allele (RRS1SLH1 with a single amino acid (leucine insertion in the WRKY DNA-binding domain. Its poor growth due to constitutive defense activation is rescued at higher temperature. Transcription profiling data indicate that RRS1SLH1-mediated defense activation overlaps substantially with AvrRps4- and PopP2-regulated responses. To better understand the genetic basis of RPS4/RRS1-dependent immunity, we performed a genetic screen to identify suppressor of slh1 immunity (sushi mutants. We show that many sushi mutants carry mutations in RPS4, suggesting that RPS4 acts downstream or in a complex with RRS1. Interestingly, several mutations were identified in a domain C-terminal to the RPS4 LRR domain. Using an Agrobacterium-mediated transient assay system, we demonstrate that the P-loop motif of RPS4 but not of RRS1SLH1 is required for RRS1SLH1 function. We also recapitulate the dominant suppression of RRS1SLH1 defense activation by wild type RRS1 and show this suppression requires an intact RRS1 P-loop. These analyses of RRS1SLH1 shed

  2. Structural basis for constitutive activity and agonist-induced activation of the enteroendocrine fat sensor GPR119

    DEFF Research Database (Denmark)

    Engelstoft, Maja Storm; Norn, C; Pedersen, Maria Hauge

    2014-01-01

    BACKGROUND AND PURPOSE: GPR119 is a Gαs-coupled 7TM receptor activated by endogenous lipids such as oleoylethanolamide (OEA) and by the dietary triglyceride metabolite 2-monoacylglycerol. GPR119 stimulates enteroendocrine hormone and insulin secretion. But despite massive drug discovery efforts...... in the field, very little is known about the basic molecular pharmacology of GPR119. EXPERIMENTAL APPROACH: GPR119 receptor signalling was studied in transfected cells. Mutational mapping (30 mutations in 23 positions) was performed on residues required for ligand-independent and agonist-induced GPR119...... activation (AR231453 and OEA). Novel Rosetta-based receptor modelling was applied, using a composite template approach with segments from different X-ray structures and fully flexible ligand docking. KEY RESULTS: The increased signalling induced by increasing the cell surface expression of GPR119...

  3. Characterization of two constitutively active prolactin receptor variants in a cohort of 95 women with multiple breast fibroadenomas.

    Science.gov (United States)

    Courtillot, Carine; Chakhtoura, Zeina; Bogorad, Roman; Genestie, Catherine; Bernichtein, Sophie; Badachi, Yasmina; Janaud, Gilbert; Akakpo, Jean-Pierre; Bachelot, Anne; Kuttenn, Frédérique; Goffin, Vincent; Touraine, Philippe

    2010-01-01

    The role of prolactin (PRL) and its receptor (hPRLR) in promoting breast tumors is debated. We recently identified a gain-of-function hPRLR variant (I146L) in four women with multiple breast fibroadenomas (MFA) and no control subject. The specific aims were to describe this cohort of women presenting with MFA to identify and functionally characterize germline variants of hPRL/hPRLR genes and compare phenotypes of all patients. Ninety-five patients prospectively underwent clinical examination, breast ultrasonography, magnetic resonance imaging, and hormonal evaluation of gonadal and lactotrope functions. We analyzed hPRL/hPRLR coding sequences and made comparisons with a control population of 194 women. Functional characterization of hPRLR variants was performed. Pathology and immunochemistry were systematically carried out after surgical removal of tumors. One third of patients had a family history of breast disease. No hormonal imbalance was observed, except 30.7% of explosive stimulated PRL. Prolactin receptor variants were identified in exon 5 (I76V: 10 patients, eight controls) and exon 10 (one patient, no control). Both I146L and I76V variants exhibited constitutive activity. Pathology showed common fibroadenomas and identified six benign phyllodes tumors. Estrogen and progesterone receptors were detected in 85 and 98% of samples, respectively. Ki-67 median staining was less than 5%. No phenotypic difference was observed between carriers and noncarriers of either hPRLR variant. We present the largest population with MFA ever described, 15% of which had a hPRLR exhibiting basal activity in vitro. This questions the involvement of the hPRLR in MFA etiology and the potential relevance of therapeutic inhibition of PRLR signaling in patients.

  4. Constitutive expression of TNF-related activation-induced cytokine (TRANCE/receptor activating NF-κB ligand (RANK-L by rat plasmacytoid dendritic cells.

    Directory of Open Access Journals (Sweden)

    Thomas Anjubault

    Full Text Available Plasmacytoid dendritic cells (pDCs are a subset of DCs whose major function relies on their capacity to produce large amount of type I IFN upon stimulation via TLR 7 and 9. This function is evolutionary conserved and place pDC in critical position in the innate immune response to virus. Here we show that rat pDC constitutively express TNF-related activation-induced cytokine (TRANCE also known as Receptor-activating NF-κB ligand (RANKL. TRANCE/RANKL is a member of the TNF superfamily which plays a central role in osteoclastogenesis through its interaction with its receptor RANK. TRANCE/RANK interaction are also involved in lymphoid organogenesis as well as T cell/DC cross talk. Unlike conventional DC, rat CD4(high pDC were shown to constitutively express TRANCE/RANKL both at the mRNA and the surface protein level. TRANCE/RANKL was also induced on the CD4(low subsets of pDC following activation by CpG. The secreted form of TRANCE/RANKL was also produced by rat pDC. Of note, levels of mRNA, surface and secreted TRANCE/RANKL expression were similar to that observed for activated T cells. TRANCE/RANKL expression was found on pDC in all lymphoid organs as well blood and BM with a maximum expression in mesenteric lymph nodes. Despite this TRANCE/RANKL expression, we were unable to demonstrate in vitro osteoclastogenesis activity for rat pDC. Taken together, these data identifies pDC as novel source of TRANCE/RANKL in the immune system.

  5. Pleiotropic enhancement of bacterial pathogenesis resulting from the constitutive activation of the Listeria monocytogenes regulatory factor PrfA.

    Science.gov (United States)

    Mueller, Kimberly J; Freitag, Nancy E

    2005-04-01

    . These experiments illuminate the diverse facets of L. monocytogenes pathogenesis that are significantly enhanced by the constitutive activation of PrfA via prfA mutations and underscore the critical role of this protein in promoting L. monocytogenes virulence.

  6. Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor positive breast cancer

    Science.gov (United States)

    Meric-Bernstam, Funda; Gonzalez-Angulo, Ana Maria; Ferrer-Lozano, Jaime; Perez-Fidalgo, Jose A.; Cristofanilli, Massimo; Gómez, Henry; Arteaga, Carlos L.; Giltnane, Jennifer; Balko, Justin M.; Cronin, Maureen T; Jarosz, Mirna; Sun, James; Hawryluk, Matthew; Lipson, Doron; Otto, Geoff; Ross, Jeffrey S; Dvir, Addie; Soussan-Gutman, Lior; Wolf, Ido; Rubinek, Tamar; Gilmore, Lauren; Schnitt, Stuart; Come, Steven E.; Pusztai, Lajos; Stephens, Philip; Brown, Myles; Miller, Vincent A.

    2014-01-01

    Purpose We undertook this study to determine the prevalence of estrogen receptor (ER) α (ESR1) mutations throughout the natural history of hormone dependent breast cancer and to delineate the functional roles of the most commonly detected alterations. Experimental Design We studied a total of 249 tumor specimens from 208 patients. The specimens include 134 ER positive (ER+/HER2–) and, as controls, 115 ER negative (ER−) tumors. The ER+ samples consist of 58 primary breast cancers and 76 metastatic samples. All tumors were sequenced to high unique coverage using next generation sequencing targeting the coding sequence of the estrogen receptor and an additional 182 cancer-related genes. Results Recurring somatic mutations in codons 537 and 538 within the ligand-binding domain of ER were detected in ER+ metastatic disease. Overall, the frequency of these mutations was 12% (9/76, 95% CI 6%-21%) in metastatic tumors and in a subgroup of patients who received an average of 7 lines of treatment the frequency was 20% (5/25, 95% CI 7%-41%). These mutations were not detected in primary or treatment naïve ER+ cancer or in any stage of ER− disease. Functional studies in cell line models demonstrate that these mutations render estrogen receptor constitutive activity and confer partial resistance to currently available endocrine treatments. Conclusions In this study we show evidence for the temporal selection of functional ESR1 mutations as potential drivers of endocrine resistance during the progression of ER positive breast cancer. PMID:24398047

  7. Auxin-activated NADH oxidase activity of soybean plasma membranes is distinct from the constitutive plasma membrane NADH oxidase and exhibits prion-like properties

    Science.gov (United States)

    Morre, D. James; Morre, Dorothy M.; Ternes, Philipp

    2003-01-01

    The hormone-stimulated and growth-related cell surface hydroquinone (NADH) oxidase activity of etiolated hypocotyls of soybeans oscillates with a period of about 24 min or 60 times per 24-h day. Plasma membranes of soybean hypocotyls contain two such NADH oxidase activities that have been resolved by purification on concanavalin A columns. One in the apparent molecular weight range of 14-17 kDa is stimulated by the auxin herbicide 2,4-dichlorophenoxyacetic acid (2,4-D). The other is larger and unaffected by 2,4-D. The 2,4-D-stimulated activity absolutely requires 2,4-D for activity and exhibits a period length of about 24 min. Also exhibiting 24-min oscillations is the rate of cell enlargement induced by the addition of 2,4-D or the natural auxin indole-3-acetic acid (IAA). Immediately following 2,4-D or IAA addition, a very complex pattern of oscillations is frequently observed. However, after several hours a dominant 24-min period emerges at the expense of the constitutive activity. A recruitment process analogous to that exhibited by prions is postulated to explain this behavior.

  8. utilizing constitutional values in constitutional comparison

    African Journals Online (AJOL)

    Administrator

    COMPARISON. Francois Venter. 1. Constitutional comparison. We are living in an era in which constitutional law has become a comparative science. This is not true .... inevitably followed by a search for authoritative native interpretation. Such a ..... an approach of "colour-blind" interpretation of the Constitution, allowing for.

  9. A physiological role of AMP-activated protein kinase in phenobarbital-mediated constitutive androstane receptor activation and CYP2B induction.

    Science.gov (United States)

    Shindo, Sawako; Numazawa, Satoshi; Yoshida, Takemi

    2007-02-01

    CAR (constitutive androstane receptor) is a nuclear receptor that regulates the transcription of target genes, including CYP (cytochrome P450) 2B and 3A. The transactivation by CAR is regulated by its subcellular localization; however, the mechanism that governs nuclear translocation has yet to be clarified. It has been reported recently that AMPK (AMP-activated protein kinase) is involved in phenobarbital-mediated CYP2B induction in a particular culture system. We therefore investigated in vivo whether AMPK is involved in the activation of CAR-dependent gene expression. Immunoblot analysis using an antibody which recognizes Thr-172-phosphorylated AMPKalpha1/2 revealed phenobarbital-induced AMPK activation in rat and mouse livers as well. Phenobarbital, however, failed to increase the liver phospho-AMPK level of tumour-bearing rats in which CAR nuclear translocation had been impaired. In in vivo reporter gene assays employing PBREM (phenobarbital-responsive enhancer module) from CYP2B1, an AMPK inhibitor 8-bromo-AMP abolished phenobarbital-induced transactivation. In addition, Cyp2b10 gene expression was attenuated by 8-bromo-AMP. Forced expression of a dominant-negative mutant and the wild-type of AMPKalpha2 in the mouse liver suppressed and further enhanced phenobarbital-induced PBREM-reporter activity respectively. Moreover, the AMPK activator AICAR (5-amino-4-imidazolecarboxamide riboside) induced PBREM transactivation and an accumulation of CAR in the nuclear fraction of the mouse liver. However, AICAR and metformin, another AMPK activator, failed to induce hepatic CYP2B in mice and rats. These observations suggest that AMPK is at least partly involved in phenobarbital-originated signalling, but the kinase activation by itself is not sufficient for CYP2B induction in vivo.

  10. Precise prediction of activators for the human constitutive androstane receptor using structure-based three-dimensional quantitative structure-activity relationship methods.

    Science.gov (United States)

    Kato, Harutoshi; Yamaotsu, Noriyuki; Iwazaki, Norihiko; Okamura, Shigeaki; Kume, Toshiyuki; Hirono, Shuichi

    2017-06-01

    The constitutive androstane receptor (CAR, NR1I3) regulates the expression of numerous drug-metabolizing enzymes and transporters. The upregulation of various enzymes, including CYP2B6, by CAR activators is a critical problem leading to clinically severe drug-drug interactions (DDIs). To date, however, few effective computational approaches for identifying CAR activators exist. In this study, we aimed to develop three-dimensional quantitative structure-activity relationship (3D-QSAR) models to predict the CAR activating potency of compounds emerging in the drug-discovery process. Models were constructed using comparative molecular field analysis (CoMFA) based on the molecular alignments of ligands binding to CAR, which were obtained from ensemble ligand-docking using 28 compounds as a training set. The CoMFA model, modified by adding a lipophilic parameter with calculated logD7.4 (S+logD7.4), demonstrated statistically good predictive ability (r2 = 0.99, q2 = 0.74). We also confirmed the excellent predictability of the 3D-QSAR model for CAR activation (r2pred = 0.71) using seven compounds as a test set for external validation. Collectively, our results indicate that the 3D-QSAR model developed in this study provides precise prediction of CAR activating potency and, thus, should be useful for selecting drug candidates with minimized DDI risk related to enzyme-induction in the early drug-discovery stage. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  11. Constitutive Retinal CD200 Expression Regulates Resident Microglia and Activation State of Inflammatory Cells during Experimental Autoimmune Uveoretinitis

    OpenAIRE

    Broderick, Cathryn; Hoek, Robert M.; Forrester, John V.; Liversidge, Janet; Sedgwick, Jonathon D.; Dick, Andrew D

    2002-01-01

    Recent evidence supports the notion that tissue OX2 (CD200) constitutively provides down-regulatory signals to myeloid-lineage cells via CD200-receptor (CD200R). Thus, mice lacking CD200 (CD200−/−) show increased susceptibility to and accelerated onset of tissue-specific autoimmunity. In the retina there is extensive expression of CD200 on neurons and retinal vascular endothelium. We show here that retinal microglia in CD200−/− mice display normal morphology, but unlike microglia from wild-ty...

  12. Extracellular ionic locks determine variation in constitutive activity and ligand potency between species orthologs of the free fatty acid receptors FFA2 and FFA3

    DEFF Research Database (Denmark)

    Hudson, Brian D; Tikhonova, Irina G; Pandey, Sunil K

    2012-01-01

    Free fatty acid receptors 2 and 3 (FFA2 and FFA3) are G protein-coupled receptors for short chain free fatty acids (SCFAs). They respond to the same set of endogenous ligands but with distinct rank-order of potency such that acetate (C2) has been described as FFA2-selective, whereas propionate (C3...... selectivity to C2 and C3 resulted from broad differences in SCFAs potency at the mouse orthologs. In studies to define the molecular basis for these observations, marked variation in ligand-independent constitutive activity was identified using a [(35)S]GTPγS assay. The orthologs with higher potency...... for the SCFAs, human FFA2 and mouse FFA3, displayed high constitutive activity in this assay, whereas the orthologs with lower potency for the agonist ligands, mouse FFA2 and human FFA3, did not. Sequence alignments of the second extracellular loop identified single negatively charged residues in FFA2 and FFA3...

  13. Constitutive expression of microRNA-150 in mammary epithelium suppresses secretory activation and impairs de novo lipogenesis.

    Science.gov (United States)

    Heinz, Richard E; Rudolph, Michael C; Ramanathan, Palani; Spoelstra, Nicole S; Butterfield, Kiel T; Webb, Patricia G; Babbs, Beatrice L; Gao, Hongwei; Chen, Shang; Gordon, Michael A; Anderson, Steve M; Neville, Margaret C; Gu, Haihua; Richer, Jennifer K

    2016-11-15

    Profiling of RNA from mouse mammary epithelial cells (MECs) isolated on pregnancy day (P)14 and lactation day (L)2 revealed that the majority of differentially expressed microRNA declined precipitously between late pregnancy and lactation. The decline in miR-150, which exhibited the greatest fold-decrease, was verified quantitatively and qualitatively. To test the hypothesis that the decline in miR-150 is crucial for lactation, MEC-specific constitutive miR-150 was achieved by crossing ROSA26-lox-STOP-lox-miR-150 mice with WAP-driven Cre recombinase mice. Both biological and foster pups nursed by bitransgenic dams exhibited a dramatic decrease in survival compared with offspring nursed by littermate control dams. Protein products of predicted miR-150 targets Fasn, Olah, Acaca, and Stat5B were significantly suppressed in MECs of bitransgenic mice with constitutive miR-150 expression as compared with control mice at L2. Lipid profiling revealed a significant reduction in fatty acids synthesized by the de novo pathway in L2 MECs of bitransgenic versus control mice. Collectively, these data support the hypothesis that a synchronized decrease in miRNAs, such as miR-150, at late pregnancy serves to allow translation of targets crucial for lactation. © 2016. Published by The Company of Biologists Ltd.

  14. 20 CFR 667.220 - What Workforce Investment Act title I functions and activities constitute the costs of...

    Science.gov (United States)

    2010-04-01

    ... providers of training services, youth activities, and appropriate education activities; (iv) Local area performance information; and (v) Information relating to supportive services and unemployment insurance claims...

  15. Use of Intraductal Adenovins Transduction to Assess the Mammary Tumorigenic Potential of a Constitutively Active Prolactin Receptor

    National Research Council Canada - National Science Library

    2000-01-01

    ... are expressed. Transgenic technology has been used to evaluate the effects of an activated prolactin receptor, aPRLR, and an activated member of the prolactin signal transduction pathway, Akt, on the mammary...

  16. Who Said Learning about the Constitution Isn't Fun? Active Lessons on the U.S. Constitution for Junior and Senior High School Students. Lessons created by participants at "Congress and the Constitution: A Summer Institute for Teachers" (Ontario, California, 1988).

    Science.gov (United States)

    Cramer, Elizabeth, Ed.; Hill, Margaret, Ed.

    Twenty-eight lesson plans developed by California teachers who attended a summer institute on Congress and the Constitution are presented in this document. Sample lesson plan titles are: (1) "Geopolitics and the Constitution," (2) "Judicial Review," (3) "Electoral College and the Constitution," (4) "First…

  17. The TLR4 D299G and T399I SNPs are constitutively active to up-regulate expression of Trif-dependent genes.

    Directory of Open Access Journals (Sweden)

    Georgina L Hold

    Full Text Available Dysregulated Toll-Like Receptor (TLR signalling and genetic polymorphisms in these proteins are linked to many human diseases. We investigated TLR4 functional variants D299G and T399I to assess the impact on LPS-induced responsiveness in comparison to wild-type TLR4. The mechanism by which this occurs in unclear as these SNPs do not lie within the lipid A binding domain or dimerisation sites of the LPS-TLR4/MD2 receptor complexes. Transfection of TLR4D299G, TLR4T399I or TLR4D299G. T399I into HEK cells resulted in constitutive activation of an NF-κB reporter gene and a blunting of the LPS-induced reporter activation compared to WT-TLR4. Unstimulated human monocyte/macrophages, from patients with the D299G and T399I SNPs demonstrated a downregulation of many genes, particularly Tram/Trif signalling pathway constitutents compared to the TLR4 wild-type subjects supporting the concept of basal receptor activity. Monocyte/macrophages from carriers of the TLR4 D299G and T399I polymorphisms stimulated with LPS showed >6 fold lower levels of NF-κB and ∼12 fold higher IFN-β gene expression levels compared to wild-type subjects (P<0.05; MWU test and dramatically altered resultant cytokine profiles. We conclude that these TLR4 SNPs affect constitutive receptor activity which impacts on the hosts ability to respond to LPS challenge leading to a dysregulated sub-optimal immune response to infection.

  18. Constitutively Active Acetylcholine-Dependent Potassium Current Increases Atrial Defibrillation Threshold by Favoring Post-Shock Re-Initiation

    Science.gov (United States)

    Bingen, Brian O.; Askar, Saïd F. A.; Neshati, Zeinab; Feola, Iolanda; Panfilov, Alexander V.; de Vries, Antoine A. F.; Pijnappels, Daniël A.

    2015-01-01

    Electrical cardioversion (ECV), a mainstay in atrial fibrillation (AF) treatment, is unsuccessful in up to 10–20% of patients. An important aspect of the remodeling process caused by AF is the constitutive activition of the atrium-specific acetylcholine-dependent potassium current (IK,ACh → IK,ACh-c), which is associated with ECV failure. This study investigated the role of IK,ACh-c in ECV failure and setting the atrial defibrillation threshold (aDFT) in optically mapped neonatal rat cardiomyocyte monolayers. AF was induced by burst pacing followed by application of biphasic shocks of 25–100 V to determine aDFT. Blocking IK,ACh-c by tertiapin significantly decreased DFT, which correlated with a significant increase in wavelength during reentry. Genetic knockdown experiments, using lentiviral vectors encoding a Kcnj5-specific shRNA to modulate IK,ACh-c, yielded similar results. Mechanistically, failed ECV was attributed to incomplete phase singularity (PS) removal or reemergence of PSs (i.e. re-initiation) through unidirectional propagation of shock-induced action potentials. Re-initiation occurred at significantly higher voltages than incomplete PS-removal and was inhibited by IK,ACh-c blockade. Whole-heart mapping confirmed our findings showing a 60% increase in ECV success rate after IK,ACh-c blockade. This study provides new mechanistic insight into failing ECV of AF and identifies IK,ACh-c as possible atrium-specific target to increase ECV effectiveness, while decreasing its harmfulness. PMID:26487066

  19. A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase

    DEFF Research Database (Denmark)

    Maile, C A; Hingst, Janne Rasmuss; Mahalingan, K K

    2017-01-01

    had significantly higher glycogen content than control horse muscle despite no difference in GS expression. GS activity was significantly higher in muscle from homozygous mutants than from heterozygote and control horses, in the absence and presence of the allosteric regulator, glucose 6 phosphate (G6......P). Muscle from homozygous mutant horses also had significantly increased GS phosphorylation at sites 2+2a and significantly higher AMPKα1 (an upstream kinase) expression than controls, likely reflecting a physiological attempt to reduce GS enzyme activity. Recombinant mutant GS was highly active...

  20. Constitutively active RAS signaling reduces 1,25 dihydroxyvitamin D-mediated gene transcription in intestinal epithelial cells by reducing vitamin D receptor expression.

    Science.gov (United States)

    DeSmet, Marsha L; Fleet, James C

    2017-10-01

    High vitamin D status is associated with reduced colon cancer risk but these studies ignore the diversity in the molecular etiology of colon cancer. RAS activating mutations are common in colon cancer and they activate pro-proliferative signaling pathways. We examined the impact of RAS activating mutations on 1,25 dihydroxyvitamin D (1,25(OH) 2 D)-mediated gene expression in cultured colon and intestinal cell lines. Transient transfection of Caco-2 cells with a constitutively active mutant K-RAS (G12 V) significantly reduced 1,25(OH) 2 D-induced activity of both a human 25-hydroxyvitamin D, 24 hydroxyase (CYP24A1) promoter-luciferase and an artificial 3X vitamin D response element (VDRE) promoter-luciferase reporter gene. Young Adult Mouse Colon (YAMC) and Rat Intestinal Epithelial (RIE) cell lines with stable expression of mutant H-RAS had suppressed 1,25(OH) 2 D-mediated induction of CYP24A1 mRNA. The RAS effects were associated with lower Vitamin D receptor (VDR) mRNA and protein levels in YAMC and RIE cells and they could be partially reversed by VDR overexpression. RAS-mediated suppression of VDR levels was not due to either reduced VDR mRNA stability or increased VDR gene methylation. However, chromatin accessibility to the VDR gene at the proximal promoter (-300bp), an enhancer region at -6kb, and an enhancer region located in exon 3 was significantly reduced in RAS transformed YAMC cells (YAMC-RAS). These data show that constitutively active RAS signaling suppresses 1,25(OH) 2 D-mediated gene transcription in colon epithelial cells by reducing VDR gene transcription but the mechanism for this suppression is not yet known. These data suggest that cancers with RAS-activating mutations may be less responsive to vitamin D mediated treatment or chemoprevention. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Methadone Induces the Expression of Hepatic Drug-Metabolizing Enzymes through the Activation of Pregnane X Receptor and Constitutive Androstane Receptor

    Science.gov (United States)

    Tolson, Antonia H.; Li, Haishan; Eddington, Natalie D.; Wang, Hongbing

    2009-01-01

    Methadone (MD) is the most established substance abuse pharmacotherapy of choice for the management of heroin dependence. To date, drug-drug interactions involving MD have been characterized asymmetrically among existing reports, which describe how other drugs affect the metabolic or pharmacokinetic profiles of MD; however, limited information is available regarding the potential for MD to influence similar fates of coadministered drugs. Moreover, little to no mechanistic evidence has been explored. Here, we show that MD induces hepatic drug-metabolizing enzymes (DMEs) through the activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Real-time polymerase chain reaction analysis of human hepatocyte cultures revealed that MD induces the mRNA expression of CYP2B6, CYP3A4, UGT1A1, and multidrug resistance 1 in a concentration-related manner, with the maximal induction of CYP2B6 challenging that of the induction by rifampicin. Furthermore, MD-mediated induction of CYP2B6 and CYP3A4 proteins was observed in Western blot analysis. In cell-based reporter assays, MD significantly increased human (h) PXR-mediated CYP2B6 reporter activities but exhibited minimal effect on hCAR activation as a result of the constitutive activity of hCAR in HepG2 cells. Further studies revealed that treatment with MD resulted in significant nuclear accumulation of adenovirus/enhanced yellow fluorescent protein tagged-hCAR in human hepatocytes, which has been regarded as the initial step of CAR activation. Additional analysis of the two enantiomers of MD, R-(–)-MD (active) and S-(+)-MD (inactive), indicates the lack of stereoselectivity pertaining to MD-mediated DME induction. Overall, our results show that MD induces the hepatic expression of multiple DMEs by activating PXR- and CAR-mediated pathways. PMID:19520773

  2. Differential regulation of metabolic pathways by androgen receptor (AR) and its constitutively active splice variant, AR-V7, in prostate cancer cells.

    Science.gov (United States)

    Shafi, Ayesha A; Putluri, Vasanta; Arnold, James M; Tsouko, Efrosini; Maity, Suman; Roberts, Justin M; Coarfa, Cristian; Frigo, Daniel E; Putluri, Nagireddy; Sreekumar, Arun; Weigel, Nancy L

    2015-10-13

    Metastatic prostate cancer (PCa) is primarily an androgen-dependent disease, which is treated with androgen deprivation therapy (ADT). Tumors usually develop resistance (castration-resistant PCa [CRPC]), but remain androgen receptor (AR) dependent. Numerous mechanisms for AR-dependent resistance have been identified including expression of constitutively active AR splice variants lacking the hormone-binding domain. Recent clinical studies show that expression of the best-characterized AR variant, AR-V7, correlates with resistance to ADT and poor outcome. Whether AR-V7 is simply a constitutively active substitute for AR or has novel gene targets that cause unique downstream changes is unresolved. Several studies have shown that AR activation alters cell metabolism. Using LNCaP cells with inducible expression of AR-V7 as a model system, we found that AR-V7 stimulated growth, migration, and glycolysis measured by ECAR (extracellular acidification rate) similar to AR. However, further analyses using metabolomics and metabolic flux assays revealed several differences. Whereas AR increased citrate levels, AR-V7 reduced citrate mirroring metabolic shifts observed in CRPC patients. Flux analyses indicate that the low citrate is a result of enhanced utilization rather than a failure to synthesize citrate. Moreover, flux assays suggested that compared to AR, AR-V7 exhibits increased dependence on glutaminolysis and reductive carboxylation to produce some of the TCA (tricarboxylic acid cycle) metabolites. These findings suggest that these unique actions represent potential therapeutic targets.

  3. Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype

    Science.gov (United States)

    Murakami, Shunichi; Balmes, Gener; McKinney, Sandra; Zhang, Zhaoping; Givol, David; de Crombrugghe, Benoit

    2004-01-01

    We generated transgenic mice that express a constitutively active mutant of MEK1 in chondrocytes. These mice showed a dwarf phenotype similar to achondroplasia, the most common human dwarfism, caused by activating mutations in FGFR3. These mice displayed incomplete hypertrophy of chondrocytes in the growth plates and a general delay in endochondral ossification, whereas chondrocyte proliferation was unaffected. Immunohistochemical analysis of the cranial base in transgenic embryos showed reduced staining for collagen type X and persistent expression of Sox9 in chondrocytes. These observations indicate that the MAPK pathway inhibits hypertrophic differentiation of chondrocytes and negatively regulates bone growth without inhibiting chondrocyte proliferation. Expression of a constitutively active mutant of MEK1 in chondrocytes of Fgfr3-deficient mice inhibited skeletal overgrowth, strongly suggesting that regulation of bone growth by FGFR3 is mediated at least in part by the MAPK pathway. Although loss of Stat1 restored the reduced chondrocyte proliferation in mice expressing an achondroplasia mutant of Fgfr3, it did not rescue the reduced hypertrophic zone, the delay in formation of secondary ossification centers, and the achondroplasia-like phenotype. These observations suggest a model in which Fgfr3 signaling inhibits bone growth by inhibiting chondrocyte differentiation through the MAPK pathway and by inhibiting chondrocyte proliferation through Stat1. PMID:14871928

  4. Constitutive membrane expression of proteinase 3 (PR3) and neutrophil activation by anti-PR3 antibodies

    NARCIS (Netherlands)

    van Rossum, AP; Rarok, AA; Huitema, MG; Fassina, G; Limburg, PC; Kallenberg, CGM

    2004-01-01

    Antineutrophil cytoplasm autoantibodies with specificity for proteinase 3 (PR3) are thought to play a major role in the pathogenesis of Wegener's granulomatosis (WG), presumably by their potential to activate neutrophils. In patients with WG, high expression of PR3 on the surface of nonprimed

  5. Constitutive cannabinoid 1 and mu opioid receptor activity in the ventral tegmental area: occurrence, function and therapeutic relevance

    NARCIS (Netherlands)

    Meye, F.J.

    2012-01-01

    Cannabinoid 1 receptors (CB1Rs) play a crucial role in regulating systems dedicated to processing rewards and emotions. It was known that in artificial systems, CB1Rs can exhibit activity that is independent of the typical agonist-driven form. However, it remained largely unclear whether this

  6. Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex

    DEFF Research Database (Denmark)

    Møller, Lisbeth Birk; Schönewolf-Greulich, Bitten; Rosengren, Thomas

    2017-01-01

    leads to the formation of an active donor splice site, resulting in three shorter alternatively spliced transcripts with premature stop codons. However a small amount of normal spliced transcript is apparently produced from the mutated allele, which might explain the milder phenotype. The gene products...

  7. Constitutive activation of transcription factor AP-2 is associated with decreased MnSOD expression in transformed human lung fibroblasts.

    Science.gov (United States)

    Zhu, C; Huang, Y; Weydert, C J; Oberley, L W; Domann, F E

    2001-06-01

    Activator protein-2 (AP-2) is a transcription factor with transactivating and transrepressing potential in different promoter contexts. AP-2 contains seven cysteines, and its in vitro DNA binding activity is redox-sensitive. Superoxide dismutase-2 (SOD2), which encodes the antioxidant enzyme manganese superoxide dismutase (MnSOD), is a putative tumor suppressor gene whose loss of expression is associated with the malignant phenotype. SOD2 promoter mutations that generate new AP-2 sites are associated with loss of MnSOD expression in cancer cells. In the current study, we have identified an inverse expression pattern between AP-2 and MnSOD in normal versus transformed human cells. MRC5 cells are a normal human lung fibroblast cell strain that is mortal and senesces after a certain number of passages in vitro. MRC5-VA is a simian virus transformed variant of MRC5. We determined the levels of expression of MnSOD and AP-2 in these two cell types at the levels of mRNA, protein, and activity. Our results indicated that MnSOD expression was significantly decreased in MRC5-VA cells compared with MRC5 cells at each level of investigation, whereas AP-2 showed an opposing pattern of expression and DNA binding activity. These results suggest that AP-2 may participate in the mechanism(s) underlying decreased expression of SOD2 in transformed cells.

  8. Extracellular Vesicles from a Helminth Parasite Suppress Macrophage Activation and Constitute an Effective Vaccine for Protective Immunity

    Directory of Open Access Journals (Sweden)

    Gillian Coakley

    2017-05-01

    Full Text Available Recent studies have demonstrated that many parasites release extracellular vesicles (EVs, yet little is known about the specific interactions of EVs with immune cells or their functions during infection. We show that EVs secreted by the gastrointestinal nematode Heligmosomoides polygyrus are internalized by macrophages and modulate their activation. EV internalization causes downregulation of type 1 and type 2 immune-response-associated molecules (IL-6 and TNF, and Ym1 and RELMα and inhibits expression of the IL-33 receptor subunit ST2. Co-incubation with EV antibodies abrogated suppression of alternative activation and was associated with increased co-localization of the EVs with lysosomes. Furthermore, mice vaccinated with EV-alum generated protective immunity against larval challenge, highlighting an important role in vivo. In contrast, ST2-deficient mice are highly susceptible to infection, and they are unable to clear parasites following EV vaccination. Hence, macrophage activation and the IL-33 pathway are targeted by H. polygyrus EVs, while neutralization of EV function facilitates parasite expulsion.

  9. Loss of the tumor suppressor gene NF2, encoding merlin, constitutively activates integrin-dependent mTORC1 signaling.

    Science.gov (United States)

    López-Lago, Miguel A; Okada, Tomoyo; Murillo, Miguel M; Socci, Nick; Giancotti, Filippo G

    2009-08-01

    Integrin signaling promotes, through p21-activated kinase, phosphorylation and inactivation of the tumor suppressor merlin, thus removing a block to mitogenesis in normal cells. However, the biochemical function of merlin and the effector pathways critical for the pathogenesis of malignant mesothelioma and other NF2-related malignancies are not known. We report that integrin-specific signaling promotes activation of mTORC1 and cap-dependent mRNA translation. Depletion of merlin rescues mTORC1 signaling in cells deprived of anchorage to a permissive extracellular matrix, suggesting that integrin signaling controls mTORC1 through inactivation of merlin. This signaling pathway controls translation of the cyclin D1 mRNA and, thereby, cell cycle progression. In addition, it promotes cell survival. Analysis of a panel of malignant mesothelioma cell lines reveals a strong correlation between loss of merlin and activation of mTORC1. Merlin-negative lines are sensitive to the growth-inhibitory effect of rapamycin, and the expression of recombinant merlin renders them partially resistant to rapamycin. Conversely, depletion of merlin restores rapamycin sensitivity in merlin-positive lines. These results indicate that integrin-mediated adhesion promotes mTORC1 signaling through the inactivation of merlin. Furthermore, they reveal that merlin-negative mesotheliomas display unregulated mTORC1 signaling and are sensitive to rapamycin, thus providing a preclinical rationale for prospective, biomarker-driven clinical studies of mTORC1 inhibitors in these tumors.

  10. Resveratrol suppresses constitutive activation of AKT via generation of ROS and induces apoptosis in diffuse large B cell lymphoma cell lines.

    Directory of Open Access Journals (Sweden)

    Azhar R Hussain

    Full Text Available BACKGROUND: We have recently shown that deregulation PI3-kinase/AKT survival pathway plays an important role in pathogenesis of diffuse large B cell lymphoma (DLBCL. In an attempt to identify newer therapeutic agents, we investigated the role of Resveratrol (trans-3,4', 5-trihydroxystilbene, a naturally occurring polyphenolic compound on a panel of diffuse large B-cell lymphoma (DLBCL cells in causing inhibition of cell viability and inducing apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the action of Resveratrol on DLBCL cells and found that Resveratrol inhibited cell viability and induced apoptosis by inhibition of constitutively activated AKT and its downstream targets via generation of reactive oxygen species (ROS. Simultaneously, Resveratrol treatment of DLBCL cell lines also caused ROS dependent upregulation of DR5; and interestingly, co-treatment of DLBCL with sub-toxic doses of TRAIL and Resveratrol synergistically induced apoptosis via utilizing DR5, on the other hand, gene silencing of DR5 abolished this effect. CONCLUSION/SIGNIFICANCE: Altogether, these data suggest that Resveratrol acts as a suppressor of AKT/PKB pathway leading to apoptosis via generation of ROS and at the same time primes DLBCL cells via up-regulation of DR5 to TRAIL-mediated apoptosis. These data raise the possibility that Resveratrol may have a future therapeutic role in DLBCL and possibly other malignancies with constitutive activation of the AKT/PKB pathway.

  11. Constitutive STAT3-activation in Sezary syndrome: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells

    DEFF Research Database (Denmark)

    Eriksen, K W; Kaltoft, K; Mikkelsen, G

    2001-01-01

    Interleukin-2 (IL-2) is a growth factor which upon binding to high-affinity receptors (IL-2Ralphabetagamma) triggers mitogenesis in T cells. IL-2Ralpha expression is restricted to T cells which have recently encountered antigen, and in healthy individuals the majority (>95%) of peripheral T cells...... are IL-2Ralpha negative. An aberrant expression of IL-2Ralpha has recently been described in cutaneous T-cell lymphoma (CTCL). Here, we study the regulation of IL-2Ralpha expression and STATs in a tumor cell line obtained from peripheral blood from a patient with Sezary syndrome (SS), a leukemic variant...... of CTCL. We show that (1) STAT3 (a transcription factor known to regulate IL-2Ralpha transcription) is constitutively tyrosine-phosphorylated in SS tumor cells, but not in non-malignant T cells; (2) STAT3 binds constitutively to a STAT-binding sequence in the promotor of the IL-2Ralpha gene; (3) the Janus...

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

    DEFF Research Database (Denmark)

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

    2007-01-01

    Cyclin D1/cyclin-dependent kinase 2 (Cdk2) complexes are present at high frequency in human breast cancer cell lines, but the significance of this observation is unknown. This report shows that expression of a cyclin D1-Cdk2 fusion protein under the control of the mouse mammary tumor virus (MMITV...... mediate some of the transforming effects that result from cyclin D1 overexpression in human breast cancers. MMTV-DIK2 cancer cells express the hepatocyte growth factor (HGF) receptor, c-Met. MMTV-D1K2 cancer cells also secrete transforming growth factor beta (TGF beta), but are relatively resistant to TGF...... beta antiproliferative effects. Fibroblasts derived from MMTV-DIK2 tumors secrete factors that stimulate the proliferation of MMTV-D1K2 cancer cells, stimulate c-Met tyrosine phosphorylation, and stimulate the phosphorylation of the downstream signaling intermediates p70(s6k) and Akt on activating...

  13. Multiple Mechanisms Cooperate to Constitutively Exclude the Transcriptional Co-Activator YAP from the Nucleus During Murine Oogenesis.

    Science.gov (United States)

    Abbassi, Laleh; Malki, Safia; Cockburn, Katie; Macaulay, Angus; Robert, Claude; Rossant, Janet; Clarke, Hugh J

    2016-05-01

    Reproduction depends on the generation of healthy oocytes. Improving therapeutic strategies to prolong or rescue fertility depends on identifying the inter- and intracellular mechanisms that direct oocyte development under physiological conditions. Growth and proliferation of multiple cell types is regulated by the Hippo signaling pathway, whose chief effectors are the transcriptional co-activator YAP and its paralogue WWTR1. To resolve conflicting results concerning the potential role of Hippo in mammalian oocyte development, we systematically investigated the expression and localization of YAP in mouse oocytes. We report that that YAP is expressed in the germ cells beginning as early as Embryonic Day 15.5 and subsequently throughout pre- and postnatal oocyte development. However, YAP is restricted to the cytoplasm at all stages. YAP is phosphorylated at serine-112 in growing and fully grown oocytes, identifying a likely mechanistic basis for its nuclear exclusion, and becomes dephosphorylated at this site during meiotic maturation. Phosphorylation at serine-112 is regulated by a mechanism dependent on cyclic AMP and protein kinase A, which is known to be active in oocytes prior to maturation. Growing oocytes also contain a subpopulation of YAP, likely dephosphorylated, that is able enter the oocyte nucleus, but it is not retained there, implying that oocytes lack the cofactors required to retain YAP in the nucleus. Thus, although YAP is expressed throughout oocyte development, phosphorylation-dependent and -independent mechanisms cooperate to ensure that it does not accumulate in the nucleus. We conclude that nuclear YAP does not play a significant physiological role during oocyte development in mammals. © 2016 by the Society for the Study of Reproduction, Inc.

  14. Expression of a constitutively active calcineurin encoded by an intron-retaining mRNA in follicular keratinocytes.

    Directory of Open Access Journals (Sweden)

    Atsushi Fujimura

    Full Text Available Hair growth is a highly regulated cyclical process. Immunosuppressive immunophilin ligands such as cyclosporin A (CsA and FK506 are known as potent hair growth modulatory agents in rodents and humans that induce active hair growth and inhibit hair follicle regression. The immunosuppressive effectiveness of these drugs has been generally attributed to inhibition of T cell activation through well-characterized pathways. Specifically, CsA and FK506 bind to intracellular proteins, principally cyclophilin A and FKBP12, respectively, and thereby inhibit the phosphatase calcineurin (Cn. The calcineurin (Cn/NFAT pathway has an important, but poorly understood, role in the regulation of hair follicle development. Here we show that a novel-splicing variant of calcineurin Aß CnAß-FK, which is encoded by an intron-retaining mRNA and is deficient in the autoinhibitory domain, is predominantly expressed in mature follicular keratinocytes but not in the proliferating keratinocytes of rodents. CnAß-FK was weakly sensitive to Ca(2+ and dephosphorylated NFATc2 under low Ca(2+ levels in keratinocytes. Inhibition of Cn/NFAT induced hair growth in nude mice. Cyclin G2 was identified as a novel target of the Cn/NFATc2 pathway and its expression in follicular keratinocytes was reduced by inhibition of Cn/NFAT. Overexpression of cyclin G2 arrested the cell cycle in follicular keratinocytes in vitro and the Cn inhibitor, cyclosporin A, inhibited nuclear localization of NFATc2, resulting in decreased cyclin G2 expression in follicular keratinocytes of rats in vivo. We therefore suggest that the calcineurin/NFAT pathway has a unique regulatory role in hair follicle development.

  15. The adhesion G protein-coupled receptor G2 (ADGRG2/GPR64) constitutively activates SRE and NFκB and is involved in cell adhesion and migration

    DEFF Research Database (Denmark)

    Cornelia Peeters, Miriam; Fokkelman, Michiel; Boogaard, Bob

    2015-01-01

    Adhesion G protein-coupled receptors (ADGRs) are believed to be activated by auto-proteolytic cleavage of their very large extracellular N-terminal domains normally acting as a negative regulator of the intrinsically constitutively active seven transmembrane domain. ADGRG2 (or GPR64) which...... intracellular signal transduction. Knockdown of ADGRG2 by siRNA in the highly motile breast cancer cell lines Hs578T and MDA-MB-231 resulted in a strong reduction in cell adhesion and subsequent cell migration which was associated with a selective reduction in RelB, an NFκB family member. It is concluded...... that the adhesion GPCR ADGRG2 is critically involved in the adhesion and migration of certain breast cancer cells through mechanisms including a non-canonical NFkB pathway and that ADGRG2 could be a target for treatment of certain types of cancer....

  16. Inhibition of STAT3 reduces astrocytoma cell invasion and constitutive activation of STAT3 predicts poor prognosis in human astrocytoma.

    Directory of Open Access Journals (Sweden)

    Qinchuan Liang

    Full Text Available Astrocytoma cells characteristically possess high invasion potentials. Recent studies have revealed that knockdown of signal transducers and activators of transcription 3 (STAT3 expression by RNAi induces apoptosis in astrocytoma cell. Nevertheless, the distinct roles of STAT3 in astrocytoma's invasion and recurrence have not been elucidated. In this study, we silenced STAT3 using Small interfering RNAs in two human glioblastoma multiforme (GBM cell lines (U251 and U87, and investigated the effect on GBM cell adhesion and invasion. Our results demonstrate that disruption of STAT3 inhibits GBM cell's adhesion and invasion. Knockdown of STAT3 significantly increased E-cadherin but decreased N-cadherin, vascular endothelial growth factor, matrix metalloproteinase 2 and matrix metalloproteinase 9. Additionally, expression of pSTAT3(Tyr705 correlates with astrocytoma WHO classification, Karnofsky performance status scale score, tumor recurrence and survival. Furthermore, pSTAT3(Tyr705 is a significant prognostic factor in astrocytoma. In conclusion, STAT3 may affect astrocytoma invasion, expression of pSTAT3(Tyr705 is a significant prognostic factor in tumor recurrence and overall survival in astrocytoma patients. Therefore, STAT3 may provide a potential target for molecular therapy in human astrocytoma, and pSTAT3(Tyr705could be an important biomarker for astrocytoma prognosis.

  17. Movimientos sociales, activismo constitucional y narrativa democrática en la Argentina contemporánea Social movements, constitutional activism and democratic narrative in contemporary Argentina

    Directory of Open Access Journals (Sweden)

    Gabriela Delamata

    2013-04-01

    Full Text Available El artículo analiza tres procesos recientes de movilización socio-legal en Argentina y subraya el rol de la Constitución y la comunidad legal garantista en su despliegue. El enfoque utilizado propone entender los procesos bajo la forma de una reactivación del patrón activista gestado en la transición democrática y señala sus efectos actuales sobre los procedimientos democráticos y la gramática de ciudadanía.The article analyzes three contemporary processes of socio-legal mobilization in Argentina and underlines the role of the Constitution and of the legal community in its enforcement. The adopted approach aims at understanding those processes as a sort of reactivation of the activist tradition born during the transition to democracy, and emphasizing the present effects of this constitutional activism on democratic procedures and the citizenship grammar.

  18. C-terminally truncated constitutively active androgen receptor variants and their biologic and clinical significance in castration-resistant prostate cancer.

    Science.gov (United States)

    Azoitei, Anca; Merseburger, Axel S; Godau, Beate; Hoda, M Raschid; Schmid, Evi; Cronauer, Marcus V

    2017-02-01

    A mechanism allowing castration resistant prostate cancer cells to escape the effects of conventional anti-hormonal treatments is the synthesis of constitutively active, C-terminally truncated androgen receptor (AR)-variants. Lacking the entire or vast parts of the ligand binding domain, the intended target of traditional endocrine therapies, these AR-variants (termed ARΔLBD) are insensitive to all traditional treatments including second generation compounds like abiraterone, enzalutamide or ARN-509. Although ARΔLBD are predominantly products of alternative splicing, they can also be products of nonsense mutations or proteolytic cleavage. In this review, we will discuss the etiology and function of c-terminally truncated AR-variants and their clinical significance as markers/targets for the treatment of castration resistant prostate cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. The Constitution by Cell

    Science.gov (United States)

    Greenhut, Stephanie; Jones, Megan

    2010-01-01

    On their visit to the National Archives Experience in Washington, D.C., students in Jenni Ashley and Gay Brock's U.S. history classes at the Potomac School in McLean, Virginia, participated in a pilot program called "The Constitution by Cell." Armed with their cell phones, a basic understanding of the Constitution, and a willingness to…

  20. Interpreting the Constitution.

    Science.gov (United States)

    Brennan, William J., Jr.

    1987-01-01

    Discusses constitutional interpretations relating to capital punishment and protection of human dignity. Points out the document's effectiveness in creating a new society by adapting its principles to current problems and needs. Considers two views of the Constitution that lead to controversy over the legitimacy of judicial decisions. (PS)

  1. Expression of constitutively active CDK1 stabilizes APC-Cdh1 substrates and potentiates premature spindle assembly and checkpoint function in G1 cells.

    Science.gov (United States)

    Ma, Yan; Yuan, Xi; Wyatt, William R; Pomerening, Joseph R

    2012-01-01

    Mitotic progression in eukaryotic cells depends upon the activation of cyclin-dependent kinase 1 (CDK1), followed by its inactivation through the anaphase-promoting complex (APC)/cyclosome-mediated degradation of M-phase cyclins. Previous work revealed that expression of a constitutively active CDK1 (CDK1AF) in HeLa cells permitted their division, but yielded G1 daughter cells that underwent premature S-phase and early mitotic events. While CDK1AF was found to impede the sustained activity of APC-Cdh1, it was unknown if this defect improperly stabilized mitotic substrates and contributed to the occurrence of these premature M phases. Here, we show that CDK1AF expression in HeLa cells improperly stabilized APC-Cdh1 substrates in G1-phase daughter cells, including mitotic kinases and the APC adaptor, Cdc20. Division of CDK1AF-expressing cells produced G1 daughters with an accelerated S-phase onset, interrupted by the formation of premature bipolar spindles capable of spindle assembly checkpoint function. Further characterization of these phenotypes induced by CDK1AF expression revealed that this early spindle formation depended upon premature CDK1 and Aurora B activities, and their inhibition induced rapid spindle disassembly. Following its normal M-phase degradation, we found that the absence of Wee1 in these prematurely cycling daughter cells permitted the endogenous CDK1 to contribute to these premature mitotic events, since expression of a non-degradable Wee1 reduced the number of cells that exhibited premature cyclin B1oscillations. Lastly, we discovered that Cdh1-ablated cells could not be forced into a premature M phase, despite cyclin B1 overexpression and proteasome inhibition. Together, these results demonstrate that expression of constitutively active CDK1AF hampers the destruction of critical APC-Cdh1 targets, and that this type of condition could prevent newly divided cells from properly maintaining a prolonged interphase state. We propose that this more

  2. Expression of constitutively active CDK1 stabilizes APC-Cdh1 substrates and potentiates premature spindle assembly and checkpoint function in G1 cells.

    Directory of Open Access Journals (Sweden)

    Yan Ma

    Full Text Available Mitotic progression in eukaryotic cells depends upon the activation of cyclin-dependent kinase 1 (CDK1, followed by its inactivation through the anaphase-promoting complex (APC/cyclosome-mediated degradation of M-phase cyclins. Previous work revealed that expression of a constitutively active CDK1 (CDK1AF in HeLa cells permitted their division, but yielded G1 daughter cells that underwent premature S-phase and early mitotic events. While CDK1AF was found to impede the sustained activity of APC-Cdh1, it was unknown if this defect improperly stabilized mitotic substrates and contributed to the occurrence of these premature M phases. Here, we show that CDK1AF expression in HeLa cells improperly stabilized APC-Cdh1 substrates in G1-phase daughter cells, including mitotic kinases and the APC adaptor, Cdc20. Division of CDK1AF-expressing cells produced G1 daughters with an accelerated S-phase onset, interrupted by the formation of premature bipolar spindles capable of spindle assembly checkpoint function. Further characterization of these phenotypes induced by CDK1AF expression revealed that this early spindle formation depended upon premature CDK1 and Aurora B activities, and their inhibition induced rapid spindle disassembly. Following its normal M-phase degradation, we found that the absence of Wee1 in these prematurely cycling daughter cells permitted the endogenous CDK1 to contribute to these premature mitotic events, since expression of a non-degradable Wee1 reduced the number of cells that exhibited premature cyclin B1oscillations. Lastly, we discovered that Cdh1-ablated cells could not be forced into a premature M phase, despite cyclin B1 overexpression and proteasome inhibition. Together, these results demonstrate that expression of constitutively active CDK1AF hampers the destruction of critical APC-Cdh1 targets, and that this type of condition could prevent newly divided cells from properly maintaining a prolonged interphase state. We

  3. A high constitutive catalase activity confers resistance to methyl viologen-promoted oxidative stress in a mutant of the cyanobacterium Nostoc punctiforme ATCC 29133.

    Science.gov (United States)

    Moirangthem, Lakshmipyari Devi; Bhattacharya, Sudeshna; Stensjö, Karin; Lindblad, Peter; Bhattacharya, Jyotirmoy

    2014-04-01

    A spontaneous methyl viologen (MV)-resistant mutant of the nitrogen-fixing cyanobacterium Nostoc punctiforme ATCC 29133 was isolated and the major enzymatic antioxidants involved in combating MV-induced oxidative stress were evaluated. The mutant displayed a high constitutive catalase activity as a consequence of which, the intracellular level of reactive oxygen species in the mutant was lower than the wild type (N. punctiforme) in the presence of MV. The superoxide dismutase (SOD) activity that consisted of a SodA (manganese-SOD) and a SodB (iron-SOD) was not suppressed in the mutant following MV treatment. The mutant was, however, characterised by a lower peroxidase activity compared with its wild type, and its improved tolerance to externally added H₂O₂ could only be attributed to enhanced catalase activity. Furthermore, MV-induced toxic effects on the wild type such as (1) loss of photosynthetic performance assessed as maximal quantum yield of photosystem II, (2) nitrogenase inactivation, and (3) filament fragmentation and cell lysis were not observed in the mutant. These findings highlight the importance of catalase in preventing MV-promoted oxidative damage and cell death in the cyanobacterium N. punctiforme. Such oxidative stress resistant mutants of cyanobacteria are likely to be a better source of biofertilisers, as they can grow and fix nitrogen in an unhindered manner in agricultural fields that are often contaminated with the herbicide MV, also commonly known as paraquat.

  4. Engineering an inducible gene expression system for Bacillus subtilis from a strong constitutive promoter and a theophylline-activated synthetic riboswitch.

    Science.gov (United States)

    Cui, Wenjing; Han, Laichuang; Cheng, Jintao; Liu, Zhongmei; Zhou, Li; Guo, Junling; Zhou, Zhemin

    2016-11-22

    Synthetic riboswitches have been increasingly used to control and tune gene expression in diverse organisms. Although a set of theophylline-responsive riboswitches have been developed for bacteria, fully functional expression elements mediated by synthetic riboswitches in Bacillus subtilis are rarely used because of the host-dependent compatibility between the promoters and riboswitches. A novel genetic element composed of the promoter P43 and a theophylline-riboswitch was developed and characterized in B. subtilis. When combined with a P43 promoter (P43'-riboE1), the theophylline-riboswitch successfully switched the constitutive expression pattern of P43 to an induced pattern. The expression mediated by the novel element could be activated at the translational level by theophylline with a relatively high induction ratio. The induction ratios for P43'-riboE1 by 4-mM theophylline were elevated during the induction period. The level of induced expression was dependent on the theophylline dose. Correspondingly, the induction ratios gradually increased in parallel with the elevated dose of theophylline. Importantly, the induced expression level was higher than three other strong constitutive promoters including PsrfA, PaprE, and the native P43. It was found that the distance between the SD sequence within the expression element and the start codon significantly influenced both the level of induced expression and the induction ratio. A 9-bp spacer was suitable for producing desirable expression level and induction ratio. Longer spacer reduced the activation efficiency. Importantly, the system successfully overexpressed β-glucuronidase at equal levels, and induction ratio was similar to that of GFP. The constructed theophylline-inducible gene expression system has broad compatibility and robustness, which has great potential in over-production of pharmaceutical and industrial proteins and utilization in building more complex gene circuits.

  5. Dimerization of inositol monophosphatase Mycobacterium tuberculosis SuhB is not constitutive, but induced by binding of the activator Mg2+

    Directory of Open Access Journals (Sweden)

    Nigou Jérôme

    2007-08-01

    Full Text Available Abstract Background The cell wall of Mycobacterium tuberculosis contains a wide range of phosphatidyl inositol-based glycolipids that play critical structural roles and, in part, govern pathogen-host interactions. Synthesis of phosphatidyl inositol is dependent on free myo-inositol, generated through dephosphorylation of myo-inositol-1-phosphate by inositol monophosphatase (IMPase. Human IMPase, the putative target of lithium therapy, has been studied extensively, but the function of four IMPase-like genes in M. tuberculosis is unclear. Results We determined the crystal structure, to 2.6 Å resolution, of the IMPase M. tuberculosis SuhB in the apo form, and analysed self-assembly by analytical ultracentrifugation. Contrary to the paradigm of constitutive dimerization of IMPases, SuhB is predominantly monomeric in the absence of the physiological activator Mg2+, in spite of a conserved fold and apparent dimerization in the crystal. However, Mg2+ concentrations that result in enzymatic activation of SuhB decisively promote dimerization, with the inhibitor Li+ amplifying the effect of Mg2+, but failing to induce dimerization on its own. Conclusion The correlation of Mg2+-driven enzymatic activity with dimerization suggests that catalytic activity is linked to the dimer form. Current models of lithium inhibition of IMPases posit that Li+ competes for one of three catalytic Mg2+ sites in the active site, stabilized by a mobile loop at the dimer interface. Our data suggest that Mg2+/Li+-induced ordering of this loop may promote dimerization by expanding the dimer interface of SuhB. The dynamic nature of the monomer-dimer equilibrium may also explain the extended concentration range over which Mg2+ maintains SuhB activity.

  6. Selection for low or high primary dormancy in Lolium rigidum Gaud seeds results in constitutive differences in stress protein expression and peroxidase activity

    Science.gov (United States)

    Goggin, Danica E.; Powles, Stephen B.; Steadman, Kathryn J.

    2011-01-01

    Seed dormancy in wild Lolium rigidum Gaud (annual ryegrass) populations is highly variable and not well characterized at the biochemical level. To identify some of the determinants of dormancy level in these seeds, the proteomes of subpopulations selected for low and high levels of primary dormancy were compared by two-dimensional polyacrylamide gel electrophoresis of extracts from mature, dry seeds. High-dormancy seeds showed higher expression of small heat shock proteins, enolase, and glyoxalase I than the low-dormancy seeds. The functional relevance of these differences in protein expression was confirmed by the fact that high-dormancy seeds were more tolerant to high temperatures imposed at imbibition and had consistently higher glyoxalase I activity over 0–42 d dark stratification. Higher expression of a putative glutathione peroxidase in low-dormancy seeds was not accompanied by higher activity, but these seeds had a slightly more oxidized glutathione pool and higher total peroxidase activity. Overall, these biochemical and physiological differences suggest that L. rigidum seeds selected for low dormancy are more prepared for rapid germination via peroxidase-mediated cell wall weakening, whilst seeds selected for high dormancy are constitutively prepared to survive environmental stresses, even in the absence of stress during seed development. PMID:20974739

  7. Deletion of Asn{sup 281} in the {alpha}-subunit of the human insulin receptor causes constitutive activation of the receptor and insulin desensitization

    Energy Technology Data Exchange (ETDEWEB)

    Desbois-Mouthon, C.; Sert-Langeron, C.; Magre, J.; Blivet, M.J. [INSERM, Paris (France)] [and others

    1996-02-01

    We studied the structure and function of the insulin receptor (IR) in two sisters with leprechaunism. The patients had inherited alterations in the IR gene and were compound heterozygotes. Their paternal IR allele carried a major deletion, including exons 10-13, which shifted the reading frame and introduced a premature chain termination codon in the IR sequence. This allele was expressed at a very low level in cultured fibroblasts (<10% of total IR messenger ribonucleic acid content) and encoded a truncated protein lacking transmembrane and tyrosine kinase domains. The maternal IR allele was deleted of 3 bp in exon 3, causing the loss of Asn{sup 281} in the {alpha}-subunit. This allele generated levels of IR messenger ribonucleic acid and cell surface receptors similar to those seen in control fibroblasts. However, IRs from patients` cells had impaired insulin binding and exhibited in vivo and in vitro constitutive activation of autophosphorylation and tyrosine kinase activity. As a result of this IR-preactivated state, the cells were desensitized to insulin stimulation of glycogen and DNA syntheses. These findings strongly suggest that Asn{sup 281} of the IR {alpha}-subunit plays a critical role in the inhibitory constraint exerted by the extracellular {alpha}-subunit over the intracellular kinase activity. 59 refs., 6 figs.

  8. Inducible but not constitutive expression of PD-L1 in human melanoma cells is dependent on activation of NF-κB.

    Directory of Open Access Journals (Sweden)

    Kavitha Gowrishankar

    Full Text Available Monoclonal antibodies against immune checkpoint blockade have proven to be a major success in the treatment of melanoma. The programmed death receptor-1 ligand-1 (PD-L1 expression on melanoma cells is believed to have an inhibitory effect on T cell responses and to be an important escape mechanism from immune attack. Previous studies have shown that PD-L1 can be expressed constitutively or can be induced by IFN-γ secreted by infiltrating lymphocytes. In the present study we have investigated the mechanism underlying these two modes of PD-L1 expression in melanoma cells including cells that had acquired resistance to the BRAF inhibitor vemurafenib. PD-L1 expression was examined by flow cytometry and immunoblotting. Specific inhibitors and siRNA knockdown approaches were used to examine the roles of the RAF/ MEK, PI3K, NF-κB, STAT3 and AP1/ c-Jun pathways. IFN-γ inducible expression of PD-L1 was dependent on NF-κB as shown by inhibition with BMS-345541, an inhibitor of IκB and the BET protein inhibitor I-BET151, as well as by siRNA knockdown of NF-κB subunits. We were unable to implicate the BRAF/MEK pathway as major regulators in PD-L1 expression on vemurafenib resistant cells. Similarly the PI3K/AKT pathway and the transcription factors STAT3 and c-Jun had only minor roles in IFN-γ induced expression of PD-L1. The mechanism underlying constitutive expression remains unresolved. We suggest these results have significance in selection of treatments that can be used in combination with monoclonal antibodies against PD1, to enhance their effectiveness and to reduce inhibitory effects melanoma cells have against cytotoxic T cell activity.

  9. Constitutive activity of inwardly rectifying K+ channel at physiological [Ca]i is mediated by Ca2+/CaMK II pathway in opossum kidney proximal tubule cells.

    Science.gov (United States)

    Mori, Yoshiaki; Yoshida, Hideyo; Miyamoto, Manabu; Sohma, Yoshiro; Kubota, Takahiro

    2008-06-01

    Using patch-clamp technique, we studied the role of the Ca2+/calmodulin kinase II (CaMK II)-mediated phosphorylation process on the K+ channel with an inward conductance of 90 pS in opossum kidney proximal tubule cells (OKPCs). The intracellular Ca2+ concentration ([Ca]i) was measured by use of the fluorescent dye fura 2. The following results were obtained: (i) In cell-attached patches, the channel activity was inhibited by a decrease in [Ca]i induced by perfusion with low Ca2+ (10(-8) M), La3+ (100 microM), or EGTA/AM (100 microM) contained in the bath solution. The application of KN-62 (10 microM) or KN-93 (5 microM), inhibitors of CaMK II, also inhibited the channel activity. (ii) The membrane potential measured with nystatin-perforated patches was significantly decreased by the fall in [Ca]i induced by the perfusion with EGTA- or La(3+)-containing solution. Also, the application of KN-62 (10 microM) or KN-93 (5 microM) to the bath significantly decreased the membrane potential. (iii) In inside-out patches, the channel activity was significantly stimulated by the application of CaMK II (300 pM) at 10(-7) M Ca2+ in the bath. Furthermore, the application of KN-62 (10 microM) to the bath significantly decreased the channel activity. Our findings show that the constitutive activity of inwardly rectifying K+ channel at physiological [Ca]i is mediated by the Ca2+/CaMK II pathway in OKPCs.

  10. Democratic constitutions and education

    OpenAIRE

    Pinzani, Alessandro

    2009-01-01

    This essay shall analyze the idea of the possibility of education to freedom through democratic institutions and the role of the constitution in this process. The question shall not be considered from an empirical perspective, but from a theoretical perspective. In the first part democratic institutions will be defined in such a way, that it is possible to speak of democratic habit as a necessary component of democracy. The second part shall introduce a concept of State constitution that take...

  11. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome.

    Science.gov (United States)

    Kanazawa, Nobuo; Okafuji, Ikuo; Kambe, Naotomo; Nishikomori, Ryuta; Nakata-Hizume, Mami; Nagai, Sonoko; Fuji, Akihiko; Yuasa, Takenosuke; Manki, Akira; Sakurai, Yoshihiko; Nakajima, Mitsuru; Kobayashi, Hiroko; Fujiwara, Ikuma; Tsutsumi, Hiroyuki; Utani, Atsushi; Nishigori, Chikako; Heike, Toshio; Nakahata, Tatsutoshi; Miyachi, Yoshiki

    2005-02-01

    Early-onset sarcoidosis (EOS) and inheritable Blau syndrome (BS) share characteristic clinical features of juvenile-onset systemic granulomatosis syndrome that mainly affects skin, joints, and eyes. However, no direct evidence has been shown for the possible common origin of these 2 diseases. Recent discovery of CARD15 mutations in BS families encouraged us to investigate similar CARD15 mutations in EOS patients. Among 10 EOS cases retrospectively collected in Japan, heterozygous missense mutations were found in 9 cases; 4 showed a 1000C>T (R334W in amino acid change) that has been reported in BS, 4 showed novel 1487A>T (H496L), 1538T>C (M513T), 1813A>C (T605P), and 2010C>A (N670K), and 1 case showed double 1146C>G (D382E)/1834G>A (A612T) mutations on different alleles. All 6 of these variants of CARD15 showed increased basal nuclear factor (NF)-kappaB activity. These findings indicate that the majority of EOS and BS cases share the common genetic etiology of CARD15 mutations that cause constitutive NF-kappaB activation.

  12. The constitutive activation of Egr-1/C/EBPa mediates the development of type 2 diabetes mellitus by enhancing hepatic gluconeogenesis.

    Science.gov (United States)

    Shen, Ning; Jiang, Shan; Lu, Jia-Ming; Yu, Xiao; Lai, Shan-Shan; Zhang, Jing-Zi; Zhang, Jin-Long; Tao, Wei-Wei; Wang, Xiu-Xing; Xu, Na; Xue, Bin; Li, Chao-Jun

    2015-02-01

    The sequential secretion of insulin and glucagon delicately maintains glucose homeostasis by inhibiting or enhancing hepatic gluconeogenesis during postprandial or fasting states, respectively. Increased glucagon/insulin ratio is believed to be a major cause of the hyperglycemia seen in type 2 diabetes. Herein, we reveal that the early growth response gene-1 (Egr-1) can be transiently activated by glucagon in hepatocytes, which mediates glucagon-regulated gluconeogenesis by increasing the expression of gluconeogenesis genes. Blockage of Egr-1 function in the liver of mice led to lower fasting blood glucose, better pyruvate tolerance, and higher hepatic glycogen content. The mechanism analysis demonstrated that Egr-1 can directly bind to the promoter of C/EBPa and regulate the expression of gluconeogenesis genes in the later phase of glucagon stimulation. The transient increase of Egr-1 by glucagon kept the glucose homeostasis after fasting for longer periods of time, whereas constitutive Egr-1 elevation found in the liver of db/db mice and high serum glucagon level overactivated the C/EBPa/gluconeogenesis pathway and resulted in hyperglycemia. Blockage of Egr-1 activation in prediabetic db/db mice was able to delay the progression of diabetes. Our results suggest that dysregulation of Egr-1/C/EBPa on glucagon stimulation may provide an alternative mechanistic explanation for type 2 diabetes. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  13. p16INK4a, but not constitutively active pRb, can impose a sustained G1 arrest: molecular mechanisms and implications for oncogenesis

    DEFF Research Database (Denmark)

    Lukas, J; Sørensen, Claus Storgaard; Lukas, C

    1999-01-01

    p16ink4 and pRb, two components of a key G1/S regulatory pathway, and tumor suppressors commonly targeted in oncogenesis, are among the candidates for gene therapy of cancer. Wild-type p16 and a constitutively active pRb(delta cdk) mutant both blocked G1 in short-term experiments, but only p16......)-expressing cells, became rapidly inhibited through restructuring diverse cyclin/CDK/p21 complexes by p16. These results provide novel insights into the roles of p16, pRb and cyclin E in G1/S control and multistep oncogenesis, with implications for gene therapy strategies....... imposed a sustained G1 arrest. Unexpectedly, cells conditionally exposed to pRb(delta cdk) entered S phase after 2 days, followed by endoreduplication between days 4-6. The distinct phenotypes evoked by p16 vs pRb(delta cdk) appear mediated by cyclin E/CDK2 which, while active in the pRb(delta cdk...

  14. The distribution of FDG at PET examinations constitutes a relative mechanism: significant effects at activity quantification in patients with a high muscular uptake

    Energy Technology Data Exchange (ETDEWEB)

    Lindholm, Henry; Johansson, Ove; Jacobsson, Hans [Karolinska University Hospital Solna, Department of Radiology, Stockholm (Sweden); Jonsson, Cathrine [Karolinska University Hospital Solna, Department of Hospital Physics, Stockholm (Sweden)

    2012-11-15

    At {sup 18}F-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) examinations a high tracer uptake of the skeletal muscles is sometimes encountered which can lead to reduced uptake in pathological lesions. This was evaluated in retrospect in patients being recalled for a repeat examination after reducing the muscular uptake. Ten patients with increased muscular tracer uptake were examined with FDG PET/CT on two occasions with a mean of 6 days. All patients showed at least one pathological lesion with increased tracer uptake. The muscular uptake was reduced at the second examination by informing the patient to refrain from physical activity together with pretreatment with diazepam. The maximum standardized uptake value (SUV{sub max}) of the pathological lesion and SUV{sub mean} of certain skeletal muscles, liver, spleen, lungs, blood and certain bone marrow portions were calculated. In all patients, the muscular uptake was reduced to a normal level at visual evaluation as well as at comparison of SUVs with 25 consecutive clinical patients exhibiting a normal FDG distribution (p < 0.001). The mean lesion SUV{sub max} increased from 2.4 to 3.7 (54 %) between the examinations (p < 0.05). All reference tissues/organs showed a significant increase of SUV at the second examination. Relating lesion SUV{sub max} to the activity of any of the reference tissues/organs there was no significant difference between the studies. The distribution of FDG constitutes a relative mechanism. This must be especially considered at longitudinal examinations in the same patient at therapy evaluations. In examinations with a somehow distorted general distribution of the activity, it may be more relevant to relate the lesion activity to a reference tissue/organ than relying on SUV assessments. (orig.)

  15. Expressing Constitutively Active Rheb in Adult Neurons after a Complete Spinal Cord Injury Enhances Axonal Regeneration beyond a Chondroitinase-Treated Glial Scar.

    Science.gov (United States)

    Wu, Di; Klaw, Michelle C; Connors, Theresa; Kholodilov, Nikolai; Burke, Robert E; Tom, Veronica J

    2015-08-05

    After a spinal cord injury (SCI), CNS axons fail to regenerate, resulting in permanent deficits. This is due to: (1) the presence of inhibitory molecules, e.g., chondroitin sulfate proteoglycans (CSPG), in the glial scar at the lesion; and (2) the diminished growth capacity of adult neurons. We sought to determine whether expressing a constitutively active form of the GTPase Rheb (caRheb) in adult neurons after a complete SCI in rats improves intrinsic growth potential to result in axon regeneration out of a growth-supportive peripheral nerve grafted (PNG) into the SCI cavity. We also hypothesized that treating the glial scar with chondroitinase ABC (ChABC), which digests CSPG, would further allow caRheb-transduced neurons to extend axons across the distal graft interface. We found that targeting this pathway at a clinically relevant post-SCI time point improves both sprouting and regeneration of axons. CaRheb increased the number of axons, but not the number of neurons, that projected into the PNG, indicative of augmented sprouting. We also saw that caRheb enhanced sprouting far rostral to the injury. CaRheb not only increased growth rostral and into the graft, it also resulted in significantly more regrowth of axons across a ChABC-treated scar into caudal spinal cord. CaRheb(+) neurons had higher levels of growth-associated-43, suggestive of a newly identified mechanism for mTOR-mediated enhancement of regeneration. Thus, we demonstrate for the first time that simultaneously addressing intrinsic and scar-associated, extrinsic impediments to regeneration results in significant regrowth beyond an extremely challenging, complete SCI site. After spinal cord injury (SCI), CNS axons fail to regenerate, resulting in permanent deficits. This is due to the diminished growth capacity of adult neurons and the presence of inhibitory molecules in the scar at the lesion. We sought to simultaneously counter both of these obstacles to achieve more robust regeneration after

  16. Ginkgolic Acid C 17:1, Derived from Ginkgo biloba Leaves, Suppresses Constitutive and Inducible STAT3 Activation through Induction of PTEN and SHP-1 Tyrosine Phosphatase

    Directory of Open Access Journals (Sweden)

    Seung Ho Baek

    2017-02-01

    Full Text Available Ginkgolic acid C 17:1 (GAC 17:1 extracted from Ginkgo biloba leaves, has been previously reported to exhibit diverse antitumor effect(s through modulation of several molecular targets in tumor cells, however the detailed mechanism(s of its actions still remains to be elucidated. Signal transducer and activator of transcription 3 (STAT3 is an oncogenic transcription factor that regulates various critical functions involved in progression of diverse hematological malignancies, including multiple myeloma, therefore attenuating STAT3 activation may have a potential in cancer therapy. We determined the anti-tumor mechanism of GAC 17:1 with respect to its effect on STAT3 signaling pathway in multiple myeloma cell lines. We found that GAC 17:1 can inhibit constitutive activation of STAT3 through the abrogation of upstream JAK2, Src but not of JAK1 kinases in U266 cells and also found that GAC can suppress IL-6-induced STAT3 phosphorylation in MM.1S cells. Treatment of protein tyrosine phosphatase (PTP inhibitor blocked suppression of STAT3 phosphorylation by GAC 17:1, thereby indicating a critical role for a PTP. We also demonstrate that GAC 17:1 can induce the substantial expression of PTEN and SHP-1 at both protein and mRNA level. Further, deletion of PTEN and SHP-1 genes by siRNA can repress the induction of PTEN and SHP-1, as well as abolished the inhibitory effect of drug on STAT3 phosphorylation. GAC 17:1 down-regulated the expression of STAT3 regulated gene products and induced apoptosis of tumor cells. Overall, GAC 17:1 was found to abrogate STAT3 signaling pathway and thus exert its anticancer effects against multiple myeloma cells.

  17. CONSTITUTIONAL FOUNDATIONS OF JURISDICTION

    Directory of Open Access Journals (Sweden)

    Alexandre Jamal Batista

    2016-06-01

    Full Text Available At the current stage of our State of Law there is no way to separate the study of the civil procedural law from the Federal Constitution, especially the jurisdiction, because it is in the Constitution that there are the legitimizing foundations of the jurisdiction institute. In this article, we carry on about the constitutional foundations of jurisdiction, such as: the principle of natural justice, principle of access to justice, principle of impartiality, principle of publicity, principle of motivation and principle of submission to res judicata. The conclusion is, after all, that jurisdiction, as one of the bulwarks of the citizen, finds in the “Citizen Constitution” of 1988 its foundations and decisive bases.

  18. Improving the police activities in ensuring the constitutional rights and freedoms of man and citizen and interaction with civil society institutions: comprehensive measures

    Directory of Open Access Journals (Sweden)

    Kirichek E.V.

    2014-12-01

    Full Text Available Russian police reform is another important step to modernize the country and public administration system. The main purpose of ongoing reforms is to create the modern and efficient law enforcement system, to form a new image of police officer in the XXI century and to change the social role of law enforcement agencies in society. Unfortunately, the results expected by society aren’t achieved. It’s stated that the reform is only at its beginning, many decisions are still to be made and implemented. The main focus is on comprehensive measures aimed at improving the police activities in ensuring the constitutional rights and freedoms of man and citizen and interaction with civil society institutions. Some features and problems of interaction between police and civil society institutions are considered. Statistics is provided. A number of constructive conclusions concerning further progressive development of interaction of police with civil society institutions are made. Despite the significant number of papers devoted to these issues, it’s necessary to note the insufficient elaboration of problems in this area. The reason is the ongoing reforms in Russia in general and police reform in particular, the instability of the current legislation regulating these issues. A lack of a clear concept of the reform, arising from a clear understanding of the police role and functions, is evident. These and other circumstances determine the topicality and practical importance of the research, the necessity of studying the peculiarities of police activities to improve its efficiency. They also indicate the need for scientific and practical recommendations.

  19. Constituting children's bodily integrity.

    Science.gov (United States)

    Hill, B Jessie

    2015-04-01

    Children have a constitutional right to bodily integrity. Courts do not hesitate to vindicate that right when children are abused by state actors. Moreover, in at least some cases, a child's right to bodily integrity applies within the family, giving the child the right to avoid unwanted physical intrusions regardless of the parents' wishes. Nonetheless, the scope of this right vis-à-vis the parents is unclear; the extent to which it applies beyond the narrow context of abortion and contraception has been almost entirely unexplored and untheorized. This Article is the first in the legal literature to analyze the constitutional right of minors to bodily integrity within the family by spanning traditionally disparate doctrinal categories such as abortion rights; corporal punishment; medical decisionmaking; and nontherapeutic physical interventions such as tattooing, piercing, and circumcision. However, the constitutional right of minors to bodily integrity raises complex philosophical questions concerning the proper relationship between family and state, as well as difficult doctrinal and theoretical issues concerning the ever-murky idea of state action. This Article canvasses those issues with the ultimate goal of delineating a constitutional right of bodily security and autonomy for children.

  20. The Constitution Debate

    Directory of Open Access Journals (Sweden)

    Heinrich Schneider

    2003-03-01

    Full Text Available The paper deals with certain questions and problems of the constitutionalization of the European Union which did not receive very much attention from the ‘Convention on the Future of Europe’ and from the observers of that Convention’s work, but which, nevertheless, may be relevant whenever the results of the Convention’s work are assessed and evaluated. The paper mainly deals with ‘background’ problems associated with traditions of political thought in general and with basic understandings of European integration in particular. The paper also expounds on how the more recent constitution discussion, initiated due to the founding of the European Union, manifests continuities with the debates that have taken place over the past decades (since the start of the integration policy based on the ‘Community method’. However, it shows that the discussion context has become more complex. In the last section of the paper, the relationship of ‘statics’ and ‘dynamics’ in relation to European constitutional conceptions is treated as a subject. The question arises as to whether and to what extent the constitution concept itself is in doubt and whether or not, in connection with this, important functions, whose very performance is expected of a constitution of the European Union, remain unfulfilled.

  1. Gender and the Constitution

    Science.gov (United States)

    Ginsburg, Ruth Bader

    1975-01-01

    In discussing the constitutional aspects of the sex-role debate in the U.S. the author traces the tradition, compares the present criterion of equal protection to the equal rights argument, and analyzes the equality principle with reference to affirmative action and to childbearing and childrearing, supporting the proposed equal rights amendment.…

  2. The Constitution Debate

    Directory of Open Access Journals (Sweden)

    Heinrich Schneider

    2003-03-01

    Full Text Available The paper deals with certain questions and problems of the constitutionalization of the European Union which did not receive very much attention from the Convention on the Future of Europe and from the observers of that Conventions work, but which, nevertheless, may be relevant whenever the results of the Conventions work are assessed and evaluated. The paper mainly deals with background problems associated with traditions of political thought in general and with basic understandings of European integration in particular. The paper also expounds on how the more recent constitution discussion, initiated due to the founding of the European Union, manifests continuities with the debates that have taken place over the past decades (since the start of the integration policy based on the Community method. However, it shows that the discussion context has become more complex. In the last section of the paper, the relationship of statics and dynamics in relation to European constitutional conceptions is treated as a subject. The question arises as to whether and to what extent the constitution concept itself is in doubt and whether or not, in connection with this, important functions, whose very performance is expected of a constitution of the European Union, remain unfulfilled.

  3. Communicative Constitution of Organizations

    DEFF Research Database (Denmark)

    Schoeneborn, Dennis; Vasquez, Consuelo

    2017-01-01

    The notion of the communicative constitution of organizations (CCO) is at the center of a growing theoretical development within organizational communication studies. CCO scholarship is based on the idea that organization emerges in and is sustained and transformed by communication. This entry...

  4. The acquisition of resistance to TNFα in breast cancer cells is associated with constitutive activation of autophagy as revealed by a transcriptome analysis using a custom microarray.

    Science.gov (United States)

    Moussay, Etienne; Kaoma, Tony; Baginska, Joanna; Muller, Arnaud; Van Moer, Kris; Nicot, Nathalie; Nazarov, Petr V; Vallar, Laurent; Chouaib, Salem; Berchem, Guy; Janji, Bassam

    2011-07-01

    While the autophagic process is mainly regulated at the post-translational level, a growing body of evidence suggests that autophagy might also be regulated at the transcriptional level. The identification of transcription factors involved in the regulation of autophagy genes has provided compelling evidence for such regulation. In this context, a powerful high throughput analysis tool to simultaneously monitor the expression level of autophagy genes is urgently needed. Here we describe setting up the first comprehensive human autophagy database (HADb, available at www.autophagy.lu) and the development of a companion Human Autophagy-dedicated cDNA Microarray which comprises 234 genes involved in or related to autophagy. The autophagy microarray tool used on breast adenocarcinoma MCF-7 cell line allowed the identification of 47 differentially expressed autophagy genes associated with the acquisition of resistance to the cytotoxic effect of TNFα. The autophagy-core machinery genes DRAM (Damage-Regulated Autophagy Modulator), BNIP3L (BCL2/adenovirus E1B 19 kDa interacting protein 3-like), BECN1 (Beclin 1), GABARAP (Gamma-AminoButyric Acid Receptor-Associated Protein) and UVRAG (UV radiation resistance associated gene) were found upregulated in TNF-resistant cells, suggesting a constitutive activation of the autophagy machinery in these cells. More interestingly, we identified NPC1 as the most upregulated genes in TNF-resistant compared to TNF-sensitive MCF-7 cells, suggesting a relation between the intracellular transport of cholesterol, the regulation of autophagy and NPC1 expression in TNF-resistant tumor cells. In conclusion, we describe here new tools that may help investigating autophagy gene regulation in various cellular models and diseases.

  5. Judiciary on Russian Constitutional System

    Directory of Open Access Journals (Sweden)

    Vladislav Arkhipov

    2013-12-01

    Full Text Available This article is about new constitutional order in Russia emphasizing fundamental areas as the role of judiciary in the Russian Constitutional System from 1993 Constitution, the one which replaced the 1978 Russian Soviet Federative Socialist Republic Constitution based on communist ideology. Therefore, it is intended to examine the principle of separation of powers, constitutionally recognized human rights and liberties, relationship between international bodies’ case law of human rights and the Russian Constitutional Court, among others issues.

  6. What constitutes information integrity?

    Directory of Open Access Journals (Sweden)

    S. Flowerday

    2007-12-01

    Full Text Available This research focused on what constitutes information integrity as this is a problem facing companies today. Moreover, information integrity is a pillar of information security and is required in order to have a sound security management programme. However, it is acknowledged that 100% information integrity is not currently achievable due to various limitations and therefore the auditing concept of reasonable assurance is adopted. This is in line with the concept that 100% information security is not achievable and the notion that adequate security is the goal, using appropriate countermeasures. The main contribution of this article is to illustrate the importance of and provide a macro view of what constitutes information integrity. The findings are in harmony with Samuel Johnson's words (1751: 'Integrity without knowledge is weak and useless, and knowledge without integrity is dangerous and dreadful.'

  7. What constitutes information integrity?

    Directory of Open Access Journals (Sweden)

    S. Flowerday

    2008-01-01

    Full Text Available This research focused on what constitutes information integrity as this is a problem facing companies today. Moreover, information integrity is a pillar of information security and is required in order to have a sound security management programme. However, it is acknowledged that 100% information integrity is not currently achievable due to various limitations and therefore the auditing concept of reasonable assurance is adopted. This is in line with the concept that 100% information security is not achievable and the notion that adequate security is the goal, using appropriate countermeasures. The main contribution of this article is to illustrate the importance of and provide a macro view of what constitutes information integrity. The findings are in harmony with Samuel Johnson's words (1751: 'Integrity without knowledge is weak and useless, and knowledge without integrity is dangerous and dreadful.'

  8. Transnational Governance and Constitutionalism

    DEFF Research Database (Denmark)

    Joerges, Christian; Sand, Inger-Johanne; Teubner, Gunther

    The term transnational governance designates untraditional types of international and regional collaboration among both public and private actors. These legally-structured or less formal arrangements link economic, scientific and technological spheres with political and legal processes. They are ......The term transnational governance designates untraditional types of international and regional collaboration among both public and private actors. These legally-structured or less formal arrangements link economic, scientific and technological spheres with political and legal processes....... They are challenging the type of governance which constitutional states were supposed to represent and ensure. They also provoke old questions: Who bears the responsibility for governance without a government? Can accountability be ensured? The term 'constitutionalism' is still widely identified with statal form...... of democratic governance. The book refers to this term as a yardstick to which then contributors feel committed even where they plead for a reconceptualisation of constitutionalism or a discussion of its functional equivalents. 'Transnational governance' is neither public nor private, nor purely international...

  9. Constitutionality of CEPA challenged

    Energy Technology Data Exchange (ETDEWEB)

    Attaran, A.

    1997-02-24

    The Canadian Environmental Protection Act (CEPA) was challenged by Hydro-Quebec in the Supreme Court of Canada. Hydro-Quebec argued that in the absence of any explicit jurisdiction, federal environmental law must be rooted in either the Constitution`s criminal law power, or in its power to legislate for the peace, order and good government of Canada. When accused under CEPA of dumping PCBs into the the St. Maurice River in 1990, Hydro-Quebec, joined in its case by the Attorney Generals of Quebec and Saskatchewan, and IPSCO Inc., argued that the law failed to meet these criteria, and is, therefore unconstitutional and invalid. The Supreme Court case focused primarily on the validity of the Federal Government`s right to declare substances toxic in its pursuit of protecting the environment from immediate or long-term harm, in as much as the criminal law power is understood to protect human life and health, but heretofore, not the environment. Although the Justices were anxious to circumscribe the limits of federal environmental jurisdiction, they also appeared disinclined to explode all of Canada`s toxic waste laws. The most likely outcome is that the CEPA will be allowed to stand, but will be severed of the environmental protection purpose, while preserving the Federal Government`s jurisdiction over toxic substances under the protection of human life and health provisions of the Constitution.

  10. Constitutionalism and Development in Nigeria: The 1999 Constitution

    African Journals Online (AJOL)

    Fr. Ikenga

    IKPEZE: Constitutionalism and Development in Nigeria: The 1999 Constitution and Role of Lawyers. Modern Constitutional concepts, which were based on Constitution as a social contract, were originated by philosophers like Thomas Hobbes who also was an English Scientist, (1588-. 1679), John Locke in English (1632 ...

  11. Comparison of constitutive and inducible transcriptional enhancement mediated by kappa B-related sequences: modulation of activity in B cells by human T-cell leukemia virus type I tax gene.

    Science.gov (United States)

    Mauxion, F; Jamieson, C; Yoshida, M; Arai, K; Sen, R

    1991-03-15

    The kappa B sequence (GGGACTTTCC) binds a factor, NF-kappa B, that is constitutively found in its functional, DNA binding form only in B lymphocytes. A factor with apparently indistinguishable sequence specificity can be induced in many other cell types, where it is used to regulate inducible gene expression. For example, kappa B-related sequences have been shown to be important for the transcription of a few inducible genes, such as the interleukin 2 receptor alpha-chain gene and the beta-interferon gene. However, these genes are not constitutively active in B lymphocytes, suggesting that other regulatory mechanisms must play a role in determining the patterns of expression. We have investigated the constitutive and inducible transcriptional activity mediated by five kappa B-related sequence elements in two different cell types. We show that in S194 plasma cells the activity of each element correlates well with the relative affinity of B-cell-derived NF-kappa B for that element. This leads to significantly lower transcription enhancement by sites derived from the interleukin 2 receptor or T-cell receptor genes in S194 cells. However, in either EL-4 (T) cells or S194 cells, both lower-affinity sites can be significantly induced by the tax gene product of human T-cell leukemia virus type I, showing that NF-kappa B activity can be modulated even in a B-cell line that constitutively expresses this factor.

  12. The E92K melanocortin 1 receptor mutant induces cAMP production and arrestin recruitment but not ERK activity indicating biased constitutive signaling

    DEFF Research Database (Denmark)

    Benned-Jensen, Tau; Mokrosinski, Jacek; Rosenkilde, Mette M

    2011-01-01

    The melanocortin 1 receptor (MC1R) constitutes a key regulator of melanism. Consequently, many naturally-occurring MC1R mutations are associated with a change in color. An example is the Glu-to-Lys substitution found at position II:20/2.60 in the top of transmembrane helix II which has been ident...

  13. The Bicentennial and State Constitutions.

    Science.gov (United States)

    Clay, Henry

    1988-01-01

    Illustrates how the Bicentennial of the U.S. Constitution provides an opportunity to teach about the broader concept of constitutionalism through study of the state constitutions. Presents an argument for teaching about state constitutions, their role in the federal system, and the values they convey. (LS)

  14. Thomas Jefferson and the Constitution.

    Science.gov (United States)

    Peterson, Merrill D.

    1987-01-01

    Examines Thomas Jefferson's role in the making and interpretation of the United States Constitution. Discusses the dominant features of Jefferson's constitutional theory; the character of Jefferson's presidency; and Jefferson's ongoing concern about constitutional preservation and change. Lists important dates in the history of the constitution.…

  15. Listeria-vectored vaccine expressing the Mycobacterium tuberculosis 30 kDa major secretory protein via the constitutively active prfA* regulon boosts BCG efficacy against tuberculosis.

    Science.gov (United States)

    Jia, Qingmei; Dillon, Barbara Jane; Masleša-Galić, Saša; Horwitz, Marcus A

    2017-06-19

    A potent vaccine against tuberculosis, one of the world's deadliest diseases, is needed to enhance the immunity of people worldwide, most of whom have been vaccinated with the partially effective BCG vaccine. Here we investigate novel live attenuated recombinant Listeria monocytogenes (rLm) vaccines expressing the Mycobacterium tuberculosis (Mtb) 30 kDa major secretory protein (r30/Ag85B) (rLm30) as heterologous booster vaccines in animals primed with BCG. Using three attenuated Lm vectors, rLm ΔactA (LmI), rLm ΔactA ΔinlB (LmII), and rLm ΔactA ΔinlBprfA* (LmIII), we constructed five rLm30 vaccine candidates expressing the r30 linked in-frame to the Lm Listeriolycin O signal sequence and driven by the hly promoter (h30) or linked in-frame to the ActA N-terminus and driven by the actA promoter (a30). All five rLm30 vaccines secreted r30 in broth and macrophages; while rLm expressing r30 via a constitutively active prfA* regulon (rLmIII/a30) expressed the greatest amount of r30 in broth culture, all five rLm vaccines expressed equivalent amounts of r30 in infected macrophages. In comparative studies, boosting BCG-immunized mice with rLmIII/a30 induced the strongest antigen-specific T-cell responses, including splenic and lung polyfunctional CD4+ T-cells expressing the three cytokines of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) (P vaccines were generally more potent booster vaccines than r30 in adjuvant and a recombinant adenovirus vaccine expressing r30. In a setting in which BCG alone was highly immunoprotective, boosting mice with rLmIII/a30, the most potent of the vaccines, significantly enhanced protection against aerosolized Mtb (P <0.01). Copyright © 2017 American Society for Microbiology.

  16. The constitutive sofa cushion

    DEFF Research Database (Denmark)

    Hanghøj, Sara

    2009-01-01

    personal values materialize through a hand-made everyday artefact, and how can the artefact constitute action and self-perception? The empirical research and analysis concerns how a former textile crafts teacher's subjective values and professional identity materialize through a hand-woven sofa cushion...... body, space and artefact, thereby revealing the materialization process. Based on results of the analysis, ANT (Actor-Network- Theory) is used in order to discuss how The Danish Folk High School's conception of simplicity as an aesthetic and gendered ideal in the formal education of female handcraft-teachers...

  17. Legal theology in imposed constitutionalism

    DEFF Research Database (Denmark)

    Abat Ninet, Antoni

    2018-01-01

    discusses both the imposition of a constitution and constitutionalism. The examples that the drafters of the Kazanistan´s constitution analysed are “successful” imposed texts such as in Germany and Japan, where both constitutions were made by elites under the humiliating supervision of foreign occupiers....... On the theme of imposed constitutionalism, the paper reflects on; the inconsistency of the idealistic discourse that permeates a constitutional text; the inability of an imposed text to be enveloped by principles that reflect the nation’s fundamental concepts; and finally, the denaturalisation...... of the understanding of a constitution as the juridification of the People or Nation. Related to the topic of imposed constitutionalism, the paper focuses on the systemic inconsistencies that imposed constitutionalism generates, such as the unviability of the idea of an implicit constitutional text (invisible ink...

  18. Computationally-predicted CB1 cannabinoid receptor mutants show distinct patterns of salt-bridges that correlate with their level of constitutive activity reflected in G protein coupling levels, thermal stability, and ligand binding.

    Science.gov (United States)

    Ahn, Kwang H; Scott, Caitlin E; Abrol, Ravinder; Goddard, William A; Kendall, Debra A

    2013-08-01

    The cannabinoid receptor 1 (CB1), a member of the class A G-protein-coupled receptor (GPCR) family, possesses an observable level of constitutive activity. Its activation mechanism, however, has yet to be elucidated. Previously we discovered dramatic changes in CB1 activity due to single mutations; T3.46A, which made the receptor inactive, and T3.46I and L3.43A, which made it essentially fully constitutively active. Our subsequent prediction of the structures of these mutant receptors indicated that these changes in activity are explained in terms of the pattern of salt-bridges in the receptor region involving transmembrane domains 2, 3, 5, and 6. Here we identified key salt-bridges, R2.37 + D6.30 and D2.63 + K3.28, critical for CB1 inactive and active states, respectively, and generated new mutant receptors that we predicted would change CB1 activity by either precluding or promoting these interactions. We find that breaking the R2.37 + D6.30 salt-bridge resulted in substantial increase in G-protein coupling activity and reduced thermal stability relative to the wild-type reflecting the changes in constitutive activity from inactive to active. In contrast, breaking the D2.63 + K3.28 salt-bridge produced the opposite profile suggesting this interaction is critical for the receptor activation. Thus, we demonstrate an excellent correlation with the predicted pattern of key salt-bridges and experimental levels of activity and conformational flexibility. These results are also consistent with the extended ternary complex model with respect to shifts in agonist and inverse agonist affinity and provide a powerful framework for understanding the molecular basis for the multiple stages of CB1 activation and that of other GPCRs in general. Copyright © 2013 Wiley Periodicals, Inc., a Wiley company.

  19. The Constitution of Partnering

    DEFF Research Database (Denmark)

    Gottlieb, Stefan Christoffer

    The constitution of partnering. Afhandlingen behandler konstitueringen af ledelseskonceptet partnering og dets anvendelse i dansk byggeri. Partnering er et udbredt koncept i byggeriet som betoner samarbejde, tillid og gensidighed mellem de deltagende parter, og konceptet har de senere år har været...... om, hvordan partnering som koncept er fremkommet og har udviklet sig og hvilke konstitutive effekter partnering har på byggeriets praksis. Det teoretiske udgangspunkt i Foucault begrundes i behovet for at fastholde en mangefacetteret og historisk analyse af partnering i modsætning til de...... ledelseskoncept (partnering) medvirker til at strukturere byggeprocesser ved at skabe bestemte muligheder for handling samtidig med at der opretholdes en betydelig stabilitet. Afhandlingen har en række praktiske implikationer ved at identificere de dispositiver eller sociale teknologier som en forandring af...

  20. Closing in on the constitution of consciousness

    Directory of Open Access Journals (Sweden)

    Steven M. Miller

    2014-11-01

    Full Text Available The science of consciousness is a nascent and thriving field of research that is founded on identifying the minimally sufficient neural correlates of consciousness. However, I have argued that it is the neural constitution of consciousness that science seeks to understand and that there are no evident strategies for distinguishing the correlates and constitution of (phenomenal consciousness. Here I review this correlation/constitution distinction problem and challenge the existing foundations of consciousness science. I present the main analyses from a longer paper in press on this issue, focusing on recording, inhibition, stimulation and combined inhibition/stimulation strategies, including proposal of the Jenga analogy to illustrate why identifying the minimally sufficient neural correlates of consciousness should not be considered the ultimate target of consciousness science. Thereafter I suggest that while combined inhibition and stimulation strategies might identify some constitutive neural activities — indeed minimally sufficient constitutive neural activities — such strategies fail to identify the whole neural constitution of consciousness and thus the correlation/constitution distinction problem is not fully solved. Various clarifications, potential objections and related scientific and philosophical issues are also discussed and I conclude by proposing new foundational claims for consciousness science.

  1. Functional importance of the Ala(116)-Pro(136) region in the calcium-sensing receptor. Constitutive activity and inverse agonism in a family C G-protein-coupled receptor

    DEFF Research Database (Denmark)

    Jensen, Anders A.; Spalding, T A; Burstein, E S

    2000-01-01

    The calcium-sensing receptor (CaR) belongs to family C of the G-protein-coupled receptor superfamily. To date 14 activating mutations in CaR showing increased sensitivity to Ca(2+) have been identified in humans with autosomal dominant hypocalcemia. Four of these activating mutations are found......, suppressed the elevated basal response of the constitutively activated Ca/1a mutants demonstrating inverse agonist activity of CPCCOEt. Taken together, our results demonstrate that the Ala(116)-Pro(136) region is of key importance for the maintenance of the inactive conformation of CaR....

  2. A newly discovered TSHR variant (L665F) associated with nonautoimmune hyperthyroidism in an Austrian family induces constitutive TSHR activation by steric repulsion between TM1 and TM7.

    Science.gov (United States)

    Jaeschke, Holger; Schaarschmidt, Joerg; Eszlinger, Markus; Huth, Sandra; Puttinger, Rudolf; Rittinger, Olaf; Meiler, Jens; Paschke, Ralf

    2014-10-01

    New in vivo mutations in G protein-coupled receptors open opportunities for insights into the mechanism of receptor activation. Here we describe the molecular mechanism of constitutive TSH receptor (TSHR) activation in an Austrian family with three generations of familial nonautoimmune hyperthyroidism. The index patient was diagnosed with hyperthyroidism during her first pregnancy. Her first two children were diagnosed with hyperthyroidism at the age of 11 and 10 years, respectively. TSH suppression was also observed in the third child at the age of 8 years, who has normal free T4 levels until now. TSH suppression in infancy was observed in the fourth child. The mother of the index patient was diagnosed with toxic multinodular goiter at the age of 36 years. DNA was extracted from blood samples from the index patient, her mother, and her four children. Screening for TSHR mutations was performed by high-resolution melting assays and subsequent sequencing. Elucidation of the underlying mechanism of TSHR activation was carried out by generation and structural analysis of TSHR transmembrane homology models and verification of model predictions by functional characterization of receptor mutations. A newly discovered TSHR mutation L665F in transmembrane helix 7 of the receptor was detected in six members of this family. Functional characterization of L665F revealed constitutive activation for the Gs pathway and thus represents the molecular cause for hyperthyroidism in this family. The constitutive activation is possibly linked to a steric clash introduced by the L665F mutation between transmembrane helices 1 and 7.

  3. The Constitutional Court and the Imperative of its Reform

    Directory of Open Access Journals (Sweden)

    Claudia Gilia

    2012-12-01

    Full Text Available Recent debates on the upcoming review of the Constitution have determined us to pay close attention to the basic institution in a democratic state, that is the Constitutional Court. Being caught in the crossfire between power and opposition, the Constitutional Court had a hard time lately, facing severe attacks. The aim of our study is to analyze the evolution of the Constitutional Court within the inland constitutional system, particularly bringing up the flaws describing the Court’s activity. We have also analyzed the proposals put forth by several bodies or experts regarding the constitutional contentious court. At the end of our study, following an analysis of different constitutional types of constitutional review, used by a number of states in Europe, we introduced several resolutions that may improve the role, the course and, last but not least, the activity of the Romanian Constitutional Court.

  4. An intracellular loop (IL2) residue confers different basal constitutive activities to the human lutropin receptor and human thyrotropin receptor through structural communication between IL2 and helix 6, via helix 3.

    Science.gov (United States)

    Feng, Xiuyan; Müller, Thomas; Mizrachi, Dario; Fanelli, Francesca; Segaloff, Deborah L

    2008-04-01

    The human lutropin receptor (hLHR) and human TSH receptor (hTSHR) are G protein-coupled receptors that play key roles in reproductive and thyroid physiology, respectively. We show using a quantitative assessment of cAMP production as a function of cell surface receptor expression that the hTSHR possesses greater basal constitutive activity than the hLHR. Further studies were undertaken to test the hypothesis that different potential Gs-coupling motifs identified in IL2 of the hTSHR and hLHR contribute to their different basal constitutive activities. Although mutating the receptors to interchange their potential Gs-coupling motifs reversed their relative activities, we show this to be due to the swapping of one IL2 residue (Q476 in the hLHR; R531 in the hTSHR). Molecular dynamics simulations show that the effect of the hLHR(Q476R) mutation, switching the structural features of the hLHR toward those of the hTSHR, is greater than the switching effect of the hTSHR(R531Q) mutant toward the hLHR. The structural model of the hLHR(Q476R) mutant can be considered as a hybrid of wild-type (wt) hTSHR and constitutively active mutant hLHR forms. In this hLHR(Q476R) mutant, IL2 adopts a structure similar to IL2 of the wt hTSHR, but it shares with the hLHR constitutively active mutant the solvent exposure and the reciprocal arrangement of helices 3, 5, and 6, including the weakening of the wt native R3.50-D6.30 interaction. Our results suggest a H3-mediated structural connection between IL2 and the cytosolic extension of H6. Thus, IL2 contributes significantly to the inactive and active state ensembles of these G protein-coupled receptors.

  5. Constitutive models in LAME.

    Energy Technology Data Exchange (ETDEWEB)

    Hammerand, Daniel Carl; Scherzinger, William Mark

    2007-09-01

    The Library of Advanced Materials for Engineering (LAME) provides a common repository for constitutive models that can be used in computational solid mechanics codes. A number of models including both hypoelastic (rate) and hyperelastic (total strain) constitutive forms have been implemented in LAME. The structure and testing of LAME is described in Scherzinger and Hammerand ([3] and [4]). The purpose of the present report is to describe the material models which have already been implemented into LAME. The descriptions are designed to give useful information to both analysts and code developers. Thus far, 33 non-ITAR/non-CRADA protected material models have been incorporated. These include everything from the simple isotropic linear elastic models to a number of elastic-plastic models for metals to models for honeycomb, foams, potting epoxies and rubber. A complete description of each model is outside the scope of the current report. Rather, the aim here is to delineate the properties, state variables, functions, and methods for each model. However, a brief description of some of the constitutive details is provided for a number of the material models. Where appropriate, the SAND reports available for each model have been cited. Many models have state variable aliases for some or all of their state variables. These alias names can be used for outputting desired quantities. The state variable aliases available for results output have been listed in this report. However, not all models use these aliases. For those models, no state variable names are listed. Nevertheless, the number of state variables employed by each model is always given. Currently, there are four possible functions for a material model. This report lists which of these four methods are employed in each material model. As far as analysts are concerned, this information is included only for the awareness purposes. The analyst can take confidence in the fact that model has been properly implemented

  6. Start Of The French Constitutionalism: Constitution Of 1791

    Directory of Open Access Journals (Sweden)

    Sergey V. Bochkarev

    2014-12-01

    Full Text Available In the present article author analyzes questions of French constitutionalism origin. Author notes that in France, over the past two centuries, a state of law, which is based on the principles of popular sovereignty has been formed; observance of human rights and freedoms by the state; parliamentary democracy; supremacy of constitution in relation to all other laws and regulations; separation of powers and institute of authorities responsibility as an organizational framework for the legal state; independence of the judiciary; compliance with commitments taken by the State during international relations. These principles were laid down in the constitutional history of the country. In the present article an attempt to explore the beginning of the French constitutionalism through the prism of the Constitution of 1791 was made. Author makes concludes that in the Constitution of 1791 the fundamental principles of constitutional law were laid, some of which are reflected in the Constitution of the Fifth Republic in France and continue to operate. Constitution of the Fifth Republic proclaimed commitment to "human rights and principles of national sovereignty as defined by the Declaration of 1789, confirmed and complemented by the Preamble to the Constitution of 1946, and despite many disputes, Constitutional Council reaffirmed inviolability of the equality before the law principle, which exists in the Declaration.

  7. Ontoteleological Constitution of Entrepreneurship

    Directory of Open Access Journals (Sweden)

    Diego Luiz Teixeira Boava

    2017-06-01

    Full Text Available Entrepreneurship is a pluri-disciplinary phenomenon, object of research in several areas of knowledge. However, studies on this theme present approaches that start to consider entrepreneurship as a field of private knowledge in the phase of epistemological construction. In this context, the aim of this investigation is to contribute to the discussions on the theme, through studies on the ontoteleological constitution of entrepreneurship, in propaedeutic character, deflagrating new approaches. Thus, there is a presentation concerning the study of entrepreneurship, which may emphasize its ontical and ontological aspects. In addition, the reason why it is complex to define entrepreneurship is investigated. Subjects regarding the philosophy of entrepreneurship are introduced, seeking to present the bases for an ontoteleological approach to the phenomenon. Such an approach assumes that the finality of the entrepreneurial act relates to the main principles and transformations required into the organization. Finally, it is concluded that man is an entrepreneurial being, the meta-entrepreneur, and his entrepreneurial actions are not determined by external factors, but rather by the condition of his potentiality.

  8. The diffusion of constitutional rights

    NARCIS (Netherlands)

    Goderis, B.V.G.; Versteeg, M.

    Constitutions are commonly regarded as uniquely national products, shaped by domestic ideals and politics. This paper develops and empirically investigates a novel hypothesis, which is that constitutions are also shaped by transnational influence, or “diffusion.” Constitutional rights can diffuse

  9. VALUATION IN THE CONSTITUTIONAL ERA

    African Journals Online (AJOL)

    Brimer

    VALUATION IN THE CONSTITUTIONAL ERA. WJ du Plessis *. Which way you ought to go depends on where you want to get to... - Lewis Carroll, Alice in Wonderland1. 1. Introduction. The Constitution established a single system of law shaped by the Constitution itself.2 It protected certain existing rights but it also initiated ...

  10. Constitutional judges (guarantee of the Constitution and responsibility

    Directory of Open Access Journals (Sweden)

    Francisco Javier Ansuátegui Roig

    2012-06-01

    Full Text Available My aim in this paper is to propose a reflection on the position and the importance that the constitutional judge has in the legal systems of contemporary constitutionalism. The figure of the judge responsible of protecting the Constitution is a key institution, without which we cannot understand the laws of constitutional democracies, their current lines of development, and the guarantee of rights and freedoms that constitute the normative core of these systems. Moreover, the reflection on the exercise of the powers of the judge, its scope and its justification is an important part of contemporary legal discussion, still relevant, albeit not exclusively - in the field of legal philosophy. The object of attention of my reflection is the judge who has the power of judicial review, in a scheme of defense of the Constitution, regardless the specific ways of this defense.

  11. Constitutionalism and Constitutional Anomie in the New Europe

    OpenAIRE

    Blokker, Paul

    2010-01-01

    The recent (re-)establishment of constitutional democracies in Central and Eastern Europe is affected by a paradoxical situation: while modern constitutionalism was significantly strenghtened by the ‘new constitutionalism’ in the region, it is itself increasingly seen as out of touch with (pluralist) reality. In the paper, I explore to what extent it can be claimed that the new constitutionalism adopted in the former communist countries is a reinvigorated version of ‘traditional’ modern const...

  12. Essential Medicines in National Constitutions

    Science.gov (United States)

    Toebes, Brigit; Hogerzeil, Hans

    2016-01-01

    Abstract A constitutional guarantee of access to essential medicines has been identified as an important indicator of government commitment to the progressive realization of the right to the highest attainable standard of health. The objective of this study was to evaluate provisions on access to essential medicines in national constitutions, to identify comprehensive examples of constitutional text on medicines that can be used as a model for other countries, and to evaluate the evolution of constitutional medicines-related rights since 2008. Relevant articles were selected from an inventory of constitutional texts from WHO member states. References to states’ legal obligations under international human rights law were evaluated. Twenty-two constitutions worldwide now oblige governments to protect and/or to fulfill accessibility of, availability of, and/or quality of medicines. Since 2008, state responsibilities to fulfill access to essential medicines have expanded in five constitutions, been maintained in four constitutions, and have regressed in one constitution. Government commitments to essential medicines are an important foundation of health system equity and are included increasingly in state constitutions. PMID:27781006

  13. Constitutive phosphorylation of Shc proteins in human tumors

    DEFF Research Database (Denmark)

    Pelicci, G; Lanfrancone, L; Salcini, A E

    1995-01-01

    cells. In tumor cells with known TK gene alterations Shc proteins were constitutively phosphorylated and complexed with the activated TK. No constitutive Shc phosphorylation was found in primary cell cultures and normal tissues. In 14 of 27 tumor cell lines with no reported TK alterations, Shc proteins...... activated TKs and that the analysis of Shc phosphorylation allow the identification of tumors with constitutive TK activation....

  14. Commission 35: Stellar Constitution

    Science.gov (United States)

    D'Antona, Francesca; Charbonnel, Corinne; Dziembowski, Wojciech; Fontaine, Gilles; Larson, Richard B.; Lattanzio, John; Liebert, Jim W.; Müller, Ewald; Weiss, Achim; Yungelson, Lev R.

    The Commission home page is maintained by Claus Leitherer and contains general information on the Commission structure and activities, including links to stellar structure resources that were made available by the owners. The resources contain evolutionary tracks and isochrones from various groups, nuclear reaction, EOS, and opacity data as well as links to main astronomical journals. As a routine activity, the Organizing Committee has commented on and ranked proposals for several IAU sponsored meetings. Our Commission acted as one of the coordinating bodies of a Symposium held at the IAU XXVI General Assembly in Prague, August 2006, (IAU Symposium No. 239 Convection in Astrophysics, and participated in the organization of the following Joint Discussions: JD05 Calibrating the Top of the Stellar Mass-Luminosity Relation, JD06 Neutron Stars and Black Holes in Star Clusters, JD08 Solar and Stellar Activity Cycles, JD11 Pre-Solar Grains as Astrophysical Tools; JD14 Modelling Dense Stellar Systems; and JD17 Highlights of Recent Progress in the Seismology of the Sun and Sun-like Stars.

  15. Constitutions compared. An introduction to comparative constitutional law

    NARCIS (Netherlands)

    Heringa, A.W.; Kiiver, P.

    2012-01-01

    This handbook provides a user-friendly introduction to comparative constitutional law. For each area of constitutional law, a general introduction and a comparative overview is provided, which is then followed by more detailed country chapters on that specific area. The subjects covered are the

  16. Constitutions compared : An introduction to comparative constitutional law

    NARCIS (Netherlands)

    Heringa, Aalt Willem

    2016-01-01

    This book provides a user-friendly introduction to comparative constitutional law. For each area of constitutional law, a general introduction and a comparative overview is provided, which is then followed by more detailed country chapters on that specific area. The subjects covered are the origins

  17. La Constitution économique parmi les Constitutions européennes

    OpenAIRE

    Kaarlo Tuori

    2011-01-01

    In the European context, the place of the revolutionary notions of constitutive power, demos and constitutional moment is occupied by the evolutionary concept of constitutionalisation. Economic constitution is merely one aspect in multi-dimensional European constitution (alisation). My tentative proposal is to distinguish between the following dimensions of constitution : economic constitution ; juridical constitution ; political constitution ; social constitution ; and security constitution....

  18. National constitutional courts in the European Constitutional Democracy

    DEFF Research Database (Denmark)

    Komárek, Jan

    2014-01-01

    This article critically assesses the transformation of national constitutional courts’ place in the law and politics of the EU and its member states. This process eliminates the difference between constitutional and ordinary national courts, which is crucial for the institutional implementation...... the EU and its member states, understood together as the European Constitutional Democracy—the central notion developed in this article in order to support an argument that should speak to both EU lawyers and national constitutionalists....... of the discourse theory of law and democracy. It also disrupts the symbiotic relationship between national constitutional democracies established after World War II and European integration. The article argues that maintaining the special place of national constitutional courts is in the vital interest of both...

  19. Eμ-BCL10 mice exhibit constitutive activation of both canonical and noncanonical NF-κB pathways generating marginal zone (MZ) B-cell expansion as a precursor to splenic MZ lymphoma

    Science.gov (United States)

    Li, Zhaoyang; Wang, Hongsheng; Xue, Liquan; Shin, Dong-Mi; Roopenian, Derry; Xu, Wu; Qi, Chen-Feng; Sangster, Mark Y.; Orihuela, Carlos J.; Tuomanen, Elaine; Rehg, Jerold E.; Cui, Xiaoli

    2009-01-01

    BCL10, required for nuclear factor κB (NF-κB) activation during antigen-driven lymphocyte responses, is aberrantly expressed in mucosa-associated lymphoid tissue-type marginal zone (MZ) lymphomas because of chromosomal translocations. Eμ-driven human BCL10 transgenic (Tg) mice, which we created and characterize here, had expanded populations of MZ B cells and reduced follicular and B1a cells. Splenic B cells from Tg mice exhibited constitutive activation of both canonical and noncanonical NF-κB signaling pathways is associated with increased expression of NF-κB target genes. These genes included Tnfsf13b, which encodes the B-cell activating factor (BAFF). In addition, levels of BAFF were significantly increased in sera from Tg mice. MZ B cells of Tg mice exhibited reduced turnover in vivo and enhanced survival in vitro, indicative of lymphoaccumulation rather than lymphoproliferation as the cause of MZ expansion. In vivo antibody responses to both T-independent, and especially T-dependent, antigens were significantly reduced in Tg mice. Mortality was accelerated in Tg animals, and some mice older than 8 months had histologic and molecular findings indicative of clonal splenic MZ lymphoma. These results suggest that, in addition to constitutive activation of BCL10 in MZ B cells, other genetic factors or environmental influences are required for short latency oncogenic transformation. PMID:19696203

  20. Constitutive rules, language, and ontology

    NARCIS (Netherlands)

    Hindriks, Frank

    It is a commonplace within philosophy that the ontology of institutions can be captured in terms of constitutive rules. What exactly such rules are, however, is not well understood. They are usually contrasted to regulative rules: constitutive rules (such as the rules of chess) make institutional

  1. Great Constitutional Ideas: Justice, Equality, and Property.

    Science.gov (United States)

    Starr, Isidore

    1987-01-01

    Examines the ideas of justice, equality, and property as they are represented in the Declaration of Independence, the U.S. Constitution and the Bill of Rights. Discusses how these ideas affect the way public schools operate and the lessons educators teach or don't teach about our society. Includes ideas for classroom activities. (JDH)

  2. Ubiquitin-Like Protein SAMP1 and JAMM/MPN+ Metalloprotease HvJAMM1 Constitute a System for Reversible Regulation of Metabolic Enzyme Activity in Archaea.

    Directory of Open Access Journals (Sweden)

    Shiyun Cao

    Full Text Available Ubiquitin/ubiquitin-like (Ub/Ubl proteins are involved in diverse cellular processes by their covalent linkage to protein substrates. Here, we provide evidence for a post-translational modification system that regulates enzyme activity which is composed of an archaeal Ubl protein (SAMP1 and a JAMM/MPN+ metalloprotease (HvJAMM1. Molybdopterin (MPT synthase activity was found to be inhibited by covalent linkage of SAMP1 to the large subunit (MoaE of MPT synthase. HvJAMM1 was shown to cleave the covalently linked inactive form of SAMP1-MoaE to the free functional individual SAMP1 and MoaE subunits of MPT synthase, suggesting reactivation of MPT synthase by this metalloprotease. Overall, this study provides new insight into the broad idea that Ub/Ubl modification is a post-translational process that can directly and reversibly regulate the activity of metabolic enzymes. In particular, we show that Ub/Ubl linkages on the active site residues of an enzyme (MPT synthase can inhibit its catalytic activity and that the enzyme can be reactivated through cleavage by a JAMM/MPN+ metalloprotease.

  3. Essential Oil from Sweet Potato Vines, a Potential New Natural Preservative, and an Antioxidant on Sweet Potato Tubers: Assessment of the Activity and the Constitution.

    Science.gov (United States)

    Yuan, Bo; Xue, Ling-Wei; Zhang, Qiu-Yue; Kong, Wan-Wan; Peng, Jun; Kou, Meng; Jiang, Ji-Hong

    2016-10-12

    Pathogenic fungi and oxidation are the major factors that cause the deterioration of sweet potatoes and also cause the loss of quality that makes consumption unsafe. In the present study, the in vitro results demonstrate that the essential oil from sweet potato vines exhibits significantly enhanced activity compared to that of the control. Furthermore, the essential oil can actively inhibit the growth of some common microorganisms inducing pathogenic bacteria and fungi (inhibition rates above 50% at low concentrations). A total of 31 constituents were identified using GC-MS and confirmed that linalool and p-hydroxybenzoic acid are the major active ingredients. The experiment involving actual tubers showed that the essential oil could retains its quality and effectiveness again the fungus disease. This suggests that it could be used in the food industry to increase the shelf life of stored produce (tubers) to ensure food safety without the use of additives or preservatives.

  4. Functional Characterization of a WWP1/Tiul1 Tumor-derived Mutant Reveals a Paradigm of Its Constitutive Activation in Human Cancer*

    Science.gov (United States)

    Courivaud, Thomas; Ferrand, Nathalie; Elkhattouti, Abdelouahid; Kumar, Santosh; Levy, Laurence; Ferrigno, Olivier; Atfi, Azeddine; Prunier, Céline

    2015-01-01

    Although E3 ubiquitin ligases are deemed to play key roles in normal cell function and homeostasis, whether their alterations contribute to cancer pathogenesis remains unclear. In this study, we sought to investigate potential mechanisms that govern WWP1/Tiul1 (WWP1) ubiquitin ligase activity, focusing on its ability to trigger degradation of TGFβ type I receptor (TβRI) in conjunction with Smad7. Our data reveal that the WWP1 protein is very stable at steady states because its autopolyubiquitination activity is silenced due to an intra-interaction between the C2 and/or WW and Hect domains that favors WWP1 monoubiquitination at the expense of its polyubiquitination or polyubiquitination of TβRI. Upon binding of WWP1 to Smad7, this functional interplay is disabled, switching its monoubiquitination activity toward a polyubiquitination activity, thereby driving its own degradation and that of TβRI as well. Intriguingly, a WWP1 point mutation found in human prostate cancer disrupts this regulatory mechanism by relieving the inhibitory effects of C2 and WW on Hect and thereby causing WWP1 hyperactivation. That cancer-driven alteration of WWP1 culminates in excessive TβRI degradation and attenuated TGFβ cytostatic signaling, a consequence that could conceivably confer tumorigenic properties to WWP1. PMID:26152726

  5. Use of a promiscuous, constitutively-active bacterial enhancer-binding protein to define the Sigma54 (RpoN) regulon of Salmonella Typhimurium LT2

    Science.gov (United States)

    Background: Sigma54, or RpoN, is an alternative s factor found widely in eubacteria. A significant complication in analysis of the global sigma54 regulon in a bacterium is that the sigma54 RNA polymerase holoenzyme requires interaction with an active bacterial enhancer-binding protein (bEBP) to init...

  6. A binuclear complex constituted by diethyldithiocarbamate and copper(I) functions as a proteasome activity inhibitor in pancreatic cancer cultures and xenografts.

    Science.gov (United States)

    Han, Jinbin; Liu, Luming; Yue, Xiaoqiang; Chang, Jinjia; Shi, Weidong; Hua, Yongqiang

    2013-12-15

    It is a therapeutic strategy for cancers including pancreatic to inhibit proteasome activity. Disulfiram (DSF) may bind copper (Cu) to form a DSF-Cu complex. DSF-Cu is capable of inducing apoptosis in cancer cells by inhibiting proteasome activity. DSF is rapidly converted to diethyldithiocarbamate (DDTC) within bodies. Copper(II) absorbed by bodies is reduced to copper(I) when it enters cells. We found that DDTC and copper(I) could form a binuclear complex which might be entitled DDTC-Cu(I), and it had been synthesized by us in the laboratory. This study is to investigate the anticancer potential of this complex on pancreatic cancer and the possible mechanism. Pancreatic cancer cell lines, SW1990, PANC-1 and BXPC-3 were used for in vitro assays. Female athymic nude mice grown SW1990 xenografts were used as animal models. Cell counting kit-8 (cck-8) assay and flow cytometry were used for analyzing apoptosis in cells. A 20S proteasome assay kit was used in proteasome activity analysis. Western blot (WB) and immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used in tumor sample analysis. The results suggest that DDTC-Cu(I) inhibit pancreatic cancer cell proliferation and proteasome activity in vitro and in vivo. Accumulation of ubiquitinated proteins, and increased p27 as well as decreased NF-κB expression were detected in tumor tissues of DDTC-Cu(I)-treated group. Our data indicates that DDTC-Cu(I) is an effective proteasome activity inhibitor with the potential to be explored as a drug for pancreatic cancer. © 2013. Published by Elsevier Inc. All rights reserved.

  7. Constitutive activation and accelerated maturation of peripheral blood t cells in healthy adults in burkina faso compared to Germany: The case of malaria?

    Directory of Open Access Journals (Sweden)

    Tiba F

    2011-12-01

    Full Text Available Abstract Objective It is not exactly known how frequent exposure to Plasmodium falciparum shapes the peripheral blood T-cell population in healthy West Africans. Methods The frequency of peripheral blood CD4+ lymphocytes responding to Plasmodium falciparum merozoite surface protein 1 (PfMSP-1 by production of interferon-gamma (IFN-γ, interleukin-2 (IL-2 or tumor necrosis factor-alpha (TNF-α was determined using a commercially available flow cytometric activation assay (Fastlmmune in 17 healthy adults in Nouna, Burkina Faso. T-cell activation and maturation in peripheral blood of healthy adults in Burkina Faso (n = 40 and Germany (n = 20 were compared using immunophenotyping and three-colour flow cytometry. Results Significant numbers of PfMSV-1 -specific CD4+ lymphocytes producing IFN-γ, IL-2 and/or TNF-α were detected in 14 healthy adults in Nouna. Cytokine profiles showed predominant production of IFN-γ and TNF-α. Compared to Germans, Burkinabé showed markedly lower proportions of CCR7+ CD45RA+ naïve CD4+ cells and slightly higher frequencies of CD95+ CD4+ T-cells and of CD38+ CD8+ T-cells. The median antibody-binding capacity of CD95dim CD4+ T-cells in Burkinabé was more than twice the value observed in Germans (263 vs. 108 binding sites per cell, p Conclusions We hypothesize that an IFN-γ-induced increase in the expression level of CD95 on CD4+ lymphocytes may lower the activation threshold of resting naïve CD4+ T-cells in healthy adults living in Burkina Faso. Bystander activation of these cells deserves further study as a molecular mechanism linking strong IFN-γ responses against Plasmodium falciparum to decreased susceptibility to parasitemia observed in specific ethnic groups in West Africa.

  8. Selective monoamine oxidase B inhibition by an Aphanizomenon flos-aquae extract and by its constitutive active principles phycocyanin and mycosporine-like amino acids.

    Science.gov (United States)

    Scoglio, Stefano; Benedetti, Yanina; Benvenuti, Francesca; Battistelli, Serafina; Canestrari, Franco; Benedetti, Serena

    2014-06-15

    Aphanizomenon flos-aquae (AFA) is a fresh water unicellular blue-green alga that has been traditionally used for over 25 years for its health-enhancing properties. Recent studies have shown the ability of a proprietary AFA extract (Klamin(®)) to improve mood, counteract anxiety, and enhance attention and learning. Aim of this study was to test the monoamine oxidase (MAO) inhibition activity of the same AFA extract and of its constituents phycocyanin (AFA-PC) and mycosporine-like aminoacids (AFA-MAAs). All compounds showed a dose-dependent selective inhibition of MAO-B activity as compared to MAO-A. The IC50 values of the AFA extract (concentration 10 mg/ml), AFA-PC and AFA-MAAs were 6.4 μl/ml, 1.33 μM and 1.98 μM, respectively, evidencing a mixed-type of inhibition for the AFA extract (Ki 0.99 μl/ml), a non-competitive inhibition for AFA-PC (Ki 1.06 μM) and a competitive inhibition for AFA-MAAs (Ki 0.585 μM). These results are important to explain the neuromodulating properties of the AFA extract Klamin(®), which is rich in phenylethylamine, a general neuromodulator, that would nevertheless rapidly destroyed by MAO-B enzymes without the inhibitory activity of the synergic active principles AFA-PC and AFA-MAAs. The present investigation thus proposes the extract as potentially relevant in clinical areas such as mood disorders and neurodegenerative diseases. Copyright © 2014 Elsevier GmbH. All rights reserved.

  9. Constitutive Modelling in Geomechanics Introduction

    CERN Document Server

    Puzrin, Alexander M

    2012-01-01

    The purpose of this book is to bridge the gap between the traditional Geomechanics and Numerical Geotechnical Modelling with applications in science and practice. Geomechanics is rarely taught within the rigorous context of Continuum Mechanics and Thermodynamics, while when it comes to Numerical Modelling, commercially available finite elements or finite differences software utilize constitutive relationships within the rigorous framework. As a result, young scientists and engineers have to learn the challenging subject of constitutive modelling from a program manual and often end up with using unrealistic models which violate the Laws of Thermodynamics.  The book is introductory, by no means does it claim any completeness and state of the art in such a dynamically developing field as numerical and constitutive modelling of soils. The author gives basic understanding of conventional continuum mechanics approaches to constitutive modelling, which can serve as a foundation for exploring more advanced theories....

  10. The significance of constitutional values

    Directory of Open Access Journals (Sweden)

    HN Nisihara

    2001-12-01

    Full Text Available This article addresses the question of the meaning and legal significance of constitutional values in contemporary times. The article attends also to related questions namely, what constituteconstitutional values” and what are the limitations of the meaning afforded to this notion. Attention is paid in the particular, to freedom, equality and democracy as value-neutral criteria of fairness and government neutrality with reference to the South African and German contexts as well as to value-neutrality as a culturally conditioned value. The author concludes with a cosmopolitan view of freedom and the right to peace with reference to the constitutional texts of Japan and the United States.

  11. Structure of the Constitutively Active Double Mutant CheY[superscript D13K Y106W] Alone and in Complex with a FliM Peptide

    Energy Technology Data Exchange (ETDEWEB)

    Dyer, Collin M.; Quillin, Michael L.; Campos, Andres; Lu, Justine; McEvoy, Megan M.; Hausrath, Andrew C.; Westbrook, Edwin M.; Matsumura, Philip; Matthews, Brian W.; Dahlquist, Frederick W. (MBC); (Oregon)

    2010-11-16

    CheY is a member of the response regulator protein superfamily that controls the chemotactic swimming response of motile bacteria. The CheY double mutant D13K Y106W (CheY**) is resistant to phosphorylation, yet is a highly effective mimic of phosphorylated CheY in vivo and in vitro. The conformational attributes of this protein that enable it to signal in a phosphorylation-independent manner are unknown. We have solved the crystal structure of selenomethionine-substituted CheY** in the presence of its target, a peptide (FliM{sub 16}) derived from the flagellar motor switch, FliM, to 1.5 {angstrom} resolution with an R-factor of 19.6%. The asymmetric unit contains four CheY** molecules, two with FliM{sub 16} bound, and two without. The two CheY** molecules in the asymmetric unit that are bound to FliM{sub 16} adopt a conformation similar to BeF{sub 3}{sup -}-activated wild-type CheY, and also bind FliM{sub 16} in a nearly identical manner. The CheY** molecules that do not bind FliM{sub 16} are found in a conformation similar to unphosphorylated wild-type CheY, suggesting that the active phenotype of this mutant is enabled by a facile interconversion between the active and inactive conformations. Finally, we propose a ligand-binding model for CheY and CheY**, in which Ile95 changes conformation in a Tyr/Trp106-dependent manner to accommodate FliM.

  12. Constitutional orders in multinational firms

    DEFF Research Database (Denmark)

    Hull Kristensen, Peer; Morgan, Glenn

    Multinationals are faced with the problem of how to coordinate different actors and stop `fiefdoms' emerging that inhibits the achievement of transnational cooperation? We identify this as a problem of `constitutional ordering' in the firm. Drawing on Varieties of Capitalism approaches, we explore...... how multinationals from different contexts seek to create constitutional orders. We argue that the models which exist appear to be destructive of coordination. We explore the implications for MNCs....

  13. The constitutive activation of the CEF-4/9E3 chemokine gene depends on C/EBPbeta in v-src transformed chicken embryo fibroblasts

    DEFF Research Database (Denmark)

    Gagliardi, M; Maynard, S; Bojovic, B

    2001-01-01

    -4 promoter composing a Src-responsive-Unit or SRU. The SRU includes a TPA responsive element, a PRDII/kappaB domain and a CAAT box. In this report, we identify C/EBPbeta as a component of the trans-acting factor interacting with the CAAT box of the CEF-4 promoter. In addition, we show that C....../EBPbeta binds to a second element located in proximity of the TRE. A mutation of this distal CAAT box impaired the activation of the CEF-4 promoter by pp60(v-src) indicating that this element is also part of the SRU. Using the RCASBP retroviral vector, we expressed a dominant negative mutant of C....../EBPbeta (designated Delta184-C/EBPbeta) in RSV-transformed CEF. Delta184-C/EBPbeta decreased the accumulation of the CEF-4 mRNA and activation of the CEF-4 promoter by pp60(v-src). The induction of the Cox-2 gene (CEF-147) was also reduced by Delta184-C/EBPbeta. The effect of the dominant negative mutant was observed...

  14. Right Product, Wrong Packaging: Not 'Constitution', but 'Constitutional Charter'

    Directory of Open Access Journals (Sweden)

    John Law

    2007-05-01

    Full Text Available The article seeks to locate the principal cause of Europe’s prevailing ratification crisis in the inappropriate title arrived at in the European Convention, Treaty Establishing a Constitution for Europe. This over-ambitious styling led the media to characterise the text as simply an ‘EU Constitution’. Yet, the text was not a Constitution as we traditionally understand the term, i.e. the founding document of a State: scholars are agreed that the EU is not, and will not become upon ratification, a State.In terms of substance, whilst the text certainly strengthened some emerging constitutional aspects, it was not a major departure from the status quo like the Single European Act and Treaty on European Union had been; and it remained technically a treaty like all its predecessors. Arguably, therefore, it did not require referenda to ratify. However, confusion over the scale and importance of what was proposed, stemming from ambiguity in the title, pushed politicians down this unfortunate path.The article identifies a high level of consensus among commentators as to the true nature of the text: most are happy designating it a treaty (noun with constitutional (adjective aspects. The early proposed title Constitutional Treaty for Europe was arguably, therefore, the correct one; but it is now too late to choose this option, as the terms Constitution and Constitutional Treaty have already been muddled in debate. A more distinctive change is required. One idea could be to follow the principle employed elsewhere in the text of codifying the generally accepted but presently unwritten legal concepts of the European Court of Justice, as was done for example for ‘primacy’ and ‘direct effect’. The Court has characterised the EU treaties as a ‘constitutional charter’ for over twenty years now, and on this basis a modified title could read Treaty Establishing a Constitutional Charter for Europe. Importantly, the term ‘charter’ is recognised

  15. Functional analysis of 14 genes that constitute the purine catabolic pathway in Bacillus subtilis and evidence for a novel regulon controlled by the PucR transcription activator

    DEFF Research Database (Denmark)

    Schultz, Anna Charlotte; Nygaard, P.; Saxild, Hans Henrik

    2001-01-01

    expression of five genes (pucA, pucB, pucC, pucD, and pucE). Uricase activity is encoded by the pucL and pucM genes, and a uric acid transport system is encoded by pucJ and pucK. Allantoinase is encoded by the pucH gene, and allantoin permease is encoded by the pucI gene. Allantoate amidohydrolase is encoded...... acid, allantoin, and uric acid were all found to function as effector molecules for PucR-dependent regulation of puc gene expression. When cells were grown in the presence of glutamate plus allantoin, a 3- to 10-fold increase in expression was seen for most of the genes. However, expression of the puc...

  16. An experimental evaluation of the anti-atherogenic potential of the plant, Piper betle, and its active constitutent, eugenol, in rats fed an atherogenic diet.

    Science.gov (United States)

    Venkadeswaran, Karuppasamy; Thomas, Philip A; Geraldine, Pitchairaj

    2016-05-01

    Hypercholesterolemia is a major risk factor for systemic atherosclerosis and subsequent cardiovascular disease. Lipoperoxidation-mediated oxidative damage is believed to contribute strongly to the progression of atherogenesis. In the current investigation, putative anti-atherogenic and antioxidative properties of an ethanolic extract of Piper betle and of its active constituent, eugenol, were sought in an experimental animal model of chronic hypercholesterolemia. Atherogenic diet-fed rats that received either Piper betle extract orally (500mg/kg b.wt) or eugenol orally (5mg/kg b.wt) for 15days (commencing 30days after the atherogenic diet had been started) exhibited the following variations in different parameters, when compared to atherogenic diet-fed rats that received only saline: (1) significantly lower mean levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol and very low density lipoprotein cholesterol in both serum and hepatic tissue samples; (2) lower mean serum levels of aspartate amino-transferase, alanine amino-transferase, alkaline phosphatase, lactate dehydrogenase and lipid-metabolizing enzymes (lipoprotein lipase, 3-hydroxy-3-methyl-glutaryl-CoA reductase; (3) significantly lower mean levels of enzymatic antioxidants (catalase, superoxide dismutase, glutathione peroxidase, glutathione-S-transferase) and non-enzymatic antioxidants (reduced glutathione, vitamin C and vitamin E) and significantly higher mean levels of malondialdehyde in haemolysate and hepatic tissue samples. Histopathological findings suggested a protective effect of the Piper betle extract and a more pronounced protective effect of eugenol on the hepatic and aortic tissues of atherogenic diet-fed (presumed atherosclerotic) rats. These results strongly suggest that the Piper betle extract and its active constituent, eugenol, exhibit anti-atherogenic effects which may be due to their anti-oxidative properties. Copyright © 2016 Elsevier Masson SAS. All rights

  17. Tissue-Mimicking Geometrical Constraints Stimulate Tissue-Like Constitution and Activity of Mouse Neonatal and Human-Induced Pluripotent Stem Cell-Derived Cardiac Myocytes

    Directory of Open Access Journals (Sweden)

    Götz Pilarczyk

    2016-01-01

    Full Text Available The present work addresses the question of to what extent a geometrical support acts as a physiological determining template in the setup of artificial cardiac tissue. Surface patterns with alternating concave to convex transitions of cell size dimensions were used to organize and orientate human-induced pluripotent stem cell (hIPSC-derived cardiac myocytes and mouse neonatal cardiac myocytes. The shape of the cells, as well as the organization of the contractile apparatus recapitulates the anisotropic line pattern geometry being derived from tissue geometry motives. The intracellular organization of the contractile apparatus and the cell coupling via gap junctions of cell assemblies growing in a random or organized pattern were examined. Cell spatial and temporal coordinated excitation and contraction has been compared on plain and patterned substrates. While the α-actinin cytoskeletal organization is comparable to terminally-developed native ventricular tissue, connexin-43 expression does not recapitulate gap junction distribution of heart muscle tissue. However, coordinated contractions could be observed. The results of tissue-like cell ensemble organization open new insights into geometry-dependent cell organization, the cultivation of artificial heart tissue from stem cells and the anisotropy-dependent activity of therapeutic compounds.

  18. Evaluation of chemical constitute, fatty acids and antioxidant activity of the fruit and seed of sea buckthorn (Hippophae rhamnoides L.) grown wild in Iran.

    Science.gov (United States)

    Saeidi, Keramatollah; Alirezalu, Abolfazl; Akbari, Zahra

    2016-01-01

    In this investigation, the chemical compositions of berries from sea buckthorn were studied. The amount of ascorbic acid and β-carotene determined by HPLC was 170 mg/100 g FW and 0.20 mg/g FW, respectively. Total phenols, anthocyanins, acidity and total soluble solids (TSS) contents were 247 mg GAE/100 g FW, 3 mg/L (cyanidin-3-glucoside), 5.32% and 13.8%, respectively. Fruit antioxidant activity determined by the ferric reducing ability of plasma (FRAP) method was 24.85 mM Fe/100 g FW. Results confirmed the presence of six dominant fatty acids (determined by GC) in fruit including linoleic (34.2%), palmitoleic (21.37%), palmitic (17.2%), oleic (12.8%), linolenic (5.37%) and stearic acid (1.67%). Five dominant fatty acids of the seeds were linoleic (42.36%), linolenic (21.27%), oleic (21.34%), palmitic (6.54%) and stearic acid (2.54%). The nitrogen content was 3.96%. The P, K, Ca, Mg, Fe, Zn, Mn, Cu, Cd and Cl contents of fruit were 491, 1674, 1290, 990, 291, 29.77, 108.37, 17.87, 0.021 and 2.18 mg/kg DW, respectively.

  19. The Spanish Constitution, the Constitutional Court and the Catalan Referendum

    DEFF Research Database (Denmark)

    Abat Ninet, Antoni

    2015-01-01

    politics in a concrete state, but they also represented the conquest of fundamental rights, liberties and the juridification of each new independent state. This epic and romantic aura helped the universal triumph of constitutionalism around the world. But at the same time, the conflict between demos...

  20. Constitutional Analysis of Intellectual Property

    Directory of Open Access Journals (Sweden)

    AJ van der Walt

    2014-04-01

    Full Text Available This article analyses the Constitutional Court’s treatment of property interests in the face of state regulation to gain an understanding of the type of state interference that is justifiable in terms of section 25(1 of the Bill of Rights. This is done by examining the Constitutional Court’s dicta relating to the meaning of deprivation and how these inform the meaning of property in the constitutional context. The methodology that the Constitutional Court has formulated to assess if state interference complies with the provisions of section 25 is explained to show the type of state regulation that has been found legitimate. We then consider how this understanding of constitutional property and the state’s legitimate exercise of its inherent police power interact in the setting of intellectual property by contrasting the various policy objectives underlying the different statutory regimes governing intellectual property. This theoretical analysis is then applied to two contemporary examples of feasible state interference with existing intellectual property interests, namely the proposed plain packaging measures which severely restrict the use of tobacco trade marks, and a fair dealing exception allowing the use of copyright works for the purpose of parody. These examples serve to illustrate the context and manner in which intellectual property interests may come before the Court and the necessary differentiation with which these interests should be treated. The appropriate judicial assessment of the true impact that state action could have on vested property interests is explained and contrasted with the balancing exercise that is employed at the earlier stage of policy making. This discussion is concluded by highlighting some of the interpretational issues that will arise and how some constitutional values could be curtailed in the absence of legislative intervention.

  1. Fetal bovine serum and human constitutive androstane receptor: Evidence for activation of the SV23 splice variant by artemisinin, artemether, and arteether in a serum-free cell culture system

    Energy Technology Data Exchange (ETDEWEB)

    Lau, Aik Jiang; Chang, Thomas K.H., E-mail: thomas.chang@ubc.ca

    2014-06-01

    The naturally occurring SV23 splice variant of human constitutive androstane receptor (hCAR-SV23) is activated by di-(2-ethylhexyl)phthalate (DEHP), which is detected as a contaminant in fetal bovine serum (FBS). In our initial experiment, we compared the effect of dialyzed FBS, charcoal-stripped, dextran-treated FBS (CS-FBS), and regular FBS on the basal activity and ligand-activation of hCAR-SV23 in a cell-based reporter gene assay. In transfected HepG2 cells cultured in medium supplemented with 10% FBS, basal hCAR-SV23 activity varied with the type of FBS (regular > dialyzed > CS). DEHP increased hCAR-SV23 activity when 10% CS-FBS, but not regular FBS or dialyzed FBS, was used. With increasing concentrations (1–10%) of regular FBS or CS-FBS, hCAR-SV23 basal activity increased, whereas in DEHP-treated cells, hCAR-SV23 activity remained similar (regular FBS) or slightly increased (CS-FBS). Subsequent experiments identified a serum-free culture condition to detect DEHP activation of hCAR-SV23. Under this condition, artemisinin, artemether, and arteether increased hCAR-SV23 activity, whereas they decreased it in cells cultured in medium supplemented with 10% regular FBS. By comparison, FBS increased the basal activity of the wild-type isoform of hCAR (hCAR-WT), whereas it did not affect the basal activity of the SV24 splice variant (hCAR-SV24) or ligand activation of hCAR-SV24 and hCAR-WT by 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO). The use of serum-free culture condition was suitable for detecting CITCO activation of hCAR-WT and hCAR-SV24. In conclusion, FBS leads to erroneous classification of pharmacological ligands of hCAR-SV23 in cell-based assays, but investigations on functional ligands of hCAR isoforms can be conducted in serum-free culture condition. - Highlights: • FBS leads to erroneous pharmacological classification of hCAR-SV23 ligands. • Artemisinin, artemether, and arteether activate h

  2. Constitutive activation of alternative nuclear factor kappa B pathway in canine diffuse large B-cell lymphoma contributes to tumor cell survival and is a target of new adjuvant therapies.

    Science.gov (United States)

    Seelig, Davis M; Ito, Daisuke; Forster, Colleen L; Yoon, Una A; Breen, Matthew; Burns, Linda J; Bachanova, Veronika; Lindblad-Toh, Kerstin; O'Brien, Timothy D; Schmechel, Stephen C; Rizzardi, Anthony E; Modiano, Jaime F; Linden, Michael A

    2017-07-01

    Activation of the classical nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway is a common molecular event observed in both human and canine diffuse large B-cell lymphoma (DLBCL). Although the oncogenic potential of the alternative NFκB pathway (ANFκBP) has also been recently identified in DLBCL, its precise role in tumor pathogenesis and potential as a treatment target is understudied. We hypothesized that up-regulation of the ANFκBP plays an important role in the proliferation and survival of canine DLBCL cells, and we demonstrate that the ANFκBP is constitutively active in primary canine DLBCL samples and a cell line (CLBL1). We further demonstrate that a small interfering RNA inhibits the activation of the NFκB pathway and induces apoptosis in canine DLBCL cells. In conclusion, the ANFκBP facilitates survival of canine DLBCL cells, and thus, dogs with spontaneous DLBCL can provide a useful large animal model to study therapies targeting the ANFκBP.

  3. Potent constitutive cyclic AMP-generating activity of XLαs implicates this imprinted GNAS product in the pathogenesis of McCune-Albright Syndrome and fibrous dysplasia of bone

    Science.gov (United States)

    Mariot, Virginie; Wu, Joy Y.; Aydin, Cumhur; Mantovani, Giovanna; Mahon, Matthew J.; Linglart, Agnès; Bastepe, Murat

    2010-01-01

    Patients with McCune-Albright syndrome (MAS), characterized primarily by hyperpigmented skin lesions, precocious puberty, and fibrous dyslasia of bone, carry postzygotic heterozygous mutations of GNAS causing constitutive cAMP signaling. GNAS encodes the α-subunit of the stimulatory G protein (Gsα), as well as a large variant (XLαs) derived from the paternal allele. The mutations causing MAS affect both GNAS products, but whether XLαs, like Gsα, can be involved in the pathogenesis remains unknown. Here, we investigated biopsy samples from four previously reported and eight new patients with MAS. Activating mutations of GNAS (Arg201 with respect to the amino acid sequence of Gsα) were present in all the previously reported and five of the new cases. The mutation was detected within the paternally expressed XLαs transcript in five and the maternally expressed NESP55 transcript in four cases. Tissues carrying paternal mutations appeared to have higher XLαs mRNA levels than maternal mutations. The human XLαs mutant analogous to Gsα-R201H (XLαs-R543H) showed markedly higher basal cAMP accumulation than wild-type XLαs in transfected cells. Wild-type XLαs demonstrated higher basal and isoproterenol-induced cAMP signaling than Gsα and co-purified with Gβ1γ2 in transduced cells. XLαs mRNA was measurable in mouse calvarial cells, with its level being significantly higher in undifferentiated cells than those expressing preosteoblastic markers osterix and alkaline phosphatase. XLαs mRNA was also expressed in murine bone marrow stromal cells and preosteoblastic MC3T3-E1 cells. Our findings are consistent with the possibility that constitutive XLαs activity adds to the molecular pathogenesis of MAS and fibrous dysplasia of bone. PMID:20887824

  4. Jonathan's Constitutional Conference in Nigeria

    African Journals Online (AJOL)

    ian

    2013-10-01

    Oct 1, 2013 ... commitment to work with recommendations of the Conference. The Conference wound up with the remarks by the. Chairman. President Jonathan, like many of the regimes before him, saw the inherent weaknesses and contradictions in the governing constitution, upon which his government had based its ...

  5. Unconstitutional constitutional amendments in Ethiopia: the practice ...

    African Journals Online (AJOL)

    Such constitutional provisions serve to confine the power to amend the constitution within the prescribed legal requirements as well as help to control arbitrary changes to the constitution, which consequently promotes constitutionalism within the country. The FDRE Constitution has been amended twice within these twenty ...

  6. In quest of constitutional principles of "neurolaw".

    Science.gov (United States)

    Pizzetti, Federico Gustavo

    2011-01-01

    The growing use of brain imaging technology and the developing of cognitive neuroscience pose unaccustomed challenges to legal systems. Until now, the fields of Law much affected are the civil and criminal law and procedure, but the constitutional dimension of "neurolaw" cannot be easily underestimated. As the capacity to investigate and to trace brain mechanisms and functional neural activities increases, it becomes urgent the recognition and definition of the unalienable rights and fundamental values in respect of this new techno-scientific power, that must be protected and safeguard at "constitutional level" of norms such as: human dignity, personal identity, authenticity and the pursuit of individual "happiness". As the same as for the law regulating research and experimentation on human genome adopted in the past years, one may also argue if the above mentioned fundamental principles of "neurolaw" must be fixed and disciplined also at European and International level.

  7. A constituição do sujeito na atividade estética da dança do ventre Constitution of subjectivity in the aesthetic activity of belly dance

    Directory of Open Access Journals (Sweden)

    Alice Casanova dos Reis

    2010-04-01

    Full Text Available O texto apresenta uma pesquisa cujo objetivo foi compreender de que modo a atividade estética da dança do ventre se concretiza e sua mediação na constituição do sujeito. Partindo de uma perspectiva histórico-cultural, a análise da entrevista com uma bailarina revelou diversas relações estéticas mediando a realização da dança: da bailarina com a técnica, com o corpo, com a música, com o público, com o sagrado, com o feminino. Compreendeu-se que nessas relações se engendram diferentes possibilidades de subjetivação, que convergem à constituição do sujeito como devir estético na dança do ventre.This text presents a research that aims to understand in which way the aesthetic activity of belly dance is concretized, and its mediation on the constitution of subjectivity. From a historical-cultural perspective, the analysis of an interview with a belly dancer revealed many aesthetic relations intervening the dance performance: how the belly dancer relates to the technique, to her body, to the music, to the public, to the sacred, to feminine conceptions. The text perceives that different possibilities of subjectivation are engendered through these relations, and converge in the constitution of the dancer as the aesthetic subject of the belly dance.

  8. Constitutions as Intergenerational Contracts: Flexible or fixed?

    Directory of Open Access Journals (Sweden)

    Jörg Tremmel

    2017-06-01

    Full Text Available Constitutions enshrine the fundamental values of a people and build a framework for a state’s public policy. With regard to intergenerational justice, their endurance gives rise to two concerns: the (forgone welfare concern and the sovereignty concern. In this paper, I outline a procedure for constitution- amending that is intergenerationally just. In its line of reasoning, the paper debates ideas such as perpetual constitutions, sunset constitutions, constitutional reform commissions and constitutional conventions both historically and analytically. It arrives at the conclusion that recurrent constitutional reform commissions in fixed time intervals strike the best balance between the necessary rigidity and the necessary flexibility of constitutions.

  9. The Constitutive Power of Twitter

    DEFF Research Database (Denmark)

    Albu, Oana Brindusa; Etter, Michael Andreas

    Twitter is an increasingly used new information and communication technology (ICT) in organizational settings. Predominant research, however, tends to adopt functionalist standpoints and investigates new ICTs as platforms of information transmission through which organizations interact...... organizations. The analysis illustrates how specific Twitter interactions, i.e., hashtags, become hypertexts—a type of authoritative texts—which simultaneously constitute an organizational actor or act as a pastiche of it. The study contributes to extant research by illustrating how hypertextuality...... with their constituents. Such focus leaves little knowledge concerning the tensions new ICTs bring to organizational life. For a more nuanced understanding of the constitutive role of new ICTs in organizing, this paper unfolds a communication centered perspective and examines the strategic Twitter use in two...

  10. Constitutional collisions of criminal law

    Directory of Open Access Journals (Sweden)

    Sergey M. Inshakov

    2016-12-01

    Full Text Available Objective to identify and resolve conflicts between the norms of constitutional and criminal law which regulate the issue of legal liability of senior officials of the state. Methods formallogical systematic comparativelegal. Results the article analyzes the embodiment of the principle of citizensrsquo equality under the law regarding the criminal responsibility of the President of the Russian Federation as one of the segments of the elite right other criminal and legal conflicts are considered associated with the creation of conditions for derogation from the principle of equality. Basing on this analysis the means of overcoming collisions between the norms of constitutional and criminal law are formulated. Scientific novelty in the article for the first time it has been shown that in the Russian criminal law there are exceptions to the principle of citizensrsquo equality under the law relating to the President of the Russian Federation the conflicts are identified between the norms of constitutional and criminal law regulating the issue of legal liability of senior officials of the state ways of overcoming conflicts are suggested. Practical significance the main provisions and conclusions of the article can be used in research and teaching in the consideration of issues of senior state officialsrsquo criminal liability.

  11. New Zimbabwe Constitution and the Right to Health Campaign 2010

    International Development Research Centre (IDRC) Digital Library (Canada)

    based organizations that aim to enhance community participation in health through a health literacy approach. This grant will enable CWCH to actively participate in the right to health campaign with a view to having it enshrined in the constitution.

  12. Modulation of regulatory T cell function by monocyte-derived dendritic cells matured through electroporation with mRNA encoding CD40 ligand, constitutively active TLR4, and CD70.

    Science.gov (United States)

    Pen, Joeri J; De Keersmaecker, Brenda; Maenhout, Sarah K; Van Nuffel, An M T; Heirman, Carlo; Corthals, Jurgen; Escors, David; Bonehill, Aude; Thielemans, Kris; Breckpot, Karine; Aerts, Joeri L

    2013-08-15

    Regulatory T cells (Tregs) counteract anticancer immune responses through a number of mechanisms, limiting dendritic cell (DC)-based anticancer immunotherapy. In this study, we investigated the influence of various DC activation stimuli on the Treg functionality. We compared DCs activated by electroporation with mRNA encoding constitutively active TLR4 (caTLR4) and CD40 ligand (DiMix-DCs), or these factors together with mRNA encoding the costimulatory molecule CD70 (TriMix-DCs) with DCs maturated in the presence of a mixture of inflammatory cytokines (DCs maturated with a combination of the cytokines IL-1β, IL-6, TNF-α, and PGE2) for their ability to counteract Tregs on different levels. We first demonstrated that there was no difference in the extent of Treg induction starting from CD4(+)CD25(-) T cells under the influence of the different DC maturation stimuli. Second, we showed that both DiMix- and TriMix-DCs could partly alleviate Treg inhibition of CD8(+) T cells. Third, we observed that CD8(+) T cells that had been precultured with DiMix-DCs or TriMix-DCs were partially protected against subsequent Treg suppression. Finally, we showed that Tregs cocultured in the presence of TriMix-DCs, but not DiMix-DCs, partially lost their suppressive capacity. This was accompanied by a decrease in CD27 and CD25 expression on Tregs, as well as an increase in the expression of T-bet and secretion of IFN-γ, TNF-α, and IL-10, suggesting a shift of the Treg phenotype toward a Th1 phenotype. In conclusion, these data suggest that TriMix-DCs are not only able to suppress Treg functions, but moreover could be able to reprogram Tregs to Th1 cells under certain circumstances.

  13. Constitutive Effects of Performance Indicators

    DEFF Research Database (Denmark)

    Dahler-Larsen, Peter

    2014-01-01

    The idea that performance indicators in public management have unintended consequences is almost as old as performance measurement itself. But, is ‘unintended consequences’ an appropriate and insightful idea? The very term rests on an identification of intentions and assumptions about validity...... that are demonstrably problematic. Based on a distinction between trivial and advanced measure fixation, an argument is made for constitutive effects that are based on less problematic assumptions. Through this conceptual move, the political dimension of performance indicators is appreciated. The conceptual dimensions...

  14. Constitutive Modeling of Geomaterials Advances and New Applications

    CERN Document Server

    Zhang, Jian-Min; Zheng, Hong; Yao, Yangping

    2013-01-01

    The Second International Symposium on Constitutive Modeling of Geomaterials: Advances and New Applications (IS-Model 2012), is to be held in Beijing, China, during October 15-16, 2012. The symposium is organized by Tsinghua University, the International Association for Computer Methods and Advances in Geomechanics (IACMAG), the Committee of Numerical and Physical Modeling of Rock Mass, Chinese Society for Rock Mechanics and Engineering, and the Committee of Constitutive Relations and Strength Theory, China Institution of Soil Mechanics and Geotechnical Engineering, China Civil Engineering Society. This Symposium follows the first successful International Workshop on Constitutive Modeling held in Hong Kong, which was organized by Prof. JH Yin in 2007.   Constitutive modeling of geomaterials has been an active research area for a long period of time. Different approaches have been used in the development of various constitutive models. A number of models have been implemented in the numerical analyses of geote...

  15. A Communicatively Constituted Online Crisis

    DEFF Research Database (Denmark)

    Valentini, Chiara; Romenti, Stefania; Kruckeberg, Dean

    2017-01-01

    This chapter presents a theoretical proposition that could serve as foundation to explain how people become aware, develop an understanding, and create meanings about specific critical situations through social media conversations and how, eventually, these transform critical situations into spec......This chapter presents a theoretical proposition that could serve as foundation to explain how people become aware, develop an understanding, and create meanings about specific critical situations through social media conversations and how, eventually, these transform critical situations...... into specific public crisis perceptions. Drawing from a communicative constitution perspective, the authors argue that if crises are perceptions or experiences of difficult situations that exceed a person’s current resources and coping mechanisms, and if perceptions and experiences in social media are typically...... by offering suggestions on how to study online critical conversations through the lens of a communicative constitution perspective that could inform how critical issues eventually transform and become crises and how crisis perceptions evolve and are discursively shaped by communicative practices occurring...

  16. Essence and constitution in Zubiri

    Directory of Open Access Journals (Sweden)

    Alfonso Gómez Fernández

    2015-03-01

    Full Text Available The aim of this article is to expound Zubiri’s concept of essence and to begin a critical discussion and evaluation of his proposal. Before explaining what essence is, it is necessary to observe that, for our author, not all things have an essence: only «reality-things» but not «meaning-things» form part of the «essentiable domain». This distinction between «reality-things» and «meaning-things» supposes a new conception of nature. (Nature is not the opposite of the artificial, as the Greek term physis is.«Reality-things» form a constitutional and «closed» system of non-causal and non-«external» characteristics or traits. These «foundational characteristics» of constitution, then, are precisely the essence. The article discusses critically the assumptions of this doctrine (reality, ontological pluralism, foundation and its possible limits in the light of contemporary science. It can be a useful theory for the philosophy of language.

  17. CONSTITUTIONAL LANDMARKS OF POLITICAL PLURALISM

    Directory of Open Access Journals (Sweden)

    ERHARD NICULESCU

    2013-05-01

    Full Text Available In order for democracy to result from freedom, the citizens’ participation in the creation and exercise of democratic power must be structured in a pluralist way. Art. 8(1 of the Romanian Constitution firstly imposes the organization of the company in parallel with the State’s organic structure as an indispensable requisite for the existence of democracy. In other words, there is no democracy without a civil society, distinct from the State. The organization of the civil society is necessary because the individual alone cannot determine a certain attitude of the political power: structuring gives weight to the action; the organization of citizens contributes to rendering their political participation more efficient. But the organization, structuring limits the freedom of people adhering to the structure.

  18. Structures of human constitutive nitric oxide synthases.

    Science.gov (United States)

    Li, Huiying; Jamal, Joumana; Plaza, Carla; Pineda, Stephanie Hai; Chreifi, Georges; Jing, Qing; Cinelli, Maris A; Silverman, Richard B; Poulos, Thomas L

    2014-10-01

    Mammals produce three isoforms of nitric oxide synthase (NOS): neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS). The overproduction of NO by nNOS is associated with a number of neurodegenerative disorders; therefore, a desirable therapeutic goal is the design of drugs that target nNOS but not the other isoforms. Crystallography, coupled with computational approaches and medicinal chemistry, has played a critical role in developing highly selective nNOS inhibitors that exhibit exceptional neuroprotective properties. For historic reasons, crystallography has focused on rat nNOS and bovine eNOS because these were available in high quality; thus, their structures have been used in structure-activity-relationship studies. Although these constitutive NOSs share more than 90% sequence identity across mammalian species for each NOS isoform, inhibitor-binding studies revealed that subtle differences near the heme active site in the same NOS isoform across species still impact enzyme-inhibitor interactions. Therefore, structures of the human constitutive NOSs are indispensible. Here, the first structure of human neuronal NOS at 2.03 Å resolution is reported and a different crystal form of human endothelial NOS is reported at 1.73 Å resolution.

  19. The Obligations on Government and Society in our Constitutional State to Respect and Support Independent Constitutional Structures

    Directory of Open Access Journals (Sweden)

    LWH Ackermann

    2000-05-01

    these institutions is vitally important for creating and sustaining an ethos of constitutionalism among the inhabitants of the Republic.The Constitution makes explicit provision for the protection of the judiciary and the other independent state institutions and thereby indirectly for the development of habits of constitutionalism. The constitutional protection and support given to the independent state institutions are very similar to that given to the courts. One important distinction is to be noted. In the case of the courts, the Constitution provides that they "are subject only to the Constitution and the law" and no provision is made for them to be accountable to any other organ of state or any other institution or person, for that matter. By contrast, the independent institutions envisaged in section 181 of the Constitution are expressly made accountable to the National Assembly and are obliged to report on their activities and the performance of their functions to the Assembly at least once a year. While the formal independence of state institutions may at all times be scrupulously recognised by the legislature and the executive, their substantive independence can easily be undermined by fiscal starvation and their ability to function properly impeded by bureaucratic administrative obstruction or obfuscation or even, quite innocently, by a lack of appreciation of what the Constitution demands from public administration in support of these institutions. Adequate financial and administrative resources are required to achieve aspects of judicial independence. All South Africans must still be vigilant to ensure, from the outset, that all state organs develop habits and practices of constitutionalism and that they do not, whether by omission, error, or otherwise endanger the independence of our independent state institutions by neglecting their constitutional obligations.For the Constitutional Court to fulfil its role as the ultimate guardian of the Constitution, it

  20. 17 CFR 200.54 - Constitutional obligations.

    Science.gov (United States)

    2010-04-01

    ... against any infringement of the constitutional rights, privileges, or immunities of those who are subject... 17 Commodity and Securities Exchanges 2 2010-04-01 2010-04-01 false Constitutional obligations... ORGANIZATION; CONDUCT AND ETHICS; AND INFORMATION AND REQUESTS Canons of Ethics § 200.54 Constitutional...

  1. Antithetical Ethics: Kenneth Burke and the Constitution.

    Science.gov (United States)

    Anderson, Virginia

    1995-01-01

    Shows how the textuality of the United States Constitution, the most venerable of classic democratic icons, might be exploited to nurture postmodern ethics. Shows how Kenneth Burke's reading of the Constitution accords with and augments the postmodern theories of J.-F. Lyotard and S. Jarratt. Discusses a postmodern Constitution and the…

  2. How Does the Constitution Secure Rights?

    Science.gov (United States)

    Goldwin, Robert A., Ed.; Schambra, William A., Ed.

    Third in a series designed to help prepare the nation for a thoughtful observance of the Constitutional bicentennial, this publication presents six essays addressing the issue of human rights and the Constitution. "How the Constitution Protects Our Rights: A Look at the Seminal Years" (Robert A. Rutland) focuses on James Madison's role…

  3. Teaching about Democratic Constitutionalism. ERIC Digest.

    Science.gov (United States)

    Patrick, John J.

    There are more than 100 democracies in the world today. All but three of them--Great Britain, Israel, and New Zealand --have written constitutions. This digest examines the importance of constitutions and constitutionalism and the teaching of these concepts through the use of comparisons. The primary objectives of civic education for democratic…

  4. The Constitution of the Republic of Estonia

    Index Scriptorium Estoniae

    2005-01-01

    Raamat sisaldab ka: The Constitution of the Republic of Estonia amendment act ; The Constitution of the Republic of Estonia implementation act ; Act to amend the Constitution of the Republic of Estonia for election of local government councils for term of four years

  5. The Constitution of the Republic of Estonia

    Index Scriptorium Estoniae

    2009-01-01

    Sisaldab ka: The Constitution of the Republic of Estonia Amendment Act. The Constitution of the Republic of Estonia Implementation Act. Act to Amend the Constitution of the Republic of Estonia for Election of Local Government Councils for Term of Four Years

  6. RECEPTING THE PRINCIPLE OF SUPREMACY OF CONSTITUTION ON THE NEW PENAL CODE

    Directory of Open Access Journals (Sweden)

    Marius ANDREESCU

    2016-07-01

    Full Text Available The supremacy of Constitution has as main consequence the compliance of entire law with the constitutional norms. Guaranteeing of the observance of this principle is essential for the rule of law, is primarily an attribute of the Constitutional Court, but also an obligation of the legislator to receive by texts adopted, within its content and form, the constitutional norms. Entering into force of the new criminal codes generated a significant jurisprudence of the Constitutional Court on the verification of constitutionality of some regulations in the Criminal Code and Criminal Procedure Code. Through this study we intend to analyze the following key issues: a how were the constitutional principles and values embodied in some criminal and criminal procedural norms of the new codes; b the effects of Constitutional Court decisions in the process of constitutionalizing of the criminal law; c applying into judicial activities of the Constitutional Court decisions, particularly those through which the new Criminal Code regulations were found unconstitutional.

  7. Change of position of constitutional judiciary

    Directory of Open Access Journals (Sweden)

    Orlović Slobodan P.

    2013-01-01

    Full Text Available Constitutional judiciary is the youngest branch of authority in the horizontal level of state power. Constitutional judiciary has, during its existence - during two centuries as an ordinary court and during one century as a special authority, changed its position, role and importance. Those characteristics of constitutional judiciary had an increasing way - the position became better, in political and law sense, its role has expanded and the importance has increased. Today, constitutional judiciary is an inevitable subject of constitutional regimes in huge number of states (between them are almost all federations but, in the same time, constitutional judiciary is an authority which is at least limited by the constitution. The constitution is "soft" to the constitutional judiciary because the judiciary interpreted the constitution in accordance to its political and law attitudes, hidden by the guise of protection. Different separation of power, a rise of executive power, requests for better protections of fundamental human rights, a changed role of state and executive power, altogether, have influenced to change of position of constitutional judiciary.

  8. The Constitution. GEMS: Greenfield Express Management System. Revised Edition.

    Science.gov (United States)

    Reese, Marianne

    Developed for eighth grade students reading on or above grade level, this self-correcting unit covers the background of the Constitution, the Preamble, the seven articles, and the amendments. Material is divided into two sections. The teacher section outlines activities, materials, evaluation options, and follow-up activities. A crossword puzzle…

  9. Constitutive and ligand-induced TCR degradation

    DEFF Research Database (Denmark)

    von Essen, Marina; Bonefeld, Charlotte Menné; Siersma, Volkert

    2004-01-01

    divergent models for TCR down-regulation and degradation have been suggested. The aims of this study were to determine the rate constants for constitutive and ligand-induced TCR degradation and to determine whether the TCR subunits segregate or are processed as an intact unit during TCR down...... to the lysosomes. Similar results were obtained in studies of primary human Vbeta8+ T cells stimulated with superantigen. Based on these results, the simplest model for TCR internalization, sorting, and degradation is proposed.......Modulation of TCR expression levels is a central event during T cell development and activation, and it probably plays an important role in adjusting T cell responsiveness. Conflicting data have been published on down-regulation and degradation rates of the individual TCR subunits, and several...

  10. Expressing Constitutively Active Rheb in Adult Dorsal Root Ganglion Neurons Enhances the Integration of Sensory Axons that Regenerate Across a Chondroitinase-Treated Dorsal Root Entry Zone Following Dorsal Root Crush.

    Science.gov (United States)

    Wu, Di; Klaw, Michelle C; Kholodilov, Nikolai; Burke, Robert E; Detloff, Megan R; Côté, Marie-Pascale; Tom, Veronica J

    2016-01-01

    While the peripheral branch of dorsal root ganglion neurons (DRG) can successfully regenerate after injury, lesioned central branch axons fail to regrow across the dorsal root entry zone (DREZ), the interface between the dorsal root and the spinal cord. This lack of regeneration is due to the limited regenerative capacity of adult sensory axons and the growth-inhibitory environment at the DREZ, which is similar to that found in the glial scar after a central nervous system (CNS) injury. We hypothesized that transduction of adult DRG neurons using adeno-associated virus (AAV) to express a constitutively-active form of the GTPase Rheb (caRheb) will increase their intrinsic growth potential after a dorsal root crush. Additionally, we posited that if we combined that approach with digestion of upregulated chondroitin sulfate proteoglycans (CSPG) at the DREZ with chondroitinase ABC (ChABC), we would promote regeneration of sensory axons across the DREZ into the spinal cord. We first assessed if this strategy promotes neuritic growth in an in vitro model of the glial scar containing CSPG. ChABC allowed for some regeneration across the once potently inhibitory substrate. Combining ChABC treatment with expression of caRheb in DRG significantly improved this growth. We then determined if this combination strategy also enhanced regeneration through the DREZ after dorsal root crush in adult rats in vivo. After unilaterally crushing C4-T1 dorsal roots, we injected AAV5-caRheb or AAV5-GFP into the ipsilateral C5-C8 DRGs. ChABC or PBS was injected into the ipsilateral dorsal horn at C5-C8 to digest CSPG, for a total of four animal groups (caRheb + ChABC, caRheb + PBS, GFP + ChABC, GFP + PBS). Regeneration was rarely observed in PBS-treated animals, whereas short-distance regrowth across the DREZ was observed in ChABC-treated animals. No difference in axon number or length between the ChABC groups was observed, which may be related to intraganglionic inflammation induced by the

  11. Constitutional and Non-Constitutional Governments...Similarities and Differences throughout History. Resource Packet.

    Science.gov (United States)

    Pallasch, Brian Thomas

    This civic education resource packet is designed to provide teachers, community leaders, and other civic educators with an understanding of the differences between constitutional and non-constitutional governments. Six papers discussing the topic are included: "The Differences bewteen Constitutional and Non-Constitutional Governments" (John…

  12. State Constitutionalism: Completing the Interdisciplinary Study of Constitutional Law and Political Theory.

    Science.gov (United States)

    Williams, Robert F.

    1993-01-01

    Argues that a complete and accurate understanding of constitutional history and constitutional law requires the study of state constitutions. Maintains that state constitutions contain a coherent political theory that is, in important respects, at variance with the concept of federalism. (CFR)

  13. Constitutional Amendment and Political Constitutionalism: The Potential Mitigation of Critiques on Judicial Review

    Directory of Open Access Journals (Sweden)

    Jairo Néia Lima

    2016-12-01

    Full Text Available The criticisms toward judicial review from Richard Bellamy and Jeremy Waldron’s political constitutionalism approach demonstrate that they do not exclude constitutional courts entirely, as they accept mechanisms of legislative responses, except constitutional amendments. This paper concludes that the high number of constitutional amendments in Brazil does not mitigate judicial review critiques. The extensive structure of the Brazilian Constitution imposes frequent changes, which do not modify its essence. Furthermore, the possibility of judicial review over constitutional amendments represents that constitutional court could overrule legislative response.

  14. CONSTITUTIONAL ECONOMICS APPROACH TO FISCAL POLICY IMPLEMENTATIONS IN TRANSITION ECONOMIE

    Directory of Open Access Journals (Sweden)

    İlter ÜNLÜKAPLAN

    2017-03-01

    Full Text Available According to the "Constitutional Economics", which formes the basic point of view of the application of the Public Choice Theory to the economic policy, it is essential to make an economic analysis of the behavior of the actors who take part in the political process in order to determine the constitutional level of the authorities of the state and the limits of the state. The view that dominated until the beginning of the 1970s in economics was that the state would be able to achieve desirable macroeconomic targets with active demand policies. However, developments that emerged in these years can not be explained by traditional economic theories have brought with it a doubt that they will lead to demandoriented economic policies. The Constitutional Economics Approach, which finds its roots from the Social Contract Theory and Public Choice Theory, argues that the behavior of the units taking part in the political and economic field, questioning the active role of the state, can be transformed into arbitrary applications by acting from the Maximand primacy is regarded as an alternative to active economic policies. In this study, the foundations, assumptions and proposals of the theory of the Constitutional Economics will be examined, then the concept of transition economy will be explained and the role of the state in transition economies will be questioned and the importance of creating a fiscal constitution in this countries will be emphasized

  15. The Jurisdiction of The Constitutional Court In Controlling The Constitutionality of Criminal Judgments: Kosovo Case

    OpenAIRE

    BRAHA, Florentina Shala; Vilard BYTYQI; VUNIQI, Dardan; Berisha, Fadil

    2016-01-01

    This paper will deal with individual requests that are submitted at the Constitutional Court in order to assess the constitutionality of criminal judicial decisions. The right to submit issues for assessing the constitutionality of criminal court decisions is a constitutionally guaranteed right. Many individuals who are dissatisfied with the decisions of the judicial instances use their right to oppose such a decision even at the Constitutional Court.Not all the cases submitted to the Court a...

  16. Autonomous Province of Vojvodina between the Constitution and the decision of the Constitutional court

    Directory of Open Access Journals (Sweden)

    Čiplić Svetozar

    2014-01-01

    Full Text Available The author deals individual assessments Constitutional court of the Competent in Law, as well as its different interpretation of constitutional and legal provisions. The author is of the opinion that the Constitutional Court amended the constitution and the law guaranteed the position of the Autonomous Province of Vojvodina and that the 'conservative interpretation of' diminished the rights of citizens by the constitution itself by.

  17. Constitutional Principles of State Control in the Republic of Armenia

    Directory of Open Access Journals (Sweden)

    Gabriel K. Balayan

    2015-12-01

    Full Text Available In the present article some of the provision of the RA Constitution’s basic principles of state control, which, in my opinion, should be guided by regulatory authorities during the inspection are discussed. These principles are considered by the author as the basis of the constitutionality of state control. Some of the control principles are divided by the author into positive and negative. Positive defines the principles that provide the freedom of action of man and citizen. Negative same principles are for government agencies, since they restrict their activities. A separate analysis is subject to the presidency on the basis of the principle of separation and balance of powers. In conclusion, author concludes that, based on the interpretation of the constitutional principles discussed, the term "law" applies only to natural and legal persons on the other hand can not be used as an analogue of the terms "authority" and "authority." According to the author, the fundamental constitutional principles of state control are expressed formally in a single system as defined in the first chapter of the Constitution of the Republic of Armenia. Compliance and reform of constitutional principles provide the synergy and the constitutionality of the process of governance.

  18. Constitutionalism and Democracy in Contemporary International Community

    OpenAIRE

    Padjen, Ivan

    1992-01-01

    Starting from the insight that jurisprudence of legal theory should be concerned primarily with,on the one hand, international law, and, on the other, constitutional developments, the paper; analyzes some prominent conceptions of constitutionalism and democracy in international community and municipal legal orders; formulates a new set of criteria for the analysis of constitutionalism and democracy in international law; and argues that Laswell and McDougal's policy oriented jurisprudence offe...

  19. Human Rights in Indonesian Constitutional Amendments

    OpenAIRE

    Kharlie, Ahmad Tholabi

    2013-01-01

    Human Rights in Indonesian Constitutional Amendments. Indonesian constitutional amendments incorporated human rights principles into the Constitution of the Republic of Indonesia 1945 (UUD NRI), especially in the second amendment in 2000. Under that amendment, the UUD NRI currently stipulates human rights principles as provided for in the Universal Declaration of Human Rights (UDHR). However, there are some important notes, which at its core is a lack of emphasis on the vision and mission of ...

  20. Inferring Mechanisms for Global Constitutional Progress

    OpenAIRE

    Rutherford, Alex; Lupu, Yonatan; Cebrian, Manuel; Rahwan, Iyad; LeVeck, Brad; Garcia-Herranz, Manuel

    2016-01-01

    Constitutions help define domestic political orders, but are known to be influenced by two international mechanisms: one that reflects global temporal trends in legal development, and another that reflects international network dynamics such as shared colonial history. We introduce the provision space; the growing set of all legal provisions existing in the world's constitutions over time. Through this we uncover a third mechanism influencing constitutional change: hierarchical dependencies b...

  1. Culture (and religion in constitutional adjudication

    Directory of Open Access Journals (Sweden)

    C Rautenbach

    2003-10-01

    Full Text Available The faculty of law of the Potchefstroom University for Christian Higher Education in corroboration with the Konrad-Adenauer-Stifttung embarked on a study on Politics, Socio-Economic Issues and Culture in Constitutional Adjudication. The aim of the project is twofold. The first aim is to analyse the influence of political, socio-economic and cultural considerations on the constitutional court’s interpretation and application of the Bill of Rights. The second aim is to develop practical guidelines (based on the findings during the analysing process for South African courts confronted with issues of a political, socio-economic and cultural nature. This article is concerned with initiating discussions of the decisions of the constitutional court with regard to cultural and religious rights.Before we can explore the role of political, socio-economic and cultural (and religious rights in the decisions of the constitutional court it is important to discuss a few preliminary issues. In this article the meaning of culture and religion within the South African context receives some attention. Secondly, some preliminary comments regarding constitutional protection of culturally and religiously based rights will be made.We are well aware that this is a daunting task, not only in view of the seemingly abysmal gap between the applicable constitutional rights and values enshrined in the 1996 Constitution that, in some instances over centuries, brought about customs and practices within “traditional” communities which, seemingly, infringe on certain constitutional values and rights.

  2. Distinguishing Limitation on Constitutional Rights from Their ...

    African Journals Online (AJOL)

    Suspension of and limitation on fundamental rights and freedoms are justified violations of constitutional rights. Temporary suspension of some fundamental rights and freedoms can be made on the ground of a state of emergency. Since most constitutional rights are not absolute, they can be limited on basis of national ...

  3. Constitutional Government: The Soul of Modern Democracy.

    Science.gov (United States)

    Mansfield, Harvey C., Jr.

    1987-01-01

    Discusses the dilemma faced by constitutionalism today: limited, constitutional government requires that people and society be independent and distrustful of the state, but if the people are too independent and capable of ruling, they may wish to extend their powers and attempt to rule over others. (PS)

  4. World Studies through a Comparative Constitutional Prism.

    Science.gov (United States)

    Robinson, Donald

    1992-01-01

    Emphasizes the importance of understanding the development of democracy around the world by comparative study of constitutions. Uses the development of the Japanese constitution after World War II as a case study. Describes the work of the team appointed by General Douglas MacArthur and the significance of the clause guaranteeing equal rights for…

  5. The Meaning of Religion: A Constitutional Perspective.

    Science.gov (United States)

    Lilly, Edward R.

    The problems of formulating a legal definition of religion as used in the U.S. Constitution may be traced through the Supreme Court's interpretation of the word. According to the U.S. Constitution, religious tests cannot be required for any office or public trust under the central government. The Bill of Rights states that the national government…

  6. Using international human rights law to promote constitutional rights ...

    African Journals Online (AJOL)

    Parliaments are guardians of human rights due to their role of representing the people in the management of public affairs. The activities of parliaments cover the entire spectrum of human rights and have an immediate impact on the enjoyment, protection andpromotion of rights. In South Africa, the Constitution requires ...

  7. A constitutional critique on the regulations relating to artificial ...

    African Journals Online (AJOL)

    2017-06-30

    Jun 30, 2017 ... donor) can be prosecuted at least as accomplices, given that they actively assisted B, the perpetrator. A constitutional critique on the regulations relating to artificial fertilisation of persons. D W Jordaan, BLC, LLB, MPPS, PGDipSI, PhD. School of Law, Howard College, University of KwaZulu-Natal, Durban, ...

  8. Developing Constitutional Rights of, in, and for Children

    Science.gov (United States)

    Burt, Robert A.

    1975-01-01

    Discusses U.S. Supreme Court decisions dealing with the constitutional rights of children and parents against state interventions on the behalf of children and attempts to generalize about the Court's stance on the permissible scope of state substitute-parenting activities. Available from Law and Contemporary Problems, Duke Station, Durham, North…

  9. State Constitution Revision: An Exercise in Federalism and Sovereignty.

    Science.gov (United States)

    Myers, J. A.

    1988-01-01

    Discusses classroom activities designed to enhance student learning about federalism and sovereignty. Describes classroom discussions on jurisdiction, federalism, and sovereignty generated by asking students to clarify the constitutional section referring to the Writ of Habeas Corpus. Concludes that this exercise clarifies the concepts and…

  10. Algumas considerações sobre o desenvolvimento da atividade de leitura e a constituição do leitor surdo/Some aspects on the development of the activity of reading and the constitution of the deaf reader

    Directory of Open Access Journals (Sweden)

    Heloísa Andréia Vicente de Matos

    2006-01-01

    Full Text Available Este trabalho aponta alguns aspectos teóricos sobre a questão da leitura e seus desdobramentos e, por conseguinte, sobre os aspectos relacionados à constituição do leitor também nas condições da surdez. Do mesmo modo, destaca questões do letramento e as implicações desse processo na constituição do leitor Surdo, também através de narrativas de sujeitos adultos (com pouca influência da oralização e relativa proficiência na leitura do Português, no presente sobre seus movimentos de formação, configurados na noção de espaço e tempo construídos pela memória dos mesmos. This paper points some theoretical aspects on the question of the reading and its unfoldings and, therefore, on the aspects related to the constitution of the reader also in the conditions of the deafness. In a similar way, it detaches questions of the literacy and the implications of this process in the constitution of the Deaf reader, also through narratives of adult deaf people (with little influence of the oralism and relative proficiency in the reading of the Portuguese, at the current moment on its movements of formation, configured in the notion of space and time constructed by the memory of the same ones.

  11. CONSTITUTIONAL INTERPRETATION OF ROMANIA: POST MODERNITY

    Directory of Open Access Journals (Sweden)

    P. RATHNASWAMY

    2017-06-01

    Full Text Available Austria had in 1920 Constitutional Court followed by Italy in 1946, Germany in 1949, Romania in 1989, South Africa in 1991, and Ethiopia in 1995. Each Constitution has its provisions on the constitutional interpretation. Romania has its own provisions and it is considered here its legality and the best possible measures and recommendations for future. Judicial power is vested in judiciary to interpret constitution, laws, and actions of other organs of government. Judicial review is the function resulted upon judicial power. Political body joins through the appointment of its members in the judicial review and it limits the independence of judiciary. It also reduces the values of separation of powers. Challenges and opportunities of growth and development do influence the spirit of separation of powers and judicial independence. The principle of inherent judicial power in judiciary inducts upon the constitutional interpretation. Thus, the principles of constitutional interpretation are varying in Romania and other similar constitutional courts of Germany, Ethiopia, and Italy but not in South Africa.

  12. [Body constitution in children in Cuentepec, Morelos].

    Science.gov (United States)

    Ramos Rodríguez, R M

    1981-01-01

    A somatometric estimation of the body constitution was made in 87 females and 72 males applying the values of weight and height, the muscle circumference and medial section of the left arm and fat area of that section. The material represented 28.57 and 23.61% respectively of the total number of the 5 to 19 years-old inhabitants of the Nahua community of Cuentepec, Morelos. Weight and height, -but specially the latter-were impaired, both in males as in females, but more markedly in the latter. The weight as expected for the height was not affected. The behavior of the total area of the arm was quite similar to that of the body weight. In contrast, in females under 14 years old, the muscle area of the arm was located as an average, slightly below the limits of normality; subsequently, it was normal. In males it was significantly lower than in females. The fat area was the most deteriorated and the defect was persistently greater in females than in males. All this means protection mechanisms of the active tissue mass (homeorrhesis) leading to a greater resistance in females, but at the same time, being responsible for a decrease in magnitude of the somatometric expression of the sexual dimorphism.

  13. [The right to health. Constitutional dimensions].

    Science.gov (United States)

    Pestalozza, C

    2007-09-01

    A fundamental "right to health" is expressly guaranteed by the constitutions of several Bundesländer, but unknown to the German Federal Constitution. Instead the Federal Constitutional Court has - especially on the basis of related human rights - developed the obligation of the State to protect everybody's life and physical integrity, which in some respects comes near to a "right to health". The State's autonomy in financial matters, the scarcity of its financial resources and the individual's natural responsibility for his own health though advise against exaggerated hopes set in a "right to health".

  14. The constitutional control system in Colombia

    Directory of Open Access Journals (Sweden)

    Luis Javier Moreno Ortiz

    2010-12-01

    Full Text Available The system of constitutional control in Colombia designed in the Legislative Act n.º 3 of 1910 is a milestone in a long and fruitful political and constitutional tradition owes much to his Hispanic roots and its American developments. Both the public action of unconstitutionality as the plea of unconstitutionality have clear precedents in the constitutionalism of Spain and the Colony were prepared by a Constituent Assembly acted with knowledge and faithfulness to that tradition and have been and are institutions of our capital social and democratic state of law.

  15. Competition And Antitrust Law In Ecuadorian Constitution

    Directory of Open Access Journals (Sweden)

    Marcelo Marín Sevilla

    2013-01-01

    Full Text Available This work allows us to establish the Economic Constitution and the Competition Law (C.L in the Constitution. Additionally, the paper analyzes whether the rules outlined in the C. L. and in doctrine are consistent and appropriate with the Constitution of Ecuador. The Competition and Antitrust Laws has rules for investigating and punishing the cartels, the abuses of power market (dominant position, the rules for merger control, the behaviors of Abuse of economic dependence, and unfair competition behaviors. Always the Antitrust Authority will analyze these behaviors in terms of welfare of both: the consumer and the market.

  16. Amino acid substitutions in the transcriptional regulator CbbR lead to constitutively active CbbR proteins that elevate expression of the cbb CO2 fixation operons in Ralstonia eutropha (Cupriavidus necator) and identify regions of CbbR necessary for gene activation.

    Science.gov (United States)

    Dangel, Andrew W; Tabita, F Robert

    2015-09-01

    CbbR is a LysR-type transcriptional regulator that activates expression of the operons containing (cbb) genes that encode the CO2 fixation pathway enzymes in Ralstonia eutropha (Cupriavidus necator) under autotrophic growth conditions. The cbb operons are stringently downregulated during chemoheterotrophic growth on organic acids such as malate. CbbR constitutive proteins (CbbR*s), typically with single amino acid substitutions, were selected and isolated that activate expression of the cbb operons under chemoheterotrophic growth conditions. A large set of CbbR*s from all major domains of the CbbR molecule were identified, except for the DNA-binding domain. The level of gene expression conferred for many of these CbbR*s under autotrophic growth was greater than that conferred by wild-type CbbR. Several of these CbbR*s increase transcription two- to threefold more than wild-type CbbR. One particular CbbR*, a truncated protein, was useful in identifying the regions of CbbR that are necessary for transcriptional activation and, by logical extension, necessary for interaction with RNA polymerase. The reductive assimilation of carbon via CO2 fixation is an important step in the cost-effective production of useful biological compounds. Enhancing CO2 fixation in Ralstonia eutropha through greater transcriptional activation of the cbb operons could prove advantageous, and the use of CbbR*s is one way to enhance product formation.

  17. Rights of Minors and Constitutional Politics in the German Länder. Legal Framework, Party Strategies, and Constitutional Amendments

    Directory of Open Access Journals (Sweden)

    Lorenz Astrid

    2015-11-01

    Full Text Available The article analyses constitutional politics in the German Länder in the field of minors’ rights. Since this issue seems a purely legal matter dealt with at the federal, European and international level, we should expect similar, almost identically shaped policies at the Länder level. However, the analysis brings considerable variations of constitutional activities in this field to the fore: time, frequency, and contents of respective initiatives vary significantly in the period from 1999 to 2014. These variations were due to different party strategies, diverging party platforms and majority constellations in the Länder. The analysis also shows that the public arguments brought forward in favour of constitutional amendments refer only weakly and randomly to legal provisions and processes at other levels. The political debate supporting extended children's rights rather refers to general observations, to the specific regional context, and constitutional provisions in other Länder. At least with regard to this issue, the multi-level system did not systematically impact on constitutional politics in the Länder. It rather can be understood as an opportunity structure providing parties with multiple realms in which they can pursue their goals. Thus the study shows that federal and regional party strategies are key factors in explaining policy diffusion in multilevel systems.

  18. Constitutional Aneuploidy in the Normal Human Brain

    National Research Council Canada - National Science Library

    Rehen, Stevens K; Yung, Yun C; McCreight, Matthew P; Kaushal, Dhruv; Yang, Amy H; Almeida, Beatriz S. V; Kingsbury, Marcy A; Cabral, Katia M. S; McConnell, Michael J; Anliker, Brigitte; Fontanoz, Marisa; Chun, Jerold

    2005-01-01

    .... Chromosome 21 aneuploid cells constitute approximately 4% of the estimated one trillion cells in the human brain and include non-neuronal cells and postmitotic neurons identified by the neuronspecific nuclear protein marker...

  19. Quantum interference distinguishes between constitutional isomers

    OpenAIRE

    Tüxen, Jens; Gerlich, Stefan; Eibenberger, Sandra; Arndt, Markus; Mayor, Marcel

    2014-01-01

    Matter waves, as introduced by de Broglie in 1923, are a fundamental quantum phenomenon, describing the delocalized center of mass motion of massive bodies and we show here their sensitivity to the molecular structure of constitutional isomers.

  20. 'i'iElectoral Systems, Constitutionalism

    African Journals Online (AJOL)

    strongly that for democratic governance and constitutionalism to be nurtured and consolidated ... big role in whether economies grow7 whether children go to school, whether human ..... Source: SAPES Trust Data Bank. M PLA. BDP. LCD.

  1. Constitutive modeling of metastable austenitic stainless steel

    NARCIS (Netherlands)

    Perdahcioglu, Emin Semih; Geijselaers, Hubertus J.M.; Huetink, Han; Khan, A.

    2010-01-01

    A physically based, macroscale constitutive model has been developed that can describe the complex mechanical behavior of metastable austenitic stainless steels. In the developed model a generalized model for the mechanically induced martensitic transformation is introduced. Mechanical tests have

  2. Dynamic constitutional frameworks for DNA biomimetic recognition.

    Science.gov (United States)

    Catana, Romina; Barboiu, Mihail; Moleavin, Ioana; Clima, Lilia; Rotaru, Alexandru; Ursu, Elena-Laura; Pinteala, Mariana

    2015-02-07

    Linear and cross-linked dynamic constitutional frameworks generated from reversibly interacting linear PEG/core constituents and cationic sites shed light on the dominant coiling versus linear DNA binding behaviours, closer to the histone DNA binding wrapping mechanism.

  3. Constituting objectivity transcendental perspectives on modern physics

    CERN Document Server

    Bitbol, Michael; Petitot, Jean

    2009-01-01

    This book pins down the methodological core of transcendental epistemology that must be used in order to throw light on the foundations of modern physics. A renewed understanding of modern physics is offered by the concept of constitution of objectivity.

  4. Social rights constitutionalism: an antagonistic endorsement

    OpenAIRE

    Christodoulidis, Emilios

    2017-01-01

    The article discusses how we might understand solidarity as the organizing concept behind the institutionalization of social rights. I argue that writing solidarity into social rights constitutionalism carries productive tension into constitutional thinking because it disturbs the smooth passage from civil to political and finally to social rights. Marshall's influential argument that social rights are continuous to civil and political rights has become both the grounding assumption in consti...

  5. Urgency of Attorney Governed by the Constitution

    Directory of Open Access Journals (Sweden)

    Rommy Patra

    2015-12-01

    Full Text Available Attorney existence in the Indonesian constitutional structure has a dilemma for this position. On one side is the Prosecutor’s law enforcement agencies to exercise power independently prosecution while on the other hand is part of a government institution under Law No. 16 of 2004 regarding the Attorney. The position of Attorney as an institution of government has been led to the independence of the Prosecutor is not optimal so that it appears stigma that the Prosecutor merely as a tool of the ruling power. In addition the terms of the arrangement just under the Act, the Attorney General has no legal standing as a constitutional organ that has the constitutional authority so that the current position does not reflect the urgency of its duties and functions. In an effort to organize the next Attorney institutions should be regulated directly by the Constitution. It is intended to make the Attorney as part of the main state organs have the same legal standing as other law enforcement agencies, the police and the courts (Supreme Court and Constitutional Court. As well as to strengthen and clarify the position as a state institution, prosecution authorities are focusing on the Attorney as central of authority, to fix the institutional relations between the members of law enforcement and related agencies and strengthen the independence of the Prosecutor in performing the function of prosecution in the constitutional structure of Indonesia.

  6. The Practice of Informal Changes to the Ethiopian Constitution

    African Journals Online (AJOL)

    Nigussie Afesha

    FDRE Constitution, informal constitutional changes, constitutional amendment, constitutional interpretation, political .... over time without textual changes, typically by means of constitutional court rulings and, less visibly, ..... indeterminate, the courts are called upon to fashion a meaning”.98 It is in this sense that “constitution ...

  7. Constitutive calcium entry and cancer: updated views and insights.

    Science.gov (United States)

    Mignen, Olivier; Constantin, Bruno; Potier-Cartereau, Marie; Penna, Aubin; Gautier, Mathieu; Guéguinou, Maxime; Renaudineau, Yves; Shoji, Kenji F; Félix, Romain; Bayet, Elsa; Buscaglia, Paul; Debant, Marjolaine; Chantôme, Aurélie; Vandier, Christophe

    2017-07-01

    Tight control of basal cytosolic Ca(2+) concentration is essential for cell survival and to fine-tune Ca(2+)-dependent cell functions. A way to control this basal cytosolic Ca(2+) concentration is to regulate membrane Ca(2+) channels including store-operated Ca(2+) channels and secondary messenger-operated channels linked to G-protein-coupled or tyrosine kinase receptor activation. Orai, with or without its reticular STIM partner and Transient Receptor Potential (TRP) proteins, were considered to be the main Ca(2+) channels involved. It is well accepted that, in response to cell stimulation, opening of these Ca(2+) channels contributes to Ca(2+) entry and the transient increase in cytosolic Ca(2+) concentration involved in intracellular signaling. However, in various experimental conditions, Ca(2+) entry and/or Ca(2+) currents can be recorded at rest, without application of any experimental stimulation. This led to the proposition that some plasma membrane Ca(2+) channels are already open/activated in basal condition, contributing therefore to constitutive Ca(2+) entry. This article focuses on direct and indirect observations supporting constitutive activity of channels belonging to the Orai and TRP families and on the mechanisms underlying their basal/constitutive activities.

  8. Between constitution and interpretation: Identity as history

    Directory of Open Access Journals (Sweden)

    Hilt Annette

    2015-01-01

    Full Text Available The paper focuses on the possibilities to constitute meaning in the „borderline- situations“ (Jaspers of the social sphere, such as the loss of validity of orientation within and experience of reality in the socially shared structures of the lifeworld. On the one hand, I will refer to A. Schutz’ and his constitution-analysis of foreign understanding and of shared meaning; on the other hand, I bear onto I. Kertész literary project to narrate the biography of an Auschwitz-survivor as close to his experiential perspective as possible. I will focus both on the concept of constitution and of interpretation with respect to their enabling of the transcending of a typologized everyday’s world which suppresses subjective meaning and its individual articulation. The main guideline is the problem how identity – i.e. a life-story – is configured out of subjective meaning without recourse to everyday reality. A. Schutz’s and Th. Luckmann’s note on a range of social transcendences and on biographical categories referring to the constitution of a socially shared meaning offer a theoretical perspective for dealing with constitutive differences within the reach of understanding social meaning; Kertész’ narrative mode expandes this theoretical stance as it problematizes exemplary subjective experience.

  9. A constitutive theory of reacting electrolyte mixtures

    Science.gov (United States)

    Costa Reis, Martina; Wang, Yongqi; Bono Maurizio Sacchi Bassi, Adalberto

    2013-11-01

    A constitutive theory of reacting electrolyte mixtures is formulated. The intermolecular interactions among the constituents of the mixture are accounted for through additional freedom degrees to each constituent of the mixture. Balance equations for polar reacting continuum mixtures are accordingly formulated and a proper set of constitutive equations is derived with basis in the Müller-Liu formulation of the second law of thermodynamics. Moreover, the non-equilibrium and equilibrium responses of the reacting mixture are investigated in detail by emphasizing the inner and reactive structures of the medium. From the balance laws and constitutive relations, the effects of molecular structure of constituents upon the fluid flow are studied. It is also demonstrated that the local thermodynamic equilibrium state can be reached without imposing that the set of independent constitutive variables is time independent, neither spatially homogeneous nor null. The resulting constitutive relations presented throughout this work are of relevance to many practical applications, such as swelling of clays, developing of bio and polymeric membranes, and use of electrorheological fluids in industrial processes. The first author acknowledges financial support from National Counsel of Technological and Scientific Development (CNPq) and German Academic Exchange Service (DAAD).

  10. Constitutive Endocytosis of VEGFR2 Protects the Receptor against Shedding.

    Science.gov (United States)

    Basagiannis, Dimitris; Christoforidis, Savvas

    2016-08-05

    VEGFR2 plays a fundamental role in blood vessel formation and in life threatening diseases, such as cancer angiogenesis and cardiovascular disorders. Although inactive growth factor receptors are mainly localized at the plasma membrane, VEGFR2 undergoes constitutive endocytosis (in the absence of ligand) and recycling. Intriguingly, the significance of these futile transport cycles of VEGFR2 remains unclear. Here we found that, unexpectedly, the function of constitutive endocytosis of VEGFR2 is to protect the receptor against plasma membrane cleavage (shedding), thereby preserving the functional state of the receptor until the time of activation by VEGF. Inhibition of constitutive endocytosis of VEGFR2, by interference with the function of clathrin, dynamin, or Rab5, increases dramatically the cleavage/shedding of VEGFR2. Shedding of VEGFR2 produces an N-terminal soluble fragment (100 kDa, s100), which is released in the extracellular space, and a residual C-terminal part (130 kDa, p130) that remains integrated at the plasma membrane. The released soluble fragment (s100) co-immunoprecipitates with VEGF, in line with the topology of the VEGF-binding domain at the N terminus of VEGFR2. Increased shedding of VEGFR2 (via inhibition of constitutive endocytosis) results in reduced response to VEGF, consistently with the loss of the VEGF-binding domain from the membrane remnant of VEGFR2. These data suggest that constitutive internalization of VEGFR2 protects the receptor against shedding and provides evidence for an unprecedented mechanism via which endocytosis can regulate the fate and activity of growth factor receptors. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Constitutional Fundamentals of Conscription and Some Aspects of the Ordinary Legal Regulation of Constitutionality

    Directory of Open Access Journals (Sweden)

    Kenstavičienė Kristina

    2015-12-01

    Full Text Available Article 139 of the Constitution of the Republic of Lithuania is one of the constitutional fundamentals of state defense and stipulates the defense of the state as the right of citizens on the one hand and the duty on the other. This article of the Constitution gives the legislative power the right of discretion to detail by law the order of the implementation of citizens’ duty to perform military or alternative country defense service. Due to the reorganization of the armed forces into a professional and volunteer army, the issue of some ordinary regulation rules concerning the constitutionality of nationwide conscription, though at present suspended but not abolished, is becoming urgent. Though the Constitutional Court of the Republic of Lithuania presented their ruling on the constitutionality of the suspension of military conscription, it does not mean that all problems related to conscription have been settled. The aim of this article is to analyze the constitutional basis of nationwide conscription as well as the constitutionality of some ordinary regulation provisions related to nationwide conscription. Therefore, the issue to be analyzed is whether nationwide conscription, if it were to be implemented, complies with the constitutional principles of human equality and military justice1. Consequently, the question is posed how the constitutional objective of ensuring the defense of the state determines conscription. Because of the growing employment of the army abroad, yet the dwindling demand for conscripts, it should be explored whether the suspension of the nationwide conscription as a part of the defense reform is further feasible in order to guarantee the defense of the state. In answering the raised questions, the author will analyze the abundant and long-lasting constitutional doctrine of Germany which provides clarifications of the Basic Law, as the legal act of the establishing power, which can doubtless be of assistance in

  12. The Trials and Tribulations of Constitutionalism and the Constitution Making Process in Zimbabwe

    OpenAIRE

    Mapuva, Jephias

    2015-01-01

    Constitutionalism in Zimbabwe has been characterised by controversy with citizens getting a raw deal. The colonial era was characterised by deprivation of basic rights and civil liberties. A plethora of constitutions were established to try and create a semblance of black representativity. The post-colonial era was informed by governance structures provided by the Lancaster House Constitutional document which was a surrender document that brought the protracted liberation struggle to an end. ...

  13. Cultural, social and economic rights in the Constitution corpus and Constitutional Court’s Case Law

    Directory of Open Access Journals (Sweden)

    Patricio Rubio

    2013-12-01

    Full Text Available This article deals with Cultural, Social and Economic Rights established in the Constitution and in Constitutional Case Law. So, after explaining its nature, state’s role according preservation and enforceability,relationship with other fundamental rights, among other key points, it isi ntended to answer, dealing with those rights, which of two scenarios have prevailed: internationalization of constitutional law or constitutionalization of international law.

  14. Extended constitutive laws for lamellar phases

    Directory of Open Access Journals (Sweden)

    Chi-Deuk Yoo

    2013-10-01

    Full Text Available Classically, stress and strain rate in linear viscoelastic materials are related by a constitutive relationship involving the viscoelastic modulus G(t. The same constitutive law, within Linear Response Theory, relates currents of conserved quantities and gradients of existing conjugate variables, and it involves the autocorrelation functions of the currents in equilibrium. We explore the consequences of the latter relationship in the case of a mesoscale model of a block copolymer, and derive the resulting relationship between viscous friction and order parameter diffusion that would result in a lamellar phase. We also explicitly consider in our derivation the fact that the dissipative part of the stress tensor must be consistent with the uniaxial symmetry of the phase. We then obtain a relationship between the stress and order parameter autocorrelation functions that can be interpreted as an extended constitutive law, one that offers a way to determine them from microscopic experiment or numerical simulation.

  15. The regularity theory of mechanistic constitution and a methodology for constitutive inference.

    Science.gov (United States)

    Harbecke, Jens

    2015-12-01

    This paper discusses a Boolean method for establishing constitutive regularity statements which, according to the regularity theory of mechanistic constitution, form the core of any mechanistic explanation in neuroscience. After presenting the regularity definition for the constitution relation, the paper develops a set of inference rules allowing one to establish constitutive hypotheses in light of certain kinds of empirical evidence. The general methodology consisting of these rules is characterized as having formed the basis of many successful explanatory projects in neuroscience. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. A constituição de 1988, vinte anos depois: suprema corte e ativismo judicial "à brasileira" The Brazilian 1988 constitution twenty years on: supreme court and activism in a "Brazilian mode"

    Directory of Open Access Journals (Sweden)

    Marcos Paulo Verissimo

    2008-12-01

    Full Text Available Este artigo examina as transformações por que vem passando o Supremo Tribunal Federal nos últimos anos, relacionando-as à sua reconfiguração institucional ocorrida por ocasião da Constituição de 1988. essas transformações são apresentadas como respostas a um duplo fenômeno (impulsionado por essa mesma reconfiguração institucional de incremento do papel político do tribunal, por um lado, e de sobrecarga extraordinária de seu volume de trabalho, por outro. Essa tensão reflete no modelo misto de controle de constitucionalidade no Brasil e parece apontar para mudanças iminentes nesse mesmo modelo, algumas das quais já vêm sendo concebidas pelo próprio tribunal.The Brazilian Supreme Court is currently changing. This process of change seems to aim at solving a important contradiction caused by the institutional redesign of the court in the 1988 Constitution that, on the one hand, has transformed it into one of the country's major political actors, but, on the other hand, has also caused its dockets to get incredibly overloaded, forcing the court to deal with more then 100,000 cases a year. The solution for such paradox will probably lead to changes in the Brazilian mixed model of judicial review, and some of these changes are already been conceived by the jurisprudence of the court itself.

  17. The Place of Constitutional Courts in the EU

    DEFF Research Database (Denmark)

    Komárek, Jan

    2013-01-01

    constitutional courts defend the scope for political autonomy – Against national constitutional courts' displacement – Simmenthal II – After the ‘Rights Revolution’ in Europe – National constitutional courts' references to the ECJ – Ordinary courts challenging national constitutional courts through......Going beyond ‘judicial dialogues’ and ‘conflict-and-power’ approaches to the analysis of national constitutional courts' role in the EU – The idea of European constitutional democracy – National constitutional courts constrain individual autonomy expanded by European integration – National...... the preliminar y reference procedure – Parallel references – National constitutional courts enforcing EU law – National constitutional courts challenging EU law...

  18. Constitutional values, therapeutic jurisprudence and legal education ...

    African Journals Online (AJOL)

    In addition to an extensive knowledge of legal principles, critical thinking and research skills, law students should critically engage with our constitutional values. The question remains: How do we transform legal education in South Africa? How do we change the way we teach law students? The introduction of concepts ...

  19. Institutional independence and the constitutionality of legislation ...

    African Journals Online (AJOL)

    The independence of the judiciary is the bedrock of the democratic system of government. Judicial independence is the gateway to the proper performance of the courts of their role of keeping all organs of state within the boundaries of their powers under the Constitution. The test for determining whether judicial ...

  20. globalisation, the development of constitutionalism and the ...

    African Journals Online (AJOL)

    Dr Tanya du Plessis

    This article will investigate the effect of globalisation on the development of constitutionalism in South Africa, ... For the purpose of this article "globalisation" means the accelerated integration of economies throughout the ... employer based in an African country, or a foreign employer who has business interests in Africa.

  1. Notes: Constitutionalism | Bazezew | Mizan Law Review

    African Journals Online (AJOL)

    Mizan Law Review. Journal Home · ABOUT · Advanced Search · Current Issue · Archives · Journal Home > Vol 3, No 2 (2009) >. Log in or Register to get access to full text downloads. Username, Password, Remember me, or Register. Notes: Constitutionalism. M Bazezew. Abstract. (No abstract). Full Text: EMAIL FREE ...

  2. LEGAL AND CONSTITUTIONAL EVALUATION OF THE NIGERIAN ...

    African Journals Online (AJOL)

    LLM (Uyo) (Barrister & solicitor of the Supreme Court of Nigeria; lecturer in law, Depart- ment of Public Law, Faculty of ..... revenues derived from oil and gas to meet the needs of the present and future generations as well as ..... the application of practicality in the interpretation of the Constitution. In. Adesanya v President of ...

  3. Legal nature of the positive constitutional responsibility

    Directory of Open Access Journals (Sweden)

    Natalia Bobrova

    2017-01-01

    Full Text Available The subject of the paper is theoretical justification of legal nature of positive constitutionalresponsibility legal institute. The evolution of views on the institution of positive constitutionalresponsibility from the first works on it (S.A. Avak`yan, Yu.P. Eremenko, F.M. Rudinsky, N.A. Bobrova to the present time is analyzed.The purpose is to clarify its role in establishment and maintaining the regime of constitutionallegality.The results, scope of application. Doubts about the legal nature of positive constitutionalresponsibility up to its complete denial are identical with doubts about the legal nature ofmany constitutional norms, the denial of their direct action. These disputes will last forever.Direct service of constitutional and legal responsibility to the quality of governance is a featureof this type of legal responsibility along with its pronounced political character, as wellas the specific guilt of the subject of constitutional tort (liability not only for their acts butfor the acts of their subordinates.The emphasis on positive moral aspect to the detriment of "sanction" (retrospective aspectof the constitutional responsibility does not meet the challenges of the new time.Proponents of affirmative responsibility had good purpose to build its high creative andeducational role from the positive side of the legal liability. However, this good purpose inpractice has not led to optimistic results.The authors come to the conclusion the legal regulation of mechanisms of responsibilityenforcement in Russia is necessary.

  4. Constitutional characteristics of zones of prostate structure

    Directory of Open Access Journals (Sweden)

    Vinnik Y.Y.

    2012-06-01

    Full Text Available The research article is devoted to the study of structural characteristics of prostate according to the young men constitution. Materials and methods: 540 vertical and horizontal sections of prostate have been investigated. Results: Size characteristics of prostate have been established in men of different somatotypes

  5. Between availability and entitlement: The Constitution, Grootboom ...

    African Journals Online (AJOL)

    Between availability and entitlement: The Constitution, Grootboom and the right to food. Danie Brand. Abstract. No Abstract. Full Text: EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT · AJOL African Journals Online. HOW TO USE AJOL... for Researchers · for Librarians ...

  6. Crushed-salt constitutive model update

    Energy Technology Data Exchange (ETDEWEB)

    Callahan, G.D.; Loken, M.C.; Mellegard, K.D. [RE/SPEC Inc., Rapid City, SD (United States); Hansen, F.D. [Sandia National Labs., Albuquerque, NM (United States)

    1998-01-01

    Modifications to the constitutive model used to describe the deformation of crushed salt are presented in this report. Two mechanisms--dislocation creep and grain boundary diffusional pressure solutioning--defined previously but used separately are combined to form the basis for the constitutive model governing the deformation of crushed salt. The constitutive model is generalized to represent three-dimensional states of stress. New creep consolidation tests are combined with an existing database that includes hydrostatic consolidation and shear consolidation tests conducted on Waste Isolation Pilot Plant and southeastern New Mexico salt to determine material parameters for the constitutive model. Nonlinear least-squares model fitting to data from the shear consolidation tests and a combination of the shear and hydrostatic consolidation tests produced two sets of material parameter values for the model. The change in material parameter values from test group to test group indicates the empirical nature of the model but demonstrates improvement over earlier work with the previous models. Key improvements are the ability to capture lateral strain reversal and better resolve parameter values. To demonstrate the predictive capability of the model, each parameter value set was used to predict each of the tests in the database. Based on the fitting statistics and the ability of the model to predict the test data, the model appears to capture the creep consolidation behavior of crushed salt quite well.

  7. Constitutive behavior of reconsolidating crushed salt

    Energy Technology Data Exchange (ETDEWEB)

    Callahan, G.D.; Mellegard, K.D. [RE/SPEC, Inc., Rapid City, SD (United States); Hansen, F.D. [Sandia National Labs., Carlsbad, NM (United States)

    1998-02-01

    The constitutive model used to describe deformation of crushed salt is presented in this paper. Two mechanisms--dislocation creep and grain boundary diffusional pressure solutioning--are combined to form the basis for the constitutive model governing deformation of crushed salt. The constitutive model is generalized to represent three-dimensional states of stress. Recently completed creep consolidation tests are combined with an existing database that includes hydrostatic consolidation and shear consolidation tests conducted on Waste Isolation Pilot Plant (WIPP) and southeastern New Mexico salt to determine material parameters for the constitutive model. Nonlinear least-squares model fitting to data from shear consolidation tests and a combination of shear and hydrostatic tests produces two sets of material parameter values for the model. Changes in material parameter values from test group to test group indicate the empirical nature of the model but show significant improvement over earlier work. To demonstrate the predictive capability of the model, each parameter value set was used to predict each of the tests in the database. Based on fitting statistics and ability of the model to predict test data, the model appears to capture the creep consolidation behavior of crushed salt quite well.

  8. Culture (and religion) in constitutional adjudication | Rautenbach ...

    African Journals Online (AJOL)

    The faculty of law of the Potchefstroom University for Christian Higher Education in corroboration with the Konrad-Adenauer-Stifttung embarked on a study on Politics, Socio-Economic Issues and Culture in Constitutional Adjudication. The aim of the project is twofold. The first aim is to analyse the influence of political, ...

  9. Language question and the constitutional challenges of ...

    African Journals Online (AJOL)

    ... rather than a curse; an asset, rather than a liability. While making Nigeria a focal point of reference, especially the language component of her constitutional history, it is posited that linguistic pluralism is no less valuable to a nation or continent than the wide variety of flowers in a garden or divergent cuisine in a community.

  10. Preliminary Validation of Composite Material Constitutive Characterization

    Science.gov (United States)

    John G. Michopoulos; Athanasios lliopoulos; John C. Hermanson; Adrian C. Orifici; Rodney S. Thomson

    2012-01-01

    This paper is describing the preliminary results of an effort to validate a methodology developed for composite material constitutive characterization. This methodology involves using massive amounts of data produced from multiaxially tested coupons via a 6-DoF robotic system called NRL66.3 developed at the Naval Research Laboratory. The testing is followed by...

  11. Language question and the constitutional challenges of ...

    African Journals Online (AJOL)

    to the analogy of the Tower of Babel_ a linguistic confusion. This paper puts multilingualism in its proper perspective as a blessing, which must be accorded a full constitutional recognition, rather than a curse; an asset, rather than a liability. While making Nigeria a focal point of reference, especially the language component ...

  12. 1 HUMAN DIGNITY - OUR SUPREME CONSTITUTIONAL VALUE ...

    African Journals Online (AJOL)

    Administrator

    BA LLB (University of Cape Town) MCL (International Islamic University, Malaysia. 3 S 10 of the Constitution of the ... the values of equality and freedom or between the value of equality and freedom. On the contrary, it is highly .... world's cultures, our forms of expression and ways of being human. It is fostered by knowledge ...

  13. A model for TRIP steel constitutive behaviour

    NARCIS (Netherlands)

    Perdahcioglu, Emin Semih; Geijselaers, Hubertus J.M.; Menari, G

    2011-01-01

    A constitutive model is developed for TRIP steel. This is a steel which contains three or four different phases in its microstructure. One of the phases in TRIP steels is metastable austenite (Retained Austenite) which transforms to martensite upon deformation. The accompanying transformation strain

  14. income tax assignment under the ethiopian constitution

    African Journals Online (AJOL)

    eliasn

    Constitution from an income tax point of view. And finally, the article ends with some concluding remarks. 1. Theories of Fiscal Federalism In Income Tax Assignment. Few countries pursue the course of decentralization on grounds of its perceived economic efficiency or equity. Political, social, cultural or historical forces are.

  15. Optimizing culture medium for debittering constitutive enzyme ...

    African Journals Online (AJOL)

    The objective of this study was to investigate nutrient requirements for extracellular constitutive naringinase production by Aspergillus oryzae JMU316. The one-factor-at-a-time method was used to determine the impact of different carbon and nitrogen sources on naringinase production. Naringin exhibited the highest ...

  16. 1 HUMAN DIGNITY - OUR SUPREME CONSTITUTIONAL VALUE ...

    African Journals Online (AJOL)

    Administrator

    structures. In short, the Constitutional Court envisions the Basic Law as a unified structure of objective principles and rights crowned by the master value of human dignity.14. 11 S v Makwanyane 1995 (6) BCLR 665 (CC); S v Makwanyane 1995 (3) SA 391 (CC). 12 Supra at par 328. 13 Jones Kant's Principle of Personality ...

  17. Constitutional Provisions And Administrative Disciplinary Powers ...

    African Journals Online (AJOL)

    The Medical and Dental Practitioners Disciplinary Tribunal is empowered to deal with all cases of professional discipline under the Medical and Dental Practitioners Act. This process of administrative adjudication is examined against the background of constitutional provision that affects the exercise of the powers of the ...

  18. Constitutional interpretation : a view from a distance

    NARCIS (Netherlands)

    Peters, Richard

    2011-01-01

    This paper explores how the notion of distance works in the practice of interpretation by studying the philosophical underpinnings of the originalism debate in American constitutionalism. Focusing on some of its most important spokespeople, the paper shows that they start from the historicist

  19. Rapping the 27 Amendments to the Constitution

    Science.gov (United States)

    Knaresborough, Adam

    2009-01-01

    Early in the year, the students of history and government at Mountain View High School in Stafford, Virginia, began to devise hand motions to help memorize the 27 amendments to the Constitution for government class. Three students in the school who are interested in hip hop music then suggested composing a rap song about the topic. Working with…

  20. Constitutional provisions regarding juristic persons | Pienaar ...

    African Journals Online (AJOL)

    The circumstances where juristic persons act as organs of state are discussed with reference to case law. Difference of opinion exists regarding the horizontal application of the Bill of Rights, that is the application of the Bill of Rights to private law relationships. In terms of the interim Constitution the Bill of Rights was applied ...

  1. Constitutive modelling of sandvik 1RK91

    NARCIS (Netherlands)

    Datta, K.; Datta, K.; Hommes, M.; Post, J.; Geijselaers, Hubertus J.M.; Huetink, Han; Beyer, J.; Onate, E; Owen, D.R.J

    2003-01-01

    A physically based constitutive equation is being developed for the maraging stainless steel Sandvik 1RK91. The steel is used to make precision parts. These parts are formed through multistage forming operations and heat treatments from cold rolled and annealed sheets. The specific alloy is designed

  2. Theoretical (dis-) position and strategic leitmotivs in constitutional ...

    African Journals Online (AJOL)

    Four leitmotivs pertinent to certain constellations of events in constitutional interpretation are discussed and their applicability and utility assessed, drawing on examples from constitutional case-law. The leitmotivs are: (i) transitional constitutionalism; (ii) transformative constitutionalism; (iii) monumental constitutionalism; and ...

  3. A PLEADING IN FAVOUR OF THE CONSTITUTIONAL COURT

    Directory of Open Access Journals (Sweden)

    Valentina BĂRBĂŢEANU

    2016-05-01

    Full Text Available Most of the European countries have chosen the centralized system of constitutional review, performed by a unique authority empowered with the competence of removing from the normative ensemble those legal provisions that do not comply with the principles and rules comprised in the Basic Law. This „European model” has proved to be more appropriate than the so-called „American model” in what concerns the compatibility with the European jurisdictional mechanism. Romania has adopted the same European trend and the Constitutional Court has become a very important actor in the Romanian legal landscape. From the very beginning of its activity, it has influenced in a great measure the national normative system. It has been sometimes criticized and accused that it interferes in an excessive way in the legislative process. Due to its competence to regulate the juridical conflicts between the public authorities and its possibility to repeal laws before their promulgation, it has been many times in the centre of heavy attacks, mostly from different political forces, often driven through mass media. Nevertheless, despite of its detractors, the Constitutional Court has proven, over the years, its ability to develop the Romanian normative system. The present paper intends to display the most significant contribution of the Romanian Constitutional Court in improving various legal regulations. In the same time and much more important, using concrete examples from the Court’s case-law, the paper also intends to demonstrate that the Constitutional Court of Romania has been a major factor of improving peoples’ life, removing unconstitutional obstacles set in front of the unimpeded exercise of their fundamental rights and freedoms.

  4. The Constitutional Court in light of interpretive decisions in normative control proceedings

    Directory of Open Access Journals (Sweden)

    Stojanović Dragan

    2016-01-01

    Full Text Available In a legal system based on the principle of the separation of powers, constitutional judicature is necessarily (given the nature of its social function at the intersection of law and politics. Thus, constitutional judiciary is required to preserve political neutrality, particularly in relation to political (legislative and executive authorities. The paper analyzes the principal issues pertaining to constitutional court interpretation, particularly in light of observing the principle of the separation of powers that the constitutional judiciary is bound to abide by and considering the role of the constitutional court as an institution standing at the intersection of law and politics. Every constitutional court is required to be politically neutral and independent from daily politics, which is the major factor in delineating not only the overall boundaries of the constitutional control of the normative framework but also in ensuring the independent and unbiased activity of the constitutional court in the process of interpreting the Constitution and the laws. The constitutional control function shall not be politicized, and it must be exercised only through legal reasoning. Consequently, in the process of constitutional interpretation, the Constitutional Court of Serbia has to develop and consistently pursue a doctrine of self-restraint, thus refraining from politically-driven assessment which is the exclusive duty of political authorities. A closer examination of the doctrine of self-restraint in recent constitutional practice shows that the most prominent elements of this doctrine are relatively new interpretative constructions and legal formulations of constitutional court, which reinforce not only the political neutrality of the constitutional judiciary but also its role as 'the negative legislator'. Yet, some of these constructions may be challenged because their excessive and often inadequate application has resulted in a kind of 'self

  5. Predominant constitutive CFTR conductance in small airways

    Directory of Open Access Journals (Sweden)

    Lytle Christian

    2005-01-01

    Full Text Available Abstract Background The pathological hallmarks of chronic obstructive pulmonary disease (COPD are inflammation of the small airways (bronchiolitis and destruction of lung parenchyma (emphysema. These forms of disease arise from chronic prolonged infections, which are usually never present in the normal lung. Despite the fact that primary hygiene and defense of the airways presumably requires a well controlled fluid environment on the surface of the bronchiolar airway, very little is known of the fluid and electrolyte transport properties of airways of less than a few mm diameter. Methods We introduce a novel approach to examine some of these properties in a preparation of minimally traumatized porcine bronchioles of about 1 mm diameter by microperfusing the intact bronchiole. Results In bilateral isotonic NaCl Ringer solutions, the spontaneous transepithelial potential (TEP; lumen to bath of the bronchiole was small (mean ± sem: -3 ± 1 mV; n = 25, but when gluconate replaced luminal Cl-, the bionic Cl- diffusion potentials (-58 ± 3 mV; n = 25 were as large as -90 mV. TEP diffusion potentials from 2:1 NaCl dilution showed that epithelial Cl- permeability was at least 5 times greater than Na+ permeability. The anion selectivity sequence was similar to that of CFTR. The bionic TEP became more electronegative with stimulation by luminal forskolin (5 μM+IBMX (100 μM, ATP (100 μM, or adenosine (100 μM, but not by ionomycin. The TEP was partially inhibited by NPPB (100 μM, GlyH-101* (5–50 μM, and CFTRInh-172* (5 μM. RT-PCR gave identifying products for CFTR, α-, β-, and γ-ENaC and NKCC1. Antibodies to CFTR localized specifically to the epithelial cells lining the lumen of the small airways. Conclusion These results indicate that the small airway of the pig is characterized by a constitutively active Cl- conductance that is most likely due to CFTR.

  6. Regulation of constitutive STAT5 phosphorylation in acute myeloid leukemia blasts

    NARCIS (Netherlands)

    Birkenkamp, KU; Geugien, M; Lemmink, HH; Kruijer, W; Vellenga, E

    2001-01-01

    In the present study, we examined the underlying mechanism, which causes the constitutive tyrosine phosphorylation of signal transducer and activator of transcription 5 (STAT5) in acute myeloid leukemia (AML) blasts. Constitutive STAT5 phosphorylation was observed in 18 of 26 (69%) patients with

  7. Constitutive description of human femoropopliteal artery aging.

    Science.gov (United States)

    Kamenskiy, Alexey; Seas, Andreas; Deegan, Paul; Poulson, William; Anttila, Eric; Sim, Sylvie; Desyatova, Anastasia; MacTaggart, Jason

    2017-04-01

    Femoropopliteal artery (FPA) mechanics play a paramount role in pathophysiology and the artery's response to therapeutic interventions, but data on FPA mechanical properties are scarce. Our goal was to characterize human FPAs over a wide population to derive a constitutive description of FPA aging to be used for computational modeling. Fresh human FPA specimens ([Formula: see text]) were obtained from [Formula: see text] predominantly male (80 %) donors 54±15 years old (range 13-82 years). Morphometric characteristics including radius, wall thickness, opening angle, and longitudinal pre-stretch were recorded. Arteries were subjected to multi-ratio planar biaxial extension to determine constitutive parameters for an invariant-based model accounting for the passive contributions of ground substance, elastin, collagen, and smooth muscle. Nonparametric bootstrapping was used to determine unique sets of material parameters that were used to derive age-group-specific characteristics. Physiologic stress-stretch state was calculated to capture changes with aging. Morphometric and constitutive parameters were derived for seven age groups. Vessel radius, wall thickness, and circumferential opening angle increased with aging, while longitudinal pre-stretch decreased ([Formula: see text]). Age-group-specific constitutive parameters portrayed orthotropic FPA stiffening, especially in the longitudinal direction. Structural changes in artery wall elastin were associated with reduction of physiologic longitudinal and circumferential stretches and stresses with age. These data and the constitutive description of FPA aging shed new light on our understanding of peripheral arterial disease pathophysiology and arterial aging. Application of this knowledge might improve patient selection for specific treatment modalities in personalized, precision medicine algorithms and could assist in device development for treatment of peripheral artery disease.

  8. BILF1 Mediated Transformation Correlates with Constitutive Signaling

    DEFF Research Database (Denmark)

    Lyngaa, Rikke Birgitte

    2009-01-01

    BIFL1 is a G protein-coupled receptor encoded by human EBV. It signals constitutively through G_alpha_i and is an orphan receptor known to down regulate MHCI expression. BILF1 also engage in dimerization with several chemokine receptors and it induced the activity of NF-kappa beta and inhibits...... the phosphorylation of PKR. My research on BILF1 has contributed to increase the knowledge of BILF1 signaling and has identified BILF1 as a potential oncogene. During the proteomics study NFAT was identified as being up-regulated in BILF1 expressing cells eventually revealing an increased NFAT activity induced...

  9. Hans Kelsen and the Austrian Constitutional Court (1918-1929)

    National Research Council Canada - National Science Library

    Sara Lagi

    2012-01-01

      This article intends to examine Hans Kelsen's contribution to the establishing of the first Austrian Constitutional court, analyzing the key differences between Kelsen's model of Constitutional court...

  10. Constitutive Equations of Rock with Shear Dilatancy

    Science.gov (United States)

    1975-04-01

    AD-AOll 402 CONSTITUTIVE EQUATIONS OF ROCK WITH SHEAR DILATANCY Alfred M. Freudenthal George Washington University Prepared for: Army Research...Freudenthal April 1975 U.S. Army Research Office - Durham Grant No. DA-ARO-D-31-124-73-G194 The George Washington University School of Engineering and...diagonalizes the matrix [A]. The Hamilton- Cayley theorem,which states that a symetric matrix satisfies its own characteristic equation, transforms Eq.(2.2

  11. How Star Wars Illuminates Constitutional Law

    OpenAIRE

    Sunstein, Cass Robert

    2015-01-01

    Human beings often see coherence and planned design when neither exists. This is so in movies, literature, history, economics, and psychoanalysis – and constitutional law. Contrary to the repeated claims of George Lucas, its principal author, the Star Wars series was hardly planned in advance; it involved a great deal of improvisation and surprise, even to Lucas himself. Serendipity and happenstance, sometimes in the forms of eruptions of new thinking, play a pervasive and overlooked role in ...

  12. Constitutive relations for multiphase flow modeling

    Energy Technology Data Exchange (ETDEWEB)

    Jacobs, H.; Vaeth, L.; Thurnay, K. [Forschungszentrum Karlsruhe GmbH Technik und Umwelt (Germany). Inst. fuer Neutronenphysik und Reaktortechnik

    1998-01-01

    The constitutive relations that are used in the three-field fluid dynamics code IVA-KA for determining the drag in three-phase mixtures and the heat transferred by radiation are described together with some comparisons of calculational results with experiments. In these experiments (QUEOS), large quantities of solid particles are injected into water. Potential deficiencies of the present drag model are discussed. (author)

  13. What's So Democratic in " democratic constitutionalism " ?

    Directory of Open Access Journals (Sweden)

    José Alcebíades de Oliveira Junior

    2016-06-01

    Full Text Available The main idea of this paper is to raise questions on the democratic character of “con- temporary constitutionalism”. In this sense, we present the ideas of four renowned scholars and the core of their theses, whose influence – especially in the “Latin world” – is undenia- ble. They are Manuel Atienza, Luigi Ferrajoli, Luis Prieto Sanchís and Gustavo Zagrebel- sky. Among the many differences that characterize them, their accounts have at least one thing in common: enthusiasm for the constitutional project. To that extent, they stress the normativity of the Constitution and the “civilizing feature” of constitutional values. We address several objections to this understanding, taking into consideration the fundamen- tal right to participate on political affairs, including issues related to substantive rights, which require political and moral developments. To do so, we must take seriously the fact of disagreement and the fact of pluralism as elements of the process of protection and realization of fundamental rights. These rights are also subject to a decision-making process.

  14. A constitutive law for degrading bioresorbable polymers.

    Science.gov (United States)

    Samami, Hassan; Pan, Jingzhe

    2016-06-01

    This paper presents a constitutive law that predicts the changes in elastic moduli, Poisson's ratio and ultimate tensile strength of bioresorbable polymers due to biodegradation. During biodegradation, long polymer chains are cleaved by hydrolysis reaction. For semi-crystalline polymers, the chain scissions also lead to crystallisation. Treating each scission as a cavity and each new crystal as a solid inclusion, a degrading semi-crystalline polymer can be modelled as a continuum solid containing randomly distributed cavities and crystal inclusions. The effective elastic properties of a degrading polymer are calculated using existing theories for such solid and the tensile strength of the degrading polymer is predicted using scaling relations that were developed for porous materials. The theoretical model for elastic properties and the scaling law for strength form a complete constitutive relation for the degrading polymers. It is shown that the constitutive law can capture the trend of the experimental data in the literature for a range of biodegradable polymers fairly well. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Association of Sasang Constitutional Type with Sarcopenia

    Directory of Open Access Journals (Sweden)

    Seung Ku Lee

    2015-01-01

    Full Text Available Sasang constitutional medicine (SCM is a unique Korean traditional medicine that classifies human beings as four distinct types named Sasang constitutional types (SCTs, based on physiologic, physical, and psychological traits. Accumulating evidence has demonstrated that specific constitutional types are associated with chronic diseases, but no study has investigated the relationship between SCTs and sarcopenia. The aim of this study was to examine the association in a large population-based study. Data from 1,204 participants who completed questionnaires for life style, anthropometric evaluation, and biochemical analysis were analyzed. Classification of the SCTs was done using an integrated diagnostic method. Sarcopenia was defined as appendicular skeletal muscle mass/height2 less than one standard deviation below the gender-specific normal mean of a younger group. Dual-energy X-ray absorptiometry was used to assess whole body composition. The prevalence of sarcopenia was 8.6% in the Tae-eum (TE type, 44.7% in the So-eum (SE type, and 20.7% in the So-yang (SY type. Multivariate analysis revealed that the SE and SY types had 9.22 (5.06–16.81; P<0.0001 and 2.90 (1.76–4.76; P<0.0001 greater odds of sarcopenia compared to the TE type, respectively. Our results show that the SE and SY types are significantly associated with increased prevalence of sarcopenia.

  16. Global Survey of National Constitutions: Mapping Constitutional Commitments to Sexual and Reproductive Health and Rights.

    Science.gov (United States)

    Pizzarossa, Lucía Berro; Perehudoff, Katrina

    2017-12-01

    General Comment No. 22, issued in 2016 by the Committee on Economic, Social and Cultural Rights (CESCR), clarifies states' legal duties to respect, protect, and fulfill the right to sexual and reproductive health (SRH). Our study analyzes domestic constitutions around the world to investigate whether and to what extent the right to sexual and reproductive health is respected, protected, and fulfilled; to what extent these provisions are inclusive and non-discriminatory; and to what degree the interlinkages between this and other human rights are acknowledged. Of the 195 constitutions accessed, 27 enshrine sexual and/or reproductive health, and seven adopt restrictive approaches to this right. In the 27 constitutions, provisions most frequently enshrine respect of one's sexual health and family planning decisions, the protection of sexual health, and the provision of reproductive health care and family planning services (fulfillment). Most of the 27 constitutions fail to adequately respect reproductive health rights; to protect reproductive health, family planning, and abortion services from third-party interference; and to fulfill all dimensions of sexual health and access to abortion. Three of the 27 constitutions enshrine a universal right to SRH, and additional constitutions protect specific vulnerable groups (such as women, children) and/or restrict the scope of rights holders to couples. Among the 27 constitutions, nine explicitly link the right to sexual and reproductive health to the rights to education, science, and/or to make autonomous decisions about sexuality and reproduction. Our results can serve as a baseline measure to track constitutional reforms in pursuit of the realization of sexual and reproductive health and rights, and as building blocks for future lawmakers committed to realizing these rights through domestic legal reform.

  17. Constitutionalism and good governance in Nigeria (1999-2014 ...

    African Journals Online (AJOL)

    Nigeria operates a governmental system based on a written constitution. The idea of constitution and constitutionalism is of a more recent one as the country has witnessed a long era of military rule. While the country, at present, has a written constitution which in reality, was derived from a military decree, there has been ...

  18. he Obligations on Government and Society in our Constitutional ...

    African Journals Online (AJOL)

    Constitutional democracy limits this principle by subjecting the democratically elected government and the will of the majority subject to a written constitution and the norms embodied in it. Such constitution is enshrined as the supreme law of the country in question. An almost universal feature of modern constitutionalism is a ...

  19. An Integrated Theory of Constitutionalism in World Society

    DEFF Research Database (Denmark)

    Kjær, Poul F.

    both been regarded a indicating a triumph as well as a failure of constitutionalism. This article circumvents this standoff by questioning the very foundation of constitutional theory in the public/private and the national/transnational distinctions. It is argued that the object of constitutions...... for compatibility between orders through constitutionalisation and the idea of constitutionalism as a way of approaching the future....

  20. Ubuntu versus the core values of the South African Constitution ...

    African Journals Online (AJOL)

    At the dawn of South Africa's new era of constitutionalism the Constitutional Court introduced “African law and legal thinking” and ubuntu to South African jurisprudence as part of the Constitution's source of democratic values. Whereas the Constitutional Court averred on the one hand that African law sustains firmly ...

  1. Habermas on European Constitution and European Identity

    Directory of Open Access Journals (Sweden)

    Éva Biró-Kaszás

    2010-12-01

    Full Text Available For the last two decades or so philosophers have been reflecting on a set of practical and political concerns in connection with the new political structural arrangements beyond the nation-state. In this article two essays by Jürgen Habermas shall be examined. An attempt shall be made to tackle Habermas’ philosophical concepts of personal and collective identity as well as the role that a constitution may play in building the post-national constellation. It has been shown that Habermas has normative answers. Firstly, according to him, the fragile balance between the legal order and the particular cultures and traditions of a community has to be protected by the constitutional state. For that reason the political culture has to be “decoupled” from the majority culture. Secondly, the democratically structured attempt to achieve shared meaning has to find the delicate balance between the context-transcending universal normative claims and the claims of particular individual and collective life. Thirdly, it is possible to expand legally mediated civil solidarity trans-nationally, across Europe – we may recognize this development as the emergence of European identity –, since the process of democratic will-formation of citizens may get loose from the structures provided by the state if both shared democratic political cultures as well as a European-wide public sphere exist. The European Constitution may have a catalytic function in materialization of these conditions. It has been shown that in his deliberations Habermas tried to find a reflective equilibrium between the normative and the empirical.

  2. The Constitutional Deficiencies of the German 'Rechtsgutslehre'

    Directory of Open Access Journals (Sweden)

    Carl-Friedrich Stuckenberg

    2013-01-01

    Full Text Available This paper questions the theoretical merits and constitutional validity of the “Rechtsgutslehre” (doctrine of the protection of legal goods, a widely held doctrine about the limits of legitimate criminalization in Germany and some other jurisdictions. The immediate cause for this reassessment is a recent decision of the German constitutional court which upheld the German incest prohibition and simultaneously rejected the traditional “Rechtsgutslehre” as constitutionally irrelevant, thereby stirring up considerable controversy among academic criminal lawyers. The paper tries to show why the court’s view is correct by pointing out the main deficiencies of the doctrine and what criteria a better theory must fulfil. Este artículo cuestiona los méritos teóricos y la validez constitucional de la "Rechtsgutslehre" (doctrina de la protección de los bienes jurídicos, una doctrina muy extendida acerca de los límites de la criminalización legítima en Alemania y algunas otras jurisdicciones. La causa inmediata de esta nueva valoración es una decisión reciente del Tribunal Constitucional alemán que ratificó la prohibición del incesto en Alemania y al mismo tiempo rechazó el tradicional "Rechtsgutslehre" por ser constitucionalmente irrelevante, lo que provocó una considerable controversia entre la comunidad académica de abogados criminalistas. El artículo trata de mostrar por qué la decisión de la corte es correcta, señalando las deficiencias principales de la doctrina y los criterios que una teoría más adecuada debe cumplir. DOWNLOAD THIS PAPER FROM SSRN: http://ssrn.com/abstract=2200870

  3. Engineering and the constitution. Technik und Verfassung

    Energy Technology Data Exchange (ETDEWEB)

    Herzog, R.

    1988-01-01

    We can see at every turn how instruments once used for the good of mankind become blunt right before our very eyes. They still serve their purpose, but each further step brings about less additional benefit ('residual benefit'). This is a fundamental problem rather than a detail problem, as it is the self-concept, reliability and stability of our public order that is at risk. 'Constitution' in this sense is more than just the legal basis of the state; as used by the author it refers to the laws governing a society's life. (orig./HSCH).

  4. Evaluation of constitutive models for crushed salt

    Energy Technology Data Exchange (ETDEWEB)

    Callahan, G.D.; Loken, M.C. [RE/SPEC, Inc., Rapid City, SD (United States); Hurtado, L.D.; Hansen, F.D.

    1996-05-01

    Three constitutive models are recommended as candidates for describing the deformation of crushed salt. These models are generalized to three-dimensional states of stress to include the effects of mean and deviatoric stress and modified to include effects of temperature, grain size, and moisture content. A database including hydrostatic consolidation and shear consolidation tests conducted on Waste Isolation Pilot Plant (WIPP) and southeastern New Mexico salt is used to determine material parameters for the models. To evaluate the capability of the models, parameter values obtained from fitting the complete database are used to predict the individual tests. Finite element calculations of a WIPP shaft with emplaced crushed salt demonstrate the model predictions.

  5. Towards constitutive equations for the deep Earth

    Science.gov (United States)

    Kennett, B. L. N.

    2017-09-01

    A new formulation of constitutive equations for states of high compression is introduced for isotropic media, exploiting a separation between hydrostatic and deviatoric components in strain energy. The strain energy is represented as functions of strain invariants, with one purely volumetric component and the other which vanishes for purely hydrostatic deformation. This approach preserves the form of familiar equations of state through the volumetric component, but allows the addition of volume and pressure dependence of the shear modulus from the deviatoric term. A suitable shear modulus representation to accompany a Keane equation of state is demonstrated.

  6. Numerically abnormal chromosome constitutions in humans

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1993-12-31

    Chapter 24, discusses numerically abnormal chromosome constitutions in humans. This involves abnormalities of human chromosome number, including polyploidy (when the number of sets of chromosomes increases) and aneuploidy (when the number of individual normal chromosomes changes). Chapter sections discuss the following chromosomal abnormalities: human triploids, imprinting and uniparental disomy, human tetraploids, hydatidiform moles, anomalies caused by chromosomal imbalance, 13 trisomy (D{sub 1} trisomy, Patau syndrome), 21 trisomy (Down syndrome), 18 trisomy syndrome (Edwards syndrome), other autosomal aneuploidy syndromes, and spontaneous abortions. The chapter concludes with remarks on the nonrandom participation of chromosomes in trisomy. 69 refs., 3 figs., 4 tabs.

  7. Ritual Slaughter in the Modern Constitutional State

    DEFF Research Database (Denmark)

    Afsah, Ebrahim

    In this proposed presentation I intend to give a historical overview of the political and constitutional debates in selected European countries – including Germany, France, Great Britain, Holland and Scandinavia – from the nineteenth century to the present day, paying special attention to the shi....... Similar in nature if not necessarily in intensity to questions of forced and/or underage marriage, male circumcision and female genital mutilation, the commitment of the secular state to animal welfare cannot summarily be rejected by demands for religious freedom....

  8. The Scottish Constitutional Tradition: A Very British Radicalism?

    Directory of Open Access Journals (Sweden)

    Bulmer W. Elliot

    2015-11-01

    Full Text Available This paper discusses recent developments in Scottish nationalist constitutional thought during the period of 2002 to 2014, showing how the Scottish constitutional conversation has diverged from, but continues to be influenced by, the UK-wide constitutional conversation at Westminster. It presents Scottish nationalist constitutional thought as a ‘very British radicalism’, which is characterised by certain constitutional forms and ideas that are radical in a British context (such as popular sovereignty, proportional representation, a written constitution, and a commitment to covenantal socio-economic and environmental provisions while at the same time retaining a persistent ‘Britishness’ in terms of specific institutional proposals and ambivalence towards the principles of constitutional government. Finally, I will discuss possible designs of a future constitutional settlement in Scotland and the United Kingdom. Notably, I will explore how far the Scottish constitutional tradition might impact on the constitutional shape of the United Kingdom.

  9. HOW STAR WARS ILLUMINATES CONSTITUTIONAL LAW

    Directory of Open Access Journals (Sweden)

    Cass R. Sunstein

    2017-02-01

    Full Text Available Human beings often see coherence and planned design when neither exists. This is so in movies, literature, history, economics, and psychoanalysis – and constitutional law. Contrary to the repeated claims of George Lucas, its principal author, the Star Wars series was hardly planned in advance; it involved a great deal of improvisation and surprise, even to Lucas himself. Serendipity and happenstance, sometimes in the forms of eruptions of new thinking, play a pervasive and overlooked role in the creative imagination, certainly in single authored works, and even more in multi-authored ones extending over time. Serendipity imposes serious demands on the search for coherence in art, literature, history, and law. That search leads many people (including Lucas to misdescribe the nature of their own creativity and authorship. The misdescription appears to respond to a serious human need for sense-making and pattern-finding, but it is a significant obstacle to understanding and critical reflection. Whether Jedi or Sith, many authors of constitutional law are a lot like the author of Star Wars, disguising the essential nature of their own creative processes.

  10. Constitutional moments in governing science and technology.

    Science.gov (United States)

    Jasanoff, Sheila

    2011-12-01

    Scholars in science and technology studies (STS) have recently been called upon to advise governments on the design of procedures for public engagement. Any such instrumental function should be carried out consistently with STS's interpretive and normative obligations as a social science discipline. This article illustrates how such threefold integration can be achieved by reviewing current US participatory politics against a 70-year backdrop of tacit constitutional developments in governing science and technology. Two broad cycles of constitutional adjustment are discerned: the first enlarging the scope of state action as well as public participation, with liberalized rules of access and sympathetic judicial review; the second cutting back on the role of the state, fostering the rise of an academic-industrial complex for technology transfer, and privatizing value debates through increasing delegation to professional ethicists. New rules for public engagement in the United Sates should take account of these historical developments and seek to counteract some of the anti-democratic tendencies observable in recent decades.

  11. The Eurozone Crisis: A Constitutional Analysis

    Directory of Open Access Journals (Sweden)

    Anna Sting

    2015-08-01

    Full Text Available “Every power comes through crisis” has long been a motif of European integration. The financial and sovereign debt crises, which have shaken the European Union (EU in recent years, are at first glance no different. Treaty reforms, intergovernmental treaties such as the Fiscal Compact and the Treaty Establishing a European Stability Mechanism (ESM Treaty have significantly altered the constitutional landscape of the EU and its Member States. The crisis has also inspired many European legal scholars to critically analyse the EU’s system of economic governance, as have other events throughout the history of the European Union, from the Empty Chair Crisis to the referenda in the aftermath of the Treaty of Maastricht and the failure of the Constitution for the European Union. What does seem to be different is the way in which scholars approach the issue of the Eurozone crisis. Instead of a purely legal perspective on economic governance, European legal scholars have realised that in order to understand and analyse the euro crisis, interdisciplinarity is the word of the moment.

  12. Relationships among certain joint constitutive models.

    Energy Technology Data Exchange (ETDEWEB)

    Segalman, Daniel Joseph; Starr, Michael James

    2004-09-01

    In a recent paper, Starr and Segalman demonstrated that any Masing model can be represented as a parallel-series Iwan model. A preponderance of the constitutive models that have been suggested for simulating mechanical joints are Masing models, and the purpose of this discussion is to demonstrate how the Iwan representation of those models can yield insight into their character. In particular, this approach can facilitate a critical comparison among numerous plausible constitutive models. It is explicitly shown that three-parameter models such as Smallwood's (Ramberg-Osgood) calculate parameters in such a manner that macro-slip is not an independent parameter, yet the model admits macro-slip. The introduction of a fourth parameter is therefore required. It is shown that when a macro-slip force is specified for the Smallwood model the result is a special case of the Segalman four-parameter model. Both of these models admit a slope discontinuity at the inception of macro-slip. A five-parameter model that has the beneficial features of Segalman's four-parameter model is proposed. This model manifests a force-displacement curve having a continuous first derivative.

  13. We the People: Indiana and the United States Constitution. Lectures in Observance of the Bicentennial of the Constitution.

    Science.gov (United States)

    Furlong, Partick J.; And Others

    These lectures, presented in observance of the U.S. Constitution bicentennial celebration, consider selected constitutionally significant law cases that occurred in Indiana. These cases are representative of U.S. constitutional development and of the relationship of Indiana to the U.S. Constitution. Patrick Furlong, in "The South Bend…

  14. Constitution and religiosity of/in the constitutional order of the National Socialist Empire

    Directory of Open Access Journals (Sweden)

    Velez, Pedro

    2017-05-01

    Full Text Available In this article, we will analyse the National Socialist regime as a politico-constitutional reality. We will do it from a new way of looking at politico-constitutional phenomena, interpreting them as registered in a religious grounding. It seeks to show that the National Socialist regime was characterised by having identified the political community – a racially interpreted and raised community to the Absolute – with an empirical historic personality regarded as eminently communitarian. It suggests that the regime constitutes a sui generis case, either in a context of regimes conventionally classified as "right-wing authoritarian and/or totalitarian" or in a larger context of contemporary politics.

  15. Splanchnic venous thrombosis driven by a constitutively activated ...

    African Journals Online (AJOL)

    Introduction: Splanchnic venous thrombosis (SVT) has varied etiology with Philadelphia-negative myeloproliferative neoplasms (MPNs) being the most frequent underlying prothrombotic factor. Hematological indices often remain within normal range because of portal hypertension and its sequelae, causing diagnostic ...

  16. Splanchnic venous thrombosis driven by a constitutively activated ...

    African Journals Online (AJOL)

    Abstract. Introduction: Splanchnic venous thrombosis (SVT) has varied etiology with Philadelphia- negative myeloproliferative neoplasms (MPNs) being the most frequent underlying prothrombotic factor. Hematological indices often remain within normal range because of portal hypertension and its sequelae, causing ...

  17. Constitutive model with time-dependent deformations

    DEFF Research Database (Denmark)

    Krogsbøll, Anette

    1998-01-01

    In many geological and Engineering problems it is necessary to transform information from one scale to another. Data collected at laboratory scale are often used to evaluate field problems on a much larger scale. This is certainly true for geological problems where extreme scale differences...... are common in time as well as size. This problem is adressed by means of a new constitutive model for soils. It is able to describe the behavior of soils at different deformation rates. The model defines time-dependent and stress-related deformations separately. They are related to each other and they occur...... simultanelously. The model is based on concepts from elasticity and viscoplasticity theories. In addition to Hooke's law for the elastic behavior, the framework for the viscoplastic behavior consists, in the general case (two-dimensional or three-dimensional), of a yield surface, an associated flow rule...

  18. Constituting objectivity: Transcendental perspectives on modern physics

    Science.gov (United States)

    Everett, Jonathan

    2012-05-01

    There is increasing interest in exploring Kantian approaches in the study of the history and philosophy of physics. The most well-known examples of this trend-Friedman's (2001), Ryckman's (2005) and DiSalle's (2006)-focus on Kantianism in the context of the development of the general theory of relativity. The edited collection Constituting Objectivity seeks to develop key Kantian insights-in the most part-in the context of later developments in physics: as well as discussing relativity the volume also provides Kantian interpretations of Bohr's development of quantum theory and continues to provide Kantian insight from later interpretations of quantum mechanics all the way through to considering noncommutative geometry and loop quantum gravity. The volume contains papers on a wide variety of subjects and offers an essential introduction to the breadth of Kantian trends in modern physics.

  19. Federal Constitutional Court. Decision of July 8, 1982 (Wyhl)

    Energy Technology Data Exchange (ETDEWEB)

    1983-04-01

    With the decision of July 8, 1982, the second senate of the Federal Constitutional Court judged the action on constitutional grounds, brought in by the municipality of Sassbach near Kaiserstuhl to achieve annulment of the construction permit for Wyhl nuclear power plant, to be inadmissible and also partly unfounded. This decision was taken unanimously. In its statement the Court explains basic ideas on the applicability of the Basic Law with regard to juristic persons within the purview of public law and activities on their part outside the scope of fulfilment of public tasks, as well as on the compatibility of material regulations of preclusion in administrative procedures with the Basic Law, especially with article 19, sub-section (4) of the Basic Law. The Court decided that a municipality is not in the position to claim the right of property as laid down in article 14, para. (1) no. 1 of the Basic Law, even if it becomes active outside the scope of fulfilment of public tasks.

  20. The Causes of Failure of the European Constitution From the Perspective of the Constitution-Making Process

    Directory of Open Access Journals (Sweden)

    Robert Podolnjak

    2006-01-01

    Full Text Available The basic argument of the article is that the main causes of failure of the European Constitution stem from an inadequate preparation and implementation of a complex procedure of constitution-making for a federation of countries on a continental scale. This process includes the issues of temporal aspects of constitutionmaking, the subject of constitution-making, the text of the constitution, the strategy of constitutional ratifi cation and the constitution-makers themselves. The principal causes of failure of the European Constitution will be presented in the form of certain preliminary assumptions, which will then be examined in the light of certain comparative experiences of constitution-making in two federal systems – the American and the Swiss system. The primary mistakes of the European constitution-making are refl ected in the lack of an appropriate moment for making the constitution, in the vagueness of the document in terms of its constitutional or contractual quality, in the creation of a text of the Constitution which is completely incomprehensible to the average citizen, in the making of the Constitution without a vision or ambition, in the complete lack of any strategy of ratifi cation of the Constitution, in the insistence on the direct participation of the people in the adoption of the Constitution, which is legally and politically considered primarily an international treaty, and in badly managed media presentation and defence of the Constitution before the European public. The most important mistakes, crucial to the failure of the Constitution, are the ambivalent approach of the European constitutionmakers to the mode of ratifi cation of the Constitution, and their disregard of the constitution-making experience of other federal countries.

  1. 3 CFR 8418 - Proclamation 8418 of September 16, 2009. Constitution Day and Citizenship Day, Constitution Week...

    Science.gov (United States)

    2010-01-01

    ... Americans have a solemn obligation to participate in our democracy so that it remains vibrant, strong, and responsive to the needs of our citizens. To succeed, the democracy established in our Constitution requires... as leaders of civic, social, and educational organizations, to conduct ceremonies and programs that...

  2. 77 FR 57981 - Constitution Day and Citizenship Day, Constitution Week, 2012

    Science.gov (United States)

    2012-09-18

    ... From the Federal Register Online via the Government Publishing Office ] Vol. 77 Tuesday, No. 181..., Constitution Week, 2012 #0; #0; #0; Presidential Documents #0; #0; #0;#0;Federal Register / Vol. 77 , No. 181... duties and responsibilities of citizenship, the Congress, by joint resolution of February 29, 1952 (36 U...

  3. The Balancing Act between the Constitutional Right to Strike and the Constitutional Right to Education

    Science.gov (United States)

    Deacon, H. J.

    2014-01-01

    While the South African Constitution enshrines both children's right to a basic education and teachers' right to strike, conflict between these two often occurs when the way in which teachers' unions conduct strike actions detracts from learners' education. This article identifies the parties affected by industrial action in the school context,…

  4. 76 FR 58705 - Constitution Day and Citizenship Day, Constitution Week, 2011

    Science.gov (United States)

    2011-09-21

    ... September 21, 2011 Part V The President Proclamation 8714--Constitution Day and Citizenship Day..., delegates from the States gathered in Philadelphia to build a new framework for our young republic. Our....) [FR Doc. 2011-24438 Filed 9-20-11; 11:15 am] Billing code 3195-W1-P ...

  5. Global Survey of National Constitutions : Mapping Constitutional Commitments to Sexual and Reproductive Health and Rights

    NARCIS (Netherlands)

    Berro Pizzarossa, Lucia; Perehudoff, Katrina

    2017-01-01

    General Comment No. 22, issued in 2016 by the Committee on Economic, Social and Cultural Rights (CESCR), clarifies states' legal duties to respect, protect, and fulfill the right to sexual and reproductive health (SRH). Our study analyzes domestic constitutions around the world to investigate

  6. Global survey of national constitutions : Mapping constitutional commitments to sexual and reproductive health and rights

    NARCIS (Netherlands)

    Berro Pizzarossa, Lucia; Perehudoff, Katrina

    2017-01-01

    General Comment No. 22 clarifies States’ legal duties to respect, protect, and fulfill the right to sexual and reproductive health (SRH). Our study analyzes domestic constitutions to investigate whether and to what extent the provisions respect, protect, and/or fulfil the right to sexual and

  7. The Theory of Global Governance, Constitutionalization and Comparative Constitutional Law

    Czech Academy of Sciences Publication Activity Database

    Blahož, Josef

    2013-01-01

    Roč. 3, č. 3 (2013), s. 195-207 ISSN 1805-8396 Institutional support: RVO:68378122 Keywords : globalization of political culture * global constitutionalism * comparative constitutional law Subject RIV: AG - Legal Sciences

  8. Approaches to a constitutional function on theory of crime

    Directory of Open Access Journals (Sweden)

    Yvan Montoya Vivanco

    2013-12-01

    Full Text Available After presenting assumptions of neo constitutionalism impact incriminal law, this article raises the possibilities of rebuild contents of categories on crime’s theory towards fundamental principles and rights recognized (explicitly or implicitly in the Constitution.

  9. Constitutive Theory Developed for Monolithic Ceramic Materials

    Science.gov (United States)

    Janosik, Lesley A.

    1998-01-01

    With the increasing use of advanced ceramic materials in high-temperature structural applications such as advanced heat engine components, the need arises to accurately predict thermomechanical behavior that is inherently time-dependent and that is hereditary in the sense that the current behavior depends not only on current conditions but also on the material's thermomechanical history. Most current analytical life prediction methods for both subcritical crack growth and creep models use elastic stress fields to predict the time-dependent reliability response of components subjected to elevated service temperatures. Inelastic response at high temperatures has been well documented in the materials science literature for these material systems, but this issue has been ignored by the engineering design community. From a design engineer's perspective, it is imperative to emphasize that accurate predictions of time-dependent reliability demand accurate stress field information. Ceramic materials exhibit different time-dependent behavior in tension and compression. Thus, inelastic deformation models for ceramics must be constructed in a fashion that admits both sensitivity to hydrostatic stress and differing behavior in tension and compression. A number of constitutive theories for materials that exhibit sensitivity to the hydrostatic component of stress have been proposed that characterize deformation using time-independent classical plasticity as a foundation. However, none of these theories allow different behavior in tension and compression. In addition, these theories are somewhat lacking in that they are unable to capture the creep, relaxation, and rate-sensitive phenomena exhibited by ceramic materials at high temperatures. The objective of this effort at the NASA Lewis Research Center has been to formulate a macroscopic continuum theory that captures these time-dependent phenomena. Specifically, the effort has focused on inelastic deformation behavior associated

  10. Keterbatasan Pengadilan untuk Melakukan Pengujian Konstitusional (Constitutional Review): Pengalaman Jepang

    OpenAIRE

    Isharyanto,

    2015-01-01

    The realm of political practice today , a mechanism for checking the legalnorms by the court to ensure the coherence of the legislation of the constitution becomes inevitable (judicial constitutional review ) . Learning the Japanese experience , that constitutionalism is the reconstruction of post-war Japan ystem ystem kenegaran of civil law -based rule by law be a constitutionalism which is based on the rule of law .

  11. STABILITY AND DYNAMICS OF THE CONSTITUTION OF UKRAINE

    OpenAIRE

    Marina Nikolaievna Lazareva

    2014-01-01

    This article contains a brief review of the constitutional events that took place in Ukraine since its Declaration of Independence to the Presidential elections in 2014. The main attention is given to the transformation of the text of the Ukrainian Constitution of 1996 and the legal instruments of its conversion, including acts of the Constitutional Court. The author emphasizes the idea of the similarity of the constitutional and legal institutions of Ukraine and Russia, comparing them with e...

  12. The Constitution of the Cultural Memory

    Directory of Open Access Journals (Sweden)

    Ute Seydel

    2015-02-01

    Full Text Available In the first half of the twentieth century, the sociologist Maurice Halbwachs and the literary critic and philosopher Walter Benjamin, published a pioneering work on the social dimension of memory as well as the first considerations about the transmission of personal experience and of what a member of a collectivity heard. Although both emphasize the importance of oral communication,it is possible to glimpse, in both texts, the seed for what since the 1980’s began to be called “cultural memory”, a memory that’s not only created on thebasis of oral stories and the everyday inteaction —that is to say, the mediumof the voice— but through the use of various media. These allow to store anddivulge the versions of the past in larger spaces than those which constitute thememory surroundings of which Halbwachs talked. Jan Assmann describes th estabilization processes of cultural memory on which the various institutionsand media intervene, while Astrid Erll explores the dynamization processes of cultural memory that occur in our current mediatic societies through remediatizationand premediatization, as well as the biggest accessibility of electronicmedia for a wide audience. Thus, it is possible to articulate memory latenciesand to question hegemonic versions of the past.

  13. Financial Accounting Constitution or its Referential Matrix

    Directory of Open Access Journals (Sweden)

    Niculae Feleaga

    2006-07-01

    Full Text Available Using a simplified approach it may be stated that the financial accounting theoretical framework is structured on three levels. At the first level, reference is made to the accounting objectives. These objectives are fundamental for the theoretical framework. At the second level, we find the accounting information characteristics and explicit mentions about the headings of financial statements. The mentioned characteristics of accounting information represent the basic issues for ensuring its utility. The headings represent the main categories of elements disclosed in the financial statements, like assets and liabilities – these two elements’ definitions brought radical changes both in the accounting thinking and practices. Overall, the second level’s components represent the basis for building the practice directives as a matter of recognition (identification and measurement (evaluation. Inside the third level, the recognition and measurement directives are being detailed, which will be further used by the accounting specialist in order to identify and apply the accounting standards. These two directives enclose postulates, principles and restrictions. Such specifications prove to be useful whenever precise answers must be given to relative financial information issues. Usually, it is accepted that the theoretical framework, also called the accounting framework is the standard-setting, metaphorically speaking is actually the constitution of financial accounting, or in other words, its reference matrix.

  14. Unquenched thirst: the need for a constitutionally recognized right to ...

    African Journals Online (AJOL)

    As demonstrated in South Africa, the codification of the right to water in its constitution has improved access to adequate water, sparked government concern and action on water and sanitation issues, and provided citizens with various avenues to compel government adherence to the constitutional right. Is constitutional ...

  15. Legitimacy of the Vidovdan Constitution and relationships established thereby

    Directory of Open Access Journals (Sweden)

    Aksić Sava

    2016-01-01

    Full Text Available The Vidovdan Constitution (1921 was the first constitution of the Kingdom of Serbs, Croats and Slovenians. Serbian ruling parties advocated that the constitution should be adopted in Parliament by a simple majority vote of Serbs, Croats and Slovenians all together, considering that it was to be the constitution of 'one nation with three names'. On the other hand, Croatian and Slovenian parties took the position that the constitution should be approved by a majority vote of each of the three nations (Serbs, Croats and Slovenians separately. The Constitution was adopted on Vidovdan (St. Vitus Day, on 28th June 1921, by the Serbian and Muslim majority. However, this constitution was not legitimate, because the provisions it rested on were not approved by the parliamentary majority of each nation separately but by the parliamentary majority of all nations together, where the three nations had unequal number of representative. Under the Vidovdan Constitution, the territory of the state was centralized, church authorities did not have the status of state authority, and the Church was only acknowledged the status of an autonomous organization. This Constitution established constitutional monarchy as a form of government. It further envisaged that the King did not have any authorities outside the Constitution, and that there were no authorities that could not be taken away from him under the Constitution.

  16. Avoiding Mazibuko : water security and constitutional rights in ...

    African Journals Online (AJOL)

    The 2009 judgment by the Constitutional Court of South Africa in Mazibuko v City of Johannesburg is seen by many as a watershed in the interpretation of the fundamental constitutional right of access to water. The Constitutional Court ruled that the right of access to sufficient water does not require that the state provide ...

  17. ALL ABOUT WORDS ON THE PROCEDURE OF CONSTITUTIONAL ...

    African Journals Online (AJOL)

    'unconstitutional declaration of unconstitutionality' of laws in Melaku's case. ... employed in the process of adjudicating constitutional issues, the ' law to re-enact for .... interpretation, but even then, courts do not follow civil procedures like that of civil suit. Constitutional interpretation is all about maintaining constitutionalism.

  18. Reflections on the Establishment of Constitutional Government in Eastern Europe.

    Science.gov (United States)

    Varat, Jonathan D.

    Establishing constitutional government involves not simply the creation of a written document that purports to create the political structure of a nation and guarantee rights to its people, but "constitutionalism" in the sense of meaningful and effective adherence to constitutional norms of democratic organization and the protection of…

  19. BOOK REVIEW Gyorfi T Against the New Constitutionalism (Edward ...

    African Journals Online (AJOL)

    MJM Venter

    2017-05-16

    May 16, 2017 ... Review. This notable addition to the series Elgar Monographs in Constitutional and. Administrative Law is a thought-provoking contribution to the "legal versus political constitutionalism" debate. The author, a Hungarian scholar working in the UK, takes a sceptical view of constitutional judicial review. He.

  20. CHAPTER FOUR LİBERTY AND TURKISH CONSTITUTIONS:

    OpenAIRE

    FENDOĞLU, Doç.Dr.Hasan Tahsin

    2014-01-01

    CHAPTER FOUR LIBERTY AND TURKISH CONSTITUTIONS: Doç.Dr.Hasan Tahsin FENDOĞLU ABSTRACT: Turkish Constitution of 1982 is the first and only Turkish Constitution that has a main purpose on strengthening the political power not the liberty or democr...

  1. Zelalem Eshetu Degifie Abstract The Constitution of the Federal ...

    African Journals Online (AJOL)

    This amending formula which is built-in the constitution serves to confine the right to amend within the prescribed legal ... Trends in Africa and Their Potential Impact on Constitutionalism, 1, 20-21 (Paper Presented at the World Congress .... eternity clauses which define the immutable elements of the constitution. At this time,.

  2. do the new Zimbabwean constitutional provisions on judicial ...

    African Journals Online (AJOL)

    RV

    BA English (Solusi University); LLB, LLM (University of Fort Hare) and and is currently undertaking a .... The Constitution of Zimbabwe stipulates, in line with international norms, that no person or organ of ..... Ex Parte Chairperson of the Constitutional Assembly: in re Certification of the Constitution of the. Republic of South ...

  3. Human Rights under the Ethiopian Constitution: A Descriptive ...

    African Journals Online (AJOL)

    This article summarizes human rights under the Ethiopian Constitution (mainly surrounding Chapter 3 of Constitution and related constitutional provisions on human and democratic rights), and forwards some insights. It, inter alia, covers various aspects of the application and interpretation of human rights provisions, ...

  4. Constitutive Laws for Geomaterials Lois constitutives pour les géomatériaux

    Directory of Open Access Journals (Sweden)

    Papamichos E.

    2006-12-01

    Full Text Available An abundance of constitutive laws exists to approximate the behavior of geomaterials under various stresses, boundary conditions and loading paths, pore pressures, temperatures and so on. The construction of constitutive laws is driven by two competing trends: the tendency for a unifying law describing the material behavior under the most general conditions, and the need for laws that can be used efficiently in practice. The latter incorporates both the possibility of calibration from available specimens and the user-friendliness of the law. For engineering purposes, the second tendency dominates and the engineer scientist has to evaluate the problem and select the most appropriate model to describe the dominant phenomena on hand. A review of various constitutive laws for geomaterials is presented with an emphasis on their application. Various examples of engineering problems and geomaterials with emphasis on petroleum applications are used to demonstrate that the law must be as simple as possible but not simpler. Il existe un nombre important de lois constitutives permettant d'approcher le comportement des géomatériaux sous diverses contraintes, conditions aux limites et divers chemins de chargement, pressions de pore, températures, etc. L'élaboration de lois constitutives suit deux tendances concurrentes : la tendance à élaborer une loi unifiée décrivant le comportement du matériau sous les conditions les plus générales, et le besoin de lois justifié par une utilisation efficace dans la pratique. La dernière tendance inclut à la fois la possibilité d'une calibration par des essais sur des échantillons disponibles, et la convivialité de la loi. À des fins d'ingénierie, la seconde tendance domine, l'ingénieur doit évaluer le problème et sélectionner le modèle le plus approprié pour décrire le phénomène dominant observé. Dans cet article, un examen des diverses lois constitutives pour les géomatériaux, et en

  5. Constitutions of Nature by Teacher Practice and Discourse in Ontario Grade 9 and 10 Academic Science

    Science.gov (United States)

    Hoeg, Darren Glen

    This thesis presents an ethnographic study, based broadly on principles and methods of institutional ethnography, on the constitution of nature by nine Ontario Grade 9 and 10 Academic Science teachers. The intent of this methodological approach is to examine how the daily practice of participants works toward constituting nature in specific ways that are coordinated by the institution (Ontario public school and/or school science). Critical Discourse Analysis and general inductive analysis were performed on interview transcripts, texts related to teaching science selected by participants, and policy documents (i.e. curriculum; assessment policy) that coordinate science teacher practice. Findings indicate specific, dominant, and relatively uniform ontological and epistemological constitutions of nature. Nature was frequently constituted as a remote object, distant from and different than students studying it. More complex representations included constituting nature as a model, machine, or mathematical algorithm. Epistemological constitutions of nature were enacted through practices that engaged students in manipulating nature; controlling nature, and dominating nature. Relatively few practices that allow students to construct different constitutions of nature than those prioritized by the institution were observed. Dominant constitutions generally assume nature is simply the material to study, from which scientific knowledge can be obtained, with little ethical or moral consideration about nature itself, or how these constitutions produce discourse and relationships that may be detrimental to nature. Dominant constitutions of nature represent a type of objective knowledge that is prioritized, and made accessible to students, through science activities that attain a position of privilege in local science teacher cultures. The activities that allow students to attain the requisite knowledge of nature are collected, collated, and shared among existing science teachers

  6. The Globalizing Turn in the Relationship Between Constitutionalism and Democracy: Some Reiterations from the Perspective of Constitutional Law

    NARCIS (Netherlands)

    Besselink, Leonard F.M.

    2011-01-01

    This essay compliments Neil Walker's Constitutionalism and the Incompleteness of Democracy: An Iterative Relationshipon, with some historical and constitutional observations. It submits that Walker's analysis is based to a large extent on reasoning derived from a particular continental European

  7. Post-Revolution Constitutionalism: The Impact of Drafting Processes on the Constitutional Documents in Tunisia and Egypt

    DEFF Research Database (Denmark)

    Elsayed, Ahmed Mohamed Abdelfattah

    2014-01-01

    This paper seeks to address the constitutional paths that followed the Arab awakening in both Tunisia and Egypt. The Tunisian constitutional process, despite some tensions, was largely peaceful and consensual. On the other hand, the process in Egypt of establishing a new constitutional arrangemen...

  8. The spirit of the constitution. The institutionalized unsociability in Greece

    Directory of Open Access Journals (Sweden)

    Savvas MAVRIDIS

    2017-08-01

    Full Text Available With this article attempts a comparison of the Greek Constitution of 1975, the constitutions of Germany, USA, Switzerland, Austria, France, UK and Italy on the issue of property relations and general interest, in order to highlight those notified differences relating to these communities and resulted in specific social situations. While the constitutions of the other countries, which are among the most representative democracies of the Western world, are characterized by an increased institutionalization of sociability, the Greek constitution on the issue of general interest takes an antisocial and, at best, neutral attitude. The convergence of the Greek constitution on this issue with the other constitutions is considered a prerequisite for overcoming the crisis and, more generally, for social development. This little effort hopes to contribute to a more social future formulation of the Greek constitution and a corresponding behaviour of Greek society.

  9. Constitution-making in the 21st century

    Directory of Open Access Journals (Sweden)

    Cheryl Saunders

    2012-04-01

    Full Text Available Constitutions have been made or changed in major ways in more than half the countries of the world in recent decades. This article deals with contemporary approaches to constitution-making, organising the analysis around three key phases: setting the agenda, in terms of both substance and process; design, drafting and approval; and implementation. It argues that, while all constitution-making processes are different, there are some distinctive features of constitution-making in the 21st century that include popular participation, the need to build trust, internationalisation in its various forms and the importance of process. The article canvasses examples of constitution-making practices that have been or are likely to be influential. It identifies and briefly explores some of the key tensions in constitution-making between, for example, international involvement and domestic ownership of a Constitution and public participation and leadership.

  10. The constitutional right subject: Beyond an analytical program

    Directory of Open Access Journals (Sweden)

    Caridad Rosa Jiménez-Morales

    2017-12-01

    Full Text Available Since the Cuban higher education must ensure the comprehensive training of students, with a strong scientific-technical, humanistic and high ideological values, political, ethical and aesthetic training, in order to achieve professional revolutionaries educated, competent independent and creators, so that they can perform successfully in the various sectors of the economy and society in general. The contribution of a group of teachers who have taught or teach the subject of Constitutional Law in the form of classroom study with the primary purpose of presentation of several curricular activities and extracurricular, as a reference point for his team, will provide an educational legacy to future generations of teachers, and assess their relevance for possible generalization in other university centers where the School of law is studied.

  11. What constitutes a "clinical trial"?: A survey of oncology professionals

    Directory of Open Access Journals (Sweden)

    Kowaleski Brenda

    2008-03-01

    Full Text Available Abstract Background What constitutes a "clinical trial" is inconsistently defined in the medical literature. With an initiative by Cancer Care Ontario (CCO to report institutional clinical trials activity across the province of Ontario, Canada, we sought to investigate the variability in the interpretation of the term by local oncology professionals. Methods A survey amongst the physicians and nurses at the Juravinski Cancer Centre at Hamilton Health Sciences, Ontario was conducted. The survey included 12 summaries of local clinical research studies, and respondents were asked which they believed represented a clinical trial. Subsequently, they were asked which of the same 12 studies they believed should be labeled as clinical trials when considering separate definitions provided by CCO and by the Ontario Cancer Research Network (OCRN. Results A total of 66 (54% of 123 surveys were completed; 32/46 (70% by physicians, 21/59 (36% by primary care nurses, and 13/18 (72% by clinical trial nurses. Without a standardized definition, all studies, 12/12, were considered to be clinical trials by at least 50% of respondents. When provided with the CCO definition only 6/12 studies were considered to be clinical trials by the majority of respondents, while with the OCRN definition it was 9/12 studies. Studies evaluating natural health products, non-traditional medical interventions, and non-randomized studies with standard interventions consistently ranked the lowest, regardless of the definition used. Conclusion Oncology professionals appear to have a broadly inclusive baseline definition of what constitutes a clinical trial. Establishing rigor and consistency in the definition of a clinical trial is important for any program, institutional or jurisdictional based comparisons of clinical trials activity, especially when used as a quality indicator of patient care.

  12. What constitutes a "clinical trial"?: a survey of oncology professionals.

    Science.gov (United States)

    Wright, James R; Kowaleski, Brenda; Sussman, Jonathan

    2008-03-03

    What constitutes a "clinical trial" is inconsistently defined in the medical literature. With an initiative by Cancer Care Ontario (CCO) to report institutional clinical trials activity across the province of Ontario, Canada, we sought to investigate the variability in the interpretation of the term by local oncology professionals. A survey amongst the physicians and nurses at the Juravinski Cancer Centre at Hamilton Health Sciences, Ontario was conducted. The survey included 12 summaries of local clinical research studies, and respondents were asked which they believed represented a clinical trial. Subsequently, they were asked which of the same 12 studies they believed should be labeled as clinical trials when considering separate definitions provided by CCO and by the Ontario Cancer Research Network (OCRN). A total of 66 (54%) of 123 surveys were completed; 32/46 (70%) by physicians, 21/59 (36%) by primary care nurses, and 13/18 (72%) by clinical trial nurses. Without a standardized definition, all studies, 12/12, were considered to be clinical trials by at least 50% of respondents. When provided with the CCO definition only 6/12 studies were considered to be clinical trials by the majority of respondents, while with the OCRN definition it was 9/12 studies. Studies evaluating natural health products, non-traditional medical interventions, and non-randomized studies with standard interventions consistently ranked the lowest, regardless of the definition used. Oncology professionals appear to have a broadly inclusive baseline definition of what constitutes a clinical trial. Establishing rigor and consistency in the definition of a clinical trial is important for any program, institutional or jurisdictional based comparisons of clinical trials activity, especially when used as a quality indicator of patient care.

  13. Governmental control of public expenditure in the constitutional State: thoughts regarding General Comptroller sanctioning powers approval on functional administrative responsibility

    Directory of Open Access Journals (Sweden)

    Erika García Cobián Castro

    2013-12-01

    Full Text Available Constitutional doctrine has little addressed on the General Comptroller of the Republic and its controlling function of public resources execution and management. Efforts have been made to explain this situation in other realities, regarding high budgetary, accounting and auditing content needed to carry out auditing activities constitutionally assigned to this kind of entities. Nevertheless, identifying competences of the General Comptroller of the Republic and its nature of autonomous constitutional body shapes an important expression of Constitutional State and the principle of powers division. This entity controls State’s Public Budget execution contributing to constitutional property protection, legality of budget implementation and the appropriate management of public resources, also the «efficiency» of social needs, proper functioning of public administration and prevention of corruption, among others duties. This article analyzes the constitutional mission of the General Comptroller in a Constitutional State promoting the process of given a constitutional status to the legal system in its area of influence, also optimizing constitutional properties protected. For such purpose, the 29622 recent law («Law that modifies the 27785 Organic Law of National Control System and the General Comptroller of the Republic extending powers in order to sanction in accordance of functional administrative responsibility» shall be used as object of constitutional analysis.

  14. ALK2 mutation in a patient with Down's syndrome and a congenital heart defect

    NARCIS (Netherlands)

    Joziasse, I.C.; Smith, K.; Chocron, S.; van Dinther, M.; Guryev, V.; van der Smagt, J.J.; Cuppen, E.; ten Dijke, P.; Mulder, B.J.M.; Maslen, C.L.; Reshey, B.; Doevendans, P.A.; Bakkers, J.

    2011-01-01

    Down's syndrome (DS), resulting from an additional copy of chromosome 21 (trisomy 21), is frequently associated with congenital heart defects (CHDs). Although the increased dosage of chromosome 21 sequences is likely to be part of the etiology of cardiac defects, only a proportion of DS patients

  15. Report between the President and Constitutional Court and its influence on the functioning of the Constitutional System in Kosovo

    Directory of Open Access Journals (Sweden)

    Florent Muçaj

    2016-07-01

    Full Text Available This paper aims at clarifying the report between the President and the Constitutional Court. If we take as a starting point the constitutional mandate of these two institutions it follows that their final mission is the same, i.e., the protection and safeguarding of the constitutional system. This paper, thus, will clarify the key points in which this report is expressed. Further, this paper examines the theoretical aspects of the report between the President and the Constitutional Court, starting from the debate over this issue between Karl Schmitt and Hans Kelsen. An important part of the paper will examine the Constitution of Kosovo, i.e., the contents of the constitutional norm and its application. The analysis focuses on the role such report between the two institutions has on the functioning of the constitutional system. In analyzing the case of Kosovo, this paper examines Constitutional Court cases in which the report between the President and the Constitutional Court has been an issue of review. Such cases assist us in clarifying the main theme of this paper. Therefore, the reader will be able to understand the key elements of the report between the President as a representative of the unity of the people on the one hand and the Constitutional Court as a guarantor of constitutionality on the other hand.

  16. Essential Medicines in National Constitutions: Progress Since 2008.

    Science.gov (United States)

    Katrina Perehudoff, S; Toebes, Brigit; Hogerzeil, Hans

    2016-06-01

    A constitutional guarantee of access to essential medicines has been identified as an important indicator of government commitment to the progressive realization of the right to the highest attainable standard of health. The objective of this study was to evaluate provisions on access to essential medicines in national constitutions, to identify comprehensive examples of constitutional text on medicines that can be used as a model for other countries, and to evaluate the evolution of constitutional medicines-related rights since 2008. Relevant articles were selected from an inventory of constitutional texts from WHO member states. References to states' legal obligations under international human rights law were evaluated. Twenty-two constitutions worldwide now oblige governments to protect and/or to fulfill accessibility of, availability of, and/or quality of medicines. Since 2008, state responsibilities to fulfill access to essential medicines have expanded in five constitutions, been maintained in four constitutions, and have regressed in one constitution. Government commitments to essential medicines are an important foundation of health system equity and are included increasingly in state constitutions.

  17. SPECIFIC CONSTITUTIONAL FEATURES OF CHILDREN INFECTED WITH TUBERCULOSIS

    Directory of Open Access Journals (Sweden)

    Yu. A. Yarovaya

    2017-01-01

    Full Text Available In order to define specific constitutional features of the children infected with tuberculosis 222 children in the age from 1 to 14 years old have been examined: 106 children with active tuberculosis; 54 children with remaining post-tuberculosis changes; 62 children infected with tuberculous mycobacteria. The following types of diatheses were identified: lymphohypoplastic, allergic, neuroarthritic, exudative-catarrhal. It has been found out that among those with active tuberculosis the children suffering from lymphohypoplastic and neuroarthritic diatheses prevail (17.0 ± 3.7%, and allergic diathesis is less common (10.4 ± 3.0% cases. Children with lymphohypoplastic diathesis have a complicated course of tuberculosis (27.8 ± 10.6% and more intensive intoxication syndrome (55.6 ± 11.7%. The frequency of allergic diathesis is higher in the children with remaining post-tuberculosis changes (29.6 ± 6.2% and those infected with tuberculosis (33.8 ± 6.1% compared to children with active tuberculosis (10.4 ± 3.0%.

  18. Territory in the Constitutional Standards of Unitary States

    Directory of Open Access Journals (Sweden)

    Marina V. Markhgeym

    2017-06-01

    Full Text Available The article is based on the analysis of the constitutions of seven European countries (Albania, Hungary, Greece, Spain, Malta, Poland, Sweden. The research allows to reveal general and specific approaches to consolidation of norms on territories in a state and give the characteristic of the corresponding constitutional norms. Given the authors ' comprehensive approach to the definition of the territory of the state declared constitutional norms were assessed from the perspective of the fundamental principles and constituent elements of the territory. Considering the specifics of the constitutional types of state territories authors suggest typical and variative models and determine the constitutions of unitary states, distinguished by their originality in the declared group of legal relations. The original constitutional language areas associated with the introduction at the state level, these types of areas that are not typical for other countries.

  19. Constitutional Crowdsourcing to Reconcile Demos with Aristos and Nomos

    DEFF Research Database (Denmark)

    Abat Ninet, Antoni

    2017-01-01

    After the failed Icelandic experience of constitutional crowdsourcing (2009-2012), some of the country’s legal community, parliamentarians and policymakers affirmed that the constitutional draft proposed by the constitutional council of 25 citizens and approved unanimously on 27 July 2011....... This paper first remarks on how revolutionary and innovative the constitutional crowdsourcing experience was. From Solon, Ephialtes and Cleisthenes that laid out the foundation of democratic Athens, to modern constitutions that have been penned by few people men, regardless of the political system in which...... it is framed, been liberal democracies or authoritarian states. Derrida stated there is a sort of “semantic indeterminacy” at the core of democracy and that constitutional crowdsourcing is a way to intervene in this indeterminacy. The Icelandic example enlightened that there is a way to mediate between...

  20. [The right to live one's own death and its constitutionality].

    Science.gov (United States)

    Bussinguer, Elda Coelho de Azevedo; Barcellos, Igor Awad

    2013-09-01

    The article seeks to reflect on the legality of the early manifestation of will, established in Brazil through Resolution No. 1.995/12 of the Federal Council of Medicine in the face of the legislative omission and considering the possible linkage of physicians and relatives of terminally ill patients in drafting the Last Will and Testament. It examines the constitutionality of these policies and, therefore, the constitutionality of the resolution itself in light of the new Brazilian constitutional paradigm.

  1. The New Ukranian Constitution: In Pursuit of a Compromise

    OpenAIRE

    Wolczuk, K

    1997-01-01

    This paper analyses the new 1996 Ukrainian constitution as a product of far-reaching compromise; in particular it looks at the resolution of the ‘national question’, the form of government and the issue of socio-economic guarantees. Constitutions are most often perceived as an instrument of restraining governments and providing a bill of civil rights and freedoms. In new states, however, constitutions purport not only to redefine but often to set up the political and socio-economic structures...

  2. Islamization in Malaysia: the constitutional and legal dimensions

    OpenAIRE

    Choo, Kah Sing

    2017-01-01

    This thesis examines the legitimacy of the Islamization of the politics, society and law in Malaysia. The Islamization plan was carried out by the federal government in the early 1980s under the Mahathir administration. The legitimacy of the Islamization plan is measured against the original intent of the Independence Constitution, with particular reference to the position of Islam in the Constitution. Those constitutional provisions which have been claimed to have granted I...

  3. Enterocyte Proliferation and Signaling Are Constitutively Altered in Celiac Disease

    Science.gov (United States)

    Maglio, Mariantonia; Kosova, Roberta; Sarno, Marco; Gaito, Alessandra; Discepolo, Valentina; Troncone, Riccardo; Auricchio, Salvatore

    2013-01-01

    Celiac disease (CD) occurs frequently, and is caused by ingestion of prolamins from cereals in subjects with a genetic predisposition. The small intestinal damage depends on an intestinal stress/innate immune response to certain gliadin peptides (e.g., A-gliadin P31-43) in association with an adaptive immune response to other gliadin peptides (e.g., A-gliadin P57-68). Gliadin and peptide P31-43 affect epithelial growth factor receptor (EGFR) signaling and CD enterocyte proliferation. The reason why the stress/innate immune and proliferative responses to certain gliadin peptides are present in CD and not in control intestine is so far unknown. The aim of this work is to investigate if, in CD, a constitutive alteration of enterocyte proliferation and signaling exists that may represent a predisposing condition to the damaging effects of gliadin. Immunofluorescence and immunohistochemistry were used to study signaling in CD fibroblasts and intestinal biopsies. Western blot (WB) analysis, immunoprecipitation, and quantitative PCR were also used. We found in CD enterocytes enhancement of both proliferation and Epidermal Growth Factor Receptor (EGFR)/ligand system. In CD enterocytes and fibroblasts we found increase of the phosphorylated downstream signaling molecule Extracellular Signal Regulated Kinase (ERK); block of the ERK activation normalizes enterocytes proliferation in CD mucosa. In conclusion the same pathway, which gliadin and gliadin peptide P31-43 can interfere with, is constitutively altered in CD cells. This observation potentially explains the specificity of the damaging effects of certain gliadin peptides on CD intestine. PMID:24204586

  4. Enterocyte proliferation and signaling are constitutively altered in celiac disease.

    Directory of Open Access Journals (Sweden)

    Merlin Nanayakkara

    Full Text Available Celiac disease (CD occurs frequently, and is caused by ingestion of prolamins from cereals in subjects with a genetic predisposition. The small intestinal damage depends on an intestinal stress/innate immune response to certain gliadin peptides (e.g., A-gliadin P31-43 in association with an adaptive immune response to other gliadin peptides (e.g., A-gliadin P57-68. Gliadin and peptide P31-43 affect epithelial growth factor receptor (EGFR signaling and CD enterocyte proliferation. The reason why the stress/innate immune and proliferative responses to certain gliadin peptides are present in CD and not in control intestine is so far unknown. The aim of this work is to investigate if, in CD, a constitutive alteration of enterocyte proliferation and signaling exists that may represent a predisposing condition to the damaging effects of gliadin. Immunofluorescence and immunohistochemistry were used to study signaling in CD fibroblasts and intestinal biopsies. Western blot (WB analysis, immunoprecipitation, and quantitative PCR were also used. We found in CD enterocytes enhancement of both proliferation and Epidermal Growth Factor Receptor (EGFR/ligand system. In CD enterocytes and fibroblasts we found increase of the phosphorylated downstream signaling molecule Extracellular Signal Regulated Kinase (ERK; block of the ERK activation normalizes enterocytes proliferation in CD mucosa. In conclusion the same pathway, which gliadin and gliadin peptide P31-43 can interfere with, is constitutively altered in CD cells. This observation potentially explains the specificity of the damaging effects of certain gliadin peptides on CD intestine.

  5. THE CONSTITUTIONAL CONCEPTS OF THE REFORM TREATY (THE LISBON TREATY

    Directory of Open Access Journals (Sweden)

    Emilian Ciongaru

    2017-12-01

    Full Text Available The Lisbon Treaty also known as the Reform Treaty provides only an amendment of the treaties considered as fundamental, namely the Treaty on the European Union and the Treaty on the functioning of the European Union and is the result of the constitutional process triggered by the Laeken Declaration adopted by the European Council. The Lisbon Treaty is still built on the content of the European Constitution from which they eliminated the most controversial provisions, first of all the title of Constitution that might produce concern and panic among the European Union population through the symbolic power it contained, and for Romania this new treaty was the first it signed in quality of a Union member state. Even if does not bear the name of European Constitution, the Lisbon Treaty is a European Constitution for the following reasons: first it is a Constitution because it gathers together most of the fundamental elements of the Constitutional Treaty, even if it does not have the structure or the name thereof, and second the treaties after the Lisbon reform have become small constitutions from the operational viewpoint, they develop the functions of a constitution, limit power and organize the operation of the organization.

  6. Thermodynamic restrictions on the constitutive equations of electromagnetic theory

    Science.gov (United States)

    Coleman, B. D.; Dill, E. H.

    1971-01-01

    Thermodynamics second law restrictions on constitutive equations of electromagnetic theory for nonlinear materials with long-range gradually fading memory, considering dissipation principle consequences

  7. On the constitutional order in/of Italian fascism

    Directory of Open Access Journals (Sweden)

    Pedro Velez

    2016-11-01

    Full Text Available In this article we will analyse the fascist regime as a politico-constitutional reality. From a new way of looking at politico-constitutional phenomena, we will interpret them as inscribed on religious grounds. We seek to show that the fascist regime was characterised as having identified the political community as Absolute. It suggests that it appears to constitute a different case in a generic politico-constitutional family of regimes that are characterised as making the political community a supreme good.

  8. The carboxyl terminus of human cytomegalovirus-encoded 7 transmembrane receptor US28 camouflages agonism by mediating constitutive endocytosis

    DEFF Research Database (Denmark)

    Waldhoer, Maria; Casarosa, Paola; Rosenkilde, Mette M

    2003-01-01

    US28 is one of four 7 transmembrane (7TM) chemokine receptors encoded by human cytomegalovirus and has been shown to both signal and endocytose in a ligand-independent, constitutively active manner. Here we show that the constitutive activity and constitutive endocytosis properties of US28...... that the cytoplasmic tail domain of US28 per se regulates receptor endocytosis, independent of the signaling ability of the core domain of US28. The constitutive endocytic property of the US28 c-tail was transposable to other 7TM receptors, the herpes virus 8-encoded ORF74 and the tachykinin NK1 receptor (ORF74-US28......-ctail and NK1-US28-ctail). Deletion of the US28 C terminus resulted in reduced constitutive endocytosis and consequently enhanced signaling capacity of all receptors tested as assessed by inositol phosphate turnover, NF-kappa B, and cAMP-responsive element-binding protein transcription assays. We...

  9. Constitutive properties of adult mammalian cardiac muscle cells

    Science.gov (United States)

    Zile, M. R.; Richardson, K.; Cowles, M. K.; Buckley, J. M.; Koide, M.; Cowles, B. A.; Gharpuray, V.; Cooper, G. 4th

    1998-01-01

    BACKGROUND: The purpose of this study was to determine whether changes in the constitutive properties of the cardiac muscle cell play a causative role in the development of diastolic dysfunction. METHODS AND RESULTS: Cardiocytes from normal and pressure-hypertrophied cats were embedded in an agarose gel, placed on a stretching device, and subjected to a change in stress (sigma), and resultant changes in cell strain (epsilon) were measured. These measurements were used to examine the passive elastic spring, viscous damping, and myofilament activation. The passive elastic spring was assessed in protocol A by increasing the sigma on the agarose gel at a constant rate to define the cardiocyte sigma-versus-epsilon relationship. Viscous damping was assessed in protocol B from the loop area between the cardiocyte sigma-versus-epsilon relationship during an increase and then a decrease in sigma. In both protocols, myofilament activation was minimized by a reduction in [Ca2+]i. Myofilament activation effects were assessed in protocol C by defining cardiocyte sigma versus epsilon during an increase in sigma with physiological [Ca2+]i. In protocol A, the cardiocyte sigma-versus-epsilon relationship was similar in normal and hypertrophied cells. In protocol B, the loop area was greater in hypertrophied than normal cardiocytes. In protocol C, the sigma-versus-epsilon relation in hypertrophied cardiocytes was shifted to the left compared with normal cells. CONCLUSIONS: Changes in viscous damping and myofilament activation in combination may cause pressure-hypertrophied cardiocytes to resist changes in shape during diastole and contribute to diastolic dysfunction.

  10. African Customary laws and the new constitution of the post ...

    African Journals Online (AJOL)

    ... of the state can be seen to be in conflict with values of majority, within the society. In the case of this article, those of the African majority versus various rights of the minorities as guaranteed in the Constitution. Keywords: Constitution, Bill of Rights, Human Rights, Gays, Lesbian, Civil Union Act, homophobia, Social Policy.

  11. Constitutional Basis for the Enforcement of ''Executive'' Policies that ...

    African Journals Online (AJOL)

    The aim of this article is to critically reflect on the status and possible constitutional basis for the enforceability of "executive" policies that give effect to socio-economic rights in South Africa. Based on the jurisprudence of courts and some examples of "executive" policies, this article demonstrates that the constitutional basis ...

  12. The U.S. Constitution and Its Development.

    Science.gov (United States)

    Yale Univ., New Haven, CT. Law School.

    The report presents a collection of articles on constitutional issues from a 1976 social studies conference. It is intended to be used by teachers in planning and implementing curriculum materials on development of the U.S. Constitution. The booklet is divided into eight articles. The first article discusses interpretive problems in the formation…

  13. Constitutionalism and Republicanism in the American Founding: 1776-1787.

    Science.gov (United States)

    Dry, Murray

    1986-01-01

    Illustrates the development of constitutionalism and republicanism from 1776 to 1787. Discusses the Declaration of Independence, arguments leading up to the Revolution, framing of the Constitution based on compromise, and opposing views of the ratification debate, all of which reveal disagreements over the precise meaning of republicanism. (TRS)

  14. The South African constitutional court's use of foreign precedent in ...

    African Journals Online (AJOL)

    ... Court or whether it is a characteristic of a court which is confident enough that its independence will remain intact in spite of its looking elsewhere for answers. KEYWORDS: transjudicialism; foreign precedent, comparative judicialism, stare decisis; foreign case law; comparative constitutionalism; Constitutional Court.

  15. Sub-National Constitutions in Ethiopia: Towards Entrenching ...

    African Journals Online (AJOL)

    4 Thus this paper offers an overview of state constitutions in Ethiopia with a view to highlighting their significance in the public life of Ethiopians. It also provides an analysis of how we can deepen and entrench constitutionalism in the states of ...

  16. Damaging the Legitimacy of the Spanish Constitutional Court

    OpenAIRE

    Urías, Joaquín

    2017-01-01

    The Spanish legislative burdens the Constitutional Court with the task to prevent Catalonia from pursuing independence. To use the Constitutional Court as the main barricade against any attempt at starting the independence process does tremendous damage to the Court itself as it undermines its perception as neutral arbiter and, thereby, its legitimation.

  17. Europe-building through private law : Lessons from constitutional theory

    NARCIS (Netherlands)

    Mak, C.

    2012-01-01

    Questioning the link between private law and the nation-state that is implied by nationalist perceptions of the law, this paper seeks to find support for a transnational (Europeanist,constitutional-patriotist or cosmopolitan) view on private law in constitutional theory. Normative theories of

  18. The emerging international constitutional order: the implications of ...

    African Journals Online (AJOL)

    The article examines the contours and implications of the emerging international constitutional order. The "constitutional" nature of this order relates to the fact that it contains certain fundamental substantive and structural norms that form a supreme legal framework for the exercise of public power. The substantive elements ...

  19. Constitutional Review and Referendums in Kenya | Kersting | Africa ...

    African Journals Online (AJOL)

    In 2005 the Kenya constitutional referendum failed. This led to a crisis in government which culminated in postelection violence in 2007. In 2008 the new power-sharing agreement re-started a constitutional process, but this time a Committee of Experts was engaged and citizen involvement was smaller. The Committee of ...

  20. Income Tax Assignment under the Ethiopian Constitution: Issues to ...

    African Journals Online (AJOL)

    This article uses the income tax assignment in the Ethiopian Constitution to highlight some of these questions and concerns. There is ample evidence to show that the assignment formula adopted by the Constitution, indeed its predecessor - the 1992 law - was motivated by the desire to divide the power of taxation over ...

  1. Educational Research as a Reflexive Science of Constitution

    Science.gov (United States)

    Packer, Martin

    2010-01-01

    "Constitution" is a relationship of mutual formation between people and their form of life. Neither can exist without the other. In the 1970s, proposals were made in various social sciences, including anthropology, political science, and sociology, for a new kind of inquiry that would focus squarely on constitution. It would be an explicitly…

  2. Author: IM Rautenbach CONSTITUTIONAL COURT 1995 – 2012 ...

    African Journals Online (AJOL)

    10332324

    Only a few of the cases noted were not reported in the Butterworths Constitutional Law Reports or the South ..... laws and actions of Parliament and actions of the President - see Rautenbach Constitutional Law. 177-178. 27 ...... Magajane v Chairperson, North West Gambling Board 2006 10 BCLR 1133 (CC), 2006 5 SA 250.

  3. a selection of constitutional perspectives on human kidney sales

    African Journals Online (AJOL)

    Bonnie

    Common law includes both the private law and the public law rules. 32. Du Plessis v De Klerk ... doctrine of constitutional supremacy.45 Constitutionalism now meant that the government could derive its ..... international community as a whole and in the enforcement of which all states have interest (Dugard International Law.

  4. Legal Pluralism, Sharia Courts and Constitutional Issues in Ethiopia ...

    African Journals Online (AJOL)

    Another option is to adopt a hands-off approach whereby the norms and practices of cultural and/or religious groups are permitted to operate and are not necessarily required to meet constitutional and human rights standards. Against the backdrop of the notion of legal pluralism adopted by the FDRE Constitution, this article ...

  5. The constitutional mandate for social welfare – systemic differences ...

    African Journals Online (AJOL)

    ... imperative to provide stronger land and housing rights. Important connections exist between these divergent constitutional imperatives that should be acknowledged to ensure the efficient realisation of social welfare concerns. KEYWORDS: property law; constitutional property law; land law; land reform; restorative justice; ...

  6. New Zimbabwe Constitution and the Right to Health Campaign 2010

    International Development Research Centre (IDRC) Digital Library (Canada)

    In September 2008 the three main political parties in Zimbabwe signed a Global Political Agreement (GPA), undertaking to engage in the development of a new democratic constitution of over the next 24 months. This project will feed into that process by promoting the inclusion of right to health in the new constitution.

  7. Page 1 CONSTITUTION OF HIBISCITRIN. PART I By P ...

    Indian Academy of Sciences (India)

    IN an earlier paper" the isolation of a new flavonol glucoside, hibiscitrin from the flowers of Hibiscus sabdariffa was described. The constitution of the aglucone, hibiscetin was also established as 3: 5: 7:8: 3': 4'; 5'- heptahydroxy-flavone (I) and later confirmed by synthesis.” The exact constitution of hibiscitrin has ...

  8. Legal and Constitutional Evaluation of the Nigerian Sovereign ...

    African Journals Online (AJOL)

    The central aim of this paper is to examine the constitutionality of Nigeria's sovereign wealth fund (SWF) which was established in August 2012, pursuant to the Nigeria Sovereign Investment Authority (Establishment etc) Act 2011 (the NSIA Act). The paper reviews and discusses how questions on the constitutionality of a ...

  9. Children's rights in the South African Constitution | Robinson ...

    African Journals Online (AJOL)

    Children were in many respects defenceless victims of discriminatory practices in 'apartheid South Africa'. In fact, discrimination on the basis of gender, race and other inequalities were inscribed in the social fabric of the previous constitutional dispensation. The constitutional dispensation that came into effect on the 27th ...

  10. South Dakota's System of Financing Public Education: Is It Constitutional?

    Science.gov (United States)

    Magnuson, Lee A.

    1979-01-01

    Analyzes the South Dakota system of financing education in light of major cases considering the constitutionality of state finance systems and of the approaches courts have used in determining constitutionality. Examines the particular finance problems that face the school systems of South Dakota. Available from University of South Dakota School…

  11. Constitutional obligations of a person and a citizen

    Directory of Open Access Journals (Sweden)

    Alexey Yu. Ogurtsov

    2011-01-01

    Full Text Available The constitution of the Russian Federation does not contain the list of obligations, but theoretically each legal right is supposed to correspond to a legal obligation. Such conformity is achieved by means of attaching obligations not only by Constitution, but by the branch legislation either.

  12. New Constitutionalism for Biosiversity vs. Neoconstitutionalism of Risk

    Directory of Open Access Journals (Sweden)

    Michele Carducci

    2016-08-01

    Full Text Available http://dx.doi.org/10.5007/2177-7055.2016v37n73p255 Based on an “eco-systemic” democracy that seeks to preserve biodiversity through the recognition of the co-evolutionary link between nature and culture, the Andean Constitutionalism emerges as the expression of a counter-hegemonic constitutionalism committed to the construction of a new institutional framework through the inclusion of new participatory and intercultural mechanisms. Departing from western constitutional paradigms, this groundbreaking constitutionalism revisits the “Gaia hypothesis” and legitimizes a real “social contract” among the people and nature, and instead of considering it as an “object” of ownership, exploitation, or conservation, it regards nature as a legal “subject” and primary source of society itself and the Constitution as its “legal grantor and protector”.

  13. STABILITY AND DYNAMICS OF THE CONSTITUTION OF UKRAINE

    Directory of Open Access Journals (Sweden)

    Marina Nikolaievna Lazareva

    2014-09-01

    Full Text Available This article contains a brief review of the constitutional events that took place in Ukraine since its Declaration of Independence to the Presidential elections in 2014. The main attention is given to the transformation of the text of the Ukrainian Constitution of 1996 and the legal instruments of its conversion, including acts of the Constitutional Court. The author emphasizes the idea of the similarity of the constitutional and legal institutions of Ukraine and Russia, comparing them with each other, and focuses on the need to comply with current legislation by all the legal subjects, primarily in the field of human rights and freedoms. Incompleteness of the constitutional process in modern Ukraine requires development and adoption of new legal solutions based on broad public support.

  14. What constitutes an ideal dental restorative material?

    Science.gov (United States)

    Rekow, E D; Bayne, S C; Carvalho, R M; Steele, J G

    2013-11-01

    Intense environmental concerns recently have prompted dentistry to evaluate the performance and environmental impact of existing restoration materials. Doing so entices us to explore the 'what if?' innovation in materials science to create more ideal restorative materials. Articulating a specification for our design and evaluation methods is proving to be more complicated than originally anticipated. Challenges exist not only in specifying how the material should be manipulated and perform clinically but also in understanding and incorporating implications of the skill of the operator placing the restoration, economic considerations, expectations patients have for their investment, cost-effectiveness, influences of the health care system on how and for whom restorations are to be placed, and global challenges that limit the types of materials available in different areas of the world. The quandary is to find ways to actively engage multiple stakeholders to agree on priorities and future actions to focus future directions on the creation of more ideal restorative materials that can be available throughout the world.

  15. Acute MUS81 depletion leads to replication fork slowing and a constitutive DNA damage response

    DEFF Research Database (Denmark)

    Xing, Meichun; Wang, Xiaohui; Palmai-Pallag, Timea

    2015-01-01

    have investigated the role of MUS81 in human cells by acutely depleting the protein using shRNAs. We found that MUS81 depletion from human fibroblasts leads to accumulation of ssDNA and a constitutive DNA damage response that ultimately activates cellular senescence. Moreover, we show that MUS81...

  16. The brazilian constitution as third generation product: convergence and differences between the latin american constitutionalism and legal garantism theory

    Directory of Open Access Journals (Sweden)

    Luiz Henrique Urquhart Cademartori

    2015-12-01

    Full Text Available This article addresses the phenomenon of the latinamerican constitutionalism, its characteristics, critical issues and its challenges facing the European constitutional models, such as the legal garantism and neoconstitutionalism. That being said, this work compares the recent theoretical proposals within the Latin American constitutional theory with the European tradition. In this way, we delimit the aspects of main Latin American constitutionalism theory and contrast European constitutional theories, such as Ferrajoli’s legal garantism and representatives of neoconstitutionalism such as Dworkin, Alexy, Müller and Haberle. In this work, we seek to understand and explain the so-called "third generation constitutions”, in order to think properly of the Brazilian constitutionalism and the influence of the new legal institutions and procedural safeguards contained in our Constitution which give means to make possible fundamental and social rights. After that, we examine the affinities that Latin American constitutionalism has found in the legal garantism theory, which enables fundamental and social rights, and which has been largely accepted in countries similar to Brazil despite of its European origins.

  17. Constitutionalism in Education for Democracy: The Continuing Relevance of Arguments on Constitutional Government of the American Founding Era.

    Science.gov (United States)

    Patrick, John J.

    This paper contends that the issues of constitutional government debated during the founding of the United States should be in the core curriculum of any school that seeks to educate students to become responsible citizens of a constitutional democracy. For purposes of teaching students, the issues debated by founding-era political thinkers can be…

  18. La légitimité de la Constitution dans la doctrine constitutionnelle japonaise The Legality of the Constitution in the Japanese constitutional Doctrine

    Directory of Open Access Journals (Sweden)

    Simon Serverin

    2010-07-01

    Full Text Available La Constitution japonaise, promulguée en novembre 1946 et entrée en vigueur en mai 1947, pose à la théorie constitutionnelle un certain nombre de problèmes qui ne sont toujours pas résolus. Adoptée sous occupation américaine, rédigée par les services du GHQ dirigés par le général MacArthur, la Constitution a en outre été promulguée comme une simple révision de la Charte impériale de 1889, dite Constitution de Meiji, alors que par les principes démocratiques nouveaux qu’elle instaurait, elle p...

  19. Prospects of the Constitutional State of Indonesia: Ideas and Reality

    Directory of Open Access Journals (Sweden)

    Hamdan Zoelva

    2015-08-01

    Full Text Available Indonesia since its inception has asserted itself as a constitutional state. It may be inferred through the clear regulation related to powers and functions of each state institution in the form of checks and balances system, the protection of human rights, the clarity of the principles of democratic mechanism, as well as the guarantee of an independent judiciary. Although the constitution has been set in such a way, efforts to achieve a constitutional state is not an easy road. Nowadays, it seems that the trip of the Indonesian as a constitutional state was still hobbled. A variety of legal issues that disturb the sense of justice continues to emerge one after another. The outcomes of the research indicate that over the last decade, Indonesia has made many changes to realize the ideal of a constitutional state. As it turns out in practice, however, legal development was still far short from the expectations. The success of building a constitutional state can not be measured by the ability to produce legislation and to create or revitalize legal institutions. Moreover, the success of a constitutional state must also be measured by the implementation and law enforcement which able to create justice for all people. Therefore, the main focus of various studies of law and legal policy, must be oriented in the judicial institutions and law enforcement.

  20. Ayurvedic genomics, constitutional psychology, and endocrinology: the missing connection.

    Science.gov (United States)

    Rizzo-Sierra, Carlos V

    2011-05-01

    A recent methodological approach for human classification, diagnosis, and therapeutics through the combination of current Western constitutional psychology somatotypes and traditional Indian medicine (prakriti) body types and mind (manas) is herein presented. The striking similarities between psychologic somatotypes and Indian medicine body types permits proposal of a finite genopsycho-somatotyping of humans. Genopsycho-somatotyping of humans consists of a set of common physiologic, physical, and psychologic attributes related to a common basic birth constitution that remains somewhat permanent during human lifetime, since it is proposed that this birth constitution is programmed in the person's DNA (genes). This mainly provides a tool for classifying the human population based on broad and finite phenotype clusters across different ethnicity, languages, geographical location, or self-reported ancestry. In spite of any social or environmental traumatic event, I propose for males that every basic constitution has an associated identification organ, a measured property or marker, a soma, and some psyche general tendencies suggesting specific behavior or recurrent conduct. Three (3) basic extreme genopsycho-somatotypes or birth constitutions are enunciated: mesomorphic or andrus (Pitta), endomorphic or thymus (Khapa), and ectomorphic or thyrus (Vata). The method further predicts that male andrus constitution across races shares similarities in androgen (An) nuclear receptor behavior, whereas thymus constitutions are mainly regulated by T-cells (Tc) nuclear receptor behavior. Moreover, it suggests that thyrus constitutions share similarities in thyroxine (Th) nuclear receptor behavior. These proposed nuclear receptors are expected to regulate the expression of specific genes, thereby controlling the embryonic development, adult homeostasis, and metabolism of the human organism in a very profound way. The method finally predicts small differences in measured property

  1. The balancing act between the constitutional right to strike and the constitutional right to education

    Directory of Open Access Journals (Sweden)

    H J (Jaco Deacon

    2014-06-01

    Full Text Available While the South African Constitution enshrines both children's right to a basic education and teachers' right to strike, conflict between these two often occurs when the way in which teachers' unions conduct strike actions detracts from learners' education. This article identifies the parties affected by industrial action in the school context, and then proceeds to examine educators' right to strike as defined by the provisions of the Labour Relations Act. The unique implications of picketing in the education environment are then discussed, covering relevant questions such as where pickets may be held, the issue of picketing rules as well as unprotected pickets. Even though we are faced with a qualified right to strike as opposed to an unqualified right to education, the South African reality seems to be that striking teachers are handled with kid gloves. It is therefore concluded that the vast range of existing laws regulating protest action should be applied more effectively. One of the most important aspects should be the picketing rules, which should clearly determine whether picketing in fact contributes to resolution of the dispute, and how learners' interests and rights may best be actualised.

  2. Stochastic Properties of Plasticity Based Constitutive Law for Concrete

    DEFF Research Database (Denmark)

    Frier, Christian; Sørensen, John Dalsgaard

    The purpose of this paper is to obtain a stochastic model for the parameters in a constitutive model for concrete based on associated plasticity theory and with emphasis placed on the pre-failure range. The constitutive model is based on a Drucker Prager yield surface augmented by a Rankine cut......-off criterion. The statistics of the material parameters are obtained by applying biaxial test results for plane concrete slabs to the constitutive model using the maximum likelihood method. Response surfaces are used to obtain the statistics for a parameter depending on other previously obtained parameters...

  3. Stohastic Properties of Plasticity Based Constitutive Law for Concrete

    DEFF Research Database (Denmark)

    Frier, Christian; Sørensen, John Dalsgaard

    1998-01-01

    The purpose of this paper is to obtain a stochastic model for the parameters in a constitutive model for concrete based on associated plasticity theory and with emphasis placed on the pre-failure range. The constitutive model is based on a Drucker Prager yield surface augmented by a Rankine cut......-off criterion. The statistics of the material parameters are obtained by applying biaxial test results for plane concrete slabs to the constitutive model using the maximum likelihood method. Response surfaces are used to obtain the statistics for a parameter depending on other previously obtained parameters...

  4. Organic Law Of Judicial Guarantees And Constitutional Control

    Directory of Open Access Journals (Sweden)

    Ernesto López Freire

    2013-01-01

    Full Text Available This paper demonstrates the various unconstitutional and fallacies of the Organic Law of Judicial guarantees and Constitutional Control. For that, there will be a comprehensive collation between the mentioned law and the Constitution of the Republic of Ecuador and force. Through this analysis shows a lack of knowledge of Ecuadorian law or legal science by their authors. This study elucidated, inter alia, the inconsistencies in matters relating to the interpretation of constitutional provisions, full compensation, material and integral; challenge administrative acts, judicial unit.

  5. Book review: Advanced Introduction to Comparative Constitutional Law.

    Directory of Open Access Journals (Sweden)

    Ainhoa Martinez

    2016-12-01

    Full Text Available Tushnet presents a thoughtful introduction to the field of comparative constitutional law through a review of recent literature and an analysis of the key contemporary issues in constitutional design and structure. In the following lines a review of his book is presented.Book review of Mark Tushnet. Advanced Introduction to Comparative Constitutional Law. Cheltenham; Northampton: Edward Elgar Publishing, 2014. ISBN (Hb 978 1 78100 731 0 £58.50, ISBN (Pb 978 1 78347 351 9 £12.76.DOWNLOAD THIS PAPER FROM SSRN: https://ssrn.com/abstract=2887014

  6. Alterations of inducible and constitutive nitric oxide synthase after hippocampal injury in rats.

    Science.gov (United States)

    Safari, M; Ghahari, L

    2009-08-15

    The aim of this study was to study the changes of inducible and constitutive Nitric Oxide Synthase (NOS) after brain injury. In order to brain injury 42 wistar rats were submitted and divided in 7 groups. Nitric oxide synthase activities were assayed at different times after injury. Present results showed that a significant increase of iNOS and cNOS activity 8 h after lesion. In conclusion, both isoformes of NOS increase at different time after brain injury.

  7. Contesting a World-Constitution? Anti-Systemic Movements and Constitutional Forms in Ireland, 1848-2008

    Directory of Open Access Journals (Sweden)

    Thomas Murray

    2016-03-01

    Full Text Available Recent accounts of constitutional development have emphasised commonalities among diverse constitutions in terms of the transnational migration of legal institutions and ideas. World-systems analysis gives critical expression to this emergent intellectual trajectory. Since the late 18th century, successive, international waves of constitution-making have tended to correspond with decisive turning points in the contested formation of the historical capitalist world-system. The present article attempts to think through the nature of this correspondence in the Irish context. Changes to the Irish constitution, I suggest, owed to certain local manifestations of anti-systemic movements within the historical capitalist world-system and to constitution-makers’ attempts to contain – militarily, politically and ideologically – these movements’ democratic and egalitarian ideals and practices. Various configurations of the balance of power in Irish society between ‘national’ (core-peripheral and ‘social’ (capital-labour/‘other’ forces crystallised in constitutional form. Thus far, conservative and nationalist constitutional projects have tended to either dominate or incorporate social democratic and radical ones, albeit a process continually contested at critical junctures by civil society and by the organised left, both old and new.

  8. AASERT: Constitutive and Failure Behavior of Granular Materials

    National Research Council Canada - National Science Library

    Zhou, Min

    2000-01-01

    .... The objective of this research is to obtain material response data and constitutive characterization for these materials at strain rates of up to 105 S-1, to analyze the evolution of load-carrying...

  9. the emerging international constitutional order: the implications of ...

    African Journals Online (AJOL)

    Dr Tanya du Plessis

    IMPLICATIONS OF HIERARCHY IN INTERNATIONAL LAW FOR THE. COHERENCE AND ... (Zurich); Professor of International Constitutional Law, Universiteit van Amsterdam, The. Netherlands; Extraordinary Professor ..... Covenant on Civil and Political Rights of 1966 (ICCPR) and the International. Covenant on Economic ...

  10. Modernity, Rationality and Constitutional Law in Muslim-Majority Countries

    DEFF Research Database (Denmark)

    Abat Ninet, Antoni

    Are Islamic law, human rights and constitutionalism compatible? In answering this question, this paper first discusses the concept of modernity (understood in terms of rationality and standardization), analysing its abrupt implementation in the MENA countries and the role that the first modern...... constitutions played in institutionalising a new sort of dominion in the newly established states. Against this background, the paper discusses the relationship between constitutionalism and Shari’a law, presenting this as a clash between two competing normative visions that are conceptually difficult...... to reconcile and which each claim exclusivity and hierarchical superiority. The paper advocates for a deconstruction of the ideas of human rights and constitutionalism in order to allow for the incorporation of elements of Muslim traditions, thus challenging the understanding of human rights...

  11. The Politics-Administration Dichotomy: Toward a Constitutional Perspective.

    NARCIS (Netherlands)

    Overeem, P.

    2012-01-01

    The politics-administration dichotomy is much mentioned and often criticized in the Public Administration literature. The Politics-Administration Dichotomy: Toward a Constitutional Perspective, Second Edition offers a book-length treatment of this classical notion. While public administration

  12. DyNAvectors: dynamic constitutional vectors for adaptive DNA transfection.

    Science.gov (United States)

    Clima, Lilia; Peptanariu, Dragos; Pinteala, Mariana; Salic, Adrian; Barboiu, Mihail

    2015-12-25

    Dynamic constitutional frameworks, based on squalene, PEG and PEI components, reversibly connected to core centers, allow the efficient identification of adaptive vectors for good DNA transfection efficiency and are well tolerated by mammalian cells.

  13. Competition is constitutional: Four fallacies in the argument that transmission access constitutes a taking

    Energy Technology Data Exchange (ETDEWEB)

    Schotland, S.D. [Gottlieb, Steen & Hamilton, Washington, DC (United States)

    1996-11-01

    New transmission regulations may cause a change in property value or property access, however, this alone does not constitute a regulatory taking. In an industry with a long history of regulation and some degree of shared transmission access, the utilities are going to be hard pressed to show that recent open access mandates are in violation of the Takings Clause of the Fifth Amendment. In a recent article, John Rowe and Paige Graening of the NEES Companies argued that transmission access is the twentieth century equivalent of {open_quotes}piracy{close_quotes} - forcing utilities to provide transmission access to third parties violates the Taking Clause of the Fifth Amendment. The authors stated that transmission access represents a permanent physical invasion of property - which is unconstitutional without {open_quotes}just compensation.{close_quotes} The same arguments have been raised by Michigan utilities in a pending court challenge to the retail wheeling experiment ordered by the Michigan Public Service Commission. Rowe and Graening complain that {open_quotes}under the Jolly Roger of open competition{close_quotes} regulators will limit utilities to {open_quotes}mere embedded costs,{close_quotes} thereby committing an act of {open_quotes}piracy.{close_quotes} Contrary to Rowe and Graening`s claim, the flag of competition is better represented by the Stars and Stripes, since orders to provide transmission access at the cost of service do not result in a regulatory taking. Four fallacies led NEES down the gangplank: (1) The authors argued that reductions in the value of an investment are necessarily takings. Regulatory impairment of property value is a fact of life. (2) Contrary to NEES, transmission access does not effect a permanent physical invasion of property. (3) NEES claimed that transmission access defeats reasonable investment expectations. (4) NEES relied on case law that affords utilities the opportunity to realize a profit.

  14. Propionate catabolism in Salmonella typhimurium LT2: two divergently transcribed units comprise the prp locus at 8.5 centisomes, prpR encodes a member of the sigma-54 family of activators, and the prpBCDE genes constitute an operon.

    Science.gov (United States)

    Horswill, A R; Escalante-Semerena, J C

    1997-02-01

    We present the initial genetic and biochemical characterization of the propionate (prp) locus at 8.5 centisomes of the Salmonella typhimurium LT2 chromosome (T. A. Hammelman et al., FEMS Microbiol. Lett. 137: 233-239, 1996). In this paper, we report the nucleotide sequences of two divergently transcribed transcriptional units. One unit is comprised of the prpR gene (1,626 bp) encoding a member of the sigma-54 family of transcriptional activators; the second unit contains an operon of four genes designated prpB (888 bp), prpC (1,170 bp), prpD (1,452 bp), and prpE (1,923 bp). The heme biosynthetic gene hemB was shown by DNA sequencing to be located immediately downstream of the prpBCDE operon; hemB is divergently transcribed from prpBCDE and is separated from prpE by a 66-bp gap. In addition, we demonstrate the involvement of PrpB, PrpC, and PrpD in propionate catabolism by complementation analysis of mutants using plasmids carrying a single prp gene under the control of the arabinose-responsive P(BAD) promoter. Expression of prpB to high levels was deleterious to the growth of a prp+ strain on minimal medium supplemented with propionate as a carbon and energy source. We also report the cloning and overexpression of prpB, prpC, prpD, and prpE in the T7 system. PrpB, PrpC, PrpD, and PrpE had molecular masses of ca. 32, ca. 44, ca. 53, and ca. 70 kDa, respectively. PrpB showed homology to carboxyphosphonoenolpyruvate phosphonomutase of Streptomyces hygroscopicus and to its homolog in the carnation Dianthus caryophyllus; PrpC was homologous to both archaeal and bacterial citrate synthases; PrpD showed homology to yeast and Bacillus subtilis proteins of unknown function; PrpE showed homology to acetyl coenzyme A synthetases. We identified a sigma-54 (RpoN)-dependent promoter with a consensus RpoN binding site upstream of the initiating methionine codon of prpB, the promoter-proximal gene of the prp operon. Consistent with this finding, an rpoN prp+ mutant failed to use

  15. Gagasan Kewenangan Mahkamah Konstitusi dalam Menyelesaikan Perkara Constitutional Complaint Berdasarkan Undang-undang Dasar 1945

    OpenAIRE

    Sari, Indah Permata; Indra, Mexsasai; ', Junaidi

    2016-01-01

    The Constitution of the Republic Indonesia 1945 and law of No. 8 of 2011 about Constitutional court haven't constitutional complaint as constitutional court's authority.that's because be important to think again will add constitutional court's authority to complete about constitutional complaint that violation of constitutional right that there is no path of its legal settlement can be handled by the constitutional court. The kind of research can be classified normative law research. The idea...

  16. A simple hysteretic constitutive model for unsaturated flow

    OpenAIRE

    Soldi, Mariangeles; Guarracino, Luis; Jougnot, Damien

    2017-01-01

    In this paper we present a constitutive model to describe unsaturated flow that considers the hysteresis phenomena. This constitutive model provides simple mathematical expressions for both saturation and hydraulic conductivity curves, and a relationship between permeability and porosity. The model is based on the assumption that the porous media can be represented by a bundle of capillary tubes with throats or "ink-bottles" and a fractal pore size distribution. Under these hypotheses, hyster...

  17. The Constitution of Intellectual Property as an Academic Subject

    OpenAIRE

    Bellido, Jose

    2017-01-01

    This essay offers a reinterpretation of the constitution of intellectual property as an academic subject by focusing on the work of Thomas Anthony Blanco White (1916–2006). His textbooks were fundamental for the development of ‘intellectual property’ in Britain and the Commonwealth. Not only did they provide the basis for a discipline in the making, their timely publication also helped to connect and, more importantly, constitute a diverse audience of articled clerks, practitioners and studen...

  18. Association and exclusion: the paradox of liberal constitutionalism

    OpenAIRE

    H.N. Hirsch

    2011-01-01

    This paper argues that a central paradox of liberal constitutionalism can be found by closely examining the freedom of association.  Freedom of association includes the right not to associate; thus a regime of individual rights facilitates the creation of marginalized individuals and groups.  These groups then seek social recognition, which liberal constitutionalism cannot easily grant, unless the state itself becomes complicit in discriminatory action.  The existence and protection ...

  19. LEGAL SYSTEM IN BRAZILIAN CONSTITUTIONALISM: PERPLEXITIES REFERRING TO CIVIL LAW

    OpenAIRE

    Iribure Júnior, Hamilton da Cunha; Guimarães, Henrique Cassalho

    2017-01-01

    The contemporaneous constitutionalism outlines a new manner to conceive and interpret the legal system, considering the alignment of law with society and society with law in order to emancipate the individual in the factual level. This results in the repercussion of humanization purpose in the Constitution of Federative Republic of Brazil of 1988 in civil law, to the extent of approaching it under a new perspective. However, such relationship involves several aspects which cannot be neglected...

  20. Adaptative displays of body constitution in gravity cyclists

    OpenAIRE

    Siriški, Damjan; Novotný, Jan

    2015-01-01

    The objective of our study was to investigate somatotype, body constitution and motor skills of elite cyclists of technical gravity disciplines (freestyle MTB, biketrial) and downhill gravity disciplines (fourcross, downhill) and to characterize the impact of specific training process on body constitution and level of motor skills. Test group consisted of 30 riders (15 technical gravity disciplines, 15 downhill gravity disciplines). We used Heath-Carter method to define somatotype and Matiegk...

  1. Adaptive displays of body constitution in gravity cyclists

    OpenAIRE

    Siriški Damjan; Novotný Jan

    2015-01-01

    The objective of our study was to investigate somatotype, body constitution and motor skills of elite cyclists of technical gravity disciplines (freestyle MTB, biketrial) and downhill gravity disciplines (fourcross, downhill) and to characterize the impact of specific training process on body constitution and level of motor skills. Test group consisted of 30 riders (15 technical gravity disciplines, 15 downhill gravity disciplines). We used Heath-Carter method to define somatotype and Matiegk...

  2. Constitutional Model and Rationality in Judicial Decisions from Proportionality Technique

    OpenAIRE

    Feio, Thiago Alves

    2016-01-01

    In the current legal systems, the content of the Constitutions consists of values that serve to limit state action. The department in charge of the control of this system is, usually, the Judiciary. This choice leads to two major problems, the tension between democracy and constitutionalism and the subjectivity that control. One of the solutions to subjectivity is weighting of principles through the proportionality technique, which aims to give rational decisions. This technique doesn’t elimi...

  3. Wide variation in understanding about what constitutes 'binge-drinking'

    OpenAIRE

    Cooke, Richard; David P French; Falko F. Sniehotta

    2010-01-01

    Two studies investigated undergraduates' knowledge of the UK government recommendations about binge drinking and sensible drinking, and also examined how labelling oneself as a binge drinker is associated with binge drinking perceptions. In Study 1, 325 undergraduates reported how many units constitute binge drinking, and labelled themselves as a 'binge drinker' or 'non-binge drinker'. Participants overestimated how many units constitute binge drinking relative to the UK government recommenda...

  4. Constitutional Reform and Political Participation in the Gulf

    OpenAIRE

    Khalaf, Abdulhadi; Luciani, Giacomo

    2006-01-01

    Abstract : This collection of ten essays adds a new and original perspective to the debate on political reform in the Gulf countries which has intensified in recent years. Rather than couching the issue in the more frequently heard terms of authoritarianism vs. democratization, the book focuses on the evolution of Gulf constitutions and on the widening of political participation. It is shown that constitutional reforms have served the purpose of consolidating the absolute power of the rulers,...

  5. The limits of authority of the Constitutional Court of Bosnia and Herzegovina in the procedure for the assessment of compliance of laws with the Constitution of Bosnia and Herzegovina

    Directory of Open Access Journals (Sweden)

    Simović Miodrag N.

    2014-01-01

    Full Text Available The Constitutional Court of Bosnia and Herzegovina is one of the pillars of rule of law and legal security as well as guarantee for preservation and development of democratic order in the constitutional framework of Bosnia and Herzegovina. It is not legislative, neither executive nor classical court authority, but a special kind of sui generis authority, acting as corrective factor for all three authority branches. In such a situation, the relationship between the Constitutional Court and legislative authority has a special significance, having in mind that legislative authority regulates, primarily through the law, legal order and, thereby, also defines social and political system of one state and that, on the other side, the Constitutional Court ensures that those laws are in accordance with the Constitution of Bosnia and Herzegovina and that, if it finds such a law has gone out of the framework of the Constitution, it may intervene by declaring the whole law or parts of it unconstitutional and put them out of force. Does the Constitutional Court in such a situation takes the role of legislator and what kind of legislator? What if the legislative authority does not comply with the decision of the Constitutional Court? Should Constitutional Court take the role of positive legislator? It is less problematic activity of the Constitutional Court as negative legislator in theory and practice. In such legal situation, the Constitutional Court in its decision finds unconstitutionality of a law provision (or the whole law and eliminates it from legal system generally after expiration of certain period of time when such provisions cease to be valid and the legislator replaces unconstitutional provisions with new ones within set time limit. However, we have a much more problematic situation when the Constitutional Court acts as positive legislation, i.e. when it makes a decision declaring validity of certain provisions of the law or instructing the

  6. Relationships among Constitution, Stress, and Discomfort in the First Trimester

    Directory of Open Access Journals (Sweden)

    Hsiao-Ling Wang

    2012-01-01

    trimester of pregnancy. We adopted a descriptive and correlational research design and collected data from 261 pregnant women during their first trimester in southern Taiwan using structured questionnaires. Results showed that (1 stress was significantly and positively correlated with Yang-Xu, Yin-Xu, and Tan-Shi-Yu-Zhi constitutions, respectively; (2 Yin-Xu and Tan-Shi-Yu-Zhi constitutions had significant correlations with all symptoms of discomfort, while Yang-Xu had significant correlations with all symptoms of discomfort except for “running nose”; (3 Tan-Shi-Yu-Zhi constitution and stress were two indicators for “fatigue”; Tan-Shi-Yu-Zhi was the indicator for “nausea”; Yang-Xu and Yin-Xu were indicators for “frequent urination.” Our findings also indicate that stress level affects constitutional changes and that stress and constitutional change affect the incidence of discomfort. This research can help healthcare professionals observe these discomforts and provide individualized care for pregnant women, to nurture pregnant women into neutral-type constitution, minimize their levels of discomfort, and promote the health of the fetus and the mother.

  7. Sasang Constitutional Medicine as a Holistic Tailored Medicine

    Directory of Open Access Journals (Sweden)

    Jong Yeol Kim

    2009-01-01

    Full Text Available Sasang constitutional medicine (SCM is a unique traditional Korean therapeutic alternative form of medicine. Based on the Yin and Yang theory and on Confucianism, humans are classified into four constitutions. These differ in terms of (i sensitivity to certain groups of herbs and medicines, (ii equilibrium among internal organic functions, (iii physical features and (iv psychological characteristics. We propose that two main axes in the physiopathology of SCM (food intake/waste discharge and consuming/storing Qi and body fluids are equivalent to the process of internal–external exchange and catabolism/anabolism in modern physiology, respectively. We then used this hypothesis to discuss the physiological and pathological principles of SCM. Constitution-based medicine is based on the theory that some medicinal herbs and remedies are only appropriate for certain constitutions and can cause adverse effects in others. The constitutional approach of SCM share the same vision as tailored medicine; an individualized therapy that can minimize the risk of adverse reaction while increasing the efficacy and an individualized self-regulation that can help prevent specific susceptible chronic disease and live healthily. There is still a long way to this goal for both SCM and tailored medicine, but we may benefit from systems approaches such as systems biology. We suggest that constitutional perspective of SCM and our hypothesis of two main processes may provide a novel insight for further studies.

  8. Constitutional Values, Therapeutic Jurisprudence and Legal Education in South Africa: Shaping our Legal Order

    Directory of Open Access Journals (Sweden)

    Elmarie Fourie

    2016-04-01

    Full Text Available Law schools have a responsibility to remind law students that by studying law they have the power to transform thoughts, policies and lives, and that practising law is not just about financial rewards, but that its greatest reward is contributing to the betterment of society and ultimately to social change. The values and philosophies that law lecturers instil in law students can contribute to the legal order of the future; a legal order that supports a transformative South Africa. A need exists to bring legal education closer to the values enshrined in our Constitution. In addition to an extensive knowledge of legal principles, critical thinking and research skills, law students should critically engage with our constitutional values. The question remains: How do we transform legal education in South Africa? How do we change the way we teach law students? The introduction of concepts such as therapeutic jurisprudence enhanced by our constitutional values will ensure that we deliver graduates that display a commitment to our constitutional vales and an ability to engage critically with these values. It is important to establish a professional legal identity amongst students from their first year as this will assist in the development of a well-rounded graduate that can contribute to the legal order of the future. Letter writing and drafting skills, the value of plain language, moot court activities, alternative dispute resolution and clinical legal education provide opportunities to integrate valuable therapeutic jurisprudence principles into the curriculum and can allow students to critically engage with our constitutional values. By embodying these values they can improve the legal system, shape our legal order and promote progress toward an equal and free democratic society as envisaged by the Constitution.

  9. Right to Freedom of Speech and Expression (constitutional legal framework and Constitutional Court practice in the Republic of Croatia)

    OpenAIRE

    Mato Arlović

    2016-01-01

    This paper analyses the connection and inter relationship of freedom as the highest value of constitutional order of the Republic of Croatia and the highest ideal of contemporary democracy and constitutional state with the right to freedom of speech and expression. By analysing that interrelationship, the intention to confirm the thesis that the right to freedom of speech and expression is just one (albeit very important)human right and fundamental freedom arises. It has been extracted from f...

  10. Rate constitutive theories for ordered thermoviscoelastic fluids: polymers

    Science.gov (United States)

    Surana, K. S.; Nunez, D.; Reddy, J. N.; Romkes, A.

    2014-03-01

    This paper presents development of rate constitutive theories for compressible as well as in incompressible ordered thermoviscoelastic fluids, i.e., polymeric fluids in Eulerian description. The polymeric fluids in this paper are considered as ordered thermoviscoelastic fluids in which the stress rate of a desired order, i.e., the convected time derivative of a desired order ` m' of the chosen deviatoric Cauchy stress tensor, and the heat vector are functions of density, temperature, temperature gradient, convected time derivatives of the chosen strain tensor up to any desired order ` n' and the convected time derivative of up to orders ` m-1' of the chosen deviatoric Cauchy stress tensor. The development of the constitutive theories is presented in contravariant and covariant bases, as well as using Jaumann rates. The polymeric fluids described by these constitutive theories will be referred to as ordered thermoviscoelastic fluids due to the fact that the constitutive theories are dependent on the orders ` m' and ` n' of the convected time derivatives of the deviatoric Cauchy stress and conjugate strain tensors. The highest orders of the convected time derivative of the deviatoric Cauchy stress and strain tensors define the orders of the polymeric fluid. The admissibility requirement necessitates that the constitutive theories for the stress tensor and heat vector satisfy conservation laws, hence, in addition to conservation of mass, balance of momenta, and conservation of energy, the second law of thermodynamics, i.e., Clausius-Duhem inequality must also be satisfied by the constitutive theories or be used in their derivations. If we decompose the total Cauchy stress tensor into equilibrium and deviatoric components, then Clausius-Duhem inequality and Helmholtz free-energy density can be used to determine the equilibrium stress in terms of thermodynamic pressure for compressible fluids and in terms of mechanical pressure for incompressible fluids, but the second

  11. The Constitutionality of a Biological Father's Recognition as a Parent

    Directory of Open Access Journals (Sweden)

    A Louw

    2010-12-01

    Full Text Available Despite the increased recognition afforded to biological fathers as legal parents, the Children's Act 38 of 2005 still does not treat fathers on the same basis as mothers as far as the automatic allocation of parental responsibilities and rights is concerned. This article investigates the constitutionality of the differential treatment of fathers in this respect, given South Africa's international obligations, especially in terms of the United Nations Convention on the Rights of the Child, to ensure that both parents have common responsibilities for the upbringing of their child. After a brief consideration of the constitutionality of the mother's position as parent, the constitutionality of the father's position is investigated, firstly, with reference to Section 9 of the Constitution and the question of whether the differentiation between mothers and fathers as far as the allocation of parental responsibilities and rights is concerned, amounts to unfair discrimination. The inquiry also considers whether the differentiation between committed fathers (that is, those who have shown the necessary commitment in terms of Sections 20 and 21 of the Children's Act to acquire parental responsibilities and rights and uncommitted fathers may amount to discrimination on an unspecified ground. Since the limitation of the father's rights to equality may be justifiable, the outcomes of both inquiries are shown to be inconclusive. Finally, the legal position of the father is considered in relation to the child's constitutional rights – the rights to parental care and the right of the child to the paramountcy of its interests embodied in Section 28 of the Constitution. While there appears to be some justification for the limitation of the child's right to committed paternal care, it is submitted that an equalisation of the legal position of mothers and fathers as far as the automatic acquisition of parental responsibilities and rights is concerned, is not

  12. Evaluation of potential crushed-salt constitutive models

    Energy Technology Data Exchange (ETDEWEB)

    Callahan, G.D.; Loken, M.C.; Sambeek, L.L. Van; Chen, R.; Pfeifle, T.W.; Nieland, J.D. [RE/SPEC Inc., Rapid City, SD (United States); Hansen, F.D. [Sandia National Labs., Albuquerque, NM (United States). Repository Isolation Systems Dept.

    1995-12-01

    Constitutive models describing the deformation of crushed salt are presented in this report. Ten constitutive models with potential to describe the phenomenological and micromechanical processes for crushed salt were selected from a literature search. Three of these ten constitutive models, termed Sjaardema-Krieg, Zeuch, and Spiers models, were adopted as candidate constitutive models. The candidate constitutive models were generalized in a consistent manner to three-dimensional states of stress and modified to include the effects of temperature, grain size, and moisture content. A database including hydrostatic consolidation and shear consolidation tests conducted on Waste Isolation Pilot Plant and southeastern New Mexico salt was used to determine material parameters for the candidate constitutive models. Nonlinear least-squares model fitting to data from the hydrostatic consolidation tests, the shear consolidation tests, and a combination of the shear and hydrostatic tests produces three sets of material parameter values for the candidate models. The change in material parameter values from test group to test group indicates the empirical nature of the models. To evaluate the predictive capability of the candidate models, each parameter value set was used to predict each of the tests in the database. Based on the fitting statistics and the ability of the models to predict the test data, the Spiers model appeared to perform slightly better than the other two candidate models. The work reported here is a first-of-its kind evaluation of constitutive models for reconsolidation of crushed salt. Questions remain to be answered. Deficiencies in models and databases are identified and recommendations for future work are made. 85 refs.

  13. Evaluation for rheological constitutive relations, using the indentation technique

    Science.gov (United States)

    Fang, Lei

    1992-01-01

    A simple experimental method of determining the rheological constitutive relations is proposed. The method relies upon an analysis of the frictionless contact of a rigid spherical indenter and the rheological materials. The proposal addresses problems in two fields: rheological constitutive models and contact mechanics. It attempts to evaluate the rheological constitutive relations using an indentation technique. A systematic, optimization-based material parameter/function indentation model is proposed. The identification algorithm is based on a modified Marquardt-Levenberg method. A new integral constitutive equation for viscoelastic materials is derived. The derivation is carried out so that a damage function is included in the model in a relatively convenient form. Inclusion of damage effects makes this constitutive equation considerably more general than the widely accepted K-BKZ integral model. The single-step and double-step stress relaxation indentation experiments on asphalt materials were performed. The K-BKZ, Wagner, and nonlinear Volterra models were evaluated. It is demonstrated that the new integral constitutive model shows a very good agreement with the experimental data. The idea of damage function is introduced not only to have a better fit of data, but the damage (or irreversibility) is observed experimentally. Also, the creep indentation tests on composites were presented. A multiaxial theory of creep deformation for particle-strengthened metal matrix composites (Zhu-Weng Theory) was evaluated. The goal of the proposed research is to develop the indentation technique for use in basic mechanical studies. From the indentation test, material response is measured. The data are used in conjunction with the material parameter identification model to optimally back calculate the constitutive relations.

  14. Implications of fault constitutive properties for earthquake prediction

    Science.gov (United States)

    Dieterich, J.H.; Kilgore, B.

    1996-01-01

    The rate- and state-dependent constitutive formulation for fault slip characterizes an exceptional variety of materials over a wide range of sliding conditions. This formulation provides a unified representation of diverse sliding phenomena including slip weakening over a characteristic sliding distance D(c), apparent fracture energy at a rupture front, time- dependent healing after rapid slip, and various other transient and slip rate effects. Laboratory observations and theoretical models both indicate that earthquake nucleation is accompanied by long intervals of accelerating slip. Strains from the nucleation process on buried faults generally could not be detected if laboratory values of D, apply to faults in nature. However, scaling of D(c) is presently an open question and the possibility exists that measurable premonitory creep may precede some earthquakes. Earthquake activity is modeled as a sequence of earthquake nucleation events. In this model, earthquake clustering arises from sensitivity of nucleation times to the stress changes induced by prior earthquakes. The model gives the characteristic Omori aftershock decay law and assigns physical interpretation to aftershock parameters. The seismicity formulation predicts large changes of earthquake probabilities result from stress changes. Two mechanisms for foreshocks are proposed that describe observed frequency of occurrence of foreshock-mainshock pairs by time and magnitude. With the first mechanism, foreshocks represent a manifestation of earthquake clustering in which the stress change at the time of the foreshock increases the probability of earthquakes at all magnitudes including the eventual mainshock. With the second model, accelerating fault slip on the mainshock nucleation zone triggers foreshocks.

  15. A Novel Moderate Constitutive Promoter Derived from Poplar (Populus tomentosa Carrière

    Directory of Open Access Journals (Sweden)

    Xin-Min An

    2013-03-01

    Full Text Available A novel sequence that functions as a promoter element for moderate constitutive expression of transgenes, designated as the PtMCP promoter, was isolated from the woody perennial Populus tomentosa. The PtMCP promoter was fused to the GUS reporter gene to characterize its expression pattern in different species. In stable Arabidopsis transformants, transcripts of the GUS reporter gene could be detected by RT-PCR in the root, stem, leaf, flower and silique. Further histochemical and fluorometric GUS activity assays demonstrated that the promoter could direct transgene expression in all tissues and organs, including roots, stems, rosette leaves, cauline leaves and flowers of seedlings and maturing plants. Its constitutive expression pattern was similar to that of the CaMV35S promoter, but the level of GUS activity was significantly lower than in CaMV35S promoter::GUS plants. We also characterized the promoter through transient expression in transgenic tobacco and observed similar expression patterns. Histochemical GUS staining and quantitative analysis detected GUS activity in all tissues and organs of tobacco, including roots, stems, leaves, flower buds and flowers, but GUS activity in PtMCP promoter::GUS plants was significantly lower than in CaMV35S promoter::GUS plants. Our results suggested that the PtMCP promoter from poplar is a constitutive promoter with moderate activity and that its function is presumably conserved in different species. Therefore, the PtMCP promoter may provide a practical choice to direct moderate level constitutive expression of transgenes and could be a valuable new tool in plant genetic engineering.

  16. Predicting Sasang Constitution Using Body-Shape Information

    Directory of Open Access Journals (Sweden)

    Eunsu Jang

    2012-01-01

    Full Text Available Objectives. Body measurement plays a pivotal role not only in the diagnosis of disease but also in the classification of typology. Sasang constitutional medicine, which is one of the forms of Traditional Korean Medicine, is considered to be strongly associated with body shape. We attempted to determine whether a Sasang constitutional analytic tool based on body shape information (SCAT-B could predict Sasang constitution (SC. Methods. After surveying 23 Oriental medical clinics, 2,677 subjects were recruited and body shape information was collected. The SCAT-Bs for males and females were developed using multinomial logistic regression. Stepwise forward-variable selection was applied using the score statistic and Wald’s test. Results. The predictive rates of the SCAT-B for Tae-eumin (TE, Soeumin (SE, and Soyangin (SY types in males and females were 80.2%, 56.9%, and 37.7% (males and 69.3%, 38.9%, and 50.0% (females in the training set and were 74%, 70.1%, and 35% (males, and 67.4%, 66.3%, and 53.7% (females in the test set, respectively. Higher constitutional probability scores showed a trend for association with higher predictability. Conclusions. This study shows that the Sasang constitutional analytic tool, which is based on body shape information, may be relatively highly predictive of TE type but may be less predictive when used for SY type.

  17. Gospel and constitutional imperatives: the right to life

    Directory of Open Access Journals (Sweden)

    S.P. Giles

    2011-06-01

    Full Text Available Gospel and constitutional imperatives: the right to life In the Republic of South Africa, Christians are called to live out gospel imperatives within the legal framework of the Constitution. Ethical issues about the right to life are considered from the perspectives of selected gospel and constitutional imperatives. Gospel imperatives impose themselves as a consequence of Christian discipleship. These are many and diverse, both explicit and implicit. Christian vocation, discipleship, witness and perseverance, are foundational and integral to the praxis of Christian daily living. These facets of Christian life are illustrated by the selected gospel imperatives, “Follow me” (Matt. 4:19 and synoptic parallels, “Love God, and your neighbour as yourself” (Matt. 22:34-40 and synoptic parallels, and “Take up your cross” (Matt. 10:38 and synoptic parallels. The central theoretical argument of this article is driven from a reformed ethical perspective. Gospel imperatives have priority over constitutional imperatives since gospel imperatives are of divine origin and constitutional imperatives of human origin. Acknowledgement of these priorities informs the Christian ethical perspective on the right to life and on abortion.

  18. Perspective of the Human Body in Sasang Constitutional Medicine

    Directory of Open Access Journals (Sweden)

    Junhee Lee

    2009-01-01

    Full Text Available The Sasang constitutional medicine (SCM, a medical tradition originating from Korea, is distinguished from the traditional Chinese medicine in its philosophical background, theoretical development and especially, the fundamental rationale that analyzes the structure and function of the human body within a quadrifocal scheme. In SCM, the structure of the body is comprehended within the Sasang quadrifocal scheme, and the function of the body is understood within the context of the energy-fluid metabolism and the water-food metabolism controlled by the four main organs (lung, spleen, liver and kidney. Also, the concept of Seong-Jeong is used to explain the structural and functional variations between different constitutional types that arise from the constitutional variations in organ system scheme, which are in turn caused by deviations in the constitutional Seong-Jeong. Therefore, understanding the SCM perspective of the human body is essential in order to fully appreciate the advantages of the constitutional typological system (which focuses on individual idiosyncrasies found in SCM.

  19. High constitutive signaling of the ghrelin receptor--identification of a potent inverse agonist

    DEFF Research Database (Denmark)

    Holst, Birgitte; Cygankiewicz, Adam; Jensen, Tine Halkjaer

    2003-01-01

    Ghrelin is a GH-releasing peptide that also has an important role as an orexigenic hormone-stimulating food intake. By measuring inositol phosphate turnover or by using a reporter assay for transcriptional activity controlled by cAMP-responsive elements, the ghrelin receptor showed strong, ligand......-independent signaling in transfected COS-7 or human embryonic kidney 293 cells. Ghrelin and a number of the known nonpeptide GH secretagogues acted as agonists stimulating inositol phosphate turnover further. In contrast, the low potency ghrelin antagonist, [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P was surprisingly...... found to be a high potency (EC50 = 5.2 nm) full inverse agonist as it decreased the constitutive signaling of the ghrelin receptor down to that observed in untransfected cells. The homologous motilin receptor functioned as a negative control as it did not display any sign of constitutive activity...

  20. New constitutionalism and the social reproduction of caring institutions.

    Science.gov (United States)

    Gill, Stephen; Bakker, Isabella

    2006-01-01

    This essay analyzes neo-liberal economic agreements and legal and political frameworks or what has been called the "new constitutionalism," a governance framework that empowers market forces to reshape economic and social development worldwide. The article highlights some consequences of new constitutionalism for caring institutions specifically, and for what feminists call social reproduction more generally: the biological reproduction of the species; the reproduction of labor power; and the reproduction of social institutions and processes associated with the creation and maintenance of communities. New constitutional governance frameworks fundamentally reshape conditions under which the care of human beings takes place. Caring institutions once governed by enabling professions geared to universal care are now determined increasingly by market values and private forces, and driven directly by the profit motive. This is one of the reasons why neo-liberalism is increasingly contested in both the North and the global South.