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Sample records for response gene-1 egr-1

  1. The study on Egr-1 promoter which is radioactive promoter

    Zhang Chunzhi; Guo Yang; Lv Zhonghong

    2006-01-01

    Radiogenetic therapy is a heated reaseach on oncotherapy. Early growth response gene-1 (Egr-1) gene promoter is a probably means in radiogenetic therapy. The article review studying on Egr-1 gene promoter and constructing regulating gene expressing system by radiation-inducible Egr-1 gene promoter. (authors)

  2. Egr-1 induction provides a genetic response to food aversion in zebrafish

    Brigitte eBoyer

    2013-05-01

    Full Text Available As soon as zebrafish larvae start eating, they exhibit a marked aversion for bitter and acidic substances, as revealed by a consumption assay, in which fluorescent Tetrahymena serve as a feeding basis, to which various stimuli can be added. Bitter and acidic substances elicited an increase in mRNA accumulation of the immediate-early response gene egr-1, as revealed by in situ hybridization. Conversely, chemostimulants that did not induce aversion did not induce egr-1 response. Maximum labelling was observed in cells located in the oropharyngeal cavity and on the gill rakers. Gustatory areas of the brain were also labelled. Interestingly, when bitter tastants were repeatedly associated with food reward, zebrafish juveniles learned to ingest food in the presence of the bitter compound. After habituation, the acquisition of acceptance for bitterness was accompanied by a loss of egr-1 labelling. Altogether, our data indicate that egr-1 participates specifically in food aversion. The existence of reward-coupled changes in taste sensitivity in humans suggests that our results are relevant to situations in humans.

  3. Egr-1 induction provides a genetic response to food aversion in zebrafish.

    Boyer, Brigitte; Ernest, Sylvain; Rosa, Frédéric

    2013-01-01

    As soon as zebrafish larvae start eating, they exhibit a marked aversion for bitter and acidic substances, as revealed by a consumption assay, in which fluorescent Tetrahymena serve as a feeding basis, to which various stimuli can be added. Bitter and acidic substances elicited an increase in mRNA accumulation of the immediate-early response gene egr-1, as revealed by in situ hybridization. Conversely, chemostimulants that did not induce aversion did not induce egr-1 response. Maximum labeling was observed in cells located in the oropharyngeal cavity and on the gill rakers. Gustatory areas of the brain were also labeled. Interestingly, when bitter tastants were repeatedly associated with food reward, zebrafish juveniles learned to ingest food in the presence of the bitter compound. After habituation, the acquisition of acceptance for bitterness was accompanied by a loss of egr-1 labeling. Altogether, our data indicate that egr-1 participates specifically in food aversion. The existence of reward-coupled changes in taste sensitivity in humans suggests that our results are relevant to situations in humans.

  4. Radiation Induced Apoptosis of Murine Bone Marrow Cells Is Independent of Early Growth Response 1 (EGR1.

    Karine Z Oben

    Full Text Available An understanding of how each individual 5q chromosome critical deleted region (CDR gene contributes to malignant transformation would foster the development of much needed targeted therapies for the treatment of therapy related myeloid neoplasms (t-MNs. Early Growth Response 1 (EGR1 is a key transcriptional regulator of myeloid differentiation located within the 5q chromosome CDR that has been shown to regulate HSC (hematopoietic stem cell quiescence as well as the master regulator of apoptosis-p53. Since resistance to apoptosis is a hallmark of malignant transformation, we investigated the role of EGR1 in apoptosis of bone marrow cells; a cell population from which myeloid malignancies arise. We evaluated radiation induced apoptosis of Egr1+/+ and Egr1-/- bone marrow cells in vitro and in vivo. EGR1 is not required for radiation induced apoptosis of murine bone marrow cells. Neither p53 mRNA (messenger RNA nor protein expression is regulated by EGR1 in these cells. Radiation induced apoptosis of bone marrow cells by double strand DNA breaks induced p53 activation. These results suggest EGR1 dependent signaling mechanisms do not contribute to aberrant apoptosis of malignant cells in myeloid malignancies.

  5. Role of alveolar epithelial Early growth response-1 (Egr-1) in CD8+ T Cell mediated Lung Injury

    Ramana, Chilakamarti V.; Cheng, Guang-Shing; Kumar, Aseem; Kwon, Hyung- Joo; Enelow, Richard I.

    2009-01-01

    Influenza infection of the distal airways results in severe lung injury, a considerable portion of which is immunopathologic and attributable to the host responses. We have used a mouse model to specifically investigate the role of antiviral CD8+ T cells in this injury, and have found that the critical effector molecule is TNF-α expressed by the T cells upon antigen recognition. Interestingly, the immunopathology which ensues is characterized by significant accumulation of host inflammatory cells, recruited by chemokines expressed by the target alveolar epithelial cells. In this study we analyzed the mechanisms involved in the induction of epithelial chemokine expression triggered by antigen-specific CD8+ T cell recognition, and demonstrate that the Early growth response-1 (Egr-1) transcription factor is rapidly induced in epithelial cells, both in vitro and ex vivo, and that this is a critical regulator of a host of inflammatory chemokines. Genetic deficiency of Egr-1 significantly abrogates both the chemokine expression and the immunopathologic injury associated with T cell recognition, and it directly regulates transcriptional activity of a model CXC chemokine, MIP-2. We further demonstrate that Egr-1 induction is triggered by TNF-α– dependent ERK activation, and inhibition of this pathway ablates Egr-1 expression. These findings suggest that Egr-1 may represent an important target in mitigating the immunopathology of severe influenza infection. PMID:19786304

  6. Role of alveolar epithelial early growth response-1 (Egr-1) in CD8+ T cell-mediated lung injury.

    Ramana, Chilakamarti V; Cheng, Guang-Shing; Kumar, Aseem; Kwon, Hyung-Joo; Enelow, Richard I

    2009-12-01

    Influenza infection of the distal airways results in severe lung injury, a considerable portion of which is immunopathologic and attributable to the host responses. We have used a mouse model to specifically investigate the role of antiviral CD8(+) T cells in this injury, and have found that the critical effector molecule is TNF-alpha expressed by the T cells upon antigen recognition. Interestingly, the immunopathology which ensues is characterized by significant accumulation of host inflammatory cells, recruited by chemokines expressed by the target alveolar epithelial cells. In this study we analyzed the mechanisms involved in the induction of epithelial chemokine expression triggered by antigen-specific CD8(+) T cell recognition, and demonstrate that the early growth response-1 (Egr-1) transcription factor is rapidly induced in epithelial cells, both in vitro and ex vivo, and that this is a critical regulator of a host of inflammatory chemokines. Genetic deficiency of Egr-1 significantly abrogates both the chemokine expression and the immunopathologic injury associated with T cell recognition, and it directly regulates transcriptional activity of a model CXC chemokine, MIP-2. We further demonstrate that Egr-1 induction is triggered by TNF-alpha-dependent ERK activation, and inhibition of this pathway ablates Egr-1 expression. These findings suggest that Egr-1 may represent an important target in mitigating the immunopathology of severe influenza infection.

  7. EGR-1 and DUSP-1 are important negative regulators of pro-allergic responses in airway epithelium.

    Golebski, Korneliusz; van Egmond, Danielle; de Groot, Esther J; Roschmann, Kristina I L; Fokkens, Wytske J; van Drunen, Cornelis M

    2015-05-01

    Primary nasal epithelium of house dust mite allergic individuals is in a permanently activated inflammatory transcriptional state. To investigate whether a deregulated expression of EGR-1 and/or DUSP-1, two potential negative regulators of pro-inflammatory responses, could contribute to the activation of the inflammatory state. We silenced the expression of EGR-1 or DUSP-1 in the airway epithelial cell line NCI-H292. The cell lines were stimulated in a 24-h time course with the house dust mite allergen or poly(I:C). RNA expression profiles of cytokines were established using q-PCR and protein levels were determined in supernatants with ELISA. The shRNA-mediated gene silencing reduced expression levels of EGR-1 by 92% (p<0.0001) and of DUSP-1 by 76% (p<0.0001). Both mutant cells lines showed an increased and prolonged response to the HDM allergen. The mRNA induction of IL-6 was 4.6 fold (p=0.02) and 2.4 fold higher (p=0.01) in the EGR-1 and DUSP-1 knock-down, respectively when compared to the induced levels in the control cell line. For IL-8, the induction levels were 4.6 fold (p=0.01) and 13.0 (p=0.001) fold higher. The outcome was largely similar, yet not identical at the secreted protein levels. Furthermore, steroids were able to suppress the poly(I:C) induced cytokine levels by 70-95%. Deregulation of EGR-1 and/or DUSP-1 in nasal epithelium could be responsible for the prolonged activated transcriptional state observed in vivo in allergic disease. This could have clinical consequences as cytokine levels after the steroid treatment in EGR-1 or DUSP-1 knock-down remained higher than in the control cell line. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. EGR-1 and DUSP-1 are important negative regulators of pro-allergic responses in airway epithelium

    Golebski, Korneliusz; van Egmond, Danielle; de Groot, Esther J.; Roschmann, Kristina I. L.; Fokkens, Wytske J.; van Drunen, Cornelis M.

    2015-01-01

    Background: Primary nasal epithelium of house dust mite allergic individuals is in a permanently activated inflammatory transcriptional state. Objective: To investigate whether a deregulated expression of EGR-1 and/or DUSP-1, two potential negative regulators of pro-inflammatory responses, could

  9. Histone Deacetylase Inhibitors Activate Tristetraprolin Expression through Induction of Early Growth Response Protein 1 (EGR1 in Colorectal Cancer Cells

    Cyril Sobolewski

    2015-08-01

    Full Text Available The RNA-binding protein tristetraprolin (TTP promotes rapid decay of mRNAs bearing 3' UTR AU-rich elements (ARE. In many cancer types, loss of TTP expression is observed allowing for stabilization of ARE-mRNAs and their pathologic overexpression. Here we demonstrate that histone deacetylase (HDAC inhibitors (Trichostatin A, SAHA and sodium butyrate promote TTP expression in colorectal cancer cells (HCA-7, HCT-116, Moser and SW480 cells and cervix carcinoma cells (HeLa. We found that HDAC inhibitors-induced TTP expression, promote the decay of COX-2 mRNA, and inhibit cancer cell proliferation. HDAC inhibitors were found to promote TTP transcription through activation of the transcription factor Early Growth Response protein 1 (EGR1. Altogether, our findings indicate that loss of TTP in tumors occurs through silencing of EGR1 and suggests a therapeutic approach to rescue TTP expression in colorectal cancer.

  10. Transcriptional regulation of the p73 gene, a member of the p53 family, by early growth response-1 (Egr-1)

    Lee, Sang-Wang; Kim, Eun-Joo; Um, Soo-Jong

    2007-01-01

    To elucidate the regulatory mechanism of p73 gene expression, we analyzed the human p73 promoter and found three putative Egr-1-binding sites located upstream of exon 1 (-1728, -321, and -38). The Egr-1 responsiveness of these sites was analyzed by transient transfection assays using 5'- and 3'-serial truncations of the p73 promoter, subcloned in a CAT reporter vector. The functional significance of the region was further confirmed by an electrophoretic mobility shift assay using the Egr-1 protein synthesized in vitro and a [ 32 P]-labeled middle site sequence, followed by competition with unlabeled wild-type or mutant oligonucleotides and supershift assays using an anti-Egr-1 antibody. When induced by either the nitric oxide donor NOC-18 or the PPARγ agonist troglitazone, Egr-1 bound to the p73 promoter, as assessed by chromatin immunoprecipitation assays, accompanied by increased expression of p73. MTT assays revealed that cell growth was significantly inhibited on treating the cells with troglitazone. Overall, our results provide direct evidence that Egr-1 positively regulated p73 expression by binding to its promoter in vivo, consistent with Egr-1 and p73 being involved in p53-independent tumor suppression

  11. A Single Dose of LSD Does Not Alter Gene Expression of the Serotonin 2A Receptor Gene (HTR2A) or Early Growth Response Genes (EGR1-3) in Healthy Subjects

    Dolder, Patrick C.; Grünblatt, Edna; Müller, Felix; Borgwardt, Stefan J.; Liechti, Matthias E.

    2017-01-01

    Rationale: Renewed interest has been seen in the use of lysergic acid diethylamide (LSD) in psychiatric research and practice. The repeated use of LSD leads to tolerance that is believed to result from serotonin (5-HT) 5-HT2A receptor downregulation. In rats, daily LSD administration for 4 days decreased frontal cortex 5-HT2A receptor binding. Additionally, a single dose of LSD acutely increased expression of the early growth response genes EGR1 and EGR2 in rat and mouse brains through 5-HT2A receptor stimulation. No human data on the effects of LSD on gene expression has been reported. Therefore, we investigated the effects of single-dose LSD administration on the expression of the 5-HT2A receptor gene (HTR2A) and EGR1-3 genes. Methods: mRNA expression levels were analyzed in whole blood as a peripheral biomarker in 15 healthy subjects before and 1.5 and 24 h after the administration of LSD (100 μg) and placebo in a randomized, double-blind, placebo-controlled, cross-over study. Results: LSD did not alter the expression of the HTR2A or EGR1-3 genes 1.5 and 24 h after administration compared with placebo. Conclusion: No changes were observed in the gene expression of LSD’s primary target receptor gene or genes that are implicated in its downstream effects. Remaining unclear is whether chronic LSD administration alters gene expression in humans. PMID:28701958

  12. Mechanisms of dietary response in mice and primates: a role for EGR1 in regulating the reaction to human-specific nutritional content.

    Kai Weng

    Full Text Available Humans have a widely different diet from other primate species, and are dependent on its high nutritional content. The molecular mechanisms responsible for adaptation to the human diet are currently unknown. Here, we addressed this question by investigating whether the gene expression response observed in mice fed human and chimpanzee diets involves the same regulatory mechanisms as expression differences between humans and chimpanzees.Using mouse and primate transcriptomic data, we identified the transcription factor EGR1 (early growth response 1 as a putative regulator of diet-related differential gene expression between human and chimpanzee livers. Specifically, we predict that EGR1 regulates the response to the high caloric content of human diets. However, we also show that close to 90% of the dietary response to the primate diet found in mice, is not observed in primates. This might be explained by changes in tissue-specific gene expression between taxa.Our results suggest that the gene expression response to the nutritionally rich human diet is partially mediated by the transcription factor EGR1. While this EGR1-driven response is conserved between mice and primates, the bulk of the mouse response to human and chimpanzee dietary differences is not observed in primates. This result highlights the rapid evolution of diet-related expression regulation and underscores potential limitations of mouse models in dietary studies.

  13. Induction of the early response protein EGR-1 in human tumour cells after ionizing radiation is correlated with a reduction of repair of lethal lesions and an increase of repair of sublethal lesions

    Franken, Nicolaas A. P.; ten Cate, Rosemarie; van Bree, Chris; Haveman, Jaap

    2004-01-01

    The role of EGR-1 in potentially lethal damage repair (PLDR) was studied. Induction of the early response protein EGR-1 and survival after ionizing radiation of two human tumour cell lines after culturing for 48 h in serum-deprived medium was investigated. The glioblastoma cell line (Gli-6) and a

  14. The progress of tumor gene-radiotherapy induced by Egr-1 promoter

    Guo Rui; Li Biao

    2010-01-01

    The promoter of early growth response gene-1 (Egr-1) is a cis-acting element of Egr-1, and its activity is regulated by inducers such as ionizing radiation, free radical. In designated gene-radiotherapy system, radiation combined with therapeutic gene (such as tumor necrosis factor-α gene, suicide gene) can spatially and temporally regulate therapeutic gene expression in the irradiated field, produced a marked effect, while little systemic toxicities were observed. The combination of radiotherapy and gene therapy is promising in tumor therapy. (authors)

  15. Egr-1 and serum response factor are involved in growth factors- and serum-mediated induction of E2-EPF UCP expression that regulates the VHL-HIF pathway.

    Lim, Jung Hwa; Jung, Cho-Rok; Lee, Chan-Hee; Im, Dong-Soo

    2008-11-01

    E2-EPF ubiquitin carrier protein (UCP) has been shown to be highly expressed in common human cancers and target von Hippel-Lindau (VHL) for proteosomal degradation in cells, thereby stabilizing hypoxia-inducible factor (HIF)-1alpha. Here, we investigated cellular factors that regulate the expression of UCP gene. Promoter deletion assay identified binding sites for early growth response-1 (Egr-1) and serum response factor (SRF) in the UCP promoter. Hepatocyte or epidermal growth factor (EGF), or phorbol 12-myristate 13-acetate induced UCP expression following early induction of Egr-1 expression in HeLa cells. Serum increased mRNA and protein levels of SRF and UCP in the cell. By electrophoretic mobility shift and chromatin immunoprecipitation assays, sequence-specific DNA-binding of Egr-1 and SRF to the UCP promoter was detected in nuclear extracts from HeLa cells treated with EGF and serum, respectively. Overexpression of Egr-1 or SRF increased UCP expression. RNA interference-mediated depletion of endogenous Egr-1 or SRF impaired EGF- or serum-mediated induction of UCP expression, which was required for cancer cell proliferation. Systemic delivery of EGF into mice also increased UCP expression following early induction of Egr-1 expression in mouse liver. The induced UCP expression by the growth factors or serum increased HIF-1alpha protein level under non-hypoxic conditions, suggesting that the Egr-1/SRF-UCP-VHL pathway is in part responsible for the increased HIF-1alpha protein level in vitro and in vivo. Thus, growth factors and serum induce expression of Egr-1 and SRF, respectively, which in turn induces UCP expression that positively regulates cancer cell growth.

  16. Regulation of tissue factor and inflammatory mediators by Egr-1 in a mouse endotoxemia model.

    Pawlinski, Rafal; Pedersen, Brian; Kehrle, Bettina; Aird, William C; Frank, Rolf D; Guha, Mausumee; Mackman, Nigel

    2003-05-15

    In septic shock, tissue factor (TF) activates blood coagulation, and cytokines and chemokines orchestrate an inflammatory response. In this study, the role of Egr-1 in lipopolysaccharide (LPS) induction of TF and inflammatory mediators in vivo was evaluated using Egr-1(+/+) and Egr-1(-/-) mice. Administration of LPS transiently increased the steady-state levels of Egr-1 mRNA in the kidneys and lungs of Egr-1(+/+) mice with maximal induction at one hour. Egr-1 was expressed in epithelial cells in the kidneys and lungs in untreated and LPS-treated mice. LPS induction of monocyte chemoattractant protein mRNA in the kidneys and lungs of Egr-1(-/-) mice was not affected at 3 hours, but its expression was significantly reduced at 8 hours compared with the expression observed in Egr-1(+/+) mice. Similarly, LPS induction of TF mRNA expression in the kidneys and lungs at 8 hours was reduced in Egr-1(-/-) mice. However, Egr-1 deficiency did not affect plasma levels of tumor necrosis factor alpha in endotoxemic mice. Moreover, Egr-1(+/+) and Egr-1(-/-) mice exhibited similar survival times in a model of acute endotoxemia. These data indicate that Egr-1 does not contribute to the early inflammatory response in the kidneys and lungs or the early systemic inflammatory response in endotoxemic mice. However, Egr-1 does contribute to the sustained expression of inflammatory mediators and to the maximal expression of TF at 8 hours in the kidneys and lungs.

  17. Atorvastatin inhibits the immediate-early response gene EGR1 and improves the functional profile of CD4+T-lymphocytes in acute coronary syndromes.

    Severino, Anna; Zara, Chiara; Campioni, Mara; Flego, Davide; Angelini, Giulia; Pedicino, Daniela; Giglio, Ada Francesca; Trotta, Francesco; Giubilato, Simona; Pazzano, Vincenzo; Lucci, Claudia; Iaconelli, Antonio; Ruggio, Aureliano; Biasucci, Luigi Marzio; Crea, Filippo; Liuzzo, Giovanna

    2017-03-14

    Background- Adaptive immune-response is associated with a worse outcome in acute coronary syndromes. Statins have anti-inflammatory activity beyond lowering lipid levels. We investigated the effects of ex-vivo and in-vivo atorvastatin treatment in acute coronary syndromes on CD4+T-cells, and the underlying molecular mechanisms.Approach and results- Blood samples were collected from 50 statin-naïve acute coronary syndrome patients. We assessed CD4+T-cell activation by flow-cytometry, the expression of 84 T-helper transcription-factors and 84 T-cell related genes by RT-qPCR, and protein expression by Western-blot, before and after 24-hours incubation with increasing doses of atorvastatin: 3-10-26 μg/ml (corresponding to blood levels achieved with doses of 10-40-80 mg, respectively). After incubation, we found a significant decrease in interferon-γ-producing CD4+CD28nullT-cells (P = 0.009) and a significant increase in interleukin-10-producing CD4+CD25highT-cells (P 3-fold changes).The in-vivo effects of atorvastatin were analyzed in 10 statin-free acute coronary syndrome patients at baseline, and after 24h and 48h of atorvastatin therapy (80 mg/daily): EGR1-gene expression decreased at 24h (P = 0.01) and 48h (P = 0.005); EGR1-protein levels decreased at 48h (P = 0.03).Conclusions-In acute coronary syndromes, the effects of atorvastatin on immune system might be partially related to the inhibition of the master regulator gene EGR1. Our finding might offer a causal explanation on why statins improve the early outcome in acute coronary syndromes.

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

    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.

  19. EGR-1 regulates Ho-1 expression induced by cigarette smoke

    Chen, Huaqun; Wang, Lijuan; Gong, Tao; Yu, Yang; Zhu, Chunhua; Li, Fen; Wang, Li; Li, Chaojun

    2010-01-01

    As an anti-oxidant molecule, heme oxygenase-1 (HO-1) has been implicated in the protection of lung injury by cigarette smoke (CS). The mechanisms regulating its expression have not been defined. In this report, the role of early growth response 1 (EGR-1) in the regulation of Ho-1 expression was investigated. In C57BL/6 mice with CS exposure, HO-1 was greatly increased in bronchial epithelial cells and alveolar inflammatory cells. In primary cultured mouse lung fibroblasts and RAW264.7 cells exposed to cigarette smoke water extract (CSE), an increase in HO-1 protein level was detected. In addition, CSE induced HO-1 expression was decreased in Egr-1 deficient mouse embryo fibroblasts (Egr-1 -/- MEFs). Nuclear localization of EGR-1 was examined in mouse lung fibroblasts after exposure to CSE. Luciferase reporter activity assays showed that the enhancer region of the Ho-1 gene containing a proposed EGR-1 binding site was responsible for the induction of HO-1. A higher increase of alveolar mean linear intercept (Lm) was observed in lung tissues, and a larger increase in the number of total cells and monocytes/macrophages from bronchial alveolar lavage fluid was found in CS-exposed mice by loss of function of EGR-1 treatment. In summary, the present data demonstrate that EGR-1 plays a critical role in HO-1 production induced by CS.

  20. Role of alveolar epithelial Early growth response-1 (Egr-1) in CD8+ T Cell mediated Lung Injury

    Ramana, Chilakamarti V.; Cheng, Guang-Shing; Kumar, Aseem; Kwon, Hyung- Joo; Enelow, Richard I.

    2009-01-01

    Influenza infection of the distal airways results in severe lung injury, a considerable portion of which is immunopathologic and attributable to the host responses. We have used a mouse model to specifically investigate the role of antiviral CD8+ T cells in this injury, and have found that the critical effector molecule is TNF-α expressed by the T cells upon antigen recognition. Interestingly, the immunopathology which ensues is characterized by significant accumulation of host inflammatory c...

  1. Egr-1 antisense oligodeoxynucleotide administration into the olfactory bulb impairs olfactory learning in the greater short-nosed fruit bat Cynopterus sphinx.

    Ganesh, Ambigapathy; Bogdanowicz, Wieslaw; Balamurugan, Krishnaswamy; Ragu Varman, Durairaj; Rajan, Koilmani Emmanuvel

    2012-08-30

    Postsynaptic densities (PSDs) contain proteins that regulate synaptic transmission. We examined two important examples of these, calcium/calmodulin-dependent protein kinase II (CaMKII) and PSD-95, in regard to the functional role of early growth response gene-1 (egr-1) in regulation of olfactory learning in the greater short-nosed fruit bat Cynopterus sphinx (family Pteropodidae). To test whether activation of egr-1 in the olfactory bulb (OB) is required for olfactory memory of these bats, bilaterally canulated individuals were infused with antisense (AS) or non-sense (NS)-oligodeoxynucleotides (ODN) of egr-1, or with phosphate buffer saline (PBS), 2h before the olfactory training. Our results showed that behavioral training significantly up-regulates immediate early gene (IEG) EGR-1 and key synaptic proteins Synaptotagmin-1(SYT-1), CaMKII and PSD-95, and phosphorylation of CaMKII in the OB at the protein level per se. Subsequently, we observed that egr-1 antisense-ODN infusion in the OB impaired olfactory memory and down regulates the expression of CaMKII and PSD-95, and the phosphorylation of CaMKII but not SYT-1. In contrast, NS-ODN or PBS had no effect on the expression of the PSDs CaMKII or PSD-95, or on the phosphorylation of CaMKII. When the egr-1 NS-ODN was infused in the OB after training for the novel odor there was no effect on olfactory memory. These findings suggest that egr-1 control the activation of CaMKII and PSD-95 during the process of olfactory memory formation. Copyright © 2012 Elsevier B.V. All rights reserved.

  2. EGR1 induces tenogenic differentiation of tendon stem cells and promotes rabbit rotator cuff repair.

    Tao, Xu; Liu, Junpeng; Chen, Lei; Zhou, You; Tang, Kanglai

    2015-01-01

    The rate of healing failure after surgical repair of chronic rotator cuff tears is considerably high. The aim of this study was to investigate the function of the zinc finger transcription factor early growth response 1 (EGR1) in the differentiation of tendon stem cells (TSCs) and in tendon formation, healing, and tendon tear repair using an animal model of rotator cuff repair. Tenocyte, adipocyte, osteocyte, and chondrocyte differentiation as well as the expression of related genes were determined in EGR1-overexpressing TSCs (EGR1-TSCs) using tissue-specific staining, immunofluorescence staining, quantitative PCR, and western blotting. A rabbit rotator cuff repair model was established, and TSCs and EGR1-TSCs in a fibrin glue carrier were applied onto repair sites. The rabbits were sacrificed 8 weeks after repair operation, and tissues were histologically evaluated and tenocyte-related gene expression was determined. EGR1 induced tenogenic differentiation of TSCs and inhibited non-tenocyte differentiation of TSCs. Furthermore, EGR1 promoted tendon repair in a rabbit model of rotator cuff injury. The BMP12/Smad1/5/8 signaling pathway was involved in EGR1-induced tenogenic differentiation and rotator cuff tendon repair. EGR1 plays a key role in tendon formation, healing, and repair through BMP12/Smad1/5/8 pathway. EGR1-TSCs is a promising treatment for rotator cuff tendon repair surgeries. © 2015 S. Karger AG, Basel.

  3. EGR1 Induces Tenogenic Differentiation of Tendon Stem Cells and Promotes Rabbit Rotator Cuff Repair

    Xu Tao

    2015-01-01

    Full Text Available Background/Aims: The rate of healing failure after surgical repair of chronic rotator cuff tears is considerably high. The aim of this study was to investigate the function of the zinc finger transcription factor early growth response 1 (EGR1 in the differentiation of tendon stem cells (TSCs and in tendon formation, healing, and tendon tear repair using an animal model of rotator cuff repair. Methods: Tenocyte, adipocyte, osteocyte, and chondrocyte differentiation as well as the expression of related genes were determined in EGR1-overexpressing TSCs (EGR1-TSCs using tissue-specific staining, immunofluorescence staining, quantitative PCR, and western blotting. A rabbit rotator cuff repair model was established, and TSCs and EGR1-TSCs in a fibrin glue carrier were applied onto repair sites. The rabbits were sacrificed 8 weeks after repair operation, and tissues were histologically evaluated and tenocyte-related gene expression was determined. Results: EGR1 induced tenogenic differentiation of TSCs and inhibited non-tenocyte differentiation of TSCs. Furthermore, EGR1 promoted tendon repair in a rabbit model of rotator cuff injury. The BMP12/Smad1/5/8 signaling pathway was involved in EGR1-induced tenogenic differentiation and rotator cuff tendon repair. Conclusion: EGR1 plays a key role in tendon formation, healing, and repair through BMP12/Smad1/5/8 pathway. EGR1-TSCs is a promising treatment for rotator cuff tendon repair surgeries.

  4. Mice Lacking EGR1 Have Impaired Clock Gene (BMAL1) Oscillation, Locomotor Activity, and Body Temperature.

    Riedel, Casper Schwartz; Georg, Birgitte; Jørgensen, Henrik L; Hannibal, Jens; Fahrenkrug, Jan

    2018-01-01

    Early growth response transcription factor 1 (EGR1) is expressed in the suprachiasmatic nucleus (SCN) after light stimulation. We used EGR1-deficient mice to address the role of EGR1 in the clock function and light-induced resetting of the clock. The diurnal rhythms of expression of the clock genes BMAL1 and PER1 in the SCN were evaluated by semi-quantitative in situ hybridization. We found no difference in the expression of PER1 mRNA between wildtype and EGR1-deficient mice; however, the daily rhythm of BMAL1 mRNA was completely abolished in the EGR1-deficient mice. In addition, we evaluated the circadian running wheel activity, telemetric locomotor activity, and core body temperature of the mice. Loss of EGR1 neither altered light-induced phase shifts at subjective night nor affected negative masking. Overall, circadian light entrainment was found in EGR1-deficient mice but they displayed a reduced locomotor activity and an altered temperature regulation compared to wild type mice. When placed in running wheels, a subpopulation of EGR1-deficient mice displayed a more disrupted activity rhythm with no measurable endogenous period length (tau). In conclusion, the present study provides the first evidence that the circadian clock in the SCN is disturbed in mice deficient of EGR1.

  5. Resveratrol upregulates Egr-1 expression and activity involving extracellular signal-regulated protein kinase and ternary complex factors

    Rössler, Oliver G.; Glatzel, Daniel; Thiel, Gerald, E-mail: gerald.thiel@uks.eu

    2015-03-01

    Many intracellular functions have been attributed to resveratrol, a polyphenolic phytoalexin found in grapes and in other plants. Here, we show that resveratrol induces the expression of the transcription factor Egr-1 in human embryonic kidney cells. Using a chromosomally embedded Egr-1-responsive reporter gene, we show that the Egr-1 activity was significantly elevated in resveratrol-treated cells, indicating that the newly synthesized Egr-1 protein was biologically active. Stimulus-transcription coupling leading to the resveratrol-induced upregulation of Egr-1 expression and activity requires the protein kinases Raf and extracellular signal-regulated protein kinase ERK, while MAP kinase phosphatase-1 functions as a nuclear shut-off device that interrupts the signaling cascade connecting resveratrol stimulation with enhanced Egr-1 expression. On the transcriptional level, Elk-1, a key transcriptional regulator of serum response element-driven gene transcription, connects the intracellular signaling cascade elicited by resveratrol with transcription of the Egr-1 gene. These data were corroborated by the observation that stimulation of the cells with resveratrol increased the transcriptional activation potential of Elk-1. The SRE as well as the GC-rich DNA binding site of Egr-1 function as resveratrol-responsive elements. Thus, resveratrol regulates gene transcription via activation of the stimulus-regulated protein kinases Raf and ERK and the stimulus-responsive transcription factors TCF and Egr-1. - Highlights: • The plant polyphenol resveratrol upregulates Egr-1 expression and activity. • The stimulation of Egr-1 requires the protein kinases ERK and Raf. • Resveratrol treatment upregulates the transcriptional activation potential of Elk-1. • Resveratrol-induced stimulation of Egr-1 requires ternary complex factors. • Two distinct resveratrol-responsive elements were identified.

  6. Resveratrol upregulates Egr-1 expression and activity involving extracellular signal-regulated protein kinase and ternary complex factors

    Rössler, Oliver G.; Glatzel, Daniel; Thiel, Gerald

    2015-01-01

    Many intracellular functions have been attributed to resveratrol, a polyphenolic phytoalexin found in grapes and in other plants. Here, we show that resveratrol induces the expression of the transcription factor Egr-1 in human embryonic kidney cells. Using a chromosomally embedded Egr-1-responsive reporter gene, we show that the Egr-1 activity was significantly elevated in resveratrol-treated cells, indicating that the newly synthesized Egr-1 protein was biologically active. Stimulus-transcription coupling leading to the resveratrol-induced upregulation of Egr-1 expression and activity requires the protein kinases Raf and extracellular signal-regulated protein kinase ERK, while MAP kinase phosphatase-1 functions as a nuclear shut-off device that interrupts the signaling cascade connecting resveratrol stimulation with enhanced Egr-1 expression. On the transcriptional level, Elk-1, a key transcriptional regulator of serum response element-driven gene transcription, connects the intracellular signaling cascade elicited by resveratrol with transcription of the Egr-1 gene. These data were corroborated by the observation that stimulation of the cells with resveratrol increased the transcriptional activation potential of Elk-1. The SRE as well as the GC-rich DNA binding site of Egr-1 function as resveratrol-responsive elements. Thus, resveratrol regulates gene transcription via activation of the stimulus-regulated protein kinases Raf and ERK and the stimulus-responsive transcription factors TCF and Egr-1. - Highlights: • The plant polyphenol resveratrol upregulates Egr-1 expression and activity. • The stimulation of Egr-1 requires the protein kinases ERK and Raf. • Resveratrol treatment upregulates the transcriptional activation potential of Elk-1. • Resveratrol-induced stimulation of Egr-1 requires ternary complex factors. • Two distinct resveratrol-responsive elements were identified

  7. Egr-1 Upregulates Siva-1 Expression and Induces Cardiac Fibroblast Apoptosis

    Karin Zins

    2014-01-01

    Full Text Available The early growth response transcription factor Egr-1 controls cell specific responses to proliferation, differentiation and apoptosis. Expression of Egr-1 and downstream transcription is closely controlled and cell specific upregulation induced by processes such as hypoxia and ischemia has been previously linked to multiple aspects of cardiovascular injury. In this study, we showed constitutive expression of Egr-1 in cultured human ventricular cardiac fibroblasts, used adenoviral mediated gene transfer to study the effects of continuous Egr-1 overexpression and studied downstream transcription by Western blotting, immunohistochemistry and siRNA transfection. Apoptosis was assessed by fluorescence microscopy and flow cytometry in the presence of caspase inhibitors. Overexpression of Egr-1 directly induced apoptosis associated with caspase activation in human cardiac fibroblast cultures in vitro assessed by fluorescence microscopy and flow cytometry. Apoptotic induction was associated with a caspase activation associated loss of mitochondrial membrane potential and transient downstream transcriptional up-regulation of the pro-apoptotic gene product Siva-1. Suppression of Siva-1 induction by siRNA partially reversed Egr-1 mediated loss of cell viability. These findings suggest a previously unknown role for Egr-1 and transcriptional regulation of Siva-1 in the control of cardiac accessory cell death.

  8. High frequency of tumor cells with nuclear Egr-1 protein expression in human bladder cancer is associated with disease progression

    Egerod, Frederikke Lihme; Bartels, Annette; Fristrup, Niels; Borre, Michael; Ørntoft, Torben F; Oleksiewicz, Martin B; Brünner, Nils; Dyrskjøt, Lars

    2009-01-01

    Egr-1 (early growth response-1 transcription factor) has been proposed to be involved in invasion and metastasis processes of human bladder cancer, but Egr-1 protein expression levels in human bladder cancer have not been investigated. In the present study we investigated the expression levels of Egr-1 protein in early stages of human bladder cancer and correlated it to later progression. Expression of Egr-1 protein in human bladder cancer was examined by immunohistochemistry, on a tissue microarray constructed from tumors from 289 patients with non-muscle invasive urothelial bladder cancer. The frequency of tumor cells with nuclear Egr-1 immunolabelling correlated to bladder cancer stage, grade and to later progression to muscle-invasive bladder cancer (T2-4). Stage T1 tumors exhibited significantly higher frequencies of tumor cells with nuclear Egr-1 immunolabelling than Ta tumors (P = 0.001). Furthermore, Kaplan-Meier survival analysis showed that a high frequency of tumor cells with nuclear Egr-1 immunolabelling was significantly associated with a higher risk of progression to stage T2-4 (log-rank test, P = 0.035). Tumor cells with nuclear Egr-1 immunolabelling were found to localize at the tumor front in some of the tumor biopsies. The results from this study support a potential involvement of Egr-1 in the progression from non-muscle invasive bladder cancers to muscle invasive bladder cancer

  9. Basic calcium phosphate crystal-induced Egr-1 expression stimulates mitogenesis in human fibroblasts

    Zeng, Xiao R.; Sun Yubo; Wenger, Leonor; Cheung, Herman S.

    2005-01-01

    Previously, we have reported that basic calcium phosphate (BCP) crystals stimulate mitogenesis and synthesis of matrix metalloproteinases in cultured human foreskin and synovial fibroblasts. However, the detailed mechanisms involved are still unclear. In the present study, using RT-PCR and Egr-1 promoter analysis we showed that BCP crystals could stimulate early growth response gene Egr-1 transcription through a PKCα-dependent p44/p42 MAPK pathway. Using a retrovirus gene expression system (Clontech) to overexpress Egr-1 in human fibroblast BJ-1 cells resulted in promotion of mitogenesis measured either by MTT cell proliferation analysis or by direct cell counting. The results demonstrate that Egr-1 may play a key role in mediating BCP crystal-induced synovial fibroblast mitogenesis

  10. Analysis list: Egr1 [Chip-atlas[Archive

    Full Text Available Egr1 Blood,Liver + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Egr1.1....tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Egr1.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Eg...r1.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Egr1.Blood.tsv,http://dbarch...ive.biosciencedbc.jp/kyushu-u/mm9/colo/Egr1.Liver.tsv http://dbarchive.bioscience

  11. Beta-Defensin 2 and 3 Promote Bacterial Clearance of Pseudomonas aeruginosa by Inhibiting Macrophage Autophagy through Downregulation of Early Growth Response Gene-1 and c-FOS

    Yongjian Wu

    2018-02-01

    Full Text Available Beta-defensins 2 and 3 (BD2 and BD3 are inducible peptides present at the sites of infection, and they are well characterized for their antimicrobial activities and immune-regulatory functions. However, no study has thoroughly investigated their immunomodulatory effects on macrophage-mediated immune responses against Pseudomonas aeruginosa (PA. Here, we use THP-1 and RAW264.7 cell lines and demonstrate that BD2 and BD3 suppressed macrophage autophagy but enhanced the engulfment of PA and Zymosan bioparticles as well as the formation of phagolysosomes, using immunofluorescence staining and confocal microscopy. Plate count assay showed that macrophage-mediated phagocytosis and intracellular killing of PA were promoted by BD2 and BD3. Furthermore, microarray and real-time PCR showed that the expression of two genes, early growth response gene-1 (EGR1 and c-FOS, was attenuated by BD2 and BD3. Western blot revealed that BD2 and BD3 inhibited the expression and nuclear translocation of EGR1 and c-FOS. Knockdown of EGR1 and c-FOS by siRNA transfection suppressed macrophage autophagy before and after PA infection; while overexpression of these two transcription factors enhanced autophagy but reversed the role of BD2 and BD3 on macrophage-mediated PA eradication. Together, these results demonstrate a novel immune defense activity of BD2 and BD3, which promotes clearance of PA by inhibiting macrophage autophagy through downregulation of EGR1 and c-FOS.

  12. The immediate early gene product EGR1 and polycomb group proteins interact in epigenetic programming during chondrogenesis.

    Frank Spaapen

    Full Text Available Initiation of and progression through chondrogenesis is driven by changes in the cellular microenvironment. At the onset of chondrogenesis, resting mesenchymal stem cells are mobilized in vivo and a complex, step-wise chondrogenic differentiation program is initiated. Differentiation requires coordinated transcriptomic reprogramming and increased progenitor proliferation; both processes require chromatin remodeling. The nature of early molecular responses that relay differentiation signals to chromatin is poorly understood. We here show that immediate early genes are rapidly and transiently induced in response to differentiation stimuli in vitro. Functional ablation of the immediate early factor EGR1 severely deregulates expression of key chondrogenic control genes at the onset of differentiation. In addition, differentiating cells accumulate DNA damage, activate a DNA damage response and undergo a cell cycle arrest and prevent differentiation associated hyper-proliferation. Failed differentiation in the absence of EGR1 affects global acetylation and terminates in overall histone hypermethylation. We report novel molecular connections between EGR1 and Polycomb Group function: Polycomb associated histone H3 lysine27 trimethylation (H3K27me3 blocks chromatin access of EGR1. In addition, EGR1 ablation results in abnormal Ezh2 and Bmi1 expression. Consistent with this functional interaction, we identify a number of co-regulated targets genes in a chondrogenic gene network. We here describe an important role for EGR1 in early chondrogenic epigenetic programming to accommodate early gene-environment interactions in chondrogenesis.

  13. Egr-1 regulates autophagy in cigarette smoke-induced chronic obstructive pulmonary disease.

    Zhi-Hua Chen

    2008-10-01

    Full Text Available Chronic obstructive pulmonary disease (COPD is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. Autophagy is a degradative process involving lysosomal turnover of cellular components, though its role in human diseases remains unclear.Increased autophagy was observed in lung tissue from COPD patients, as indicated by electron microscopic analysis, as well as by increased activation of autophagic proteins (microtubule-associated protein-1 light chain-3B, LC3B, Atg4, Atg5/12, Atg7. Cigarette smoke extract (CSE is an established model for studying the effects of cigarette smoke exposure in vitro. In human pulmonary epithelial cells, exposure to CSE or histone deacetylase (HDAC inhibitor rapidly induced autophagy. CSE decreased HDAC activity, resulting in increased binding of early growth response-1 (Egr-1 and E2F factors to the autophagy gene LC3B promoter, and increased LC3B expression. Knockdown of E2F-4 or Egr-1 inhibited CSE-induced LC3B expression. Knockdown of Egr-1 also inhibited the expression of Atg4B, a critical factor for LC3B conversion. Inhibition of autophagy by LC3B-knockdown protected epithelial cells from CSE-induced apoptosis. Egr-1(-/- mice, which displayed basal airspace enlargement, resisted cigarette-smoke induced autophagy, apoptosis, and emphysema.We demonstrate a critical role for Egr-1 in promoting autophagy and apoptosis in response to cigarette smoke exposure in vitro and in vivo. The induction of autophagy at early stages of COPD progression suggests novel therapeutic targets for the treatment of cigarette smoke induced lung injury.

  14. Valsartan independent of AT1 receptor inhibits tissue factor, TLR-2 and-4 expression by regulation of Egr-1 through activation of AMPK in diabetic conditions

    Ha, Yu Mi; Park, Eun Jung; Kang, Young Jin; Park, Sang Won; Kim, Hye Jung; Chang, Ki Churl

    2014-01-01

    Patients suffering from diabetes mellitus (DM) are at a severe risk of atherothrombosis. Early growth response (Egr)-1 is well characterized as a central mediator in vascular pathophysiology. We tested whether valsartan independent of Ang II type 1 receptor (AT1R) can reduce tissue factor (TF) and toll-like receptor (TLR)-2 and-4 by regulating Egr-1 in THP-1 cells and aorta in streptozotocin-induced diabetic mice. High glucose (HG, 15 mM) increased expressions of Egr-1, TF, TLR-2 and-4 which were significantly reduced by valsartan. HG increased Egr-1 expression by activation of PKC and ERK1/2 in THP-1 cells. Valsartan increased AMPK phosphorylation in a concentration and time-dependent manner via activation of LKB1. Valsartan inhibited Egr-1 without activation of PKC or ERK1/2. The reduced expression of Egr-1 by valsartan was reversed by either silencing Egr-1, or compound C, or DN-AMPK-transfected cells. Valsartan inhibited binding of NF-κB and Egr-1 to TF promoter in HG condition. Furthermore, valsartan reduced inflammatory cytokine (TNF-α, IL-6 and IL-1β) production and NF-κB activity in HG-activated THP-1 cells. Interestingly, these effects of valsartan were not affected by either silencing AT1R in THP-1 cells or CHO cells, which were devoid of AT1R. Importantly, administration of valsartan (20 mg/kg, i.p) for 8 weeks significantly reduced plasma TF activity, expression of Egr-1, TLR-2,-4 and TF in thoracic aorta and improved glucose tolerance of streptozotocin-induced diabetic mice. Taken together, we concluded that valsartan may reduce atherothrombosis in diabetic conditions through AMPK/Egr-1 regulation. PMID:25109475

  15. Valsartan independent of AT₁ receptor inhibits tissue factor, TLR-2 and -4 expression by regulation of Egr-1 through activation of AMPK in diabetic conditions.

    Ha, Yu Mi; Park, Eun Jung; Kang, Young Jin; Park, Sang Won; Kim, Hye Jung; Chang, Ki Churl

    2014-10-01

    Patients suffering from diabetes mellitus (DM) are at a severe risk of atherothrombosis. Early growth response (Egr)-1 is well characterized as a central mediator in vascular pathophysiology. We tested whether valsartan independent of Ang II type 1 receptor (AT1R) can reduce tissue factor (TF) and toll-like receptor (TLR)-2 and -4 by regulating Egr-1 in THP-1 cells and aorta in streptozotocin-induced diabetic mice. High glucose (HG, 15 mM) increased expressions of Egr-1, TF, TLR-2 and -4 which were significantly reduced by valsartan. HG increased Egr-1 expression by activation of PKC and ERK1/2 in THP-1 cells. Valsartan increased AMPK phosphorylation in a concentration and time-dependent manner via activation of LKB1. Valsartan inhibited Egr-1 without activation of PKC or ERK1/2. The reduced expression of Egr-1 by valsartan was reversed by either silencing Egr-1, or compound C, or DN-AMPK-transfected cells. Valsartan inhibited binding of NF-κB and Egr-1 to TF promoter in HG condition. Furthermore, valsartan reduced inflammatory cytokine (TNF-α, IL-6 and IL-1β) production and NF-κB activity in HG-activated THP-1 cells. Interestingly, these effects of valsartan were not affected by either silencing AT1R in THP-1 cells or CHO cells, which were devoid of AT1R. Importantly, administration of valsartan (20 mg/kg, i.p) for 8 weeks significantly reduced plasma TF activity, expression of Egr-1, TLR-2, -4 and TF in thoracic aorta and improved glucose tolerance of streptozotocin-induced diabetic mice. Taken together, we concluded that valsartan may reduce atherothrombosis in diabetic conditions through AMPK/Egr-1 regulation. © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  16. Intermedilysin induces EGR-1 expression through calcineurin/NFAT pathway in human cholangiocellular carcinoma cells

    Susilowati, Heni; Okamura, Hirohiko; Hirota, Katsuhiko; Shono, Masayuki; Yoshida, Kaya; Murakami, Keiji; Tabata, Atsushi; Nagamune, Hideaki; Haneji, Tatsuji; Miyake, Yoichiro

    2011-01-01

    Research highlights: → ILY leads to the accumulation of [Ca 2+ ]i in the nucleus in HuCCT1 cells. → ILY induced activation of NFAT1 through a calcineurin-dependent pathway. → Calcineuri/NFAT pathway is involved in EGR-1 expression in response to ILY treatment. -- Abstract: Intermedilysin (ILY) is a cholesterol-dependent cytolysin produced by Streptococcus intermedius, which is associated with human brain and liver abscesses. Although intrahepatic bile duct cells play a valuable role in the pathogenesis of liver abscess, the molecular mechanism of ILY-treated intrahepatic bile duct cells remains unknown. In this study, we report that ILY induced a nuclear accumulation of intracellular calcium ([Ca 2+ ]i) in human cholangiocellular cells HuCCT1. We also demonstrate that 10 ng/ml ILY induced NFAT1 dephosphorylation and its nuclear translocation in HuCCT1 cells. In contrast to the result that ILY induced NF-κB translocation in human hepatic HepG2 cells, ILY did not affect NF-κB localization in HuCCT1 cells. Dephosphorylation and nuclear translocation of NFAT1 caused by ILY were prevented by [Ca 2+ ]i calcium chelator, BAPTA/AM, and calcineurin inhibitors, cyclosporine A and tacrolimus. ILY induced early growth response-1 (EGR-1) expression and it was inhibited by the pre-treatment with cyclosporine A, indicating that the calcineurin/NFAT pathway was involved in EGR-1 expression in response to ILY. ILY-induced calcineurin/NFAT1 activation and sequential EGR-1 expression might be related to the pathogenesis of S. intermedius in human bile duct cells.

  17. Intermedilysin induces EGR-1 expression through calcineurin/NFAT pathway in human cholangiocellular carcinoma cells

    Susilowati, Heni [Department of Oral Microbiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504 (Japan); Okamura, Hirohiko [Department of Histology and Oral Histology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504 (Japan); Hirota, Katsuhiko, E-mail: hirota@dent.tokushima-u.ac.jp [Department of Oral Microbiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504 (Japan); Shono, Masayuki [Support Center for Advanced Medical Sciences, The University of Tokushima, Tokushima 770-8504 (Japan); Yoshida, Kaya [Department of Fundamental Oral Health Science, School of Oral Health and Welfare, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504 (Japan); Murakami, Keiji [Department of Oral Microbiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504 (Japan); Tabata, Atsushi; Nagamune, Hideaki [Department of Biological Science and Technology, Life System, Institute of Technology and Science, The University of Tokushima Graduate School, Tokushima 770-8506 (Japan); Haneji, Tatsuji [Department of Histology and Oral Histology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504 (Japan); Miyake, Yoichiro [Department of Oral Microbiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8504 (Japan)

    2011-01-07

    Research highlights: {yields} ILY leads to the accumulation of [Ca{sup 2+}]i in the nucleus in HuCCT1 cells. {yields} ILY induced activation of NFAT1 through a calcineurin-dependent pathway. {yields} Calcineuri/NFAT pathway is involved in EGR-1 expression in response to ILY treatment. -- Abstract: Intermedilysin (ILY) is a cholesterol-dependent cytolysin produced by Streptococcus intermedius, which is associated with human brain and liver abscesses. Although intrahepatic bile duct cells play a valuable role in the pathogenesis of liver abscess, the molecular mechanism of ILY-treated intrahepatic bile duct cells remains unknown. In this study, we report that ILY induced a nuclear accumulation of intracellular calcium ([Ca{sup 2+}]i) in human cholangiocellular cells HuCCT1. We also demonstrate that 10 ng/ml ILY induced NFAT1 dephosphorylation and its nuclear translocation in HuCCT1 cells. In contrast to the result that ILY induced NF-{kappa}B translocation in human hepatic HepG2 cells, ILY did not affect NF-{kappa}B localization in HuCCT1 cells. Dephosphorylation and nuclear translocation of NFAT1 caused by ILY were prevented by [Ca{sup 2+}]i calcium chelator, BAPTA/AM, and calcineurin inhibitors, cyclosporine A and tacrolimus. ILY induced early growth response-1 (EGR-1) expression and it was inhibited by the pre-treatment with cyclosporine A, indicating that the calcineurin/NFAT pathway was involved in EGR-1 expression in response to ILY. ILY-induced calcineurin/NFAT1 activation and sequential EGR-1 expression might be related to the pathogenesis of S. intermedius in human bile duct cells.

  18. Estrogen-induced transcription factor EGR1 regulates c-Kit transcription in the mouse uterus to maintain uterine receptivity for embryo implantation.

    Park, Mira; Kim, Hye-Ryun; Kim, Yeon Sun; Yang, Seung Chel; Yoon, Jung Ah; Lyu, Sang Woo; Lim, Hyunjung Jade; Hong, Seok-Ho; Song, Haengseok

    2018-07-15

    Early growth response 1 (Egr1) is a key transcription factor that mediates the action of estrogen (E 2 ) to establish uterine receptivity for embryo implantation. However, few direct target genes of EGR1 have been identified in the uterus. Here, we demonstrated that E 2 induced EGR1-regulated transcription of c-Kit, which plays a crucial role in cell fate decisions. Spatiotemporal expression of c-Kit followed that of EGR1 in uteri of ovariectomized mice at various time points after E 2 treatment. E 2 activated ERK1/2 and p38 to induce EGR1, which then activated c-Kit expression in the uterus. EGR1 transfection produced rapid and transient induction of c-KIT in a time- and dose-dependent manner. Furthermore, luciferase assays to measure c-Kit promoter activity confirmed that a functional EGR1 binding site(s) (EBS) was located within -1 kb of the c-Kit promoter. Site-directed mutagenesis and chromatin immunoprecipitation-PCR for three putative EBS within -1 kb demonstrated that the EBS at -818/-805 was critical for EGR1-dependent c-Kit transcription. c-Kit expression was significantly increased in the uterus on day 4 and administration of Masitinib, a c-Kit inhibitor, effectively interfered with embryo implantation. Collectively, our results showed that estrogen induces transcription factor EGR1 to regulate c-Kit transcription for uterine receptivity for embryo implantation in the mouse uterus. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Atherogenic ω-6 Lipids Modulate PPAR- EGR-1 Crosstalk in Vascular Cells

    Jia Fei

    2011-01-01

    Full Text Available Atherogenic ω-6 lipids are physiological ligands of peroxisome proliferator-activated receptors (PPARs and elicit pro- and antiatherogenic responses in vascular cells. The objective of this study was to investigate if ω-6 lipids modulated the early growth response-1 (Egr-1/PPAR crosstalk thereby altering vascular function. Rat aortic smooth muscle cells (RASMCs were exposed to ω-6 lipids, linoleic acid (LA, or its oxidized form, 13-HPODE (OxLA in the presence or absence of a PPARα antagonist (MK886 or PPARγ antagonist (GW9662 or PPAR-specific siRNA. Our results demonstrate that ω-6 lipids, induced Egr-1 and monocyte chemotactic protein-1 (MCP-1 mRNA and protein levels at the acute phase (1–4 hrs when PPARα was downregulated and at subacute phase (4–12 hrs by modulating PPARγ, thus resulting in altered monocyte adhesion to RASMCs. We provide novel insights into the mechanism of action of ω-6 lipids on Egr-1/PPAR interactions in vascular cells and their potential in altering vascular function.

  20. File list: Oth.Bld.10.Egr1.AllCell [Chip-atlas[Archive

    Full Text Available Oth.Bld.10.Egr1.AllCell mm9 TFs and others Egr1 Blood SRX122513,SRX122511,SRX122510...,SRX122512 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.10.Egr1.AllCell.bed ...

  1. File list: Oth.ALL.50.Egr1.AllCell [Chip-atlas[Archive

    Full Text Available Oth.ALL.50.Egr1.AllCell mm9 TFs and others Egr1 All cell types SRX204724,SRX122513,...SRX122511,SRX122510,SRX122512 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.ALL.50.Egr1.AllCell.bed ...

  2. File list: Oth.Bld.05.Egr1.AllCell [Chip-atlas[Archive

    Full Text Available Oth.Bld.05.Egr1.AllCell mm9 TFs and others Egr1 Blood SRX122511,SRX122510,SRX122512...,SRX122513 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.05.Egr1.AllCell.bed ...

  3. In vivo oestrogenic modulation of Egr1 and Pitx1 gene expression in female rat pituitary gland.

    Gajewska, Alina; Herman, Andrzej P; Wolińska-Witort, Ewa; Kochman, Kazimierz; Zwierzchowski, Lech

    2014-12-01

    EGR1 and PITX1 are transcription factors required for gonadotroph cell Lhb promoter activation. To determine changes in Egr1 and Pitx1 mRNA levels in central and peripheral pituitary stimulations, an in vivo model based on i.c.v. pulsatile (1 pulse/0.5 h over 2 h) GnRH agonist (1.5 nM buserelin) or antagonist (2 nM antide) microinjections was used. The microinjections were given to ovariectomised and 17β-oestradiol (E2) (3×20 μg), ERA (ESR1) agonist propyl pyrazole triol (PPT) (3×0.5 mg), ERB (ESR2) agonist diarylpropionitrile (DPN) (3×0.5 mg) s.c. pre-treated rats 30 min after last pulse anterior pituitaries were excised. Relative mRNA expression was determined by quantitative RT-PCR (qRT-PCR). Results revealed a gene-specific response for GnRH and/or oestrogenic stimulations in vivo. Buserelin pulses enhanced Egr1 expression by 66% in ovariectomised rats, whereas the oestradiol-supplemented+i.c.v. NaCl-microinjected group showed a 50% increase in Egr1 mRNA expression. The oestrogenic signal was transmitted via ERA (ESR1) and ERB (ESR2) activation as administration of PPT and DPN resulted in 97 and 62%, respectively, elevation in Egr1 mRNA expression. A synergistic action of GnRH agonist and 17β-oestradiol (E2) stimulation of the Egr1 gene transcription in vivo were found. GnRHR activity did not affect Pitx1 mRNA expression; regardless of NaCl, buserelin or antide i.c.v. pulses, s.c. oestrogenic supplementation (with E2, PPT or DPN) consistently decreased (by -46, -48 and -41% respectively) the Pitx1 mRNA in the anterior pituitary gland. Orchestrated Egr1 and Pitx1 activities depending on specific central and peripheral regulatory inputs could be responsible for physiologically variable Lhb gene promoter activation in vivo. © 2014 Society for Endocrinology.

  4. Early growth response protein 1 (EGR1) regulates pro-inflammatory gene expression in response to palmitate and TNF alpha in human placenta cells and is induced in obese placenta

    Maternal obesity has been hypothesized to induce a pro-inflammatory response in the placenta. However, the specific factors contributing to this pro-infalmmatory response are yet to be determined. Our objective was to examine the effects of palmitic acid (PA), tumor necrosis factor alpha (TNF alph...

  5. Apelin-13 upregulates Egr-1 expression in rat vascular smooth muscle cells through the PI3K/Akt and PKC signaling pathways

    Liu, Qi-Feng [Department of Cardiology, The First Affiliated Hospital of Liaoning Medical University, Jinzhou 121001 (China); Yu, Hong-Wei [Department of Cardiology, Jinzhou Central Hospital, Jinzhou 121001 (China); Sun, Li-Li [Department of Ophthalmology, The Third Affiliated Hospital of Liaoning Medical University, Jinzhou 121001 (China); You, Lu; Tao, Gui-Zhou [Department of Cardiology, The First Affiliated Hospital of Liaoning Medical University, Jinzhou 121001 (China); Qu, Bao-Ze, E-mail: qubaoze1971@hotmail.com [Department of Cardiology, The First Affiliated Hospital of Liaoning Medical University, Jinzhou 121001 (China)

    2015-12-25

    Previous studies have shown that Apelin-13 upregulates early growth response factor-1 (Egr-1) via the extracellular signal-regulated protein kinase (ERK) signaling pathway. Apelin-13 induces proliferation and migration of vascular smooth muscle cells (VSMCs) as well as the upregulation of osteopontin (OPN) via the upregulation of Egr-1. This study was designed to further explore the activity of Apelin-13 in VSMCs by investigating members of the mitogen-activated protein kinase (MAPK) family, in particular Jun kinase (JNK) and p38 mitogen-activated protein kinase (P38). We also examined whether the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) and protein kinase C (PKC) signaling pathways were involved in the regulation of Egr-1 by Apelin-13. We treated rat aortic VSMCs with Apelin-13 and examined the expression of JNK, p-JNK, P38, and p-P38 to investigate whether Apelin-13-mediated increases in Egr-1 occurred through the JNK and P38 signaling pathways. We then pretreated VSMCs with the Gi protein inhibitor pertussis toxin (PTX) and the Gq inhibitor YM254890, added Apelin-13 and looked for changes in Egr-1 expression. Finally, we pretreated with the PI3K inhibitor LY294002 and the PKC inhibitor GF109203X, and treated with Apelin-13. Our results showed that JNK and P38 did not participate in Apelin-13-mediated increase in Egr-1. Instead, Apelin-13 upregulation of Egr-1 was mediated by a PTX-sensitive Gi protein. Apelin-13 did increase ERK phosphorylation through the PI3K/Akt and PKC signaling pathways, resulting in changes in Egr-1 expression. These data provide important targets for future studies to modulate vascular remodeling. - Highlights: • Apelin-13 mediates Egr-1 upregulation in vascular smooth muscle cells via ERK1/2. • The underlying mechanisms are unknown, but exclude Jnk or p38 pathway activation. • Apelin-13 binds to Gi, activating the PI3K/Akt and PKC signaling cascades. • Consequent ERK phosphorylation results in increased Egr-1

  6. Feasibility of a novel positive feedback effect of 131I-promoted Bac-Egr1-hNIS expression in malignant glioma via baculovirus

    Guo Rui; Tian Lipeng; Han Bing; Xu Haoping; Zhang Miao; Li Biao

    2011-01-01

    Purpose: As intracellular iodine is released rapidly, increased expression of sodium/iodide symporter (NIS) is required for effective radioiodine treatment of tumor. As Egr1 promoter is activated by 131 I and may promote human NIS (hNIS) expression, hNIS also induces 131 I uptake and activates Egr1, so the existence of a positive feedback effect of 131 I-promoted Egr1-hNIS expression is possible. Our purpose was to investigate the possible existence of this positive feedback effect through a series of in vitro pioneer studies. Method: Recombinant baculovirus (Bac-Egr1-hNIS) encoding the hNIS gene under the control of a radiation-inducible Egrl promoter was constructed. To test 131 I-promoted hNIS expression, human malignant glioma U87 cells were transfected with Bac-Egr1-hNIS, stimulated with or without 131 I; the expression of hNIS protein was detected by immunofluorescence and flow cytometry test. In addition, the uptake and efflux of 131 I were determined after the incubation of Bac-Egr1-hNIS-transfected U87 cells with or without 131 I. Results: Immunocytochemical staining and flow cytometry test showed a higher hNIS protein expression in Bac-Egr1-hNIS-transfected U87 cells with 131 I stimulation than in cells without stimulation. Bac-Egr1-hNIS-transfected U87 cells accumulated up to about 4.05 times of 131 I after 131 I stimulation. The amount of 131 I uptake in both groups showed a baculovirus dose-dependent manner. However, rapid efflux of radioactivity was observed in both groups, with 50% lost during the first 2 min after the 131 I-containing medium had been replaced by a nonradioactive medium. Conclusion: Our results indicated that an improved transgene expression of 131 I-stimulated hNIS in U87 cells using a baculovirus vector containing the Egr1 promoter is possible, and the increased expression of hNIS is responsible for a higher 131 I uptake. It might provide a reference for the existence of a positive feedback effect in 131 I-promoted Bac-Egr1-h

  7. Apelin-13 upregulates Egr-1 expression in rat vascular smooth muscle cells through the PI3K/Akt and PKC signaling pathways

    Liu, Qi-Feng; Yu, Hong-Wei; Sun, Li-Li; You, Lu; Tao, Gui-Zhou; Qu, Bao-Ze

    2015-01-01

    Previous studies have shown that Apelin-13 upregulates early growth response factor-1 (Egr-1) via the extracellular signal-regulated protein kinase (ERK) signaling pathway. Apelin-13 induces proliferation and migration of vascular smooth muscle cells (VSMCs) as well as the upregulation of osteopontin (OPN) via the upregulation of Egr-1. This study was designed to further explore the activity of Apelin-13 in VSMCs by investigating members of the mitogen-activated protein kinase (MAPK) family, in particular Jun kinase (JNK) and p38 mitogen-activated protein kinase (P38). We also examined whether the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) and protein kinase C (PKC) signaling pathways were involved in the regulation of Egr-1 by Apelin-13. We treated rat aortic VSMCs with Apelin-13 and examined the expression of JNK, p-JNK, P38, and p-P38 to investigate whether Apelin-13-mediated increases in Egr-1 occurred through the JNK and P38 signaling pathways. We then pretreated VSMCs with the Gi protein inhibitor pertussis toxin (PTX) and the Gq inhibitor YM254890, added Apelin-13 and looked for changes in Egr-1 expression. Finally, we pretreated with the PI3K inhibitor LY294002 and the PKC inhibitor GF109203X, and treated with Apelin-13. Our results showed that JNK and P38 did not participate in Apelin-13-mediated increase in Egr-1. Instead, Apelin-13 upregulation of Egr-1 was mediated by a PTX-sensitive Gi protein. Apelin-13 did increase ERK phosphorylation through the PI3K/Akt and PKC signaling pathways, resulting in changes in Egr-1 expression. These data provide important targets for future studies to modulate vascular remodeling. - Highlights: • Apelin-13 mediates Egr-1 upregulation in vascular smooth muscle cells via ERK1/2. • The underlying mechanisms are unknown, but exclude Jnk or p38 pathway activation. • Apelin-13 binds to Gi, activating the PI3K/Akt and PKC signaling cascades. • Consequent ERK phosphorylation results in increased Egr-1

  8. Context-Dependent Egr1 Expression in the Avian Hippocampus.

    Grella, Stephanie L; Guigueno, Mélanie F; White, David J; Sherry, David F; Marrone, Diano F

    2016-01-01

    In mammals, episodic memory and spatial cognition involve context-specific recruitment of unique ensembles in the hippocampal formation (HF). Despite their capacity for sophisticated spatial (e.g., for migration) and episodic-like (e.g., for food-caching) memory, the mechanisms underlying contextual representation in birds is not well understood. Here we demonstrate environment-specific Egr1 expression as male brown-headed cowbirds (Molothrus ater) navigate environments for food reward, showing that the avian HF, like its mammalian counterpart, recruits distinct neuronal ensembles to represent different contexts.

  9. Variation in social relationships relates to song preferences and EGR1 expression in a female songbird.

    Schubloom, Hannah E; Woolley, Sarah C

    2016-09-01

    Social experiences can profoundly shape social behavior and the underlying neural circuits. Across species, the formation of enduring social relationships is associated with both neural and behavioral changes. However, it remains unclear how longer-term relationships between individuals influence brain and behavior. Here, we investigated how variation in social relationships relates to variation in female preferences for and neural responses to song in a pair-bonding songbird. We assessed variation in the interactions between individuals in male-female zebra finch pairs and found that female preferences for their mate's song were correlated with the degree of affiliation and amount of socially modulated singing, but not with the frequency of aggressive interactions. Moreover, variation in measures of pair quality and preference correlated with variation in the song-induced expression of EGR1, an immediate early gene related to neural activity and plasticity, in brain regions important for auditory processing and social behavior. For example, females with weaker preferences for their mate's song had greater EGR1 expression in the nucleus Taeniae, the avian homologue of the mammalian medial amygdala, in response to playback of their mate's courtship song. Our data indicate that the quality of social interactions within pairs relates to variation in song preferences and neural responses to ethologically relevant stimuli and lend insight into neural circuits sensitive to social information. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1029-1040, 2016. © 2016 Wiley Periodicals, Inc.

  10. Egr-1 activation by cancer-derived extracellular vesicles promotes endothelial cell migration via ERK1/2 and JNK signaling pathways.

    Yae Jin Yoon

    Full Text Available Various mammalian cells, including cancer cells, shed extracellular vesicles (EVs, also known as exosomes and microvesicles, into surrounding tissues. These EVs play roles in tumor growth and metastasis by promoting angiogenesis. However, the detailed mechanism of how cancer-derived EVs elicit endothelial cell activation remains unknown. Here, we provide evidence that early growth response-1 (Egr-1 activation in endothelial cells is involved in the angiogenic activity of colorectal cancer cell-derived EVs. Both RNA interference-mediated downregulation of Egr-1 and ERK1/2 or JNK inhibitor significantly blocked EV-mediated Egr-1 activation and endothelial cell migration. Furthermore, lipid raft-mediated endocytosis inhibitor effectively blocked endothelial Egr-1 activation and migration induced by cancer-derived EVs. Our results suggest that Egr-1 activation in endothelial cells may be a key mechanism involved in the angiogenic activity of cancer-derived EVs. These findings will improve our understanding regarding the proangiogenic activities of EVs in diverse pathological conditions including cancer, cardiovascular diseases, and neurodegenerative diseases.

  11. Klotho down-regulates Egr-1 by inhibiting TGF-β1/Smad3 signaling in high glucose treated human mesangial cells

    Li, Yang; Hu, Fang; Xue, Meng; Jia, Yi-Jie; Zheng, Zong-Ji; Wang, Ling; Guan, Mei-Ping; Xue, Yao-Ming

    2017-01-01

    Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease worldwide and is associated with glomerular mesangial cell (MC) proliferation and excessive extracellular matrix (ECM) production. Klotho can attenuate renal fibrosis in part by inhibiting TGF-β1/Smad3 signaling in DKD. Early growth response factor 1 (Egr-1) has been shown to play a key role in renal fibrosis in part by facilitating the formation of a positive feedback loop involving TGF-β1. However, whether Klotho down-regulates Egr-1 by inhibiting TGF-β1/Smad3 signaling in DKD is unclear. In the present study, we assessed human MCs that were incubated under high-glucose conditions to mimic diabetes. Then, we transfected the cells with Klotho plasmid or siRNA to overexpress or knock down Klotho gene and protein expression. Klotho, Egr-1, fibronectin (FN), collagen type I (Col I), Smad3 and phosphorylated Smad3 (p-Smad3) gene and protein expression levels were determined by RT-qPCR and western blotting respectively. High glucose time-dependently down-regulated Klotho mRNA and protein expression in cultured human MCs. pcDNA3.1-Klotho transfection-mediated Klotho overexpression down-regulated Egr-1, FN and Col I expression and the p-Smad3/Smad3 ratio in human MCs. Conversely, siRNA-mediated Klotho silencing up-regulated Egr-1, FN, and Col I expression and the p-Smad3/Smad3 ratio. Moreover, the effects of si-Klotho on Egr-1 expression were abolished by the TGF-β1 inhibitor SB-431542. Klotho overexpression can prevent mesangial ECM production in high-glucose-treated human MCs, an effect that has been partially attributed to Egr-1 down-regulation facilitated by TGF-β1/Smad3 signaling inhibition. - Highlights: • High glucose time-dependently down-regulated Klotho mRNA and protein expression in cultured human MCs. • Klotho overexpression down-regulated Egr-1 and prevented mesangial ECM production in high-glucose-treated human MCs. • Klotho down-regulated Egr-1 by inhibiting

  12. Construction of Egr1-mediated human truncated apoptosis inducing factor expression vector and its expression regularity induced by radiation in breast cancer MCF-7 cells

    Wang Jianfeng; Gong Shouliang; Wang Zhicheng; Fang Fang; Liu Yang; Wu Jiahui

    2012-01-01

    Objective: To clone human truncated apoptosis inducing factor (AIF) cDNA sequence, and to construct early growth response 1 (Egr1)-mediated recombinant expression vector pcDNA 3.1-Egr1-AIF Δ1-480 (pEgr1-AIFΔ 1-480 ), and to observe its regularity induced by radiation in human breast cancer MCF-7 cells. Methods: The total mRNA extracted from human leukemia Jurkat cells used as template, and the human AIFΔ 1-480 was acquired by RT-PCR, and it was linked to pMD18T vector for sequencing. Egr1 fragment was digested from pMD19T-Egr1 by restrictive enzyme, and the Egr1-mediated expression plasmid pEgr1-AIFΔ 1-480 was constructed by gene recombination. There were control group, pcDNA3.1 group, pAIFΔ 1-480 group and pEgr1-AIFΔ 1-480 group in the experiment. After the plasmids in various groups were transfected into human breast cancer MCF-7 cells, the AIF and AIFΔ 1-480 protein expression time-effect (0, 2, 4, 12, 24 and 48 h after 2.0 Gy irradiation) and dose-effect (24 h after 0, 0.2, 0.5, 1.0, 2.0 and 5.0 Gy irradiation) regularity were measured by Western blotting method. Results: The sequencing results showed that the AIFΔ 1-480 acquired by RT-PCR was consistent with the sequence expected, the pEgr-AIFΔ 1-480 was confirmed by PCR and restrictive enzyme digestion. After 0-48 h the MCF-7 cells were irradiated by 2.0 Gy, and the AIF protein expressed in the cells in each group, and it increased significantly from 4 h and the AIF expressions in 4, 12, 24 and 48 h groups were higher than that in 0 h group (P<0.05), and it reached to maximum value at 48 h. But the AIFΔ 1-480 protein expressed in the cells in pAIFΔ 1-480 and pEgr1-AIFΔ 1-480 groups from 2 h (P<0.05), and it reached to peak value at 24 h. The AIFΔ 1-480 expressions in pEgr1-AIFΔ 1-480 group were higher than those in pAIFΔ 1-480 group at and 48 h (P<0.05). After the MCF-7 cells were irradiated by 0-5 Gy for 24 h, the AIF protein expressed in the cells in each group, but the AIFΔ 1-480 protein

  13. TRAIL overexpression co-regulated by Egr1 and HRE enhances radiosensitivity of hypoxic A549 cells depending on its apoptosis inducing role.

    Yang, Yan-Ming; Fang, Fang; Li, Xin; Yu, Lei; Wang, Zhi-Cheng

    2017-01-01

    Ionizing radiation can upregulate the expression levels of TRAIL and enhance tumor cell apoptosis. While Early growth response 1 (Egr1) gene promoter has radiation inducible characteristics, the expression for exogenous gene controlled by Egr1 promoter could be enhanced by ionizing radiation, but its efficiency is limited by tissue hypoxia. Hypoxia response elements (HREs) are important hypoxic response regulatory sequences and sensitivity enhancers. Therefore, we chose TRAIL as the gene radiotherapy to observe whether it is regulated by Egr1 and HER and its effects on A549 cells and its mechanism. The pcDNA3.1-Egr1-TRAIL (pc-E-hsT) and pcDNA3.1-HRE/Egr1-TRAIL (pc-H/E-hsT) plasmids containing Egr1-hsTRAIL and HRE/Egr1-hsTRAIL were transfected into A549 cells, the cells were treated by hypoxia and radiation. The TRAIL mRNA in the cells and protein concentration in the culture supernatants were measured by RT-PCR and ELISA, respectively. Mean lethal dose D0 value was evaluated with colony forming assay. The cell apoptotic rates were analyzed by FCM and TUNEL assay. Expression of DR4, DR5 and cleaved caspase-3 proteins were analyzed by western blotting. It showed that TRAIL mRNA expression and TRAIL concentration all significantly increased under hypoxia and/or radiation. D0 value of pc-H/E‑hsT transfected cells under hypoxia was lowest, indicating more high radiosensitivity. Hypoxia could not cause the pc-E-hsT transfected cell apoptotic rate increase, but there were promoting effects in pc-H/E-hsT transfected cells. DR4 had not obvious change in pc-E-hsT and pc-H/E-hsT transfected cells under normoxic and hypoxic condition, otherwise, DR5 and cleaved caspase-3 increased mostly in pc-H/E-hsT transfected cells under hypoxic condition. TRAIL overexpression was co-regulated by Egr1 and HRE. TRAIL might promote hypoxic A549 cell radiosensitivity and induce apoptosis depending on DR5 to caspase-3 pathways.

  14. Regulation of glucose transport and c-fos and egr-1 expression in cells with mutated or endogenous growth hormone receptors

    Gong, T W; Meyer, D J; Liao, J

    1998-01-01

    To identify mechanisms by which GH receptors (GHR) mediate downstream events representative of growth and metabolic responses to GH, stimulation by GH of c-fos and egr-1 expression and glucose transport activity were examined in Chinese hamster ovary (CHO) cells expressing mutated GHR. In CHO cel...

  15. γ-Oryzanol suppresses COX-2 expression by inhibiting reactive oxygen species-mediated Erk1/2 and Egr-1 signaling in LPS-stimulated RAW264.7 macrophages.

    Shin, Soon Young; Kim, Heon-Woong; Jang, Hwan-Hee; Hwang, Yu-Jin; Choe, Jeong-Sook; Kim, Jung-Bong; Lim, Yoongho; Lee, Young Han

    2017-09-16

    Cyclooxygenase (COX)-2 produces prostanoids, which contribute to inflammatory responses. Nuclear factor (NF)-κB is a key transcription factor mediating COX-2 expression. γ-Oryzanol is an active component in rice bran oil, which inhibits lipopolysaccharide (LPS)-mediated COX-2 expression by inhibiting NF-κB. However, the inhibition of COX-2 expression by γ-oryzanol independently of NF-κB is poorly understood. We found that LPS upregulated Egr-1 expression at the transcriptional level. Forced expression of Egr-1 trans-activated the Cox-2 promoter independently of NF-κB. In contrast, silencing of Egr-1 abrogated LPS-mediated COX-2 expression. LPS produced reactive oxygen species (ROS), which, in turn, induced Egr-1 expression via the Erk1/2 MAPK pathway. ROS scavenging activity of γ-oryzanol suppressed Egr-1 expression by inhibiting the Erk1/2 MAPK pathway. Our results suggest that γ-oryzanol inhibits LPS-mediated COX-2 expression by suppressing Erk1/2-mediated Egr-1 expression. This study supports that γ-oryzanol may be useful for ameliorating LPS-mediated inflammatory responses. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Expression and prognostic value of EGR1 and EGR3 in gliomas

    Møldrup Knudsen, Arnon

    Introduction Gliomas are the most frequent primary brain tumors. For the most malignant glioma – the glioblastoma - the median survival is below 15 months. Since only few prognostic biomarkers are of benefit in daily practice, new markers are urgently needed. EGR1 and EGR3 are transcription factors...... involved in the regulation of cell-cycle, but they have also been associated with the migration of cancer cells. Studies have shown prognostic potential of EGR1 and EGR3 in breast-, gastric-, colorectal-, and prostate cancer. The purpose of this study was to investigate the expression and potential....... Cox proportional hazards regression showed that a high EGR1 fraction remained a significant prognostic variable when adjusted for confounders, both in all gliomas as one group (P=0.048) and glioblastomas exclusively (P=0.011). The combination of EGR1 high/EGR3 low in glioblastomas also remained...

  17. Inhibition of cell growth by EGR-1 in human primary cultures from malignant glioma

    Gagliardi Franco

    2004-01-01

    Full Text Available Abstract Background The aim of this work was to investigate in vitro the putative role of EGR-1 in the growth of glioma cells. EGR-1 expression was examined during the early passages in vitro of 17 primary cell lines grown from 3 grade III and from 14 grade IV malignant astrocytoma explants. The explanted tumors were genetically characterized at the p53, MDM2 and INK4a/ARF loci, and fibronectin expression and growth characteristics were examined. A recombinant adenovirus overexpressing EGR-1 was tested in the primary cell lines. Results Low levels of EGR-1 protein were found in all primary cultures examined, with lower values present in grade IV tumors and in cultures carrying wild-type copies of p53 gene. The levels of EGR-1 protein were significantly correlated to the amount of intracellular fibronectin, but only in tumors carrying wild-type copies of the p53 gene (R = 0,78, p = 0.0082. Duplication time, plating efficiency, colony formation in agarose, and contact inhibition were also altered in the p53 mutated tumor cultures compared to those carrying wild-type p53. Growth arrest was achieved in both types of tumor within 1–2 weeks following infection with a recombinant adenovirus overexpressing EGR-1 but not with the control adenovirus. Conclusions Suppression of EGR-1 is a common event in gliomas and in most cases this is achieved through down-regulation of gene expression. Expression of EGR-1 by recombinant adenovirus infection almost completely abolishes the growth of tumor cells in vitro, regardless of the mutational status of the p53 gene.

  18. IL-1beta signals through the EGF receptor and activates Egr-1 through MMP-ADAM.

    Estella Sanchez-Guerrero

    Full Text Available The immediate-early gene Egr-1 controls the inducible expression of many genes implicated in the pathogenesis of a range of vascular disorders, yet our understanding of the mechanisms controlling the rapid expression of this prototypic zinc finger transcription factor is poor. Here we show that Egr-1 expression induced by IL-1beta is dependent on metalloproteinases (MMP and a disintegrin and a metalloproteinase (ADAM. Pharmacologic MMP/ADAM inhibitors and siRNA knockdown prevent IL-1beta induction of Egr-1. Further, IL-1beta activates Egr-1 via the epidermal growth factor receptor (EGFR. This is blocked by EGFR tyrosine kinase inhibition and EGFR knockdown. IL-1beta induction of Egr-1 expression is reduced in murine embryonic fibroblasts (mEFs deficient in ADAM17 despite unbiased expression of EGFR and IL-1RI in ADAM17-deficient and wild-type mEFs. Finally, we show that IL-1beta-inducible wound repair after mechanical injury requires both EGFR and MMP/ADAM. This study reports for the first time that Egr-1 induction by IL-1beta involves EGFR and MMP/ADAM-dependent EGFR phosphorylation.

  19. Study on cloning of the Egr-1 promoter and its radiation-inducible property

    Wu Congmei; Li Xiuyi; Liu Shuzheng

    2001-01-01

    Objective: Egr-1 promoter was amplified and Egr-PGL plasmid was constructed to study the expression of luciferase in transfected NIH3T3 cells after different doses of X-ray irradiation. Methods: Egr-1p was amplified by PCR and inserted into PGL3-E vector. The expression of luciferase induced by X-ray was studied by counting the light of luciferase and substrate. Results: Egr-1 cDNA was obtained by PCR and was sequenced. The results indicated the sequence was almost correct. The Egr-1p was connected with PGL3 vector and was detected by electrophoresis. The constructs were used to transfect mouse NIH3T3 cells to characterize the regulatory function of Egr-1p after exposure to X-ray irradiation. The results indicate that the expression of luciferase of all groups irradiated is higher than that of 0 Gy group. The expression of groups irradiated is about 5-7.5 times greater than that of 0 Gy group. Conclusion: Egr-1p obtained can induce the expression of its downstream gene after different doses of X-ray irradiation. Low dose irradiation also can do it and it is may be more important in tumor gene therapy

  20. pH Modulates the Binding of EGR1 Transcription Factor to DNA

    Mikles, David C.; Bhat, Vikas; Schuchardt, Brett J.; Deegan, Brian J.; Seldeen, Kenneth L.; McDonald, Caleb B.; Farooq, Amjad

    2013-01-01

    EGR1 transcription factor orchestrates a plethora of signaling cascades involved in cellular homeostasis and its down-regulation has been implicated in the development of prostate cancer. Herein, using a battery of biophysical tools, we show that the binding of EGR1 to DNA is tightly regulated by solution pH. Importantly, the binding affinity undergoes an enhancement of more than an order of magnitude with increasing pH from 5 to 8, implying that the deprotonation of an ionizable residue accounts for such behavior. This ionizable residue is identified as H382 by virtue of the fact that its substitution to non-ionizable residues abolishes pH-dependence of the binding of EGR1 to DNA. Notably, H382 inserts into the major groove of DNA and stabilizes the EGR1-DNA interaction via both hydrogen bonding and van der Waals contacts. Remarkably, H382 is predominantly conserved across other members of EGR1 family, implying that histidine protonation-deprotonation may serve as a molecular switch for modulating protein-DNA interactions central to this family of transcription factors. Collectively, our findings uncover an unexpected but a key step in the molecular recognition of EGR1 family of transcription factors and suggest that they may act as sensors of pH within the intracellular environment. PMID:23718776

  1. Construction of recombinant adenovirus with Egr-1 promoter and Smad7 cDNA and study of the Egr-1 promoter's biological activity

    Cai Xuwei; Fu Xiaolong; Yang Jian; Song Houyan

    2005-01-01

    Objective: To construct a recombinant replication-defective adenovirus containing Egr-1 promoter and Smad7 cDNA, then to evaluate the biological activity of Egr-1 promoter. Methods: Based on Adeno- X TM expression system, CMV promoter of the pShuttle vector was replaced by Egr-1 promoter, and the Smad7 cDNA was subcloned into the MCS(multiple cloning site) of pShuttle. The recombinant pShuttle was then sub-cloned into the Adeno-X TM genome, which was transformed into E. coli to get recombinant Adeno-X TM plasmid DNA. The recombinant adenovirus was packaged and amplified in the transfected HEK293 cells before it was purified and tested for viral titer. The fibroblasts (3T6 cells) infected by the recombinant adenovirus were irradiated , and the activity of Egr-1 promoter was quantitively determined by the amount of Smad7 protein expressed in the 3T6 cells using Western blot. Results: Identified by restriction endonuclease analysis and PCR, the recombinant adenovirus containing Egr-1 promoter and Smad7 cDNA was constructed successfully, with a viral titer of 1.0 x 10 11 TCID 50 /ml. The expressed amount of Smad7 protein varied at different dose levels and different time points post-irradiation in the 3T6 cells infected with the recombinant adenovirus. The amount of Smad7 protein increased along with the rising of the irradiation dose, and remained at a high expression level from 8 Gy to 15 Gy. The amount of Smad7 protein started to increase at 2 hours post-irradiation, and maintained a relatively high level for the next 5 hours before it descended, which was not observed in the control 3T6 cells. Conclusions: With the aid of Adeno-X TM expression system and molecular cloning techniques, construction of recombinant adenovirus could be quick and efficient. The recombined Egr-1 promoter has the activity of regulating the expression of downstream Smad7 cDNA. The increase in Smad7 expression under control of Egr-1 promoter induced by ionizing radiation is time- and dose

  2. The transcription factor EGR1 localizes to the nucleolus and is linked to suppression of ribosomal precursor synthesis.

    Ponti, Donatella; Bellenchi, Gian Carlo; Puca, Rosa; Bastianelli, Daniela; Maroder, Marella; Ragona, Giuseppe; Roussel, Pascal; Thiry, Marc; Mercola, Dan; Calogero, Antonella

    2014-01-01

    EGR1 is an immediate early gene with a wide range of activities as transcription factor, spanning from regulation of cell growth to differentiation. Numerous studies show that EGR1 either promotes the proliferation of stimulated cells or suppresses the tumorigenic growth of transformed cells. Upon interaction with ARF, EGR1 is sumoylated and acquires the ability to bind to specific targets such as PTEN and in turn to regulate cell growth. ARF is mainly localized to the periphery of nucleolus where is able to negatively regulate ribosome biogenesis. Since EGR1 colocalizes with ARF under IGF-1 stimulation we asked the question of whether EGR1 also relocate to the nucleolus to interact with ARF. Here we show that EGR1 colocalizes with nucleolar markers such as fibrillarin and B23 in the presence of ARF. Western analysis of nucleolar extracts from HeLa cells was used to confirm the presence of EGR1 in the nucleolus mainly as the 100 kDa sumoylated form. We also show that the level of the ribosomal RNA precursor 47S is inversely correlated to the level of EGR1 transcripts. The EGR1 iseffective to regulate the synthesis of the 47S rRNA precursor. Then we demonstrated that EGR1 binds to the Upstream Binding Factor (UBF) leading us to hypothesize that the regulating activity of EGR1 is mediated by its interaction within the transcriptional complex of RNA polymerase I. These results confirm the presence of EGR1 in the nucleolus and point to a role for EGR1 in the control of nucleolar metabolism.

  3. The transcription factor EGR1 localizes to the nucleolus and is linked to suppression of ribosomal precursor synthesis.

    Donatella Ponti

    Full Text Available EGR1 is an immediate early gene with a wide range of activities as transcription factor, spanning from regulation of cell growth to differentiation. Numerous studies show that EGR1 either promotes the proliferation of stimulated cells or suppresses the tumorigenic growth of transformed cells. Upon interaction with ARF, EGR1 is sumoylated and acquires the ability to bind to specific targets such as PTEN and in turn to regulate cell growth. ARF is mainly localized to the periphery of nucleolus where is able to negatively regulate ribosome biogenesis. Since EGR1 colocalizes with ARF under IGF-1 stimulation we asked the question of whether EGR1 also relocate to the nucleolus to interact with ARF. Here we show that EGR1 colocalizes with nucleolar markers such as fibrillarin and B23 in the presence of ARF. Western analysis of nucleolar extracts from HeLa cells was used to confirm the presence of EGR1 in the nucleolus mainly as the 100 kDa sumoylated form. We also show that the level of the ribosomal RNA precursor 47S is inversely correlated to the level of EGR1 transcripts. The EGR1 iseffective to regulate the synthesis of the 47S rRNA precursor. Then we demonstrated that EGR1 binds to the Upstream Binding Factor (UBF leading us to hypothesize that the regulating activity of EGR1 is mediated by its interaction within the transcriptional complex of RNA polymerase I. These results confirm the presence of EGR1 in the nucleolus and point to a role for EGR1 in the control of nucleolar metabolism.

  4. High frequency of tumor cells with nuclear Egr-1 protein expression in human bladder cancer is associated with disease progression

    Egerod, Frederikke N S Lihme; Bartels, Annette; Fristrup, Niels

    2009-01-01

    bladder cancer. RESULTS: The frequency of tumor cells with nuclear Egr-1 immunolabelling correlated to bladder cancer stage, grade and to later progression to muscle-invasive bladder cancer (T2-4). Stage T1 tumors exhibited significantly higher frequencies of tumor cells with nuclear Egr-1 immunolabelling...... than Ta tumors (P = 0.001). Furthermore, Kaplan-Meier survival analysis showed that a high frequency of tumor cells with nuclear Egr-1 immunolabelling was significantly associated with a higher risk of progression to stage T2-4 (log-rank test, P = 0.035). Tumor cells with nuclear Egr-1 immunolabelling...

  5. 转录因子Egr-1参与长期性恐惧记忆和焦虑%Transcription factor Egr-1 is required for long-term fear memory and anxiety

    Shanelle; W.Ko; 敖虎山; Amelia; Gallitano-Mendel; 邱长申; 魏峰; Jeffrey; Milbrandt; 卓敏

    2005-01-01

    The zinc finger transcription factor Egr-1 is critical for coupling extracellular signals to changes in cellular gene expression.In the hippocampus and amygdala, two major central regions for memory formation and storage, Egr-1 is up-regulated by long-term potentiation (LTP) and learning paradigms. Using Egr-1 knockout mice, we showed that Egr-1 was selectively required for late auditory fear memory while short term, trace and contextual memory were not affected. Additionally, synaptic potentiation induced by theta burst stimulation in the amygdala and auditory cortex was significantly reduced or blocked in Egr-1 knockout mice. Our study suggests that the transcription factor Egr-1 plays a selective role in late auditory fear memory.%锌指转录因子Egr-1在将细胞外信号和胞内基因表达的变化相耦联过程中发挥重要的作用.海马和杏仁体是记忆形成和储存的两个主要的脑区.在海马和杏仁体中,Egr-1可被长时程增强(long-term potentiation,LTP)和学习过程上调.在Egr-1敲除小鼠上观察到晚时相声音恐惧记忆受损,而短时的痕迹和场景记忆却不受影响;另外,在Egr-1敲除小鼠上,用thetaburst刺激杏仁体和听觉皮层所引起的突触增强被明显减弱或完全阻断.因此,我们的研究表明,转录因子Egr-1选择性地在晚时相听觉恐惧记忆中发挥作用.

  6. Urotensin II contributes to collagen synthesis and up-regulates Egr-1 expression in cultured pulmonary arterial smooth muscle cells through the ERK1/2 pathway

    Li, Wei [Biomedical Engineering Institute, School of Control Science and Engineering, Shandong University, Jinan 250061 (China); Cai, Zhifeng; Liu, Mengmeng [Department of Pediatrics, Qilu Hospital, Shandong University, Jinan 250012 (China); Zhao, Cuifen, E-mail: zhaocuifen@sdu.edu.cn [Department of Pediatrics, Qilu Hospital, Shandong University, Jinan 250012 (China); Li, Dong [Research Room of Hypothermia Medicine, Qilu Hospital, Shandong University, Jinan 250012 (China); Lv, Chenguang; Wang, Yuping; Xu, Tengfei [Biomedical Engineering Institute, School of Control Science and Engineering, Shandong University, Jinan 250061 (China)

    2015-11-27

    Aim: The objective of this study was to investigate the effects of urotensin II (UII) treatment on the proliferation and collagen synthesis of cultured rat pulmonary arterial smooth muscle cells (PASMCs) and to explore whether these effects are mediated by mitogen-activated protein kinase (MAPK) signaling pathways and early growth response 1 (Egr-1). Methods: The proliferation of cultured PASMCs stimulated with different doses of UII was detected by BrdU incorporation. The mRNA expression levels of procollagen I (procol I), procollagen III (procol III), extracellular regulated protein kinase 1/2 (ERK1/2), stress-stimulated protein kinase (Sapk), p38 MAPK (p38), and Egr-1 mRNA in cultured PASMCs after treatment with UII, the UII-specific antagonist urantide, and the ERK1/2 inhibitor PD98059 were detected by real-time polymerase chain reaction (PCR), and the protein expression levels of procol I, procol III, phosphorylated (p)-ERK1/2, p-Sapk, p-p38, and Egr-1 were detected by Western blotting. Results: Treatment with UII increased the proliferation of cultured PASMCs in a dose-dependent manner (P < 0.05). However, treatment with urantide and PD98059 inhibited the promoting effect of UII on PASMC proliferation (P < 0.05). Real-time PCR analysis showed that UII up-regulated the expression of procol I, procol III, ERK1/2, Sapk, and Egr-1 mRNA (P < 0.05), but not p38 mRNA. However, the up-regulating effect of UII was inhibited by PD98059 and urantide. Western blotting analysis showed that UII increased the synthesis of collagen I, collagen III, p-ERK1/2, p-Sapk, and Egr-1, and these effects also were inhibited by PD98059 and urantide (P < 0.05). Conclusions: Egr-1 participates in the UII-mediated proliferation and collagen synthesis of cultured rat PASMCs via activation of the ERK1/2 signaling pathway.

  7. Expression of Egr1 and p53 in human carotid plaques and apoptosis induced by 7-oxysterol or p53.

    Miah, Sayem; Zadeh, Shahram Nour Mohammad; Yuan, Xi-Ming; Li, Wei

    2013-07-01

    Egr-1 and p53 are involved in pathology of both atherosclerosis and cancer. However, it is unknown whether p53 and Egr1 are interactively involved in apoptosis in atherosclerosis. We found that in human carotid plaques, the expression of p53 was inversely correlated with Egr1. In U937 cells, 7β-hydroxycholesterol and 7-ketocholesterol induced production of reactive oxygen species (ROS), transient up-regulation of Egr1 followed by late induction of p53 and apoptosis. Cells with nuclear fragmentation induced by 7-oxysterol or p53 showed increased levels of p53, but decreased levels of Egr1. In conclusion, ROS induced by 7-oxysterols may function as an early initiator of Egr1 expression. The late induced p53 by 7-oxysterols contributes to apoptotic cell death and is linked to the reduction of Egr1 levels, which resembles the differential expression of p53 and Egr1 in human atheroma progression. Copyright © 2012 Elsevier GmbH. All rights reserved.

  8. Early growth response-1 negative feedback regulates skeletal muscle postprandial insulin sensitivity via activating Ptp1b transcription.

    Wu, Jing; Tao, Wei-Wei; Chong, Dan-Yang; Lai, Shan-Shan; Wang, Chuang; Liu, Qi; Zhang, Tong-Yu; Xue, Bin; Li, Chao-Jun

    2018-03-15

    Postprandial insulin desensitization plays a critical role in maintaining whole-body glucose homeostasis by avoiding the excessive absorption of blood glucose; however, the detailed mechanisms that underlie how the major player, skeletal muscle, desensitizes insulin action remain to be elucidated. Herein, we report that early growth response gene-1 ( Egr-1) is activated by insulin in skeletal muscle and provides feedback inhibition that regulates insulin sensitivity after a meal. The inhibition of the transcriptional activity of Egr-1 enhanced the phosphorylation of the insulin receptor (InsR) and Akt, thus increasing glucose uptake in L6 myotubes after insulin stimulation, whereas overexpression of Egr-1 decreased insulin sensitivity. Furthermore, deletion of Egr-1 in the skeletal muscle improved systemic insulin sensitivity and glucose tolerance, which resulted in lower blood glucose levels after refeeding. Mechanistic analysis demonstrated that EGR-1 inhibited InsR phosphorylation and glucose uptake in skeletal muscle by binding to the proximal promoter region of protein tyrosine phosphatase-1B (PTP1B) and directly activating transcription. PTP1B knockdown largely restored insulin sensitivity and enhanced glucose uptake, even under conditions of EGR-1 overexpression. Our results indicate that EGR-1/PTP1B signaling negatively regulates postprandial insulin sensitivity and suggest a potential therapeutic target for the prevention and treatment of excessive glucose absorption.-Wu, J., Tao, W.-W., Chong, D.-Y., Lai, S.-S., Wang, C., Liu, Q., Zhang, T.-Y., Xue, B., Li, C.-J. Early growth response-1 negative feedback regulates skeletal muscle postprandial insulin sensitivity via activating Ptp1b transcription.

  9. Androgen Modulates Functions of Endothelial Progenitor Cells through Activated Egr1 Signaling

    Yizhou Ye

    2016-01-01

    Full Text Available Researches show that androgens have important effects on migration of endothelial cells and endothelial protection in coronary heart disease. Endothelial progenitor cells (EPCs as a progenitor cell type that can differentiate into endothelial cells, have a critical role in angiogenesis and endothelial protection. The relationship between androgen and the functions of EPCs has animated much interest and controversy. In this study, we investigated the angiogenic and migratory functions of EPCs after treatment by dihydrotestosterone (DHT and the molecular mechanisms as well. We found that DHT treatment enhanced the incorporation of EPCs into tubular structures formed by HUVECs and the migratory activity of EPCs in the transwell assay dose dependently. Moreover, microarray analysis was performed to explore how DHT changes the gene expression profiles of EPCs. We found 346 differentially expressed genes in androgen-treated EPCs. Angiogenesis-related genes like Egr-1, Vcan, Efnb2, and Cdk2ap1 were identified to be regulated upon DHT treatment. Furthermore, the enhanced angiogenic and migratory abilities of EPCs after DHT treatment were inhibited by Egr1-siRNA transfection. In conclusion, our findings suggest that DHT markedly enhances the vessel forming ability and migration capacity of EPCs. Egr1 signaling may be a possible pathway in this process.

  10. Long-term recognition memory of individual conspecifics is associated with telencephalic expression of Egr-1 in the electric fish Apteronotus leptorhynchus.

    Harvey-Girard, Erik; Tweedle, Jessica; Ironstone, Joel; Cuddy, Martin; Ellis, William; Maler, Leonard

    2010-07-15

    Primates and songbirds can learn to recognize individual conspecifics based on complex sensory cues; this requires a large, highly differentiated dorsal telencephalon. Here we show that the electric fish Apteronotus leptorhynchus can learn to recognize individual conspecifics based on a simple cue, the beat frequency of their summed sinusoidal electric organ discharges (EOD). Male fish produce transient communication signals (chirps) in response to mimic EODs. The chirp response habituates over repeated stimulus presentations within one experimental session, continues to habituate over successive daily sessions and is nearly extinguished after 5-7 days. Habituation of the chirp response was specific to the presented beat frequency. The conversion of short- to long-term habituation could be disrupted by cooling the head 30 minutes after the daily habituation trials. Consolidation of long-term memory in mammals is thought to involve induced expression of an immediate early gene, Egr-1. We cloned the Apteronotid homolog of the Egr-1 gene and found that chirp-evoking stimuli induced strong expression of its mRNA within the dorsal (Dd), central (DC), and lateral (DL) subdivisions of the dorsal telencephalon. Interestingly, the dorsolateral region is hypothesized to be homologous to the amniote hippocampal formation. We conclude that A. leptorhynchus can learn to identify individual conspecifics based on their EOD frequency and can remember these frequencies for several days. We hypothesize that this form of learning, as in primates and songbirds, requires a subset of dorsal telencephalic areas and involves a consolidation-like process that includes the expression of the transcription factor AptEgr-1.

  11. Egr-1 mediated cardiac miR-99 family expression diverges physiological hypertrophy from pathological hypertrophy.

    Ramasamy, Subbiah; Velmurugan, Ganesan; Rekha, Balakrishnan; Anusha, Sivakumar; Shanmugha Rajan, K; Shanmugarajan, Suresh; Ramprasath, Tharmarajan; Gopal, Pandi; Tomar, Dhanendra; Karthik, Karuppusamy V; Verma, Suresh Kumar; Garikipati, Venkata Naga Srikanth; Sudarsan, Rajan

    2018-04-01

    The physiological cardiac hypertrophy is an adaptive condition without myocyte cell death, while pathological hypertrophy is a maladaptive condition associated with myocyte cell death. This study explores the miRNome of α-2M-induced physiologically hypertrophied cardiomyocytes and the role of miRNA-99 family during cardiac hypertrophy. Physiological and pathological cardiac hypertrophy was induced in H9c2 cardiomyoblast cell lines using α-2M and isoproterenol respectively. Total RNA isolation and small RNA sequencing were executed for physiological hypertrophy model. The differentially expressed miRNAs and its target mRNAs were validated in animal models. Transcription factor binding sites were predicted in the promoter of specific miRNAs and validated by ChIP-PCR. Subsequently, the selected miRNA was functionally characterized by overexpression and silencing. The effects of silencing of upstream regulator and downstream target gene were studied. Analysis of small RNA reads revealed the differential expression of a large set of miRNAs during hypertrophy, of which miR-99 family was highly downregulated upon α-2M treatment. However, this miR-99 family expression was upregulated during pathological hypertrophy and confirmed in animal models. ChIP-PCR confirms the binding of Egr-1 transcription factor to the miR-99 promoter. Further, silencing of Egr-1 decreased the expression of miR-99. The overexpression or silencing of miR-99 diverges the physiological hypertrophy to pathological hypertrophy and vice versa by regulating Akt-1 pathway. Silencing of Akt-1 replicates the effect of overexpression of miR-99. The results proved Egr-1 mediated regulation of miR-99 family that plays a key role in determining the fate of cardiac hypertrophy by regulating Akt-1 signaling. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. Real-imaging cDNA-AFLP transcript profiling of pancreatic cancer patients: Egr-1 as a potential key regulator of muscle cachexia

    Skorokhod, Alexander [Division of Preventive Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg (Germany); Institute of Molecular Biology and Genetics, Ukrainian Academy of Sciences, Zabolotnogo str. 150, 03143, Kiev (Ukraine); Bachmann, Jeannine [Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich (Germany); Giese, Nathalia A [Department of General Surgery, University of Heidelberg, ImNeuenheimer Feld, 110 69120, Heidelberg (Germany); Martignoni, Marc E [Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich (Germany); Krakowski-Roosen, Holger [Division of Preventive Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120, Heidelberg (Germany)

    2012-06-21

    Cancer cachexia is a progressive wasting syndrome and the most prevalent characteristic of cancer in patients with advanced pancreatic adenocarcinoma. We hypothesize that genes expressed in wasted skeletal muscle of pancreatic cancer patients may determine the initiation and severity of cachexia syndrome. We studied gene expression in skeletal muscle biopsies from pancreatic cancer patients with and without cachexia utilizing Real-Imaging cDNA-AFLP-based transcript profiling for genome-wide expression analysis. Our approach yielded 183 cachexia-associated genes. Ontology analysis revealed characteristic changes for a number of genes involved in muscle contraction, actin cytoskeleton rearrangement, protein degradation, tissue hypoxia, immediate early response and acute-phase response. We demonstrate that Real-Imaging cDNA-AFLP analysis is a robust method for high-throughput gene expression studies of cancer cachexia syndrome in patients with pancreatic cancer. According to quantitative RT-PCR validation, the expression levels of genes encoding the acute-phase proteins α-antitrypsin and fibrinogen α and the immediate early response genes Egr-1 and IER-5 were significantly elevated in the skeletal muscle of wasted patients. By immunohistochemical and Western immunoblotting analysis it was shown, that Egr-1 expression is significantly increased in patients with cachexia and cancer. This provides new evidence that chronic activation of systemic inflammatory response might be a common and unifying factor of muscle cachexia.

  13. Real-imaging cDNA-AFLP transcript profiling of pancreatic cancer patients: Egr-1 as a potential key regulator of muscle cachexia

    Skorokhod, Alexander; Bachmann, Jeannine; Giese, Nathalia A; Martignoni, Marc E; Krakowski-Roosen, Holger

    2012-01-01

    Cancer cachexia is a progressive wasting syndrome and the most prevalent characteristic of cancer in patients with advanced pancreatic adenocarcinoma. We hypothesize that genes expressed in wasted skeletal muscle of pancreatic cancer patients may determine the initiation and severity of cachexia syndrome. We studied gene expression in skeletal muscle biopsies from pancreatic cancer patients with and without cachexia utilizing Real-Imaging cDNA-AFLP-based transcript profiling for genome-wide expression analysis. Our approach yielded 183 cachexia-associated genes. Ontology analysis revealed characteristic changes for a number of genes involved in muscle contraction, actin cytoskeleton rearrangement, protein degradation, tissue hypoxia, immediate early response and acute-phase response. We demonstrate that Real-Imaging cDNA-AFLP analysis is a robust method for high-throughput gene expression studies of cancer cachexia syndrome in patients with pancreatic cancer. According to quantitative RT-PCR validation, the expression levels of genes encoding the acute-phase proteins α-antitrypsin and fibrinogen α and the immediate early response genes Egr-1 and IER-5 were significantly elevated in the skeletal muscle of wasted patients. By immunohistochemical and Western immunoblotting analysis it was shown, that Egr-1 expression is significantly increased in patients with cachexia and cancer. This provides new evidence that chronic activation of systemic inflammatory response might be a common and unifying factor of muscle cachexia

  14. HTLV-1 Tax upregulates early growth response protein 1 through nuclear factor-κB signaling.

    Huang, Qingsong; Niu, Zhiguo; Han, Jingxian; Liu, Xihong; Lv, Zhuangwei; Li, Huanhuan; Yuan, Lixiang; Li, Xiangping; Sun, Shuming; Wang, Hui; Huang, Xinxiang

    2017-08-01

    Human T cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that causes adult T cell leukemia (ATL) in susceptible individuals. The HTLV-1-encoded oncoprotein Tax induces persistent activation of the nuclear factor-κB (NF-κB) pathway. Early growth response protein 1 (EGR1) is overexpressed in HTLV-1-infected T cell lines and ATL cells. Here, we showed that both Tax expression and HTLV-1 infection promoted EGR1 overexpression. Loss of the NF-κB binding site in the EGR1 promotor or inhibition of NF-κB activation reduced Tax-induced EGR1 upregulation. Tax mutants unable to activate NF-κB induced only slight EGR1 upregulation as compared with wild-type Tax, confirming NF-κB pathway involvement in EGR1 regulation. Tax also directly interacted with the EGR1 protein and increased endogenous EGR1 stability. Elevated EGR1 in turn promoted p65 nuclear translocation and increased NF-κB activation. These results demonstrate a positive feedback loop between EGR1 expression and NF-κB activation in HTLV-1-infected and Tax-expressing cells. Both NF-κB activation and Tax-induced EGR1 stability upregulated EGR1, which in turn enhanced constitutive NF-κB activation and facilitated ATL progression in HTLV-1-infected cells. These findings suggest EGR1 may be an effective anti-ATL therapeutic target.

  15. PPARa and PPAR¿ coactivation rapidly induces Egr-1 in the nuclei of the dorsal and ventral urinary bladder and kidney pelvis urothelium of rats

    Egerod, Frederikke Lihme; Svendsen, Jette Eldrup; Hinley, Jennifer

    2009-01-01

    in the dorsal and ventral bladder urothelium, arguing against involvement of urinary solids. Egr-1 induction sometimes occurred in a localized fashion, indicating physiological microheterogeneity in the urothelium. The rapid kinetics supported that Egr-1 induction occurred as a result of pharmacological...... activation of PPAR alpha and PPAR gamma, which are coexpressed at high levels in the rat urothelium. Finally, our demonstration of a nuclear localization supports that the Egr-1 induced by PPAR alpha and PPAR gamma coactivation in the rat urothelium may be biologically active....

  16. Regulation of the voltage-gated Ca2+ channel CaVα2δ-1 subunit expression by the transcription factor Egr-1.

    González-Ramírez, Ricardo; Martínez-Hernández, Elizabeth; Sandoval, Alejandro; Gómez-Mora, Kimberly; Felix, Ricardo

    2018-04-23

    It is well known that the Ca V α 2 δ auxiliary subunit regulates the density of high voltage-activated Ca 2+ channels in the plasma membrane and that alterations in their functional expression might have implications in the pathophysiology of diverse human diseases such as neuropathic pain. However, little is known concerning the transcriptional regulation of this protein. We previously characterized the promoter of Ca V α 2 δ, and here we report its regulation by the transcription factor Egr-1. Using the neuroblastoma N1E-115 cells, we found that Egr-1 interacts specifically with its binding site in the promoter, affecting the transcriptional regulation of Ca V α 2 δ. Overexpression and knockdown analysis of Egr-1 showed significant changes in the transcriptional activity of the Ca V α 2 δ promoter. Egr-1 also regulated the expression of Ca V α 2 δ at the level of protein. Also, functional studies showed that Egr-1 knockdown significantly decreases Ca 2+ currents in dorsal root ganglion (DRG) neurons, while overexpression of the transcription factor increased Ca 2+ currents in the F11 cell line, a hybrid of DRG and N18TG2 neuroblastoma cells. Studying the effects of Egr-1 on the transcriptional expression of Ca V α 2 δ could help to understand the regulatory mechanisms of this protein in both health and disease. Copyright © 2018 Elsevier B.V. All rights reserved.

  17. An Evaluation on Transfection Efficiency of pHRE-Egr1-EGFP in Hepatocellular Carcinoma Cells Bel-7402 Mediated by PEI-MZF-NPs

    Mei Lin

    2011-01-01

    Full Text Available To improve transfection and expression efficiency of target gene, especially under cancer anoxic microenvironment, we have developed pHRE-Egr1-EGFP/PEI-MZF-NPs nanosystem, in which pHRE-Egr1-EGFP, eukaryotic gene expression plasmid, is constructed by combining radiation promoter Egr1 with anoxia induction components (HRE, forming anoxic radiation double sensitive HRE/Egr1 promoter to activate reporter gene EGFP expression. MZF-NPs (Mn0.5 Zn0.5 Fe2O4 magnetic nanoparticles, obtained by coprecipitation method, are coated with cation poly(ethylenimine (PEI. We transferred pHRE-Egr1-EGFP into hepatocellular carcinoma Bel-7402 cells, using PEI-MZF-NPs as the carrier and tested some relevant efficacy. The results show that PEI-MZF-NPs have good DNA-binding ability, protection ability, release ability, little toxicity, and high transfection efficiency, obviously superior to those of the liposome method and electricity perforation method. Moreover, the expression level of EGFP gene induced by anoxia and radiation was significantly higher than that of single radiation activation. It is therefore concluded that HRE/Egr1 can induce and improve target gene expression efficiency in cancer anoxic microenvironment, and that PEI-MZF-NPs can be used as a novel nonviral gene vector which offers a viable approach to the mediated radiation gene therapy of cancer.

  18. Attenuation of pCREB and Egr1 expression in the insular and anterior cingulate cortices associated with enhancement of CFA-evoked mechanical hypersensitivity after repeated forced swim stress.

    Imbe, Hiroki; Kimura, Akihisa

    2017-09-01

    The perception and response to pain are severely impacted by exposure to stressors. In some animal models, stress increases pain sensitivity, which is termed stress-induced hyperalgesia (SIH). The insular cortex (IC) and anterior cingulate cortex (ACC), which are typically activated by noxious stimuli, affect pain perception through the descending pain modulatory system. In the present study, we examined the expression of phospho-cAMP response element-binding protein (pCREB) and early growth response 1 (Egr1) in the IC and ACC at 3h (the acute phase of peripheral tissue inflammation) after complete Freund's adjuvant (CFA) injection in naïve rats and rats preconditioned with forced swim stress (FS) to clarify the effect of FS, a stressor, on cortical cell activities in the rats showing SIH induced by FS. The CFA injection into the hindpaw induced mechanical hypersensitivity and increased the expression of the pCREB and Egr1 in the IC and ACC at 3h after the injection. FS (day 1, 10min; days 2-3, 20min) prior to the CFA injection enhanced the CFA-induced mechanical hypersensitivity and attenuated the increase in the expression of pCREB and Egr1 in the IC and ACC. These findings suggested that FS modulates the CFA injection-induced neuroplasticity in the IC and ACC to enhance the mechanical hypersensitivity. These findings are thought to signify stressor-induced dysfunction of the descending pain modulatory system. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Function of the EGR-1/TIS8 radiation inducible promoter in a minimal HSV-1 amplicon system

    Spear, M.A.; Sakamoto, K.M.; Herrlinger, U.; Pechan, P.; Breakefield, X.O.

    1997-01-01

    Purpose: To evaluate function of the EGR-1/TIS8 promoter region in minimal HSV-1 amplicon system in order to determine the feasibility of using the system to regulate vector replication with radiation. Materials and Methods: A 600-base pair 5' upstream region of the EGR-1 promoter linked to chloramphenicol acetyltransferase (CAT) was recombined into a minimal HSV-1 amplicon vector system (pONEC). pONEC or a control plasmid was transfected into U87 glioma cells using the Lipofectamine method. Thirty-six hours later one aliquot of cells from each transfection was irradiated to a dose of 20 Gy and another identical aliquot served as a control. CAT activity was assayed 8 hours after irradiation. Results: pONEC transfected cells irradiated with 20 Gy demonstrated 2.0 fold increase in CAT activity compared to non-irradiated cells. Cells transfected with control plasmid showed no change in CAT activity. Unirradiated pONEC cells had CAT activity 1.3 times those transfected with control plasmid. Conclusion: We have previously created HSV-1 gene therapy amplicon vector systems which allow virus-amplicon interdependent replication, with the intent of regulating replication. The above data demonstrates that a minimal amplicon system will allow radiation dependent regulation by the EGR-1 promoter, thus indicating the possibility of using this system to regulate onsite, spatially and temporally regulated vector production. Baseline CAT activity was higher and relative induction lower than other reported expression constructs, which raises concern for the ability of the system to produce a differential in transcription levels sufficient for this purpose. This is possibly the result of residual promoter/enhancer elements remaining in the HSV-1 sequences. We are attempting to create constructs lacking these elements. Addition of secondary promoter sequences may also be of use. We are also currently evaluating the efficacy of the putative IEX-1 radiation inducible promoter region in

  20. Dual‑sensitive HRE/Egr1 promoter regulates Smac overexpression and enhances radiation‑induced A549 human lung adenocarcinoma cell death under hypoxia.

    Li, Chang-Feng; Chen, Li-Bo; Li, Dan-Dan; Yang, Lei; Zhang, Bao-Gang; Jin, Jing-Peng; Zhang, Ying; Zhang, Bin

    2014-08-01

    The aim of this study was to construct an expression vector carrying the hypoxia/radiation dual‑sensitive chimeric hypoxia response element (HRE)/early growth response 1 (Egr‑1) promoter in order to overexpress the therapeutic second mitochondria‑derived activator of caspases (Smac). Using this expression vector, the present study aimed to explore the molecular mechanism underlying radiotherapy‑induced A549 human lung adenocarcinoma cell death and apoptosis under hypoxia. The plasmids, pcDNA3.1‑Egr1‑Smac (pE‑Smac) and pcDNA3.1‑HRE/Egr-1‑Smac (pH/E‑Smac), were constructed and transfected into A549 human lung adenocarcinoma cells using the liposome method. CoCl2 was used to chemically simulate hypoxia, followed by the administration of 2 Gy X‑ray irradiation. An MTT assay was performed to detect cell proliferation and an Annexin V‑fluorescein isothiocyanate apoptosis detection kit was used to detect apoptosis. Quantitative polymerase chain reaction and western blot analyses were used for the detection of mRNA and protein expression, respectively. Infection with the pE‑Smac and pH/E‑Smac plasmids in combination with radiation and/or hypoxia was observed to enhance the expression of Smac. Furthermore, Smac overexpression was found to enhance the radiation‑induced inhibition of cell proliferation and promotion of cycle arrest and apoptosis. The cytochrome c/caspase‑9/caspase‑3 pathway was identified to be involved in this regulation of apoptosis. Plasmid infection in combination with X‑ray irradiation was found to markedly induce cell death under hypoxia. In conclusion, the hypoxia/radiation dual‑sensitive chimeric HRE/Egr‑1 promoter was observed to enhance the expression of the therapeutic Smac, as well as enhance the radiation‑induced inhibition of cell proliferation and promotion of cycle arrest and apoptosis under hypoxia. This apoptosis was found to involve the mitochondrial pathway.

  1. Radioprotective effect of hematopoietic growth factor gene therapy regulated by Egr-1 promoter on radiation injury of SCID mice

    Du Nan; Pei Xuetao; Luo Chengji; Su Yongping; Cheng Tianmin

    2002-01-01

    Objective: To explore the radioprotective effect of the expression of hematopoietic growth factors regulated by radio-inducible promoter on radiation injury. Methods: The human FL cDNA and EGFP cDNA were linked together with an internal ribosome entry site (IRES) and then inserted into the eukaryotic expression vector pCI-neo with the Egr-1 promoter (Egr-EF), and further transduced into bone marrow stromal cell lines HFCL (HFCL/EF). The HFCL/EF and CD34 + cells from human umbilical cord blood were transplanted i.v. one after the other into sublethally irradiated severe combined immunodeficient (SCID) mice. The number of peripheral blood WBC and human cells engrafted in recipient mice were detected by flow cytometry and CFU-GM assay. Results: In contrast to two control groups (HFCL and HFCL/F), HFCL/EF (the Egr-1 regulatory element-driven expression of FL gene therapy) resulted in a proportionally obvious increase in the number of the WBC at early stage after irradiation. Significant differences were found for CD45 + , CD34 + , CFU-GM, and nucleated cells in the bone marrow. Conclusion: Hematopoietic growth factor gene therapy regulated by radio-inducible promoter has radioprotective effect on radiation hematopoietic injury

  2. Inhibitory effects of recombinant plasmid pshuttle-Egr1-shTRAIL transfection in combination with X-irradiation on growth of liver cancer cells SMMC7721

    Chen Zhiyong; Liu Min; Dong Lihua; Gong Shouliang

    2011-01-01

    Objective: To investigate the effect of recombinant plasmid pshuttle-Egr1-shTRAIL stable transfection in combination with X-ray irradiation on the TRAIL protein expression and the apoptosis in human SMMC7721 hepatoma cells. Methods: The pshuttle-Egr1-shTRAIL packaged with liposome was stably transfected into SMMC7721 cells in vitro. The shTRAIL protein expression were measured with ELISA assay, Annexin V-FITC kit was adopted to measure the apoptosis of pshuttle-Egr1-shTRAIL cells, and the changes in survival rate of SMMC7721 cells measured with cell cloning assay. Results: The TRAIL protein expressions in pshuttle-Egr1-shTRAIL plus different doses of irradiation groups were significantly increased compared with 0 Gy group (P<0.001). The percentage of apoptotic cells was significantly higher than that in 0 Gy group (P<0.05 or P<0.001), and the survival rate of SMMC7721 cells was decreased significantly (P<0.05 or P<0.001). Conclusion: The pshuttle-Egr1-shTRAIL stable transfection in combination with irradiation can significantly induce the apoptosis of SMMC7721 tumor cells and inhibit the cell proliferation. (authors)

  3. Odor discrimination learning in the Indian greater short-nosed fruit bat (Cynopterus sphinx): differential expression of Egr-1, C-fos and PP-1 in the olfactory bulb, amygdala and hippocampus.

    Mukilan, Murugan; Bogdanowicz, Wieslaw; Marimuthu, Ganapathy; Rajan, Koilmani Emmanuvel

    2018-04-19

    Activity-dependent expression of immediate-early genes (IEGs) is induced by exposure to odor. The present study was designed to investigate whether there is differential expression of IEGs ( Egr-1 , C-fos ) in the brain region mediating olfactory memory in the Indian greater short-nosed fruit bat Cynopterus sphinx We assumed that differential expression of IEGs in different brain regions may orchestrate a preference odor (PO) and aversive odor (AO) memory in C. sphinx We used preferred (0.8% wt/wt of cinnamon powder) and aversive (0.4% wt/vol of citral) odor substances, with freshly-prepared chopped apple, to assess the behavioural response and induction of IEGs in the olfactory bulb, hippocampus and amygdala. After experiencing PO and AO, the bats initially responded to both, later only engaging in feeding bouts in response to the PO food. The expression pattern of Egr-1 and C-fos in the olfactory bulb, hippocampus and amygdala was similar at different time points (15, 30 and 60 min) following the response to PO, but different for AO. The response to AO elevated the level of C-fos expression within 30 min and reduced it at 60 min in both the olfactory bulb and the hippocampus, as opposed to the continuous increase noted in the amygdala. In addition, we tested whether an epigenetic mechanism entailing protein phosphatase-1 (PP-1) acts on IEG expression. The observed PP-1 expression and the level of unmethylated/methylated promoter revealed that the C-fos expression is possibly controlled by an odor-mediated regulation of PP-1. These results in turn imply that the differential expression of C-fos in the hippocampus and amygdala may contribute to olfactory learning and memory in C. sphinx . © 2018. Published by The Company of Biologists Ltd.

  4. Antibacterial activity and immune responses of a molluscan macrophage expressed gene-1 from disk abalone, Haliotis discus discus.

    Bathige, S D N K; Umasuthan, Navaneethaiyer; Whang, Ilson; Lim, Bong-Soo; Won, Seung Hwan; Lee, Jehee

    2014-08-01

    The membrane-attack complex/perforin (MACPF) domain-containing proteins play an important role in the innate immune response against invading microbial pathogens. In the current study, a member of the MACPF domain-containing proteins, macrophage expressed gene-1 (MPEG1) encoding 730 amino acids with the theoretical molecular mass of 79.6 kDa and an isoelectric point (pI) of 6.49 was characterized from disk abalone Haliotis discus discus (AbMPEG1). We found that the characteristic MACPF domain (Val(131)-Tyr(348)) and transmembrane segment (Ala(669)-Ile(691)) of AbMPEG1 are located in the N- and C-terminal ends of the protein, respectively. Ortholog comparison revealed that AbMPEG1 has the highest sequence identity with its pink abalone counterpart, while sequences identities of greater than 90% were observed with MPEG1 members from other abalone species. Likewise, the furin cleavage site KRRRK was highly conserved in all abalone species, but not in other species investigated. We identified an intron-less genomic sequence within disk abalone AbMPEG1, which was similar to other mammalian, avian, and reptilian counterparts. Transcription factor binding sites, which are important for immune responses, were identified in the 5'-flanking region of AbMPEG1. qPCR revealed AbMPEG1 transcripts are present in every tissues examined, with the highest expression level occurring in mantle tissue. Significant up-regulation of AbMPEG1 transcript levels was observed in hemocytes and gill tissues following challenges with pathogens (Vibrio parahemolyticus, Listeria monocytogenes and viral hemorrhagic septicemia virus) as well as pathogen-associated molecular patterns (PAMPs: lipopolysaccharides and poly I:C immunostimulant). Finally, the antibacterial activity of the MACPF domain was characterized against Gram-negative and -positive bacteria using a recombinant peptide. Taken together, these results indicate that the biological significance of the AbMPEG1 gene includes a role in

  5. Zif268/Egr1 gain of function facilitates hippocampal synaptic plasticity and long-term spatial recognition memory.

    Penke, Zsuzsa; Morice, Elise; Veyrac, Alexandra; Gros, Alexandra; Chagneau, Carine; LeBlanc, Pascale; Samson, Nathalie; Baumgärtel, Karsten; Mansuy, Isabelle M; Davis, Sabrina; Laroche, Serge

    2014-01-05

    It is well established that Zif268/Egr1, a member of the Egr family of transcription factors, is critical for the consolidation of several forms of memory; however, it is as yet uncertain whether increasing expression of Zif268 in neurons can facilitate memory formation. Here, we used an inducible transgenic mouse model to specifically induce Zif268 overexpression in forebrain neurons and examined the effect on recognition memory and hippocampal synaptic transmission and plasticity. We found that Zif268 overexpression during the establishment of memory for objects did not change the ability to form a long-term memory of objects, but enhanced the capacity to form a long-term memory of the spatial location of objects. This enhancement was paralleled by increased long-term potentiation in the dentate gyrus of the hippocampus and by increased activity-dependent expression of Zif268 and selected Zif268 target genes. These results provide novel evidence that transcriptional mechanisms engaging Zif268 contribute to determining the strength of newly encoded memories.

  6. Comparison of alterations in c-fos and Egr-1 (zif268) expression throughout the rat brain following acute administration of different classes of antidepressant compounds.

    Slattery, David A; Morrow, John A; Hudson, Alan L; Hill, David R; Nutt, David J; Henry, Brian

    2005-07-01

    The majority of immediate-early gene (IEG) studies focus on a few key brain regions associated with the class of psychoactive compound being studied. Recently, using a meta-analysis of the c-fos literature, we demonstrated the utility of c-fos profiling to classify such compounds. The present study examined acute delivery of a range of antidepressant classes; fluoxetine, imipramine, LiCl, and mirtazapine. The dual aims were to study the IEG profiles of these varying classes of antidepressants throughout the rat brain and to compare the utility of c-fos or Egr-1 as IEGs to classify clinically efficacious antidepressants. All antidepressants increased c-fos mRNA in the central amygdala, as previously shown, while c-fos was also increased in the anterior insular cortex and significantly decreased within the septum. Although acute antidepressant administration altered c-fos expression in a number of brain regions, Egr-1 expression was only significantly altered in the central amygdala, suggesting that Egr-1 may not be as useful a marker to investigate acute antidepressant treatment. The fact that these drugs, including the previously unclassified antidepressant mirtazapine, share a number of common loci of activation, which are implicated by human and animal studies in depression, adds further support to the use of IEG mapping to classify psychoactive compounds.

  7. Hypomethylation of inflammatory genes (COX2, EGR1, and SOCS3) and increased urinary 8-nitroguanine in arsenic-exposed newborns and children

    Phookphan, Preeyaphan; Navasumrit, Panida [Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Laksi, Bangkok (Thailand); Post-graduate Program in Environmental Toxicology, Chulabhorn Graduate Institute, Laksi, Bangkok (Thailand); Center of Excellence on Environmental Health, Toxicology (EHT), Office of the Higher Education Commission, Ministry of Education (Thailand); Waraprasit, Somchamai; Promvijit, Jeerawan; Chaisatra, Krittinee; Ngaotepprutaram, Thitirat [Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Laksi, Bangkok (Thailand); Ruchirawat, Mathuros, E-mail: mathuros@cri.or.th [Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Laksi, Bangkok (Thailand); Center of Excellence on Environmental Health, Toxicology (EHT), Office of the Higher Education Commission, Ministry of Education (Thailand)

    2017-02-01

    Early-life exposure to arsenic increases risk of developing a variety of non-malignant and malignant diseases. Arsenic-induced carcinogenesis may be mediated through epigenetic mechanisms and pathways leading to inflammation. Our previous study reported that prenatal arsenic exposure leads to increased mRNA expression of several genes related to inflammation, including COX2, EGR1, and SOCS3. This study aimed to investigate the effects of arsenic exposure on promoter DNA methylation and mRNA expression of these inflammatory genes (COX2, EGR1, and SOCS3), as well as the generation of 8-nitroguanine, which is a mutagenic DNA lesion involved in inflammation-related carcinogenesis. Prenatally arsenic-exposed newborns had promoter hypomethylation of COX2, EGR1, and SOCS3 in cord blood lymphocytes (p < 0.01). A follow-up study in these prenatally arsenic-exposed children showed a significant hypomethylation of these genes in salivary DNA (p < 0.01). In vitro experiments confirmed that arsenite treatment at short-term high doses (10–100 μM) and long-term low doses (0.5–1 μM) in human lymphoblasts (RPMI 1788) caused promoter hypomethylation of these genes, which was in concordance with an increase in their mRNA expression. Additionally, the level of urinary 8-nitroguanine was significantly higher (p < 0.01) in exposed newborns and children, by 1.4- and 1.8-fold, respectively. Arsenic accumulation in toenails was negatively correlated with hypomethylation of these genes and positively correlated with levels of 8-nitroguanine. These results indicated that early-life exposure to arsenic causes hypomethylation of COX2, EGR1, and SOCS3, increases mRNA expression of these genes, and increases 8-nitroguanine formation. These effects may be linked to mechanisms of arsenic-induced inflammation and cancer development later in life. - Highlight: • Early-life arsenic exposure caused promoter hypomethylation of COX2, EGR1 and SOCS3. • Hypomethylation of these genes is

  8. Hypomethylation of inflammatory genes (COX2, EGR1, and SOCS3) and increased urinary 8-nitroguanine in arsenic-exposed newborns and children

    Phookphan, Preeyaphan; Navasumrit, Panida; Waraprasit, Somchamai; Promvijit, Jeerawan; Chaisatra, Krittinee; Ngaotepprutaram, Thitirat; Ruchirawat, Mathuros

    2017-01-01

    Early-life exposure to arsenic increases risk of developing a variety of non-malignant and malignant diseases. Arsenic-induced carcinogenesis may be mediated through epigenetic mechanisms and pathways leading to inflammation. Our previous study reported that prenatal arsenic exposure leads to increased mRNA expression of several genes related to inflammation, including COX2, EGR1, and SOCS3. This study aimed to investigate the effects of arsenic exposure on promoter DNA methylation and mRNA expression of these inflammatory genes (COX2, EGR1, and SOCS3), as well as the generation of 8-nitroguanine, which is a mutagenic DNA lesion involved in inflammation-related carcinogenesis. Prenatally arsenic-exposed newborns had promoter hypomethylation of COX2, EGR1, and SOCS3 in cord blood lymphocytes (p < 0.01). A follow-up study in these prenatally arsenic-exposed children showed a significant hypomethylation of these genes in salivary DNA (p < 0.01). In vitro experiments confirmed that arsenite treatment at short-term high doses (10–100 μM) and long-term low doses (0.5–1 μM) in human lymphoblasts (RPMI 1788) caused promoter hypomethylation of these genes, which was in concordance with an increase in their mRNA expression. Additionally, the level of urinary 8-nitroguanine was significantly higher (p < 0.01) in exposed newborns and children, by 1.4- and 1.8-fold, respectively. Arsenic accumulation in toenails was negatively correlated with hypomethylation of these genes and positively correlated with levels of 8-nitroguanine. These results indicated that early-life exposure to arsenic causes hypomethylation of COX2, EGR1, and SOCS3, increases mRNA expression of these genes, and increases 8-nitroguanine formation. These effects may be linked to mechanisms of arsenic-induced inflammation and cancer development later in life. - Highlight: • Early-life arsenic exposure caused promoter hypomethylation of COX2, EGR1 and SOCS3. • Hypomethylation of these genes is

  9. Role of early growth response 1 in arteriogenesis: impact on vascular cell proliferation and leukocyte recruitment in vivo.

    Pagel, Judith-Irina; Ziegelhoeffer, Tibor; Heil, Matthias; Fischer, Silvia; Fernández, Borja; Schaper, Wolfgang; Preissner, Klaus T; Deindl, Elisabeth

    2012-03-01

    Based on previous findings that early growth response 1 (Egr-1) participates in leukocyte recruitment and cell proliferation in vitro, this study was designed to investigate its mode of action during arteriogenesis in vivo. In a model of peripheral arteriogenesis, Egr-1 was significantly upregulated in growing collaterals of wild-type (WT) mice, both on mRNA and protein level. Egr-1(-/-) mice demonstrated delayed arteriogenesis after femoral artery ligation. They further showed increased levels of monocytes and granulocytes in the circulation, but reduced levels in adductor muscles under baseline conditions. After femoral artery ligation, elevated numbers of macrophages were detected in the perivascular zone of collaterals in Egr-1(-/-) mice and mRNA of leukocyte recruitment mediators was upregulated. Other Egr family members (Egr-2 to -4) were significantly upregulated only in Egr-1(-/-) mice, suggesting a mechanism of counterbalancing Egr-1 deficiency. Moreover, splicing factor-1, downregulated in WT mice after femoral artery ligation in the process of increased vascular cell proliferation, was upregulated in Egr-1(-/-) mice. αSM-actin on the other hand, significantly downregulated in WT mice, showed no differential expression in Egr-1(-/-) mice. While cell cycle regulator cyclin E and cdc20 were upregulated in Egr-1(-/-) mice, cyclin D1 expression decreased below the detection limit in collaterals, and the proliferation marker ki67 was not differentially expressed. In conclusion, compensation for deficiency in Egr-1 function in leukocyte recruitment can presumably be mediated by other transcription factors; however, Egr-1 is indispensable for effective vascular cell cycle progression in arteriogenesis.

  10. Tet1 overexpression leads to anxiety-like behavior and enhanced fear memories via the activation of calcium-dependent cascade through Egr1 expression in mice.

    Kwon, Wookbong; Kim, Hyeng-Soo; Jeong, Jain; Sung, Yonghun; Choi, Minjee; Park, Song; Lee, Jinhee; Jang, Soyoung; Kim, Sung Hyun; Lee, Sanggyu; Kim, Myoung Ok; Ryoo, Zae Young

    2018-01-01

    Ten-eleven translocation methylcytosine dioxygenase 1 ( Tet1 ) initiates DNA demethylation by converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) at CpG-rich regions of genes, which have key roles in adult neurogenesis and memory. In addition, the overexpression of Tet1 with 5-hmC alteration in patients with psychosis has also been reported, for instance in schizophrenia and bipolar disorders. The mechanism underlying Tet1 overexpression in the brain; however, is still elusive. In the present study, we found that Tet1-transgenic (Tet1-TG) mice displayed abnormal behaviors involving elevated anxiety and enhanced fear memories. We confirmed that Tet1 overexpression affected adult neurogenesis with oligodendrocyte differentiation in the hippocampal dentate gyrus of Tet1-TG mice. In addition, Tet1 overexpression induced the elevated expression of immediate early genes, such as Egr1 , c-fos , Arc , and Bdnf , followed by the activation of intracellular calcium signals ( i.e. , CamKII, ERK, and CREB) in prefrontal and hippocampal neurons. The expression of GABA receptor subunits ( Gabra2 and Gabra4 ) fluctuated in the prefrontal cortex and hippocampus. We evaluated the effects of Tet1 overexpression on intracellular calcium-dependent cascades by activating the Egr1 promoter in vitro Tet1 enhanced Egr1 expression, which may have led to alterations in Gabra2 and Gabra4 expression in neurons. Taken together, we suggest that the Tet1 overexpression in our Tet1-TG mice can be applied as an effective model for studying various stress-related diseases that show hyperactivation of intracellular calcium-dependent cascades in the brain.-Kwon, W., Kim, H.-S., Jeong, J., Sung, Y., Choi, M., Park, S., Lee, J., Jang, S., Kim, S. H., Lee, S., Kim, M. O., Ryoo, Z. Y. Tet1 overexpression leads to anxiety-like behavior and enhanced fear memories via the activation of calcium-dependent cascade through Egr1 expression in mice. © FASEB.

  11. Arabidopsis ETR1 and ERS1 Differentially Repress the Ethylene Response in Combination with Other Ethylene Receptor Genes1[W

    Liu, Qian; Wen, Chi-Kuang

    2012-01-01

    The ethylene response is negatively regulated by a family of five ethylene receptor genes in Arabidopsis (Arabidopsis thaliana). The five members of the ethylene receptor family can physically interact and form complexes, which implies that cooperativity for signaling may exist among the receptors. The ethylene receptor gene mutations etr1-1(C65Y)(for ethylene response1-1), ers1-1(I62P) (for ethylene response sensor1-1), and ers1C65Y are dominant, and each confers ethylene insensitivity. In this study, the repression of the ethylene response by these dominant mutant receptor genes was examined in receptor-defective mutants to investigate the functional significance of receptor cooperativity in ethylene signaling. We showed that etr1-1(C65Y), but not ers1-1(I62P), substantially repressed various ethylene responses independent of other receptor genes. In contrast, wild-type receptor genes differentially supported the repression of ethylene responses by ers1-1(I62P); ETR1 and ETHYLENE INSENSITIVE4 (EIN4) supported ers1-1(I62P) functions to a greater extent than did ERS2, ETR2, and ERS1. The lack of both ETR1 and EIN4 almost abolished the repression of ethylene responses by ers1C65Y, which implied that ETR1 and EIN4 have synergistic effects on ers1C65Y functions. Our data indicated that a dominant ethylene-insensitive receptor differentially repressed ethylene responses when coupled with a wild-type ethylene receptor, which supported the hypothesis that the formation of a variety of receptor complexes may facilitate differential receptor signal output, by which ethylene responses can be repressed to different extents. We hypothesize that plants can respond to a broad ethylene concentration range and exhibit tissue-specific ethylene responsiveness with differential cooperation of the multiple ethylene receptors. PMID:22227969

  12. Honey bee foraging induces upregulation of early growth response protein 1, hormone receptor 38 and candidate downstream genes of the ecdysteroid signalling pathway.

    Singh, A S; Shah, A; Brockmann, A

    2018-02-01

    In honey bees, continuous foraging at an artificial feeder induced a sustained upregulation of the immediate early genes early growth response protein 1 (Egr-1) and hormone receptor 38 (Hr38). This gene expression response was accompanied by an upregulation of several Egr-1 candidate downstream genes: ecdysone receptor (EcR), dopamine/ecdysteroid receptor (DopEcR), dopamine decarboxylase and dopamine receptor 2. Hr38, EcR and DopEcR are components of the ecdysteroid signalling pathway, which is highly probably involved in learning and memory processes in honey bees and other insects. Time-trained foragers still showed an upregulation of Egr-1 when the feeder was presented at an earlier time of the day, suggesting that the genomic response is more dependent on the food reward than training time. However, presentation of the feeder at the training time without food was still capable of inducing a transient increase in Egr-1 expression. Thus, learnt feeder cues, or even training time, probably affect Egr-1 expression. In contrast, whole brain Egr-1 expression changes did not differ between dancing and nondancing foragers. On the basis of our results we propose that food reward induced continuous foraging ultimately elicits a genomic response involving Egr-1 and Hr38 and their downstream genes. Furthermore this genomic response is highly probably involved in foraging-related learning and memory responses. © 2017 The Royal Entomological Society.

  13. The electrostatic role of the Zn-Cys2His2 complex in binding of operator DNA with transcription factors: mouse EGR-1 from the Cys2His2 family.

    Chirgadze, Y N; Boshkova, E A; Polozov, R V; Sivozhelezov, V S; Dzyabchenko, A V; Kuzminsky, M B; Stepanenko, V A; Ivanov, V V

    2018-01-07

    The mouse factor Zif268, known also as early growth response protein EGR-1, is a classical representative for the Cys2His2 transcription factor family. It is required for binding the RNA polymerase with operator dsDNA to initialize the transcription process. We have shown that only in this family of total six Zn-finger protein families the Zn complex plays a significant role in the protein-DNA binding. Electrostatic feature of this complex in the binding of factor Zif268 from Mus musculus with operator DNA has been considered. The factor consists of three similar Zn-finger units which bind with triplets of coding DNA. Essential contacts of the factor with the DNA phosphates are formed by three conservative His residues, one in each finger. We describe here the results of calculations of the electrostatic potentials for the Zn-Cys2His2 complex, Zn-finger unit 1, and the whole transcription factor. The potential of Zif268 has a positive area on the factor surface, and it corresponds exactly to the binding sites of each of Zn-finger units. The main part of these areas is determined by conservative His residues, which form contacts with the DNA phosphate groups. Our result shows that the electrostatic positive potential of this histidine residue is enhanced due to the Zn complex. The other contacts of the Zn-finger with DNA are related to nucleotide bases, and they are responsible for the sequence-specific binding with DNA. This result may be extended to all other members of the Cys2His2 transcription factor family.

  14. Regulation of radiation-induced apoptosis by early growth response-1 gene in solid tumors

    Ahmed, M.

    2003-01-01

    Ionizing radiation exposure is associated with activation of certain immediate-early genes that function as transcription factors. These include members of jun or fos and early growth response (EGR) gene families. In particular, the functional role of EGR-1 in radiation-induced signaling is pivotal since the promoter of EGR-1 contains radiation-inducible CArG DNA sequences. The Egr-1 gene belongs to a family of Egr genes that includes EGR-2, EGR-3, EGR-4, EGR-α and the tumor suppressor, Wilms' tumor gene product, WT1. The Egr-1 gene product, EGR-1, is a nuclear protein that contains three zinc fingers of the C 2 H 2 subtype. The EGR-1 GC-rich consensus target sequence, 5'-GCGT/GGGGCG-3' or 5'-TCCT/ACCTCCTCC-3', has been identified in the promoter regions of transcription factors, growth factors, receptors, cell cycle regulators and pro-apoptotic genes. The gene targets mediated by Egr-1 in response to ionizing radiation include TNF-α , p53, Rb and Bax, all these are effectors of apoptosis. Based on these targets, Egr-1 is a pivotal gene that initiates early signal transduction events in response to ionizing radiation leading to either growth arrest or cell death in tumor cells. There are two potential application of Egr-1 gene in therapy of cancer. First, the Egr-1 promoter contains information for appropriate spatial and temporal expression in-vivo that can be regulated by ionizing radiation to control transcription of genes that have pro-apoptotic and suicidal function. Secondly, EGR-1 protein can eliminate 'induced-radiation resistance' by inhibiting the functions of radiation-induced pro-survival genes (NFκB activity and bcl-2 expression) and activate pro-apoptotic genes (such as bax) to confer a significant radio-sensitizing effect. Together, the reported findings from my laboratory demonstrate clearly that EGR-1 is an early central gene that confers radiation sensitivity and its pro-apoptotic functions are synergized by abrogation of induced radiation

  15. The HMGA1 Pseudogene 7 Induces miR-483 and miR-675 Upregulation by Activating Egr1 through a ceRNA Mechanism

    Marco De Martino

    2017-11-01

    Full Text Available Several studies have established that pseudogene mRNAs can work as competing endogenous RNAs and, when deregulated, play a key role in the onset of human neoplasias. Recently, we have isolated two HMGA1 pseudogenes, HMGA1P6 and HMGA1P7. These pseudogenes have a critical role in cancer progression, acting as micro RNA (miRNA sponges for HMGA1 and other cancer-related genes. HMGA1 pseudogenes were found overexpressed in several human carcinomas, and their expression levels positively correlate with an advanced cancer stage and a poor prognosis. In order to investigate the molecular alterations following HMGA1 pseudogene 7 overexpression, we carried out miRNA sequencing analysis on HMGA1P7 overexpressing mouse embryonic fibroblasts. Intriguingly, the most upregulated miRNAs were miR-483 and miR-675 that have been described as key regulators in cancer progression. Here, we report that HMGA1P7 upregulates miR-483 and miR-675 through a competing endogenous RNA mechanism with Egr1, a transcriptional factor that positively regulates miR-483 and miR-675 expression.

  16. Amitriptyline induces early growth response-1 gene expression via ERK and JNK mitogen-activated protein kinase pathways in rat C6 glial cells.

    Chung, Eun Young; Shin, Soon Young; Lee, Young Han

    2007-07-05

    Astrocytes play important roles in guiding the construction of the nervous system, controlling extracellular ions and neurotransmitters, and regulating CNS synaptogenesis. Egr-1 is a transcription factor involved in neuronal differentiation and astrocyte cell proliferation. In this study, we investigated whether the tricyclic antidepressant (TCA) amitriptyline induces Egr-1 expression in astrocytes using rat C6 glioma cells as a model. We found that amitriptyline increased the expression of Egr-1 in a dose- and time-dependent manner. The amitriptyline-induced Egr-1 expression was mediated through serum response elements (SREs) in the Egr-1 promoter. SREs were activated by the Ets-domain transcription factor Elk-1 through the ERK and JNK mitogen-activated protein (MAP) kinase pathways. The inhibition of the ERK and JNK MAP kinase signals attenuated amitriptyline-induced transactivation of Gal4-Elk-1 and Egr-1 promoter activity. Our findings suggest that the induction of Egr-1 expression in astrocytes may be required to attain the therapeutic effects of antidepressant drugs.

  17. Fos and Egr1 Expression in the Rat Brain in Response to Olfactory Cue after Taste-Potentiated Odor Aversion Retrieval

    Cattarelli, Martine; Dardou, David; Datiche, Frederique

    2006-01-01

    When an odor is paired with a delayed illness, rats acquire a relatively weak odor aversion. In contrast, rats develop a strong aversion to an olfactory cue paired with delayed illness if it is presented simultaneously with a gustatory cue. Such a conditioning effect has been referred to as taste-potentiated odor aversion learning (TPOA). TPOA is…

  18. Rice Ethylene-Response AP2/ERF Factor OsEATB Restricts Internode Elongation by Down-Regulating a Gibberellin Biosynthetic Gene1[W][OA

    Qi, Weiwei; Sun, Fan; Wang, Qianjie; Chen, Mingluan; Huang, Yunqing; Feng, Yu-Qi; Luo, Xiaojin; Yang, Jinshui

    2011-01-01

    Plant height is a decisive factor in plant architecture. Rice (Oryza sativa) plants have the potential for rapid internodal elongation, which determines plant height. A large body of physiological research has shown that ethylene and gibberellin are involved in this process. The APETALA2 (AP2)/Ethylene-Responsive Element Binding Factor (ERF) family of transcriptional factors is only present in the plant kingdom. This family has various developmental and physiological functions. A rice AP2/ERF gene, OsEATB (for ERF protein associated with tillering and panicle branching) was cloned from indica rice variety 9311. Bioinformatic analysis suggested that this ERF has a potential new function. Ectopic expression of OsEATB showed that the cross talk between ethylene and gibberellin, which is mediated by OsEATB, might underlie differences in rice internode elongation. Analyses of gene expression demonstrated that OsEATB restricts ethylene-induced enhancement of gibberellin responsiveness during the internode elongation process by down-regulating the gibberellin biosynthetic gene, ent-kaurene synthase A. Plant height is negatively correlated with tiller number, and higher yields are typically obtained from dwarf crops. OsEATB reduces rice plant height and panicle length at maturity, promoting the branching potential of both tillers and spikelets. These are useful traits for breeding high-yielding crops. PMID:21753115

  19. Top-Down Effect of Direct Current Stimulation on the Nociceptive Response of Rats.

    Luiz Fabio Dimov

    Full Text Available Transcranial direct current stimulation (tDCS is an emerging, noninvasive technique of neurostimulation for treating pain. However, the mechanisms and pathways involved in its analgesic effects are poorly understood. Therefore, we investigated the effects of direct current stimulation (DCS on thermal and mechanical nociceptive thresholds and on the activation of the midbrain periaqueductal gray (PAG and the dorsal horn of the spinal cord (DHSC in rats; these central nervous system areas are associated with pain processing. Male Wistar rats underwent cathodal DCS of the motor cortex and, while still under stimulation, were evaluated using tail-flick and paw pressure nociceptive tests. Sham stimulation and naive rats were used as controls. We used a randomized design; the assays were not blinded to the experimenter. Immunoreactivity of the early growth response gene 1 (Egr-1, which is a marker of neuronal activation, was evaluated in the PAG and DHSC, and enkephalin immunoreactivity was evaluated in the DHSC. DCS did not change the thermal nociceptive threshold; however, it increased the mechanical nociceptive threshold of both hind paws compared with that of controls, characterizing a topographical effect. DCS decreased the Egr-1 labeling in the PAG and DHSC as well as the immunoreactivity of spinal enkephalin. Altogether, the data suggest that DCS disinhibits the midbrain descending analgesic pathway, consequently inhibiting spinal nociceptive neurons and causing an increase in the nociceptive threshold. This study reinforces the idea that the motor cortex participates in the neurocircuitry that is involved in analgesia and further clarifies the mechanisms of action of tDCS in pain treatment.

  20. 20(S)-protopanaxadiol (PPD) alleviates scopolamine-induced memory impairment via regulation of cholinergic and antioxidant systems, and expression of Egr-1, c-Fos and c-Jun in mice.

    Lu, Cong; Dong, Liming; Lv, Jingwei; Wang, Yan; Fan, Bei; Wang, Fengzhong; Liu, Xinmin

    2018-01-05

    20(S)-protopanaxadiol (PPD) possesses various biological properties, including anti-inflammatory, antitumor and anti-fatigue properties. Recent studies found that PPD functioned as a neurotrophic agent to ameliorate the sensory deficit caused by glutamate-induced excitotoxicity through its antioxidant effects and exhibited strong antidepressant-like effects in vivo. The objective of the present study was first to investigate the effect of PPD in scopolamine (SCOP)-induced memory deficit in mice and the potential mechanisms involved. In this study, mice were pretreated with PPD (20 and 40 μmol/kg) and donepezil (1.6 mg/kg) intraperitoneally (i.p) for 14 days. Then, open field test was used to assess the effect of PPD on the locomotor activity and mice were daily injected with SCOP (0.75 mg/kg) to induce cognitive deficits and then subjected to behavioral tests by object location recognition (OLR) experiment and Morris water maze (MWM) task. The cholinergic system function, oxidative stress biomarkers and protein expression of Egr-1, c-Fos, and c-Jun in mouse hippocampus were examined. PPD was found to significantly improve the performance of amnesia mice in OLR and MWM tests. PPD regulated cholinergic function by inhibiting SCOP-induced elevation of acetylcholinesterase (AChE) activity, decline of choline acetyltransferase (ChAT) activity and decrease of acetylcholine (Ach) level. PPD suppressed oxidative stress by increasing activities of antioxidant enzymes such as superoxide dismutase (SOD) and lowering maleic diadehyde (MDA) level. Additionally, PPD significantly elevated the expression of Egr-1, c-Fos, and c-Jun in hippocampus at protein level. Taken together, all these results suggested that 20(S)-protopanaxadiol (PPD) may be a candidate compound for the prevention against memory loss in some neurodegenerative diseases such as Alzheimer's disease (AD). Copyright © 2017. Published by Elsevier B.V.

  1. Activation of PKCβII and PKCθ is essential for LDL-induced cell proliferation of human aortic smooth muscle cells via Gi-mediated Erk1/2 activation and Egr-1 upregulation

    Heo, Kyung-Sun; Kim, Dong-Uk; Kim, Lila; Nam, Miyoung; Baek, Seung-Tae; Park, Song-Kyu; Park, Youngwoo; Myung, Chang-Seon; Hwang, Sung-Ook; Hoe, Kwang-Lae

    2008-01-01

    Native LDL may be a mitogenic stimulus of VSMC proliferation in lesions where endothelial disruption occurs. Recent studies have demonstrated that the mitogenic effects of LDL are accompanied by Erk1/2 activation via an unknown G-protein-coupled receptor (GPCR). In this article, we report that LDL translocated PKCβ II and PKCθ from cytosol to plasma membrane, and inhibition of PKCβ II and PKCθ decreased LDL effects via the deactivation of Erk1/2. Moreover, pertussis toxin, but not cholera toxin or heparin, inhibited LDL-induced translocation of PKCβ II and PKCθ, suggesting that Gi protein plays a role in LDL effects. Of LPA, S1P, and LDL, whose signaling is conveyed via Gi/o proteins, only LDL induced translocation of PKCβ II and PKCθ. Inhibition of PKCβ II or PKCθ, as well as of Erk1/2 and GPCR, decreases LDL-induced upregulation of Egr-1, which is critical for cell proliferation. This is the first report, to our knowledge, that the participation of PKCθ in VSMC proliferation is unique

  2. Neural activity patterns in response to interspecific and intraspecific variation in mating calls in the túngara frog.

    Mukta Chakraborty

    2010-09-01

    Full Text Available During mate choice, individuals must classify potential mates according to species identity and relative attractiveness. In many species, females do so by evaluating variation in the signals produced by males. Male túngara frogs (Physalaemus pustulosus can produce single note calls (whines and multi-note calls (whine-chucks. While the whine alone is sufficient for species recognition, females greatly prefer the whine-chuck when given a choice.To better understand how the brain responds to variation in male mating signals, we mapped neural activity patterns evoked by interspecific and intraspecific variation in mating calls in túngara frogs by measuring expression of egr-1. We predicted that egr-1 responses to conspecific calls would identify brain regions that are potentially important for species recognition and that at least some of those brain regions would vary in their egr-1 responses to mating calls that vary in attractiveness. We measured egr-1 in the auditory brainstem and its forebrain targets and found that conspecific whine-chucks elicited greater egr-1 expression than heterospecific whines in all but three regions. We found no evidence that preferred whine-chuck calls elicited greater egr-1 expression than conspecific whines in any of eleven brain regions examined, in contrast to predictions that mating preferences in túngara frogs emerge from greater responses in the auditory system.Although selectivity for species-specific signals is apparent throughout the túngara frog brain, further studies are necessary to elucidate how neural activity patterns vary with the attractiveness of conspecific mating calls.

  3. Rapid behavioral and genomic responses to social opportunity.

    Sabrina S Burmeister

    2005-11-01

    Full Text Available From primates to bees, social status regulates reproduction. In the cichlid fish Astatotilapia (Haplochromis burtoni, subordinate males have reduced fertility and must become dominant to reproduce. This increase in sexual capacity is orchestrated by neurons in the preoptic area, which enlarge in response to dominance and increase expression of gonadotropin-releasing hormone 1 (GnRH1, a peptide critical for reproduction. Using a novel behavioral paradigm, we show for the first time that subordinate males can become dominant within minutes of an opportunity to do so, displaying dramatic changes in body coloration and behavior. We also found that social opportunity induced expression of the immediate-early gene egr-1 in the anterior preoptic area, peaking in regions with high densities of GnRH1 neurons, and not in brain regions that express the related peptides GnRH2 and GnRH3. This genomic response did not occur in stable subordinate or stable dominant males even though stable dominants, like ascending males, displayed dominance behaviors. Moreover, egr-1 in the optic tectum and the cerebellum was similarly induced in all experimental groups, showing that egr-1 induction in the anterior preoptic area of ascending males was specific to this brain region. Because egr-1 codes for a transcription factor important in neural plasticity, induction of egr-1 in the anterior preoptic area by social opportunity could be an early trigger in the molecular cascade that culminates in enhanced fertility and other long-term physiological changes associated with dominance.

  4. pH modulates the binding of early growth response protein 1 transcription factor to DNA.

    Mikles, David C; Bhat, Vikas; Schuchardt, Brett J; Deegan, Brian J; Seldeen, Kenneth L; McDonald, Caleb B; Farooq, Amjad

    2013-08-01

    The transcription factor early growth response protein (EGR)1 orchestrates a plethora of signaling cascades involved in cellular homeostasis, and its downregulation has been implicated in the development of prostate cancer. Herein, using a battery of biophysical tools, we show that the binding of EGR1 to DNA is tightly regulated by solution pH. Importantly, the binding affinity undergoes an enhancement of more than an order of magnitude with an increase in pH from 5 to 8, implying that the deprotonation of an ionizable residue accounts for such behavior. This ionizable residue is identified as His382 by virtue of the fact that its replacement by nonionizable residues abolishes the pH dependence of the binding of EGR1 to DNA. Notably, His382 inserts into the major groove of DNA, and stabilizes the EGR1-DNA interaction via both hydrogen bonding and van der Waals contacts. Remarkably, His382 is mainly conserved across other members of the EGR family, implying that histidine protonation-deprotonation may serve as a molecular switch for modulating the protein-DNA interactions that are central to this family of transcription factors. Collectively, our findings reveal an unexpected but a key step in the molecular recognition of the EGR family of transcription factors, and suggest that they may act as sensors of pH within the intracellular environment. © 2013 FEBS.

  5. Genetic Variation for Lettuce Seed Thermoinhibition Is Associated with Temperature-Sensitive Expression of Abscisic Acid, Gibberellin, and Ethylene Biosynthesis, Metabolism, and Response Genes1[C][W][OA

    Argyris, Jason; Dahal, Peetambar; Hayashi, Eiji; Still, David W.; Bradford, Kent J.

    2008-01-01

    Lettuce (Lactuca sativa ‘Salinas’) seeds fail to germinate when imbibed at temperatures above 25°C to 30°C (termed thermoinhibition). However, seeds of an accession of Lactuca serriola (UC96US23) do not exhibit thermoinhibition up to 37°C in the light. Comparative genetics, physiology, and gene expression were analyzed in these genotypes to determine the mechanisms governing the regulation of seed germination by temperature. Germination of the two genotypes was differentially sensitive to abscisic acid (ABA) and gibberellin (GA) at elevated temperatures. Quantitative trait loci associated with these phenotypes colocated with a major quantitative trait locus (Htg6.1) from UC96US23 conferring germination thermotolerance. ABA contents were elevated in Salinas seeds that exhibited thermoinhibition, consistent with the ability of fluridone (an ABA biosynthesis inhibitor) to improve germination at high temperatures. Expression of many genes involved in ABA, GA, and ethylene biosynthesis, metabolism, and response was differentially affected by high temperature and light in the two genotypes. In general, ABA-related genes were more highly expressed when germination was inhibited, and GA- and ethylene-related genes were more highly expressed when germination was permitted. In particular, LsNCED4, a gene encoding an enzyme in the ABA biosynthetic pathway, was up-regulated by high temperature only in Salinas seeds and also colocated with Htg6.1. The temperature sensitivity of expression of LsNCED4 may determine the upper temperature limit for lettuce seed germination and may indirectly influence other regulatory pathways via interconnected effects of increased ABA biosynthesis. PMID:18753282

  6. Occupational Styrene Exposure Induces Stress-Responsive Genes Involved in Cytoprotective and Cytotoxic Activities

    Strafella, Elisabetta; Bracci, Massimo; Staffolani, Sara; Manzella, Nicola; Giantomasi, Daniele; Valentino, Matteo; Amati, Monica; Tomasetti, Marco; Santarelli, Lory

    2013-01-01

    Objective The aim of this study was to evaluate the expression of a panel of genes involved in toxicology in response to styrene exposure at levels below the occupational standard setting. Methods Workers in a fiber glass boat industry were evaluated for a panel of stress- and toxicity-related genes and associated with biochemical parameters related to hepatic injury. Urinary styrene metabolites (MA+PGA) of subjects and environmental sampling data collected for air at workplace were used to estimate styrene exposure. Results Expression array analysis revealed massive upregulation of genes encoding stress-responsive proteins (HSPA1L, EGR1, IL-6, IL-1β, TNSF10 and TNFα) in the styrene-exposed group; the levels of cytokines released were further confirmed in serum. The exposed workers were then stratified by styrene exposure levels. EGR1 gene upregulation paralleled the expression and transcriptional protein levels of IL-6, TNSF10 and TNFα in styrene exposed workers, even at low level. The activation of the EGR1 pathway observed at low-styrene exposure was associated with a slight increase of hepatic markers found in highly exposed subjects, even though they were within normal range. The ALT and AST levels were not affected by alcohol consumption, and positively correlated with urinary styrene metabolites as evaluated by multiple regression analysis. Conclusion The pro-inflammatory cytokines IL-6 and TNFα are the primary mediators of processes involved in the hepatic injury response and regeneration. Here, we show that styrene induced stress responsive genes involved in cytoprotection and cytotoxicity at low-exposure, that proceed to a mild subclinical hepatic toxicity at high-styrene exposure. PMID:24086524

  7. T-cell activation and early gene response in dogs.

    Sally-Anne Mortlock

    Full Text Available T-cells play a crucial role in canine immunoregulation and defence against invading pathogens. Proliferation is fundamental to T-cell differentiation, homeostasis and immune response. Initiation of proliferation following receptor mediated stimuli requires a temporally programmed gene response that can be identified as immediate-early, mid- and late phases. The immediate-early response genes in T-cell activation engage the cell cycle machinery and promote subsequent gene activation events. Genes involved in this immediate-early response in dogs are yet to be identified. The present study was undertaken to characterise the early T-cell gene response in dogs to improve understanding of the genetic mechanisms regulating immune function. Gene expression profiles were characterised using canine gene expression microarrays and quantitative reverse transcription PCR (qRT-PCR, and paired samples from eleven dogs. Significant functional annotation clusters were identified following stimulation with phytohemagluttinin (PHA (5μg/ml, including the Toll-like receptor signaling pathway and phosphorylation pathways. Using strict statistical criteria, 13 individual genes were found to be differentially expressed, nine of which have ontologies that relate to proliferation and cell cycle control. These included, prostaglandin-endoperoxide synthase 2 (PTGS2/COX2, early growth response 1 (EGR1, growth arrest and DNA damage-inducible gene (GADD45B, phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1, V-FOS FBJ murine osteosarcoma viral oncogene homolog (FOS, early growth response 2 (EGR2, hemogen (HEMGN, polo-like kinase 2 (PLK2 and polo-like kinase 3 (PLK3. Differential gene expression was re-examined using qRT-PCR, which confirmed that EGR1, EGR2, PMAIP1, PTGS2, FOS and GADD45B were significantly upregulated in stimulated cells and ALAS2 downregulated. PTGS2 and EGR1 showed the highest levels of response in these dogs. Both of these genes are involved in

  8. Topology of transmembrane channel-like gene 1 protein.

    Labay, Valentina; Weichert, Rachel M; Makishima, Tomoko; Griffith, Andrew J

    2010-10-05

    Mutations of transmembrane channel-like gene 1 (TMC1) cause hearing loss in humans and mice. TMC1 is the founding member of a family of genes encoding proteins of unknown function that are predicted to contain multiple transmembrane domains. The goal of our study was to define the topology of mouse TMC1 expressed heterologously in tissue culture cells. TMC1 was retained in the endoplasmic reticulum (ER) membrane of five tissue culture cell lines that we tested. We used anti-TMC1 and anti-HA antibodies to probe the topologic orientation of three native epitopes and seven HA epitope tags along full-length TMC1 after selective or complete permeabilization of transfected cells with digitonin or Triton X-100, respectively. TMC1 was present within the ER as an integral membrane protein containing six transmembrane domains and cytosolic N- and C-termini. There is a large cytoplasmic loop, between the fourth and fifth transmembrane domains, with two highly conserved hydrophobic regions that might associate with or penetrate, but do not span, the plasma membrane. Our study is the first to demonstrate that TMC1 is a transmembrane protein. The topologic organization revealed by this study shares some features with that of the shaker-TRP superfamily of ion channels.

  9. Identification of cornifelin and early growth response-1 gene as novel biomarkers for in vitro eye irritation using a 3D reconstructed human cornea model MCTT HCE™.

    Choi, Seunghye; Lee, Miri; Lee, Su-Hyon; Jung, Haeng-Sun; Kim, Seol-Yeong; Chung, Tae-Young; Choe, Tae-boo; Chun, Young-Jin; Lim, Kyung-Min

    2015-09-01

    Evaluation of the eye irritation is essential in the development of new cosmetic products. Draize rabbit eye irritation test has been widely used in which chemicals are directly applied to rabbit eye, and the symptoms and signs of eyes are scored. However, due to the invasive procedure, it causes substantial pain and discomfort to animals. Recently, we reported in vitro eye irritation test method using a 3D human corneal epithelial model (MCTT HCE™) which is reconstructed from remaining human tissues after a corneal transplantation. This model exhibited an excellent predictive capacity for 25 reference chemicals (sensitivity 100%, specificity 77% and accuracy 88% vs. GHS). To improve the test performance, we explored new biomarkers for the eye irritation through transcriptomic approach. Three surfactants were selected as model eye irritants that include sodium lauryl sulfate, benzalkonium chloride and triton X-100. After test chemicals were treated, we investigated differentially expressed genes through a whole-gene microarray (Affymetrix GeneChip(®) Human Gene 2.0 ST Array, 48,000 probes). As a result, we identified that mRNAs of cornifelin (CNFN), a constituent of the insoluble cornified cell envelope of stratified squamous epithelia, and early growth response-1 (EGR1), a nuclear transcriptional regulator, were significantly up-regulated by all three irritants. Up-regulation of CNFN and EGR1 was further confirmed by Q-RT-PCR, and immunohistochemistry revealed increased level of CNFN in irritant-treated tissues, supporting the relevance of CNFN and EGR1 as new biomarkers for eye irritation.

  10. Plasticity-Related Gene 1 Affects Mouse Barrel Cortex Function via Strengthening of Glutamatergic Thalamocortical Transmission.

    Unichenko, Petr; Kirischuk, Sergei; Yang, Jenq-Wei; Baumgart, Jan; Roskoden, Thomas; Schneider, Patrick; Sommer, Angela; Horta, Guilherme; Radyushkin, Konstantin; Nitsch, Robert; Vogt, Johannes; Luhmann, Heiko J

    2016-07-01

    Plasticity-related gene-1 (PRG-1) is a brain-specific protein that modulates glutamatergic synaptic transmission. Here we investigated the functional role of PRG-1 in adolescent and adult mouse barrel cortex both in vitro and in vivo. Compared with wild-type (WT) animals, PRG-1-deficient (KO) mice showed specific behavioral deficits in tests assessing sensorimotor integration and whisker-based sensory discrimination as shown in the beam balance/walking test and sandpaper tactile discrimination test, respectively. At P25-31, spontaneous network activity in the barrel cortex in vivo was higher in KO mice compared with WT littermates, but not at P16-19. At P16-19, sensory evoked cortical responses in vivo elicited by single whisker stimulation were comparable in KO and WT mice. In contrast, at P25-31 evoked responses were smaller in amplitude and longer in duration in WT animals, whereas KO mice revealed no such developmental changes. In thalamocortical slices from KO mice, spontaneous activity was increased already at P16-19, and glutamatergic thalamocortical inputs to Layer 4 spiny stellate neurons were potentiated. We conclude that genetic ablation of PRG-1 modulates already at P16-19 spontaneous and evoked excitability of the barrel cortex, including enhancement of thalamocortical glutamatergic inputs to Layer 4, which distorts sensory processing in adulthood. © The Author 2016. Published by Oxford University Press.

  11. Expression of immediate-early genes in the inferior colliculus and auditory cortex in salicylate-induced tinnitus in rat.

    Hu, S S; Mei, L; Chen, J Y; Huang, Z W; Wu, H

    2014-03-12

    Tinnitus could be associated with neuronal hyperactivity in the auditory center. As a neuronal activity marker, immediate-early gene (IEG) expression is considered part of a general neuronal response to natural stimuli. Some IEGs, especially the activity-dependent cytoskeletal protein (Arc) and the early growth response gene-1 (Egr-1), appear to be highly correlated with sensory-evoked neuronal activity. We hypothesize, therefore, an increase of Arc and Egr-1 will be observed in a tinnitus model. In our study, we used the gap prepulse inhibition of acoustic startle (GPIAS) paradigm to confirm that salicylate induces tinnitus-like behavior in rats. However, expression of the Arc gene and Egr-1 gene were decreased in the inferior colliculus (IC) and auditory cortex (AC), in contradiction of our hypothesis. Expression of N-methyl d-aspartate receptor subunit 2B (NR2B) was increased and all of these changes returned to normal 14 days after treatment with salicylate ceased. These data revealed long-time administration of salicylate induced tinnitus markedly but reversibly and caused neural plasticity changes in the IC and the AC. Decreased expression of Arc and Egr-1 might be involved with instability of synaptic plasticity in tinnitus.

  12. Expression of immediate-early genes in the inferior colliculus and auditory cortex in salicylate-induced tinnitus in rat

    S.S. Hu

    2014-03-01

    Full Text Available Tinnitus could be associated with neuronal hyperactivity in the auditory center. As a neuronal activity marker, immediate-early gene (IEG expression is considered part of a general neuronal response to natural stimuli. Some IEGs, especially the activity-dependent cytoskeletal protein (Arc and the early growth response gene-1 (Egr-1, appear to be highly correlated with sensory-evoked neuronal activity. We hypothesize, therefore, an increase of Arc and Egr-1 will be observed in a tinnitus model. In our study, we used the gap prepulse inhibition of acoustic startle (GPIAS paradigm to confirm that salicylate induces tinnitus-like behavior in rats. However, expression of the Arc gene and Egr-1 gene were decreased in the inferior colliculus (IC and auditory cortex (AC, in contradiction of our hypothesis. Expression of N-methyl d-aspartate receptor subunit 2B (NR2B was increased and all of these changes returned to normal 14 days after treatment with salicylate ceased. These data revealed long-time administration of salicylate induced tinnitus markedly but reversibly and caused neural plasticity changes in the IC and the AC. Decreased expression of Arc and Egr-1 might be involved with instability of synaptic plasticity in tinnitus.

  13. Persistent effects of chronic clozapine on the cellular and behavioral responses to LSD in mice

    Moreno, José L.; Holloway, Terrell; Umali, Adrienne; Rayannavar, Vinayak; Sealfon, Stuart C.

    2013-01-01

    Rationale In schizophrenia patients, optimal treatment with antipsychotics requires weeks to months of sustained drug therapy. However, single administration of antipsychotic drugs can reverse schizophrenia-like behavioral alterations in rodent models of psychosis. This raises questions about the physiological relevance of such antipsychotic-like activity. Objective This study evaluates the effects of chronic treatment with clozapine on the cellular and behavioral responses induced by the hallucinogenic serotonin 5-HT2A receptor agonist lysergic acid diethylamide (LSD) as a mouse model of psychosis. Method Mice were treated chronically (21 days) with 25 mg/kg/day clozapine. Experiments were conducted 1, 7, 14, and 21 days after the last clozapine administration. [3H]Ketanserin binding and 5-HT2A mRNA expression were determined in mouse somatosensory cortex. Head-twitch behavior, expression of c-fos, which is induced by all 5-HT2A agonists, and expression of egr-1 and egr-2, which are LSD-like specific, were assayed. Results Head-twitch response was decreased and [3H]ketanserin binding was downregulated in 1, 7, and 14 days after chronic clozapine. 5-HT2A mRNA was reduced 1 day after chronic clozapine. Induction of c-fos, but not egr-1 and egr-2, was rescued 7 days after chronic clozapine. These effects were not observed after short treatment (2 days) with clozapine or chronic haloperidol (1 mg/kg/day). Conclusion Our findings provide a murine model of chronic atypical antipsychotic drug action and suggest downregulation of the 5-HT2A receptor as a potential mechanism involved in these persistent therapeutic-like effects. PMID:22842765

  14. The transcription factor EGR1 regulates metastatic potential of v-src transformed sarcoma cells

    Čermák, Vladimír; Kosla, Jan; Plachý, Jiří; Trejbalová, Kateřina; Hejnar, Jiří; Dvořák, Michal

    2010-01-01

    Roč. 67, č. 20 (2010), s. 3557-3568 ISSN 1420-682X R&D Projects: GA AV ČR KAN200520801; GA MŠk(CZ) LC06061; GA ČR(CZ) GA204/07/1030 Institutional research plan: CEZ:AV0Z50520514 Keywords : smooth muscle cells * endothelial kinase * Rho kinase Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 7.047, year: 2010

  15. Plasticity-Related Gene 1 Affects Mouse Barrel Cortex Function via Strengthening of Glutamatergic Thalamocortical Transmission

    Unichenko, Petr; Kirischuk, Sergei; Yang, Jenq-Wei; Baumgart, Jan; Roskoden, Thomas; Schneider, Patrick; Sommer, Angela; Horta, Guilherme; Radyushkin, Konstantin; Nitsch, Robert; Vogt, Johannes; Luhmann, Heiko J.

    2016-01-01

    Plasticity-related gene-1 (PRG-1) is a brain-specific protein that modulates glutamatergic synaptic transmission. Here we investigated the functional role of PRG-1 in adolescent and adult mouse barrel cortex both in vitro and in vivo. Compared with wild-type (WT) animals, PRG-1-deficient (KO) mice showed specific behavioral deficits in tests assessing sensorimotor integration and whisker-based sensory discrimination as shown in the beam balance/walking test and sandpaper tactile discriminatio...

  16. Enhanced efficacy of radiation-induced gene therapy in mice bearing lung adenocarcinoma xenografts using hypoxia responsive elements

    Wang Wei-dong; Chen Zheng-tang; Li De-zhi; Duan Yu-zhong; Cao Zheng-huai; Li Rong

    2005-01-01

    The aim of the present study was to investigate whether the hypoxia responsive element (HRE) could be used to enhance suicide gene (HSV-tk) expression and tumoricidal activity in radiation-controlled gene therapy of human lung adenocarcinoma xenografts. A chimeric promoter, HRE-Egr, was generated by directly linking a 0.3-kb fragment of HRE to a 0.6-kb human Egr-1 promoter. Retroviral vectors containing luciferase or the HSV-tk gene driven by Egr-1 or HRE-Egr were constructed. A human adenocarcinoma cell line (A549) was stably transfected with the above vectors using the lipofectamine method. The sensitivity of transfected cells to prodrug ganciclovir (GCV) and cell survival rates were analyzed after exposure to a dose of 2 Gy radiation and hypoxia (1%). In vivo, tumor xenografts in BALB/c mice were transfected with the constructed retroviruses and irradiated to a total dose of 6 Gy, followed by GCV treatment (20 mg/kg for 14 days). When the HSV-tk gene controlled by the HRE-Egr promoter was introduced into A549 cells by a retroviral vector, the exposure to 1% O 2 and 2 Gy radiation induced significant enhancement of GCV cytotoxicity to the cells. Moreover, in nude mice bearing solid tumor xenografts, only the tumors infected with the hybrid promoter-containing virus gradually disappeared after GCV administration and radiation. These results indicate that HRE can enhance transgene expression and tumoricidal activity in HSV-tk gene therapy controlled by ionizing radiation in hypoxic human lung adenocarcinoma. (author)

  17. Expression of immediate-early genes in the dorsal cochlear nucleus in salicylate-induced tinnitus.

    Hu, Shou-Sen; Mei, Ling; Chen, Jian-Yong; Huang, Zhi-Wu; Wu, Hao

    2016-02-01

    Spontaneous neuronal activity in dorsal cochlear nucleus (DCN) may be involved in the physiological processes underlying salicylate-induced tinnitus. As a neuronal activity marker, immediate-early gene (IEG) expression, especially activity-dependent cytoskeletal protein (Arc/Arg3.1) and the early growth response gene-1 (Egr-1), appears to be highly correlated with sensory-evoked neuronal activity. However, their relationships with tinnitus induced by salicylate have rarely been reported in the DCN. In this study, we assessed the effect of acute and chronic salicylate treatment on the expression of N-methyl D-aspartate receptor subunit 2B (NR2B), Arg3.1, and Egr-1. We also observed ultrastructural alterations in the DCN synapses in an animal model of tinnitus. Levels of mRNA and protein expression of NR2B and Arg3.1 were increased in rats that were chronically administered salicylate (200 mg/kg, twice daily for 3, 7, or 14 days). These levels returned to baseline 14 days after cessation of treatment. However, no significant changes were observed in Egr-1 gene expression in any groups. Furthermore, rats subjected to long-term salicylate administration showed more presynaptic vesicles, thicker and longer postsynaptic densities, and increased synaptic interface curvature. Alterations of Arg3.1 and NR2B may be responsible for the changes in the synaptic ultrastructure. These changes confirm that salicylate can cause neural plasticity changes at the DCN level.

  18. Response

    Higgins, Chris

    2012-01-01

    This article presents the author's response to the reviews of his book, "The Good Life of Teaching: An Ethics of Professional Practice." He begins by highlighting some of the main concerns of his book. He then offers a brief response, doing his best to address the main criticisms of his argument and noting where the four reviewers (Charlene…

  19. TGF-beta-induced early gene-1 overexpression promotes oxidative stress protection and actin cytoskeleton rearrangement in human skin fibroblasts.

    Leduc, Chloe; Sobilo, Lauren; Toumi, Hechmi; Mondon, Philippe; Lespessailles, Eric; Ossant, Fédéric; Kurfurst, Robin; Pichon, Chantal

    2016-06-01

    Transforming growth factor beta inducible early gene-1 (TIEG-1), a member of the Krüppel-like factor, was identified as a primary response gene for TGF-β. The role of TIEG-1 in skin repair has been mainly addressed in vivo on TIEG-1 null mice model and the mechanism remains unexplored. We investigated the modulation of TIEG-1 expression in normal human skin fibroblasts by either down-expressing or overexpressing the gene. We evaluated reactive oxygen species production and the cell viability of treated cells. The effect of TIEG-1 overexpression was monitored by wound healing assay and immunofluorescence staining of actin fibers organization and alpha-smooth muscle actin (α-SMA). Western blots were carried out to identify the level of expression or phosphorylation of key proteins such as cofilin, Rho GTPases, and p38 mitogen-activated protein kinase (p38 MAPK). TIEG-1 down-regulation had a deleterious effect on the cell viability. It was significantly reduced (65±5%) and exposure to ultraviolet further increased this effect (47±3%). By contrast, cells overexpressing TIEG-1 had a reduced reactive oxygen species production (75%) compared to control and mock-transfected cells. This overexpression also resulted in formation of actin stress fibers and increased α-SMA expression and an enhanced wound healing feature. RhoB GTPase was upregulated and phosphorylation of cofilin and p38 MAPK was observed. TIEG-1 overexpression in normal human skin fibroblasts results in improved resistance to oxidative stress, myofibroblast-like conversion that involved RhoB signaling pathway with cofilin and p38 MAPK proteins activation. This study enlightens the role of TIEG-1 role in skin biology. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. The noncoding RNA taurine upregulated gene 1 is required for differentiation of the murine retina.

    Young, T L; Matsuda, T; Cepko, C L

    2005-03-29

    With the advent of genome-wide analyses, it is becoming evident that a large number of noncoding RNAs (ncRNAs) are expressed in vertebrates. However, of the thousands of ncRNAs identified, the functions of relatively few have been established. In a screen for genes upregulated by taurine in developing retinal cells, we identified a gene that appears to be a ncRNA. Taurine Upregulated Gene 1 (TUG1) is a spliced, polyadenylated RNA that does not encode any open reading frame greater than 82 amino acids in its full-length, 6.7 kilobase (kb) RNA sequence. Analyses of Northern blots and in situ hybridization revealed that TUG1 is expressed in the developing retina and brain, as well as in adult tissues. In the newborn retina, knockdown of TUG1 with RNA interference (RNAi) resulted in malformed or nonexistent outer segments of transfected photoreceptors. Immunofluorescent staining and microarray analyses suggested that this loss of proper photoreceptor differentiation is a result of the disregulation of photoreceptor gene expression. A function for a newly identified ncRNA, TUG1, has been established. TUG1 is necessary for the proper formation of photoreceptors in the developing rodent retina.

  1. Dual responsive promoters to target therapeutic gene expression to radiation-resistant hypoxic tumor cells

    Chadderton, Naomi; Cowen, Rachel L.; Sheppard, Freda C.D.; Robinson, Suzanne; Greco, Olga; Scott, Simon D.; Stratford, Ian J.; Patterson, Adam V.; Williams, Kaye J.

    2005-01-01

    Purpose: Tumor hypoxia is unequivocally linked to poor radiotherapy outcome. This study aimed to identify enhancer sequences that respond maximally to a combination of radiation and hypoxia for use in genetic radiotherapy approaches. Methods and materials: The influence of radiation (5 Gy) and hypoxia (1% O 2 ) on reporter-gene expression driven by hypoxia (HRE) and radiation (Egr-1) responsive elements was evaluated in tumor cells grown as monolayers or multicellular spheroids. Hypoxia-inducible factor-1α (HIF-1α) and HIF-2α protein expression was monitored in parallel. Results: Of the sequences tested, an HRE from the phosphoglycerate kinase-1 gene (PGK-18[5+]) was maximally induced in response to hypoxia plus radiation in all 5 cell lines tested. The additional radiation treatment afforded a significant increase in the induction of PGK-18[5+] compared with hypoxia alone in 3 cell lines. HIF-1α/2α were induced by radiation but combined hypoxia/radiation treatment did not yield a further increase. The dual responsive nature of HREs was maintained when spheroids were irradiated after delivery of HRE constructs in a replication-deficient adenovirus. Conclusions: Hypoxia-responsive enhancer element sequences are dually responsive to combined radiation and hypoxic treatment. Their use in genetic radiotherapy in vivo could maximize expression in the most radio-resistant population at the time of radiation and also exploit microenvironmental changes after radiotherapy to yield additional switch-on

  2. The pituitary tumor transforming gene 1 (PTTG-1: An immunological target for multiple myeloma

    Gagliano Nicoletta

    2008-04-01

    Full Text Available Abstract Background Multiple Myeloma is a cancer of B plasma cells, which produce non-specific antibodies and proliferate uncontrolled. Due to the potential relapse and non-specificity of current treatments, immunotherapy promises to be more specific and may induce long-term immunity in patients. The pituitary tumor transforming gene 1 (PTTG-1 has been shown to be a novel oncogene, expressed in the testis, thymus, colon, lung and placenta (undetectable in most other tissues. Furthermore, it is over expressed in many tumors such as the pituitary adenoma, breast, gastrointestinal cancers, leukemia, lymphoma, and lung cancer and it seems to be associated with tumorigenesis, angiogenesis and cancer progression. The purpose was to investigate the presence/rate of expression of PTTG-1 in multiple myeloma patients. Methods We analyzed the PTTG-1 expression at the transcriptional and the protein level, by PCR, immunocytochemical methods, Dot-blot and ELISA performed on patient's sera in 19 multiple myeloma patients, 6 different multiple myeloma cell lines and in normal human tissue. Results We did not find PTTG-1 presence in the normal human tissue panel, but PTTG-1 mRNA was detectable in 12 of the 19 patients, giving evidence of a 63% rate of expression (data confirmed by ELISA. Four of the 6 investigated cell lines (66.6% were positive for PTTG-1. Investigations of protein expression gave evidence of 26.3% cytoplasmic expression and 16% surface expression in the plasma cells of multiple myeloma patients. Protein presence was also confirmed by Dot-blot in both cell lines and patients. Conclusion We established PTTG-1's presence at both the transcriptional and protein levels. These data suggest that PTTG-1 is aberrantly expressed in multiple myeloma plasma cells, is highly immunogenic and is a suitable target for immunotherapy of multiple myeloma.

  3. A novel role of astrocyte elevated gene-1 (AEG-1) in regulating nonalcoholic steatohepatitis (NASH).

    Srivastava, Jyoti; Robertson, Chadia L; Ebeid, Kareem; Dozmorov, Mikhail; Rajasekaran, Devaraja; Mendoza, Rachel; Siddiq, Ayesha; Akiel, Maaged A; Jariwala, Nidhi; Shen, Xue-Ning; Windle, Jolene J; Subler, Mark A; Mukhopadhyay, Nitai D; Giashuddin, Shah; Ghosh, Shobha; Lai, Zhao; Chen, Yidong; Fisher, Paul B; Salem, Aliasger K; Sanyal, Arun J; Sarkar, Devanand

    2017-08-01

    Nonalcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease in the Western world. However, an optimum therapy for NASH is yet to be established, mandating more in-depth investigation into the molecular pathogenesis of NASH to identify novel regulatory molecules and develop targeted therapies. Here, we unravel a unique function of astrocyte elevated gene-1(AEG-1)/metadherin in NASH using a transgenic mouse with hepatocyte-specific overexpression of AEG-1 (Alb/AEG-1) and a conditional hepatocyte-specific AEG-1 knockout mouse (AEG-1 ΔHEP ). Alb/AEG-1 mice developed spontaneous NASH whereas AEG-1 ΔHEP mice were protected from high-fat diet (HFD)-induced NASH. Intriguingly, AEG-1 overexpression was observed in livers of NASH patients and wild-type (WT) mice that developed steatosis upon feeding HFD. In-depth molecular analysis unraveled that inhibition of peroxisome proliferator-activated receptor alpha activity resulting in decreased fatty acid β-oxidation, augmentation of translation of fatty acid synthase resulting in de novo lipogenesis, and increased nuclear factor kappa B-mediated inflammation act in concert to mediate AEG-1-induced NASH. Therapeutically, hepatocyte-specific nanoparticle-delivered AEG-1 small interfering RNA provided marked protection from HFD-induced NASH in WT mice. AEG-1 might be a key molecule regulating initiation and progression of NASH. AEG-1 inhibitory strategies might be developed as a potential therapeutic intervention in NASH patients. (Hepatology 2017;66:466-480). © 2017 by the American Association for the Study of Liver Diseases.

  4. [Clinical characteristics of human recombination activating gene 1 mutations in 8 immunodeficiency patients with diverse phenotypes].

    Yu, G; Wang, W J; Liu, D R; Tao, Z F; Hui, X Y; Hou, J; Sun, J Q; Wang, X C

    2018-03-02

    Objective: To investigate the clinical characteristics of 8 immunodeficiency cases caused by human recombination activating gene 1 (RAG1) mutations, and to explore the relationship among genotypes, clinical manifestations and immunophenotypes. Methods: Clinical data were collected and analyzed from patients with RAG1 mutations who visited the Department of Clinical Immunology, Children's Hospital of Fudan University between October 2013 and June 2017. The data included clinical manifestations, immunophenotypes and genotypes. Results: A total of 8 patients were diagnosed with RAG1 deficiency (6 boys and 2 girls). The minimum age of onset was 2 months, and the maximum age was 4 months. The minimum age of diagnosis was 2 months, and the maximum age was 13 years. Four patients had a family history of infant death due to severe infections. Two cases were born to the same consanguineous parents. All cases had recurrent infections, including involvement of respiratory tract (8 cases), digestive tract (6 cases), urinary tract (1 case), and central nervous system (1 case). The pathogens of infection included bacteria, viruses and fungi. Rotavirus was found in 3 cases, cytomegalovirus (CMV) in 5 cases, bacillus Calmette-Guérin adverse reaction in 2 cases (1 of whom had a positive acid-fast smear from lymph node puncture fluid), fungal infection in 3 cases. One case had multiple nodular space-occupying lesions in lungs and abdominal cavity complicated with multiple bone destruction. The peripheral blood lymphocyte counts of all patients ranged between 0.1 ×10(9)/L and 3.3×10(9)/L (median, 0.65×10(9)/L). Eosinophilia was found in 3 cases (range, (0.48-1.69) ×10(9)/L). The patients were classified according to immunophenotype as severe combined immunodeficiency phenotype (4 cases), leaky severe combined immunodeficiency (2 cases), Omenn syndrome (1 case) and combined immunodeficiency (1 case) . Decreased serum IgG levels were found in 3 cases, increased serum IgM levels in

  5. Activation of Tax protein by c-Jun-N-terminal kinase is not dependent on the presence or absence of the early growth response-1 gene product.

    Parra, Eduardo; Gutierréz, Luís; Ferreira, Jorge

    2016-02-01

    The Tax protein of human T cell leukemia virus type 1 plays a major role in the pathogenesis of adult T cell leukemia (ATL), an aggressive neoplasia of CD4+ T cells. In the present study, we investigated whether the EGR-1 pathway is involved in the regulation of Tax-induced JNK expression in human Jurkat T cells transfected to express the Tax protein in the presence or absence of PMA or ionomycin. Overexpression of EGR-1 in Jurkat cells transfected to express Tax, promoted the activation of several genes, with the most potent being those that contained AP-1 (Jun/c-Fos), whereas knockdown of endogenous EGR-1 by small interfering RNA (siRNA) somewhat reduced Tax-mediated JNK-1 transcription. Additionally, luciferase-based AP-1 and NF-κB reporter gene assays demonstrated that inhibition of EGR-1 expression by an siRNA did not affect the transcriptional activity of a consensus sequence of either AP-1 or NF-κB. On the other hand, the apoptosis assay, using all-trans retinoic acid (ATRA) as an inducer of apoptosis, confirmed that siRNA against EGR-1 failed to suppress ATRA-induced apoptosis in Jurkat and Jurkat-Tax cells, as noted by the low levels of both DEVDase activity and DNA fragmentation, indicating that the induction of apoptosis by ATRA was Egr-1-independent. Finally, our data showed that activation of Tax by JNK-1 was not dependent on the EGR-1 cascade of events, suggesting that EGR-1 is important but not a determinant for the activity for Tax-induced proliferation of Jurkat cells.

  6. Chlamydia trachomatis induces an upregulation of molecular biomarkers podoplanin, Wilms' tumour gene 1, osteopontin and inflammatory cytokines in human mesothelial cells.

    De Filippis, Anna; Buommino, Elisabetta; Domenico, Marina Di; Feola, Antonia; Brunetti-Pierri, Raffaella; Rizzo, Antonietta

    2017-05-01

    Chlamydia trachomatis is the most prevalent infection of the genital tract in women worldwide. C. trachomatis has a tendency to cause persistent infection and induce a state of chronic inflammation, which has been reported to play a role in carcinogenesis. We report that persistent C. trachomatis infection increases the expression of inflammatory tumour cytokines and upregulates molecular biomarkers such as podoplanin, Wilms' tumour gene 1 and osteopontin in primary cultures of mesothelial cells (Mes1) and human mesothelioma cells (NCI). Infection experiments showed that Mes1 and NCI supported the growth of C. trachomatisin vitro, and at an m.o.i. of 4, the inclusion-forming units/cell showed many intracellular inclusion bodies after 3 days of infection. However, after 7 days of incubation, increased proliferative and invasive activity was also observed in Mes1 cells, which was more evident after 14 days of incubation. ELISA analysis revealed an increase in vascular endothelial growth factor, IL-6, IL-8, and TNF-α release in Mes1 cells infected for a longer period (14 days). Finally, real-time PCR analysis revealed a strong induction of podoplanin, Wilms' tumour gene 1 and osteopontin gene expression in infected Mes1 cells. The aim of the present study was to investigate the inflammatory response elicited by C. trachomatis persistent infection and the role played by inflammation in cell proliferation, secretion of proinflammatory cytokines and molecular biomarkers of cancer. The results of this study suggest that increased molecular biomarkers of cancer by persistent inflammation from C. trachomatis infection might support cellular transformation, thus increasing the risk of cancer.

  7. Comparison of Nasal Epithelial Smoking-Induced Gene Expression on Affymetrix Exon 1.0 and Gene 1.0 ST Arrays

    Xiaoling Zhang

    2013-01-01

    Full Text Available We have previously defined the impact of tobacco smoking on nasal epithelium gene expression using Affymetrix Exon 1.0 ST arrays. In this paper, we compared the performance of the Affymetrix GeneChip Human Gene 1.0 ST array with the Human Exon 1.0 ST array for detecting nasal smoking-related gene expression changes. RNA collected from the nasal epithelium of five current smokers and five never smokers was hybridized to both arrays. While the intersample correlation within each array platform was relatively higher in the Gene array than that in the Exon array, the majority of the genes most changed by smoking were tightly correlated between platforms. Although neither array dataset was powered to detect differentially expressed genes (DEGs at a false discovery rate (FDR <0.05, we identified more DEGs than expected by chance using the Gene ST array. These findings suggest that while both platforms show a high degree of correlation for detecting smoking-induced differential gene expression changes, the Gene ST array may be a more cost-effective platform in a clinical setting for gene-level genomewide expression profiling and an effective tool for exploring the host response to cigarette smoking and other inhaled toxins.

  8. Expression of hypoxia-inducible factor 1 alpha and oligodendrocyte lineage gene-1 in cultured brain slices after oxygen-glucose deprivation☆

    Cui, Hong; Han, Weijuan; Yang, Lijun; Chang, Yanzhong

    2013-01-01

    Oligodendrocyte lineage gene-1 expressed in oligodendrocytes may trigger the repair of neuronal myelin impairment, and play a crucial role in myelin repair. Hypoxia-inducible factor 1α, a transcription factor, is of great significance in premature infants with hypoxic-ischemic brain damage. There is little evidence of direct regulatory effects of hypoxia-inducible factor 1α on oligodendrocyte lineage gene-1. In this study, brain slices of Sprague-Dawley rats were cultured and subjected to oxy...

  9. A mouse strain less responsive to dioxin-induced prostaglandin E2 synthesis is resistant to the onset of neonatal hydronephrosis.

    Aida-Yasuoka, Keiko; Yoshioka, Wataru; Kawaguchi, Tatsuya; Ohsako, Seiichiroh; Tohyama, Chiharu

    2014-10-01

    Dioxin is a ubiquitous environmental pollutant that induces toxicity when bound to the aryl hydrocarbon receptor (AhR). Significant differences in susceptibility of mouse strains to dioxin toxicity are largely accounted for by the dissociation constant of binding to dioxins of AhR subtypes encoded by different alleles. We showed that cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1), components of a prostanoid synthesis pathway, play essential roles in the onset of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced hydronephrosis of neonatal mice. Although C57BL/6J and BALB/cA mice harbor AhR receptors highly responsive to TCDD, they were found by chance to differ significantly in the incidence of TCDD-induced hydronephrosis. Therefore, the goal of the present study was to determine the molecular basis of this difference in susceptibility to TCDD toxicity. For this purpose, we administered C57BL/6J and BALB/cA dams' TCDD at an oral dose of 15 or 80 μg/kg on postnatal day (PND) 1 to expose pups to TCDD via lactation, and the pups' kidneys were collected on PND 7. The incidence of hydronephrosis in C57BL/6J pups (64%) was greater than in BALB/cA pups (0%, p hydronephrosis in these mouse strains paralleled the levels of renal mPGES-1 mRNA and early growth response 1 (Egr-1) that modulates mPGES-1 gene expression, as well as PGE2 concentrations in urine. Although these mouse strains possess AhR alleles tightly bound to TCDD, their difference in incidence and severity of hydronephrosis can be explained, in part, by differences in the expression of mPGES-1 and Egr-1. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  10. The EP4 receptor antagonist, L-161,982, blocks prostaglandin E2-induced signal transduction and cell proliferation in HCA-7 colon cancer cells

    Cherukuri, Durga Prasad; Chen, Xiao B.O.; Goulet, Anne-Christine; Young, Robert N.; Han, Yongxin; Heimark, Ronald L.; Regan, John W.; Meuillet, Emmanuelle; Nelson, Mark A.

    2007-01-01

    Accumulating evidence indicates that elevated levels of prostaglandin E 2 (PGE 2 ) can increase intestinal epithelial cell proliferation, and thus play a role in colorectal tumorigenesis. PGE 2 exerts its effects through four G-protein-coupled PGE receptor (EP) subtypes, named the EP1, EP2, EP3, and EP4. Increased phosphorylation of extracellular regulated kinases (ERK1/2) is required for PGE 2 to stimulate cell proliferation of human colon cancer cells. However, the EP receptor(s) that are involved in this process remain unknown. We provide evidence that L-161,982, a selective EP4 receptor antagonist, completely blocks PGE 2 -induced ERK phosphorylation and cell proliferation of HCA-7 cells. In order to identify downstream target genes of ERK1/2 signaling, we found that PGE 2 induces expression of early growth response gene-1 (EGR-1) downstream of ERK1/2 and regulates its expression at the level of transcription. PGE 2 treatment induces phosphorylation of cyclic AMP response element binding protein (CREB) at Ser133 residue and CRE-mediated luciferase activity in HCA-7 cells. Studies with dominant-negative CREB mutant (ACREB) provide clear evidence for the involvement of CREB in PGE 2 driven egr-1 transcription in HCA-7 cells. In conclusion, this study reveals that egr-1 is a target gene of PGE 2 in HCA-7 cells and is regulated via the newly identified EP4/ERK/CREB pathway. Finally our results support the notion that antagonizing EP4 receptors may provide a novel therapeutic approach to the treatment of colon cancer

  11. Taurine up-regulated gene 1 functions as a master regulator to coordinate glycolysis and metastasis in hepatocellular carcinoma.

    Lin, Yang-Hsiang; Wu, Meng-Han; Huang, Ya-Hui; Yeh, Chau-Ting; Cheng, Mei-Ling; Chi, Hsiang-Cheng; Tsai, Chung-Ying; Chung, I-Hsiao; Chen, Ching-Ying; Lin, Kwang-Huei

    2018-01-01

    Cancer cells display altered glucose metabolism characterized by a preference for aerobic glycolysis. The aerobic glycolytic phenotype of hepatocellular carcinoma (HCC) is often correlated with tumor progression and poorer clinical outcomes. However, the issue of whether glycolytic metabolism influences metastasis in HCC remains unclear. In the current study, we showed that knockdown of taurine up-regulated gene 1 (TUG1) induces marked inhibition of cell migration, invasion, and glycolysis through suppression of microRNA (miR)-455-3p. MiR-455-3p, which is transcriptionally repressed by p21, directly targets the 3' untranslated region of adenosine monophosphate-activated protein kinase subunit beta 2 (AMPKβ2). The TUG1/miR-455-3p/AMPKβ2 axis regulates cell growth, metastasis, and glycolysis through regulation of hexokinase 2 (HK2). TUG1 is clearly associated with HK2 overexpression and unfavorable prognosis in HCC patients. Our data collectively highlight that novel regulatory associations among TUG1, miR-455-3p, AMPKβ2, and HK2 are an important determinant of glycolytic metabolism and metastasis in HCC cells and support the potential utility of targeting TUG1/HK2 as a therapeutic strategy for HCC. (Hepatology 2018;67:188-203). © 2017 by the American Association for the Study of Liver Diseases.

  12. Taurine‑upregulated gene 1: A vital long non‑coding RNA associated with cancer in humans (Review).

    Wang, Wen-Yu; Wang, Yan-Fen; Ma, Pei; Xu, Tong-Peng; Shu, Yong-Qian

    2017-11-01

    It is widely reported that long non‑coding RNAs (lncRNAs) are involved in regulating cell differentiation, proliferation, apoptosis and other biological processes. Certain lncRNAs have been found to be crucial in various types of tumor. Taurine‑upregulated gene 1 (TUG1) has been shown to be expressed in a tissue‑specific pattern and exert oncogenic or tumor suppressive functions in different types of cancer in humans. According to previous studies, TUG1 is predominantly located in the nucleus and may regulate gene expression at the transcriptional level. It mediates chromosomal remodeling and coordinates with polycomb repressive complex 2 (PRC2) to regulate gene expression. Although the mechanisms of how TUG1 affects the tumor genesis process remain to be fully elucidated, increasing studies have suggested that TUG1 offers potential as a diagnostic and prognostic biomarker, and as a therapeutic target in certain types of tumor. This review aims to summarize current evidence concerning the characteristics, mechanisms and associations with cancer of TUG1.

  13. Knockdown of astrocyte elevated gene-1 inhibits proliferation and enhancing chemo-sensitivity to cisplatin or doxorubicin in neuroblastoma cells

    Xie Li

    2009-02-01

    Full Text Available Abstract Background Astrocyte elevated gene-1 (AEG-1 was originally characterized as a HIV-1-inducible gene in primary human fetal astrocyte. Recent studies highlight a potential role of AEG-1 in promoting tumor progression and metastasis. The aim of this study was to investigate if AEG-1 serves as a potential therapeutic target of human neuroblastoma. Methods We employed RNA interference to reduce AEG-1 expression in human neuroblastoma cell lines and analyzed their phenotypic changes. Results We found that the knockdown of AEG-1 expression in human neuroblastoma cells significantly inhibited cell proliferation and apoptosis. The specific downregulation induced cell arrest in the G0/G1 phase of cell cycle. In the present study, we also observed a significant enhancement of chemo-sensitivity to cisplatin and doxorubicin by knockdown of AEG-1. Conclusion Our study suggests that overexpressed AEG-1 enhance the tumorogenic properties of neuroblastoma cells. The inhibition of AEG-1 expression could be a new adjuvant therapy for neuroblastoma.

  14. Interactions between BMP-7 and USAG-1 (uterine sensitization-associated gene-1 regulate supernumerary organ formations.

    Honoka Kiso

    Full Text Available Bone morphogenetic proteins (BMPs are highly conserved signaling molecules that are part of the transforming growth factor (TGF-beta superfamily, and function in the patterning and morphogenesis of many organs including development of the dentition. The functions of the BMPs are controlled by certain classes of molecules that are recognized as BMP antagonists that inhibit BMP binding to their cognate receptors. In this study we tested the hypothesis that USAG-1 (uterine sensitization-associated gene-1 suppresses deciduous incisors by inhibition of BMP-7 function. We learned that USAG-1 and BMP-7 were expressed within odontogenic epithelium as well as mesenchyme during the late bud and early cap stages of tooth development. USAG-1 is a BMP antagonist, and also modulates Wnt signaling. USAG-1 abrogation rescued apoptotic elimination of odontogenic mesenchymal cells. BMP signaling in the rudimentary maxillary incisor, assessed by expressions of Msx1 and Dlx2 and the phosphorylation of Smad protein, was significantly enhanced. Using explant culture and subsequent subrenal capsule transplantation of E15 USAG-1 mutant maxillary incisor tooth primordia supplemented with BMP-7 demonstrated in USAG-1+/- as well as USAG-1-/- rescue and supernumerary tooth development. Based upon these results, we conclude that USAG-1 functions as an antagonist of BMP-7 in this model system. These results further suggest that the phenotypes of USAG-1 and BMP-7 mutant mice reported provide opportunities for regenerative medicine and dentistry.

  15. Attenuated hypertrophic response to pressure overload in a lamin A/C haploinsufficiency mouse.

    Cupesi, Mihaela; Yoshioka, Jun; Gannon, Joseph; Kudinova, Anastacia; Stewart, Colin L; Lammerding, Jan

    2010-06-01

    Inherited mutations cause approximately 30% of all dilated cardiomyopathy cases, with autosomal dominant mutations in the LMNA gene accounting for more than one third of these. The LMNA gene encodes the nuclear envelope proteins lamins A and C, which provide structural support to the nucleus and also play critical roles in transcriptional regulation. Functional deletion of a single allele is sufficient to trigger dilated cardiomyopathy in humans and mice. However, whereas Lmna(-/-) mice develop severe muscular dystrophy and dilated cardiomyopathy and die by 8 weeks of age, heterozygous Lmna(+/-) mice have a much milder phenotype, with changes in ventricular function and morphology only becoming apparent at 1 year of age. Here, we studied 8- to 20-week-old Lmna(+/-) mice and wild-type littermates in a pressure overload model to examine whether increased mechanical load can accelerate or exacerbate myocardial dysfunction in the heterozygotes. While overall survival was similar between genotypes, Lmna(+/-) animals had a significantly attenuated hypertrophic response to pressure overload as evidenced by reduced ventricular mass and myocyte size. Analysis of pressure overload-induced transcriptional changes suggested that the reduced hypertrophy in the Lmna(+/-) mice was accompanied by impaired activation of the mechanosensitive gene Egr-1. In conclusion, our findings provide further support for a critical role of lamins A and C in regulating the cellular response to mechanical stress in cardiomyocytes and demonstrate that haploinsufficiency of lamins A and C alone is sufficient to alter hypertrophic responses and cardiac function in the face of pressure overload in the heart. (c) 2009 Elsevier Ltd. All rights reserved.

  16. Correlation of N-myc downstream-regulated gene 1 subcellular localization and lymph node metastases of colorectal neoplasms

    Song, Yan [Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014 (China); Lv, Liyang [Department of Health, Jinan Military Area Command, Jinan 250022 (China); Du, Juan; Yue, Longtao [Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014 (China); Cao, Lili, E-mail: cllly22@163.com [Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014 (China)

    2013-09-20

    Highlights: •We clarified NDRG1 subcellular location in colorectal cancer. •We found the changes of NDRG1 distribution during colorectal cancer progression. •We clarified the correlation between NDRG1 distribution and lymph node metastasis. •It is possible that NDRG1 subcellular localization may determine its function. •Maybe NDRG1 is valuable early diagnostic markers for metastasis. -- Abstract: In colorectal neoplasms, N-myc downstream-regulated gene 1 (NDRG1) is a primarily cytoplasmic protein, but it is also expressed on the cell membrane and in the nucleus. NDRG1 is involved in various stages of tumor development in colorectal cancer, and it is possible that the different subcellular localizations may determine the function of NDRG1 protein. Here, we attempt to clarify the characteristics of NDRG1 protein subcellular localization during the progression of colorectal cancer. We examined NDRG1 expression in 49 colorectal cancer patients in cancerous, non-cancerous, and corresponding lymph node tissues. Cytoplasmic and membrane NDRG1 expression was higher in the lymph nodes with metastases than in those without metastases (P < 0.01). Nuclear NDRG1 expression in colorectal neoplasms was significantly higher than in the normal colorectal mucosa, and yet the normal colorectal mucosa showed no nuclear expression. Furthermore, our results showed higher cytoplasmic NDRG1 expression was better for differentiation, and higher membrane NDRG1 expression resulted in a greater possibility of lymph node metastasis. These data indicate that a certain relationship between the cytoplasmic and membrane expression of NDRG1 in lymph nodes exists with lymph node metastasis. NDRG1 expression may translocate from the membrane of the colorectal cancer cells to the nucleus, where it is involved in lymph node metastasis. Combination analysis of NDRG1 subcellular expression and clinical variables will help predict the incidence of lymph node metastasis.

  17. Correlation of N-myc downstream-regulated gene 1 subcellular localization and lymph node metastases of colorectal neoplasms

    Song, Yan; Lv, Liyang; Du, Juan; Yue, Longtao; Cao, Lili

    2013-01-01

    Highlights: •We clarified NDRG1 subcellular location in colorectal cancer. •We found the changes of NDRG1 distribution during colorectal cancer progression. •We clarified the correlation between NDRG1 distribution and lymph node metastasis. •It is possible that NDRG1 subcellular localization may determine its function. •Maybe NDRG1 is valuable early diagnostic markers for metastasis. -- Abstract: In colorectal neoplasms, N-myc downstream-regulated gene 1 (NDRG1) is a primarily cytoplasmic protein, but it is also expressed on the cell membrane and in the nucleus. NDRG1 is involved in various stages of tumor development in colorectal cancer, and it is possible that the different subcellular localizations may determine the function of NDRG1 protein. Here, we attempt to clarify the characteristics of NDRG1 protein subcellular localization during the progression of colorectal cancer. We examined NDRG1 expression in 49 colorectal cancer patients in cancerous, non-cancerous, and corresponding lymph node tissues. Cytoplasmic and membrane NDRG1 expression was higher in the lymph nodes with metastases than in those without metastases (P < 0.01). Nuclear NDRG1 expression in colorectal neoplasms was significantly higher than in the normal colorectal mucosa, and yet the normal colorectal mucosa showed no nuclear expression. Furthermore, our results showed higher cytoplasmic NDRG1 expression was better for differentiation, and higher membrane NDRG1 expression resulted in a greater possibility of lymph node metastasis. These data indicate that a certain relationship between the cytoplasmic and membrane expression of NDRG1 in lymph nodes exists with lymph node metastasis. NDRG1 expression may translocate from the membrane of the colorectal cancer cells to the nucleus, where it is involved in lymph node metastasis. Combination analysis of NDRG1 subcellular expression and clinical variables will help predict the incidence of lymph node metastasis

  18. Alteration of Pituitary Tumor Transforming Gene-1 Regulates Trophoblast Invasion via the Integrin/Rho-Family Signaling Pathway.

    Seung Mook Lim

    Full Text Available Trophoblast invasion ability is an important factor in early implantation and placental development. Recently, pituitary tumor transforming gene 1 (PTTG1 was shown to be involved in invasion and proliferation of cancer. However, the role of PTTG1 in trophoblast invasion remains unknown. Thus, in this study we analyzed PTTG1 expression in trophoblasts and its effect on trophoblast invasion activity and determined the mechanism through which PTTG1 regulates trophoblast invasion. Trophoblast proliferation and invasion abilities, regardless of PTTG1 expression, were analyzed by quantitative real-time polymerase chain reaction, fluorescence-activated cell sorting analysis, invasion assay, western blot, and zymography after treatment with small interfering RNA against PTTG1 (siPTTG1. Additionally, integrin/Rho-family signaling in trophoblasts by PTTG1 alteration was analyzed. Furthermore, the effect of PTTG1 on trophoblast invasion was evaluated by microRNA (miRNA mimic and inhibitor treatment. Trophoblast invasion was significantly reduced through decreased matrix metalloproteinase (MMP-2 and MMP-9 expression when PTTG1 expression was inhibited by siPTTG1 (p < 0.05. Furthermore, knockdown of PTTG1 increased expression of integrin alpha 4 (ITGA4, ITGA5, and integrin beta 1 (ITGB1; otherwise, RhoA expression was significantly decreased (p < 0.05. Treatment of miRNA-186-5p mimic and inhibitor controlled trophoblast invasion ability by altering PTTG1 and MMP expression. PTTG1 can control trophoblast invasion ability via regulation of MMP expression through integrin/Rho-family signaling. In addition, PTTG1 expression and its function were regulated by miRNA-186-5p. These results help in understanding the mechanism through which PTTG1 regulates trophoblast invasion and thereby implantation and placental development.

  19. Cardiomyopathy-Associated Gene 1-Sensitive PKC-Dependent Connexin 43 Expression and Phosphorylation in Left Ventricular Noncompaction Cardiomyopathy

    Yuanyuan Xie

    2017-11-01

    Full Text Available Background/Aims: Cardiomyopathy-associated gene 1 (CMYA1 plays an important role in embryonic cardiac development, postnatal cardiac remodeling and myocardial injury repair. Abnormal CMYA1 expression may be involved in cardiac dysplasia and primary cardiomyopathy. Our study aims to establish the relationship between CMYA1 and Left ventricular noncompaction cardiomyopathy (LVNC pathogenesis. Methods: We explored the effects of CMYA1 on connexins (Cx, which contribute to gap junction intercellular communication (GJIC, and the underlying signaling pathway in human normal tissues, LVNC myocardial tissues and HL1 cells by means of western blotting, RT-qPCR, immunohistochemistry, immunofluorescence, co-immunoprecipitation and scrape loading-dye transfer. Results: CMYA1 expression was inversely associated with Cx43 and Cx40 expression, as determined by gap junction PCR array analysis. An increased expression and disordered distribution of CMYA1 at the intercalated discs in LVNC myocardial tissue was also observed. CMYA1 and Cx43 are co-expressed and interact in myocardial cells. CMYA1 expression was positively correlated with p-Cx43 (S368 via the Protein kinase C (PKC signaling pathway in myocardial tissue and HL1 cells. The diffusion distance of Lucifer Yellow in the HL1 cells in which CMYA1 was over-expressed or knocked down was significantly less or more than that of the control group, respectively. Conclusion: Abnormal CMYA1 expression affects the expression and phosphorylation of Cx43 through the PKC signaling pathway, which is involved in the regulation of GJIC. CMYA1 participates in the molecular mechanism of LVNC pathogenesis.

  20. Promoter sequence of 3-phosphoglycerate kinase gene 1 of lactic acid-producing fungus rhizopus oryzae and a method of expressing a gene of interest in fungal species

    Gao, Johnway [Richland, WA; Skeen, Rodney S [Pendleton, OR

    2002-10-15

    The present invention provides the promoter clone discovery of phosphoglycerate kinase gene 1 of a lactic acid-producing filamentous fungal strain, Rhizopus oryzae. The isolated promoter can constitutively regulate gene expression under various carbohydrate conditions. In addition, the present invention also provides a design of an integration vector for the transformation of a foreign gene in Rhizopus oryzae.

  1. Synthesis of bacteriophage-coded gene products during infection of Escherichia coli with amber mutants of T3 and T7 defective in gene 1

    Issinger, O G; Hausmann, R

    1973-01-01

    During nonpermissive infection by a T7 amber mutant in gene 1 (phage RNA polymerase-deficient), synthesis of the products of the phage genes 3 (endonuclease), 3, 5 (lysozyme), 5 (DNA polymerase), and 17 (serum blocking power) was shown to occur at about half the rate as during wild-type infection...

  2. Functional study of the novel multidrug resistance gene HA117 and its comparison to multidrug resistance gene 1

    Chen Tingfu

    2010-07-01

    Full Text Available Abstract Background The novel gene HA117 is a multidrug resistance (MDR gene expressed by all-trans retinoic acid-resistant HL-60 cells. In the present study, we compared the multidrug resistance of the HA117 with that of the classical multidrug resistance gene 1 (MDR1 in breast cancer cell line 4T1. Methods Transduction of the breast cancer cell line 4T1 with adenoviral vectors encoding the HA117 gene and the green fluorescence protein gene (GFP (Ad-GFP-HA117, the MDR1 and GFP (Ad-GFP-MDR1 or GFP (Ad-GFP was respectively carried out. The transduction efficiency and the multiplicity of infection (MOI were detected by fluorescence microscope and flow cytometry. The transcription of HA117 gene and MDR1 gene were detected by reverse transcription polymerase chain reaction (RT-PCR. Western blotting analysis was used to detect the expression of P-glycoprotein (P-gp but the expression of HA117 could not be analyzed as it is a novel gene and its antibody has not yet been synthesized. The drug-excretion activity of HA117 and MDR1 were determined by daunorubicin (DNR efflux assay. The drug sensitivities of 4T1/HA117 and 4T1/MDR1 to chemotherapeutic agents were detected by Methyl-Thiazolyl-Tetrazolium (MTT assay. Results The transducted efficiency of Ad-GFP-HA117 and Ad-GFP-MDR1 were 75%-80% when MOI was equal to 50. The transduction of Ad-GFP-HA117 and Ad-GFP-MDR1 could increase the expression of HA117 and MDR1. The drug resistance index to Adriamycin (ADM, vincristine (VCR, paclitaxel (Taxol and bleomycin (BLM increased to19.8050, 9.0663, 9.7245, 3.5650 respectively for 4T1/HA117 and 24.2236, 11.0480, 11.3741, 0.9630 respectively for 4T1/MDR1 as compared to the control cells. There were no significant differences in drug sensitivity between 4T1/HA117 and 4T1/MDR1 for the P-gp substrates (ADM, VCR and Taxol (P Conclusions These results confirm that HA117 is a strong MDR gene in both HL-60 and 4T1 cells. Furthermore, our results indicate that the MDR

  3. N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom

    Kalaydjieva, L.; Gresham, D.; Gooding, R.; Heather, L.; Baas, F.; de Jonge, R.; Blechschmidt, K.; Angelicheva, D.; Chandler, D.; Worsley, P.; Rosenthal, A.; King, R. H.; Thomas, P. K.

    2000-01-01

    Hereditary motor and sensory neuropathies, to which Charcot-Marie-Tooth (CMT) disease belongs, are a common cause of disability in adulthood. Growing awareness that axonal loss, rather than demyelination per se, is responsible for the neurological deficit in demyelinating CMT disease has focused

  4. Lack of Association of Multidrug Resistance Gene-1 Polymorphisms with Treatment Outcome in Chronic Myeloid Leukemia Patients Treated with Imatinib

    Yaya Kassogue

    2015-10-01

    Full Text Available Background: Despite the impressive results obtained with imatinib, inadequate response or resistance are observed in certain patients. It is known that imatinib is a substrate of a multidrug resistance gene (MDR1. Thus, interindividual genetic differences linked to single nucleotide polymorphisms in MDR1 may influence the metabolism of imatinib. The present study has aimed to examine the impact of MDR1 polymorphisms on the hematologic and cytogenetic responses in 70 chronic myeloid leukemia patients who received imatinib. Methods: We used a polymerase chain reaction followed by restriction fragment length polymorphism to identify different profiles of 1236C>T, 2677G>T and 3435C>T in MDR1. Results: The distribution of the three SNPs in responders and poor responders did not show any particular trend (P>0.05. The T allele was slightly higher in responders, but not significantly regardless of the type of SNP (40.3% vs. 33.8% for 1236C>T; 25% vs. 14.7% for 2677G>T and 33.3% vs. 22% for 3435C>T. The dominant model showed a similar trend (P>0.05. Diplotypes composed by the T allele in different exons were frequent in responders. Haplotype analysis showed that 1236C-2677G-3435C was slightly higher in poor responders (60.02% compared to responders (50.42%. However, 1236T-2677T-3435T was frequent in responders (16.98% compared to poor responders (13.1%. Overall, none of the haplotypes were associated with IM response in our cohort (global haplotype association test, P=0.39. Conclusion: The identification of 1236C>T, 2677G>T and 3435C>T polymorphisms may not be advantageous to predict imatinib response for our chronic myeloid leukemia patients.

  5. The genome-wide landscape of DNA methylation and hydroxymethylation in response to sleep deprivation impacts on synaptic plasticity genes.

    Massart, R; Freyburger, M; Suderman, M; Paquet, J; El Helou, J; Belanger-Nelson, E; Rachalski, A; Koumar, O C; Carrier, J; Szyf, M; Mongrain, V

    2014-01-21

    Sleep is critical for normal brain function and mental health. However, the molecular mechanisms mediating the impact of sleep loss on both cognition and the sleep electroencephalogram remain mostly unknown. Acute sleep loss impacts brain gene expression broadly. These data contributed to current hypotheses regarding the role for sleep in metabolism, synaptic plasticity and neuroprotection. These changes in gene expression likely underlie increased sleep intensity following sleep deprivation (SD). Here we tested the hypothesis that epigenetic mechanisms coordinate the gene expression response driven by SD. We found that SD altered the cortical genome-wide distribution of two major epigenetic marks: DNA methylation and hydroxymethylation. DNA methylation differences were enriched in gene pathways involved in neuritogenesis and synaptic plasticity, whereas large changes (>4000 sites) in hydroxymethylation where observed in genes linked to cytoskeleton, signaling and neurotransmission, which closely matches SD-dependent changes in the transcriptome. Moreover, this epigenetic remodeling applied to elements previously linked to sleep need (for example, Arc and Egr1) and synaptic partners of Neuroligin-1 (Nlgn1; for example, Dlg4, Nrxn1 and Nlgn3), which we recently identified as a regulator of sleep intensity following SD. We show here that Nlgn1 mutant mice display an enhanced slow-wave slope during non-rapid eye movement sleep following SD but this mutation does not affect SD-dependent changes in gene expression, suggesting that the Nlgn pathway acts downstream to mechanisms triggering gene expression changes in SD. These data reveal that acute SD reprograms the epigenetic landscape, providing a unique molecular route by which sleep can impact brain function and health.

  6. Distress call-induced gene expression in the brain of the Indian short-nosed fruit bat, Cynopterus sphinx.

    Ganesh, Ambigapathy; Raghuram, Hanumanthan; Nathan, Parthasarathy T; Marimuthu, Ganapathy; Rajan, Koilmani Emmanuvel

    2010-02-01

    Individuals in distress emit audible vocalizations to either warn or inform conspecifics. The Indian short-nosed fruit bat, Cynopterus sphinx, emits distress calls soon after becoming entangled in mist nets, which appear to attract conspecifics. Phase I of these distress calls is longer and louder, and includes a secondary peak, compared to phase II. Activity-dependent expression of egr-1 was examined in free-ranging C. sphinx following the emissions and responses to a distress call. We found that the level of expression of egr-1 was higher in bats that emitted a distress call, in adults that responded, and in pups than in silent bats. Up-regulated cDNA was amplified to identify the target gene (TOE1) of the protein Egr-1. The observed expression pattern Toe1 was similar to that of egr-1. These findings suggest that the neuronal activity related to recognition of a distress call and an auditory feedback mechanism induces the expression of Egr-1. Co-expression of egr-1 with Toe1 may play a role in initial triggering of the genetic mechanism that could be involved in the consolidation or stabilization of distress call memories.

  7. S(+)-ibuprofen destabilizes MYC/MYCN and AKT, increases p53 expression, and induces unfolded protein response and favorable phenotype in neuroblastoma cell lines.

    Ikegaki, Naohiko; Hicks, Sakeenah L; Regan, Paul L; Jacobs, Joshua; Jumbo, Amina S; Leonhardt, Payton; Rappaport, Eric F; Tang, Xao X

    2014-01-01

    Neuroblastoma is a common pediatric solid tumor that exhibits a striking clinical bipolarity: favorable and unfavorable. The survival rate of children with unfavorable neuroblastoma remains low among all childhood cancers. MYCN and MYC play a crucial role in determining the malignancy of unfavorable neuroblastomas, whereas high-level expression of the favorable neuroblastoma genes is associated with a good disease outcome and confers growth suppression of neuroblastoma cells. A small fraction of neuroblastomas harbors TP53 mutations at diagnosis, but a higher proportion of the relapse cases acquire TP53 mutations. In this study, we investigated the effect of S(+)-ibuprofen on neuroblastoma cell lines, focusing on the expression of the MYCN, MYC, AKT, p53 proteins and the favorable neuroblastoma genes in vitro as biomarkers of malignancy. Treatment of neuroblastoma cell lines with S(+)-ibuprofen resulted in a significant growth suppression. This growth effect was accompanied by a marked decrease in the expression of MYC, MYCN, AKT and an increase in p53 expression in neuroblastoma cell lines without TP53 mutation. In addition, S(+)-ibuprofen enhanced the expression of some favorable neuroblastoma genes (EPHB6, CD44) and genes involved in growth suppression and differentiation (EGR1, EPHA2, NRG1 and SEL1L). Gene expression profile and Ingenuity pathway analyses using TP53-mutated SKNAS cells further revealed that S(+)-ibuprofen suppressed molecular pathways associated with cell growth and conversely enhanced those of cell cycle arrest and the unfolded protein response. Collectively, these results suggest that S(+)-ibuprofen or its related compounds may have the potential for therapeutic and/or palliative use for unfavorable neuroblastoma.

  8. E-cigarette use results in suppression of immune and inflammatory-response genes in nasal epithelial cells similar to cigarette smoke.

    Martin, Elizabeth M; Clapp, Phillip W; Rebuli, Meghan E; Pawlak, Erica A; Glista-Baker, Ellen; Benowitz, Neal L; Fry, Rebecca C; Jaspers, Ilona

    2016-07-01

    Exposure to cigarette smoke is known to result in impaired host defense responses and immune suppressive effects. However, the effects of new and emerging tobacco products, such as e-cigarettes, on the immune status of the respiratory epithelium are largely unknown. We conducted a clinical study collecting superficial nasal scrape biopsies, nasal lavage, urine, and serum from nonsmokers, cigarette smokers, and e-cigarette users and assessed them for changes in immune gene expression profiles. Smoking status was determined based on a smoking history and a 3- to 4-wk smoking diary and confirmed using serum cotinine and urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) levels. Total RNA from nasal scrape biopsies was analyzed using the nCounter Human Immunology v2 Expression panel. Smoking cigarettes or vaping e-cigarettes resulted in decreased expression of immune-related genes. All genes with decreased expression in cigarette smokers (n = 53) were also decreased in e-cigarette smokers. Additionally, vaping e-cigarettes was associated with suppression of a large number of unique genes (n = 305). Furthermore, the e-cigarette users showed a greater suppression of genes common with those changed in cigarette smokers. This was particularly apparent for suppressed expression of transcription factors, such as EGR1, which was functionally associated with decreased expression of 5 target genes in cigarette smokers and 18 target genes in e-cigarette users. Taken together, these data indicate that vaping e-cigarettes is associated with decreased expression of a large number of immune-related genes, which are consistent with immune suppression at the level of the nasal mucosa. Copyright © 2016 the American Physiological Society.

  9. Downregulation of the long non-coding RNA taurine-upregulated gene 1 inhibits glioma cell proliferation and invasion and promotes apoptosis.

    Zhao, Zhijun; Wang, Bin; Hao, Junhai; Man, Weitao; Chang, Yongkai; Ma, Shunchang; Hu, Yeshuai; Liu, Fusheng; Yang, Jun

    2018-03-01

    Expression of the long non-coding RNA taurine-upregulated gene 1 (TUG1) is associated with various aggressive tumors. The present study aimed to investigate the biological function of TUG1 in regulating apoptosis, proliferation, invasion and cell cycle distribution in human glioma U251 cells. Lentivirus-mediated TUG1-specific microRNA was transfected into U251 cells to abrogate the expression of TUG1. Flow cytometry analysis was used to examine the cell cycle distribution and apoptosis of U251 cells. Cellular proliferation was examined using Cell Counting Kit-8 (CCK-8) assays and invasion was examined by Transwell assays. The apoptotic rate of cells in the TUG1-knockdown group was significantly higher than in the negative control (NC) group (11.58 vs. 9.14%, PTUG1-knockdown group was lower compared with that of the NC group. A Transwell invasion assay was performed, which revealed that the number of invaded cells from the TUG1-knockdown group was the less compared with that of the NC group. In addition, the G 0 /G 1 phase population was significantly increased within the treated group (44.85 vs. 38.45%, PTUG1 may inhibit proliferation and invasion, and promote glioma U251 cell apoptosis. In addition, knockdown of TUG1 may have an effect on cell cycle arrest. The data presented in the current study indicated that TUG1 may be a novel therapeutic target for glioma.

  10. LncRNA Taurine-Upregulated Gene 1 Promotes Cell Proliferation by Inhibiting MicroRNA-9 in MCF-7 Cells.

    Zhao, Xiao-Bo; Ren, Guo-Sheng

    2016-12-01

    This study was designed to investigate the role of taurine-upregulated gene 1 ( TUG1 ) in MCF-7 breast cancer cells and the molecular mechanism involved in the regulation of microRNA-9 (miR-9). The expression of TUG1 in breast cancer tissues and cells was evaluated using quantitative reverse transcription polymerase chain reaction. Cell viability was examined using a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay; cell cycle progression and apoptosis were analyzed using flow cytometry. A dual luciferase reporter assay was used to detect the relationship between TUG1 and miR-9. The expression of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) was measured by western blot. Higher expression of TUG1 was observed in breast cancer tissues and cell lines than in the corresponding controls. TUG1 knockdown reduced proliferation, suppressed cell cycle progression, and promoted apoptosis of MCF-7 cells. The dual luciferase reporter assay showed that TUG1 could negatively regulate the expression of miR-9. MiR-9 inhibition abrogated the effect of TUG1 knockdown on the proliferation, cell cycle progression, and apoptosis of MCF-7 cells. TUG1 positively regulated the expression of MTHFD2 in breast cancer cells. TUG1 knockdown was significantly associated with decreased cell proliferation and it promoted apoptosis of breast cancer cells through the regulation of miR-9.

  11. The N-Myc down regulated Gene1 (NDRG1) Is a Rab4a effector involved in vesicular recycling of E-cadherin.

    Kachhap, Sushant K; Faith, Dennis; Qian, David Z; Shabbeer, Shabana; Galloway, Nathan L; Pili, Roberto; Denmeade, Samuel R; DeMarzo, Angelo M; Carducci, Michael A

    2007-09-05

    Cell to cell adhesion is mediated by adhesion molecules present on the cell surface. Downregulation of molecules that form the adhesion complex is a characteristic of metastatic cancer cells. Downregulation of the N-myc down regulated gene1 (NDRG1) increases prostate and breast metastasis. The exact function of NDRG1 is not known. Here by using live cell confocal microscopy and in vitro reconstitution, we report that NDRG1 is involved in recycling the adhesion molecule E-cadherin thereby stabilizing it. Evidence is provided that NDRG1 recruits on recycling endosomes in the Trans Golgi network by binding to phosphotidylinositol 4-phosphate and interacts with membrane bound Rab4aGTPase. NDRG1 specifically interacts with constitutively active Rab4aQ67L mutant protein and not with GDP-bound Rab4aS22N mutant proving NDRG1 as a novel Rab4a effector. Transferrin recycling experiments reveals NDRG1 colocalizes with transferrin during the recycling phase. NDRG1 alters the kinetics of transferrin recycling in cells. NDRG1 knockdown cells show a delay in recycling transferrin, conversely NDRG1 overexpressing cells reveal an increase in rate of transferrin recycling. This novel finding of NDRG1 as a recycling protein involved with recycling of E-cadherin will aid in understanding NDRG1 role as a metastasis suppressor protein.

  12. The N-Myc down regulated Gene1 (NDRG1 Is a Rab4a effector involved in vesicular recycling of E-cadherin.

    Sushant K Kachhap

    2007-09-01

    Full Text Available Cell to cell adhesion is mediated by adhesion molecules present on the cell surface. Downregulation of molecules that form the adhesion complex is a characteristic of metastatic cancer cells. Downregulation of the N-myc down regulated gene1 (NDRG1 increases prostate and breast metastasis. The exact function of NDRG1 is not known. Here by using live cell confocal microscopy and in vitro reconstitution, we report that NDRG1 is involved in recycling the adhesion molecule E-cadherin thereby stabilizing it. Evidence is provided that NDRG1 recruits on recycling endosomes in the Trans Golgi network by binding to phosphotidylinositol 4-phosphate and interacts with membrane bound Rab4aGTPase. NDRG1 specifically interacts with constitutively active Rab4aQ67L mutant protein and not with GDP-bound Rab4aS22N mutant proving NDRG1 as a novel Rab4a effector. Transferrin recycling experiments reveals NDRG1 colocalizes with transferrin during the recycling phase. NDRG1 alters the kinetics of transferrin recycling in cells. NDRG1 knockdown cells show a delay in recycling transferrin, conversely NDRG1 overexpressing cells reveal an increase in rate of transferrin recycling. This novel finding of NDRG1 as a recycling protein involved with recycling of E-cadherin will aid in understanding NDRG1 role as a metastasis suppressor protein.

  13. Association of Differentiation-Related Gene-1 (DRG1) with Breast Cancer Survival and in Vitro Impact of DRG1 Suppression

    Baig, Ruqia Mehmood; Sanders, Andrew J.; Kayani, Mahmood Akhtar; Jiang, Wen G.

    2012-01-01

    Differentiation-related gene-1, DRG1, is a metastasis suppressor gene whose expression has been shown to be dysregulated in a number of malignancies. The current study examines the expression of DRG1 in a clinical breast cohort and its association with a number of clinical pathological factors using quantitative polymerase chain reaction. Additionally, DRG1 expression is targeted in vitro using ribozyme transgene technology to explore the function of DRG1 in two human breast cancer cell lines. Low levels of DRG1 were found in patients who developed metastasis (p = 0.036) and who died of breast cancer (p = 0.0048) compared to disease free patients. Knockdown of DRG1 also resulted in significantly increased invasion and motility, but decreased matrix-adhesion in MCF7 cells. Knockdown of DRG1 seemed to have minimal impact on the cellular functions of the MDA-MB-231 breast cancer cell line causing no significant differences in cell growth, invasion, motility or matrix-adhesion. Thus, DRG1 appears to be linked to development of metastasis and death in patients who died as a result of breast cancer and may be useful as a prognostic factor as its knockdown appears to be linked with increased invasion and motility and decreased adhesion in MCF7 breast cancer cells

  14. Neurospora crassa glucose - repressible gene -1(Grg-1) promoter controls the expression of neurospora tyrosinase gene in a clock-controlled manner

    Tarawneh, A. K

    1997-01-01

    In this study sphareroplastes of white Neurospora crassa mutant auxotroph for aromatic am no acids a rom 9 q a-2 inv, was transformed by the pKF-Tyr7-wt DNA construct. This construct contains the promoter of neurospora crassa glucose-repressible gene-1 (G rg-1) usp stream of Neurospora tyrosinase gene. The co transformation of this mutant with pKF-Tyr-7-wt cincture's and the pKAL-1, a plasmid which contains the Neurospora q a-2+ gene transform it to photophor. The transform ant contains the tyrosinase gene which catalyzes the unique step in the synthesis of the black pigment melanin. The activity of the tyrosinase in this transform ant was followed by measuring the absorbance of the dark coloured pigment at 332 nm. The maximum of the tyrosinase activity was shown at 16.36 and 56 hours after the shift of the transformed mycelia from constant light (L L) to constant dark (Dd). The rate of the enzyme activity was changed according to ci radian cycle of 20 hours. This G rg 1/tyrosinase construct provides a good system to study to study the temporal control of gene expression and the interaction between the different environmental c uses that affects gene expression. (author). 20 refs., 4 figs

  15. Long Noncoding RNA Taurine-Upregulated Gene 1 Promotes Cell Proliferation and Invasion in Gastric Cancer via Negatively Modulating miRNA-145-5p.

    Ren, Kewei; Li, Zhen; Li, Yahua; Zhang, Wenzhe; Han, Xinwei

    2017-05-24

    Long noncoding RNA (lncRNA) taurine-upregulated gene 1 (TUG1) is involved in the development and carcinogenesis of various tumors, suggesting the diagnostic potential of TUG1 in these cancers. However, the exact role of TUG1 and its underlying mechanism in gastric cancer (GC) remain unknown. In this study, the expression of TUG1 and miR-145-5p in GC cell lines and nonmalignant gastric epithelial cell lines was detected by qRT-PCR. BGC-823 and SGC-7901 cells were transfected with si-TUG1, pcDNA 3.1-TUG1, miR-145-5p mimics, or matched controls. The biological function of TUG1 and miR-145-5p in GC cell proliferation and invasion in vitro and tumor growth in vivo was investigated by MTT assay, Transwell invasion assay, and tumor xenograft experiments. The regulating relationship between TUG1 and miR-145-5 was confirmed by luciferase reporter assay. The results showed that TUG1 was significantly overexpressed and miR-145-5p was dramatically downregulated in GC cell lines. TUG1 knockdown strikingly inhibited cell proliferation and invasion in vitro and markedly suppressed tumor growth in vivo. Furthermore, TUG1 could directly bind to miR-145-5p and repress miR-145-5p expression. TUG1 overexpression significantly relieved the inhibition on GC cell proliferation and invasion in vitro and tumor growth in vivo, mediated by miR-145-5p overexpression. In conclusion, TUG1 promotes cell proliferation and invasion in GC via negatively modulating miRNA-145-5p, which undoubtedly contributes to understanding the mechanism of GC occurrence and development.

  16. N-myc downstream-regulated gene 1 promotes oxaliplatin-triggered apoptosis in colorectal cancer cells via enhancing the ubiquitination of Bcl-2.

    Yang, Xiao; Zhu, Fan; Yu, Chaoran; Lu, Jiaoyang; Zhang, Luyang; Lv, Yanfeng; Sun, Jing; Zheng, Minhua

    2017-07-18

    N-myc downstream-regulated gene1 (NDRG1) has been identified as a potent tumor suppressor gene. The molecular mechanisms of anti-tumor activity of NDRG1 involve its suppressive effects on a variety of tumorigenic signaling pathways. The purpose of this study was to investigate the role of NDRG1 in the apoptosis of colorectal cancer (CRC) cells. We first collected the clinical data of locally advanced rectal cancer (LARC) patients receiving oxaliplatin-based neoadjuvant chemotherapy in our medical center. Correlation analysis revealed that NDRG1 positively associated with the downstaging rates and prognosis of patients. Then, the effects of over-expression and depletion of NDRG1 gene on apoptosis of colorectal cancer were tested in vitro and in vivo. NDRG1 over-expression promoted apoptosis in colorectal cancer cells whereas depletion of NDRG1 resulted in resistance to oxaliplatin treatment. Furthermore, we observed that Bcl-2, a major anti-apoptotic protein, was regulated by NDRG1 at post-transcriptional level. By binding Protein kinase Cα (PKCα), a classical regulating factor of Bcl-2, NDRG1 enhanced the ubiquitination and degradation of Bcl-2, thus promoting apoptosis in CRC cells. In addition, NDRG1 inhibited tumor growth and promoted apoptosis in mouse xenograft model. In conclusion,NDRG1 promotes oxaliplatin-triggered apoptosis in colorectal cancer. Therefore, colorectal cancer patients can be stratified by the expression level of NDRG1. NDRG1-positive patients may benefit from oxaliplatin-containing chemotherapy regimens whereas those with negative NDRG1 expression should avoid the usage of this cytotoxic drug.

  17. Knockdown of astrocyte elevated gene-1 inhibits tumor growth and modifies microRNAs expression profiles in human colorectal cancer cells

    Huang, Sujun [East Department of Gastroenterology, Institute of Geriatrics, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080 (China); Southern Medical University, Guangzhou, Guangdong 510515 (China); Wu, Binwen, E-mail: wubinwengd@aliyun.com [East Department of Gastroenterology, Institute of Geriatrics, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080 (China); Li, Dongfeng; Zhou, Weihong; Deng, Gang; Zhang, Kaijun; Li, Youjia [East Department of Gastroenterology, Institute of Geriatrics, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080 (China)

    2014-02-14

    Highlights: • AEG-1 expression in CRC cell lines and down-regulation or upregulation of AEG-1 in vitro. • Knockdown of AEG-1 inhibits cell proliferation, colony formation and invasion. • Upregulation of AEG-1 enhances proliferation, invasion and colony formation. • Knockdown of AEG-1 accumulates G0/G1-phase cells and promotes apoptosis in CRC cells. • AEG-1 knockdown increases 5-FU cytotoxicity. - Abstract: Astrocyte elevated gene-1 (AEG-1), upregulated in various types of malignancies including colorectal cancer (CRC), has been reported to be associated with the carcinogenesis. MicroRNAs (miRNAs) are widely involved in the initiation and progression of cancer. However, the functional significance of AEG-1 and the relationship between AEG-1 and microRNAs in human CRC remains unclear. The aim of this study was to investigate whether AEG-1 could serve as a potential therapeutic target of human CRC and its possible mechanism. We adopted a strategy of ectopic overexpression or RNA interference to upregulate or downregulate expression of AEG-1 in CRC models. Their phenotypic changes were analyzed by Western blot, MTT and transwell matrix penetration assays. MicroRNAs expression profiles were performed using microarray analysis followed by validation using qRT-PCR. Knockdown of AEG-1 could significantly inhibit colon cancer cell proliferation, colony formation, invasion and promotes apoptosis. Conversely, upregulation of AEG-1 could significantly enhance cell proliferation, invasion and reduced apoptisis. AEG-1 directly contributes to resistance to chemotherapeutic drug. Targeted downregulation of AEG-1 might improve the expression of miR-181a-2{sup ∗}, -193b and -193a, and inversely inhibit miR-31 and -9{sup ∗}. Targeted inhibition of AEG-1 can lead to modification of key elemental characteristics, such as miRNAs, which may become a potential effective therapeutic strategy for CRC.

  18. Liver-Enriched Gene 1, a Glycosylated Secretory Protein, Binds to FGFR and Mediates an Anti-stress Pathway to Protect Liver Development in Zebrafish.

    Minjie Hu

    2016-02-01

    Full Text Available Unlike mammals and birds, teleost fish undergo external embryogenesis, and therefore their embryos are constantly challenged by stresses from their living environment. These stresses, when becoming too harsh, will cause arrest of cell proliferation, abnormal cell death or senescence. Such organisms have to evolve a sophisticated anti-stress mechanism to protect the process of embryogenesis/organogenesis. However, very few signaling molecule(s mediating such activity have been identified. liver-enriched gene 1 (leg1 is an uncharacterized gene that encodes a novel secretory protein containing a single domain DUF781 (domain of unknown function 781 that is well conserved in vertebrates. In the zebrafish genome, there are two copies of leg1, namely leg1a and leg1b. leg1a and leg1b are closely linked on chromosome 20 and share high homology, but are differentially expressed. In this report, we generated two leg1a mutant alleles using the TALEN technique, then characterized liver development in the mutants. We show that a leg1a mutant exhibits a stress-dependent small liver phenotype that can be prevented by chemicals blocking the production of reactive oxygen species. Further studies reveal that Leg1a binds to FGFR3 and mediates a novel anti-stress pathway to protect liver development through enhancing Erk activity. More importantly, we show that the binding of Leg1a to FGFR relies on the glycosylation at the 70th asparagine (Asn(70 or N(70, and mutating the Asn(70 to Ala(70 compromised Leg1's function in liver development. Therefore, Leg1 plays a unique role in protecting liver development under different stress conditions by serving as a secreted signaling molecule/modulator.

  19. Paclitaxel-resistant HeLa cells have up-regulated levels of reactive oxygen species and increased expression of taxol resistance gene 1.

    Bi, Wenxiang; Wang, Yuxia; Sun, Gaoying; Zhang, Xiaojin; Wei, Yongqing; Li, Lu; Wang, Xiaoyuan

    2014-07-01

    This study is to establish a paclitaxel (PTX)-resistant human cervical carcinoma HeLa cell line (HeLa/PTX) and to investigate its redox characteristics and the expression of taxol resistance gene 1 (Txr1). HeLa cells were treated with PTX and effects of PTX on cell proliferation were detected through cell counting and the MTT assay. Levels of cellular reactive oxygen species (ROS), reduced glutathione (GSH), and oxidized glutathione (GSSG) as well as the ratio of GSH to GSSG were measured by the 2,7-difluorescein diacetate (DCFH-DA) method and the 5,5'dithiobis(2-nitrobenzoic acid) (DTNB) method. Activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were determined by the nitrite formation method, the molybdate colorimetric method, and the DTNB colorimetric method, respectively. The level of Txr1 mRNA was determined by real-time PCR. Compared with the regular HeLa cells, HeLa/PTX cells were larger in size and had more cytoplasmic granules. The population doubling time for HeLa/PTX cells was 1.32 times of that of HeLa cells (PHeLa/PTX cells showed stronger resistance to PTX than HeLa cells with a resistance index of 122.69. HeLa/PTX cells had higher levels of ROS (PHeLa cells. HeLa/PTX cells, with higher levels of ROS and Txr1 mRNA expression, are more resistant to PTX than HeLa cells.

  20. RNAi-mediated knockdown of pituitary tumor-transforming gene-1 (PTTG1) suppresses the proliferation and invasive potential of PC3 human prostate cancer cells

    Huang, S.Q.; Liao, Q.J.; Wang, X.W.; Xin, D.Q.; Chen, S.X.; Wu, Q.J.; Ye, G.

    2012-01-01

    Pituitary tumor-transforming gene-1 (PTTG1) is a proto-oncogene that promotes tumorigenesis and metastasis in numerous cell types and is overexpressed in a variety of human tumors. We have demonstrated that PTTG1 expression was up-regulated in both human prostate cancer specimens and prostate cancer cell lines. For a more direct assessment of the function of PTTG1 in prostate tumorigenesis, RNAi-mediated knockdown was used to selectively decrease PTTG1 expression in PC3 human prostate tumor cells. After three weeks of selection, colonies stably transfected with PTTG1-targeted RNAi (the knockdown PC3 cell line) or empty vector (the control PC3 cell line) were selected and expanded to investigate the role of PTTG1 expression in PC3 cell growth and invasion. Cell proliferation rate was significantly slower (28%) in the PTTG1 knockdown line after 6 days of growth as indicated by an MTT cell viability assay (P < 0.05). Similarly, a soft agar colony formation assay revealed significantly fewer (66.7%) PTTG1 knockdown PC3 cell colonies than control colonies after three weeks of growth. In addition, PTTG1 knockdown resulted in cell cycle arrest at G1 as indicated by fluorescence-activated cell sorting. The PTTG1 knockdown PC3 cell line also exhibited significantly reduced migration through Matrigel in a transwell assay of invasive potential, and down-regulation of PTTG1 could lead to increased sensitivity of these prostate cancer cells to a commonly used anticancer drug, taxol. Thus, PTTG1 expression is crucial for PC3 cell proliferation and invasion, and could be a promising new target for prostate cancer therapy

  1. Knockdown of astrocyte elevated gene-1 inhibits tumor growth and modifies microRNAs expression profiles in human colorectal cancer cells

    Huang, Sujun; Wu, Binwen; Li, Dongfeng; Zhou, Weihong; Deng, Gang; Zhang, Kaijun; Li, Youjia

    2014-01-01

    Highlights: • AEG-1 expression in CRC cell lines and down-regulation or upregulation of AEG-1 in vitro. • Knockdown of AEG-1 inhibits cell proliferation, colony formation and invasion. • Upregulation of AEG-1 enhances proliferation, invasion and colony formation. • Knockdown of AEG-1 accumulates G0/G1-phase cells and promotes apoptosis in CRC cells. • AEG-1 knockdown increases 5-FU cytotoxicity. - Abstract: Astrocyte elevated gene-1 (AEG-1), upregulated in various types of malignancies including colorectal cancer (CRC), has been reported to be associated with the carcinogenesis. MicroRNAs (miRNAs) are widely involved in the initiation and progression of cancer. However, the functional significance of AEG-1 and the relationship between AEG-1 and microRNAs in human CRC remains unclear. The aim of this study was to investigate whether AEG-1 could serve as a potential therapeutic target of human CRC and its possible mechanism. We adopted a strategy of ectopic overexpression or RNA interference to upregulate or downregulate expression of AEG-1 in CRC models. Their phenotypic changes were analyzed by Western blot, MTT and transwell matrix penetration assays. MicroRNAs expression profiles were performed using microarray analysis followed by validation using qRT-PCR. Knockdown of AEG-1 could significantly inhibit colon cancer cell proliferation, colony formation, invasion and promotes apoptosis. Conversely, upregulation of AEG-1 could significantly enhance cell proliferation, invasion and reduced apoptisis. AEG-1 directly contributes to resistance to chemotherapeutic drug. Targeted downregulation of AEG-1 might improve the expression of miR-181a-2 ∗ , -193b and -193a, and inversely inhibit miR-31 and -9 ∗ . Targeted inhibition of AEG-1 can lead to modification of key elemental characteristics, such as miRNAs, which may become a potential effective therapeutic strategy for CRC

  2. The GnRH receptor and the response of gonadotrope cells to GnRH pulse frequency code. A story of an atypical adaptation of cell function relying on a lack of receptor homologous desensitization.

    Christian Bleux

    2010-01-01

    Full Text Available Brain control of the reproductive system is mediated through hypothalamic gonadotropin-releasing hormone (GnRH which activates specific receptors (GnRHR present at the surface of the pituitary gonadotropes to trigger secretion of the two gonadotropins LH and FSH. A unique feature of this system is the high dependence on the secretion mode of GnRH, which is basically pulsatile but undergoes considerable fluctuations in pulse frequency pattern in response to endogenous or external factors. How the physiological fluctuations of GnRH secretion that orchestrate normal reproduction are decoded by the gonadotrope cell machinery to ultimately control gonadotropin release and/or subunit gene transcription has been the subject of intensive studies during the past decades. Surprisingly, the mammalian GnRHR is unique among G protein-coupled receptor family as it lacks the carboxy-terminal tail usually involved in classical endocytotic process. Accordingly, it does not desensitize properly and internalizes very poorly. Both this atypical intrinsic property and post-receptor events may thus contribute to decode the GnRH signal. This includes the participation of a network of signaling pathways that differently respond to GnRH together with a growing amount of genes differentially sensitive to pulse frequency. Among these are two pairs of genes, the transcription factors EGR-1 and NAB, and the regulatory factors activin and follistatin, that function as intracellular autoregulatory feedback loops controlling respectively LHbeta and FSHbeta gene expression and hence, LH and FSH synthesis. Pituitary gonadotropes thus represent a unique model of cells functionally adapted to respond to a considerably fluctuating neuroendocrine stimulation, from short individual pulses to sustained GnRH as observed at the proestrus of ovarian cycle. Altogether, the data emphasize the adaptative reciprocal complementarity of hypothalamic GnRH neurones and pituitary gonadotropes to

  3. Activation of ERK mitogen-activated protein kinase in human cells by the mycotoxin patulin

    Wu, T.-S.; Yu, F.-Y.; Su, C.-C.; Kan, J.-C.; Chung, C.-P.; Liu, B.-H.

    2005-01-01

    Patulin (PAT), a mycotoxin produced by certain species of Penicillium and Aspergillus, is often detectable in moldy fruits and their derivative products. PAT led to a concentration-dependent and time-dependent increase in phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in human embryonic kidney (HEK293) cells, human peripheral blood mononuclear cells (PBMCs), and Madin-Darby canine kidney (MDCK) cells. Exposure of HEK293 cells to concentrations above 5 μM PAT for 30 min induced ERK1/2 phosphorylation; activation of ERK1/2 was also observed after 24 h incubation with 0.05 μM of PAT. Treatment of human PBMCs for 30 min with 30 μM PAT dramatically increased the phosphorylated ERK1/2 levels. Both MEK1/2 inhibitors, U0126 and PD98059, suppressed ERK1/2 activation in either HEK293 or MDCK cells. In HEK293 cells, U0126-mediated inhibition of PAT-induced ERK1/2 phosphorylation resulted in a significant decrease in levels of DNA damage, expressed as tail moment values, in the single cell gel electrophoresis assay. Conversely, U0126 did not affect cell viability, lactate dehydrogenase release, and the DNA synthesis rate in PAT-treated cultures. Exposure of HEK293 cells for 90 min to 15 μM PAT elevated the levels of early growth response gene-1 (egr-1) mRNA, but not of c-fos, fosB, and junB mRNAs. These results indicate that in human cells, PAT causes a rapid and persistent activation of ERK1/2 and this signaling pathway plays an important role in mediating PAT-induced DNA damage and egr-1 gene expression

  4. Lentivirus-Mediated Knockdown of Astrocyte Elevated Gene-1 Inhibits Growth and Induces Apoptosis through MAPK Pathways in Human Retinoblastoma Cells.

    Ying Chang

    Full Text Available To explore expression and function of astrocyte elevated gene-1 (AEG-1 in human retinoblastoma (RB.The expression of AEG-1 in histological sections of human RBs and in RB cell lines was examined using immunohistochemical staining and RT-PCR and Western blotting respectively. We knocked down AEG-1 gene levels by AEG-1-siRNA lentivirus transfection of human RB cell lines SO-RB50 and Y79, and using an MTT assay, we assessed the role of AEG-1 on RB cell proliferation. The biological significance of lentivirus transfection induced AEG-1 down-regulation was examined by assessing the apoptosis rate in the transfected RB cells by Annexin V-APC staining and flow cytometry. We additionally measured the expression of Bcl-2, Bax, cleaved-caspase-3 and caspase-3, and the phosphorylation and non-phosphorylation alternation of MAPKs.AEG-1 expression was detected to be strongly positive in the histological slides of 35 out of 54 (65% patients with RB. AEG-1 expression increased significantly (P<0.05 with tumor stage. In the RB cell lines SO-RB50, Y79 and WERI-RB1 as compared with retinal pigment epithelium cells, expression of AEG-1 mRNA and AEG-1 protein was significantly higher. In AEG-1-siRNA lentivirus transfected cell cultures as compared with negative control lentivirus transfected cell cultures, levels of AEG-1 mRNA and of AEG-1 protein (P<0.05 and cell growth rates (P<0.01 were significantly lower, and apoptosis rate (P<0.001, Bax/Bcl-2 ratio and cleaved-caspase-3 protein level were significantly increased. The P-ERK/ERK ratio was significantly decreased in the AEG-1-siRNA lentivirus transfected cell lines.Expression of AEG-1 was associated with RB, in histological slides of patients and in cell culture experiments. Lentivirus transfection induced knockdown of AEG-1 had a tumor suppressive effect, potentially by tumor cell apoptosis induction through inhibition of ERK.

  5. Evaluation of the BeTha gene 1 kit for the qualitative detection of the eight most common Mediterranean beta-thalassemia mutations.

    Ugozzoli, L A; Lowery, J D; Reyes, A A; Lin, C I; Re, A; Locati, F; Galanello, R; Macioni, L; Maggio, A; Giambona, A; Loutradi, A; Boussiou, M; Wallace, R B

    1998-11-01

    We describe the evaluation of the Bio-Rad BeTha Gene 1 kit (Bio-Rad Laboratories, Hercules, CA), a DNA-probe assay designed for the qualitative determination of the eight most common Mediterranean beta-thalassemia mutations. The kit utilizes the principle of allele-specific oligonucleotide (ASO) hybridization. Following sample preparation and in vitro DNA amplification by the polymerase chain reaction (PCR), an allele-specific detection of the amplified products by a nonradioactive enzymatic assay is performed. Genomic DNA is prepared from an individual's whole blood with a DNA purification matrix. In a second step, the beta-globin gene is amplified in a multiplex PCR reaction containing four 5' biotinylated oligonucleotide primers. In a final step, an aliquot of the PCR reaction is first chemically denatured and then captured in two eight-well strips of a 96-well enzyme-linked immunosorbent assay (ELISA) plate by hybridization to an immobilized ASO probe. Each DNA sequence at each of the eight mutation sites is represented by one normal and one mutant ASO. During this capture/hybridization step, which is performed at 37 degrees C, only perfectly matched PCR products will be captured by an ASO. Subsequently, the allele-specific captured biotin-labeled PCR products are detected by a colorimetric enzymatic reaction. The system permits the detection of 16 beta-thalassemia alleles using a high-throughput format that can be automated easily. A clinical feasibility study was performed to evaluate the functionality (method comparison study, assay validity using samples previously collected and stored at various temperatures for different periods of time, interference on kit performance, and assay validity for prenatal diagnosis) and the usability (ease of use, sample throughput) of the kit. The analysis of 110 samples previously studied with reference methods showed 100% clinical sensitivity and specificity. We demonstrate here that the procedure not only increases the

  6. Effect of diclofenac sodium on the level of non-steroidal anti-inflammatory drug-activated gene-1 in patients with post-ERCP pancreatitis

    HU Cui

    2018-03-01

    Full Text Available ObjectiveTo investigate the effect of diclofenac sodium on the level of non-steroidal anti-inflammatory drug-activated gene-1 (NAG-1 in patients with post-ERCP pancreatitis (PEP. MethodsA total of 120 patients who underwent ERCP in The First Affiliated Hospital of Anhui Medical University from September 2012 to October 2013 were enrolled and randomly divided into diclofenac sodium group and control group, with 60 patients in each group. The patients in the diclofenac sodium group were given intramuscular injection of Olfen (containing diclofenac sodium 75 mg immediately after ERCP. Blood samples were collected before surgery and at 3 and 24 hours after surgery, and the level of amylase was measured. The incidence of abdominal pain was also observed and the incidence rate of PEP was calculated for both groups. RT-PCR and Western blot were used to measure the mRNA and protein expression of NAG-1 in plasma. An repeated-measures analysis of variance was used for comparison of continuous data, a univariate analysis of variance was used for data meeting the requirements of sphericity test, and the Greenhouse-Geisser correction method was used for data which did not meet the requirements of sphericity test. The chi-square test was used for comparison of categorical data between groups. ResultsThe diclofenac sodium group had a significantly lower incidence rate of PEP than the control group [6.67% (4/60 vs 20.00% (12/60, χ2=4.62, P=0.03]. The diclofenac sodium group had a significantly lower level of amylase than the control group at 3 and 24 hours after surgery (at 3 hours after surgery: 202.70±120.44 U/L vs 283.57±178.39 U/L, t=2.06, P<0.05, at 24 hours after surgery: 209.13±157.14 U/L vs 30597±20869 U/L, t=2.03, P<0.05. At 3 hours after ERCP, the diclofenac sodium group had significant increases in the mRNA and protein expression of NAG-1 in plasma and significantly higher mRNA and protein expression of NAG-1 than the control group

  7. Construction of pEgr.p-TNFα and its expression in NIH3T3 cells induced by ionizing irradiation

    Wu Congmei; Li Xiuyi; Liu Shuzheng

    2001-01-01

    Objective: To isolate and amplify Egr-1 promoter, construct pEgr.p-TNFα and study its response to different doses of ionizing radiation. Methods: Egr-1 promote was isolated from genomic DNA by PCR to construct pEgr.p-TNFα expression plasmid. Plasmids were transfected into NIH3T3 cells with liposome and the expression level of TNFα was detected by ELISA after irradiation with different doses of X-ray. Results: The sequence of Egr-1 promoter obtained was essentially same as reported. Egr-1 promoter and TNF α cDNA were inserted into expression vector correctly. Eight hours after irradiation with different doses of X-rays, the expression level of TNFα was higher than that of nonirradiated group (P< 0.05-0.001). Conclusion: Egr-1 promoter obtained can be activated by ionizing irradiation and regulate the expression of downstream gene. Low dose irradiation is for the first time found to be able to induce the expression of the downstream gene. the observation may be of potential significance in tumor therapy

  8. Transcriptional response of rat frontal cortex following acute In Vivo exposure to the pyrethroid insecticides permethrin and deltamethrin

    Tornero-Velez Rogelio

    2008-11-01

    Full Text Available Abstract Background Pyrethroids are neurotoxic pesticides that interact with membrane bound ion channels in neurons and disrupt nerve function. The purpose of this study was to characterize and explore changes in gene expression that occur in the rat frontal cortex, an area of CNS affected by pyrethroids, following an acute low-dose exposure. Results Rats were acutely exposed to either deltamethrin (0.3 – 3 mg/kg or permethrin (1 – 100 mg/kg followed by collection of cortical tissue at 6 hours. The doses used range from those that cause minimal signs of intoxication at the behavioral level to doses well below apparent no effect levels in the whole animal. A statistical framework based on parallel linear (SAM and isotonic regression (PIR methods identified 95 and 53 probe sets as dose-responsive. The PIR analysis was most sensitive for detecting transcripts with changes in expression at the NOAEL dose. A sub-set of genes (Camk1g, Ddc, Gpd3, c-fos and Egr1 was then confirmed by qRT-PCR and examined in a time course study. Changes in mRNA levels were typically less than 3-fold in magnitude across all components of the study. The responses observed are consistent with pyrethroids producing increased neuronal excitation in the cortex following a low-dose in vivo exposure. In addition, Significance Analysis of Function and Expression (SAFE identified significantly enriched gene categories common for both pyrethroids, including some relating to branching morphogenesis. Exposure of primary cortical cell cultures to both compounds resulted in an increase (~25% in the number of neurite branch points, supporting the results of the SAFE analysis. Conclusion In the present study, pyrethroids induced changes in gene expression in the frontal cortex near the threshold for decreases in ambulatory motor activity in vivo. The penalized regression methods performed similarly in detecting dose-dependent changes in gene transcription. Finally, SAFE analysis of

  9. Parathyroid hormone inhibition of Na{sup +}/H{sup +} exchanger 3 transcription: Intracellular signaling pathways and transcription factor expression

    Neri, Elida Adalgisa; Bezerra, Camila Nogueira Alves, E-mail: camilab@icb.usp.br; Queiroz-Leite, Gabriella Duarte; Polidoro, Juliano Zequini; Rebouças, Nancy Amaral

    2015-06-12

    The main transport mechanism of reabsorption of sodium bicarbonate and fluid in the renal proximal tubules involves Na{sup +}/H{sup +} exchanger 3 (NHE3), which is acutely and chronically downregulated by parathyroid hormone (PTH). Although PTH is known to exert an inhibitory effect on NHE3 expression and transcription, the molecular mechanisms involved remain unclear. Here, we demonstrated that, in opossum kidney proximal tubule (OKP) cells, PTH-induced inhibition of Nhe3 gene promoter occurs even in the core promoter that controls expression of the reporter gene. We found that inhibition of the protein kinase A (PKA) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways transformed PTH from an inhibitor of promoter activity into an activator of that same activity, as did point mutations in the EGR1, Sp1, and Sp3 binding consensus elements in the promoter. In nuclear extracts of PTH-treated OKP cells, we also observed increased expression of EGR1 mRNA and of some Sp3 isoforms. Electrophoretic mobility shift assay showed a supershift of the −61 to −42-bp probe with an anti-EGR1 antibody in PTH-treated cells, suggesting that EGR1 binding is relevant for the inhibitory activity of PTH. We conclude that PTH-induced inhibition of NHE3 transcription is related to higher EGR1 expression; to EGR1 binding to the proximal and core promoters; and to PKA and JAK/STAT pathway activation. This mechanism might be responsible, at least in part, for lower NHE3 expression and sodium reabsorption in renal proximal tubules in the presence of high PTH levels. - Highlights: • PTH regulation of Nhe3 promoter depends on EGR1 binding. • EGR1, PKA and JAK/STAT are involved in PTH inhibition of the Nhe3 promoter. • PTH alters expression of EGR1 and Sp3. • PTH inhibits the Nhe3 promoter by regulating PKA and JAK/STAT signaling.

  10. Responsibility and Responsiveness

    Nissen, Ulrik Becker

    2011-01-01

    The debate on the role and identity of Christian social ethics in liberal democracy touches upon the question about the relationship between universality and speci-ficity. Rather than argue for the difference between these approaches, it can be argued that they are to be understood in a different......The debate on the role and identity of Christian social ethics in liberal democracy touches upon the question about the relationship between universality and speci-ficity. Rather than argue for the difference between these approaches, it can be argued that they are to be understood...... contemporary positions of communicative ethics, H. Richard Niebuhr’s understanding of responsibility as responsiveness, and Dietrich Bonhoeffer’s Christological concept of responsibility in a constructive dialogue with each other, the article has attempted to outline main tenets of a responsive concept...

  11. Carbon monoxide induced PPARγ SUMOylation and UCP2 block inflammatory gene expression in macrophages.

    Arvand Haschemi

    Full Text Available Carbon monoxide (CO dampens pro-inflammatory responses in a peroxisome proliferator-activated receptor-γ (PPARγ and p38 mitogen-activated protein kinase (MAPK dependent manner. Previously, we demonstrated that CO inhibits lipopolysaccharide (LPS-induced expression of the proinflammatory early growth response-1 (Egr-1 transcription factor in macrophages via activation of PPARγ. Here, we further characterize the molecular mechanisms by which CO modulates the activity of PPARγ and Egr-1 repression. We demonstrate that CO enhances SUMOylation of PPARγ which we find was attributed to mitochondrial ROS generation. Ectopic expression of a SUMOylation-defective PPARγ-K365R mutant partially abolished CO-mediated suppression of LPS-induced Egr-1 promoter activity. Expression of a PPARγ-K77R mutant did not impair the effect of CO. In addition to PPARγ SUMOylation, CO-activated p38 MAPK was responsible for Egr-1 repression. Blocking both CO-induced PPARγ SUMOylation and p38 activation, completely reversed the effects of CO on inflammatory gene expression. In primary macrophages isolated form C57/BL6 male mice, we identify mitochondrial ROS formation by CO as the upstream trigger for the observed effects on Egr-1 in part through uncoupling protein 2 (UCP2. Macrophages derived from bone marrow isolated from Ucp2 gene Knock-Out C57/BL6 mice (Ucp2(-/-, produced significantly less ROS with CO exposure versus wild-type macrophages. Moreover, absence of UCP2 resulted in a complete loss of CO mediated Egr-1 repression. Collectively, these results indentify p38 activation, PPARγ-SUMOylation and ROS formation via UCP2 as a cooperative system by which CO impacts the inflammatory response.

  12. Effects of prenatal cocaine exposure on social development in mice.

    Kabir, Zeeba D; Kennedy, Bruce; Katzman, Aaron; Lahvis, Garet P; Kosofsky, Barry E

    2014-01-01

    Prenatal cocaine exposure (PCE) in humans and animals has been shown to impair social development. Molecules that mediate synaptic plasticity and learning in the medial prefrontal cortex (mPFC), specifically brain-derived neurotrophic factor (BDNF) and its downstream signaling molecule, early growth response protein 1 (egr1), have been shown to affect the regulation of social interactions (SI). In this study we determined the effects of PCE on SI and the corresponding ultrasonic vocalizations (USVs) in developing mice. Furthermore, we studied the PCE-induced changes in the constitutive expression of BDNF, egr1 and their transcriptional regulators in the mPFC as a possible molecular mechanism mediating the altered SI. In prenatal cocaine-exposed (PCOC) mice we identified increased SI and USV production at postnatal day (PD) 25, and increased SI but not USVs at PD35. By PD45 the expression of both social behaviors normalized in PCOC mice. At the molecular level, we found increased BDNF exon IV and egr1 mRNA in the mPFC of PCOC mice at PD30 that normalized by PD45. This was concurrent with increased EGR1 protein in the mPFC of PCOC mice at PD30, suggesting a role of egr1 in the enhanced SI observed in juvenile PCOC mice. Additionally, by measuring the association of acetylation of histone 3 at lysine residues 9 and 14 (acH3K9,14) and MeCP2 at the promoters of BDNF exons I and IV and egr1, our results provide evidence of promoter-specific alterations in the mPFC of PCOC juvenile mice, with increased association of acH3K9,14 only at the BDNF exon IV promoter. These results identify a potential PCE-induced molecular alteration as the underlying neurobiological mechanism mediating the altered social development in juvenile mice. © 2014 S. Karger AG, Basel.

  13. Corporate Responsibility

    Waddock, Sandra; Rasche, Andreas

    2015-01-01

    We define and discuss the concept of corporate responsibility. We suggest that corporate responsibility has some unique characteristics, which makes it different from earlier conceptions of corporate social responsibility. Our discussion further shows commonalities and differences between corporate...... responsibility and related concepts, such as corporate citizenship and business ethics. We also outline some ways in which corporations have implemented corporate responsibility in practice....

  14. Responsible drinking

    Alcohol use disorder - responsible drinking; Drinking alcohol responsibly; Drinking in moderation; Alcoholism - responsible drinking ... 2016. National Institute on Alcohol Abuse and Alcoholism. Alcohol use disorder. www.niaaa.nih.gov/alcohol-health/overview-alcohol- ...

  15. Expression of Transketolase like gene 1 (TKTL1 predicts disease-free survival in patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy

    Hofmann Wolf-Karsten

    2011-08-01

    Full Text Available Abstract Background For patients with locally advanced rectal cancer (LARC neoadjuvant chemoradiotherapy is recommended as standard therapy. So far, no predictive or prognostic molecular factors for patients undergoing multimodal treatment are established. Increased angiogenesis and altered tumour metabolism as adaption to hypoxic conditions in cancers play an important role in tumour progression and metastasis. Enhanced expression of Vascular-endothelial-growth-factor-receptor (VEGF-R and Transketolase-like-1 (TKTL1 are related to hypoxic conditions in tumours. In search for potential prognostic molecular markers we investigated the expression of VEGFR-1, VEGFR-2 and TKTL1 in patients with LARC treated with neoadjuvant chemoradiotherapy and cetuximab. Methods Tumour and corresponding normal tissue from pre-therapeutic biopsies of 33 patients (m: 23, f: 10; median age: 61 years with LARC treated in phase-I and II trials with neoadjuvant chemoradiotherapy (cetuximab, irinotecan, capecitabine in combination with radiotherapy were analysed by quantitative PCR. Results Significantly higher expression of VEGFR-1/2 was found in tumour tissue in pre-treatment biopsies as well as in resected specimen after neoadjuvant chemoradiotherapy compared to corresponding normal tissue. High TKTL1 expression significantly correlated with disease free survival. None of the markers had influence on early response parameters such as tumour regression grading. There was no correlation of gene expression between the investigated markers. Conclusion High TKTL-1 expression correlates with poor prognosis in terms of 3 year disease-free survival in patients with LARC treated with intensified neoadjuvant chemoradiotherapy and may therefore serve as a molecular prognostic marker which should be further evaluated in randomised clinical trials.

  16. Relational responsibilities in responsive evaluation

    Visse, M.A.; Abma, T.A.; Widdershoven, G.A.M.

    2012-01-01

    This article explores how we can enhance our understanding of the moral responsibilities in daily, plural practices of responsive evaluation. It introduces an interpretive framework for understanding the moral aspects of evaluation practice. The framework supports responsive evaluators to better

  17. Sexual dimorphism of stress response and immune/ inflammatory reaction: the corticotropin releasing hormone perspective

    Vamvakopoulos, Nicholas V.

    1995-01-01

    This review higlghts key aspects of corticotropin releasing hormone (CRH) biology of potential relevance to the sexual dimorphism of the stress response and immune/inflammatory reaction, and introduces two important new concepts based on the regulatory potential of the human (h) CRH gene: (1) a proposed mechanism to account for the tissue-specific antithetical responses of hCRH gene expression to glucocorticolds, that may also explain the frequently observed antithetical effects of chronic gl...

  18. Corporate Responsibility

    World Bank

    2004-01-01

    Appeals to corporate responsibility often simply take for granted that businesses have ethical responsibilities that go beyond just respecting the law. This paper addresses arguments to the effect that businesses have no such responsibilities. The interesting claim is not that businesses have no ethical responsibility at all but that their primal responsibility is to increase their profits. The extent to which there is reason to take such arguments seriously delineates the limits of corporate...

  19. Expression analysis of the N-Myc downstream-regulated gene 1 indicates that myelinating Schwann cells are the primary disease target in hereditary motor and sensory neuropathy-Lom.

    Berger, Philipp; Sirkowski, Erich E; Scherer, Steven S; Suter, Ueli

    2004-11-01

    Mutations in the gene encoding N-myc downstream-regulated gene-1 (NDRG1) lead to truncations of the encoded protein and are associated with an autosomal recessive demyelinating neuropathy--hereditary motor and sensory neuropathy-Lom. NDRG1 protein is highly expressed in peripheral nerve and is localized in the cytoplasm of myelinating Schwann cells, including the paranodes and Schmidt-Lanterman incisures. In contrast, sensory and motor neurons as well as their axons lack NDRG1. NDRG1 mRNA levels in developing and injured adult sciatic nerves parallel those of myelin-related genes, indicating that the expression of NDRG1 in myelinating Schwann cells is regulated by axonal interactions. Oligodendrocytes also express NDRG1, and the subtle CNS deficits of affected patients may result from a lack of NDRG1 in these cells. Our data predict that the loss of NDRG1 leads to a Schwann cell autonomous phenotype resulting in demyelination, with secondary axonal loss.

  20. Responsibility navigator

    Kuhlmann, Stefan; Edler, Jakob; Ordonez Matamoros, Hector Gonzalo; Randles, Sally; Walhout, Bart; Walhout, Bart; Gough, Clair; Lindner, Ralf; Lindner, Ralf; Kuhlmann, Stefan; Randles, Sally; Bedsted, Bjorn; Gorgoni, Guido; Griessler, Erich; Loconto, Allison; Mejlgaard, Niels

    2016-01-01

    Research and innovation activities need to become more responsive to societal challenges and concerns. The Responsibility Navigator, developed in the Res-AGorA project, supports decision-makers to govern such activities towards more conscious responsibility. What is considered “responsible” will

  1. HuR/ELAVL1 RNA binding protein modulates interleukin-8 induction by muco-active ribotoxin deoxynivalenol

    Choi, Hye Jin; Yang, Hyun; Park, Seong Hwan; Moon, Yuseok

    2009-01-01

    HuR/Elav-like RNA binding protein 1 (ELAVL1) positively regulates mRNA stability of AU-rich elements (ARE)-containing transcript such as pro-inflammatory cytokines. Ribotoxic stresses can trigger the production of pro-inflammatory mediators by enhancing mRNA stability and the transcriptional activity. We investigated the effects of ribotoxin deoxynivalenol (DON) on HuR translocation and its involvement in the regulation of the pro-inflammatory interleukin-8 (IL-8) mRNA stability. Exposure to the muco-active DON induced nuclear export of both endogenous and exogenous HuR RNA binding protein in human intestinal epithelial cells. Moreover, the interference with HuR protein production suppressed ribotoxic DON-induced IL-8 secretion and its mRNA stability. Cytoplasmic HuR protein interacted with IL-8 mRNA and the complex stabilization was due to the presence of 3'-untranslated region of the transcript. Partly in terms of IL-8-modulating transcription factors, HuR protein was demonstrated to be positively and negatively associated with DON-induced early growth response gene 1 (EGR-1) and activating transcription factor 3 (ATF3), respectively. HuR was a critical mechanistic link between ribotoxic stress and the pro-inflammatory cytokine production, and may have a broader functional significance with regard to mucosal insults since ribotoxic stress responses are also produced upon interactions with the diverse environment of gut.

  2. Down-Regulation of miR-129-5p and the let-7 Family in Neuroendocrine Tumors and Metastases Leads to Up-Regulation of Their Targets Egr1, G3bp1, Hmga2 and Bach1

    Dossing, Kristina B. V.; Binderup, Tina; Kaczkowski, Bogumil

    2014-01-01

    by miR-129-5p. let-7 overexpression inhibited growth of carcinoid cell lines, and let-7 inhibition increased protein content of the transcription factor BACH1 and its targets MMP1 and HMGA2, all known to promote bone metastases. Immunohistochemistry analysis revealed that let-7 targets are highly...

  3. Regulatory Architecture of the LβT2 Gonadotrope Cell Underlying the Response to Gonadotropin-Releasing Hormone

    Frederique Ruf-Zamojski

    2018-02-01

    Full Text Available The LβT2 mouse pituitary cell line has many characteristics of a mature gonadotrope and is a widely used model system for studying the developmental processes and the response to gonadotropin-releasing hormone (GnRH. The global epigenetic landscape, which contributes to cell-specific gene regulatory mechanisms, and the single-cell transcriptome response variation of LβT2 cells have not been previously investigated. Here, we integrate the transcriptome and genome-wide chromatin accessibility state of LβT2 cells during GnRH stimulation. In addition, we examine cell-to-cell variability in the transcriptional response to GnRH using Gel bead-in-Emulsion Drop-seq technology. Analysis of a bulk RNA-seq data set obtained 45 min after exposure to either GnRH or vehicle identified 112 transcripts that were regulated >4-fold by GnRH (FDR < 0.05. The top regulated transcripts constitute, as determined by Bayesian massive public data integration analysis, a human pituitary-relevant coordinated gene program. Chromatin accessibility [assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq] data sets generated from GnRH-treated LβT2 cells identified more than 58,000 open chromatin regions, some containing notches consistent with bound transcription factor footprints. The study of the most prominent open regions showed that 75% were in transcriptionally active promoters or introns, supporting their involvement in active transcription. Lhb, Cga, and Egr1 showed significantly open chromatin over their promoters. While Fshb was closed over its promoter, several discrete significantly open regions were found at −40 to −90 kb, which may represent novel upstream enhancers. Chromatin accessibility determined by ATAC-seq was associated with high levels of gene expression determined by RNA-seq. We obtained high-quality single-cell Gel bead-in-Emulsion Drop-seq transcriptome data, with an average of >4,000 expressed genes

  4. Responsible nations

    Lippert-Rasmussen, Kasper

    2009-01-01

    In National Responsibility and Global Justice, David Miller defends the view that a member of a nation can be collectively responsible for an outcome despite the fact that: (i) she did not control it; (ii) she actively opposed those of her nation's policies that produced the outcome; and (iii......) actively opposing the relevant policy was costly for her. I argue that Miller's arguments in favor of this strong externalist view about responsibility and control are insufficient. Specifically, I show that Miller's two models of synchronic collective responsibility*the like-minded group model...

  5. Competing responsibly

    Jeurissen, R.J.M.; Ven, van de B.W.

    2005-01-01

    In this paper we examine the effects of different competitive conditions on the determination and evaluation of strategies of corporate social responsibility (CSR). Although the mainstream of current thinking in business ethics recognizes that a firm should invest in social responsibility, the

  6. Query responses

    Paweł Łupkowski

    2017-05-01

    Full Text Available In this article we consider the phenomenon of answering a query with a query. Although such answers are common, no large scale, corpus-based characterization exists, with the exception of clarification requests. After briefly reviewing different theoretical approaches on this subject, we present a corpus study of query responses in the British National Corpus and develop a taxonomy for query responses. We point at a variety of response categories that have not been formalized in previous dialogue work, particularly those relevant to adversarial interaction. We show that different response categories have significantly different rates of subsequent answer provision. We provide a formal analysis of the response categories in the framework of KoS.

  7. Phylogenetic Relationships of Pseudorasbora, Pseudopungtungia, and Pungtungia (Teleostei; Cypriniformes; Gobioninae Inferred from Multiple Nuclear Gene Sequences

    Keun-Yong Kim

    2013-01-01

    Full Text Available Gobionine species belonging to the genera Pseudorasbora, Pseudopungtungia, and Pungtungia (Teleostei; Cypriniformes; Cyprinidae have been heavily studied because of problems on taxonomy, threats of extinction, invasion, and human health. Nucleotide sequences of three nuclear genes, that is, recombination activating protein gene 1 (rag1, recombination activating gene 2 (rag2, and early growth response 1 gene (egr1, from Pseudorasbora, Pseudopungtungia, and Pungtungia species residing in China, Japan, and Korea, were analyzed to elucidate their intergeneric and interspecific phylogenetic relationships. In the phylogenetic tree inferred from their multiple gene sequences, Pseudorasbora, Pseudopungtungia and Pungtungia species ramified into three phylogenetically distinct clades; the “tenuicorpa” clade composed of Pseudopungtungia tenuicorpa, the “parva” clade composed of all Pseudorasbora species/subspecies, and the “herzi” clade composed of Pseudopungtungia nigra, and Pungtungia herzi. The genus Pseudorasbora was recovered as monophyletic, while the genus Pseudopungtungia was recovered as polyphyletic. Our phylogenetic result implies the unstable taxonomic status of the genus Pseudopungtungia.

  8. Rapid selection of Plasmodium falciparum chloroquine resistance transporter gene and multidrug resistance gene-1 haplotypes associated with past chloroquine and present artemether-lumefantrine use in Inhambane District, southern Mozambique

    Thomsen, Thomas T; Madsen, Laura B; Hansson, Helle H

    2013-01-01

    Chloroquine (CQ) use in Mozambique was stopped in 2002 and artemether-lumefantrine (AL) was implemented in 2008. In light of no use of CQ and extensive use of AL, we determined the frequency of molecular markers of Plasmodium falciparum drug resistance/tolerance to CQ and AL in persons living...... in Linga-Linga, an isolated peninsula and in Furvela village, which is located 8 km inland. The P. falciparum chloroquine resistance transporter gene CVMNK wild type increased in frequency from 43.9% in 2009 to 66.4% in 2010 (P = 0.001), and combined P. falciparum multidrug resistance gene 1 N86-184F-D1246...... haplotype increased significantly between years (P = 0.039). The combination of P. falciparum chloroquine resistance transporter gene CVMNK and P. falciparum multidrug resistance gene NFD increased from 24.3% (2009) to 45.3% in (2010, P = 0.017). The rapid changes observed may largely be caused by decreased...

  9. Response Cries.

    Goffman, Erving

    1978-01-01

    Considers utterances that appear to violate the interdependence assumed by the interactionist view, entering the stream of behavior at peculiar and unnatural places, producing communicative effects but no dialogue. Self-talk, imprecations, and response cries are discussed. (EJS)

  10. Sexual dimorphism of stress response and immune/ inflammatory reaction: the corticotropin releasing hormone perspective

    Nicholas V. Vamvakopoulos

    1995-01-01

    Full Text Available This review higlghts key aspects of corticotropin releasing hormone (CRH biology of potential relevance to the sexual dimorphism of the stress response and immune/inflammatory reaction, and introduces two important new concepts based on the regulatory potential of the human (h CRH gene: (1 a proposed mechanism to account for the tissue-specific antithetical responses of hCRH gene expression to glucocorticolds, that may also explain the frequently observed antithetical effects of chronic glucocorticoid administration in clinical practice and (2 a heuristic diagram to illustrate the proposed modulation of the stress response and immune/ inflammatory reaction by steroid hormones, from the perspective of the CRH system.

  11. Long non-coding RNA taurine-upregulated gene 1 correlates with poor prognosis, induces cell proliferation, and represses cell apoptosis via targeting aurora kinase A in adult acute myeloid leukemia.

    Wang, Xinfeng; Zhang, Lina; Zhao, Fan; Xu, Ruirong; Jiang, Jie; Zhang, Chenglu; Liu, Hong; Huang, Hongming

    2018-04-13

    This study aimed to investigate the correlation of long non-coding RNA (lncRNA) taurine-upregulated gene 1 (TUG1) with clinicopathological feature and prognosis, and to explore its effect on cell proliferation and apoptosis as well as the relevant target genes in adult acute myeloid leukemia (AML). LncRNA TUG1 expression was detected in bone marrow samples from 186 AML patients and 62 controls. Blank mimic, lncRNA TUG1 mimic, blank inhibitor, and lncRNA TUG1 inhibitor lentivirus vectors were transfected in KG-1 cells. Rescue experiment was performed by transfection of lncRNA TUG1 inhibitor and aurora kinase A (AURKA) mimic lentivirus vectors. Cell proliferation, apoptosis, RNA, and protein expressions were determined by CKK-8, annexin V-FITC-propidium iodide, quantitative polymerase chain reaction, and western blot assays. LncRNA TUG1 expression was higher in AML patients compared to controls and correlated with higher white blood cell counts, monosomal karyotype, FLT3-ITD mutation, poor-risk stratification, and poor prognosis, which independently predicted worse event-free survival and overall survival. In vitro, lncRNA TUG1 expression was higher in AML cell lines (KG-1, MOLM-14, HL-60, NB-4, and THP-1 cells) compared to controls. LncRNA TUG1 mimic promoted cell proliferation and decreased cell apoptosis rate, while lncRNA TUG1 inhibitor repressed cell proliferation and increased cell apoptosis rate. Rescue experiment showed that AURKA attenuated the influence of lncRNA TUG1 on AML cell proliferation and apoptosis. In conclusion, lncRNA TUG1 associates with advanced disease and worse prognosis in adult AML patients, and it induces AML cell proliferation and represses cell apoptosis via targeting AURKA.

  12. Lactose binding to human galectin-7 (p53-induced gene 1) induces long-range effects through the protein resulting in increased dimer stability and evidence for positive cooperativity

    Ermakova, Elena; Miller, Michelle C; Nesmelova, Irina V; López-Merino, Lara; Berbís, Manuel Alvaro; Nesmelov, Yuri; Tkachev, Yaroslav V; Lagartera, Laura; Daragan, Vladimir A; André, Sabine; Cañada, F Javier; Jiménez-Barbero, Jesús; Solís, Dolores; Gabius, Hans-Joachim; Mayo, Kevin H

    2013-01-01

    The product of p53-induced gene 1 is a member of the galectin family, i.e., galectin-7 (Gal-7). To move beyond structural data by X-ray diffraction, we initiated the study of the lectin by nuclear magnetic resonance (NMR) and circular dichroism spectroscopies, and molecular dynamics (MD) simulations. In concert, our results indicate that lactose binding to human Gal-7 induces long-range effects (minor conformational shifts and changes in structural dynamics) throughout the protein that result in stabilization of the dimer state, with evidence for positive cooperativity. Monte Carlo fits of 15N-Gal-7 HSQC titrations with lactose using a two-site model yield K1 = 0.9 ± 0.6 × 103 M−1 and K2 = 3.4 ± 0.8 × 103 M−1. Ligand binding-induced stabilization of the Gal-7 dimer was supported by several lines of evidence: MD-based calculations of interaction energies between ligand-loaded and ligand-free states, gel filtration data and hetero-FRET spectroscopy that indicate a highly reduced tendency for dimer dissociation in the presence of lactose, CD-based thermal denaturation showing that the transition temperature of the lectin is significantly increased in the presence of lactose, and saturation transfer difference (STD) NMR using a molecular probe of the monomer state whose presence is diminished in the presence of lactose. MD simulations with the half-loaded ligand-bound state also provided insight into how allosteric signaling may occur. Overall, our results reveal long-range effects on Gal-7 structure and dynamics, which factor into entropic contributions to ligand binding and allow further comparisons with other members of the galectin family. PMID:23376190

  13. Genetic errors of the human caspase recruitment domain-B-cell lymphoma 10-mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (CBM) complex: Molecular, immunologic, and clinical heterogeneity.

    Pérez de Diego, Rebeca; Sánchez-Ramón, Silvia; López-Collazo, Eduardo; Martínez-Barricarte, Rubén; Cubillos-Zapata, Carolina; Ferreira Cerdán, Antonio; Casanova, Jean-Laurent; Puel, Anne

    2015-11-01

    Three members of the caspase recruitment domain (CARD) family of adaptors (CARD9, CARD10, and CARD11) are known to form heterotrimers with B-cell lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma-translocation gene 1 (MALT1). These 3 CARD-BCL10-MALT1 (CBM) complexes activate nuclear factor κB in both the innate and adaptive arms of immunity. Human inherited defects of the 3 components of the CBM complex, including the 2 adaptors CARD9 and CARD11 and the 2 core components BCL10 and MALT1, have recently been reported. Biallelic loss-of-function mutant alleles underlie several different immunologic and clinical phenotypes, which can be assigned to 2 distinct categories. Isolated invasive fungal infections of unclear cellular basis are associated with CARD9 deficiency, whereas a broad range of clinical manifestations, including those characteristic of T- and B-lymphocyte defects, are associated with CARD11, MALT1, and BCL10 deficiencies. Interestingly, human subjects with these mutations have some features in common with the corresponding knockout mice, but other features are different between human subjects and mice. Moreover, germline and somatic gain-of-function mutations of MALT1, BCL10, and CARD11 have also been found in patients with other lymphoproliferative disorders. This broad range of germline and somatic CBM lesions, including loss-of-function and gain-of-function mutations, highlights the contribution of each of the components of the CBM complex to human immunity. Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  14. In Response

    Egeland, Janice A.; Shaw, Jon A.; Endicott, Jean; Allen, Cleona R.; Hostetter, Abram M.

    2005-01-01

    This article features the response to the important commentary by Dr. Carlson. The Amish Study represents, as she notes, a special research population for investigation of "classic" bipolar disorder viewed against a homogeneous cultural landscape where emerging biological and behavioral prodromal features can be identified. Dr. Carlson questions…

  15. Responsible tourism

    Birkaš E.

    2012-01-01

    Full Text Available Realising tourism in the context of responsibility is a problem of historical-social and economic time-space continuum; the problem of possibility of temporal unification of these parts. The study aims to emphasize that the essence of problem can only be understood in the depth of a general problematic of tourism, as a question of temporalisation of historical-social space, which, however, leads to a grand question of today: does the human activity which creates temporalised spaces have its own gravitational direction? Ad deliberandum. The study proposes the viewpoint that the context of responsibility requires overcoming the dimension of interpretation where the subject is understood as an ultimate human-singularity and a perfect match of responsibility with a dominant and current form of temporalisation of time suggests a paradigm of participating consciousness, the consciousness of unity, which, in Berdyaev's words, is never logical, but existential. The study, on the basis of a meticulous studying of a new narrative of tourism, primarily due to volume restrictions does not go beyond presenting the key attributes of this ever-expanding understanding of tourism - with a demonstration of a concrete practice - but all this with an emphasis that qualification of the actors' activities is possible only along the lines of a previous consideration of comprehension of structure of space and time - along the revalorisation of a motivational horison (Anzenbacher, A 1987, 264.p. and also the very term of responsibility and freedom. Responsibility can only then become an orientation of tourist activities, if the primary focus is set on re-comprehension (revalorisation of civilisational legacies in a timeless perspective.

  16. Responsive Innovation

    Pedersen, Carsten

    Although the importance of stakeholder networks has been recognized in recent years, a non-teleological model that incorporates their collective sensing into innovation processes has so far not been developed. Hence, this paper argues that traditional linear and sequential innovation models...... are insufficient in hypercompetitive environments. Instead, it is proposed that companies should ground their innovation processes in the collective sensing of frontline-employees and customers that operate around the organizational periphery. This frames the concept of responsive innovation, where key...... stakeholders engaged in the organization’s ongoing business activities collectively identify issues that central managers subsequently can resolve....

  17. Sustainable responsibilities?

    Lystbæk, Christian Tang

    2015-01-01

    , which have pervaded all areas of daily life, including the world of business. At local, national, international and global levels, policies have been formulated to encourage corporations to take responsibility for their social and environmental performance (Laszlo, 2007). In the European Union, the EU......, people and the natural environment have traditionally been viewed as available resources, which are taken for granted and, thus, treated as externalities (Livesey & Graham, 2007). But the last decade has seen increasing recognition of environmental problems such as climate change and resource depletion...

  18. Corporate responsibility

    Jensen, Karsten Klint

    2007-01-01

    Is it legitimate for a business to concentrate on profits under respect for the law and ethical custom? On the one hand, there seems to be good reasons for claiming that a corporation has a duty to act for the benefit of all its stakeholders. On the other hand, this seems to dissolve the notion...... of a private business; but then again, a private business would appear to be exempted from ethical responsibility. This is what Kenneth Goodpaster has called the stakeholder paradox: either we have ethics without business or we have business without ethics. Through a different route, I reach the same solution...

  19. Emotional Responses

    Hansen, Flemming; Christensen, Sverre Riis; Lundsteen, Steen

    2007-01-01

    Recent neurological research has pointed to the importance of fundamental emotional processes for most kinds of human behaviour. Measures of emotional response tendencies towards brands seem to reveal intangible aspects of brand equity, particularly in a marketing context. In this paper a procedure...... for estimating such emotional brand equity is presented and findings from two successive studies of more than 100 brands are reported. It demonstrates how changes that occur between two years are explainable in terms of factors identifiable in the markets, and that the measures otherwise are stable over time...

  20. Naturalizing Responsibility.

    Zullo, Silvia

    2016-10-01

    In the contemporary debate on the use of the neurosciences in ethics and law, numerous arguments have been bandied about among scientists and philosophers looking to uphold or reject the reliability and validity of scientific findings obtained by brain imaging technologies. Among the most vexing questions is, Can we trust that technology? One point of disagreement is whether brain scans offer a window through which to observe the functioning of the mind, in such a way as to enable lawyers, judges, physicians, and lawmakers to detect anomalies in brain function that may account for criminal unconscious behavior. Those who stand behind brain imaging believe that this can indeed be achieved, whereas those in opposition stress that brain scans are highly open to interpretation and that the data they provide is insufficient to establish causal connections. The question essentially comes down to whether technology can reliably be used to determine the intentions of the individual, thus establishing mens rea, for example, and hence responsibility. This article focuses on the latter notion and explores whether we can rely on the neurosciences to shed light on a complex form of moral and legal reasoning, as well as the role of the neurosciences in reawakening a philosophical and legal interest in trying to set responsibility on an empirical basis.

  1. Responsible innovation

    De Woot, Philippe

    2015-01-01

    Economic development is rooted in disruption, not in equilibrium. And a powerful engine of economic development is innovation; but is this innovation always for the common good? The dark side of the extraordinary dynamism of innovation lies precisely in its destructive power. If simply left to market forces, it could lead to social chaos and great human suffering. To face the challenges of our time, we must create the proper climate and culture to develop strong entrepreneurial drive. But, more than ever, we must give this entrepreneurial drive its ethical and societal dimensions. Responsible innovation means a more voluntary orientation towards the great problems of the 21st century, e.g. depletion of the planet's resources, rising inequality, and new scientific developments potentially threatening freedom, democracy and human integrity. We need to transform our ceaseless creativity into real progress for humankind. In this respect, the rapid development of social innovation opens the door for new methods an...

  2. Induction of human microsomal prostaglandin E synthase 1 by activated oncogene RhoA GTPase in A549 human epithelial cancer cells

    Choi, Hye Jin [Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Lee, Dong-Hyung [Department of Obstetrics and Gynecology, Medical Research Institute, Pusan National University, Busan (Korea, Republic of); Park, Seong-Hwan; Kim, Juil; Do, Kee Hun [Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); An, Tae Jin; Ahn, Young Sup; Park, Chung Berm [Department of Herbal Crop Research, NIHHS, RDA, Eumseong (Korea, Republic of); Moon, Yuseok, E-mail: moon@pnu.edu [Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Medical Research Institute and Research Institute for Basic Sciences, Pusan National University, Busan (Korea, Republic of)

    2011-09-30

    Highlights: {yields} As a target of oncogene RhoA-linked signal, a prostaglandin metabolism is assessed. {yields} RhoA activation increases PGE{sub 2} levels and its metabolic enzyme mPGES-1. {yields} RhoA-activated NF-{kappa}B and EGR-1 are positively involved in mPGES-1 induction. -- Abstract: Oncogenic RhoA GTPase has been investigated as a mediator of pro-inflammatory responses and aggressive carcinogenesis. Among the various targets of RhoA-linked signals, pro-inflammatory prostaglandin E{sub 2} (PGE{sub 2}), a major prostaglandin metabolite, was assessed in epithelial cancer cells. RhoA activation increased PGE{sub 2} levels and gene expression of the rate-limiting PGE{sub 2} producing enzymes, cyclooxygenase-2 and microsomal prostaglandin E synthase 1 (mPGES-1). In particular, human mPGES-1 was induced by RhoA via transcriptional activation in control and interleukin (IL)-1{beta}-activated cancer cells. To address the involvement of potent signaling pathways in RhoA-activated mPGES-1 induction, various signaling inhibitors were screened for their effects on mPGES-1 promoter activity. RhoA activation enhanced basal and IL-1{beta}-mediated phosphorylated nuclear factor-{kappa}B and extracellular signal-regulated kinase1/2 proteins, all of which were positively involved in RhoA-induced gene expression of mPGES-1. As one potent down-stream transcription factor of ERK1/2 signals, early growth response gene 1 product also mediated RhoA-induced gene expression of mPGES-1 by enhancing transcriptional activity. Since oncogene-triggered PGE{sub 2} production is a critical modulator of epithelial tumor cells, RhoA-associated mPGES-1 represents a promising chemo-preventive or therapeutic target for epithelial inflammation and its associated cancers.

  3. Duodenal ulcer promoting gene 1 (dupA1 is associated with A2147G clarithromycin-resistance mutation but not interleukin-8 secretion from gastric mucosa in Iraqi patients

    N.R. Hussein

    2015-07-01

    Full Text Available Helicobacter pylori causes peptic ulceration and gastric adenocarcinoma. The aims were to study the influence of dupA1 positivity upon interleukin-8 (IL-8 secretion from gastric mucosa and determine the prevalence of mutations responsible for clarithromycin and fluoroquinolone resistance. DNA was extracted from 74 biopsies and the virulence factors were studied. Levels of IL-8 in gastric mucosa were measured using ELISA and the mutations responsible for clarithromycin and fluoroquinolone resistance were determined using a GenoType-HelicoDR assay. The prevalence of cagA in strains isolated from gastric ulcer (GU and duodenal ulcer (DU was significantly higher than those isolated from non-ulcer disease (NUD (90% and 57.9% versus 33.3%; p 0.01. The vacA s1m1 genotype was more prevalent in patients with DU (73.7% and GU (70% than in those with NUD (13.3% (p 0.01. The prevalence of dupA1 was higher in DU patients (36.8% than those with GU (10% and NUD (8.9% (p 0.01. Multivariate analysis showed that a cagA+/vacA s1i1m2 virulence gene combination was independently associated with the developing peptic ulcer disease (PUD with increased odds of developing PUD (p 0.03; OR = 2.1. We found no significant difference in the levels of IL-8 secretion in gastric mucosa infected with H. pylori dupA-negative and H. pylori dupA1-positive strains (dupA-negative: mean ± median: 28 ± 26 versus 30 ± 27.1 for dupA1; p 0.6. While 12 strains were clarithromycin resistant, only three isolates were levofloxacin resistant. A significant association was found between dupA1 genotype and A2147G clarithromycin resistance mutation (p <0.01. Further study is needed to explore the relationship between virulence factors and disease process and treatment failure.

  4. Duodenal ulcer promoting gene 1 (dupA1) is associated with A2147G clarithromycin-resistance mutation but not interleukin-8 secretion from gastric mucosa in Iraqi patients.

    Hussein, N R; Tunjel, I; Majed, H S; Yousif, S T; Aswad, S I; Assafi, M S

    2015-07-01

    Helicobacter pylori causes peptic ulceration and gastric adenocarcinoma. The aims were to study the influence of dupA1 positivity upon interleukin-8 (IL-8) secretion from gastric mucosa and determine the prevalence of mutations responsible for clarithromycin and fluoroquinolone resistance. DNA was extracted from 74 biopsies and the virulence factors were studied. Levels of IL-8 in gastric mucosa were measured using ELISA and the mutations responsible for clarithromycin and fluoroquinolone resistance were determined using a GenoType-HelicoDR assay. The prevalence of cagA in strains isolated from gastric ulcer (GU) and duodenal ulcer (DU) was significantly higher than those isolated from non-ulcer disease (NUD) (90% and 57.9% versus 33.3%; p 0.01). The vacA s1m1 genotype was more prevalent in patients with DU (73.7%) and GU (70%) than in those with NUD (13.3%) (p 0.01). The prevalence of dupA1 was higher in DU patients (36.8%) than those with GU (10%) and NUD (8.9%) (p 0.01). Multivariate analysis showed that a cagA+/vacA s1i1m2 virulence gene combination was independently associated with the developing peptic ulcer disease (PUD) with increased odds of developing PUD (p 0.03; OR = 2.1). We found no significant difference in the levels of IL-8 secretion in gastric mucosa infected with H. pylori dupA-negative and H. pylori dupA1-positive strains (dupA-negative: mean ± median: 28 ± 26 versus 30 ± 27.1 for dupA1; p 0.6). While 12 strains were clarithromycin resistant, only three isolates were levofloxacin resistant. A significant association was found between dupA1 genotype and A2147G clarithromycin resistance mutation (p <0.01). Further study is needed to explore the relationship between virulence factors and disease process and treatment failure.

  5. Technology and responsibility

    Zimmerli, W.C.

    1987-01-01

    Philosophical reflections on the concepts of responsibility and type of responsibility are presented and discussed with regard to the developments of technology. The author states that neither the relationship between liability and responsibility has changed, nor the structure of responsibility. Any individual still is responsible for his actions and their consequences. What has changed, however, is the former restriction to the concept of internal responsibility and the overlapping of acting subject and responsible subject. (DG) [de

  6. A Luciferase Reporter Gene Assay to Measure Ebola Virus Viral Protein 35-Associated Inhibition of Double-Stranded RNA-Stimulated, Retinoic Acid-Inducible Gene 1-Mediated Induction of Interferon β.

    Cannas, Valeria; Daino, Gian Luca; Corona, Angela; Esposito, Francesca; Tramontano, Enzo

    2015-10-01

    During Ebola virus (EBOV) infection, the type I interferon α/β (IFN-α/β) innate immune response is suppressed by EBOV viral protein 35 (VP35), a validated drug target. Identification of EBOV VP35 inhibitors requires a cellular system able to assess the VP35-based inhibitory functions of viral double-stranded RNA (dsRNA) IFN-β induction. We established a miniaturized luciferase gene reporter assay in A549 cells that measures IFN-β induction by viral dsRNA and is dose-dependently inhibited by VP35 expression. When compared to influenza A virus NS1 protein, EBOV VP35 showed improved inhibition of viral dsRNA-based IFN-β induction. This assay can be used to screen for EBOV VP35 inhibitors. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  7. Reacquisition of cocaine conditioned place preference and its inhibition by previous social interaction preferentially affect D1-medium spiny neurons in the accumbens corridor.

    Prast, Janine M; Schardl, Aurelia; Schwarzer, Christoph; Dechant, Georg; Saria, Alois; Zernig, Gerald

    2014-01-01

    We investigated if counterconditioning with dyadic (i.e., one-to-one) social interaction, a strong inhibitor of the subsequent reacquisition of cocaine conditioned place preference (CPP), differentially modulates the activity of the diverse brain regions oriented along a mediolateral corridor reaching from the interhemispheric sulcus to the anterior commissure, i.e., the nucleus of the vertical limb of the diagonal band, the medial septal nucleus, the major island of Calleja, the intermediate part of the lateral septal nucleus, and the medial accumbens shell and core. We also investigated the involvement of the lateral accumbens core and the dorsal caudate putamen. The anterior cingulate 1 (Cg1) region served as a negative control. Contrary to our expectations, we found that all regions of the accumbens corridor showed increased expression of the early growth response protein 1 (EGR1, Zif268) in rats 2 h after reacquisition of CPP for cocaine after a history of cocaine CPP acquisition and extinction. Previous counterconditioning with dyadic social interaction inhibited both the reacquisition of cocaine CPP and the activation of the whole accumbens corridor. EGR1 activation was predominantly found in dynorphin-labeled cells, i.e., presumably D1 receptor-expressing medium spiny neurons (D1-MSNs), with D2-MSNs (immunolabeled with an anti-DRD2 antibody) being less affected. Cholinergic interneurons or GABAergic interneurons positive for parvalbumin, neuropeptide Y or calretinin were not involved in these CPP-related EGR1 changes. Glial cells did not show any EGR1 expression either. The present findings could be of relevance for the therapy of impaired social interaction in substance use disorders, depression, psychosis, and autism spectrum disorders.

  8. Genotypic differences in intruder-evoked immediate early gene activation in male, but not female, vasopressin 1b receptor knockout mice.

    Witchey, Shannah K; Stevenson, Erica L; Caldwell, Heather K

    2016-11-24

    The neuropeptide arginine vasopressin (Avp) modulates social behaviors via its two centrally expressed receptors, the Avp 1a receptor and the Avp 1b receptor (Avpr1b). Recent work suggests that, at least in mice, Avp signaling through Avpr1b within the CA2 region of the hippocampus is critical for normal aggressive behaviors and social recognition memory. However, this brain area is just one part of a larger neural circuit that is likely to be impacted in Avpr1b knockout (-/-) mice. To identify other brain areas that are affected by altered Avpr1b signaling, genotypic differences in immediate early gene activation, i.e. c-FOS and early growth response factor 1 (EGR-1), were quantified using immunocytochemistry following a single exposure to an intruder. In females, no genotypic differences in intruder-evoked c-FOS or EGR-1 immunoreactivity were observed in any of the brain areas measured. In males, while there were no intruder-evoked genotypic differences in c-FOS immunoreactivity, genotypic differences were observed in EGR-1 immunoreactivity within the ventral bed nucleus of the stria terminalis and the anterior hypothalamus; with Avpr1b -/- males having less EGR-1 immunoreactivity in these regions than controls. These data are the first to identify specific brain areas that may be a part of a neural circuit that includes Avpr1b-expressing cells in the CA2 region of the hippocampus. It is thought that this circuit, when working properly, plays a role in how an animal evaluates its social context.

  9. Optimal Responsible Investment

    Jessen, Pernille

    The paper studies retail Socially Responsible Investment and portfolio allocation. It extends conventional portfolio theory by allowing for a personal value based investment decision. When preferences for responsibility enter the framework for mean-variance analysis, it yields an optimal...... responsible investment model. An example of index investing illustrates the theory. Results show that it is crucial for the responsible investor to consider portfolio risk, expected return, and responsibility simultaneously in order to obtain an optimal portfolio. The model enables responsible investors...

  10. Glucose ingestion stimulates atherothrombotic inflammation in polycystic ovary syndrome

    Kirwan, John P.; Rote, Neal S.; Minium, Judi

    2013-01-01

    Women with polycystic ovary syndrome (PCOS) have chronic low-grade inflammation that can increase the risk of atherothrombosis. We performed a cross-sectional study to examine the effect of glucose ingestion on markers of atherothrombotic inflammation in mononuclear cells (MNC) of 16 women with PCOS (8 lean, 8 obese) and 16 weight-matched controls. Activator protein-1 (AP-1) activation and the protein content of early growth response-1 (EGR-1), matrix matalloproteinases-2 (MMP2), and tissue factor (TF) were quantified from MNC obtained from blood drawn fasting and 2 h after glucose ingestion. Plasma MMP9 and C-reactive protein (CRP) were measured from fasting blood samples. Truncal fat was determined by DEXA. Lean women with PCOS exhibited greater AP-1 activation and MMP2 protein content after glucose ingestion and higher plasma MMP9 and CRP levels than lean controls. Obese women with PCOS exhibited greater EGR-1 and TF protein content after glucose ingestion, and plasma CRP levels were even higher compared with lean subjects regardless of PCOS status. Truncal fat correlated with MMP9 and CRP levels and glucose-stimulated increases in AP-1 activation and EGR-1 and TF protein content. Testosterone correlated with glucose-stimulated AP-1 activation, and androstenedione correlated with MMP9 and CRP levels and glucose-stimulated AP-1 activation. Thus, both PCOS and obesity contribute to an atherothrombotic state in which excess abdominal adiposity and hyperandrogenism may be specific risk factors for developing atherothrombosis. PMID:23249695

  11. Responsibility for what? Fairness and individual responsibility

    Cappelen, Alexander Wright; Sørensen, Erik Øiolf; Tungodden, Bertil

    2010-01-01

    -This is the author's version of the article: "Responsibility for what? Fairness and individual responsibility", European Economic Review, Volume 54, Issue 3, April 2010, Pages 429–441. What should individuals be held responsible for? This is a fundamental question in much of the contemporary debate on distributive justice. Different fairness ideals, such as strict egalitarianism, and different versions of equal opportunity ethics and libertarianism give different answers to this question....

  12. Playful hyper responsibility

    Knudsen, Hanne; Andersen, Niels Åkerstrøm

    2014-01-01

    Over the past 10–15 years, state-funded schools have begun to require parents to assume an undefined and infinite personal responsibility. In this article, we investigate how schools organize responsibility games to respond to this challenge and how these games affect the concept of responsibility....... We point to a dislocation in the way parents are assigned responsibility, because the definition of responsibility is not only a question of formulating rules or providing advice. We argue that what emerges is a kind of playful hyper responsibility that identifies responsibility as the participation...

  13. Zoospore exudates from Phytophthora nicotianae affect immune responses in Arabidopsis.

    Kong, Ping; McDowell, John M; Hong, Chuanxue

    2017-01-01

    Zoospore exudates play important roles in promoting zoospore communication, homing and germination during plant infection by Phytophthora. However, it is not clear whether exudates affect plant immunity. Zoospore-free fluid (ZFF) and zoospores of P. nicotianae were investigated comparatively for effects on resistance of Arabidopsis thaliana Col-0 and mutants that affect signaling mediated by salicylic acid (SA) and jasmonic acid (JA): eds16 (enhanced disease susceptibility16), pad4 (phytoalexin deficient4), and npr1 (nonexpressor of pathogenesis-related genes1). Col-0 attracted more zoospores and had severe tissue damage when flooded with a zoospore suspension in ZFF. Mutants treated with ZFF alone developed disease symptoms similar to those inoculated with zoospores and requirements of EDS16 and PAD4 for plant responses to zoospores and the exudates was apparent. Zoospore and ZFFs also induced expression of the PR1 and PDF1.2 marker genes for defense regulated by SA and JA, respectively. However, ZFF affected more JA defense signaling, down regulating PR1 when SA signaling or synthesis is deficient, which may be responsible for Arabidopsis mutant plants more susceptible to infection by high concentration of P. nicotianae zoospores. These results suggest that zoospore exudates can function as virulence factors and inducers of plant immune responses during plant infection by Phytophthora.

  14. Zoospore exudates from Phytophthora nicotianae affect immune responses in Arabidopsis.

    Ping Kong

    Full Text Available Zoospore exudates play important roles in promoting zoospore communication, homing and germination during plant infection by Phytophthora. However, it is not clear whether exudates affect plant immunity. Zoospore-free fluid (ZFF and zoospores of P. nicotianae were investigated comparatively for effects on resistance of Arabidopsis thaliana Col-0 and mutants that affect signaling mediated by salicylic acid (SA and jasmonic acid (JA: eds16 (enhanced disease susceptibility16, pad4 (phytoalexin deficient4, and npr1 (nonexpressor of pathogenesis-related genes1. Col-0 attracted more zoospores and had severe tissue damage when flooded with a zoospore suspension in ZFF. Mutants treated with ZFF alone developed disease symptoms similar to those inoculated with zoospores and requirements of EDS16 and PAD4 for plant responses to zoospores and the exudates was apparent. Zoospore and ZFFs also induced expression of the PR1 and PDF1.2 marker genes for defense regulated by SA and JA, respectively. However, ZFF affected more JA defense signaling, down regulating PR1 when SA signaling or synthesis is deficient, which may be responsible for Arabidopsis mutant plants more susceptible to infection by high concentration of P. nicotianae zoospores. These results suggest that zoospore exudates can function as virulence factors and inducers of plant immune responses during plant infection by Phytophthora.

  15. Responsive web design workflow

    LAAK, TIMO

    2013-01-01

    Responsive Web Design Workflow is a literature review about Responsive Web Design, a web standards based modern web design paradigm. The goals of this research were to define what responsive web design is, determine its importance in building modern websites and describe a workflow for responsive web design projects. Responsive web design is a paradigm to create adaptive websites, which respond to the properties of the media that is used to render them. The three key elements of responsi...

  16. The functions of WHIRLY1 and REDOX-RESPONSIVE TRANSCRIPTION FACTOR 1 in cross tolerance responses in plants: a hypothesis.

    Foyer, Christine H; Karpinska, Barbara; Krupinska, Karin

    2014-04-19

    Chloroplasts are important sensors of environment change, fulfilling key roles in the regulation of plant growth and development in relation to environmental cues. Photosynthesis produces a repertoire of reductive and oxidative (redox) signals that provide information to the nucleus facilitating appropriate acclimation to a changing light environment. Redox signals are also recognized by the cellular innate immune system allowing activation of non-specific, stress-responsive pathways that underpin cross tolerance to biotic-abiotic stresses. While these pathways have been intensively studied in recent years, little is known about the different components that mediate chloroplast-to-nucleus signalling and facilitate cross tolerance phenomena. Here, we consider the properties of the WHIRLY family of proteins and the REDOX-RESPONSIVE TRANSCRIPTION FACTOR 1 (RRTF1) in relation to chloroplast redox signals that facilitate the synergistic co-activation of gene expression pathways and confer cross tolerance to abiotic and biotic stresses. We propose a new hypothesis for the role of WHIRLY1 as a redox sensor in chloroplast-to-nucleus retrograde signalling leading to cross tolerance, including acclimation and immunity responses. By virtue of its association with chloroplast nucleoids and with nuclear DNA, WHIRLY1 is an attractive candidate coordinator of the expression of photosynthetic genes in the nucleus and chloroplasts. We propose that the redox state of the photosynthetic electron transport chain triggers the movement of WHIRLY1 from the chloroplasts to the nucleus, and draw parallels with the regulation of NONEXPRESSOR OF PATHOGENESIS-RELATED GENES 1 (NPR1).

  17. DNA damage response pathway in radioadaptive response.

    Sasaki, Masao S; Ejima, Yosuke; Tachibana, Akira; Yamada, Toshiko; Ishizaki, Kanji; Shimizu, Takashi; Nomura, Taisei

    2002-07-25

    Radioadaptive response is a biological defense mechanism in which low-dose ionizing irradiation elicits cellular resistance to the genotoxic effects of subsequent irradiation. However, its molecular mechanism remains largely unknown. We previously demonstrated that the dose recognition and adaptive response could be mediated by a feedback signaling pathway involving protein kinase C (PKC), p38 mitogen activated protein kinase (p38MAPK) and phospholipase C (PLC). Further, to elucidate the downstream effector pathway, we studied the X-ray-induced adaptive response in cultured mouse and human cells with different genetic background relevant to the DNA damage response pathway, such as deficiencies in TP53, DNA-PKcs, ATM and FANCA genes. The results showed that p53 protein played a key role in the adaptive response while DNA-PKcs, ATM and FANCA were not responsible. Wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), mimicked the priming irradiation in that the inhibitor alone rendered the cells resistant against the induction of chromosome aberrations and apoptosis by the subsequent X-ray irradiation. The adaptive response, whether it was afforded by low-dose X-rays or wortmannin, occurred in parallel with the reduction of apoptotic cell death by challenging doses. The inhibitor of p38MAPK which blocks the adaptive response did not suppress apoptosis. These observations indicate that the adaptive response and apoptotic cell death constitute a complementary defense system via life-or-death decisions. The p53 has a pivotal role in channeling the radiation-induced DNA double-strand breaks (DSBs) into an adaptive legitimate repair pathway, where the signals are integrated into p53 by a circuitous PKC-p38MAPK-PLC damage sensing pathway, and hence turning off the signals to an alternative pathway to illegitimate repair and apoptosis. A possible molecular mechanism of adaptive response to low-dose ionizing irradiation has been discussed in relation to

  18. Current status and future prospect of FSHD region gene 1

    It seemingly affects muscle physiology in normal individuals but in FSHD, where it is found to behighly upregulated, might be involved in disruption of face, scapula and humeral skeletal muscle. Literature on FRG1,reviewed from 1996 to 2016, reveals that it is primarily associated with muscle development and maintenance.

  19. fibroblast growth factor, MTDH/Astrocyte elevated gene-1

    2012-12-05

    Dec 5, 2012 ... Expression of basic FGF, MTDH/AEG-1, APC, matrix metalloproteinase 9, and COX-2 markers in prostate carcinomas many genetic and epigenetic alterations have been detected in human PC.[1]. Basic fibroblast growth factor (bFGF), also known as. FGF2 is a member of the FGF family, a group of more.

  20. What are the genes? 1 -O-O ...

    In this issue of Resonance that celebrates the doscoveries of T H Morgan,itis only appropriate that the reader is exposed first hand to the sharp intellect and the critical nature of his thinking. Reproduced below is a brief passage on the concept of the gene, excerpted from his Nobel lecture. (The complete lecture can be seen ...

  1. Toward a molecular pathogenic pathway for Yersinia pestis YopM

    Annette M. Uittenbogaard

    2012-12-01

    Full Text Available YopM is one of the six effector Yops of the human-pathogenic Yersinia, but its mechanism has not been defined. After delivery to J774A.1 monocyte-like cells, YopM can rapidly bind and activate the serine/threonine kinases RSK1 and PRK2. However, in infected mice, effects of Y. pestis YopM have been seen only after 24 to 48 h post infection (p.i.. To identify potential direct effects of YopM in vivo we tested for effects of YopM at 1h and 16-18h p.i. in mice infected systemically with 106 bacteria. At 16 h p.i., there was a robust host response to both parent and yopM-1 Y. pestis KIM5. Compared to cells from non-infected mice, CD11b+ cells from spleens of infected mice produced more than 100-fold greater IFN. In the corresponding sera there were more than 100-fold greater amounts of IFN, G-CSF, and CXCL9, as well as more than 10-fold greater amounts of IL-6, CXCL10, and CXCL1. The only YopM-related differences were slightly lower CXCL10 and IL-6 in sera from mice infected 16 h with parent compared to yopM-1 Y. pestis. Microarray analysis of the CD11b+ cells did not identify consistent transcriptional differences of > 4 fold at 18 h p.i. However, at 1 h p.i. mRNA for early growth response transcription factor 1 (Egr1 was decreased when YopM was present. Bone marrow-derived macrophages infected for 1 h also expressed lower Egr1 message when YopM was present. Infected J774A.1 cells showed greater expression of Egr1 at 1 h p.i. when YopM was present, but this pattern reversed at 3 h. At 6 h p.i., Cxcl10 mRNA was lower in parent-strain infected cells. We conclude that decreased Egr1 expression is a very early transcriptional effect of YopM and speculate that a pathway may exist from RSK1 through Egr1. These studies revealed novel early transcriptional effects of YopM but point to a time after 18 h of infection when critical transitional events lead to later major effects on cytokine gene transcription.

  2. Biological Responses to Materials

    Anderson, James M.

    2001-08-01

    All materials intended for application in humans as biomaterials, medical devices, or prostheses undergo tissue responses when implanted into living tissue. This review first describes fundamental aspects of tissue responses to materials, which are commonly described as the tissue response continuum. These actions involve fundamental aspects of tissue responses including injury, inflammatory and wound healing responses, foreign body reactions, and fibrous encapsulation of the biomaterial, medical device, or prosthesis. The second part of this review describes the in vivo evaluation of tissue responses to biomaterials, medical devices, and prostheses to determine intended performance characteristics and safety or biocompatibility considerations. While fundamental aspects of tissue responses to materials are important from research and development perspectives, the in vivo evaluation of tissue responses to these materials is important for performance, safety, and regulatory reasons.

  3. Decoupling Responsible Management Education

    Rasche, Andreas; Gilbert, Dirk Ulrich

    Business schools increasingly aim to embed corporate responsibility, sustainability, and ethics into their curricular and extracurricular activities. This paper examines under what conditions business schools may decouple the structural effects of their engagement in responsible management educat...

  4. Responsibility and Capacities

    Ryberg, Jesper

    2014-01-01

    That responsible moral agency presupposes certain mental capacities, constitutes a widely accepted view among theorists. Moreover, it is often assumed that degrees in the development of the relevant capacities co-vary with degrees of responsibility. In this article it is argued that, the move from...... the view that responsibility requires certain mental capacities to the position that degrees of responsibility co-vary with degrees of the development of the mental capacities, is premature....

  5. Instant responsive web design

    Simmons, Cory

    2013-01-01

    A step-by-step tutorial approach which will teach the readers what responsive web design is and how it is used in designing a responsive web page.If you are a web-designer looking to expand your skill set by learning the quickly growing industry standard of responsive web design, this book is ideal for you. Knowledge of CSS is assumed.

  6. Risk and response

    Warner, F W

    1980-12-01

    A discussion of nuclear power and public acceptability can quite properly begin with a general consideration of the nature of response to risk. Response follows perception and builds up from individual through group response to the judgement of society expressed in governmental decisions on what is acceptable. The subject is analysed in some detail, with examples.

  7. Risk and response

    Warner, F [Cremer and Warner (UK)

    1981-01-01

    A discussion of nuclear power and public acceptability can quite properly begin with a general consideration of the nature of response to risk. Response follows perception, and builds up from the individual through group response to the judgement of society expressed in governmental decisions on what is acceptable. Various types of risk, and public reaction, are discussed.

  8. National Response Team

    Response planning and coordination (not direct response itself) is accomplished at the federal level through the U.S. National Response Team (NRT), an interagency group co-chaired by EPA and U.S. Coast Guard. NRT distributes information, plans, and trains.

  9. Self-Responsibility and Responsibility for Others

    Philip Buckley

    2016-09-01

    Full Text Available Because of the transcendent nature of the experience of my own self, responsibility for myself necessarily leads to responsibility for others. The aim of this paper is to approach this experience of the transcendence of the self and to show how it relates to a new sense of responsibility which transcends the self through a number of stages. First, the author outlines what might be called the "standard" view of authenticity in Husserl and how this particular view yields a certain view of responsibility as the ability to answer completely for "who" one is and "what" one does. Second, this standard view is challenged with another reading of the "self" in Husserl – one that emphasizes a necessary and productive division within the self. Thus, the author suggests that it is this second view of the self which is developed by Heidegger. Third, he demonstrates how this different view of the "authentic" self, that is inextricably linked to a "loss" of self, leads to a radically distinct view of responsibility for oneself, and for others.

  10. Redox rhythm reinforces the circadian clock to gate immune response.

    Zhou, Mian; Wang, Wei; Karapetyan, Sargis; Mwimba, Musoki; Marqués, Jorge; Buchler, Nicolas E; Dong, Xinnian

    2015-07-23

    Recent studies have shown that in addition to the transcriptional circadian clock, many organisms, including Arabidopsis, have a circadian redox rhythm driven by the organism's metabolic activities. It has been hypothesized that the redox rhythm is linked to the circadian clock, but the mechanism and the biological significance of this link have only begun to be investigated. Here we report that the master immune regulator NPR1 (non-expressor of pathogenesis-related gene 1) of Arabidopsis is a sensor of the plant's redox state and regulates transcription of core circadian clock genes even in the absence of pathogen challenge. Surprisingly, acute perturbation in the redox status triggered by the immune signal salicylic acid does not compromise the circadian clock but rather leads to its reinforcement. Mathematical modelling and subsequent experiments show that NPR1 reinforces the circadian clock without changing the period by regulating both the morning and the evening clock genes. This balanced network architecture helps plants gate their immune responses towards the morning and minimize costs on growth at night. Our study demonstrates how a sensitive redox rhythm interacts with a robust circadian clock to ensure proper responsiveness to environmental stimuli without compromising fitness of the organism.

  11. Optimal Responsible Investment

    Jessen, Pernille

    Numerous institutions are now engaged in Socially Responsible Investment or have signed the "UN Principles for Responsible Investment". Retail investors, however, are still lacking behind. This is peculiar since the sector constitutes key stakeholders in environmental, social and governmental...... standards. This paper considers optimal responsible investment for a small retail investor. It extends conventional portfolio theory by allowing for a personal-value based investment decision. Preferences for responsibility are defined in the framework of mean-variance analysis and an optimal responsible...... investment model identified. Implications of the altered investment problem are investigated when the dynamics between portfolio risk, expected return and responsibility is considered. Relying on the definition of a responsible investor, it is shown how superior investment opportunities can emerge when...

  12. Early growth response gene-2 (Egr-2 regulates the development of B and T cells.

    Suling Li

    2011-04-01

    Full Text Available Understanding of how transcription factors are involved in lymphocyte development still remains a challenge. It has been shown that Egr-2 deficiency results in impaired NKT cell development and defective positive selection of T cells. Here we investigated the development of T, B and NKT cells in Egr-2 transgenic mice and the roles in the regulation of distinct stages of B and T cell development.The expression of Egr1, 2 and 3 were analysed at different stages of T and B cell development by RT-PCT and results showed that the expression was strictly regulated at different stages. Forced expression of Egr-2 in CD2(+ lymphocytes resulted in a severe reduction of CD4(+CD8(+ (DP cells in thymus and pro-B cells in bone marrow, which was associated with reduced expression of Notch1 in ISP thymocytes and Pax5 in pro-B cells, suggesting that retraction of Egr-2 at the ISP and pro-B cell stages is important for the activation of lineage differentiation programs. In contrast to reduction of DP and pro-B cells, Egr-2 enhanced the maturation of DP cells into single positive (SP T and NKT cells in thymus, and immature B cells into mature B cells in bone marrow.Our results demonstrate that Egr-2 expressed in restricted stages of lymphocyte development plays a dynamic, but similar role for the development of T, NKT and B cells.

  13. High glucose increases Cdk5 activity in podocytes via transforming growth factor-β1 signaling pathway

    Zhang, Yue; Li, Hongbo; Hao, Jun; Zhou, Yi; Liu, Wei

    2014-01-01

    Podocytes are highly specialized and terminally differentiated glomerular cells that play a vital role in the development and progression of diabetic nephropathy (DN). Cyclin-dependent kinase 5 (Cdk5), who is an atypical but essential member of the Cdk family of proline-directed serine/threonine kinases, has been shown as a key regulator of podocyte differentiation, proliferation and morphology. Our previous studies demonstrated that the expression of Cdk5 was significantly increased in podocytes of diabetic rats, and was closely related with podocyte injury of DN. However, the mechanisms of how expression and activity of Cdk5 are regulated under the high glucose environment have not yet been fully elucidated. In this study, we showed that high glucose up-regulated the expression of Cdk5 and its co-activator p35 with a concomitant increase in Cdk5 kinase activity in conditionally immortalized mouse podocytes in vitro. When exposed to 30 mM glucose, transforming growth factor-β1 (TGF-β1) was activated. Most importantly, we found that SB431542, the Tgfbr1 inhibitor, significantly decreased the expression of Cdk5 and p35 and Cdk5 kinase activity in high glucose-treated podocytes. Moreover, high glucose increased the expression of early growth response-1 (Egr-1) via TGF-β1-ERK1/2 pathway in podocytes and inhibition of Egr-1 by siRNA decreased p35 expression and Cdk5 kinase activity. Furthermore, inhibition of Cdk5 kinase activity effectively alleviated podocyte apoptosis induced by high glucose or TGF-β1. Thus, the TGF-β1-ERK1/2-Egr-1 signaling pathway may regulate the p35 expression and Cdk5 kinase activity in high glucose-treated podocytes, which contributes to podocyte injury of DN. - Highlights: • HG up-regulated the expression of Cdk5 and p35, and Cdk5 activity in podocytes. • HG activated TGF-β1 pathway and SB431542 inhibited Cdk5 expression and activity. • HG increased the expression of Egr-1 via TGF-β1-ERK1/2 pathway. • Inhibition of Egr-1

  14. Responsible geographies and geographies of response

    Grindsted, Thomas Skou

    This dissertation engages with Danish University geographers at work and their explication of the role of geography in shaping socio-environmental debates in an era of the anthropocene. Situating sustainability concepts in a historygeographical context the dissertation examines responses and resp......This dissertation engages with Danish University geographers at work and their explication of the role of geography in shaping socio-environmental debates in an era of the anthropocene. Situating sustainability concepts in a historygeographical context the dissertation examines responses...... in higher education literature. The methodological framework is based on the social nature approach that tangles these quite distinct epistemological communities by consulting the socio-natures produced. It is concluded that though geographers find sustainability themes important to geography......, sustainability is more often implicit than it is explicit. This produces a number of dilemmas and contradictions since geographers both seek to distance themselves from produced politics while at the same time elucidating them. Geographies of response and responsibilities address the battleground over...

  15. Responsibility and climate change

    Jamieson, Dale

    2015-01-01

    Ibegin by providing some background to conceptions of responsibility. I note the extent of disagreement in this area, the diverse and cross-cutting distinctions that are deployed, and the relative neglect of some important problems. These facts make it difficult to attribute responsibility for climate change, but so do some features of climate change itself which I go on to illuminate. Attributions of responsibility are often contested sites because such attributions are fundamentally pragmat...

  16. Radiological Emergency Response Data

    U.S. Environmental Protection Agency — Quality Data Asset includes all current and historical emergency radiological response event and incident of national significance data and surveillance, monitoring,...

  17. Environmentally Responsible Aviation Project

    National Aeronautics and Space Administration — Created in 2009 as part of NASA's Aeronautics Research Mission Directorate's Integrated Systems Research Program, the Environmentally Responsible Aviation...

  18. Biological response modifiers

    Weller, R.E.

    1991-10-01

    Much of what used to be called immunotherapy is now included in the term biological response modifiers. Biological response modifiers (BRMs) are defined as those agents or approaches that modify the relationship between the tumor and host by modifying the host's biological response to tumor cells with resultant therapeutic effects.'' Most of the early work with BRMs centered around observations of spontaneous tumor regression and the association of tumor regression with concurrent bacterial infections. The BRM can modify the host response in the following ways: Increase the host's antitumor responses through augmentation and/or restoration of effector mechanisms or mediators of the host's defense or decrease the deleterious component by the host's reaction; Increase the host's defenses by the administration of natural biologics (or the synthetic derivatives thereof) as effectors or mediators of an antitumor response; Augment the host's response to modified tumor cells or vaccines, which might stimulate a greater response by the host or increase tumor-cell sensitivity to an existing response; Decrease the transformation and/or increase differentiation (maturation) of tumor cells; or Increase the ability of the host to tolerate damage by cytotoxic modalities of cancer treatment.

  19. Oil Spill Response Manual

    Marieke Zeinstra; Sandra Heins; Wierd Koops

    2014-01-01

    A two year programme has been carried out by the NHL University of Applied Sciences together with private companies in the field of oil and chemical spill response to finalize these manuals on oil and chemical spill response. These manuals give a good overview of all aspects of oil and chemical

  20. Indicators of responsible investing

    Scholtens, Bert

    Responsible investment has witnessed significant changes in the past decade. It is estimated that about one fifth of assets under management in the US and about half of all assets under management in the EU are done on the basis of one of the seven responsible investment strategies. This paper

  1. Eastern Frequency Response Study

    Miller, N.W.; Shao, M.; Pajic, S.; D' Aquila, R.

    2013-05-01

    This study was specifically designed to investigate the frequency response of the Eastern Interconnection that results from large loss-of-generation events of the type targeted by the North American Electric Reliability Corp. Standard BAL-003 Frequency Response and Frequency Bias Setting (NERC 2012a), under possible future system conditions with high levels of wind generation.

  2. Rapid response systems.

    Lyons, Patrick G; Edelson, Dana P; Churpek, Matthew M

    2018-07-01

    Rapid response systems are commonly employed by hospitals to identify and respond to deteriorating patients outside of the intensive care unit. Controversy exists about the benefits of rapid response systems. We aimed to review the current state of the rapid response literature, including evolving aspects of afferent (risk detection) and efferent (intervention) arms, outcome measurement, process improvement, and implementation. Articles written in English and published in PubMed. Rapid response systems are heterogeneous, with important differences among afferent and efferent arms. Clinically meaningful outcomes may include unexpected mortality, in-hospital cardiac arrest, length of stay, cost, and processes of care at end of life. Both positive and negative interventional studies have been published, although the two largest randomized trials involving rapid response systems - the Medical Early Response and Intervention Trial (MERIT) and the Effect of a Pediatric Early Warning System on All-Cause Mortality in Hospitalized Pediatric Patients (EPOCH) trial - did not find a mortality benefit with these systems, albeit with important limitations. Advances in monitoring technologies, risk assessment strategies, and behavioral ergonomics may offer opportunities for improvement. Rapid responses may improve some meaningful outcomes, although these findings remain controversial. These systems may also improve care for patients at the end of life. Rapid response systems are expected to continue evolving with novel developments in monitoring technologies, risk prediction informatics, and work in human factors. Copyright © 2018 Elsevier B.V. All rights reserved.

  3. Responsible Hospitality. Prevention Updates

    Colthurst, Tom

    2004-01-01

    Responsible Hospitality (RH)--also called Responsible Beverage Service (RBS)--encompasses a variety of strategies for reducing risks associated with the sale and service of alcoholic beverages. RH programs have three goals: (1) to prevent illegal alcohol service to minors; (2) to reduce the likelihood of drinkers becoming intoxicated; and (3) to…

  4. Collective Responsibility for Oppression

    Stahl, Titus

    2017-01-01

    Many contemporary forms of oppression are not primarily the result of formally organized collective action nor are they an unintended outcome of a combination of individual actions. This raises the question of collective responsibility. I argue that we can only determine who is responsible for

  5. Mechanical response of composites

    Camanho, Pedro P.; Dávila, C.G.; Pinho, Silvestre T.; Remmers, J.J.C.

    2008-01-01

    This book contains twelve selected papers presented at the ECCOMAS Thematic Conference ? Mechanical Response of Composites, and the papers presented by the three plenary speakers. It describes recent advances in the field of analysis models for the mechanical response of advanced composite

  6. Electrodermal Response in Gaming

    J. Christopher Westland

    2011-01-01

    Full Text Available Steady improvements in technologies that measure human emotional response offer new possibilities for making computer games more immersive. This paper reviews the history of designs a particular branch of affective technologies that acquire electrodermal response readings from human subjects. Electrodermal response meters have gone through continual improvements to better measure these nervous responses, but still fall short of the capabilities of today's technology. Electrodermal response traditionally have been labor intensive. Protocols and transcription of subject responses were recorded on separate documents, forcing constant shifts of attention between scripts, electrodermal measuring devices and of observations and subject responses. These problems can be resolved by collecting more information and integrating it in a computer interface that is, by adding relevant sensors in addition to the basic electrodermal resistance reading to untangle (1 body resistance; (2 skin resistance; (3 grip movements; other (4 factors affecting the neural processing for regulation of the body. A device that solves these problems is presented and discussed. It is argued that the electrodermal response datastreams can be enriched through the use of added sensors and a digital acquisition and processing of information, which should further experimentation and use of the technology.

  7. Response Surface Methodology

    Kleijnen, Jack P.C.

    2014-01-01

    Abstract: This chapter first summarizes Response Surface Methodology (RSM), which started with Box and Wilson’s article in 1951 on RSM for real, non-simulated systems. RSM is a stepwise heuristic that uses first-order polynomials to approximate the response surface locally. An estimated polynomial

  8. Responsive Space Program Brief

    Dors, Eric E. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2014-03-11

    The goal of the Responsive Space program is to make significant, integrated science and technology contributions to the end-to-end missions of the U.S. Government that protect against global emerging and nuclear threats, from the earliest adversary planning through resilient event response report describes the LANL space program, mission, and other activities. The report describes some of their activities.

  9. Aligning Responsible Business Practices

    Weller, Angeli E.

    2017-01-01

    This article offers an in-depth case study of a global high tech manufacturer that aligned its ethics and compliance, corporate social responsibility, and sustainability practices. Few large companies organize their responsible business practices this way, despite conceptual relevance and calls t...... and managers interested in understanding how responsible business practices may be collectively organized.......This article offers an in-depth case study of a global high tech manufacturer that aligned its ethics and compliance, corporate social responsibility, and sustainability practices. Few large companies organize their responsible business practices this way, despite conceptual relevance and calls...... to manage them comprehensively. A communities of practice theoretical lens suggests that intentional effort would be needed to bridge meaning between the relevant managers and practices in order to achieve alignment. The findings call attention to the important role played by employees who broker...

  10. Oil spill response plan

    1999-08-01

    The plan outlined in this document specifies the actions that the Canadian Wildlife Service Atlantic Region is mandated to take in the event of an oil spill, or on discovering oiled migratory birds in terrestrial, fresh water, marine and inter-tidal habitats. In addition to describing the role and responsibilities of the Canadian Wildlife Service, the document also describes response plans of other agencies for dealing with all wildlife species affected by oil spills. Reporting paths, the lead agency concept, shared responsibilities with other Canadian Wildlife Service regional offices, provincial agencies, Heritage Canada, non-government wildlife response agencies, oil spill response organizations, and international organizations are outlined. An overview of the reporting and communications process is also provided

  11. Neutron response study

    Endres, G.W.R.; Fix, J.J.; Thorson, M.R.; Nichols, L.L.

    1981-01-01

    Neutron response of the albedo type dosimeter is strongly dependent on the energy of the incident neutrons as well as the moderating material on the backside of the dosimeter. This study characterizes the response of the Hanford dosimeter for a variety of neutron energies for both a water and Rando phantom (a simulated human body consisting of an actual human skeleton with plastic for body muscles and certain organs). The Hanford dosimeter response to neutrons of different energies is typical of albedo type dosimeters. An approximate two orders of magnitude difference in response is observed between neutron energies of 100 keV and 10 MeV. Methods were described to compensate for the difference in dosimeter response between a laboratory neutron spectrum and the different spectra encountered at various facilities in the field. Generally, substantial field support is necessary for accurate neutron dosimetry

  12. Geospatial Information Response Team

    Witt, Emitt C.

    2010-01-01

    Extreme emergency events of national significance that include manmade and natural disasters seem to have become more frequent during the past two decades. The Nation is becoming more resilient to these emergencies through better preparedness, reduced duplication, and establishing better communications so every response and recovery effort saves lives and mitigates the long-term social and economic impacts on the Nation. The National Response Framework (NRF) (http://www.fema.gov/NRF) was developed to provide the guiding principles that enable all response partners to prepare for and provide a unified national response to disasters and emergencies. The NRF provides five key principles for better preparation, coordination, and response: 1) engaged partnerships, 2) a tiered response, 3) scalable, flexible, and adaptable operations, 4) unity of effort, and 5) readiness to act. The NRF also describes how communities, tribes, States, Federal Government, privatesector, and non-governmental partners apply these principles for a coordinated, effective national response. The U.S. Geological Survey (USGS) has adopted the NRF doctrine by establishing several earth-sciences, discipline-level teams to ensure that USGS science, data, and individual expertise are readily available during emergencies. The Geospatial Information Response Team (GIRT) is one of these teams. The USGS established the GIRT to facilitate the effective collection, storage, and dissemination of geospatial data information and products during an emergency. The GIRT ensures that timely geospatial data are available for use by emergency responders, land and resource managers, and for scientific analysis. In an emergency and response capacity, the GIRT is responsible for establishing procedures for geospatial data acquisition, processing, and archiving; discovery, access, and delivery of data; anticipating geospatial needs; and providing coordinated products and services utilizing the USGS' exceptional pool of

  13. Frequency Response Analysis Tool

    Etingov, Pavel V. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Kosterev, Dmitry [Pacific Northwest National Lab. (PNNL), Richland, WA (United States); Dai, T. [Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

    2014-12-01

    Frequency response has received a lot of attention in recent years at the national level, which culminated in the development and approval of North American Electricity Reliability Corporation (NERC) BAL-003-1 Frequency Response and Frequency Bias Setting Reliability Standard. This report is prepared to describe the details of the work conducted by Pacific Northwest National Laboratory (PNNL) in collaboration with the Bonneville Power Administration and Western Electricity Coordinating Council (WECC) Joint Synchronized Information Subcommittee (JSIS) to develop a frequency response analysis tool (FRAT). The document provides the details on the methodology and main features of the FRAT. The tool manages the database of under-frequency events and calculates the frequency response baseline. Frequency response calculations are consistent with frequency response measure (FRM) in NERC BAL-003-1 for an interconnection and balancing authority. The FRAT can use both phasor measurement unit (PMU) data, where available, and supervisory control and data acquisition (SCADA) data. The tool is also capable of automatically generating NERC Frequency Response Survey (FRS) forms required by BAL-003-1 Standard.

  14. Emergency response strategies

    Carrilo, D.; Dias de la Cruz, F.

    1984-01-01

    In the present study is estimated, on the basis of a release category (PWR4) and several accident scenarios previously set up, the emergency response efficacy obtained in the application of different response strategies on each of the above mentioned scenarios. The studied strategies contemplate the following protective measures: evacuation, shelter and relocation. The radiological response has been obtained by means of CRAC2 (Calculation of Reactor Accident Consequences) code, and calculated in terms of absorbed dose equivalent (Whole body and thyroid), as well as early and latent biological effects. (author)

  15. On being responsible

    Davies, Sarah Rachael; Glerup, Cecilie; Horst, Maja

    2014-01-01

    as to enable innovation. To call for responsibility has, indeed, become somewhat trite. In this essay we take not the normative demand for responsibility, but its operationalisation, as our analytical focus, arguing that it is important not to underestimate the term’s practical flexibility and discursive...... multiplicity. To illustrate this point we consider firstly the range of ways in which ‘responsibility’ is articulated within the literature on higher education and sociology of science; and, secondly, how notions of responsible development are understood, and acted upon, in two different US sites: an academic...

  16. Socially responsible investment engagement

    Goessling, T.; Buijter, Bas; Freeman, R.E.; Kujala, J.; Sachs, S.

    2017-01-01

    This study explores engagement in socially responsible investment (SRI) processes. More specifically, it researches the impact of shareholder salience on the success of engagement activities. The research question asks: What is the relationship between shareholder salience and engagement effort

  17. The EEG Photoparoxysmal Response

    J Gordon Millichap

    2008-03-01

    Full Text Available Types of photosensitivity, prevalence and other characteristics of the photoparoxysmal response (PPR, associated seizures, effect of video games, and drug therapy are reviewed by the director of electroencephalography at the University of Illinois, Chicago.

  18. Responses to the contributors

    Garrett Barden

    2011-09-01

    Full Text Available A set of responses to the papers on Garrett Barden's and Tim Murphy's book Law and Justice in Community (Oxford: OUP, 2010 published in this special issue of Nordicum-Mediterraneum.

  19. Responsive design high performance

    Els, Dewald

    2015-01-01

    This book is ideal for developers who have experience in developing websites or possess minor knowledge of how responsive websites work. No experience of high-level website development or performance tweaking is required.

  20. NOAA Emergency Response Imagery

    National Oceanic and Atmospheric Administration, Department of Commerce — The imagery posted on this site is in response to natural disasters. The aerial photography missions were conducted by the NOAA Remote Sensing Division. The majority...

  1. Immune responses to metastases

    Herberman, R.B.; Wiltrout, R.H.; Gorelik, E.

    1987-01-01

    The authors present the changes in the immune system in tumor-bearing hosts that may influence the development of progression of metastases. Included are mononuclear cell infiltration of metastases; alterations in natural resistance mediated by natural killer cells and macrophages; development of specific immunity mediated by T-lymphocytes or antibodies; modulation of tumor-associated antigen expression; and the down-regulation of the immune response to the tumor by several suppressor mechanisms; the augmentation of the immune response and its potential for therapeutic application; includes the prophylaxis of metastases formation by NK cells; the therapy of metastases by augmentation NK-, macrophage-, or T-lymphocyte-mediated responses by biological response modifiers; and the transfer of anticancer activity by cytoxic T-lymphocytes or immunoconjugates of monoclonal antibodies with specificity for tumors

  2. Drones and Responsibility

    How does the use of military drones affect the legal, political, and moral responsibility of different actors involved in their deployment and design? This volume offers a fresh contribution to the ethics of drone warfare by providing, for the first time, a systematic interdisciplinary discussion...... of different responsibility issues raised by military drones. The book discusses four main sets of questions: First, from a legal point of view, we analyse the ways in which the use of drones makes the attribution of criminal responsibility to individuals for war crimes more complicated and what adjustments...... may be required in international criminal law and in military practices to avoid ’responsibility gaps’ in warfare. From a moral and political perspective, the volume looks at the conditions under which the use of military drones by states is impermissible, permissible, or even obligatory and what...

  3. OEM Emergency Response Information

    U.S. Environmental Protection Agency — The Office of Emergency Management retains records of all incident responses in which it participates. This data asset includes three major sources of information:...

  4. CV equipment responsibilities

    Pirollet, B

    2008-01-01

    This document describes the limits of the responsibilities of the TS/CV for fire fighting equipment at the LHC. The various interfaces, providers and users of the water supply systems and clean water raising systems are described.

  5. Social Responsibility Instruments

    Katarzyna Mizera

    2008-09-01

    Full Text Available Responsible business notion is more and more present in Polish economy, however the results of the research carried out in Polish business still shows a low level of CRS idea knowledge, especially in small and medium companies. Although responsible business notion is generally known, its details, ways of preparing strategy, instruments and what is more its benefits are still narrowly spread. Many business people face the lack of knowledge and information, which on one hand make it easier to spread and deepen wrong stereotypes connected with this notion and on the other hand make business people unwilling to implement CRS in their companies. The subjects of this article are examples of instruments which are responsible for realization of social responsibility strategy.

  6. Pathological responses to terrorism.

    Yehuda, Rachel; Bryant, Richard; Marmar, Charles; Zohar, Joseph

    2005-10-01

    Many important gains have been made in understanding PTSD and other responses to trauma as a result of neuroscience-based observations. Yet there are many gaps in our knowledge that currently impede our ability to predict those who will develop pathologic responses. Such knowledge is essential for developing appropriate strategies for mounting a mental health response in the aftermath of terrorism and for facilitating the recovery of individuals and society. This paper reviews clinical and biological studies that have led to an identification of pathologic responses following psychological trauma, including terrorism, and highlights areas of future-research. It is important to not only determine risk factors for the development of short- and long-term mental health responses to terrorism, but also apply these risk factors to the prediction of such responses on an individual level. It is also critical to consider the full spectrum of responses to terrorism, as well as the interplay between biological and psychological variables that contribute to these responses. Finally, it is essential to remove the barriers to collecting data in the aftermath of trauma by creating a culture of education in which the academic community can communicate to the public what is and is not known so that survivors of trauma and terrorism will understand the value of their participation in research to the generation of useful knowledge, and by maintaining the acquisition of knowledge as a priority for the government and those involved in the immediate delivery of services in the aftermath of large-scale disaster or trauma.

  7. Emergency response workers workshop

    Agapeev, S.A.; Glukhikh, E.N.; Tyurin, R.L.

    2012-01-01

    A training workshop entitled Current issues and potential improvements in Rosatom Corporation emergency prevention and response system was held in May-June, 2012. The workshop combined theoretical training with full-scale practical exercise that demonstrated the existing innovative capabilities for radiation reconnaissance, diving equipment and robotics, aircraft, emergency response and rescue hardware and machinery. This paper describes the activities carried out during the workshop [ru

  8. Advances in Crash Response

    2009-06-29

    In this podcast, Dr. Richard C. Hunt, Director of CDC's Division of Injury Response, provides an overview on the benefits of using an Advanced Automatic Collision Notification system, or AACN, to help with emergency triage of people injured in vehicle crashes.  Created: 6/29/2009 by National Center for Injury Prevention and Control (NCIPC), Division of Injury Response (DIR).   Date Released: 6/29/2009.

  9. National Response Framework: Annexes

    2008-01-01

    response Environmental short- and long-term cleanup ESF #11 – Agriculture and Natural Resources Nutrition assistance Animal and plant disease and pest ...continental United States, the Virgin Islands and Puerto Rico, and other U.S. territories and possession other than Alaska and U.S. territories in the...on the Pacific, Atlantic , and Gulf coasts, to provide response capabilities, technical advice, documentation and support assistance, communications

  10. Corporate Social Responsibility

    Kampf, Constance

    2007-01-01

    Understanding Corporate Social Responsibility (CSR) as having explicit policies and implicit norms situated in cultural systems highlights the connections between institutional and cultural structures of nation states and business' commitment to CSR as reflected in the strategies used to communic......Understanding Corporate Social Responsibility (CSR) as having explicit policies and implicit norms situated in cultural systems highlights the connections between institutional and cultural structures of nation states and business' commitment to CSR as reflected in the strategies used...

  11. Social responsibility of corporations

    Babić Jovan

    2007-01-01

    Full Text Available The issue at stake in the article is corporate social responsibility. There are two rival theories regarding this issue. According to the classical theory managers are responsible to owners (stockholders and their obligation is to pursue the goal of maximizing the profit. According to the other, stakeholder theory, the interests of all corporate stakeholders, all those affected by business, not only stockholders, must be taken in consideration. In the paper these two theories are subject of thorough ethical analysis.

  12. Social Responsibility of Accounting

    JINNAI, Yoshiaki

    2011-01-01

    Historical and theoretical inquiries into the function of accounting have provided fruitful insights into social responsibility of accounting, which is, and should be, based on accounts kept through everyday accounting activities. However, at the current stage of capitalist accounting, keeping accounts is often regarded as merely a preparatory process for creating financial statements at the end of an accounting period. Thus, discussions on the social responsibility of accounting tend to conc...

  13. Responsability of nuclear industry

    Cadiz Deleito, J.C.

    1985-01-01

    Since the beginning of nuclear industry, civil responsibility with damages to the public health and properties was a critical problem, because the special conditions of this industry (nuclear accident, damages could be very high but probability of these events is very low). Legal precepts, universally accepted, in the first 60 years for all countries interested in nuclear energy are being revised, then 20 years of experience. The civil responsibility limited is being questioned and indemnities updated. (author)

  14. Discord of response

    Roga, W; Illuminati, F; Giampaolo, S M

    2014-01-01

    The presence of quantum correlations in a quantum state is related to the state's response to local unitary perturbations. Such a response is quantified by the distance between the unperturbed and perturbed states, minimized with respect to suitably identified sets of local unitary operations. In order to be a bona fide measure of quantum correlations, the distance function must be chosen among those that are contractive under completely positive and trace preserving (CPTP) maps. The most relevant instances of such physically well-behaved metrics include the trace, the Bures, and the Hellinger distance. To each of these metrics one can associate the corresponding discord of response, namely the trace, or Hellinger, or Bures minimum distance from the set of unitarily perturbed states. All these three discords of response satisfy the basic axioms for a proper measure of quantum correlations. In the present work we focus in particular on the Bures distance, which enjoys the unique property of being both Riemannian and contractive under CPTP maps, and admits important operational interpretations in terms of state distinguishability. We compute analytically the Bures discord of response for two-qubit states with maximally mixed marginals and we compare it with the corresponding Bures geometric discord, namely the geometric measure of quantum correlations defined as the Bures distance from the set of classical-quantum states. Finally, we investigate and identify the maximally quantum correlated two-qubit states according to the Bures discord of response. These states exhibit a remarkable nonlinear dependence on the global state purity. (paper)

  15. Enviromental responsability and corporate social responsability

    Jesús Marí Farinós

    2015-12-01

    Full Text Available The environmental management of companies and organizations in general is going to be internalized in the operation and management structures, linking conceptual and chronologically to improve corporate reputation, management excellence, knowledge and innovation. Embracing, undoubtedly too, with the assumption of an ethical commitment of the company to society: environmental sustainability and generational solidarity in the transmission of culture and values of that nature. The existing need to know the potential impact of business operations on society and the environment results in the appearance of a document, which may well be called a Sustainability Report or Social Balance, which is compiled from a series social indicators, which are the instruments responsible to reflect the value of the shares held by the company in social and environmental fields.

  16. Planned home birth: the professional responsibility response.

    Chervenak, Frank A; McCullough, Laurence B; Brent, Robert L; Levene, Malcolm I; Arabin, Birgit

    2013-01-01

    This article addresses the recrudescence of and new support for midwife-supervised planned home birth in the United States and the other developed countries in the context of professional responsibility. Advocates of planned home birth have emphasized patient safety, patient satisfaction, cost effectiveness, and respect for women's rights. We provide a critical evaluation of each of these claims and identify professionally appropriate responses of obstetricians and other concerned physicians to planned home birth. We start with patient safety and show that planned home birth has unnecessary, preventable, irremediable increased risk of harm for pregnant, fetal, and neonatal patients. We document that the persistently high rates of emergency transport undermines patient safety and satisfaction, the raison d'etre of planned home birth, and that a comprehensive analysis undermines claims about the cost-effectiveness of planned home birth. We then argue that obstetricians and other concerned physicians should understand, identify, and correct the root causes of the recrudescence of planned home birth; respond to expressions of interest in planned home birth by women with evidence-based recommendations against it; refuse to participate in planned home birth; but still provide excellent and compassionate emergency obstetric care to women transported from planned home birth. We explain why obstetricians should not participate in or refer to randomized clinical trials of planned home vs planned hospital birth. We call on obstetricians, other concerned physicians, midwives and other obstetric providers, and their professional associations not to support planned home birth when there are safe and compassionate hospital-based alternatives and to advocate for a safe home-birth-like experience in the hospital. Copyright © 2013 Mosby, Inc. All rights reserved.

  17. Structural building response review

    1980-01-01

    The integrity of a nuclear power plant during a postulated seismic event is required to protect the public against radiation. Therefore, a detailed set of seismic analyses of various structures and equipment is performed while designing a nuclear power plant. This report describes the structural response analysis method, including the structural model, soil-structure interaction as it relates to structural models, methods for seismic structural analysis, numerical integration methods, methods for non-seismic response analysis approaches for various response combinations, structural damping values, nonlinear response, uncertainties in structural properties, and structural response analysis using random properties. The report describes the state-of-the-art in these areas for nuclear power plants. It also details the past studies made at Sargent and Lundy to evaluate different alternatives and the conclusions reached for the specific purposes that those studies were intended. These results were incorporated here because they fall into the general scope of this report. The scope of the present task does not include performing new calculations

  18. The nuclear response function

    Bertsch, G.F.

    1983-01-01

    These lectures present the theory of the nuclear response in the Random Phase Approximation (RPA). In the first lecture, various relations are derived between densities and currents which give rise to the well-known sum rules. Then RPA is derived via the time-dependent Hartree theory. The various formulations of RPA are shown: the configuration space representation, the coordinate space representation, the Landau theory of infinite systems and the RPA for separable interactions constrained by consistency. The remarkable success of RPA in describing the collective density oscillations of closed shell nuclei is illustrated with a few examples. In the final lecture, the σtau response is discussed with the application of simple theoretical considerations to the empirical data. Finally, we point out several problems which remain in the response theory. (author)

  19. Radio-adaptive response

    Ikushima, T.

    1992-01-01

    Knowledge about cellular events in mammalian cells exposed to low doses of ionizing radiation is meager. Recent works showed that human lymphocytes become resistant to radiation-induced chromosomal damage after exposure to low doses of ionizing radiation. Experimental evidence for radio-adaptive response (RAR) in cultured mammalian cells was obtained. Exposure to very low doses of gamma-rays or tritium beta-rays make cells less susceptible to the induction of micronuclei and sister chromatid exchanges by subsequent higher doses. Many important characteristics of the novel response suggest that RAR is a stress response resulting in the enhanced repair of chromosomal DNA damage in cell under restricted conditions. Experiments are still in progress in order to elucidate the molecular basis for RAR processes. (author). 13 refs.; 2 figs., 1 tab

  20. Radio-adaptive response

    Ikushima, Takaji

    1991-01-01

    An adaptive response to radiation stress was found in cultured Chinese hamster V79 cells, as a suppressed induction of micronuclei (MNs) and sister chromatid exchanges (SCEs) in the cells conditioned by very low doses. The important characteristics of the novel chromosomal response, called radio-adaptive response (RAR), that have newly emerged in this study are: 1) Low doses of beta-rays from tritiated water (HTO) as well as tritiated thymidine can cause the RAR. 2) Thermal neutrons, a high LET radiation, can not act as tritium beta-rays or gamma-rays. 3) The RAR expression is suppressed by an inhibition of protein synthesis. 4) Several proteins are newly synthesized concurrently with the RAR expression after adapting doses, viewed by two-dimensional electrophoresis of cellular proteins. These results suggest that the RAR is an adaptive chromosomal DNA repair induced by very low doses of low LET radiations under restricted conditions, accompanying the inducible specific gene expression. (author)

  1. Photovoltaic spectral responsivity measurements

    Emery, K.; Dunlavy, D.; Field, H.; Moriarty, T. [National Renewable Energy Lab., Golden, CO (United States)

    1998-09-01

    This paper discusses the various elemental random and nonrandom error sources in typical spectral responsivity measurement systems. The authors focus specifically on the filter and grating monochrometer-based spectral responsivity measurement systems used by the Photovoltaic (PV) performance characterization team at NREL. A variety of subtle measurement errors can occur that arise from a finite photo-current response time, bandwidth of the monochromatic light, waveform of the monochromatic light, and spatial uniformity of the monochromatic and bias lights; the errors depend on the light source, PV technology, and measurement system. The quantum efficiency can be a function of he voltage bias, light bias level, and, for some structures, the spectral content of the bias light or location on the PV device. This paper compares the advantages and problems associated with semiconductor-detector-based calibrations and pyroelectric-detector-based calibrations. Different current-to-voltage conversion and ac photo-current detection strategies employed at NREL are compared and contrasted.

  2. Disaster mitigation: initial response.

    Kennedy, George; Richards, Michael; Chicarelli, Michael; Ernst, Amy; Harrell, Andrew; Stites, Danniel

    2013-01-01

    The objective of this review is to stimulate the reader's considerations for developing community disaster mitigation. Disaster mitigation begins long before impact and is defined as the actions taken by a community to eliminate or minimize the impact of a disaster. The assessment of vulnerabilities, the development of infrastructure, memoranda of understanding, and planning for a sustainable response and recovery are parts of the process. Empowering leadership and citizens with knowledge of available resources through the planning and development of a disaster response can strengthen a community's resilience, which can only add to the viability and quality of life enjoyed by the entire community.

  3. Wind emergency response system

    Garrett, A.J.; Buckner, M.R.; Mueller, R.A.

    1981-01-01

    The WIND system is an automated emergency response system for real-time predictions of the consequences of liquid and airborne releases from SRP. The system consists of a minicomputer and associated peripherals necessary for acquisition and handling of large amounts of meteorological data from a local tower network and the National Weather Service. The minicomputer uses these data and several predictive models to assess the impact of accidental releases. The system is fast and easy to use, and output is displayed both in tabular form and as trajectory map plots for quick interpretation. The rapid response capabilities of the WIND system have been demonstrated in support of SRP operations

  4. Radiation response of tumours

    Twentyman, P.R.

    1988-01-01

    In this chapter knowledge regarding cellular radiation response and the factors which modify it is related to the volume changes and probability of control of irradiated solid tumors. After a discussion of the different cell populations present within solid tumors the cell population kinetics of the neoplastic cells are considered in more detail. The influence of factors related to the three-dimensional geometry of the tumor, particularly hypoxia, are considered, and also the role of the tumor vasculature in radiation response. Repair of sublethal damage (SLD) and potentially lethal damage (PLD) is dealt with and finally the relationship between the various end-points of tumor radioresponsiveness is discussed

  5. Response to Arend Flick

    RiCharde, R. Stephen

    2009-01-01

    This article presents the author's response to Arend Flick. The author states that Flick is correct that the issue of rubrics is broader than interrater reliability, though it is the assessment practitioner's primary armament against what the author has heard dubbed "refried bean counting" (insinuating that assessment statistics are not just bean…

  6. When Immediate Responses Fail

    Dothan, Shai

    2018-01-01

    a disproportionately forceful response. The laws of war, criminal law, and international sales law all face some situations of uncertainty. This paper argues that each of these legal fields adopts a strategy of many-tits-for-many-tats to address conditions of acute uncertainty....

  7. Luxury organizations and responsibility

    Montesa, Farah; Rohrbeck, René

    2014-01-01

    In this article, findings from previous research, almost forty examples of responsible practices in luxury firms, were clustered and eight generic tools were revealed to advance sustainability. These tools are posed as questions to assess the luxury firm’s level of sustainability and to plan deve...

  8. Responsible Internet Use.

    Truett, Carol; And Others

    1997-01-01

    Provides advice for making school Internet-use guidelines. Outlines responsible proactive use of the Internet for educators and librarians, discusses strengths and weaknesses of Internet blocking software and rating systems, and describes acceptable-use policies (AUP). Lists resources for creating your own AUP, Internet filtering software, and…

  9. Socially responsible firms

    Ferrell, A.; Liang, Hao; Renneboog, Luc

    2016-01-01

    In the corporate finance tradition, starting with Berle and Means (1932), corporations should generally be run to maximize shareholder value. The agency view of corporate social responsibility (CSR) considers CSR an agency problem and a waste of corporate resources. Given our identification strategy

  10. Critical Response Protocol

    Ellingson, Charlene; Roehrig, Gillian; Bakkum, Kris; Dubinsky, Janet M.

    2016-01-01

    This article introduces the Critical Response Protocol (CRP), an arts-based technique that engages students in equitable critical discourse and aligns with the "Next Generation Science Standards" vision for providing students opportunities for language learning while advancing science learning (NGSS Lead States 2013). CRP helps teachers…

  11. Professionalization: Whose Responsibility?

    Carter, Marcia J.; And Others

    One requisite of a profession is that its practitioners hold a credential certifying that the individual is competent to provide needed services. In the fields of health, physical education, recreation, and dance, diverse groups compete in credentialing practitioners. The four papers in this collection discuss who is, or should be, responsible for…

  12. Overcoming the "Run" Response

    Swanson, Patricia E.

    2013-01-01

    Recent research suggests that it is not simply experiencing anxiety that affects mathematics performance but also how one responds to and regulates that anxiety (Lyons and Beilock 2011). Most people have faced mathematics problems that have triggered their "run response." The issue is not whether one wants to run, but rather…

  13. Implementing Responsibility Centre Budgeting

    Vonasek, Joseph

    2011-01-01

    Recently, institutes of higher education (universities) have shown a renewed interest in organisational structures and operating methodologies that generate productivity and innovation; responsibility centre budgeting (RCB) is one such process. This paper describes the underlying principles constituting RCB, its origin and structural elements, and…

  14. The Chronic Responsibility

    Ravn, Iben M; Frederiksen, Kirsten; Beedholm, Kirsten

    2016-01-01

    behavior to be the main factors influencing susceptibility to chronic diseases. We argue that this discursive construction naturalizes a division between people who can actively manage responsible self-care and those who cannot. Such discourses may serve the interests of those patients who are already...

  15. Radio-adaptive response

    Ikushima, T.

    1992-01-01

    An adaptive response to radiation stress was found as a suppressed induction of chromosomal damage including micronuclei and sister chromatid exchanges in cultured Chinese hamster V79 cells pre-exposed to very low doses of ionizing radiations. The mechanism underlying this novel chromosomal response, called 'radio-adaptive response (RAR)' has been studied progressively. The following results were obtained in recent experiments. 1. Low doses of β-rays from tritiated water (HTO) as well as tritium-thymidine can cause RAR. 2. Thermal neutrons, a high LET radiation, can not act as tritium β-rays or γ-rays. 3. The RAR expression is suppressed not only by the treatment with an inhibitor of protein synthesis but also by RNA synthesis inhibition. 4. Several proteins are newly synthesized concurrently with the RAR expression after the adapting doses, viewed by two-dimensional electrophoresis of cellular proteins. These results suggests that the RAR might be a cellular stress response to a signal produced preferentially by very low doses of low LET radiation under restricted conditions, accompany the inducible specific gene expression. (author)

  16. Response to Tom Cobb

    Nation, Paul

    2016-01-01

    In this article Paul Nation responds to Thomas Cobb's "Numbers or Numerology? A Response to Nation (2014) and McQuillan (2016)" (EJ1117024). Nation begins by clarifying his own position on vocabulary learning and goes on to highlight points made in Cobb's article with which he is in agreement, while drawing from his 2014 article,…

  17. Responsibility and Integrated Thinking

    Robinson, SJ

    2014-01-01

    Integrated thinking is essentially focused in dialogue and communication. This is partly because relationships and related purpose focus on action, which itself acts as a means of integration, and partly because critical dialogue enables better, more responsive, integrated thinking and action.

  18. Whistleblowing & Professional Responsibilities.

    Professional Engineer, 1979

    1979-01-01

    Discussed are the moral dilemmas encountered daily by professionals and how the teaching of ethics may help resolve the conflicts individuals face with respect to whistleblowing. Included are consideration of responsibilities, role of ethics codes, and courses on professional ethics. (CS)

  19. Response to Mackenzie

    Peers, Chris

    2014-01-01

    Chris Peers begins his response to Jim Mackenzie's article, "Peers on Socrates and Plato" by asking "What is the 'masculine imaginary?'" Peers defines the term "imaginary" as it is applied in his article, "Freud, Plato and Irigaray: A Morpho-Logic of Teaching and Learning" (2012) and draws…

  20. Voice Response Systems Technology.

    Gerald, Jeanette

    1984-01-01

    Examines two methods of generating synthetic speech in voice response systems, which allow computers to communicate in human terms (speech), using human interface devices (ears): phoneme and reconstructed voice systems. Considerations prior to implementation, current and potential applications, glossary, directory, and introduction to Input Output…

  1. Response to Trachtman's Article

    Bardon, Jack I.

    1985-01-01

    This response to Trachtman's article (TM 510 399) argues that the Trachtman paper is inappropriate due to the time elapsed since the original Bardon proposal. The author acknowledges the difference in perspective between Trachtman and himself. He expresses the hope that discussion concerning this aspect of school psychology politics may be ended.…

  2. Plagiarism and Responsibility.

    Martin, Brian

    1984-01-01

    There are several kinds of plagiarism, and its significance varies with its circumstances. College administrations seem to avoid responsibility for examining allegations of academic plagiarism, and few procedures exist for addressing them. Until standard and open procedures are established and accepted, rigid and unrealistic attitudes will prevail…

  3. The desmoplastic response

    Fearns, C.

    1989-04-01

    Desmoplasia, a process in which excessive connective tissue is deposited in a neoplasm, is discussed. To study the process, a human malignant melanoma cell line (UCT-Mel 7) was used, that was established in the laboratory, and when injected into athymic mice, it gave rise to tumours that showed a number of interesting features. The tumour induced a marked desmoplastic response and the desmoplasia was associated in UCT-Mel 7-derived tumours with an unusual phasic pattern of growth. Two possible mechanisms were identified by which UCT-Mel 7 cells could have induced the desmoplastic response. UCT-Mel 7 cells were shown to be chemotactic for mouse macrophages and human foreskin fibroblasts were stimulated, in a dose-dependent manner, to synthesize increased amounts of collagen when co-cultured with mouse peritoneal exudate cells. Tumour cells were also found to act directly. Co-culture of UCT-Mel 7 cells and fibroblasts resulted in increased collagen synthesis by the fibroblasts. DNA synthesis was not required. Dexamethasone, retinoic acid and the tumour promoter, phorbol myristate acetate, had significant primary effects on fibroblast collagen synthesis but did not modify the response to melanoma cells. Recombinant basic fibroblast growth factor did not seem to be involved in the desmoplastic response. A surprising finding was the production of a potent inhibitor of collagen synthesis by superinduced cells of the mouse macrophage cell line, P388D 1 . This inhibitor has not been fully characterised. 49 figs., 33 tabs., 362 refs

  4. Socially Responsible Firms

    Renneboog, L.D.R.; Liang, H.; Ferrell, A.

    2014-01-01

    In the corporate finance tradition starting with Berle & Means (1923), corporations should generally be run so as to maximize shareholder value. The agency view of corporate social responsibility (CSR) generally considers CSR as a managerial agency problem and a waste of corporate resources, since

  5. Developing Responsible Learners

    Gautum, Satyen; Jangam, Sachin; Loh, Kai Chee

    2018-01-01

    Developing responsible learners is one of the key education challenges of our time. Education literature suggests that for students to see themselves as active and necessary participants in their own learning, it is important that they view themselves as stakeholders in education. This research aims at exploring the effectiveness of instructional…

  6. Chores and Responsibility

    ... out on some valuable learning experiences, and their development of a sense of responsibility and initiative may not happen until later in life, if ever. As a result, whenever demands are placed upon these children, they appear to procrastinate or dawdle, never having ...

  7. Corporate social responsibility

    Arsić Zoran

    2011-01-01

    Full Text Available Corporate Social Responsibility (CSR is a concept whereby companies integrate social and environmental concerns in their business operations and in their interaction with their stakeholders on a voluntary basis. Definition emphasizes three basic characteristics of CSR. CSR is voluntary concept, it covers environmental issues and interaction with stakeholders, not only shareholders, is taken into account.

  8. [Responsibility, compassion and ethics].

    Furstenberg, Cécile

    2016-01-01

    The concepts of responsibility and compassion are fundamental in ethics. These notions help to safeguard humaneness, especially in the field of health care and notably in palliative care. These concepts can be put into practice by caregivers and applied to daily practice. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  9. Individual heat stress response

    Havenith, G.

    1997-01-01

    In 5 experiments, heterogeneous subject groups (large variations in _VO2 max, regular daily activity level, mass, body surface area (AD), % body fat, and AD/mass ratio) were tested for their physiological response while exercising on a cycle ergometer at a relative (45% _VO2 max; REL) or an absolute

  10. Emergency preparedness and response

    Griffiths, M.

    1996-01-01

    After the Chernobyl accident, it became painfully obvious to the international community that there was an urgent need to establish a system for the coordination of international disaster assistance. It became the task of the United Nations Office for Disaster Relief (UNDRO) to develop such a system. The former UNDRO was subsumed into the Department of Humanitarian Affairs (DHA), established in January 1992 on the basis of UN General Assembly Resolution 46/182 adopted in December 1991, and the disaster relief system presently found in DHA is a further evolution of the system established by UNDRO. One particular importance in relation to nuclear accidents is the fact that UNDRO and the International Atomic Energy Agency (IAEA) signed a Memorandum of Understanding defining their respective responsibilities and the need for cooperation in case of accidents involving the unintentional release of nuclear radiation. In essence, the MOU makes it clear that the responsibilities of the IAEA, in connection with accidents at Nuclear Power Plants, related to the technical and radiological aspects, in particular to accident prevention, to the on-site preparedness, and to remedial measures within the 30-km zone outside the NPP. DHA's responsibilities, on the other hand, relate to the general preparedness and the rescue efforts outside the 30 km zone. In this respect, the preparedness and emergency response system is no different from the system employed in any other type of sudden-onset emergency

  11. Rethinking Moral Responsibility

    Vedder, A.H.; Johnson, D.; Moor, J.; Tavani, H.

    2000-01-01

    Questions regarding the moral responsibility of Internet access and service providers relating to possible negative aspects of information on the Internet call for a reassessment of the ways in which we think about attributing blame, guilt, and duties of reparation and compensation. They invite us

  12. Advances in Crash Response

    In this podcast, Dr. Richard C. Hunt, Director of CDC's Division of Injury Response, provides an overview on the benefits of using an Advanced Automatic Collision Notification system, or AACN, to help with emergency triage of people injured in vehicle crashes.

  13. Decoupling Responsible Management Education

    Rasche, Andreas; Gilbert, Dirk Ulrich

    2015-01-01

    This article examines under what conditions business schools may decouple the structural effects of their engagement in responsible management education from actual organizational practices. We argue that schools may be unable to match rising institutional pressures to publicly commit to responsi......This article examines under what conditions business schools may decouple the structural effects of their engagement in responsible management education from actual organizational practices. We argue that schools may be unable to match rising institutional pressures to publicly commit...... to responsible management education with their limited internal capacity for change. Our analysis proposes that decoupling is likely if schools (a) are exposed to resource stringency, (b) face overt or covert resistance against change processes, (c) are confronted with competing institutional pressures, and (d......) perceive institutional demands as ambiguous. We discuss two implications of this proposition. On one hand, decoupling can cause dissonant legitimacy perceptions, leading to cynicism around responsible management education within business schools. On the other hand, a temporary inconsistency between talk...

  14. Early biomarkers and potential mediators of ventilation-induced lung injury in very preterm lambs

    Davis Peter G

    2009-03-01

    Full Text Available Abstract Background Bronchopulmonary dysplasia (BPD is closely associated with ventilator-induced lung injury (VILI in very preterm infants. The greatest risk of VILI may be in the immediate period after birth, when the lungs are surfactant deficient, still partially filled with liquid and not uniformly aerated. However, there have been very few studies that have examined this immediate post-birth period and identified the initial injury-related pathways that are activated. We aimed to determine if the early response genes; connective tissue growth factor (CTGF, cysteine rich-61 (CYR61 and early growth response 1 (EGR1, were rapidly induced by VILI in preterm lambs and whether ventilation with different tidal volumes caused different inflammatory cytokine and early response gene expression. Methods To identify early markers of VILI, preterm lambs (132 d gestational age; GA, term ~147 d were resuscitated with an injurious ventilation strategy (VT 20 mL/kg for 15 min then gently ventilated (5 mL/kg for 15, 30, 60 or 120 min (n = 4 in each. To determine if early response genes and inflammatory cytokines were differentially regulated by different ventilation strategies, separate groups of preterm lambs (125 d GA; n = 5 in each were ventilated from birth with a VT of 5 (VG5 or 10 mL/kg (VG10 for 135 minutes. Lung gene expression levels were compared to levels prior to ventilation in age-matched control fetuses. Results CTGF, CYR61 and EGR1 lung mRNA levels were increased ~25, 50 and 120-fold respectively (p CTGF, CYR61, EGR1, IL1-β, IL-6 and IL-8 mRNA levels compared to control levels. CTGF, CYR61, IL-6 and IL-8 expression levels were higher in VG10 than VG5 lambs; although only the IL-6 and CYR61 mRNA levels reached significance. Conclusion CTGF, CYR61 and EGR1 may be novel early markers of lung injury and mechanical ventilation from birth using relatively low tidal volumes may be less injurious than using higher tidal volumes.

  15. Corporate Social Responsibility

    Liempd, Dennis van; Warming-Rasmussen, Bent; Abild-Nielsen, Jens

    2007-01-01

    Målet med denne artikel er at klargøre, at der findes forskellige teoretiske tilgange til ansvarlig leverandørstyring og Corporate Social Responsibility (i det følgende kaldt CSR). Endvidere er det målet at belyse, at området er i kraftig udvikling og forventes at få øget betydning for revisor i...... ansvarlig leverandørstyring og CSR. I artiklen konkluderes følgende: - at udviklingen i Corporate Social Responsibility indikerer, at etik er den mest betydende faktor (driver); (jf. afsnit 1)- at etik som primær driver vil betyde, at virksomheden vil gå ud over lovens minimumkrav, og stræbe efter de...

  16. Dynamic alarm response procedures

    Martin, J.; Gordon, P.; Fitch, K.

    2006-01-01

    The Dynamic Alarm Response Procedure (DARP) system provides a robust, Web-based alternative to existing hard-copy alarm response procedures. This paperless system improves performance by eliminating time wasted looking up paper procedures by number, looking up plant process values and equipment and component status at graphical display or panels, and maintenance of the procedures. Because it is a Web-based system, it is platform independent. DARP's can be served from any Web server that supports CGI scripting, such as Apache R , IIS R , TclHTTPD, and others. DARP pages can be viewed in any Web browser that supports Javascript and Scalable Vector Graphics (SVG), such as Netscape R , Microsoft Internet Explorer R , Mozilla Firefox R , Opera R , and others. (authors)

  17. Responsible conduct of research

    Shamoo, Adil E

    2015-01-01

    Since the early 2000s, the field of Responsible Conduct of Research has become widely recognized as essential to scientific education, investigation, and training. At present, research institutions with public funding are expected to have some minimal training and education in RCR for their graduate students, fellows and trainees. These institutions also are expected to have a system in place for investigating and reporting misconduct in research or violations of regulations in research with human subjects, or in their applications to federal agencies for funding. Public scrutiny of the conduct of scientific researchers remains high. Media reports of misconduct scandals, biased research, violations of human research ethics rules, and moral controversies in research occur on a weekly basis. Since the 2009 publication of the 2nd edition of Shamoo and Resnik's Responsible Conduct of Research, there has been a vast expansion in the information, knowledge, methods, and diagnosis of problems related to RCR and the ...

  18. Aesthetic responses to music

    Istok, Eva; Brattico, Elvira; Jacobsen, Thomas

    2009-01-01

    We explored the content and structure of the cognitive, knowledge-based concept underlying aesthetic responses to music. To this aim, we asked 290 Finnish students to verbally associate the aesthetic value of music and to write down a list of appropriate adjectives within a given time limit....... No music was presented during the task. In addition, information about participants' musical background was collected. A variety of analysis techniques was used to determine the key results of our study. The adjective "beautiful" proved to be the core item of the concept under question. Interestingly......, the adjective "touching" was often listed together with "beautiful". In addition, we found music-specific vocabulary as well as adjectives related to emotions and mood states indicating that affective processes are an essential part of aesthetic responses to music. Differences between music experts and laymen...

  19. Quantal Response: Nonparametric Modeling

    2017-01-01

    capture the behavior of observed phenomena. Higher-order polynomial and finite-dimensional spline basis models allow for more complicated responses as the...flexibility as these are nonparametric (not constrained to any particular functional form). These should be useful in identifying nonstandard behavior via... deviance ∆ = −2 log(Lreduced/Lfull) is defined in terms of the likelihood function L. For normal error, Lfull = 1, and based on Eq. A-2, we have log

  20. Structural response synthesis

    Ozisik, H.; Keltie, R.F.

    1988-12-01

    The open loop control technique of predicting a conditioned input signal based on a specified output response for a second order system has been analyzed both analytically and numerically to gain a firm understanding of the method. Differences between this method of control and digital closed loop control using pole cancellation were investigated as a follow up to previous experimental work. Application of the technique to diamond turning using a fast tool is also discussed.

  1. National Response Framework

    2013-05-01

    community who may be affected by incidents and as a potential means of supporting response efforts. This includes those with household pets , service and...plans should also include provisions for their animals, including household pets or service animals. During an actual disaster, emergency, or threat...welfare of their employees in the workplace . In addition, some businesses play an essential role in protecting critical infrastructure systems and

  2. Conceptualising environmental responsibility

    Lenzen, Manfred; Murray, Joy

    2010-01-01

    Downstream responsibility is rarely addressed in the academic literature and in corporate sustainability reporting. We conceptualise downstream responsibility for the example of carbon emissions, by establishing a terminology as well as a framework for quantifying downstream carbon footprints. By extracting emissions-intensive sales chains for a number of Australian industry sectors, and comparing these to emissions-intensive supply chains, we demonstrated the ability of input-output analysis to quantify emissions responsibility in both directions. We extend the definition of downstream responsibility beyond the product use and disposal phases, to include what we call 'enabled' emissions. This term implies that whatever is sold downstream enables our customers to operate and emit, irrespective of whether it is our product that is combusted, or that directly combusts fuels, or not. Our structural path analyses and threshold-capture relationships reveal stark differences between industries with regard to the data collection efforts necessary to achieve a reasonably complete footprint assessment. Industries appear to have their own specific carbon footprint profiles, and one cannot design generic relevance tests that tell which data to collect. Moreover we conclude that current completeness standards in carbon reporting cannot be satisfied using relevance thresholds. Input-output analysis and structural path analysis are excellent tools that can help companies undertake screening exercises, which in turn help prioritising and streamlining the collection of data needed to establish a corporate downstream carbon footprint. Compared to conventional manual approaches, hybrid life-cycle assessments assisted by input-output analysis and structural path analysis achieve more complete results, with substantially less staff, money and time. (author)

  3. Cell response to surgery.

    Ni Choileain, Niamh

    2012-02-03

    OBJECTIVES: To describe the profound alterations in host immunity that are produced by major surgery as demonstrated by experimental and clinical studies, and to evaluate the benefits of therapeutic strategies aimed at attenuating perioperative immune dysfunction. DATA SOURCES: A review of the English-language literature was conducted, incorporating searches of the MEDLINE, EMBASE, and Cochrane collaboration databases to identify laboratory and clinical studies investigating the cellular response to surgery. STUDY SELECTION: Original articles and case reports describing immune dysfunction secondary to surgical trauma were included. DATA EXTRACTION: The results were compiled to show outcomes of different studies and were compared. DATA SYNTHESIS: Current evidence indicates that the early systemic inflammatory response syndrome observed after major surgery that is characterized by proinflammatory cytokine release, microcirculatory disturbance, and cell-mediated immune dysfunction is followed by a compensatory anti-inflammatory response syndrome, which predisposes the patient to opportunistic infection, multiple organ dysfunction syndrome, and death. Because there are currently no effective treatment options for multiple organ dysfunction syndrome, measures to prevent its onset should be initiated at an early stage. Accumulating experimental evidence suggests that targeted therapeutic strategies involving immunomodulatory agents such as interferon gamma, granulocyte colony-stimulating factor, the prostaglandin E(2) antagonist, indomethacin, and pentoxifylline may be used for the treatment of systemic inflammatory response syndrome to prevent the onset of multiple organ dysfunction syndrome. CONCLUSIONS: Surgical trauma produces profound immunological dysfunction. Therapeutic strategies directed at restoring immune homeostasis should aim to redress the physiological proinflammatory-anti-inflammatory cell imbalance associated with major surgery.

  4. Realizing Corporate Responsibility

    Girschik, Verena

    and practices at the nascent stages of institutional change. To address this question, the dissertation develops a micro-sociological approach to institutional change that brings to light how actors struggle over meaning in power relations by focusing on processes of positioning and framing. The three articles...... in this dissertation unfold distinct yet interdependent processes of positioning and framing that constitute new ways of performing and understanding corporate responsibility....

  5. Material Response Characterization

    1977-08-01

    models fit to vertical UX and TX data and a mean stress tension cutoff criterion. Because tests on the Kayenta sands one materials had revealed a definite...parameters. 9 This data characterizing the anisotropic response of the upper 30 feet of Kayenta material should not just be filed away; it should be used...9. Johnson, J. N., et al, "Anisotropic Mechanical Properties of Kayenta Sandstone (MIXED COMPANY Site) for Ground Motion Calculations," Terra Tek TR

  6. Strategic Corporate Social Responsibility

    Planer-Friedrich, Lisa; Sahm, Marco

    2017-01-01

    We examine the strategic use of Corporate Social Responsibility (CSR) in imperfectly competitive markets. The level of CSR determines the weight a firm puts on consumer surplus in its objective function before it decides upon supply. First, we consider symmetric Cournot competition and show that the endogenous level of CSR is positive for any given number of firms. However, positive CSR levels imply smaller equilibrium profits. Second, we find that an incumbent monopolist can use CSR as an en...

  7. Undefined and unpredictable responsibility

    Bove, Dorthe Gaby; Zakrisson, Ann-Britt; Midtgaard, Julie

    2016-01-01

    experienced ambiguity about expectations from their private and the health professionals' surroundings. The informal caregiver spouses wanted to provide meaningful care for their partners, but sought knowledge and support from the health professionals. RELEVANCE TO CLINICAL PRACTICE: We recommend that nurses...... take on the responsibility for including the informal caregiver spouses in those aspects of decision-making that involve the common life of the patients and their spouses....

  8. The Responsive Organization

    Andersen, Torben Juul; Fredens, Kjeld

    Modern cognitive science identifies a dynamic system of interacting fast and slow processes as essential to human thinking. The fast system observes and reacts to environmental stimuli and the slow system interprets events and reasons about future actions. When the fast and slow processes interact...... considerations that take place around the top-management echelons. This identifies the responsive organization that is able to observe and react to frequent and often abrupt environmental changes and thereby adapt organizational activities to the changing reality....

  9. Low pH induces co-ordinate regulation of gene expression in oesophageal cells.

    Duggan, Shane P; Gallagher, William M; Fox, Edward J P; Abdel-Latif, Mohammed M; Reynolds, John V; Kelleher, Dermot

    2006-02-01

    The development of gastro-oesophageal reflux disease (GORD) is known to be a causative risk factor in the evolution of adenocarcinoma of the oesophagus. The major component of this reflux is gastric acid. However, the impact of low pH on gene expression has not been extensively studied in oesophageal cells. This study utilizes a transcriptomic and bioinformatic approach to assess regulation of gene expression in response to low pH. In more detail, oesophageal adenocarcinoma cell lines were exposed to a range of pH environments. Affymetrix microarrays were used for gene-expression analysis and results were validated using cycle limitation and real-time RT-PCR analysis, as well as northern and western blotting. Comparative promoter transcription factor binding site (TFBS) analysis (MatInspector) of hierarchically clustered gene-expression data was employed to identify the elements which may co-ordinately regulate individual gene clusters. Initial experiments demonstrated maximal induction of EGR1 gene expression at pH 6.5. Subsequent array experimentation revealed significant induction of gene expression from such functional categories as DNA damage response (EGR1-4, ATF3) and cell-cycle control (GADD34, GADD45, p57). Changes in expression of EGR1, EGR3, ATF3, MKP-1, FOSB, CTGF and CYR61 were verified in separate experiments and in a variety of oesophageal cell lines. TFBS analysis of promoters identified transcription factors that may co-ordinately regulate gene-expression clusters, Cluster 1: Oct-1, AP4R; Cluster 2: NF-kB, EGRF; Cluster 3: IKRS, AP-1F. Low pH has the ability to induce genes and pathways which can provide an environment suitable for the progression of malignancy. Further functional analysis of the genes and clusters identified in this low pH study is likely to lead to new insights into the pathogenesis and therapeutics of GORD and oesophageal cancer.

  10. RELIGIOUS RESPONSES TO GLOBALISATION

    Hatib A. Kadir

    2011-08-01

    Full Text Available Sociological discussion of globalisation is preoccupied with the political, economic, and military dimension of it, with little attention to its religious aspect. This paper attempts to trace the impacts of globalisation on religion and religious responses, the argument of which derives mainly from the so-called “Bridge-Building Program” organised by CRCS & ICRS-UGM in 2008. It argues that though they share a common concern, people of different faiths are at risk of deepening the problems rather than offering solutions in view of their different responses for which we categorise them into different but overlapping categories -ideological, ambivalent, integrative, exclusive, and imitative. It then leads to a more fundamental question of whether interfaith cooperation is possible given those different and sometime opposing responses. [Dalam kajian sosiologi, diskusi mengenai globalisasi kerap kali semata-mata ditinjau dari sisi politik, enonomi dan militer, sementara dimensi agama sering kali dikesampingkan. Artikel ini membahas dampak globalisasi terhadap agama dan respon komunitas agama terhadap globalisasi. Data yang muncul dalam artikel ini diambil dari sebuah workshop berjudul“Bridge- Building Program.” Melalui artikel ini, saya berpendapat bahwa, meskikomunitas agama-agama memiliki keprihatinan yang sama terhadap dampak globalisasi, namun respon mereka cenderung mempertajam persoalan yang diakibatkan globalisasi, ketimbang memberikan solusi. Respon tersebut dalam dikategorikan –meski tidak kaku- dalam: respon ideologis, ambivalen, integratif, ekslusif dan imitatif. Selanjutnya, artikel juga mengulas pada pertanyaan mendasar mengenai apakah kerjasama antar agama mungkin dilakukan menyimak ragam respon yang saling bertentangan tersebut.

  11. Load responsive hydrodynamic bearing

    Kalsi, Manmohan S.; Somogyi, Dezso; Dietle, Lannie L.

    2002-01-01

    A load responsive hydrodynamic bearing is provided in the form of a thrust bearing or journal bearing for supporting, guiding and lubricating a relatively rotatable member to minimize wear thereof responsive to relative rotation under severe load. In the space between spaced relatively rotatable members and in the presence of a liquid or grease lubricant, one or more continuous ring shaped integral generally circular bearing bodies each define at least one dynamic surface and a plurality of support regions. Each of the support regions defines a static surface which is oriented in generally opposed relation with the dynamic surface for contact with one of the relatively rotatable members. A plurality of flexing regions are defined by the generally circular body of the bearing and are integral with and located between adjacent support regions. Each of the flexing regions has a first beam-like element being connected by an integral flexible hinge with one of the support regions and a second beam-like element having an integral flexible hinge connection with an adjacent support region. A least one local weakening geometry of the flexing region is located intermediate the first and second beam-like elements. In response to application of load from one of the relatively rotatable elements to the bearing, the beam-like elements and the local weakening geometry become flexed, causing the dynamic surface to deform and establish a hydrodynamic geometry for wedging lubricant into the dynamic interface.

  12. Ontario demand response scenarios

    Rowlands, I.H.

    2005-09-01

    Strategies for demand management in Ontario were examined via 2 scenarios for a commercial/institutional building with a normal summertime peak load of 300 kW between 14:00 and 18:00 during a period of high electricity demand and high electricity prices. The first scenario involved the deployment of a 150 kW on-site generator fuelled by either diesel or natural gas. The second scenario involved curtailing load by 60 kW during the same periods. Costs and benefits of both scenarios were evaluated for 3 groups: consumers, system operators and society. Benefits included electricity cost savings, deferred transmission capacity development, lower system prices for electricity, as well as environmental changes, economic development, and a greater sense of corporate social responsibility. It was noted that while significant benefits were observed for all 3 groups, they were not substantial enough to encourage action, as the savings arising from deferred generation capacity development do not accrue to individual players. The largest potential benefit was identified as lower prices, spread across all users of electricity in Ontario. It was recommended that representative bodies cooperate so that the system-wide benefits can be reaped. It was noted that if 10 municipal utilities were able to have 250 commercial or institutional customers engaged in distributed response, then a total peak demand reduction of 375 MW could be achieved, representing more than 25 per cent of Ontario's target for energy conservation. It was concluded that demand response often involves the investment of capital and new on-site procedures, which may affect reactions to various incentives. 78 refs., 10 tabs., 5 figs

  13. Mobile emergency response unit

    Kadi, W.J.; Trolan, R.T.; Becker, J.F.

    1979-01-01

    The Hotspot quick-response unit was the solution to a requirement to find, identify, and control areas of radioactive contamination at the scene of a nuclear weapons accident. The unit consists of two trucks and two trailers, and is designed to be transported by one U.S. Air Force C-141. One truck (generator truck) carries a 40 kW generator-heater-air conditioner combination, spare tires, and accessories. The other (water truck) carries supplies and a 250-gal water tank. One trailer (counting trailer) contains detecting, counting, and recording equipment. The other (decontaminating trailer) contains a shower, sink, 30-gal hot water tank, and supplies

  14. TMD: it's our responsibility.

    Dale, R

    1999-01-01

    Temporomandibular disorder (TMD) is a reality. Surveys place the incidence at about 20-50%. For decades debate has raged as to whether this is a medical or dental problem. Scientific study of anatomy, biochemistry, physiology, and objective analysis with kinesiology, electromyography and sonography, along with case history all point to the same thing; occlusion affects the joint and the muscles. This is our profession's "crown jewel". We diagnose, construct and modify our patient's occlusion. It is about time we all agree, understand, take responsibility and start cooperating in preventing and treating this common malady that seriously affects the quality of life of many.

  15. Dangerous goods emergency response

    Price, K.

    1991-01-01

    This paper reports on a general overview of the State of Western Australia including: the legal framework of the Dangerous Goods and Emergency response management scenarios (which consist mainly of fuel products such as LP gas); particular problems unique to the Western Australian environment; what has been done to overcome those problems. Western Australia has an area of about two and a half million square kilometers. The demography of the State is such that the population is concentrated in the south-west corner of the State with isolated pockets, mainly associated with mineral development but also associated with agriculture, scattered throughout the State

  16. The Responsibilities of Accountants

    Ronald F Duska

    2005-01-01

    An accountant is a good accountant if in practicing his craft he is superb in handling the numbers. But a good accountant in handling the numbers can use that skill to misstate earnings to cover a multitude of problems with a company's books while staying within the law. So, the notion of a moral or ethical accountant is not the same as the notion of a good accountant. Our general principle would be that to be ethical a person has a responsibility to fulfil one's role or roles, as long as tha...

  17. [Responsibilities of ethics committees].

    von Bergmann, K

    2000-05-01

    Increasing numbers of clinical research projects are submitted to ethical committees (institutional review boards) for approval. New therapeutic developments have to be evaluated by these committees to protect patients/volunteers. Thus, the responsibility of ethical committees is increasing. The "Nürnberger Kodex" and the "Declaration of Helsinki" are the background for these evaluations. According to the German drug law the physician is obligated by law to submit the protocol to such a committee. In addition, local state physician authorities require such a procedure. Important considerations during the review process besides ethical aspects are the informed consent, which should be written in an understandable form, and the obligations of the insurance.

  18. Crisis response to schools.

    Johnson, K

    2000-01-01

    While community based crisis response teams offer needed resources to schools impacted by crisis, they are often not asked to help. Reports from crisis team leaders at the school shooting incidents at James W. Parker Middle School, Edinboro, Pennsylvania and Columbine High School, Littleton, Colorado are contrasted regarding utilization of community resources. Factors limiting the usefulness of community based teams include unfamiliarity with school organization, culture, and procedures. Key differences in school vs. community team precepts, decision-making, and strategic paradigms render team coordination difficult. Successful cross training presents opportunities for school-community partnership and utilization of community teams for school duty.

  19. Science's social responsibility

    Sandvik, Kjetil

    2014-01-01

    like Science in the City in which the science institutions communicate and discuss science with interested citizens. It can be done in relation to strategic plans: solving medical, environmental, socio-political problems for which the state or commercial actors provide funding. But it can also be what...... this is kind of funny, it has some kind of serious core to it in that part of science responsibility to society is to figure out the meaning of the questions that we want to pose – and furthermore: which questions can be asked. Doing this may not be limited to short-term processes, to strategic considerations...

  20. Multilevel corporate environmental responsibility.

    Karassin, Orr; Bar-Haim, Aviad

    2016-12-01

    The multilevel empirical study of the antecedents of corporate social responsibility (CSR) has been identified as "the first knowledge gap" in CSR research. Based on an extensive literature review, the present study outlines a conceptual multilevel model of CSR, then designs and empirically validates an operational multilevel model of the principal driving factors affecting corporate environmental responsibility (CER), as a measure of CSR. Both conceptual and operational models incorporate three levels of analysis: institutional, organizational, and individual. The multilevel nature of the design allows for the assessment of the relative importance of the levels and of their components in the achievement of CER. Unweighted least squares (ULS) regression analysis reveals that the institutional-level variables have medium relationships with CER, some variables having a negative effect. The organizational level is revealed as having strong and positive significant relationships with CER, with organizational culture and managers' attitudes and behaviors as significant driving forces. The study demonstrates the importance of multilevel analysis in improving the understanding of CSR drivers, relative to single level models, even if the significance of specific drivers and levels may vary by context. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Emotional response to advertising

    Bogdan Anastasiei

    2014-11-01

    Full Text Available Emotions can transcend cultural, linguistic, demographic, and social boundaries. Emotions affect information processing and create a positive attitude toward the ad, which becomes associated with the brand. Objectives. This study investigates the role of pleasure (P, arousal (A and domination (D emotions in mobile’s photo camera advertisement and how each of them is influencing consumer attitude towards the advertisement and brand. Prior Work. Holbrook and Batra (1987 developed their own emotional scale based on these three dimensions (PAD, showing that these emotions mediate consumer responses to advertising. Approach. A 1*4 factorial experiment design method was adopted in order to measure the impact of independent variables (emotion type on dependent variables (attitude toward ad, attitude toward brand. Results. The results revealed that emotions like Pleasure (loving, friendly, grateful and Arousal (active, interested, excited, entertained influence consumers' attitudes towards brand and advertising. Value. Marketers need to understand the role of pleasure and arousal emotions when making advertising campaign; an effective promotion leads to persuading consumers. The results indicate that marketing practitioners should measure affective responses when testing an advertisement, as long as this action would predict brand attitude.

  2. State responses to biotechnology.

    Harris, Rebecca C

    2015-01-01

    This article reviews biotechnology legislation in the 50 states for 11 policy areas spanning 1990-2010, an era of immense growth in biotechnology, genetic knowledge, and significant policy development. Policies regarding health insurance, life insurance, long-term care insurance, DNA data bank collection, biotech research protection, biotech promotion and support, employment discrimination, genetic counselor licensing, human cloning, and genetic privacy each represent major policy responses arising from biotechnology and coinciding with key areas of state regulation (insurance, criminal justice, economic development, labor law, health and safety, privacy, and property rights). This analysis seeks to answer three questions regarding biotechnology legislation at the state level: who is acting (policy adoption), when is policy adopted (policy timing), and what is policy doing (policy content). Theoretical concerns examine state ideology (conservative or liberal), policy type (economic or moral), and the role of external events (federal law, news events, etc.) on state policy adoption. Findings suggest ideological patterns in adoption, timing, and content of biotech policy. Findings also suggest economic policies tend to be more uniform in content than moral policies, and findings also document a clear link between federal policy development, external events, and state policy response.

  3. Human sexual response.

    Basson, Rosemary

    2015-01-01

    The human sexual response to sexually arousing stimuli is a motivational incentive-based cycle comprising subjective experience and physiologic changes. Clinical and empirical data support a circular model of overlapping phases of variable order. Brain imaging data of sexual arousal identify areas of cerebral activation and inhibition reflecting a complex network of cognitive, motivational, emotional, and autonomic components. Psychologic and biologic factors influence the brain's appraisal and processing of sexual stimuli to allow or disallow subsequent arousal. The sexual and non-sexual outcomes influence motivation to future sexual intimacy. Variability is marked both between individuals and within a person's sexual life, influenced by multiple factors, including stage of life cycle, mental health, and relationship happiness. Neurologic disease can interrupt the cycle at many points: by limiting motivation, reducing ability to attend to and feel sexual stimuli, and accomplishing the movements needed to stimulate and experience intercourse. Impairments to genital congestion, penile erection, and orgasm may also occur. Disease-associated changes to the interpersonal relationship and self-image plus frequently comorbid depression will tend to lessen motivation and temper the brain's appraisal of sexual stimuli, so precluding arousal. Therapy begins by explaining the sexual response cycle, clarifying the points of interruption in the patient's own cycle so as to guide treatment. © 2015 Elsevier B.V. All rights reserved.

  4. THE RESPONSIBILITY PRINCIPLE

    Elena ANGHEL

    2015-07-01

    Full Text Available "I'm wishing Law this: all legal obligations sholud be executed with the scrupulosity with which moral obligations are being performed by those people who feel bound by them ...", so beautifully portraited by Nicolae Titulescu`s words1. Life in the society means more than a simple coexistence of human beings, it actually means living together, collaborating and cooperating; that is why I always have to relate to other people and to be aware that only by limiting my freedom of action, the others freedom is feasible. Neminem laedere should be a principle of life for each of us. The individual is a responsible being. But responsibility exceeds legal prescriptions. Romanian Constitution underlines that I have to exercise my rights and freedoms in good faith, without infringing the rights and freedoms of others. The legal norm, developer of the constitutional principles, is endowed with sanction, which grants it exigibility. But I wonder: If I choose to obey the law, is my decision essentially determined only due of the fear of punishment? Is it not because I am a rational being, who developed during its life a conscience towards values, and thus I understand that I have to respect the law and I choose to comply with it?

  5. Exercise Responses after Inactivity

    Convertino, Victor A.

    1986-01-01

    The exercise response after bed rest inactivity is a reduction in the physical work capacity and is manifested by significant decreases in oxygen uptake. The magnitude of decrease in maximal oxygen intake V(dot)O2max is related to the duration of confinement and the pre-bed-rest level of aerobic fitness; these relationships are relatively independent of age and gender. The reduced exercise performance and V(dot)O2max following bed rest are associated with various physiological adaptations including reductions in blood volume, submaximal and maximal stroke volume, maximal cardiac output, sceletal muscle tone and strength, and aerobic enzyme capacities, as well as increases in venous compliance and submaximal and maximal heart rate. This reduction in physiological capacity can be partially restored by specific countermeasures that provide regular muscular activity or orhtostatic stress or both during the bed rest exposure. The understanding of these physiological and physical responses to exercise following bed rest inactivity has important implications for the solution to safety and health problems that arise in clinical medicine, aerospace medicine, sedentary living, and aging.

  6. Mechanical Stress and Antioxidant Protection in the Retina of Hindlimb Suspended Rats

    Glass, Aziza; Theriot, Corey A.; Alway, Stephen E.; Zanello, Susana B.

    2012-01-01

    It has been postulated that hindlimb suspension (HS) causes a cephalad fluid shift in quadrupeds similar to that occurring to humans in microgravity. Therefore, HS may provide a suitable animal model in which to recapitulate the ocular changes observed in the human Visual Impairment and Intracranial Pressure (VIIP) syndrome. This work reports preliminary results from a tissue sharing project using 34 week-old Brown Norway rats. Two different experiments compared normal posture controls and HS rats for 2 weeks and rats exposed to HS for 2 weeks but allowed to recover in normal posture for 2 additional weeks. The effects of two nutritional countermeasures, green tea extract (GT) and plant polyphenol resveratrol (Rv), were also evaluated. Green tea contains the antioxidant epigallocatechin gallate (EGCG). qPCR gene expression analysis of selected targets was performed on RNA from isolated retinas, and histologic analysis was done on one fixed eye per rat. The transcription factor early growth response protein 1 (Egr1) was upregulated almost 2-fold in HS retinas relative to controls (P = 0.059), and its expression returned to control levels after 2 weeks of recovery in normal posture (P = 0.023). HS-induced upregulation of Egr1 was attenuated (but not significantly) in retinas from rats fed an antioxidant rich (GT extract) diet. In rats fed the GT-enriched diet, antioxidant enzymes were induced, evidenced by the upregulation of the gene heme oxygenase 1 (Hmox1) (P = 0.042) and the gene superoxide dismutase 2 (Sod2) (P = 0.0001). Egr1 is a stretch-activated transcription factor, and the Egr1 mechanosensitive response to HS may have been caused by a change in the translaminal pressure and/or mechanical deformation of the eye globe. The observed histologic measurements of the various retinal layers in the HS rats were lower in value than those of the control animal (n = 1), however insufficient data were available for statistical analysis. Aquaporin 4, a water

  7. The business value of demand response for balance responsible parties

    Jonsson, Mattias

    2014-01-01

    By using IT-solutions, the flexibility on the demand side in the electrical systems could be increased. This is called demand response and is part of the larger concept called smart grids. Previous work in this area has concerned the utilization of demand response by grid owners. In this thesis the focus will instead be shifted towards the electrical companies that have balance responsibility, and how they could use demand response in order to make profits. By investigating electrical applian...

  8. Playful Hyper Responsibility: Toward a Dislocation of Parents' Responsibility?

    Knudsen, Hanne; Andersen, Niels Åkerstrøm

    2014-01-01

    Over the past 10-15?years, state-funded schools have begun to require parents to assume an undefined and infinite personal responsibility. In this article, we investigate how schools organize responsibility games to respond to this challenge and how these games affect the concept of responsibility. We point to a dislocation in the way parents are…

  9. Energy crisis: policy response

    Nemetz, P N [ed.

    1981-01-01

    Resource-management techniques must be applied to assess the risks, benefits, priorities, and potentials of the different energy options as prospective slowdowns in the flow of crude oil threaten recurring energy crises. The 23 contributors to this book use various managerial approaches in the formulation of energy policies. There is little agreement among the remedies put forth as to which policies will best achieve a balanced energy system. While some experts argue that Canadian energy policy should emphasize intensive development of coal, others claim that it ought to strive for greater reliance on electricity, and still others contend that the transition to soft energy paths is a preferable policy approach. The essays offer a broad range of policy responses, examining not only technical and economic possibilities, but political and institutional alternatives as well. 147 references, 18 figures, 30 tables.

  10. Risk and response

    Warner, F

    1980-12-01

    There is little correlation between public response to perceived risks and the life-expectancy statistics for hazardous occupations. Case studies show that the public reacts more strongly to conflicting information from the warnings of experts and the media, giving more credence to individual situations than to statistical probabilities. The impact of a large-scale accident intensifies the perception of risk even though the situation may be safer over time. These factors affect the public's ability to accept nuclear power and its insistence on public debate, which may shift from the area of facts and documentation to that of values. Decision makers may need to compromise by shifting expenditures to actions that involve low levels of risk. 2 references, 1 figure, 2 tables. (DCK)

  11. Responsible technology acceptance

    Toft, Madeleine Broman; Schuitema, Geertje; Thøgersen, John

    2014-01-01

    As a response to climate change and the desire to gain independence from imported fossil fuels, there is a pressure to increase the proportion of electricity from renewable sources which is one of the reasons why electricity grids are currently being turned into Smart Grids. In this paper, we focus...... on private consumers’ acceptance of having Smart Grid technology installed in their home. We analyse acceptance in a combined framework of the Technology Acceptance Model and the Norm Activation Model. We propose that individuals are only likely to accept Smart Grid technology if they assess usefulness...... in terms of a positive impact for society and the environment. Therefore, we expect that Smart Grid technology acceptance can be better explained when the well-known technology acceptance parameters included in the Technology Acceptance Model are supplemented by moral norms as suggested by the Norm...

  12. Multimodal responsive action

    Oshima, Sae

    ; Raymond 2003; Schegloff and Lerner 2009), including those with multimodal actions (e.g. Olsher 2004; Fasulo & Monzoni 2009). Some responsive actions can also be completed with bodily behavior alone, such as: when an agreement display is achieved by using only nonvocal actions (Jarmon 1996), when...... the recipient’s gaze shift becomes a significant part of the speaker’s turn construction (Goodwin 1980), and when head nods show the recipient’s affiliation with the speaker’s stance (Stivers 2008). Still, much room remains for extending our current understanding of responding actions that necessarily involve...... a hairstylist and a client negotiate the quality of the service that has been provided. Here, the first action is usually the stylist’s question and/or explanation of the new cut that invites the client’s assessment/(dis)agreement, accompanied with embodied actions that project an imminent self...

  13. Responsive acoustic surfaces

    Peters, Brady; Tamke, Martin; Nielsen, Stig Anton

    2011-01-01

    Acoustic performance is defined by the parameter of reverberation time; however, this does not capture the acoustic experience in some types of open plan spaces. As many working and learning activities now take place in open plan spaces, it is important to be able to understand and design...... for the acoustic conditions of these spaces. This paper describes an experimental research project that studied the design processes necessary to design for sound. A responsive acoustic surface was designed, fabricated and tested. This acoustic surface was designed to create specific sonic effects. The design...... was simulated using custom integrated acoustic software and also using Odeon acoustic analysis software. The research demonstrates a method for designing space- and sound-defining surfaces, defines the concept of acoustic subspace, and suggests some new parameters for defining acoustic subspaces....

  14. Hanford Emergency Response Plan

    Wagoner, J.D.

    1994-04-01

    The Hanford Emergency Response Plan for the US Department of Energy (DOE), Richland Operations Office (RL), incorporates into one document an overview of the emergency management program for the Hanford Site. The program has been developed in accordance with DOE orders, and state and federal regulations to protect worker and public health and safety and the environment in the event of an emergency at or affecting the Hanford Site. This plan provides a description of how the Hanford Site will implement the provisions of DOE 5500 series and other applicable Orders in terms of overall policies and concept of operations. It should be used as the basis, along with DOE Orders, for the development of specific contractor and RL implementing procedures

  15. Socially Responsible Investing

    Parisi, Cristiana; Stang, Andreas

    This paper analyzes the Scandinavian market for Socially Responsible Investing (SRI) mutual funds in order to determine the returns from discriminatory investment decision compared to the return from conventional portfolios. The analysis is conducted on 642 Scandinavian equity mutual funds...... counterparts. In the case of Norway no statistical difference in return is found when conducting the three factor regression. The Scandinavian market is considered particularly relevant for the interest of the investors in SRI mutual funds. However, to the authors’ knowledge, this is the first study to present....... The methodology adopts the Sharpe ratio to establish the risk return relationship. Moreover, the Capital Asset Pricing Model (CAPM) and the Fama and French Three Factor model are used to test the hypotheses. The results indicate the underperformance of Swedish and Danish SRI funds relative to their conventional...

  16. Consumer responses to ecolabels

    Thøgersen, John; Haugaard, Pernille; Olesen, Anja

    2010-01-01

    Purpose - The purpose of this paper is to develop and apply a framework for understanding consumer responses to ecolabelling. Design/methodology/approach - From a consumer perspective, ecolabels are tools for supporting decision making with regard to environmentally significant products. The paper...... process. Starting the adoption process depends on both motivation (intention to buy sustainable fish products) and ability (issue-relevant knowledge). Whether and how quickly the consumer completes the adoption depends on his or her motivation, past experience with using ecolabels, and trust...... scoring highly on both issue-relevant knowledge and motivation are the most likely innovators and early adopters. Their high level of expertise means that they do not need a lot of explanation for understanding the label and its self-relevance and their strong motivation means that they will search...

  17. Hanford Emergency Response Plan

    Wagoner, J.D.

    1994-04-01

    The Hanford Emergency Response Plan for the US Department of Energy (DOE), Richland Operations Office (RL), incorporates into one document an overview of the emergency management program for the Hanford Site. The program has been developed in accordance with DOE orders, and state and federal regulations to protect worker and public health and safety and the environment in the event of an emergency at or affecting the Hanford Site. This plan provides a description of how the Hanford Site will implement the provisions of DOE 5500 series and other applicable Orders in terms of overall policies and concept of operations. It should be used as the basis, along with DOE Orders, for the development of specific contractor and RL implementing procedures.

  18. Complex Deployed Responsive Service

    Parry, Glenn; McLening, Marc; Caldwell, Nigel; Thompson, Rob

    A pizza restaurant must provide product, in the form of the food and drink, and service in the way this is delivered to the customer. Providing this has distinct operational challenges, but what if the restaurant also provides a home delivery service? The service becomes deployed as the customer is no-longer co-located with the production area. The business challenge is complicated as service needs to be delivered within a geographic region, to time or the pizza will be cold, and within a cost that is not ­prohibitive. It must also be responsive to short term demand; needing to balance the number of staff it has available to undertake deliveries against a forecast of demand.

  19. Gut Bacteria Affect Immunotherapy Response

    Three new studies have identified intestinal bacteria that appear to influence the response to checkpoint inhibitors. This Cancer Currents blog post explains how the researchers think their findings could be used to improve patients’ responses to these immunotherapy drugs.

  20. Corporate social responsibility in Islam

    Elasrag, Hussein

    2015-01-01

    The aim of this study is to review the Islamic principles of CSR, and the definition of a structured social corporate responsibility (CSR), and based on this responsibility. And provide a practical through the international financial institutions that can implement CSR policies framework. This study provides the basis of social responsibilities that apply to those derived from divine sources of international financial institutions.

  1. Corporate responses to stakeholder activism

    Uldam, Julie; Krause Hansen, Hans

    2017-01-01

    Corporations are increasingly expected to act responsibly. The purpose of this paper is to examine two types of corporate responses to these expectations: overt and covert responses. Specifically, it examines oil companies’ involvement in multi-stakeholder initiatives and sponsorships (overt...

  2. Can Arousal Modulate Response Inhibition?

    Weinbach, Noam; Kalanthroff, Eyal; Avnit, Amir; Henik, Avishai

    2015-01-01

    The goal of the present study was to examine if and how arousal can modulate response inhibition. Two competing hypotheses can be drawn from previous literature. One holds that alerting cues that elevate arousal should result in an impulsive response and therefore impair response inhibition. The other suggests that alerting enhances processing of…

  3. The systemic inflammatory response syndrome.

    Robertson, Charles M; Coopersmith, Craig M

    2006-04-01

    The systemic inflammatory response syndrome (SIRS) is the body's response to an infectious or noninfectious insult. Although the definition of SIRS refers to it as an "inflammatory" response, it actually has pro- and anti-inflammatory components. This review outlines the pathophysiology of SIRS and highlights potential targets for future therapeutic intervention in patients with this complex entity.

  4. Pushing the Margins of Responsibility

    Santoni de Sio, Filippo; Di Nucci, Ezio

    2018-01-01

    David Shoemaker has claimed that a binary approach to moral responsibility leaves out something important, namely instances of marginal agency, cases where agents seem to be eligible for some responsibility responses but not others. In this paper we endorse and extend Shoemaker’s approach by pres...

  5. Treatment response in oncology

    Pandit-Taskar, Neeta; Batraki, Maria; Divgi, Chaitanya

    2004-01-01

    Full text: Currently, the evaluation of response to therapy in Oncology consists of determination of changes in size of lesions measurable by structural imaging, notably computerized tomography. These criteria, formalized using RECIST (Response Evaluation Criteria in Solid Tumors), are the current standard for evaluation (http://www3.cancer. gov/dip/RECIST.htm). An increasing body of evidence suggests that functional changes in tumors precede structural changes, and that methodologies that measure such changes may be able to evaluate the potential of therapy, allowing for better and earlier selection of these potentially cytotoxic therapies. Nuclear Medicine imaging is distinguished by its ability to determine functional characteristics. These include: 1. Receptor status - for example, the presence of sodium iodide symporters detected by radioiodine or pertechnetate imaging, the presence of somatostatin or norepinephrine receptors by pentetreotide or metaiodobenzylguanidine (mIBG) imaging respectively. Such imaging can help guide appropriate therapies with iodine-131, somatostatin analogues (radiolabeled or otherwise) or iodine-131 labeled mIBG. 2. Metabolic status - for example, glycolytic status (with fluorine-18 labeled fluorodeoxyglucose); amino acid metabolism (e.g. using carbon-11 labeled methionine), or tumor proliferation (using radiolabeled thymidine or deoxyuridine). These methods have advantages over structural imaging because in the vast majority of tumors, changes in the functional or molecular status of tumors are seen earlier than are structural changes. 3. Overall cellular status - these imaging agents are still in their early development but hold great promise for the determination of cellular viability. Annexin imaging is the archetype of such imaging modalities that predict the overall fate of the cell, in this instance its entry into the apoptotic pathway. This review will highlight the uses of functional imaging using radiotracers in all three

  6. Dopa-responsive dystonia

    Đurić Gordana

    2009-01-01

    Full Text Available Backgrround/Aim. Dystonia is considered to be a prolonged involuntary contractions of the muscles leading to twisting, repetitive movements or irregular postures. Etiologically, it could be classified as primary and secondary dystonia. Dopa-responsive dystonia (DRD belongs to a group of primary dystonia. The aim of this study was to detect the presence of gene GCH-I mutation in our population in patients with dopa-responsive dystonic dyskinesia and to analyze clinical specificity of the affected. Methods. Out of the group of patients with dystonia of different distribution four patients were separated whose clinical picture indicated the diagnosis of DRD. Two patients had a positive family anamnesis while the other two were sporadic. Genetic analysis was performed by the use of a standard protocol, which included PCR amplification and DNK sequencing according to the method of Senger and autoradiografy. Results. In the patients from the family DRD-1 new hetaerazygote point mutation 520G→A in 4-m exson gene GCH-I was revealed. First symptoms of the disease showed in the age of seven by the torsion of the left foot, progressively advanced and got into the evolution of numbness in the legs, aggravated gait, tending to worsen in the evening, and the therapy with levodopa (500 mg produced a dramatic effect. The second mutation in the female patient from the family DRD-2 was homozygote deletion in1-m intron gene GCH-I (IVS1-85delA. Unwilling torsion of the foot, feeling of weakness in the lower extremities (that caused falling without loss of the consciousness were clinical demonstrations of the disease. The application of levodopa (300 mg caused regression of the symptoms of the disease. Hetaerazygote deletion of adenine in the position 209 in the first exon (209del A was identificated in the patient DRD-3 with negative family anamnesis, in who in the age of ten the torsion of the foot inside occurred for the first time following by trembling of

  7. Chronic ciguatoxin treatment induces synaptic scaling through voltage gated sodium channels in cortical neurons.

    Martín, Víctor; Vale, Carmen; Rubiolo, Juan A; Roel, Maria; Hirama, Masahiro; Yamashita, Shuji; Vieytes, Mercedes R; Botana, Luís M

    2015-06-15

    Ciguatoxins are sodium channels activators that cause ciguatera, one of the most widespread nonbacterial forms of food poisoning, which presents with long-term neurological alterations. In central neurons, chronic perturbations in activity induce homeostatic synaptic mechanisms that adjust the strength of excitatory synapses and modulate glutamate receptor expression in order to stabilize the overall activity. Immediate early genes, such as Arc and Egr1, are induced in response to activity changes and underlie the trafficking of glutamate receptors during neuronal homeostasis. To better understand the long lasting neurological consequences of ciguatera, it is important to establish the role that chronic changes in activity produced by ciguatoxins represent to central neurons. Here, the effect of a 30 min exposure of 10-13 days in vitro (DIV) cortical neurons to the synthetic ciguatoxin CTX 3C on Arc and Egr1 expression was evaluated using real-time polymerase chain reaction approaches. Since the toxin increased the mRNA levels of both Arc and Egr1, the effect of CTX 3C in NaV channels, membrane potential, firing activity, miniature excitatory postsynaptic currents (mEPSCs), and glutamate receptors expression in cortical neurons after a 24 h exposure was evaluated using electrophysiological and western blot approaches. The data presented here show that CTX 3C induced an upregulation of Arc and Egr1 that was prevented by previous coincubation of the neurons with the NaV channel blocker tetrodotoxin. In addition, chronic CTX 3C caused a concentration-dependent shift in the activation voltage of NaV channels to more negative potentials and produced membrane potential depolarization. Moreover, 24 h treatment of cortical neurons with 5 nM CTX 3C decreased neuronal firing and induced synaptic scaling mechanisms, as evidenced by a decrease in the amplitude of mEPSCs and downregulation in the protein level of glutamate receptors that was also prevented by tetrodotoxin

  8. Personal Responsibility and Lifestyle Diseases

    Andersen, Martin Marchman; Nielsen, Morten Ebbe Juul

    2016-01-01

    What does it take for an individual to be personally responsible for behaviors that lead to increased risk of disease? We examine three approaches to responsibility that cover the most important aspects of the discussion of responsibility and spell out what it takes, according to each of them......, to be responsible for behaviors leading to increased risk of disease. We show that only what we call the causal approach can adequately accommodate widely shared intuitions to the effect that certain causal influences—such as genetic make-up or certain social circumstances—diminish, or undermine personal...... risk of disease rests on premises so shaky that personal responsibility is probably impossible....

  9. Social responsibility and SOE restructuring

    沈志渔; 刘兴国; 周小虎

    2009-01-01

    SOE social responsibility has undergone three stages of evolution.In essence,corporate social responsibility includes social obligations and social expectations.Public attention to SOE social responsibility issues has affected the thinking surrounding SOE restructuring,including the promulgating of objectives and methods.Based on corporate social responsibility,SOE managers must set up a perfect SOE social responsibility system and strengthen supervisory mechanisms;in respect to corporate governance models,SOEs should undertake reform for the corporate citizen governance model.

  10. Corporate social responsibility in hospitality

    Snježana Gagić

    2016-01-01

    Full Text Available Responsible management of global hospitality companies increasingly recognizes how important are concerns about the society, the environment as well as all stakeholders in maintaining a good market position. In Serbia, the concept of corporate social responsibility is relatively unknown and insufficiently researched in all business areas, especially in the hospitality industry where small businesses are dominated. The papers task is to present particular activities that demonstrate social responsibility to employees, customers-guests, local communities as well as the environment. The paper aims to highlight the benefits of adopting the principles of corporate social responsibility and innovation applied in catering enterprises as an example of good corporate social responsibility practices.

  11. Spill response exercises and lessons learned : a response organization's perspective

    Taylor, E.; Green, M.

    2001-01-01

    In the past five years, Burrard Clean Operations (BCO) has demonstrated its' oil spill response capabilities through different types of exercises. Such exercises are necessary for certification of Response Organizations in Canada. The exercises can be performed through actual response to spills or through simulated situations. Both can provide an opportunity to practice different levels of response to a range of conditions in various settings. They also provide the opportunity to focus on specific themes that can be part of a response and to identify areas for improvement in response actions. They also make it possible to interface with government agencies, industry and others that participate in spill responses. The exercise program for BCO is aimed at maintaining certification and to assist the Canadian Coast Guard. The exercises broaden the lessons learned and set a course for future enhancement to spill readiness should a real incident occur. The goals of the exercise program are to provide real time drills that show the operational capability of a representative sample of BCO equipment, management and trained spill responders. The response functions of the BCO exercise program are: notification, response organization activation, contractor activation, situation analysis, strategy development for marine oil spill response, site safety, equipment deployment, containment, recovery, shoreline assessment, cleanup, communications, decontamination, logistics, and financial management. The BCO experience has led to the basic conclusions that there is a need to vary the exercise design and format and that there is a need to implement follow-up actions provided during exercise evaluations. 7 refs., 3 tabs

  12. The innate immune response in fetal lung mesenchymal cells targets VEGFR2 expression and activity.

    Medal, Rachel M; Im, Amanda M; Yamamoto, Yasutoshi; Lakhdari, Omar; Blackwell, Timothy S; Hoffman, Hal M; Sahoo, Debashis; Prince, Lawrence S

    2017-06-01

    In preterm infants, soluble inflammatory mediators target lung mesenchymal cells, disrupting airway and alveolar morphogenesis. However, how mesenchymal cells respond directly to microbial stimuli remains poorly characterized. Our objective was to measure the genome-wide innate immune response in fetal lung mesenchymal cells exposed to the bacterial endotoxin lipopolysaccharide (LPS). With the use of Affymetrix MoGene 1.0st arrays, we showed that LPS induced expression of unique innate immune transcripts heavily weighted toward CC and CXC family chemokines. The transcriptional response was different between cells from E11, E15, and E18 mouse lungs. In all cells tested, LPS inhibited expression of a small core group of genes including the VEGF receptor Vegfr2 Although best characterized in vascular endothelial populations, we demonstrated here that fetal mouse lung mesenchymal cells express Vegfr2 and respond to VEGF-A stimulation. In mesenchymal cells, VEGF-A increased cell migration, activated the ERK/AKT pathway, and promoted FOXO3A nuclear exclusion. With the use of an experimental coculture model of epithelial-mesenchymal interactions, we also showed that VEGFR2 inhibition prevented formation of three-dimensional structures. Both LPS and tyrosine kinase inhibition reduced three-dimensional structure formation. Our data suggest a novel mechanism for inflammation-mediated defects in lung development involving reduced VEGF signaling in lung mesenchyme. Copyright © 2017 the American Physiological Society.

  13. Marine oil spill response organizations

    Hendry, C.

    1997-01-01

    The obligations under the law relative to the prevention of marine oil spills and the type of emergency plans needed to mitigate any adverse effects caused by a marine oil spill were discussed. The organizational structure, spill response resources and operational management capabilities of Canada's newly created Response Organizations (ROs) were described. The overall range of oil spill response services that the RO provides to the domestic oil handling, oil transportation and the international shipping industries were reviewed. Amendments to the Canada Shipping Act which require that certain ships and oil handling facilities take oil spill preparedness and response measures, including having an arrangement with an RO certified by the Canadian Coast Guard, were outlined. Canadians now benefit from five ROs established to provide coast-to-coast oil spill response coverage. These include the Western Canada Marine Response Corporation, the Canadian Marine Response Management Corporation, the Great Lakes Response Corporation, the Eastern Canada Response Corporation and the Atlantic Emergency Response Team Ltd. ROs have the expertise necessary to organize and manage marine oil spill response services. They can provide equipment, personnel and operational management for the containment, recovery and cleanup of oil spilled on water

  14. Environmental Ethics and Responsibility

    Luiz Paulo Rouanet

    2015-09-01

    Full Text Available http://dx.doi.org/10.5007/1677-2954.2015v14n3p382 This paper resumes a previous discussion on Environmental Ethics and Irreversibility, which was presented in 2005. There I first faced the problem. Now I would like to reevaluate the issue. Was my paper “catastrophist”? Or was it, instead, realistic? Which are today the main issues confronting Environmental Ethics? Plainly speaking, what can we really do? These are some of the questions I would like to bring in to the debate with my colleagues and the public. In other words, instead of focusing in the aspect of “irreversibility”, I prefer here to focus on the “responsibility” of agents and institutions. It rescues the so-called “Principle of Responsibility”, by Hans Jonas. There is also some debate with Karl-Otto Appel and Habermas. If, on one hand, there are irreversible damages to nature, as the extinction of species and even of natural locations, as rivers and other natural accidents, there are, on the other hand, many actions that can and must be taken in order to preserve or deter the grave consequences of the environmental degradation. In this paper, I try to discuss some of the problems and propose some solutions, but the more important thing is to call everyone – individuals, groups, or institutions – to responsibility face the Earth, the Human and not-human beings, and mainly the future generations.

  15. Emergency Response Guideline Development

    Gary D Storrick

    2007-01-01

    Task 5 of the collaborative effort between ORNL, Brazil, and Westinghouse for the International Nuclear Energy Research Initiative entitled 'Development of Advanced Instrumentation and Control for an Integrated Primary System Reactor' focuses on operator control and protection system interaction, with particular emphasis on developing emergency response guidelines (ERGs). As in the earlier tasks, we will use the IRIS plant as a specific example of an integrated primary system reactor (IPSR) design. The present state of the IRIS plant design--specifically, the lack of a detailed secondary system design--precludes establishing detailed emergency procedures at this time. However, we can create a structure for their eventual development. This report summarizes our progress to date. Section 1.2 describes the scope of this effort. Section 2 compares IPSR ERG development to the recent AP1000 effort, and identifies three key plant differences that affect the ERGs and control room designs. The next three sections investigate these differences in more detail. Section 3 reviews the IRIS Safety-by-Design philosophy and its impact on the ERGs. Section 4 looks at differences between the IRIS and traditional loop PWR I and C Systems, and considers their implications for both control room design and ERG development. Section 5 examines the implications of having one operating staff control multiple reactor units. Section 6 provides sample IRIS emergency operating procedures (EOPs). Section 7 summarizes our conclusions

  16. Response to Glenn

    Stephen Arons

    1998-01-01

    Full Text Available Arons responds to what he considers to be Glenn's misrepresentations of the tone and content of Short Route To Chaos. He writes that Glenn "appears to be attempting to construct the book's message into just one more salvo fired in the endless school wars. It is anything but....Reading Glenn's review, one is left with the impression that the book is a Christian-bashing, left-leaning, work of communitarian fuzziness in which a legal scholar unaccountably refuses to confine himself to ... technical explication of existing constitutional doctrine." In his response, Arons affirmatively sets out some of the book's main themes of political /cultural conflict over standardized schooling, corrects some of what he sees as Glenn's misunderstandings, and notes that the book itself invites readers to eschew partisanship and recognize that there are deep structural problems in American public education. In closing, Arons uses an example of Glenn's partisan misunderstanding that leads Arons to recommend to the reader that it would be better to read Short Route to Chaos for oneself.

  17. Magnetically responsive enzyme powders

    Pospiskova, Kristyna, E-mail: kristyna.pospiskova@upol.cz [Regional Centre of Advanced Technologies and Materials, Palacky University, Slechtitelu 11, 783 71 Olomouc (Czech Republic); Safarik, Ivo, E-mail: ivosaf@yahoo.com [Regional Centre of Advanced Technologies and Materials, Palacky University, Slechtitelu 11, 783 71 Olomouc (Czech Republic); Department of Nanobiotechnology, Institute of Nanobiology and Structural Biology of GCRC, Na Sadkach 7, 370 05 Ceske Budejovice (Czech Republic)

    2015-04-15

    Powdered enzymes were transformed into their insoluble magnetic derivatives retaining their catalytic activity. Enzyme powders (e.g., trypsin and lipase) were suspended in various liquid media not allowing their solubilization (e.g., saturated ammonium sulfate and highly concentrated polyethylene glycol solutions, ethanol, methanol, 2-propanol) and subsequently cross-linked with glutaraldehyde. Magnetic modification was successfully performed at low temperature in a freezer (−20 °C) using magnetic iron oxides nano- and microparticles prepared by microwave-assisted synthesis from ferrous sulfate. Magnetized cross-linked enzyme powders were stable at least for two months in water suspension without leakage of fixed magnetic particles. Operational stability of magnetically responsive enzymes during eight repeated reaction cycles was generally without loss of enzyme activity. Separation of magnetically modified cross-linked powdered enzymes from reaction mixtures was significantly simplified due to their magnetic properties. - Highlights: • Cross-linked enzyme powders were prepared in various liquid media. • Insoluble enzymes were magnetized using iron oxides particles. • Magnetic iron oxides particles were prepared by microwave-assisted synthesis. • Magnetic modification was performed under low (freezing) temperature. • Cross-linked powdered trypsin and lipase can be used repeatedly for reaction.

  18. Photoallergic responses to chemicals

    Kochievar, I E [Columbia Univ., New York (USA). Coll. of Physicians and Surgeons

    1979-10-01

    Photochemical and immunologic knowledge about photoallergy to chemicals is briefly summarized. Studies in in vitro systems have demonstrated that photoallergic compounds can covalently bond to proteins through a photochemical reaction. The immunologic nature of the photoallergic response is based mainly on clinical observations, induction of photoallergy in man and in guinea-pigs and on results of in vitro immunologic tests. Studies of the photoreactions of the photoallergic compound, 3,3',4',5-tetrachlorosalicylanilide (TCSA) with proteins are discussed. TSCA noncovalently bonds to human serum albumin prior to irradiation. Prior interaction is essential for formation of a photoaddition product indicating that a short-lived reactive species derived from TCSA is involved in the photoaddition and limiting the number of skin proteins which can participate in antigen formation. By fragmentation of the TCSA-albumin photoadduct with CNBr, it was determined that TCSA can bond to at least three sites on the albumin molecule. TCSA alone can sensitize the photooxidation of histidine in albumin.

  19. Social Economy and Responsibility

    Eva Abramuszkinová Pavlíková

    2012-01-01

    Full Text Available Given the importance of entrepreneurial activities as an engine of economic growth and poverty alleviation, the issue of business development and entrepreneurial activities, has received increasing attention from a number of interested parties worldwide and also in the Czech Republic. The focus of this paper is on a social economy, a social responsibility and social enterprises. The development of the social economy framework will be introduced in the European context and specifically in the Czech Republic. A case study of a Czech social entrepreneur will be introduced based on qualitative research, namely the biographical narrative method.Social enterprises can support activities of various target groups, such as economic activities of mentally and physically handicapped people, which often operate in economically and socially marginalized situations, including stereotyped images. They give them a chance to become active members of society. In this way they can help to reduce the poverty on a local level. The aim of this paper is to introduce a social entrepreneurship as important part of social economy development in the Czech Republic.

  20. Think, ! responsible sexuality !

    Mayelín Bosque Cruz

    2011-06-01

    Full Text Available This article is aimed at supporting the social health worker 's job to motivate teenagers and young people to learn easily about differe nt topics concerning sexuality by increasing the information they already have, and by stating how dangerous an irresponsible sexual behaviour can be, thus reinforcing the value of responsibility. The software “Sexualidad Responsable” provides informatio n on sexual education taking into account the following subject matters: Couple Relationship, Adolescent Pregnancy, Methods of Contraception, Sexually Transmitted Infections (HIV/AIDS, Moral Value Acquisition, Family Role, Violence and its expressions, D eviation and Sexual Preferences, among others. It also has didactic games, a gallery with pictures, videos and curiosities.There is a glossary of scientific terms included and the software’s tutorial section that orients us how to use them. In the software the health workers will find a very useful and supporting tool to work out the theme Sexuality with teenagers and young people, this software will foster the creation of scientific societies and supporting groups. The social health workers can also sear ch information on the topics, learn and then debate them among the members of different dysfunctional families or even in their own families if necessary.

  1. Vaccines, our shared responsibility.

    Pagliusi, Sonia; Jain, Rishabh; Suri, Rajinder Kumar

    2015-05-05

    The Developing Countries Vaccine Manufacturers' Network (DCVMN) held its fifteenth annual meeting from October 27-29, 2014, New Delhi, India. The DCVMN, together with the co-organizing institution Panacea Biotec, welcomed over 240 delegates representing high-profile governmental and nongovernmental global health organizations from 36 countries. Over the three-day meeting, attendees exchanged information about their efforts to achieve their shared goal of preventing death and disability from known and emerging infectious diseases. Special praise was extended to all stakeholders involved in the success of polio eradication in South East Asia and highlighted challenges in vaccine supply for measles-rubella immunization over the coming decades. Innovative vaccines and vaccine delivery technologies indicated creative solutions for achieving global immunization goals. Discussions were focused on three major themes including regulatory challenges for developing countries that may be overcome with better communication; global collaborations and partnerships for leveraging investments and enable uninterrupted supply of affordable and suitable vaccines; and leading innovation in vaccines difficult to develop, such as dengue, Chikungunya, typhoid-conjugated and EV71, and needle-free technologies that may speed up vaccine delivery. Moving further into the Decade of Vaccines, participants renewed their commitment to shared responsibility toward a world free of vaccine-preventable diseases. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. Technical risk - individual responsibility

    Herzog, R.

    1984-01-01

    The author, vice-president of the Federal Constitutional Court, delivered this opening address at the international symposium on nuclear liability held in Munich in September 1984 by OECD/NEA and IAEA. He starts by asking: Where does danger begin, where does risk end. It is the true and original task of the state to keep damage away from its citizens: this entails the obligation for additional garantees - not withstanding an almost greatest possible degree of safety - to at least helpfully compensate damage incurred, should such damage arise. In case of really severe accidents the essential thing is not the operator's liability but the entry of the state into that obligation, and this fact remains unchanged even if the maximum limits of liability were raised or in case of their removal. Therefore it is not necessary to be cautious about the question of unlimited liability, i.e. the unlimited entry of the state into such obligations, especially as all those responsible are convinced that there is practically no risk of that contingency occurring. (HSCH) [de

  3. Orosensory responsiveness and alcohol behaviour.

    Thibodeau, Margaret; Bajec, Martha; Pickering, Gary

    2017-08-01

    Consumption of alcoholic beverages is widespread through much of the world, and significantly impacts human health and well-being. We sought to determine the contribution of orosensation ('taste') to several alcohol intake measures by examining general responsiveness to taste and somatosensory stimuli in a convenience sample of 435 adults recruited from six cohorts. Each cohort was divided into quantiles based on their responsiveness to sweet, sour, bitter, salty, umami, metallic, and astringent stimuli, and the resulting quantiles pooled for analysis (Kruskal-Wallis ANOVA). Responsiveness to bitter and astringent stimuli was associated in a non-linear fashion with intake of all alcoholic beverage types, with the highest consumption observed in middle quantiles. Sourness responsiveness tended to be inversely associated with all measures of alcohol consumption. Regardless of sensation, the most responsive quantiles tended to drink less, although sweetness showed little relationship between responsiveness and intake. For wine, increased umami and metallic responsiveness tended to predict lower total consumption and frequency. A limited examination of individuals who abstain from all alcohol indicated a tendency toward higher responsiveness than alcohol consumers to sweetness, sourness, bitterness, and saltiness (biserial correlation), suggesting that broadly-tuned orosensory responsiveness may be protective against alcohol use and possibly misuse. Overall, these findings confirm the importance of orosensory responsiveness in mediating consumption of alcohol, and indicate areas for further research. Copyright © 2017. Published by Elsevier Inc.

  4. Hidden Markov Item Response Theory Models for Responses and Response Times.

    Molenaar, Dylan; Oberski, Daniel; Vermunt, Jeroen; De Boeck, Paul

    2016-01-01

    Current approaches to model responses and response times to psychometric tests solely focus on between-subject differences in speed and ability. Within subjects, speed and ability are assumed to be constants. Violations of this assumption are generally absorbed in the residual of the model. As a result, within-subject departures from the between-subject speed and ability level remain undetected. These departures may be of interest to the researcher as they reflect differences in the response processes adopted on the items of a test. In this article, we propose a dynamic approach for responses and response times based on hidden Markov modeling to account for within-subject differences in responses and response times. A simulation study is conducted to demonstrate acceptable parameter recovery and acceptable performance of various fit indices in distinguishing between different models. In addition, both a confirmatory and an exploratory application are presented to demonstrate the practical value of the modeling approach.

  5. Regulation of disease-responsive genes mediated by epigenetic factors: interaction of Arabidopsis-Pseudomonas.

    De-La-Peña, Clelia; Rangel-Cano, Alicia; Alvarez-Venegas, Raúl

    2012-05-01

    Genes in eukaryotic organisms function within the context of chromatin, and the mechanisms that modulate the structure of chromatin are defined as epigenetic. In Arabidopsis, pathogen infection induces the expression of at least one histone deacetylase, suggesting that histone acetylation/deacetylation has an important role in the pathogenic response in plants. How/whether histone methylation affects gene response to pathogen infection is unknown. To gain a better understanding of the epigenetic mechanisms regulating the interaction between Pseudomonas syringae and Arabidopsis thaliana, we analysed three different Arabidopsis ash1-related (absent, small or homeotic discs 1) mutants. We found that the loss of function of ASHH2 and ASHR1 resulted in faster hypersensitive responses (HRs) to both mutant (hrpA) and pathogenic (DC3000) strains of P. syringae, whereas control (Col-0) and ashr3 mutants appeared to be more resistant to the infection after 2 days. Furthermore, we showed that, in the ashr3 background, the PR1 gene (PATHOGENESIS-RELATED GENE 1) displayed the highest expression levels on infection with DC3000, correlating with increased resistance against this pathogen. Our results show that, in both the ashr1 and ashh2 backgrounds, the histone H3 lysine 4 dimethylation (H3K4me2) levels decreased at the promoter region of PR1 on infection with the DC3000 strain, suggesting that an epigenetically regulated PR1 expression is involved in the plant defence. Our results suggest that histone methylation in response to pathogen infection may be a critical component in the signalling and defence processes occurring between plants and microbes. © 2011 THE AUTHORS. MOLECULAR PLANT PATHOLOGY © 2011 BSPP AND BLACKWELL PUBLISHING LTD.

  6. Stress Responses in Staphylococcus aureus

    Frees, Dorte; Ingmer, Hanne

    2016-01-01

    stress responses allowing it to sense and adapt to its very different niches. The stress responses often involve dramatic cellular reprogramming, and the technological advances provided by the access to whole genome sequences have let to an unprecedented insight into the global reorganization of gene...... and protein expression following stress-exposure. Characterization of global gene responses has been very helpful both in identifying regulators sensing specific environmental stress signals and overlaps between different stress responses. In this chapter we review the recent progress in our understanding...... of the specific and general S. aureusstress responses, with a special emphasis on how stress responses contribute to virulence and antibiotic resistance in this important human pathogen....

  7. Responsible nanotechnology development

    Forloni, Gianluigi

    2012-08-01

    the nanotoxicology. The establishment of an effective strategy cannot ignore the distinction between different nanoparticles on their use and the type of exposure to which we are subjected. Categorization is essential to orchestrate toxicological rules realistic and effective. The responsible development of nanotechnology means a common effort, by scientists, producers, stakeholders, and public institutions to develop appropriate programs to systematically approach the complex issue of the nanotoxicology.

  8. Improving tumour response

    Bentzen, S.

    2003-01-01

    Radiation oncology is in the middle of the most exciting developments in its 100-year history. Progress in treatment planning and delivery, in medical imaging and in basic cancer and normal tissue biology is likely to change the indication for radiotherapy as well as the way it is prescribed and delivered. Technological and conceptual advances, in particular the development of the multi-leaf collimator and the concept of inverse treatment planning, have led to the introduction of intensity modulated radiation therapy (IMRT) with its capability to plan and deliver non-uniform dose distributions in the clinic. This has forced us to re-think radiation oncology: refining the indication for radiotherapy, optimizing the prescription of dose distributions and considering how, based on clinical evidence, radiation can best be combined with other treatment modalities, surgery, cytotoxic chemotherapy and biologically targeted therapies. The attraction of radiation therapy as an element of multi-modality cancer therapy is that it induces DNA damage that can be modulated in space and time. Progress in basic cancer biology, genomics and proteomics, as well as biological imaging provides novel avenues for individualization of cancer therapy and for biological optimization of radiotherapy. In improving cancer care, it is the therapeutic ratio, rather than tumour control per se, that must be optimised. Interestingly, the two main avenues for improving the effectiveness of radiotherapy currently being actively pursued in the clinic generally aim at different sides of the therapeutic ratio: 3D conformal radiotherapy and IMRT predominantly aim to reduce normal-tissue side effects - and by doing this, open the way for dose escalation that may lead to increased tumour control rates - whereas combined radio-chemotherapy aims to improve tumour response - while keeping the fingers crossed that this will not increase normal-tissue complications to the same extent. In parallel with these

  9. Increasing paternal responsibility.

    Cutright, P

    1985-01-01

    Increasing numbers of fathers of children born out of wedlock are not contributing to these children's economic support. In 1981, a tiny minority (14%) of the 1.7 million never-married mothers living with a child with an absent father had a child-support award, and of these, just 112,000 actually received some payment in 1981. The high rates of noncompliance, and the low level of legal efforts to enforce child support, are the result of attempts to collect payments through inefficient traditional methods, not the inability of fathers to pay, a Wisconsin study has shown. A basic problem with collecting child support under the present system is that it relies on fathers to control their expenditures and voluntarily to send the payment on a weekly, biweekly or monthly basis, year after year. As a Wisconsin study shows, full compliance with court-ordered payments dropped from 38% in the 1st year to below 20% by the 5th year among 163 ex-husbands tracked. A proposal by researchers at the University of Wisconsin's Institute for Research on Poverty calls for an "absent-parent tax." The Wisconsin Plan, as it is known, is simply a withholding tax based on the father's gross income and the number of his absent children. If his income falls below a certain level, payments will stop automatically, but will resume if and when it rises above the cutoff point. The Wisconsin plan removes all judicial discretion and lawyer's skill as factors in child-support awards, thus eliminating erratic awards. It also insures that support payments will be maintained during periods of conflict between the father and mother. However, before the Wisconsin Plan can effectively protect children both out of wedlock, a feature needs to be added that will establish paternity at birth. Imposing a real child-support obligation on fathers of children born outside of marriage will introduce a potentially powerful economic incentive for responsible male reproductive and parental behavior.

  10. Responsible nanotechnology development

    Forloni, Gianluigi

    2012-01-01

    to the nanotoxicology. The establishment of an effective strategy cannot ignore the distinction between different nanoparticles on their use and the type of exposure to which we are subjected. Categorization is essential to orchestrate toxicological rules realistic and effective. The responsible development of nanotechnology means a common effort, by scientists, producers, stakeholders, and public institutions to develop appropriate programs to systematically approach the complex issue of the nanotoxicology.

  11. Transport accident emergency response plan

    Vallette-Fontaine, M.; Frantz, P.

    1998-01-01

    To comply with the IAEA recommendations for the implementation of an Emergency Response Plan as described in Safety Series 87, Transnucleaire, a company deeply involved in the road and rail transports of the fuel cycle, masters means of Emergency Response in the event of a transport accident. This paper aims at analyzing the solutions adopted for the implementation of an Emergency Response Plan and the development of a technical support and adapted means for the recovery of heavy packagings. (authors)

  12. Property Rights, Restrictions and Responsibilities

    Enemark, Stig

    more to a social, ethical commitment or attitude to environmental sustainability and good husbandry. This paper provides an overall understanding of the concept of land administration systems for dealing with rights, restrictions and responsibilities in future spatially enabled government. Finally......Land Administration Systems are the basis for conceptualizing rights, restrictions and responsibilities related to people, policies and places. Property rights are normally concerned with ownership and tenure whereas restrictions usually control use and activities on land. Responsibilities relate...

  13. Network Culture, Performance & Corporate Responsibility

    Silvio M. Brondoni

    2003-01-01

    The growth and sustainability of free market economies highlights the need to define rules more suited to the current condition of market globalisation and also encourages firms to adopt more transparent and accountable corporate responsibility (and corporate social responsibility, namely the relationship between the company, environment and social setting). From a managerial perspective, corporate responsibility is linked to ensure the lasting pursuit of the company mission, seeking increasi...

  14. Corporate social responsibility in Ukraine

    Polyakova, E.

    2013-01-01

    In the article are considered essence of corporate social responsibility and terms necessary for realization of social activity management subjects. Hikes over are brought to realization of corporate social responsibility, meaningfulness of large and middle business is certain in becoming of social responsibility of enterprises. It is set that exactly midsize business must come forward as a main motor of economic development of Ukraine. Becoming features and modern state of corporate social r...

  15. Demand response in energy markets

    Skytte, K.; Birk Mortensen, J.

    2004-11-01

    Improving the ability of energy demand to respond to wholesale prices during critical periods of the spot market can reduce the total costs of reliably meeting demand, and the level and volatility of the prices. This fact has lead to a growing interest in the short-run demand response. There has especially been a growing interest in the electricity market where peak-load periods with high spot prices and occasional local blackouts have recently been seen. Market concentration at the supply side can result in even higher peak-load prices. Demand response by shifting demand from peak to base-load periods can counteract the market power in the peak-load. However, demand response has so far been modest since the current short-term price elasticity seems to be small. This is also the case for related markets, for example, green certificates where the demand is determined as a percentage of the power demand, or for heat and natural gas markets. This raises a number of interesting research issues: 1) Demand response in different energy markets, 2) Estimation of price elasticity and flexibility, 3) Stimulation of demand response, 4) Regulation, policy and modelling aspects, 5) Demand response and market power at the supply side, 6) Energy security of supply, 7) Demand response in forward, spot, ancillary service, balance and capacity markets, 8) Demand response in deviated markets, e.g., emission, futures, and green certificate markets, 9) Value of increased demand response, 10) Flexible households. (BA)

  16. Rights and responsibilities in Darfur

    Katherine Reyes

    2009-09-01

    Full Text Available A combined UN-military-police-humanitarian initiative hasbeen promoting civic rights and responsibilities among IDPsin order to increase security throughout Kalma camp and itssurroundings.

  17. SOCIAL RESPONSABILITY OF INSURANCE COMPANIES

    MĂRĂCINE MIHAELA SIMONA

    2013-06-01

    Full Text Available The role of corporate social responsibility has increased significantly nowadays. The studies conducted have shown that consumers are increasingly no longer interested only in buying good quality and reliable products, but they are also interested whether they were produced in a socially responsible manner. In the recent years investors have increasingly realised that investing in social responsibility regarding the social and environmental areas, greatly contributes to the growth of the internal and external image of management. This paper aims at presenting a number of interesting issues related to social responsibility manifested by the insurance companies.

  18. Emotional response towards food packaging

    Liao, Lewis Xinwei; Corsi, Armando M.; Chrysochou, Polymeros

    2015-01-01

    In this paper we investigate consumers’ emotional responses to food packaging. More specifically, we use self-report and physiological measures to jointly assess emotional responses to three typical food packaging elements: colours (lowwavelength vs. high-wavelength), images (positive vs. negative...... response that can only be measured by self-report measures. We propose that a joint application of selfreport and physiological measures can lead to richer information and wider interpretation of consumer emotional responses to food packaging elements than using either measure alone....

  19. Leadership Development: A Supervisory Responsibility

    French, David

    2000-01-01

    .... This is a recurring theme found throughout leadership literature and speeches. The US Air Force clearly establishes subordinate development as a supervisory responsibility in top-level doctrine...

  20. Response Strategies and Response Styles in Cross-Cultural Surveys

    Morren, M.H.; Gelissen, J.P.T.M.; Vermunt, J.K.

    2012-01-01

    This article addresses the following research questions: Do respondents participating in cross-cultural surveys differ in their response style when responding to attitude statements? If so, are characteristics of the response process associated with their ethnicity and generation of immigration? To

  1. Item Response Data Analysis Using Stata Item Response Theory Package

    Yang, Ji Seung; Zheng, Xiaying

    2018-01-01

    The purpose of this article is to introduce and review the capability and performance of the Stata item response theory (IRT) package that is available from Stata v.14, 2015. Using a simulated data set and a publicly available item response data set extracted from Programme of International Student Assessment, we review the IRT package from…

  2. The Value of Response Times in Item Response Modeling

    Molenaar, Dylan

    2015-01-01

    A new and very interesting approach to the analysis of responses and response times is proposed by Goldhammer (this issue). In his approach, differences in the speed-ability compromise within respondents are considered to confound the differences in ability between respondents. These confounding effects of speed on the inferences about ability can…

  3. PENGARUH PENGUNGKAPAN CORPORATE SOCIAL RESPONSIBILITY TERHADAP EARNING RESPONSE COEFFICIENT

    MI Mitha Dwi Restuti

    2012-03-01

    Full Text Available Tujuan penelitian ini adalah untuk mengetahui pengaruh negatif pengungkapan Corporate Sosial Responsibility (CSR disclosure terhadap Earning Response Coefficient (ERC. Alat analisis yang digunakan dalam penelitian ini menggunakan metode analisis regresi berganda.Sampel yang digunakan adalah sebanyak 150 perusahaan yang terdaftar pada Bursa Efek Indonesia pada tahun 2010. Berdasarkan hasil penelitian ditemukan bahwa pengungkapan Corporate Social Responsibility tidak berpengaruh terhadap Earning Response Coefficient (ERC. Hal ini dapat dikatakan bahwa investor belum memperhatikan informasi-informasi sosial yang diungkapkan dalam laporan tahunan perusahaan sebagai informasi yang dapat mempengaruhi investor dalam melakukan keputusan investasi. Investor masih mengganggap informasi laba lebih bermanfaat dalam menilai perusahaan dan dianggap lebih mampu memberikan informasi untuk mendapatkan return saham yang diharapkan oleh investor dibandingkan dengan informasi sosial yang diungkapkan oleh perusahaan.The purpose of this study is to determine the negative effect of Corporate Social Responsibility disclosure (CSR disclosure of Earnings Response Coefficient (ERC. Multiple regressions were used to analyze the data. The samples were 150 companies listed on the Indonesia Stock Exchange in 2010. Based on the research, the result was the disclosures of Corporate Social Responsibility did not influence Earning Response Coefficient (ECR. It can be said that investors did not pay attention to social information that was disclosed in the company’s annual report as information that could affect investors in making investment decisions. Investor did not consider sosial information; they only consider profit information to assess the company value and their investment return

  4. Oncogenic N-Ras Stimulates SRF-Mediated Transactivation via H3 Acetylation at Lysine 9

    Sun-Ju Yi

    2018-01-01

    Full Text Available Signal transduction pathways regulate the gene expression by altering chromatin dynamics in response to mitogens. Ras proteins are key regulators linking extracellular stimuli to a diverse range of biological responses associated with gene regulation. In mammals, the three ras genes encode four Ras protein isoforms: H-Ras, K-Ras4A, K-Ras4B, and N-Ras. Although emerging evidence suggests that Ras isoforms differentially regulate gene expressions and are functionally nonredundant, the mechanisms underlying Ras specificity and Ras signaling effects on gene expression remain unclear. Here, we show that oncogenic N-Ras acts as the most potent regulator of SRF-, NF-κB-, and AP-1-dependent transcription. N-Ras-RGL2 axis is a distinct signaling pathway for SRF target gene expression such as Egr1 and JunB, as RGL2 Ras binding domain (RBD significantly impaired oncogenic N-Ras-induced SRE activation. By monitoring the effect of Ras isoforms upon the change of global histone modifications in oncogenic Ras-overexpressed cells, we discovered that oncogenic N-Ras elevates H3K9ac/H3K23ac levels globally in the chromatin context. Importantly, chromatin immunoprecipitation (ChIP assays revealed that H3K9ac is significantly enriched at the promoter and coding regions of Egr1 and JunB. Collectively, our findings define an undocumented role of N-Ras in modulating of H3 acetylation and in gene regulation.

  5. Environmental Protection Agency Award Recipient Responsibilities

    Itemized Award Phase information. Information about the Recipient's Responsibilities Upon Notification of the Award, The EPA Project Officer Responsibilities, and EPA Grant Specialists Responsibilities.

  6. Caregiver Responsiveness to the Family Bereavement Program: What predicts responsiveness? What does responsiveness predict?

    Schoenfelder, Erin N.; Sandler, Irwin N.; Millsap, Roger E.; Wolchik, Sharlene A.; Berkel, Cady; Ayers, Timothy S.

    2013-01-01

    The study developed a multi-dimensional measure to assess participant responsiveness to a preventive intervention, and applied this measure to study how participant baseline characteristics predict responsiveness and how responsiveness predicts program outcomes. The study was conducted with caregivers who participated in the parenting-focused component of the Family Bereavement Program (FBP), a prevention program for families that have experienced parental death. The sample consisted of 89 ca...

  7. Affected pathways and transcriptional regulators in gene expression response to an ultra-marathon trail: Global and independent activity approaches.

    Maria Maqueda

    Full Text Available Gene expression (GE analyses on blood samples from marathon and half-marathon runners have reported significant impacts on the immune and inflammatory systems. An ultra-marathon trail (UMT represents a greater effort due to its more testing conditions. For the first time, we report the genome-wide GE profiling in a group of 16 runners participating in an 82 km UMT competition. We quantified their differential GE profile before and after the race using HuGene2.0st microarrays (Affymetrix Inc., California, US. The results obtained were decomposed by means of an independent component analysis (ICA targeting independent expression modes. We observed significant differences in the expression levels of 5,084 protein coding genes resulting in an overrepresentation of 14% of the human biological pathways from the Kyoto Encyclopedia of Genes and Genomes database. These were mainly clustered on terms related with protein synthesis repression, altered immune system and infectious diseases related mechanisms. In a second analysis, 27 out of the 196 transcriptional regulators (TRs included in the Open Regulatory Annotation database were overrepresented. Among these TRs, we identified transcription factors from the hypoxia-inducible factors (HIF family EPAS1 (p< 0.01 and HIF1A (p<0.001, and others jointly described in the gluconeogenesis program such as HNF4 (p< 0.001, EGR1 (p<0.001, CEBPA (p< 0.001 and a highly specific TR, YY1 (p<0.01. The five independent components, obtained from ICA, further revealed a down-regulation of 10 genes distributed in the complex I, III and V from the electron transport chain. This mitochondrial activity reduction is compatible with HIF-1 system activation. The vascular endothelial growth factor (VEGF pathway, known to be regulated by HIF, also emerged (p<0.05. Additionally, and related to the brain rewarding circuit, the endocannabinoid signalling pathway was overrepresented (p<0.05.

  8. Response moderation models for conditional dependence between response time and response accuracy.

    Bolsinova, Maria; Tijmstra, Jesper; Molenaar, Dylan

    2017-05-01

    It is becoming more feasible and common to register response times in the application of psychometric tests. Researchers thus have the opportunity to jointly model response accuracy and response time, which provides users with more relevant information. The most common choice is to use the hierarchical model (van der Linden, 2007, Psychometrika, 72, 287), which assumes conditional independence between response time and accuracy, given a person's speed and ability. However, this assumption may be violated in practice if, for example, persons vary their speed or differ in their response strategies, leading to conditional dependence between response time and accuracy and confounding measurement. We propose six nested hierarchical models for response time and accuracy that allow for conditional dependence, and discuss their relationship to existing models. Unlike existing approaches, the proposed hierarchical models allow for various forms of conditional dependence in the model and allow the effect of continuous residual response time on response accuracy to be item-specific, person-specific, or both. Estimation procedures for the models are proposed, as well as two information criteria that can be used for model selection. Parameter recovery and usefulness of the information criteria are investigated using simulation, indicating that the procedure works well and is likely to select the appropriate model. Two empirical applications are discussed to illustrate the different types of conditional dependence that may occur in practice and how these can be captured using the proposed hierarchical models. © 2016 The British Psychological Society.

  9. Gender and international crisis response

    Eklund, Lisa; Tellier, Siri

    2012-01-01

    For more than a decade the humanitarian community has been mandated to mainstream gender in its response to crises. One element of this mandate is a repeated call for sex-disaggregated data to help guide the response. This study examines available analyses, assessments and academic literature to ...

  10. Lobbying and the Responsible Firm

    Anastasiadis, Stephanos; Moon, Jeremy; Humphreys, Michael

    2018-01-01

    Responsible lobbying” is an increasingly salient topic within business and management. We make a contribution to the literature on “responsible lobbying” in three ways. First, we provide novel definitions and, thereby, make a clear distinction between lobbying and corporate political activity. W...

  11. RESULTS, RESPONSIBILITY, FAULT AND CONTROL

    Evgeniy Stoyanov

    2016-09-01

    Full Text Available The paper focuses on the responsibility arising from the registered financial results. The analysis of this responsibility presupposes its evaluation and determination of the role of fault in the formation of negative results. The search for efficiency in this whole process is justified by the understanding of the mechanisms that regulate the behavior of economic actors.

  12. Modelling sequentially scored item responses

    Akkermans, W.

    2000-01-01

    The sequential model can be used to describe the variable resulting from a sequential scoring process. In this paper two more item response models are investigated with respect to their suitability for sequential scoring: the partial credit model and the graded response model. The investigation is

  13. Stationary and Transient Response Statistics

    Madsen, Peter Hauge; Krenk, Steen

    1982-01-01

    The covariance functions for the transient response of a linear MDOF-system due to stationary time limited excitation with an arbitrary frequency content are related directly to the covariance functions of the stationary response. For rational spectral density functions closed form expressions fo...

  14. Stimuli-Responsive Polymeric Nanoparticles.

    Liu, Xiaolin; Yang, Ying; Urban, Marek W

    2017-07-01

    There is increasing evidence that stimuli-responsive nanomaterials have become significantly critical components of modern materials design and technological developments. Recent advances in synthesis and fabrication of stimuli-responsive polymeric nanoparticles with built-in stimuli-responsive components (Part A) and surface modifications of functional nanoparticles that facilitate responsiveness (Part B) are outlined here. The synthesis and construction of stimuli-responsive spherical, core-shell, concentric, hollow, Janus, gibbous/inverse gibbous, and cocklebur morphologies are discussed in Part A, with the focus on shape, color, or size changes resulting from external stimuli. Although inorganic/metallic nanoparticles exhibit many useful properties, including thermal or electrical conductivity, catalytic activity, or magnetic properties, their assemblies and formation of higher order constructs are often enhanced by surface modifications. Section B focuses on selected surface reactions that lead to responsiveness achieved by decorating nanoparticles with stimuli-responsive polymers. Although grafting-to and grafting-from dominate these synthetic efforts, there are opportunities for developing novel synthetic approaches facilitating controllable recognition, signaling, or sequential responses. Many nanotechnologies utilize a combination of organic and inorganic phases to produce ceramic or metallic nanoparticles. One can envision the development of new properties by combining inorganic (metals, metal oxides) and organic (polymer) phases into one nanoparticle designated as "ceramers" (inorganics) and "metamers" (metallic). © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Bringing Professional Responsibility Back in

    Solbrekke, Tone Dyrdal; Englund, Tomas

    2011-01-01

    Research on how higher education institutions work with professional formation indicates that insufficient attention is currently paid to issues of professional responsibility and ethics. In the light of such findings, there is increasing concern about issues related to learning professional responsibility. This article concentrates on different…

  16. Randomized Item Response Theory Models

    Fox, Gerardus J.A.

    2005-01-01

    The randomized response (RR) technique is often used to obtain answers on sensitive questions. A new method is developed to measure latent variables using the RR technique because direct questioning leads to biased results. Within the RR technique is the probability of the true response modeled by

  17. Psychophysiological responses to Salsa dance.

    Laura Guidetti

    Full Text Available Speculation exists whether dance provides physiological stimuli adequate to promote health and fitness benefits. Unfortunately, research to date has not addressed the affective and exertional responses to dance. These responses are of interest as positive affective and exertional responses experienced during physical activity may play an important role in predicting adherence. The present study aims to examine the psychophysiological responses of different Salsa dance styles. Ten pairs of dancers performed two different structured lessons of Salsa dance, including Typical Salsa and Rueda de Casino lessons, and a non-structured Salsa dance at a night club. Physiological responses (i.e., percent of heart rate reserve; %HRR were continuously assessed and perceived exertion and affective valence were rated every 15 min throughout the trials. %HRR responses differed between the Salsa dance styles (%HRR from 41.3 to 51.9%, and participants were dancing at intensities near their ventilatory threshold. Specifically, Typical Salsa lesson elicited lower %HRR responses than Rueda de Casino lesson (p 0.05. Surprisingly, exertional (from 8 to 11 and affective (from +3 to +5 responses were unaffected by Salsa dance styles (p > 0.05. These data support that different Salsa dance styles provide physiological stimuli adequate to promote health and fitness benefits, and perhaps more importantly, produce pleasurable experiences, which in turn might lead to an increase in adherence to Salsa dancing which likely provides exercise-like health benefits.

  18. Responsibility is More than Accountability

    Vetterlein, Antje

    2018-01-01

    This paper critically assesses the notion of responsibility and argues that by adopting a broader understanding as going beyond accountability will shift our focus from regulatory to negotiated governance. Negotiated governance emphasizes the origin of rules and regulations and their contestation...... over the focus on compliance and enforcement. In order to elaborate this argument, I use the case of corporate social responsibility (CSR). The paper takes departure in the governance literature. Reviewing that scholarship, I develop a typology of responsibility to first substantiate the paper's claim...... that responsibility is more than accountability. In a second step, I derive a taxonomy of CSR practices that are loosely associated with different meanings of responsibility. The taxonomy highlights two specific problems that the literature focusing on accountability leaves unanswered, these are the moral...

  19. Who is More Responsible? Preparatory Class Students’ Perceptions of Responsibility

    Cesur, Kürşat; Ertaş, Abdullah

    2014-01-01

     The main aim of this study is to explore learners’ perceptions of their own responsibility in learning English. The question of whether our learners in Canakkale Onsekiz Mart University (hereafter COMU) Compulsory and Voluntary English Language Prep Classes are responsible enough for their own learning or not is the main focus of this study. Whether some variables like gender, the type of the prep class education (compulsory or voluntary) and the students’ departments will affect their perce...

  20. Seismic response of structures by the response spectrum method

    Hadjian, A.H.

    1981-01-01

    The problems of the acceleration profile at the lower elevations of cantilever structures and the response of relatively rigid structures are explored. It is shown that the use of the conventional methods for the above problems provide very approximate results. An alternate combination of the modal responses is proposed that not only resolves the above problems but also provides better estimates of response for the complete range of structure frequencies. The procedure treats the relative and rigid body responses separately and then appropriately combines the two results. For the rigid range of frequencies (fundamental frequencies greater than about 2 Hz), the proposed procedure does not encounter any numerical difficulties because of the additive nature of the component responses; however, the application of the proposed procedure for very flexible structures causes accuracy problems since the rigid body effects tend to be subtractive from the flexural response of about equal magnitude. For this latter class of problems, the conventional approach of modal combination provides adequate results and avoids the above mentioned numerical difficulties. (orig.)

  1. Responsive self-preservation: Towards an anthropological concept of responsiveness

    Kasper Lysemose

    2013-12-01

    Full Text Available The aim of this paper is to catch up with a conjecture designated by the term ‘responsive self-preservation’. This term appears neither strikingly beautiful nor intuitively understandable. Obviously it is a convoluted terminus technicus in need of conceptual clarification. The reasons for introducing it should therefore be good. That this is the case cannot be guaranteed from the outset. What can be offered here is a substitution of good reasons with high ambitions: the concept of ‘responsive self-preservation’ is designed to illuminate the conditio humana. In all brevity the claim is that human beings are responsive beings. This means that they do not just exist. In order to do so, they must respond to their existence. On the one hand the inner drive and utmost aspiration in human responsiveness therefore lies in self-preservation. On the other hand self-preservation is thoroughly transformed when embedded into human responsiveness. The article will thus use the concept of responsiveness and the concept of self-preservation to mutually clarify each other – in order to open the possibilities and avoid the pitfalls in each of them. In doing so, it aspires to intervene in contemporary philosophical anthropology.

  2. Potential for all-trans retinoic acid (tretinoin) to enhance interferon-alpha treatment response in chronic myelogenous leukemia, melanoma, myeloma and renal cell carcinoma.

    Kast, Richard E

    2008-10-01

    This note mechanistically accounts for recent unexplained findings that all-trans retinoic acid (ATRA, also termed tretinoin) exerts an anti-viral effect against hepatitis C virus (HCV) in chronically infected patients, in whom ATRA also showed synergy with interferon-alpha. How HCV replication was suppressed was unclear. Both effects of ATRA can be accounted for by ATRA's upregulation of RIG protein, an 18 kDa product of retinoic induced gene-1. Increased RIG then couples ATRA to increased Type 1 interferons' production. Details of this mechanism predict that ATRA will similarly augment interferon-a activity in treating chronic myelogenous leukemia, melanoma, myeloma and renal cell carcinoma and that the addition of ribavirin and/or bexarotene will each incrementally enhance interferon-a responses in these cancers.

  3. Aberrant methylation patterns affect the molecular pathogenesis of rheumatoid arthritis.

    Lin, Yang; Luo, Zhengqiang

    2017-05-01

    This study aims to investigate DNA methylation signatures in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA), and to explore the relationship with transcription factors (TFs) that help to distinguish RA from osteoarthritis (OA). Microarray dataset of GSE46346, including six FLS samples from patients with RA and five FLS samples from patients with OA, was downloaded from the Gene Expression Omnibus database. RA and OA samples were screened for differentially methylated loci (DMLs). The corresponding differentially methylated genes (DMGs) were identified, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analysis. A transcriptional regulatory network was built with TFs and their corresponding DMGs. Overall, 280 hypomethylated loci and 561 hypermethylated loci were screened. Genes containing hypermethylated loci were enriched in pathways in cancer, ECM-receptor interaction, focal adhesion and neurotrophin signaling pathways. Genes containing hypomethylated loci were enriched in the neurotrophin signaling pathway. Moreover, we found that CCCTC-binding factor (CTCF), Yin Yang 1 (YY1), v-myc avian myelocytomatosis viral oncogene homolog (c-MYC), and early growth response 1 (EGR1) were important TFs in the transcriptional regulatory network. Therefore, DMGs might participate in the neurotrophin signaling pathway, pathways in cancer, ECM-receptor interaction and focal adhesion pathways in RA. Furthermore, CTCF, c-MYC, YY1, and EGR1 may play important roles in RA through regulating DMGs. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Maternal Pre-Gravid Obesity Changes Gene Expression Profiles Towards Greater Inflammation and Reduced Insulin Sensitivity in Umbilical Cord

    Thakali, Keshari M.; Saben, Jessica; Faske, Jennifer B.; Lindsey, Forrest; Gomez-Acevedo, Horacio; Lowery, Curtis L.; Badger, Thomas M.; Andres, Aline; Shankar, Kartik

    2014-01-01

    Background Maternal obesity is associated with unfavorable outcomes, which may be reflected in the as yet undiscovered gene expression profiles of the umbilical cord (UC). Methods UCs from 12 lean (pre-gravid BMI obese (OW/OB, pre-gravid BMI ≥25) women without gestational diabetes were collected for gene expression analysis using Human Primeview microarrays (Affymetrix). Metabolic parameters were assayed in mother’s plasma and cord blood. Results Although offspring birth weight and adiposity (at 2-wk) did not differ between groups, expression of 232 transcripts was affected in UC from OW/OB compared to those of lean mothers. GSEA analysis revealed an up-regulation of genes related to metabolism, stimulus and defense response and inhibitory to insulin signaling in the OW/OB group. We confirmed that EGR1, periostin, and FOSB mRNA expression was induced in UCs from OW/OB moms, while endothelin receptor B, KFL10, PEG3 and EGLN3 expression was decreased. Messenger RNA expression of EGR1, FOSB, MEST and SOCS1 were positively correlated (pmaternal obesity and changes in UC gene expression profiles favoring inflammation and insulin resistance, potentially predisposing infants to develop metabolic dysfunction later on in life. PMID:24819376

  5. A role for nitric oxide-driven retrograde signaling in the consolidation of a fear memory

    Kathie A Overeem

    2010-02-01

    Full Text Available In both invertebrate and vertebrate models of synaptic plasticity, signaling via the putative “retrograde messenger” nitric oxide (NO has been hypothesized to serve as a critical link between functional and structural alterations at pre- and postsynaptic sites. However, while in vitro models of synaptic plasticity have consistently implicated NO signaling in linking postsynaptic induction mechanisms with accompanying presynaptic changes, a convincing role of such “retrograde signaling” in mammalian memory formation has remained elusive. Using auditory Pavlovian fear conditioning, we show that synaptic plasticity and NO signaling in the lateral nucleus of the amygdala (LA regulate the expression of the ERK-driven immediate early gene early growth response gene I (EGR-1 in regions of the auditory thalamus that are presynaptic to the LA. Further, antisense knockdown of EGR-1 in the auditory thalamus impairs both fear memory consolidation and the training-induced elevation of two presynaptically localized proteins in the LA. These findings indicate that synaptic plasticity and NO signaling in the LA during auditory fear conditioning promote alterations in ERK-driven gene expression in auditory thalamic neurons that are required for both fear memory consolidation as well as presynaptic correlates of fear memory formation in the LA, and provide general support for a role of NO as a “retrograde signal” in mammalian memory formation.

  6. Mapping "Social Responsibility" in Science

    Horst, Maja; Glerup, Cecilie

    The paper investigates the discourse on social responsibility in science as it appears in academic journals. Through database searches a collection of more than 300 papers have been analysed in order to map their answers to the following three questions: - What is the central problem that threatens...... responsibility in science? - What are the central aspects of science or its relation to society that need to be regulated or changed? - What kinds of solutions are imagined and how are these solutions supposed to be put into place? On this basis the paper explores how different interpretations of the notion...... of social responsibility of science imply different forms of governance of and within science. The paper employs a Foucaldian discourse analysis to understand how a particular conceptualisation of responsibility implies a political rationality, i.e. a particular form of governance of science. The analysis...

  7. Water Soluble Responsive Polymer Brushes

    Andrew J. Parnell

    2011-12-01

    Full Text Available Responsive polymer brushes possess many interesting properties that enable them to control a range of important interfacial behaviours, including adhesion, wettability, surface adsorption, friction, flow and motility. The ability to design a macromolecular response to a wide variety of external stimuli makes polymer brushes an exciting class of functional materials, and has been made possible by advances in modern controlled polymerization techniques. In this review we discuss the physics of polymer brush response along with a summary of the techniques used in their synthesis. We then review the various stimuli that can be used to switch brush conformation; temperature, solvent quality, pH and ionic strength as well as the relatively new area of electric field actuation We discuss examples of devices that utilise brush conformational change, before highlighting other potential applications of responsive brushes in real world devices.

  8. Emotional response to musical repetition.

    Livingstone, Steven R; Palmer, Caroline; Schubert, Emery

    2012-06-01

    Two experiments examined the effects of repetition on listeners' emotional response to music. Listeners heard recordings of orchestral music that contained a large section repeated twice. The music had a symmetric phrase structure (same-length phrases) in Experiment 1 and an asymmetric phrase structure (different-length phrases) in Experiment 2, hypothesized to alter the predictability of sensitivity to musical repetition. Continuous measures of arousal and valence were compared across music that contained identical repetition, variation (related), or contrasting (unrelated) structure. Listeners' emotional arousal ratings differed most for contrasting music, moderately for variations, and least for repeating musical segments. A computational model for the detection of repeated musical segments was applied to the listeners' emotional responses. The model detected the locations of phrase boundaries from the emotional responses better than from performed tempo or physical intensity in both experiments. These findings indicate the importance of repetition in listeners' emotional response to music and in the perceptual segmentation of musical structure.

  9. Immediate response to cigarette smoke

    Rees, P.J.; Chowienczyk, P.J.; Clark, T.J.

    1982-06-01

    Using an automated method of calculating airways resistance in the body plethysmograph, we have investigated changes occurring immediately after inhalation of cigarette smoke. Decreases in specific conductance occurred by the time of the first measurement seven or eight seconds after exposure to single inhalations of cigarette smoke in 12 smokers and 12 non-smokers. Less than half of the initial change was present 40 seconds after the inhalation. Initial responses were greater in the non-smokers. Responses recurred with repeated inhalations in smokers and non-smokers. Prior administration of salbutamol and ipratropium bromide significantly inhibited the response and this inhibition appeared to be greater in non-smokers. Sodium cromoglycate inhaled as a dry powder had no effect on the response.

  10. Social responsibility in nursing education.

    Mayo, K

    1996-03-01

    Nurses will be key participants in health care reform as health care shifts from a hospital-based disease orientation to a community-centered health promotion focus. Nursing in communities, the environmental context of clients' everyday lives, requires attention to social, economic, and political circumstances that influence health status and access to health care. Therefore, nursing educators have the responsibility to prepare future nurses for community-based practice by instilling moral and professional practice obligations, cultural sensitivity, and other facets of social responsibility. In this article, social responsibility and journaling, a teaching/learning strategy suggested by the new paradigm approach of the curriculum revolution, are explored. A qualitative research study of more than 100 nursing student journal entries illustrates the concept of social responsibility and how it developed in a group of baccalaureate nursing students during a clinical practicum in a large urban homeless shelter.

  11. Immune response to H pylori

    Suarez, Giovanni; Reyes, Victor E; Beswick, Ellen J

    2006-01-01

    The gastric mucosa separates the underlying tissue from the vast array of antigens that traffic through the stomach lumen. While the extreme pH of this environment is essential in aiding the activation of enzymes and food digestion, it also renders the gastric epithelium free from bacterial colonization, with the exception of one important human pathogen, H pylori. This bacterium has developed mechanisms to survive the harsh environment of the stomach, actively move through the mucosal layer, attach to the epithelium, evade immune responses, and achieve persistent colonization. While a hallmark of this infection is a marked inflammatory response with the infiltration of various immune cells into the infected gastric mucosa, the host immune response is unable to clear the infection and may actually contribute to the associated pathogenesis. Here, we review the host responses involved during infection with H pylori and how they are influenced by this bacterium. PMID:17007009

  12. DRIVING CORPORATE SOCIAL RESPONSIBILITY (CSR ...

    henk

    express reference is made to companies' social responsibility (which is commonly referred to as CSR),4 ...... deceptive representations. S 22 of the Act ... South Africa, which requires transparent and effective communication with stakeholders ...

  13. Why Pandemic Response is Unique

    Bækkeskov, Erik; Rubin, Olivier

    2014-01-01

    , the case studies of media coverage in the USA and Denmark demonstrate that the response was bureaucratized in the public health agencies (CDC and DMHA, respectively). Hence, while natural disaster responses appear to follow a political logic, the response to pandemics appears to be more strongly instituted......Purpose – The purpose of this paper is to show that 2009 H1N1 “swine” influenza pandemic vaccination policies deviated from predictions established in the theory of political survival, and to propose that pandemic response deviated because it was ruled by bureaucratized experts rather than...... by elected politicians. Design/methodology/approach – Focussing on the 2009 H1N1 pandemic, the paper employs descriptive statistical analysis of vaccination policies in nine western democracies. To probe the plausibility of the novel explanation, it uses quantitative and qualitative content analyses of media...

  14. Venezuelan equine encephalitis virus infection causes modulation of inflammatory and immune response genes in mouse brain

    Puri Raj K

    2008-06-01

    Full Text Available Abstract Background Neurovirulent Venezuelan equine encephalitis virus (VEEV causes lethal encephalitis in equines and is transmitted to humans by mosquitoes. VEEV is highly infectious when transmitted by aerosol and has been developed as a bio-warfare agent, making it an important pathogen to study from a military and civilian standpoint. Molecular mechanisms of VEE pathogenesis are poorly understood. To study these, the gene expression profile of VEEV infected mouse brains was investigated. Changes in gene expression were correlated with histological changes in the brain. In addition, a molecular framework of changes in gene expression associated with progression of the disease was studied. Results Our results demonstrate that genes related to important immune pathways such as antigen presentation, inflammation, apoptosis and response to virus (Cxcl10, CxCl11, Ccl5, Ifr7, Ifi27 Oas1b, Fcerg1,Mif, Clusterin and MHC class II were upregulated as a result of virus infection. The number of over-expressed genes (>1.5-fold level increased as the disease progressed (from 197, 296, 400, to 1086 at 24, 48, 72 and 96 hours post infection, respectively. Conclusion Identification of differentially expressed genes in brain will help in the understanding of VEEV-induced pathogenesis and selection of biomarkers for diagnosis and targeted therapy of VEEV-induced neurodegeneration.

  15. Procedure for determining the SSE response from the OBE response

    Curreri, J.

    1985-01-01

    Regulatory Guide 1.61 specifies the damping that should be used for all modes that are considered in an elastic spectral or time history dynamic seismic analysis of Seismic Category I components. Table 1 of R.G 1.61 specifies damping values for dynamic analysis for two different earthquakes, the Safe Shutdown Earthquake and the Operating Basis Earthquake. The guide specifies that ''...if the maximum stresses due to static, seismic and other dynamic loading are significantly lower than the yield stresses and 1/2 yield stress for SSE and 1/2 SSE respectively, in any structure a component damping values lower than those specified in Table 1 ....should be used .... to avoid underestimating the amplitude of vibration of dynamic stress.'' The guide requires that the appropiate damping values be used which reflect the state of stress that will be experienced by the equipment. In applying these values to the response of equipment, to an OBE and to an SSE, the selected damping should result in a dynamic response for the SSE that is greater than the response due to the OBE, all other factors being equal. The purpose of the statement in the guide is to note that at higher stress levels, the higher damping values could be used, but at lower stress levels, the lower values of damping should be used. Current procedures that are used in implementing R.G. 1.61 frequently result in an OBE response that is greater than the SSE response. This is because the higher damping under the SSE is used at all stress levels, low as well as high. This is obviously not the intent of the Regulatory Guide. A procedure has been developed which derives an expression relating the SSE response to the OBE response. Two factors are involved in the equation. The first involves the damping ratios for the SSE and OBE events and the second is the ratio between the levels of the OBE and SSE

  16. The Brazilian emergency response system

    Santos, Raul dos

    1997-01-01

    With the objective of improving the response actions to potential or real emergency situations generated by radiological or nuclear accidents, the Brazilian National Nuclear Energy Commission (CNEN) installed an integrated response system on a 24 hours basis. All the natiowide notifications on events that may start an emergency situation are converged to this system. Established since July 1990, this system has received around 300 notifications in which 5% were classified as potential emergency situation. (author)

  17. Distributed Dynamic Condition Response Structures

    Hildebrandt, Thomas; Mukkamala, Raghava Rao

    We present distributed dynamic condition response structures as a declarative process model inspired by the workflow language employed by our industrial partner and conservatively generalizing labelled event structures. The model adds to event structures the possibility to 1) finitely specify...... as a labelled transition system. Exploration of the relationship between dynamic condition response structures and traditional models for concurrency, application to more complex scenarios, and further extensions of the model is left to future work....

  18. The Diffraction Response Interpolation Method

    Jespersen, Søren Kragh; Wilhjelm, Jens Erik; Pedersen, Peder C.

    1998-01-01

    Computer modeling of the output voltage in a pulse-echo system is computationally very demanding, particularly whenconsidering reflector surfaces of arbitrary geometry. A new, efficient computational tool, the diffraction response interpolationmethod (DRIM), for modeling of reflectors in a fluid...... medium, is presented. The DRIM is based on the velocity potential impulseresponse method, adapted to pulse-echo applications by the use of acoustical reciprocity. Specifically, the DRIM operates bydividing the reflector surface into planar elements, finding the diffraction response at the corners...

  19. Emotion, motivation, and cardiovascular response

    Kreibig Sylvia D

    2012-01-01

    Cardiovascular (CV) response consists of changes in CV parameters such as heart rate blood pressure and heart contraction force in reaction to an event or set of events. It is significant for multiple reasons perhaps most notably because research suggests that it affects the development and progression of heart disease. Disease models vary but most assume that characteristically strong and prolonged CV responses confer health risk. Psychologists have long suspected linkages between motivation...

  20. Evaluation of concurrent peak responses

    Wang, P.C.; Curreri, J.; Reich, M.

    1983-01-01

    This report deals with the problem of combining two or more concurrent responses which are induced by dynamic loads acting on nuclear power plant structures. Specifically, the acceptability of using the square root of the sum of the squares (SRSS) value of peak values as the combined response is investigated. Emphasis is placed on the establishment of a simplified criterion that is convenient and relatively easy to use by design engineers

  1. Complex responses to alkylating agents

    Samson, L.D.

    2003-01-01

    Using Affymetrix oligonucleotide GeneChip analysis, we previously found that, upon exposure to the simple alkylating agent methylmethane sulfonate, the transcript levels for about one third of the Saccharomyces cerevisiae genome (∼2,000 transcripts) are induced or repressed during the first hour or two after exposure. In order to determine whether the responsiveness of these genes has any relevance to the protection of cells against alkylating agents we have undertaken several follow-up studies. First, we explored the specificity of this global transcriptional response to MMS by measuring the global response of S. cerevisiae to a broad range of agents that are known to induce DNA damage. We found that each agent produced a very different mRNA transcript profile, even though the exposure doses produced similar levels of toxicity. We also found that the selection of genes that respond to MMS is highly dependent upon what cell cycle phase the cells are in at the time of exposure. Computational clustering analysis of the dataset derived from a large number of exposures identified several promoter motifs that are likely to control some of the regulons that comprise this large set of genes that are responsive to DNA damaging agents. However, it should be noted that these agents damage cellular components other than DNA, and that the responsiveness of each gene need not be in response to DNA damage per se. We have also begun to study the response of other organisms to alkylating agents, and these include E. coli, cultured mouse and human cells, and mice. Finally, we have developed a high throughput phenotypic screening method to interrogate the role of all non-essential S. cerevisiae genes (about 4,800) in protecting S. cerevisiae against the deleterious effects of alkylating agents; we have termed this analysis 'genomic phenotyping'. This study has uncovered a plethora of new pathways that play a role in the recovery of eukaryotic cells after exposure to toxic

  2. Response

    CERN. Geneva

    2015-01-01

    ALICE is the LHC experiment dedicated to the study of Heavy Ion collisions. In particular, the detector features low momentum tracking and vertexing, and comprehensive particle identification capabilities. In a single central heavy ion collision at the LHC, thousands of particles per unit rapidity are produced, making the data volume, track reconstruction and search of rare signals particularly challenging. Data science and machine learning techniques could help to tackle some of the challenges outlined above. In this talk, we will discuss some early attempts to use these techniques for the processing of detector signals and for the physics analysis. We will also highlight the most promising areas for the application of these methods.

  3. Response

    CERN. Geneva

    2015-01-01

    Neuromorphic silicon chips have been developed over the last 30 years, inspired by the design of biological nervous systems and offering an alternative paradigm for computation, with real-time massively parallel operation and potentially large power savings with respect to conventional computing architectures. I will present the general principles with a brief investigation of the design choices that have been explored, and I'll discuss how such hardware has been applied to problems such as classification.

  4. Response

    CERN. Geneva

    2015-01-01

    Starting from a brief historical perspective on scientific discovery, this talk will review some of the theory and open problems of deep learning and describe how to design efficient feedforward and recursive deep learning architectures for applications in the natural sciences. In particular, the focus will be on multiple particle problems at different scales: in biology (e.g. prediction of protein structures), chemistry (e.g. prediction of molecular properties and reactions), and high-energy physics (e.g. detection of exotic particles, jet substructure and tagging, "dark matter and dark knowledge")

  5. Response

    Hartman, Nancy C.

    1974-01-01

    Suggests more stringent use of task analysis in identifying and teaching reading subskills and the use of reinforcement contingencies which make it worthwhile for the child to tolerate frustration when teaching remedial reading to children with low frustration tolerance levels. (TO)

  6. Response

    CERN. Geneva

    2015-01-01

    Stochastic optimization, among which bio-inspired algorithms, is gaining momentum in areas where more classical optimization algorithms fail to deliver satisfactory results, or simply cannot be directly applied. This presentation will introduce baseline stochastic optimization algorithms, and illustrate their efficiency in different domains, from continuous non-convex problems to combinatorial optimization problem, to problems for which a non-parametric formulation can help exploring unforeseen possible solution spaces.

  7. Response spectra in alluvial soils

    Chandrasekharan, A.R.; Paul, D.K.

    1975-01-01

    For aseismic design of structures, the ground motion data is assumed either in the form of ground acceleration as a function of time or indirectly in the form of response spectra. Though the response spectra approach has limitations like not being applicable for nonlinear problems, it is usually used for structures like nuclear power plants. Fifty accelerograms recorded at alluvial sites have been processed. Since different empirical formulas relating acceleration with magnitude and distance give a wide scatter of values, peak ground acceleration alone cannot be the parameter as is assumed by a number of authors. The spectra corresponding to 5% damping have been normalised with respect to three parameters, namely, peak ground acceleration, peak ground velocity and a nondimensional quantity ad/v 2 . Envelopee of maxima and minima as well as average response spectra has been obtained. A comparison with the USAEC spectra has been made. A relation between ground acceleration, ground velocity and ad/v 2 has been obtained which would nearly give the same magnification of the response. A design response spectra for alluvial soils has been recommended. (author)

  8. Heart rate response to breathing

    Mehlsen, J; Pagh, K; Nielsen, J S

    1987-01-01

    Heart rate responses to stepwise and periodic changes in lung volume were studied in seven young healthy males. Stepwise inspiration and expiration both resulted in an increase in heart rate followed by a rapid decrease in heart rate. The fastest heart rate was reached in 1.6 +/- 0.5 s and in 3.......6 +/- 1.4 s in response to inspiration and expiration, respectively (P less than 0.01). The slowest heart rate was reached in 4.8 +/- 1.0 s and in 7.6 +/- 1.9 s in response to inspiration and expiration, respectively (P less than 0.01). Following this biphasic change the heart rate returned to a steady...... level. The difference between the fastest and the slowest heart rates was significantly larger in response to inspiration (21.7 +/- 7.3 beats per minute) than in response to expiration (12.0 +/- 7.3 beats per minute; P less than 0.01). Periodic changes in lung volume were performed with frequencies from...

  9. Methodology for combining dynamic responses

    Cudlin, R.; Hosford, S.; Mattu, R.; Wichman, K.

    1978-09-01

    The NRC has historically required that the structural/mechanical responses due to various accident loads and loads caused by natural phenomena, (such as earthquakes) be combined when analyzing structures, systems, and components important to safety. Several approaches to account for the potential interaction of loads resulting from accidents and natural phenomena have been used. One approach, the so-called absolute or linear summation (ABS) method, linearly adds the peak structural responses due to the individual dynamic loads. In general, the ABS method has also reflected the staff's conservative preference for the combination of dynamic load responses. A second approach, referred to as SRSS, yields a combined response equal to the square root of the sum of the squares of the peak responses due to the individual dynamic loads. The lack of a physical relationship between some of the loads has raised questions as to the proper methodology to be used in the design of nuclear power plants. An NRR Working Group was constituted to examine load combination methodologies and to develop a recommendation concerning criteria or conditions for their application. Evaluations of and recommendations on the use of the ABS and SRSS methods are provided in the report

  10. Characterization of human dopamine responsive protein DRG-1 that binds to p75NTR-associated cell death executor NADE.

    Yu, Yao; Wang, Jiadong; Yuan, Hanying; Qin, Feng; Wang, Jing; Zhang, Nailing; Li, Yu-Yang; Liu, Jianping; Lu, Hong

    2006-07-19

    Expression of human dopamine responsive gene-1 (DRG-1) is up-regulated in response to treatment of dopamine in the rat astrocytes. However, its functions are not clear up to now. In the presented studies, DRG-1 was identified to be a conserved gene in the vertebrate and expressed abundantly in human testis, brain and skeletal muscle. DRG-1 was shown to interact with human p75NTR-associated cell death executor (NADE) in vivo and in vitro, and the interaction occurred in cytoplasm. The regions required for the interaction were subsequently mapped to the N-terminal of DRG-1 and the C-terminal of NADE. Furthermore, MTT assay showed that stable expression of DRG-1 in 293 cells could promote cell proliferation, and this promotion was suppressed by overexpression of NADE. In flow cytometry cell cycle analysis, overexpression of DRG-1 in 293 or PC12 cells increased the population of cells in the S phase with a concomitant decrease in G0/G1 population. These findings suggest that DRG-1 may contribute to the dopamine-induced cell growth, which is negatively regulated by NADE.

  11. Response problems in a vacation panel study

    Christine A. Vogt; Susan I. Stewart

    2001-01-01

    This paper investigates response problems encountered in a panel study of travel behavior. Though the overall response rate to the three-wave panel study was acceptable (over 60%), three types of response problems were encountered: refusal, non-response, and attrition. In a follow-up phone survey, a sample of individuals from each problem response group was questioned...

  12. Corporate Social Responsibility in Aviation

    Phillips, Edwin D.

    2006-01-01

    The dialog within aviation management education regarding ethics is incomplete without a discussion of corporate social responsibility (CSR). CSR research requires discussion involving: (a) the current emphasis on CSR in business in general and aviation specifically; (b) business and educational theory that provide a basis for aviation companies to engage in socially responsible actions; (c) techniques used by aviation and aerospace companies to fulfill this responsibility; and (d) a glimpse of teaching approaches used in university aviation management classes. The summary of this research suggests educators explain CSR theory and practice to students in industry and collegiate aviation management programs. Doing so extends the discussion of ethical behavior and matches the current high level of interest and activity within the aviation industry toward CSR.

  13. Abscisic Acid Synthesis and Response

    Finkelstein, Ruth

    2013-01-01

    Abscisic acid (ABA) is one of the “classical” plant hormones, i.e. discovered at least 50 years ago, that regulates many aspects of plant growth and development. This chapter reviews our current understanding of ABA synthesis, metabolism, transport, and signal transduction, emphasizing knowledge gained from studies of Arabidopsis. A combination of genetic, molecular and biochemical studies has identified nearly all of the enzymes involved in ABA metabolism, almost 200 loci regulating ABA response, and thousands of genes regulated by ABA in various contexts. Some of these regulators are implicated in cross-talk with other developmental, environmental or hormonal signals. Specific details of the ABA signaling mechanisms vary among tissues or developmental stages; these are discussed in the context of ABA effects on seed maturation, germination, seedling growth, vegetative stress responses, stomatal regulation, pathogen response, flowering, and senescence. PMID:24273463

  14. Towards accurate emergency response behavior

    Sargent, T.O.

    1981-01-01

    Nuclear reactor operator emergency response behavior has persisted as a training problem through lack of information. The industry needs an accurate definition of operator behavior in adverse stress conditions, and training methods which will produce the desired behavior. Newly assembled information from fifty years of research into human behavior in both high and low stress provides a more accurate definition of appropriate operator response, and supports training methods which will produce the needed control room behavior. The research indicates that operator response in emergencies is divided into two modes, conditioned behavior and knowledge based behavior. Methods which assure accurate conditioned behavior, and provide for the recovery of knowledge based behavior, are described in detail

  15. Children's psychological responses to hospitalization.

    Vessey, Judith A

    2003-01-01

    The data-based literature addressing children's psychological responses to hospitalization was reviewed using methods outlined by Cooper (1989). Using a developmental science perspective, early research was reviewed and a model of variables that contribute to children's responses was constructed. This model consists of three major foci, including maturational and cognitive variables (developmental level, experience, coping style), ecological variables (family and hospital milieu), and biological variables (inborn factors and pathophysiology). Coping serves as the overarching framework for examining these variables and their contributions to children's responses to hospitalization. A variety of theoretical perspectives from the social sciences have been used, with psychoanalytic and stress and adaptation theories predominating. The majority of the research used simple case study, descriptive, or pre- and post-test designs. Methodologic issues were common. Little qualitative work has been done. Future research directions call for studies to adopt new theoretical and empirical models that are methodologically rigorous and clinically relevant and that embrace the precepts of developmental science.

  16. Abiotic stressors and stress responses

    Sulmon, Cecile; Van Baaren, Joan; Cabello-Hurtado, Francisco

    2015-01-01

    Abstract Organisms are regularly subjected to abiotic stressors related to increasing anthropogenic activities, including chemicals and climatic changes that induce major stresses. Based on various key taxa involved in ecosystem functioning (photosynthetic microorganisms, plants, invertebrates), we...... review how organisms respond and adapt to chemical- and temperature-induced stresses from molecular to population level. Using field-realistic studies, our integrative analysis aims to compare i) how molecular and physiological mechanisms related to protection, repair and energy allocation can impact...... life history traits of stressed organisms, and ii) to what extent trait responses influence individual and population responses. Common response mechanisms are evident at molecular and cellular scales but become rather difficult to define at higher levels due to evolutionary distance and environmental...

  17. Plant Responses to Nanoparticle Stress

    Zahed Hossain

    2015-11-01

    Full Text Available With the rapid advancement in nanotechnology, release of nanoscale materials into the environment is inevitable. Such contamination may negatively influence the functioning of the ecosystems. Many manufactured nanoparticles (NPs contain heavy metals, which can cause soil and water contamination. Proteomic techniques have contributed substantially in understanding the molecular mechanisms of plant responses against various stresses by providing a link between gene expression and cell metabolism. As the coding regions of genome are responsible for plant adaptation to adverse conditions, protein signatures provide insights into the phytotoxicity of NPs at proteome level. This review summarizes the recent contributions of plant proteomic research to elaborate the complex molecular pathways of plant response to NPs stress.

  18. Risk, responsibility and political action

    Halskov Jensen, Elisabeth

    2004-01-01

    action was transformed into a moral respon-sibility on the part of the national and European politicians, constrained by economic and technical-scientific reality and represented as taking place only in the public sphere. KEY WORDS: CDA, World Risk Society, argumentation, media discourse, argumentation......ABSTRACT. This paper presents an argumentative case study of the discursive representation of risk, responsibility and political action in the Spanish media. The study uses a critical discourse analytical approach combined with theories on risk, agency and political communication in the media....... It is argued that an application of the Toulmin model is useful for eliciting systematic overall repre-sentations of responsibility and agency in environmental crises such as the mad cow crisis as well as for revealing relationships between social domains such as moral, politics, economics and science...

  19. Mapping 'Social Responsibility' in Science

    Glerup, Cecilie; Horst, Maja

    2014-01-01

    This article employs the Foucauldian notion of ‘political rationality’ to map discussions and ideals about the responsibility of science toward society. By constructing and analyzing an archive of 263 journal papers, four political rationalities were identified: the Demarcation rationality, which......, which insists that responsible science should live up to public demands for innovation and democracy; and the Integration rationality, which advocates that science should be co-constructed with societal actors in order to be socially responsible. While each rationality is distinct, the article argues...... that all of them address the issue of a boundary (or integration) between science and society. Hence, it is not possible for scientists to avoid ‘a relationship’ with society. The political question is how this relationship is to be defined and regulated....

  20. Comparative immunology of allergic responses.

    Gershwin, Laurel J

    2015-01-01

    Allergic responses occur in humans, rodents, non-human primates, avian species, and all of the domestic animals. These responses are mediated by immunoglobulin E (IgE) antibodies that bind to mast cells and cause release/synthesis of potent mediators. Clinical syndromes include naturally occurring asthma in humans and cats; atopic dermatitis in humans, dogs, horses, and several other species; food allergies; and anaphylactic shock. Experimental induction of asthma in mice, rats, monkeys, sheep, and cats has helped to reveal mechanisms of pathogenesis of asthma in humans. All of these species share the ability to develop a rapid and often fatal response to systemic administration of an allergen--anaphylactic shock. Genetic predisposition to development of allergic disease (atopy) has been demonstrated in humans, dogs, and horses. Application of mouse models of IgE-mediated allergic asthma has provided evidence for a role of air pollutants (ozone, diesel exhaust, environmental tobacco smoke) in enhanced sensitization to allergens.

  1. Step response and frequency response of an air conditioning system

    Crommelin, R.D.; Jackman, P.J.

    1978-01-01

    A system of induction units of an existing air conditioning system has been analyzed with respect to its dynamic properties. Time constants were calculated and measured by analogue models. Comparison with measurements at the installation itself showed a reasonable agreement. Frequency responses were

  2. Counterconditioned Fear Responses Exhibit Greater Renewal than Extinguished Fear Responses

    Holmes, Nathan M.; Leung, Hiu T.; Westbrook, R. Frederick

    2016-01-01

    This series of experiments used rats to compare counterconditioning and extinction of conditioned fear responses (freezing) with respect to the effects of a context shift. In each experiment, a stimulus was paired with shock in context A, extinguished or counterconditioned through pairings with sucrose in context B, and then tested for renewal…

  3. "Responsibility in Mobility": International Students and Social Responsibility

    Tran, Ly Thi; Vu, Thao Thi Phuong

    2017-01-01

    Enhancing the educational experience and social connectedness for international students is the responsibility of different involved parties among whom international students themselves and host institutions play a key role. However, the question of how the condition of cross-border mobility has shaped and re-shaped international students'…

  4. Response: Critical Realism--Response to Longhofer and Floersch

    Briar-Lawson, Katharine

    2012-01-01

    This article addresses key challenges posed by critical realism, proposed by Longhofer and Floersch, as a philosophical underpinning for a science of social work. As a response to Longhofer and Floersch, it is argued that critical realism may be instructive in debates about structural conditions that dictate more inclusive interventions and…

  5. The path to corporate responsibility.

    Zadek, Simon

    2004-12-01

    Nike's tagline,"Just do it," is an inspirational call to action for the millions who wear the company's athletic gear. But in terms of corporate responsibility, Nike didn't always follow its own advice. In the 1990s, protesters railed against sweatshop conditions at some of its overseas suppliers and made Nike the global poster child for corporate ethical fecklessness. The intense pressure that activists exerted on the athletic apparel giant forced it to take a long, hard look at corporate responsibility--sooner than it might have otherwise. In this article, Simon Zadek, CEO of the UK-based institute AccountAbility, describes the bumpy route Nike has traveled to get to a better ethical place, one that cultivates and champions responsible business practices. Organizations learn in unique ways, Zadek contends, but they inevitably pass through five stages of corporate responsibility, from defensive ("It's not our fault") to compliance ("We'll do only what we have to") to managerial ("It's the business") to strategic ("It gives us a competitive edge") and, finally, to civil ("We need to make sure everybody does it"). He details Nike's arduous trek through these stages-from the company's initial defensive stance, when accusations about working conditions arose, all the way to its engagement today in the international debate about business's role in society and in public policy. As he outlines this evolution, Zadek offers valuable insights to executives grappling with the challenge of managing responsible business practices. Beyond just getting their own houses in order, the author argues, companies need to stay abreast of the public's evolving ideas about corporate roles and responsibilities. Organizations that do both will engage in what he calls"civil learning".

  6. Impaired reward responsiveness in schizophrenia.

    Taylor, Nicholas; Hollis, Jeffrey P; Corcoran, Sarah; Gross, Robin; Cuthbert, Bruce; Swails, Lisette W; Duncan, Erica

    2018-03-08

    Anhedonia is a core negative symptom of schizophrenia. Schizophrenia patients report largely intact pleasure in consuming rewards, but have impairments in generating motivated behavior to pursue rewards, and show reduced fMRI activation of the reward pathway during presentation of rewarded stimuli. A computer based task measuring the development of a response bias in favor of rewarded stimuli permits assessment of reward-induced motivation. We hypothesized that subjects with schizophrenia would be impaired on this task. 58 schizophrenia subjects (SCZ) and 52 healthy controls (CON) were studied with a signal detection task to assess reward responsiveness. In multiple trials over three blocks subjects were asked to correctly identify two stimuli that were paired with unequal chance of monetary reward. The critical outcome variable was response bias, the development of a greater percent correct identification of the stimulus that was rewarded more often. An ANOVA on response bias with Block as a repeated-measures factor and Diagnosis as a between-group factor indicated that SCZ subjects achieved a lower bias to rewarded stimuli than CON subjects (F(1,105)=8.82, p=0.004, η 2 =0.078). Post hoc tests indicated that SCZ subjects had significantly impaired bias in Block 1 (p=0.002) and Block 2 (p=0.05), indicating that SCZ were slower to achieve normal levels of bias during the session. SCZ subjects were slower to develop response bias to rewarded stimuli than CON subjects. This finding is consonant with the hypothesis that people with schizophrenia have a blunted capacity to modify behavior in response to reward. Copyright © 2018. Published by Elsevier B.V.

  7. Shallow End Response from ATEM

    Vetrov, A.

    2014-12-01

    Different geological, hydrological, environmental and engineering targets are located shallow underground. The information collected with ATEM systems might be very useful for their study; although there are many deeper targets that the ATEM systems are traditionally used for. The idea to raise magnetic moment output and get deeper penetration response was one of the goals of ATEM systems development during the last decade. The shallow geology response was a trade for such systems, which sometimes were almost blind in the first hundred meter under surface. The possibility to achieve shallow end response from ATEM systems has become significant subject in last years. Several airborne TDEM systems got second higher frequency and lower magnetic moment signal to pick up shallow response together with deep one. Having a potential advantage such implementation raises complication and cost of the system. There's no need to receive 500 meter deep response when exploring shallow geology. P-THEM system having a compact size transmitter and relatively light weight is working on one base frequency at a time, but this frequency can be preset before a flight considering survey goals. A study of shallow geology response of the P-THEM system working on different base frequency has been conducted in 2014 in Ontario. The Alliston test area located in Southern Ontario has been flown with the P-THEM system working on base frequencies 30Hz and 90Hz. Results of the observations will be discussed in the presentation. The shallow end data can be used for mineral exploration applications and also for hydrological and environmental studies.

  8. Designing a responsive web site

    Fejzić , Diana

    2016-01-01

    Due to the increasing prevalence of smartphones and tablet computers design became a crucial part of web design. For a user, responsive web design enables the best user experience, regardless of whether a user is visiting the site via a mobile phone, a tablet or a computer. This thesis covers the process of planning, designing and responsive web site development, for a fictitious company named “Creative Design d.o.o.”, with the help of web technologies. In the initial part of the thesis, w...

  9. IPCC SRES revisited: a response

    Nakicenovic, Nebojsa; Gruebler, A.; Gaffin, S.

    2003-01-01

    This article gives details of the response to the criticism of the Special Report on Emission Scenarios (SRES) and of some aspects of IPCC assessments. The criticism claims that market exchange rates (MER) were used instead of purchasing power parities (PPP) and that scenarios using Gross Domestic Product (GDP) growth in developing regions were flawed. Points raised in the response included that scenarios of GDP growth are typically expressed as MER, that the IPCC scenarios did include PPP-based scenarios, and that long-term emissions are based on more than just economic growth

  10. Statistical and low dose response

    Thorson, M.R.; Endres, G.W.R.

    1981-01-01

    The low dose response and the lower limit of detection of the Hanford dosimeter depend upon may factors, including the energy of the radiation, whether the exposure is to be a single radiation or mixed fields, annealing cycles, environmental factors, and how well various batches of TLD materials are matched in the system. A careful statistical study and sensitivity analysis were performed to determine how these factors influence the response of the dosimeter system. Estimates have been included in this study of the standard deviation of calculated dose for various mixed field exposures from 0 to 1000 mrem

  11. Magnetically responsive calcium carbonate microcrystals.

    Fakhrullin, Rawil F; Bikmullin, Aidar G; Nurgaliev, Danis K

    2009-09-01

    Here we report the fabrication of magnetically responsive calcium carbonate microcrystals produced by coprecipitation of calcium carbonate in the presence of citrate-stabilized iron oxide nanoparticles. We demonstrate that the calcite microcrystals obtained possess superparamagnetic properties due to incorporated magnetite nanoparticles and can be manipulated by an external magnetic field. The microcrystals doped with magnetic nanoparticles were utilized as templates for the fabrication of hollow polyelectrolyte microcapsules, which retain the magnetic properties of the sacrificial cores and might be spatially manipulated using a permanent magnet, thus providing the magnetic-field-facilitated delivery and separation of materials templated on magnetically responsive calcite microcrystals.

  12. Light Influences How the Fungal Toxin Deoxynivalenol Affects Plant Cell Death and Defense Responses

    Khairul I. Ansari

    2014-02-01

    Full Text Available The Fusarium mycotoxin deoxynivalenol (DON can cause cell death in wheat (Triticum aestivum, but can also reduce the level of cell death caused by heat shock in Arabidopsis (Arabidopsis thaliana cell cultures. We show that 10 μg mL−1 DON does not cause cell death in Arabidopsis cell cultures, and its ability to retard heat-induced cell death is light dependent. Under dark conditions, it actually promoted heat-induced cell death. Wheat cultivars differ in their ability to resist this toxin, and we investigated if the ability of wheat to mount defense responses was light dependent. We found no evidence that light affected the transcription of defense genes in DON-treated roots of seedlings of two wheat cultivars, namely cultivar CM82036 that is resistant to DON-induced bleaching of spikelet tissue and cultivar Remus that is not. However, DON treatment of roots led to genotype-dependent and light-enhanced defense transcript accumulation in coleoptiles. Wheat transcripts encoding a phenylalanine ammonia lyase (PAL gene (previously associated with Fusarium resistance, non-expressor of pathogenesis-related genes-1 (NPR1 and a class III plant peroxidase (POX were DON-upregulated in coleoptiles of wheat cultivar CM82036 but not of cultivar Remus, and DON-upregulation of these transcripts in cultivar CM82036 was light enhanced. Light and genotype-dependent differences in the DON/DON derivative content of coleoptiles were also observed. These results, coupled with previous findings regarding the effect of DON on plants, show that light either directly or indirectly influences the plant defense responses to DON.

  13. Responses of plants to air pollution

    Mudd, J. Brian; Kozlowski, T. T

    1975-01-01

    .... KOZLOWSKI Pollution, 1975 ELROY L. RICE. Allelopathy, (Eds.). Fire and Ecosystems, 1974 (Eds.). Responses of Plants to Air Responses of Plants to Air PollutionRESPONSES OF PLANTS TO AIR POLLUTION E...

  14. Partiality of Responsibility: Ethics in Sustainability Consulting

    Earhart, R.S.

    2011-01-01

    Sustainability, Socially Responsible Investment (SRI) and Corporate Social Responsibility (CSR) are both highly normative fields of professional practice, framed by various narratives: capitalist versus environmentalist, waste versus respect for the planet, consumerism versus responsibility;

  15. Partnerships for corporate social responsability

    Bruijn, de T.J.N.M. (Theo)

    2007-01-01

    The purpose of this paper is to conceptualise the extent to which partnerships with non-governmental organisations (NGOs) are a necessity for successful efforts of businesses in the area of corporate social responsibility (CSR). The main findings are based on an analysis of existing literature on

  16. A Shared Responsibility for Skills

    Clough, Bert

    2011-01-01

    Co-investment between the state, employer, and employee is an intrinsic feature of most vocational and education training systems. The government's strategy is to "profoundly" shift responsibility for funding learning and skills from the state to individuals and businesses. At a time of stringent cuts in publicly-funded further education…

  17. Responsive media in HTML5

    Libby, Alex

    2014-01-01

    If you are a web designer with a good understanding of CSS, jQuery, and HTML, but new to creating responsive sites, then this book is for you. The prerequisite is a good understanding of CSS and HTML; the demos will suit those who have some prior knowledge of Less CSS, WordPress, or Bootstrap.

  18. Perceptions of Corporate Social Responsibility

    Gavin, James F.; Maynard, William S.

    1975-01-01

    This study investigated the possible implications of Corporate Social Responsibility (CSR) for employee expectations and satisfactions. Specifically, interest centered on the question of how perceptions of an organization's involvement in the resolution of current societal problems might relate to members' expectations of equitable job rewards and…

  19. Plant responses to multiple herbivory

    Li, Yehua

    2016-01-01

    This thesis explores whether aphid-infestation interferes with the plant response to chewing herbivores and whether this impacts performance and behaviour of individual chewing insect herbivores and their natural enemies, as well as the entire insect community. I investigated this using three

  20. Emergency response planning in Saskatchewan

    Irwin, R.W.

    1998-01-01

    Release reporting and spill clean-up requirements by Saskatchewan Energy and Mines were reviewed. Wascana's experience in response planning was discussed. It was suggested that the key to prevention was up-front due diligence, including facility and oil well analysis. Details of Wascana's emergency plan, and details of Saskatchewan Energy and Mines release reporting procedures were also provided

  1. Counselor Responsiveness to Client Religiousness.

    Kelly, Eugene W., Jr.

    1990-01-01

    Presents eight categories of client attitudes toward religion and suggests opportunities for religiously oriented counselor responses. Uses four categories to describes how religion may be associated with specific client issues. Contends that an informed appreciation of clients' religiousness and the religious dimensions of many client issues can…

  2. Responsibility for the Ecological Crisis

    Wright, Richard T.

    1970-01-01

    Critically analyzes the thesis of Christian responsibility for the ecological crisis and leads to its rejection. Present day environmental misuse results from greed, carelessness, and ignorance." Advocates ecological strategy of corrective action, with supplementary theological strategy" for church-influenced citizens. (AL)

  3. Electric response in superfluid helium

    Chagovets, Tymofiy

    2016-01-01

    Roč. 488, May (2016), s. 62-66 ISSN 0921-4526 R&D Projects: GA ČR GP13-03806P Institutional support: RVO:68378271 Keywords : superfluid helium * electric response * second sound * ions in He II Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 1.386, year: 2016

  4. Nested Dynamic Condition Response Graphs

    Hildebrandt, Thomas; Mukkamala, Raghava Rao; Slaats, Tijs

    2012-01-01

    We present an extension of the recently introduced declarative process model Dynamic Condition Response Graphs ( DCR Graphs) to allow nested subgraphs and a new milestone relation between events. The extension was developed during a case study carried out jointly with our industrial partner...

  5. Information Science and Responsive Evaluation

    Stake, Robert E.

    2014-01-01

    Responsive evaluation builds upon the methods of informal evaluation in disciplined ways: getting personally acquainted with the evaluand, observation of activities, interviewing people who are in different ways familiar with the evaluand, searching documents that reveal what happened in the past or somewhere else. It calls for sustained effort to…

  6. Predicting response to epigenetic therapy

    Treppendahl, Marianne B; Sommer Kristensen, Lasse; Grønbæk, Kirsten

    2014-01-01

    of good pretreatment predictors of response is of great value. Many clinical parameters and molecular targets have been tested in preclinical and clinical studies with varying results, leaving room for optimization. Here we provide an overview of markers that may predict the efficacy of FDA- and EMA...

  7. Internal Displacement: Livelihood saving responses

    Deborah Hines

    2001-01-01

    Deborah Hines explores how to assist the internally displaced and those prone to displacement. She considers the major causes of internal displacement, making the case for a more comprehensive set of policy and operational actions in response to situations of internal displacement. Development (2001) 44, 34–39. doi:10.1057/palgrave.development.1110289

  8. Green taxation and individual responsibility

    Ballet, Jerome [C3ED Centre of Economics and Ethics for Environment and Development, UVSQ, University of Versailles, Saint-Quentin-en-Yvelines (France); Bazin, Damien [EMAFI Macroeconomics and International Finance Research Centre at University of Nice Sophia Antipolis, 28, avenue Valrose, BP 2135, 06103 Nice (France); Lioui, Abraham [Department of Economics, Bar Ilan University, Ramat Gan (Israel); Touahri, David [LEST Institute of Labor Econmics and Industrial Sociology and Mediterranean University Aix-Marseille II, Marseille (France)

    2007-09-15

    The current article aims at studying the effects of taxation on environmental quality, in an economy where its agents are responsible. Individual responsibility towards nature is modelized by the voluntary effort to which the households have agreed insofar as the improvement of environmental quality is concerned. It is an original way to show that the individuals may feel committed towards the environment and assume obligations towards it as well as towards environmental public policy. Given that, in our model, such effort is taken from one's allocated time for leisure, its opportunity cost is that of the sacrificed time for leisure, and is therefore equal to the individual's wage. We shall highlight that State intervention through the introduction of a (green) tax always crowds out individual responsibility. However, the intensity of this crowding-out depends on the performance of the State. Moreover, State intervention could, depending on the amount of crowding-out, reduce the overall quality of the environment. In a general equilibrium setting, we show that the crowding-out effect is not systematic. This is because there will then be an interaction between effort (or work time) and the cost of that effort (linked to the individual's wage, and therefore to production and finally to work/effort). In this article, we shall discuss the conditions under which public policy crowds out individual responsibility within this context. (author)

  9. Globalisation, Responsibility and Virtual Schools

    Russell, Glenn

    2006-01-01

    The intersection of globalisation and information technology influences ethical positions and notions of responsibility within businesses and in distance education for school students. As the spatial and temporal distance between student and teacher increases, and is mediated by computers, there have been changes to the ways in which individuals…

  10. Nonlocal Response in Plasmonic Nanostructures

    Wubs, Martijn; Mortensen, N. Asger

    2016-01-01

    After a brief overview of nanoplasmonics experiments that defy explanation with classical electrodynamics, we introduce nonlocal response as a main reason for non-classical effects. This concept is first introduced phenomenologically, and afterwards based on the semi-classical hydrodynamic Drude...

  11. Being a potentially responsible party

    Ronan, J.T.

    1989-01-01

    This paper reports on CERCLA II- ability for the unlucky potentially responsible parties (PRPs) which is a Draconian form of strict, joint and several liability with limited statutory defenses that in most cases are impossible to establish. CERCLA vigorously employs these legal concepts, stretching a PRP's financial exposure to the limits necessary to meet the enormous financial costs of remediation

  12. Education for Responsible Citizenship: Conversation

    Waghid, Yusef

    2009-01-01

    There is an abundance of literature on citizenship education. This essay is an attempt to show how deliberation is used in university classroom pedagogy, to engender in students a commitment to becoming responsible citizens of a post-apartheid South Africa. Firstly, I show that controversy can be attended to through deliberation, with specific…

  13. Host response to Eimeria infections

    Swinkels, W.J.C.

    2008-01-01

    The protozoan parasite Eimeria is responsible for the disease coccidiosis and has a worldwide distribution. Intestinal Eimeria infections are the dominating class of diseases in poultry causing great economical damage and considerably affecting animal welfare. In the Netherlands in chickens raised

  14. Demand Response in Smart Grids

    Hansen, Jacob; Knudsen, Jesper Viese; Annaswamy, Anuradha M.

    2014-01-01

    In recent decades, moves toward higher integration of Renewable Energy Resources have called for fundamental changes in both the planning and operation of the overall power grid. One such change is the incorporation of Demand Response (DR), the process by which consumers can adjust their demand...

  15. SICOEM: emergency response data system

    Martin, A.; Villota, C.; Francia, L.

    1993-01-01

    The main characteristics of the SICOEM emergency response system are: -direct electronic redundant transmission of certain operational parameters and plant status informations from the plant process computer to a computer at the Regulatory Body site, - the system will be used in emergency situations, -SICOEM is not considered as a safety class system. 1 fig

  16. SICOEM: emergency response data system

    Martin, A.; Villota, C.; Francia, L. (UNESA, Madrid (Spain))

    1993-01-01

    The main characteristics of the SICOEM emergency response system are: -direct electronic redundant transmission of certain operational parameters and plant status informations from the plant process computer to a computer at the Regulatory Body site, - the system will be used in emergency situations, -SICOEM is not considered as a safety class system. 1 fig.

  17. The Glocalization of Responsible Investment

    Gond, Jean-Pascal; Boxenbaum, Eva

    2013-01-01

    This study investigates the institutional work that underlies the diffusion of responsible investment (RI) and enhances its adaptation to local settings. Building on institutional theory and actor–network theory, we advance the concept of contextualization work to describe the institutional work...

  18. Causation and International State Responsibility

    Castellanos-Jankiewicz, L.

    2012-01-01

    This work studies causation in the law of international State responsibility. It is submitted that the absence of causation as an element of the internationally wrongful act owes more to the structure of international law, than to the inadequateness of causation as a conceptual and legal construct

  19. Dose response relationship and Alara

    Hubert, P.

    1986-09-01

    In this paper, it will be shown how dose-response relationships allow to give quantitative figures for the detriment of irradiation. At this stage, the detriment is expressed directly as a certain number of health effects, whose valuation is not dealt with here. The present tools for quantifying, their weaknesses and their strenghts, and their scientific basis will be developed

  20. Light intensity and thermal responses

    te Kulve, M.; Schellen, L.; Schlangen, L.; Frijns, A.J.H.; van Marken Lichtenbelt, W.D.; Nicol, Fergus; Roaf, Susan; Brotas, Luisa; Humphreys, Michael

    2016-01-01

    Temperature and light are both major factors in the design of a comfortable indoor environment. Moreover, there might be an interaction between light exposure and human thermal responses. However, results of experiments conducted so far are inconclusive and current understanding of the relation