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Sample records for activation modulates radioresistance

  1. Radiation-induced Akt activation modulates radioresistance in human glioblastoma cells

    PubMed Central

    Li, Hui-Fang; Kim, Jung-Sik; Waldman, Todd

    2009-01-01

    Background Ionizing radiation (IR) therapy is a primary treatment for glioblastoma multiforme (GBM), a common and devastating brain tumor in humans. IR has been shown to induce PI3K-Akt activation in many cell types, and activation of the PI3K-Akt signaling pathway has been correlated with radioresistance. Methods Initially, the effects of IR on Akt activation were assessed in multiple human GBM cell lines. Next, to evaluate a potential causative role of IR-induced Akt activation on radiosensitivity, Akt activation was inhibited during IR with several complementary genetic and pharmacological approaches, and radiosensitivity measured using clonogenic survival assays. Results Three of the eight cell lines tested demonstrated IR-induced Akt activation. Further studies revealed that IR-induced Akt activation was dependent upon the presence of a serum factor, and could be inhibited by the EGFR inhibitor AG1478. Inhibition of PI3K activation with LY294002, or with inducible wild-type PTEN, inhibition of EGFR, as well as direct inhibition of Akt with two Akt inhibitors during irradiation increased the radiosensitivity of U87MG cells. Conclusion These results suggest that Akt may be a central player in a feedback loop whereby activation of Akt induced by IR increases radioresistance of GBM cells. Targeting the Akt signaling pathway may have important therapeutic implications when used in combination with IR in the treatment of a subset of brain tumor patients. PMID:19828040

  2. Reduced RKIP enhances nasopharyngeal carcinoma radioresistance by increasing ERK and AKT activity

    PubMed Central

    Yuan, Li; Yi, Hong-Mei; Yi, Hong; Qu, Jia-Quan; Zhu, Jin-Feng; Li, Li-Na; Xiao, Ta; Zheng, Zhen; Lu, Shan-Shan; Xiao, Zhi-Qiang

    2016-01-01

    Raf kinase inhibitory protein (RKIP) functions as a chemo-immunotherapeutic sensitizer of cancers, but regulation of RKIP on tumor radiosensitivity remains largely unexplored. In this study, we investigate the role and mechanism of RKIP in nasopharyngeal carcinoma (NPC) radioresistance. The results showed that RKIP was frequently downregulated in the radioresistant NPC tissues compared with radiosensitive NPC tissues, and its reduction correlated with NPC radioresistance and poor patient survival, and was an independent prognostic factor. In vitro radioresponse assay showed that RKIP overexpression decreased while RKIP knockdown increased NPC cell radioresistance. In the NPC xenografts, RKIP overexpression decreased while RKIP knockdown increased tumor radioresistance. Mechanistically, RKIP reduction promoted NPC cell radioresistance by increasing ERK and AKT activity, and AKT may be a downstream transducer of ERK signaling. Moreover, the levels of phospho-ERK−1/2 and phospho-AKT were increased in the radioresistant NPC tissues compared with radiosensitive ones, and negatively associated with RKIP expression, indicating that RKIP-regulated NPC radioresponse is mediated by ERK and AKT signaling in the clinical samples. Our data demonstrate that RKIP is a critical determinant of NPC radioresponse, and its reduction enhances NPC radioresistance through increasing ERK and AKT signaling activity, highlighting the therapeutic potential of RKIP-ERK-AKT signaling axis in NPC radiosensitization. PMID:26862850

  3. Phosphorylation of Deinococcus radiodurans RecA Regulates Its Activity and May Contribute to Radioresistance.

    PubMed

    Rajpurohit, Yogendra S; Bihani, Subhash C; Waldor, Matthew K; Misra, Hari S

    2016-08-01

    Deinococcus radiodurans has a remarkable capacity to survive exposure to extreme levels of radiation that cause hundreds of DNA double strand breaks (DSBs). DSB repair in this bacterium depends on its recombinase A protein (DrRecA). DrRecA plays a pivotal role in both extended synthesis-dependent strand annealing and slow crossover events of DSB repair during the organism's recovery from DNA damage. The mechanisms that control DrRecA activity during the D. radiodurans response to γ radiation exposure are unknown. Here, we show that DrRecA undergoes phosphorylation at Tyr-77 and Thr-318 by a DNA damage-responsive serine threonine/tyrosine protein kinase (RqkA). Phosphorylation modifies the activity of DrRecA in several ways, including increasing its affinity for dsDNA and its preference for dATP over ATP. Strand exchange reactions catalyzed by phosphorylated versus unphosphorylated DrRecA also differ. In silico analysis of DrRecA structure support the idea that phosphorylation can modulate crucial functions of this protein. Collectively, our findings suggest that phosphorylation of DrRecA enables the recombinase to selectively use abundant dsDNA substrate present during post-irradiation recovery for efficient DSB repair, thereby promoting the extraordinary radioresistance of D. radiodurans. PMID:27255712

  4. Transition in Survival From Low-Dose Hyper-Radiosensitivity to Increased Radioresistance Is Independent of Activation of ATM SER1981 Activity

    SciTech Connect

    Krueger, Sarah A.; Collis, Spencer J.; Joiner, Michael C.; Wilson, George D.; Marples, Brian

    2007-11-15

    Purpose: The molecular basis of low-dose hyper-radiosensitivity (HRS) is only partially understood. The aim of this study was to define the roles of ataxia telangiectasia mutated (ATM) activity and the downstream ATM-dependent G{sub 2}-phase cell cycle checkpoint in overcoming HRS and triggering radiation resistance. Methods and Materials: Survival was measured using a high-resolution clonogenic assay. ATM Ser1981 activation was measured by Western blotting. The role of ATM was determined in survival experiments after molecular (siRNA) and chemical (0.4 mM caffeine) inhibition and chemical (20 {mu}g/mL chloroquine, 15 {mu}M genistein) activation 4-6 h before irradiation. Checkpoint responsiveness was assessed in eight cell lines of differing HRS status using flow cytometry to quantify the progression of irradiated (0-2 Gy) G{sub 2}-phase cells entering mitosis, using histone H3 phosphorylation analysis. Results: The dose-response pattern of ATM activation was concordant with the transition from HRS to radioresistance. However, ATM activation did not play a primary role in initiating increased radioresistance. Rather, a relationship was discovered between the function of the downstream ATM-dependent early G{sub 2}-phase checkpoint and the prevalence and overcoming of HRS. Four cell lines that exhibited HRS failed to show low-dose (<0.3-Gy) checkpoint function. In contrast, four HRS-negative cell lines exhibited immediate cell cycle arrest for the entire 0-2-Gy dose range. Conclusion: Overcoming HRS is reliant on the function of the early G{sub 2}-phase checkpoint. These data suggest that clinical exploitation of HRS could be achieved by combining radiotherapy with chemotherapeutic agents that modulate this cell cycle checkpoint.

  5. Telomere-Binding Protein TPP1 Modulates Telomere Homeostasis and Confers Radioresistance to Human Colorectal Cancer Cells

    PubMed Central

    Hu, Liu; Yang, Xiaoxi; Zhong, Juan; Li, Zheng; Yang, Hui; Lei, Han; Yu, Haijun; Liao, ZhengKai; Zhou, Fuxiang; Xie, Conghua; Zhou, Yunfeng

    2013-01-01

    Background Radiotherapy is one of the major therapeutic strategies in cancer treatment. The telomere-binding protein TPP1 is an important component of the shelterin complex at mammalian telomeres. Our previous reports showed that TPP1 expression was elevated in radioresistant cells, but the exact effects and mechanisms of TPP1 on radiosensitivity is unclear. Principal Findings In this study, we found that elevated TPP1 expression significantly correlated with radioresistance and longer telomere length in human colorectal cancer cell lines. Moreover, TPP1 overexpression showed lengthened telomere length and a significant decrease of radiosensitivity to X-rays. TPP1 mediated radioresistance was correlated with a decreased apoptosis rate after IR exposure. Furthermore, TPP1 overexpression showed prolonged G2/M arrest mediated by ATM/ATR-Chk1 signal pathway after IR exposure. Moreover, TPP1 overexpression accelerated the repair kinetics of total DNA damage and telomere dysfunction induced by ionizing radiation. Conclusions We demonstrated that elevated expressions of TPP1 in human colorectal cancer cells could protect telomere from DNA damage and confer radioresistance. These results suggested that TPP1 may be a potential target in the radiotherapy of colorectal cancer. PMID:24260532

  6. The radioresistance to killing of A1-5 cells derives from activation of the Chk1 pathway

    NASA Technical Reports Server (NTRS)

    Hu, B.; Zhou, X. Y.; Wang, X.; Zeng, Z. C.; Iliakis, G.; Wang, Y.

    2001-01-01

    Checkpoints respond to DNA damage by arresting the cell cycle to provide time for facilitating repair. In mammalian cells, the G(2) checkpoint prevents the Cdc25C phosphatase from removing inhibitory phosphate groups from the mitosis-promoting kinase Cdc2. Both Chk1 and Chk2, the checkpoint kinases, can phosphorylate Cdc25C and inactivate its in vitro phosphatase activity. Therefore, both Chk1 and Chk2 are thought to regulate the activation of the G(2) checkpoint. Here we report that A1-5, a transformed rat embryo fibroblast cell line, shows much more radioresistance associated with a much stronger G(2) arrest response when compared with its counterpart, B4, although A1-5 and B4 cells have a similar capacity for nonhomologous end-joining DNA repair. These phenotypes of A1-5 cells are accompanied by a higher Chk1 expression and a higher phosphorylation of Cdc2. On the other hand, Chk2 expression increases slightly following radiation; however, it has no difference between A1-5 and B4 cells. Caffeine or UCN-01 abolishes the extreme radioresistance with the strong G(2) arrest and at the same time reduces the phosphorylation of Cdc2 in A1-5 cells. In addition, Chk1 but not Chk2 antisense oligonucleotide sensitizes A1-5 cells to radiation-induced killing and reduces the G(2) arrest of the cells. Taken together these results suggest that the Chk1/Cdc25C/Cdc2 pathway is the major player for the radioresistance with G(2) arrest in A1-5 cells.

  7. MiR-20a Induces Cell Radioresistance by Activating the PTEN/PI3K/Akt Signaling Pathway in Hepatocellular Carcinoma

    SciTech Connect

    Zhang, Yuqin; Zheng, Lin; Ding, Yi; Li, Qi; Wang, Rong; Liu, Tongxin; Sun, Quanquan; Yang, Hua; Peng, Shunli; Wang, Wei; Chen, Longhua

    2015-08-01

    Purpose: To investigate the role of miR-20a in hepatocellular carcinoma (HCC) cell radioresistance, which may reveal potential strategies to improve treatment. Methods and Materials: The expression of miR-20a and PTEN were detected in HCC cell lines and paired primary tissues by quantitative real-time polymerase chain reaction. Cell radiation combined with colony formation assays was administrated to discover the effect of miR-20a on radiosensitivity. Bioinformatics prediction and luciferase assay were used to identify the target of miR-20a. The phosphatidylinositol 3-kinase inhibitor LY294002 was used to inhibit phosphorylation of Akt, to verify whether miR-20a affects HCC cell radioresistance through activating the PTEN/PI3K/Akt pathway. Results: MiR-20a levels were increased in HCC cell lines and tissues, whereas PTEN was inversely correlated with it. Overexpression of miR-20a in Bel-7402 and SMMC-7721 cells enhances their resistance to the effect of ionizing radiation, and the inhibition of miR-20a in HCCLM3 and QGY-7701 cells sensitizes them to it. PTEN was identified as a direct functional target of miR-20a for the induction of radioresistance. Overexpression of miR-20a activated the PTEN/PI3K/Akt signaling pathway. Additionally, the kinase inhibitor LY294002 could reverse the effect of miR-20a–induced radioresistance. Conclusion: MiR-20a induces HCC cell radioresistance by activating the PTEN/PI3K/Akt pathway, which suggests that miR-20a/PTEN/PI3K/Akt might represent a target of investigation for developing effective therapeutic strategies against HCC.

  8. Depletion of hepatoma-derived growth factor-related protein-3 induces apoptotic sensitization of radioresistant A549 cells via reactive oxygen species-dependent p53 activation

    SciTech Connect

    Yun, Hong Shik; Hong, Eun-Hee; Lee, Su-Jae; Baek, Jeong-Hwa; Lee, Chang-Woo; Yim, Ji-Hye; Um, Hong-Duck; Hwang, Sang-Gu

    2013-09-27

    Highlights: •HRP-3 is a radiation- and anticancer drug-responsive protein in A549 cells. •Depletion of HRP-3 induces apoptosis of radio- and chemoresistant A549 cells. •Depletion of HRP-3 promotes ROS generation via inhibition of the Nrf2/HO-1 pathway. •Depletion of HRP-3 enhances ROS-dependent p53 activation and PUMA expression. -- Abstract: Biomarkers based on functional signaling have the potential to provide greater insight into the pathogenesis of cancer and may offer additional targets for anticancer therapeutics. Here, we identified hepatoma-derived growth factor-related protein-3 (HRP-3) as a radioresistance-related gene and characterized the molecular mechanism by which its encoded protein regulates the radio- and chemoresistant phenotype of lung cancer-derived A549 cells. Knockdown of HRP-3 promoted apoptosis of A549 cells and potentiated the apoptosis-inducing action of radio- and chemotherapy. This increase in apoptosis was associated with a substantial generation of reactive oxygen species (ROS) that was attributable to inhibition of the Nrf2/HO-1 antioxidant pathway and resulted in enhanced ROS-dependent p53 activation and p53-dependent expression of PUMA (p53 upregulated modulator of apoptosis). Therefore, the HRP-3/Nrf2/HO-1/ROS/p53/PUMA cascade is an essential feature of the A549 cell phenotype and a potential radiotherapy target, extending the range of targets in multimodal therapies against lung cancer.

  9. Association of ATM activation and DNA repair with induced radioresistance after low-dose irradiation.

    PubMed

    Enns, L; Rasouli-Nia, A; Hendzel, M; Marples, B; Weinfeld, M

    2015-09-01

    Mammalian cells often exhibit a hyper-radiosensitivity (HRS) to radiation doses <20 cGy, followed by increased radioresistance (IRR) at slightly higher doses (∼20-30 cGy). Here, the influence of DNA double-strand break repair (DSBR) on IRR was examined. The failure of Ataxia telangiectasia (AT) cells to undergo IRR reported by others was confirmed. Flow cytometric analysis indicated that normal cells fail to show a measurable increase in serine 1981 phosphorylated AT-mutated (ATM) protein after 10 cGy up to 4 h post irradiation, but a two- to fourfold increase after 25 cGy. Similarly, more proficient reduction of phosphorylated histone H2AX was observed 24 h after 25 cGy than after 10 cGy, suggesting that DSBR is more efficient during IRR than HRS. A direct examination of the consequences of inefficient DNA repair per se (as opposed to ATM-mediated signal transduction/cell cycle responses), by determining the clonogenic survival of cells lacking the DNA repair enzyme polynucleotide kinase/phosphatase, indicated that these cells have a response similar to AT cells, i.e. HRS but no IRR, strongly linking IRR to DSBR. PMID:25904696

  10. Natural cytotoxicity in immunodeficiency diseases: preservation of natural killer activity and the in vivo appearance of radioresistant killing

    SciTech Connect

    Pierce, G.F.; Polmar, S.H.; Schacter, B.Z.; Brovall, C.; Hornick, D.L.; Sorensen, R.U.

    1986-01-01

    We studied spontaneous natural killer (NK) cell activity and radiation-resistant NK mediated cytotoxicity in four patients with clinically documented severe combined immune deficiency disease (SCID), and in one subject each with intestinal lymphangiectasia and cartilage-hair hypoplasia. We observed the preservation of spontaneous NK activity in all patients despite the presence of profound B- and T-lymphocytopenia and clinical immunodeficiency. NK activity was associated with relatively normal circulating numbers of OKM1+ lymphocytes, a population known to contain NK effectors. Spontaneous NK activity resistant to 3000 rad was increased in all patients, indicating the presence of activated natural killer cells in vivo. The concept of a chronically activated immune system in these patients was further supported by the presence of increased Ia positive T cells in all subjects tested, suggesting that radioresistant NK activity may be a useful parameter to measure when assessing in vivo immune activation. Our data, as well as that of others, supports the hypothesis that at least one population of NK cells is a distinct lineage arising at the differentiation level of myeloid and lymphoid stem cells in the bone marrow.

  11. Radioresistance of Brain Tumors

    PubMed Central

    Kelley, Kevin; Knisely, Jonathan; Symons, Marc; Ruggieri, Rosamaria

    2016-01-01

    Radiation therapy (RT) is frequently used as part of the standard of care treatment of the majority of brain tumors. The efficacy of RT is limited by radioresistance and by normal tissue radiation tolerance. This is highlighted in pediatric brain tumors where the use of radiation is limited by the excessive toxicity to the developing brain. For these reasons, radiosensitization of tumor cells would be beneficial. In this review, we focus on radioresistance mechanisms intrinsic to tumor cells. We also evaluate existing approaches to induce radiosensitization and explore future avenues of investigation. PMID:27043632

  12. Acquisition of epithelial–mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance

    PubMed Central

    Chang, L; Graham, P H; Hao, J; Ni, J; Bucci, J; Cozzi, P J; Kearsley, J H; Li, Y

    2013-01-01

    Radioresistance is a major challenge in prostate cancer (CaP) radiotherapy (RT). In this study, we investigated the role and association of epithelial–mesenchymal transition (EMT), cancer stem cells (CSCs) and the PI3K/Akt/mTOR signaling pathway in CaP radioresistance. We developed three novel CaP radioresistant (RR) cell lines (PC-3RR, DU145RR and LNCaPRR) by radiation treatment and confirmed their radioresistance using a clonogenic survival assay. Compared with untreated CaP-control cells, the CaP-RR cells had increased colony formation, invasion ability and spheroid formation capability (P<0.05). In addition, enhanced EMT/CSC phenotypes and activation of the checkpoint proteins (Chk1 and Chk2) and the PI3K/Akt/mTOR signaling pathway proteins were also found in CaP-RR cells using immunofluorescence, western blotting and quantitative real-time PCR (qRT-PCR). Furthermore, combination of a dual PI3K/mTOR inhibitor (BEZ235) with RT effectively increased radiosensitivity and induced more apoptosis in CaP-RR cells, concomitantly correlated with the reduced expression of EMT/CSC markers and the PI3K/Akt/mTOR signaling pathway proteins compared with RT alone. Our findings indicate that CaP radioresistance is associated with EMT and enhanced CSC phenotypes via activation of the PI3K/Akt/mTOR signaling pathway, and that the combination of BEZ235 with RT is a promising modality to overcome radioresistance in the treatment of CaP. This combination approach warrants future in vivo animal study and clinical trials. PMID:24157869

  13. miR-185-3p regulates nasopharyngeal carcinoma radioresistance by targeting WNT2B in vitro

    PubMed Central

    Li, Guo; Wang, Yunyun; Liu, Yong; Su, Zhongwu; Liu, Chao; Ren, Shuling; Deng, Tengbo; Huang, Donghai; Tian, Yongquan; Qiu, Yuanzheng

    2014-01-01

    Aberrant microRNA (miRNA) expression contributes to a series of malignant cancer behaviors, including radioresistance. Our previous study showed differential expression of miR-185-3p in post-radiation nasopharyngeal carcinoma (NPC) cells. To investigate the role of miR-185-3p in NPC radioresistance, CNE-2 and 5-8F cells were transfected with miR-185-3p mimic and miR-185-3p inhibitor, respectively. CCK-8 assay and colony formation experiment confirmed that the expression of miR-185-3p affected the radioresistance of NPC cells. A negative correlation between miR-185-3p and WNT2B expression was observed in NPC cells and tissues. Luciferase reporter assays confirmed that miR-185-3p directly targeted the coding region of WNT2B. Furthermore, we found radioresistance decreased in WNT2B-silenced NPC cells. Activation of the WNT2B/β-catenin pathway was accompanied by epithelial–mesenchymal transition biomarker changes in NPC. We concluded that miR-185-3p contributed to the radioresistance of NPC via modulation of WNT2B expression in vitro. PMID:25297925

  14. K-RAS(V12) Induces Autocrine Production of EGFR Ligands and Mediates Radioresistance Through EGFR-Dependent Akt Signaling and Activation of DNA-PKcs

    SciTech Connect

    Minjgee, Minjmaa; Toulany, Mahmoud; Kehlbach, Rainer; Giehl, Klaudia; Rodemann, H. Peter

    2011-12-01

    Purpose: It is known that postirradiation survival of tumor cells presenting mutated K-RAS is mediated through autocrine activation of epidermal growth factor receptor (EGFR). In this study the molecular mechanism of radioresistance of cells overexpressing mutated K-RAS(V12) was investigated. Methods and Materials: Head-and-neck cancer cells (FaDu) presenting wild-type K-RAS were transfected with empty vector or vector expressing mutated K-RAS(V12). The effect of K-RAS(V12) on autocrine production of EGFR ligands, activation of EGFR downstream pathways, DNA damage repair, and postirradiation survival was analyzed. Results: Conditioned medium collected from K-RAS(V12)-transfected cells enhanced activation of the phosphatidylinositol-3-kinase-Akt pathway and increased postirradiation survival of wild-type K-RAS parental cells when compared with controls. These effects were reversed by amphiregulin (AREG)-neutralizing antibody. In addition, secretion of the EGFR ligands AREG and transforming growth factor {alpha} was significantly increased upon overexpression of K-RAS(V12). Expression of mutated K-RAS(V12) resulted in an increase in radiation-induced DNA-dependent protein kinase catalytic subunit (DNA-PKcs) phosphorylation at S2056. This increase was accompanied by increased repair of DNA double-strand breaks. Abrogation of DNA-PKcs phosphorylation by serum depletion or AREG-neutralizing antibody underscored the role of autocrine production of EGFR ligands, namely, AREG, in regulating DNA-PKcs activation in K-RAS mutated cells. Conclusions: These data indicate that radioresistance of K-RAS mutated tumor cells is at least in part due to constitutive production of EGFR ligands, which mediate enhanced repair of DNA double-strand breaks through the EGFR-phosphatidylinositol-3-kinase-Akt cascade.

  15. Vitamin K2-derived compounds induce growth inhibition in radioresistant cancer cells.

    PubMed

    Amalia, Helfi; Sasaki, Ryohei; Suzuki, Yoko; Demizu, Yusuke; Bito, Toshinori; Nishimura, Hideki; Okamoto, Yoshiaki; Yoshida, Kenji; Miyawaki, Daisuke; Kawabe, Tetsuya; Mizushina, Yoshiyuki; Sugimura, Kazuro

    2010-01-01

    A strategy to overcome radioresistance in cancer treatment has been expected. To evaluate the strategy, appropriate experimental models are needed. Radioresistant tumour models were originally established from human colon cancer cells, and we evaluated their molecular basis. Next, the growth inhibitory effects of newly synthesized vitamin K2 (VK2)-related compounds were tested. Here, we showed that these novel compounds have growth inhibitory effects not only on cancer cells of various origins, but also on radioresistant cells, through the generation of reactive oxygen species (ROS). Human colon, lung, and breast cancer cell lines were used for testing the growth inhibitory activities of several chemical compounds. Radioresistant tumour models were established by fractionated radiation exposure. Irradiated cells were selected by a single cell cloning method, and their sensitivity to ionizing radiation was evaluated by a colony-forming assay. The VK2 derivatives (named MQ-1, MQ-2, and MQ-3) were chemically synthesized. To evaluate the generation of ROS, flow cytometer analyses were performed. A radioresistant tumour model was established from the HCT116 human colon cancer cell line. The radioresistant cells from HCT116 also showed resistance to cisplatin. In the radioresistant cells, NF-κB was highly activated. MQ-1, MQ-2, and MQ-3 showed greater growth inhibitory activities than VK2 not only in various cancer cells but also in radioresistant cells through the generation of ROS. In conclusion, a radioresistant tumour model was originally established from colon cancer cell lines through NF-κB activation, and it could be a useful tool for evaluating anti-tumour agents. Newly synthesized VK2 derivatives (MQ-1, MQ-2 and MQ-3) seemed to be potential anti-tumour agents in various cancers and radioresistant cancers. The efficacy of those compounds was related to the generation of ROS. These findings together might pave the way for the treatment of radioresistant or

  16. Macroeconomic Activity Module - NEMS Documentation

    EIA Publications

    2014-01-01

    Documents the objectives, analytical approach, and development of the National Energy Modeling System (NEMS) Macroeconomic Activity Module (MAM) used to develop the Annual Energy Outlook for 2014 (AEO2014). The report catalogues and describes the module assumptions, computations, methodology, parameter estimation techniques, and mainframe source code

  17. Macroeconomic Activity Module - NEMS Documentation

    EIA Publications

    2016-01-01

    Documents the objectives, analytical approach, and development of the National Energy Modeling System (NEMS) Macroeconomic Activity Module (MAM) used to develop the Annual Energy Outlook for 2016 (AEO2016). The report catalogues and describes the module assumptions, computations, methodology, parameter estimation techniques, and mainframe source code

  18. Cancer-associated adipocytes promotes breast tumor radioresistance

    SciTech Connect

    Bochet, Ludivine; Meulle, Aline; Imbert, Sandrine; Salles, Bernard; Valet, Philippe; Muller, Catherine

    2011-07-22

    Highlights: {yields} Tumor-surrounding adipocytes contribute to breast cancer progression. {yields} Breast tumor cells previously co-cultivated with mature adipocytes exhibit radioresistance. {yields} Increased in Chk1 phosphorylation is observed in irradiated co-cultivated tumor cells. {yields} IL-6 is over-expressed in tumor cells co-cultivated with adipocytes. {yields} IL-6 exposure confers increased Chk1 phosphorylation and radioresistance in tumor cells. -- Abstract: Mature adipocytes are excellent candidates to influence tumor behavior through heterotypic signaling processes since these cells produce hormones, growth factors, cytokines and other molecules, a heterogeneous group of molecules named adipokines. Using a 2D coculture system, we demonstrate that breast tumor cells previously co-cultivated with mature adipocytes exhibit radioresistance and an earlier and higher increase in the effector kinase Chk1, a phenotype that was associated with decreased cell death as compared to tumor cells grown alone. Interestingly, the adipocytes-induced tumor changes taking place during the coculture time preceding the exposure to IR were sufficient to confer the radioresistant effect. Notorious among the changes brought by adipocytes was the significant increase of IL-6 expression in tumor cells, whose activity may well account for the observed tumor cell protection from IR toxicity. Indeed, our data confirmed the protective role of this cytokine as tumor cells incubated after irradiation with recombinant IL-6 exhibit an increased in Chk1 phosphorylation and a radioresistant phenotype, thus far recapitulating the effects observed in the presence of adipocytes. Our current study sheds light on a new role of tumor-surrounding adipocytes in fostering a radioresistant phenotype in breast tumors, a finding that might have important clinical implications in obese patients that frequently exhibit aggressive diseases.

  19. Activation of mitochondrial promoter P{sub H}-binding protein in a radio-resistant Chinese hamster cell strain associated with Bcl-2

    SciTech Connect

    Roychoudhury, Paromita; Ghosh, Utpal . E-mail: keyachaudhuri@yahoo.com

    2006-11-17

    The cellular response to ionizing radiation is mediated by a complex interaction of number of proteins involving different pathways. Previously, we have shown that up regulation of mitochondrial genes ND1, ND4, and COX1 transcribed from the heavy strand promoter (P{sub H}) has been increased in a radio-resistant cell strain designated as M5 in comparison with the parental Chinese hamster V79 cells. These genes are also up regulated in Chinese hamster V79 cells VB13 that express exogenous human Bcl2. In the present study, the expression of the gene ND6 that is expressed from the light strand promoter (P{sub L}) was found to be similar in both the cell lines, as determined by RT-PCR. To test the possibility that this differential expression of mitochondrial genes under these two promoters was mediated by differences in proteins' affinity to interact with these promoters, we have carried out electrophoretic mobility shift assay (EMSA) using mitochondrial cell extracts from these two cell lines. Our result of these experiments revealed that two different proteins formed complex with the synthetic promoters and higher amount of protein from M5 cell extracts interacted with the P{sub H} promoter in comparison to that observed with cell extracts from Chinese hamster V79 cells. The promoter-specific differential binding of proteins was also observed in VB13. These results showed that differential mitochondrial gene expression observed earlier in the radio-resistant M5 cells was due to enhanced interaction proteins with the promoters P{sub H} and mediated by the expression of Bcl2.

  20. Inflammation-induced radioresistance is mediated by ROS-dependent inactivation of protein phosphatase 1 in non-small cell lung cancer cells.

    PubMed

    Kim, Wanyeon; Youn, HyeSook; Kang, ChulHee; Youn, BuHyun

    2015-09-01

    Inflammation plays a pivotal role in modulating the radiation responsiveness of tumors. We determined that an inflammation response prior to irradiation contributes to radiotherapy resistance in non-small cell lung cancer (NSCLC) cells. In the clonogenic survival assay, activation of the inflammation response by lipopolysaccharide (LPS) decreased the degree of radiosensitivity in NCI-H460 cells (relatively radiosensitive cells), but had no effect in A549 cells (relatively radioresistant cells). LPS-induced radioresistance of NCI-H460 cells was also confirmed with a xenograft mouse model. The radioresistant effect observed in NCI-H460 cells was correlated with inhibition of apoptotic cell death due to reduced Caspase 3/7 activity. Moreover, we found that the levels of reactive oxygen species (ROS) were synergistically elevated in NCI-H460 cells by treatment with LPS and radiation. Increased ROS generation negatively affected the activity of protein phosphatase 1 (PP1). Decreased PP1 activity did not lead to Bad dephosphorylation, consequently resulting in the inhibition of irradiation-induced mitochondrial membrane potential loss and apoptosis. We confirmed that pre-treatment with a PP1 activator and LPS sensitized NCI-H460 cells to radiation. Taken together, our findings provided evidence that PP1 activity is critical for radiosensitization in NSCLC cells and PP1 activators can serve as promising radiosensitizers to improve therapeutic efficacy. PMID:26033480

  1. Leukemia inhibitory factor promotes nasopharyngeal carcinoma progression and radioresistance

    PubMed Central

    Liu, Shu-Chen; Tsang, Ngan-Ming; Chiang, Wen-Che; Chang, Kai-Ping; Hsueh, Chuen; Liang, Ying; Juang, Jyh-Lyh; Chow, Kai-Ping N.; Chang, Yu-Sun

    2013-01-01

    Radioresistance of EBV-associated nasopharyngeal carcinoma (NPC) is associated with poor prognosis for patients with this form of cancer. Here, we found that NPC patients had increased serum levels of leukemia inhibitory factor (LIF) and that higher LIF levels correlated with local tumor recurrence. Furthermore, in vitro studies with NPC cells and in vivo xenograft mouse studies demonstrated that LIF critically contributes to NPC tumor growth and radioresistance. Using these model systems, we found that LIF treatment activated the mTORC1/p70S6K signaling pathway, enhanced tumor growth, inhibited DNA damage responses, and enhanced radioresistance. Treatment with either soluble LIF receptor (sLIFR), a LIF antagonist, or the mTOR inhibitor rapamycin reversed LIF-mediated effects, resulting in growth arrest and increased sensitivity to γ irradiation. Immunohistochemical (IHC) analyses of human NPC biopsies revealed that LIF and LIFR were overexpressed in tumor cells and that LIF expression correlated with the presence of the activated p-p70S6K. Finally, we found that the EBV-encoded protein latent membrane protein 1 (LMP1) enhances LIF production. Together, our findings indicate that LIF promotes NPC tumorigenesis and suggest that serum LIF levels may predict local recurrence and radiosensitivity in NPC patients. PMID:24270418

  2. LIG4 mediates Wnt signalling-induced radioresistance.

    PubMed

    Jun, Sohee; Jung, Youn-Sang; Suh, Han Na; Wang, Wenqi; Kim, Moon Jong; Oh, Young Sun; Lien, Esther M; Shen, Xi; Matsumoto, Yoshihisa; McCrea, Pierre D; Li, Lei; Chen, Junjie; Park, Jae-Il

    2016-01-01

    Despite the implication of Wnt signalling in radioresistance, the underlying mechanisms are unknown. Here we find that high Wnt signalling is associated with radioresistance in colorectal cancer (CRC) cells and intestinal stem cells (ISCs). We find that LIG4, a DNA ligase in DNA double-strand break repair, is a direct target of β-catenin. Wnt signalling enhances non-homologous end-joining repair in CRC, which is mediated by LIG4 transactivated by β-catenin. During radiation-induced intestinal regeneration, LIG4 mainly expressed in the crypts is conditionally upregulated in ISCs, accompanied by Wnt/β-catenin signalling activation. Importantly, among the DNA repair genes, LIG4 is highly upregulated in human CRC cells, in correlation with β-catenin hyperactivation. Furthermore, blocking LIG4 sensitizes CRC cells to radiation. Our results reveal the molecular mechanism of Wnt signalling-induced radioresistance in CRC and ISCs, and further unveils the unexpected convergence between Wnt signalling and DNA repair pathways in tumorigenesis and tissue regeneration. PMID:27009971

  3. LIG4 mediates Wnt signalling-induced radioresistance

    PubMed Central

    Jun, Sohee; Jung, Youn-Sang; Suh, Han Na; Wang, Wenqi; Kim, Moon Jong; Oh, Young Sun; Lien, Esther M.; Shen, Xi; Matsumoto, Yoshihisa; McCrea, Pierre D.; Li, Lei; Chen, Junjie; Park, Jae-Il

    2016-01-01

    Despite the implication of Wnt signalling in radioresistance, the underlying mechanisms are unknown. Here we find that high Wnt signalling is associated with radioresistance in colorectal cancer (CRC) cells and intestinal stem cells (ISCs). We find that LIG4, a DNA ligase in DNA double-strand break repair, is a direct target of β-catenin. Wnt signalling enhances non-homologous end-joining repair in CRC, which is mediated by LIG4 transactivated by β-catenin. During radiation-induced intestinal regeneration, LIG4 mainly expressed in the crypts is conditionally upregulated in ISCs, accompanied by Wnt/β-catenin signalling activation. Importantly, among the DNA repair genes, LIG4 is highly upregulated in human CRC cells, in correlation with β-catenin hyperactivation. Furthermore, blocking LIG4 sensitizes CRC cells to radiation. Our results reveal the molecular mechanism of Wnt signalling-induced radioresistance in CRC and ISCs, and further unveils the unexpected convergence between Wnt signalling and DNA repair pathways in tumorigenesis and tissue regeneration. PMID:27009971

  4. Leukotriene activity modulation in asthma.

    PubMed

    Spector, S L

    1997-09-01

    Leukotrienes constitute a class of inflammatory mediators synthesised from arachidonic acid, a product of cell membrane metabolism. Synthesis occurs in the 5-lipoxygenase enzyme pathway, which produces several species of leukotrienes, each with characteristic biological activities. With regard to asthma, the leukotrienes are particularly important because of their ability to directly and potently mediate bronchoconstriction; in addition, they specifically stimulate the secretion of mucus into the airways and the extravasation of fluids and proteins into the airway tissues, both of which contribute to airway obstruction. A number of antileukotriene agents have been developed with the goal of modulating the inflammatory process in various disease states. These agents fall into 2 general classes: leukotriene receptor antagonists and leukotriene synthesis inhibitors. Results of antileukotriene agents in preclinical and clinical trials indicate that antileukotriene agents attenuate the response to challenges with inhaled leukotrienes, cold air, exercise, aspirin and allergen; in addition, they have shown efficacy in clinical asthma and have not been associated with serious adverse effects. Although results to date indicate that these medications are well tolerated and effective in the treatment of asthma, the recent approval by the FDA of 2 antileukotriene agents will give physicians further insight into how patients with asthma respond to them. PMID:9279501

  5. Submillimeter Confocal Imaging Active Module

    NASA Technical Reports Server (NTRS)

    Hong, John; Mehdi, Imran; Siegel, Peter; Chattopadhyay, Goutam; Cwik, Thomas; Rowell, Mark; Hacker, John

    2009-01-01

    The term submillimeter confocal imaging active module (SCIAM) denotes a proposed airborne coherent imaging radar system that would be suitable for use in reconnaissance, surveillance, and navigation. The development of the SCIAM would include utilization and extension of recent achievements in monolithic microwave integrated circuits capable of operating at frequencies up to and beyond a nominal radio frequency of 340 GHz. Because the SCIAM would be primarily down-looking (in contradistinction to primarily side-looking), it could be useful for imaging shorter objects located between taller ones (for example, objects on streets between buildings). The SCIAM would utilize a confocal geometry to obtain high cross-track resolution, and would be amenable to synthetic-aperture processing of its output to obtain high along-track resolution. The SCIAM (see figure) would include multiple (two in the initial version) antenna apertures, separated from each other by a cross-track baseline of suitable length (e.g., 1.6 m). These apertures would both transmit the illuminating radar pulses and receive the returns. A common reference oscillator would generate a signal at a controllable frequency of (340 GHz + (Delta)f)/N, where (Delta)f is an instantaneous swept frequency difference and N is an integer. The output of this oscillator would be fed to a frequency- multiplier-and-power-amplifier module to obtain a signal, at 340 GHz + (Delta)f, that would serve as both the carrier signal for generating the transmitted pulses and a local-oscillator (LO) signal for a receiver associated with each antenna aperture. Because duplexers in the form of circulators or transmit/receive (T/R) switches would be lossy and extremely difficult to implement, the antenna apertures would be designed according to a spatial-diplexing scheme, in which signals would be coupled in and out via separate, adjacent transmitting and receiving feed horns. This scheme would cause the transmitted and received beams

  6. Active combustion flow modulation valve

    DOEpatents

    Hensel, John Peter; Black, Nathaniel; Thorton, Jimmy Dean; Vipperman, Jeffrey Stuart; Lambeth, David N; Clark, William W

    2013-09-24

    A flow modulation valve has a slidably translating hollow armature with at least one energizable coil wound around and fixably attached to the hollow armature. The energizable coil or coils are influenced by at least one permanent magnet surrounding the hollow armature and supported by an outer casing. Lorentz forces on the energizable coils which are translated to the hollow armature, increase or decrease the flow area to provide flow throttling action. The extent of hollow armature translation depends on the value of current supplied and the direction of translation depends on the direction of current flow. The compact nature of the flow modulation valve combined with the high forces afforded by the actuator design provide a flow modulation valve which is highly responsive to high-rate input control signals.

  7. Radioresistant human lung adenocarcinoma cells that survived multiple fractions of ionizing radiation are sensitive to HSP90 inhibition.

    PubMed

    Gomez-Casal, Roberto; Epperly, Michael W; Wang, Hong; Proia, David A; Greenberger, Joel S; Levina, Vera

    2015-12-29

    Despite the common usage of radiotherapy for the treatment of NSCLC, outcomes for these cancers when treated with ionizing radiation (IR) are still unsatisfactory. A better understanding of the mechanisms underlying resistance to IR is needed to design approaches to eliminate the radioresistant cells and prevent tumor recurrence and metastases. Using multiple fractions of IR we generated radioresistant cells from T2821 and T2851 human lung adenocarcinoma cells. The radioresistant phenotypes present in T2821/R and T2851/R cells include multiple changes in DNA repair genes and proteins expression, upregulation of EMT markers, alterations of cell cycle distribution, upregulation of PI3K/AKT signaling and elevated production of growth factors, cytokines, important for lung cancer progression, such as IL-6, PDGFB and SDF-1 (CXCL12). In addition to being radioresistant these cells were also found to be resistant to cisplatin.HSP90 is a molecular chaperone involved in stabilization and function of multiple client proteins implicated in NSCLC cell survival and radioresistance. We examined the effect of ganetespib, a novel HSP90 inhibitor, on T2821/R and T2851/R cell survival, migration and radioresistance. Our data indicates that ganetespib has cytotoxic activity against parental T2821 and T2851 cells and radioresistant T2821/R and T2851/R lung tumor cells. Ganetespib does not affect proliferation of normal human lung fibroblasts. Combining IR with ganetespib completely abrogates clonogenic survival of radioresistant cells.Our data show that HSP90 inhibition can potentiate the effect of radiotherapy and eliminate radioresistant and cisplatin -resistant residual cells, thus it may aid in reducing NSCLC tumor recurrence after fractionated radiotherapy. PMID:26517240

  8. Radioresistant human lung adenocarcinoma cells that survived multiple fractions of ionizing radiation are sensitive to HSP90 inhibition

    PubMed Central

    Gomez-Casal, Roberto; Epperly, Michael W.; Wang, Hong; Proia, David A.; Greenberger, Joel S.; Levina, Vera

    2015-01-01

    Despite the common usage of radiotherapy for the treatment of NSCLC, outcomes for these cancers when treated with ionizing radiation (IR) are still unsatisfactory. A better understanding of the mechanisms underlying resistance to IR is needed to design approaches to eliminate the radioresistant cells and prevent tumor recurrence and metastases. Using multiple fractions of IR we generated radioresistant cells from T2821 and T2851 human lung adenocarcinoma cells. The radioresistant phenotypes present in T2821/R and T2851/R cells include multiple changes in DNA repair genes and proteins expression, upregulation of EMT markers, alterations of cell cycle distribution, upregulation of PI3K/AKT signaling and elevated production of growth factors, cytokines, important for lung cancer progression, such as IL-6, PDGFB and SDF-1 (CXCL12). In addition to being radioresistant these cells were also found to be resistant to cisplatin. HSP90 is a molecular chaperone involved in stabilization and function of multiple client proteins implicated in NSCLC cell survival and radioresistance. We examined the effect of ganetespib, a novel HSP90 inhibitor, on T2821/R and T2851/R cell survival, migration and radioresistance. Our data indicates that ganetespib has cytotoxic activity against parental T2821 and T2851 cells and radioresistant T2821/R and T2851/R lung tumor cells. Ganetespib does not affect proliferation of normal human lung fibroblasts. Combining IR with ganetespib completely abrogates clonogenic survival of radioresistant cells. Our data show that HSP90 inhibition can potentiate the effect of radiotherapy and eliminate radioresistant and cisplatin -resistant residual cells, thus it may aid in reducing NSCLC tumor recurrence after fractionated radiotherapy. PMID:26517240

  9. Health Activities Project (HAP): Breathing Fitness Module.

    ERIC Educational Resources Information Center

    Buller, Dave; And Others

    Contained within this Health Activities Project (HAP) learning packet are activities for children in grades 5-8. Design of the activities centers around the idea that students can control their own health and safety. Within this module are teacher and student folios describing four activities which involve students in learning how to measure their…

  10. Cancer stem cells and signaling pathways in radioresistance

    PubMed Central

    Chang, Lei; Graham, Peter; Hao, Jingli; Ni, Jie; Deng, Junli; Bucci, Joseph; Malouf, David; Gillatt, David; Li, Yong

    2016-01-01

    Radiation therapy (RT) is one of the most important strategies in cancer treatment. Radioresistance (the failure to RT) results in locoregional recurrence and metastasis. Therefore, it is critically important to investigate the mechanisms leading to cancer radioresistance to overcome this problem and increase patients' survival. Currently, the majority of the radioresistance-associated researches have focused on preclinical studies. Although the exact mechanisms of cancer radioresistance have not been fully uncovered, accumulating evidence supports that cancer stem cells (CSCs) and different signaling pathways play important roles in regulating radiation response and radioresistance. Therefore, targeting CSCs or signaling pathway proteins may hold promise for developing novel combination modalities and overcoming radioresistance. The present review focuses on the key evidence of CSC markers and several important signaling pathways in cancer radioresistance and explores innovative approaches for future radiation treatment. PMID:26716904

  11. Performance Based Education. Technology Activity Modules.

    ERIC Educational Resources Information Center

    Custer, Rodney L., Ed.

    These Technology Activity Modules are designed to serve as an implementation resource for technology education teachers as they integrate technology education with Missouri's Academic Performance Standards and provide a source of activities and activity ideas that can be used to integrate and reinforce learning across the curriculum. The modules…

  12. Impairing the radioresistance of cancer cells by hydrogenated nanodiamonds.

    PubMed

    Grall, Romain; Girard, Hugues; Saad, Lina; Petit, Tristan; Gesset, Céline; Combis-Schlumberger, Mathilde; Paget, Vincent; Delic, Jozo; Arnault, Jean-Charles; Chevillard, Sylvie

    2015-08-01

    Hydrogenated nanodiamonds (H-NDs) exhibit a negative electron affinity that confers a high reactivity with oxygen species and a positive charge in aqueous solutions. It allows electron emission from H-NDs following irradiation by photons and in consequence may enhance the effects of radiation on cancer cells. By using three human radioresistant cancer cell lines, we showed a potentialization of cytotoxicity after a co-exposure to H-NDs and irradiation; an event occurring through the induction of DNA damage and reactive oxygen species. This occurred together with a decrease in cell impedance, the activation of G1/S, an unlocking of G2 cell cycle check-points and early low cell death rate. At later stage of exposure, persistent increases in heterochromatinization, large γ-H2AX foci and β-galactosidase activity were detected providing evidence of cells' entrance into senescence. Similar potentialization was observed with neocarzinostatin (NCS), a radiomimetic drug. This original finding underlines a wide clinical potential of H-NDs to intensify radiation effects on radio-resistant cancer cells. PMID:26010122

  13. EBV-LMP1 suppresses the DNA damage response through DNA-PK/AMPK signaling to promote radioresistance in nasopharyngeal carcinoma.

    PubMed

    Lu, Jingchen; Tang, Min; Li, Hongde; Xu, Zhijie; Weng, Xinxian; Li, Jiangjiang; Yu, Xinfang; Zhao, Luqing; Liu, Hongwei; Hu, Yongbin; Tan, Zheqiong; Yang, Lifang; Zhong, Meizuo; Zhou, Jian; Fan, Jia; Bode, Ann M; Yi, Wei; Gao, Jinghe; Sun, Lunquan; Cao, Ya

    2016-09-28

    We conducted this research to explore the role of latent membrane protein 1 (LMP1) encoded by the Epstein-Barr virus (EBV) in modulating the DNA damage response (DDR) and its regulatory mechanisms in radioresistance. Our results revealed that LMP1 repressed the repair of DNA double strand breaks (DSBs) by inhibiting DNA-dependent protein kinase (DNA-PK) phosphorylation and activity. Moreover, LMP1 reduced the phosphorylation of AMP-activated protein kinase (AMPK) and changed its subcellular location after irradiation, which appeared to occur through a disruption of the physical interaction between AMPK and DNA-PK. The decrease in AMPK activity was associated with LMP1-mediated glycolysis and resistance to apoptosis induced by irradiation. The reactivation of AMPK significantly promoted radiosensitivity both in vivo and in vitro. The AMPKα (Thr172) reduction was associated with a poorer clinical outcome of radiation therapy in NPC patients. Our data revealed a new mechanism of LMP1-mediated radioresistance and provided a mechanistic rationale in support of the use of AMPK activators for facilitating NPC radiotherapy. PMID:27255972

  14. Stathmin1 increases radioresistance by enhancing autophagy in non-small-cell lung cancer cells

    PubMed Central

    Zhang, Xi; Ji, Jingfen; Yang, Yu; Zhang, Juan; Shen, Liangfang

    2016-01-01

    Radioresistance has been demonstrated to be involved in the poor prognosis of patients with non-small-cell lung cancer (NSCLC). However, the underlying mechanism remains largely unclear. Investigation on special therapeutic targets associated with radioresistance shows promises for the enhancement of clinical radiotherapy effect toward NSCLC. This study aimed to reveal the role of Stathmin1 (STMN1) in radioresistance in NSCLC as well as the underlying mechanism. Our data showed that the protein levels of STMN1 were significantly upregulated in NSCLC cells subjected to radiation, accompanied with the activation of autophagy. Knockdown of STMN1 expression enhanced the sensitivity of NSCLC cells to X-ray, and the radiation-induced autophagy was also inhibited. Molecular mechanism investigation showed that knockdown of STMN1 expression upregulated the activity of phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway in NSCLC cells. Moreover, the activation of PI3K/mTOR signaling showed an inhibitory effect on the autophagy and radioresistance induced by STMN1 in NSCLC cells. In addition, luciferase reporter assay data indicated that STMN1 was a direct target gene of miR-101, which had been reported to be an inhibitor of autophagy. Based on these data, we suggest that as a target gene of miR-101, STMN1 promotes the radioresistance by induction of autophagy through PI3K/mTOR signaling pathway in NSCLC. Therefore, STMN1 may become a potential therapeutic target for NSCLC radiotherapy. PMID:27199567

  15. Stathmin1 increases radioresistance by enhancing autophagy in non-small-cell lung cancer cells.

    PubMed

    Zhang, Xi; Ji, Jingfen; Yang, Yu; Zhang, Juan; Shen, Liangfang

    2016-01-01

    Radioresistance has been demonstrated to be involved in the poor prognosis of patients with non-small-cell lung cancer (NSCLC). However, the underlying mechanism remains largely unclear. Investigation on special therapeutic targets associated with radioresistance shows promises for the enhancement of clinical radiotherapy effect toward NSCLC. This study aimed to reveal the role of Stathmin1 (STMN1) in radioresistance in NSCLC as well as the underlying mechanism. Our data showed that the protein levels of STMN1 were significantly upregulated in NSCLC cells subjected to radiation, accompanied with the activation of autophagy. Knockdown of STMN1 expression enhanced the sensitivity of NSCLC cells to X-ray, and the radiation-induced autophagy was also inhibited. Molecular mechanism investigation showed that knockdown of STMN1 expression upregulated the activity of phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway in NSCLC cells. Moreover, the activation of PI3K/mTOR signaling showed an inhibitory effect on the autophagy and radioresistance induced by STMN1 in NSCLC cells. In addition, luciferase reporter assay data indicated that STMN1 was a direct target gene of miR-101, which had been reported to be an inhibitor of autophagy. Based on these data, we suggest that as a target gene of miR-101, STMN1 promotes the radioresistance by induction of autophagy through PI3K/mTOR signaling pathway in NSCLC. Therefore, STMN1 may become a potential therapeutic target for NSCLC radiotherapy. PMID:27199567

  16. Gaia Payload Module Testing and Analysis Activities

    NASA Astrophysics Data System (ADS)

    Soula, Laurent

    2012-07-01

    The Gaia objective is to produce a very accurate catalogue of 1 billion of sky objects in our galaxy and beyond. ASTRIUM’s extensive experience on silicon carbide (SiC) instruments has helped developing the latest-generation payload module. It integrates the most sensitive and stable telescopes ever made, mounted on a SiC torus structure supported by three bipods. This payload module has been tested in June 2011 by ASTRIUM at INTESPACE facilities in Toulouse. To conduct the sine qualification tests and support the data analyses in real-time, advanced tools have been used. Most of them have been developed in a previous ESA R&D project [1] “DYNamics: AssessMent and Improvement of TEst Data (DYNAMITED)” and implemented in a DynaWorks® environment. Mass Operator calculation, to evaluate the payload module interface loads from measured accelerations, or automatic correlation through a criterion based on FRF from tests or predictions, are part of these tools. Testing such a structure also revealed some piloting difficulties due to a quite low and varying damping of the structure and a strong coupling with the shaker. To take into account such phenomena in the correlation work, enhanced simulations have also been performed considering multi-points phased excitations. These analyses demonstrate the payload module qualification status and allow derivate a more representative model to be used in further coupled system activities.

  17. Role of glutathione in the intrinsic radioresistance of cell lines from a mouse squamous cell carcinoma

    SciTech Connect

    Miura, M.; Sasaki, T. )

    1991-05-01

    The role of glutathione (GSH) in determining the intrinsic cellular radioresistance under aerobic conditions was studied with the parent cell line MSCC and its radioresistant subclone R1 isolated from a mouse squamous cell carcinoma. The mean inactivation doses (D) of the survival curves were 2.1 and 4.0 Gy for exponentially growing MSCC and R1 cells, respectively. The corresponding GSH content was 22.6 and 13.4 nmol/10(6) cells. There was no significant difference in either the distribution of GSH between nucleus and cytoplasm or the turnover rate of GSH between the two cell lines. Thus it appeared that the radioresistance of R1 cells resulted from mechanisms unrelated to GSH. However, R1 cells became progressively more radiosensitive with a decrease of the GSH content with buthionine sulfoximine (BSO) treatment until about 20 h, and the radiosensitivity showed little change thereafter. The MSCC cells showed little change in the radiosensitivity with the same treatment. In fact, dose-survival curves showed that the enhancement ratio of D with the 24-h BSO treatment was 1.1 for MSCC and 1.4 for R1 cells, although the GSH content was reduced to 1 to 2% of the untreated level for both cell lines. There was no significant difference in the activities of GSH S-transferase and GSH reductase between MSCC and R1 cells before and after BSO treatment, or between BSO-treated and untreated cells of the same cell lines. Although the exact mechanisms of GSH-related radioresistance of R1 cells are unclear, these results suggest that there may exist GSH-related mechanisms in addition to radical scavenging which determine the intrinsic cellular radioresistance under aerobic conditions.

  18. MET inhibitor PHA-665752 suppresses the hepatocyte growth factor-induced cell proliferation and radioresistance in nasopharyngeal carcinoma cells

    SciTech Connect

    Liu, Tongxin; Li, Qi; Sun, Quanquan; Zhang, Yuqin; Yang, Hua; Wang, Rong; Chen, Longhua; Wang, Wei

    2014-06-20

    Highlights: • We demonstrated that irradiation induced MET overexpression and activation. • The aberrant MET signal mediated by HGF induced proliferation and radioresistance of NPC cells. • MET inhibitor PHA-665752 effectively suppressed HGF induced cell proliferation and radioresistance in NPC cells. • PHA-665752 suppressed the three downstream pathway of HGF/MET signal in a dose-dependent manner. - Abstract: Although ionizing radiation (IR) has provided considerable improvements in nasopharyngeal carcinoma (NPC), in subsets of patients, radioresistance is still a major problem in the treatment. In this study, we demonstrated that irradiation induced MET overexpression and activation, and the aberrant MET signal mediated by hepatocyte growth factor (HGF) induced radioresistance. We also found that MET inhibitor PHA-665752 effectively suppressed HGF induced cell proliferation and radioresistance in NPC cells. Further investigation indicated that PHA-665752 suppressed the phosphorylation of the Akt, ERK1/2, and STAT3 proteins in a dose-dependent manner. Our data indicated that the combination of IR with a MET inhibitor, such as PHA-665752, might be a promising therapeutic strategy for NPC.

  19. Targeting the AKT/GSK3{beta}/Cyclin D1/Cdk4 Survival Signaling Pathway for Eradication of Tumor Radioresistance Acquired by Fractionated Radiotherapy

    SciTech Connect

    Shimura, Tsutomu; Kakuda, Satoshi; Ochiai, Yasushi; Kuwahara, Yoshikazu; Takai, Yoshihiro; Fukumoto, Manabu

    2011-06-01

    Purpose: Radioresistance is a major cause of treatment failure of radiotherapy (RT) in human cancer. We have recently revealed that acquired radioresistance of tumor cells induced by fractionated radiation is attributable to cyclin D1 overexpression as a consequence of the downregulation of GSK3{beta}-dependent cyclin D1 proteolysis mediated by a constitutively activated serine-threonine kinase, AKT. This prompted us to hypothesize that targeting the AKT/GSK3{beta}/cyclin D1 pathway may improve fractionated RT by suppressing acquired radioresistance of tumor cells. Methods and Materials: Two human tumor cell lines with acquired radioresistance were exposed to X-rays after incubation with either an AKT inhibitor, AKT/PKB signaling inhibitor-2 (API-2), or a Cdk4 inhibitor (Cdk4-I). Cells were then subjected to immunoblotting, clonogenic survival assay, cell growth analysis, and cell death analysis with TUNEL and annexin V staining. In vivo radiosensitivity was assessed by growth of human tumors xenografted into nude mice. Results: Treatment with API-2 resulted in downregulation of cyclin D1 expression in cells with acquired radioresistance. Cellular radioresistance disappeared completely both in vitro and in vivo with accompanying apoptosis when treated with API-2. Furthermore, inhibition of cyclin D1/Cdk4 by Cdk4-I was sufficient for abolishing radioresistance. Treatment with either API-2 or Cdk4-I was also effective in suppressing resistance to cis-platinum (II)-diamine-dichloride in the cells with acquired radioresistance. Interestingly, the radiosensitizing effect of API-2 was canceled by overexpression of cyclin D1 whereas Cdk4-I was still able to sensitize cells with cyclin D1 overexpression. Conclusion: Cyclin D1/Cdk4 is a critical target of the AKT survival signaling pathway responsible for tumor radioresistance. Targeting the AKT/GSK3{beta}/cyclin D1/Cdk4 pathway would provide a novel approach to improve fractionated RT and would have an impact on tumor

  20. Lysyl oxidase mediates hypoxia-induced radioresistance in non-small cell lung cancer A549 cells.

    PubMed

    Gong, Chongwen; Gu, Runxia; Jin, Honglin; Sun, Yao; Li, Zhenyu; Chen, Jing; Wu, Gang

    2016-02-01

    Hypoxia-induced radioresistance has been well known as the main obstacle in cancer radiotherapy. Lysyl oxidase (LOX) was previously demonstrated to play an important role in hypoxia-induced biological behaviors, such as metastasis and angiogenesis, through hypoxia-inducible factor-1α (HIF-1α), which is an important contributing factor to radioresistance in tumor cells. However, how LOX plays a role in hypoxia-induced radioresistance has yet to be determined. Here, we found that LOX expression was in accordance with HIF-1α expression, and LOX expression at the mRNA and protein level, and enzymatic activity were remarkably upregulated in the hypoxic A549 cells, compared with normoxic A549 cells. Inhibition of LOX resulted in the reduction of the ability to repair double-stranded breaks (DSBs), promotion of apoptosis, relief of G2/M cycle arrest, and eventually reduction of hypoxia-induced radioresistance in the hypoxic A549 cells. This suggests that LOX may play an important role in hypoxia-induced radioresistance. Together, our results might suggest a novel potential therapeutic target in the management of non-small cell lung cancer (NSCLC). PMID:26515140

  1. World Energy Projection System Plus (WEPS ): Global Activity Module

    EIA Publications

    2013-01-01

    World Energy Projection System Plus Model Documentation: Global Activity Module Documents the objectives, analytical approach, and development of the World Energy Projection Plus (WEPS ) Global Activity Module (GAM) used to develop the International Energy Outlook for 2013 (IEO2013). The report catalogues and describes the module assumptions, computations, methodology, parameter estimation techniques, and mainframe source code.

  2. Hypoxia-inducible factor 1–mediated characteristic features of cancer cells for tumor radioresistance

    PubMed Central

    Harada, Hiroshi

    2016-01-01

    Tumor hypoxia has been attracting increasing attention in the fields of radiation biology and oncology since Thomlinson and Gray detected hypoxic cells in malignant solid tumors and showed that they exert a negative impact on the outcome of radiation therapy. This unfavorable influence has, at least partly, been attributed to cancer cells acquiring a radioresistant phenotype through the activation of the transcription factor, hypoxia-inducible factor 1 (HIF-1). On the other hand, accumulating evidence has recently revealed that, even though HIF-1 is recognized as an important regulator of cellular adaptive responses to hypoxia, it may not become active and induce tumor radioresistance under hypoxic conditions only. The mechanisms by which HIF-1 is activated in cancer cells not only under hypoxic conditions, but also under normoxic conditions, through cancer-specific genetic alterations and the resultant imbalance in intermediate metabolites have been summarized herein. The relevance of the HIF-1–mediated characteristic features of cancer cells, such as the production of antioxidants through reprogramming of the glucose metabolic pathway and cell cycle regulation, for tumor radioresistance has also been reviewed. PMID:26983985

  3. Involvement of cdc25c in cell cycle alteration of a radioresistant lung cancer cell line established with fractionated ionizing radiation.

    PubMed

    Li, Jie; Yang, Chun-Xu; Mei, Zi-Jie; Chen, Jing; Zhang, Shi-Min; Sun, Shao-Xing; Zhou, Fu-Xiang; Zhou, Yun-Feng; Xie, Cong-Hua

    2013-01-01

    Cancer patients often suffer from local tumor recurrence after radiation therapy. Cell cycling, an intricate sequence of events which guarantees high genomic fidelity, has been suggested to affect DNA damage responses and eventual radioresistant characteristics of cancer cells. Here, we established a radioresistant lung cancer cell line, A549R , by exposing the parental A549 cells to repeated γ-ray irradiation with a total dose of 60 Gy. The radiosensitivity of A549 and A549R was confirmed using colony formation assays. We then focused on examination of the cell cycle distribution between A549 and A549R and found that the proportion of cells in the radioresistant S phase increased, whereas that in the radiosensitive G1 phase decreased. When A549 and A549R cells were exposed to 4 Gy irradiation the total differences in cell cycle redistribution suggested that G2-M cell cycle arrest plays a predominant role in mediating radioresistance. In order to further explore the possible mechanisms behind the cell cycle related radioresistance, we examined the expression of Cdc25 proteins which orchestrate cell cycle transitions. The results showed that expression of Cdc25c increased accompanied by the decrease of Cdc25a and we proposed that the quantity of Cdc25c, rather than activated Cdc25c or Cdc25a, determines the radioresistance of cells. PMID:24289569

  4. CpG Oligodeoxynucleotide1826 combined with radioresistant cancer cell vaccine confers significant antitumor effects.

    PubMed

    Zhuang, X B; Xing, N; Zhang, Q; Yuan, S J; Chen, W; Qiao, T K

    2015-01-01

    Immunotherapy is a hot issue in cancer research over the years and tumor cell vaccine is one of the increasing number of studies. Although the whole tumor cell vaccine can provide the best source of immunizing antigens, there is still a limitation that most tumors are not naturally immunogenic. CpG Oligodeoxynucleotides (CpG ODNs), synthetic oligonucleotides containing a cytosine-phosphate-guanine(CpG) motif, was shown to enhance immune responses to a wide variety of antigens. In this study, we generated the radioresistant Lewis lung cancer cell by repeated X-ray radiation and inactivated it as a whole tumor cell vaccine to enhance the immunogenicity of tumor cell vaccine. Mice were subcutaneously immunized with this inactivated vaccine combined with CpG ODN1826 and then inoculated with autologous Lewis lung cancer (LLC) to estimate the antitumor efficacy. The results showed that the radioresistant tumor cell vaccine combined with CpG ODN1826 could significantly inhibit tumor growth, increased survival of the mice and with 20% of the mice surviving tumor free in vivo compared with the unimmunized mice bearing LLC tumor. A significant increase of apoptosis was also observed in the tumor prophylactically immunized with vaccine of inactivated radioresistant tumor cell plus CpG ODN1826. The potent antitumor effect correlated with higher secretion levels of tumor necrosis factor-alpha(TNF-α) and lower levels of interleukin-10(IL-10) concentration in serum. Furthermore, the results suggested that the antitumor mechanism was probably depended on the decreased level of programmed death ligand-1(PD-L1) which plays an important role in the negative regulation of immune response by the inhibition of tumor antigen-specific T cell activation. These findings clearly demonstrated that the radioresistant tumor cell vaccine combined with CpG ODN1826 as an appropriate adjuvant could induce effective antitumor immunity in vivo. PMID:26458317

  5. Revision of the DELFIC Particle Activity Module

    SciTech Connect

    Hooper, David A; Jodoin, Vincent J

    2010-09-01

    The Defense Land Fallout Interpretive Code (DELFIC) was originally released in 1968 as a tool for modeling fallout patterns and for predicting exposure rates. Despite the continual advancement of knowledge of fission yields, decay behavior of fission products, and biological dosimetry, the decay data and logic of DELFIC have remained mostly unchanged since inception. Additionally, previous code revisions caused a loss of conservation of radioactive nuclides. In this report, a new revision of the decay database and the Particle Activity Module is introduced and explained. The database upgrades discussed are replacement of the fission yields with ENDF/B-VII data as formatted in the Oak Ridge Isotope Generation (ORIGEN) code, revised decay constants, revised exposure rate multipliers, revised decay modes and branching ratios, and revised boiling point data. Included decay logic upgrades represent a correction of a flaw in the treatment of the fission yields, extension of the logic to include more complex decay modes, conservation of nuclides (including stable nuclides) at all times, and conversion of key variables to double precision for nuclide conservation. Finally, recommended future work is discussed with an emphasis on completion of the overall radiation physics upgrade, particularly for dosimetry, induced activity, decay of the actinides, and fractionation.

  6. Radiation-induced microrna-622 causes radioresistance in colorectal cancer cells by down-regulating Rb

    PubMed Central

    Liang, Li; Zhang, Yan; Ding, Yi; Lin, Xiaoshan; Li, Guoxin; Ding, Yanqing

    2015-01-01

    The standard treatment for patients with locally advanced rectal cancer is preoperative 5-fluorouracil-based chemoradiotherapy followed by total mesorectal excision. However, tumor response to standard dose radiation varies. In this study, we found that miR-622 was increased significantly in ionizing radiation-treated colorectal cancer (CRC) cells compared to the cells cultured with irradiated medium, and persisted stably in surviving cells treated with continuous low-dose radiation. Overexpression of miR-622 induced the radioresistance in vitro. In addition, miR-622 inhibited Rb expression by directly targeting RB1-3′UTR. Overexpression of Rb reversed miR-622-induced radioresistance in vitro. In response to ionizing radiation, the Rb-E2F1-P/CAF complex activated proapoptotic genes. Importantly, miR-622 was highly expressed in tumors of rectal cancer patients with non-regression after standard dose radiotherapy. In conclusion, miR-622 overexpressing cells are induced or selected by radiotherapy, causing in turn radioresistance and poor response to further therapy. MiR-622 is a potential biomarker of responders for radiotherapy and a potential therapeutic target. PMID:25961730

  7. E-Cadherin loss associated with EMT promotes radioresistance in human tumor cells

    PubMed Central

    Theys, Jan; Jutten, Barry; Habets, Roger; Paesmans, Kim; Groot, Arjan J.; Lambin, Philippe; Wouters, Brad G.

    2016-01-01

    Background and purpose Hypoxia is a hallmark of solid cancers and associated with metastases and treatment failure. During tumor progression epithelial cells often acquire mesenchymal features, a phenomenon known as epithelial-to-mesenchymal transition (EMT). Intratumoral hypoxia has been linked to EMT induction. We hypothesized that signals from the tumor microenvironment such as growth factors and tumor oxygenation collaborate to promote EMT and thereby contribute to radioresistance. Materials and methods Gene expression changes under hypoxia were analyzed using microarray and validated by qRT-PCR. Conversion of epithelial phenotype upon hypoxic exposure, TGFβ addition or oncogene activation was investigated by Western blot and immunofluorescence. Cell survival following ionizing radiation was assayed using clonogenic survival. Results Upon hypoxia, TGFβ addition or EGFRvIII expression, MCF7, A549 and NMuMG epithelial cells acquired a spindle shape and lost cell–cell contacts. Expression of epithelial markers such as E-cadherin decreased, whereas mesenchymal markers such as vimentin and N-cadherin increased. Combining hypoxia with TGFβ or EGFRvIII expression, lead to more rapid and pronounced EMT-like phenotype. Interestingly, E-cadherin expression and the mesenchymal appearance were reversible upon reoxygenation. Mesenchymal conversion and E-cadherin loss were associated with radioresistance. Conclusions Our findings describe a mechanism by which the tumor microenvironment may contribute to tumor radioresistance via E-cadherin loss and EMT. PMID:21680037

  8. Deinococcus radiodurans pprI expression enhances the radioresistance of eukaryotes.

    PubMed

    Wen, Ling; Yue, Ling; Shi, Yi; Ren, Lili; Chen, Tingting; Li, Na; Zhang, Shuyu; Yang, Wei; Yang, Zhanshan

    2016-03-29

    PprI accelerates radiation-induced DNA damage repair via regulating the expression of DNA repair genes and enhances antioxidative enzyme activity in Deinococcus radiodurans after radiation. The main aim of our study was to determine whether the expression of pprI gene could fulfil its DNA repair function in eukaryotes and enhance the radioresistance of eukaryotic organism or not. In this study, we constructed pEGFP-c1-pprI eukaryotic expression vector and established a human lung epithelial cell line BEAS-2B with stable integration of pprI gene. We found that pprIexpression enhanced radioresistance of BEAS-2B cells, decreased γ-H2AX foci formation and apoptosis in irradiated BEAS-2B cells and alleviated radiation induced G2/M arrest of BEAS-2B cells. Moreover, we transferred pEGFP-c1-pprI vector into muscle of BALB/c mice by in vivo electroporation and studied the protective effect of prokaryotic pprI gene in irradiated mice. We found that pprI expression alleviated acute radiation induced hematopoietic system, lung, small intestine and testis damage and increased survival rate of irradiated mice via regulating Rad51 expression in different organs. These findings suggest that prokaryotic pprI gene expression in mammalian cells could enhance radioresistance in vitro and in vivo. PMID:26992215

  9. Deinococcus radiodurans pprI expression enhances the radioresistance of eukaryotes

    PubMed Central

    Wen, Ling; Yue, Ling; Shi, Yi; Ren, Lili; Chen, Tingting; Li, Na; Zhang, Shuyu; Yang, Wei; Yang, Zhanshan

    2016-01-01

    PprI accelerates radiation-induced DNA damage repair via regulating the expression of DNA repair genes and enhances antioxidative enzyme activity in Deinococcus radiodurans after radiation. The main aim of our study was to determine whether the expression of pprI gene could fulfil its DNA repair function in eukaryotes and enhance the radioresistance of eukaryotic organism or not. In this study, we constructed pEGFP-c1-pprI eukaryotic expression vector and established a human lung epithelial cell line BEAS-2B with stable integration of pprI gene. We found that pprIexpression enhanced radioresistance of BEAS-2B cells, decreased γ-H2AX foci formation and apoptosis in irradiated BEAS-2B cells and alleviated radiation induced G2/M arrest of BEAS-2B cells. Moreover, we transferred pEGFP-c1-pprI vector into muscle of BALB/c mice by in vivo electroporation and studied the protective effect of prokaryotic pprI gene in irradiated mice. We found that pprI expression alleviated acute radiation induced hematopoietic system, lung, small intestine and testis damage and increased survival rate of irradiated mice via regulating Rad51 expression in different organs. These findings suggest that prokaryotic pprI gene expression in mammalian cells could enhance radioresistance in vitro and in vivo. PMID:26992215

  10. Hypoxia-induced autophagy as an additional mechanism in human osteosarcoma radioresistance.

    PubMed

    Feng, Helin; Wang, Jin; Chen, Wei; Shan, Baoen; Guo, Yin; Xu, Jianfa; Wang, Ling; Guo, Peng; Zhang, Yingze

    2016-06-01

    Osteosarcoma (OS) responds poorly to radiotherapy, but the mechanism is unclear. We found OS tumor tissues expressed high level of protein HIF-1α, a common biological marker indicative of hypoxia. It is known that hypoxic cells are generally radioresistant because of reduced production of irradiation-induced DNA-damaging reactive oxygen species (ROS) in the anaerobic condition. Here we report another mechanism how hypoxia induces radioresistance. In MG-63 human osteosarcoma cells, hypoxic pretreatment increased the cellular survival in irradiation. These hypoxia-exposed cells displayed compartmental recruitment of GFP-tagged LC3 and expression of protein LC3-II, and restored the radiosensitivity upon autophagy inhibition. The following immunohistochemistry of OS tumor tissue sections revealed upregulated LC3 expression in a correlation with HIF-1α protein level, implying the possibly causative link between hypoxia and autophagy. Further studies in MG-63 cells demonstrated hypoxic pretreatment reduced cellular and mitochondrial ROS production during irradiation, while inhibition of autophagy re-elicited them. Taken together, our study suggests hypoxia can confer cells resistance to irradiation through activated autophagy to accelerate the clearance of cellular ROS products. This might exist in human osteosarcoma as an additional mechanism for radioresistance. PMID:27335774

  11. Rotavirus infection activates the UPR but modulates its activity

    PubMed Central

    2011-01-01

    Background Rotaviruses are known to modulate the innate antiviral defense response driven by IFN. The purpose of this study was to identify changes in the cellular proteome in response to rotavirus infection in the context of the IFN response. We also sought to identify proteins outside the IFN induction and signaling pathway that were modulated by rotavirus infection. Methods 2D-DIGE and image analysis were used to identify cellular proteins that changed in levels of expression in response to rotavirus infection, IFN treatment, or IFN treatment prior to infection. Immunofluorescence microscopy was used to determine the subcellular localization of proteins associated with the unfolded protein response (UPR). Results The data show changes in the levels of multiple proteins associated with cellular stress in infected cells, including levels of ER chaperones GRP78 and GRP94. Further investigations showed that GRP78, GRP94 and other proteins with roles in the ER-initiated UPR including PERK, CHOP and GADD34, were localized to viroplasms in infected cells. Conclusions Together the results suggest rotavirus infection activates the UPR, but modulates its effects by sequestering sensor, transcription factor, and effector proteins in viroplasms. The data consequently also suggest that viroplasms may directly or indirectly play a fundamental role in regulating signaling pathways associated with cellular defense responses. PMID:21774819

  12. Radiation response mechanisms of the extremely radioresistant bacterium Deinococcus radiodurans.

    PubMed

    Kobayashi, Yasuhiko; Narumi, Issay; Satoh, Katsuya; Funayama, Tomoo; Kikuchi, Masahiro; Kitayama, Shigeru; Watanabe, Hiroshi

    2004-11-01

    Effect of microgravity on recovery of bacterial cells from radiation damage was examined in IML-2, S/MM-4 and S/MM-9 experiments using the extremely radioresistant bacterium Deinococcus radiodurans. The cells were irradiated with gamma rays before the space flight and incubated on board the Space Shuttle. The survival of the wild type cells incubated in space increased compared with the ground controls, suggesting that the recovery of this bacterium from radiation damage was enhanced under the space environment. No difference was observed between the survivals of radiosensitive mutant rec30 cells incubated in space and on the ground. The amount of DNA-repair related RecA protein induced under microgravity was similar to those of ground controls, however, induction of PprA protein, product of a unique radiation-inducible gene (designated pprA) responsible for loss of radiation resistance in repair-deficient mutant, KH311, was enhanced under microgravity compared with ground controls. Recent investigation in vitro showed that PprA preferentially bound to double-stranded DNA carrying strand breaks, inhibited Escherichia coli exonuclease III activity, and stimulated the DNA end-joining reaction catalyzed by DNA ligases. These results suggest that D. radiodurans has a radiation-induced non-homologous end-joining (NHEJ) repair mechanism in which PprA plays a critical role. PMID:15858357

  13. Space station group activities habitability module study

    NASA Technical Reports Server (NTRS)

    Nixon, David

    1986-01-01

    This study explores and analyzes architectural design approaches for the interior of the Space Station Habitability Module (originally defined as Habitability Module 1 in Space Station Reference Configuration Decription, JSC-19989, August 1984). In the Research Phase, architectural program and habitability design guidelines are specified. In the Schematic Design Phase, a range of alternative concepts is described and illustrated with drawings, scale-model photographs and design analysis evaluations. Recommendations are presented on the internal architectural, configuration of the Space Station Habitability Module for such functions as the wardroom, galley, exercise facility, library and station control work station. The models show full design configurations for on-orbit performance.

  14. mRNA and microRNA expression profiles of radioresistant NCI-H520 non-small cell lung cancer cells

    PubMed Central

    GUO, WEI; XIE, LI; ZHAO, LONG; ZHAO, YUEHUAN

    2015-01-01

    To elucidate the mechanism of radioresistance in non-small cell lung cancer (NSCLC) cells and to identify key molecules conferring radioresistance, the radioresistant subclone NCI-H520/R, derived from the NCI-H520 NSCLC cell line, was established with eight rounds of sublethal irradiation. The radioresistant features were subsequently assessed using a clonogenic assay, analysis of apoptosis and an MTT assay, the gene expression levels were examined using an Agilent Whole Human Genome 4×44 k Oligo microarray and Agilent Human miRCURY™ LNA array, and confirmed by reverse transcription-quantitative polymerase chain reaction. Pathway analysis and Gene Ontology (GO) analysis were performed to determine the biological functions of the subset of differentially expressed genes. miRNA-mRNA correlation analysis between the expression levels of each miRNA and all its predicted target genes was performed to further understand the radioresistance in the NCI-H520 cells. Following eight rounds of sublethal irradiation, a total of 2,862 mRNAs were significantly differentially expressed in the NCI-H520/R cells, including 893 upregulated genes and 1,969 downregulated genes. A total of 162 upregulated miRNAs and 274 downregulated miRNAs were significantly deregulated in the NCI-H520/R cells. Multiple core regulatory processes and signaling pathways were identified as being of likely relevance to radioresistance in NCI-H520/R cells, including the mitogen-activated protein kinase signaling pathway and neurotrophin signaling pathway. The expression of genes associated with radioresistance reflects the complex biological processes involved in clinical cancer cell eradication and requires further investigation for future enhancement of therapy. PMID:25873351

  15. mRNA and microRNA expression profiles of radioresistant NCI-H520 non-small cell lung cancer cells.

    PubMed

    Guo, Wei; Xie, Li; Zhao, Long; Zhao, Yuehuan

    2015-08-01

    To elucidate the mechanism of radioresistance in non-small cell lung cancer (NSCLC) cells and to identify key molecules conferring radioresistance, the radioresistant subclone NCI-H520/R, derived from the NCI-H520 NSCLC cell line, was established with eight rounds of sublethal irradiation. The radioresistant features were subsequently assessed using a clonogenic assay, analysis of apoptosis and an MTT assay, the gene expression levels were examined using an Agilent Whole Human Genome 4 x 44 k Oligo microarray and Agilent Human miRCURY(™) LNA array, and confirmed by reverse transcription-quantitative polymerase chain reaction. Pathway analysis and Gene Ontology (GO) analysis were performed to determine the biological functions of the subset of differentially expressed genes. miRNA-mRNA correlation analysis between the expression levels of each miRNA and all its predicted target genes was performed to further understand the radioresistance in the NCI-H520 cells. Following eight rounds of sublethal irradiation, a total of 2,862 mRNAs were significantly differentially expressed in the NCI-H520/R cells, including 893 upregulated genes and 1,969 downregulated genes. A total of 162 upregulated miRNAs and 274 downregulated miRNAs were significantly deregulated in the NCI-H520/R cells. Multiple core regulatory processes and signaling pathways were identified as being of likely relevance to radioresistance in NCI-H520/R cells, including the mitogen-activated protein kinase signaling pathway and neurotrophin signaling pathway. The expression of genes associated with radioresistance reflects the complex biological processes involved in clinical cancer cell eradication and requires further investigation for future enhancement of therapy. PMID:25873351

  16. 2-Methoxyestradiol, an Endogenous Estrogen Metabolite, Sensitizes Radioresistant MCF-7/FIR Breast Cancer Cells Through Multiple Mechanisms

    SciTech Connect

    Salama, Salama; Diaz-Arrastia, Concepcion; Patel, Deepa; Botting, Shaleen; Hatch, Sandra

    2011-05-01

    Purpose: The requirement for a well-tolerated and highly effective radiosensitizer that preferentially sensitizes tumor cells at multiple levels of radioresistance remains largely unmet. 2-Methoxyestradiol (2ME) has polypharmacological profiles that target multiple signaling pathways involved in the development of radioresistance. In the current study, we investigated the radiosensitizing effect of 2ME on the radioresistant breast cancer MCF-7/FIR cell line and explored the underlying mechanisms. Methods and Materials: The radiosensitizing effect of 2ME was evaluated on the basis of cell death and clonogenic survival. Formation of reactive oxygen species (ROS), apoptosis, and cell cycle progression were assessed by flow cytometry. Radiation-induced DNA damage was evaluated on the basis of histone {gamma}-H2AX phosphorylation and foci formation. Immunoblotting was used to assess the effects of {gamma} radiation and/or 2ME on radioresistance pathways. Results: Our data demonstrate that MCF-7/FIR cells expressed higher levels of Bcl-2 and HIF-1{alpha} and displayed a lower ROS phenotype than the parental MCF-7 cells. Treatment of parental MCF-7 cells with 2ME (0.5 {mu}M) had minimal effect on {gamma} radiation-induced cell proliferation and surviving fractions. On the contrary, in MCF-7/FIR cells, treatment with 2ME significantly enhanced {gamma} radiation-induced reduction in cell proliferation and surviving fraction. This combination was effective in activating apoptosis, arresting the cell cycle at the G{sub 2}/M phase, and increasing the level of {gamma} radiation-induced ROS and the number of {gamma}-H2AX foci. In addition, 2ME significantly ameliorated {gamma} radiation-induced expression of the HIF-1{alpha} transcription factor and its downstream targets AKT/mTOR. Conclusion: 2ME preferentially sensitizes radioresistant MCF-7/FIR cells to {gamma} radiation by targeting multiple signaling pathways involved in the development of radioresistance. This

  17. DIFFERENTIAL CONTRIBUTION OF β-ADRENERGIC RECEPTORS EXPRESSED ON RADIOSENSITIVE VERSUS RADIORESISTANT CELLS TO PROTECTION AGAINST INFLAMMATION AND MORTALITY IN MURINE ENDOTOXEMIA

    PubMed Central

    Walker-Brown, Jill; Roberts, Margo R.

    2010-01-01

    The sympathetic nervous system modulates immune responses via the secretion of catecholamines and subsequent activation of adrenergic receptors (ARs), and systemic catecholamine levels increase markedly in the setting of endotoxemia and sepsis. Previous studies have demonstrated that stimulation of β-ARs by pharmacological agonists attenuates the inflammatory response to LPS observed in vitro, and can increase survival in animal models of endotoxemia and sepsis. However, the consequences of β-AR activation by endogenous catecholamines have not been explored in these settings. Furthermore, the relative contribution of β-ARs expressed on immune versus non-immune cells to LPS-mediated inflammation and mortality is not known. Our first goal was therefore to determine the impact of β-AR stimulation by endogenous catecholamines released during endotoxemia on LPS-mediated inflammation and mortality in vivo. To address this question, we examined the LPS response of mice lacking all three known βAR subtypes, β1-, β2- and β3-AR, and demonstrated that these β-less mice exhibited a net increase in inflammation (increased TNF-α levels and decreased IL-10 levels in serum) and a 50% decrease in survival relative to wildtype animals. The second goal of our study was to determine the relative contribution of β-ARs expressed on radiosensitive immune versus radioresistant cells to the protective action of β-ARs in the setting of endotoxemia. We therefore examined the LPS response of bone marrow chimeras generated between β-less and wildtype mice, and concluded that β-ARs expressed on radioresistant cells play the dominant role in protecting against LPS-mediated mortality and attenuating systemic TNF-α responses. Finally, we determined that β3-AR subtype does not play a significant role in regulating LPS-mediated mortality and inflammation, by evaluating mice lacking the β1- and β2-AR subtypes only. PMID:19333138

  18. PICALM modulates autophagy activity and tau accumulation

    PubMed Central

    Moreau, Kevin; Fleming, Angeleen; Imarisio, Sara; Lopez Ramirez, Ana; Mercer, Jacob L.; Jimenez-Sanchez, Maria; Bento, Carla F.; Puri, Claudia; Zavodszky, Eszter; Siddiqi, Farah; Lavau, Catherine P.; Betton, Maureen; O’Kane, Cahir J.; Wechsler, Daniel S.; Rubinsztein, David C.

    2014-01-01

    Genome-wide association studies have identified several loci associated with Alzheimer’s disease (AD), including proteins involved in endocytic trafficking such as PICALM/CALM (phosphatidylinositol binding clathrin assembly protein). It is unclear how these loci may contribute to AD pathology. Here we show that CALM modulates autophagy and alters clearance of tau, a protein which is a known autophagy substrate and which is causatively linked to AD, both in vitro and in vivo. Furthermore, altered CALM expression exacerbates tau-mediated toxicity in zebrafish transgenic models. CALM influences autophagy by regulating the endocytosis of SNAREs, such as VAMP2, VAMP3 and VAMP8, which have diverse effects on different stages of the autophagy pathway, from autophagosome formation to autophagosome degradation. This study suggests that the AD genetic risk factor CALM modulates autophagy, and this may affect disease in a number of ways including modulation of tau turnover. PMID:25241929

  19. miRNA-148b regulates radioresistance in non-small lung cancer cells via regulation of MutL homologue 1.

    PubMed

    Zhai, Guangsheng; Li, Gaozhong; Xu, Bo; Jia, Tongfu; Sun, Yinping; Zheng, Jianbo; Li, Jianbin

    2016-07-01

    Radioresistance represents a major obstacle in cancer treatment, the underlying mechanism of which is complex and not well understood. miR-148b has been reported to be implicated regulating radioresistance in lymphoma cells. However, this function has not been investigated in lung cancer cells. Microarray analysis was performed in A549 cells 48 h after exposure to 8 Gy of γ-irradiation or sham irradiation to identify differentially expressed miRNAs. miR-148b mimic and inhibitor were transfected, followed by clonogenic survival assay to examine response to irradiation in A549 cells. Western Blot and luciferase assay were performed to investigate the direct target of miR-148b Xenograft mouse models were used to examine in vivo function of miR-148b Our data showed that expression of miR-148b was significantly down-regulated in both serum and cancerous tissues of radioresistant lung cancer patients compared with radiosensitive patients. Overexpression of miR-148b reversed radioresistance in A549 cells. MutL homologue 1 (MLH1) is the direct target of miR-148b which is required for the regulatory role of miR-148b in radioresistance. miR-148b mimic sensitized A549 xenografts to irradiation in vivo Our study demonstrated that miR-148b regulates radioresistance of lung cancer cells by modulating MLH1 expression level. miR-148b may represent a new therapeutic target for the intervention of lung cancer. PMID:26759383

  20. Basic Activated Sludge. Training Module 2.115.2.77.

    ERIC Educational Resources Information Center

    Kirkwood Community Coll., Cedar Rapids, IA.

    This document is an instructional module package prepared in objective form for use by an instructor familiar with operation of activated sludge wastewater treatment plants. Included are objectives, instructor guides, student handouts, and transparency masters. This is the first of a three module series and considers definition of terms, design…

  1. Intermediate Activated Sludge. Training Module 2.116.3.77.

    ERIC Educational Resources Information Center

    Kirkwood Community Coll., Cedar Rapids, IA.

    This document is an instructional module package prepared in objective form for use by an instructor familiar with operation of activated sludge wastewater treatment plants. Included are objectives, instructor guides, student handouts and transparency masters. This is the second level of a three module series and considers aeration devices,…

  2. Infant Smiling during Social Interaction: Arousal Modulation or Activation Indicator?

    ERIC Educational Resources Information Center

    Ewy, Richard

    In a study of infant smiling, 20 mother-infant dyads were videotaped in normal face-to-face interaction when the infants were 9 and 14 weeks of age. Videotapes were used to determine which of two classes of smiling behavior models, either arousal modulation or activation indicator, was most supported by empirical data. Arousal modulation models…

  3. Advanced Activated Sludge. Training Module 2.117.4.77.

    ERIC Educational Resources Information Center

    Kirkwood Community Coll., Cedar Rapids, IA.

    This document is an instructional module package prepared in objective form for use by an instructor familiar with operation of activated sludge wastewater treatment plants. Included are objectives, instructor guides, student handouts and transparency masters. This is the third level of a three module series and considers design and operation…

  4. Intercultural Orientation Activities for International ESL Students: 50 Module Lessons.

    ERIC Educational Resources Information Center

    Villarreal, Linda

    Fifty modules are presented for increasing the cultural and linguistic fluency of English-as-a-Second-Language (ESL) students by integrating cultural awareness activities with language practice. The modules are intended for international students at an intermediate language level; they can, however, be used or adapted for beginning or advanced…

  5. Conditional Radioresistance of tet-Inducible Manganese Superoxide Dismutase Bone Marrow Stromal Cell Lines

    PubMed Central

    Epperly, Michael W.; Chaillet, J. Richard; Kalash, Ronny; Shaffer, Ben; Goff, Julie; Franicola, Darcy; Zhang, Xichen; Dixon, Tracy; Houghton, Frank; Wang, Hong; Berhane, Hebist; Romero, Cynthia; Kim, Jee-Hong; Greenberger, Joel S.

    2013-01-01

    Mitochondrial targeted manganese superoxide dismutase is a major antioxidant enzyme, the levels of which modulate the response of cells, tissues and organs to ionizing irradiation. We developed a Tet-regulated MnSOD mouse (MnSODtet) to examine the detailed relationship between cellular MnSOD concentration and radioresistance and carried out in vitro studies using bone marrow culture derived stromal cell lines (mesenchymal stem cells). Homozygous MnSODtet/tet cells had low levels of MnSOD, reduced viability and proliferation, increased radiosensitivity, elevated overall antioxidant stores, and defects in cell proliferation and DNA strand-break repair. Doxycycline (doxy) treatment of MnSODtet/tet cells increased MnSOD levels and radioresistance from ñ of 2.79 ± 1.04 to 8.69 ± 1.09 (P = 0.0060) and normalized other biologic parameters. In contrast, MnSODtet/tet cells showed minimal difference in baseline and radiation induced mRNA and protein levels of TGF-β, Nrf2 and NF-κB and radiation induced cell cycle arrest was not dependent upon MnSOD level. These novel MnSODtet/tet mouse derived cells should be valuable for elucidating several parameters of the oxidative stress response to ionizing radiation. PMID:23862693

  6. Conditional radioresistance of Tet-inducible manganese superoxide dismutase bone marrow stromal cell lines.

    PubMed

    Epperly, Michael W; Chaillet, J Richard; Kalash, Ronny; Shaffer, Ben; Goff, Julie; Franicola, Darcy; Zhang, Xichen; Dixon, Tracy; Houghton, Frank; Wang, Hong; Berhane, Hebist; Romero, Cynthia; Kim, Jee-Hong; Greenberger, Joel S

    2013-08-01

    Mitochondrial targeted manganese superoxide dismutase is a major antioxidant enzyme, the levels of which modulate the response of cells, tissues and organs to ionizing irradiation. We developed a Tet-regulated MnSOD mouse (MnSOD(tet)) to examine the detailed relationship between cellular MnSOD concentration and radioresistance and carried out in vitro studies using bone marrow culture derived stromal cell lines (mesenchymal stem cells). Homozygous MnSOD(tet/tet) cells had low levels of MnSOD, reduced viability and proliferation, increased radiosensitivity, elevated overall antioxidant stores, and defects in cell proliferation and DNA strand-break repair. Doxycycline (doxy) treatment of MnSOD(tet/tet) cells increased MnSOD levels and radioresistance from ñ of 2.79 ± 1.04 to 8.69 ± 1.09 (P = 0.0060) and normalized other biologic parameters. In contrast, MnSOD(tet/tet) cells showed minimal difference in baseline and radiation induced mRNA and protein levels of TGF-β, Nrf2 and NF-κB and radiation induced cell cycle arrest was not dependent upon MnSOD level. These novel MnSOD(tet/tet) mouse derived cells should be valuable for elucidating several parameters of the oxidative stress response to ionizing radiation. PMID:23862693

  7. Wireless multi-level terahertz amplitude modulator using active metamaterial-based spatial light modulation.

    PubMed

    Rout, Saroj; Sonkusale, Sameer

    2016-06-27

    The ever increasing demand for bandwidth in wireless communication systems will inevitably lead to the extension of operating frequencies toward the terahertz (THz) band known as the 'THz gap'. Towards closing this gap, we present a multi-level amplitude shift keying (ASK) terahertz wireless communication system using terahertz spatial light modulators (SLM) instead of traditional voltage mode modulation, achieving higher spectral efficiency for high speed communication. The fundamental principle behind this higher efficiency is the conversion of a noisy voltage domain signal to a noise-free binary spatial pattern for effective amplitude modulation of a free-space THz carrier wave. Spatial modulation is achieved using an an active metamaterial array embedded with pseudomorphic high-electron mobility (pHEMT) designed in a consumer-grade galium-arsenide (GaAs) integrated circuit process which enables electronic control of its THz transmissivity. Each array is assembled as individually controllable tiles for transmissive terahertz spatial modulation. Using the experimental data from our metamaterial based modulator, we show that a four-level ASK digital communication system has two orders of magnitude improvement in symbol error rate (SER) for a degradation of 20 dB in transmit signal-to-noise ratio (SNR) using spatial light modulation compared to voltage controlled modulation. PMID:27410614

  8. Lin28-let7 Modulates Radiosensitivity of Human Cancer Cells With Activation of K-Ras

    SciTech Connect

    Oh, Jee-Sun.; Kim, Jae-Jin; Byun, Ju-Yeon; Kim, In-Ah

    2010-01-15

    Purpose: To evaluate the potential of targeting Lin28-let7 microRNA regulatory network for overcoming the radioresistance of cancer cells having activated K-Ras signaling. Methods and Materials: A549 lung carcinoma cells and ASPC1 pancreatic cancer cells possessing K-RAS mutation were transfected with pre-let7a microRNA or Lin28 siRNA, respectively. Clonogenic assay, quantitative reverse transcription polymerase chain reaction, and Western analysis were performed. The effects of Lin28 on SQ20B cells having wild-type K-RAS, and a normal fibroblast were also assessed. Results: The overexpression of let-7a decreased expression of K-Ras and radiosensitized A549 cells. Inhibition of Lin28, a repressor of let-7, attenuated K-Ras expression and radiosensitized A549 and ASPC1 cells. Neither SQ20B cells expressing wild-type K-RAS nor HDF, the normal human fibroblasts, were radiosensitized by this approach. Conclusions: The Lin28-let7 regulatory network may be a potentially useful therapeutic target for overcoming the radioresistance of human cancers having activated K-Ras signaling.

  9. [Radiosensitivity and/or radioresistance of head and neck cancers: Biological angle].

    PubMed

    Guy, Jean-Baptiste; Rancoule, Chloé; Méry, Benoîte; Espenel, Sophie; Wozny, Anne-Sophie; Simonet, Stéphanie; Vallard, Alexis; Alphonse, Gersende; Ardail, Dominique; Rodriguez-Lafrasse, Claire; Magné, Nicolas

    2016-01-01

    Radiation therapy is a cornerstone of head and neck cancer management. Technological improvements in recent years in radiation therapy, with intensity-modulated techniques, reinforce even more its role. However, both local and locoregional relapses are still observed. Understanding biological mechanisms of treatment resistance is a topic of major interest. From the cancer cell itself, its ability to repair and proliferate, its microenvironment and oxygenation conditions, migratory and invasive capacity, to biological parameters related to the patient, there are many mechanisms involving radiosensitivity and/or radioresistance of head and neck cancer. The present study explores the main biological mechanisms involved in radiation resistance of head and neck cancer, and describes promising therapeutic approaches. PMID:26702507

  10. The acquired radioresistance in HeLa cells under conditions mimicking hypoxia was attenuated by a decreased expression of HIF subunit genes induced by RNA interference

    SciTech Connect

    Doi, Nobutaka; Ogawa, Ryohei; Cui, Zheng-Guo; Morii, Akihiro; Watanabe, Akihiko; Kanayama, Shinji; Yoneda, Yuko; Kondo, Takashi

    2015-05-01

    The cancer cells residing in the hypoxic layer are resistant to radiation and these are ones responsible for cancer recurrence after radiation therapy. One of the reasons why hypoxic cancer cells acquire radioresistance may be attributable to changes in the gene expression profile by the activation of hypoxia inducible factors (HIFs). However, the details underlying this process remain unknown. In this study, we investigated the effects of knockdown of HIF subunit genes to elucidate how HIF subunit genes may be involved in the radioresistance acquired by HeLa cells following exposure to a hypoxia mimic. Interestingly, HIF-1α and HIF-2α seemed mutually complementary for each other when either of them was suppressed. We thus suppressed the expression of both genes simultaneously. To do this, we developed a short hairpin RNA (shRNA) targeting a high homology region between HIF-1α and HIF-2α. It was shown that the expression of the shRNA effectively suppressed the acquisition of radioresistance following the hypoxia mimic. Moreover, it was confirmed that suppression of both subunits resulted in the downregulation of stem cell markers and the suppression of spheroid formation during the hypoxia mimicking-conditions. This shRNA-mediated knockdown method targeting a common region shared by a family of genes may offer a new candidate cancer treatment. - Highlights: • Incubation with CoCl{sub 2} confers radioresistance to HeLa cells. • Both HIF-1α and HIF-2α are involved in the acquisition of radioresistance. • An shRNA to a homology region of HIF-1α and HIF-2α suppressed the radioresistance. • The shRNA decreased cells with stem cell markers and a stem cell phenotype.

  11. PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways.

    PubMed

    Chang, L; Graham, P H; Hao, J; Ni, J; Bucci, J; Cozzi, P J; Kearsley, J H; Li, Y

    2014-01-01

    The PI3K/Akt/mTOR pathway has a central role in cancer metastasis and radiotherapy. To develop effective therapeutics to improve radiosensitivity, understanding the possible pathways of radioresistance involved and the effects of a combination of the PI3K/Akt/mTOR inhibitors with radiotherapy on prostate cancer (CaP) radioresistant cells is needed. We found that compared with parent CaP cells, CaP-radioresistant cells demonstrated G0/G1 and S phase arrest, activation of cell cycle check point, autophagy and DNA repair pathway proteins, and inactivation of apoptotic proteins. We also demonstrated that compared with combination of single PI3K or mTOR inhibitors (BKM120 or Rapamycin) and radiation, low-dose of dual PI3K/mTOR inhibitors (BEZ235 or PI103) combined with radiation greatly improved treatment efficacy by repressing colony formation, inducing more apoptosis, leading to the arrest of the G2/M phase, increased double-strand break levels and less inactivation of cell cycle check point, autophagy and non-homologous end joining (NHEJ)/homologous recombination (HR) repair pathway proteins in CaP-radioresistant cells. This study describes the possible pathways associated with CaP radioresistance and demonstrates the putative mechanisms of the radiosensitization effect in CaP-resistant cells in the combination treatment. The findings from this study suggest that the combination of dual PI3K/Akt/mTOR inhibitors (BEZ235 or PI103) with radiotherapy is a promising modality for the treatment of CaP to overcome radioresistance. PMID:25275598

  12. Nonlinear active wave modulation approach for microdamage detection

    NASA Astrophysics Data System (ADS)

    Wu, Hwai-Chung; Warnemuende, Kraig

    2001-07-01

    Several nondestructive testing methods can be used to estimate the extents of damage in a concrete structure. Pulse-velocity and amplitude attenuation, are very common in nondestructive ultrasonic evaluation. Velocity of propagation is not very sensitive to the degrees of damage unless a great deal of micro-damage having evolving into localized macro-damage. Amplitude attenuation is potentially more sensitive than pulse-velocity. However, this method depends strongly on the coupling conditions between transducers and concrete, hence unreliable. A new active modulation approach, Nonlinear Active Wave Modulation Spectroscopy, is adopted in our study. In this procedure, a probe wave will be passed through the system in a similar fashion to regular acoustics. Simultaneously, a second, low frequency modulating wave will be applied to the system to effectively change the size and stiffness of flaws microscopically and cyclically, thereby causing the frequency modulation to change cyclically as well. The resulting amplified modulations will be correlated to the extents of damage with the effect that even slight damage should become quantifiable. This study unveils the potential of nonlinear frequency analysis methods for micro-damage detection and evaluation using actively modulated acoustic signals. This method can interrogate materials exaggerating the nonlinearly that exists due to microcracking and deterioration.

  13. Radiation-induced radioresistance of mammals and risk assessment

    NASA Astrophysics Data System (ADS)

    Smirnova, O.; Yonezawa, M.

    It is shown experimentally that a preliminary low dose exposure can induce radioresistance in mice in two (early and late) periods after preirradiation. The manifestation of such effects is reduced mortality of pre-exposed specimens after challenge acute irradiation, the reason of the animal death being the hematopoietic subsyndrome of the acute radiation syndrome. Therefore, proceeding from the radiobiological concept of the critical system, the theoretical investigation of the influence of preirradiation on mammalian radiosensitivity is conducted by making use of mathematical models of the vital body system, hematopoiesis. Modeling results make it possible to elucidate the mechanisms of the radioprotection effect of low level priming irradiation on mammals. Specifically, the state of acquired radioresistance in mice is caused by reduced radiosensitivity of lymphopoietic and thrombocytopoietic systems in the early period and by reduced radiosensitivity of granulocytopoietic system in the late period after preirradiation. It is important to emphasize that the evaluations of the duration of the early and late periods of postirradiation radioresistance in mice, carried out on the basis of the modeling and experimental investigations, practically coincide. All this demonstrates the effectiveness of joint modeling and experimental methods in studies and predictions of modification effects of preirradiation on mammalian radiosensitivity. The results obtained show the importance of accounting such effects in radiation risk assessments for cosmonauts and astronauts on long-term missions.

  14. Role of Natural Radiosensitizers and Cancer Cell Radioresistance: An Update

    PubMed Central

    Sultana, Misbah; Qazi, Aamer; Qazi, Mahmood Husain; Parveen, Gulshan; Waquar, Sulayman; Ashraf, Abdul Basit; Rasool, Mahmood

    2016-01-01

    Cancer originates from genetic mutations accumulation. Cancer stem cells have been depicted as tumorigenic cells that can differentiate and self-renew. Cancer stem cells are thought to be resistant to conventional therapy like chemotherapy and radiation therapy. Radiation therapy and chemotherapy damage carcinomic DNA cells. Because of the ability of cancer stem cells to self-renew and reproduce malignant tumors, they are the subject of intensive research. In this review, CSCs radioresistant mechanisms which include DNA damage response and natural radiosensitizers have been summed up. Reactive oxygen species play an important role in different physiological processes. ROS scavenging is responsible for regulation of reactive oxygen species generation. A researcher has proved that microRNAs regulate tumor radiation resistance. Ionizing radiation does not kill the cancer cells; rather, IR just slows down the signs and symptoms. Ionizing radiation damages DNA directly/indirectly. IR is given mostly in combination with other chemo/radiotherapies. We briefly described here the behavior of cancer stem cells and radioresistance therapies in cancer treatment. To overcome radioresistance in treatment of cancer, strategies like fractionation modification, treatment in combination, inflammation modification, and overcoming hypoxic tumor have been practiced. Natural radiosensitizers, for example, curcumin, genistein, and quercetin, are more beneficial than synthetic compounds. PMID:26998418

  15. Mitochondrial targeting of a catalase transgene product by plasmid liposomes increases radioresistance in vitro and in vivo.

    PubMed

    Epperly, Michael W; Melendez, J A; Zhang, Xichen; Nie, Suhua; Pearce, Linda; Peterson, James; Franicola, Darcy; Dixon, Tracy; Greenberger, Benjamin A; Komanduri, Paavani; Wang, Hong; Greenberger, Joel S

    2009-05-01

    To determine whether increased mitochondrially localized catalase was radioprotective, a human catalase transgene was cloned into a small pSVZeo plasmid and localized to the mitochondria of 32D cl 3 cells by adding the mitochondrial localization sequence of MnSOD (mt-catalase). The cell lines 32D-Cat and 32D-mt-Cat had increased catalase biochemical activity as confirmed by Western blot analysis compared to the 32D cl 3 parent cells. The MnSOD-overexpressing 32D cl 3 cell line, 2C6, had decreased baseline catalase activity that was increased in 2C6-Cat and 2C6-mt-Cat subclonal cell lines. 32D-mt-Cat cells were more radioresistant than 32D-Cat cells, but both were radioresistant relative to 32D cl 3 cells. 2C6-mt-Cat cells but not 2C6-Cat cells were radioresistant compared to 2C6 cells. Intratracheal injection of the mt-catalase-plasmid liposome complex (mt-Cat-PL) but not the catalase-plasmid liposome complex (Cat-PL) increased the resistance of C57BL/6NHsd female mice to 20 Gy thoracic irradiation compared to MnSOD-plasmid liposomes. Thus mitochondrially targeted overexpression of the catalase transgene is radioprotective in vitro and in vivo. PMID:19580494

  16. A calcium-insensitive attenuated nitrosative stress response contributes significantly in the radioresistance of Sf9 insect cells.

    PubMed

    Suman, Shubhankar; Seth, Rakesh Kumar; Chandna, Sudhir

    2011-09-01

    Lepidopteran insects/insect cells display 50-100 times higher radioresistance than humans, and are evolutionarily closest to mammals amongst all radioresistant organisms known. Compared to mammalian cells, Lepidopteran cells (TN-368, Sf9) display more efficient antioxidant system and DNA repair and suffer considerably less radiation-induced DNA/cytogenetic damage and apoptosis. Recent studies indicate that a considerably lower radiation-induced oxidative stress may significantly reduce macromolecular damage in Lepidopteran cells. Since nitrosative stress contributes in radiation-induced cellular damage, we investigated its nature in the γ-irradiated Sf9 cells (derived from Spodoptera frugiperda; order Lepidoptera; family Noctuidae) and compared with BMG-1 human cell line having significant NOS expression. Radiation induced considerably less ROS/RNS in Sf9 cells, which remained unchanged on treatment with NOS inhibitor l-NMMA. Surprisingly, growth of Sf9 cultures or irradiation could not induce NO or its metabolites, indicating negligible basal/radiation-induced NOS activity that remained unchanged even after supplementation with arginine. Cytosolic calcium release following high-dose (1000-2000Gy at 61.1cGys(-1)) γ-irradiation or H(2)O(2) (250μM) treatment also failed to generate NO in Sf9 cells having high constitutive levels of calmodulin, whereas BMG-1 cells displayed considerable calcium-dependent NO generation even following 10Gy dose. These results strongly imply the lack of calcium-mediated NOS activity in Sf9 cells. Addition of exogenous NO from GSH-NO caused considerable increase in radiation-induced apoptosis, indicating significant contribution of constitutively attenuated nitrosative stress response into the radioresistance of Lepidopteran cells. Our study demonstrates for the first time that a calcium-insensitive, attenuated nitrosative stress response may contribute significantly in the unusual radioresistance displayed by Lepidopteran insect cells

  17. Modulation of Brain Activity during Phonological Familiarization

    ERIC Educational Resources Information Center

    Majerus, S.; Van der Linden, M.; Collette, F.; Laureys, S.; Poncelet, M.; Degueldre, C.; Delfiore, G.; Luxen, A.; Salmon, E.

    2005-01-01

    We measured brain activity in 12 adults for the repetition of auditorily presented words and nonwords, before and after repeated exposure to their phonological form. The nonword phoneme combinations were either of high (HF) or low (LF) phonotactic frequency. After familiarization, we observed, for both word and nonword conditions, decreased…

  18. DANGER is involved in high glucose-induced radioresistance through inhibiting DAPK-mediated anoikis in non-small cell lung cancer

    PubMed Central

    Kim, Daehoon; Seong, Ki Moon; Park, Sungkyun; Kim, Wanyeon; Youn, BuHyun

    2016-01-01

    18F-labeled fluorodeoxyglucose (FDG) uptake during FDG positron emission tomography seems to reflect increased radioresistance. However, the exact molecular mechanism underlying high glucose (HG)-induced radioresistance is unclear. In the current study, we showed that ionizing radiation-induced activation of the MEK-ERK-DAPK-p53 signaling axis is required for anoikis (anchorage-dependent apoptosis) of non-small cell lung cancer (NSCLC) cells in normal glucose media. Phosphorylation of DAPK at Ser734 by ERK was essential for p53 transcriptional activity and radiosensitization. In HG media, overexpressed DANGER directly bound to the death domain of DAPK, thus inhibiting the catalytic activity of DAPK. In addition, inhibition of the DAPK-p53 signaling axis by DANGER promoted anoikis-resistance and epithelial-mesenchymal transition (EMT), resulting in radioresistance of HG-treated NSCLC cells. Notably, knockdown of DANGER enhanced anoikis, EMT inhibition, and radiosensitization in a mouse xenograft model of lung cancer. Taken together, our findings offered evidence that overexpression of DANGER and the subsequent inhibitory effect on DAPK kinase activity are critical responses that account for HG-induced radioresistance of NSCLC. PMID:26769850

  19. [Peptidergic modulation of the hippocampus synaptic activity].

    PubMed

    Skrebitskiĭ, V G; Kondratenko, R V; Povarov, I S; Dereviagin, V I

    2011-11-01

    Effects of two newly synthesized nootropic and anxiolytic dipeptides: Noopept and Selank on inhibitory synaptic transmission in hippocampal CA1 pyramidal cells were investigated using patch-clamp technique in whole-cell configuration. Bath application of Noopept (1 microM) or Selank (2 microM) significantly increased the frequency of spike-dependent spontaneous m1PSCs, whereas spike-independent mlPSCs remained unchanged. It was suggested that both peptides mediated their effect sue to activation of inhibitory interneurons terminating on CA1 pyramidal cells. Results of current clamp recording of inhibitory interneurons residing in stratum radiatum confirmed this suggestion, at least for Noonent. PMID:22390072

  20. Infraslow EEG activity modulates cortical excitability in postanoxic encephalopathy

    PubMed Central

    Tjepkema-Cloostermans, Marleen C.; Hofmeijer, Jeannette

    2015-01-01

    Infraslow activity represents an important component of physiological and pathological brain function. We study infraslow activity (<0.1 Hz) in 41 patients with postanoxic coma after cardiac arrest, including the relationship between infraslow activity and EEG power in the 3–30 Hz range, using continuous full-band scalp EEG. In all patients, infraslow activity (0.015–0.06 Hz) was present, irrespective of neurological outcome or EEG activity in the conventional frequency bands. In two patients, low-amplitude (10–30 μV) infraslow activity was present while the EEG showed no rhythmic activity above 0.5 Hz. In 13/15 patients with a good outcome and 20/26 patients with a poor one, EEG power in the 3–30 Hz frequency range was correlated with the phase of infraslow activity, quantified by the modulation index. In 9/14 patients with burst-suppression with identical bursts, bursts appeared in clusters, phase-locked to the infraslow oscillations. This is substantiated by a simulation of burst-suppression in a minimal computational model. Infraslow activity is preserved in postanoxic encephalopathy and modulates cortical excitability. The strongest modulation is observed in patients with severe postanoxic encephalopathy and burst-suppression with identical bursts. PMID:25695645

  1. Epithelial sodium channel modulates platelet collagen activation.

    PubMed

    Cerecedo, Doris; Martínez-Vieyra, Ivette; Alonso-Rangel, Lea; Benítez-Cardoza, Claudia; Ortega, Arturo

    2014-03-01

    Activated platelets adhere to the exposed subendothelial extracellular matrix and undergo a rapid cytoskeletal rearrangement resulting in shape change and release of their intracellular dense and alpha granule contents to avoid hemorrhage. A central step in this process is the elevation of the intracellular Ca(2+) concentration through its release from intracellular stores and on throughout its influx from the extracellular space. The Epithelial sodium channel (ENaC) is a highly selective Na(+) channel involved in mechanosensation, nociception, fluid volume homeostasis, and control of arterial blood pressure. The present study describes the expression, distribution, and participation of ENaC in platelet migration and granule secretion using pharmacological inhibition with amiloride. Our biochemical and confocal analysis in suspended and adhered platelets suggests that ENaC is associated with Intermediate filaments (IF) and with Dystrophin-associated proteins (DAP) via α-syntrophin and β-dystroglycan. Migration assays, quantification of soluble P-selectin, and serotonin release suggest that ENaC is dispensable for migration and alpha and dense granule secretion, whereas Na(+) influx through this channel is fundamental for platelet collagen activation. PMID:24679405

  2. Muscle metaboreceptor modulation of cutaneous active vasodilation

    NASA Technical Reports Server (NTRS)

    Crandall, C. G.; Stephens, D. P.; Johnson, J. M.

    1998-01-01

    PURPOSE: Isometric handgrip exercise in hyperthermia has been shown to reduce cutaneous vascular conductance (CVC) by inhibiting the cutaneous active vasodilator system. METHODS: To identify whether this response was initiated by muscle metaboreceptors, in seven subjects two 3-min bouts of isometric handgrip exercise in hyperthermia were performed, followed by 2 min of postexercise ischemia (PEI). An index of forearm skin blood flow (laser-Doppler flowmetry) was measured on the contralateral arm at an unblocked site and at a site at which adrenergic vasoconstrictor function was blocked via bretylium iontophoresis to reveal active cutaneous vasodilator function unambiguously. Sweat rate was measured via capacitance hygrometry, CVC was indexed from the ratio of skin blood flow to mean arterial pressure and was expressed as a percentage of maximal CVC at that site. In normothermia, neither isometric exercise nor PEI affected CVC (P > 0.05). RESULTS: The first bout of isometric handgrip exercise in hyperthermia reduced CVC at control sites and this reduction persisted through PEI (pre-exercise: 59.8 +/- 5.4, exercise: 49.8 +/- 4.9, PEI: 49.7 +/- 5.3% of maximum; both P < 0.05), whereas there were no significant changes in CVC at the bretylium treated sites. The succeeding bout of isometric exercise in hyperthermia significantly reduced CVC at both untreated (pre-exercise: 59.0 +/- 4.8, exercise: 47.3 +/- 4.0, PEI: 50.1 +/- 4.1% of maximum; both P < 0.05) and bretylium treated sites (pre-exercise: 61.4 +/- 7.3, exercise: 50.6 +/- 5.1, PEI: 53.9 +/- 6.0% of maximum, both P < 0.05). At both sites, CVC during PEI was lower than during the pre-exercise period (P < 0.05). Sweat rate rose significantly during both bouts of isometric exercise and remained elevated during PEI. CONCLUSIONS: These data suggest that the reduction in CVC during isometric exercise in hyperthermia, including the inhibition of the active vasodilator system, is primarily mediated by muscle

  3. Phosphorylation Modulates Catalytic Activity of Mycobacterial Sirtuins

    PubMed Central

    Yadav, Ghanshyam S.; Ravala, Sandeep K.; Malhotra, Neha; Chakraborti, Pradip K.

    2016-01-01

    Sirtuins are NAD+-dependent deacetylases involved in the regulation of diverse cellular processes and are conserved throughout phylogeny. Here we report about in vitro transphosphorylation of the only NAD+-dependent deacetylase (mDAC) present in the genome of Mycobacterium tuberculosis by eukaryotic-type Ser/Thr kinases, particularly PknA. The phosphorylated mDAC displayed decreased deacetylase activity compared to its unphosphorylated counterpart. Mass-spectrometric study identified seven phosphosites in mDAC; however, mutational analysis highlighted major contribution of Thr-214 for phosphorylation of the protein. In concordance to this observation, variants of mDAC substituting Thr-214 with either Ala (phospho-ablated) or Glu (phosphomimic) exhibited significantly reduced deacetylase activity suggesting phosphorylation mediated control of enzymatic activity. To assess the role of phosphorylation towards functionality of mDAC, we opted for a sirtuin knock-out strain of Escherichia coli (Δdac), where interference of endogenous mycobacterial kinases could be excluded. The Δdac strain in nutrient deprived acetate medium exhibited compromised growth and complementation with mDAC reversed this phenotype. The phospho-ablated or phosphomimic variant, on the other hand, was unable to restore the functionality of mDAC indicating the role of phosphorylation per se in the process. We further over-expressed mDAC or mDAC-T214A as His-tagged protein in M. smegmatis, where endogenous eukaryotic-type Ser/Thr kinases are present. Anti-phosphothreonine antibody recognized both mDAC and mDAC-T214A proteins in western blotting. However, the extent of phosphorylation as adjudged by scanning the band intensity, was significantly low in the mutant protein (mDAC-T214A) compared to that of the wild-type (mDAC). Furthermore, expression of PknA in the mDAC complemented Δdac strain was able to phosphorylate M. tuberculosis sirtuin. The growth profile of this culture in acetate medium was

  4. Total Cellular RNA Modulates Protein Activity.

    PubMed

    Majumder, Subhabrata; DeMott, Christopher M; Reverdatto, Sergey; Burz, David S; Shekhtman, Alexander

    2016-08-16

    RNA constitutes up to 20% of a cell's dry weight, corresponding to ∼20 mg/mL. This high concentration of RNA facilitates low-affinity protein-RNA quinary interactions, which may play an important role in facilitating and regulating biological processes. In the yeast Pichia pastoris, the level of ubiquitin-RNA colocalization increases when cells are grown in the presence of dextrose and methanol instead of methanol as the sole carbon source. Total RNA isolated from cells grown in methanol increases β-galactosidase activity relative to that seen with RNA isolated from cells grown in the presence of dextrose and methanol. Because the total cellular RNA content changes with growth medium, protein-RNA quinary interactions can alter in-cell protein biochemistry and may play an important role in cell adaptation, critical to many physiological and pathological states. PMID:27456029

  5. Chemoprotective activity of boldine: modulation of drug-metabolizing enzymes.

    PubMed

    Kubínová, R; Machala, M; Minksová, K; Neca, J; Suchý, V

    2001-03-01

    Possible chemoprotective effects of the naturally occurring alkaloid boldine, a major alkaloid of boldo (Peumus boldus Mol.) leaves and bark, including in vitro modulations of drug-metabolizing enzymes in mouse hepatoma Hepa-1 cell line and mouse hepatic microsomes, were investigated. Boldine manifested inhibition activity on hepatic microsomal CYP1A-dependent 7-ethoxyresorufin O-deethylase and CYP3A-dependent testosterone 6 beta-hydroxylase activities and stimulated glutathione S-transferase activity in Hepa-1 cells. In addition to the known antioxidant activity, boldine could decrease the metabolic activation of other xenobiotics including chemical mutagens. PMID:11265593

  6. Staufen Negatively Modulates MicroRNA Activity in Caenorhabditis elegans

    PubMed Central

    Ren, Zhiji; Veksler-Lublinsky, Isana; Morrissey, David; Ambros, Victor

    2016-01-01

    The double-stranded RNA-binding protein Staufen has been implicated in various posttranscriptional gene regulatory processes. Here, we demonstrate that the Caenorhabditis elegans homolog of Staufen, STAU-1, functionally interacts with microRNAs. Loss-of-function mutations of stau-1 significantly suppress phenotypes of let-7 family microRNA mutants, a hypomorphic allele of dicer, and a lsy-6 microRNA partial loss-of-function mutant. Furthermore, STAU-1 modulates the activity of lin-14, a target of lin-4 and let-7 family microRNAs, and this modulation is abolished when the 3′ untranslated region of lin-14 is removed. Deep sequencing of small RNA cDNA libraries reveals no dramatic change in the levels of microRNAs or other small RNA populations between wild-type and stau-1 mutants, with the exception of certain endogenous siRNAs in the WAGO pathway. The modulation of microRNA activity by STAU-1 does not seem to be associated with the previously reported enhanced exogenous RNAi (Eri) phenotype of stau-1 mutants, since eri-1 exhibits the opposite effect on microRNA activity. Altogether, our results suggest that STAU-1 negatively modulates microRNA activity downstream of microRNA biogenesis, possibly by competing with microRNAs for binding on the 3′ untranslated region of target mRNAs. PMID:26921297

  7. Staufen Negatively Modulates MicroRNA Activity in Caenorhabditis elegans.

    PubMed

    Ren, Zhiji; Veksler-Lublinsky, Isana; Morrissey, David; Ambros, Victor

    2016-01-01

    The double-stranded RNA-binding protein Staufen has been implicated in various posttranscriptional gene regulatory processes. Here, we demonstrate that the Caenorhabditis elegans homolog of Staufen, STAU-1, functionally interacts with microRNAs. Loss-of-function mutations of stau-1 significantly suppress phenotypes of let-7 family microRNA mutants, a hypomorphic allele of dicer, and a lsy-6 microRNA partial loss-of-function mutant. Furthermore, STAU-1 modulates the activity of lin-14, a target of lin-4 and let-7 family microRNAs, and this modulation is abolished when the 3' untranslated region of lin-14 is removed. Deep sequencing of small RNA cDNA libraries reveals no dramatic change in the levels of microRNAs or other small RNA populations between wild-type and stau-1 mutants, with the exception of certain endogenous siRNAs in the WAGO pathway. The modulation of microRNA activity by STAU-1 does not seem to be associated with the previously reported enhanced exogenous RNAi (Eri) phenotype of stau-1 mutants, since eri-1 exhibits the opposite effect on microRNA activity. Altogether, our results suggest that STAU-1 negatively modulates microRNA activity downstream of microRNA biogenesis, possibly by competing with microRNAs for binding on the 3' untranslated region of target mRNAs. PMID:26921297

  8. Hydrophobic Core Flexibility Modulates Enzyme Activity in HIV-1 Protease

    SciTech Connect

    Mittal, Seema; Cai, Yufeng; Nalam, Madhavi N.L.; Bolon, Daniel N.A.; Schiffer, Celia A.

    2012-09-11

    Human immunodeficiency virus Type-1 (HIV-1) protease is crucial for viral maturation and infectivity. Studies of protease dynamics suggest that the rearrangement of the hydrophobic core is essential for enzyme activity. Many mutations in the hydrophobic core are also associated with drug resistance and may modulate the core flexibility. To test the role of flexibility in protease activity, pairs of cysteines were introduced at the interfaces of flexible regions remote from the active site. Disulfide bond formation was confirmed by crystal structures and by alkylation of free cysteines and mass spectrometry. Oxidized and reduced crystal structures of these variants show the overall structure of the protease is retained. However, cross-linking the cysteines led to drastic loss in enzyme activity, which was regained upon reducing the disulfide cross-links. Molecular dynamics simulations showed that altered dynamics propagated throughout the enzyme from the engineered disulfide. Thus, altered flexibility within the hydrophobic core can modulate HIV-1 protease activity, supporting the hypothesis that drug resistant mutations distal from the active site can alter the balance between substrate turnover and inhibitor binding by modulating enzyme activity.

  9. Curcumin Modulates the Radiosensitivity of Colorectal Cancer Cells by Suppressing Constitutive and Inducible NF-{kappa}B Activity

    SciTech Connect

    Sandur, Santosh K.; Deorukhkar, Amit; Pandey, Manoj K.; Pabon, Ana Maria B.S.; Shentu, Shujun; Guha, Sushovan; Aggarwal, Bharat B.; Krishnan, Sunil

    2009-10-01

    Purpose: Radiation therapy is an integral part of the preoperative treatment of rectal cancers. However, only a minority of patients achieve a complete pathologic response to therapy because of resistance of these tumors to radiation therapy. This resistance may be mediated by constitutively active pro-survival signaling pathways or by inducible/acquired mechanisms in response to radiation therapy. Simultaneous inhibition of these pathways can sensitize these tumors to radiation therapy. Methods and Materials: Human colorectal cancer cells were exposed to clinically relevant doses of gamma rays, and the mechanism of their radioresistance was investigated. We characterized the transcription factor nuclear factor-{kappa}B (NF-{kappa}B) activation as a mechanism of inducible radioresistance in colorectal cancer and used curcumin, the active ingredient in the yellow spice turmeric, to overcome this resistance. Results: Curcumin inhibited the proliferation and the post-irradiation clonogenic survival of multiple colorectal cancer cell lines. Radiation stimulated NF-{kappa}B activity in a dose- and time-dependent manner, whereas curcumin suppressed this radiation-induced NF-{kappa}B activation via inhibition of radiation-induced phosphorylation and degradation of inhibitor of {kappa}B alpha, inhibition of inhibitor of {kappa}B kinase activity, and inhibition of Akt phosphorylation. Curcumin also suppressed NF-{kappa}B-regulated gene products (Bcl-2, Bcl-x{sub L}, inhibitor of apoptosis protein-2, cyclooxygenase-2, and cyclin D1). Conclusions: Our results suggest that transient inducible NF-{kappa}B activation provides a prosurvival response to radiation that may account for development of radioresistance. Curcumin blocks this signaling pathway and potentiates the antitumor effects of radiation therapy.

  10. Anthranilate-Activating Modules from Fungal Nonribosomal Peptide Assembly Lines†

    PubMed Central

    Ames, Brian D.; Walsh, Christopher T.

    2010-01-01

    Fungal natural products containing benzodiazepinone- and quinazolinone-fused ring systems can be assembled by nonribosomal peptide synthetases (NRPS) using the conformationally restricted β-amino acid anthranilate as one of the key building blocks. We validated that the first module of the acetylaszonalenin synthetase of Neosartorya fischeri NRRL 181 activates anthranilate to anthranilyl-AMP. With this as starting point, we then used bioinformatic predictions about fungal adenylation domain selectivities to identify and confirm an anthranilate-activating module in the fumiquinazoline A producer Aspergillus fumigatus Af293 as well as a second anthranilate-activating NRPS in N. fischeri. This establishes an anthranilate adenylation domain code for fungal NRPS and should facilitate detection and cloning of gene clusters for benzodiazepine- and quinazoline-containing polycyclic alkaloids with a wide range of biological activities. PMID:20225828

  11. Alcohol Usage and Abrupt Cessation Modulate Diurnal Activity

    PubMed Central

    Norrell, Stacy; Reyes-Vasquez, Cruz; Burau, Keith; Dafny, Nachum

    2010-01-01

    Alcohol has many effects throughout the body. The effect on circadian rhythms and the correlation of these effects to withdrawal effects of alcohol present interesting findings. By measuring 3 planes of activity of female Sprague-Dawley rats during alcohol usage and continuing study through the first two days following withdrawal of alcohol allow for the observation of a drastic modulation of the circadian pattern of activity. PMID:20615456

  12. Improved Angiostatic Activity of Dasatinib by Modulation with Hydrophobic Chains

    PubMed Central

    2015-01-01

    Dasatinib is an orally active nonselective tyrosine kinase inhibitor used to treat certain types of adult leukemia. By inhibiting PDGFR-β and SFKs in both tumor cells and tumor-associated endothelial cells, dasatinib inhibits tumor growth and angiogenesis. Herein, dasatinib derivatives modified with hydrophobic chains were prepared and evaluated for their in vitro antiproliferative selectivity and their in vivo antiangiogenic activity. For one of the derivatives, modified with a long perfluorinated chain, a significant enhancement in antiangiogenic activity was observed. Combined, these results suggest a possible generic route to modulate the angiostatic activity of drugs. PMID:25815152

  13. Enhanced induction of apoptosis in a radio-resistant bladder tumor cell line by combined treatments with X-rays and wortmannin.

    PubMed

    Ortiz, Trinidad; Burguillos, Miguel Angel; López-Lluch, Guillermo; Navas, Plácido; Herrador, Miguel; González, Isabel; Piñero, Joaquín

    2008-11-01

    The radiosensitizing effect of wortmannin (WM) treatment during and after irradiation was studied in radioresistant bladder tumor cell lines with normal (MGH-U1 cells) or defective p53 activity (RT112 cells). WM modulated G(2)/M cell cycle arrest induced by higher X-ray doses (10 Gy) in both cell lines, although the alteration was significant only in RT112 cells. The observation suggests that WM activity is independent of p53. Constitutive expression of DNA-PKcs was found to be higher in RT112 cells than in MGH-U1. Treatment with WM enhanced radiation-induced apoptosis significantly in RT112 cells while it had no effect on MGH-U1 cells. Although a variety of PI3-kinases and PI3-K like kinases (including ATM) could be inhibited by WM, our observation of increased early lethality by WM treatment in RT112 is in agreement with previous results. They suggest that the WM-dependent radiosensitization of RT112 is a direct consequence of the inhibition of DNA-PK, resulting in the inhibition of DSB repair in the fast component. This early effect in the p53 deficient cell line could also indicate that processes other than apoptosis may contribute to the increased radiosensitization. In our opinion, the expression level of DNA-PKcs in human tumor cells may be a good predictor for the success of DNA-PKcs inhibitors when used as radiosensitizers. PMID:18787832

  14. World Energy Projection System Plus (WEPS ): Global Activity Module

    EIA Publications

    2016-01-01

    The World Energy Projection System Plus (WEPS ) is a comprehensive, mid?term energy forecasting and policy analysis tool used by EIA. WEPS projects energy supply, demand, and prices by country or region, given assumptions about the state of various economies, international energy markets, and energy policies. The Global Activity Module (GLAM) provides projections of economic driver variables for use by the supply, demand, and conversion modules of WEPS . GLAM’s baseline economic projection contains the economic assumptions used in WEPS to help determine energy demand and supply. GLAM can also provide WEPS with alternative economic assumptions representing a range of uncertainty about economic growth. The resulting economic impacts of such assumptions are inputs to the remaining supply and demand modules of WEPS .

  15. Module Packaging Research and Reliability: Activities and Capabilities

    SciTech Connect

    McMahon, T. J.; delCueto, J.; Glick, S.; Jorgensen, G.; Kempe, M.; Pern, J.; Terwilliger, K.

    2005-11-01

    Our team activities are directed at improving PV module reliability by incorporating new, more effective, and less expensive packaging materials and techniques. New and existing materials or designs are evaluated before and during accelerated environmental exposure for the following properties: (1) Adhesion and cohesion: peel strength and lap shear. (2) Electrical conductivity: surface, bulk, interface and transients. (3) Water vapor transmission: solubility and diffusivity. (4) Accelerated weathering: ultraviolet, temperature, and damp heat tests. (5) Module and cell failure diagnostics: infrared imaging, individual cell shunt characterization, coring. (6) Fabrication improvements: SiOxNy barrier coatings and enhanced wet adhesion. (7) Numerical modeling: Moisture ingress/egress, module and cell performance, and cell-to-frame leakage current. (8) Rheological properties of polymer encapsulant and sheeting materials. Specific examples are described.

  16. Module Design, Materials, and Packaging Research Team: Activities and Capabilities

    SciTech Connect

    McMahon, T. J.; del Cueto, J.; Glick, S.; Jorgensen, G.; Kempe, M.; Kennedy, C.; Pern, J.; Terwilliger, K

    2005-01-01

    Our team activities are directed at improving PV module reliability by incorporating new, more effective, and less expensive packaging materials and techniques. New and existing materials or designs are evaluated before and during accelerated environmental exposure for the following properties: (1) Adhesion and cohesion: peel strength and lap shear. (2) Electrical conductivity: surface, bulk, interface and transients. (3) Water vapor transmission: solubility and diffusivity. (4) Accelerated weathering: ultraviolet, temperature, and damp heat tests. (5) Module and cell failure diagnostics: infrared imaging, individual cell shunt characterization, coring. (6) Fabrication improvements: SiOxNy barrier coatings and enhanced wet adhesion. (7) Numerical modeling: Moisture ingress/egress, module and cell performance, and cell-to-frame leakage current. (8) Rheological properties of polymer encapsulant and sheeting materials. Specific examples will be described.

  17. Contextual modulation of hippocampal activity during picture naming.

    PubMed

    Llorens, A; Dubarry, A-S; Trébuchon, A; Chauvel, P; Alario, F-X; Liégeois-Chauvel, C

    2016-08-01

    Picture naming is a standard task used to probe language processes in healthy and impaired speakers. It recruits a broad neural network of language related areas, among which the hippocampus is rarely included. However, the hippocampus could play a role during picture naming, subtending, for example, implicit learning of the links between pictured objects and their names. To test this hypothesis, we recorded hippocampal activity during plain picture naming, without memorization requirement; we further assessed whether this activity was modulated by contextual factors such as repetition priming and semantic interference. Local field potentials recorded from intracerebral electrodes implanted in the healthy hippocampi of epileptic patients revealed a specific and reliable pattern of activity, markedly modulated by repetition priming and semantic context. These results indicate that the hippocampus is recruited during picture naming, presumably in relation to implicit learning, with contextual factors promoting differential hippocampal processes, possibly subtended by different sub-circuitries. PMID:27380274

  18. Draft Genome Sequence of the Radioresistant Bacterium Deinococcus grandis, Isolated from Freshwater Fish in Japan

    PubMed Central

    Onodera, Takefumi; Omoso, Kota; Takeda-Yano, Kiyoko; Katayama, Takeshi; Oono, Yutaka; Narumi, Issay

    2016-01-01

    Deinococcus grandis is a radioresistant bacterium isolated from freshwater fish in Japan. Here we reported the draft genome sequence of D. grandis (4.1 Mb), which will be useful for elucidating the common principles of radioresistance in Deinococcus species through the comparative analysis of genomic sequences. PMID:26868384

  19. Solar activity and modulation of the cosmic ray intensity

    NASA Technical Reports Server (NTRS)

    Akasofu, S.-I.; Olmsted, C.; Lockwood, J. A.

    1985-01-01

    Since its discovery by Forbush (1954), the 11-year cycle modulation of the cosmic ray intensity has been studied extensively. Bowe and Hatton (1982) obtained a well-behaved transfer function F between the solar activity S and the cosmic ray intensity modulation Io-I. They suggested that the 11-year variation for sunspot cycle 20 can be attributed to the modulating effect of solar flare-induced shocks propagating through the heliosphere. The cosmic ray intensity in the absence of solar activity is denoted by Io, while I denotes the observed intensity. Bowe and Hatton infer that the boundary of the heliosphere is located at a distance of 70-90 AU. Since their conclusion is of great importance in understanding the mechanism of the 11-year modulation, the present investigation is concerned with a repetition of their study for two cycles, taking into account the use of a slightly modified method. The obtained results confirm the conclusions reached by Bowe and Hatton that there is a well-behaved transfer function for solar flares.

  20. Biological activity of a polypeptide modulator of TRPV1 receptor.

    PubMed

    Dyachenko, I A; Andreev, Ya A; Logashina, Yu A; Murashev, A N; Grishin, E V

    2015-11-01

    This paper presents data on the activity of a new APHC2 polypeptide modulator of TRPV1 receptors, which was isolated from the sea anemone Heteractis crispa. It has been shown that APHC2 has an analgesic activity, does not impair normal motor activity, and does not change body temperature of experimental animals, which has a great practical value for design of potent analgesics of a new generation. Further study of the characteristics of binding of the polypeptide to the TRPV1 receptor may show approaches to the development of other antagonists of this receptor that do not influence the body temperature. PMID:26725234

  1. Capsaicin modulates proliferation, migration, and activation of hepatic stellate cells.

    PubMed

    Bitencourt, Shanna; Mesquita, Fernanda; Basso, Bruno; Schmid, Júlia; Ferreira, Gabriela; Rizzo, Lucas; Bauer, Moises; Bartrons, Ramon; Ventura, Francesc; Rosa, Jose Luis; Mannaerts, Inge; van Grunsven, Leo Adrianus; Oliveira, Jarbas

    2014-03-01

    Capsaicin, the active component of chili pepper, has been reported to have antiproliferative and anti-inflammatory effects on a variety of cell lines. In the current study, we aimed to investigate the effects of capsaicin during HSC activation and maintenance. Activated and freshly isolated HSCs were treated with capsaicin. Proliferation was measured by incorporation of EdU. Cell cycle arrest and apoptosis were investigated using flow cytometry. The migratory response to chemotactic stimuli was evaluated by a modified Boyden chamber assay. Activation markers and inflammatory cytokines were determined by qPCR, immunocytochemistry, and flow cytometry. Our results show that capsaicin reduces HSC proliferation, migration, and expression of profibrogenic markers of activated and primary mouse HSCs. In conclusion, the present study shows that capsaicin modulates proliferation, migration, and activation of HSC in vitro. PMID:23955514

  2. Downregulation of Ubiquitin-conjugating Enzyme UBE2D3 Promotes Telomere Maintenance and Radioresistance of Eca-109 Human Esophageal Carcinoma Cells

    PubMed Central

    Yang, Hui; Wu, Lin; Ke, Shaobo; Wang, Wenbo; Yang, Lei; Gao, Xiaojia; Fang, Hongyan; Yu, Haijun; Zhong, Yahua; Xie, Conghua; Zhou, Fuxiang; Zhou, Yunfeng

    2016-01-01

    Ubiquitin-conjugating enzyme UBE2D3 is an important member of the ubiquitin-proteasome pathways. Our previous study showed that the expression of UBE2D3 was negatively related to human telomerase reverse transcriptase (hTERT) and radioresistance in human breast cancer cells. However, in esophageal carcinoma, the exact effects and mechanisms of UBE2D3 in radioresistance remain unclear. This study shows that UBE2D3 knockdown was associated with significant increases in radioresistance to X-rays, telomerase activity, telomere length, and telomere shelterins. UBE2D3 knockdown-mediated radioresistance was related to a decrease in the spontaneous and ionizing radiation-induced apoptosis, resulting from a decrease in the Bax/Bcl-2 ratio. Furthermore, UBE2D3 downregulation was associated with increased G1-S phase transition and prolonged IR-induced G2/M arrest through over expression of cyclin D1, decrease of CDC25A expression and promotion of the ATM/ATR-Chk1-CDC25C pathway. Moreover, UBE2D3 downregulation reduced spontaneous DNA double-strand breaks and accelerated the repair of DNA damage induced by IR. The current data thus demonstrate that UBE2D3 downregulation enhances radioresistance by increased telomere homeostasis and prolonged IR-induced G2/M arrest, but decreases the IR-induced apoptosis and the number of DNA damage foci. These results suggest that UBE2D3 might be a potential molecular target to improve radiotherapy effects in esophageal carcinoma. PMID:27326259

  3. Neuronal modulation of calcium channel activity in cultured rat astrocytes

    SciTech Connect

    Corvalan, V.; Cole, R.; De Vellis, J.; Hagiwara, Susumu )

    1990-06-01

    The patch-clamp technique was used to study whether cocultivation of neurons and astrocytes modulates the expression of calcium channel activity in astrocytes. Whole-cell patch-clamp recordings from rat brain astrocytes cocultured with rat embryonic neurons revealed two types of voltage-dependent inward currents carried by Ca{sup 2+} and blocked by either Cd{sup 2+} or Co{sup 2+} that otherwise were not detected in purified astrocytes. This expression of calcium channel activity in astrocytes was neuron dependent and was not observed when astrocytes were cocultured with purified oligodendrocytes.

  4. Sphingosine, a modulator of human translesion DNA polymerase activity.

    PubMed

    Kamath-Loeb, Ashwini S; Balakrishna, Sharath; Whittington, Dale; Shen, Jiang-Cheng; Emond, Mary J; Okabe, Takayoshi; Masutani, Chikahide; Hanaoka, Fumio; Nishimura, Susumu; Loeb, Lawrence A

    2014-08-01

    Translesion (TLS) DNA polymerases are specialized, error-prone enzymes that synthesize DNA across bulky, replication-stalling DNA adducts. In so doing, they facilitate the progression of DNA synthesis and promote cell proliferation. To potentiate the effect of cancer chemotherapeutic regimens, we sought to identify inhibitors of TLS DNA polymerases. We screened five libraries of ∼ 3000 small molecules, including one comprising ∼ 600 nucleoside analogs, for their effect on primer extension activity of DNA polymerase η (Pol η). We serendipitously identified sphingosine, a lipid-signaling molecule that robustly stimulates the activity of Pol η by ∼ 100-fold at low micromolar concentrations but inhibits it at higher concentrations. This effect is specific to the Y-family DNA polymerases, Pols η, κ, and ι. The addition of a single phosphate group on sphingosine completely abrogates this effect. Likewise, the inclusion of other sphingolipids, including ceramide and sphingomyelin to extension reactions does not elicit this response. Sphingosine increases the rate of correct and incorrect nucleotide incorporation while having no effect on polymerase processivity. Endogenous Pol η activity is modulated similarly as the recombinant enzyme. Importantly, sphingosine-treated cells exhibit increased lesion bypass activity, and sphingosine tethered to membrane lipids mimics the effects of free sphingosine. Our studies have uncovered sphingosine as a modulator of TLS DNA polymerase activity; this property of sphingosine may be associated with its known role as a signaling molecule in regulating cell proliferation in response to cellular stress. PMID:24928506

  5. Local modulation of steroid action: rapid control of enzymatic activity

    PubMed Central

    Charlier, Thierry D.; Cornil, Charlotte A.; Patte-Mensah, Christine; Meyer, Laurence; Mensah-Nyagan, A. Guy; Balthazart, Jacques

    2015-01-01

    Estrogens can induce rapid, short-lived physiological and behavioral responses, in addition to their slow, but long-term, effects at the transcriptional level. To be functionally relevant, these effects should be associated with rapid modulations of estrogens concentrations. 17β-estradiol is synthesized by the enzyme aromatase, using testosterone as a substrate, but can also be degraded into catechol-estrogens via hydroxylation by the same enzyme, leading to an increase or decrease in estrogens concentration, respectively. The first evidence that aromatase activity (AA) can be rapidly modulated came from experiments performed in Japanese quail hypothalamus homogenates. This rapid modulation is triggered by calcium-dependent phosphorylations and was confirmed in other tissues and species. The mechanisms controlling the phosphorylation status, the targeted amino acid residues and the reversibility seem to vary depending of the tissues and is discussed in this review. We currently do not know whether the phosphorylation of the same amino acid affects both aromatase and/or hydroxylase activities or whether these residues are different. These processes provide a new general mechanism by which local estrogen concentration can be rapidly altered in the brain and other tissues. PMID:25852459

  6. Radiotherapy diagnostic biomarkers in radioresistant human H460 lung cancer stem-like cells

    PubMed Central

    Yun, Hong Shik; Baek, Jeong-Hwa; Yim, Ji-Hye; Um, Hong-Duck; Park, Jong Kuk; Song, Jie-Young; Park, In-Chul; Kim, Jae-Sung; Lee, Su-Jae; Lee, Chang-Woo; Hwang, Sang-Gu

    2016-01-01

    ABSTRACT Tumor cell radioresistance is a major contributor to radiotherapy failure, highlighting the importance of identifying predictive biomarkers for radioresistance. In this work, we established a radioresistant H460 (RR-H460) cell line from parental radiosensitive H460 lung cancer cells by exposure to fractionated radiation. The radiation-resistant, anti-apoptotic phenotype of RR-H460 cell lines was confirmed by their enhanced clonogenic survival and increased expression of the radioresistance genes Hsp90 and Her-3. RR-H460 cells displayed characteristics of cancer stem-like cells (CSCs), including induction of the surface marker CD44 and stem cell markers Nanog, Oct4, and Sox2. RR-H460 cells also exhibited sphere formation and malignant behavior, further supporting a CSC phenotype. Using proteomic analyses, we identified 8 proteins that were up-regulated in RR-H460 CSC lines and therefore potentially involved in radioresistance and CSC-related biological processes. Notably, 4 of these—PAI-2, NOMO2, KLC4, and PLOD3—have not been previously linked to radioresistance. Depletion of these individual genes sensitized RR-H460 cells to radiotoxicity and additively enhancing radiation-induced apoptosis. Our findings suggest the possibility of integrating molecular targeted therapy with radiotherapy as a strategy for resolving the radioresistance of lung tumors. PMID:26901847

  7. Radiotherapy diagnostic biomarkers in radioresistant human H460 lung cancer stem-like cells.

    PubMed

    Yun, Hong Shik; Baek, Jeong-Hwa; Yim, Ji-Hye; Um, Hong-Duck; Park, Jong Kuk; Song, Jie-Young; Park, In-Chul; Kim, Jae-Sung; Lee, Su-Jae; Lee, Chang-Woo; Hwang, Sang-Gu

    2016-02-01

    Tumor cell radioresistance is a major contributor to radiotherapy failure, highlighting the importance of identifying predictive biomarkers for radioresistance. In this work, we established a radioresistant H460 (RR-H460) cell line from parental radiosensitive H460 lung cancer cells by exposure to fractionated radiation. The radiation-resistant, anti-apoptotic phenotype of RR-H460 cell lines was confirmed by their enhanced clonogenic survival and increased expression of the radioresistance genes Hsp90 and Her-3. RR-H460 cells displayed characteristics of cancer stem-like cells (CSCs), including induction of the surface marker CD44 and stem cell markers Nanog, Oct4, and Sox2. RR-H460 cells also exhibited sphere formation and malignant behavior, further supporting a CSC phenotype. Using proteomic analyses, we identified 8 proteins that were up-regulated in RR-H460 CSC lines and therefore potentially involved in radioresistance and CSC-related biological processes. Notably, 4 of these-PAI-2, NOMO2, KLC4, and PLOD3-have not been previously linked to radioresistance. Depletion of these individual genes sensitized RR-H460 cells to radiotoxicity and additively enhancing radiation-induced apoptosis. Our findings suggest the possibility of integrating molecular targeted therapy with radiotherapy as a strategy for resolving the radioresistance of lung tumors. PMID:26901847

  8. Cholesterol modulates alkaline phosphatase activity of rat intestinal microvillus membranes.

    PubMed

    Brasitus, T A; Dahiya, R; Dudeja, P K; Bissonnette, B M

    1988-06-25

    Experiments were conducted, using a nonspecific lipid transfer protein, to vary the cholesterol/phospholipid molar ratio of rat proximal small intestinal microvillus membranes in order to assess the possible role of cholesterol in modulating enzymatic activities of this plasma membrane. Cholesterol/phospholipid molar ratios from 0.71 to 1.30 were produced from a normal value of 1.05 by incubation with the transfer protein and an excess of either phosphatidylcholine or cholesterol/phosphatidylcholine liposomes for 60 min at 37 degrees C. Cholesterol loading or depletion of the membranes was accompanied by a decrease or increase, respectively, in their lipid fluidity, as assessed by steady-state fluorescence polarization techniques using the lipid-soluble fluorophore 1,6-diphenyl-1,3,5-hexatriene. Increasing the cholesterol/phospholipid molar ratio also decreased alkaline phosphatase specific activity by approximately 20-30%, whereas decreasing this ratio increased this enzymatic activity by 20-30%. Sucrase, maltase, and lactase specific activities were not affected in these same preparations. Since the changes in alkaline phosphatase activity could be secondary to alterations in fluidity, cholesterol, or both, additional experiments were performed using benzyl alcohol, a known fluidizer. Benzyl alcohol (25 mM) restored the fluidity of cholesterol-enriched preparations to control levels, did not change the cholesterol/phospholipid molar ratio, and failed to alter alkaline phosphatase activity. These findings, therefore, indicate that alterations in the cholesterol content and cholesterol/phospholipid molar ratio of microvillus membranes can modulate alkaline phosphatase but not sucrase, maltase, or lactase activities. Moreover, membrane fluidity does not appear to be an important physiological regulator of these enzymatic activities. PMID:3379034

  9. Decorin binds myostatin and modulates its activity to muscle cells

    SciTech Connect

    Miura, Takayuki; Kishioka, Yasuhiro; Wakamatsu, Jun-ichi; Hattori, Akihito; Hennebry, Alex; Berry, Carole J.; Sharma, Mridula; Kambadur, Ravi; Nishimura, Takanori . E-mail: nishi@anim.agr.hokudai.ac.jp

    2006-02-10

    Myostatin, a member of TGF-{beta} superfamily of growth factors, acts as a negative regulator of skeletal muscle mass. The mechanism whereby myostatin controls the proliferation and differentiation of myogenic cells is mostly clarified. However, the regulation of myostatin activity to myogenic cells after its secretion in the extracellular matrix (ECM) is still unknown. Decorin, a small leucine-rich proteoglycan, binds TGF-{beta} and regulates its activity in the ECM. Thus, we hypothesized that decorin could also bind to myostatin and participate in modulation of its activity to myogenic cells. In order to test the hypothesis, we investigated the interaction between myostatin and decorin by surface plasmon assay. Decorin interacted with mature myostatin in the presence of concentrations of Zn{sup 2+} greater than 10 {mu}M, but not in the absence of Zn{sup 2+}. Kinetic analysis with a 1:1 binding model resulted in dissociation constants (K {sub D}) of 2.02 x 10{sup -8} M and 9.36 x 10{sup -9} M for decorin and the core protein of decorin, respectively. Removal of the glycosaminoglycan chain by chondroitinase ABC digestion did not affect binding, suggesting that decorin could bind to myostatin with its core protein. Furthermore, we demonstrated that immobilized decorin could rescue the inhibitory effect of myostatin on myoblast proliferation in vitro. These results suggest that decorin could trap myostatin and modulate its activity to myogenic cells in the ECM.

  10. Brg1 modulates enhancer activation in mesoderm lineage commitment

    SciTech Connect

    Alexander, Jeffrey M.; Hota, Swetansu K.; He, Daniel; Thomas, Sean; Ho, Lena; Pennacchio, Len A.; Bruneau, B. G.

    2015-03-26

    The interplay between different levels of gene regulation in modulating developmental transcriptional programs, such as histone modifications and chromatin remodeling, is not well understood. Here, we show that the chromatin remodeling factor Brg1 is required for enhancer activation in mesoderm induction. In an embryonic stem cell-based directed differentiation assay, the absence of Brg1 results in a failure of cardiomyocyte differentiation and broad deregulation of lineage-specific gene expression during mesoderm induction. We find that Brg1 co-localizes with H3K27ac at distal enhancers and is required for robust H3K27 acetylation at distal enhancers that are activated during mesoderm induction. Brg1 is also required to maintain Polycomb-mediated repression of non-mesodermal developmental regulators, suggesting cooperativity between Brg1 and Polycomb complexes. Thus, Brg1 is essential for modulating active and repressive chromatin states during mesoderm lineage commitment, in particular the activation of developmentally important enhancers. In conclusion, these findings demonstrate interplay between chromatin remodeling complexes and histone modifications that, together, ensure robust and broad gene regulation during crucial lineage commitment decisions.

  11. Brg1 modulates enhancer activation in mesoderm lineage commitment

    DOE PAGESBeta

    Alexander, Jeffrey M.; Hota, Swetansu K.; He, Daniel; Thomas, Sean; Ho, Lena; Pennacchio, Len A.; Bruneau, B. G.

    2015-03-26

    The interplay between different levels of gene regulation in modulating developmental transcriptional programs, such as histone modifications and chromatin remodeling, is not well understood. Here, we show that the chromatin remodeling factor Brg1 is required for enhancer activation in mesoderm induction. In an embryonic stem cell-based directed differentiation assay, the absence of Brg1 results in a failure of cardiomyocyte differentiation and broad deregulation of lineage-specific gene expression during mesoderm induction. We find that Brg1 co-localizes with H3K27ac at distal enhancers and is required for robust H3K27 acetylation at distal enhancers that are activated during mesoderm induction. Brg1 is also requiredmore » to maintain Polycomb-mediated repression of non-mesodermal developmental regulators, suggesting cooperativity between Brg1 and Polycomb complexes. Thus, Brg1 is essential for modulating active and repressive chromatin states during mesoderm lineage commitment, in particular the activation of developmentally important enhancers. In conclusion, these findings demonstrate interplay between chromatin remodeling complexes and histone modifications that, together, ensure robust and broad gene regulation during crucial lineage commitment decisions.« less

  12. Antioxidant, antimicrobial and neutrophil-modulating activities of herb extracts.

    PubMed

    Denev, Petko; Kratchanova, Maria; Ciz, Milan; Lojek, Antonin; Vasicek, Ondrej; Blazheva, Denitsa; Nedelcheva, Plamena; Vojtek, Libor; Hyrsl, Pavel

    2014-01-01

    The present study provides a comprehensive data on the antioxidant, antimicrobial and neutrophil-modulating activities of extracts from six medicinal plants--blackberry (Rubus fruticosus) leaves, chokeberry (Aronia melanocarpa) leaves, hawthorn (Crataegus monogyna) leaves, lady's mantle (Alchemilla glabra) aerial parts, meadowsweet (Filipendula ulmaria) aerial parts and raspberry (Rubus idaeus) leaves. In order to analyze the antioxidant activity of the herbs, several methods (ORAC, TRAP, HORAC and inhibition of lipid peroxidation) were used. Blackberry leaves and meadowsweet extracts revealed the highest antioxidant activities via all methods. All extracts studied blocked almost completely the opsonized zymosan particle-activated ROS production by neutrophils from human whole blood. On the other hand, the effect of extracts on phorbol myristate acetate-activated ROS production was much milder and even nonsignificant in the case of chokeberry leaves. This latter result suggests that extracts (apart from their antioxidative activity) interfere with the signaling cascade of phagocyte activation upstream of the protein kinase C activation. The antimicrobial activity of the investigated extracts against 11 human pathogens was investigated using three different methods. Meadowsweet and blackberry leaves extracts had the highest antimicrobial effect and the lowest minimal inhibiting concentrations (MICs) against the microorganisms tested. PMID:24945135

  13. [The role of genetic factors in human radioresistance].

    PubMed

    Tel'nov, V I

    2005-01-01

    The role of genetic factors in the development of chronic radiation disease (CRD), mostly caused by occupational external gamma-exposure, was evaluated. The data of molecular genetic survey of a cohort of 985 workers at the nuclear power plant, the Mayak PA, were analyzed. Among the genetic markers tested, an association between the haptoglobin (Hp) genetic system and the development of CRD was established. It was demonstrated that the contribution of genetic factors to the CRD onset was realized not within the whole, but in a relatively narrow dose interval (70 to 400 cGy), i.e., was relative. Furthermore, at equal irradiation doses, relatively higher risk of CRD was observed among the Hp 2-2 phenotype carriers (1.96) compared to lower risk among the Hp 1-1 and Hp 2-1 phenotype carriers (0.64). It was shown that with the increase of the irradiation dose, genotypic differences in the CRD frequency decreased to the point of their complete disappearance. Comparison of the roles of the genetic factors in the onset of such deterministic irradiation effect as CRD, with their roles in the onset of lung cancer in tobacco smokers revealed similar patterns. A scheme of the relationships between the effector intensity and the differences in the genetically determined radioresistance is presented. The data obtained do not support the idea that the survivals of the atomic bombing of Hiroshima and Nagasaki were the most radioresistant individuals, who are not representative for evaluating the radiation risk. PMID:15771255

  14. Active dielectric antenna on chip for spatial light modulation

    PubMed Central

    Qiu, Ciyuan; Chen, Jianbo; Xia, Yang; Xu, Qianfan

    2012-01-01

    Integrated photonic resonators are widely used to manipulate light propagation in an evanescently-coupled waveguide. While the evanescent coupling scheme works well for planar optical systems that are naturally waveguide based, many optical applications are free-space based, such as imaging, display, holographics, metrology and remote sensing. Here we demonstrate an active dielectric antenna as the interface device that allows the large-scale integration capability of silicon photonics to serve the free-space applications. We show a novel perturbation-base diffractive coupling scheme that allows a high-Q planer resonator to directly interact with and manipulate free-space waves. Using a silicon-based photonic crystal cavity whose resonance can be rapidly tuned with a p-i-n junction, a compact spatial light modulator with an extinction ratio of 9.5 dB and a modulation speed of 150 MHz is demonstrated. Method to improve the modulation speed is discussed. PMID:23152946

  15. Regulating the regulators: modulators of transcription factor activity.

    PubMed

    Everett, Logan; Hansen, Matthew; Hannenhalli, Sridhar

    2010-01-01

    Gene transcription is largely regulated by DNA-binding transcription factors (TFs). However, the TF activity itself is modulated via, among other things, post-translational modifications (PTMs) by specific modification enzymes in response to cellular stimuli. TF-PTMs thus serve as "molecular switchboards" that map upstream signaling events to the downstream transcriptional events. An important long-term goal is to obtain a genome-wide map of "regulatory triplets" consisting of a TF, target gene, and a modulator gene that specifically modulates the regulation of the target gene by the TF. A variety of genome-wide data sets can be exploited by computational methods to obtain a rough map of regulatory triplets, which can guide directed experiments. However, a prerequisite to developing such computational tools is a systematic catalog of known instances of regulatory triplets. We first describe PTM-Switchboard, a recent database that stores triplets of genes such that the ability of one gene (the TF) to regulate a target gene is dependent on one or more PTMs catalyzed by a third gene, the modifying enzyme. We also review current computational approaches to infer regulatory triplets from genome-wide data sets and conclude with a discussion of potential future research. PTM-Switchboard is accessible at http://cagr.pcbi.upenn.edu/PTMswitchboard / PMID:20827600

  16. Modulation of inferotemporal cortex activation during verbal working memory maintenance

    PubMed Central

    Fiebach, Christian J.; Rissman, Jesse; D'Esposito, Mark

    2015-01-01

    Summary Regions of the left inferotemporal cortex are involved in visual word recognition and semantics. We utilized functional magnetic resonance imaging to localize an inferotemporal language area and to demonstrate that this area is involved in the active maintenance of visually presented words in working memory. Maintenance activity in this inferotemporal area showed an effect of memory load for words, but not pseudowords. The selective modulation of this language-related inferotemporal area for the maintenance of words, in the absence of visual input, is accompanied by an increased functional connectivity with left prefrontal cortex. These results are the first demonstration of an involvement of inferotemporal cortex in verbal working memory. They provide neurophysiological support for the notion that nonphonological language representations can be recruited in the service of verbal working memory. More generally, they suggest that verbal working memory should be conceptualized as the frontally-guided, sustained activation of pre-existing cortical language representations. PMID:16846859

  17. Modulating enzyme activity using ionic liquids or surfactants.

    PubMed

    Goldfeder, Mor; Fishman, Ayelet

    2014-01-01

    One of the important strategies for modulating enzyme activity is the use of additives to affect their microenvironment and subsequently make them suitable for use in different industrial processes. Ionic liquids (ILs) have been investigated extensively in recent years as such additives. They are a class of solvents with peculiar properties and a "green" reputation in comparison to classical organic solvents. ILs as co-solvents in aqueous systems have an effect on substrate solubility, enzyme structure and on enzyme-water interactions. These effects can lead to higher reaction yields, improved selectivity, and changes in substrate specificity, and thus there is great potential for IL incorporation in biocatalysis. The use of surfactants, which are usually denaturating agents, as additives in enzymatic reactions is less reviewed in recent years. However, interesting modulations in enzyme activity in their presence have been reported. In the case of surfactants there is a more pronounced effect on the enzyme structure, as can be observed in a number of crystal structures obtained in their presence. For each additive and enzymatic process, a specific optimization process is needed and there is no one-fits-all solution. Combining ILs and surfactants in either mixed micelles or water-in-IL microemulsions for use in enzymatic reaction systems is a promising direction which may further expand the range of enzyme applications in industrial processes. While many reviews exist on the use of ILs in biocatalysis, the present review centers on systems in which ILs or surfactants were able to modulate and improve the natural activity of enzymes in aqueous systems. PMID:24281758

  18. Active stiffness modulation of fins using macro fiber composites

    NASA Astrophysics Data System (ADS)

    Kancharala, Ashok K.; Philen, Michael K.

    2013-04-01

    Studies on the role of body flexibility in propulsion suggest that fish have the ability to control or modulate the stiffness of the fin for optimized propulsive performance. Fins with certain stiffness might be efficient for a particular set of operating parameters but may be inefficient for other parameters. Therefore active stiffness modulation of a fin can improve the propulsive performance for a range of operating conditions. This paper discusses the preliminary experimental work on the open loop active deformation control of heaving flexible fins using Macro Fiber Composites (MFCs). The effect of important parameters such as oscillation frequency, flexibility of the fin, applied voltage and the phase difference between applied voltage and heaving on propulsive performance are studied and reported. The results indicate that propulsive performance can be improved by active control of the fins. The mean thrust improved by 30- 38% for the fins used in the experiments. The phase difference of ~90° is found to be optimal for maximized propulsive performance for the parameters considered in the study. Furthermore, there exists an optimal voltage magnitude at which the propulsive performance is a maximum for the range of operating conditions.

  19. Modulation of nitric oxide synthase activity in macrophages

    PubMed Central

    Jorens, P. G.; Matthys, K. E.

    1995-01-01

    L-Arginine is converted to the highly reactive and unstable nitric oxide (NO) and L-citrulline by an enzyme named nitric oxide synthase (NOS). NO decomposes into other nitrogen oxides such as nitrite (NO2-) and nitrate (NO2-), and in the presence of superoxide anion to the potent oxidizing agent peroxynitrite (ONOO−). Activated rodent macrophages are capable of expressing an inducible form of this enzyme (iNOS) in response to appropriate stimuli, i.e., lipopolysaccharide (LPS) and interferon-γ (IFNγ). Other cytokines can modulate the induction of NO biosynthesis in macrophages. NO is a major effector molecule of the anti-microbial and cytotoxic activity of rodent macrophages against certain micro-organisms and tumour cells, respectively. The NO synthesizing pathway has been demonstrated in human monocytes and other cells, but its role in host defence seems to be accessory. A delicate functional balance between microbial stimuli, host-derived cytokines and hormones in the microenvironment regulates iNOS expression. This review will focus mainly on the known and proposed mechanisms of the regulation of iNOS induction, and on agents that can modulate NO release once the active enzyme has been expressed in the macrophage. PMID:18475620

  20. Target cell-specific modulation of neuronal activity by astrocytes

    NASA Astrophysics Data System (ADS)

    Kozlov, A. S.; Angulo, M. C.; Audinat, E.; Charpak, S.

    2006-06-01

    Interaction between astrocytes and neurons enriches the behavior of brain circuits. By releasing glutamate and ATP, astrocytes can directly excite neurons and modulate synaptic transmission. In the rat olfactory bulb, we demonstrate that the release of GABA by astrocytes causes long-lasting and synchronous inhibition of mitral and granule cells. In addition, astrocytes release glutamate, leading to a selective activation of granule-cell NMDA receptors. Thus, by releasing excitatory and inhibitory neurotransmitters, astrocytes exert a complex modulatory control on the olfactory network. glutamate | GABA | inhibition | olfactory bulb | synchronization

  1. Visual Experience Modulates Spatio-Temporal Dynamics of Circuit Activation

    PubMed Central

    Wang, Lang; Fontanini, Alfredo; Maffei, Arianna

    2011-01-01

    Persistent reduction in sensory drive in early development results in multiple plastic changes of different cortical synapses. How these experience-dependent modifications affect the spatio-temporal dynamics of signal propagation in neocortical circuits is poorly understood. Here we demonstrate that brief visual deprivation significantly affects the propagation of electrical signals in the primary visual cortex. The spatio-temporal spread of circuit activation upon direct stimulation of its input layer (Layer 4) is reduced, as is the activation of L2/3 – the main recipient of the output from L4. Our data suggest that the decrease in spatio-temporal activation of L2/3 depends on reduced L4 output, and is not intrinsically generated within L2/3. The data shown here suggest that changes in the synaptic components of the visual cortical circuit result not only in alteration of local integration of excitatory and inhibitory inputs, but also in a significant decrease in overall circuit activation. Furthermore, our data indicate a differential effect of visual deprivation on L4 and L2/3, suggesting that while feedforward activation of L2/3 is reduced, its activation by long range, within layer inputs is unaltered. Thus, brief visual deprivation induces experience-dependent circuit re-organization by modulating not only circuit excitability, but also the spatio-temporal patterns of cortical activation within and between layers. PMID:21743804

  2. Modulation of locomotor activation by the rostromedial tegmental nucleus.

    PubMed

    Lavezzi, Heather N; Parsley, Kenneth P; Zahm, Daniel S

    2015-02-01

    The rostromedial tegmental nucleus (RMTg) is a strong inhibitor of dopamine neurons in the ventral tegmental area (VTA) reported to influence neurobiological and behavioral responses to reward omission, aversive and fear-eliciting stimuli, and certain drugs of abuse. Insofar as previous studies implicate ventral mesencephalic dopamine neurons as an essential component of locomotor activation, we hypothesized that the RMTg also should modulate locomotion activation. We observed that bilateral infusions into the RMTg of the gamma-aminobutyric acid A (GABAA) agonist, muscimol, indeed activate locomotion. Alternatively, bilateral RMTg infusions of the GABAA receptor antagonist, bicuculline, suppress robust activations of locomotion elicited in two distinct ways: (1) by disinhibitory stimulation of neurons in the lateral preoptic area and (2) by return of rats to an environment previously paired with amphetamine administration. The possibility that suppressive locomotor effects of RMTg bicuculline infusions were due to unintended spread of drug to the nearby VTA was falsified by a control experiment showing that bilateral infusions of bicuculline into the VTA produce activation rather than suppression of locomotion. These results objectively implicate the RMTg in the regulation of locomotor activation. The effect is important because much evidence reported in the literature suggests that locomotor activation can be an involuntary behavioral expression of expectation and/or want without which the willingness to execute adaptive behaviors is impaired. PMID:25164249

  3. EarthScope Content Module for IRIS Active Earth Monitor

    NASA Astrophysics Data System (ADS)

    McQuillan, P. J.; Welti, R.; Johnson, J. A.; Shiffman, C. R.; Olds, S. E.

    2012-12-01

    The Active Earth Monitor (AEM) is an interactive computer-based display for university lobbies, museums, visitor centers, schools and libraries. AEM runs in a standard Internet web browser in full screen mode. The display consists of a customizable set of content pages about plate tectonics, earthquakes, volcanoes and tsunamis. Low-cost and simple-to-implement, the Active Earth Monitor provides a way to engage audiences with earth science information without spending resources on a large exhibit. The EarthScope Active Earth Monitor content set highlights the connections between the landscape and the research and monitoring being conducted by EarthScope in partnership with regional monitoring networks. Modules consist of chapters that focus on What is EarthScope?, EarthScope Observatories, and EarthScope Research Results. Content topics are easily explored using a web page button type navigation interface via a touch screen or mouse. A formative evaluation of general public users informed the interface design. Chapters in the modules start with a general overview and proceed to detailed specifics. Each chapter utilizes at least one set of live or near real-time research data (often more than one). This exposes the general public to active ongoing research that is engaging, relevant to the individual user, and explained in easy to understand terms. All live content is updated each time a user accesses the individual page displaying the live data. Leading questions are presented allowing the user to examine the content before accessing the answer via pop-up box. Diagrams and charts of research data have explanatory keys that allow users to self explore all content. Content pages can be created and inserted in the Active Earth Monitor by utilizing the simple HTML/CSS coding.;

  4. Simulations of the equatorial thermosphere anomaly: Geomagnetic activity modulation

    NASA Astrophysics Data System (ADS)

    Lei, Jiuhou; Wang, Wenbin; Thayer, Jeffrey P.; Luan, Xiaoli; Dou, Xiankang; Burns, Alan G.; Solomon, Stanley C.

    2014-08-01

    The modulation of geomagnetic activity on the equatorial thermosphere anomaly (ETA) in thermospheric temperature under the high solar activity condition is investigated using the Thermosphere Ionosphere Electrodynamics General Circulation Model simulations. The model simulations during the geomagnetically disturbed interval, when the north-south component of the interplanetary magnetic field (Bz) oscillates between southward and northward directions, are analyzed and also compared with those under the quiet time condition. Our results show that ionospheric electron densities increase greatly in the equatorial ionization anomaly (EIA) crest region and decrease around the magnetic equator during the storm time, resulting from the enhanced eastward electric fields. The impact of both the direct heat deposition at high latitudes and the modulation of the storm time enhanced EIA crests on the ETA are subsequently studied. The increased plasma densities over the EIA crest region enhance the field-aligned ion drag that accelerates the poleward meridional winds and consequently their associated adiabatic cooling effect. This process alone produces a deeper temperature trough over the magnetic equator as a result of the enhanced divergence of meridional winds. Moreover, the enhanced plasma-neutral collisional heating at higher latitudes associated with the ionospheric positive storm effect causes a weak increase of the ETA crests. On the other hand, strong changes of the neutral temperature are mainly confined to higher latitudes. Nevertheless, the changes of the ETA purely due to the increased plasma density are overwhelmed by those associated with the storm time heat deposition, which is the major cause of an overall elevated temperature in both the ETA crests and trough during the geomagnetically active period. Associated with the enhanced neutral temperature at high latitudes due to the heat deposition, the ETA crest-trough differences become larger under the minor

  5. Modulation of human motoneuron activity by a mental arithmetic task.

    PubMed

    Bensoussan, Laurent; Duclos, Yann; Rossi-Durand, Christiane

    2012-10-01

    This study aimed to determine whether the performance of a mental task affects motoneuron activity. To this end, the tonic discharge pattern of wrist extensor motor units was analyzed in healthy subjects while they were required to maintain a steady wrist extension force and to concurrently perform a mental arithmetic (MA) task. A shortening of the mean inter-spike interval (ISI) and a decrease in ISI variability occurred when MA task was superimposed to the motor task. Aloud and silent MA affected equally the rate and variability of motoneuron discharge. Increases in surface EMG activity and force level were consistent with the modulation of the motor unit discharge rate. Trial-by-trial analysis of the characteristics of motor unit firing revealed that performing MA increases activation of wrist extensor SMU. It is suggested that increase in muscle spindle afferent activity, resulting from fusimotor drive activation by MA, may have contributed to the increase in synaptic inputs to motoneurons during the mental task performance, likely together with enhancement in the descending drive. The finding that a mental task affects motoneuron activity could have consequences in assessment of motor disabilities and in rehabilitation in motor pathologies. PMID:23159444

  6. Light/dark modulation of enzyme activity in photosynthesis

    SciTech Connect

    Anderson, L.E.; Ashton, A.R.; Mohamed, A.H.; Scheibe, R.

    1982-02-01

    In photosynthetic species ranging from cyanobacteria to higher plants, many enzymes are light modulated. Most of the known light modulated enzymes are chloroplastic. Four mechanisms of modulation have been proposed. One function of light modulation is probably the autocatalytic build-up of reductive pentose phosphate cycle intermediates during the induction period of photosynthetic CO/sub 2/ fixation.

  7. Integrated Brain Circuits: Astrocytic Networks Modulate Neuronal Activity and Behavior

    PubMed Central

    Halassa, Michael M.; Haydon, Philip G.

    2011-01-01

    The past decade has seen an explosion of research on roles of neuron-astrocyte interactions in the control of brain function. We highlight recent studies performed on the tripartite synapse, the structure consisting of pre- and postsynaptic elements of the synapse and an associated astrocytic process. Astrocytes respond to neuronal activity and neuro-transmitters, through the activation of metabotropic receptors, and can release the gliotransmitters ATP, D-serine, and glutamate, which act on neurons. Astrocyte-derived ATP modulates synaptic transmission, either directly or through its metabolic product adenosine. D-serine modulates NMDA receptor function, whereas glia-derived glutamate can play important roles in relapse following withdrawal from drugs of abuse. Cell type–specific molecular genetics has allowed a new level of examination of the function of astrocytes in brain function and has revealed an important role of these glial cells that is mediated by adenosine accumulation in the control of sleep and in cognitive impairments that follow sleep deprivation. PMID:20148679

  8. Dopamine Modulates the Activity of Sensory Hair Cells

    PubMed Central

    Toro, Cecilia; Trapani, Josef G.; Pacentine, Itallia; Maeda, Reo; Sheets, Lavinia; Mo, Weike

    2015-01-01

    The senses of hearing and balance are subject to modulation by efferent signaling, including the release of dopamine (DA). How DA influences the activity of the auditory and vestibular systems and its site of action are not well understood. Here we show that dopaminergic efferent fibers innervate the acousticolateralis epithelium of the zebrafish during development but do not directly form synapses with hair cells. However, a member of the D1-like receptor family, D1b, tightly localizes to ribbon synapses in inner ear and lateral-line hair cells. To assess modulation of hair-cell activity, we reversibly activated or inhibited D1-like receptors (D1Rs) in lateral-line hair cells. In extracellular recordings from hair cells, we observed that D1R agonist SKF-38393 increased microphonic potentials, whereas D1R antagonist SCH-23390 decreased microphonic potentials. Using ratiometric calcium imaging, we found that increased D1R activity resulted in larger calcium transients in hair cells. The increase of intracellular calcium requires Cav1.3a channels, as a Cav1 calcium channel antagonist, isradipine, blocked the increase in calcium transients elicited by the agonist SKF-38393. Collectively, our results suggest that DA is released in a paracrine fashion and acts at ribbon synapses, likely enhancing the activity of presynaptic Cav1.3a channels and thereby increasing neurotransmission. SIGNIFICANCE STATEMENT The neurotransmitter dopamine acts in a paracrine fashion (diffusion over a short distance) in several tissues and bodily organs, influencing and regulating their activity. The cellular target and mechanism of the action of dopamine in mechanosensory organs, such as the inner ear and lateral-line organ, is not clearly understood. Here we demonstrate that dopamine receptors are present in sensory hair cells at synaptic sites that are required for signaling to the brain. When nearby neurons release dopamine, activation of the dopamine receptors increases the activity of

  9. Space station group activities habitability module study: A synopsis

    NASA Technical Reports Server (NTRS)

    Nixon, David; Glassman, Terry

    1987-01-01

    Space station habitability was studied by investigating crew activity routines, proximities, ergonomic envelopes, and group volumes. Ten alternative schematic interior designs were proposed. Preliminary conclusions include: (1) in-service interior modifications may be necessary and should be planned for; (2) design complexity will be increased if the module cluster is reduced from five to three; (3) the increased crew circulation attendant upon enhancement of space station activity may produce human traffic bottlenecks and should be planned for; (4) a single- or two-person quiet area may be desirable to provide crew members with needed solitude during waking hours; and (5) the decision to choose a two-shift or three-shift daily cycle will have a significant impact on the design configuration and operational efficiency of the human habitat.

  10. Ligand Mobility Modulates Immunological Synapse Formation and T Cell Activation

    PubMed Central

    Hsu, Chih-Jung; Hsieh, Wan-Ting; Waldman, Abraham; Clarke, Fiona; Huseby, Eric S.; Burkhardt, Janis K.; Baumgart, Tobias

    2012-01-01

    T cell receptor (TCR) engagement induces clustering and recruitment to the plasma membrane of many signaling molecules, including the protein tyrosine kinase zeta-chain associated protein of 70 kDa (ZAP70) and the adaptor SH2 domain-containing leukocyte protein of 76 kDa (SLP76). This molecular rearrangement results in formation of the immunological synapse (IS), a dynamic protein array that modulates T cell activation. The current study investigates the effects of apparent long-range ligand mobility on T cell signaling activity and IS formation. We formed stimulatory lipid bilayers on glass surfaces from binary lipid mixtures with varied composition, and characterized these surfaces with respect to diffusion coefficient and fluid connectivity. Stimulatory ligands coupled to these surfaces with similar density and orientation showed differences in their ability to activate T cells. On less mobile membranes, central supramolecular activation cluster (cSMAC) formation was delayed and the overall accumulation of CD3ζ at the IS was reduced. Analysis of signaling microcluster (MC) dynamics showed that ZAP70 MCs exhibited faster track velocity and longer trajectories as a function of increased ligand mobility, whereas movement of SLP76 MCs was relatively insensitive to this parameter. Actin retrograde flow was observed on all surfaces, but cell spreading and subsequent cytoskeletal contraction were more pronounced on mobile membranes. Finally, increased tyrosine phosphorylation and persistent elevation of intracellular Ca2+ were observed in cells stimulated on fluid membranes. These results point to ligand mobility as an important parameter in modulating T cell responses. PMID:22384241

  11. Modulation of CD44 Activity by A6-Peptide

    PubMed Central

    Finlayson, Malcolm

    2015-01-01

    Hyaluronan (HA) is a non-sulfated glycosaminoglycan distributed throughout the extracellular matrix that plays a major role in cell adhesion, migration, and proliferation. CD44, a multifunctional cell surface glycoprotein, is a receptor for HA. In addition, CD44 is known to interact with other receptors and ligands, and to mediate a number of cellular functions as well as disease progression. Studies have shown that binding of HA to CD44 in cancer cells activates survival pathways resulting in cancer cell survival. This effect can be blocked by anti-CD44 monoclonal antibodies. A6 is a capped, eight l-amino acid peptide (Ac-KPSSPPEE-NH2) derived from the biologically active connecting peptide domain of the serine protease, human urokinase plasminogen activator (uPA). A6 neither binds to the uPA receptor (uPAR) nor interferes with uPA/uPAR binding. A6 binds to CD44 resulting in the inhibition of migration, invasion, and metastasis of tumor cells, and the modulation of CD44-mediated cell signaling. A6 has been shown to have no dose-limiting toxicity in animal studies. A6 has demonstrated efficacy and an excellent safety profile in Phase 1a, 1b, and 2 clinical trials. In animal models, A6 has also exhibited promising results for the treatment of diabetic retinopathy and wet age-related macular degeneration through the reduction of retinal vascular permeability and inhibition of choroidal neovascularization, respectively. Recently, A6 has been shown to be directly cytotoxic for B-lymphocytes obtained from patients with chronic lymphocytic leukemia expressing the kinase, ZAP-70. This review will discuss the activity of A6, A6 modulation of HA and CD44, and a novel strategy for therapeutic intervention in disease. PMID:25870596

  12. Dietary fat modulates serum paraoxonase 1 activity in rats.

    PubMed

    Kudchodkar, B J; Lacko, A G; Dory, L; Fungwe, T V

    2000-10-01

    We examined the effects of dietary fats with specific fatty acid compositions, on serum paraoxonase (PON1) activity in rats. Male adult Sprague-Dawley rats were divided randomly into four dietary groups. One group received the control diet [AIN 93M with soybean oil (5 g/100 g diet)], whereas the remaining three groups received the modified control diet supplemented with (15 g/100 g diet) triolein, tripalmitin or fish oil, respectively. After 20 d, blood was obtained after overnight food deprivation and PON1 activity was determined. Serum lipids and lipid components of lipoproteins were also determined. Serum PON1 activity [micromol/(L.min)] was significantly (P: < 0.05) higher in triolein (98 +/- 6) and lower in fish oil (41 +/- 4), compared with tripalmitin-fed rats (63 +/- 11). Serum PON1 activity in tripalmitin-fed rats was comparable to that of controls (67 +/- 9). Serum PON1 activity correlated significantly with serum lecithin:cholesterol acyltransferase (LCAT) activity (r = 0.77, P: < 0.001) and was transported in blood principally in association with the denser subfraction of HDL, very high density lipoprotein (VHDL; d > 1.15 kg/L). Serum PON1 activity correlated strongly with serum lipids as well as lipids of VLDL, HDL and its subfractions. Multiple linear regression analysis, however, showed a significant relationship of serum PON1 activity, principally with the phospholipids of VHDL (r = 0.47, P: < 0.002). These data suggest that the modulation of serum PON1 activity by dietary fat may be mediated via the effect of the specific fatty acids on the synthesis and secretion of VHDL, the subfraction of HDL that transports the majority of PON1 in the blood. PMID:11015468

  13. Modulation of cortical oscillatory activity during transcranial magnetic stimulation.

    PubMed

    Brignani, Debora; Manganotti, Paolo; Rossini, Paolo M; Miniussi, Carlo

    2008-05-01

    Transcranial magnetic stimulation (TMS) can transiently modulate cortical excitability, with a net effect depending on the stimulation frequency (< or =1 Hz inhibition vs. > or =5 Hz facilitation, at least for the motor cortex). This possibility has generated interest in experiments aiming to improve deficits in clinical settings, as well as deficits in the cognitive domain. The aim of the present study was to investigate the on-line effects of low frequency (1 Hz) TMS on the EEG oscillatory activity in the healthy human brain, focusing particularly on the outcome of these modulatory effects in relation to the duration of the TMS stimulation. To this end, we used the event-related desynchronization/synchronization (ERD/ERS) approach to determine the patterns of oscillatory activity during two consecutive trains of sham and real TMS. Each train of stimulation was delivered to the left primary motor cortex (MI) of healthy subjects over a period of 10 min, while EEG rhythms were simultaneously recorded. Results indicated that TMS induced an increase in the power of brain rhythms that was related to the period of the stimulation, i.e. the synchronization of the alpha band increased with the duration of the stimulation, and this increase was inversely correlated with motor-evoked potentials (MEPs) amplitude. In conclusion, low frequency TMS over primary motor cortex induces a synchronization of the background oscillatory activity on the stimulated region. This induced modulation in brain oscillations seems to increase coherently with the duration of stimulation, suggesting that TMS effects may involve short-term modification of the neural circuitry sustaining MEPs characteristics. PMID:17557296

  14. Cinobufagin Modulates Human Innate Immune Responses and Triggers Antibacterial Activity

    PubMed Central

    Xie, Shanshan; Spelmink, Laura; Codemo, Mario; Subramanian, Karthik; Pütsep, Katrin

    2016-01-01

    The traditional Chinese medicine Chan-Su is widely used for treatment of cancer and cardiovascular diseases, but also as a remedy for infections such as furunculosis, tonsillitis and acute pharyngitis. The clinical use of Chan-Su suggests that it has anti-infective effects, however, the mechanism of action is incompletely understood. In particular, the effect on the human immune system is poorly defined. Here, we describe previously unrecognized immunomodulatory activities of cinobufagin (CBG), a major bioactive component of Chan-Su. Using human monocyte-derived dendritic cells (DCs), we show that LPS-induced maturation and production of a number of cytokines was potently inhibited by CBG, which also had a pro-apoptotic effect, associated with activation of caspase-3. Interestingly, CBG triggered caspase-1 activation and significantly enhanced IL-1β production in LPS-stimulated cells. Finally, we demonstrate that CBG upregulates gene expression of the antimicrobial peptides (AMPs) hBD-2 and hBD-3 in DCs, and induces secretion of HNP1-3 and hCAP-18/LL-37 from neutrophils, potentiating neutrophil antibacterial activity. Taken together, our data indicate that CBG modulates the inflammatory phenotype of DCs in response to LPS, and triggers an antibacterial innate immune response, thus proposing possible mechanisms for the clinical effects of Chan-Su in anti-infective therapy. PMID:27529866

  15. Superoxide radical and iron modulate aconitase activity in mammalian cells.

    PubMed

    Gardner, P R; Raineri, I; Epstein, L B; White, C W

    1995-06-01

    Aconitase is a member of a family of iron-sulfur-containing (de)hydratases whose activities are modulated in bacteria by superoxide radical (O2-.)-mediated inactivation and iron-dependent reactivation. The inactivation-reactivation of aconitase(s) in cultured mammalian cells was explored since these reactions may impact important and diverse aconitase functions in the cytoplasm and mitochondria. Conditions which increase O2-. production including exposure to the redox-cycling agent phenazine methosulfate (PMS), inhibitors of mitochondrial ubiquinol-cytochrome c oxidoreductase, or hyperoxia inactivated aconitase in mammalian cells. Overproduction of mitochondrial Mn-superoxide dismutase protected aconitase from inactivation by PMS or inhibitors of ubiquinol-cytochrome c oxidoreductase, but not from normobaric hyperoxia. Aconitase activity was reactivated (t1/2 of 12 +/- 3 min) upon removal of PMS. The iron chelator deferoxamine impaired reactivation and increased net inactivation of aconitase by O2-.. The ability of ubiquinol-cytochrome c oxidoreductase-generated O2-. to inactivate aconitase in several cell types correlated with the fraction of the aconitase activity localized in mitochondria. Extracellular O2-. generated with xanthine oxidase did not affect aconitase activity nor did exogenous superoxide dismutase decrease aconitase inactivation by PMS. The results demonstrate a dynamic and cyclical O2-.-mediated inactivation and iron-dependent reactivation of the mammalian [4Fe-4S] aconitases under normal and stress conditions and provide further evidence for the membrane compartmentalization of O2-.. PMID:7768942

  16. Cinobufagin Modulates Human Innate Immune Responses and Triggers Antibacterial Activity.

    PubMed

    Xie, Shanshan; Spelmink, Laura; Codemo, Mario; Subramanian, Karthik; Pütsep, Katrin; Henriques-Normark, Birgitta; Olliver, Marie

    2016-01-01

    The traditional Chinese medicine Chan-Su is widely used for treatment of cancer and cardiovascular diseases, but also as a remedy for infections such as furunculosis, tonsillitis and acute pharyngitis. The clinical use of Chan-Su suggests that it has anti-infective effects, however, the mechanism of action is incompletely understood. In particular, the effect on the human immune system is poorly defined. Here, we describe previously unrecognized immunomodulatory activities of cinobufagin (CBG), a major bioactive component of Chan-Su. Using human monocyte-derived dendritic cells (DCs), we show that LPS-induced maturation and production of a number of cytokines was potently inhibited by CBG, which also had a pro-apoptotic effect, associated with activation of caspase-3. Interestingly, CBG triggered caspase-1 activation and significantly enhanced IL-1β production in LPS-stimulated cells. Finally, we demonstrate that CBG upregulates gene expression of the antimicrobial peptides (AMPs) hBD-2 and hBD-3 in DCs, and induces secretion of HNP1-3 and hCAP-18/LL-37 from neutrophils, potentiating neutrophil antibacterial activity. Taken together, our data indicate that CBG modulates the inflammatory phenotype of DCs in response to LPS, and triggers an antibacterial innate immune response, thus proposing possible mechanisms for the clinical effects of Chan-Su in anti-infective therapy. PMID:27529866

  17. Bacteria activate sensory neurons that modulate pain and inflammation

    PubMed Central

    Chiu, Isaac M.; Heesters, Balthasar A.; Ghasemlou, Nader; Von Hehn, Christian A.; Zhao, Fan; Tran, Johnathan; Wainger, Brian; Strominger, Amanda; Muralidharan, Sriya; Horswill, Alexander R.; Wardenburg, Juliane Bubeck; Hwang, Sun Wook; Carroll, Michael C.; Woolf, Clifford J.

    2013-01-01

    Summary Nociceptor sensory neurons are specialized to detect potentially damaging stimuli, protecting the organism by initiating the sensation of pain and eliciting defensive behaviors. Bacterial infections produce pain by unknown molecular mechanisms, although they are presumed secondary to immune activation. Here we demonstrate that bacteria directly activate nociceptors, and that the immune response mediated through TLR2, MyD88, T cells, B cells, and neutrophils/monocytes is not necessary for Staphylococcus aureus induced pain in mice. Mechanical and thermal hyperalgesia parallels live bacterial load rather than tissue swelling or immune activation. Bacteria induce calcium flux and action potentials in nociceptor neurons, in part via bacterial N-formylated peptides and the pore-forming toxin alpha-hemolysin through distinct mechanisms. Specific ablation of Nav1.8-lineage neurons, which include nociceptors, abrogated pain during bacterial infection, but concurrently increased local immune infiltration and lymphadenopathy of the draining lymph node. Thus, bacterial pathogens produce pain by directly activating sensory neurons that modulate inflammation, an unsuspected role for the nervous system in host-pathogen interactions. PMID:23965627

  18. Coco is a dual activity modulator of TGFβ signaling

    PubMed Central

    Deglincerti, Alessia; Haremaki, Tomomi; Warmflash, Aryeh; Sorre, Benoit; Brivanlou, Ali H.

    2015-01-01

    The TGFβ signaling pathway is a crucial regulator of developmental processes and disease. The activity of TGFβ ligands is modulated by various families of soluble inhibitors that interfere with the interactions between ligands and receptors. In an unbiased, genome-wide RNAi screen to identify genes involved in ligand-dependent signaling, we unexpectedly identified the BMP/Activin/Nodal inhibitor Coco as an enhancer of TGFβ1 signaling. Coco synergizes with TGFβ1 in both cell culture and Xenopus explants. Molecularly, Coco binds to TGFβ1 and enhances TGFβ1 binding to its receptor Alk5. Thus, Coco acts as both an inhibitor and an enhancer of signaling depending on the ligand it binds. This finding raises the need for a global reconsideration of the molecular mechanisms regulating TGFβ signaling. PMID:26116664

  19. Workshop Physics Activity Guide, Module 4: Electricity and Magnetism

    NASA Astrophysics Data System (ADS)

    Laws, Priscilla W.

    2004-05-01

    The Workshop Physics Activity Guide is a set of student workbooks designed to serve as the foundation for a two-semester calculus-based introductory physics course. It consists of 28 units that interweave text materials with activities that include prediction, qualitative observation, explanation, equation derivation, mathematical modeling, quantitative experiments, and problem solving. Students use a powerful set of computer tools to record, display, and analyze data, as well as to develop mathematical models of physical phenomena. The design of many of the activities is based on the outcomes of physics education research. The Workshop Physics Activity Guide is supported by an Instructor's Website that: (1) describes the history and philosophy of the Workshop Physics Project; (2) provides advice on how to integrate the Guide into a variety of educational settings; (3) provides information on computer tools (hardware and software) and apparatus; and (4) includes suggested homework assignments for each unit. Log on to the Workshop Physics Project website at http://physics.dickinson.edu/ Workshop Physics is a component of the Physics Suite--a collection of materials created by a group of educational reformers known as the Activity Based Physics Group. The Physics Suite contains a broad array of curricular materials that are based on physics education research, including:

      Understanding Physics, by Cummings, Laws, Redish and Cooney (an introductory textbook based on the best-selling text by Halliday/Resnick/Walker) RealTime Physics Laboratory Modules Physics by Inquiry (intended for use in a workshop setting) Interactive Lecture Demonstration Tutorials in Introductory Physics Activity Based Tutorials (designed primarily for use in recitations)

    • Auditory Cortex Basal Activity Modulates Cochlear Responses in Chinchillas

      PubMed Central

      León, Alex; Elgueda, Diego; Silva, María A.; Hamamé, Carlos M.; Delano, Paul H.

      2012-01-01

      Background The auditory efferent system has unique neuroanatomical pathways that connect the cerebral cortex with sensory receptor cells. Pyramidal neurons located in layers V and VI of the primary auditory cortex constitute descending projections to the thalamus, inferior colliculus, and even directly to the superior olivary complex and to the cochlear nucleus. Efferent pathways are connected to the cochlear receptor by the olivocochlear system, which innervates outer hair cells and auditory nerve fibers. The functional role of the cortico-olivocochlear efferent system remains debated. We hypothesized that auditory cortex basal activity modulates cochlear and auditory-nerve afferent responses through the efferent system. Methodology/Principal Findings Cochlear microphonics (CM), auditory-nerve compound action potentials (CAP) and auditory cortex evoked potentials (ACEP) were recorded in twenty anesthetized chinchillas, before, during and after auditory cortex deactivation by two methods: lidocaine microinjections or cortical cooling with cryoloops. Auditory cortex deactivation induced a transient reduction in ACEP amplitudes in fifteen animals (deactivation experiments) and a permanent reduction in five chinchillas (lesion experiments). We found significant changes in the amplitude of CM in both types of experiments, being the most common effect a CM decrease found in fifteen animals. Concomitantly to CM amplitude changes, we found CAP increases in seven chinchillas and CAP reductions in thirteen animals. Although ACEP amplitudes were completely recovered after ninety minutes in deactivation experiments, only partial recovery was observed in the magnitudes of cochlear responses. Conclusions/Significance These results show that blocking ongoing auditory cortex activity modulates CM and CAP responses, demonstrating that cortico-olivocochlear circuits regulate auditory nerve and cochlear responses through a basal efferent tone. The diversity of the obtained effects

  1. MCT SWIR modules for passive and active imaging applications

    NASA Astrophysics Data System (ADS)

    Breiter, R.; Benecke, M.; Eich, D.; Figgemeier, H.; Weber, A.; Wendler, J.; Sieck, A.

    2016-05-01

    Based on AIM's state-of-the-art MCT IR technology, detector modules for the SWIR spectral range have been developed, fabricated and characterized. While LPE grown MCT FPAs with extended 2.5μm cut-off have been fabricated and integrated also MBE grown MCT on GaAs is considered for future production. Two imaging applications have been in focus operating either in passive mode by making use of e.g. the night glow, or in active mode by laser illumination for gated viewing. Dedicated readout integrated circuits (ROIC), realized in 0.18μm Si-CMOS technology providing the required functionality for passive imaging and gated imaging, have been designed and implemented. For both designs a 640x512 15μm pitch format was chosen. The FPAs are integrated in compact dewar cooler configurations using AIM's split linear coolers. A command and control electronics (CCE) provides supply voltages, biasing, clocks, control and video digitization for easy system interfacing. For imaging under low-light conditions a low-noise 640x512 15μm pitch ROIC with CTIA input stages and correlated double sampling was designed. The ROIC provides rolling shutter and snapshot integration. To reduce size, weight, power and cost (SWaP-C) a 640x512 format detector in a 10μm pitch is under development. The module makes use of the extended SWIR spectral cut-off up to 2.5μm. To be used for active gated-viewing operation SWIR MCT avalanche photodiodes have been implemented and characterized on FPA level in a 640x512 15μm pitch format. The specific ROIC provides also the necessary functions for range gate control and triggering by the laser illumination. First lab and field tests of a gated viewing demonstrator have been carried out. The paper will present the development status and performance results of AIM's MCT based SWIR Modules for imaging applications.

  2. Characterization of monofunctional catalase KatA from radioresistant bacterium Deinococcus radiodurans.

    PubMed

    Kobayashi, Issei; Tamura, Takashi; Sghaier, Haitham; Narumi, Issay; Yamaguchi, Shotaro; Umeda, Koichi; Inagaki, Kenji

    2006-04-01

    Catalase plays a key role in protecting cells against toxic reactive oxygen species. Here we report on the cloning, purification and characterization of a catalase (KatA, DR1998) from the extremely radioresistant bacterium Deinococcus radiodurans. The size of purified D. radiodurans KatA monomer was 65 kDa while gel filtration revealed that the size of the enzyme was 240 kDa, suggesting that KatA formed a homotetramer in solution. Purified KatA displayed a final specific activity of 68,800 U/mg of protein. The catalase activity of KatA was inhibited by sodium azide, sodium cyanide and 3-amino-1,2,4-triazole. The absorption spectrum of KatA exhibited a Soret band at 408 nm. The position of the spectral peak remained unchanged following reduction of KatA with dithionite. No peroxidase activity was found for KatA. These results demonstrate that D. radiodurans KatA is a typical monofunctional heme-containing catalase. The stability of KatA with respect to H2O2 stress was superior to that of commercially available Aspergillus niger and bovine liver catalases. The relative abundance of KatA in cells in addition to the H2O2 resistance property may play a role in the survival strategy of D. radiodurans against oxidative damage. PMID:16716939

  3. A human phospholipid phosphatase activated by a transmembrane control module[S

    PubMed Central

    Halaszovich, Christian R.; Leitner, Michael G.; Mavrantoni, Angeliki; Le, Audrey; Frezza, Ludivine; Feuer, Anja; Schreiber, Daniela N.; Villalba-Galea, Carlos A.; Oliver, Dominik

    2012-01-01

    In voltage-sensitive phosphatases (VSPs), a transmembrane voltage sensor domain (VSD) controls an intracellular phosphoinositide phosphatase domain, thereby enabling immediate initiation of intracellular signals by membrane depolarization. The existence of such a mechanism in mammals has remained elusive, despite the presence of VSP-homologous proteins in mammalian cells, in particular in sperm precursor cells. Here we demonstrate activation of a human VSP (hVSP1/TPIP) by an intramolecular switch. By engineering a chimeric hVSP1 with enhanced plasma membrane targeting containing the VSD of a prototypic invertebrate VSP, we show that hVSP1 is a phosphoinositide-5-phosphatase whose predominant substrate is PI(4,5)P2. In the chimera, enzymatic activity is controlled by membrane potential via hVSP1’s endogenous phosphoinositide binding motif. These findings suggest that the endogenous VSD of hVSP1 is a control module that initiates signaling through the phosphatase domain and indicate a role for VSP-mediated phosphoinositide signaling in mammals. PMID:22896666

  4. Caenorhabditis elegans glia modulate neuronal activity and behavior

    PubMed Central

    Stout Jr., Randy F.; Verkhratsky, Alexei; Parpura, Vladimir

    2014-01-01

    Glial cells of Caenorhabditis elegans can modulate neuronal activity and behavior, which is the focus of this review. Initially, we provide an overview of neuroglial evolution, making a comparison between C. elegans glia and their genealogical counterparts. What follows is a brief discussion on C. elegans glia characteristics in terms of their exact numbers, germ layers origin, their necessity for proper development of sensory organs, and lack of their need for neuronal survival. The more specific roles that various glial cells have on neuron-based activity/behavior are succinctly presented. The cephalic sheath glia are important for development, maintenance and activity of central synapses, whereas the amphid glia seem to set the tone of sensory synapses; these glial cell types are ectoderm-derived. Mesoderm-derived Glial-Like cells in the nerve Ring (GLRs) appear to be a part of the circuit for production of motor movement of the worm anterior. Finally, we discuss tools and approaches utilized in studying C. elegans glia, which are assets available for this animal, making it an appealing model, not only in neurosciences, but in biology in general. PMID:24672428

  5. D-Limonene modulates T lymphocyte activity and viability.

    PubMed

    Lappas, Courtney M; Lappas, Nicholas T

    2012-09-01

    d-Limonene, a cyclic terpene that is a major component of several plant essential oils, is used widely as an additive in perfumes, soaps, foods and beverages, and has also been shown to possess chemopreventative and chemotherapeutic activity. A limited number of studies have been conducted investigating the effect of d-limonene on immune system function. We show that d-limonene and its metabolites limonene-1-2-diol and perillic acid inhibit the production by CD3(+)CD4(+) T cells of IFN-γ, IL-2, TNF-α, IL-4 and IL-13, and the production by CD3(+)CD8(+) T cells of IFN-γ, IL-2, and TNF-α. Additionally, the upregulation of CD25, CD69 and CD40L by activated T lymphocytes is modulated by d-limonene, limonene-1-2-diol and perillic acid treatment. Furthermore, high concentrations of d-limonene, limonene-1-2-diol and perillic acid induce T lymphocyte cell death. These data suggest that d-limonene possesses immunomodulatory activity that must be considered when utilizing the compound for therapeutic or commercial purposes. PMID:23059811

  6. Caenorhabditis elegans glia modulate neuronal activity and behavior.

    PubMed

    Stout, Randy F; Verkhratsky, Alexei; Parpura, Vladimir

    2014-01-01

    Glial cells of Caenorhabditis elegans can modulate neuronal activity and behavior, which is the focus of this review. Initially, we provide an overview of neuroglial evolution, making a comparison between C. elegans glia and their genealogical counterparts. What follows is a brief discussion on C. elegans glia characteristics in terms of their exact numbers, germ layers origin, their necessity for proper development of sensory organs, and lack of their need for neuronal survival. The more specific roles that various glial cells have on neuron-based activity/behavior are succinctly presented. The cephalic sheath glia are important for development, maintenance and activity of central synapses, whereas the amphid glia seem to set the tone of sensory synapses; these glial cell types are ectoderm-derived. Mesoderm-derived Glial-Like cells in the nerve Ring (GLRs) appear to be a part of the circuit for production of motor movement of the worm anterior. Finally, we discuss tools and approaches utilized in studying C. elegans glia, which are assets available for this animal, making it an appealing model, not only in neurosciences, but in biology in general. PMID:24672428

  7. Cytosolic Hsp60 Can Modulate Proteasome Activity in Yeast*

    PubMed Central

    Kalderon, Bella; Kogan, Gleb; Bubis, Ettel; Pines, Ophry

    2015-01-01

    Hsp60, an essential oligomeric molecular mitochondrial chaperone, has been subject to rigorous basic and clinical research. With yeast as a model system, we provide evidence for the ability of cytosolic yHsp60 to inhibit the yeast proteasome. (i) Following biological turnover of murine Bax (a proteasome substrate), we show that co-expression of cytosolic yHsp60 stabilizes Bax, enhances its association with mitochondria, and enhances its killing capacity. (ii) Expression of yHsp60 in the yeast cytosol (yHsp60c) inhibits degradation of a cytosolic protein ΔMTS-Aco1 tagged with the degron SL17 (a ubiquitin-proteasome substrate). (iii) Conditions under which Hsp60 accumulates in the cytosol (elevated Hsp60c or growth at 37 °C) correlate with reduced 20 S peptidase activity in proteasomes purified from cell extracts. (iv) Elevated yHsp60 in the cytosol correlate with accumulation of polyubiquitinated proteins. (v) According to 20 S proteasome pulldown experiments, Hsp60 is physically associated with proteasomes in extracts of cells expressing Hsp60c or grown at 37 °C. Even mutant Hsp60 proteins, lacking chaperone activity, were still capable of proteasome inhibition. The results support the hypothesis that localization of Hsp60 to the cytosol may modulate proteasome activity according to cell need. PMID:25525272

  8. Promotion of radioresistance by metallothionein induction prior to irradiation

    SciTech Connect

    Matsubara, J.; Tajima, Y.; Karasawa, M.

    1987-06-01

    A striking radioresistance has been found in mice which were subjected to various pretreatments to induce metallothionein synthesis in the liver prior to irradiation. The tolerance to lethal damage from an LD50 level of radiation during a 30-day postirradiation period was demonstrated by a highly significant difference (P less than 0.01) in mortality rate between mice given subcutaneously manganese, cadmium, or zinc injection or surgical skin excision of mice and the control mice (no pretreatment). A typical loss in body weight that generally reached a peak 2 weeks after irradiation was observed in the control mice, but mice given a dose of 10 mg manganese per kilogram body weight showed a steady weight increase even a few days after irradiation. The normal level of metallothionein in mouse liver is 20 micrograms/g tissue. This level increased up to 70 micrograms/g tissue following irradiation at 6.3 Gy. Among irradiated mice, metallothionein levels in the liver increased approximately 200-800% after cadmium, manganese, or zinc injection compared to levels of irradiated mice without pretreatment. Mice undergoing 2 X 2-cm/sup 2/ dermal excision also demonstrated a similar reduction of mortality and high metallothionein contents in liver, i.e., 150-400 micrograms/g. The present results, together with our previous findings suggest that the body's protective mechanism against radiation strongly correlates with the biosynthesis of metallothionein or metallothionein itself acting as a scavenger of radiation-induced peroxides.

  9. Helicobacter pylori antigens as potential modulators of lymphocytes' cytotoxic activity.

    PubMed

    Rudnicka, Karolina; Włodarczyk, Marcin; Moran, Anthony P; Rechciński, Tomasz; Miszczyk, Eliza; Matusiak, Agnieszka; Szczęsna, Ewelina; Walencka, Maria; Rudnicka, Wiesława; Chmiela, Magdalena

    2012-01-01

    Helicobacter pylori (H.p) colonizes human gastric mucosa and causes gastric and duodenal ulcer disease or gastric cancer. Various H.p compounds may modulate the host immune response in regards to tolerance of the infection or disease development. The aim of this study was to determine whether H.p lipopolysaccharide (LPS) and glycine acid extract antigens (GE) or E. coli LPS influence the cytotoxic activity of peripheral blood lymphocytes from H.p infected - H.p (+) or uninfected - H.p (-) individuals, in the presence or absence of exogenous interleukin (IL)12. Individual H.p status was defined by the urea breath test. Lymphocytes, stimulated or not with H.p, and control antigens, with or without IL-12, were used as effector cells and epithelial HeLa cells as targets. The cytotoxicity of lymphocytes was expressed as the percentage of dead target cells unable to reduce tetrazolium salt. The supernatants from HeLa/lymphocyte cultures were used for detection of the cellular cytotoxicity markers granzyme B and caspase 8. The natural cytotoxic activity of lymphocytes from H.p (+) was less than that of H.p (-) donors. This may have been due to fewer natural killer cells of CD3(-) CD56(+) Nkp46(+) phenotype in H.p (+) in comparison to H.p (-) subjects. H.p GE and standard E. coli LPS enhanced the cytotoxicity of lymphocytes towards target cells whereas H.p LPS downregulated this activity. The decrease in lymphocyte cytotoxicity in response to H.p LPS correlated with a lack of IL-2 and IL-12 production, inhibition of interferon-γ production, and low IL-10 secretion by mononuclear leukocytes. IL-12 significantly enhanced the natural as well as H.p LPS and H.p GE driven cytotoxic capacity of lymphocytes. In conclusion, H.p LPS may negatively modulate natural cytotoxic activity and cytokine secretion by immunocompetent cells and thus be involved in the maintenance of infection and development of gastric pathologies. PMID:22040089

  10. Star Power: Providing for the Gifted & Talented. Module 5. Enrichment Activities for the Gifted/Talented.

    ERIC Educational Resources Information Center

    Mallis, Jackie; Gilman, Sharlene

    The document presents Module 5, enrichment activities for the gifted/talented, of the Star Power modules developed for school personnel who have an interest in or a need to explore the area of gifted and talented education. It is explained in an introductory section that the modules can be used for independent study, for small group interaction,…

  11. Alterations in transcription factor binding in radioresistant human melanoma cells after ionizing radiation

    SciTech Connect

    Sahijdak, W.M.; Yang, Chin-Rang; Zuckerman, J.S.; Meyers, M.; Boothman, D.A.

    1994-04-01

    We analyzed alterations in transcription factor binding to specific, known promoter DNA consensus sequences between irradiated and unirradiated radioresistant human melanoma (U1-Mel) cells. The goal of this study was to begin to investigate which transcription factors and DNA-binding sites are responsible for the induction of specific transcripts and proteins after ionizing radiation. Transcription factor binding was observed using DNA band-shift assays and oligonucleotide competition analyses. Confluence-arrested U1-Mel cells were irradiated (4.5 Gy) and harvested at 4 h. Double-stranded oligonucleotides containing known DNA-binding consensus sites for specific transcription factors were used. Increased DNA binding activity after ionizing radiation was noted with oligonucleotides containing the CREB, NF-kB and Sp1 consensus sites. No changes in protein binding to AP-1, AP-2, AP-3, or CTF/NF1, GRE or Oct-1 consensus sequences were noted. X-ray activation of select transcription factors, which bind certain consensus sites in promoters, may cause specific induction or repression of gene transcription. 22 refs., 2 figs.

  12. Materials and Process Activities for NASA's Composite Crew Module

    NASA Technical Reports Server (NTRS)

    Polis, Daniel L.

    2012-01-01

    In January 2007, the NASA Administrator and Associate Administrator for the Exploration Systems Mission Directorate chartered the NASA Engineering and Safety Center (NESC) to design, build, and test a full-scale Composite Crew Module (CCM). The overall goal of the CCM project was to develop a team from the NASA family with hands-on experience in composite design, manufacturing, and testing in anticipation of future space exploration systems being made of composite materials. The CCM project was planned to run concurrently with the Orion project s baseline metallic design within the Constellation Program so that features could be compared and discussed without inducing risk to the overall Program. The materials and process activities were prioritized based on a rapid prototype approach. This approach focused developmental activities on design details with greater risk and uncertainty, such as out-of-autoclave joining, over some of the more traditional lamina and laminate building block levels. While process development and associated building block testing were performed, several anomalies were still observed at the full-scale level due to interactions between process robustness and manufacturing scale-up. This paper describes the process anomalies that were encountered during the CCM development and the subsequent root cause investigations that led to the final design solutions. These investigations highlight the importance of full-scale developmental work early in the schedule of a complex composite design/build project.

  13. Active Desiccant Dehumidification Module Integration with Rooftop Packaged HVAC

    SciTech Connect

    Fischer, J

    2002-04-17

    This report summarizes a research and development program that produced a stand-alone active desiccant module (ADM) that can be easily integrated with new or existing packaged cooling equipment. The program also produced a fully integrated hybrid system, combining the active desiccant section with a conventional direct expansion air-conditioning unit, that resulted in a compact, low-cost, energy-efficient end product. Based upon the results of this investigation, both systems were determined to be highly viable products for commercialization. Major challenges--including wheel development, compact packaging, regeneration burner development, control optimization, and low-cost design--were all successfully addressed by the final prototypes produced and tested as part of this program. Extensive laboratory testing was completed in the SEMCO laboratory for each of the two ADM system approaches. This testing confirmed the performance of the ADM systems to be attractive compared with that of alternate approaches currently used to precondition outdoor air, where a return air path is not readily available for passive desiccant recovery or where first cost is the primary design criterion. Photographs, schematics, and performance maps are provided for the ADM systems that were developed; and many of the control advantages are discussed. Based upon the positive results of this research and development program, field tests are under way for fully instrumented pilot installations of ADM systems in both a hotel/motel and a restaurant.

  14. Modulation of Group I Ribozyme Activity by Cationic Porphyrins

    PubMed Central

    Matsumura, Shigeyoshi; Ito, Tatsunobu; Tanaka, Takahiro; Furuta, Hiroyuki; Ikawa, Yoshiya

    2015-01-01

    The effects of cationic porphyrins on the catalytic activities of four group I ribozymes were investigated. A cationic porphyrin possessing four pyridinium moieties (pPyP) inhibited two group IC3 ribozymes (Syn Rz and Azo Rz) and a group IC1 ribozyme (Tet Rz). In the case of a group IA2 ribozyme (Td Rz), however, pPyP served not only as an inhibitor but also as an activator, and the effects of pPyP were dependent on its concentration. To analyze the structural and electronic factors determining the effects of pPyP on group I ribozymes, three cationic porphyrins (pPyNCP, pPyF4P, and TMPyP) were also examined. As interactions between small organic molecules and nucleic acids are attractive and important issues in biochemistry and biotechnology, this study contributes to the development of porphyrin-based molecules that can modulate functions of structured RNA molecules. PMID:25811638

  15. Physiological mechanisms for the modulation of pannexin 1 channel activity

    PubMed Central

    Sandilos, Joanna K; Bayliss, Douglas A

    2012-01-01

    It is widely recognized that ATP, along with other nucleotides, subserves important intercellular signalling processes. Among various nucleotide release mechanisms, the relatively recently identified pannexin 1 (Panx1) channel is gaining prominence by virtue of its ability to support nucleotide permeation and release in a variety of different tissues. Here, we review recent advances in our understanding of the factors that control Panx1 channel activity. By using electrophysiological and biochemical approaches, diverse mechanisms that dynamically regulate Panx1 channel function have been identified in various settings; these include, among others, activation by caspase-mediated channel cleavage in apoptotic immune cells, by G protein-coupled receptors in vascular smooth muscle, by low oxygen tension in erythrocytes and neurons, by high extracellular K+ in various cell types and by stretch/strain in airway epithelia. Delineating the distinct mechanisms of Panx1 modulation that prevail in different physiological contexts provides the possibility that these channels, and ATP release, could ultimately be targeted in a context-dependent manner. PMID:23070703

  16. Multiplicative and Additive Modulation of Neuronal Tuning with Population Activity Affects Encoded Information.

    PubMed

    Arandia-Romero, Iñigo; Tanabe, Seiji; Drugowitsch, Jan; Kohn, Adam; Moreno-Bote, Rubén

    2016-03-16

    Numerous studies have shown that neuronal responses are modulated by stimulus properties and also by the state of the local network. However, little is known about how activity fluctuations of neuronal populations modulate the sensory tuning of cells and affect their encoded information. We found that fluctuations in ongoing and stimulus-evoked population activity in primate visual cortex modulate the tuning of neurons in a multiplicative and additive manner. While distributed on a continuum, neurons with stronger multiplicative effects tended to have less additive modulation and vice versa. The information encoded by multiplicatively modulated neurons increased with greater population activity, while that of additively modulated neurons decreased. These effects offset each other so that population activity had little effect on total information. Our results thus suggest that intrinsic activity fluctuations may act as a "traffic light" that determines which subset of neurons is most informative. PMID:26924437

  17. Coincident Helminth Infection Modulates Systemic Inflammation and Immune Activation in Active Pulmonary Tuberculosis

    PubMed Central

    George, Parakkal Jovvian; Kumar, Nathella Pavan; Sridhar, Rathinam; Hanna, Luke E.; Nair, Dina; Banurekha, Vaithilingam V.; Nutman, Thomas B.; Babu, Subash

    2014-01-01

    Background Helminth infections are known to modulate innate and adaptive immune responses in active and latent tuberculosis (TB). However, the role of helminth infections in modulating responses associated with inflammation and immune activation (reflecting disease activity and/or severity) in TB is not known. Methodology We measured markers of inflammation and immune activation in active pulmonary TB individuals (ATB) with co-incidental Strongyloides stercoralis (Ss) infection. These included systemic levels of acute phase proteins, matrix metalloproteinases and their endogenous inhibitors and immune activation markers. As a control, we measured the systemic levels of the same molecules in TB-uninfected individuals (NTB) with or without Ss infection. Principal Findings Our data confirm that ATB is associated with elevated levels of the various measured molecules when compared to those seen in NTB. Our data also reveal that co-incident Ss infection in ATB individuals is associated with significantly decreased circulating levels of acute phase proteins, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases as well as the systemic immune activation markers, sCD14 and sCD163. These changes are specific to ATB since they are absent in NTB individuals with Ss infection. Conclusions Our data therefore reveal a profound effect of Ss infection on the markers associated with TB disease activity and severity and indicate that co-incidental helminth infections might dampen the severity of TB disease. PMID:25375117

  18. Antileishmanial Activity of the Estrogen Receptor Modulator Raloxifene

    PubMed Central

    Reimão, Juliana Q.; Miguel, Danilo C.; Taniwaki, Noemi N.; Trinconi, Cristiana T.; Yokoyama-Yasunaka, Jenicer K. U.; Uliana, Silvia R. B.

    2014-01-01

    Background The treatment of leishmaniasis relies mostly on parenteral drugs with potentially serious adverse effects. Additionally, parasite resistance in the treatment of leishmaniasis has been demonstrated for the majority of drugs available, making the search for more effective and less toxic drugs and treatment regimens a priority for the control of leishmaniasis. The aims of this study were to evaluate the antileishmanial activity of raloxifene in vitro and in vivo and to investigate its mechanism of action against Leishmania amazonensis. Methodology/Principal Findings Raloxifene was shown to possess antileishmanial activity in vitro against several species with EC50 values ranging from 30.2 to 38.0 µM against promastigotes and from 8.8 to 16.2 µM against intracellular amastigotes. Raloxifene's mechanism of action was investigated through transmission electron microscopy and labeling with propidium iodide, DiSBAC2(3), rhodamine 123 and monodansylcadaverine. Microscopic examinations showed that raloxifene treated parasites displayed autophagosomes and mitochondrial damage while the plasma membrane remained continuous. Nonetheless, plasma membrane potential was rapidly altered upon raloxifene treatment with initial hyperpolarization followed by depolarization. Loss of mitochondrial membrane potential was also verified. Treatment of L. amazonensis – infected BALB/c mice with raloxifene led to significant decrease in lesion size and parasite burden. Conclusions/Significance The results of this work extend the investigation of selective estrogen receptor modulators as potential candidates for leishmaniasis treatment. The antileishmanial activity of raloxifene was demonstrated in vitro and in vivo. Raloxifene produces functional disorder on the plasma membrane of L. amazonensis promastigotes and leads to functional and morphological disruption of mitochondria, which culminate in cell death. PMID:24810565

  19. Enhancer-specific modulation of E protein activity.

    PubMed

    Markus, Maurice; Du, Zhimei; Benezra, Robert

    2002-02-22

    Homodimeric complexes of members of the E protein family of basic helix-loop-helix (bHLH) transcription factors are important for tissue-specific activation of genes in B lymphocytes (Bain, G., Gruenwald, S., and Murre, C. (1993) Mol. Cell Biol. 13, 3522-3529; Shen, C. P., and Kadesch, T. (1995) Mol. Cell Biol. 15, 4518-4524; Jacobs, Y., et al. (1994) Mol. Cell Biol. 14, 4087-4096; Wilson, R. B., et al. (1991) Mol. Cell Biol. 11, 6185-6191). These homodimers, however, have little activity on myogenic enhancers (Weintraub, H., Genetta, T., and Kadesch, T. (1994) Genes Dev. 8, 2203-2211). We report here the identification of a novel cis-acting transcriptional repression domain in the E protein family of bHLH transcription factors. This domain, the Rep domain, is present in each of the known vertebrate E proteins. Extensive mapping analysis demonstrates that this domain is an acidic region of 30 amino acids with a predicted loop structure. Fusion studies indicate that the Rep domain can repress both of the E protein transactivation domains (AD1 and AD2). Physiologically, the Rep domain plays a key role in maintaining E protein homodimers in an inactive state on myogenic enhancers. In addition, we demonstrate that Rep domain mediated repression of AD1 is a necessary for the function of MyoD-E protein heterodimeric complexes. These studies demonstrate that the Rep domain is important for modulating the transcriptional activity of E proteins and provide key insights into both the selectivity and mechanism of action of E protein containing bHLH protein complexes. PMID:11724804

  20. Platelet activation and apoptosis modulate monocyte inflammatory responses in dengue

    PubMed Central

    Hottz, Eugenio D.; Medeiros-de-Moraes, Isabel M.; Vieira-de-Abreu, Adriana; de Assis, Edson F.; Vals-de-Souza, Rogério; Castro-Faria-Neto, Hugo C.; Weyrich, Andrew S.; Zimmerman, Guy A.; Bozza, Fernando A.; Bozza, Patrícia T.

    2014-01-01

    Background Dengue is the most prevalent human arbovirus disease in the world. Dengue infection has a large spectrum of clinical manifestations from self-limited febrile illness to severe syndromes accompanied by bleeding and shock. Thrombocytopenia and vascular leak with altered cytokine profiles in plasma are features of severe dengue. Although monocytes have been recognized as important sources of cytokines in dengue, the contributions of platelet-monocyte interactions to inflammatory responses in dengue have not been addressed. Patients/Methods Patients with dengue were investigated for platelet-monocyte aggregate formation and markers of monocyte activation. Platelet-induced cytokine responses by monocytes and underlying mechanisms were also investigated in vitro. Results We observed increased levels of platelet-monocyte aggregates in blood samples from patients with dengue, especially patients with thrombocytopenia and increased vascular permeability. Moreover, the exposure of monocytes from healthy volunteers to platelets from patients with dengue induced the secretion of the cytokines IL-1β, IL-8, IL-10 and MCP-1, while the exposure to platelets from healthy volunteers only induced the secretion of MCP-1. In addition to the well-established modulation of monocyte cytokine responses by activated platelets through P-selectin binding, we found that interaction of monocytes with apoptotic platelets mediate IL-10 secretion through phosphatidylserine recognition in platelet-monocyte aggregates. Moreover, IL-10 secretion required platelet-monocyte contact but not phagocytosis. Conclusions Together, our results demonstrate that activated and apoptotic platelets aggregate with monocytes during dengue infection and signal specific cytokine responses that may contribute to the pathogenesis of dengue. PMID:25015827

  1. Rare earth activated yttrium aluminate phosphors with modulated luminescence.

    PubMed

    Muresan, L E; Popovici, E J; Perhaita, I; Indrea, E; Oro, J; Casan Pastor, N

    2016-06-01

    Yttrium aluminate (Y3 A5 O12 ) was doped with different rare earth ions (i.e. Gd(3+) , Ce(3+) , Eu(3+) and/or Tb(3+) ) in order to obtain phosphors (YAG:RE) with general formula,Y3-x-a Gdx REa Al5 O12 (x = 0; 1.485; 2.97 and a = 0.03). The synthesis of the phosphor samples was done using the simultaneous addition of reagents technique. This study reveals new aspects regarding the influence of different activator ions on the morpho-structural and luminescent characteristics of garnet type phosphor. All YAG:RE phosphors are well crystallized powders containing a cubic-Y3 Al5 O12 phase as major component along with monoclinic-Y4 Al2 O9 and orthorhombic-YAlO3 phases as the impurity. The crystallites dimensions of YAG:RE phosphors vary between 38 nm and 88 nm, while the unit cell slowly increase as the ionic radius of the activator increases. Under UV excitation, YAG:Ce exhibits yellow emission due to electron transition in Ce(3+) from the 5d level to the ground state levels ((2) F5/2 , (2) F7/2 ). The emission intensity of Ce(3+) is enhanced in the presence of the Tb(3+) ions and is decreased in the presence of Eu(3+) ions due to some radiative or non-radiative processes that take place between activator ions. By varying the rare earth ions, the emission colour can be modulated from green to white and red. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26553167

  2. Active space debris removal by a hybrid propulsion module

    NASA Astrophysics Data System (ADS)

    DeLuca, L. T.; Bernelli, F.; Maggi, F.; Tadini, P.; Pardini, C.; Anselmo, L.; Grassi, M.; Pavarin, D.; Francesconi, A.; Branz, F.; Chiesa, S.; Viola, N.; Bonnal, C.; Trushlyakov, V.; Belokonov, I.

    2013-10-01

    During the last 40 years, the mass of the artificial objects in orbit increased quite steadily at the rate of about 145 metric tons annually, leading to a total tally of approximately 7000 metric tons. Now, most of the cross-sectional area and mass (97% in LEO) is concentrated in about 4600 intact objects, i.e. abandoned spacecraft and rocket bodies, plus a further 1000 operational spacecraft. Simulations and parametric analyses have shown that the most efficient and effective way to prevent the outbreak of a long-term exponential growth of the catalogued debris population would be to remove enough cross-sectional area and mass from densely populated orbits. In practice, according to the most recent NASA results, the active yearly removal of approximately 0.1% of the abandoned intact objects would be sufficient to stabilize the catalogued debris in low Earth orbit, together with the worldwide adoption of mitigation measures. The candidate targets for removal would have typical masses between 500 and 1000 kg, in the case of spacecraft, and of more than 1000 kg, in the case of rocket upper stages. Current data suggest that optimal active debris removal missions should be carried out in a few critical altitude-inclination bands. This paper deals with the feasibility study of a mission in which the debris is removed by using a hybrid propulsion module as propulsion unit. Specifically, the engine is transferred from a servicing platform to the debris target by a robotic arm so to perform a controlled disposal. Hybrid rocket technology for de-orbiting applications is considered a valuable option due to high specific impulse, intrinsic safety, thrust throttle ability, low environmental impact and reduced operating costs. Typically, in hybrid rockets a gaseous or liquid oxidizer is injected into the combustion chamber along the axial direction to burn a solid fuel. However, the use of tangential injection on a solid grain Pancake Geometry allows for more compact design of

  3. KNK437, abrogates hypoxia-induced radioresistance by dual targeting of the AKT and HIF-1{alpha} survival pathways

    SciTech Connect

    Oommen, Deepu; Prise, Kevin M.

    2012-05-11

    Highlights: Black-Right-Pointing-Pointer KNK437, a benzylidene lactam compound, is a novel radiosensitizer. Black-Right-Pointing-Pointer KNK437 inhibits AKT signaling and abrogates the accumulation of HIF-1{alpha} under hypoxia. Black-Right-Pointing-Pointer KNK437 abrogates hypoxia induced resistance to radiation. -- Abstract: KNK437 is a benzylidene lactam compound known to inhibit stress-induced synthesis of heat shock proteins (HSPs). HSPs promote radioresistance and play a major role in stabilizing hypoxia inducible factor-1{alpha} (HIF-1{alpha}). HIF-1{alpha} is widely responsible for tumor resistance to radiation under hypoxic conditions. We hypothesized that KNK437 sensitizes cancer cells to radiation and overrides hypoxia-induced radioresistance via destabilizing HIF-1{alpha}. Treatment of human cancer cells MDA-MB-231 and T98G with KNK437 sensitized them to ionizing radiation (IR). Surprisingly, IR did not induce HSPs in these cell lines. As hypothesized, KNK437 abrogated the accumulation of HIF-1{alpha} in hypoxic cells. However, there was no induction of HSPs under hypoxic conditions. Moreover, the proteosome inhibitor MG132 did not restore HIF-1{alpha} levels in KNK437-treated cells. This suggested that the absence of HIF-1{alpha} in hypoxic cells was not due to the enhanced protein degradation. HIF-1{alpha} is mainly regulated at the level of post-transcription and AKT is known to modulate the translation of HIF-1{alpha} mRNA. Interestingly, pre-treatment of cells with KNK437 inhibited AKT signaling. Furthermore, down regulation of AKT by siRNA abrogated HIF-1{alpha} levels under hypoxia. Interestingly, KNK437 reduced cell survival in hypoxic conditions and inhibited hypoxia-induced resistance to radiation. Taken together, these data suggest that KNK437 is an effective radiosensitizer that targets multiple pro-survival stress response pathways.

  4. Fractionated irradiation-induced EMT-like phenotype conferred radioresistance in esophageal squamous cell carcinoma

    PubMed Central

    Zhang, Hongfang; Luo, Honglei; Jiang, Zhenzhen; Yue, Jing; Hou, Qiang; Xie, Ruifei; Wu, Shixiu

    2016-01-01

    The efficacy of radiotherapy, one major treatment modality for esophageal squamous cell carcinoma (ESCC) is severely attenuated by radioresistance. Epithelial-to-mesenchymal transition (EMT) is a cellular process that determines therapy response and tumor progression. However, whether EMT is induced by ionizing radiation and involved in tumor radioresistance has been less studied in ESCC. Using multiple fractionated irradiation, the radioresistant esophageal squamous cancer cell line KYSE-150R had been established from its parental cell line KYSE-150. We found KYSE-150R displayed a significant EMT phenotype with an elongated spindle shape and down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker N-cadherin in comparison with KYSE-150. Furthermore, KYSE-150R also possessed some stemness-like properties characterized by density-dependent growth promotion and strong capability for sphere formation and tumorigenesis in NOD-SCID mice. Mechanical studies have revealed that WISP1, a secreted matricellular protein, is highly expressed in KYSE-150R and mediates EMT-associated radioresistance both in ESCC cells and in xenograft tumor models. Moreover, WISP1 has been demonstrated to be closely associated with the EMT phenotype observed in ESCC patients and to be an independent prognosis factor of ESCC patients treated with radiotherapy. Our study highlighted WISP1 as an attractive target to reverse EMT-associated radioresistance in ESCC and can be used as an independent prognostic factor of patients treated with radiotherapy. PMID:27125498

  5. Cancer Stem Cells and Radioresistance: Rho/ROCK Pathway Plea Attention.

    PubMed

    Pranatharthi, Annapurna; Ross, Cecil; Srivastava, Sweta

    2016-01-01

    Radiation is the most potent mode of cancer therapy; however, resistance to radiation therapy results in tumor relapse and subsequent fatality. The cancer stem cell (CSC), which has better DNA repair capability, has been shown to contribute to tumor resistance and is an important target for treatment. Signaling molecules such as Notch, Wnt, and DNA repair pathways regulate molecular mechanisms in CSCs; however, none of them have been translated into therapeutic targets. The RhoGTPases and their effector ROCK-signaling pathway, though important for tumor progression, have not been well studied in the context of radioresistance. There are reports that implicate RhoA in radioresistance. ROCK2 has also been shown to interact with BRCA2 in the regulation of cell division. Incidentally, statins (drug for cardiovascular ailment) are functional inhibitors of RhoGTPases. Studies suggest that patients on statins have a better prognosis in cancers. Data from our lab suggest that ROCK signaling regulates radioresistance in cervical cancer cells. Collectively, these findings suggest that Rho/ROCK signaling may be important for radiation resistance. In this review, we enumerate the role of Rho/ROCK signaling in stemness and radioresistance and highlight the need to explore these molecules for a better understanding of radioresistance and development of therapeutics. PMID:27597870

  6. Cancer Stem Cells and Radioresistance: Rho/ROCK Pathway Plea Attention

    PubMed Central

    Pranatharthi, Annapurna; Ross, Cecil

    2016-01-01

    Radiation is the most potent mode of cancer therapy; however, resistance to radiation therapy results in tumor relapse and subsequent fatality. The cancer stem cell (CSC), which has better DNA repair capability, has been shown to contribute to tumor resistance and is an important target for treatment. Signaling molecules such as Notch, Wnt, and DNA repair pathways regulate molecular mechanisms in CSCs; however, none of them have been translated into therapeutic targets. The RhoGTPases and their effector ROCK-signaling pathway, though important for tumor progression, have not been well studied in the context of radioresistance. There are reports that implicate RhoA in radioresistance. ROCK2 has also been shown to interact with BRCA2 in the regulation of cell division. Incidentally, statins (drug for cardiovascular ailment) are functional inhibitors of RhoGTPases. Studies suggest that patients on statins have a better prognosis in cancers. Data from our lab suggest that ROCK signaling regulates radioresistance in cervical cancer cells. Collectively, these findings suggest that Rho/ROCK signaling may be important for radiation resistance. In this review, we enumerate the role of Rho/ROCK signaling in stemness and radioresistance and highlight the need to explore these molecules for a better understanding of radioresistance and development of therapeutics. PMID:27597870

  7. FGFR1 Induces Glioblastoma Radioresistance through the PLCγ/Hif1α Pathway.

    PubMed

    Gouazé-Andersson, Valérie; Delmas, Caroline; Taurand, Marion; Martinez-Gala, Judith; Evrard, Solène; Mazoyer, Sandrine; Toulas, Christine; Cohen-Jonathan-Moyal, Elizabeth

    2016-05-15

    FGF2 signaling in glioblastoma induces resistance to radiotherapy, so targeting FGF2/FGFR pathways might offer a rational strategy for tumor radiosensitization. To investigate this possibility, we evaluated a specific role for FGFR1 in glioblastoma radioresistance as modeled by U87 and LN18 glioblastomas in mouse xenograft models. Silencing FGFR1 decreased radioresistance in a manner associated with radiation-induced centrosome overduplication and mitotic cell death. Inhibiting PLCγ (PLCG1), a downstream effector signaling molecule for FGFR1, was sufficient to produce similar effects, arguing that PLCγ is an essential mediator of FGFR1-induced radioresistance. FGFR1 silencing also reduced expression of HIF1α, which in addition to its roles in hypoxic responses exerts an independent effect on radioresistance. Finally, FGFR1 silencing delayed the growth of irradiated tumor xenografts, in a manner that was associated with reduced HIF1α levels but not blood vessel alterations. Taken together, our results offer a preclinical proof of concept that FGFR1 targeting can degrade radioresistance in glioblastoma, a widespread problem in this tumor, prompting clinical investigations of the use of FGFR1 inhibitors for radiosensitization. Cancer Res; 76(10); 3036-44. ©2016 AACR. PMID:26896280

  8. Promotion of radioresistance by metallothionein induction prior to irradiation.

    PubMed

    Matsubara, J; Tajima, Y; Karasawa, M

    1987-06-01

    A striking radioresistance has been found in mice which were subjected to various pretreatments to induce metallothionein synthesis in the liver prior to irradiation. The tolerance to lethal damage from an LD50 level of radiation during a 30-day postirradiation period was demonstrated by a highly significant difference (P less than 0.01) in mortality rate between mice given subcutaneously manganese, cadmium, or zinc injection or surgical skin excision of mice and the control mice (no pretreatment). A typical loss in body weight that generally reached a peak 2 weeks after irradiation was observed in the control mice, but mice given a dose of 10 mg manganese per kilogram body weight showed a steady weight increase even a few days after irradiation. The normal level of metallothionein in mouse liver is 20 micrograms/g tissue. This level increased up to 70 micrograms/g tissue following irradiation at 6.3 Gy. Among irradiated mice, metallothionein levels in the liver increased approximately 200-800% after cadmium, manganese, or zinc injection compared to levels of irradiated mice without pretreatment. Mice undergoing 2 X 2-cm2 dermal excision also demonstrated a similar reduction of mortality and high metallothionein contents in liver, i.e., 150-400 micrograms/g. The present results, together with our previous findings (Matsubara et al., 1982, 1983, 1984; Matsubara, 1986), suggest that the body's protective mechanism against radiation strongly correlates with the biosynthesis of metallothionein or metallothionein itself acting as a scavenger of radiation-induced peroxides. PMID:3556159

  9. Promoting Active Learning with Cases and Instructional Modules.

    ERIC Educational Resources Information Center

    Richards, Larry G.; And Others

    1995-01-01

    Proposes the use of cases and instructional modules to teach invention, engineering design, and technology management. Discusses the case method in graduate business education, cases and modules in engineering education, using cases in class, and the development and distribution of cases. Presents examples of using cases about total quality…

  10. Nicotinic modulation of serotonergic activity in the dorsal raphe nucleus.

    PubMed

    Hernandez-Lopez, Salvador; Garduño, Julieta; Mihailescu, Stefan

    2013-01-01

    Cholinergic signaling mediated by nicotinic receptors has been associated to a large number of physiological and behavioral processes such as learning, memory, attention, food-intake and mood disorders. Although it is well established that many nicotinic actions are mediated through an increase in serotonin (5-HT) release, the physiological mechanisms by which nicotine produces these effects are still unclear. The dorsal raphe nucleus (DRN) contains the major amount of 5-HT neurons projecting to different parts of the brain. DRN also contains nicotinic acetylcholine receptors (nAChRs) located at somatic and presynaptic elements. Nicotine produces both inhibitory and excitatory effects on different subpopulations of 5-HT DRN neurons. In this review, we describe the presynaptic and postsynaptic mechanisms by which nicotine increases the excitability of DRN neurons as well as the subtypes of nAChRs involved. We also describe the inhibitory effects of nicotine and the role of 5-HT1A receptors in this effect. These nicotinic actions modulate the activity of different neuronal subpopulations in the DRN, changing the 5-HT tone in the brain areas where these groups of neurons project. Some of the physiological implications of nicotine-induced 5-HT release are discussed. PMID:24021594

  11. Behavioral State Modulates the Activity of Brainstem Sensorimotor Neurons

    PubMed Central

    McArthur, Kimberly L.

    2011-01-01

    Sensorimotor processing must be modulated according to the animal's behavioral state. A previous study demonstrated that motion responses were strongly state dependent in birds. Vestibular eye and head responses were significantly larger and more compensatory during simulated flight, and a flight-specific vestibular tail response was also characterized. In the current study, we investigated the neural substrates for these state-dependent vestibular behaviors by recording extracellularly from neurons in the vestibular nuclear complex and comparing their spontaneous activity and sensory responses during default and simulated flight states. We show that motion-sensitive neurons in the lateral vestibular nucleus are state dependent. Some neurons increased their spontaneous firing rates during flight, though their increased excitability was not reflected in higher sensory gains. However, other neurons exhibited state-dependent gating of sensory inputs, responding to rotational stimuli only during flight. These results demonstrate that vestibular processing in the brainstem is state dependent and lay the foundation for future studies to investigate the synaptic mechanisms responsible for these modifications. PMID:22090497

  12. Sexual Experience Modulates Neuronal Activity in Male Japanese Quail

    PubMed Central

    Can, Adem; Domjan, Michael; Delville, Yvon

    2008-01-01

    After an initial increase, repeated exposure to a particular stimulus or familiarity with an event results in lower immediate early gene expression levels in relevant brain structures. We predicted that similar effects would occur in Japanese quail after repeated sexual experience within brain areas involved in sexual behavior, namely, the medial preoptic nucleus (POM), the bed nucleus of stria terminalis (BST), and the nucleus taeniae of the amygdala (TnA), an avian homolog of medial amygdala. High experience subjects copulated with a female once on each of 16 consecutive days, whereas low experience subjects were allowed to copulate either once or twice. Control subjects were never exposed to a female. High experience subjects were faster to initiate sexual interaction, performed more cloacal contacts, and completed each cloacal contact faster than low experience subjects. Low experience subjects showed an increase in egr-1 (ZENK) expression, an immediate early gene product used as marker of neural activation in birds, in the areas of interest. In contrast, in high experience animals, egr-1 expression in the POM, BST and the periaqueductal gray (PAG) was not different than the level of expression in unmated controls. These results show that experience modulates the level of immediate early gene expression in the case of sexual behavior. Our results also indicate that immediate early gene expression in specific brain areas is not necessarily related to behavioral output, but depends on the behavioral history of the subjects. PMID:17826778

  13. Cucurbitacin E Potently Modulates the Activity of Encephalitogenic Cells.

    PubMed

    Jevtić, Bojan; Djedović, Neda; Stanisavljević, Suzana; Despotović, Jovana; Miljković, Djordje; Timotijević, Gordana

    2016-06-22

    Cucurbitacin E (CucE) is a highly oxidized steroid consisting of a tetracyclic triterpene. It is a member of a Cucurbitacin family of biomolecules that are predominantly found in Cucurbitaceae plants. CucE has already been identified as a potent anti-inflammatory compound. Here, its effects on CD4(+) T helper (Th) cells and macrophages, as the major encephalitogenic cells in the autoimmunity of the central nervous system, were investigated. Production of major pathogenic Th cell cytokines: interferon-gamma and interleukin-17 were inhibited under the influence of CucE. The effects of CucE on CD4(+) T cells were mediated through the modulation of aryl hydrocarbon receptor, STAT3, NFκB, p38 MAPK, and miR-146 signaling. Further, production of nitric oxide and reactive oxygen species, as well as phagocytic ability, were inhibited in macrophages treated with CucE. These results imply that CucE possesses powerful antiencephalitogenic activity. PMID:27225664

  14. Extracellular magnesium and calcium blockers modulate macrophage activity.

    PubMed

    Libako, Patrycja; Nowacki, Wojciech; Castiglioni, Sara; Mazur, Andrzej; Maier, Jeanette A M

    2016-03-01

    Magnesium (Mg) possesses anti-inflammatory properties, partly because it antagonizes calcium (Ca) and inhibits L-type Ca channels. Our aim was to determine the effects of different concentrations of extracellular Mg, with or without Ca-channel blockers, in macrophages. A macrophage-like cell line J774.E was cultured in different concentrations of extracellular Mg and exposed to i) the phorbol ester PMA to induce the production of reactive oxygen species ii) lipopolysaccharide to induce the production of pro-inflammatory cytokines, or iii) ovalbumin to study endocytosis. The Ca antagonists verapamil and/or TMB-8 were used to interfere with Ca homeostasis. Different concentrations of extracellular Mg did not impact on endocytosis, while Ca antagonists markedly decreased it. Low extracellular Mg exacerbated, whereas Ca antagonists inhibited, PMA-induced production of free radicals. Ca blockers prevented lipopolysaccharide-induced transcription and release of IL-1β, IL-6 and TNF-α, while extracellular Mg had only a marginal effect. Ca channel inhibitors markedly reduced the activity of J774.E cells, thus underscoring the critical role of Ca in the non-specific immune response, a role which was, in some instances, also modulated by extracellular Mg. PMID:27160489

  15. Transketolase activity modulates glycerol-3-phosphate levels in Escherichia coli.

    PubMed

    Vimala, A; Harinarayanan, R

    2016-04-01

    Transketolase activity provides an important link between the metabolic pathways of glycolysis and pentose phosphate shunt and catalyzes inter-conversions between pentose phosphates and glycolytic intermediates. It is widely conserved in life forms. A genetic screen for suppression of the growth defect of Escherichia coli tktA tktB mutant in LB medium revealed two mutations, one that rendered the glpK expression constitutive and another that inactivated deoB. Characterizing these mutations aided in uncovering the role of ribose-5-P (a transketolase substrate) as an inhibitor of glycerol assimilation and de novo glycerol-3-P synthesis. Using lacZ fusions, we show that ribose-5-P enhances GlpR-mediated repression of the glpFKX operon and inhibits glycerol assimilation. Electrophoretic Mobility Shift Assay (EMSA) showed ribose-5-P made the DNA-GlpR complex less sensitive to the inducer glycerol-3-P. In addition to inhibition of glycerol assimilation, obstruction of ribose-5-P metabolism retards growth from glycerol-3-P limitation. Glucose helps to overcome this limitation through a mechanism involving catabolite repression. To our knowledge, this report is the first to show ribose-5-P can modulate glycerol-3-P concentration in the cell by regulation of glycerol assimilation as well as its de novo synthesis. This regulation could be prevalent in other organisms. PMID:26691989

  16. CD83 Modulates B Cell Activation and Germinal Center Responses.

    PubMed

    Krzyzak, Lena; Seitz, Christine; Urbat, Anne; Hutzler, Stefan; Ostalecki, Christian; Gläsner, Joachim; Hiergeist, Andreas; Gessner, André; Winkler, Thomas H; Steinkasserer, Alexander; Nitschke, Lars

    2016-05-01

    CD83 is a maturation marker for dendritic cells. In the B cell lineage, CD83 is expressed especially on activated B cells and on light zone B cells during the germinal center (GC) reaction. The function of CD83 during GC responses is unclear. CD83(-/-) mice have a strong reduction of CD4(+) T cells, which makes it difficult to analyze a functional role of CD83 on B cells during GC responses. Therefore, in the present study we generated a B cell-specific CD83 conditional knockout (CD83 B-cKO) model. CD83 B-cKO B cells show defective upregulation of MHC class II and CD86 expression and impaired proliferation after different stimuli. Analyses of GC responses after immunization with various Ags revealed a characteristic shift in dark zone and light zone B cell numbers, with an increase of B cells in the dark zone of CD83 B-cKO mice. This effect was not accompanied by alterations in the level of IgG immune responses or by major differences in affinity maturation. However, an enhanced IgE response was observed in CD83 B-cKO mice. Additionally, we observed a strong competitive disadvantage of CD83-cKO B cells in GC responses in mixed bone marrow chimeras. Furthermore, infection of mice with Borrelia burgdorferi revealed a defect in bacterial clearance of CD83 B-cKO mice with a shift toward a Th2 response, indicated by a strong increase in IgE titers. Taken together, our results show that CD83 is important for B cell activation and modulates GC composition and IgE Ab responses in vivo. PMID:26983787

  17. Allergy Enhances Neurogenesis and Modulates Microglial Activation in the Hippocampus

    PubMed Central

    Klein, Barbara; Mrowetz, Heike; Thalhamer, Josef; Scheiblhofer, Sandra; Weiss, Richard; Aigner, Ludwig

    2016-01-01

    Allergies and their characteristic TH2-polarized inflammatory reactions affect a substantial part of the population. Since there is increasing evidence that the immune system modulates plasticity and function of the central nervous system (CNS), we investigated the effects of allergic lung inflammation on the hippocampus—a region of cellular plasticity in the adult brain. The focus of the present study was on microglia, the resident immune cells of the CNS, and on hippocampal neurogenesis, i.e., the generation of new neurons. C57BL/6 mice were sensitized with a clinically relevant allergen derived from timothy grass pollen (Phl p 5). As expected, allergic sensitization induced high serum levels of allergen-specific immunoglobulins (IgG1 and IgE) and of TH2 cytokines (IL-5 and IL-13). Surprisingly, fewer Iba1+ microglia were found in the granular layer (GL) and subgranular zone (SGZ) of the hippocampal dentate gyrus and also the number of Iba1+MHCII+ cells was lower, indicating a reduced microglial surveillance and activation in the hippocampus of allergic mice. Neurogenesis was analyzed by labeling of proliferating cells with bromodeoxyuridine (BrdU) and determining their fate 4 weeks later, and by quantitative analysis of young immature neurons, i.e., cells expressing doublecortin (DCX). The number of DCX+ cells was clearly increased in the allergy animals. Moreover, there were more BrdU+ cells present in the hippocampus of allergic mice, and these newly born cells had differentiated into neurons as indicated by a higher number of BrdU+NeuN+ cells. In summary, allergy led to a reduced microglia presence and activity and to an elevated level of neurogenesis in the hippocampus. This effect was apparently specific to the hippocampus, as we did not observe these alterations in the subventricular zone (SVZ)/olfactory bulb (OB) system, also a region of high cellular plasticity and adult neurogenesis. PMID:27445696

  18. Behavioral activation system modulation on brain activation during appetitive and aversive stimulus processing.

    PubMed

    Barrós-Loscertales, Alfonso; Ventura-Campos, Noelia; Sanjuán-Tomás, Ana; Belloch, Vicente; Parcet, Maria-Antònia; Avila, César

    2010-03-01

    The reinforcement sensitivity theory (RST) proposed the behavioral activation system (BAS) as a neurobehavioral system that is dependent on dopamine-irrigated structures and that mediates the individual differences in sensitivity and reactivity to appetitive stimuli associated with BAS-related personality traits. Theoretical developments propose that high BAS sensitivity is associated with both enhanced appetitive stimuli processing and the diminished processing of aversive stimuli. The objective of this study was to analyze how individual differences in BAS functioning were associated with brain activation during erotic and aversive picture processing while subjects were involved in a simple goal-directed task. Forty-five male participants took part in this study. The task activation results confirm the activation of the reward and punishment brain-related structures while viewing erotic and aversive pictures, respectively. The SR scores show a positive correlation with activation of the left lateral prefrontal cortex, the mesial prefrontal cortex and the right occipital cortex while viewing erotic pictures, and a negative correlation with the right lateral prefrontal cortex and the left occipital cortex while viewing aversive pictures. In summary, the SR scores modulate the activity of the cortical areas in the prefrontal and the occipital cortices that are proposed to modulate the BAS and the BIS-FFFS. PMID:20147458

  19. Behavioral activation system modulation on brain activation during appetitive and aversive stimulus processing

    PubMed Central

    Ventura-Campos, Noelia; Sanjuán-Tomás, Ana; Belloch, Vicente; Parcet, Maria-Antònia; Ávila, César

    2010-01-01

    The reinforcement sensitivity theory (RST) proposed the behavioral activation system (BAS) as a neurobehavioral system that is dependent on dopamine-irrigated structures and that mediates the individual differences in sensitivity and reactivity to appetitive stimuli associated with BAS-related personality traits. Theoretical developments propose that high BAS sensitivity is associated with both enhanced appetitive stimuli processing and the diminished processing of aversive stimuli. The objective of this study was to analyze how individual differences in BAS functioning were associated with brain activation during erotic and aversive picture processing while subjects were involved in a simple goal-directed task. Forty-five male participants took part in this study. The task activation results confirm the activation of the reward and punishment brain-related structures while viewing erotic and aversive pictures, respectively. The SR scores show a positive correlation with activation of the left lateral prefrontal cortex, the mesial prefrontal cortex and the right occipital cortex while viewing erotic pictures, and a negative correlation with the right lateral prefrontal cortex and the left occipital cortex while viewing aversive pictures. In summary, the SR scores modulate the activity of the cortical areas in the prefrontal and the occipital cortices that are proposed to modulate the BAS and the BIS-FFFS. PMID:20147458

  20. Telmisartan Modulates Glial Activation: In Vitro and In Vivo Studies.

    PubMed

    Torika, Nofar; Asraf, Keren; Danon, Abraham; Apte, Ron N; Fleisher-Berkovich, Sigal

    2016-01-01

    The circulating renin-angiotensin system (RAS), including the biologically active angiotensin II, is a fundamental regulatory mechanism of blood pressure conserved through evolution. Angiotensin II components of the RAS have also been identified in the brain. In addition to pro-inflammatory cytokines, neuromodulators, such as angiotensin II can induce (through angiotensin type 1 receptor (AT1R)) some of the inflammatory actions of brain glial cells and influence brain inflammation. Moreover, in Alzheimer's disease (AD) models, where neuroinflammation occurs, increased levels of cortical AT1Rs have been shown. Still, the precise role of RAS in neuroinflammation is not completely clear. The overall aim of the present study was to elucidate the role of RAS in the modulation of glial functions and AD pathology. To reach this goal, the specific aims of the present study were a. to investigate the long term effect of telmisartan (AT1R blocker) on tumor necrosis factor-α (TNF-α), interleukin 1-β (IL1-β) and nitric oxide (NO) release from glial cells. b. to examine the effect of intranasally administered telmisartan on amyloid burden and microglial activation in 5X familial AD (5XFAD) mice. Telmisartan effects in vivo were compared to those of perindopril (angiotensin converting enzyme inhibitor). Long-term-exposure of BV2 microglia to telmisartan significantly decreased lipopolysaccharide (LPS) -induced NO, inducible NO synthase, TNF-α and IL1-β synthesis. The effect of Telmisartan on NO production in BV2 cells was confirmed also in primary neonatal rat glial cells. Intranasal administration of telmisartan (1 mg/kg/day) for up to two months significantly reduced amyloid burden and CD11b expression (a marker for microglia) both in the cortex and hipoccampus of 5XFAD. Based on the current view of RAS and our data, showing reduced amyloid burden and glial activation in the brains of 5XFAD transgenic mice, one may envision potential intervention with the progression of

  1. Telmisartan Modulates Glial Activation: In Vitro and In Vivo Studies

    PubMed Central

    Torika, Nofar; Asraf, Keren; Danon, Abraham; Apte, Ron N.; Fleisher-Berkovich, Sigal

    2016-01-01

    The circulating renin-angiotensin system (RAS), including the biologically active angiotensin II, is a fundamental regulatory mechanism of blood pressure conserved through evolution. Angiotensin II components of the RAS have also been identified in the brain. In addition to pro-inflammatory cytokines, neuromodulators, such as angiotensin II can induce (through angiotensin type 1 receptor (AT1R)) some of the inflammatory actions of brain glial cells and influence brain inflammation. Moreover, in Alzheimer’s disease (AD) models, where neuroinflammation occurs, increased levels of cortical AT1Rs have been shown. Still, the precise role of RAS in neuroinflammation is not completely clear. The overall aim of the present study was to elucidate the role of RAS in the modulation of glial functions and AD pathology. To reach this goal, the specific aims of the present study were a. to investigate the long term effect of telmisartan (AT1R blocker) on tumor necrosis factor-α (TNF-α), interleukin 1-β (IL1-β) and nitric oxide (NO) release from glial cells. b. to examine the effect of intranasally administered telmisartan on amyloid burden and microglial activation in 5X familial AD (5XFAD) mice. Telmisartan effects in vivo were compared to those of perindopril (angiotensin converting enzyme inhibitor). Long-term-exposure of BV2 microglia to telmisartan significantly decreased lipopolysaccharide (LPS) -induced NO, inducible NO synthase, TNF-α and IL1-β synthesis. The effect of Telmisartan on NO production in BV2 cells was confirmed also in primary neonatal rat glial cells. Intranasal administration of telmisartan (1 mg/kg/day) for up to two months significantly reduced amyloid burden and CD11b expression (a marker for microglia) both in the cortex and hipoccampus of 5XFAD. Based on the current view of RAS and our data, showing reduced amyloid burden and glial activation in the brains of 5XFAD transgenic mice, one may envision potential intervention with the progression

  2. Increased radioresistance of tumor cells exposed to metallothionein-inducing agents

    SciTech Connect

    Renan, M.J.; Dowman, P.I. )

    1989-12-01

    In this study, we have determined the radiosensitivity parameters of cells exposed in vitro to metallothionein-inducing agents. Three well-characterized tumor cell lines were chosen for investigation: HeLa, B16, and WHFIB. We have shown that exposure of cells in vitro to a heavy metal (cadmium), followed by irradiation, enhances cell survival for two out of three cell lines studied. As measured by the mean inactivation dose, the radioresistance increases by a factor of 1.6 for HeLa cells, 1.4 for WHFIB, and a negligible factor for B16 cells. An additional effect was noted when different classes of metallothionein inducers (such as serum factors, cadmium, and dexamethasone) were allowed to act together. Also, we found that the increase in radioresistance exhibits a peak at exposure times of approximately 10 h; longer exposure to inducing agents results in a reduction in radioresistance.

  3. Unified active and reactive power modulation of HVDC transmission systems

    NASA Astrophysics Data System (ADS)

    Grund, C. E.; Pohl, R. V.

    1981-11-01

    The power modulation of a high voltage direct current (HVDC) system for stabilization of an ac/dc network was investigated. It was found that simultaneous modulation of both dc current and voltage was more effective than just current modulation by itself, since the dc voltage modulation could be used to minimize the reactive power changes resulting from a change of the dc current. This helps stabilize the ac busbar voltages at the converters, which reduces undesirable load flow changes to voltage dependent ac loads, thus improving the effectiveness of the dc power modulation. This unified modulation control concept was evaluated by means of digital computer studies as well as a special purpose HVDC simulator. Several combined ac/dc power transmission systems were synthesized for testing of different modulation controller concepts. An optimum controller design incorporating a linear quadratic control algorithm with full state feedback was first studied. This provided a basis for comparison of suboptimal controller designs utilizing reduced state feedback and a Kalman filter state reconstruction technique.

  4. Molecularly targeted radiosensitization chances towards gene aberration-due organ confined/regionally advanced prostate cancer radioresistance

    PubMed Central

    ALBERTI, C.

    2015-01-01

    Considering that the prostate cancer radioresistance occurs in a significant percentage – as 20–40% of prostate cancer (PCa) patients undergone external beam radiation therapy developing, within ten years, recurrent and more aggressive tumor – the resort to customized radiosensitizer measures, focusly targeting PCa radioresistance-linked individual molecular aberrations, can increase the successful outcomes of PCa radiotherapy. PMID:26188759

  5. Critical Role of Aberrant Angiogenesis in the Development of Tumor Hypoxia and Associated Radioresistance

    PubMed Central

    Multhoff, Gabriele; Radons, Jürgen; Vaupel, Peter

    2014-01-01

    Newly formed microvessels in most solid tumors show an abnormal morphology and thus do not fulfil the metabolic demands of the growing tumor mass. Due to the chaotic and heterogeneous tumor microcirculation, a hostile tumor microenvironment develops, that is characterized inter alia by local hypoxia, which in turn can stimulate the HIF-system. The latter can lead to tumor progression and may be involved in hypoxia-mediated radioresistance of tumor cells. Herein, cellular and molecular mechanisms in tumor angiogenesis are discussed that, among others, might impact hypoxia-related radioresistance. PMID:24717239

  6. Toxin-Antitoxin Modules Are Pliable Switches Activated by Multiple Protease Pathways

    PubMed Central

    Muthuramalingam, Meenakumari; White, John C.; Bourne, Christina R.

    2016-01-01

    Toxin-antitoxin (TA) modules are bacterial regulatory switches that facilitate conflicting outcomes for cells by promoting a pro-survival phenotypic adaptation and/or by directly mediating cell death, all through the toxin activity upon degradation of antitoxin. Intensive study has revealed specific details of TA module functions, but significant gaps remain about the molecular details of activation via antitoxin degradation used by different bacteria and in different environments. This review summarizes the current state of knowledge about the interaction of antitoxins with cellular proteases Lon and ClpP to mediate TA module activation. An understanding of these processes can answer long-standing questions regarding stochastic versus specific activation of TA modules and provide insight into the potential for manipulation of TA modules to alter bacterial growth. PMID:27409636

  7. Modulation of Leishmania major aquaglyceroporin activity by a mitogen-activated protein kinase

    PubMed Central

    Mandal, Goutam; Sharma, Mansi; Kruse, Martin; Sander-Juelch, Claudia; Munro, Laura Anne; Wang, Yong; Vilg, Jenny Veide; Tamás, Markus J; Bhattacharjee, Hiranmoy; Wiese, Martin; Mukhopadhyay, Rita

    2012-01-01

    Summary Leishmania major aquaglyceroporin (LmjAQP1) adventitiously facilitates the uptake of antimonite [Sb(III)], an active form of Pentostam® or Glucantime®, which are the first line of defense against all forms of leishmaniasis. The present paper shows that LmjAQP1 activity is modulated by the mitogen-activated protein kinase, LmjMPK2. Leishmania parasites co-expressing LmjAQP1 and LmjMPK2 show increased Sb(III) uptake and increased Sb(III) sensitivity. When subjected to a hypo-osmotic stress, these cells show faster volume recovery than cells expressing LmjAQP1 alone. LmjAQP1 is phosphorylated in vivo at Thr197 and this phosphorylation requires LmjMPK2 activity. Lys42 of LmjMPK2 is critical for its kinase activity. Cells expressing altered T197A LmjAQP1 or K42A LmjMPK2 showed decreased Sb(III) influx and a slower volume recovery than cells expressing wild type proteins. Phosphorylation of LmjAQP1 led to a decrease in its turnover rate affecting LmjAQP1 activity. Although LmjAQP1 is localized to the flagellum of promastigotes, upon phosphorylation, it is relocalized to the entire surface of the parasite. L. mexicana promastigotes with an MPK2 deletion showed reduced Sb(III) uptake and slower volume recovery than wild type cells. This is the first report where a parasite aquaglyceroporin activity is post-translationally modulated by a MAP kinase. PMID:22779703

  8. Blackout!: An Event-Based Science Module. Teacher's Guide. Electricity and Solar Activity Module.

    ERIC Educational Resources Information Center

    Wright, Russell G.

    This book is designed for middle school earth science or physical science teachers to help their students learn scientific literacy through event-based science. Unlike traditional curricula, the event- based earth science module is a student-centered, interdisciplinary, inquiry-oriented program that emphasizes cooperative learning, teamwork,…

  9. Multiple facets of the DNA damage response contribute to the radioresistance of mouse mesenchymal stromal cell lines.

    PubMed

    Sugrue, Tara; Brown, James A L; Lowndes, Noel F; Ceredig, Rhodri

    2013-01-01

    The regeneration of the hematopoietic system following total body irradiation is supported by host-derived mesenchymal stromal cells (MSCs) within the bone marrow. The mechanisms used by MSCs to survive radiation doses that are lethal to the hematopoietic system are poorly understood. The DNA damage response (DDR) represents a cohort of signaling pathways that enable cells to execute biological responses to genotoxic stress. Here, we examine the role of the DDR in mediating the resistance of MSCs to ionizing radiation (IR) treatment using two authentic clonal mouse MSC lines, MS5 and ST2, and primary bulk mouse MSCs. We show that multiple DDR mechanisms contribute to the radio-resistance of MSCs: robust DDR activation via rapid γ-H2AX formation, activation of effective S and G(2)/M DNA damage checkpoints, and efficient repair of IR-induced DNA double-strand breaks. We show that MSCs are intrinsically programmed to maximize survival following IR treatment by expressing high levels of key DDR proteins including ATM, Chk2, and DNA Ligase IV; high levels of the anti-apoptotic, Bcl-2 and Bcl-(XL); and low levels of the pro-apoptotic, Bim and Puma. As a result, we demonstrate that irradiated mouse MSCs withstand IR-induced genotoxic stress, continue to proliferate, and retain their capacity to differentiate long-term along mesenchymal-derived lineages. We have shown, for the first time, that the DDR plays key roles in mediating the radioresistance of mouse MSCs which may have important implications for the study and application of MSCs in allogeneic bone marrow transplantation, graft-versus-host disease, and cancer treatment. PMID:22961695

  10. PV Cell and Module Calibration Activities at NREL

    SciTech Connect

    Emery, K.; Anderberg, A.; Kiehl, J.; Mack, C.; Moriarty, T.; Ottoson, L.; Rummel, S.

    2005-11-01

    The performance of PV cells and modules with respect to standard reference conditions is a key indicator of progress of a given technology. This task provides the U.S. terrestrial PV community with the most accurate measurements that are technically possible in a timely fashion. The international module certification and accreditation program PVGap requires certification laboratories to maintain their calibration traceability path to groups like this one. The politics of a "world record" efficiency requires that an independent laboratory perform these measurements for credibility. Most manufacturers base their module peak watt rating upon standards and reference cells calibrated under this task. This task has been involved in reconciling disputes between manufacturers and their cell suppliers in terms of expected versus actual performance. This task has also served as a resource to the PV community for consultation on solar simulation, current versus voltage measurement instrumentation, measurement procedures and measurement artifacts.

  11. Activity of catalytic silver nanoparticles modulated by capping agent hydrophobicity.

    PubMed

    Janani, Seralathan; Stevenson, Priscilla; Veerappan, Anbazhagan

    2014-05-01

    In this paper, a facile in situ method is reported for the preparation of catalytic silver nanoparticles (AgNPs) using N-acyl tyramine (NATA) with variable hydrophobic acyl length. Scanning electron microscopic analysis shows that NATA exists initially as larger aggregates in alkaline aqueous solution. The addition of AgNO3 dissociates these larger aggregate and subsequently promotes the formation of self-assembled NATA and AgNPs. Characterization of AgNPs using UV-vis spectroscopy, scanning electron microscope and transmission electron microscope revealed that the hydrophobic acyl chain length of NATA does not influence the particle size, shape and morphology. All NATA-AgNPs yielded relatively identical values in full width at half-maximum (FWHM) analysis, indicating that the AgNPs prepared with NATA are relatively polydispersed at all tested acyl chain lengths. These nanoparticles are able to efficiently catalyze the reduction of 4-nitro phenol to 4-amino phenol, 2-nitro aniline to 1,2-diamino benzene, 2,4,6-trinitro phenol to 2,4,6-triamino phenol by NaBH4 in an aqueous environment. The reduction reaction rate is determined to be pseudo-first order and the apparent rate constant is linearly dependent on the hydrophobic acyl chain length of the NATA. All reaction kinetics presented an induction period, which is dependent on the N-acyl chain length, indicating that the hydrophobic effects play a critical role in bringing the substrate to the metal nanoparticle surface to induce the catalytic reaction. In this study, however, the five catalytic systems have similar size and polydispersity, differing only in terms of capping agent hydrophobicity, and shows different catalytic activity with respect to the alkyl chain length of the capping agent. As discussed, the ability to modulate the metal nanoparticles catalytic property, by modifying the capping agent hydrophobicity represents a promising future for developing an efficient nanocatalyst without altering the size

  12. Anhydrobiosis-Associated Nuclear DNA Damage and Repair in the Sleeping Chironomid: Linkage with Radioresistance

    PubMed Central

    Vanyagina, Veronica; Malutina, Ludmila; Cornette, Richard; Sakashita, Tetsuya; Hamada, Nobuyuki; Kikawada, Takahiro; Kobayashi, Yasuhiko; Okuda, Takashi

    2010-01-01

    Anhydrobiotic chironomid larvae can withstand prolonged complete desiccation as well as other external stresses including ionizing radiation. To understand the cross-tolerance mechanism, we have analyzed the structural changes in the nuclear DNA using transmission electron microscopy and DNA comet assays in relation to anhydrobiosis and radiation. We found that dehydration causes alterations in chromatin structure and a severe fragmentation of nuclear DNA in the cells of the larvae despite successful anhydrobiosis. Furthermore, while the larvae had restored physiological activity within an hour following rehydration, nuclear DNA restoration typically took 72 to 96 h. The DNA fragmentation level and the recovery of DNA integrity in the rehydrated larvae after anhydrobiosis were similar to those of hydrated larvae irradiated with 70 Gy of high-linear energy transfer (LET) ions (4He). In contrast, low-LET radiation (gamma-rays) of the same dose caused less initial damage to the larvae, and DNA was completely repaired within within 24 h. The expression of genes encoding the DNA repair enzymes occurred upon entering anhydrobiosis and exposure to high- and low-LET radiations, indicative of DNA damage that includes double-strand breaks and their subsequent repair. The expression of antioxidant enzymes-coding genes was also elevated in the anhydrobiotic and the gamma-ray-irradiated larvae that probably functions to reduce the negative effect of reactive oxygen species upon exposure to these stresses. Indeed the mature antioxidant proteins accumulated in the dry larvae and the total activity of antioxidants increased by a 3–4 fold in association with anhydrobiosis. We conclude that one of the factors explaining the relationship between radioresistance and the ability to undergo anhydrobiosis in the sleeping chironomid could be an adaptation to desiccation-inflicted nuclear DNA damage. There were also similarities in the molecular response of the larvae to damage caused by

  13. Anhydrobiosis-associated nuclear DNA damage and repair in the sleeping chironomid: linkage with radioresistance.

    PubMed

    Gusev, Oleg; Nakahara, Yuichi; Vanyagina, Veronica; Malutina, Ludmila; Cornette, Richard; Sakashita, Tetsuya; Hamada, Nobuyuki; Kikawada, Takahiro; Kobayashi, Yasuhiko; Okuda, Takashi

    2010-01-01

    Anhydrobiotic chironomid larvae can withstand prolonged complete desiccation as well as other external stresses including ionizing radiation. To understand the cross-tolerance mechanism, we have analyzed the structural changes in the nuclear DNA using transmission electron microscopy and DNA comet assays in relation to anhydrobiosis and radiation. We found that dehydration causes alterations in chromatin structure and a severe fragmentation of nuclear DNA in the cells of the larvae despite successful anhydrobiosis. Furthermore, while the larvae had restored physiological activity within an hour following rehydration, nuclear DNA restoration typically took 72 to 96 h. The DNA fragmentation level and the recovery of DNA integrity in the rehydrated larvae after anhydrobiosis were similar to those of hydrated larvae irradiated with 70 Gy of high-linear energy transfer (LET) ions ((4)He). In contrast, low-LET radiation (gamma-rays) of the same dose caused less initial damage to the larvae, and DNA was completely repaired within within 24 h. The expression of genes encoding the DNA repair enzymes occurred upon entering anhydrobiosis and exposure to high- and low-LET radiations, indicative of DNA damage that includes double-strand breaks and their subsequent repair. The expression of antioxidant enzymes-coding genes was also elevated in the anhydrobiotic and the gamma-ray-irradiated larvae that probably functions to reduce the negative effect of reactive oxygen species upon exposure to these stresses. Indeed the mature antioxidant proteins accumulated in the dry larvae and the total activity of antioxidants increased by a 3-4 fold in association with anhydrobiosis. We conclude that one of the factors explaining the relationship between radioresistance and the ability to undergo anhydrobiosis in the sleeping chironomid could be an adaptation to desiccation-inflicted nuclear DNA damage. There were also similarities in the molecular response of the larvae to damage caused by

  14. Radio-resistant mesenchymal stem cells: mechanisms of resistance and potential implications for the clinic

    PubMed Central

    Nicolay, Nils H.; Perez, Ramon Lopez; Saffrich, Rainer; Huber, Peter E.

    2015-01-01

    Mesenchymal stem cells (MSCs) comprise a heterogeneous population of multipotent stromal cells and can be isolated from various tissues and organs. Due to their regenerative potential, they have been subject to intense research efforts, and they may provide an efficient means for treating radiation-induced tissue damage. MSCs are relatively resistant to ionizing radiation and retain their stem cell characteristics even after high radiation doses. The underlying mechanisms for the observed MSC radioresistance have been extensively studied and may involve efficient DNA damage recognition, double strand break repair and evasion of apoptosis. Here, we present a concise review of the published scientific data on the radiobiological features of MSCs. The involvement of different DNA damage recognition and repair pathways in the creation of a radioresistant MSC phenotype is outlined, and the roles of apoptosis, senescence and autophagy regarding the reported radioresistance are summarized. Finally, potential influences of the radioresistant MSCs for the clinic are discussed with respect to the repair and radioprotection of irradiated tissues. PMID:26203772

  15. HIF-1 and NDRG2 contribute to hypoxia-induced radioresistance of cervical cancer Hela cells

    SciTech Connect

    Liu, Junye; Zhang, Jing; Wang, Xiaowu; Li, Yan; Chen, Yongbin; Li, Kangchu; Zhang, Jian; Yao, Libo; Guo, Guozhen

    2010-07-15

    Hypoxia inducible factor 1 (HIF-1), the key mediator of hypoxia signaling pathways, has been shown involved in hypoxia-induced radioresistance. However, the underlying mechanisms are unclear. The present study demonstrated that both hypoxia and hypoxia mimetic cobalt chloride could increase the radioresistance of human cervical cancer Hela cells. Meanwhile, ectopic expression of HIF-1 could enhance the resistance of Hela cells to radiation, whereas knocking-down of HIF-1 could increase the sensitivity of Hela cells to radiation in the presence of hypoxia. N-Myc downstream-regulated gene 2 (NDRG2), a new HIF-1 target gene identified in our lab, was found to be upregulated by hypoxia and radiation in a HIF-1-dependent manner. Overexpression of NDRG2 resulted in decreased sensitivity of Hela cells to radiation while silencing NDRG2 led to radiosensitization. Moreover, NDRG2 was proved to protect Hela cells from radiation-induced apoptosis and abolish radiation-induced upregulation of Bax. Taken together, these data suggest that both HIF-1 and NDRG2 contribute to hypoxia-induced tumor radioresistance and that NDRG2 acts downstream of HIF-1 to promote radioresistance through suppressing radiation-induced Bax expression. It would be meaningful to further explore the clinical application potential of HIF-1 and NDRG2 blockade as radiosensitizer for tumor therapy.

  16. DNA Repair and Cytokines: TGF-β, IL-6, and Thrombopoietin as Different Biomarkers of Radioresistance.

    PubMed

    Centurione, Lucia; Aiello, Francesca B

    2016-01-01

    Double strand breaks (DSBs) induced by radiotherapy are highly cytotoxic lesions, leading to chromosomal aberrations and cell death. Ataxia-telangiectasia-mutated (ATM)-dependent DNA-damage response, non-homologous end joining, and homologous recombination pathways coordinately contribute to repairing DSBs in higher eukaryotes. It is known that the expression of DSB repair genes is increased in tumors, which is one of the main reasons for radioresistance. The inhibition of DSB repair pathways may be useful to increase tumor cell radiosensitivity and may target stem cell-like cancer cells, known to be the most radioresistant tumor components. Commonly overexpressed in neoplastic cells, cytokines confer radioresistance by promoting proliferation, survival, invasion, and angiogenesis. Unfortunately, tumor irradiation increases the expression of various cytokines displaying these effects, including transforming growth factor-beta and interleukin-6. Recently, the capabilities of these cytokines to support DNA repair pathways and the ATM-dependent DNA response have been demonstrated. Thrombopoietin, essential for megakaryopoiesis and very important for hematopoietic stem cell (HSC) homeostasis, has also been found to promote DNA repair in a highly selective manner. These findings reveal a novel mechanism underlying cytokine-related radioresistance, which may be clinically relevant. Therapies targeting specific cytokines may be used to improve radiosensitivity. Specific inhibitors may be chosen in consideration of different tumor microenvironments. Thrombopoietin may be useful in fending off irradiation-induced loss of HSCs. PMID:27500125

  17. DNA Repair and Cytokines: TGF-β, IL-6, and Thrombopoietin as Different Biomarkers of Radioresistance

    PubMed Central

    Centurione, Lucia; Aiello, Francesca B.

    2016-01-01

    Double strand breaks (DSBs) induced by radiotherapy are highly cytotoxic lesions, leading to chromosomal aberrations and cell death. Ataxia-telangiectasia-mutated (ATM)-dependent DNA-damage response, non-homologous end joining, and homologous recombination pathways coordinately contribute to repairing DSBs in higher eukaryotes. It is known that the expression of DSB repair genes is increased in tumors, which is one of the main reasons for radioresistance. The inhibition of DSB repair pathways may be useful to increase tumor cell radiosensitivity and may target stem cell-like cancer cells, known to be the most radioresistant tumor components. Commonly overexpressed in neoplastic cells, cytokines confer radioresistance by promoting proliferation, survival, invasion, and angiogenesis. Unfortunately, tumor irradiation increases the expression of various cytokines displaying these effects, including transforming growth factor-beta and interleukin-6. Recently, the capabilities of these cytokines to support DNA repair pathways and the ATM-dependent DNA response have been demonstrated. Thrombopoietin, essential for megakaryopoiesis and very important for hematopoietic stem cell (HSC) homeostasis, has also been found to promote DNA repair in a highly selective manner. These findings reveal a novel mechanism underlying cytokine-related radioresistance, which may be clinically relevant. Therapies targeting specific cytokines may be used to improve radiosensitivity. Specific inhibitors may be chosen in consideration of different tumor microenvironments. Thrombopoietin may be useful in fending off irradiation-induced loss of HSCs. PMID:27500125

  18. Active cancellation of residual amplitude modulation in a frequency-modulation based Fabry-Perot interferometer.

    PubMed

    Yu, Yinan; Wang, Yicheng; Pratt, Jon R

    2016-03-01

    Residual amplitude modulation (RAM) is one of the most common noise sources known to degrade the sensitivity of frequency modulation spectroscopy. RAM can arise as a result of the temperature dependent birefringence of the modulator crystal, which causes the orientation of the crystal's optical axis to shift with respect to the polarization of the incident light with temperature. In the fiber-based optical interferometer used on the National Institute of Standards and Technology calculable capacitor, RAM degrades the measured laser frequency stability and correlates with the environmental temperature fluctuations. We have demonstrated a simple approach that cancels out excessive RAM due to polarization mismatch between the light and the optical axis of the crystal. The approach allows us to measure the frequency noise of a heterodyne beat between two lasers individually locked to different resonant modes of a cavity with an accuracy better than 0.5 ppm, which meets the requirement to further determine the longitudinal mode number of the cavity length. Also, this approach has substantially mitigated the temperature dependency of the measurements of the cavity length and consequently the capacitance. PMID:27036752

  19. Active cancellation of residual amplitude modulation in a frequency-modulation based Fabry-Perot interferometer

    NASA Astrophysics Data System (ADS)

    Yu, Yinan; Wang, Yicheng; Pratt, Jon R.

    2016-03-01

    Residual amplitude modulation (RAM) is one of the most common noise sources known to degrade the sensitivity of frequency modulation spectroscopy. RAM can arise as a result of the temperature dependent birefringence of the modulator crystal, which causes the orientation of the crystal's optical axis to shift with respect to the polarization of the incident light with temperature. In the fiber-based optical interferometer used on the National Institute of Standards and Technology calculable capacitor, RAM degrades the measured laser frequency stability and correlates with the environmental temperature fluctuations. We have demonstrated a simple approach that cancels out excessive RAM due to polarization mismatch between the light and the optical axis of the crystal. The approach allows us to measure the frequency noise of a heterodyne beat between two lasers individually locked to different resonant modes of a cavity with an accuracy better than 0.5 ppm, which meets the requirement to further determine the longitudinal mode number of the cavity length. Also, this approach has substantially mitigated the temperature dependency of the measurements of the cavity length and consequently the capacitance.

  20. Reciprocal Regulation of Hypoxia-Inducible Factor 2α and GLI1 Expression Associated With the Radioresistance of Renal Cell Carcinoma

    SciTech Connect

    Zhou, Jiancheng; Wu, Kaijie; Gao, Dexuan; Zhu, Guodong; Wu, Dapeng; Wang, Xinyang; Chen, Yule; Du, Yuefeng; Song, Wenbin; Ma, Zhenkun; Authement, Craig; Saha, Debabrata; Hsieh, Jer-Tsong; He, Dalin

    2014-11-15

    Purpose: Renal cell carcinoma (RCC) is often considered a radioresistant tumor, but the molecular mechanism underlying its radioresistance is poorly understood. This study explored the roles of hypoxia-inducible factor 2α (HIF2α) and sonic hedgehog (SHH)-GLI1 signaling in mediating the radioresistance of RCC cells and to unveil the interaction between these 2 signaling pathways. Methods and Materials: The activities of SHH-GLI1 signaling pathway under normoxia and hypoxia in RCC cells were examined by real-time polymerase chain reaction, Western blot, and luciferase reporter assay. The expression of HIF2α and GLI1 in RCC patients was examined by immunohistochemistry, and their correlation was analyzed. Furthermore, RCC cells were treated with HIF2α-specific shRNA (sh-HIF2α), GLI1 inhibitor GANT61, or a combination to determine the effect of ionizing radiation (IR) on RCC cells based on clonogenic assay and double-strand break repair assay. Results: RCC cells exhibited elevated SHH-GLI1 activities under hypoxia, which was mediated by HIF2α. Hypoxia induced GLI1 activation through SMO-independent pathways that could be ablated by PI3K inhibitor or MEK inhibitor. Remarkably, the SHH-GLI1 pathway also upregulated HIF2α expression in normoxia. Apparently, there was a positive correlation between HIF2α and GLI1 expression in RCC patients. The combination of sh-HIF2α and GLI1 inhibitor significantly sensitized RCC cells to IR. Conclusions: Cross-talk between the HIF2α and SHH-GLI1 pathways was demonstrated in RCC. Cotargeting these 2 pathways, significantly sensitizing RCC cells to IR, provides a novel strategy for RCC treatment.

  1. Energy-Storage Modules for Active Solar Heating and Cooling

    NASA Technical Reports Server (NTRS)

    Parker, J. C.

    1982-01-01

    34 page report describes a melting salt hydrate that stores 12 times as much heat as rocks and other heavy materials. Energy is stored mostly as latent heat; that is, heat that can be stored and recovered without any significant change in temperature. Report also describes development, evaluation and testing of permanently sealed modules containing salt hydrate mixture.

  2. Activity of a gelsolin-like actin modulator in rat skeletal muscle under protein catabolic conditions.

    PubMed Central

    D'Haese, J; Rutschmann, M; Dahlmann, B; Hinssen, H

    1987-01-01

    A gelsolin-like actin-modulating protein was isolated from rat skeletal muscle and characterized with respect to its interaction with actin. The protein, with a molecular mass of approx. 85 kDa, forms a stoichiometric complex with two actin molecules and is activated by micromolar concentrations of Ca2+. It effectively severs actin filaments and promotes nucleation of actin polymerization. The activity of this protein is detectable already in crude extracts by its capability to reduce the steady state viscosity of actin. Actin-modulating activities were determined in muscle extracts of rats kept under protein catabolic conditions, i.e. as generated by corticosterone treatment and starvation. In both cases we found a marked increase of modulator activity. The possibility is discussed that the increased activity of actin modulator indicates a fragmentation of actin filaments prior to the proteolytic degradation of actin. Images Fig. 2. PMID:3435453

  3. Concomitant TLR/RLH signaling of radioresistant and radiosensitive cells is essential for protection against vesicular stomatitis virus infection.

    PubMed

    Spanier, Julia; Lienenklaus, Stefan; Paijo, Jennifer; Kessler, Annett; Borst, Katharina; Heindorf, Sabrina; Baker, Darren P; Kröger, Andrea; Weiss, Siegfried; Detje, Claudia N; Staeheli, Peter; Kalinke, Ulrich

    2014-09-15

    Several studies indicated that TLR as well as retinoic acid-inducible gene I-like helicase (RLH) signaling contribute to vesicular stomatitis virus (VSV)-mediated triggering of type I IFN (IFN-I) responses. Nevertheless, TLR-deficient MyD88(-/-)Trif(-/-) mice and RLH-deficient caspase activation and recruitment domain adaptor inducing IFN-β (Cardif)(-/-) mice showed only marginally enhanced susceptibility to lethal VSV i.v. infection. Therefore, we addressed whether concomitant TLR and RLH signaling, or some other additional mechanism, played a role. To this end, we generated MyD88(-/-)Trif(-/-)Cardif(-/-) (MyTrCa(-/-)) mice that succumbed to low-dose i.v. VSV infection with similar kinetics as IFN-I receptor-deficient mice. Three independent approaches (i.e., analysis of IFN-α/β serum levels, experiments with IFN-β reporter mice, and investigation of local IFN-stimulated gene induction) revealed that MyTrCa(-/-) mice did not mount IFN-I responses following VSV infection. Of note, treatment with rIFN-α protected the animals, qualifying MyTrCa(-/-) mice as a model to study the contribution of different immune cell subsets to the production of antiviral IFN-I. Upon adoptive transfer of wild-type plasmacytoid dendritic cells and subsequent VSV infection, MyTrCa(-/-) mice displayed significantly reduced viral loads in peripheral organs and showed prolonged survival. On the contrary, adoptive transfer of wild-type myeloid dendritic cells did not have such effects. Analysis of bone marrow chimeric mice revealed that TLR and RLH signaling of radioresistant and radiosensitive cells was required for efficient protection. Thus, upon VSV infection, plasmacytoid dendritic cell-derived IFN-I primarily protects peripheral organs, whereas concomitant TLR and RLH signaling of radioresistant stroma cells as well as of radiosensitive immune cells is needed to effectively protect against lethal disease. PMID:25127863

  4. Membrane stretch and cytoplasmic Ca2+ independently modulate stretch-activated BK channel activity.

    PubMed

    Zhao, Hu-Cheng; Agula, Hasi; Zhang, Wei; Wang, Fa; Sokabe, Masahiro; Li, Lu-Ming

    2010-11-16

    Large conductance Ca(2+)-activated K(+) (BK) channels are responsible for changes in chemical and physical signals such as Ca(2+), Mg(2+) and membrane potentials. Previously, we reported that a BK channel cloned from chick heart (SAKCaC) is activated by membrane stretch. Molecular cloning and subsequent functional characterization of SAKCaC have shown that both the membrane stretch and intracellular Ca(2+) signal allosterically regulate the channel activity via the linker of the gating ring complex. Here we investigate how these two gating principles interact with each other. We found that stretch force activated SAKCaC in the absence of cytoplasmic Ca(2+). Lack of Ca(2+) bowl (a calcium binding motif) in SAKCaC diminished the Ca(2+)-dependent activation, but the mechanosensitivity of channel was intact. We also found that the abrogation of STREX (a proposed mechanosensing apparatus) in SAKCaC abolished the mechanosensitivity without altering the Ca(2+) sensitivity of channels. These observations indicate that membrane stretch and intracellular Ca(2+) could independently modulate SAKCaC activity. PMID:20673577

  5. Modulation of pulmonary macrophage superoxide release and tumoricidal activity following activation by biological response modifiers.

    PubMed

    Drath, D B

    1986-10-01

    Following immunologic activation, pulmonary macrophages may prevent or cause regression of lung metastases by mechanisms which remain largely unknown. The studies described here were designed to determine if enhanced oxygen metabolite release was related to postactivation tumoricidal activity. We have shown that in vitro activation of Fischer 344 rat pulmonary macrophages by either free or liposome-encapsulated muramyl dipeptide leads to both enhanced release of superoxide anions and marked tumoricidal activity against syngenic (Fischer 13762), allogeneic (Schmidt-Ruppin RR 1022) and xenogeneic (Fibrosarcoma MCA-F) 125I-deoxyuridine-labeled target cells. This immune modulator did not, however, metabolically activate pulmonary macrophages as effectively as liposome-encapsulated lipopolysaccharide. A 24-h in vitro incubation with either 150 U or 300 U of interferon-gamma (3 X 10(6) U/mg) or 30 U, 150 U or 300 U of interferon-alpha (6 X 10(5) U/mg) caused a significant elevation in superoxide release above controls, whereas short-term exposure (2 or 4 h) had little or no effect. Free or encapsulated 6-O-stearoyl muramyl dipeptide, on the other hand, did increase superoxide levels at all 3 time periods. When either interferon-gamma or free or encapsulated muramyl dipeptide derivative were administered to intact rats by either i.v. injection, intratracheal instillation or osmotic minipump infusion, pulmonary macrophage tumoricidal activity was observed 96 h after cell harvesting. Zymosan-stimulated superoxide release, however, was not consistently elevated above control or empty liposome treatment following this course of in vivo activation. The data collectively suggest that in vivo pulmonary macrophage activation to a tumoricidal state and metabolic activation resulting in enhanced superoxide may be separable events. PMID:3021650

  6. Radiation-induced mitotic cell death and glioblastoma radioresistance: a new regulating pathway controlled by integrin-linked kinase, hypoxia-inducible factor 1 alpha and survivin in U87 cells.

    PubMed

    Lanvin, Olivia; Monferran, Sylvie; Delmas, Caroline; Couderc, Bettina; Toulas, Christine; Cohen-Jonathan-Moyal, Elizabeth

    2013-09-01

    We have previously shown that integrin-linked kinase (ILK) regulates U87 glioblastoma cell radioresistance by modulating the main radiation-induced cell death mechanism in solid tumours, the mitotic cell death. To decipher the biological pathways involved in these mechanisms, we constructed a U87 glioblastoma cell model expressing an inducible shRNA directed against ILK (U87shILK). We then demonstrated that silencing ILK enhanced radiation-induced centrosome overduplication, leading to radiation-induced mitotic cell death. In this model, ionising radiations induce hypoxia-inducible factor 1 alpha (HIF-1α) stabilisation which is inhibited by silencing ILK. Moreover, silencing HIF-1α in U87 cells reduced the surviving fraction after 2 Gy irradiation by increasing cell sensitivity to radiation-induced mitotic cell death and centrosome amplification. Because it is known that HIF-1α controls survivin expression, we then looked at the ILK silencing effect on survivin expression. We show that survivin expression is decreased in U87shILK cells. Furthermore, treating U87 cells with the specific survivin suppressor YM155 significantly increased the percentage of giant multinucleated cells, centrosomal overduplication and thus U87 cell radiosensitivity. In consequence, we decipher here a new pathway of glioma radioresistance via the regulation of radiation-induced centrosome duplication and therefore mitotic cell death by ILK, HIF-1α and survivin. This work identifies new targets in glioblastoma with the intention of radiosensitising these highly radioresistant tumours. PMID:23747271

  7. Bcl-2 inhibitors potentiate the cytotoxic effects of radiation in Bcl-2 overexpressing radioresistant tumor cells

    SciTech Connect

    Hara, Takamitsu; Omura-Minamisawa, Motoko . E-mail: momuram@med.yokohama-cu.ac.jp; Chao Cheng; Nakagami, Yoshihiro; Ito, Megumi; Inoue, Tomio

    2005-02-01

    Purpose: Bcl-2, an inhibitor of apoptosis frequently shows elevated expression in human tumors, thus resulting in resistance to radiation therapy. Therefore, inhibiting Bcl-2 function may enhance the radiosensitivity of tumor cells. Tetrocarcin A (TC-A) and bcl-2 antisense oligonucleotides exhibit antitumor activity by inhibiting Bcl-2 function and transcription, respectively. We investigated whether these antitumor agents would enhance the cytotoxic effects of radiation in tumor cells overexpressing Bcl-2. Methods and materials: We used HeLa/bcl-2 cells, a stable Bcl-2-expressing cell line derived from wild-type HeLa (HeLa/wt) cells. Cells were incubated with TC-A and bcl-2 antisense oligonucleotides for 24 h after irradiation, and cell viability was then determined. Apoptotic cells were quantified by flow cytometric assay. Results: The HeLa/bcl-2 cells were more resistant to radiation than HeLa/wt cells. At concentrations that are not inherently cytotoxic, both TC-A and bcl-2 antisense oligonucleotides increased the cytotoxic effects of radiation in HeLa/bcl-2 cells, but not in HeLa/wt cells. However, in HeLa/bcl-2 cells, additional treatment with TC-A in combination with radiation did not significantly increase apoptosis. Conclusions: The present results suggest that TC-A and bcl-2 antisense oligonucleotides reduce radioresistance of tumor cells overexpressing Bcl-2. Therefore, a combination of radiotherapy and Bcl-2 inhibitors may prove to be a useful therapeutic approach for treating tumors that overexpress Bcl-2.

  8. Therapeutic Efficacy of Astatine-211-Labeled Trastuzumab on Radioresistant SKOV-3 Tumors in Nude Mice

    SciTech Connect

    Palm, Stig Baeck, Tom; Claesson, Ingela; Danielsson, Anna; Elgqvist, Joergen; Frost, Sofia; Hultborn, Ragnar; Jensen, Holger; Lindegren, Sture; Jacobsson, Lars

    2007-10-01

    Purpose: To investigate the potential use of astatine-211 ({sup 211}At)-labeled trastuzumab for the treatment of HER-2-positive, radioresistant ovarian carcinoma. Methods and Materials: Four-week-old nude mice were inoculated intraperitoneally with 5 . 10{sup 6} SKOV-3 cells in 0.4 mL saline on Day 0. The endpoint was the total tumor weight in each mouse on Day 63. Three experiments were performed in which the response to single-dose and fractionated treatment with unlabeled and {sup 211}At-labeled antibody was evaluated. Results: Experiment 1 showed, for the same total amount of trastuzumab, a dose-response relationship between {sup 211}At activity (0-400 kBq on Day 7) and therapeutic efficacy (p = 0.001). The effect of varying the amount of unlabeled trastuzumab was studied in Experiment 2. All mice, except for the controls, received 400 kBq {sup 211}At-trastuzumab, and different groups received 5, 50, or 500 {mu}g trastuzumab on Day 7. The increase from 5 to 50 {mu}g trastuzumab reduced the tumors by 78% in weight. No tumors were present in mice given 500 {mu}g trastuzumab. In Experiment 3, the effect of a fractionated treatment regimen was studied. Mice that received 100 kBq {sup 211}At-trastuzumab on Days 7 and 8 had a 42% smaller tumor burden than did controls. Groups of mice injected with 200 + 100 kBq on Days 7 and 21 and mice injected with 100 kBq on Days 7, 8, and 21 both had 24% less tumor weight than the corresponding controls. Conclusion: The combination of 500 {mu}g trastuzumab and 400 kBq {sup 211}At-trastuzumab had the greatest effect, with complete eradication of the tumors in this nude mouse model.

  9. Russian Activities in Space Photovoltaic Power Modules with Concentrators

    NASA Technical Reports Server (NTRS)

    Andreev, Vyacheslav M.; Rumyantsev, Valeri D.

    2004-01-01

    Space concentrator modules with point-and line-focus Fresnel lenses and with reflective parabolic troughs have been developed recently at Ioffe Physico-Technical Institute. PV receivers for these modules are based: on the single junction LPE and MOCVD AlGaAs/GaAs solar cells characterized by AM0 efficiencies of 23.5 - 24% at 20 - 50 suns and 24 - 24.75 at 50 - 200 suns; on the mechanically stacked tandem AlGaAs/GaAs-GaSb cells with efficiency of 27 - 28 at 20 - 100 suns. MOCVD AlGaAs/GaAs cells with internal Bragg reflector have shown a higher radiation resistance as compared to a traditional structure. Monolithic two-terminal tandems AlGaAs (top)-GaAs (bottom) for space application and GaSb (top) - InGaAsSb (bottom) for TRV application are under development as well.

  10. Same Modulation but Different Starting Points: Performance Modulates Age Differences in Inferior Frontal Cortex Activity during Word-Retrieval

    PubMed Central

    Meinzer, Marcus; Flaisch, Tobias; Seeds, Lauren; Harnish, Stacy; Antonenko, Daria; Witte, Veronica; Lindenberg, Robert; Crosson, Bruce

    2012-01-01

    The neural basis of word-retrieval deficits in normal aging has rarely been assessed and the few previous functional imaging studies found enhanced activity in right prefrontal areas in healthy older compared to younger adults. However, more pronounced right prefrontal recruitment has primarily been observed during challenging task conditions. Moreover, increased task difficulty may result in enhanced activity in the ventral inferior frontal gyrus (vIFG) bilaterally in younger participants as well. Thus, the question arises whether increased activity in older participants represents an age-related phenomenon or reflects task difficulty effects. In the present study, we manipulated task difficulty during overt semantic and phonemic word-generation and used functional magnetic resonance imaging to assess activity patterns in the vIFG in healthy younger and older adults (N = 16/group; mean age: 24 vs. 69 years). Both groups produced fewer correct responses during the more difficult task conditions. Overall, older participants produced fewer correct responses and showed more pronounced task-related activity in the right vIFG. However, increased activity during the more difficult conditions was found in both groups. Absolute degree of activity was correlated with performance across groups, tasks and difficulty levels. Activity modulation (difficult vs. easy conditions) was correlated with the respective drop in performance across groups and tasks. In conclusion, vIFG activity levels and modulation of activity were mediated by performance accuracy in a similar way in both groups. Group differences in the right vIFG activity were explained by performance accuracy which needs to be considered in future functional imaging studies of healthy and pathological aging. PMID:22438970

  11. Same modulation but different starting points: performance modulates age differences in inferior frontal cortex activity during word-retrieval.

    PubMed

    Meinzer, Marcus; Flaisch, Tobias; Seeds, Lauren; Harnish, Stacy; Antonenko, Daria; Witte, Veronica; Lindenberg, Robert; Crosson, Bruce

    2012-01-01

    The neural basis of word-retrieval deficits in normal aging has rarely been assessed and the few previous functional imaging studies found enhanced activity in right prefrontal areas in healthy older compared to younger adults. However, more pronounced right prefrontal recruitment has primarily been observed during challenging task conditions. Moreover, increased task difficulty may result in enhanced activity in the ventral inferior frontal gyrus (vIFG) bilaterally in younger participants as well. Thus, the question arises whether increased activity in older participants represents an age-related phenomenon or reflects task difficulty effects. In the present study, we manipulated task difficulty during overt semantic and phonemic word-generation and used functional magnetic resonance imaging to assess activity patterns in the vIFG in healthy younger and older adults (N = 16/group; mean age: 24 vs. 69 years). Both groups produced fewer correct responses during the more difficult task conditions. Overall, older participants produced fewer correct responses and showed more pronounced task-related activity in the right vIFG. However, increased activity during the more difficult conditions was found in both groups. Absolute degree of activity was correlated with performance across groups, tasks and difficulty levels. Activity modulation (difficult vs. easy conditions) was correlated with the respective drop in performance across groups and tasks. In conclusion, vIFG activity levels and modulation of activity were mediated by performance accuracy in a similar way in both groups. Group differences in the right vIFG activity were explained by performance accuracy which needs to be considered in future functional imaging studies of healthy and pathological aging. PMID:22438970

  12. DNA-dependent protein kinase catalytic subunit inhibitor reverses acquired radioresistance in lung adenocarcinoma by suppressing DNA repair.

    PubMed

    Li, Yong; Li, Hang; Peng, Wen; He, Xin-Yun; Huang, Min; Qiu, Dong; Xue, Ying-Bo; Lu, Liang

    2015-07-01

    The mechanisms underlying lung cancer radioresistance remain to be fully elucidated. The DNA repair pathway is a predominant target of radiotherapy, which is considered to be involved in the acquired radioresistance of cancer cells. The present study aimed to establish a radioresistant cell model using the A549 human lung cancer cell line, and to further investigate the potential mechanisms underlying the radioresistance. The A549R radioresistant lung cancer cell variant was established by exposing the parental A549 cells to repeated γ-ray irradiation at a total dose of 60 Gy. Colony formation assays were then used to determine cell survival following γ-ray exposure. The established radioresistant cells were subsequently treated with or without the NU7026 DNA-PKcs inhibitor. The levels of DNA damage were determined by counting the number of fluorescent γ-H2AX foci in the cells. The cellular capacity for DNA repair was assessed using antibodies for the detection of various DNA repair pathway proteins. The radioresistant sub-clones exhibited significantly decreased survival following NU7026 treatment, compared with the parental cells, as determined by colony formation assays (P<0.05), and this finding was found to be dose-dependent. Treatment with the DNA-dependent protein kinase (DNA-PK) inhibitor significantly reduced γ-H2AX foci formation (P<0.05) following acute radiation exposure in the radioresistant sub-clones, compared with the parental control cells. The decreased levels of γ-H2AX were accompanied by an increase in the percentage of apoptotic cells in the radioresistant cell line following post-radiation treatment with the DNA-PKcs inhibitor. The expression levels of proteins associated with the DNA repair pathway were altered markedly in the cells treated with NU7026. The results of the present study suggested that radioresistance may be associated with enhanced DNA repair following exposure to radiation, resulting in reduced apoptosis. Therefore, the

  13. Finite Element Learning Modules as Active Learning Tools

    ERIC Educational Resources Information Center

    Brown, Ashland O.; Jensen, Daniel; Rencis, Joseph; Wood, Kristin; Wood, John; White, Christina; Raaberg, Kristen Kaufman; Coffman, Josh

    2012-01-01

    The purpose of active learning is to solicit participation by students beyond the passive mode of traditional classroom lectures. Reading, writing, participating in discussions, hands-on activities, engaging in active problem solving, and collaborative learning can all be involved. The skills acquired during active learning tend to go above and…

  14. Inhibitory effect of traditional oriental medicine-derived monoamine oxidase B inhibitor on radioresistance of non-small cell lung cancer

    PubMed Central

    Son, Beomseok; Jun, Se Young; Seo, HyunJeong; Youn, HyeSook; Yang, Hee Jung; Kim, Wanyeon; Kim, Hyung Kook; Kang, ChulHee; Youn, BuHyun

    2016-01-01

    Increased survival of cancer cells mediated by high levels of ionizing radiation (IR) reduces the effectiveness of radiation therapy for non-small cell lung cancer (NSCLC). In the present study, danshensu which is a selected component of traditional oriental medicine (TOM) compound was found to reduce the radioresistance of NSCLC by inhibiting the nuclear factor-κB (NF-κB) pathway. Of the various TOM compounds reported to inhibit the IR activation of NF-κB, danshensu was chosen as a final candidate based on the results of structural comparisons with human metabolites and monoamine oxidase B (MAOB) was identified as the putative target enzyme. Danshensu decreased the activation of NF-κB by inhibiting MAOB activity in A549 and NCI-H1299 NSCLC cells. Moreover, it suppressed IR-induced epithelial-to-mesenchymal transition, expressions of NF-κB-regulated prosurvival and proinflammatory genes, and in vivo radioresistance of mouse xenograft models. Taken together, this study shows that danshensu significantly reduces MAOB activity and attenuates NF-κB signaling to elicit the radiosensitization of NSCLC. PMID:26906215

  15. Variable Glutamine-Rich Repeats Modulate Transcription Factor Activity

    PubMed Central

    Gemayel, Rita; Chavali, Sreenivas; Pougach, Ksenia; Legendre, Matthieu; Zhu, Bo; Boeynaems, Steven; van der Zande, Elisa; Gevaert, Kris; Rousseau, Frederic; Schymkowitz, Joost; Babu, M. Madan; Verstrepen, Kevin J.

    2015-01-01

    Summary Excessive expansions of glutamine (Q)-rich repeats in various human proteins are known to result in severe neurodegenerative disorders such as Huntington’s disease and several ataxias. However, the physiological role of these repeats and the consequences of more moderate repeat variation remain unknown. Here, we demonstrate that Q-rich domains are highly enriched in eukaryotic transcription factors where they act as functional modulators. Incremental changes in the number of repeats in the yeast transcriptional regulator Ssn6 (Cyc8) result in systematic, repeat-length-dependent variation in expression of target genes that result in direct phenotypic changes. The function of Ssn6 increases with its repeat number until a certain threshold where further expansion leads to aggregation. Quantitative proteomic analysis reveals that the Ssn6 repeats affect its solubility and interactions with Tup1 and other regulators. Thus, Q-rich repeats are dynamic functional domains that modulate a regulator’s innate function, with the inherent risk of pathogenic repeat expansions. PMID:26257283

  16. Peroxisome proliferator-activated receptor β/δ induces myogenesis by modulating myostatin activity.

    PubMed

    Bonala, Sabeera; Lokireddy, Sudarsanareddy; Arigela, Harikumar; Teng, Serena; Wahli, Walter; Sharma, Mridula; McFarlane, Craig; Kambadur, Ravi

    2012-04-13

    Classically, peroxisome proliferator-activated receptor β/δ (PPARβ/δ) function was thought to be restricted to enhancing adipocyte differentiation and development of adipose-like cells from other lineages. However, recent studies have revealed a critical role for PPARβ/δ during skeletal muscle growth and regeneration. Although PPARβ/δ has been implicated in regulating myogenesis, little is presently known about the role and, for that matter, the mechanism(s) of action of PPARβ/δ in regulating postnatal myogenesis. Here we report for the first time, using a PPARβ/δ-specific ligand (L165041) and the PPARβ/δ-null mouse model, that PPARβ/δ enhances postnatal myogenesis through increasing both myoblast proliferation and differentiation. In addition, we have identified Gasp-1 (growth and differentiation factor-associated serum protein-1) as a novel downstream target of PPARβ/δ in skeletal muscle. In agreement, reduced Gasp-1 expression was detected in PPARβ/δ-null mice muscle tissue. We further report that a functional PPAR-responsive element within the 1.5-kb proximal Gasp-1 promoter region is critical for PPARβ/δ regulation of Gasp-1. Gasp-1 has been reported to bind to and inhibit the activity of myostatin; consistent with this, we found that enhanced secretion of Gasp-1, increased Gasp-1 myostatin interaction and significantly reduced myostatin activity upon L165041-mediated activation of PPARβ/δ. Moreover, we analyzed the ability of hGASP-1 to regulate myogenesis independently of PPARβ/δ activation. The results revealed that hGASP-1 protein treatment enhances myoblast proliferation and differentiation, whereas silencing of hGASP-1 results in defective myogenesis. Taken together these data revealed that PPARβ/δ is a positive regulator of skeletal muscle myogenesis, which functions through negatively modulating myostatin activity via a mechanism involving Gasp-1. PMID:22362769

  17. Pre-stimulus BOLD-network activation modulates EEG spectral activity during working memory retention.

    PubMed

    Kottlow, Mara; Schlaepfer, Anthony; Baenninger, Anja; Michels, Lars; Brandeis, Daniel; Koenig, Thomas

    2015-01-01

    Working memory (WM) processes depend on our momentary mental state and therefore exhibit considerable fluctuations. Here, we investigate the interplay of task-preparatory and task-related brain activity as represented by pre-stimulus BOLD-fluctuations and spectral EEG from the retention periods of a visual WM task. Visual WM is used to maintain sensory information in the brain enabling the performance of cognitive operations and is associated with mental health. We tested 22 subjects simultaneously with EEG and fMRI while performing a visuo-verbal Sternberg task with two different loads, allowing for the temporal separation of preparation, encoding, retention and retrieval periods. Four temporally coherent networks (TCNs)-the default mode network (DMN), the dorsal attention, the right and the left WM network-were extracted from the continuous BOLD data by means of a group ICA. Subsequently, the modulatory effect of these networks' pre-stimulus activation upon retention-related EEG activity in the theta, alpha, and beta frequencies was analyzed. The obtained results are informative in the context of state-dependent information processing. We were able to replicate two well-known load-dependent effects: the frontal-midline theta increase during the task and the decrease of pre-stimulus DMN activity. As our main finding, these two measures seem to depend on each other as the significant negative correlations at frontal-midline channels suggested. Thus, suppressed pre-stimulus DMN levels facilitated later task related frontal midline theta increases. In general, based on previous findings that neuronal coupling in different frequency bands may underlie distinct functions in WM retention, our results suggest that processes reflected by spectral oscillations during retention seem not only to be "online" synchronized with activity in different attention-related networks but are also modulated by activity in these networks during preparation intervals. PMID:25999828

  18. Pre-stimulus BOLD-network activation modulates EEG spectral activity during working memory retention

    PubMed Central

    Kottlow, Mara; Schlaepfer, Anthony; Baenninger, Anja; Michels, Lars; Brandeis, Daniel; Koenig, Thomas

    2015-01-01

    Working memory (WM) processes depend on our momentary mental state and therefore exhibit considerable fluctuations. Here, we investigate the interplay of task-preparatory and task-related brain activity as represented by pre-stimulus BOLD-fluctuations and spectral EEG from the retention periods of a visual WM task. Visual WM is used to maintain sensory information in the brain enabling the performance of cognitive operations and is associated with mental health. We tested 22 subjects simultaneously with EEG and fMRI while performing a visuo-verbal Sternberg task with two different loads, allowing for the temporal separation of preparation, encoding, retention and retrieval periods. Four temporally coherent networks (TCNs)—the default mode network (DMN), the dorsal attention, the right and the left WM network—were extracted from the continuous BOLD data by means of a group ICA. Subsequently, the modulatory effect of these networks' pre-stimulus activation upon retention-related EEG activity in the theta, alpha, and beta frequencies was analyzed. The obtained results are informative in the context of state-dependent information processing. We were able to replicate two well-known load-dependent effects: the frontal-midline theta increase during the task and the decrease of pre-stimulus DMN activity. As our main finding, these two measures seem to depend on each other as the significant negative correlations at frontal-midline channels suggested. Thus, suppressed pre-stimulus DMN levels facilitated later task related frontal midline theta increases. In general, based on previous findings that neuronal coupling in different frequency bands may underlie distinct functions in WM retention, our results suggest that processes reflected by spectral oscillations during retention seem not only to be “online” synchronized with activity in different attention-related networks but are also modulated by activity in these networks during preparation intervals. PMID

  19. Identification of New Genes Contributing to the Extreme Radioresistance of Deinococcus radiodurans Using a Tn5-Based Transposon Mutant Library

    PubMed Central

    Passot, Fanny; Dutertre, Murielle; Porteron, Martine; Confalonieri, Fabrice; Sommer, Suzanne; Pasternak, Cécile

    2015-01-01

    Here, we have developed an extremely efficient in vivo Tn5-based mutagenesis procedure to construct a Deinococcus radiodurans insertion mutant library subsequently screened for sensitivity to genotoxic agents such as γ and UV radiations or mitomycin C. The genes inactivated in radiosensitive mutants belong to various functional categories, including DNA repair functions, stress responses, signal transduction, membrane transport, several metabolic pathways, and genes of unknown function. Interestingly, preliminary characterization of previously undescribed radiosensitive mutants suggests the contribution of cyclic di-AMP signaling in the recovery of D. radiodurans cells from genotoxic stresses, probably by modulating several pathways involved in the overall cell response. Our analyses also point out a new transcriptional regulator belonging to the GntR family, encoded by DR0265, and a predicted RNase belonging to the newly described Y family, both contributing to the extreme radioresistance of D. radiodurans. Altogether, this work has revealed new cell responses involved either directly or indirectly in repair of various cell damage and confirmed that D. radiodurans extreme radiation resistance is determined by a multiplicity of pathways acting as a complex network. PMID:25884619

  20. An active lighting module with natural light guiding system and solid state source for indoor illumination

    NASA Astrophysics Data System (ADS)

    Chen, Chi-An; Chen, Yi-Yung; Whang, Allen Jong-Woei

    2009-08-01

    Recently, many researches focus on healthy lighting with sunlight. A Natural Light Guiding System includes collecting, transmitting, and lighting parts. In general, the lighting module of the Natural Light Guiding System only uses scattering element, such as diffuser, to achieve uniform illumination. With the passive lighting module, the application of the Natural Light Guiding System is limited because sunlight is dynamic source. When the sunlight is weak at morning, at evening, or on cloudy day, the illumination system is fail. In this paper, we provide an active lighting module that includes the lighting part of Natural Light Guiding System, LED auxiliary sources, optical elements, and optical detector. We use optical simulation tool to design and simulate the efficiency of the active module. The optical element can redistribute the sunlight only, LED light only, or sunlight with LED light to achieve uniform illumination. With the feedback of the detector, the active lighting module will adjust the intensity of LED to provide a steady illumination. Moreover, the module could replace the backlight module of LCD TV when the house has Natural Light Guiding System for saving energy and higher performance of image.

  1. Structure-Activity Relations In Enzymes: An Application Of IR-ATR Modulation Spectroscopy

    NASA Astrophysics Data System (ADS)

    Fringeli, Urs P.; Ahlstrom, Peter; Vincenz, Claudius; Fringeli, Marianna

    1985-12-01

    Relations between structure and specific activity in immobilized acetylcholinesterase (ACNE) have been studied by means of pH- and Ca++-modulation technique combined with attenuated total reflection (ATR) infrared (IR) spectroscopy and enzyme activity measurement. Periodic modulation of pH and Ca++-concentration enabled a periodic on-off switching of about 40% of the total enzyme activity. It was found that about 0.5 to 1% of the amino acids were involved in this process. These 15 to 30 amino acids assumed antiparallel pleated sheet structure in the inhibited state and random and/or helical structure in the activated state.

  2. Myelin-Derived Lipids Modulate Macrophage Activity by Liver X Receptor Activation

    PubMed Central

    Huynh-Thu, Vân Anh; Irrthum, Alexandre; Smeets, Hubert J. M.; Gustafsson, Jan-Åke; Steffensen, Knut R.; Mulder, Monique; Stinissen, Piet; Hellings, Niels; Hendriks, Jerome J. A.

    2012-01-01

    Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system in which macrophages and microglia play a central role. Foamy macrophages and microglia, containing degenerated myelin, are abundantly found in active multiple sclerosis lesions. Recent studies have described an altered macrophage phenotype after myelin internalization. However, it is unclear by which mechanisms myelin affects the phenotype of macrophages and how this phenotype can influence lesion progression. Here we demonstrate, by using genome wide gene expression analysis, that myelin-phagocytosing macrophages have an enhanced expression of genes involved in migration, phagocytosis and inflammation. Interestingly, myelin internalization also induced the expression of genes involved in liver-X-receptor signaling and cholesterol efflux. In vitro validation shows that myelin-phagocytosing macrophages indeed have an increased capacity to dispose intracellular cholesterol. In addition, myelin suppresses the secretion of the pro-inflammatory mediator IL-6 by macrophages, which was mediated by activation of liver-X-receptor β. Our data show that myelin modulates the phenotype of macrophages by nuclear receptor activation, which may subsequently affect lesion progression in demyelinating diseases such as multiple sclerosis. PMID:22984598

  3. Myelin-derived lipids modulate macrophage activity by liver X receptor activation.

    PubMed

    Bogie, Jeroen F J; Timmermans, Silke; Huynh-Thu, Vân Anh; Irrthum, Alexandre; Smeets, Hubert J M; Gustafsson, Jan-Åke; Steffensen, Knut R; Mulder, Monique; Stinissen, Piet; Hellings, Niels; Hendriks, Jerome J A

    2012-01-01

    Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system in which macrophages and microglia play a central role. Foamy macrophages and microglia, containing degenerated myelin, are abundantly found in active multiple sclerosis lesions. Recent studies have described an altered macrophage phenotype after myelin internalization. However, it is unclear by which mechanisms myelin affects the phenotype of macrophages and how this phenotype can influence lesion progression. Here we demonstrate, by using genome wide gene expression analysis, that myelin-phagocytosing macrophages have an enhanced expression of genes involved in migration, phagocytosis and inflammation. Interestingly, myelin internalization also induced the expression of genes involved in liver-X-receptor signaling and cholesterol efflux. In vitro validation shows that myelin-phagocytosing macrophages indeed have an increased capacity to dispose intracellular cholesterol. In addition, myelin suppresses the secretion of the pro-inflammatory mediator IL-6 by macrophages, which was mediated by activation of liver-X-receptor β. Our data show that myelin modulates the phenotype of macrophages by nuclear receptor activation, which may subsequently affect lesion progression in demyelinating diseases such as multiple sclerosis. PMID:22984598

  4. Shuttle extravehicular activity signal processor pulse amplitude modulation decommutator

    NASA Technical Reports Server (NTRS)

    Noble, D. E.; Conrad, W. M.

    1974-01-01

    To provide data with long-term stability and accuracy, the pulse amplitude modulation (PAM) decommutator was synchronized to the PAM-return to zero wavetrain, and each channel was sampled with a common sample and hold circuit and digitized sequentially. The digital value of each channel was then scaled by the digital value of the calibration channels. The corrected digital value of each channel was stored for one complete frame and then transferred to the multiplexer-demultiplexer at a high rate in one block of serial digital data. A test model was built to demonstrate this design approach taken for the PAM decom and performance data was provided. The accuracies obtained with various signal to noise ratios are shown.

  5. Staphylococcal Enterotoxin O Exhibits Cell Cycle Modulating Activity

    PubMed Central

    Hodille, Elisabeth; Alekseeva, Ludmila; Berkova, Nadia; Serrier, Asma; Badiou, Cedric; Gilquin, Benoit; Brun, Virginie; Vandenesch, François; Terman, David S.; Lina, Gerard

    2016-01-01

    Maintenance of an intact epithelial barrier constitutes a pivotal defense mechanism against infections. Staphylococcus aureus is a versatile pathogen that produces multiple factors including exotoxins that promote tissue alterations. The aim of the present study is to investigate the cytopathic effect of staphylococcal exotoxins SEA, SEG, SEI, SElM, SElN and SElO on the cell cycle of various human cell lines. Among all tested exotoxins only SEIO inhibited the proliferation of a broad panel of human tumor cell lines in vitro. Evaluation of a LDH release and a DNA fragmentation of host cells exposed to SEIO revealed that the toxin does not induce necrosis or apoptosis. Analysis of the DNA content of tumor cells synchronized by serum starvation after exposure to SEIO showed G0/G1 cell cycle delay. The cell cycle modulating feature of SEIO was confirmed by the flow cytometry analysis of synchronized cells exposed to supernatants of isogenic S. aureus strains wherein only supernatant of the SElO producing strain induced G0/G1 phase delay. The results of yeast-two-hybrid analysis indicated that SEIO’s potential partner is cullin-3, involved in the transition from G1 to S phase. In conclusion, we provide evidence that SEIO inhibits cell proliferation without inducing cell death, by delaying host cell entry into the G0/G1 phase of the cell cycle. We speculate that this unique cell cycle modulating feature allows SEIO producing bacteria to gain advantage by arresting the cell cycle of target cells as part of a broader invasive strategy. PMID:27148168

  6. Staphylococcal Enterotoxin O Exhibits Cell Cycle Modulating Activity.

    PubMed

    Hodille, Elisabeth; Alekseeva, Ludmila; Berkova, Nadia; Serrier, Asma; Badiou, Cedric; Gilquin, Benoit; Brun, Virginie; Vandenesch, François; Terman, David S; Lina, Gerard

    2016-01-01

    Maintenance of an intact epithelial barrier constitutes a pivotal defense mechanism against infections. Staphylococcus aureus is a versatile pathogen that produces multiple factors including exotoxins that promote tissue alterations. The aim of the present study is to investigate the cytopathic effect of staphylococcal exotoxins SEA, SEG, SEI, SElM, SElN and SElO on the cell cycle of various human cell lines. Among all tested exotoxins only SEIO inhibited the proliferation of a broad panel of human tumor cell lines in vitro. Evaluation of a LDH release and a DNA fragmentation of host cells exposed to SEIO revealed that the toxin does not induce necrosis or apoptosis. Analysis of the DNA content of tumor cells synchronized by serum starvation after exposure to SEIO showed G0/G1 cell cycle delay. The cell cycle modulating feature of SEIO was confirmed by the flow cytometry analysis of synchronized cells exposed to supernatants of isogenic S. aureus strains wherein only supernatant of the SElO producing strain induced G0/G1 phase delay. The results of yeast-two-hybrid analysis indicated that SEIO's potential partner is cullin-3, involved in the transition from G1 to S phase. In conclusion, we provide evidence that SEIO inhibits cell proliferation without inducing cell death, by delaying host cell entry into the G0/G1 phase of the cell cycle. We speculate that this unique cell cycle modulating feature allows SEIO producing bacteria to gain advantage by arresting the cell cycle of target cells as part of a broader invasive strategy. PMID:27148168

  7. ROMA: Representation and Quantification of Module Activity from Target Expression Data

    PubMed Central

    Martignetti, Loredana; Calzone, Laurence; Bonnet, Eric; Barillot, Emmanuel; Zinovyev, Andrei

    2016-01-01

    In many analyses of high-throughput data in systems biology, there is a need to quantify the activity of a set of genes in individual samples. A typical example is the case where it is necessary to estimate the activity of a transcription factor (which is often not directly measurable) from the expression of its target genes. We present here ROMA (Representation and quantification Of Module Activities) Java software, designed for fast and robust computation of the activity of gene sets (or modules) with coordinated expression. ROMA activity quantification is based on the simplest uni-factor linear model of gene regulation that approximates the expression data of a gene set by its first principal component. The proposed algorithm implements novel functionalities: it provides several method modifications for principal components computation, including weighted, robust and centered methods; it distinguishes overdispersed modules (based on the variance explained by the first principal component) and coordinated modules (based on the significance of the spectral gap); finally, it computes statistical significance of the estimated module overdispersion or coordination. ROMA can be applied in many contexts, from estimating differential activities of transcriptional factors to finding overdispersed pathways in single-cell transcriptomics data. We describe here the principles of ROMA providing several practical examples of its use. ROMA source code is available at https://github.com/sysbio-curie/Roma. PMID:26925094

  8. Pivotal role for skin transendothelial radio-resistant anti-inflammatory macrophages in tissue repair

    PubMed Central

    Barreiro, Olga; Cibrian, Danay; Clemente, Cristina; Alvarez, David; Moreno, Vanessa; Valiente, Íñigo; Bernad, Antonio; Vestweber, Dietmar; Arroyo, Alicia G; Martín, Pilar; von Andrian, Ulrich H; Sánchez Madrid, Francisco

    2016-01-01

    Heterogeneity and functional specialization among skin-resident macrophages are incompletely understood. In this study, we describe a novel subset of murine dermal perivascular macrophages that extend protrusions across the endothelial junctions in steady-state and capture blood-borne macromolecules. Unlike other skin-resident macrophages that are reconstituted by bone marrow-derived progenitors after a genotoxic insult, these cells are replenished by an extramedullary radio-resistant and UV-sensitive Bmi1+ progenitor. Furthermore, they possess a distinctive anti-inflammatory transcriptional profile, which cannot be polarized under inflammatory conditions, and are involved in repair and remodeling functions for which other skin-resident macrophages appear dispensable. Based on all their properties, we define these macrophages as Skin Transendothelial Radio-resistant Anti-inflammatory Macrophages (STREAM) and postulate that their preservation is important for skin homeostasis. DOI: http://dx.doi.org/10.7554/eLife.15251.001 PMID:27304075

  9. Learning new gait patterns: Exploratory muscle activity during motor learning is not predicted by motor modules.

    PubMed

    Ranganathan, Rajiv; Krishnan, Chandramouli; Dhaher, Yasin Y; Rymer, William Z

    2016-03-21

    The motor module hypothesis in motor control proposes that the nervous system can simplify the problem of controlling a large number of muscles in human movement by grouping muscles into a smaller number of modules. Here, we tested one prediction of the modular organization hypothesis by examining whether there is preferential exploration along these motor modules during the learning of a new gait pattern. Healthy college-aged participants learned a new gait pattern which required increased hip and knee flexion during the swing phase while walking in a lower-extremity robot (Lokomat). The new gait pattern was displayed as a foot trajectory in the sagittal plane and participants attempted to match their foot trajectory to this template. We recorded EMG from 8 lower-extremity muscles and we extracted motor modules during both baseline walking and target-tracking using non-negative matrix factorization (NMF). Results showed increased trajectory variability in the first block of learning, indicating that participants were engaged in exploratory behavior. Critically, when we examined the muscle activity during this exploratory phase, we found that the composition of motor modules changed significantly within the first few strides of attempting the new gait pattern. The lack of persistence of the motor modules under even short time scales suggests that motor modules extracted during locomotion may be more indicative of correlated muscle activity induced by the task constraints of walking, rather than reflecting a modular control strategy. PMID:26916510

  10. Sug1 modulates yeast transcription activation by Cdc68.

    PubMed Central

    Xu, Q; Singer, R A; Johnston, G C

    1995-01-01

    The Cdc68 protein is required for the transcription of a variety of genes in the yeast Saccharomyces cerevisiae. In a search for proteins involved in the activity of the Cdc68 protein, we identified four suppressor genes in which mutations reverse the temperature sensitivity caused by the cdc68-1 allele. We report here the molecular characterization of mutations in one suppressor gene, the previously identified SUG1 gene. The Sug1 protein has been implicated in both transcriptional regulation and proteolysis. sug1 suppressor alleles reversed most aspects of the cdc68-1 mutant phenotype but did not suppress the lethality of a cdc68 null allele, indicating that sug1 suppression is by restoration of Cdc68 activity. Our evidence suggests that suppression by sug1 is unlikely to be due to increased stability of mutant Cdc68 protein, despite the observation that Sug1 affected proteolysis of mutant Cdc68. We report here that attenuated Sug1 activity strengthens mutant Cdc68 activity, whereas increased Sug1 activity further inhibits enfeebled Cdc68 activity, suggesting that Sug1 antagonizes the activator function of Cdc68 for transcription. Consistent with this hypothesis, we find that Sug1 represses transcription in vivo. PMID:7565755

  11. The Brain Microenvironment Preferentially Enhances the Radioresistance of CD133+ Glioblastoma Stem-like Cells

    PubMed Central

    Jamal, Muhammad; Rath, Barbara H; Tsang, Patricia S; Camphausen, Kevin; Tofilon, Philip J

    2012-01-01

    Brain tumor xenografts initiated from glioblastoma (GBM) CD133+ tumor stem-like cells (TSCs) are composed of TSC and non-TSC subpopulations, simulating the phenotypic heterogeneity of GBMs in situ. Given that the discrepancies between the radiosensitivity of GBM cells in vitro and the treatment response of patients suggest a role for the microenvironment in GBM radioresistance, we compared the response of TSCs and non-TSCs irradiated under in vitro and orthotopic conditions. As a measure of radioresponse determined at the individual cell level, γH2AX and 53BP1 foci were quantified in CD133+ cells and their differentiated (CD133-) progeny. Under in vitro conditions, no difference was detected between CD133+ and CD133- cells in foci induction or dispersal after irradiation. However, irradiation of orthotopic xenografts initiated from TSCs resulted in the induction of fewer γH2AX and 53BP1 foci in CD133+ cells compared to their CD133- counterparts within the same tumor. Xenograft irradiation resulted in a tumor growth delay of approximately 7 days with a corresponding increase in the percentage of CD133+ cells at 7 days after radiation, which persisted to the onset of neurologic symptoms. These results suggest that, although the radioresponse of TSCs and non-TSCs does not differ under in vitro growth conditions, CD133+ cells are relatively radioresistant under intracerebral growth conditions. Whereas these findings are consistent with the suspected role for TSCs as a determinant of GBM radioresistance, these data also illustrate the dependence of the cellular radioresistance on the brain microenvironment. PMID:22431923

  12. Bmi-1 confers adaptive radioresistance to KYSE-150R esophageal carcinoma cells

    SciTech Connect

    Wang, Guanyu; Liu, Luying; Sharma, Sherven; Liu, Hai; Yang, Weifang; Sun, Xiaonan; Dong, Qinghua

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Adaptive radioresistant KYSE-150R cells expressed high level of Bmi-1. Black-Right-Pointing-Pointer Bmi-1 depletion sensitized KYSE-150R cells to RT. Black-Right-Pointing-Pointer Bmi-1 depletion increased the generation of ROS in KYSE-150R cells exposed to radiation. Black-Right-Pointing-Pointer Bmi-1 depletion impaired DNA repair capacities in KYSE-150R cells exposed to radiation. -- Abstract: Radiotherapy (RT) is a major modality of cancer treatment. However, tumors often acquire radioresistance, which causes RT to fail. The exact mechanisms by which tumor cells subjected to fractionated irradiation (FIR) develop an adaptive radioresistance are largely unknown. Using the radioresistant KYSE-150R esophageal squamous cell carcinoma (ESCC) model, which was derived from KYSE-150 parental cells using FIR, the role of Bmi-1 in mediating the radioadaptive response of ESCC cells to RT was investigated. The results showed that the level of Bmi-1 expression was significantly higher in KYSE-150R cells than in the KYSE-150 parental cells. Bmi-1 depletion sensitized the KYSE-150R cells to RT mainly through the induction of apoptosis, partly through the induction of senescence. A clonogenic cell survival assay showed that Bmi-1 depletion significantly decreased the radiation survival fraction in KYSE-150R cells. Furthermore, Bmi-1 depletion increased the generation of reactive oxygen species (ROS) and the expression of oxidase genes (Lpo, Noxo1 and Alox15) in KYSE-150R cells exposed to irradiation. DNA repair capacities assessed by {gamma}-H2AX foci formation were also impaired in the Bmi-1 down-regulated KYSE-150R cells. These results suggest that Bmi-1 plays an important role in tumor radioadaptive resistance under FIR and may be a potent molecular target for enhancing the efficacy of fractionated RT.

  13. Reward sensitivity modulates brain activity in the prefrontal cortex, ACC and striatum during task switching.

    PubMed

    Fuentes-Claramonte, Paola; Ávila, César; Rodríguez-Pujadas, Aina; Ventura-Campos, Noelia; Bustamante, Juan C; Costumero, Víctor; Rosell-Negre, Patricia; Barrós-Loscertales, Alfonso

    2015-01-01

    Current perspectives on cognitive control acknowledge that individual differences in motivational dispositions may modulate cognitive processes in the absence of reward contingencies. This work aimed to study the relationship between individual differences in Behavioral Activation System (BAS) sensitivity and the neural underpinnings involved in processing a switching cue in a task-switching paradigm. BAS sensitivity was hypothesized to modulate brain activity in frontal regions, ACC and the striatum. Twenty-eight healthy participants underwent fMRI while performing a switching task, which elicited activity in fronto-striatal regions during the processing of the switch cue. BAS sensitivity was negatively associated with activity in the lateral prefrontal cortex, anterior cingulate cortex and the ventral striatum. Combined with previous results, our data indicate that BAS sensitivity modulates the neurocognitive processes involved in task switching in a complex manner depending on task demands. Therefore, individual differences in motivational dispositions may influence cognitive processing in the absence of reward contingencies. PMID:25875640

  14. Reward Sensitivity Modulates Brain Activity in the Prefrontal Cortex, ACC and Striatum during Task Switching

    PubMed Central

    Fuentes-Claramonte, Paola; Ávila, César; Rodríguez-Pujadas, Aina; Ventura-Campos, Noelia; Bustamante, Juan C.; Costumero, Víctor; Rosell-Negre, Patricia; Barrós-Loscertales, Alfonso

    2015-01-01

    Current perspectives on cognitive control acknowledge that individual differences in motivational dispositions may modulate cognitive processes in the absence of reward contingencies. This work aimed to study the relationship between individual differences in Behavioral Activation System (BAS) sensitivity and the neural underpinnings involved in processing a switching cue in a task-switching paradigm. BAS sensitivity was hypothesized to modulate brain activity in frontal regions, ACC and the striatum. Twenty-eight healthy participants underwent fMRI while performing a switching task, which elicited activity in fronto-striatal regions during the processing of the switch cue. BAS sensitivity was negatively associated with activity in the lateral prefrontal cortex, anterior cingulate cortex and the ventral striatum. Combined with previous results, our data indicate that BAS sensitivity modulates the neurocognitive processes involved in task switching in a complex manner depending on task demands. Therefore, individual differences in motivational dispositions may influence cognitive processing in the absence of reward contingencies. PMID:25875640

  15. Hypothalamic modulation of splenic natural killer cell activity in rats.

    PubMed Central

    Katafuchi, T; Ichijo, T; Take, S; Hori, T

    1993-01-01

    1. The cytotoxic activity of splenic natural killer cells measured by a standard chromium release assay in urethane and alpha-chloralose-anaesthetized rats was significantly suppressed 20 min after bilateral ablation of the medial part of the preoptic hypothalamus (MPO). The suppression was completely blocked by prior splenic denervation. The splenic natural killer cell activity of MPO sham-lesioned rats or thalamus-lesioned rats, both having an intact splenic innervation, were not different from that of a non-treated control group. 2. Electrical stimulation of the bilateral MPO (0.1 ms, 0.1-0.3 mA, 5-100 Hz) suppressed the efferent activity of the splenic nerve in all six rats examined. The reduction of the nerve activity was accompanied by a transient fall in blood pressure. An I.V. injection of phenylephrine (3 micrograms/0.3 ml) also evoked a suppression of the nerve activity, which was accompanied by transient hypertension, suggesting that the suppressive effect of the MPO stimulation was independent of changes in blood pressure. On the other hand, a bilateral lesion of the MPO resulted in a sustained increase in the electrical activity of the splenic sympathetic nerve filaments which lasted for more than 2 h. 3. Microinjection of monosodium-L-glutamate (0.1 and 0.01 M in 0.1 microliters saline) unilaterally into the MPO evoked a transient suppression of the efferent discharge rate of the splenic nerve activity within 1 min, which was also accompanied by a decrease in blood pressure. The injection of saline (0.1 microliter) into the MPO had no effect. The microinjection of recombinant human interferon-alpha (200 and 2000 U in 0.1 microliter saline) into the MPO dose dependently increased the splenic nerve activity without any change in blood pressure. 4. In contrast, microinjection of interferon-alpha into the paraventricular nucleus of the hypothalamus (PVN) had no effect on splenic nerve activity, although an injection of glutamate increased the nerve

  16. Fuzzy Behavior Modulation with Threshold Activation for Autonomous Vehicle Navigation

    NASA Technical Reports Server (NTRS)

    Tunstel, Edward

    2000-01-01

    This paper describes fuzzy logic techniques used in a hierarchical behavior-based architecture for robot navigation. An architectural feature for threshold activation of fuzzy-behaviors is emphasized, which is potentially useful for tuning navigation performance in real world applications. The target application is autonomous local navigation of a small planetary rover. Threshold activation of low-level navigation behaviors is the primary focus. A preliminary assessment of its impact on local navigation performance is provided based on computer simulations.

  17. Thermal Analysis of ISS Service Module Active TCS

    NASA Technical Reports Server (NTRS)

    Altov, Vladimir V.; Zaletaev, Sergey V.; Belyavskiy, Evgeniy P.

    2000-01-01

    ISS Service Module mission must begin in July 2000. The verification of design thermal requirements is mostly due to thermal analysis. The thermal analysis is enough difficult problem because of large number of ISS configurations that had to be investigated and various orbital environments. Besides the ISS structure has articulating parts such as solar arrays and radiators. The presence of articulating parts greatly increases computation times and requires accurate approach to organization of calculations. The varying geometry needs us to calculate the view factors several times during the orbit, while in static geometry case we need do it only once. In this paper we consider the thermal mathematical model of SM that includes the TCS and construction thermal models and discuss the results of calculations for ISS configurations 1R and 9Al. The analysis is based on solving the nodal heat balance equations for ISS structure by Kutta-Merson method and analytical solutions of heat transfer equations for TCS units. The computations were performed using thermal software TERM [1,2] that will be briefly described.

  18. miR-620 promotes tumor radioresistance by targeting 15-hydroxyprostaglandin dehydrogenase (HPGD)

    PubMed Central

    Huang, Xiaoyong; Taeb, Samira; Jahangiri, Sahar; Korpela, Elina; Cadonic, Ivan; Yu, Nancy; Krylov, Sergey N.; Fokas, Emmanouil; Boutros, Paul C.; Liu, Stanley K.

    2015-01-01

    MicroRNA contribute to tumor radiation resistance, which is an important clinical problem, and thus we are interested in identifying and characterizing their function. We demonstrate that miR-620 contributes to radiation resistance in cancer cells by increasing proliferation, and decreasing the G2/M block. We identify the hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (HPGD/15-PGDH) tumor suppressor gene as a direct miR-620 target, which results in increased prostaglandin E2 (PGE2) levels. Furthermore, we show that siRNA targeting of HPGD or administration of exogenous PGE2 recapitulates radioresistance. Targeting of the EP2 receptor that responds to PGE2 using pharmacological or genetic approaches, abrogates radioresistance. Tumor xenograft experiments confirm that miR-620 increases proliferation and tumor radioresistance in vivo. Regulation of PGE2 levels via targeting of HPGD by miR-620 is an innovative manner by which a microRNA can induce radiation resistance. PMID:26068950

  19. Modulation of Motor Area Activity during Observation of Unnatural Body Movements

    ERIC Educational Resources Information Center

    Shimada, Sotaro; Oki, Kazuma

    2012-01-01

    The mirror neuron system (MNS) is activated when observing the actions of others. However, it remains unclear whether the MNS responds more strongly to natural bodily actions in the observer's motor repertoire than to unnatural actions. We investigated whether MNS activity is modulated by the unnaturalness of an observed action by inserting short…

  20. Modulation of spontaneous fMRI activity in human visual cortex by behavioral state

    PubMed Central

    Bianciardi, Marta; Fukunaga, Masaki; van Gelderen, Peter; Horovitz, Silvina G.; de Zwart, Jacco A.; Duyn, Jeff H.

    2009-01-01

    The phenomenon of spontaneous fMRI activity is increasingly being exploited to investigate the connectivity of functional networks in human brain with high spatial-resolution. Although mounting evidence points towards a neuronal contribution to this activity, its functional role and dependence on behavioral state remain unclear. In this work, we used BOLD fMRI at 7 T to study the modulation of spontaneous activity in occipital areas by various behavioral conditions, including resting with eyes closed, eyes open with visual fixation, and eyes open with fixation and focal visual stimulation. Spontaneous activity was separated from evoked activity and from signal fluctuations related to cardiac and respiratory cycles. We found that spontaneous activity in visual areas was substantially reduced (amplitude (44%) and coherence (25%)) with the fixation conditions relative to the eyes-closed condition. No significant further modulation was observed when the visual stimulus was added. The observed dependence on behavioral condition suggests that part of spontaneous fMRI signal fluctuations represents neuronal activity. Possible mechanisms for the modulation of spontaneous activity by behavioral state are discussed. The observed linear superposition of spontaneous fMRI activity with focal evoked activity related to visual processing has important implications for fMRI studies, which ideally should take into account the effect of spontaneous activity to properly define brain activations during task conditions. PMID:19028588

  1. Modulation of the protein kinase activity of mTOR.

    PubMed

    Lawrence, J C; Lin, T A; McMahon, L P; Choi, K M

    2004-01-01

    mTOR is a founding member of a family of protein kinases having catalytic domains homologous to those in phosphatidylinositol 3-OH kinase. mTOR participates in the control by insulin of the phosphorylation of lipin, which is required for adipocyte differentiation, and the two translational regulators, p70S6K and PHAS-I. The phosphorylation of mTOR, itself, is stimulated by insulin in Ser2448, a site that is also phosphorylated by protein kinase B (PKB) in vitro and in response to activation of PKB activity in vivo. Ser2448 is located in a short stretch of amino acids not found in the two TOR proteins in yeast. A mutant mTOR lacking this stretch exhibited increased activity, and binding of the antibody, mTAb-1, to this region markedly increased mTOR activity. In contrast, rapamycin-FKBP12 inhibited mTOR activity towards both PHAS-I and p70S6K, although this complex inhibited the phosphorylation of some sites more than that of others. Mutating Ser2035 to Ile in the FKBP12-rapamycin binding domain rendered mTOR resistant to inhibition by rapamycin. Unexpectedly, this mutation markedly decreased the ability of mTOR to phosphorylate certain sites in both PHAS-I and p70S6K. The results support the hypotheses that rapamycin disrupts substrate recognition instead of directly inhibiting phosphotransferase activity and that mTOR activity in cells is controlled by the phosphorylation of an inhibitory regulatory domain containing the mTAb-1 epitope. PMID:14560959

  2. Phospholipase Cε Modulates Rap1 Activity and the Endothelial Barrier.

    PubMed

    DiStefano, Peter V; Smrcka, Alan V; Glading, Angela J

    2016-01-01

    The phosphoinositide-specific phospholipase C, PLCε, is a unique signaling protein with known roles in regulating cardiac myocyte growth, astrocyte inflammatory signaling, and tumor formation. PLCε is also expressed in endothelial cells, however its role in endothelial regulation is not fully established. We show that endothelial cells of multiple origins, including human pulmonary artery (HPAEC), human umbilical vein (HUVEC), and immortalized brain microvascular (hCMEC/D3) endothelial cells, express PLCε. Knockdown of PLCε in arterial endothelial monolayers decreased the effectiveness of the endothelial barrier. Concomitantly, RhoA activity and stress fiber formation were increased. PLCε-deficient arterial endothelial cells also exhibited decreased Rap1-GTP levels, which could be restored by activation of the Rap1 GEF, Epac, to rescue the increase in monolayer leak. Reintroduction of PLCε rescued monolayer leak with both the CDC25 GEF domain and the lipase domain of PLCε required to fully activate Rap1 and to rescue endothelial barrier function. Finally, we demonstrate that the barrier promoting effects PLCε are dependent on Rap1 signaling through the Rap1 effector, KRIT1, which we have previously shown is vital for maintaining endothelial barrier stability. Thus we have described a novel role for PLCε PIP2 hydrolytic and Rap GEF activities in arterial endothelial cells, where PLCε-dependent activation of Rap1/KRIT1 signaling promotes endothelial barrier stability. PMID:27612188

  3. Valsalva maneuver: Insights into baroreflex modulation of human sympathetic activity

    NASA Technical Reports Server (NTRS)

    Smith, Michael L.; Eckberg, Dwain L.; Fritsch, Janice M.; Beightol, Larry A.; Ellenbogen, Kenneth A.

    1991-01-01

    Valsalva's maneuver, voluntary forced expiration against a closed glottis, is a well-characterized research tool, used to assess the integrity of human autonomic cardiovascular control. Valsalva straining provokes a stereotyped succession of alternating positive and negative arterial pressure and heart rate changes mediated in part by arterial baroreceptors. Arterial pressure changes result primarily from fluctuating levels of venous return to the heart and changes of sympathetic nerve activity. Muscle sympathetic activity was measured directly in nine volunteers to explore quantitatively the relation between arterial pressure and human sympathetic outflow during pressure transients provoked by controlled graded Valsalva maneuvers. Our results underscore several properties of sympathetic regulation during Valsalva straining. First, muscle sympathetic nerve activity changes as a mirror image of changes in arterial pressure. Second, the magnitude of sympathetic augmentation during Valsalva straining predicts phase 4 arterial pressure elevations. Third, post-Valsalva sympathetic inhibition persists beyond the return of arterial and right atrial pressures to baseline levels which reflects an alteration of the normal relation between arterial pressure and muscle sympathetic activity. Therefore, Valsalva straining may have some utility for investigating changes of reflex control of sympathetic activity after space flight; however, measurement of beat-to-beat arterial pressure is essential for this use. The utility of this technique in microgravity can not be determined from these data. Further investigations are necessary to determine whether these relations are affected by the expansion of intrathoracic blood volume associated with microgravity.

  4. Cell proliferation in vitro modulates fibroblast collagenase activity

    SciTech Connect

    Lindblad, W.J.; Flood, L.

    1986-05-01

    Collagenase enzyme activity is regulated by numerous control mechanisms which prevent excessive release and activation of this protease. A primary mechanism for regulating enzyme extracellular activity may be linked to cell division, therefore they have examined the release of collagenase by fibroblasts in vitro in response to cellular proliferation. Studies were performed using fibroblasts derived from adult rat dermis maintained in DMEM containing 10% newborn calf serum, 25 mM tricine buffer, and antibiotics. Cells between subculture 10 and 19 were used with enzyme activity determined with a /sup 14/C-labelled soluble Type I collagen substrate with and without trypsin activation. Fibroblasts, trypsinized and plated at low density secreted 8.5 fold more enzyme than those cells at confluence (975 vs. 115 dpm/..mu..g DNA). This diminution occurred gradually as the cells went from logrithmic growth towards confluence. Confluent fibroblast monolayers were scraped in a grid arrangement, stimulating the remaining cells to divide, without exposure to trypsin. Within 24-48 hr postscraping enzyme levels had increased 260-400%, accompanied by enhanced incorporation of /sup 3/H-thymidine and /sup 3/H-uridine into cell macromolecules. The burst of enzyme release began to subside 12 hr later. These results support a close relationship between fibroblast proliferation and collagenase secretion.

  5. Epothilone B Confers Radiation Dose Enhancement in DAB2IP Gene Knock-Down Radioresistant Prostate Cancer Cells

    SciTech Connect

    Kong Zhaolu; Raghavan, Pavithra; Xie Daxing; Boike, Thomas; Burma, Sandeep; Chen, David; Chakraborty, Arup; Hsieh, Jer-Tsong; Saha, Debabrata

    2010-11-15

    Purpose: In metastatic prostate cancer, DOC-2/DAB2 interactive protein (DAB2IP) is often downregulated and has been reported as a possible prognostic marker to predict the risk of aggressive prostate cancer (PCa). Our preliminary results show that DAB2IP-deficient PCa cells are radioresistant. In this study, we investigated the anticancer drug Epothilone B (EpoB) for the modulation of radiosensitivity in DAB2IP-deficient human PCa cells. Methods and Materials: We used a stable DAB2IP-knock down human PCa cell line, PC3 shDAB2IP, treated with EpoB, ionizing radiation (IR), or the combined treatment of EpoB and IR. The modulation of radiosensitivity was determined by surviving fraction, cell cycle distribution, apoptosis, and DNA double-strand break (DSB) repair. For in vivo studies, the PC3shDAB2IP xenograft model was used in athymic nude mice. Results: Treatment with EpoB at IC{sub 50} dose (33.3 nM) increased cellular radiosensitivity in the DAB2IP-deficient cell line with a dose enhancement ratio of 2.36. EpoB delayed the DSB repair kinetics after IR and augmented the induction of apoptosis in irradiated cells after G{sub 2}/M arrest. Combined treatment of EpoB and radiation enhanced tumor growth delay with an enhancement factor of 1.2. Conclusions: We have demonstrated a significant radiation dose enhancement using EpoB in DAB2IP-deficient prostate cancer cells. This radiosensitization can be attributed to delayed DSB repair, prolonged G{sub 2} block, and increased apoptosis in cells entering the cell cycle after G{sub 2}/M arrest.

  6. Regular exercise improves cardiac contractile activation by modulating MHC isoforms and SERCA activity in orchidectomized rats.

    PubMed

    Vutthasathien, Pavarana; Wattanapermpool, Jonggonnee

    2015-10-01

    Data from the trial known as Testosterone in Older Men with Mobility Limitations (TOM) has indicated an association between testosterone administration and a greater risk for adverse cardiovascular events. We therefore propose that regular exercise is a cardioprotective alternative that prevents detrimental changes in contractile activation when a deficiency in male sex hormones exists. Ten-week-old orchidectomized (ORX) rats were subjected to a 9-wk treadmill running program at moderate intensity starting 1 wk after surgery. Although exercise-induced cardiac hypertrophy was observed both in rats that underwent ORX and sham surgery, regular exercise enhanced cardiac myofilament Ca(2+) sensitivity and myosin light-chain 2 phosphorylation only in rats that underwent a sham operation. Although the rats that had sham surgery and and given exercise exhibited no change in maximum developed tension, regular running prevented the suppression of maximum active tension in the hearts of ORX rats. Regular exercise also prevented a shift in myosin heavy chain (MHC) isoforms toward β-MHC, a reduction in sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) activity, and an increase in SERCA sensitivity in the hearts of ORX rats. Neither SERCA content nor its modulating component, phospholamban (PLB), was altered by exercise in either sham-operated or ORX rats. However, decreases in the phosphorylated Thr(17) form of PLB and the phosphorylated Thr(287) form of Ca(2+)/calmodulin-dependent kinase II in the hearts of ORX rats were abolished after regular exercise. These results thus support the use of regular running as a cardioprotective alternative to testosterone replacement in hypogonadal conditions. PMID:26272317

  7. Activity-Dependent Modulation of Neural Circuit Synaptic Connectivity

    PubMed Central

    Tessier, Charles R.; Broadie, Kendal

    2009-01-01

    In many nervous systems, the establishment of neural circuits is known to proceed via a two-stage process; (1) early, activity-independent wiring to produce a rough map characterized by excessive synaptic connections, and (2) subsequent, use-dependent pruning to eliminate inappropriate connections and reinforce maintained synapses. In invertebrates, however, evidence of the activity-dependent phase of synaptic refinement has been elusive, and the dogma has long been that invertebrate circuits are “hard-wired” in a purely activity-independent manner. This conclusion has been challenged recently through the use of new transgenic tools employed in the powerful Drosophila system, which have allowed unprecedented temporal control and single neuron imaging resolution. These recent studies reveal that activity-dependent mechanisms are indeed required to refine circuit maps in Drosophila during precise, restricted windows of late-phase development. Such mechanisms of circuit refinement may be key to understanding a number of human neurological diseases, including developmental disorders such as Fragile X syndrome (FXS) and autism, which are hypothesized to result from defects in synaptic connectivity and activity-dependent circuit function. This review focuses on our current understanding of activity-dependent synaptic connectivity in Drosophila, primarily through analyzing the role of the fragile X mental retardation protein (FMRP) in the Drosophila FXS disease model. The particular emphasis of this review is on the expanding array of new genetically-encoded tools that are allowing cellular events and molecular players to be dissected with ever greater precision and detail. PMID:19668708

  8. Modulation of muscle sympathetic nerve activity by low-frequency physiological activation of the vestibular utricle in awake humans.

    PubMed

    Hammam, Elie; Kwok, Kenny; Macefield, Vaughan G

    2013-09-01

    We recently showed that selective stimulation of one set of otolithic organs-those located in the utricle, sensitive to displacement in the horizontal axis-causes a marked entrainment of skin sympathetic nerve activity (SSNA). Here, we assessed whether muscle sympathetic nerve activity (MSNA) is similarly modulated. MSNA was recorded via tungsten microelectrodes inserted into cutaneous fascicles of the common peroneal nerve in 12 awake subjects, seated (head vertical, eyes closed) on a motorised platform. Slow sinusoidal accelerations-decelerations (±4 mG) were applied in the X (antero-posterior) or Y (medio-lateral) direction at 0.08 Hz. Cross-correlation analysis revealed partial entrainment of MSNA: vestibular modulation was 32 ± 3 % for displacements in the X-axis and 29 ± 3 % in the Y-axis; these were significantly smaller than those evoked in SSNA (97 ± 3 and 91 ± 5 %, respectively). For each sinusoidal cycle, there were two peaks of modulation-one associated with acceleration as the platform moved forward or to the side and one associated with acceleration in the opposite direction. We believe the two peaks reflect inertial displacement of the stereocilia within the utricle during sinusoidal acceleration, which evokes vestibulosympathetic reflexes that are expressed as vestibular modulation of MSNA as well as of SSNA. The smaller vestibular modulation of MSNA can be explained by the dominant modulation of MSNA by the arterial baroreceptors. PMID:23852323

  9. How Orthography Modulates Morphological Priming: Subliminal Kanji Activation in Japanese

    PubMed Central

    Nakano, Yoko; Ikemoto, Yu; Jacob, Gunnar; Clahsen, Harald

    2016-01-01

    The current study investigates to what extent masked morphological priming is modulated by language-particular properties, specifically by its writing system. We present results from two masked priming experiments investigating the processing of complex Japanese words written in less common (moraic) scripts. In Experiment 1, participants performed lexical decisions on target verbs; these were preceded by primes which were either (i) a past-tense form of the same verb, (ii) a stem-related form with the epenthetic vowel -i, (iii) a semantically-related form, and (iv) a phonologically-related form. Significant priming effects were obtained for prime types (i), (ii), and (iii), but not for (iv). This pattern of results differs from previous findings on languages with alphabetic scripts, which found reliable masked priming effects for morphologically related prime/target pairs of type (i), but not for non-affixal and semantically-related primes of types (ii), and (iii). In Experiment 2, we measured priming effects for prime/target pairs which are neither morphologically, semantically, phonologically nor - as presented in their moraic scripts—orthographically related, but which—in their commonly written form—share the same kanji, which are logograms adopted from Chinese. The results showed a significant priming effect, with faster lexical-decision times for kanji-related prime/target pairs relative to unrelated ones. We conclude that affix-stripping is insufficient to account for masked morphological priming effects across languages, but that language-particular properties (in the case of Japanese, the writing system) affect the processing of (morphologically) complex words. PMID:27065895

  10. How Orthography Modulates Morphological Priming: Subliminal Kanji Activation in Japanese.

    PubMed

    Nakano, Yoko; Ikemoto, Yu; Jacob, Gunnar; Clahsen, Harald

    2016-01-01

    The current study investigates to what extent masked morphological priming is modulated by language-particular properties, specifically by its writing system. We present results from two masked priming experiments investigating the processing of complex Japanese words written in less common (moraic) scripts. In Experiment 1, participants performed lexical decisions on target verbs; these were preceded by primes which were either (i) a past-tense form of the same verb, (ii) a stem-related form with the epenthetic vowel -i, (iii) a semantically-related form, and (iv) a phonologically-related form. Significant priming effects were obtained for prime types (i), (ii), and (iii), but not for (iv). This pattern of results differs from previous findings on languages with alphabetic scripts, which found reliable masked priming effects for morphologically related prime/target pairs of type (i), but not for non-affixal and semantically-related primes of types (ii), and (iii). In Experiment 2, we measured priming effects for prime/target pairs which are neither morphologically, semantically, phonologically nor - as presented in their moraic scripts-orthographically related, but which-in their commonly written form-share the same kanji, which are logograms adopted from Chinese. The results showed a significant priming effect, with faster lexical-decision times for kanji-related prime/target pairs relative to unrelated ones. We conclude that affix-stripping is insufficient to account for masked morphological priming effects across languages, but that language-particular properties (in the case of Japanese, the writing system) affect the processing of (morphologically) complex words. PMID:27065895

  11. Calcium Modulation of Plant Plasma Membrane-Bound Atpase Activities

    NASA Technical Reports Server (NTRS)

    Caldwell, C.

    1983-01-01

    The kinetic properties of barley enzyme are discussed and compared with those of other plants. Possibilities for calcium transport in the plasma membrane by proton pump and ATPase-dependent calcium pumps are explored. Topics covered include the ph phase of the enzyme; high affinity of barley for calcium; temperature dependence, activation enthalpy, and the types of ATPase catalytic sites. Attention is given to lipids which are both screened and bound by calcium. Studies show that barley has a calmodulin activated ATPase that is found in the presence of magnesium and calcium.

  12. FEF-microstimulation causes task-dependent modulation of occipital fMRI activity.

    PubMed

    Premereur, Elsie; Janssen, Peter; Vanduffel, Wim

    2013-02-15

    Electrical microstimulation of FEF (FEF-EM) modulates neuronal activity in area V4 (Moore and Armstrong, 2003) and elicits functional magnetic resonance imaging (fMRI) activations in visual cortex in a bottom-up dependent manner (Ekstrom et al., 2008). Here we test the hypothesis that FEF-EM-induced modulations of fMRI activity are also function of task demands, which would suggest top-down dependent gating of FEF signals in early visual cortex. We scanned two monkeys performing a visually guided saccade task; a passive fixation task with a very similar visual display; and a passive fixation task without peripheral dots. We found increased effects of FEF-EM on fMRI-activity in visual cortex during saccades compared to fixation, indicating that the FEF-EM induced modulation is task-dependent. Finally, the effect of FEF-EM is mainly present in voxels which were less activated by visual stimuli in the absence of electrical stimulation. Our results show that the FEF-EM-induced pattern of activation in early visual cortex is topographically specific and more pronounced during increased task demands. These results fit with models suggesting that FEF is an important source modulating activity in early sensory cortex and that these influences can be enhanced by coincident bottom-up or top-down signals. PMID:23186918

  13. Hsp90 Activity Modulation by Plant Secondary Metabolites.

    PubMed

    Dal Piaz, Fabrizio; Terracciano, Stefania; De Tommasi, Nunziatina; Braca, Alessandra

    2015-09-01

    Hsp90 is an evolutionarily conserved adenosine triphosphate-dependent molecular chaperone and is one of the most abundant proteins in the cells (1-3 %). Hsp90 is induced when a cell undergoes various types of environmental stresses such as heat, cold, or oxygen deprivation. It is involved in the turnover, trafficking, and activity of client proteins, including apoptotic factors, protein kinases, transcription factors, signaling proteins, and a number of oncoproteins. Most of the Hsp90 client proteins are involved in cell growth, differentiation, and survival, and include kinases, nuclear hormone receptors, transcription factors, and other proteins associated with almost all the hallmarks of cancer. Consistent with these diverse activities, genetic and biochemical studies have demonstrated the implication of Hsp90 in a range of diseases, including cancer, making this chaperone an interesting target for drug research.During the last few decades, plant secondary metabolites have been studied as a major source for lead compounds in drug discovery. Recently, several plant-derived small molecules have been discovered exhibiting inhibitory activity towards Hsp90, such as epigallocatechin gallate, gedunin, lentiginosine, celastrol, and deguelin. In this work, an overview of plant secondary metabolites interfering with Hsp90 activities is provided. PMID:26227505

  14. Social status modulates neural activity in the mentalizing network

    PubMed Central

    Muscatell, Keely A.; Morelli, Sylvia A.; Falk, Emily B.; Way, Baldwin M.; Pfeifer, Jennifer H.; Galinsky, Adam D.; Lieberman, Matthew D.; Dapretto, Mirella; Eisenberger, Naomi I.

    2013-01-01

    The current research explored the neural mechanisms linking social status to perceptions of the social world. Two fMRI studies provide converging evidence that individuals lower in social status are more likely to engage neural circuitry often involved in ‘mentalizing’ or thinking about others' thoughts and feelings. Study 1 found that college students' perception of their social status in the university community was related to neural activity in the mentalizing network (e.g., DMPFC, MPFC, precuneus/PCC) while encoding social information, with lower social status predicting greater neural activity in this network. Study 2 demonstrated that socioeconomic status, an objective indicator of global standing, predicted adolescents' neural activity during the processing of threatening faces, with individuals lower in social status displaying greater activity in the DMPFC, previously associated with mentalizing, and the amygdala, previously associated with emotion/salience processing. These studies demonstrate that social status is fundamentally and neurocognitively linked to how people process and navigate their social worlds. PMID:22289808

  15. Antihelminthic niclosamide modulates dendritic cells activation and function.

    PubMed

    Wu, Chieh-Shan; Li, Yi-Rong; Chen, Jeremy J W; Chen, Ying-Che; Chu, Chiang-Liang; Pan, I-Hong; Wu, Yu-Shan; Lin, Chi-Chen

    2014-01-01

    Dendritic cells (DCs) link the sensing of the environment by the innate immune system to the initiation of adaptive immune responses. Accordingly, DCs are considered to be a major target in the development of immunomodulating compounds. In this study, the effect of niclosamide, a Food and Drug Administration-approved antihelminthic drug, on the activation of lipopolysaccharide (LPS)-stimulated murine bone marrow-derived DCs was examined. Our experimental results show that niclosamide reduced the pro-inflammatory cytokine and chemokine expression of LPS-activated DCs. In addition, niclosamide also affected the expression of MHC and costimulatory molecules and influenced the ability of the cells to take up antigens. Therefore, in mixed cell cultures composed of syngeneic OVA-specific T cells and DCs, niclosamide-treated DCs showed a decreased ability to stimulate T cell proliferation and IFN-γ production. Furthermore, intravenous injection of niclosamide also attenuated contact hypersensitivity (CHS) in mice during sensitization with 2,4-dinitro-1-fluorobenzene. Blocking the LPS-induced activation of MAPK-ERK, JNK and NF-κB may contribute to the inhibitory effect of niclosamide on DC activation. Collectively, our findings suggest that niclosamide can manipulate the function of DCs. These results provide new insight into the immunopharmacological role of niclosamide and suggest that it may be useful for the treatment of chronic inflammatory disorders or DC-mediated autoimmune diseases. PMID:24561310

  16. Modulation of Erythrocyte Plasma Membrane Redox System Activity by Curcumin

    PubMed Central

    Singh, Prabhakar; Kesharwani, Rajesh Kumar; Misra, Krishna; Rizvi, Syed Ibrahim

    2016-01-01

    Plasma membrane redox system (PMRS) is an electron transport chain system ubiquitously present throughout all cell types. It transfers electron from intracellular substrates to extracellular acceptors for regulation of redox status. Curcumin, isolated from Curcuma longa, has modulatory effects on cellular physiology due to its membrane interaction ability and antioxidant potential. The present study investigates the effect of curcumin on PMRS activity of erythrocytes isolated from Wistar rats in vitro and in vivo and validated through an in silico docking simulation study using Molegro Virtual Docker (MVD). Effects of curcumin were also evaluated on level of glutathione (GSH) and the oxidant potential of plasma measured in terms of plasma ferric equivalent oxidative potentials (PFEOP). Results show that curcumin significantly (p < 0.01) downregulated the PMRS activity in a dose-dependent manner. Molecular docking results suggest that curcumin interacts with amino acids at the active site cavity of cytochrome b5 reductase, a key constituent of PMRS. Curcumin also increased the GSH level in erythrocytes and plasma while simultaneously decreasing the oxidant potential (PFEOP) of plasma. Altered PMRS activity and redox status are associated with the pathophysiology of several health complications including aging and diabetes; hence, the above finding may explain part of the role of curcumin in health beneficial effects. PMID:26904287

  17. ModuleBlast: identifying activated sub-networks within and across species

    PubMed Central

    Zinman, Guy E.; Naiman, Shoshana; O'Dee, Dawn M.; Kumar, Nishant; Nau, Gerard J.; Cohen, Haim Y.; Bar-Joseph, Ziv

    2015-01-01

    Identifying conserved and divergent response patterns in gene networks is becoming increasingly important. A common approach is integrating expression information with gene association networks in order to find groups of connected genes that are activated or repressed. In many cases, researchers are also interested in comparisons across species (or conditions). Finding an active sub-network is a hard problem and applying it across species requires further considerations (e.g. orthology information, expression data and networks from different sources). To address these challenges we devised ModuleBlast, which uses both expression and network topology to search for highly relevant sub-networks. We have applied ModuleBlast to expression and interaction data from mouse, macaque and human to study immune response and aging. The immune response analysis identified several relevant modules, consistent with recent findings on apoptosis and NFκB activation following infection. Temporal analysis of these data revealed cascades of modules that are dynamically activated within and across species. We have experimentally validated some of the novel hypotheses resulting from the analysis of the ModuleBlast results leading to new insights into the mechanisms used by a key mammalian aging protein. PMID:25428368

  18. ModuleBlast: identifying activated sub-networks within and across species.

    PubMed

    Zinman, Guy E; Naiman, Shoshana; O'Dee, Dawn M; Kumar, Nishant; Nau, Gerard J; Cohen, Haim Y; Bar-Joseph, Ziv

    2015-02-18

    Identifying conserved and divergent response patterns in gene networks is becoming increasingly important. A common approach is integrating expression information with gene association networks in order to find groups of connected genes that are activated or repressed. In many cases, researchers are also interested in comparisons across species (or conditions). Finding an active sub-network is a hard problem and applying it across species requires further considerations (e.g. orthology information, expression data and networks from different sources). To address these challenges we devised ModuleBlast, which uses both expression and network topology to search for highly relevant sub-networks. We have applied ModuleBlast to expression and interaction data from mouse, macaque and human to study immune response and aging. The immune response analysis identified several relevant modules, consistent with recent findings on apoptosis and NFκB activation following infection. Temporal analysis of these data revealed cascades of modules that are dynamically activated within and across species. We have experimentally validated some of the novel hypotheses resulting from the analysis of the ModuleBlast results leading to new insights into the mechanisms used by a key mammalian aging protein. PMID:25428368

  19. Left brain cortical activity modulates stress effects on social behavior.

    PubMed

    Lee, Eunee; Hong, Jiso; Park, Young-Gyun; Chae, Sujin; Kim, Yong; Kim, Daesoo

    2015-01-01

    When subjected to stress, some individuals develop maladaptive symptoms whereas others retain normal behavior. The medial prefrontal cortex (mPFC) is known to control these adaptive responses to stress. Here, we show that mPFC neurons in the left hemisphere control stress effects on social behavior. Mice made socially avoidant by the stress of chronic social defeats showed depressed neural activity in the left mPFC. Photoactivation of these neurons reversed social avoidance and restored social activity. Despite social defeats, resilient mice with normal sociability showed normal firing rates in the left mPFC; however, photoinhibition of these neurons induced social avoidance. The same photomodulation administered to the right mPFC caused no significant effects. These results explain how stressed individuals develop maladaptive behaviors through left cortical depression, as reported in mood and anxiety disorders. PMID:26302668

  20. Modulation of phospholipase A2 activity in human fibroblasts.

    PubMed Central

    Solito, E.; Parente, L.

    1989-01-01

    1. Human embryonic skin fibroblasts (HSF) incubated overnight with either human recombinant interleukin-1 alpha (rIL-1 alpha) or interleukin-1 beta (rIL-1 beta) released large amounts of prostaglandin E2 (PGE2). 2. rIL-1 beta, bradykinin (Bk) and arachidonic acid (AA) significantly stimulated PGE2 release from HSF incubated overnight in the presence of either interleukin. 3. Hydrocortisone inhibited the PGE2 release induced by rIL-1 beta and Bk, but not by AA. 4. The steroid inhibitory effect was reversed by actinomycin D as well as by an anti-lipocortin monoclonal antibody. 5. The results suggest that in HSF, rIL-1 beta is able to stimulate both cyclo-oxygenase and phospholipase A2 (PLA2) activity. 6. The stimulation of PLA2 activity by rIL-1 beta is inhibited by hydrocortisone, probably via induction of lipocortin-like proteins. PMID:2785834

  1. Language modulates brain activity underlying representation of kinship terms

    PubMed Central

    Wu, Haiyan; Ge, Yue; Tang, Honghong; Luo, Yue-Jia; Mai, Xiaoqin; Liu, Chao

    2015-01-01

    Kinship terms have been found to be highly diverse across languages. Here we investigated the brain representation of kinship terms in two distinct populations, native Chinese and Caucasian English speakers, with a five-element kinship identification (FEKI) task. The neuroimaging results showed a common extensive frontal and parietal lobe brain activation pattern for different kinship levels for both Chinese and Caucasian English speakers. Furthermore, Chinese speakers had longer reaction times and elicited more fronto-parietal brain networks activation compared to English speakers in level three (e.g., uncle and nephew) and four (e.g., cousin), including an association between the middle frontal gyrus and superior parietal lobe, which might be associated with higher working memory, attention control, and social distance representation load in Chinese kinship system processing. These results contribute to our understanding of the representation of kinship terms in the two languages. PMID:26685907

  2. Left brain cortical activity modulates stress effects on social behavior

    PubMed Central

    Lee, Eunee; Hong, Jiso; Park, Young-Gyun; Chae, Sujin; Kim, Yong; Kim, Daesoo

    2015-01-01

    When subjected to stress, some individuals develop maladaptive symptoms whereas others retain normal behavior. The medial prefrontal cortex (mPFC) is known to control these adaptive responses to stress. Here, we show that mPFC neurons in the left hemisphere control stress effects on social behavior. Mice made socially avoidant by the stress of chronic social defeats showed depressed neural activity in the left mPFC. Photoactivation of these neurons reversed social avoidance and restored social activity. Despite social defeats, resilient mice with normal sociability showed normal firing rates in the left mPFC; however, photoinhibition of these neurons induced social avoidance. The same photomodulation administered to the right mPFC caused no significant effects. These results explain how stressed individuals develop maladaptive behaviors through left cortical depression, as reported in mood and anxiety disorders. PMID:26302668

  3. MDMA (ecstasy) modulates locomotor and prefrontal cortex sensory evoked activity.

    PubMed

    Atkins, Kristal; Burks, Tilithia; Swann, Alan C; Dafny, Nachum

    2009-12-11

    Ingestion of 3, 4-methylenedioxymethamphetamine (MDMA) leads to heightened response to sensory stimulation; thus, MDMA is referred to as "ecstasy" because it produces pleasurable enhancement of such sensation. There have been no electrophysiological studies that report the consequences of MDMA on sensory input. The present study was initiated to study the effects of acute and chronic MDMA on locomotor activity and sensory evoked field potential from freely behaving rats previously implanted with permanent electrodes in the prefrontal cortex (PFC). The main findings of this study are that: (1) acute MDMA augments locomotor behavior and attenuates the incoming sensory input, (2) chronic treatment of MDMA elicits behavioral sensitization, (3) chronic administration of MDMA results in attenuation of the baseline activity of the sensory evoked field potential, and (4) administration of rechallenge MDMA result in enhancement of the PFC sensory evoked field potential. PMID:19769950

  4. Crystallinity Modulation of Layered Carbon Nitride for Enhanced Photocatalytic Activities.

    PubMed

    Wang, Jianhai; Shen, Yanfei; Li, Ying; Liu, Songqin; Zhang, Yuanjian

    2016-08-22

    As an emerging metal-free semiconductor, covalently bonded carbon nitride (CN) has attracted much attention in photocatalysis. However, drawbacks such as a high recombination rate of excited electrons and holes hinder its potential applications. Tailoring the crystallinity of semiconductors is an important way to suppress unwanted charge recombination, but has rarely been applied to CN so far. Herein, a simple method to synthesize CN of high crystallinity by protonation of specific intermediate species during conventional polymerization is reported. Interestingly, the as-obtained CN exhibited improved photocatalytic activities of up to seven times those of the conventional bulk CN. This approach, with only a slight change to the conventional method, provides a facile way to effectively regulate the crystallinity of bulk CN to improve its photocatalytic activities and sheds light on large-scale industrial applications of CN with high efficiency for sustainable energy. PMID:27436164

  5. Acetylcholinesterase modulates presenilin-1 levels and γ-secretase activity.

    PubMed

    Campanari, Maria-Letizia; García-Ayllón, María-Salud; Belbin, Olivia; Galcerán, Joan; Lleó, Alberto; Sáez-Valero, Javier

    2014-01-01

    The cholinergic enzyme acetylcholinesterase (AChE) and the catalytic component of the γ-secretase complex, presenilin-1 (PS1), are known to interact. In this study, we investigate the consequences of AChE-PS1 interactions, particularly the influence of AChE in PS1 levels and γ-secretase activity. PS1 is able to co-immunoprecipitate all AChE variants (AChE-R and AChE-T) and molecular forms (tetramers and light subunits) present in the human brain. Overexpression of AChE-R or AChE-T, or their respective inactive mutants, all trigger an increase in PS1 protein levels. The AChE species capable of triggering the biggest increase in PS1 levels is a complex of AChE with the membrane anchoring subunit proline-rich membrane anchor (PRiMA), which restricts the localization of the resulting AChE tetramer to the outer plasma membrane. Incubation of cultured cells with soluble AChE demonstrates that AChE is able to increase PS1 at both the protein and transcript levels. However, the increase of PS1 caused by soluble AChE is accompanied by a decrease in γ-secretase activity as shown by the reduction of the processing of the amyloid-β protein precursor. This inhibitory effect of AChE on γ-secretase activity was also demonstrated by directly assessing accumulation of CTF-AβPP in cell-free membrane preparations incubated with AChE. Our data suggest that AChE may function as an inhibitor of γ-secretase activity. PMID:24699279

  6. An Essential Viral Transcription Activator Modulates Chromatin Dynamics

    PubMed Central

    Gibeault, Rebecca L.; Bildersheim, Michael D.

    2016-01-01

    Although ICP4 is the only essential transcription activator of herpes simplex virus 1 (HSV-1), its mechanisms of action are still only partially understood. We and others propose a model in which HSV-1 genomes are chromatinized as a cellular defense to inhibit HSV-1 transcription. To counteract silencing, HSV-1 would have evolved proteins that prevent or destabilize chromatinization to activate transcription. These proteins should act as HSV-1 transcription activators. We have shown that HSV-1 genomes are organized in highly dynamic nucleosomes and that histone dynamics increase in cells infected with wild type HSV-1. We now show that whereas HSV-1 mutants encoding no functional ICP0 or VP16 partially enhanced histone dynamics, mutants encoding no functional ICP4 did so only minimally. Transient expression of ICP4 was sufficient to enhance histone dynamics in the absence of other HSV-1 proteins or HSV-1 DNA. The dynamics of H3.1 were increased in cells expressing ICP4 to a greater extent than those of H3.3. The dynamics of H2B were increased in cells expressing ICP4, whereas those of canonical H2A were not. ICP4 preferentially targets silencing H3.1 and may also target the silencing H2A variants. In infected cells, histone dynamics were increased in the viral replication compartments, where ICP4 localizes. These results suggest a mechanism whereby ICP4 activates transcription by disrupting, or preventing the formation of, stable silencing nucleosomes on HSV-1 genomes. PMID:27575707

  7. Detection and characterisation of delamination in PV modules by active infrared thermography

    NASA Astrophysics Data System (ADS)

    Sinha, A.; Sastry, O. S.; Gupta, R.

    2016-01-01

    The paper presents a fast and efficient method for the detection and characterisation of delamination in photovoltaic (PV) modules by using active infrared thermography approach. A discrete part of PV module was irradiated by step heating and its thermal image sequence was used to detect and analyse delamination. Different types of heating source for thermal excitation for this application have been studied. An electro-thermal model was developed to simulate the active thermography approach for the characterisation of delamination in PV module by equivalent resistance-capacitance (RC) network using a circuit simulator. This simulation approach was used to estimate the extent of delamination in the module and to determine the optimum parameters for the characterisation of delamination. Different applications based on front and backsides of heating the module were also proposed in this paper. The proposed method has the potential to be employed for the quality check of PV modules during inline production as well as for the predictive maintenance of outdoor PV plants.

  8. Allatotropin Modulates Myostimulatory and Cardioacceleratory Activities in Rhodnius prolixus (Stal).

    PubMed Central

    Villalobos-Sambucaro, María José; Lorenzo-Figueiras, Alicia Nieves; Riccillo, Fernando Luis; Diambra, Luis Anibal; Noriega, Fernando Gabriel; Ronderos, Jorge Rafael

    2015-01-01

    Haematophagous insects can ingest large quantities of blood in a single meal and eliminate high volumes of urine in the next few hours. This rise in diuresis is possible because the excretory activity of the Malpighian tubules is facilitated by an increase in haemolymph circulation as a result of intensification of aorta contractions combined with an increase of the anterior midgut peristaltic waves. It has been previously described that haemolymph circulation during post-prandial diuresis is stimulated by the synergistic activity of allatotropin (AT) and serotonin in the kissing bug Triatoma infestans; resulting in an increase in aorta contractions. In the same species, AT stimulates anterior midgut and rectum muscle contractions to mix urine and feces and facilitate the voiding of the rectum. Furthermore, levels of AT in midgut and Malpighian tubules increased in the afternoon when insects are getting ready for nocturnal feeding. In the present study we describe the synergistic effect of AT and serotonin increasing the frequency of contractions of the aorta in Rhodnius prolixus. The basal frequency of contractions of the aorta in the afternoon is higher that the observed during the morning, suggesting the existence of a daily rhythmic activity. The AT receptor is expressed in the rectum, midgut and dorsal vessel, three critical organs involved in post-prandial diuresis. All together these findings provide evidence that AT plays a role as a myoregulatory and cardioacceleratory peptide in R. prolixus. PMID:25897783

  9. PPARγ Activation Attenuates Opioid Consumption and Modulates Mesolimbic Dopamine Transmission

    PubMed Central

    de Guglielmo, Giordano; Melis, Miriam; De Luca, Maria Antonietta; Kallupi, Marsida; Li, Hong Wu; Niswender, Kevin; Giordano, Antonio; Senzacqua, Martina; Somaini, Lorenzo; Cippitelli, Andrea; Gaitanaris, George; Demopulos, Gregory; Damadzic, Ruslan; Tapocik, Jenica; Heilig, Markus; Ciccocioppo, Roberto

    2015-01-01

    PPARγ is one of the three isoforms identified for the peroxisome proliferator-activated receptors (PPARs) and is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. PPARγ has been long studied for its role in adipogenesis and glucose metabolism, but the discovery of the localization in ventral tegmental area (VTA) neurons opens new vistas for a potential role in the regulation of reward processing and motivated behavior in drug addiction. Here, we demonstrate that activation of PPARγ by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. These effects are associated with a marked reduction of heroin-induced increase in phosphorylation of DARPP-32 protein in the nucleus accumbens (NAc) and with a marked and selective reduction of acute heroin-induced elevation of extracellular dopamine (DA) levels in the NAc shell, as measured by in vivo microdialysis. Through ex vivo electrophysiology in acute midbrain slices, we also show that stimulation of PPARγ attenuates opioid-induced excitation of VTA DA neurons via reduction of presynaptic GABA release from the rostromedial tegmental nucleus (RMTg). Consistent with this finding, site-specific microinjection of pioglitazone into the RMTg but not into the VTA reduced heroin taking. Our data illustrate that activation of PPARγ may represent a new pharmacotherapeutic option for the treatment of opioid addiction. PMID:25311134

  10. Lipid metabolizing enzyme activities modulated by phospholipid substrate lateral distribution.

    PubMed

    Salinas, Dino G; Reyes, Juan G; De la Fuente, Milton

    2011-09-01

    Biological membranes contain many domains enriched in phospholipid lipids and there is not yet clear explanation about how these domains can control the activity of phospholipid metabolizing enzymes. Here we used the surface dilution kinetic theory to derive general equations describing how complex substrate distributions affect the activity of enzymes following either the phospholipid binding kinetic model (which assumes that the enzyme molecules directly bind the phospholipid substrate molecules), or the surface-binding kinetic model (which assumes that the enzyme molecules bind to the membrane before binding the phospholipid substrate). Our results strongly suggest that, if the enzyme follows the phospholipid binding kinetic model, any substrate redistribution would increase the enzyme activity over than observed for a homogeneous distribution of substrate. Besides, enzymes following the surface-binding model would be independent of the substrate distribution. Given that the distribution of substrate in a population of micelles (each of them a lipid domain) should follow a Poisson law, we demonstrate that the general equations give an excellent fit to experimental data of lipases acting on micelles, providing reasonable values for kinetic parameters--without invoking special effects such as cooperative phenomena. Our theory will allow a better understanding of the cellular-metabolism control in membranes, as well as a more simple analysis of the mechanisms of membrane acting enzymes. PMID:21108012

  11. Implicitly perceived vocal attractiveness modulates prefrontal cortex activity.

    PubMed

    Bestelmeyer, Patricia E G; Latinus, Marianne; Bruckert, Laetitia; Rouger, Julien; Crabbe, Frances; Belin, Pascal

    2012-06-01

    Social interactions involve more than "just" language. As important is a more primitive nonlinguistic mode of communication acting in parallel with linguistic processes and driving our decisions to a much higher degree than is generally suspected. Amongst the "honest signals" that influence our behavior is perceived vocal attractiveness. Not only does vocal attractiveness reflect important biological characteristics of the speaker, it also influences our social perceptions according to the "what sounds beautiful is good" phenomenon. Despite the widespread influence of vocal attractiveness on social interactions revealed by behavioral studies, its neural underpinnings are yet unknown. We measured brain activity while participants listened to a series of vocal sounds ("ah") and performed an unrelated task. We found that voice-sensitive auditory and inferior frontal regions were strongly correlated with implicitly perceived vocal attractiveness. While the involvement of auditory areas reflected the processing of acoustic contributors to vocal attractiveness ("distance to mean" and spectrotemporal regularity), activity in inferior prefrontal regions (traditionally involved in speech processes) reflected the overall perceived attractiveness of the voices despite their lack of linguistic content. These results suggest the strong influence of hidden nonlinguistic aspects of communication signals on cerebral activity and provide an objective measure of this influence. PMID:21828348

  12. Allatotropin modulates myostimulatory and cardioacceleratory activities in Rhodnius prolixus (Stal).

    PubMed

    Villalobos-Sambucaro, María José; Lorenzo-Figueiras, Alicia Nieves; Riccillo, Fernando Luis; Diambra, Luis Anibal; Noriega, Fernando Gabriel; Ronderos, Jorge Rafael

    2015-01-01

    Haematophagous insects can ingest large quantities of blood in a single meal and eliminate high volumes of urine in the next few hours. This rise in diuresis is possible because the excretory activity of the Malpighian tubules is facilitated by an increase in haemolymph circulation as a result of intensification of aorta contractions combined with an increase of the anterior midgut peristaltic waves. It has been previously described that haemolymph circulation during post-prandial diuresis is stimulated by the synergistic activity of allatotropin (AT) and serotonin in the kissing bug Triatoma infestans; resulting in an increase in aorta contractions. In the same species, AT stimulates anterior midgut and rectum muscle contractions to mix urine and feces and facilitate the voiding of the rectum. Furthermore, levels of AT in midgut and Malpighian tubules increased in the afternoon when insects are getting ready for nocturnal feeding. In the present study we describe the synergistic effect of AT and serotonin increasing the frequency of contractions of the aorta in Rhodnius prolixus. The basal frequency of contractions of the aorta in the afternoon is higher that the observed during the morning, suggesting the existence of a daily rhythmic activity. The AT receptor is expressed in the rectum, midgut and dorsal vessel, three critical organs involved in post-prandial diuresis. All together these findings provide evidence that AT plays a role as a myoregulatory and cardioacceleratory peptide in R. prolixus. PMID:25897783

  13. Dopamine Transporter Activity Is Modulated by α-Synuclein.

    PubMed

    Butler, Brittany; Saha, Kaustuv; Rana, Tanu; Becker, Jonas P; Sambo, Danielle; Davari, Paran; Goodwin, J Shawn; Khoshbouei, Habibeh

    2015-12-01

    The duration and strength of the dopaminergic signal are regulated by the dopamine transporter (DAT). Drug addiction and neurodegenerative and neuropsychiatric diseases have all been associated with altered DAT activity. The membrane localization and the activity of DAT are regulated by a number of intracellular proteins. α-Synuclein, a protein partner of DAT, is implicated in neurodegenerative disease and drug addiction. Little is known about the regulatory mechanisms of the interaction between DAT and α-synuclein, the cellular location of this interaction, and the functional consequences of this interaction on the basal, amphetamine-induced DAT-mediated dopamine efflux, and membrane microdomain distribution of the transporter. Here, we found that the majority of DAT·α-synuclein protein complexes are found at the plasma membrane of dopaminergic neurons or mammalian cells and that the amphetamine-mediated increase in DAT activity enhances the association of these proteins at the plasma membrane. Further examination of the interaction of DAT and α-synuclein revealed a transient interaction between these two proteins at the plasma membrane. Additionally, we found DAT-induced membrane depolarization enhances plasma membrane localization of α-synuclein, which in turn increases dopamine efflux and enhances DAT localization in cholesterol-rich membrane microdomains. PMID:26442590

  14. Turbulent electromagnetic filaments in actively modulated toroidal plasma edge

    NASA Astrophysics Data System (ADS)

    Spolaore, M.; Agostini, M.; Momo, B.; Rea, C.; Vianello, N.; Zuin, M.; Cavazzana, R.; De Masi, G.; Innocente, P.; Marrelli, L.; Martines, E.; Mazzi, A.; Puiatti, M. E.; Spagnolo, S.; Spizzo, G.; Scarin, P.; Terranova, D.; Zanca, P.

    2015-06-01

    Filament or blob structures have been observed in all magnetic configurations with very similar features despite the difference in the magnetic geometry, and are believed to play an important role in convecting particles and energy towards the wall. Despite their different generation mechanism, turbulent structures and edge-localized mode (ELM) filaments share some common physical features. The electromagnetic effects on filament structures deserve particular interest, among others reasons for the implication they could have for ELM, related for instance to their dynamics in the transition region between closed and open field lines or to the possibility, at high beta regimes, of causing line bending which could enhance the interaction of blobs with the first wall. A direct characterization of the effects of active modification of the edge topology on EM turbulent filament structures is presented, comparing reversed field pinch and tokamak configurations. Measurements are obtained in the RFX-mod device, which allows operation in both configurations and with different equilibria. The RFX-mod experiment versatility is exploited also from the point of view of the active control of the edge magnetic topology, equipped with an advanced system for edge boundary feedback control. Three different case studies of actively controlled magnetic perturbations are shown, focusing on the filament interaction with local magnetic islands. High-frequency fluctuations, characterizing electrostatic and magnetic filament features, and the associated transport coefficients have been observed to be strongly affected by the island proximity and topology.

  15. Modulation of bone remodeling via mechanically activated ion channels

    NASA Technical Reports Server (NTRS)

    Duncan, Randall L. (Principal Investigator)

    1996-01-01

    A critical factor in the maintenance of bone mass is the physical forces imposed upon the skeleton. Removal of these forces, such as in a weightless environment, results in a rapid loss of bone, whereas application of exogenous mechanical strain has been shown to increase bone formation. Numerous flight and ground-based experiments indicate that the osteoblast is the key bone cell influenced by mechanical stimulation. Aside from early transient fluctuations in response to unloading, osteoclast number and activity seem unaffected by removal of strain. However, bone formation is drastically reduced in weightlessness and osteoblasts respond to mechanical strain with an increase in the activity of a number of second messenger pathways resulting in increased anabolic activity. Unfortunately, the mechanism by which the osteoblast converts physical stimuli into a biochemical message, a process we have termed biochemical coupling, remains elusive. Prior to the application of this grant, we had characterized a mechanosensitive, cation nonselective channel (SA-cat) in osteoblast-like osteosarcoma cells that we proposed is the initial signalling mechanism for mechanotransduction. During the execution of this grant, we have made considerable progress to further characterize this channel as well as to determine its role in the osteoblastic response to mechanical strain. To achieve these goals, we combined electrophysiologic techniques with cellular and molecular biology methods to examine the role of these channels in the normal function of the osteoblast in vitro.

  16. Multifractal detrended fluctuation analysis of optogenetic modulation of neural activity

    NASA Astrophysics Data System (ADS)

    Kumar, S.; Gu, L.; Ghosh, N.; Mohanty, S. K.

    2013-02-01

    Here, we introduce a computational procedure to examine whether optogenetically activated neuronal firing recordings could be characterized as multifractal series. Optogenetics is emerging as a valuable experimental tool and a promising approach for studying a variety of neurological disorders in animal models. The spiking patterns from cortical region of the brain of optogenetically-stimulated transgenic mice were analyzed using a sophisticated fluctuation analysis method known as multifractal detrended fluctuation analysis (MFDFA). We observed that the optogenetically-stimulated neural firings are consistent with a multifractal process. Further, we used MFDFA to monitor the effect of chemically induced pain (formalin injection) and optogenetic treatment used to relieve the pain. In this case, dramatic changes in parameters characterizing a multifractal series were observed. Both the generalized Hurst exponent and width of singularity spectrum effectively differentiates the neural activities during control and pain induction phases. The quantitative nature of the analysis equips us with better measures to quantify pain. Further, it provided a measure for effectiveness of the optogenetic stimulation in inhibiting pain. MFDFA-analysis of spiking data from other deep regions of the brain also turned out to be multifractal in nature, with subtle differences in the parameters during pain-induction by formalin injection and inhibition by optogenetic stimulation. Characterization of neuronal firing patterns using MFDFA will lead to better understanding of neuronal response to optogenetic activation and overall circuitry involved in the process.

  17. Modulating Photoluminescence of Monolayer Molybdenum Disulfide by Metal-Insulator Phase Transition in Active Substrates.

    PubMed

    Hou, Jiwei; Wang, Xi; Fu, Deyi; Ko, Changhyun; Chen, Yabin; Sun, Yufei; Lee, Sangwook; Wang, Kevin X; Dong, Kaichen; Sun, Yinghui; Tongay, Sefaattin; Jiao, Liying; Yao, Jie; Liu, Kai; Wu, Junqiao

    2016-08-01

    The atomic thickness and flatness allow properties of 2D semiconductors to be modulated with influence from the substrate. Reversible modulation of these properties requires an "active," reconfigurable substrate, i.e., a substrate with switchable functionalities that interacts strongly with the 2D overlayer. In this work, the photoluminescence (PL) of monolayer molybdenum disulfide (MoS2 ) is modulated by interfacing it with a phase transition material, vanadium dioxide (VO2 ). The MoS2 PL intensity is enhanced by a factor of up to three when the underlying VO2 undergoes the thermally driven phase transition from the insulating to metallic phase. A nonvolatile, reversible way to rewrite the PL pattern is also demonstrated. The enhancement effect is attributed to constructive optical interference when the VO2 turns metallic. This modulation method requires no chemical or mechanical processes, potentially finding applications in new switches and sensors. PMID:27335137

  18. Respiratory modulation of sympathetic nerve activity is enhanced in male rat offspring following uteroplacental insufficiency.

    PubMed

    Menuet, C; Wlodek, M E; Fong, A Y; Allen, A M

    2016-06-01

    Sympathetic nerve activity to the cardiovascular system displays prominent respiratory-related modulation which leads to the generation of rhythmic oscillations in blood pressure called Traube-Hering waves. An amplification of this respiratory modulation of sympathetic activity is observed in hypertension of both genetic, the spontaneously hypertensive rat, and induced, chronic intermittent hypoxia or maternal protein restriction during gestation, origin. Male offspring of mothers with uteroplacental insufficiency, induced by bilateral uterine vessel ligation at 18 days of gestation, are also hypertensive in adulthood. In this study we examined whether these male offspring display altered respiratory modulation of sympathetic activity at pre-hypertensive ages compared to controls. Respiratory, cardiovascular and sympathetic parameters were examined using the working heart-brainstem preparation in 35 day old male rats that had reduced birth weight due to uteroplacental insufficiency. Whilst all respiratory parameters were not different between groups, we observed an enhanced respiratory-related burst of thoracic sympathetic nerve activity and amplified Traube-Hering waves in the growth-restricted group. This group also showed an increased sympathetic and bradycardic response to activation of peripheral chemoreceptors. The observations add support to the view that altered respiratory modulation of sympathetic activity represents a common mechanism involved in the development of several forms of hypertension. PMID:26593642

  19. Activation of the Endoperoxide Ascaridole Modulates Its Sensitizing Capacity.

    PubMed

    Krutz, Nora L; Hennen, Jennifer; Korb, Corinna; Schellenberger, Mario T; Gerberick, G Frank; Blömeke, Brunhilde

    2015-10-01

    The monoterpene ascaridole, a fairly stable endoperoxide found in essential oils such as tea tree oil can provoke allergic contact dermatitis which has been evidenced under patch test conditions. However, concomitantly we observed irritative skin reactions that demand further data underlining the sensitization potential of ascaridole. Here, we studied the effects of ascaridole on dendritic cell (DC) activation and protein reactivity, 2 key steps of chemical-induced skin sensitization. Treatment of human monocyte-derived DC with ascaridole found support for full DC maturation, a capability of sensitizers but not irritants. It induced significant upregulation of the expression of the costimulatory molecules CD86, CD80, CD40, and the adhesion molecule CD54 in a time-dependent manner. Maturation was accompanied by release of proinflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, and IL-8. Similar to other chemical skin sensitizers including hydroperoxides, we observed a certain reactivity of ascaridole toward cysteine- but not lysine-containing peptides. During recent years, evidence accumulated for a radical mechanism as trigger for protein reactivity of peroxides. Treatment of the fairly stable endoperoxide ascaridole with iron as radical inducer ("activated ascaridole") resulted in cysteine peptide reactivity exceeding by far that of ascaridole itself. Furthermore, activated ascaridole showed increased potential for induction of the Nrf2 target gene heme oxygenase 1 and upregulation of CD86 and CD54 on THP-1 cells, an established DC surrogate. These results indicate that radical formation could be involved in the steps leading to skin sensitization induced by the endoperoxide ascaridole. PMID:26185204

  20. Control of Foxp3 stability through modulation of TET activity.

    PubMed

    Yue, Xiaojing; Trifari, Sara; Äijö, Tarmo; Tsagaratou, Ageliki; Pastor, William A; Zepeda-Martínez, Jorge A; Lio, Chan-Wang J; Li, Xiang; Huang, Yun; Vijayanand, Pandurangan; Lähdesmäki, Harri; Rao, Anjana

    2016-03-01

    Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine and other oxidized methylcytosines, intermediates in DNA demethylation. In this study, we examine the role of TET proteins in regulating Foxp3, a transcription factor essential for the development and function of regulatory T cells (T reg cells), a distinct lineage of CD4(+) T cells that prevent autoimmunity and maintain immune homeostasis. We show that during T reg cell development in the thymus, TET proteins mediate the loss of 5mC in T reg cell-specific hypomethylated regions, including CNS1 and CNS2, intronic cis-regulatory elements in the Foxp3 locus. Similar to CNS2-deficient T reg cells, the stability of Foxp3 expression is markedly compromised in T reg cells from Tet2/Tet3 double-deficient mice. Vitamin C potentiates TET activity and acts through Tet2/Tet3 to increase the stability of Foxp3 expression in TGF-β-induced T reg cells. Our data suggest that targeting TET enzymes with small molecule activators such as vitamin C might increase induced T reg cell efficacy. PMID:26903244

  1. Control of Foxp3 stability through modulation of TET activity

    PubMed Central

    Yue, Xiaojing; Trifari, Sara; Äijö, Tarmo; Tsagaratou, Ageliki; Pastor, William A.; Zepeda-Martínez, Jorge A.; Lio, Chan-Wang J.; Li, Xiang; Huang, Yun; Vijayanand, Pandurangan; Lähdesmäki, Harri

    2016-01-01

    Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine and other oxidized methylcytosines, intermediates in DNA demethylation. In this study, we examine the role of TET proteins in regulating Foxp3, a transcription factor essential for the development and function of regulatory T cells (T reg cells), a distinct lineage of CD4+ T cells that prevent autoimmunity and maintain immune homeostasis. We show that during T reg cell development in the thymus, TET proteins mediate the loss of 5mC in T reg cell–specific hypomethylated regions, including CNS1 and CNS2, intronic cis-regulatory elements in the Foxp3 locus. Similar to CNS2-deficient T reg cells, the stability of Foxp3 expression is markedly compromised in T reg cells from Tet2/Tet3 double-deficient mice. Vitamin C potentiates TET activity and acts through Tet2/Tet3 to increase the stability of Foxp3 expression in TGF-β–induced T reg cells. Our data suggest that targeting TET enzymes with small molecule activators such as vitamin C might increase induced T reg cell efficacy. PMID:26903244

  2. OASIS modulates hypoxia pathway activity to regulate bone angiogenesis

    PubMed Central

    Cui, Min; Kanemoto, Soshi; Cui, Xiang; Kaneko, Masayuki; Asada, Rie; Matsuhisa, Koji; Tanimoto, Keiji; Yoshimoto, Yuki; Shukunami, Chisa; Imaizumi, Kazunori

    2015-01-01

    OASIS/CREB3L1, an endoplasmic reticulum (ER)-resident transcription factor, plays important roles in osteoblast differentiation. In this study, we identified new crosstalk between OASIS and the hypoxia signaling pathway, which regulates vascularization during bone development. RT-PCR and real-time PCR analyses revealed significant decreases in the expression levels of hypoxia-inducible factor-1α (HIF-1α) target genes such as vascular endothelial growth factor A (VEGFA) in OASIS-deficient (Oasis−/−) mouse embryonic fibroblasts. In coimmunoprecipitation experiments, the N-terminal fragment of OASIS (OASIS-N; activated form of OASIS) bound to HIF-1α through the bZIP domain. Luciferase assays showed that OASIS-N promoted the transcription activities of a reporter gene via a hypoxia-response element (HRE). Furthermore, the expression levels of an angiogenic factor Vegfa was decreased in Oasis−/− osteoblasts. Immunostaining and metatarsal angiogenesis assay showed retarded vascularization in bone tissue of Oasis−/− mice. These results suggest that OASIS affects the expression of HIF-1α target genes through the protein interaction with HIF-1α, and that OASIS-HIF-1α complexes may play essential roles in angiogenesis during bone development. PMID:26558437

  3. The Wnt receptor Frizzled-4 modulates ADAM13 metalloprotease activity

    PubMed Central

    Abbruzzese, Genevieve; Gorny, Anne-Kathrin; Kaufmann, Lilian T.; Cousin, Hélène; Kleino, Iivari; Steinbeisser, Herbert; Alfandari, Dominique

    2015-01-01

    ABSTRACT Cranial neural crest (CNC) cells are a transient population of stem cells that originate at the border of the neural plate and the epidermis, and migrate ventrally to contribute to most of the facial structures including bones, cartilage, muscles and ganglia. ADAM13 is a cell surface metalloprotease that is essential for CNC cell migration. Here, we show in Xenopus laevis embryos that the Wnt receptor Fz4 binds to the cysteine-rich domain of ADAM13 and negatively regulates its proteolytic activity in vivo. Gain of Fz4 function inhibits CNC cell migration and can be rescued by gain of ADAM13 function. Loss of Fz4 function also inhibits CNC cell migration and induces a reduction of mature ADAM13, together with an increase in the ADAM13 cytoplasmic fragment that is known to translocate into the nucleus to regulate gene expression. We propose that Fz4 associates with ADAM13 during its transport to the plasma membrane to regulate its proteolytic activity. PMID:25616895

  4. VISUAL ELEMENTS OF SUBJECTIVE PREFERENCE MODULATE AMYGDALA ACTIVATION

    PubMed Central

    Bar, Moshe; Neta, Maital

    2010-01-01

    What are the basic visual cues that determine our preference towards mundane everyday objects? We previously showed that a highly potent cue is the nature of the object’s contour: people generally like objects with a curved contour compared with objects that have pointed features and a sharp-angled contour. This bias is hypothesized here to stem from an implicit perception of potential threat conveyed by sharp elements. Using human neuroimaging to test this hypothesis, we report that the amygdala, a brain structure that is involved in fear processing and has been shown to exhibit activation level that is proportional to arousal in general, is significantly more active for everyday sharp objects (e.g., a sofa with sharp corners) compared with their curved-contour counterparts. Therefore, our results indicate that a preference bias towards a visual object can be induced by low-level perceptual properties, independent of semantic meaning, via visual elements that on some level could be associated with threat. We further present behavioral results that provide initial support for the link between the sharpness of the contour and threat perception. Our brains might be organized to extract these basic contour elements rapidly for deriving an early warning signal in the presence of potential danger. PMID:17462678

  5. The Geography of Greenhouse Gas Emissions: Hands-On! Developing Active Learning Modules on the Human Dimensions of Global Change.

    ERIC Educational Resources Information Center

    Liverman, Diana; Solem, Michael

    This learning module aims to engage students in problem solving, critical thinking, scientific inquiry, and cooperative learning. The module is appropriate for use in any introductory or intermediate undergraduate course that focuses on human-environment relationships. The module examines the geography of human activities that produce the major…

  6. Modulation of P-glycoprotein ATPase activity by some phytoconstituents.

    PubMed

    Najar, I A; Sachin, B S; Sharma, S C; Satti, N K; Suri, K A; Johri, R K

    2010-03-01

    In the present investigation 16 phytoconstituents, which are active moieties found in several medicinal herbs, have been evaluated for their P-glycoprotein (P-gp) stimulation/inhibition profiles using a P-gp-dependent ATPase assay in rat jejunal membrane (in vitro). Acteoside, agnuside, catechin, chlorogenic acid, picroside -II and santonin showed an inhibitory effect. Negundoside, picroside -I and oleanolic acid caused a stimulatory effect. Andrographolide, apocyanin, berberine, glycyrrhizin, magniferin and piperine produced a biphasic response (stimulation at low concentration and inhibition at high concentration). The results suggested that a possible interaction of these phytoconstituents at the level of P-gp, could be an important parameter in determining their role in several key pharmacodynamic events. PMID:19653312

  7. Bradykinin actively modulates pulmonary vascular pressure-cardiac index relationships.

    PubMed

    Nyhan, D P; Clougherty, P W; Goll, H M; Murray, P A

    1987-07-01

    Our objectives were to investigate the pulmonary vascular effects of exogenously administered bradykinin at normal and reduced levels of cardiac index in intact conscious dogs and to assess the extent to which the pulmonary vascular response to bradykinin is the result of either cyclooxygenase pathway activation or reflex activation of sympathetic beta-adrenergic and -cholinergic receptors. Multipoint pulmonary vascular pressure-cardiac index (P/Q) plots were constructed during normoxia in conscious dogs by step-wise constriction of the thoracic inferior vena cava to reduce Q. In intact dogs, bradykinin (2 micrograms X kg-1 X min-1 iv) caused systemic vasodilation, i.e., systemic arterial pressure was slightly decreased (P less than 0.05), Q was markedly increased (P less than 0.01), and mixed venous PO2 and oxygen saturation (SO2) were increased (P less than 0.01). Bradykinin decreased (P less than 0.01) the pulmonary vascular pressure gradient (pulmonary arterial pressure-pulmonary capillary wedge pressure) over the entire range of Q studied (140-60 ml X min-1 X kg-1) in intact dogs. During cyclooxygenase pathway inhibition with indomethacin, bradykinin again decreased (P less than 0.05) pulmonary arterial pressure-pulmonary capillary wedge pressure at every level of Q, although the magnitude of the vasodilator response was diminished at lower levels of Q (60 ml X min-1 X kg-1). Following combined administration of sympathetic beta-adrenergic and -cholinergic receptor antagonists, bradykinin still decreased (P less than 0.01) pulmonary arterial pressure-pulmonary capillary wedge pressure over the range of Q from 160 to 60 ml X min-1 X kg-1.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3114215

  8. Modulation of insulin degrading enzyme activity and liver cell proliferation

    PubMed Central

    Pivovarova, Olga; von Loeffelholz, Christian; Ilkavets, Iryna; Sticht, Carsten; Zhuk, Sergei; Murahovschi, Veronica; Lukowski, Sonja; Döcke, Stephanie; Kriebel, Jennifer; de las Heras Gala, Tonia; Malashicheva, Anna; Kostareva, Anna; Lock, Johan F; Stockmann, Martin; Grallert, Harald; Gretz, Norbert; Dooley, Steven; Pfeiffer, Andreas FH; Rudovich, Natalia

    2015-01-01

    Diabetes mellitus type 2 (T2DM), insulin therapy, and hyperinsulinemia are independent risk factors of liver cancer. Recently, the use of a novel inhibitor of insulin degrading enzyme (IDE) was proposed as a new therapeutic strategy in T2DM. However, IDE inhibition might stimulate liver cell proliferation via increased intracellular insulin concentration. The aim of this study was to characterize effects of inhibition of IDE activity in HepG2 hepatoma cells and to analyze liver specific expression of IDE in subjects with T2DM. HepG2 cells were treated with 10 nM insulin for 24 h with or without inhibition of IDE activity using IDE RNAi, and cell transcriptome and proliferation rate were analyzed. Human liver samples (n = 22) were used for the gene expression profiling by microarrays. In HepG2 cells, IDE knockdown changed expression of genes involved in cell cycle and apoptosis pathways. Proliferation rate was lower in IDE knockdown cells than in controls. Microarray analysis revealed the decrease of hepatic IDE expression in subjects with T2DM accompanied by the downregulation of the p53-dependent genes FAS and CCNG2, but not by the upregulation of proliferation markers MKI67, MCM2 and PCNA. Similar results were found in the liver microarray dataset from GEO Profiles database. In conclusion, IDE expression is decreased in liver of subjects with T2DM which is accompanied by the dysregulation of p53 pathway. Prolonged use of IDE inhibitors for T2DM treatment should be carefully tested in animal studies regarding its potential effect on hepatic tumorigenesis. PMID:25945652

  9. Chemical and thermal modulation of molecular motor activities

    NASA Astrophysics Data System (ADS)

    Hong, Weili

    Molecular motors of kinesin and dynein families are responsible for various intracellular activities, from long distance movement of organelles, vesicles, protein complexes, and mRNAs to powering mitotic processes. They can take nanometer steps using chemical energy from the hydrolysis of ATP (adenosine triphosphate), and their dysfunction is involved in many neurodegenerative diseases that require long distance transport of cargos. Here I report on the study of the properties of molecular motors at a single-molecule level using optical trappings. I first studied the inhibition properties of kinesin motors by marine natural compound adociasulfates. I showed that adociasulfates compete with microtubules for binding to kinesins and thus inhibit kinesins' activity. Although adociasulfates are a strong inhibitor for all kinesin members, they show a much higher inhibition effect for conventional kinesins than for mitotic kinesins. Thus adociasulfates can be used to specifically inhibit conventional kinesins. By comparing the inhibition of kinesins by two structurally similar adociasulfates, one can see that the negatively charged sulfate residue of adociasulfates can be replaced by other negative residues and thus make it possible for adociasulfate-derived compounds to be more cell permeable. Kinesins and dyneins move cargos towards opposite directions along a microtubule. Cargos with both kinesins and dyneins attached often move bidirectionally due to undergoing a tug-of-war between the oppositely moving kinesin and dynein motors. Here I studied the effect of temperature on microtubule-based kinesin and dynein motor transport. While kinesins' and dyneins' velocities are closely matched above 15 °C, below this temperature the dyneins' velocity decreases much faster than the kinesins'. The kinesins' and dyneins' forces do not measurably change with temperature. The results suggest that temperature has significant effects on bidirectional transport and can be used to

  10. Active transport of vesicles in neurons is modulated by mechanical tension

    NASA Astrophysics Data System (ADS)

    Ahmed, Wylie W.; Saif, Taher A.

    2014-03-01

    Effective intracellular transport of proteins and organelles is critical in cells, and is especially important for ensuring proper neuron functionality. In neurons, most proteins are synthesized in the cell body and must be transported through thin structures over long distances where normal diffusion is insufficient. Neurons transport subcellular cargo along axons and neurites through a stochastic interplay of active and passive transport. Mechanical tension is critical in maintaining proper function in neurons, but its role in transport is not well understood. To this end, we investigate the active and passive transport of vesicles in Aplysia neurons while changing neurite tension via applied strain, and quantify the resulting dynamics. We found that tension in neurons modulates active transport of vesicles by increasing the probability of active motion, effective diffusivity, and induces a retrograde bias. We show that mechanical tension modulates active transport processes in neurons and that external forces can couple to internal (subcellular) forces and change the overall transport dynamics.

  11. Urokinase and type I plasminogen activator inhibitor production by normal human hepatocytes: modulation by inflammatory agents.

    PubMed

    Busso, N; Nicodeme, E; Chesne, C; Guillouzo, A; Belin, D; Hyafil, F

    1994-07-01

    We examined the effects of inflammatory cytokines (interleukin-1 beta, tumor necrosis factor-alpha and transforming growth factor-beta) on the plasminogen activator system (urokinase, tissue-type plasminogen activator, type 1 plasminogen activator inhibitor) in primary cultures of human hepatocytes. We show that interleukin-1 beta and tumor necrosis factor-alpha increase urokinase-type plasminogen activator production, reinforcing the concept that increased urokinase production is associated with inflammatory processes. By contrast, the same agents (i.e., interleukin-1 beta and tumor necrosis factor-alpha) do not stimulate plasminogen activator inhibitor type 1 production. This latter observation rules out hepatocytes as a major cellular source of plasmatic plasminogen activator inhibitor type 1 during acute-phase-related responses. Among the inflammatory agents used, transforming growth factor-beta was found to be the most effective modulator of both urokinase-type plasminogen activator and plasminogen activator inhibitor type 1, inducing severalfold increases of activity of urokinase-type plasminogen activator, antigen and the corresponding mRNA and increasing plasminogen activator inhibitor type 1 antigen and mRNA levels. Urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 modulation by transforming growth factor-beta may play a critical role in hepatic pathophysiology. PMID:8020888

  12. Selective Estrogen Receptor Modulation Increases Hippocampal Activity during Probabilistic Association Learning in Schizophrenia

    PubMed Central

    Kindler, Jochen; Weickert, Cynthia Shannon; Skilleter, Ashley J; Catts, Stanley V; Lenroot, Rhoshel; Weickert, Thomas W

    2015-01-01

    People with schizophrenia show probabilistic association learning impairment in conjunction with abnormal neural activity. The selective estrogen receptor modulator (SERM) raloxifene preserves neural activity during memory in healthy older men and improves memory in schizophrenia. Here, we tested the extent to which raloxifene modifies neural activity during learning in schizophrenia. Nineteen people with schizophrenia participated in a twelve-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of the SERM raloxifene administered orally at 120 mg daily to assess brain activity during probabilistic association learning using functional magnetic resonance imaging (fMRI). Raloxifene improved probabilistic association learning and significantly increased fMRI BOLD activity in the hippocampus and parahippocampal gyrus relative to placebo. A separate region of interest confirmatory analysis in 21 patients vs 36 healthy controls showed a positive association between parahippocampal neural activity and learning in patients, but no such relationship in the parahippocampal gyrus of healthy controls. Thus, selective estrogen receptor modulation by raloxifene concurrently increases activity in the parahippocampal gyrus and improves probabilistic association learning in schizophrenia. These results support a role for estrogen receptor modulation of mesial temporal lobe neural activity in the remediation of learning disabilities in both men and women with schizophrenia. PMID:25829142

  13. Local atomic structure modulations activate metal oxide as electrocatalyst for hydrogen evolution in acidic water

    PubMed Central

    Li, Yu Hang; Liu, Peng Fei; Pan, Lin Feng; Wang, Hai Feng; Yang, Zhen Zhong; Zheng, Li Rong; Hu, P.; Zhao, Hui Jun; Gu, Lin; Yang, Hua Gui

    2015-01-01

    Modifications of local structure at atomic level could precisely and effectively tune the capacity of materials, enabling enhancement in the catalytic activity. Here we modulate the local atomic structure of a classical but inert transition metal oxide, tungsten trioxide, to be an efficient electrocatalyst for hydrogen evolution in acidic water, which has shown promise as an alternative to platinum. Structural analyses and theoretical calculations together indicate that the origin of the enhanced activity could be attributed to the tailored electronic structure by means of the local atomic structure modulations. We anticipate that suitable structure modulations might be applied on other transition metal oxides to meet the optimal thermodynamic and kinetic requirements, which may pave the way to unlock the potential of other promising candidates as cost-effective electrocatalysts for hydrogen evolution in industry. PMID:26286479

  14. Actively mode-locked fiber ring laser by intermodal acousto-optic modulation.

    PubMed

    Bello-Jiménez, M; Cuadrado-Laborde, C; Sáez-Rodríguez, D; Diez, A; Cruz, J L; Andrés, M V

    2010-11-15

    We report an actively mode-locked fiber ring laser. A simple and low-insertion-loss acousto-optic modulator driven by standing flexural waves, which couples core-to-cladding modes in a standard single-mode optical fiber, is used as an active mechanism for mode locking. Among the remarkable features of the modulator, we mention its high modulation depth (72%), broad bandwidth (187 GHz), easy tunability in the optical wavelength, and low insertion losses (0.7 dB). The narrowest optical pulses obtained were of 95 ps time width, 21 mW peak power, repetition rate of 4.758 MHz, and 110 mW of pump power. PMID:21081995

  15. Local atomic structure modulations activate metal oxide as electrocatalyst for hydrogen evolution in acidic water.

    PubMed

    Li, Yu Hang; Liu, Peng Fei; Pan, Lin Feng; Wang, Hai Feng; Yang, Zhen Zhong; Zheng, Li Rong; Hu, P; Zhao, Hui Jun; Gu, Lin; Yang, Hua Gui

    2015-01-01

    Modifications of local structure at atomic level could precisely and effectively tune the capacity of materials, enabling enhancement in the catalytic activity. Here we modulate the local atomic structure of a classical but inert transition metal oxide, tungsten trioxide, to be an efficient electrocatalyst for hydrogen evolution in acidic water, which has shown promise as an alternative to platinum. Structural analyses and theoretical calculations together indicate that the origin of the enhanced activity could be attributed to the tailored electronic structure by means of the local atomic structure modulations. We anticipate that suitable structure modulations might be applied on other transition metal oxides to meet the optimal thermodynamic and kinetic requirements, which may pave the way to unlock the potential of other promising candidates as cost-effective electrocatalysts for hydrogen evolution in industry. PMID:26286479

  16. Integrins are Mechanosensors That Modulate Human Eosinophil Activation

    PubMed Central

    Ahmadzai, Mustafa; Small, Mike; Sehmi, Roma; Gauvreau, Gail; Janssen, Luke J.

    2015-01-01

    Eosinophil migration to the lung is primarily regulated by the eosinophil-selective family of eotaxin chemokines, which mobilize intracellular calcium (Ca2+) and orchestrate myriad changes in cell structure and function. Eosinophil function is also known to be flow-dependent, although the molecular cognate of this mechanical response has yet to be adequately characterized. Using confocal fluorescence microscopy, we determined the effects of fluid shear stress on intracellular calcium concentration ([Ca2+]i) in human peripheral blood eosinophils by perfusing cells in a parallel-plate flow chamber. Our results indicate that fluid perfusion evokes a calcium response that leads to cell flattening, increase in cell area, shape change, and non-directional migration. None of these changes are seen in the absence of a flow stimulus, and all are blocked by chelation of intracellular Ca2+ using BAPTA. These changes are enhanced by stimulating the cells with eotaxin-1. The perfusion-induced calcium response (PICR) could be blocked by pre-treating cells with selective (CDP-323) and non-selective (RGD tripeptides) integrin receptor antagonists, suggesting that α4β7/α4β1 integrins mediate this response. Overall, our study provides the first pharmacological description of a molecular mechanosensor that may collaborate with the eotaxin-1 signaling program in order to control human eosinophil activation. PMID:26539194

  17. Novel positive allosteric modulators of GABAA receptors with anesthetic activity

    PubMed Central

    Maldifassi, Maria C.; Baur, Roland; Pierce, David; Nourmahnad, Anahita; Forman, Stuart A.; Sigel, Erwin

    2016-01-01

    GABAA receptors are the main inhibitory neurotransmitter receptors in the brain and are targets for numerous clinically important drugs such as benzodiazepines, anxiolytics and anesthetics. We previously identified novel ligands of the classical benzodiazepine binding pocket in α1β2γ2 GABAA receptors using an experiment-guided virtual screening (EGVS) method. This screen also identified novel ligands for intramembrane low affinity diazepam site(s). In the current study we have further characterized compounds 31 and 132 identified with EGVS as well as 4-O-methylhonokiol. We investigated the site of action of these compounds in α1β2γ2 GABAA receptors expressed in Xenopus laevis oocytes using voltage-clamp electrophysiology combined with a benzodiazepine site antagonist and transmembrane domain mutations. All three compounds act mainly through the two β+/α− subunit transmembrane interfaces of the GABAA receptors. We then used concatenated receptors to dissect the involvement of individual β+/α− interfaces. We further demonstrated that these compounds have anesthetic activity in a small aquatic animal model, Xenopus laevis tadpoles. The newly identified compounds may serve as scaffolds for the development of novel anesthetics. PMID:27198062

  18. Vinpocetine modulates metabolic activity and function during retinal ischemia.

    PubMed

    Nivison-Smith, Lisa; O'Brien, Brendan J; Truong, Mai; Guo, Cindy X; Kalloniatis, Michael; Acosta, Monica L

    2015-05-01

    Vinpocetine protects against a range of degenerative conditions and insults of the central nervous system via multiple modes of action. Little is known, however, of its effects on metabolism. This may be highly relevant, as vinpocetine is highly protective against ischemia, a process that inhibits normal metabolic function. This study uses the ischemic retina as a model to characterize vinpocetine's effects on metabolism. Vinpocetine reduced the metabolic demand of the retina following ex vivo hypoxia and ischemia to normal levels based on lactate dehydrogenase activity. Vinpocetine delivered similar effects in an in vivo model of retinal ischemia-reperfusion, possibly through increasing glucose availability. Vinpocetine's effects on glucose also appeared to improve glutamate homeostasis in ischemic Müller cells. Other actions of vinpocetine following ischemia-reperfusion, such as reduced cell death and improved retinal function, were possibly a combination of the drug's actions on metabolism and other retinal pathways. Vinpocetine's metabolic effects appeared independent of its other known actions in ischemia, as it recovered retinal function in a separate metabolic model where the glutamate-to-glutamine metabolic pathway was inhibited in Müller cells. The results of this study indicate that vinpocetine mediates ischemic damage partly through altered metabolism and has potential beneficial effects as a treatment for ischemia of neuronal tissues. PMID:25696811

  19. Gait transition dynamics are modulated by concurrent cognitive activity.

    PubMed

    Abdolvahab, Mohammad

    2015-10-01

    In tasks with two categorically distinct behavioral possibilities a person beginning with one option will typically switch to the other at a higher value of a control parameter in an ascending (increasing) sequence than in a descending (decreasing) sequence. For example, the switch from walking to running on an accelerating treadmill occurs at a higher speed than the switch from running to walking on a decelerating treadmill. The reported research posed the question of whether this variant of behavioral hysteresis was affected by concurrent cognitive activity. Participants walked or ran on a treadmill with a constant acceleration or deceleration while counting backwards by sevens or ones, or not counting. The degree of hysteresis, the difference between walk-to-run and run-to-walk transition speeds, increased with cognitive difficulty. Specifically, the increased hysteresis was shown to be due to lower run-to-walk transition speeds for the more difficult concurrent cognitive tasks. These results support the hypothesis that cognitive load occupies attentional resources that contribute to triggering human gait transitions. PMID:26092304

  20. Varying modulation of HIV-1 LTR activity by Baf complexes.

    PubMed

    Van Duyne, Rachel; Guendel, Irene; Narayanan, Aarthi; Gregg, Edward; Shafagati, Nazly; Tyagi, Mudit; Easley, Rebecca; Klase, Zachary; Nekhai, Sergei; Kehn-Hall, Kylene; Kashanchi, Fatah

    2011-08-19

    The human immunodeficiency virus type 1 (HIV-1) long terminal repeat is present on both ends of the integrated viral genome and contains regulatory elements needed for transcriptional initiation and elongation. Post-integration, a highly ordered chromatin structure consisting of at least five nucleosomes, is found at the 5' long terminal repeat, the location and modification state of which control the state of active viral replication as well as silencing of the latent HIV-1 provirus. In this context, the chromatin remodeling field rapidly emerges as having a critical role in the control of viral gene expression. In the current study, we focused on unique Baf subunits that are common to the most highly recognized of chromatin remodeling proteins, the SWI/SNF (switching-defective-sucrose non-fermenting) complexes. We find that at least two Baf proteins, Baf53 and Baf170, are highly regulated in HIV-1-infected cells. Previously, studies have shown that the depletion of Baf53 in uninfected cells leads to the expansion of chromosomal territories and the decompaction of the chromatin. Baf53, in the presence of HIV-1 infection, co-elutes off of a chromatographic column as a different-sized complex when compared to uninfected cells and appears to be predominantly phosphorylated. The innate function of Baf53-containing complexes appears to be transcriptionally suppressive, in that knocking down Baf53 increases viral gene expression from cells both transiently and chronically infected with HIV-1. Additionally, cdk9/cyclin T in the presence of Tat is able to phosphorylate Baf53 in vitro, implying that this posttranslationally modified form relieves the suppressive effect and allows for viral transcription to proceed. PMID:21699904

  1. Preference for Sucrose Solutions Modulates Taste Cortical Activity in Humans.

    PubMed

    Jacquin-Piques, Agnès; Mouillot, Thomas; Gigot, Vincent; Meillon, Sophie; Leloup, Corinne; Penicaud, Luc; Brondel, Laurent

    2016-09-01

    High time resolution is required to reliably measure neuronal activity in the gustatory cortex in response to taste stimuli. Hedonic aspects of gustatory processing have never been explored using gustatory evoked potentials (GEPs), a high-time-resolution technique. Our aim was to study cerebral processing of hedonic taste in humans using GEPs in response to sucrose solutions in subjects with different ratings of pleasantness regarding sucrose. In this exploratory study, 30 healthy volunteers were randomly stimulated with 3 sucrose solutions. The sucrose stimulus was presented to the tongue for 1s 20 times. GEPs were recorded from 9 cortical sites with EEG sensors at Cz, Fz, Pz, C3, C4, F3, F4, Fp1, and Fp2 (10/20 system). The main result was that subjects who preferred the high-concentration (20g/100mL) sucrose solution had higher GEP amplitudes on the Pz, Cz, and Fz electrodes than did subjects who preferred the low-concentration (5g/100mL) or the moderate-concentration (10g/100mL) solutions regardless of stimulus intensity. The difference in P1N1 amplitude on the Pz, Cz, and Fz electrodes according to sucrose preference of the subjects was described with stronger significance with stimulation by the 20 g-sucrose solution than by the 5 and 10g sucrose solutions. Using the reliable and safe GEP technique, we provide an original demonstration of variability of the gustatory response on the Pz, Cz, and Fz electrodes according to a sweet preference in humans. Further studies are needed to correlate the electric signal recorded by surface electrodes to the neural generator. PMID:27235187

  2. Vestibular Activation Differentially Modulates Human Early Visual Cortex and V5/MT Excitability and Response Entropy

    PubMed Central

    Guzman-Lopez, Jessica; Arshad, Qadeer; Schultz, Simon R; Walsh, Vincent; Yousif, Nada

    2013-01-01

    Head movement imposes the additional burdens on the visual system of maintaining visual acuity and determining the origin of retinal image motion (i.e., self-motion vs. object-motion). Although maintaining visual acuity during self-motion is effected by minimizing retinal slip via the brainstem vestibular-ocular reflex, higher order visuovestibular mechanisms also contribute. Disambiguating self-motion versus object-motion also invokes higher order mechanisms, and a cortical visuovestibular reciprocal antagonism is propounded. Hence, one prediction is of a vestibular modulation of visual cortical excitability and indirect measures have variously suggested none, focal or global effects of activation or suppression in human visual cortex. Using transcranial magnetic stimulation-induced phosphenes to probe cortical excitability, we observed decreased V5/MT excitability versus increased early visual cortex (EVC) excitability, during vestibular activation. In order to exclude nonspecific effects (e.g., arousal) on cortical excitability, response specificity was assessed using information theory, specifically response entropy. Vestibular activation significantly modulated phosphene response entropy for V5/MT but not EVC, implying a specific vestibular effect on V5/MT responses. This is the first demonstration that vestibular activation modulates human visual cortex excitability. Furthermore, using information theory, not previously used in phosphene response analysis, we could distinguish between a specific vestibular modulation of V5/MT excitability from a nonspecific effect at EVC. PMID:22291031

  3. Skin Sympathetic Nerve Activity is Modulated during Slow Sinusoidal Linear Displacements in Supine Humans.

    PubMed

    Bolton, Philip S; Hammam, Elie; Kwok, Kenny; Macefield, Vaughan G

    2016-01-01

    Low-frequency sinusoidal linear acceleration (0.08 Hz, ±4 mG) modulates skin sympathetic nerve activity (SSNA) in seated subjects (head vertical), suggesting that activation of the utricle in the peripheral vestibular labyrinth modulates SSNA. The aim of the current study was to determine whether SSNA is also modulated by input from the saccule. Tungsten microelectrodes were inserted into the common peroneal nerve to record oligounitary SSNA in 8 subjects laying supine on a motorized platform with the head aligned with the longitudinal axis of the body. Slow sinusoidal (0.08 Hz, 100 cycles) linear acceleration-decelerations (peak ±4 mG) were applied rostrocaudally to predominately activate the saccules, or mediolaterally to predominately activate the utricles. Cross-correlation histograms were constructed between the negative-going sympathetic spikes and the positive peaks of the sinusoidal stimuli. Sinusoidal linear acceleration along the rostrocaudal axis or mediolateral axis both resulted in sinusoidal modulation of SSNA (Median, IQR 27.0, 22-33% and 24.8, 17-39%, respectively). This suggests that both otolith organs act on sympathetic outflow to skin and muscle in a similar manner during supine displacements. PMID:26909019

  4. Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity.

    PubMed

    Pasquel, Danielle; Doricakova, Aneta; Li, Hao; Kortagere, Sandhya; Krasowski, Matthew D; Biswas, Arunima; Walton, William G; Redinbo, Matthew R; Dvorak, Zdenek; Mani, Sridhar

    2016-09-01

    Pregnane X receptor (PXR) is a major transcriptional regulator of xenobiotic metabolism and transport pathways in the liver and intestines, which are critical for protecting organisms against potentially harmful xenobiotic and endobiotic compounds. Inadvertent activation of drug metabolism pathways through PXR is known to contribute to drug resistance, adverse drug-drug interactions, and drug toxicity in humans. In both humans and rodents, PXR has been implicated in non-alcoholic fatty liver disease, diabetes, obesity, inflammatory bowel disease, and cancer. Because of PXR's important functions, it has been a therapeutic target of interest for a long time. More recent mechanistic studies have shown that PXR is modulated by multiple PTMs. Herein we provide the first investigation of the role of acetylation in modulating PXR activity. Through LC-MS/MS analysis, we identified lysine 109 (K109) in the hinge as PXR's major acetylation site. Using various biochemical and cell-based assays, we show that PXR's acetylation status and transcriptional activity are modulated by E1A binding protein (p300) and sirtuin 1 (SIRT1). Based on analysis of acetylation site mutants, we found that acetylation at K109 represses PXR transcriptional activity. The mechanism involves loss of RXRα dimerization and reduced binding to cognate DNA response elements. This mechanism may represent a promising therapeutic target using modulators of PXR acetylation levels. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. PMID:26855179

  5. Skin Sympathetic Nerve Activity is Modulated during Slow Sinusoidal Linear Displacements in Supine Humans

    PubMed Central

    Bolton, Philip S.; Hammam, Elie; Kwok, Kenny; Macefield, Vaughan G.

    2016-01-01

    Low-frequency sinusoidal linear acceleration (0.08 Hz, ±4 mG) modulates skin sympathetic nerve activity (SSNA) in seated subjects (head vertical), suggesting that activation of the utricle in the peripheral vestibular labyrinth modulates SSNA. The aim of the current study was to determine whether SSNA is also modulated by input from the saccule. Tungsten microelectrodes were inserted into the common peroneal nerve to record oligounitary SSNA in 8 subjects laying supine on a motorized platform with the head aligned with the longitudinal axis of the body. Slow sinusoidal (0.08 Hz, 100 cycles) linear acceleration-decelerations (peak ±4 mG) were applied rostrocaudally to predominately activate the saccules, or mediolaterally to predominately activate the utricles. Cross-correlation histograms were constructed between the negative-going sympathetic spikes and the positive peaks of the sinusoidal stimuli. Sinusoidal linear acceleration along the rostrocaudal axis or mediolateral axis both resulted in sinusoidal modulation of SSNA (Median, IQR 27.0, 22–33% and 24.8, 17–39%, respectively). This suggests that both otolith organs act on sympathetic outflow to skin and muscle in a similar manner during supine displacements. PMID:26909019

  6. MODULATION OF EASTERN OYSTER HEMOCYTE ACTIVITIES BY PERKINSUS MARINUS EXTRACELLULAR PROTEINS

    EPA Science Inventory

    The oyster pathogen Perkinsus marinusproduces many extracellular proteins (ECP) in vitro. Analysis of this ECP revealed a battery of hydrolytic enzymes. Some of these enzymes are known to modulate the activity of host defense cells. Although information on the effects of P. marin...

  7. Engineering a hyper-catalytic enzyme by photo-activated conformation modulation

    SciTech Connect

    Agarwal, Pratul K

    2012-01-01

    Enzyme engineering for improved catalysis has wide implications. We describe a novel chemical modification of Candida antarctica lipase B that allows modulation of the enzyme conformation to promote catalysis. Computational modeling was used to identify dynamical enzyme regions that impact the catalytic mechanism. Surface loop regions located distal to active site but showing dynamical coupling to the reaction were connected by a chemical bridge between Lys136 and Pro192, containing a derivative of azobenzene. The conformational modulation of the enzyme was achieved using two sources of light that alternated the azobenzene moiety in cis and trans conformations. Computational model predicted that mechanical energy from the conformational fluctuations facilitate the reaction in the active-site. The results were consistent with predictions as the activity of the engineered enzyme was found to be enhanced with photoactivation. Preliminary estimations indicate that the engineered enzyme achieved 8-52 fold better catalytic activity than the unmodulated enzyme.

  8. Light/dark modulation of enzyme activity in developing barley leaves

    SciTech Connect

    Sibley, M.H.; Anderson, L.E. )

    1989-12-01

    Light/dark modulation of the ribulose-5-phosphate kinase, NADP{sup +}-glyceraldehyde-3-phosphate dehydrogenase, and fructose-1,6-bisphosphatase activity was measured in the developing primary leaf of barley (Hordeum vulgare L.) seedlings. Ribulose-5-phosphate kinase and NADP{sup +}-glyceraldehyde-3-phosphate dehydrogenase were fully light activated even at the earliest developmental stage sampled. In contrast, light modulation of fructose-1,6-bisphosphatase exhibited a complex response to leaf developmental status. Light stimulation of fructose-1,6-bisphosphatase activity (measured at pH 8.0) increased progressively during leaf development. On the other hand, acid fructose-1,6-bisphosphatase activity (measured at pH 6.0) was inhibited by light, and this light inhibition was greater in the base of the leaf than in the tip of the leaf.

  9. Docosahexaenoic acid modulates inflammatory and antineurogenic functions of activated microglial cells.

    PubMed

    Antonietta Ajmone-Cat, Maria; Lavinia Salvatori, Maria; De Simone, Roberta; Mancini, Melissa; Biagioni, Stefano; Bernardo, Antonietta; Cacci, Emanuele; Minghetti, Luisa

    2012-03-01

    The complex process of microglial activation encompasses several functional activation states associated either with neurotoxic/antineurogenic or with neurotrophic/proneurogenic properties, depending mainly on the extent of activation and the nature of the activating stimuli. Several studies have demonstrated that acute exposure to the prototypical activating agent lipopolysaccharide (LPS) confers antineurogenic properties upon microglial cells. Acutely activated microglia ortheir conditioned media (CM) reduce neural stem progenitor cell (NPC) survival and prevent NPC differentiation into neurons. The present study tested the hypothesis that docosahexaenoic acid (DHA), a long-chain polyunsatured fatty acid (L-PUFA) with potent immunomodulatory properties, could dampen microglial proinflammatory functions and modulate their antineurogenic effect. We demonstrate that DHA dose dependently inhibits the synthesis of inflammatory products in activated microglia without inducing an alternative antiinflammatory phenotype. Among the possible DHA mechanisms of action, we propose the inhibition of p38 MAPK phosphorylation and the activation of the nuclear receptor peroxisome proliferator activated receptor (PPAR)-γ. The attenuation of M1 proinflammatory phenotype has relevant consequences for the survival and differentiation of NPC, because DHA reverses the antineurogenic activities of conditioned media from LPS-activated microglia. Our study identifies new relevant potentially protective and proneurogenic functions of DHA, exerted through the modulation of microglial functions, that could be exploited to sustain or promote neuroregenerative processes in damaged/aged brain. PMID:22057807

  10. Active ingredients of ginger as potential candidates in the prevention and treatment of diseases via modulation of biological activities

    PubMed Central

    Rahmani, Arshad H; shabrmi, Fahad M Al; Aly, Salah M

    2014-01-01

    The current mode of treatment based on synthetic drugs is expensive and also causes genetic and metabolic alterations. However, safe and sound mode of treatment is needed to control the diseases development and progression. In this regards, medicinal plant and its constituents play an important role in diseases management via modulation of biological activities. Ginger, the rhizome of the Zingiber officinale, has shown therapeutic role in the health management since ancient time and considered as potential chemopreventive agent. Numerous studies based on clinical trials and animal model has shown that ginger and its constituents shows significant role in the prevention of diseases via modulation of genetic and metabolic activities. In this review, we focused on the therapeutics effects of ginger and its constituents in the diseases management, and its impact on genetic and metabolic activities. PMID:25057339

  11. Noninvasive transcranial focused ultrasonic-magnetic stimulation for modulating brain oscillatory activity

    NASA Astrophysics Data System (ADS)

    Yuan, Yi; Chen, Yudong; Li, Xiaoli

    2016-02-01

    A novel technique, transcranial focused ultrasonic-magnetic stimulation (tFUMS), has been developed for noninvasive brain modulation in vivo. tFUMS has a higher spatial resolution (<2 mm) and a higher penetration depth than other noninvasive neuromodulation methods. The in vivo animal experimental results show that tFUMS can not only increase the power of local field potentials and the firing rate of the neurons, but also enhance the effect of transcranial focused ultrasound stimulation on the neuromodulation. The results demonstrate that tFUMS can modulate brain oscillatory activities by stimulating brain tissues.

  12. Measuring of object vibration using sinusoidal-modulation laser-diode active interferometer

    NASA Astrophysics Data System (ADS)

    Ai, Yong; Cao, Qinfeng; Lu, Su

    1996-09-01

    Using the character that the emitting optical frequency of the laser diode is controlled by the injected current, the ability of eliminating environmental disturbance of the sinusoidal modulation laser diode active interferometer will be raised by more than one hundred times through putting the disturbed interference signal produced by the environment into the interferometer. When vibrating frequency of objects is different from that of the sinusoidol modulation, 'beat- frequency' will be produced in the interfere signal, which can be analyzed to get the vibrating frequency of objects. This paper described the operation principle and theoretical delusion of the 'beat-frequency' method.

  13. [Peptide components of Geolycosa spider venom modulate P2X receptor activity of rat sensory neurons].

    PubMed

    Savchenko, H A; Vasylevs'kyĭ, A A; Pluzhnykov, K A; Korol'kova, Iu V; Mamenko, M V; Volkova, T M; Maksymiuk, O P; Boĭchuk, Ia A; Hrishyn, Ie V; Kryshtal', O O

    2009-01-01

    Almost each natural venom comprises a considerable combinatorial library of bioactive substances that have been optimized during evolution. Particular attention is devoted currently on a search for new modulators of ion channels from the venoms of arthropods. We have studied the effect of peptidous compounds of the Lycosa spider venom on the activity of P2X receptors in DRG neurons of rats. As a result, at least 7 proteins modulating various P2X receptor-operated ionic currents in the sensory neurons of rats have been found. PMID:19526843

  14. Identification of Martian biota using their radioresistance ability and specific isotopic composition

    NASA Astrophysics Data System (ADS)

    Pavlov, A. K.; Kalinin, V.; Konstantinov, A.; Shelegedin, V.; Pavlov, A. A.

    2003-04-01

    Because of a thin atmosphere and weak magnetic field, Martian surface is a subject to high levels of ionizing radiation. On the other hand, variations in Martian obliquity produce the global climate oscillations (with the main period ~120000 years) of the great magnitude. Martian biota would accumulate large radiation dosage during the periods of cold climate, when it would be in the dormant state and would rebuild its population during the periods of warm climate. Therefore, all types of hypothetical Martian microorganisms living in subsurface layers of soil have to posses very high radiation tolerance. In our experiments, we find that "ordinary" bacteria (Escherichia coli and two species of Bacillus ) can develop radioresistance ability after a number of cycles of exposure to the high (almost lethal) radiation dosages, followed by recovery of the bacterial population. We show that natural cycles of this kind could take place only on Mars. On the other hand, high radiation tolerance is hardly necessary for the survival in any natural environment on Earth. A few number of terrestrial microorganisms (radioresistant bacteria) posses this peculiar ability (Deinococus radiodurance , Rubrobacter radiotolerance, Rubrobacter xylanophilus ). The radiation background on Earth, including vicinity of natural nuclear reactor Oklo is many orders of magnitude lower than the lethal dose for these microorganisms. We show that such radioresistance can be "trained" only in the Martian conditions. Therefore, we propose that Earth has been infected several times by the Martian biota on Martian meteorites. We propose that high radioresistance could be a strong sign of the Martian origin for potential microorganisms acquired in the sample return missions. Another way to identify "Martian" microorganisms and exclude contamination in returned samples involves analysis of the radionuclides abundance (being produced by the high energy cosmic rays in the Martian soil). We show that these

  15. Modulation of Adult Mesenchymal Stem Cells Activity by Toll-Like Receptors: Implications on Therapeutic Potential

    PubMed Central

    DelaRosa, Olga; Lombardo, Eleuterio

    2010-01-01

    Mesenchymal stem cells (MSCs) are of special interest as therapeutic agents in the settings of both chronic inflammatory and autoimmune diseases. Toll-like receptors (TLR) ligands have been linked with the perpetuation of inflammation in a number of chronic inflammatory diseases due to the permanent exposure of the immune system to TLR-specific stimuli. Therefore, MSCs employed in therapy can be potentially exposed to TLR ligands, which may modulate MSC therapeutic potential in vivo. Recent results demonstrate that MSCs are activated by TLR ligands leading to modulation of the differentiation, migration, proliferation, survival, and immunosuppression capacities. However inconsistent results among authors have been reported suggesting that the source of MSCs, TLR stimuli employed or culture conditions play a role. Notably, activation by TLR ligands has not been reported to modulate the “immunoprivileged” phenotype of MSCs which is of special relevance regarding the use of allogeneic MSC-based therapies. In this review, we discuss the available data on the modulation of MSCs activity through TLR signalling. PMID:20628526

  16. Bicarbonate and Ca2+ Sensing Modulators Activate Photoreceptor ROS-GC1 Synergistically

    PubMed Central

    Duda, Teresa; Pertzev, Alexandre; Makino, Clint L.; Sharma, Rameshwar K.

    2016-01-01

    Photoreceptor ROS-GC1, a prototype subfamily member of the membrane guanylate cyclase family, is a central component of phototransduction. It is a single transmembrane-spanning protein, composed of modular blocks. In rods, guanylate cyclase activating proteins (GCAPs) 1 and 2 bind to its juxtamembrane domain (JMD) and the C-terminal extension, respectively, to accelerate cyclic GMP synthesis when Ca2+ levels are low. In cones, the additional expression of the Ca2+-dependent guanylate cyclase activating protein (CD-GCAP) S100B which binds to its C-terminal extension, supports acceleration of cyclic GMP synthesis at high Ca2+ levels. Independent of Ca2+, ROS-GC1 activity is also stimulated directly by bicarbonate binding to the core catalytic domain (CCD). Several enticing molecular features of this transduction system are revealed in the present study. In combination, bicarbonate and Ca2+-dependent modulators raised maximal ROS-GC activity to levels that exceeded the sum of their individual effects. The F514S mutation in ROS-GC1 that causes blindness in type 1 Leber’s congenital amaurosis (LCA) severely reduced basal ROS-GC1 activity. GCAP2 and S100B Ca2+ signaling modes remained functional, while the GCAP1-modulated mode was diminished. Bicarbonate nearly restored basal activity as well as GCAP2- and S100B-stimulated activities of the F514S mutant to normal levels but could not resurrect GCAP1 stimulation. We conclude that GCAP1 and GCAP2 forge distinct pathways through domain-specific modules of ROS-GC1 whereas the S100B and GCAP2 pathways may overlap. The synergistic interlinking of bicarbonate to GCAPs- and S100B-modulated pathways intensifies and tunes the dependence of cyclic GMP synthesis on intracellular Ca2+. Our study challenges the recently proposed GCAP1 and GCAP2 “overlapping” phototransduction model (Peshenko et al., 2015b). PMID:26858600

  17. Bicarbonate and Ca(2+) Sensing Modulators Activate Photoreceptor ROS-GC1 Synergistically.

    PubMed

    Duda, Teresa; Pertzev, Alexandre; Makino, Clint L; Sharma, Rameshwar K

    2016-01-01

    Photoreceptor ROS-GC1, a prototype subfamily member of the membrane guanylate cyclase family, is a central component of phototransduction. It is a single transmembrane-spanning protein, composed of modular blocks. In rods, guanylate cyclase activating proteins (GCAPs) 1 and 2 bind to its juxtamembrane domain (JMD) and the C-terminal extension, respectively, to accelerate cyclic GMP synthesis when Ca(2+) levels are low. In cones, the additional expression of the Ca(2+)-dependent guanylate cyclase activating protein (CD-GCAP) S100B which binds to its C-terminal extension, supports acceleration of cyclic GMP synthesis at high Ca(2+) levels. Independent of Ca(2+), ROS-GC1 activity is also stimulated directly by bicarbonate binding to the core catalytic domain (CCD). Several enticing molecular features of this transduction system are revealed in the present study. In combination, bicarbonate and Ca(2+)-dependent modulators raised maximal ROS-GC activity to levels that exceeded the sum of their individual effects. The F(514)S mutation in ROS-GC1 that causes blindness in type 1 Leber's congenital amaurosis (LCA) severely reduced basal ROS-GC1 activity. GCAP2 and S100B Ca(2+) signaling modes remained functional, while the GCAP1-modulated mode was diminished. Bicarbonate nearly restored basal activity as well as GCAP2- and S100B-stimulated activities of the F(514)S mutant to normal levels but could not resurrect GCAP1 stimulation. We conclude that GCAP1 and GCAP2 forge distinct pathways through domain-specific modules of ROS-GC1 whereas the S100B and GCAP2 pathways may overlap. The synergistic interlinking of bicarbonate to GCAPs- and S100B-modulated pathways intensifies and tunes the dependence of cyclic GMP synthesis on intracellular Ca(2+). Our study challenges the recently proposed GCAP1 and GCAP2 "overlapping" phototransduction model (Peshenko et al., 2015b). PMID:26858600

  18. A critical role of toll-like receptor 2 (TLR2) and its’ in vivo ligands in radio-resistance

    PubMed Central

    Gao, Fu; Zhang, Chaoxiong; Zhou, Chuanfeng; Sun, Weimin; Liu, Xin; Zhang, Pei; Han, Jiaqi; Xian, Linfeng; Bai, Dongchen; Liu, Hu; Cheng, Ying; Li, Bailong; Cui, Jianguo; Cai, Jianming; Liu, Cong

    2015-01-01

    The role of Toll-like receptor-2 (TLR2) in radio-resistance remained largely unknown. TLR2 knockout (TLR2−/−) mice received radiation of 6.5 Gy, and then were studied. We found that radiation resulted in more severe mortality and morbidity rates in TLR2−/− mice. The cause of death in TLR2−/− mice may be severe and persistent bone marrow cell loss. Injection of the TLR2 agonist Pam3CSK4 into wild type (WT) mice induced radio-resistance. Myd88−/− mice were more susceptible to radiation. In conclusion, our data indicate that, similar to TLR4, TLR2 plays a critical role in radio-resistance. PMID:26268450

  19. ERK/p38 MAPK inhibition reduces radio-resistance to a pulsed proton beam in breast cancer stem cells

    NASA Astrophysics Data System (ADS)

    Jung, Myung-Hwan; Park, Jeong Chan

    2015-10-01

    Recent studies have identified highly tumorigenic cells with stem cell-like characteristics, termed cancer stem cells (CSCs) in human cancers. CSCs are resistant to conventional radiotherapy and chemotherapy owing to their high DNA repair ability and oncogene overexpression. However, the mechanisms regulating CSC radio-resistance, particularly proton beam resistance, remain unclear. We isolated CSCs from the breast cancer cell lines MCF-7 and MDA-MB-231, which expressed the characteristic breast CSC membrane protein markers CD44+/CD24-/ low , and irradiated the CSCs with pulsed proton beams. We confirmed that CSCs were resistant to pulsed proton beams and showed that treatment with p38 and ERK inhibitors reduced CSC radio-resistance. Based on these results, BCSC radio-resistance can be reduced during proton beam therapy by co-treatment with ERK1/2 or p38 inhibitors, a novel approach to breast cancer therapy.

  20. A critical role of toll-like receptor 2 (TLR2) and its' in vivo ligands in radio-resistance.

    PubMed

    Gao, Fu; Zhang, Chaoxiong; Zhou, Chuanfeng; Sun, Weimin; Liu, Xin; Zhang, Pei; Han, Jiaqi; Xian, Linfeng; Bai, Dongchen; Liu, Hu; Cheng, Ying; Li, Bailong; Cui, Jianguo; Cai, Jianming; Liu, Cong

    2015-01-01

    The role of Toll-like receptor-2 (TLR2) in radio-resistance remained largely unknown. TLR2 knockout (TLR2(-/-)) mice received radiation of 6.5 Gy, and then were studied. We found that radiation resulted in more severe mortality and morbidity rates in TLR2(-/-) mice. The cause of death in TLR2(-/-) mice may be severe and persistent bone marrow cell loss. Injection of the TLR2 agonist Pam3CSK4 into wild type (WT) mice induced radio-resistance. Myd88(-/-) mice were more susceptible to radiation. In conclusion, our data indicate that, similar to TLR4, TLR2 plays a critical role in radio-resistance. PMID:26268450

  1. Modulation of WNT/β-catenin pathway in melanoma by biologically active components derived from plants.

    PubMed

    Gajos-Michniewicz, Anna; Czyz, Malgorzata

    2016-03-01

    Metastatic melanoma is an aggressive cancer, often resistant to treatment. Therefore, it is essential to determine the molecular mechanisms leading to melanoma or underlying resistance to therapy, and the response to targeted inhibition of the RAS/BRAF/MEK/ERK pathway was a good lesson in this respect. Aberrant WNT/β-catenin pathway is observed in melanoma, and the modulators of this signaling cascade have been under investigation in the context of therapy as well as chemoprevention. Several natural compounds were recognized as being capable of targeting elements of the WNT/β-catenin pathway in various cancers, however, only a few of them can modulate this pathway in melanoma. This review examines recent research on the role of the WNT/β-catenin pathway in tumor development and maintenance, as well as summarizes the current knowledge concerning the modulation of this pathway in melanoma by active compounds of natural origin. PMID:26851176

  2. Performance Evaluation of a High Bandwidth Liquid Fuel Modulation Valve for Active Combustion Control

    NASA Technical Reports Server (NTRS)

    Saus, Joseph R.; DeLaat, John C.; Chang, Clarence T.; Vrnak, Daniel R.

    2012-01-01

    At the NASA Glenn Research Center, a characterization rig was designed and constructed for the purpose of evaluating high bandwidth liquid fuel modulation devices to determine their suitability for active combustion control research. Incorporated into the rig s design are features that approximate conditions similar to those that would be encountered by a candidate device if it were installed on an actual combustion research rig. The characterized dynamic performance measures obtained through testing in the rig are planned to be accurate indicators of expected performance in an actual combustion testing environment. To evaluate how well the characterization rig predicts fuel modulator dynamic performance, characterization rig data was compared with performance data for a fuel modulator candidate when the candidate was in operation during combustion testing. Specifically, the nominal and off-nominal performance data for a magnetostrictive-actuated proportional fuel modulation valve is described. Valve performance data were collected with the characterization rig configured to emulate two different combustion rig fuel feed systems. Fuel mass flows and pressures, fuel feed line lengths, and fuel injector orifice size was approximated in the characterization rig. Valve performance data were also collected with the valve modulating the fuel into the two combustor rigs. Comparison of the predicted and actual valve performance data show that when the valve is operated near its design condition the characterization rig can appropriately predict the installed performance of the valve. Improvements to the characterization rig and accompanying modeling activities are underway to more accurately predict performance, especially for the devices under development to modulate fuel into the much smaller fuel injectors anticipated in future lean-burning low-emissions aircraft engine combustors.

  3. Leishmania amazonensis: PKC-like protein kinase modulates the (Na++K+)ATPase activity.

    PubMed

    Almeida-Amaral, Elmo Eduardo de; Caruso-Neves, Celso; Lara, Lucienne Silva; Pinheiro, Carla Mônica; Meyer-Fernandes, José Roberto

    2007-08-01

    The present study aimed to identify the presence of protein kinase C-like (PKC-like) in Leishmania amazonensis and to elucidate its possible role in the modulation of the (Na(+)+K(+))ATPase activity. Immunoblotting experiments using antibody against a consensus sequence (Ac 543-549) of rabbit protein kinase C (PKC) revealed the presence of a protein kinase of 80 kDa in L. amazonensis. Measurements of protein kinase activity showed the presence of both (Ca(2+)-dependent) and (Ca(2+)-independent) protein kinase activity in plasma membrane and cytosol. Phorbol ester (PMA) activation of the Ca(2+)-dependent protein kinase stimulated the (Na(+)+K(+))ATPase activity, while activation of the Ca(2+)-independent protein kinase was inhibitory. Both effects of protein kinase on the (Na(+)+K(+))ATPase of the plasma membrane were lower than that observed in intact cells. PMA induced the translocation of protein kinase from cytosol to plasma membrane, indicating that the maximal effect of protein kinase on the (Na(+)+K(+))ATPase activity depends on the synergistic action of protein kinases from both plasma membrane and cytosol. This is the first demonstration of a protein kinase activated by PMA in L. amazonensis and the first evidence for a possible role in the regulation of the (Na(+)+K(+))ATPase activity in this trypanosomatid. Modulation of the (Na(+)+K(+))ATPase by protein kinase in a trypanosomatid opens up new possibilities to understand the regulation of ion homeostasis in this parasite. PMID:17475255

  4. Sympathetic Neurotransmitters Modulate Osteoclastogenesis and Osteoclast Activity in the Context of Collagen-Induced Arthritis

    PubMed Central

    Muschter, Dominique; Schäfer, Nicole; Stangl, Hubert; Straub, Rainer H.; Grässel, Susanne

    2015-01-01

    Excessive synovial osteoclastogenesis is a hallmark of rheumatoid arthritis (RA). Concomitantly, local synovial changes comprise neuronal components of the peripheral sympathetic nervous system. Here, we wanted to analyze if collagen-induced arthritis (CIA) alters bone marrow-derived macrophage (BMM) osteoclastogenesis and osteoclast activity, and how sympathetic neurotransmitters participate in this process. Therefore, BMMs from Dark Agouti rats at different CIA stages were differentiated into osteoclasts in vitro and osteoclast number, cathepsin K activity, matrix resorption and apoptosis were analyzed in the presence of acetylcholine (ACh), noradrenaline (NA) vasoactive intestinal peptide (VIP) and assay-dependent, adenylyl cyclase activator NKH477. We observed modulation of neurotransmitter receptor mRNA expression in CIA osteoclasts without affecting protein level. CIA stage-dependently altered marker gene expression associated with osteoclast differentiation and activity without affecting osteoclast number or activity. Neurotransmitter stimulation modulated osteoclast differentiation, apoptosis and activity. VIP, NA and adenylyl cyclase activator NKH477 inhibited cathepsin K activity and osteoclastogenesis (NKH477, 10-6M NA) whereas ACh mostly acted pro-osteoclastogenic. We conclude that CIA alone does not affect metabolism of in vitro generated osteoclasts whereas stimulation with NA, VIP plus specific activation of adenylyl cyclase induced anti-resorptive effects probably mediated via cAMP signaling. Contrary, we suggest pro-osteoclastogenic and pro-resorptive properties of ACh mediated via muscarinic receptors. PMID:26431344

  5. Is Brain Activity during Action Observation Modulated by the Perceived Fairness of the Actor?

    PubMed

    Etzel, Joset A; Valchev, Nikola; Gazzola, Valeria; Keysers, Christian

    2016-01-01

    Perceiving other people's actions triggers activity in premotor and parietal areas, brain areas also involved in executing and sensing our own actions. Paralleling this phenomenon, observing emotional states (including pain) in others is associated with activity in the same brain areas as activated when experiencing similar emotions directly. This emotion perception associated activity has been shown to be affected by the perceived fairness of the actor, and in-group membership more generally. Here, we examine whether action observation associated brain activity is also affected by the perceived social fairness of the actors. Perceived fairness was manipulated using an alternating iterated Prisoner's Dilemma game between the participant and two confederates, one of whom played fairly and the other unfairly. During fMRI scanning the participants watched movies of the confederates performing object-directed hand actions, and then performed hand actions themselves. Mass-univariate analysis showed that observing the actions triggered robust activation in regions associated with action execution, but failed to identify a strong modulation of this activation based on perceived fairness. Multivariate pattern analysis, however, identified clusters potentially carrying information about the perceived fairness of the actor in the middle temporal gyrus, left postcentral gyrus, right inferior parietal lobule, right middle cingulate cortex, right angular gyrus, and right superioroccipital gyrus. Despite being identified by a whole-brain searchlight analysis (and so without anatomical restriction), these clusters fall into areas frequently associated with action observation. We conclude that brain activity during action observation may be modulated by perceived fairness, but such modulation is subtle; robust activity is associated with observing the actions of both fair and unfair individuals. PMID:26820995

  6. Is Brain Activity during Action Observation Modulated by the Perceived Fairness of the Actor?

    PubMed Central

    Gazzola, Valeria; Keysers, Christian

    2016-01-01

    Perceiving other people’s actions triggers activity in premotor and parietal areas, brain areas also involved in executing and sensing our own actions. Paralleling this phenomenon, observing emotional states (including pain) in others is associated with activity in the same brain areas as activated when experiencing similar emotions directly. This emotion perception associated activity has been shown to be affected by the perceived fairness of the actor, and in-group membership more generally. Here, we examine whether action observation associated brain activity is also affected by the perceived social fairness of the actors. Perceived fairness was manipulated using an alternating iterated Prisoner’s Dilemma game between the participant and two confederates, one of whom played fairly and the other unfairly. During fMRI scanning the participants watched movies of the confederates performing object-directed hand actions, and then performed hand actions themselves. Mass-univariate analysis showed that observing the actions triggered robust activation in regions associated with action execution, but failed to identify a strong modulation of this activation based on perceived fairness. Multivariate pattern analysis, however, identified clusters potentially carrying information about the perceived fairness of the actor in the middle temporal gyrus, left postcentral gyrus, right inferior parietal lobule, right middle cingulate cortex, right angular gyrus, and right superioroccipital gyrus. Despite being identified by a whole-brain searchlight analysis (and so without anatomical restriction), these clusters fall into areas frequently associated with action observation. We conclude that brain activity during action observation may be modulated by perceived fairness, but such modulation is subtle; robust activity is associated with observing the actions of both fair and unfair individuals. PMID:26820995

  7. Activation Characteristics of Fuel Breeding Blanket Module in Fusion Driven Subcritical System

    NASA Astrophysics Data System (ADS)

    Huang, Qun-Ying; Li, Jian-Gang; Chen, Yi-Xue

    2004-12-01

    Shortage of energy resources and production of long-lived radioactivity wastes from fission reactors are among the main problems which will be faced in the world in the near future. The conceptual design of a fusion driven subcritical system (FDS) is underway in Institute of Plasma Physics, Chinese Academy of Sciences. There are alternative designs for multi-functional blanket modules of the FDS, such as fuel breeding blanket module (FBB) to produce fuels for fission reactors, tritium breeding blanket module to produce the fuel, i.e. tritium, for fusion reactor and waste transmutation blanket module to try to permanently dispose of long-lived radioactivity wastes from fission reactors, etc. Activation of the fuel breeding blanket of the fusion driven subcritical system (FDS-FBB) by D-T fusion neutrons from the plasma and fission neutrons from the hybrid blanket are calculated and analysed under the neutron wall loading 0.5 MW/m2 and neutron fluence 15 MW.yr/m2. The neutron spectrum is calculated with the worldwide-used transport code MCNP/4C and activation calculations are carried out with the well known European inventory code FISPACT/99 with the latest released IAEA Fusion Evaluated Nuclear Data Library FENDL-2.0 and the ENDF/B-V uranium evaluated data. Induced radioactivities, dose rates and afterheats, etc, for different components of the FDS-FBB are compared and analysed.

  8. Amygdala and anterior cingulate cortex activation during affective startle modulation: a PET study of fear.

    PubMed

    Pissiota, Anna; Frans, Orjan; Michelgård, Asa; Appel, Lieuwe; Långström, Bengt; Flaten, Magne Arve; Fredrikson, Mats

    2003-09-01

    The human startle response is modulated by emotional experiences, with startle potentiation associated with negative affect. We used positron emission tomography with 15O-water to study neural networks associated with startle modulation by phobic fear in a group of subjects with specific snake or spider phobia, but not both, during exposure to pictures of their feared and non-feared objects, paired and unpaired with acoustic startle stimuli. Measurement of eye electromyographic activity confirmed startle potentiation during the phobic as compared with the non-phobic condition. Employing a factorial design, we evaluated brain correlates of startle modulation as the interaction between startle and affect, using the double subtraction contrast (phobic startle vs. phobic alone) vs. (non-phobic startle vs. non-phobic alone). As a result of startle potentiation, a significant increase in regional cerebral blood flow was found in the left amygdaloid-hippocampal region, and medially in the affective division of the anterior cingulate cortex (ACC). These results provide evidence from functional brain imaging for a modulatory role of the amygdaloid complex on startle reactions in humans. They also point to the involvement of the affective ACC in the processing of startle stimuli during emotionally aversive experiences. The co-activation of these areas may reflect increased attention to fear-relevant stimuli. Thus, we suggest that the amygdaloid area and the ACC form part of a neural system dedicated to attention and orientation to danger, and that this network modulates startle during negative affect. PMID:12956731

  9. [Potential of pharmacological modulation of level and activity incretins on diabetes mellitus type 2].

    PubMed

    Spasov, A A; Chepljaeva, N I

    2015-01-01

    This review summarizes data on the main approaches used for the search of biologically active compounds modulating the level and physiological activity of incretins. Currently two groups of drugs are used in clinical practice: they either replenish the deficit of incretins (glucagon-like peptide-1 receptor agonists) or inhibit the degradation processes (dipeptidyl peptidase 4 inhibitors). In addition, new groups of substances are actively searched. These include non-peptide agonists of glucagon-like peptide-1 receptors, agonists/antagonists of glucose-dependent insulinotropic peptide, the hybrid polypeptides based on glucagon-like peptide-1 and glucagon. PMID:26350740

  10. Screening and characterization of molecules that modulate the biological activity of IFNs-I.

    PubMed

    Bürgi, Milagros; Zapol'skii, Viktor A; Hinkelmann, Bettina; Köster, Mario; Kaufmann, Dieter E; Sasse, Florenz; Hauser, Hansjörg; Etcheverrigaray, Marina; Kratje, Ricardo; Bollati-Fogolín, Mariela; Oggero, Marcos

    2016-09-10

    Type I Interferons (IFNs-I) are species-specific glycoproteins which play an important role as primary defence against viral infections and that can also modulate the adaptive immune system. In some autoimmune diseases, interferons (IFNs) are over-produced. IFNs are widely used as biopharmaceuticals for a variety of cancer indications, chronic viral diseases, and for their immuno-modulatory action in patients with multiple sclerosis; therefore, increasing their therapeutic efficiency and decreasing their side effects is of high clinical value. In this sense, it is interesting to find molecules that can modulate the activity of IFNs. In order to achieve that, it was necessary to establish a simple, fast and robust assay to analyze numerous compounds simultaneously. We developed four reporter gene assays (RGAs) to identify IFN activity modulator compounds by using WISH-Mx2/EGFP, HeLa-Mx2/EGFP, A549-Mx2/EGFP, and HEp2-Mx2/EGFP reporter cell lines (RCLs). All of them present a Z' factor higher than 0.7. By using these RGAs, natural and synthetic compounds were analyzed simultaneously. A total of 442 compounds were studied by the Low Throughput Screening (LTS) assay using the four RCLs to discriminate between their inhibitory or enhancing effects on IFN activity. Some of them were characterized and 15 leads were identified. Finally, one promising candidate with enhancing effect on IFN-α/-β activity and five compounds with inhibitory effect were described. PMID:27346232

  11. Functional insights into modulation of BKCa channel activity to alter myometrial contractility

    PubMed Central

    Lorca, Ramón A.; Prabagaran, Monali; England, Sarah K.

    2014-01-01

    The large-conductance voltage- and Ca2+-activated K+ channel (BKCa) is an important regulator of membrane excitability in a wide variety of cells and tissues. In myometrial smooth muscle, activation of BKCa plays essential roles in buffering contractility to maintain uterine quiescence during pregnancy and in the transition to a more contractile state at the onset of labor. Multiple mechanisms of modulation have been described to alter BKCa channel activity, expression, and cellular localization. In the myometrium, BKCa is regulated by alternative splicing, protein targeting to the plasma membrane, compartmentation in membrane microdomains, and posttranslational modifications. In addition, interaction with auxiliary proteins (i.e., β1- and β2-subunits), association with G-protein coupled receptor signaling pathways, such as those activated by adrenergic and oxytocin receptors, and hormonal regulation provide further mechanisms of variable modulation of BKCa channel function in myometrial smooth muscle. Here, we provide an overview of these mechanisms of BKCa channel modulation and provide a context for them in relation to myometrial function. PMID:25132821

  12. Insights into structure-activity relationship of GABAA receptor modulating coumarins and furanocoumarins.

    PubMed

    Singhuber, Judith; Baburin, Igor; Ecker, Gerhard F; Kopp, Brigitte; Hering, Steffen

    2011-10-01

    The coumarins imperatorin and osthole are known to exert anticonvulsant activity. We have therefore analyzed the modulation of GABA-induced chloride currents (I(GABA)) by a selection of 18 coumarin derivatives on recombinant α(1)β(2)γ(2S) GABA(A) receptors expressed in Xenopus laevis oocytes by means of the two-microelectrode voltage clamp technique. Osthole (EC(50)=14 ± 1 μM) and oxypeucedanin (EC(50)=25 ± 8 μM) displayed the highest efficiency with I(GABA) potentiation of 116 ± 4 % and 547 ± 56 %, respectively. I(GABA) enhancement by osthole and oxypeucedanin was not inhibited by flumazenil (1 μM) indicating an interaction with a binding site distinct from the benzodiazepine binding site. In general, prenyl residues are essential for the positive modulatory activity, while longer side chains or bulkier residues (e.g. geranyl residues) diminish I(GABA) modulation. Generation of a binary classification tree revealed the importance of polarisability, which is sufficient to distinguish actives from inactives. A 4-point pharmacophore model based on oxypeucedanin - comprising three hydrophobic and one aromatic feature - identified 6 out of 7 actives as hits. In summary, (oxy-)prenylated coumarin derivatives from natural origin represent new GABA(A) receptor modulators. PMID:21749864

  13. Endogenous heparan sulfate and heparin modulate bone morphogenetic protein-4 signaling and activity.

    PubMed

    Khan, Shaukat A; Nelson, Matthew S; Pan, Chendong; Gaffney, Patrick M; Gupta, Pankaj

    2008-06-01

    Bone morphogenetic proteins (BMPs) and their endogenous antagonists are important for brain and bone development and tumor initiation and progression. Heparan sulfate (HS) proteoglycans (HSPG) modulate the activities of BMPs and their antagonists. How glycosaminoglycans (GAGs) influence BMP activity in various malignancies and in inherited abnormalities of GAG metabolism, and the structural features of GAGs essential for modulation of BMP signaling, remain incompletely defined. We examined whether chemically modified soluble heparins, the endogenous HS in malignant cells and the HS accumulated in Hurler syndrome cells influence BMP-4 signaling and activity. We show that both exogenous (soluble) and endogenous GAGs modulate BMP-4 signaling and activity, and that this effect is dependent on specific sulfate residues of GAGs. Our studies suggest that endogenous sulfated GAGs promote the proliferation and impair differentiation of malignant human cells, providing the rationale for investigating whether pharmacological agents that inhibit GAG synthesis or function might reverse this effect. Our demonstration of impairment of BMP-4 signaling by GAGs in multipotent stem cells in human Hurler syndrome identifies a mechanism that might contribute to the progressive neurological and skeletal abnormalities in Hurler syndrome and related mucopolysaccharidoses. PMID:18385288

  14. Boronic Acid-Appended Molecular Glues for ATP-Responsive Activity Modulation of Enzymes.

    PubMed

    Okuro, Kou; Sasaki, Mizuki; Aida, Takuzo

    2016-05-01

    Water-soluble linear polymers GumBAn (m/n = 18/6, 12/12, and 6/18) with multiple guanidinium ion (Gu(+)) and boronic acid (BA) pendants in their side chains were synthesized as ATP-responsive modulators for enzyme activity. GumBAn polymers strongly bind to the phosphate ion (PO4(-)) and 1,2-diol units of ATP via the Gu(+) and BA pendants, respectively. As only the Gu(+) pendants can be used for proteins, GumBAn is able to modulate the activity of enzymes in response to ATP. As a proof-of-concept study, we demonstrated that trypsin (Trp) can be deactivated by hybridization with GumBAn. However, upon addition of ATP, Trp was liberated to retrieve its hydrolytic activity due to a higher preference of GumBAn toward ATP than Trp. This event occurred in a much lower range of [ATP] than reported examples. Under cellular conditions, the hydrolytic activity of Trp was likewise modulated. PMID:27087468

  15. Movement-related parameters modulate cortical activity during imaginary isometric plantar-flexions.

    PubMed

    do Nascimento, Omar Feix; Nielsen, Kim Dremstrup; Voigt, Michael

    2006-05-01

    A multitude of studies have demonstrated a clear activation of the motor cortex during imagination of various motor tasks; however, it is still unclear if movement-related parameters (movement direction, range of motion, speed, force level and rate of force development) specifically modulate cortical activation as they do during the execution of actual motor tasks. Accordingly, this study examined whether the rate of torque development (RTD) and/or the torque amplitude modulates cortical potentials generated during imaginary motor tasks. Fifteen subjects imagined four different left-sided isometric plantar-flexion tasks, while EEG and EMG recordings were being performed. The averaged EEG activity was analyzed in terms of movement-related potentials (MRPs), consisting of readiness potential (RP), motor potential (MP) and movement-monitoring potential (MMP). It was demonstrated that RTD and torque amplitude indeed modulate cortical activity during imaginary motor tasks. Information concerning movement-related parameters for imaginary plantar-flexion tasks seems to be encoded in the supplementary motor area (SMA) and the primary motor cortex (M1). A comparison between MRPs of imaginary and actual motor tasks revealed that early MRPs were morphologically similar, but differed significantly in amplitude. One of the possible suggestions to explain such a difference may be an "abortion" of ongoing motor programs. PMID:16320044

  16. [Radioresistance parameters in head and neck cancers and methods to radiosensitize].

    PubMed

    Biau, J; Chautard, E; Miroir, J; Lapeyre, M

    2015-08-01

    Head and neck cancers have been widely studied concerning their sensitivity to radiation therapy. Several parameters affect tumour response to radiation therapy. Some parameters are linked to the tumour. Large or invasive tumours, localization, such as oral cavity or adenopathy, are factors of radioresistance. Others parameters are linked to the patients themselves. Tobacco intoxication during radiotherapy and a low hemoglobin level contribute to radioresistance. More recently, a positive human papilloma virus (HPV) status has been reported to positively affect radiosensitivity. Finally, other parameters are related to tumour biology. Hypoxia, intrinsic radiosensitivity of tumour cells, tumour differentiation and repopulation (provided by Ki-67 index or EGFR level) are components of radiosensitivity. Currently, concurrent chemoradiotherapy is one of the gold standard treatments to overcome clinical outcome of locally advanced head and neck cancer. This combination increases locoregional control and survival. Taxane-based induction chemotherapy can also be an alternative. Another validated approach is the association of radiotherapy with cetuximab (EGFR targeting) but only one randomized study has been published. Fractionation modifications, especially hyperfractionation, have given positive results on both tumour control and survival. Strategies targeting hypoxia improve locoregional control but have less clinical impact. PMID:26119219

  17. A role for chromosomal instability in the development of and selection for radioresistant cell variants

    NASA Technical Reports Server (NTRS)

    Limoli, C. L.; Corcoran, J. J.; Jordan, R.; Morgan, W. F.; Schwartz, J. L.

    2001-01-01

    Chromosome instability is a common occurrence in tumour cells. We examined the hypothesis that the elevated rate of mutation formation in unstable cells can lead to the development of clones of cells that are resistant to the cancer therapy. To test this hypothesis, we compared chromosome instability to radiation sensitivity in 30 independently isolated clones of GM10115 human-hamster hybrid cells. There was a broader distribution of radiosensitivity and a higher mean SF(2)in chromosomally unstable clones. Cytogenetic and DNA double-strand break rejoining assays suggest that sensitivity was a function of DNA repair efficiency. In the unstable population, the more radioresistant clones also had significantly lower plating efficiencies. These observations suggest that chromosome instability in GM10115 cells can lead to the development of cell variants that are more resistant to radiation. In addition, these results suggest that the process of chromosome breakage and recombination that accompanies chromosome instability might provide some selective pressure for more radioresistant variants. Copyright 2001 Cancer Research Campaign.

  18. Erythropoietin Modulates Cerebral and Serum Degradation Products from Excess Calpain Activation following Prenatal Hypoxia-Ischemia.

    PubMed

    Jantzie, Lauren L; Winer, Jesse L; Corbett, Christopher J; Robinson, Shenandoah

    2016-01-01

    Preterm infants suffer central nervous system (CNS) injury from hypoxia-ischemia and inflammation - termed encephalopathy of prematurity. Mature CNS injury activates caspase and calpain proteases. Erythropoietin (EPO) limits apoptosis mediated by activated caspases, but its role in modulating calpain activation has not yet been investigated extensively following injury to the developing CNS. We hypothesized that excess calpain activation degrades developmentally regulated molecules essential for CNS circuit formation, myelination and axon integrity, including neuronal potassium-chloride co-transporter (KCC2), myelin basic protein (MBP) and phosphorylated neurofilament (pNF), respectively. Further, we predicted that post-injury EPO treatment could mitigate CNS calpain-mediated degradation. Using prenatal transient systemic hypoxia-ischemia (TSHI) in rats to mimic CNS injury from extreme preterm birth, and postnatal EPO treatment with a clinically relevant dosing regimen, we found sustained postnatal excess cortical calpain activation following prenatal TSHI, as shown by the cleavage of alpha II-spectrin (αII-spectrin) into 145-kDa αII-spectrin degradation products (αII-SDPs) and p35 into p25. Postnatal expression of the endogenous calpain inhibitor calpastatin was also reduced following prenatal TSHI. Calpain substrate expression following TSHI, including cortical KCC2, MBP and NF, was modulated by postnatal EPO treatment. Calpain activation was reflected in serum levels of αII-SDPs and KCC2 fragments, and notably, EPO treatment also modulated KCC2 fragment levels. Together, these data indicate that excess calpain activity contributes to the pathogenesis of encephalopathy of prematurity. Serum biomarkers of calpain activation may detect ongoing cerebral injury and responsiveness to EPO or similar neuroprotective strategies. PMID:26551007

  19. Induction and modulation of persistent activity in a layer V PFC microcircuit model.

    PubMed

    Papoutsi, Athanasia; Sidiropoulou, Kyriaki; Cutsuridis, Vassilis; Poirazi, Panayiota

    2013-01-01

    Working memory refers to the temporary storage of information and is strongly associated with the prefrontal cortex (PFC). Persistent activity of cortical neurons, namely the activity that persists beyond the stimulus presentation, is considered the cellular correlate of working memory. Although past studies suggested that this type of activity is characteristic of large scale networks, recent experimental evidence imply that small, tightly interconnected clusters of neurons in the cortex may support similar functionalities. However, very little is known about the biophysical mechanisms giving rise to persistent activity in small-sized microcircuits in the PFC. Here, we present a detailed biophysically-yet morphologically simplified-microcircuit model of layer V PFC neurons that incorporates connectivity constraints and is validated against a multitude of experimental data. We show that (a) a small-sized network can exhibit persistent activity under realistic stimulus conditions. (b) Its emergence depends strongly on the interplay of dADP, NMDA, and GABAB currents. (c) Although increases in stimulus duration increase the probability of persistent activity induction, variability in the stimulus firing frequency does not consistently influence it. (d) Modulation of ionic conductances (I h , I D , I sAHP, I caL, I caN, I caR) differentially controls persistent activity properties in a location dependent manner. These findings suggest that modulation of the microcircuit's firing characteristics is achieved primarily through changes in its intrinsic mechanism makeup, supporting the hypothesis of multiple bi-stable units in the PFC. Overall, the model generates a number of experimentally testable predictions that may lead to a better understanding of the biophysical mechanisms of persistent activity induction and modulation in the PFC. PMID:24130519

  20. Subthalamic stimulation modulates cortical motor network activity and synchronization in Parkinson's disease.

    PubMed

    Weiss, Daniel; Klotz, Rosa; Govindan, Rathinaswamy B; Scholten, Marlieke; Naros, Georgios; Ramos-Murguialday, Ander; Bunjes, Friedemann; Meisner, Christoph; Plewnia, Christian; Krüger, Rejko; Gharabaghi, Alireza

    2015-03-01

    Dynamic modulations of large-scale network activity and synchronization are inherent to a broad spectrum of cognitive processes and are disturbed in neuropsychiatric conditions including Parkinson's disease. Here, we set out to address the motor network activity and synchronization in Parkinson's disease and its modulation with subthalamic stimulation. To this end, 20 patients with idiopathic Parkinson's disease with subthalamic nucleus stimulation were analysed on externally cued right hand finger movements with 1.5-s interstimulus interval. Simultaneous recordings were obtained from electromyography on antagonistic muscles (right flexor digitorum and extensor digitorum) together with 64-channel electroencephalography. Time-frequency event-related spectral perturbations were assessed to determine cortical and muscular activity. Next, cross-spectra in the time-frequency domain were analysed to explore the cortico-cortical synchronization. The time-frequency modulations enabled us to select a time-frequency range relevant for motor processing. On these time-frequency windows, we developed an extension of the phase synchronization index to quantify the global cortico-cortical synchronization and to obtain topographic differentiations of distinct electrode sites with respect to their contributions to the global phase synchronization index. The spectral measures were used to predict clinical and reaction time outcome using regression analysis. We found that movement-related desynchronization of cortical activity in the upper alpha and beta range was significantly facilitated with 'stimulation on' compared to 'stimulation off' on electrodes over the bilateral parietal, sensorimotor, premotor, supplementary-motor, and prefrontal areas, including the bilateral inferior prefrontal areas. These spectral modulations enabled us to predict both clinical and reaction time improvement from subthalamic stimulation. With 'stimulation on', interhemispheric cortico

  1. Exogenously induced brain activation regulates neuronal activity by top-down modulation: conceptualized model for electrical brain stimulation.

    PubMed

    Spezia Adachi, Lauren Naomi; Quevedo, Alexandre Silva; de Souza, Andressa; Scarabelot, Vanessa Leal; Rozisky, Joanna Ripoll; de Oliveira, Carla; Marques Filho, Paulo Ricardo; Medeiros, Liciane Fernandes; Fregni, Felipe; Caumo, Wolnei; Torres, Iraci L S

    2015-05-01

    Physiological and exogenous factors are able to adjust sensory processing by modulating activity at different levels of the nervous system hierarchy. Accordingly, transcranial direct current stimulation (tDCS) may use top-down mechanisms to control the access for incoming information along the neuroaxis. To test the hypothesis that brain activation induced by tCDS is able to initiate top-down modulation and that chronic stress disrupts this effect, 60-day-old male Wistar rats (n = 78) were divided into control; control + tDCS; control + sham-tDCS; stress; stress + tDCS; and stress + sham-tDCS. Chronic stress was induced using a restraint stress model for 11 weeks, and then, the treatment was applied over 8 days. BDNF levels were used to assess neuronal activity at spinal cord, brainstem, and hippocampus. Mechanical pain threshold was assessed by von Frey test immediately and 24 h after the last tDCS-intervention. tDCS was able to decrease BDNF levels in the structures involved in the descending systems (spinal cord and brainstem) only in unstressed animals. The treatment was able to reverse the stress-induced allodynia and to increase the pain threshold in unstressed animals. Furthermore, there was an inverse relation between pain sensitivity and spinal cord BDNF levels. Accordingly, we propose the addition of descending systems in the current brain electrical modulation model. PMID:25665871

  2. Positive affect modulates activity in the visual cortex to images of high calorie foods.

    PubMed

    Killgore, William D S; Yurgelun-Todd, Deborah A

    2007-05-01

    Activity within the visual cortex can be influenced by the emotional salience of a stimulus, but it is not clear whether such cortical activity is modulated by the affective status of the individual. This study used functional magnetic resonance imaging (fMRI) to examine the relationship between affect ratings on the Positive and Negative Affect Schedule and activity within the occipital cortex of 13 normal-weight women while viewing images of high calorie and low calorie foods. Regression analyses revealed that when participants viewed high calorie foods, Positive Affect correlated significantly with activity within the lingual gyrus and calcarine cortex, whereas Negative Affect was unrelated to visual cortex activity. In contrast, during presentations of low calorie foods, affect ratings, regardless of valence, were unrelated to occipital cortex activity. These findings suggest a mechanism whereby positive affective state may affect the early stages of sensory processing, possibly influencing subsequent perceptual experience of a stimulus. PMID:17464782

  3. In Vivo Modulation of T-DNA Encoded Amidohydrolase Activity in Transformed Tobacco Cells 1

    PubMed Central

    Kuleck, Gary A.; Binns, Andrew N.; Black, Robert C.

    1991-01-01

    Auxin autonomous growth of most crown gall tumor cells requires the expression of two auxin biosynthesizing genes (tms 1 and tms 2) from the T-DNA of Agrobacterium tumefaciens. The potential role of the tms 2 locus to affect auxin accumulation was studied by measuring the activity of its gene product, indoleacetamide hydrolase (AH), in cloned cells of tobacco (Nicotiana tabacum) transformed by the A6 strain of Agrobacterium tumefaciens. AH activity followed a consistent pattern over a 30 day culture cycle with a peak at 10 to 14 days. This same pattern was observed in a number of independently isolated clones as well as in uncioned tumor tissue, suggesting that AH activation is a regular process in wounded, transformed cells. Transfer of unwounded tissue to fresh media resulted in a similar pattern of AH activation, but with the peak activity only about 50 percent of the cut tissues. These results show that the tms 2 encoded AH activity is modulated over the culture cycle, and that the modulation is affected by wounding and supplying fresh nutrients in the medium. AH activity correlated closely with free indoleacetic acid levels which suggests that it can be an important determinant in controlling free IAA levels in transformed cells. PMID:16668084

  4. Modulation of Activity Profiles for Largazole-Based HDAC Inhibitors through Alteration of Prodrug Properties

    PubMed Central

    2014-01-01

    Largazole is a potent and class I-selective histone deacetylase (HDAC) inhibitor purified from marine cyanobacteria and was demonstrated to possess antitumor activity. Largazole employs a unique prodrug strategy, via a thioester moiety, to liberate the bioactive species largazole thiol. Here we report alternate prodrug strategies to modulate the pharmacokinetic and pharmacodynamics profiles of new largazole-based compounds. The in vitro effects of largazole analogues on cancer cell proliferation and enzymatic activities of purified HDACs were comparable to the natural product. However, in vitro and in vivo histone hyperacetylation in HCT116 cells and implanted tumors, respectively, showed differences, particularly in the onset of action and oral bioavailability. These results indicate that, by employing a different approach to disguise the “warhead” moiety, the functional consequence of these prodrugs can be significantly modulated. Our data corroborate the role of the pharmacokinetic properties of this class of compounds to elicit the desired and timely functional response. PMID:25147612

  5. Aloe vera: Potential candidate in health management via modulation of biological activities

    PubMed Central

    Rahmani, Arshad H.; Aldebasi, Yousef H.; Srikar, Sauda; Khan, Amjad A.; Aly, Salah M.

    2015-01-01

    Treatment based on natural products is rapidly increasing worldwide due to the affordability and fewer side effects of such treatment. Various plants and the products derived from them are commonly used in primary health treatment, and they play a pivotal role in the treatment of diseases via modulation of biochemical and molecular pathways. Aloe vera, a succulent species, produces gel and latex, plays a therapeutic role in health management through antioxidant, antitumor, and anti-inflammatory activities, and also offers a suitable alternative approach for the treatment of various types of diseases. In this review, we summarize the possible mechanism of action and the therapeutic implications of Aloe vera in health maintenance based on its modulation of various biological activities. PMID:26392709

  6. Synthetic ceramide analogues increase amyloid-β 42 production by modulating γ-secretase activity.

    PubMed

    Takasugi, Nobumasa; Sasaki, Tomoki; Shinohara, Mitsuru; Iwatsubo, Takeshi; Tomita, Taisuke

    2015-02-01

    γ-Secretase cleaves amyloid β-precursor protein (APP) to generate amyloid-β peptide (Aβ), which is a causative molecule of Alzheimer disease (AD). The C-terminal length of Aβ, which is determined by γ-secretase activity, determines the aggregation and deposition profiles of Aβ, thereby affecting the onset of AD. In this study, we found that the synthetic ceramide analogues dl-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) and (1S,2R-d-erythro-2-N-myristoylamino)-1-phenyl-1-propanol (DMAPP) modulated γ-secretase-mediated cleavage to increase Aβ42 production. Unexpectedly, PDMP and DMAPP upregulated Aβ42 production independent of alteration of ceramide metabolism. Our results propose that synthetic ceramide analogues function as novel γ-secretase modulators that increase Aβ42, and this finding might lead to the understanding of the effect of the lipid environment on γ-secretase activity. PMID:25545059

  7. Aloe vera: Potential candidate in health management via modulation of biological activities.

    PubMed

    Rahmani, Arshad H; Aldebasi, Yousef H; Srikar, Sauda; Khan, Amjad A; Aly, Salah M

    2015-01-01

    Treatment based on natural products is rapidly increasing worldwide due to the affordability and fewer side effects of such treatment. Various plants and the products derived from them are commonly used in primary health treatment, and they play a pivotal role in the treatment of diseases via modulation of biochemical and molecular pathways. Aloe vera, a succulent species, produces gel and latex, plays a therapeutic role in health management through antioxidant, antitumor, and anti-inflammatory activities, and also offers a suitable alternative approach for the treatment of various types of diseases. In this review, we summarize the possible mechanism of action and the therapeutic implications of Aloe vera in health maintenance based on its modulation of various biological activities. PMID:26392709

  8. Phenolic composition and antioxidant activity in sparkling wines: modulation by the ageing on lees.

    PubMed

    Stefenon, C A; Bonesi, C De M; Marzarotto, V; Barnabé, D; Spinelli, F R; Webber, V; Vanderlinde, R

    2014-02-15

    Sparkling wines (SW) have a special biological ageing on lees that is performed using two distinct methods: in the bottle (Champenoise) or in isobaric tanks (Charmat method). The objective of this study was to compare the levels of phenolic compounds, β-Glucosidase and antioxidant activity during the ageing on lees, in samples of SW produced at industrial scale by both methods. The β-Glucosidase activity has been constant over time, showing a close relationship with all the polyphenols studied (resveratrol, piceid, tyrosol, gallic, caffeic and ferulic acids), which were affected by the sur lie time. With these cross-reactions, the biological properties of the SW were also modulated. The results showed that the long period of ageing decreased the antioxidant potential in all samples. This work demonstrates that the sur lie is more important than the production method itself, due to its ability to modulate the necessary changes to achieve the specific objective. PMID:24128480

  9. Social touch modulates endogenous μ-opioid system activity in humans.

    PubMed

    Nummenmaa, Lauri; Tuominen, Lauri; Dunbar, Robin; Hirvonen, Jussi; Manninen, Sandra; Arponen, Eveliina; Machin, Anna; Hari, Riitta; Jääskeläinen, Iiro P; Sams, Mikko

    2016-09-01

    In non-human primates, opioid-receptor blockade increases social grooming, and the endogenous opioid system has therefore been hypothesized to support maintenance of long-term relationships in humans as well. Here we tested whether social touch modulates opioidergic activation in humans using in vivo positron emission tomography (PET). Eighteen male participants underwent two PET scans with [11C]carfentanil, a ligand specific to μ-opioid receptors (MOR). During the social touch scan, the participants lay in the scanner while their partners caressed their bodies in a non-sexual fashion. In the baseline scan, participants lay alone in the scanner. Social touch triggered pleasurable sensations and increased MOR availability in the thalamus, striatum, and frontal, cingulate, and insular cortices. Modulation of activity of the opioid system by social touching might provide a neurochemical mechanism reinforcing social bonds between humans. PMID:27238727

  10. Different Mechanisms of Cell Death in Radiosensitive and Radioresistant P53 Mutated Head and Neck Squamous Cell Carcinoma Cell Lines Exposed to Carbon Ions and X-Rays

    SciTech Connect

    Maalouf, Mira; Alphonse, Gersende; Colliaux, Anthony; Beuve, Michael Ph.D.; Trajkovic-Bodennec, Selena; Battiston-Montagne, Priscillia B.Sc.; Testard, Isabelle; Chapet, Olivier; Bajard, Marcel; Taucher-Scholz, Gisela; Fournier, Claudia; Rodriguez-Lafrasse, Claire

    2009-05-01

    Purpose: We initiated studies on the mechanisms of cell death in head and neck squamous cell carcinoma cell lines (HNSCC) since recent clinical trials have shown that local treatment of HNSCC by carbon hadrontherapy is less efficient than it is in other radioresistant cancers. Methods and Materials: Two p53-mutated HNSCC cell lines displaying opposite radiosensitivity were used. Different types of cell death were determined after exposure to carbon ions (33.6 and 184 keV/{mu}m) or X-rays. Results: Exposure to radiation with high linear energy transfer (LET) induced clonogenic cell death for SCC61 (radiosensitive) and SQ20B (radioresistant) cells, the latter systematically showing less sensitivity. Activation of an early p53-independent apoptotic process occurred in SCC61 cells after both types of irradiation, which increased with time, dose and LET. In contrast, SQ20B cells underwent G2/M arrest associated with Chk1 activation and Cdc2 phosphorylation. This inhibition was transient after X-rays, compared with a more prolonged and LET-dependent accumulation after carbon irradiation. After release, a LET-dependent increase of polyploid and multinucleated cells, both typical signs of mitotic catastrophe, was identified. However, a subpopulation of SQ20B cells was able to escape mitotic catastrophe and continue to proliferate. Conclusions: High LET irradiation induced distinct types of cell death in HNSCC cell lines and showed an increased effectiveness compared with X-rays. However, the reproliferation of SQ20B may explain the potential locoregional recurrence observed among some HNSCC patients treated by hadrontherapy. An adjuvant treatment forcing the tumor cells to enter apoptosis may therefore be necessary to improve the outcome of radiotherapy.

  11. Metal-mediated modulation of streptococcal cysteine protease activity and its biological implications.

    PubMed

    Chella Krishnan, Karthickeyan; Mukundan, Santhosh; Landero Figueroa, Julio A; Caruso, Joseph A; Kotb, Malak

    2014-07-01

    Streptococcal cysteine protease (SpeB), the major secreted protease produced by group A streptococcus (GAS), cleaves both host and bacterial proteins and contributes importantly to the pathogenesis of invasive GAS infections. Modulation of SpeB expression and/or its activity during invasive GAS infections has been shown to affect bacterial virulence and infection severity. Expression of SpeB is regulated by the GAS CovR-CovS two-component regulatory system, and we demonstrated that bacteria with mutations in the CovR-CovS two-component regulatory system are selected for during localized GAS infections and that these bacteria lack SpeB expression and exhibit a hypervirulent phenotype. Additionally, in a separate study, we showed that expression of SpeB can also be modulated by human transferrin- and/or lactoferrin-mediated iron chelation. Accordingly, the goal of this study was to investigate the possible roles of iron and other metals in modulating SpeB expression and/or activity in a manner that would potentiate bacterial virulence. Here, we report that the divalent metals zinc and copper inhibit SpeB activity at the posttranslational level. Utilizing online metal-binding site prediction servers, we identified two putative metal-binding sites in SpeB, one of which involves the catalytic-dyad residues (47)Cys and (195)His. Based on our findings, we propose that zinc and/or copper availability in the bacterial microenvironment can modulate the proteolytic activity of SpeB in a manner that preserves the integrity of several other virulence factors essential for bacterial survival and dissemination within the host and thereby may exacerbate the severity of invasive GAS infections. PMID:24799625

  12. Metal-Mediated Modulation of Streptococcal Cysteine Protease Activity and Its Biological Implications

    PubMed Central

    Chella Krishnan, Karthickeyan; Mukundan, Santhosh; Landero Figueroa, Julio A.; Caruso, Joseph A.

    2014-01-01

    Streptococcal cysteine protease (SpeB), the major secreted protease produced by group A streptococcus (GAS), cleaves both host and bacterial proteins and contributes importantly to the pathogenesis of invasive GAS infections. Modulation of SpeB expression and/or its activity during invasive GAS infections has been shown to affect bacterial virulence and infection severity. Expression of SpeB is regulated by the GAS CovR-CovS two-component regulatory system, and we demonstrated that bacteria with mutations in the CovR-CovS two-component regulatory system are selected for during localized GAS infections and that these bacteria lack SpeB expression and exhibit a hypervirulent phenotype. Additionally, in a separate study, we showed that expression of SpeB can also be modulated by human transferrin- and/or lactoferrin-mediated iron chelation. Accordingly, the goal of this study was to investigate the possible roles of iron and other metals in modulating SpeB expression and/or activity in a manner that would potentiate bacterial virulence. Here, we report that the divalent metals zinc and copper inhibit SpeB activity at the posttranslational level. Utilizing online metal-binding site prediction servers, we identified two putative metal-binding sites in SpeB, one of which involves the catalytic-dyad residues 47Cys and 195His. Based on our findings, we propose that zinc and/or copper availability in the bacterial microenvironment can modulate the proteolytic activity of SpeB in a manner that preserves the integrity of several other virulence factors essential for bacterial survival and dissemination within the host and thereby may exacerbate the severity of invasive GAS infections. PMID:24799625

  13. Robust Stimulation of W1282X-CFTR Channel Activity by a Combination of Allosteric Modulators

    PubMed Central

    Wang, Wei; Hong, Jeong S.; Rab, Andras; Sorscher, Eric J.; Kirk, Kevin L.

    2016-01-01

    W1282X is a common nonsense mutation among cystic fibrosis patients that results in the production of a truncated Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Here we show that the channel activity of the W1282X-CFTR polypeptide is exceptionally low in excised membrane patches at normally saturating doses of ATP and PKA (single channel open probability (PO) < 0.01). However, W1282X-CFTR channels were stimulated by two CFTR modulators, the FDA-approved VX-770 and the dietary compound curcumin. Each of these compounds is an allosteric modulator of CFTR gating that promotes channel activity in the absence of the native ligand, ATP. Although W1282X-CFTR channels were stimulated by VX-770 in the absence of ATP their activities remained dependent on PKA phosphorylation. Thus, activated W1282X-CFTR channels should remain under physiologic control by cyclic nucleotide signaling pathways in vivo. VX-770 and curcumin exerted additive effects on W1282X-CFTR channel gating (opening/closing) in excised patches such that the Po of the truncated channel approached unity (> 0.9) when treated with both modulators. VX-770 and curcumin also additively stimulated W1282X-CFTR mediated currents in polarized FRT epithelial monolayers. In this setting, however, the stimulated W1282X-CFTR currents were smaller than those mediated by wild type CFTR (3–5%) due presumably to lower expression levels or cell surface targeting of the truncated protein. Combining allosteric modulators of different mechanistic classes is worth considering as a treatment option for W1282X CF patients perhaps when coupled with maneuvers to increase expression of the truncated protein. PMID:27007499

  14. Robust Stimulation of W1282X-CFTR Channel Activity by a Combination of Allosteric Modulators.

    PubMed

    Wang, Wei; Hong, Jeong S; Rab, Andras; Sorscher, Eric J; Kirk, Kevin L

    2016-01-01

    W1282X is a common nonsense mutation among cystic fibrosis patients that results in the production of a truncated Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Here we show that the channel activity of the W1282X-CFTR polypeptide is exceptionally low in excised membrane patches at normally saturating doses of ATP and PKA (single channel open probability (PO) < 0.01). However, W1282X-CFTR channels were stimulated by two CFTR modulators, the FDA-approved VX-770 and the dietary compound curcumin. Each of these compounds is an allosteric modulator of CFTR gating that promotes channel activity in the absence of the native ligand, ATP. Although W1282X-CFTR channels were stimulated by VX-770 in the absence of ATP their activities remained dependent on PKA phosphorylation. Thus, activated W1282X-CFTR channels should remain under physiologic control by cyclic nucleotide signaling pathways in vivo. VX-770 and curcumin exerted additive effects on W1282X-CFTR channel gating (opening/closing) in excised patches such that the Po of the truncated channel approached unity (> 0.9) when treated with both modulators. VX-770 and curcumin also additively stimulated W1282X-CFTR mediated currents in polarized FRT epithelial monolayers. In this setting, however, the stimulated W1282X-CFTR currents were smaller than those mediated by wild type CFTR (3-5%) due presumably to lower expression levels or cell surface targeting of the truncated protein. Combining allosteric modulators of different mechanistic classes is worth considering as a treatment option for W1282X CF patients perhaps when coupled with maneuvers to increase expression of the truncated protein. PMID:27007499

  15. Transcranial Direct Current Stimulation Modulates Neuronal Activity and Learning in Pilot Training

    PubMed Central

    Choe, Jaehoon; Coffman, Brian A.; Bergstedt, Dylan T.; Ziegler, Matthias D.; Phillips, Matthew E.

    2016-01-01

    Skill acquisition requires distributed learning both within (online) and across (offline) days to consolidate experiences into newly learned abilities. In particular, piloting an aircraft requires skills developed from extensive training and practice. Here, we tested the hypothesis that transcranial direct current stimulation (tDCS) can modulate neuronal function to improve skill learning and performance during flight simulator training of aircraft landing procedures. Thirty-two right-handed participants consented to participate in four consecutive daily sessions of flight simulation training and received sham or anodal high-definition-tDCS to the right dorsolateral prefrontal cortex (DLPFC) or left motor cortex (M1) in a randomized, double-blind experiment. Continuous electroencephalography (EEG) and functional near infrared spectroscopy (fNIRS) were collected during flight simulation, n-back working memory, and resting-state assessments. tDCS of the right DLPFC increased midline-frontal theta-band activity in flight and n-back working memory training, confirming tDCS-related modulation of brain processes involved in executive function. This modulation corresponded to a significantly different online and offline learning rates for working memory accuracy and decreased inter-subject behavioral variability in flight and n-back tasks in the DLPFC stimulation group. Additionally, tDCS of left M1 increased parietal alpha power during flight tasks and tDCS to the right DLPFC increased midline frontal theta-band power during n-back and flight tasks. These results demonstrate a modulation of group variance in skill acquisition through an increasing in learned skill consistency in cognitive and real-world tasks with tDCS. Further, tDCS performance improvements corresponded to changes in electrophysiological and blood-oxygenation activity of the DLPFC and motor cortices, providing a stronger link between modulated neuronal function and behavior. PMID:26903841

  16. Transcranial Direct Current Stimulation Modulates Neuronal Activity and Learning in Pilot Training.

    PubMed

    Choe, Jaehoon; Coffman, Brian A; Bergstedt, Dylan T; Ziegler, Matthias D; Phillips, Matthew E

    2016-01-01

    Skill acquisition requires distributed learning both within (online) and across (offline) days to consolidate experiences into newly learned abilities. In particular, piloting an aircraft requires skills developed from extensive training and practice. Here, we tested the hypothesis that transcranial direct current stimulation (tDCS) can modulate neuronal function to improve skill learning and performance during flight simulator training of aircraft landing procedures. Thirty-two right-handed participants consented to participate in four consecutive daily sessions of flight simulation training and received sham or anodal high-definition-tDCS to the right dorsolateral prefrontal cortex (DLPFC) or left motor cortex (M1) in a randomized, double-blind experiment. Continuous electroencephalography (EEG) and functional near infrared spectroscopy (fNIRS) were collected during flight simulation, n-back working memory, and resting-state assessments. tDCS of the right DLPFC increased midline-frontal theta-band activity in flight and n-back working memory training, confirming tDCS-related modulation of brain processes involved in executive function. This modulation corresponded to a significantly different online and offline learning rates for working memory accuracy and decreased inter-subject behavioral variability in flight and n-back tasks in the DLPFC stimulation group. Additionally, tDCS of left M1 increased parietal alpha power during flight tasks and tDCS to the right DLPFC increased midline frontal theta-band power during n-back and flight tasks. These results demonstrate a modulation of group variance in skill acquisition through an increasing in learned skill consistency in cognitive and real-world tasks with tDCS. Further, tDCS performance improvements corresponded to changes in electrophysiological and blood-oxygenation activity of the DLPFC and motor cortices, providing a stronger link between modulated neuronal function and behavior. PMID:26903841

  17. Exploring the structure-activity relationships of ABCC2 modulators using a screening approach.

    PubMed

    Wissel, Gloria; Kudryavtsev, Pavel; Ghemtio, Leo; Tammela, Päivi; Wipf, Peter; Yliperttula, Marjo; Finel, Moshe; Urtti, Arto; Kidron, Heidi; Xhaard, Henri

    2015-07-01

    ABCC2 is a transporter with key influence on liver and kidney pharmacokinetics. In order to explore the structure-activity relationships of compounds that modulate ABCC2, and by doing so gain insights into drug-drug interactions, we screened a library of 432 compounds for modulators of radiolabeled β-estradiol 17-(β-d-glucuronide) (EG) and fluorescent 5(6)-carboxy-2',7'-dichlorofluorescein transport (CDCF) in membrane vesicles. Following the primary screen at 80μM, dose-response curves were used to investigate in detail 86 compounds, identifying 16 low μM inhibitors and providing data about the structure-activity relationships in four series containing 19, 24, 10, and eight analogues. Measurements with the CDCF probe were consistently more robust than for the EG probe. Only one compound was clearly probe-selective with a 50-fold difference in the IC50s obtained by the two assays. We built 24 classification models using the SVM and fused-XY Kohonen methods, revealing molecular descriptors related to number of rings, solubility and lipophilicity as important to distinguish inhibitors from inactive compounds. This study is to the best of our knowledge the first to provide details about structure-activity relationships in ABCC2 modulation. PMID:25935289

  18. Allosteric modulation of metabotropic glutamate receptor 4 activates IDO1-dependent, immunoregulatory signaling in dendritic cells

    PubMed Central

    Volpi, Claudia; Mondanelli, Giada; Pallotta, Maria T.; Vacca, Carmine; Iacono, Alberta; Gargaro, Marco; Albini, Elisa; Bianchi, Roberta; Belladonna, Maria L.; Celanire, Sylvain; Mordant, Céline; Heroux, Madeleine; Royer-Urios, Isabelle; Schneider, Manfred; Vitte, Pierre-Alain; Cacquevel, Mathias; Galibert, Laurent; Poli, Sonia-Maria; Solari, Aldo; Bicciato, Silvio; Calvitti, Mario; Antognelli, Cinzia; Puccetti, Paolo; Orabona, Ciriana; Fallarino, Francesca; Grohmann, Ursula

    2016-01-01

    Metabotropic glutamate receptor 4 (mGluR4) possesses immune modulatory properties in vivo, such that a positive allosteric modulator (PAM) of the receptor confers protection on mice with relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE). ADX88178 is a newly-developed, one such mGluR4 modulator with high selectivity, potency, and optimized pharmacokinetics. Here we found that application of ADX88178 in the RR-EAE model system converted disease into a form of mild—yet chronic—neuroinflammation that remained stable for over two months after discontinuing drug treatment. In vitro, ADX88178 modulated the cytokine secretion profile of dendritic cells (DCs), increasing production of tolerogenic IL-10 and TGF-β. The in vitro effects required activation of a Gi-independent, alternative signaling pathway that involved phosphatidylinositol-3-kinase (PI3K), Src kinase, and the signaling activity of indoleamine 2,3-dioxygenase 1 (IDO1). A PI3K inhibitor as well as small interfering RNA targeting Ido1—but not pertussis toxin, which affects Gi protein-dependent responses—abrogated the tolerogenic effects of ADX88178-conditioned DCs in vivo. Thus our data indicate that, in DCs, highly selective and potent mGluR4 PAMs such as ADX88178 may activate a Gi-independent, long-lived regulatory pathway that could be therapeutically exploited in chronic autoimmune diseases such as multiple sclerosis. PMID:26522434

  19. Modulation of Runx2 Activity by Estrogen Receptor-α: Implications for Osteoporosis and Breast Cancer

    PubMed Central

    Khalid, Omar; Baniwal, Sanjeev K.; Purcell, Daniel J.; Leclerc, Nathalie; Gabet, Yankel; Stallcup, Michael R.; Coetzee, Gerhard A.; Frenkel, Baruch

    2008-01-01

    The transcription factors Runx2 and estrogen receptor-α (ERα) are involved in numerous normal and disease processes, including postmenopausal osteoporosis and breast cancer. Using indirect immunofluorescence microscopy and pull-down techniques, we found them to colocalize and form complexes in a ligand-dependent manner. Estradiol-bound ERα strongly interacted with Runx2 directly through its DNA-binding domain and only indirectly through its N-terminal and ligand-binding domains. Runx2’s amino acids 417–514, encompassing activation domain 3 and the nuclear matrix targeting sequence, were sufficient for interaction with ERα’s DNA-binding domain. As a consequence of the interaction, Runx2’s transcriptional activation activity was strongly repressed, as shown by reporter assays in COS7 cells, breast cancer cells, and late-stage MC3T3-E1 osteoblast cultures. Metaanalysis of gene expression in 779 breast cancer biopsies indicated negative correlation between the expression of ERα and Runx2 target genes. Selective ER modulators (SERM) induced ERα-Runx2 interactions but led to various functional outcomes. The regulation of Runx2 by ERα may play key roles in osteoblast and breast epithelial cell growth and differentiation; hence, modulation of Runx2 by native and synthetic ERα ligands offers new avenues in selective ER modulator evaluation and development. PMID:18755791

  20. Amplitude-modulated stimuli reveal auditory-visual interactions in brain activity and brain connectivity

    PubMed Central

    Laing, Mark; Rees, Adrian; Vuong, Quoc C.

    2015-01-01

    The temporal congruence between auditory and visual signals coming from the same source can be a powerful means by which the brain integrates information from different senses. To investigate how the brain uses temporal information to integrate auditory and visual information from continuous yet unfamiliar stimuli, we used amplitude-modulated tones and size-modulated shapes with which we could manipulate the temporal congruence between the sensory signals. These signals were independently modulated at a slow or a fast rate. Participants were presented with auditory-only, visual-only, or auditory-visual (AV) trials in the fMRI scanner. On AV trials, the auditory and visual signal could have the same (AV congruent) or different modulation rates (AV incongruent). Using psychophysiological interaction analyses, we found that auditory regions showed increased functional connectivity predominantly with frontal regions for AV incongruent relative to AV congruent stimuli. We further found that superior temporal regions, shown previously to integrate auditory and visual signals, showed increased connectivity with frontal and parietal regions for the same contrast. Our findings provide evidence that both activity in a network of brain regions and their connectivity are important for AV integration, and help to bridge the gap between transient and familiar AV stimuli used in previous studies. PMID:26483710

  1. Modulation of cortical activity as a result of voluntary postural sway direction: an EEG study

    PubMed Central

    Slobounov, Semyon; Hallett, Mark; Cao, Cheng; Newell, Karl

    2008-01-01

    There is increasing evidence demonstrating the role of the cerebral cortex in human postural control. Modulation of EEG both in voltage and frequency domains has been observed preceding and following self-paced postural movements and those induced by external perturbations. The current study set out to provide additional evidence regarding the role of cerebral cortex in human postural control by specifically examining modulation of EEG as a function of postural sway direction. Twelve neurologically normal subjects were instructed to produce self-paced voluntary postural sways in the anterior-posterior (AP) and medial-lateral (ML) directions. The center of pressure dynamics and EEG both in voltage and frequency domains were extracted by averaging and Morlet wavelet techniques, respectively. The amplitude of movement-related cortical potentials (MRCP) was significantly higher preceding ML sways. Also, time-frequency wavelet coefficients (TF) indicated differential modulation of EEG within alpha, beta and gamma bands as a function of voluntary postural sway direction. Thus, ML sway appear to be more difficult and energy demanding tasks than the AP sway as reflected in differential modulation of EEG. These results are discussed within the conceptual framework of differential patterns of brain activation as a result of postural task complexity. PMID:18639613

  2. Cells in the monkey ponto-medullary reticular formation modulate their activity with slow finger movements

    PubMed Central

    Soteropoulos, Demetris S; Williams, Elizabeth R; Baker, Stuart N

    2012-01-01

    Recent work has shown that the primate reticulospinal tract can influence spinal interneurons and motoneurons involved in control of the hand. However, demonstrating connectivity does not reveal whether reticular outputs are modulated during the control of different types of hand movement. Here, we investigated how single unit discharge in the pontomedullary reticular formation (PMRF) modulated during performance of a slow finger movement task in macaque monkeys. Two animals performed an index finger flexion–extension task to track a target presented on a computer screen; single units were recorded both from ipsilateral PMRF (115 cells) and contralateral primary motor cortex (M1, 210 cells). Cells in both areas modulated their activity with the task (M1: 87%, PMRF: 86%). Some cells (18/115 in PMRF; 96/210 in M1) received sensory input from the hand, showing a short-latency modulation in their discharge following a rapid passive extension movement of the index finger. Effects in ipsilateral electromyogram to trains of stimuli were recorded at 45 sites in the PMRF. These responses involved muscles controlling the digits in 13/45 sites (including intrinsic hand muscles, 5/45 sites). We conclude that PMRF may contribute to the control of fine finger movements, in addition to its established role in control of more proximal limb and trunk movements. This finding may be especially important in understanding functional recovery after brain lesions such as stroke. PMID:22641776

  3. Cells in the monkey ponto-medullary reticular formation modulate their activity with slow finger movements.

    PubMed

    Soteropoulos, Demetris S; Williams, Elizabeth R; Baker, Stuart N

    2012-08-15

    Recent work has shown that the primate reticulospinal tract can influence spinal interneurons and motoneurons involved in control of the hand. However, demonstrating connectivity does not reveal whether reticular outputs are modulated during the control of different types of hand movement. Here, we investigated how single unit discharge in the pontomedullary reticular formation (PMRF) modulated during performance of a slow finger movement task in macaque monkeys. Two animals performed an index finger flexion–extension task to track a target presented on a computer screen; single units were recorded both from ipsilateral PMRF (115 cells) and contralateral primary motor cortex (M1, 210 cells). Cells in both areas modulated their activity with the task (M1: 87%, PMRF: 86%). Some cells (18/115 in PMRF; 96/210 in M1) received sensory input from the hand, showing a short-latency modulation in their discharge following a rapid passive extension movement of the index finger. Effects in ipsilateral electromyogram to trains of stimuli were recorded at 45 sites in the PMRF. These responses involved muscles controlling the digits in 13/45 sites (including intrinsic hand muscles, 5/45 sites). We conclude that PMRF may contribute to the control of fine finger movements, in addition to its established role in control of more proximal limb and trunk movements. This finding may be especially important in understanding functional recovery after brain lesions such as stroke. PMID:22641776

  4. Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity.

    PubMed

    Holst, P J; Rosenkilde, M M; Manfra, D; Chen, S C; Wiekowski, M T; Holst, B; Cifire, F; Lipp, M; Schwartz, T W; Lira, S A

    2001-12-01

    ORF74 (or KSHV-vGPCR) is a highly constitutively active G protein-coupled receptor encoded by HHV8 that is regulated both positively and negatively by endogenous chemokines. When expressed in transgenic mice, this chemokine receptor induces an angioproliferative disease closely resembling Kaposi sarcoma (KS). Here we demonstrate that several lines of mice carrying mutated receptors deficient in either constitutive activity or chemokine regulation fail to develop KS-like disease. In addition, animals expressing a receptor that preserves chemokine binding and constitutive activity but that does not respond to agonist stimulation have a much lower incidence of angiogenic lesions and tumors. These results indicate that induction of the KS-like disease in transgenic mice by ORF74 requires not only high constitutive signaling activity but also modulation of this activity by endogenous chemokines. PMID:11748262

  5. Tumorigenesis induced by the HHV8-encoded chemokine receptor requires ligand modulation of high constitutive activity

    PubMed Central

    Holst, Peter J.; Rosenkilde, Mette M.; Manfra, Denise; Chen, Shu-Cheng; Wiekowski, Maria T.; Holst, Birgitte; Cifire, Felix; Lipp, Martin; Schwartz, Thue W.; Lira, Sergio A.

    2001-01-01

    ORF74 (or KSHV-vGPCR) is a highly constitutively active G protein–coupled receptor encoded by HHV8 that is regulated both positively and negatively by endogenous chemokines. When expressed in transgenic mice, this chemokine receptor induces an angioproliferative disease closely resembling Kaposi sarcoma (KS). Here we demonstrate that several lines of mice carrying mutated receptors deficient in either constitutive activity or chemokine regulation fail to develop KS-like disease. In addition, animals expressing a receptor that preserves chemokine binding and constitutive activity but that does not respond to agonist stimulation have a much lower incidence of angiogenic lesions and tumors. These results indicate that induction of the KS-like disease in transgenic mice by ORF74 requires not only high constitutive signaling activity but also modulation of this activity by endogenous chemokines. PMID:11748262

  6. TRPV1 regulates activation and modulation of TRPA1 by Ca2+

    PubMed Central

    Patil, Mayur J.; Jeske, Nathaniel A.; Akopian, Armen N.

    2010-01-01

    The transient receptor potential A1 (TRPA1) channel contributes to nociceptive signaling in certain pain models. It has been suggested that Ca2+, which activates and modulates TRPA1, could play a critical regulatory role in this process. Since TRPA1 and TRPV1 channels are co-expressed and interact in neurons, we investigated whether activation and modulation of TRPA1 by Ca2+ is regulated by TRPV1. Cell-attached recordings showed that TRPA1 is activated by extracellular Ca2+ ([Ca2+]e) in concentration-response fashion. This activation, especially by 2mM [Ca2+]e was substantially suppressed by co-expression with TRPV1. Inside-out recordings demonstrated that intracellular Ca2+ ([Ca2+]i)-triggered activation of TRPA1 was attenuated by the presence of TRPV1 only at 2 mM [Ca2+]e, but not in Ca2+-free conditions. Further, depletion of internal Ca2+ stores by thapsigargin generated TRPA1-mediated currents, which is affected by TRPV1 in both Chinee hamster ovary cells and sensory neurons. Since mustard oil current (IMO) is modulated by [Ca2+]e, we next examined whether alterations in the Ca2+-permeability of TRPV1 by mutating Y671 effect IMO properties. First it was demonstrated that the mutations in TRPV1 did not affect association of the TRPA1 and TRPV1 channels. However, these TRPV1 mutations, particularly Y671K, altered the following characteristics of TRPA1: magnitude of IMO in presence and absence of [Ca2+]e; the influence of [Ca2+]e on the voltage-dependency of IMO, and open probability of single-channel IMO. In summary, activation of TRPA1 by [Ca2+]e and [Ca2+]i is controlled by the TRPV1 channel, and characteristics of IMO depend on Ca2+ permeability of the TRPV1 channel. PMID:20884333

  7. Intracellular mechanisms modulating gamma band activity in the pedunculopontine nucleus (PPN).

    PubMed

    Luster, Brennon R; Urbano, Francisco J; Garcia-Rill, Edgar

    2016-06-01

    The pedunculopontine nucleus is a part of the reticular activating system, and is active during waking and REM sleep. Previous results showed that all PPN cells tested fired maximally at gamma frequencies when depolarized. This intrinsic membrane property was shown to be mediated by high-threshold N- and P/Q-type Ca(2+) channels. Recent studies show that the PPN contains three independent populations of neurons which can generate gamma band oscillations through only N-type channels, only P/Q-type channels, or both N- and P/Q-type channels. This study investigated the intracellular mechanisms modulating gamma band activity in each population of neurons. We performed in vitro patch-clamp recordings of PPN neurons from Sprague-Dawley rat pups, and applied 1-sec ramps to induce intrinsic membrane oscillations. Our results show that there are two pathways modulating gamma band activity in PPN neurons. We describe populations of neurons mediating gamma band activity through only N-type channels and the cAMP/PKA pathway (presumed "REM-on" neurons), through only P/Q-type channels and the CaMKII pathway (presumed "Wake-on" neurons), and a third population which can mediate gamma activity through both N-type channels and cAMP/PK and P/Q-type channels and CaMKII (presumed "Wake/REM-on" neurons). These novel results suggest that PPN gamma oscillations are modulated by two independent pathways related to different Ca(2+) channel types. PMID:27354537

  8. Selective attention modulates high-frequency activity in the face-processing network.

    PubMed

    Müsch, Kathrin; Hamamé, Carlos M; Perrone-Bertolotti, Marcela; Minotti, Lorella; Kahane, Philippe; Engel, Andreas K; Lachaux, Jean-Philippe; Schneider, Till R

    2014-11-01

    Face processing depends on the orchestrated activity of a large-scale neuronal network. Its activity can be modulated by attention as a function of task demands. However, it remains largely unknown whether voluntary, endogenous attention and reflexive, exogenous attention to facial expressions equally affect all regions of the face-processing network, and whether such effects primarily modify the strength of the neuronal response, the latency, the duration, or the spectral characteristics. We exploited the good temporal and spatial resolution of intracranial electroencephalography (iEEG) and recorded from depth electrodes to uncover the fast dynamics of emotional face processing. We investigated frequency-specific responses and event-related potentials (ERP) in the ventral occipito-temporal cortex (VOTC), ventral temporal cortex (VTC), anterior insula, orbitofrontal cortex (OFC), and amygdala when facial expressions were task-relevant or task-irrelevant. All investigated regions of interest (ROI) were clearly modulated by task demands and exhibited stronger changes in stimulus-induced gamma band activity (50-150 Hz) when facial expressions were task-relevant. Observed latencies demonstrate that the activation is temporally coordinated across the network, rather than serially proceeding along a processing hierarchy. Early and sustained responses to task-relevant faces in VOTC and VTC corroborate their role for the core system of face processing, but they also occurred in the anterior insula. Strong attentional modulation in the OFC and amygdala (300 msec) suggests that the extended system of the face-processing network is only recruited if the task demands active face processing. Contrary to our expectation, we rarely observed differences between fearful and neutral faces. Our results demonstrate that activity in the face-processing network is susceptible to the deployment of selective attention. Moreover, we show that endogenous attention operates along the whole

  9. Antiallergic activity of rosmarinic acid esters is modulated by hydrophobicity, and bulkiness of alkyl side chain.

    PubMed

    Zhu, Fengxian; Xu, Zhongming; Yonekura, Lina; Yang, Ronghua; Tamura, Hirotoshi

    2015-01-01

    Methyl, propyl and hexyl esters of rosmarinic, caffeic and p-coumaric acids were tested for antiallergic activity, and rosmarinic acid propyl ester exhibited the greatest β-hexosaminidase release suppression (IC50, 23.7 μM). Quadratic correlations between pIC50 and cLogP (r(2) = 0.94, 0.98, and 1.00, respectively) were observed in each acid ester series. The antiallergic activity is modulated by hydrophobicity, and alkyl chain bulkiness. PMID:25686361

  10. Preferential binding of allosteric modulators to active and inactive conformational states of metabotropic glutamate receptors

    PubMed Central

    Yanamala, Naveena; Tirupula, Kalyan C; Klein-Seetharaman, Judith

    2008-01-01

    Metabotropic glutamate receptors (mGluRs) are G protein coupled receptors that play important roles in synaptic plasticity and other neuro-physiological and pathological processes. Allosteric mGluR ligands are particularly promising drug targets because of their modulatory effects – enhancing or suppressing the response of mGluRs to glutamate. The mechanism by which this modulation occurs is not known. Here, we propose the hypothesis that positive and negative modulators will differentially stabilize the active and inactive conformations of the receptors, respectively. To test this hypothesis, we have generated computational models of the transmembrane regions of different mGluR subtypes in two different conformations. The inactive conformation was modeled using the crystal structure of the inactive, dark state of rhodopsin as template and the active conformation was created based on a recent model of the light-activated state of rhodopsin. Ligands for which the nature of their allosteric effects on mGluRs is experimentally known were docked to the modeled mGluR structures using ArgusLab and Autodock softwares. We find that the allosteric ligand binding pockets of mGluRs are overlapping with the retinal binding pocket of rhodopsin, and that ligands have strong preferences for the active and inactive states depending on their modulatory nature. In 8 out of 14 cases (57%), the negative modulators bound the inactive conformations with significant preference using both docking programs, and 6 out of 9 cases (67%), the positive modulators bound the active conformations. Considering results by the individual programs only, even higher correlations were observed: 12/14 (86%) and 8/9 (89%) for ArgusLab and 10/14 (71%) and 7/9 (78%) for AutoDock. These findings strongly support the hypothesis that mGluR allosteric modulation occurs via stabilization of different conformations analogous to those identified in rhodopsin where they are induced by photochemical isomerization

  11. Dark/light transition and vigilance states modulate jaw-closing muscle activity level in mice.

    PubMed

    Katayama, Keisuke; Mochizuki, Ayako; Kato, Takafumi; Ikeda, Minako; Ikawa, Yasuha; Nakamura, Shiro; Nakayama, Kiyomi; Wakabayashi, Noriyuki; Baba, Kazuyoshi; Inoue, Tomio

    2015-12-01

    Bruxism is associated with an increase in the activity of the jaw-closing muscles during sleep and wakefulness. However, the changes in jaw-closing muscle activity across states of vigilance over a 24-h period are unclear. In this study, we investigated the effects of dark/light transition and sleep/wake state on EMG activity of the masseter (jaw-closing) muscle in comparison with the activity of the upper trapezius muscle (a neck muscle) over a 24-h period in mice. The activities of the masseter and neck muscles during wakefulness were much greater than during non-REM and REM sleep. In contrast, the activities of both muscles slightly, but significantly, decreased during the transition period from dark to light. Histograms of masseter activity during wakefulness and non-REM sleep showed bimodal distributions, whereas the neck muscle showed unimodal activation in all states. These results suggest that the activities of jaw-closing and neck muscles are modulated by both sleep/wake state and dark/light transition, with the latter being to a lesser degree. Furthermore, even during non-REM sleep, jaw-closing muscles display bimodal activation, which may contribute to the occurrence of exaggerated aberrant muscle activity, such as sleep bruxism. PMID:26188127

  12. Identification and validation of modulators of exchange protein activated by cAMP (Epac) activity: structure-function implications for Epac activation and inhibition.

    PubMed

    Brown, Loren M; Rogers, Kathleen E; McCammon, J Andrew; Insel, Paul A

    2014-03-21

    The signaling molecule cAMP primarily mediates its effects by activating PKA and/or exchange protein activated by cAMP (Epac). Epac has been implicated in many responses in cells, but its precise roles have been difficult to define in the absence of Epac inhibitors. Epac, a guanine nucleotide exchange factor for the low molecular weight G protein Rap, is directly activated by cAMP. Using a bioluminescence resonance energy transfer-based assay (CAMYEL) to examine modulators of Epac activity, we took advantage of its intramolecular movement that occurs upon cAMP binding to assess Epac activation. We found that the use of CAMYEL can detect the binding of cAMP analogs to Epac and their modulation of its activity and can distinguish between agonists (cAMP), partial agonists (8-chlorophenylthio-cAMP), and super agonists (8-chlorophenylthio-2'-O-Me-cAMP). The CAMYEL assay can also identify competitive and uncompetitive Epac inhibitors, e.g. (Rp)-cAMPS and CE3F4, respectively. To confirm the results with the CAMYEL assay, we used Swiss 3T3 cells and assessed the ability of cyclic nucleotide analogs to modulate the activity of Epac or PKA, determined by Rap1 activity or VASP phosphorylation, respectively. We used computational molecular modeling to analyze the interaction of analogs with Epac1. The results reveal a rapid means to identify modulators (potentially including allosteric inhibitors) of Epac activity that also provides insight into the mechanisms of Epac activation and inhibition. PMID:24497631

  13. Modulation of neural activity during object naming: effects of time and practice.

    PubMed

    van Turennout, Miranda; Bielamowicz, Lisa; Martin, Alex

    2003-04-01

    Repeated exposure to objects improves our ability to identify and name them, even after a long delay. Previous brain imaging studies have demonstrated that this experience-related facilitation of object naming is associated with neural changes in distinct brain regions. We used event-related functional magnetic resonance imaging (fMRI) to examine the modulation of neural activity in the object naming system as a function of experience and time. Pictures of common objects were presented repeatedly for naming at different time intervals (1 h, 6 h and 3 days) before scanning, or at 30 s intervals during scanning. The results revealed that as objects became more familiar with experience, activity in occipitotemporal and left inferior frontal regions decreased while activity in the left insula and basal ganglia increased. In posterior regions, reductions in activity as a result of multiple repetitions did not interact with time, whereas in left inferior frontal cortex larger decreases were observed when repetitions were spaced out over time. This differential modulation of activity in distinct brain regions provides support for the idea that long-lasting object priming is mediated by two neural mechanisms. The first mechanism may involve changes in object-specific representations in occipitotemporal cortices, the second may be a form of procedural learning involving a reorganization in brain circuitry that leads to more efficient name retrieval. PMID:12631567

  14. Pharmacological and dietary modulators of paraoxonase 1 (PON1) activity and expression: the hunt goes on*

    PubMed Central

    Costa, Lucio G.; Giordano, Gennaro; Furlong, Clement E.

    2010-01-01

    Paraoxonase 1 (PON1) is a high density lipoprotein (HDL)-associated enzyme displaying esterase and lactonase activity. PON1 hydrolyzes several organophosphorus (OP) insecticides and nerve agents, a number of exogenous and endogenous lactones, and metabolizes toxic oxidized lipids of low density lipoproteins (LDL) and HDL. As such, PON1 plays a relevant role in determining susceptibility to OP toxicity, cardiovascular diseases and several other diseases. Serum PON1 activity in a given population can vary by at least 40-fold. Most of this variation can be accounted for by genetic polymorphisms in the coding region (Q192R, L55M) and in the promoter region (T-108C). However, exogenous factors may also modulate PON1 activity and/or level of expression. This paper examines various factors that have been found to positively modulate PON1. Certain drugs (e.g. hypolipemic and anti-diabetic compounds), dietary factors (antioxidants, polyphenols), and life-style factors (moderate alcohol consumption) appear to increase PON1 activity. Given the relevance of PON1 in protecting from certain environmental exposure and from cardiovascular and other diseases, there is a need for further mechanistic, animal, and clinical research in this area, and for consideration of possible alternative strategies for increasing the levels and activity of PON1. PMID:21093416

  15. Low-power sensor module for long-term activity monitoring.

    PubMed

    Leuenberger, Kaspar; Gassert, Roger

    2011-01-01

    Wearable sensor modules are a promising approach to collecting data on functional motor activities, both for repeated and long-term assessments, as well as to investigate the transfer of therapy to activities of daily living at home, but have so far either had limited sensing capabilities, or were not laid out for long-term monitoring. This paper presents ReSense, a miniature sensor unit optimized for long-term monitoring of functional activity. Inertial MEMS sensors capture accelerations along six degrees of freedom and a barometric pressure sensor serves as a precise altimeter. Data is written to an integrated memory card. The realized module measures Ø25 × 10 mm, weighs 10 g and can record continuously for 27 h at 25 Hz and over 22 h at 100 Hz. The integrated power-management system detects inactivity and extends the operating time by about a factor of two, as shown by initial 24 h recordings on five energetic healthy adults. The integrated barometric pressure sensor allowed to identify activities incorporating a change in altitude, such as going up/down stairs or riding an elevator. By taking into account data from the inertial sensors during the altitude changes, it becomes possible to distinguish between these two activities. PMID:22254785

  16. Sequences flanking the core-binding site modulate glucocorticoid receptor structure and activity.

    PubMed

    Schöne, Stefanie; Jurk, Marcel; Helabad, Mahdi Bagherpoor; Dror, Iris; Lebars, Isabelle; Kieffer, Bruno; Imhof, Petra; Rohs, Remo; Vingron, Martin; Thomas-Chollier, Morgane; Meijsing, Sebastiaan H

    2016-01-01

    The glucocorticoid receptor (GR) binds as a homodimer to genomic response elements, which have particular sequence and shape characteristics. Here we show that the nucleotides directly flanking the core-binding site, differ depending on the strength of GR-dependent activation of nearby genes. Our study indicates that these flanking nucleotides change the three-dimensional structure of the DNA-binding site, the DNA-binding domain of GR and the quaternary structure of the dimeric complex. Functional studies in a defined genomic context show that sequence-induced changes in GR activity cannot be explained by differences in GR occupancy. Rather, mutating the dimerization interface mitigates DNA-induced changes in both activity and structure, arguing for a role of DNA-induced structural changes in modulating GR activity. Together, our study shows that DNA sequence identity of genomic binding sites modulates GR activity downstream of binding, which may play a role in achieving regulatory specificity towards individual target genes. PMID:27581526

  17. TRAF-mediated modulation of NF-kB AND JNK activation by TNFR2.

    PubMed

    Cabal-Hierro, Lucía; Rodríguez, Montserrat; Artime, Noelia; Iglesias, Julián; Ugarte, Lorea; Prado, Miguel A; Lazo, Pedro S

    2014-12-01

    Tumor Necrosis Factor Receptor 2 (TNFR2) activates transcription factor κB (NF-κB) and c-Jun N-terminal kinase (JNK). Most of the biological activities triggered by TNFR2 depend on the recruitment of TNF Receptor-Associated Factor 2 (TRAF2) to the intracellular region of the receptor. The intracellular region of TNFR2 contains five highly conserved amino acid sequences, three of which appear implicated in receptor signaling. In this work we have studied the interaction of TNFR2 with TRAF proteins as well as the functional consequences of this interaction. We show that TRAF1, TRAF2 and TRAF3 bind to the receptor through two different binding sites located at conserved modules IV and V of its intracellular region, respectively. We also show that TRAF1 and TRAF3 have opposite effects to TRAF2 on NF-κB and JNK activation by TNFR2. Moreover, we show that TNFR2 is able to induce JNK activation in a TRAF2-independent fashion. This new receptor activity relies on a sequence located in the conserved module III. This region is also responsible for the ability of TNFR2 to induce TRAF2 degradation, thus emphasizing the role of conserved module III (amino acids 338-379) on receptor signaling and regulation. We show that only TNFR2 can induce TRAF2 degradation while TRAF1 or TRAF3 is not subjected to this regulatory mechanism and that TRAF1, but not TRAF3, is able to inhibit TRAF2 degradation. PMID:25152365

  18. The Contribution of Non-catalytic Carbohydrate Binding Modules to the Activity of Lytic Polysaccharide Monooxygenases*

    PubMed Central

    Crouch, Lucy I.; Labourel, Aurore; Walton, Paul H.; Davies, Gideon J.; Gilbert, Harry J.

    2016-01-01

    Lignocellulosic biomass is a sustainable industrial substrate. Copper-dependent lytic polysaccharide monooxygenases (LPMOs) contribute to the degradation of lignocellulose and increase the efficiency of biofuel production. LPMOs can contain non-catalytic carbohydrate binding modules (CBMs), but their role in the activity of these enzymes is poorly understood. Here we explored the importance of CBMs in LPMO function. The family 2a CBMs of two monooxygenases, CfLPMO10 and TbLPMO10 from Cellulomonas fimi and Thermobispora bispora, respectively, were deleted and/or replaced with CBMs from other proteins. The data showed that the CBMs could potentiate and, surprisingly, inhibit LPMO activity, and that these effects were both enzyme-specific and substrate-specific. Removing the natural CBM or introducing CtCBM3a, from the Clostridium thermocellum cellulosome scaffoldin CipA, almost abolished the catalytic activity of the LPMOs against the cellulosic substrates. The deleterious effect of CBM removal likely reflects the importance of prolonged presentation of the enzyme on the surface of the substrate for efficient catalytic activity, as only LPMOs appended to CBMs bound tightly to cellulose. The negative impact of CtCBM3a is in sharp contrast with the capacity of this binding module to potentiate the activity of a range of glycoside hydrolases including cellulases. The deletion of the endogenous CBM from CfLPMO10 or the introduction of a family 10 CBM from Cellvibrio japonicus LPMO10B into TbLPMO10 influenced the quantity of non-oxidized products generated, demonstrating that CBMs can modulate the mode of action of LPMOs. This study demonstrates that engineered LPMO-CBM hybrids can display enhanced industrially relevant oxygenations. PMID:26801613

  19. Cucurbitacin IIb exhibits anti-inflammatory activity through modulating multiple cellular behaviors of mouse lymphocytes.

    PubMed

    Wang, Yao; Zhao, Gao-Xiang; Xu, Li-Hui; Liu, Kun-Peng; Pan, Hao; He, Jian; Cai, Ji-Ye; Ouyang, Dong-Yun; He, Xian-Hui

    2014-01-01

    Cucurbitacin IIb (CuIIb) is one of the major active compounds in Hemsleyadine tablets which have been used for clinical treatment of bacillary dysentery, enteritis and acute tonsilitis. However, its action mechanism has not been completely understood. This study aimed to explore the anti-inflammatory activity of CuIIb and its underlying mechanism in mitogen-activated lymphocytes isolated from mouse mesenteric lymph nodes. The results showed that CuIIb inhibited the proliferation of concanavalin A (Con A)-activated lymphocytes in a time- and dose-dependent manner. CuIIb treatment arrested their cell cycle in S and G2/M phases probably due to the disruption of the actin cytoskeleton and the modulation of p27(Kip1) and cyclin levels. Moreover, the surface expression of activation markers CD69 and CD25 on Con A-activated CD3(+) T lymphocytes was suppressed by CuIIb treatment. Both Con A- and phorbol ester plus ionomycin-induced expression of TNF-α, IFN-γ and IL-6 proteins was attenuated upon exposure to CuIIb. Mechanistically, CuIIb treatment suppressed the phosphorylation of JNK and Erk1/2 but not p38 in Con A-activated lymphocytes. Although CuIIb unexpectedly enhanced the phosphorylation of IκB and NF-κB (p65), it blocked the nuclear translocation of NF-κB (p65). In support of this, CuIIb significantly decreased the mRNA levels of IκBα and TNF-α, two target genes of NF-κB, in Con A-activated lymphocytes. In addition, CuIIb downregulated Con A-induced STAT3 phosphorylation and increased cell apoptosis. Collectively, these results suggest that CuIIb exhibits its anti-inflammatory activity through modulating multiple cellular behaviors and signaling pathways, leading to the suppression of the adaptive immune response. PMID:24587010

  20. Cucurbitacin IIb Exhibits Anti-Inflammatory Activity through Modulating Multiple Cellular Behaviors of Mouse Lymphocytes

    PubMed Central

    Liu, Kun-Peng; Pan, Hao; He, Jian; Cai, Ji-Ye; Ouyang, Dong-Yun; He, Xian-Hui

    2014-01-01

    Cucurbitacin IIb (CuIIb) is one of the major active compounds in Hemsleyadine tablets which have been used for clinical treatment of bacillary dysentery, enteritis and acute tonsilitis. However, its action mechanism has not been completely understood. This study aimed to explore the anti-inflammatory activity of CuIIb and its underlying mechanism in mitogen-activated lymphocytes isolated from mouse mesenteric lymph nodes. The results showed that CuIIb inhibited the proliferation of concanavalin A (Con A)-activated lymphocytes in a time- and dose-dependent manner. CuIIb treatment arrested their cell cycle in S and G2/M phases probably due to the disruption of the actin cytoskeleton and the modulation of p27Kip1 and cyclin levels. Moreover, the surface expression of activation markers CD69 and CD25 on Con A-activated CD3+ T lymphocytes was suppressed by CuIIb treatment. Both Con A- and phorbol ester plus ionomycin-induced expression of TNF-α, IFN-γ and IL-6 proteins was attenuated upon exposure to CuIIb. Mechanistically, CuIIb treatment suppressed the phosphorylation of JNK and Erk1/2 but not p38 in Con A-activated lymphocytes. Although CuIIb unexpectedly enhanced the phosphorylation of IκB and NF-κB (p65), it blocked the nuclear translocation of NF-κB (p65). In support of this, CuIIb significantly decreased the mRNA levels of IκBα and TNF-α, two target genes of NF-κB, in Con A-activated lymphocytes. In addition, CuIIb downregulated Con A-induced STAT3 phosphorylation and increased cell apoptosis. Collectively, these results suggest that CuIIb exhibits its anti-inflammatory activity through modulating multiple cellular behaviors and signaling pathways, leading to the suppression of the adaptive immune response. PMID:24587010

  1. Activation of murine invariant NKT cells promotes susceptibility to candidiasis by IL-10 induced modulation of phagocyte antifungal activity.

    PubMed

    Haraguchi, Norihiro; Kikuchi, Norihiro; Morishima, Yuko; Matsuyama, Masashi; Sakurai, Hirofumi; Shibuya, Akira; Shibuya, Kazuko; Taniguchi, Masaru; Ishii, Yukio

    2016-07-01

    Invariant NKT (iNKT) cells play an important role in a variety of antimicrobial immune responses due to their ability to produce high levels of immune-modulating cytokines. Here, we investigated the role of iNKT cells in host defense against candidiasis using Jα18-deficient mice (Jα18(-/-) ), which lack iNKT cells. Jα18(-/-) mice were more resistant to the development of lethal candidiasis than wild-type (WT) mice. In contrast, treatment of WT mice with the iNKT cell activating ligand α-galactosylceramide markedly enhanced their mortality after infection with Candida albicans. Serum IL-10 levels were significantly elevated in WT mice in response to infection with C. albicans. Futhermore, IL-10 production increased after in vitro coculture of peritoneal macrophages with iNKT cells and C. albicans. The numbers of peritoneal macrophages, the production of IL-1β and IL-18, and caspase-1 activity were also significantly elevated in Jα18(-/-) mice after infection with C. albicans. The adoptive transfer of iNKT cells or exogenous administration of IL-10 into Jα18(-/-) reversed susceptibility to candidiasis to the level of WT mice. These results suggest that activation of iNKT cells increases the initial severity of C. albicans infection, most likely mediated by IL-10 induced modulation of macrophage antifungal activity. PMID:27151377

  2. Active engagement improves primary auditory cortical neurons’ ability to discriminate temporal modulation

    PubMed Central

    Niwa, Mamiko; Johnson, Jeffrey S.; O’Connor, Kevin N.; Sutter, Mitchell L.

    2012-01-01

    The effect of attention on single neuron responses in the auditory system is unresolved. We found that when monkeys discriminated temporally amplitude modulated (AM) from unmodulated sounds, primary auditory cortical (A1) neurons better discriminated those sounds than when the monkeys were not discriminating them. This was observed for both average firing rate and vector strength (VS), a measure of how well neurons temporally follow the stimulus’ temporal modulation. When data were separated by non-synchronized and synchronized responses, the firing rate of non-synchronized responses best distinguished AM-noise from unmodulated noise followed by VS for synchronized responses, with firing rate for synchronized neurons providing the poorest AM discrimination. Firing rate-based AM discrimination for synchronized neurons, however, improved most with task engagement, showing that the least sensitive code in the passive condition improves the most with task-engagement. Rate coding improved due to larger increases in absolute firing-rate at higher modulation depths than for lower depths and unmodulated sounds. Relative to spontaneous activity (which increased with engagement), the response to unmodulated sounds decreased substantially. The temporal coding improvement -- responses more precisely temporally following a stimulus when animals were required to attend to it -- expands the framework of possible mechanisms of attention to include increasing temporal precision of stimulus following. These findings provide a crucial step to understanding the coding of temporal modulation, and support a model where rate and temporal coding work in parallel, permitting a multiplexed code for temporal modulation, and for a complementary representation of rate and temporal coding. PMID:22764239

  3. Mangroves Build Land. "Mangroves are a Valuable Resource." Grades 7 and 8. A Two Lesson Unit. Student Learning Activity Module.

    ERIC Educational Resources Information Center

    Frank, James

    This module is an activity and film-oriented unit focusing on the importance of mangroves in the South Florida ecosystem. The module is part of a series designed to be used by teachers, students, and community members to help them utilize community resources in developing and teaching environmental concepts and responsibility, and in seeking ways…

  4. LIGHT MODULATION OF RUBISCO ACTIVATION IN SPECIES WITHOUT A LARGER ACTIVASE ISOFORM - EXISTANCE OF AN ACTIVASE REGULATORY PROTEIN?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Rubisco activase in some species like tobacco consists of only the shorter isoform. In Arabidopsis lack of the redox regulated, larger isoform results in an inability to modulate Rubisco activity in response to light intensity. However, light modulation can be observed in tobacco with characteristic...

  5. Light Activated Escape Circuits: A Behavior and Neurophysiology Lab Module using Drosophila Optogenetics

    PubMed Central

    Titlow, Josh S.; Johnson, Bruce R.; Pulver, Stefan R.

    2015-01-01

    The neural networks that control escape from predators often show very clear relationships between defined sensory inputs and stereotyped motor outputs. This feature provides unique opportunities for researchers, but it also provides novel opportunities for neuroscience educators. Here we introduce new teaching modules using adult Drosophila that have been engineered to express csChrimson, a red-light sensitive channelrhodopsin, in specific sets of neurons and muscles mediating visually guided escape behaviors. This lab module consists of both behavior and electrophysiology experiments that explore the neural basis of flight escape. Three preparations are described that demonstrate photo-activation of the giant fiber circuit and how to quantify these behaviors. One of the preparations is then used to acquire intracellular electrophysiology recordings from different flight muscles. The diversity of action potential waveforms and firing frequencies observed in the flight muscles make this a rich preparation to study the ionic basic of cellular excitability. By activating different cells within the giant fiber pathway we also demonstrate principles of synaptic transmission and neural circuits. Beyond conveying core neurobiological concepts it is also expected that using these cutting edge techniques will enhance student motivation and attitudes towards biological research. Data collected from students and educators who have been involved in development of the module are presented to support this notion. PMID:26240526

  6. Pre-irradiation testing of actively cooled Be-Cu divertor modules

    SciTech Connect

    Linke, J.; Duwe, R.; Kuehnlein, W.

    1995-09-01

    A set of neutron irradiation tests is prepared on different plasma facing materials (PFM) candidates and miniaturized components for ITER. Beside beryllium the irradiation program which will be performed in the High Flux Reactor (HFR) in Petten, includes different carbon fiber composites (CFQ) and tungsten alloys. The target values for the neutron irradiation will be 0.5 dpa at temperatures of 350{degrees}C and 700{degrees}C, resp.. The post irradiation examination (PIE) will cover a wide range of mechanical tests; in addition the degradation of thermal conductivity will be investigated. To determine the high heat flux (HHF) performance of actively cooled divertor modules, electron beam tests which simulate the expected heat loads during the operation of ITER, are scheduled in the hot cell electron beam facility JUDITH. These tests on a selection of different actively cooled beryllium-copper and CFC-copper divertor modules are performed before and after neutron irradiation; the pre-irradiation testing is an essential part of the program to quantify the zero-fluence high heat flux performance and to detect defects in the modules, in particular in the brazed joints.

  7. A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells.

    PubMed

    Singer, Meromit; Wang, Chao; Cong, Le; Marjanovic, Nemanja D; Kowalczyk, Monika S; Zhang, Huiyuan; Nyman, Jackson; Sakuishi, Kaori; Kurtulus, Sema; Gennert, David; Xia, Junrong; Kwon, John Y H; Nevin, James; Herbst, Rebecca H; Yanai, Itai; Rozenblatt-Rosen, Orit; Kuchroo, Vijay K; Regev, Aviv; Anderson, Ana C

    2016-09-01

    Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8(+) tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and we use CRISPR-Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8(+) TILs. Our results open novel avenues for targeting dysfunctional T cell states while leaving activation programs intact. PMID:27610572

  8. Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

    PubMed Central

    Zhang, Hai-Ying; Gao, Ming; Liu, Qing-Rong; Bi, Guo-Hua; Li, Xia; Yang, Hong-Ju; Gardner, Eliot L.; Wu, Jie

    2014-01-01

    Cannabinoid CB2 receptors (CB2Rs) have been recently reported to modulate brain dopamine (DA)-related behaviors; however, the cellular mechanisms underlying these actions are unclear. Here we report that CB2Rs are expressed in ventral tegmental area (VTA) DA neurons and functionally modulate DA neuronal excitability and DA-related behavior. In situ hybridization and immunohistochemical assays detected CB2 mRNA and CB2R immunostaining in VTA DA neurons. Electrophysiological studies demonstrated that activation of CB2Rs by JWH133 or other CB2R agonists inhibited VTA DA neuronal firing in vivo and ex vivo, whereas microinjections of JWH133 into the VTA inhibited cocaine self-administration. Importantly, all of the above findings observed in WT or CB1−/− mice are blocked by CB2R antagonist and absent in CB2−/− mice. These data suggest that CB2R-mediated reduction of VTA DA neuronal activity may underlie JWH133's modulation of DA-regulated behaviors. PMID:25368177

  9. Functional characterization of neurotransmitter activation and modulation in a nematode model ligand-gated ion channel.

    PubMed

    Heusser, Stephanie A; Yoluk, Özge; Klement, Göran; Riederer, Erika A; Lindahl, Erik; Howard, Rebecca J

    2016-07-01

    The superfamily of pentameric ligand-gated ion channels includes neurotransmitter receptors that mediate fast synaptic transmission in vertebrates, and are targets for drugs including alcohols, anesthetics, benzodiazepines, and anticonvulsants. However, the mechanisms of ion channel opening, gating, and modulation in these receptors leave many open questions, despite their pharmacological importance. Subtle conformational changes in both the extracellular and transmembrane domains are likely to influence channel opening, but have been difficult to characterize given the limited structural data available for human membrane proteins. Recent crystal structures of a modified Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in multiple states offer an appealing model system for structure-function studies. However, the pharmacology of the crystallographic GluCl construct is not well established. To establish the functional relevance of this system, we used two-electrode voltage-clamp electrophysiology in Xenopus oocytes to characterize activation of crystallographic and native-like GluCl constructs by L-glutamate and ivermectin. We also tested modulation by ethanol and other anesthetic agents, and used site-directed mutagenesis to explore the role of a region of Loop F which was implicated in ligand gating by molecular dynamics simulations. Our findings indicate that the crystallographic construct functionally models concentration-dependent agonism and allosteric modulation of pharmacologically relevant receptors. Specific substitutions at residue Leu174 in loop F altered direct L-glutamate activation, consistent with computational evidence for this region's role in ligand binding. These insights demonstrate conservation of activation and modulation properties in this receptor family, and establish a framework for GluCl as a model system, including new possibilities for drug discovery. In this study, we elucidate the validity of a modified glutamate

  10. Protein expression of nucleophosmin, annexin A3 and nm23-H1 correlates with human nasopharyngeal carcinoma radioresistance in vivo

    PubMed Central

    QU, SONG; LI, XIAO-YU; LIANG, ZHONG-GUO; LI, LING; HUANG, SHI-TING; LI, JIA-QUAN; LI, DAN-RONG; ZHU, XIAO-DONG

    2016-01-01

    Radioresistance is a significant obstacle in the treatment of endemic nasopharyngeal carcinoma (NPC). The present study aimed to identify proteins associated with radioresistance in NPC in vitro and in vivo. Proteomics analyses were conducted to screen for differentially-expressed proteins (DEPs) in parental CNE-2 cells and CNE-2R cells. Using proteomics approaches, 16 DEPs were identified. Of these DEPs, nucleophosmin (NPM1), annexin A3 and nm23-H1, were verified using western blot analyses. The tumorigenicity was investigated using mouse xenograft tumorigenicity assays, and tumor growth curves were generated. The protein expression of NPM1, annexin A3 and nm23-H1 was examined by immunohistochemically staining tumor tissues. NPM1 and annexin A3 protein levels were downregulated in the CNE-2R cells, whereas nm23-H1 expression was upregulated. In vivo tests showed that compared with the CNE-2 tumors, CNE-2R tumor growth was significantly retarded (P<0.05). CNE-2 tumor progression was inhibited by irradiation, but CNE-2R tumor progression was not, indicating that the CNE-2R cells were also radioresistant in vivo. NPM1 and annexin A3 expression was significantly lower in non-irradiated (NIR)-CNE-2R tumors compared with NIR-CNE-2 tumors (P<0.01). However, Nm23-H1 protein levels were significantly higher (P<0.05). Overall, the present study established comparable radioresistant and radiosensitive tumor models of human NPC, and identified candidate biomarkers that may correlate with radioresistance. The data showed that dysregulation of NPM1, annexin A3 and nm23-H1 expression correlated with the cellular and tumor radioresponse. These proteins are involved in the regulation of intracellular functions, including stress responses, cell proliferation and DNA repair. However, further clinical evaluations are required. PMID:27347189

  11. Model documentation report: Macroeconomic Activity Module (MAM) of the National Energy Modeling System

    SciTech Connect

    1997-02-01

    This report documents the objectives, analytical approach, and development of the National Energy Modeling System (NEMS) Macroeconomic Activity Module (MAM) used to develop the Annual Energy Outlook for 1997 (AEO 97). The report catalogues and describes the module assumptions, computations, methodology, parameter estimation techniques, and mainframe source code. This document serves three purposes. First it is a reference document providing a detailed description of the NEMS MAM used for the AEO 1997 production runs for model analysts, users, and the public. Second, this report meets the legal requirement of the Energy Information Administration (EIA) to provide adequate documentation in support of its models. Third, it facilitates continuity in model development by providing documentation from which energy analysts can undertake model enhancements, data updates, and parameter refinements as future projects.

  12. Model documentation report: Macroeconomic Activity Module (MAM) of the National Energy Modeling System

    SciTech Connect

    Not Available

    1994-02-07

    This report documents the objectives, analytical approach, and development of the National Energy Modeling System (NEMS) Macroeconomic Activity Module (MAM) used to develop the Annual Energy Outlook for 1994 (AEO94). The report catalogues and describes the module assumptions, computations, methodology, parameter estimation techniques, and mainframe source code. This document serves three purposes. First, it is a reference document providing a detailed description of the NEMS MAM used for the AEO 1994 production runs for model analysts, users, and the public. Second, this report meets the legal requirement of the Energy Information Administration (EIA) to provide adequate documentation in support of its models (Public Law 94-385, section 57.b.2). Third, it facilitates continuity in model development by providing documentation from which energy analysts can undertake model enhancements, data updates, and parameter refinements as future projects.

  13. Environmental Test Activity on the Flight Modules of the GLAST LAT Tracker

    SciTech Connect

    Brigida, M.; Caliandro, A.; Favuzzi, C.; Fusco, P.; Gargano, F.; Giglietto, N.; Giordano, F.; Loparco, F.; Marangelli, B.; Mazziotta, M.N.; Mirizzi, N.; Raino, S.; Spinelli, P.; /Bari U. /INFN, Bari

    2007-02-15

    The GLAST Large Area Telescope (LAT) is a gamma-ray telescope consisting of a silicon micro-strip detector tracker followed by a segmented CsI calorimeter and covered by a segmented scintillator anticoincidence system that will search for {gamma}-rays in the 20 MeV-300 GeV energy range. The results of the environmental tests performed on the flight modules (towers) of the Tracker are presented. The aim of the environmental tests is to verify the performance of the silicon detectors in the expected mission environment. The tower modules are subjected to dynamic tests that simulate the launch environment and thermal vacuum test that reproduce the thermal gradients expected on orbit. The tower performance is continuously monitored during the whole test sequence. The environmental test activity, the results of the tests and the silicon tracker performance are presented.

  14. Different pulse pattern generation by frequency detuning in pulse modulated actively mode-locked ytterbium doped fiber laser

    NASA Astrophysics Data System (ADS)

    Chen, He; Chen, Sheng-Ping; Si, Lei; Zhang, Bin; Jiang, Zong-Fu

    2015-10-01

    We report the results of our recent experimental investigation of the modulation frequency detuning effect on the output pulse dynamics in a pulse modulated actively mode-locked ytterbium doped fiber laser. The experimental study shows the existence of five different mode-locking states that mainly depend on the modulation frequency detuning, which are: (a) amplitude-even harmonic/fundamental mode-locking, (b) Q-switched harmonic/fundamental mode-locking, (c) sinusoidal wave modulation mode, (d) pulses bundle state, and (e) noise-like state. A detailed experimental characterization of the output pulses dynamics in each operating mode is presented.

  15. Astrocytes Modulate Neural Network Activity by Ca2+-Dependent Uptake of Extracellular K+

    PubMed Central

    Wang, Fushun; Smith, Nathan A.; Xu, Qiwu; Fujita, Takumi; Baba, Akemichi; Matsuda, Toshio; Takano, Takahiro; Bekar, Lane; Nedergaard, Maiken

    2012-01-01

    Astrocytes are electrically nonexcitable cells that display increases in cytosolic calcium ion (Ca2+) in response to various neurotransmitters and neuromodulators. However, the physiological role of astrocytic Ca2+ signaling remains controversial. We show here that astrocytic Ca2+ signaling ex vivo and in vivo stimulated the Na+,K+-ATPase (Na+- and K+-dependent adenosine triphosphatase), leading to a transient decrease in the extracellular potassium ion (K+) concentration. This in turn led to neuronal hyperpolarization and suppressed baseline excitatory synaptic activity, detected as a reduced frequency of excitatory postsynaptic currents. Synaptic failures decreased in parallel, leading to an increase in synaptic fidelity. The net result was that astrocytes, through active uptake of K+, improved the signal-to-noise ratio of synaptic transmission. Active control of the extracellular K+ concentration thus provides astrocytes with a simple yet powerful mechanism to rapidly modulate network activity. PMID:22472648

  16. Modulation of HMG-CoA reductase activity by pantetheine/pantethine.

    PubMed

    Cighetti, G; Del Puppo, M; Paroni, R; Galli Kienle, M

    1988-11-25

    The ability of pantetheine/pantethine to modulate the activity of HMG-CoA reductase (EC 1.1.1.34) was determined in vitro with rat liver microsomes. The decay of the activity was obtained with pantethine in the 10(-5)-10(-4) M range, whereas stimulation by pantetheine occurred at 10(-3)-10(-2) M, as previously reported for GSSG and GSH, respectively. Inhibition of HMG-CoA by pantethine in isolated liver cells was also investigated by measuring the enzyme activity in microsomes isolated from hepatocytes incubated without or with 1 mM pantethine under conditions previously shown by us to induce inhibition of cholesterol synthesis from acetate. The enzyme amount was not modified by pantethine, but in cells treated with the disulphide, the relative amounts of the thiolic active forms of the enzyme, both phosphorylated and dephosphorylated, were decreased to about half compared to controls. PMID:3196742

  17. Anionic Lipids Modulate the Activity of the Aquaglyceroporin GlpF

    PubMed Central

    Klein, Noreen; Hellmann, Nadja; Schneider, Dirk

    2015-01-01

    The structure and composition of a biological membrane can severely influence the activity of membrane-embedded proteins. Here, we show that the E. coli aquaglyceroporin GlpF has only little activity in lipid bilayers formed from native E. coli lipids. Thus, at first glance, GlpF appears to not be optimized for its natural membrane environment. In fact, we found that GlpF activity was severely affected by negatively charged lipids regardless of the exact chemical nature of the lipid headgroup, whereas GlpF was not sensitive to changes in the lateral membrane pressure. These observations illustrate a potential mechanism by which the activity of an α-helical membrane protein is modulated by the negative charge density around the protein. PMID:26287624

  18. Female pheromones modulate flight muscle activation patterns during preflight warm-up

    PubMed Central

    Vickers, Neil J.; Goller, Franz

    2013-01-01

    At low ambient temperature Helicoverpa zea male moths engage in warm-up behavior prior to taking flight in response to an attractive female pheromone blend. Male H. zea warm up at a faster rate when sensing the attractive pheromone blend compared with unattractive blends or blank controls (Crespo et al. 2012), but the mechanisms involved in this olfactory modulation of the heating rate during preflight warm-up are unknown. Here, we test three possible mechanisms for increasing heat production: 1) increased rate of muscle contraction; 2) reduction in mechanical movement by increased overlap in activation of the antagonistic flight muscles; and 3) increased activation of motor units. To test which mechanisms play a role, we simultaneously recorded electrical activation patterns of the main flight muscles (dorsolongitudinal and dorsoventral muscles), wing movement, and thoracic temperature in moths exposed to both the attractive pheromone blend and a blank control. Results indicate that the main mechanism responsible for the observed increase in thoracic heating rate with pheromone stimulation is the differential activation of motor units during each muscle contraction cycle in both antagonistic flight muscles. This additional activation lengthens the contracted state within each cycle and thus accounts for the greater heat production. Interestingly, the rate of activation (frequency of contraction cycles) of motor units, which is temperature dependent, did not vary between treatments. This result suggests that the activation rate is determined by a temperature-dependent oscillator, which is not affected by the olfactory stimulus, but activation of motor units is modulated during each cycle. PMID:23699056

  19. Female odours promote the activation of sheltered kissing bug Rhodnius prolixus males and modulate their orientation.

    PubMed

    Pontes, G; Zacharias, C A; Manrique, G; Lorenzo, M G

    2014-09-01

    The existence of a pheromone emitted during copulation has been reported for Rhodnius prolixus (Hemiptera: Reduviidae) Stål. Adults possess one pair of metasternal glands (MGs) from which female R. prolixus release volatiles mainly at night. We investigated whether these volatiles emitted by adult R. prolixus can modulate sexual-related behaviours of opposite and/or same sex individuals. We first used a shelter bioassay to test if adult activity patterns can be affected by chemical signals emitted by opposite sex conspecifics. We observed that males left the shelter more frequently in the presence of females, showing higher activity and an increase of intrasexual copulation attempts. Females showed no shelter-related activation in the presence of male odours. Second, we used a locomotion compensator device to investigate whether females or males show oriented responses to odours emitted by adults. We found that males oriented towards air currents carrying female odours but females did not orient towards odours emitted by adults. Finally, we observed that males oriented towards the female MG compounds. Thus, a volatile chemical signal emitted by females from their MGs promoted the activation of sheltered males and modulated orientation to air currents. PMID:25855829

  20. Modulation of Brain Activity during Action Observation: Influence of Perspective, Transitivity and Meaningfulness

    PubMed Central

    Hétu, Sébastien; Mercier, Catherine; Eugène, Fanny; Michon, Pierre-Emmanuel; Jackson, Philip L.

    2011-01-01

    The coupling process between observed and performed actions is thought to be performed by a fronto-parietal perception-action system including regions of the inferior frontal gyrus and the inferior parietal lobule. When investigating the influence of the movements' characteristics on this process, most research on action observation has focused on only one particular variable even though the type of movements we observe can vary on several levels. By manipulating the visual perspective, transitivity and meaningfulness of observed movements in a functional magnetic resonance imaging study we aimed at investigating how the type of movements and the visual perspective can modulate brain activity during action observation in healthy individuals. Importantly, we used an active observation task where participants had to subsequently execute or imagine the observed movements. Our results show that the fronto-parietal regions of the perception action system were mostly recruited during the observation of meaningless actions while visual perspective had little influence on the activity within the perception-action system. Simultaneous investigation of several sources of modulation during active action observation is probably an approach that could lead to a greater ecological comprehension of this important sensorimotor process. PMID:21931832

  1. Protein kinase C modulates transcriptional activation by the juvenile hormone receptor methoprene-tolerant.

    PubMed

    Ojani, Reyhaneh; Liu, Pengcheng; Fu, Xiaonan; Zhu, Jinsong

    2016-03-01

    Juvenile hormone (JH) controls many biological events in insects by triggering dramatic changes in gene expression in target cells. The Methoprene-tolerant (MET) protein, an intracellular JH receptor, acts as a transcriptional regulator and binds to the promoters of tissue- and stage-specific JH target genes when JH is present. Our recent study has demonstrated that the transcriptional activation by MET is modulated by a membrane-initiated JH signaling pathway, involving phospholipase C (PLC) and calcium/calmodulin-dependent protein kinase II (CaMKII). Here we report that protein kinase C (PKC) is another essential intermediate of this pathway. PKC was activated by JH and this action was PLC-dependent. Inhibition of the PKC activity substantially weakened the JH-induced gene expression in mosquito cells. RNAi experiments indicated that several PKC isoforms were involved in the JH action during the post-emergence development of adult female mosquitoes. JH treatment considerably increased the binding of MET to the promoters of JH response genes in cultured mosquito abdomens that were collected from newly emerged female adults. The JH-induced DNA binding of MET was hindered when the abdomens were treated with a PKC inhibitor and JH. Therefore, the results suggest that PKC modulates the transactivation activity of MET by enhancing the binding of MET to JH response elements in the JH target genes. This mechanism may allow for variable and stage- and tissue-specific genomic responses to JH. PMID:26689644

  2. Lasting modulation of in vitro oscillatory activity with weak direct current stimulation

    PubMed Central

    Bikson, Marom; Parra, Lucas C.

    2014-01-01

    Transcranial direct current stimulation (tDCS) is emerging as a versatile tool to affect brain function. While the acute neurophysiological effects of stimulation are well understood, little is know about the long-term effects. One hypothesis is that stimulation modulates ongoing neural activity, which then translates into lasting effects via physiological plasticity. Here we used carbachol-induced gamma oscillations in hippocampal rat slices to establish whether prolonged constant current stimulation has a lasting effect on endogenous neural activity. During 10 min of stimulation, the power and frequency of gamma oscillations, as well as multiunit activity, were modulated in a polarity specific manner. Remarkably, the effects on power and multiunit activity persisted for more than 10 min after stimulation terminated. Using a computational model we propose that altered synaptic efficacy in excitatory and inhibitory pathways could be the source of these lasting effects. Future experimental studies using this novel in vitro preparation may be able to confirm or refute the proposed hypothesis. PMID:25505103

  3. Modulation of the Activity of Secretory Phospholipase A2 by Antimicrobial Peptides

    PubMed Central

    Zhao, Hongxia; Kinnunen, Paavo K. J.

    2003-01-01

    The antimicrobial peptides magainin 2, indolicidin, and temporins B and L were found to modulate the hydrolytic activity of secretory phospholipase A2 (sPLA2) from bee venom and in human lacrimal fluid. More specifically, hydrolysis of phosphatidylcholine (PC) liposomes by bee venom sPLA2 at 10 μM Ca2+ was attenuated by these peptides while augmented product formation was observed in the presence of 5 mM Ca2+. The activity of sPLA2 towards anionic liposomes was significantly enhanced by the antimicrobial peptides at low [Ca2+] and was further enhanced in the presence of 5 mM Ca2+. Similarly, with 5 mM Ca2+ the hydrolysis of anionic liposomes was enhanced significantly by human lacrimal fluid sPLA2, while that of PC liposomes was attenuated. These results indicate that concerted action of antimicrobial peptides and sPLA2 could improve the efficiency of the innate response to infections. Interestingly, inclusion of a cationic gemini surfactant in the vesicles showed an essentially similar pattern on sPLA2 activity, suggesting that the modulation of the enzyme activity by the antimicrobial peptides may involve also charge properties of the substrate surface. PMID:12604528

  4. A giant local interneuron modulates the rhythmic activities of the antennal lobe in Pupae Drosophila.

    PubMed

    Xu, Yanyang; Yan, Ying; He, Mintong; Liao, Zhiheng; Ran, Dongzhi; Sun, Xicui; Liu, Yulou; Wang, Xutian; Huang, Yingcheng; Xu, Hanhong; Gu, Huaiyu

    2015-10-01

    In Drosophila, olfaction is tightly related to feeding and reproduction. There are three classes of neurons forming synapses in the olfactory circuit: the olfactory receptor neurons (ORNs), projection neurons (PNs), and local interneurons (LNs). Here, we showed that giant local interneurons named GLNs, which were different from the classical neurons in the olfactory circuits, displayed distinctive rhythmic activities in the dorsolateral side of antennal lobe (AL) in Drosophila Pupae. Anatomically, GLNs were much larger than ipsilateral LNs and extended arborizations throughout the AL. Electrophysiologically, GLN exhibited typical 4-phased rhythmic spontaneous membrane activities, and the surrounding cells were dye-coupled when biocytin was injected into the cell body of GLN. Our study demonstrated that spontaneous activities of GLNs correlated with that of LNs and PNs. After the GLNs were damaged, the membrane activities of ipsilateral LNs and PNs became smaller, but faster. By depressing the firing frequencies of PNs and LNs, GLNs modulated the synchronization of AL and might play an important role as a "modulator" in the local circuit. PMID:26200249

  5. Chemical Modulation of the Biological Activity of Reutericyclin: a Membrane-Active Antibiotic from Lactobacillus reuteri

    PubMed Central

    Cherian, Philip T.; Wu, Xiaoqian; Maddox, Marcus M.; Singh, Aman P.; Lee, Richard E.; Hurdle, Julian G.

    2014-01-01

    Whilst the development of membrane-active antibiotics is now an attractive therapeutic concept, progress in this area is disadvantaged by poor knowledge of the structure-activity relationship (SAR) required for optimizing molecules to selectively target bacteria. This prompted us to explore the SAR of the Lactobacillus reuteri membrane-active antibiotic reutericyclin, modifying three key positions about its tetramic acid core. The SAR revealed that lipophilic analogs were generally more active against Gram-positive pathogens, but introduction of polar and charged substituents diminished their activity. This was confirmed by cytometric assays showing that inactive compounds failed to dissipate the membrane potential. Radiolabeled substrate assays indicated that dissipation of the membrane potential by active reutericyclins correlated with inhibition of macromolecular synthesis in cells. However, compounds with good antibacterial activities also showed cytotoxicity against Vero cells and hemolytic activity. Although this study highlights the challenge of optimizing membrane-active antibiotics, it shows that by increasing antibacterial potency the selectivity index could be widened, allowing use of lower non-cytotoxic doses. PMID:24739957

  6. Oscillatory phase modulates the timing of neuronal activations and resulting behavior.

    PubMed

    Coon, W G; Gunduz, A; Brunner, P; Ritaccio, A L; Pesaran, B; Schalk, G

    2016-06-01

    Human behavioral response timing is highly variable from trial to trial. While it is generally understood that behavioral variability must be due to trial-by-trial variations in brain function, it is still largely unknown which physiological mechanisms govern the timing of neural activity as it travels through networks of neuronal populations, and how variations in the timing of neural activity relate to variations in the timing of behavior. In our study, we submitted recordings from the cortical surface to novel analytic techniques to chart the trajectory of neuronal population activity across the human cortex in single trials, and found joint modulation of the timing of this activity and of consequent behavior by neuronal oscillations in the alpha band (8-12Hz). Specifically, we established that the onset of population activity tends to occur during the trough of oscillatory activity, and that deviations from this preferred relationship are related to changes in the timing of population activity and the speed of the resulting behavioral response. These results indicate that neuronal activity incurs variable delays as it propagates across neuronal populations, and that the duration of each delay is a function of the instantaneous phase of oscillatory activity. We conclude that the results presented in this paper are supportive of a general model for variability in the effective speed of information transmission in the human brain and for variability in the timing of human behavior. PMID:26975551

  7. Long-term physical activity modulates brain processing of somatosensory stimuli: Evidence from young male twins.

    PubMed

    Tarkka, Ina M; Savić, Andrej; Pekkola, Elina; Rottensteiner, Mirva; Leskinen, Tuija; Kaprio, Jaakko; Kujala, Urho M

    2016-05-01

    Leisure-time physical activity is a key contributor to physical and mental health. Yet the role of physical activity in modulating cortical function is poorly known. We investigated whether precognitive sensory brain functions are associated with the level of physical activity. Physical activity history (3-yr-LTMET), physiological measures and somatosensory mismatch response (sMMR) in EEG were recorded in 32 young healthy twins. In all participants, 3-yr-LTMET correlated negatively with body fat%, r=-0.77 and positively with VO2max, r=0.82. The fat% and VO2max differed between 15 physically active and 17 inactive participants. Trend toward larger sMMR was seen in inactive compared to active participants. This finding was significant in a pairwise comparison of 9 monozygotic twin pairs discordant for physical activity. Larger sMMR reflecting stronger synchronous neural activity may reveal diminished gating of precognitive somatosensory information in physically inactive healthy young men compared to the active ones possibly rendering them more vulnerable to somatosensory distractions from their surroundings. PMID:26860901

  8. Radioresistance of granulation tissue-derived cells from skin wounds combined with total body irradiation.

    PubMed

    Dai, Tingyu; Chen, Zelin; Tan, Li; Shi, Chunmeng

    2016-04-01

    Combined radiation and wound injury (CRWI) occurs following nuclear explosions and accidents, radiological or nuclear terrorism, and radiation therapy combined with surgery. CRWI is complicated and more difficult to heal than single injuries. Stem cell‑based therapy is a promising treatment strategy for CRWI, however, sourcing stem cells remains a challenge. In the present study, the granulation tissue-derived cells (GTCs) from the skin wounds (SWs) of CRWI mice (C‑GTCs) demonstrated a higher radioresistance to the damage caused by combined injury, and were easier to isolate and harvest when compared with bone marrow‑derived mesenchymal stromal cells (BMSCs). Furthermore, the C-GTCs exhibited similar stem cell-associated properties, such as self-renewal and multilineage differentiation capacity, when compared with neonatal dermal stromal cells (DSCs) and GTCs from unirradiated SWs. Granulation tissue, which is easy to access, may present as an optimal autologous source of stem/progenitor cells for therapeutic applications in CRWI. PMID:26936439

  9. Benefit of Carbon Ion Radiotherapy in the Treatment of Radio-resistant Tumors

    NASA Astrophysics Data System (ADS)

    Kamada, Tadashi; Tsujii, Hirohiko; Tsuji, Hiroshi; Yanagi, Tsuyoshi; Imai, Reiko; Mizoe, Jun-etsu; Miyamoto, Tadaaki; Kato, Hirotoshi; Yamada, Shigeru; Kato, Shingo; Yoshikawa, Kyousan; Kandatsu, Susumu

    2003-08-01

    The Heavy Ion Medical Accelerator in Chiba (HIMAC) is the world's first heavy ion accelerator complex dedicated to medical use in a hospital environment. Heavy ions have superior depth-dose distribution and greater cell-killing ability. In June 1994, clinical research for the treatment of cancer was begun using carbon ions generated by HIMAC. Until August 2002, a total of 1,297 patients were enrolled in clinical trials. Most of the patients had locally advanced and/or medically inoperable tumors. Tumors radio-resistant and/or located near critical organs were also included. The clinical trials revealed that carbon ion radiotherapy provided definite local control and offered a survival advantage without unacceptable morbidity in a variety of tumors that were hard to cure by other modalities.

  10. Rational design of cancer-targeted BSA protein nanoparticles as radiosensitizer to overcome cancer radioresistance.

    PubMed

    Huang, Yanyu; Luo, Yi; Zheng, Wenjie; Chen, Tianfeng

    2014-01-01

    Radiotherapy displays curative potential for cervical cancer management, but radioresistance occurs during long-term therapy. To overcome this limitation, tumor-targeted nanotechnology has been proposed to enhance the radiosensitivity of solid tumors. Herein, we used biocompatible bovine serum albumin nanoparticles (BSANPs) as carriers of organic selenocompound (PSeD) with folate (FA) as the targeting ligand to fabricate a cancer-targeted nanosystem. The combination of PSeD and BSANPs endowed the nanosystem with higher light absorption and reactive oxygen species (ROS) generation owing to their properties of surface plasmon resonance (SPR) effect, heavy metal effect, high refractive index and nanoparticulate interfacial effect. The combined treatment drastically increased the ROS overproduction, VEGF/VEGFR2 inactivation and inhibition of XRCC-1-mediated repair of DNA damage, thus triggering G2/M phase arrest and apoptosis. Taken together, our findings demonstrate the utility of FA-BSANPs as a promising radiosensitizer to improve cancer radiotherapy. PMID:25314331

  11. Benefit of Carbon Ion Radiotherapy in the Treatment of Radio-resistant Tumors

    SciTech Connect

    Kamada, Tadashi; Tsujii, Hirohiko; Tsuji, Hiroshi; Yanagi, Tsuyoshi; Imai, Reiko; Mizoe, Jun-etsu; Miyamoto, Tadaaki; Kato, Hirotoshi; Yamada, Shigeru; Kato, Shingo; Yoshikawa, Kyousan; Kandatsu, Susumu

    2003-08-26

    The Heavy Ion Medical Accelerator in Chiba (HIMAC) is the world's first heavy ion accelerator complex dedicated to medical use in a hospital environment. Heavy ions have superior depth-dose distribution and greater cell-killing ability. In June 1994, clinical research for the treatment of cancer was begun using carbon ions generated by HIMAC. Until August 2002, a total of 1,297 patients were enrolled in clinical trials. Most of the patients had locally advanced and/or medically inoperable tumors. Tumors radio-resistant and/or located near critical organs were also included. The clinical trials revealed that carbon ion radiotherapy provided definite local control and offered a survival advantage without unacceptable morbidity in a variety of tumors that were hard to cure by other modalities.

  12. Investigating the Radioresistant Properties of Lung Cancer Stem Cells in the Context of the Tumor Microenvironment.

    PubMed

    Chan, Ryan; Sethi, Pallavi; Jyoti, Amar; McGarry, Ronald; Upreti, Meenakshi

    2016-02-01

    Lung cancer is the most common cause of cancer-related deaths worldwide and non-small cell lung cancer (NSCLC) accounts for ~85% of all lung cancer. While recent research has shown that cancer stem cells (CSC) exhibit radioresistant and chemoresistant properties, current cancer therapy targets the bulk of the tumor burden without accounting for the CSC and the contribution of the tumor microenvironment. CSC interaction with the stroma enhances NSCLC survival, thus limiting the efficacy of treatment. The aim of this study was to elucidate the role of CSC and the microenvironment in conferring radio- or chemoresistance in an in vitro tumor model for NSCLC. The novel in vitro three-dimensional (3D) NSCLC model of color-coded tumor tissue analogs (TTA) that we have developed is comprised of human lung adenocarcinoma cells, fibroblasts, endothelial cells and NSCLC cancer stem cells maintained in low oxygen conditions (5% O2) to recapitulate the physiologic conditions in tumors. Using this model, we demonstrate that a single 5 Gy radiation dose does not inhibit growth of TTA containing CSC and results in elevated expression of cytokines (TGF-α, RANTES, ENA-78) and factors (vimentin, MMP and TIMP), indicative of an invasive and aggressive phenotype. However, combined treatment of single dose or fractionated doses with cisplatin was found to either attenuate or decrease the proliferative effect that radiation exposure alone had on TTA containing CSC maintained in hypoxic conditions. In summary, we utilized a 3D NSCLC model, which had characteristics of the tumor microenvironment and tumor cell heterogeneity, to elucidate the multifactorial nature of radioresistance in tumors. PMID:26836231

  13. Dose Escalation for Metastatic Spinal Cord Compression in Patients With Relatively Radioresistant Tumors

    SciTech Connect

    Rades, Dirk; Freundt, Katja; Meyners, Thekla; Bajrovic, Amira; Basic, Hiba; Karstens, Johann H.; Adamietz, Irenaeus A.; Wildfang, Ingeborg; Rudat, Volker; Schild, Steven E.; Dunst, Juergen

    2011-08-01

    Purpose: Radiotherapy alone is the most common treatment for metastatic spinal cord compression (MSCC) from relatively radioresistant tumors such as renal cell carcinoma, colorectal cancer, and malignant melanoma. However, the results of the 'standard' regimen 30 Gy/10 fractions need to be improved with respect to functional outcome. This study investigated whether a dose escalation beyond 30 Gy can improve treatment outcomes. Methods and Materials: A total of 91 patients receiving 30 Gy/10 fractions were retrospectively compared to 115 patients receiving higher doses (37.5 Gy/15 fractions, 40 Gy/20 fractions) for motor function and local control of MSCC. Ten further potential prognostic factors were evaluated: age, gender, tumor type, performance status, number of involved vertebrae, visceral or other bone metastases, interval from tumor diagnosis to radiotherapy, pretreatment ambulatory status, and time developing motor deficits before radiotherapy. Results: Motor function improved in 18% of patients after 30 Gy and in 22% after higher doses (p = 0.81). On multivariate analysis, functional outcome was associated with visceral metastases (p = 0.030), interval from tumor diagnosis to radiotherapy (p = 0.010), and time developing motor deficits (p < 0.001). The 1-year local control rates were 76% after 30 Gy and 80% after higher doses, respectively (p = 0.64). On multivariate analysis, local control was significantly associated with visceral metastases (p = 0.029) and number of involved vertebrae (p = 0.043). Conclusions: Given the limitations of a retrospective study, escalation of the radiation dose beyond 30 Gy/10 fractions did not significantly improve motor function and local control of MSCC in patients with relatively radioresistant tumors.

  14. Development and testing of thermal-energy-storage modules for use in active solar heating and cooling systems. Final report

    SciTech Connect

    Parker, J.C.

    1981-04-01

    Additional development work on thermal-energy-storage modules for use with active solar heating and cooling systems is summarized. Performance testing, problems, and recommendations are discussed. Installation, operation, and maintenance instructions are included. (MHR)

  15. Modulation of cocaine-induced activity by intracerebral administration of CXCL12.

    PubMed

    Trecki, J; Unterwald, E M

    2009-06-16

    The role of chemokines in immune function is clearly established. Recent evidence suggests that these molecules also play an important role in the central nervous system as modulators of neuronal activity. The chemokine CXCL12 has been identified in several regions of the adult rat brain including the substantia nigra, ventral tegmental area and caudate putamen. CXCR4, a receptor activated by CXCL12, is expressed by dopaminergic neurons in the substantia nigra. The present study tested the effects of intracranial injections of CXCL12 on cocaine-induced locomotion and stereotypic activity in adult male Sprague-Dawley rats. Results demonstrate that intracerebral ventricular administration of CXCL12 (25 ng/4 microl) 15 min prior to cocaine (20 mg/kg intraperitoneal (i.p.)) produced a significant potentiation of both ambulatory and stereotypic activity as compared to cocaine alone. The effects of CXCL12 were blocked by administration of the selective CXCR4 antagonist, AMD 3100. Administration of CXCL12 into specific brain regions was performed to further understand the site of action of CXCL12. Bilateral administration of CXCL12 (25 ng/0.5 microl) into the ventral tegmental area 15 min prior to cocaine (20 mg/kg i.p.) significantly potentiated cocaine-induced ambulatory activity, whereas microinjections of CXCL12 into the caudate putamen selectively increased stereotypy. Conversely, administration of CXCL12 into the lateral shell of the nucleus accumbens resulted in an inhibition of cocaine-stimulated ambulatory activity. No alterations in ambulatory or stereotypic activity were observed following CXCL12 administration into the core of the nucleus accumbens. These results demonstrate that CXCL12 can modulate the behavioral effects produced by cocaine in a brain region-specific manner. PMID:19303923

  16. Activation of Neuropeptide Y Receptors Modulates Retinal Ganglion Cell Physiology and Exerts Neuroprotective Actions In Vitro

    PubMed Central

    Martins, João; Elvas, Filipe; Brudzewsky, Dan; Martins, Tânia; Kolomiets, Bogdan; Tralhão, Pedro; Gøtzsche, Casper R.; Cavadas, Cláudia; Castelo-Branco, Miguel; Woldbye, David P. D.; Picaud, Serge; Santiago, Ana R.

    2015-01-01

    Neuropeptide Y (NPY) is expressed in mammalian retina but the location and potential modulatory effects of NPY receptor activation remain largely unknown. Retinal ganglion cell (RGC) death is a hallmark of several retinal degenerative diseases, particularly glaucoma. Using purified RGCs and ex vivo rat retinal preparations, we have measured RGC intracellular free calcium concentration ([Ca2+]i) and RGC spiking activity, respectively. We found that NPY attenuated the increase in the [Ca2+]i triggered by glutamate mainly via Y1 receptor activation. Moreover, (Leu31, Pro34)−NPY, a Y1/Y5 receptor agonist, increased the initial burst response of OFF-type RGCs, although no effect was observed on RGC spontaneous spiking activity. The Y1 receptor activation was also able to directly modulate RGC responses by attenuating the NMDA-induced increase in RGC spiking activity. These results suggest that Y1 receptor activation, at the level of inner or outer plexiform layers, leads to modulation of RGC receptive field properties. Using in vitro cultures of rat retinal explants exposed to NMDA, we found that NPY pretreatment prevented NMDA-induced cell death. However, in an animal model of retinal ischemia-reperfusion injury, pretreatment with NPY or (Leu31, Pro34)−NPY was not able to prevent apoptosis or rescue RGCs. In conclusion, we found modulatory effects of NPY application that for the first time were detected at the level of RGCs. However, further studies are needed to evaluate whether NPY neuroprotective actions detected in retinal explants can be translated into animal models of retinal degenerative diseases. PMID:26311075

  17. The strength of gradually accruing probabilistic evidence modulates brain activity during a categorical decision

    PubMed Central

    Wheeler, Mark E.; Woo, Sarah G.; Ansel, Tobin; Tremel, Joshua J.; Collier, Amanda L.; Velanova, Katerina; Ploran, Elisabeth J.; Yang, Tianming

    2014-01-01

    The evolution of neural activity during a perceptual decision is well characterized by the evidence parameter in sequential sampling models. However, it is not known whether accumulating signals in human neuroimaging are related to the integration of evidence. Our aim was to determine whether activity accumulates in a non-perceptual task by identifying brain regions tracking the strength of probabilistic evidence. Functional magnetic resonance imaging was used to measure whole-brain activity as choices were informed by integrating a series of learned prior probabilities. Subjects first learned the predictive relationship between a set of shape stimuli and one of two choices. During scanned testing, they made binary choices informed by the sum of the predictive strengths of individual shapes. Sequences of shapes adhered to three distinct rates of evidence (RoE), rapid, gradual, and switch. We predicted that activity in regions informing the decision would modulate as a function of RoE prior to the choice. Activity in some regions, including premotor areas, changed as a function of RoE and response hand, indicating a role in forming an intention to respond. Regions in occipital, temporal, and parietal lobes modulated as a function of RoE only, suggesting a pre-response stage of evidence processing. In all of these regions, activity was greatest on rapid trials and least on switch trials, which is consistent with an accumulation-to-boundary account. In contrast, activity in a set of frontal and parietal regions was greatest on switch and least on rapid trials, which is consistent with an effort or time-on-task account. PMID:25313658

  18. A Role for Intersubunit Interactions in Maintaining SAGA Deubiquitinating Module Structure and Activity

    SciTech Connect

    Samara, Nadine L.; Ringel, Alison E.; Wolberger, Cynthia

    2012-08-31

    The deubiquitinating module (DUBm) of the SAGA coactivator contains the Ubp8 isopeptidase, Sgf11, Sus1, and Sgf73, which form a highly interconnected complex. Although Ubp8 contains a canonical USP catalytic domain, it is only active when in complex with the other DUBm subunits. The Sgf11 zinc finger (Sgf11-ZnF) binds near the Ubp8 active site and is essential for full activity, suggesting that the Sgf11-ZnF helps maintain the active conformation of Ubp8. We report structural and solution studies showing that deletion of the Sgf11-ZnF destabilizes incorporation of Ubp8 within the DUBm, giving rise to domain swapping with a second complex and misaligning active site residues. Activating mutations in Ubp8 that partially restore activity in the absence of the Sgf11-ZnF promote the monomeric form of the DUBm. Our data suggest an unexpected role for Sgf11 in compensating for the absence of structural features that maintain the active conformation of Ubp8.

  19. Baroreflex modulation of muscle sympathetic nerve activity during cold pressor test in humans

    NASA Technical Reports Server (NTRS)

    Cui, Jian; Wilson, Thad E.; Crandall, Craig G.

    2002-01-01

    The purpose of this project was to test the hypothesis that baroreceptor modulation of muscle sympathetic nerve activity (MSNA) and heart rate is altered during the cold pressor test. Ten subjects were exposed to a cold pressor test by immersing a hand in ice water for 3 min while arterial blood pressure, heart rate, and MSNA were recorded. During the second and third minute of the cold pressor test, blood pressure was lowered and then raised by intravenous bolus infusions of sodium nitroprusside and phenylephrine HCl, respectively. The slope of the relationship between MSNA and diastolic blood pressure was more negative (P < 0.005) during the cold pressor test (-244.9 +/- 26.3 units x beat(-1) x mmHg(-1)) when compared with control conditions (-138.8 +/- 18.6 units x beat(-1) x mmHg(-1)), whereas no significant change in the slope of the relationship between heart rate and systolic blood pressure was observed. These data suggest that baroreceptors remain capable of modulating MSNA and heart rate during a cold pressor test; however, the sensitivity of baroreflex modulation of MSNA is elevated without altering the sensitivity of baroreflex control of heart rate.

  20. Rotational modulation of the chromospheric activity in the young solar-type star, X-1 Orionis

    NASA Technical Reports Server (NTRS)

    Boesgaard, A. M.; Simon, T.

    1982-01-01

    The IUE satellite was used to observe one of the youngest G stars (GO V) for which Duncan (1981) derives an age of 6 x 10 to the 8th power years from the Li abundance. Rotational modulation was looked for in the emission flux in the chromospheric and transition region lines of this star. Variations in the Ca 11 K-lines profile were studied with the CHF telescope at Mauna Kea. Results show that the same modulation of the emission flux of Ca 11 due to stellar rotation is present in the transition region feature of C IV and probably of He II. For other UV lines the modulation is not apparent, due to a more complex surface distribution of the active areas or supergranulation network, or a shorter lifetime of the conditions which give rise to these features, or to the uncertainities in the measured line strengths. The Mg II emission flux is constant to within + or - 3.4% implying a rather uniform distribution of Mg II emission areas. The Ca II emission not only shows a measurable variation in intensity but also variations in detailed line profile shape when observed at high resolution.

  1. Modulation of Backbone Flexibility for Effective Dissociation of Antibacterial and Hemolytic Activity in Cyclic Peptides.

    PubMed

    Oddo, Alberto; Thomsen, Thomas T; Britt, Hannah M; Løbner-Olesen, Anders; Thulstrup, Peter W; Sanderson, John M; Hansen, Paul R

    2016-08-11

    Bacterial resistance to antibiotic therapy is on the rise and threatens to evolve into a worldwide emergency: alternative solutions to current therapies are urgently needed. Cationic amphipathic peptides are potent membrane-active agents that hold promise as the next-generation therapy for multidrug-resistant infections. The peptides' behavior upon encountering the bacterial cell wall is crucial, and much effort has been dedicated to the investigation and optimization of this amphipathicity-driven interaction. In this study we examined the interaction of a novel series of nine-membered flexible cyclic AMPs with liposomes mimicking the characteristics of bacterial membranes. Employed techniques included circular dichroism and marker release assays, as well as microbiological experiments. Our analysis was aimed at correlating ring flexibility with their antimicrobial, hemolytic, and membrane activity. By doing so, we obtained useful insights to guide the optimization of cyclic antimicrobial peptides via modulation of their backbone flexibility without loss of activity. PMID:27563396

  2. Modulating antibiotic activity towards respiratory bacterial pathogens by co-medications: a multi-target approach.

    PubMed

    Vandevelde, Nathalie M; Tulkens, Paul M; Van Bambeke, Françoise

    2016-07-01

    Non-antibiotic drugs can modulate bacterial physiology and/or antibiotic activity, opening perspectives for innovative therapeutic strategies. Focusing on respiratory pathogens and considering in vitro, in vivo, and clinical data, here we examine the effect of these drugs on the expression of resistance mechanisms, biofilm formation, and intracellular survival, as well as their influence on the activity of antibiotics on bacteria. Beyond the description of the effects observed, we also comment on concentrations that are active and discuss the mechanisms of drug-drug or drug-target interactions. This discussion should be helpful in defining useful targets for adjuvant therapy and establishing the corresponding pharmacophores for further drug fine-tuning. PMID:27094105

  3. HERC2/USP20 coordinates CHK1 activation by modulating CLASPIN stability.

    PubMed

    Zhu, Min; Zhao, Hongchang; Liao, Ji; Xu, Xingzhi

    2014-12-01

    CLASPIN is an essential mediator in the DNA replication checkpoint, responsible for ATR (ataxia telangiectasia and Rad3-related protein)-dependent activation of CHK1 (checkpoint kinase 1). Here we found a dynamic signaling pathway that regulates CLASPIN turn over. Under unperturbed conditions, the E3 ubiquitin ligase HERC2 regulates the stability of the deubiquitinating enzyme USP20 by promoting ubiquitination-mediated proteasomal degradation. Under replication stress, ATR-mediated phosphorylation of USP20 results in the disassociation of HERC2 from USP20. USP20 in turn deubiquitinates K48-linked-polyubiquitinated CLASPIN, stabilizing CLASPIN and ultimately promoting CHK1 phosphorylation and CHK1-directed checkpoint activation. Inhibition of USP20 expression promotes chromosome instability and xenograft tumor growth. Taken together, our findings demonstrated a novel function of HERC2/USP20 in coordinating CHK1 activation by modulating CLASPIN stability, which ultimately promotes genome stability and suppresses tumor growth. PMID:25326330

  4. Modulating protein activity using tethered ligands with mutually exclusive binding sites

    PubMed Central

    Schena, Alberto; Griss, Rudolf; Johnsson, Kai

    2015-01-01

    The possibility to design proteins whose activities can be switched on and off by unrelated effector molecules would enable applications in various research areas, ranging from biosensing to synthetic biology. We describe here a general method to modulate the activity of a protein in response to the concentration of a specific effector. The approach is based on synthetic ligands that possess two mutually exclusive binding sites, one for the protein of interest and one for the effector. Tethering such a ligand to the protein of interest results in an intramolecular ligand–protein interaction that can be disrupted through the presence of the effector. Specifically, we introduce a luciferase controlled by another protein, a human carbonic anhydrase whose activity can be controlled by proteins or small molecules in vitro and on living cells, and novel fluorescent and bioluminescent biosensors. PMID:26198003

  5. System-in-package solution for a low-power active electrode module.

    PubMed

    Gaio, Nikolas; Gao, Linping; Cai, Jinhe; Zhang, Jinyong; Wang, Lei

    2014-01-01

    This paper presents the design of system in package for a low-power active electrode module. The main aim of this research is to provide a low-cost, high-density, and high-quality module, exploiting the features of a System-in-Package (SiP) solution. To the best knowledge of the authors, this is the first time that SiP technology has been used in the development of a modular active electrode. Two SiPs have been designed and one of them has been fabricated and tested. The dimensions of the latter are 7×7×1 mm and it was designed taking in account the necessity of soldering it by hand. On the contrary, the other package dimensions are 4.5×4.5×1 mm and it was designed for fully exploiting the latest technologies available to authors. The SiPs have been designed to be reused in different electrocardiogram (ECG) systems and are easy to solder using ball grids arrays (BGA) and land grids arrays (LGA) as second level interconnection; both these features allow to reduce the time to market of the supra-system including the module. The active electrode presents a bandwidth which ranges from 7.9 mHz to 300 Hz and it has a mid-band gain which can be set to a maximum value of 40 dB. The fabricated SiP has been tested on a printed circuit board (PCB), with an input signal generated by a Dimetek iBUSS-P biomedical signal simulator showing a satisfying functioning of the SiP. PMID:25571119

  6. Modulation of expression and activity of intestinal multidrug resistance-associated protein 2 by xenobiotics.

    PubMed

    Tocchetti, Guillermo Nicolás; Rigalli, Juan Pablo; Arana, Maite Rocío; Villanueva, Silvina Stella Maris; Mottino, Aldo Domingo

    2016-07-15

    The multidrug resistance-associated protein 2 (MRP2/ABCC2) is a transporter that belongs to the ATP-binding cassette (ABC) superfamily. In the intestine, it is localized to the apical membrane of the enterocyte and plays a key role in limiting the absorption of xenobiotics incorporated orally. MRP2 may also play a role in systemic clearance of xenobiotics available from the serosal side of the intestine. MRP2 transports a wide range of substrates, mainly organic anions conjugated with glucuronic acid, glutathione and sulfate and its expression can be modulated by xenobiotics at transcriptional- and post-transcriptional levels. Transcriptional regulation is usually mediated by a group of nuclear receptors. The pregnane X receptor (PXR) is a major member of this group. Relevant drugs described to up-regulate intestinal MRP2 via PXR are rifampicin, spironolactone and carbamazepine, among others. The constitutive androstane receptor (CAR, NR1I3) was also reported to modulate MRP2 expression, phenobarbital being a typical activator. Dietary compounds, including micronutrients and other natural products, are also capable of regulating intestinal MRP2 expression transcriptionally. We have given them particular attention since the composition of the food ingested daily is not necessarily supervised and may result in interactions with therapeutic drugs. Post-transcriptional regulation of MRP2 activity by xenobiotics, e.g. as a consequence of inhibitory actions, is also described in this review. Unfortunately, only few studies report on drug-drug or nutrient-drug interactions as a consequence of modulation of intestinal MRP2 activity by xenobiotics. Future clinical studies are expected to identify additional interactions resulting in changes in efficacy or safety of therapeutic drugs. PMID:27155371

  7. Structure-activity relationships of the plasminogen modulator SMTP with respect to the inhibition of soluble epoxide hydrolase.

    PubMed

    Matsumoto, Naoki; Suzuki, Eriko; Tsujihara, Kota; Nishimura, Yuuichi; Hasumi, Keiji

    2015-11-01

    A family of fungal metabolites, SMTP, is a small-molecule plasminogen modulator that enhances plasminogen activation, leading to thrombolysis. We recently demonstrated that SMTP-7 effectively treats ischemic stroke due to its thrombolytic activity as well as anti-inflammatory action, which is attributable to soluble epoxide hydrolase (sEH) inhibition. In this paper, we studied detailed structure-activity relationships of plasminogen modulation and sEH inhibition using 25 SMTP congeners including six newly synthesized ones. The results clearly demonstrate that the structure of the N-linked side chain of SMTP congeners markedly affect their activities toward plasminogen modulation and inhibitions of the two activities of sEH (C-terminal epoxide hydrolase and N-terminal phosphatase). A slight change in the N-linked side chain results in affording selectivity of SMTP congeners. Many congeners, which lacked plasminogen modulation activity, differently inhibited the two sEH activities depending on the structures of the N-linked side chain. Some congeners were active in plasminogen modulation and inhibition of both activities of sEH. These results help comprehensive understanding of ideal design of a drug useful for ischemic diseases that are associated with inflammation, such as stroke. PMID:25966853

  8. Interactions Between Odorant Functional Group and Hydrocarbon Structure Influence Activity in Glomerular Response Modules in the Rat Olfactory Bulb

    PubMed Central

    Johnson, Brett A.; Farahbod, Haleh; Leon, Michael

    2008-01-01

    To investigate the effect of odorant hydrocarbon structure on spatial representations in the olfactory bulb systematically, we exposed rats to odorant chemicals possessing one of four different oxygen-containing functional groups on one of five different hydrocarbon backbones. We also used several hydrocarbon odorants lacking other functional groups. Hydrocarbon structural categories included straight-chained, branched, double-bonded, alicyclic, and aromatic features. Activity throughout the entire glomerular layer was measured as uptake of [14C]2-deoxyglucose and was mapped into anatomically standardized data matrices for statistical comparisons across different animals. Patterns evoked by straight-chained aliphatic odorants confirmed an association of activity in particular glomerular response modules with particular functional groups. However, the amount of activity in these same modules also was affected significantly by differences in hydrocarbon structure. Thus, the molecular features recognized by receptors projecting to these response modules appear to involve both functional group and hydrocarbon structural elements. In addition, particular benzyl and cyclohexyl odorants evoked activity in dorsal modules previously associated with the ketone functional group, which represents an exception to the rule of one feature per response module that had emerged from our previous studies. These dorsal modules also responded to nitrogen-containing aromatic compounds involving pyridine and pyrazine rings. The unexpected overlap in modular responses to ketones and odorants seemingly unrelated to ketones may reflect some covert shared molecular feature, the existence of odorant sensory neurons with multiple specificities, or a mosaic of sensory neuron projections to these particular modules. PMID:15678471

  9. Thalamic Modulation of Cingulate Seizure Activity Via the Regulation of Gap Junctions in Mice Thalamocingulate Slice

    PubMed Central

    Chang, Wei-Pang; Wu, José Jiun-Shian; Shyu, Bai-Chuang

    2013-01-01

    The thalamus is an important target for deep brain stimulation in the treatment of seizures. However, whether the modulatory effect of thalamic inputs on cortical seizures occurs through the modulation of gap junctions has not been previously studied. Therefore, we tested the effects of different gap junction blockers and couplers in a drug-resistant seizure model and studied the role of gap junctions in the thalamic modulation on cortical seizures. Multielectrode array and calcium imaging were used to record the cortical seizures induced by 4-aminopyridine (250 µM) and bicuculline (5–50 µM) in a novel thalamocingulate slice preparation. Seizure-like activity was significantly attenuated by the pan-gap junction blockers carbenoxolone and octanol and specific neuronal gap junction blocker mefloquine. The gap junction coupler trimethylamine significantly enhanced seizure-like activity. Gap junction blockers did not influence the initial phase of seizure-like activity, but they significantly decreased the amplitude and duration of the maintenance phase. The development of seizures is regulated by extracellular potassium concentration. Carbenoxolone partially restored the amplitude and duration after removing the thalamic inputs. A two-dimensional current source density analysis showed that the sink and source signals shifted to deeper layers after removing the thalamic inputs during the clonic phase. These results indicate that the regulatory mechanism of deep brain stimulation in the thalamus occurs partially though gap junctions. PMID:23690968

  10. Modulation of PPAR Expression and Activity in Response to Polyphenolic Compounds in High Fat Diets

    PubMed Central

    Domínguez-Avila, J. Abraham; González-Aguilar, Gustavo A.; Alvarez-Parrilla, Emilio; de la Rosa, Laura A.

    2016-01-01

    Peroxisome proliferator-activated receptors (PPAR) are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD) can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP) found in vegetable foodstuffs are capable of positively modulating this pathway. We therefore focused this review on the possible effects that PP can have on PPAR when administered together with HFD. We found that PP from diverse sources, such as coffee, olives, rice, berries and others, are capable of inducing the expression of genes involved in a decrease of adipose mass, liver and serum lipids and lipid biosynthesis in animal and cell models of HFD. Since cells or gut bacteria can transform PP into different metabolites, it is possible that a synergistic or antagonistic effect ultimately occurs. PP molecules from vegetable sources are an interesting option to maintain or return to a state of energy homeostasis, possibly due to an adequate PPAR expression and activity. PMID:27367676

  11. Significant Modules and Biological Processes between Active Components of Salvia miltiorrhiza Depside Salt and Aspirin

    PubMed Central

    Xie, Yanming; Wang, Lianxin; Zhang, Yingying; Gu, Hao; Chai, Yan

    2016-01-01

    The aim of this study is to examine and compare the similarities and differences between active components of S. miltiorrhiza depside salt and aspirin using perspective of pharmacological molecular networks. Active components of S. miltiorrhiza depside salt and aspirin's related genes were identified via the STITCH4.0 and GeneCards Database. A text search engine (Agilent Literature Search 2.71) and MCODE software were applied to construct network and divide modules, respectively. Finally, 32, 2, and 28 overlapping genes, modules, and pathways were identified between active components of S. miltiorrhiza depside salt and aspirin. A multidimensional framework of drug network showed that two networks reflected commonly in human aortic endothelial cells and atherosclerosis process. Aspirin plays a more important role in metabolism, such as the well-known AA metabolism pathway and other lipid or carbohydrate metabolism pathways. S. miltiorrhiza depside salt still plays a regulatory role in type II diabetes mellitus, insulin resistance, and adipocytokine signaling pathway. Therefore, this study suggests that aspirin combined with S. miltiorrhiza depside salt may be more efficient in treatment of CHD patients, especially those with diabetes mellitus or hyperlipidemia. Further clinical trials to confirm this hypothesis are still needed. PMID:27069488

  12. Optogenetic micro-electrocorticography for modulating and localizing cerebral cortex activity

    NASA Astrophysics Data System (ADS)

    Richner, Thomas J.; Thongpang, Sanitta; Brodnick, Sarah K.; Schendel, Amelia A.; Falk, Ryan W.; Krugner-Higby, Lisa A.; Pashaie, Ramin; Williams, Justin C.

    2014-02-01

    Objective. Spatial localization of neural activity from within the brain with electrocorticography (ECoG) and electroencephalography remains a challenge in clinical and research settings, and while microfabricated ECoG (micro-ECoG) array technology continues to improve, complementary methods to simultaneously modulate cortical activity while recording are needed. Approach. We developed a neural interface utilizing optogenetics, cranial windowing, and micro-ECoG arrays fabricated on a transparent polymer. This approach enabled us to directly modulate neural activity at known locations around micro-ECoG arrays in mice expressing Channelrhodopsin-2. We applied photostimuli varying in time, space and frequency to the cortical surface, and we targeted multiple depths within the cortex using an optical fiber while recording micro-ECoG signals. Main results. Negative potentials of up to 1.5 mV were evoked by photostimuli applied to the entire cortical window, while focally applied photostimuli evoked spatially localized micro-ECoG potentials. Two simultaneously applied focal stimuli could be separated, depending on the distance between them. Photostimuli applied within the cortex with an optical fiber evoked more complex micro-ECoG potentials with multiple positive and negative peaks whose relative amplitudes depended on the depth of the fiber. Significance. Optogenetic ECoG has potential applications in the study of epilepsy, cortical dynamics, and neuroprostheses.

  13. Reputation in an economic game modulates premotor cortex activity during action observation.

    PubMed

    Farmer, Harry; Apps, Matthew; Tsakiris, Manos

    2016-09-01

    Our interactions with other people - and our processing of their actions - are shaped by their reputation. Research has identified an Action Observation Network (AON) which is engaged when observing other people's actions. Yet, little is known about how the processing of others' actions is influenced by another's reputation. Is the response of the AON modulated by the reputation of the actor? We developed a variant of the ultimatum game in which participants watched either the visible or occluded actions of two 'proposers'. These actions were tied to decisions of how to split a pot of money although the proposers' decisions on each trial were not known to participants when observing the actions. One proposer made fair offers on the majority of trials, establishing a positive reputation, whereas the other made predominantly, unfair offers resulting in a negative reputation. We found significant activations in two regions of the left dorsal premotor cortex (dPMC). The first of these showed a main effect of reputation with greater activation for the negative reputation proposer than the positive reputation proposer. Furthermore individual differences in trust ratings of the two proposers covaried with activation in the right primary motor cortex (M1). The second showed an interaction between visibility and reputation driven by a greater effect of reputation when participants were observing an occluded action. Our findings show that the processing of others' actions in the AON is modulated by an actor's reputation, and suggest a predictive role for the PMC during action observation. PMID:27364606

  14. Optogenetic micro-electrocorticography for modulating and localizing cerebral cortex activity

    PubMed Central

    Richner, Thomas J.; Thongpang, Sanitta; Brodnick, Sarah K.; Schendel, Amelia A.; Falk, Ryan W.; Krugner-Higby, Lisa A.; Pashaie, Ramin; Williams, Justin C.

    2014-01-01

    Objective Spatial localization of neural activity from within the brain with electrocorticography (ECoG) and electroencephalography (EEG) remains a challenge in clinical and research settings, and while microfabricated ECoG (micro-ECoG) array technology continues to improve, complimentary methods to simultaneously modulate cortical activity while recording are needed. Approach We developed a neural interface utilizing optogenetics, cranial windowing, and micro-ECoG arrays fabricated on a transparent polymer. This approach enabled us to directly modulate neural activity at known locations around micro-ECoG arrays in mice expressing Channelrhodopsin-2 (ChR2). We applied photostimuli varying in time, space and frequency to the cortical surface, and we targeted multiple depths within the cortex using an optical fiber while recording micro-ECoG signals. Main Results Negative potentials of up to 1.5 mV were evoked by photostimuli applied to the entire cortical window, while focally applied photostimuli evoked spatially localized micro-ECoG potentials. Two simultaneously applied focal stimuli could be separated, depending on the distance between them. Photostimuli applied within the cortex with an optical fiber evoked more complex micro-ECoG potentials with multiple positive and negative peaks whose relative amplitudes depended on the depth of the fiber. Significance Optogenetic ECoG has potential applications in the study of epilepsy, cortical dynamics, and neuroprostheses. PMID:24445482

  15. Modulation of PPAR Expression and Activity in Response to Polyphenolic Compounds in High Fat Diets.

    PubMed

    Domínguez-Avila, J Abraham; González-Aguilar, Gustavo A; Alvarez-Parrilla, Emilio; de la Rosa, Laura A

    2016-01-01

    Peroxisome proliferator-activated receptors (PPAR) are transcription factors that modulate energy metabolism in liver, adipose tissue and muscle. High fat diets (HFD) can negatively impact PPAR expression or activity, favoring obesity, dyslipidemia, insulin resistance and other conditions. However, polyphenols (PP) found in vegetable foodstuffs are capable of positively modulating this pathway. We therefore focused this review on the possible effects that PP can have on PPAR when administered together with HFD. We found that PP from diverse sources, such as coffee, olives, rice, berries and others, are capable of inducing the expression of genes involved in a decrease of adipose mass, liver and serum lipids and lipid biosynthesis in animal and cell models of HFD. Since cells or gut bacteria can transform PP into different metabolites, it is possible that a synergistic or antagonistic effect ultimately occurs. PP molecules from vegetable sources are an interesting option to maintain or return to a state of energy homeostasis, possibly due to an adequate PPAR expression and activity. PMID:27367676

  16. Development of active edge pixel sensors and four-side buttable modules using vertical integration technologies

    NASA Astrophysics Data System (ADS)

    Macchiolo, A.; Andricek, L.; Moser, H.-G.; Nisius, R.; Richter, R. H.; Terzo, S.; Weigell, P.

    2014-11-01

    We present an R&D activity focused on the development of novel modules for the upgrade of the ATLAS pixel system at the High Luminosity LHC (HL-LHC). The modules consist of n-in-p pixel sensors, 100 or 200 μm thick, produced at VTT (Finland) with an active edge technology, which considerably reduces the dead area at the periphery of the device. The sensors are interconnected with solder bump-bonding to the ATLAS FE-I3 and FE-I4 read-out chips, and characterised with radioactive sources and beam tests at the CERN-SPS and DESY. The results of these measurements will be discussed for devices before and after irradiation up to a fluence of 5 ×1015neq /cm2. We will also report on the R&D activity to obtain Inter Chip Vias (ICVs) on the ATLAS read-out chip in collaboration with the Fraunhofer Institute EMFT. This step is meant to prove the feasibility of the signal transport to the newly created readout pads on the backside of the chips allowing for four side buttable devices without the presently used cantilever for wire bonding. The read-out chips with ICVs will be interconnected to thin pixel sensors, 75 μm and 150 μm thick, with the Solid Liquid Interdiffusion (SLID) technology, which is an alternative to the standard solder bump-bonding.

  17. Modulation of the chaperone-like activity of bovine alpha-crystallin.

    PubMed

    Clark, J I; Huang, Q L

    1996-12-24

    The effects of pantethine, glutathione, and selected chemical reagents on the anti-aggregation activity of alpha-crystallin was evaluated. Protein aggregation was monitored by light scattering of solutions of denatured beta L-crystallin or alcohol dehydrogenase (ADH). The ratios of beta L-crystallin/alpha-crystallin and ADH/alpha-crystallin were adjusted so that partial inhibition of protein aggregation at 60 degrees C or 37 degrees C, respectively, was observed and modulation of the chaperone action of alpha-crystallin could be evaluated easily with selected endogenous metabolites. Enhancement of the anti-aggregation activity in the beta L-crystallin assay was strongest with pantethine, which appeared to interact with alpha-crystallin. Enhancement of the anti-aggregation activity in the ADH assay was strongest with glutathione which appeared to interact with ADH. The results indicated that the products of common metabolic pathways can modulate the chaperone-like effects of alpha-crystallin on protein aggregation. PMID:8986785

  18. Modulation of electroencephalograph activity by manual acupuncture stimulation in healthy subjects: An autoregressive spectral analysis

    NASA Astrophysics Data System (ADS)

    Yi, Guo-Sheng; Wang, Jiang; Deng, Bin; Wei, Xi-Le; Han, Chun-Xiao

    2013-02-01

    To investigate whether and how manual acupuncture (MA) modulates brain activities, we design an experiment where acupuncture at acupoint ST36 of the right leg is used to obtain electroencephalograph (EEG) signals in healthy subjects. We adopt the autoregressive (AR) Burg method to estimate the power spectrum of EEG signals and analyze the relative powers in delta (0 Hz-4 Hz), theta (4 Hz-8 Hz), alpha (8 Hz-13 Hz), and beta (13 Hz-30 Hz) bands. Our results show that MA at ST36 can significantly increase the EEG slow wave relative power (delta band) and reduce the fast wave relative powers (alpha and beta bands), while there are no statistical differences in theta band relative power between different acupuncture states. In order to quantify the ratio of slow to fast wave EEG activity, we compute the power ratio index. It is found that the MA can significantly increase the power ratio index, especially in frontal and central lobes. All the results highlight the modulation of brain activities with MA and may provide potential help for the clinical use of acupuncture. The proposed quantitative method of acupuncture signals may be further used to make MA more standardized.

  19. Significant Modules and Biological Processes between Active Components of Salvia miltiorrhiza Depside Salt and Aspirin.

    PubMed

    Li, Yuan; Xie, Yanming; Wang, Lianxin; Zhang, Yingying; Gu, Hao; Chai, Yan

    2016-01-01

    The aim of this study is to examine and compare the similarities and differences between active components of S. miltiorrhiza depside salt and aspirin using perspective of pharmacological molecular networks. Active components of S. miltiorrhiza depside salt and aspirin's related genes were identified via the STITCH4.0 and GeneCards Database. A text search engine (Agilent Literature Search 2.71) and MCODE software were applied to construct network and divide modules, respectively. Finally, 32, 2, and 28 overlapping genes, modules, and pathways were identified between active components of S. miltiorrhiza depside salt and aspirin. A multidimensional framework of drug network showed that two networks reflected commonly in human aortic endothelial cells and atherosclerosis process. Aspirin plays a more important role in metabolism, such as the well-known AA metabolism pathway and other lipid or carbohydrate metabolism pathways. S. miltiorrhiza depside salt still plays a regulatory role in type II diabetes mellitus, insulin resistance, and adipocytokine signaling pathway. Therefore, this study suggests that aspirin combined with S. miltiorrhiza depside salt may be more efficient in treatment of CHD patients, especially those with diabetes mellitus or hyperlipidemia. Further clinical trials to confirm this hypothesis are still needed. PMID:27069488

  20. AMP-activated Protein Kinase Signaling Activation by Resveratrol Modulates Amyloid-β Peptide Metabolism*

    PubMed Central

    Vingtdeux, Valérie; Giliberto, Luca; Zhao, Haitian; Chandakkar, Pallavi; Wu, Qingli; Simon, James E.; Janle, Elsa M.; Lobo, Jessica; Ferruzzi, Mario G.; Davies, Peter; Marambaud, Philippe

    2010-01-01

    Alzheimer disease is an age-related neurodegenerative disorder characterized by amyloid-β (Aβ) peptide deposition into cerebral amyloid plaques. The natural polyphenol resveratrol promotes anti-aging pathways via the activation of several metabolic sensors, including the AMP-activated protein kinase (AMPK). Resveratrol also lowers Aβ levels in cell lines; however, the underlying mechanism responsible for this effect is largely unknown. Moreover, the bioavailability of resveratrol in the brain remains uncertain. Here we show that AMPK signaling controls Aβ metabolism and mediates the anti-amyloidogenic effect of resveratrol in non-neuronal and neuronal cells, including in mouse primary neurons. Resveratrol increased cytosolic calcium levels and promoted AMPK activation by the calcium/calmodulin-dependent protein kinase kinase-β. Direct pharmacological and genetic activation of AMPK lowered extracellular Aβ accumulation, whereas AMPK inhibition reduced the effect of resveratrol on Aβ levels. Furthermore, resveratrol inhibited the AMPK target mTOR (mammalian target of rapamycin) to trigger autophagy and lysosomal degradation of Aβ. Finally, orally administered resveratrol in mice was detected in the brain where it activated AMPK and reduced cerebral Aβ levels and deposition in the cortex. These data suggest that resveratrol and pharmacological activation of AMPK have therapeutic potential against Alzheimer disease. PMID:20080969

  1. Pushing the Limits: Chronotype and Time of Day Modulate Working Memory-Dependent Cerebral Activity

    PubMed Central

    Schmidt, Christina; Collette, Fabienne; Reichert, Carolin F.; Maire, Micheline; Vandewalle, Gilles; Peigneux, Philippe; Cajochen, Christian

    2015-01-01

    Morning-type individuals experience more difficulties to maintain optimal attentional performance throughout a normal waking day than evening types. However, time-of-day modulations may differ across cognitive domains. Using functional magnetic resonance imaging (fMRI), we investigated how chronotype and time of day interact with working memory at different levels of cognitive load/complexity in a N-back paradigm (N0-, N2-, and N3-back levels). Extreme morning- and evening-type individuals underwent two fMRI sessions during N-back performance, one 1.5 h (morning) and one 10.5 h (evening) after wake-up time scheduled according to their habitual sleep–wake preference. At the behavioral level, increasing working memory load resulted in lower accuracy while chronotype and time of day only exerted a marginal impact on performance. Analyses of neuroimaging data disclosed an interaction between chronotype, time of day, and the modulation of cerebral activity by working memory load in the thalamus and in the middle frontal cortex. In the subjective evening hours, evening types exhibited higher thalamic activity than morning types at the highest working memory load condition only (N3-back). Conversely, morning-type individuals exhibited higher activity than evening-type participants in the middle frontal gyrus during the morning session in the N3-back condition. Our data emphasize interindividual differences in time-of-day preferences and underlying cerebral activity, which should be taken into account when investigating vigilance state effects in task-related brain activity. These results support the hypothesis that higher task complexity leads to a chronotype-dependent increase in thalamic and frontal brain activity, permitting stabilization of working memory performance across the day. PMID:26441819

  2. Pushing the Limits: Chronotype and Time of Day Modulate Working Memory-Dependent Cerebral Activity.

    PubMed

    Schmidt, Christina; Collette, Fabienne; Reichert, Carolin F; Maire, Micheline; Vandewalle, Gilles; Peigneux, Philippe; Cajochen, Christian

    2015-01-01

    Morning-type individuals experience more difficulties to maintain optimal attentional performance throughout a normal waking day than evening types. However, time-of-day modulations may differ across cognitive domains. Using functional magnetic resonance imaging (fMRI), we investigated how chronotype and time of day interact with working memory at different levels of cognitive load/complexity in a N-back paradigm (N0-, N2-, and N3-back levels). Extreme morning- and evening-type individuals underwent two fMRI sessions during N-back performance, one 1.5 h (morning) and one 10.5 h (evening) after wake-up time scheduled according to their habitual sleep-wake preference. At the behavioral level, increasing working memory load resulted in lower accuracy while chronotype and time of day only exerted a marginal impact on performance. Analyses of neuroimaging data disclosed an interaction between chronotype, time of day, and the modulation of cerebral activity by working memory load in the thalamus and in the middle frontal cortex. In the subjective evening hours, evening types exhibited higher thalamic activity than morning types at the highest working memory load condition only (N3-back). Conversely, morning-type individuals exhibited higher activity than evening-type participants in the middle frontal gyrus during the morning session in the N3-back condition. Our data emphasize interindividual differences in time-of-day preferences and underlying cerebral activity, which should be taken into account when investigating vigilance state effects in task-related brain activity. These results support the hypothesis that higher task complexity leads to a chronotype-dependent increase in thalamic and frontal brain activity, permitting stabilization of working memory performance across the day. PMID:26441819

  3. Integration of Optical Manipulation and Electrophysiological Tools to Modulate and Record Activity in Neural Networks

    NASA Astrophysics Data System (ADS)

    Difato, F.; Schibalsky, L.; Benfenati, F.; Blau, A.

    2011-07-01

    We present an optical system that combines IR (1064 nm) holographic optical tweezers with a sub-nanosecond-pulsed UV (355 nm) laser microdissector for the optical manipulation of single neurons and entire networks both on transparent and non-transparent substrates in vitro. The phase-modulated laser beam can illuminate the sample concurrently or independently from above or below assuring compatibility with different types of microelectrode array and patch-clamp electrophysiology. By combining electrophysiological and optical tools, neural activity in response to localized stimuli or injury can be studied and quantified at sub-cellular, cellular, and network level.

  4. Modulation of Cell-adhesive Activity of Fibronectin by the Alternatively Spliced EDA Segment

    PubMed Central

    Manabe, Ri-ichiroh; Oh-e, Naoko; Maeda, Toshinaga; Fukuda, Tomohiko; Sekiguchi, Kiyotoshi

    1997-01-01

    Fibronectin (FN) has a complex pattern of alternative splicing at the mRNA level. One of the alternatively spliced segments, EDA, is prominently expressed during biological processes involving substantial cell migration and proliferation, such as embryonic development, malignant transformation, and wound healing. To examine the function of the EDA segment, we overexpressed recombinant FN isoforms with or without EDA in CHO cells and compared their cell-adhesive activities using purified proteins. EDA+ FN was significantly more potent than EDA− FN in promoting cell spreading and cell migration, irrespective of the presence or absence of a second alternatively spliced segment, EDB. The cell spreading activity of EDA+ FN was not affected by antibodies recognizing the EDA segment but was abolished by antibodies against integrin α5 and β1 subunits and by Gly-Arg-Gly-Asp-Ser-Pro peptide, indicating that the EDA segment enhanced the cell-adhesive activity of FN by potentiating the interaction of FN with integrin α5β1. In support of this conclusion, purified integrin α5β1 bound more avidly to EDA+ FN than to EDA− FN. Augmentation of integrin binding by the EDA segment was, however, observed only in the context of the intact FN molecule, since the difference in integrin-binding activity between EDA+ FN and EDA− FN was abolished after limited proteolysis with thermolysin. Consistent with this observation, binding of integrin α5β1 to a recombinant FN fragment, consisting of the central cell-binding domain and the adjacent heparin-binding domain Hep2, was not affected by insertion of the EDA segment. Since the insertion of an extra type III module such as EDA into an array of repeated type III modules is expected to rotate the polypeptide up to 180° at the position of the insertion, the conformation of the FN molecule may be globally altered upon insertion of the EDA segment, resulting in an increased exposure of the RGD motif in III10 module and/or local

  5. Towards using a Monolithic Active Pixel Sensor for in vivo beam monitoring of Intensity Modulated Radiotherapy

    NASA Astrophysics Data System (ADS)

    Page, R. F.; Abbott, N. L.; Davies, J.; Dyke, E. L.; Randles, H. J.; Velthuis, J. J.; Fletcher, S.; Gregory, S. D.; Hall, C.; John, A.; Lawrence, H.; Stevens, P. H.; Hugtenburg, R. P.; Tunbridge, V.

    2013-12-01

    The use of Intensity Modulated Radiotherapy (IMRT) for cancer treatments is entering wider use. These treatments involve using a complex configuration of field modifying components, known as Multileaf Collimators (MLC), to dynamically shape the beam. A treatment consists of a sequence of irregular shaped fields, which means real time monitoring and verification is essential. In the current framework the treatment plans are verified before the patient is treated, but not during. The aim of our collaboration is to monitor the treatment being given to the patient. This is achieved by placing a camera system using an ultra-thin Monolithic Active Pixel Sensor (MAPS) upstream of the patient.

  6. S152 (CD27). A modulating disulfide-linked T cell activation antigen.

    PubMed

    Bigler, R D; Bushkin, Y; Chiorazzi, N

    1988-07-01

    A large subset of normal resting peripheral blood T cells express a protein at low density defined by the murine mAb S152. Reactive T cells are present in both the CD4+ and CD8+ subpopulations. This determinant, however, is not expressed on growth factor-independent T cell lines. After activation of mononuclear cells by either Con A or PHA, greater than 80% of the cells stained at a mean fluorescence intensity that was more than six times that seen on resting cells. When PWM- or mixed lymphocyte reaction-activated cultures were studied, 7 to 22% of S152+ cells stained at high intensity whereas most cells stained at the baseline low intensity. The increased fraction of S152+ cells staining at high intensity after activation paralleled both the increased percentage of anti-Tac+ and 5E9+ cells and cellular proliferation measured by thymidine incorporation. Modulation of the S152 Ag was induced when either Con A- or PHA-activated mononuclear cells were placed into secondary cultures containing S152 mAb. Expression of the S152 Ag began to decrease after 2 h and reached a minimum after 6 h. Resting T cells, however, did not appear to modulate when cultured with S152 mAb. Immunoprecipitation and gel electrophoresis analysis revealed the S152 molecule to have a mobility of 120 kDa before reduction. After reduction the molecule was shown to be composed of two 55-kDa molecules with an isoelectric point of 5 to 6 indicating that the S152 Ag is a disulfide-linked homodimer. These studies confirm that the S152 mAb reacts with the newly defined CD27 molecule. The presence of the S152 Ag on resting and activated cells, its parallel increase with the Tac and 5E9 Ag, and its ability to modulate on activated cells suggest that this molecule may play a functional role during T cell activation. PMID:2837508

  7. Modulation of Hepatocarcinoma Cell Morphology and Activity by Parylene-C Coating on PDMS

    PubMed Central

    Guimard, Denis; Arakawa, Yasuhiko; Sakai, Yasuyuki; Fujii, Teruo

    2010-01-01

    Background The ability to understand and locally control the morphogenesis of mammalian cells is a fundamental objective of cell and developmental biology as well as tissue engineering research. We present parylene-C (ParC) deposited on polydimethylsiloxane (PDMS) as a new substratum for in vitro advanced cell culture in the case of Human Hepatocarcinoma (HepG2) cells. Principal Findings Our findings establish that the intrinsic properties of ParC-coated PDMS (ParC/PDMS) influence and modulate initial extracellular matrix (ECM; here, type-I collagen) surface architecture, as compared to non-coated PDMS substratum. Morphological changes induced by the presence of ParC on PDMS were shown to directly affect liver cell metabolic activity and the expression of transmembrane receptors implicated in cell adhesion and cell-cell interaction. These changes were characterized by atomic force microscopy (AFM), which elucidated differences in HepG2 cell adhesion, spreading, and reorganization into two- or three-dimensional structures by neosynthesis of ECM components. Local modulation of cell aggregation was successfully performed using ParC/PDMS micropatterns constructed by simple microfabrication. Conclusion/Significance We demonstrated for the first time the modulation of HepG2 cells' behavior in relation to the intrinsic physical properties of PDMS and ParC, enabling the local modulation of cell spreading in a 2D or 3D manner by simple microfabrication techniques. This work will provide promising insights into the development of cell-based platforms that have many applications in the field of in vitro liver tissue engineering, pharmacology and therapeutics. PMID:20300511

  8. Subthalamic stimulation modulates cortical motor network activity and synchronization in Parkinson’s disease

    PubMed Central

    Klotz, Rosa; Govindan, Rathinaswamy B.; Scholten, Marlieke; Naros, Georgios; Ramos-Murguialday, Ander; Bunjes, Friedemann; Meisner, Christoph; Plewnia, Christian; Krüger, Rejko

    2015-01-01

    Dynamic modulations of large-scale network activity and synchronization are inherent to a broad spectrum of cognitive processes and are disturbed in neuropsychiatric conditions including Parkinson’s disease. Here, we set out to address the motor network activity and synchronization in Parkinson’s disease and its modulation with subthalamic stimulation. To this end, 20 patients with idiopathic Parkinson’s disease with subthalamic nucleus stimulation were analysed on externally cued right hand finger movements with 1.5-s interstimulus interval. Simultaneous recordings were obtained from electromyography on antagonistic muscles (right flexor digitorum and extensor digitorum) together with 64-channel electroencephalography. Time-frequency event-related spectral perturbations were assessed to determine cortical and muscular activity. Next, cross-spectra in the time-frequency domain were analysed to explore the cortico-cortical synchronization. The time-frequency modulations enabled us to select a time-frequency range relevant for motor processing. On these time-frequency windows, we developed an extension of the phase synchronization index to quantify the global cortico-cortical synchronization and to obtain topographic differentiations of distinct electrode sites with respect to their contributions to the global phase synchronization index. The spectral measures were used to predict clinical and reaction time outcome using regression analysis. We found that movement-related desynchronization of cortical activity in the upper alpha and beta range was significantly facilitated with ‘stimulation on’ compared to ‘stimulation off’ on electrodes over the bilateral parietal, sensorimotor, premotor, supplementary-motor, and prefrontal areas, including the bilateral inferior prefrontal areas. These spectral modulations enabled us to predict both clinical and reaction time improvement from subthalamic stimulation. With ‘stimulation on’, interhemispheric cortico

  9. Smad2/3-Regulated Expression of DLX2 Is Associated with Radiation-Induced Epithelial-Mesenchymal Transition and Radioresistance of A549 and MDA-MB-231 Human Cancer Cell Lines

    PubMed Central

    Choi, Yeo-Jin; Baek, Ga-Young; Park, Hae-Ran; Jo, Sung-Kee; Jung, Uhee

    2016-01-01

    The control of radioresistance and metastatic potential of surviving cancer cells is important for improving cancer eradication by radiotheraphy. The distal-less homeobox2 (DLX2) gene encodes for a homeobox transcription factor involved in morphogenesis and its deregulation was found in human solid tumors and hematologic malignancies. Here we investigated the role of DLX2 in association with radiation-induced epithelial to mesenchymal transition (EMT) and stem cell-like properties and its regulation by Smad2/3 signaling in irradiated A549 and MDA-MB-231 human cancer cell lines. In irradiated A549 and MDA-MB-231 cells, EMT was induced as demonstrated by EMT marker expression, phosphorylation of Smad2/3, and migratory and invasive ability. Also, irradiated A549 and MDA-MB-231 cells showed increased cancer stem cells (CSCs) marker. Interestingly, DLX2 was overexpressed upon irradiation. Therefore, we examined the role of DLX2 in radiation-induced EMT and radioresistance. The overexpression of DLX2 alone induced EMT, migration and invasion, and CSC marker expression. The reduced colony-forming ability in irradiated cells was partially restored by DLX2 overexpression. On the other hand, the depletion of DLX2 using si-RNA abolished radiation-induced EMT, CSC marker expression, and phosphorylation of Smad2/3 in irradiated A549 and MDA-MB-231 cells. Also, depletion of DLX2 increased the radiation sensitivity in both cell lines. Moreover, knockdown of Smad2/3, a key activator of TGF-β1 pathway, abrogated the radiation-induced DLX2 expression, indicating that radiation-induced DLX2 expression is dependent on Smad2/3 signaling. These results demonstrated that DLX2 plays a crucial role in radioresistance, radiation-induced EMT and CSC marker expression, and the expression of DLX2 is regulated by Smad2/3 signaling in A549 and MDA-MB-231 cell lines. PMID:26799321

  10. Smad2/3-Regulated Expression of DLX2 Is Associated with Radiation-Induced Epithelial-Mesenchymal Transition and Radioresistance of A549 and MDA-MB-231 Human Cancer Cell Lines.

    PubMed

    Choi, Yeo-Jin; Baek, Ga-Young; Park, Hae-Ran; Jo, Sung-Kee; Jung, Uhee

    2016-01-01

    The control of radioresistance and metastatic potential of surviving cancer cells is important for improving cancer eradication by radiotheraphy. The distal-less homeobox2 (DLX2) gene encodes for a homeobox transcription factor involved in morphogenesis and its deregulation was found in human solid tumors and hematologic malignancies. Here we investigated the role of DLX2 in association with radiation-induced epithelial to mesenchymal transition (EMT) and stem cell-like properties and its regulation by Smad2/3 signaling in irradiated A549 and MDA-MB-231 human cancer cell lines. In irradiated A549 and MDA-MB-231 cells, EMT was induced as demonstrated by EMT marker expression, phosphorylation of Smad2/3, and migratory and invasive ability. Also, irradiated A549 and MDA-MB-231 cells showed increased cancer stem cells (CSCs) marker. Interestingly, DLX2 was overexpressed upon irradiation. Therefore, we examined the role of DLX2 in radiation-induced EMT and radioresistance. The overexpression of DLX2 alone induced EMT, migration and invasion, and CSC marker expression. The reduced colony-forming ability in irradiated cells was partially restored by DLX2 overexpression. On the other hand, the depletion of DLX2 using si-RNA abolished radiation-induced EMT, CSC marker expression, and phosphorylation of Smad2/3 in irradiated A549 and MDA-MB-231 cells. Also, depletion of DLX2 increased the radiation sensitivity in both cell lines. Moreover, knockdown of Smad2/3, a key activator of TGF-β1 pathway, abrogated the radiation-induced DLX2 expression, indicating that radiation-induced DLX2 expression is dependent on Smad2/3 signaling. These results demonstrated that DLX2 plays a crucial role in radioresistance, radiation-induced EMT and CSC marker expression, and the expression of DLX2 is regulated by Smad2/3 signaling in A549 and MDA-MB-231 cell lines. PMID:26799321

  11. Hippocampal cannabinoid transmission modulates dopamine neuron activity: impact on rewarding memory formation and social interaction.

    PubMed

    Loureiro, Michael; Renard, Justine; Zunder, Jordan; Laviolette, Steven R

    2015-05-01

    Disturbances in cannabinoid type 1 receptor (CB1R) signaling have been linked to emotional and cognitive deficits characterizing neuropsychiatric disorders, including schizophrenia. Thus, there is growing interest in characterizing the relationship between cannabinoid transmission, emotional processing, and dopamine (DA)-dependent behavioral deficits. The CB1R is highly expressed in the mammalian nervous system, particularly in the hippocampus. Activation of the ventral hippocampal subregion (vHipp) is known to increase both the activity of DAergic neurons located in the ventral tegmental area (VTA) and DA levels in reward-related brain regions, particularly the nucleus accumbens (NAc). However, the possible functional relationship between hippocampal CB1R transmission and VTA DA neuronal activity is not currently understood. In this study, using in vivo neuronal recordings in rats, we demonstrate that activation of CB1R in the vHipp strongly increases VTA DA neuronal firing and bursting activity, while simultaneously decreasing the activity of VTA non-DA neurons. Furthermore, using a conditioned place preference procedure and a social interaction test, we report that intra-vHipp CB1R activation potentiates the reward salience of normally sub-threshold conditioning doses of opiates and induces deficits in natural sociability and social recognition behaviors. Finally, these behavioral effects were prevented by directly blocking NAc DAergic transmission. Collectively, these findings identify hippocampal CB1R transmission as a critical modulator of the mesolimbic DA pathway and in the processing of reward and social-related behavioral phenomena. PMID:25510937

  12. The Interplay of Attention and Emotion: Top-down Attention Modulates Amygdala Activation in Psychopathy

    PubMed Central

    Larson, Christine L.; Baskin-Sommers, Arielle R.; Stout, Daniel M.; Balderston, Nicholas L.; Curtin, John J.; Schultz, Douglas H.; Kiehl, Kent A.; Newman, Joseph P.

    2013-01-01

    Psychopathic behavior has long been attributed to a fundamental deficit in fear that arises from impaired amygdala function. Growing evidence demonstrates that fear potentiated startle (FPS) and other psychopathy-related deficits are moderated by focus of attention but, to date, no work on adult psychopathy has examined attentional modulation of the amygdala, or concomitant recruitment of relevant attention-related circuitry. Consistent with previous FPS findings, here we report that psychopathy-related differences in amygdala activation appear and disappear as a function of goal-directed attention. Specifically, decreased amygdala activity was observed in psychopathic offenders only when attention was engaged in an alternative goal-relevant task prior to presenting threat-relevant information. Under this condition, psychopaths also exhibited greater activation in selective attention regions of the lateral prefrontal cortex (LPFC) than non-psychopaths, and this increased LPFC activation mediated psychopathy’s association with decreased amygdala activation. In contrast, when explicitly attending to threat, amygdala activation in psychopaths did not differ from non-psychopaths. This pattern of amygdala activation highlights the potential role of LPFC in mediating the failure of psychopathic individuals to process fear and other important information when it is peripheral to the primary focus of goal-directed attention. PMID:23712665

  13. Expanding Voluntary Active-learning Opportunities for Pharmacy Students in a Respiratory Physiology Module

    PubMed Central

    Ernst, Hardy; Colthorpe, Kay

    2008-01-01

    Objectives To expand voluntary active-learning opportunities for bachelor of pharmacy students enrolled in a third-year human physiology and pharmacology course and determine whether the additional course components improved learning outcomes. Design Additional voluntary active-learning opportunities including a large-class tutorial, additional formative assessment, and an online discussion were added to the Respiratory Physiology Module of the course. Examination scores were compared with those from previous years. A questionnaire was administered to assess students' perception of the active-learning components. Assessment Mean examination scores increased from 69.3% ± 24.4% in 2003 to 88.9% ± 13.4% in 2004 and 86.9% ± 17.6% in 2005, after the addition of the active-learning components. Students' overall perception of the value of the active-learning activities was positive. Summary The addition of voluntary active-learning course components to a required pharmacy course resulted in improved student examination scores, and decreased failure rate, and were accomplished at low cost and with little additional staff time. PMID:18483596

  14. A systematic method to identify modulation of transcriptional regulation via chromatin activity reveals regulatory network during mESC differentiation.

    PubMed

    Duren, Zhana; Wang, Yong

    2016-01-01

    Chromatin regulators (CRs) are crucial for connecting the chromatin level and transcriptome level by modulating chromatin structures, establishing, and maintaining epigenetic modifications. We present a systematic method to identify MOdulation of transcriptional regulation via CHromatin Activity (MOCHA) from gene expression data and demonstrate its advantage in associating CRs to their chromatin localization and understand CRs' function. We first re-construct the CRs modulation network by integrating the correlation and conditional correlation concepts. Then we quantify the chromatin activity as hidden variable in network by integrating the upstream and downstream information. We applied MOCHA to systematically explore the interplay of CRs, TFs, and target genes in mouse embryonic stem cells (ESC). As a result, MOCHA identified 420 chromatin regulators with modulation preference, including Pou5f1 and Eed. We found that BAF complex, NuRD complex, and polycomb-group proteins, regulate the delicate balance between pluripotency and differentiation by modulating key TFs including Klf4, Tcf3, and Max; NuRD complex members Mbd3 and Hdac1 may modulate Klf4 to achieve its dual functional roles in pluripotent and differentiation stages;Imprinted gene H19 and Igf2 are modulated by DNA methylation, histone acetylation, and insulator CTCF. Finally, we analyzed CR's combinational modulation pattern by constructing a CR-CR interaction network. PMID:26949222

  15. A systematic method to identify modulation of transcriptional regulation via chromatin activity reveals regulatory network during mESC differentiation

    PubMed Central

    Duren, Zhana; Wang, Yong

    2016-01-01

    Chromatin regulators (CRs) are crucial for connecting the chromatin level and transcriptome level by modulating chromatin structures, establishing, and maintaining epigenetic modifications. We present a systematic method to identify MOdulation of transcriptional regulation via CHromatin Activity (MOCHA) from gene expression data and demonstrate its advantage in associating CRs to their chromatin localization and understand CRs’ function. We first re-construct the CRs modulation network by integrating the correlation and conditional correlation concepts. Then we quantify the chromatin activity as hidden variable in network by integrating the upstream and downstream information. We applied MOCHA to systematically explore the interplay of CRs, TFs, and target genes in mouse embryonic stem cells (ESC). As a result, MOCHA identified 420 chromatin regulators with modulation preference, including Pou5f1 and Eed. We found that BAF complex, NuRD complex, and polycomb-group proteins, regulate the delicate balance between pluripotency and differentiation by modulating key TFs including Klf4, Tcf3, and Max; NuRD complex members Mbd3 and Hdac1 may modulate Klf4 to achieve its dual functional roles in pluripotent and differentiation stages;Imprinted gene H19 and Igf2 are modulated by DNA methylation, histone acetylation, and insulator CTCF. Finally, we analyzed CR’s combinational modulation pattern by constructing a CR-CR interaction network. PMID:26949222

  16. Surfactant protein A integrates activation signal strength to differentially modulate T cell proliferation.

    PubMed

    Mukherjee, Sambuddho; Giamberardino, Charles; Thomas, Joseph; Evans, Kathy; Goto, Hisatsugu; Ledford, Julie G; Hsia, Bethany; Pastva, Amy M; Wright, Jo Rae

    2012-02-01

    Pulmonary surfactant lipoproteins lower the surface tension at the alveolar-airway interface of the lung and participate in host defense. Previous studies reported that surfactant protein A (SP-A) inhibits lymphocyte proliferation. We hypothesized that SP-A-mediated modulation of T cell activation depends upon the strength, duration, and type of lymphocyte activating signals. Modulation of T cell signal strength imparted by different activating agents ex vivo and in vivo in different mouse models and in vitro with human T cells shows a strong correlation between strength of signal (SoS) and functional effects of SP-A interactions. T cell proliferation is enhanced in the presence of SP-A at low SoS imparted by exogenous mitogens, specific Abs, APCs, or in homeostatic proliferation. Proliferation is inhibited at higher SoS imparted by different doses of the same T cell mitogens or indirect stimuli such as LPS. Importantly, reconstitution with exogenous SP-A into the lungs of SP-A(-/-) mice stimulated with a strong signal also resulted in suppression of T cell proliferation while elevating baseline proliferation in unstimulated T cells. These signal strength and SP-A-dependent effects are mediated by changes in intracellular Ca(2+) levels over time, involving extrinsic Ca(2+)-activated channels late during activation. These effects are intrinsic to the global T cell population and are manifested in vivo in naive as well as memory phenotype T cells. Thus, SP-A appears to integrate signal thresholds to control T cell proliferation. PMID:22219327

  17. Touching moments: desire modulates the neural anticipation of active romantic caress

    PubMed Central

    Ebisch, Sjoerd J.; Ferri, Francesca; Gallese, Vittorio

    2014-01-01

    A romantic caress is a basic expression of affiliative behavior and a primary reinforcer. Given its inherent affective valence, its performance also would imply the prediction of reward values. For example, touching a person for whom one has strong passionate feelings likely is motivated by a strong desire for physical contact and associated with the anticipation of hedonic experiences. The present study aims at investigating how the anticipatory neural processes of active romantic caress are modulated by the intensity of the desire for affective contact as reflected by passionate feelings for the other. Functional magnetic resonance imaging scanning was performed in romantically involved partners using a paradigm that allowed to isolate the specific anticipatory representations of active romantic caress, compared with control caress, while testing for the relationship between neural activity and measures of feelings of passionate love for the other. The results demonstrated that right posterior insula activity in anticipation of romantic caress significantly co-varied with the intensity of desire for union with the other. This effect was independent of the sensory-affective properties of the performed touch, like its pleasantness. Furthermore, functional connectivity analysis showed that the same posterior insula cluster interacted with brain regions related to sensory-motor functions as well as to the processing and anticipation of reward. The findings provide insight on the neural substrate mediating between the desire for and the performance of romantic caress. In particular, we propose that anticipatory activity patterns in posterior insula may modulate subsequent sensory-affective processing of skin-to-skin contact. PMID:24616676

  18. Activation and modulation of recombinantly expressed serotonin receptor type 3A by terpenes and pungent substances.

    PubMed

    Ziemba, Paul M; Schreiner, Benjamin S P; Flegel, Caroline; Herbrechter, Robin; Stark, Timo D; Hofmann, Thomas; Hatt, Hanns; Werner, Markus; Gisselmann, Günter

    2015-11-27

    Serotonin receptor type 3 (5-HT3 receptor) is a ligand-gated ion channel that is expressed in the central nervous system (CNS) as well as in the peripheral nervous system (PNS). The receptor plays an important role in regulating peristalsis of the gastrointestinal tract and in functions such as emesis, cognition and anxiety. Therefore, a variety of pharmacologically active substances target the 5-HT3 receptor to treat chemotherapy-induced nausea and vomiting. The 5-HT3 receptors are activated, antagonized, or modulated by a wide range of chemically different substances, such as 2-methyl-serotonin, phenylbiguanide, setrones, or cannabinoids. Whereas the action of all of these substances is well described, less is known about the effect of terpenoids or fragrances on 5-HT3A receptors. In this study, we screened a large number of natural odorous and pungent substances for their pharmacological action on recombinantly expressed human 5-HT3A receptors. The receptors were functionally expressed in Xenopus oocytes and characterized by electrophysiological recordings using the two-electrode voltage-clamp technique. A screening of two odorous mixes containing a total of 200 substances revealed that the monoterpenes, thymol and carvacrol, act as both weak partial agonists and positive modulators on the 5-HT3A receptor. In contrast, the most effective blockers were the terpenes, citronellol and geraniol, as well as the pungent substances gingerol, capsaicin and polygodial. In our study, we identified new modulators of 5-HT3A receptors out of the classes of monoterpenes and vanilloid substances that frequently occur in various plants. PMID:26456648

  19. A principal mechanism for the cancer chemopreventive activity of phenethyl isothiocyanate is modulation of carcinogen metabolism.

    PubMed

    Ioannides, Costas; Konsue, Nattaya

    2015-08-01

    Isothiocyanates are small molecules characterized by high chemical reactivity that allows them to interact readily with cellular constituents eliciting a plethora of biological activities. They are present exclusively in cruciferous vegetables, as glucosinolates, the intake of which has been associated with cancer chemoprevention. When the physical structure of these vegetables is disturbed, e.g. during mastication, the enzyme myrosinase is released and converts the glucosinolates to isothiocyanates (R-N=C=S), where R can be aliphatic or aromatic. Although sulforaphane, an aliphatic isothiocyanate, has received most attention worldwide, the most extensively studied aromatic isothiocyanate is phenethyl isothiocyanate (PEITC), and there are substantial differences in biological activity between the two sub-classes. In animal cancer models, PEITC effectively antagonized the carcinogenicity of chemicals, especially nitrosocompounds. A principal mechanism of their action is to protect the integrity of DNA by decreasing the levels of the genotoxic metabolites of chemical carcinogens. Extensive studies established that PEITC modulates the metabolism of the tobacco-specific carcinogenic nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by inhibiting its cytochrome P450-mediated bioactivation. Moreover, PEITC is a potent inducer of detoxification enzymes such as quinone reductase, glutathione S-transferase and glucuronosyl transferase. PEITC is rapidly absorbed and is characterized by a large bioavailability; Cmax concentrations achieved in plasma after dietary intake are sufficient to modulate carcinogen metabolism. PEITC is primarily metabolized by glutathione conjugation and is excreted in the urine and bile as the mercapturate. The ability of PEITC to perturb carcinogen metabolism through modulation of cytochrome P450 and phase II detoxification enzymes is comprehensively and critically reviewed. PMID:26119477

  20. Locomotion and task demands differentially modulate thalamic audiovisual processing during active search

    PubMed Central

    Williamson, Ross S.; Hancock, Kenneth E.; Shinn-Cunningham, Barbara G.; Polley, Daniel B.

    2015-01-01

    SUMMARY Active search is a ubiquitous goal-driven behavior wherein organisms purposefully investigate the sensory environment to locate a target object. During active search, brain circuits analyze a stream of sensory information from the external environment, adjusting for internal signals related to self-generated movement or “top-down” weighting of anticipated target and distractor properties. Sensory responses in the cortex can be modulated by internal state [1–9], though the extent and form of modulation arising in the cortex de novo versus an inheritance from subcortical stations is not clear [4, 8–12]. We addressed this question by simultaneously recording from auditory and visual regions of the thalamus (MG and LG, respectively) while mice used dynamic auditory or visual feedback to search for a hidden target within an annular track. Locomotion was associated with strongly suppressed responses and reduced decoding accuracy in MG but a subtle increase in LG spiking. Because stimuli in one modality provided critical information about target location while the other served as a distractor, we could also estimate the importance of task relevance in both thalamic subdivisions. In contrast to the effects of locomotion, we found that LG responses were reduced overall yet decoded stimuli more accurately when vision was behaviorally relevant, whereas task relevance had little effect on MG responses. This double dissociation between the influences of task relevance and movement in MG and LG highlights a role for extrasensory modulation in the thalamus but also suggests key differences in the organization of modulatory circuitry between the auditory and visual pathways. PMID:26119749

  1. Activation of glycine receptors modulates spontaneous epileptiform activity in the immature rat hippocampus

    PubMed Central

    Chen, Rongqing; Okabe, Akihito; Sun, Haiyan; Sharopov, Salim; Hanganu-Opatz, Ileana L; Kolbaev, Sergei N; Fukuda, Atsuo; Luhmann, Heiko J; Kilb, Werner

    2014-01-01

    While the expression of glycine receptors in the immature hippocampus has been shown, no information about the role of glycine receptors in controlling the excitability in the immature CNS is available. Therefore, we examined the effect of glycinergic agonists and antagonists in the CA3 region of an intact corticohippocampal preparation of the immature (postnatal days 4–7) rat using field potential recordings. Bath application of 100 μm taurine or 10 μm glycine enhanced the occurrence of recurrent epileptiform activity induced by 20 μm 4-aminopyridine in low Mg2+ solution. This proconvulsive effect was prevented by 3 μm strychnine or after incubation with the loop diuretic bumetanide (10 μm), suggesting that it required glycine receptors and an active NKCC1-dependent Cl− accumulation. Application of higher doses of taurine (≥1 mm) or glycine (100 μm) attenuated recurrent epileptiform discharges. The anticonvulsive effect of taurine was also observed in the presence of the GABAA receptor antagonist gabazine and was attenuated by strychnine, suggesting that it was partially mediated by glycine receptors. Bath application of the glycinergic antagonist strychnine (0.3 μm) induced epileptiform discharges. We conclude from these results that in the immature hippocampus, activation of glycine receptors can mediate both pro- and anticonvulsive effects, but that a persistent activation of glycine receptors is required to suppress epileptiform activity. In summary, our study elucidated the important role of glycine receptors in the control of neuronal excitability in the immature hippocampus. PMID:24665103

  2. Laterality of brain activity during motor imagery is modulated by the provision of source level neurofeedback.

    PubMed

    Boe, Shaun; Gionfriddo, Alicia; Kraeutner, Sarah; Tremblay, Antoine; Little, Graham; Bardouille, Timothy

    2014-11-01

    Motor imagery (MI) may be effective as an adjunct to physical practice for motor skill acquisition. For example, MI is emerging as an effective treatment in stroke neurorehabilitation. As in physical practice, the repetitive activation of neural pathways during MI can drive short- and long-term brain changes that underlie functional recovery. However, the lack of feedback about MI performance may be a factor limiting its effectiveness. The provision of feedback about MI-related brain activity may overcome this limitation by providing the opportunity for individuals to monitor their own performance of this endogenous process. We completed a controlled study to isolate neurofeedback as the factor driving changes in MI-related brain activity across repeated sessions. Eighteen healthy participants took part in 3 sessions comprised of both actual and imagined performance of a button press task. During MI, participants in the neurofeedback group received source level feedback based on activity from the left and right sensorimotor cortex obtained using magnetoencephalography. Participants in the control group received no neurofeedback. MI-related brain activity increased in the sensorimotor cortex contralateral to the imagined movement across sessions in the neurofeedback group, but not in controls. Task performance improved across sessions but did not differ between groups. Our results indicate that the provision of neurofeedback during MI allows healthy individuals to modulate regional brain activity. This finding has the potential to improve the effectiveness of MI as a tool in neurorehabilitation. PMID:24999037

  3. Restoring wtp53 activity in HIPK2 depleted MCF7 cells by modulating metallothionein and zinc.

    PubMed

    Puca, Rosa; Nardinocchi, Lavinia; Bossi, Gianluca; Sacchi, Ada; Rechavi, Gideon; Givol, David; D'Orazi, Gabriella

    2009-01-01

    The maintenance of p53 transactivation activity is important for p53 apoptotic function. We have shown that stable knockdown of HIPK2 induces p53 misfolding with inhibition of p53 target gene transcription. In this study we established a lentiviral-based system for doxycyclin (Dox)-induced conditional interference of HIPK2 expression to evaluate the molecular mechanisms involved in p53 deregulation. We found that HIPK2 knockdown induced metallothionein 2A (MT2A) upregulation as assessed by RT-PCR analysis, increased promoter acetylation, and increased promoter luciferase activity. The MT2A upregulation correlated with resistance to Adriamycin (ADR)-driven apoptosis and with p53 inhibition. Thus, acute knockdown of HIPK2 (HIPK2i) induced misfolded p53 protein in MCF7 breast cancer cells and inhibited p53 DNA-binding and transcription activities in response to ADR treatment. Previous works show that MT may modulate p53 activity through zinc exchange. Here, we found that inhibition of MT2A expression by siRNA in the HIPK2i cells restored p53 transcription activity. Similarly zinc supplementation to HIPK2i cells restored p53 transcription activity and drug-induced apoptosis. These data support the notion that MT2A is involved in p53 deregulation and strengthen the possibility that combination of chemotherapy and zinc might be useful to treat tumors with inactive wtp53. PMID:18996371

  4. Modulation of plasma membrane H+-ATPase activity differentially activates wound and pathogen defense responses in tomato plants.

    PubMed Central

    Schaller, A; Oecking, C

    1999-01-01

    Systemin is an important mediator of wound-induced defense gene activation in tomato plants, and it elicits a rapid alkalinization of the growth medium of cultured Lycopersicon peruvianum cells. A possible mechanistic link between proton fluxes across the plasma membrane and the induction of defense genes was investigated by modulating plasma membrane H+-ATPase activity. Inhibitors of H+-ATPase (erythrosin B, diethyl stilbestrol, and vanadate) were found to alkalinize the growth medium of L. peruvianum cell cultures and to induce wound response genes in whole tomato plants. Conversely, an activator of the H+-ATPase (fusicoccin) acidified the growth medium of L. peruvianum cell cultures and suppressed systemin-induced medium alkalinization. Likewise, in fusicoccin-treated tomato plants, the wound- and systemin-triggered accumulation of wound-responsive mRNAs was found to be suppressed. However, fusicoccin treatment of tomato plants led to the accumulation of salicylic acid and the expression of pathogenesis-related genes. Apparently, the wound and pathogen defense signaling pathways are differentially regulated by changes in the proton electrochemical gradient across the plasma membrane. In addition, alkalinization of the L. peruvianum cell culture medium was found to depend on the influx of Ca2+ and the activity of a protein kinase. Reversible protein phosphorylation was also shown to be involved in the induction of wound response genes. The plasma membrane H+-ATPase as a possible target of a Ca2+-activated protein kinase and its role in defense signaling are discussed. PMID:9927643

  5. Lung protease/anti-protease network and modulation of mucus production and surfactant activity.

    PubMed

    Garcia-Verdugo, Ignacio; Descamps, Delphyne; Chignard, Michel; Touqui, Lhousseine; Sallenave, Jean-Michel

    2010-11-01

    Lung epithelium guarantees gas-exchange (performed in the alveoli) and protects from external insults (pathogens, pollutants…) present within inhaled air. Both functions are facilitated by secretions lining airway surface liquid, mucus (in the upper airways) and pulmonary surfactant (in the alveoli). Mucins, the main glycoproteins present within the mucus, are responsible for its rheologic properties and participate in lung defense mechanisms. In parallel, lung collectins are pattern recognition molecules present in pulmonary surfactant that also modulate lung defense. During chronic airways diseases, excessive protease activity can promote mucus hypersecretion and degradation of lung collectins and therefore contribute to the pathophysiology of these diseases. Importantly, secretion of local and systemic anti-proteases might be crucial to equilibrate the protease/anti-protease unbalance and therefore preserve the function of lung host defense compounds and airway surface liquid homeostasis. In this review we will present information relative to proteases able to modulate mucin production and lung collectin integrity, two important compounds of innate immune defense. One strategy to preserve physiological mucus production and collectin integrity during chronic airways diseases might be the over-expression of local 'alarm' anti-proteases such as SLPI and elafin. Interestingly, a cross-talk between lung collectins and anti-protease activity has recently been described, implicating the presence within the lung of a complex network between proteases, anti-proteases and pattern recognition molecules, which aims to keep or restore homeostasis in resting or inflamed lungs. PMID:20493919

  6. Spatial profile and differential recruitment of GABAB modulate oscillatory activity in auditory cortex

    PubMed Central

    Oswald, Anne-Marie M.; Doiron, Brent; Rinzel, John; Reyes, Alex D.

    2009-01-01

    The interplay between inhibition and excitation is at the core of cortical network activity. In many cortices, including auditory cortex (ACx), interactions between excitatory and inhibitory neurons generate synchronous network gamma oscillations (30–70 Hz). Here, we show that differences in the connection patterns and synaptic properties of excitatory-inhibitory microcircuits permit the spatial extent of network inputs to modulate the magnitude of gamma oscillations. Simultaneous multiple whole-cell recordings from connected fast-spiking (FS) interneurons and pyramidal cells (PC) in L2/3 of mouse ACx slices revealed that for intersomatic distances <50 µm, most inhibitory connections occurred in reciprocally connected (RC) pairs; at greater distances, inhibitory connections were equally likely in RC and non-reciprocally connected (nRC) pairs. Furthermore, the GABAB mediated inhibition in RC pairs was weaker than in nRC pairs. Simulations with a network model that incorporated these features showed strong, gamma-band oscillations only when the network inputs were confined to a small area. These findings suggest a novel mechanism by which oscillatory activity can be modulated by adjusting the spatial distribution of afferent input. PMID:19692606

  7. White noise improves learning by modulating activity in dopaminergic midbrain regions and right superior temporal sulcus.

    PubMed

    Rausch, Vanessa H; Bauch, Eva M; Bunzeck, Nico

    2014-07-01

    In neural systems, information processing can be facilitated by adding an optimal level of white noise. Although this phenomenon, the so-called stochastic resonance, has traditionally been linked with perception, recent evidence indicates that white noise may also exert positive effects on cognitive functions, such as learning and memory. The underlying neural mechanisms, however, remain unclear. Here, on the basis of recent theories, we tested the hypothesis that auditory white noise, when presented during the encoding of scene images, enhances subsequent recognition memory performance and modulates activity within the dopaminergic midbrain (i.e., substantia nigra/ventral tegmental area, SN/VTA). Indeed, in a behavioral experiment, we can show in healthy humans that auditory white noise-but not control sounds, such as a sinus tone-slightly improves recognition memory. In an fMRI experiment, white noise selectively enhances stimulus-driven phasic activity in the SN/VTA and auditory cortex. Moreover, it induces stronger connectivity between SN/VTA and right STS, which, in addition, exhibited a positive correlation with subsequent memory improvement by white noise. Our results suggest that the beneficial effects of auditory white noise on learning depend on dopaminergic neuromodulation and enhanced connectivity between midbrain regions and the STS-a key player in attention modulation. Moreover, they indicate that white noise could be particularly useful to facilitate learning in conditions where changes of the mesolimbic system are causally related to memory deficits including healthy and pathological aging. PMID:24345178

  8. Phasic and Tonic mGlu7 Receptor Activity Modulates the Thalamocortical Network.

    PubMed

    Tassin, Valériane; Girard, Benoît; Chotte, Apolline; Fontanaud, Pierre; Rigault, Delphine; Kalinichev, Mikhail; Perroy, Julie; Acher, Francine; Fagni, Laurent; Bertaso, Federica

    2016-01-01

    Mutation of the metabotropic glutamate receptor type 7 (mGlu7) induces absence-like epileptic seizures, but its precise role in the somatosensory thalamocortical network remains unknown. By combining electrophysiological recordings, optogenetics, and pharmacology, we dissected the contribution of the mGlu7 receptor at mouse thalamic synapses. We found that mGlu7 is functionally expressed at both glutamatergic and GABAergic synapses, where it can inhibit neurotransmission and regulate short-term plasticity. These effects depend on the PDZ-ligand of the receptor, as they are lost in mutant mice. Interestingly, the very low affinity of mGlu7 receptors for glutamate raises the question of how it can be activated, namely at GABAergic synapses and in basal conditions. Inactivation of the receptor activity with the mGlu7 negative allosteric modulator (NAM), ADX71743, enhances thalamic synaptic transmission. In vivo administration of the NAM induces a lethargic state with spindle and/or spike-and-wave discharges accompanied by a behavioral arrest typical of absence epileptic seizures. This provides evidence for mGlu7 receptor-mediated tonic modulation of a physiological function in vivo preventing synchronous and potentially pathological oscillations. PMID:27199672

  9. Modulation of bladder function by luminal adenosine turnover and A1 receptor activation

    PubMed Central

    Prakasam, H. Sandeep; Herrington, Heather; Roppolo, James R.; Jackson, Edwin K.

    2012-01-01

    The bladder uroepithelium transmits information to the underlying nervous and musculature systems, is under constant cyclical strain, expresses all four adenosine receptors (A1, A2A, A2B, and A3), and is a site of adenosine production. Although adenosine has a well-described protective effect in several organs, there is a lack of information about adenosine turnover in the uroepithelium or whether altering luminal adenosine concentrations impacts bladder function or overactivity. We observed that the concentration of extracellular adenosine at the mucosal surface of the uroepithelium was regulated by ecto-adenosine deaminase and by equilibrative nucleoside transporters, whereas adenosine kinase and equilibrative nucleoside transporters modulated serosal levels. We further observed that enriching endogenous adenosine by blocking its routes of metabolism or direct activation of mucosal A1 receptors with 2-chloro-N6-cyclopentyladenosine (CCPA), a selective agonist, stimulated bladder activity by lowering the threshold pressure for voiding. Finally, CCPA did not quell bladder hyperactivity in animals with acute cyclophosphamide-induced cystitis but instead exacerbated their irritated bladder phenotype. In conclusion, we find that adenosine levels at both surfaces of the uroepithelium are modulated by turnover, that blocking these pathways or stimulating A1 receptors directly at the luminal surface promotes bladder contractions, and that adenosine further stimulates voiding in animals with cyclophosphamide-induced cystitis. PMID:22552934

  10. FOXP3 can modulate TAL1 transcriptional activity through interaction with LMO2.

    PubMed

    Fleskens, V; Mokry, M; van der Leun, A M; Huppelschoten, S; Pals, C E G M; Peeters, J; Coenen, S; Cardoso, B A; Barata, J T; van Loosdregt, J; Coffer, P J

    2016-08-01

    T-cell acute lymphoblastic leukemia (T-ALL) frequently involves aberrant expression of TAL1 (T-cell acute lymphocytic leukemia 1) and LMO2, oncogenic members of the TAL1 transcriptional complex. Transcriptional activity of the TAL1-complex is thought to have a pivotal role in the transformation of thymocytes and is associated with a differentiation block and self-renewal. The transcription factor Forkhead Box P3 (FOXP3) was recently described to be expressed in a variety of malignancies including T-ALL. Here we show that increased FOXP3 levels negatively correlate with expression of genes regulated by the oncogenic TAL1-complex in human T-ALL patient samples as well as a T-ALL cell line ectopically expressing FOXP3. In these cells, FOXP3 expression results in altered regulation of cell cycle progression and reduced cell viability. Finally, we demonstrate that FOXP3 binds LMO2 in vitro, resulting in decreased interaction between LMO2 and TAL1, providing a molecular mechanism for FOXP3-mediated transcriptional modulation in T-ALL. Collectively, our findings provide initial evidence for a novel role of FOXP3 as a tumor suppressor in T-ALL through modulation of TAL1 transcriptional activity. PMID:26686090

  11. Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity