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  1. 77 FR 26413 - Promoting International Regulatory Cooperation

    Science.gov (United States)

    2012-05-04

    ... environment while promoting economic growth, innovation, competitiveness, and job creation. In an increasingly global economy, international regulatory cooperation, consistent with domestic law and prerogatives and U... Regulatory Cooperation By the authority vested in me as President by the Constitution and the laws of...

  2. Ex Vivo Costimulatory Blockade to Generate Regulatory T Cells From Patients Awaiting Kidney Transplantation.

    Science.gov (United States)

    Guinan, E C; Cole, G A; Wylie, W H; Kelner, R H; Janec, K J; Yuan, H; Oppatt, J; Brennan, L L; Turka, L A; Markmann, J

    2016-07-01

    Short-term outcomes of kidney transplantation have improved dramatically, but chronic rejection and regimen-related toxicity continue to compromise overall patient outcomes. Development of regulatory T cells (Tregs) as a means to decrease alloresponsiveness and limit the need for pharmacologic immunosuppression is an active area of preclinical and clinical investigation. Nevertheless, the immunomodulatory effects of end-stage renal disease on the efficacy of various strategies to generate and expand recipient Tregs for kidney transplantation are incompletely characterized. In this study, we show that Tregs can be successfully generated from either freshly isolated or previously cryopreserved uremic recipient (responder) and healthy donor (stimulator) peripheral blood mononuclear cells using the strategy of ex vivo costimulatory blockade with belatacept during mixed lymphocyte culture. Moreover, these Tregs maintain a CD3(+) CD4(+) CD25(+) CD127(lo) surface phenotype, high levels of intracellular FOXP3 and significant demethylation of the FOXP3 Treg-specific demethylation region on allorestimulation with donor stimulator cells. These data support evaluation of this simple, brief Treg production strategy in clinical trials of mismatched kidney transplantation. PMID:26790369

  3. Regulatory Promotion of Emergent CCS Technology

    Energy Technology Data Exchange (ETDEWEB)

    Davies, Lincoln; Uchitel, Kirsten; Johnson, David

    2014-01-01

    Despite the growing inevitability of climate change and the attendant need for mitigation strategies, carbon capture and sequestration (CCS) has yet to gain much traction in the United States. Recent regulatory proposals by the U.S. Environmental Protection Agency (EPA), limited in scope to new-build power plants, represent the only significant policy initiative intended to mandate diffusion of CCS technology. Phase I of this Project assessed barriers to CCS deployment as prioritized by the CCS community. That research concluded that there were four primary barriers: (1) cost, (2) lack of a carbon price, (3) liability, and (4) lack of a comprehensive regulatory regime. Phase II of this Project, as presented in this Report, assesses potential regulatory models for CCS and examines where those models address the hurdles to diffusing CCS technology identified in Phase I. It concludes (1) that a CCS-specific but flexible standard, such as a technology performance standard or a very particular type of market-based regulation, likely will promote CCS diffusion, and (2) that these policies cannot work alone, but rather, should be combined with other measures, such as liability limits and a comprehensive CCS regulatory regime.

  4. Blockade of Retinol Metabolism Protects T Cell-Induced Hepatitis by Increasing Migration of Regulatory T Cells.

    Science.gov (United States)

    Lee, Young-Sun; Yi, Hyon-Seung; Suh, Yang-Gun; Byun, Jin-Seok; Eun, Hyuk Soo; Kim, So Yeon; Seo, Wonhyo; Jeong, Jong-Min; Choi, Won-Mook; Kim, Myung-Ho; Kim, Ji Hoon; Park, Keun-Gyu; Jeong, Won-Il

    2015-11-01

    Retinols are metabolized into retinoic acids by alcohol dehydrogenase (ADH) and retinaldehyde dehydrogenase (Raldh). However, their roles have yet to be clarified in hepatitis despite enriched retinols in hepatic stellate cells (HSCs). Therefore, we investigated the effects of retinols on Concanavalin A (Con A)-mediated hepatitis. Con A was injected into wild type (WT), Raldh1 knock-out (Raldh1(-/-)), CCL2(-/-) and CCR2(-/-) mice. For migration study of regulatory T cells (Tregs), we used in vivo and ex vivo adoptive transfer systems. Blockade of retinol metabolism in mice given 4-methylpyrazole, an inhibitor of ADH, and ablated Raldh1 gene manifested increased migration of Tregs, eventually protected against Con A-mediated hepatitis by decreasing interferon-γ in T cells. Moreover, interferon-γ treatment increased the expression of ADH3 and Raldh1, but it suppressed that of CCL2 and IL-6 in HSCs. However, the expression of CCL2 and IL-6 was inversely increased upon the pharmacologic or genetic ablation of ADH3 and Raldh1 in HSCs. Indeed, IL-6 treatment increased CCR2 expression of Tregs. In migration assay, ablated CCR2 in Tregs showed reduced migration to HSCs. In adoptive transfer of Tregs in vivo and ex vivo, Raldh1-deficient mice showed more increased migration of Tregs than WT mice. Furthermore, inhibited retinol metabolism increased survival rate (75%) compared with that of the controls (25%) in Con A-induced hepatitis. These results suggest that blockade of retinol metabolism protects against acute liver injury by increased Treg migration, and it may represent a novel therapeutic strategy to control T cell-mediated acute hepatitis. PMID:26537191

  5. Regulatory T Cell-Dependent and -Independent Mechanisms of Immune Suppression by CD28/B7 and CD40/CD40L Costimulation Blockade.

    Science.gov (United States)

    Vogel, Isabel; Verbinnen, Bert; Van Gool, Stefaan; Ceuppens, Jan L

    2016-07-15

    Blocking of costimulatory CD28/B7 and CD40/CD40L interactions is an experimental approach to immune suppression and tolerance induction. We previously reported that administration of a combination of CTLA-4Ig and MR1 (anti-CD40L mAb) for blockade of these interactions induces tolerance in a fully mismatched allogeneic splenocyte transfer model in mice. We now used this model to study whether regulatory T cells (Tregs) contribute to immune suppression and why both pathways have to be blocked simultaneously. Mice were injected with allogeneic splenocytes, CD4(+) T cells, or CD8(+) T cells and treated with MR1 mAb and different doses of CTLA-4Ig. The graft-versus-host reaction of CD4(+) T cells, but not of CD8(+) T cells, was inhibited by MR1. CTLA-4Ig was needed to cover CD8(+) T cells but had only a weak effect on CD4(+) T cells. Consequently, only the combination provided full protection when splenocytes were transferred. Importantly, MR1 and low-dose CTLA-4Ig treatment resulted in a relative increase in Tregs, and immune suppressive efficacy was abolished in the absence of Tregs. High-dose CTLA-4Ig treatment, in contrast, prevented Treg expansion and activity, and in combination with MR1 completely inhibited CD4(+) and CD8(+) T cell activation in a Treg-independent manner. In conclusion, MR1 and CTLA-4Ig act synergistically as they target different T cell populations. The contribution of Tregs to immune suppression by costimulation blockade depends on the concentration of CTLA-4Ig and thus on the degree of available CD28 costimulation. PMID:27288533

  6. Late engagement of CD86 after influenza virus clearance promotes recovery in a FoxP3+ regulatory T cell dependent manner.

    Directory of Open Access Journals (Sweden)

    Emily K Moser

    2014-08-01

    Full Text Available Influenza A virus (IAV infection in the respiratory tract triggers robust innate and adaptive immune responses, resulting in both virus clearance and lung inflammation and injury. After virus clearance, resolution of ongoing inflammation and tissue repair occur during a distinct recovery period. B7 family co-stimulatory molecules such as CD80 and CD86 have important roles in modulating T cell activity during the initiation and effector stages of the host response to IAV infection, but their potential role during recovery and resolution of inflammation is unknown. We found that antibody-mediated CD86 blockade in vivo after virus clearance led to a delay in recovery, characterized by increased numbers of lung neutrophils and inflammatory cytokines in airways and lung interstitium, but no change in conventional IAV-specific T cell responses. However, CD86 blockade led to decreased numbers of FoxP3+ regulatory T cells (Tregs, and adoptive transfer of Tregs into αCD86 treated mice rescued the effect of the blockade, supporting a role for Tregs in promoting recovery after virus clearance. Specific depletion of Tregs late after infection mimicked the CD86 blockade phenotype, confirming a role for Tregs during recovery after virus clearance. Furthermore, we identified neutrophils as a target of Treg suppression since neutrophil depletion in Treg-depleted mice reduced excess inflammatory cytokines in the airways. These results demonstrate that Tregs, in a CD86 dependent mechanism, contribute to the resolution of disease after IAV infection, in part by suppressing neutrophil-driven cytokine release into the airways.

  7. Modelling the conditional regulatory activity of methylated and bivalent promoters

    OpenAIRE

    Budden, David M.; Hurley, Daniel G.; Edmund J Crampin

    2015-01-01

    Background Predictive modelling of gene expression is a powerful framework for the in silico exploration of transcriptional regulatory interactions through the integration of high-throughput -omics data. A major limitation of previous approaches is their inability to handle conditional interactions that emerge when genes are subject to different regulatory mechanisms. Although chromatin immunoprecipitation-based histone modification data are often used as proxies for chromatin accessibility, ...

  8. Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

    DEFF Research Database (Denmark)

    Færch, Louise H; Thorsteinsson, Birger; Tarnow, Lise;

    2015-01-01

    INTRODUCTION: High spontaneous activity of the renin-angiotensin system (RAS) results in more pronounced cognitive impairment and more prolonged QTc interval during hypoglycaemia in type 1 diabetes. We tested whether angiotensin II receptor blockade improves cerebral and cardiovascular function...

  9. 77 FR 59702 - Promoting U.S. EC Regulatory Compatibility

    Science.gov (United States)

    2012-09-28

    ... greater transatlantic regulatory compatibility generally. Concrete ideas on how greater compatibility.... We also invite you to share your concrete ideas on how greater compatibility could be achieved in a... (.doc) or Adobe Acrobat (.pdf). If the submission is in an application other than those two,...

  10. ANXA3/JNK Signaling Promotes Self-Renewal and Tumor Growth, and Its Blockade Provides a Therapeutic Target for Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Man Tong

    2015-07-01

    Full Text Available Frequent tumor relapse in hepatocellular carcinoma (HCC has been commonly attributed to the presence of residual cancer stem cells (CSCs after conventional treatments. We have previously identified and characterized CD133 to mark a specific CSC subset in HCC. In the present study, we found endogenous and secretory annexin A3 (ANXA3 to play pivotal roles in promoting cancer and stem cell-like features in CD133+ liver CSCs through a dysregulated JNK pathway. Blockade of ANXA3 with an anti-ANXA3 monoclonal antibody in vitro as well as in human HCC xenograft models resulted in a significant reduction in tumor growth and self-renewal. Clinically, ANXA3 expression in HCC patient sera closely associated with aggressive clinical features. Our results suggest that ANXA3 can serve as a novel diagnostic biomarker and that the inhibition of ANXA3 may be a viable therapeutic option for the treatment of CD133+ liver-CSC-driven HCC.

  11. Effective Separation between Regulatory Function and Promotional Function in the Government of Uganda

    International Nuclear Information System (INIS)

    The increasing demand for clean and sustainable energy has resulted in many countries considering nuclear energy as one of the options. In 2009, the IAEA noted a wide use of radioactive sources and ionizing radiation and clearly indicated that many countries expressed the need to introduce nuclear power into their national energy mix. However, the plans for developing nuclear power programme in some countries were faster than the establishment of the necessary infrastructure and capabilities. Uganda is one of the countries that are considering introducing nuclear power into their energy mix, and thus, in 2009, established the Atomic Energy Council to regulate the peaceful application of ionizing radiation. Although the government of Uganda has done much to establish an independent regulatory body, the regulatory personnel should guard against pressure from government institutions and stake holders that can unduly influence regulatory decision making. In addition, they need to be fully aware of their authority. The purpose of this paper was to assess the perceived regulatory independence of regulatory staff as one of the basic personal attributes for effective and efficient execution of regulatory activities. Furthermore, effective separation between regulatory function and promotional function in Uganda was noted as one of the fundamental requisites for effective regulatory performance especially during the early infancy period of a regulatory body. The study assessed the perceived regulatory independence in comparison with the theoretical independence. The results showed a good sense of independence by the staff and thus, the approach can be used for regulatory body self-assessment. However, more appropriate forums such as the Integrated Regulatory Review Services or the Convention on Nuclear Safety are suggested as the best ways of assessing regulatory independence

  12. Andrographolide Ameliorate Rheumatoid Arthritis by Promoting the Development of Regulatory T Cells

    OpenAIRE

    Muhaimin Rifa’i

    2010-01-01

    Andrographolide is important material present in Andrographis paniculata. This material can promote T cell to develop into regulatory T cell, CD4+CD25+. CD4+CD25+ regulatory T (Treg) cells, a component of the innate immune response, which play a key role in the maintenance of self-tolerance, have become the focus of numerous studies over the last decade. These cells have the potential to be exploited to treat autoimmune disease. These cells inhibit the immune respo...

  13. Positional bias of general and tissue-specific regulatory motifs in mouse gene promoters

    Directory of Open Access Journals (Sweden)

    Farré Domènec

    2007-12-01

    Full Text Available Abstract Background The arrangement of regulatory motifs in gene promoters, or promoter architecture, is the result of mutation and selection processes that have operated over many millions of years. In mammals, tissue-specific transcriptional regulation is related to the presence of specific protein-interacting DNA motifs in gene promoters. However, little is known about the relative location and spacing of these motifs. To fill this gap, we have performed a systematic search for motifs that show significant bias at specific promoter locations in a large collection of housekeeping and tissue-specific genes. Results We observe that promoters driving housekeeping gene expression are enriched in particular motifs with strong positional bias, such as YY1, which are of little relevance in promoters driving tissue-specific expression. We also identify a large number of motifs that show positional bias in genes expressed in a highly tissue-specific manner. They include well-known tissue-specific motifs, such as HNF1 and HNF4 motifs in liver, kidney and small intestine, or RFX motifs in testis, as well as many potentially novel regulatory motifs. Based on this analysis, we provide predictions for 559 tissue-specific motifs in mouse gene promoters. Conclusion The study shows that motif positional bias is an important feature of mammalian proximal promoters and that it affects both general and tissue-specific motifs. Motif positional constraints define very distinct promoter architectures depending on breadth of expression and type of tissue.

  14. Fanconi anemia core complex gene promoters harbor conserved transcription regulatory elements.

    Directory of Open Access Journals (Sweden)

    Daniel Meier

    Full Text Available The Fanconi anemia (FA gene family is a recent addition to the complex network of proteins that respond to and repair certain types of DNA damage in the human genome. Since little is known about the regulation of this novel group of genes at the DNA level, we characterized the promoters of the eight genes (FANCA, B, C, E, F, G, L and M that compose the FA core complex. The promoters of these genes show the characteristic attributes of housekeeping genes, such as a high GC content and CpG islands, a lack of TATA boxes and a low conservation. The promoters functioned in a monodirectional way and were, in their most active regions, comparable in strength to the SV40 promoter in our reporter plasmids. They were also marked by a distinctive transcriptional start site (TSS. In the 5' region of each promoter, we identified a region that was able to negatively regulate the promoter activity in HeLa and HEK 293 cells in isolation. The central and 3' regions of the promoter sequences harbor binding sites for several common and rare transcription factors, including STAT, SMAD, E2F, AP1 and YY1, which indicates that there may be cross-connections to several established regulatory pathways. Electrophoretic mobility shift assays and siRNA experiments confirmed the shared regulatory responses between the prominent members of the TGF-β and JAK/STAT pathways and members of the FA core complex. Although the promoters are not well conserved, they share region and sequence specific regulatory motifs and transcription factor binding sites (TBFs, and we identified a bi-partite nature to these promoters. These results support a hypothesis based on the co-evolution of the FA core complex genes that was expanded to include their promoters.

  15. Regulatory fit effects for injunctive versus descriptive social norms: Evidence from the promotion of sustainable products

    NARCIS (Netherlands)

    Melnyk, V.; Herpen, van E.; Fischer, A.R.H.; Trijp, van J.C.M.

    2013-01-01

    Consumers face marketing messages using social norms in many situations where different goals are dominant. This research examines moderating effects of regulatory focus for descriptive and injunctive norms in the promotion of sustainable products. More specifically, it shows that descriptive norms

  16. Statistically Significant Strings are Related to Regulatory Elements in the Promoter Regions of Saccharomyces cerevisiae

    CERN Document Server

    Hu, R; Hu, Rui; Wang, Bin

    2000-01-01

    Finding out statistically significant words in DNA and protein sequences forms the basis for many genetic studies. By applying the maximal entropy principle, we give one systematic way to study the nonrandom occurrence of words in DNA or protein sequences. Through comparison with experimental results, it was shown that patterns of regulatory binding sites in Saccharomyces cerevisiae(yeast) genomes tend to occur significantly in the promoter regions. We studied two correlated gene family of yeast. The method successfully extracts the binding sites varified by experiments in each family. Many putative regulatory sites in the upstream regions are proposed. The study also suggested that some regulatory sites are a ctive in both directions, while others show directional preference.

  17. Andrographolide Ameliorate Rheumatoid Arthritis by Promoting the Development of Regulatory T Cells

    Directory of Open Access Journals (Sweden)

    Muhaimin Rifa’i

    2010-10-01

    Full Text Available Andrographolide is important material present in Andrographis paniculata. This material can promote T cell to develop into regulatory T cell, CD4+CD25+. CD4+CD25+ regulatory T (Treg cells, a component of the innate immune response, which play a key role in the maintenance of self-tolerance, have become the focus of numerous studies over the last decade. These cells have the potential to be exploited to treat autoimmune disease. These cells inhibit the immune response in an Ag-nonspecific manner, interacting with other T cells. These T cell populations actively control the properties of other immune cells by suppressing their functional activity to prevent autoimmunity but also influence the immune response to allergens as well as against tumor cells and pathogens. In this experiment we showed that active compound from Andrographis paniculata namely andrographolide can induce active regulatory T cell that has an efficacy to cure rheumatoid arthritis mice model.

  18. A multistep bioinformatic approach detects putative regulatory elements in gene promoters

    Directory of Open Access Journals (Sweden)

    Pizzi Cinzia

    2005-05-01

    Full Text Available Abstract Background Searching for approximate patterns in large promoter sequences frequently produces an exceedingly high numbers of results. Our aim was to exploit biological knowledge for definition of a sheltered search space and of appropriate search parameters, in order to develop a method for identification of a tractable number of sequence motifs. Results Novel software (COOP was developed for extraction of sequence motifs, based on clustering of exact or approximate patterns according to the frequency of their overlapping occurrences. Genomic sequences of 1 Kb upstream of 91 genes differentially expressed and/or encoding proteins with relevant function in adult human retina were analyzed. Methodology and results were tested by analysing 1,000 groups of putatively unrelated sequences, randomly selected among 17,156 human gene promoters. When applied to a sample of human promoters, the method identified 279 putative motifs frequently occurring in retina promoters sequences. Most of them are localized in the proximal portion of promoters, less variable in central region than in lateral regions and similar to known regulatory sequences. COOP software and reference manual are freely available upon request to the Authors. Conclusion The approach described in this paper seems effective for identifying a tractable number of sequence motifs with putative regulatory role.

  19. A multistep bioinformatic approach detects putative regulatory elements in gene promoters

    Science.gov (United States)

    Bortoluzzi, Stefania; Coppe, Alessandro; Bisognin, Andrea; Pizzi, Cinzia; Danieli, Gian Antonio

    2005-01-01

    Background Searching for approximate patterns in large promoter sequences frequently produces an exceedingly high numbers of results. Our aim was to exploit biological knowledge for definition of a sheltered search space and of appropriate search parameters, in order to develop a method for identification of a tractable number of sequence motifs. Results Novel software (COOP) was developed for extraction of sequence motifs, based on clustering of exact or approximate patterns according to the frequency of their overlapping occurrences. Genomic sequences of 1 Kb upstream of 91 genes differentially expressed and/or encoding proteins with relevant function in adult human retina were analyzed. Methodology and results were tested by analysing 1,000 groups of putatively unrelated sequences, randomly selected among 17,156 human gene promoters. When applied to a sample of human promoters, the method identified 279 putative motifs frequently occurring in retina promoters sequences. Most of them are localized in the proximal portion of promoters, less variable in central region than in lateral regions and similar to known regulatory sequences. COOP software and reference manual are freely available upon request to the Authors. Conclusion The approach described in this paper seems effective for identifying a tractable number of sequence motifs with putative regulatory role. PMID:15904489

  20. Depletion of regulatory T cells leads to an exacerbation of delayed-type hypersensitivity arthritis in C57BL/6 mice that can be counteracted by IL-17 blockade.

    Science.gov (United States)

    Atkinson, Sara Marie; Hoffmann, Ute; Hamann, Alf; Bach, Emil; Danneskiold-Samsøe, Niels Banhos; Kristiansen, Karsten; Serikawa, Kyle; Fox, Brian; Kruse, Kim; Haase, Claus; Skov, Søren; Nansen, Anneline

    2016-04-01

    Rodent models of arthritis have been extensively used in the elucidation of rheumatoid arthritis (RA) pathogenesis and are instrumental in the development of therapeutic strategies. Here we utilise delayed-type hypersensitivity arthritis (DTHA), a model in C57BL/6 mice affecting one paw with synchronised onset, 100% penetrance and low variation. We investigate the role of regulatory T cells (Tregs) in DTHA through selective depletion of Tregsand the role of IL-17 in connection with Tregdepletion. Given the relevance of Tregsin RA, and the possibility of developing Treg-directed therapies, this approach could be relevant for advancing the understanding of Tregsin inflammatory arthritis. Selective depletion of Tregswas achieved using aFoxp3-DTR-eGFPmouse, which expresses the diphtheria toxin receptor (DTR) and enhanced green fluorescent protein (eGFP) under control of theFoxp3gene. Anti-IL-17 monoclonal antibody (mAb) was used for IL-17 blockade. Numbers and activation of Tregsincreased in the paw and its draining lymph node in DTHA, and depletion of Tregsresulted in exacerbation of disease as shown by increased paw swelling, increased infiltration of inflammatory cells, increased bone remodelling and increased production of inflammatory mediators, as well as increased production of anti-citrullinated protein antibodies. Anti-IL-17 mAb treatment demonstrated that IL-17 is important for disease severity in both the presence and absence of Tregs, and that IL-17 blockade is able to rescue mice from the exacerbated disease caused by Tregdepletion and caused a reduction in RANKL, IL-6 and the number of neutrophils. We show that Tregsare important for the containment of inflammation and bone remodelling in DTHA. To our knowledge, this is the first study using theFoxp3-DTR-eGFPmouse on a C57BL/6 background for Tregdepletion in an arthritis model, and we here demonstrate the usefulness of the approach to study the role of Tregsand IL-17 in arthritis. PMID:26822477

  1. A regulatory toolbox of MiniPromoters to drive selective expression in the brain.

    Science.gov (United States)

    Portales-Casamar, Elodie; Swanson, Douglas J; Liu, Li; de Leeuw, Charles N; Banks, Kathleen G; Ho Sui, Shannan J; Fulton, Debra L; Ali, Johar; Amirabbasi, Mahsa; Arenillas, David J; Babyak, Nazar; Black, Sonia F; Bonaguro, Russell J; Brauer, Erich; Candido, Tara R; Castellarin, Mauro; Chen, Jing; Chen, Ying; Cheng, Jason C Y; Chopra, Vik; Docking, T Roderick; Dreolini, Lisa; D'Souza, Cletus A; Flynn, Erin K; Glenn, Randy; Hatakka, Kristi; Hearty, Taryn G; Imanian, Behzad; Jiang, Steven; Khorasan-zadeh, Shadi; Komljenovic, Ivana; Laprise, Stéphanie; Liao, Nancy Y; Lim, Jonathan S; Lithwick, Stuart; Liu, Flora; Liu, Jun; Lu, Meifen; McConechy, Melissa; McLeod, Andrea J; Milisavljevic, Marko; Mis, Jacek; O'Connor, Katie; Palma, Betty; Palmquist, Diana L; Schmouth, Jean-François; Swanson, Magdalena I; Tam, Bonny; Ticoll, Amy; Turner, Jenna L; Varhol, Richard; Vermeulen, Jenny; Watkins, Russell F; Wilson, Gary; Wong, Bibiana K Y; Wong, Siaw H; Wong, Tony Y T; Yang, George S; Ypsilanti, Athena R; Jones, Steven J M; Holt, Robert A; Goldowitz, Daniel; Wasserman, Wyeth W; Simpson, Elizabeth M

    2010-09-21

    The Pleiades Promoter Project integrates genomewide bioinformatics with large-scale knockin mouse production and histological examination of expression patterns to develop MiniPromoters and related tools designed to study and treat the brain by directed gene expression. Genes with brain expression patterns of interest are subjected to bioinformatic analysis to delineate candidate regulatory regions, which are then incorporated into a panel of compact human MiniPromoters to drive expression to brain regions and cell types of interest. Using single-copy, homologous-recombination "knockins" in embryonic stem cells, each MiniPromoter reporter is integrated immediately 5' of the Hprt locus in the mouse genome. MiniPromoter expression profiles are characterized in differentiation assays of the transgenic cells or in mouse brains following transgenic mouse production. Histological examination of adult brains, eyes, and spinal cords for reporter gene activity is coupled to costaining with cell-type-specific markers to define expression. The publicly available Pleiades MiniPromoter Project is a key resource to facilitate research on brain development and therapies. PMID:20807748

  2. An integrative computational approach to effectively guide experimental identification of regulatory elements in promoters

    Directory of Open Access Journals (Sweden)

    Deyneko Igor V

    2012-08-01

    Full Text Available Abstract Background Transcriptional activity of genes depends on many factors like DNA motifs, conformational characteristics of DNA, melting etc. and there are computational approaches for their identification. However, in real applications, the number of predicted, for example, DNA motifs may be considerably large. In cases when various computational programs are applied, systematic experimental knock out of each of the potential elements obviously becomes nonproductive. Hence, one needs an approach that is able to integrate many heterogeneous computational methods and upon that suggest selected regulatory elements for experimental verification. Results Here, we present an integrative bioinformatic approach aimed at the discovery of regulatory modules that can be effectively verified experimentally. It is based on combinatorial analysis of known and novel binding motifs, as well as of any other known features of promoters. The goal of this method is the identification of a collection of modules that are specific for an established dataset and at the same time are optimal for experimental verification. The method is particularly effective on small datasets, where most statistical approaches fail. We apply it to promoters that drive tumor-specific gene expression in tumor-colonizing Gram-negative bacteria. The method successfully identified a number of potential modules, which required only a few experiments to be verified. The resulting minimal functional bacterial promoter exhibited high specificity of expression in cancerous tissue. Conclusions Experimental analysis of promoter structures guided by bioinformatics has proved to be efficient. The developed computational method is able to include heterogeneous features of promoters and suggest combinatorial modules for experimental testing. Expansibility and robustness of the methodology implemented in the approach ensures good results for a wide range of problems.

  3. CTLA-4 promotes Foxp3 induction and regulatory T cell accumulation in the intestinal lamina propria

    OpenAIRE

    Barnes, M. J.; Griseri, T; Johnson, A M F; Young, W; Powrie, F; Izcue, A

    2012-01-01

    Thymic induction of CD4+Foxp3+ regulatory T (Treg) cells relies on CD28 costimulation and high-affinity T-cell receptor (TCR) signals, whereas Foxp3 (forkhead box P3) induction on activated peripheral CD4+ T cells is inhibited by these signals. Accordingly, the inhibitory molecule CTLA-4 (cytotoxic T-lymphocyte antigen 4) promoted, but was not essential for CD4+ T-cell Foxp3 induction in vitro. We show that CTLA-4-deficient cells are equivalent to wild-type cells in the thymic induction of Fo...

  4. Repressive BMP2 gene regulatory elements near the BMP2 promoter

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Shan [Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry (UMDNJ), New Jersey Medical School (NJMS), Newark, NJ (United States); Chandler, Ronald L. [Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN (United States); Fritz, David T. [Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry (UMDNJ), New Jersey Medical School (NJMS), Newark, NJ (United States); Mortlock, Douglas P. [Department of Molecular Physiology and Biophysics, Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN (United States); Rogers, Melissa B., E-mail: rogersmb@umdnj.edu [Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry (UMDNJ), New Jersey Medical School (NJMS), Newark, NJ (United States)

    2010-02-05

    The level of bone morphogenetic protein 2 (BMP2) profoundly influences essential cell behaviors such as proliferation, differentiation, apoptosis, and migration. The spatial and temporal pattern of BMP2 synthesis, particular in diverse embryonic cells, is highly varied and dynamic. We have identified GC-rich sequences within the BMP2 promoter region that strongly repress gene expression. These elements block the activity of a highly conserved, osteoblast enhancer in response to FGF2 treatment. Both positive and negative gene regulatory elements control BMP2 synthesis. Detecting and mapping the repressive motifs is essential because they impede the identification of developmentally regulated enhancers necessary for normal BMP2 patterns and concentration.

  5. Repressive BMP2 gene regulatory elements near the BMP2 promoter

    International Nuclear Information System (INIS)

    The level of bone morphogenetic protein 2 (BMP2) profoundly influences essential cell behaviors such as proliferation, differentiation, apoptosis, and migration. The spatial and temporal pattern of BMP2 synthesis, particular in diverse embryonic cells, is highly varied and dynamic. We have identified GC-rich sequences within the BMP2 promoter region that strongly repress gene expression. These elements block the activity of a highly conserved, osteoblast enhancer in response to FGF2 treatment. Both positive and negative gene regulatory elements control BMP2 synthesis. Detecting and mapping the repressive motifs is essential because they impede the identification of developmentally regulated enhancers necessary for normal BMP2 patterns and concentration.

  6. A regulatory potential of the Xist gene promoter in vole M. rossiaemeridionalis.

    Directory of Open Access Journals (Sweden)

    Konstantin E Orishchenko

    Full Text Available X chromosome inactivation takes place in the early development of female mammals and depends on the Xist gene expression. The mechanisms of Xist expression regulation have not been well understood so far. In this work, we compared Xist promoter region of vole Microtus rossiaemeridionalis and other mammalian species. We observed three conserved regions which were characterized by computational analysis, DNaseI in vitro footprinting, and reporter construct assay. Regulatory factors potentially involved in Xist activation and repression in voles were determined. The role of CpG methylation in vole Xist expression regulation was established. A CTCF binding site was found in the 5' flanking region of the Xist promoter on the active X chromosome in both males and females. We suggest that CTCF acts as an insulator which defines an inactive Xist domain on the active X chromosome in voles.

  7. Robust and regulatory expression of defensin A gene driven by vitellogenin promoter in transgenic Anopheles stephensi

    Institute of Scientific and Technical Information of China (English)

    CHEN XiaoGuang; ZHANG YaJing; ZHENG XueLi; WANG ChunMei

    2007-01-01

    The use of genetically modified mosquitoes to reduce or replace field populations is a new strategy to control mosquito-borne diseases. The precondition of the implementation of this strategy is the ability to manipulate the genome of mosquitoes and to induce specific expression of the effector molecules driven by a suitable promoter. The objective of this study is to evaluate the expression of defensin A gene of Anopheles sinensis under the control of a vitellogenin promoter in transgenic Anopheles stephensi. The regulatory region of Anopheles gambiae vitellogenin was cloned and subcloned into transfer vector pSLFa consisting of an expression cassette with defensin A coding sequence. Then, the expression cassette was transferred into transformation vector pBac[3xP3-DsRedafm] using Asc I digestion. The recombinant plasmid DNA of pBac[3xP3DsRed-AgVgT2-DefA] and helper plasmid DNA of phsp-pBac were micro-injected into embryos of An. stephensi. The positive transgenic mosquitoes were screened by observing specific red fluorescence in the eyes of G1 larvae. Southern blot analysis showed that a single-copy transgene integrated into the genome of An. stephensi. RT-PCR analysis showed that the defensin A gene expressed specifically in fat bodies of female mosquitoes after a blood meal. Interestingly, the mRNA of defensin A is more stable compared with that of the endogenous vitellogenin gene. After multiple blood meals, the expression of defensin A appeared as a reducible and non-cycling type, a crucial feature for its anti-pathogen effect. From data above, we concluded that the regulatory function of the Vg promoter and the expression of defensin A gene were relatively conserved in different species of anopheles mosquitoes. These molecules could be used as candidates in the development of genetically modified mosquitoes.

  8. Intra-articular nuclear factor-κB blockade ameliorates collagen-induced arthritis in mice by eliciting regulatory T cells and macrophages.

    Science.gov (United States)

    Min, S-Y; Yan, M; Du, Y; Wu, T; Khobahy, E; Kwon, S-R; Taneja, V; Bashmakov, A; Nukala, S; Ye, Y; Orme, J; Sajitharan, D; Kim, H-Y; Mohan, C

    2013-05-01

    Nuclear factor (NF)-κB is a transcription factor implicated in the pathogenesis of autoimmune disorders such as rheumatoid arthritis (RA). Here we have examined the effect of intra-articular administration of the IKK inhibitor, NEMO-binding domain peptide (NBD), on the severity of collagen-induced arthritis (CIA). NBD peptides were injected intra-articularly into the knee joints of DBA/1J mice after the onset of disease. Collagen-injected mice given a scrambled peptide served as controls. Arthritis severity was determined by visual examination of paws. Intra-articular NBD injection reduced the arthritis score and ameliorated morphological signs of bone destruction compared to the controls. Serum levels of type-II collagen-specific immunoglobulin (Ig)G2a antibodies were lower in NBD-treated mice versus the control mice, whereas the levels of type-II collagen-specific IgG1 antibodies were increased by NBD treatment. NBD treatment diminished the proinflammatory cytokines interleukin (IL)-17 and interferon (IFN)-γ in serum, but increased the regulatory cytokine IL-10. NBD-treated CIA mice exhibited significantly higher percentages and numbers of forkhead box protein 3 (FoxP3(+)) CD4(+) CD25(+) regulatory T cells than controls. Immunofluorescence analysis of NBD-treated mice revealed that FoxP3 and Ym1, a marker of alternatively activated macrophages, were juxtaposed to each other within draining inguinal lymph nodes. Intra-articular administration of NBD peptide is effective as an experimental therapy in a murine model of RA. Nevertheless, the intra-articular treatment modality is still associated with systemic effects on the immune system. PMID:23574318

  9. Conserved cis-regulatory modules in promoters of genes encoding wheat high-molecular-weight glutenin subunits

    Directory of Open Access Journals (Sweden)

    Catherine eRAVEL

    2014-11-01

    Full Text Available The concentration and composition of the gliadin and glutenin seed storage proteins (SSPs in wheat flour are the most important determinants of its end-use value. In cereals, the synthesis of SSPs is predominantly regulated at the transcriptional level by a complex network involving at least five cis-elements in gene promoters. The high-molecular-weight glutenin subunits (HMW-GS are encoded by two tightly linked genes located on the long arms of group 1 chromosomes. Here, we sequenced and annotated the HMW-GS gene promoters of 22 electrophoretic wheat alleles to identify putative cis-regulatory motifs. We focused on 24 motifs known to be involved in SSP gene regulation. Most of them were identified in at least one HMW-GS gene promoter sequence. A common regulatory framework was observed in all the HMW-GS gene promoters, as they shared conserved cis-regulatory modules including all the five motifs known to regulate the transcription of SSP genes. This common regulatory framework comprises a composite box made of the GATA motifs and GCN4-like Motifs (GLMs and was shown to be functional as the GLMs are able to bind a bZIP transcriptional factor SPA (Storage Protein Activator. In addition to this regulatory framework, each HMW-GS gene promoter had additional motifs organized differently. The promoters of most highly expressed x-type HMW-GS genes contain an additional box predicted to bind R2R3-MYB transcriptional factors. However, the differences in annotation between promoter alleles could not be related to their level of expression. In summary, we identified a common modular organization of HMW-GS gene promoters but the lack of correlation between the cis-motifs of each HMW-GS gene promoter and their level of expression suggests that other cis-elements or other mechanisms regulate HMW-GS gene expression.

  10. Sexual fidelity trade-offs promote regulatory variation in the prairie vole brain.

    Science.gov (United States)

    Okhovat, Mariam; Berrio, Alejandro; Wallace, Gerard; Ophir, Alexander G; Phelps, Steven M

    2015-12-11

    Individual variation in social behavior seems ubiquitous, but we know little about how it relates to brain diversity. Among monogamous prairie voles, levels of vasopressin receptor (encoded by the gene avpr1a) in brain regions related to spatial memory predict male space use and sexual fidelity in the field. We find that trade-offs between the benefits of male fidelity and infidelity are reflected in patterns of territorial intrusion, offspring paternity, avpr1a expression, and the evolutionary fitness of alternative avpr1a alleles. DNA variation at the avpr1a locus includes polymorphisms that reliably predict the epigenetic status and neural expression of avpr1a, and patterns of DNA diversity demonstrate that avpr1a regulatory variation has been favored by selection. In prairie voles, trade-offs in the fitness consequences of social behaviors seem to promote neuronal and molecular diversity. PMID:26659055

  11. V1R promoters are well conserved and exhibit common putative regulatory motifs

    Directory of Open Access Journals (Sweden)

    Lane Robert P

    2007-07-01

    Full Text Available Abstract Background The mouse vomeronasal organ (VNO processes chemosensory information, including pheromone signals that influence reproductive behaviors. The sensory neurons of the VNO express two types of chemosensory receptors, V1R and V2R. There are ~165 V1R genes in the mouse genome that have been classified into ~12 divergent subfamilies. Each sensory neuron of the apical compartment of the VNO transcribes only one of the repertoire of V1R genes. A model for mutually exclusive V1R transcription in these cells has been proposed in which each V1R gene might compete stochastically for a single transcriptional complex. This model predicts that the large repertoire of divergent V1R genes in the mouse genome contains common regulatory elements. In this study, we have characterized V1R promoter regions by comparative genomics and by mapping transcription start sites. Results We find that transcription is initiated from ~1 kb promoter regions that are well conserved within V1R subfamilies. While cross-subfamily homology is not evident by traditional methods, we developed a heuristic motif-searching tool, LogoAlign, and applied this tool to identify motifs shared within the promoters of all V1R genes. Our motif-searching tool exhibits rapid convergence to a relatively small number of non-redundant solutions (97% convergence. We also find that the best motifs contain significantly more information than those identified in controls, and that these motifs are more likely to be found in the immediate vicinity of transcription start sites than elsewhere in gene blocks. The best motifs occur near transcription start sites of ~90% of all V1R genes and across all of the divergent subfamilies. Therefore, these motifs are candidate binding sites for transcription factors involved in V1R co-regulation. Conclusion Our analyses show that V1R subfamilies have broad and well conserved promoter regions from which transcription is initiated. Results from a new

  12. Combinatorial regulation modules on GmSBP2 promoter: a distal cis-regulatory domain confines the SBP2 promoter activity to the vascular tissue in vegetative organs.

    Science.gov (United States)

    Waclawovsky, Alessandro J; Freitas, Rejane L; Rocha, Carolina S; Contim, Luis Antônio S; Fontes, Elizabeth P B

    2006-01-01

    The Glycine max sucrose binding protein (GmSBP2) promoter directs phloem-specific expression of reporter genes in transgenic tobacco. Here, we identified cis-regulatory domains (CRD) that contribute with positive and negative regulation for the tissue-specific pattern of the GmSPB2 promoter. Negative regulatory elements in the distal CRD-A (-2000 to -700) sequences suppressed expression from the GmSBP2 promoter in tissues other than seed tissues and vascular tissues of vegetative organs. Deletion of this region relieved repression resulting in a constitutive promoter highly active in all tissues analyzed. Further deletions from the strong constitutive -700GmSBP2 promoter delimited several intercalating enhancer-like and repressing domains that function in a context-dependent manner. Histochemical examination revealed that the CRD-C (-445 to -367) harbors both negative and positive elements. This region abolished promoter expression in roots and in all tissues of stems except for the inner phloem. In contrast, it restores root meristem expression when fused to the -132pSBP2-GUS construct, which contains root meristem expression-repressing determinants mapped to the 44-bp CRD-G (-136 to -92). Thus, the GmSBP2 promoter is functionally organized into a proximal region with the combinatorial modular configuration of plant promoters and a distal domain, which restricts gene expression to the vascular tissues in vegetative organs. PMID:16574256

  13. Identification of a negative regulatory domain in the human papillomavirus type 18 promoter: interaction with the transcriptional repressor YY1.

    Science.gov (United States)

    Bauknecht, T; Angel, P; Royer, H D; zur Hausen, H

    1992-01-01

    The human papillomavirus type 18 (HPV-18) promoter contains a TPA responsive element (TRE) which confers TPA responsiveness on a heterologous promoter. In the context of the HPV-18 promoter, however, this AP-1 site is inactive. We have identified a negative regulatory domain in the HPV-18 promoter which represses the constitutive and TPA-induced AP-1 activity. This negative regulatory sequence has been mapped to 44 nucleotides (OL13). We identified this element as a transcriptional silencer based on its ability to interfere with transcriptional initiation. This HPV-18 silencer domain was narrowed down further to 23 nucleotides, the OL13B element, which bears similarity to three other silencer sequences, present in the mouse N-ras gene upstream regulatory region, the mouse albumin gene enhancer and the adeno-associated virus P5 promoter. The transcriptional repressor protein YY1, which negatively regulates the P5 promoter, binds to the HPV-18 silencer with high affinity. Mutation of the YY1 binding site leads to an enhanced activity of the HPV-18 promoter, strongly suggesting that YY1 plays an important role in controlling HPV-18 early gene expression. Images PMID:1330541

  14. Reg4, triggering a positive feedback regulatory circuit, promotes peritoneal metastasis of gastric cancer

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Objective:To establish a positive feedback circuit triggered by Reg4 and investigates its signiifcance in peritoneal metastasis of gastric cancer.Methods: Reg4 expression was detected in gastric cancer samples by immunohistochemistry staining. Reg4 overexpressed and knocked down cells were used to investigate its biological function. Activation of EGFR pathway and promotion of Reg4 were evaluated upon EGFR ligand stimulation. Mass spectrometry was performed to identify Reg4 receptor. ADAM phosphorylation and EGFR ligand shedding was detected after upstream manipulation. Possible downstream effectors were investigated by PCR array.Results:Expression of Reg4 was higher in gastric cancer tissues. Reg4 enhanced prometastatic abilities of gastric cancer cells. EGFR ligand was able to induce Reg4 expression through sequential EGFR pathway activation. Reg4 receptor was identified by mass spectrometry. ADAM phosphorylation and EGFR ligand shedding were enhanced after Reg4 overexpression. PCR array showed several promising downstream effectors.Conclusion:Reg4 is able to trigger a positive feedback regulatory circuit that promotes peritoneal metastasis of gastric cancer.

  15. CTLA-4 promotes Foxp3 induction and regulatory T cell accumulation in the intestinal lamina propria.

    Science.gov (United States)

    Barnes, M J; Griseri, T; Johnson, A M F; Young, W; Powrie, F; Izcue, A

    2013-03-01

    Thymic induction of CD4(+)Foxp3(+) regulatory T (Treg) cells relies on CD28 costimulation and high-affinity T-cell receptor (TCR) signals, whereas Foxp3 (forkhead box P3) induction on activated peripheral CD4(+) T cells is inhibited by these signals. Accordingly, the inhibitory molecule CTLA-4 (cytotoxic T-lymphocyte antigen 4) promoted, but was not essential for CD4(+) T-cell Foxp3 induction in vitro. We show that CTLA-4-deficient cells are equivalent to wild-type cells in the thymic induction of Foxp3 and maintenance of Foxp3 populations in the spleen and mesenteric lymph nodes, but their accumulation in the colon, where Treg cells specific for commensal bacteria accumulate, is impaired. In a T cell-transfer model of colitis, the two known CTLA-4 ligands, B7-1 and B7-2, had largely redundant roles in inducing inflammation and promoting Treg cell function. However, B7-2 proved more efficient than B7-1 in inducing Foxp3 in vitro and in vivo. Our data reveal an unappreciated role for CTLA-4 in establishing the Foxp3(+) compartment in the intestine. PMID:22910217

  16. Enhancing Brain Pregnenolone May Protect Cannabis Intoxication but Should Not Be Considered as an Anti-addiction Therapeutic: Hypothesizing Dopaminergic Blockade and Promoting Anti- Reward

    Directory of Open Access Journals (Sweden)

    Kenneth Blum

    2015-02-01

    Full Text Available Many US states now embrace the medical and recreational use of Cannabis. Changes in the laws have heightened interest and encouraged research into both cannabinoid products and the potential harms of Cannabis use, addiction, and intoxication. Some research into those harms will be reviewed here and misgivings about the use of Pregnenolone, to treat cannabis addiction and intoxication explained. Pregnenolone considered the inactive precursor of all steroid hormones, has recently been shown to protect the brain from Cannabis intoxication. The major active ingredient of Cannabis sativa (marijuana, Δ9-tetrahydrocannabinol (THC enhances Pregnenolone synthesis in the brain via stimulation of the type-1 cannabinoid (CB1 receptor. This steroid has been shown to inhibit the activity of the CB1 receptor thereby reducing many of the effects of THC. While this mechanism seems correct, in our opinion, Vallee et al., incorrectly suggest that blocking CB1 receptors could open unforeseen approaches to the treatment of cannabis intoxication and addiction. In this hypothesis, we caution the scientific community that, other CB1 receptor blockers, such as, Rimonabant (SR141718 have been pulled off the market in Europe. In addition, CB1 receptor blockers were rejected by the FDA due to mood changes including suicide ideation. Blocking CB1 receptors would result in reduced neuronal release of Dopamine by disinhibition of GABA signaling. Longterm blockade of cannabinoid receptors could occur with raising Pregnenolone brain levels, may induce a hypodopaminergic state, and lead to aberrant substance and nonsubstance (behavioral addictions.

  17. Functional promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor specific methylation

    OpenAIRE

    Hanafusa, Tadashi; Shinji, Toshiyuki; Shiraha, Hidenori; Nouso, Kazuhiro; Iwasaki, Yoshiaki; Yumoto, Eichiro; Ono, Toshiro; Koide, Norio

    2005-01-01

    Background: Insulin-like growth factor binding protein (IGFBP)-3 functions as a carrier of insulinlikegrowth factors (IGFs) in circulation and a mediator of the growth suppression signal in cells. There are two reported p53 regulatory regions in the IGFBP3 gene; one upstream of the promoter and one intronic. We previously reported a hot spot of promoter hypermethylation of IGFBP-3 inhuman hepatocellular carcinomas and derivative cell lines. As the hot spot locates at the putative upstream p53...

  18. Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance.

    Science.gov (United States)

    Soroosh, Pejman; Doherty, Taylor A; Duan, Wei; Mehta, Amit Kumar; Choi, Heonsik; Adams, Yan Fei; Mikulski, Zbigniew; Khorram, Naseem; Rosenthal, Peter; Broide, David H; Croft, Michael

    2013-04-01

    Airway tolerance is the usual outcome of inhalation of harmless antigens. Although T cell deletion and anergy are likely components of tolerogenic mechanisms in the lung, increasing evidence indicates that antigen-specific regulatory T cells (inducible Treg cells [iTreg cells]) that express Foxp3 are also critical. Several lung antigen-presenting cells have been suggested to contribute to tolerance, including alveolar macrophages (MØs), classical dendritic cells (DCs), and plasmacytoid DCs, but whether these possess the attributes required to directly promote the development of Foxp3(+) iTreg cells is unclear. Here, we show that lung-resident tissue MØs coexpress TGF-β and retinal dehydrogenases (RALDH1 and RALDH 2) under steady-state conditions and that their sampling of harmless airborne antigen and presentation to antigen-specific CD4 T cells resulted in the generation of Foxp3(+) Treg cells. Treg cell induction in this model depended on both TGF-β and retinoic acid. Transfer of the antigen-pulsed tissue MØs into the airways correspondingly prevented the development of asthmatic lung inflammation upon subsequent challenge with antigen. Moreover, exposure of lung tissue MØs to allergens suppressed their ability to generate iTreg cells coincident with blocking airway tolerance. Suppression of Treg cell generation required proteases and TLR-mediated signals. Therefore, lung-resident tissue MØs have regulatory functions, and strategies to target these cells might hold promise for prevention or treatment of allergic asthma. PMID:23547101

  19. Trichostatin A Promotes the Generation and Suppressive Functions of Regulatory T Cells

    Directory of Open Access Journals (Sweden)

    Cristian Doñas

    2013-01-01

    Full Text Available Regulatory T cells are a specific subset of lymphocytes that suppress immune responses and play a crucial role in the maintenance of self-tolerance. They can be generated in the thymus as well as in the periphery through differentiation of naïve CD4+ T cells. The forkhead box P3 transcription factor (Foxp3 is a crucial molecule regulating the generation and function of Tregs. Here we show that the foxp3 gene promoter becomes hyperacetylated in in vitro differentiated Tregs compared to naïve CD4+ T cells. We also show that the histone deacetylase inhibitor TSA stimulated the in vitro differentiation of naïve CD4+ T cells into Tregs and that this induction was accompanied by a global increase in histone H3 acetylation. Importantly, we also demonstrated that Tregs generated in the presence of TSA have phenotypical and functional differences from the Tregs generated in the absence of TSA. Thus, TSA-generated Tregs showed increased suppressive activities, which could potentially be explained by a mechanism involving the ectonucleotidases CD39 and CD73. Our data show that TSA could potentially be used to enhance the differentiation and suppressive function of CD4+Foxp3+ Treg cells.

  20. MeCP2 enforces Foxp3 expression to promote regulatory T cells' resilience to inflammation.

    Science.gov (United States)

    Li, Chaoran; Jiang, Shan; Liu, Si-Qi; Lykken, Erik; Zhao, Lin-tao; Sevilla, Jose; Zhu, Bo; Li, Qi-Jing

    2014-07-01

    Forkhead box P3(+) (Foxp3(+)) regulatory T cells (Tregs) are crucial for peripheral tolerance. During inflammation, steady Foxp3 expression in Tregs is essential for maintaining their lineage identity and suppressive function. However, the molecular machinery governing Tregs' resilience to inflammation-induced Foxp3 destabilization remains elusive. Here, we demonstrate that methyl-CpG binding protein 2 (MeCP2), an eminent epigenetic regulator known primarily as the etiological factor of Rett syndrome, is critical to sustain Foxp3 expression in Tregs during inflammation. In response to inflammatory stimuli, MeCP2 is specifically recruited to the Conserved Non-Coding sequence 2 region of the foxp3 locus, where it collaborates with cAMP responsive element binding protein 1 to promote local histone H3 acetylation, thereby counteracting inflammation-induced epigenetic silencing of foxp3. Consequently, Treg-specific deletion of MeCP2 causes spontaneous immune activation in mice and failure in protection against autoimmunity. Furthermore, we demonstrate that Foxp3 expression in MeCP2-deficient Tregs diminishes with time, resulting in their failure to suppress effector T-cell-mediated colitis. Thus, MeCP2 serves as a critical safeguard that confers Tregs with resilience against inflammation. PMID:24958888

  1. MeCP2 enforces Foxp3 expression to promote regulatory T cells’ resilience to inflammation

    Science.gov (United States)

    Li, Chaoran; Jiang, Shan; Liu, Si-Qi; Lykken, Erik; Zhao, Lin-tao; Sevilla, Jose; Zhu, Bo; Li, Qi-Jing

    2014-01-01

    Forkhead box P3+ (Foxp3+) regulatory T cells (Tregs) are crucial for peripheral tolerance. During inflammation, steady Foxp3 expression in Tregs is essential for maintaining their lineage identity and suppressive function. However, the molecular machinery governing Tregs’ resilience to inflammation-induced Foxp3 destabilization remains elusive. Here, we demonstrate that methyl-CpG binding protein 2 (MeCP2), an eminent epigenetic regulator known primarily as the etiological factor of Rett syndrome, is critical to sustain Foxp3 expression in Tregs during inflammation. In response to inflammatory stimuli, MeCP2 is specifically recruited to the Conserved Non-Coding sequence 2 region of the foxp3 locus, where it collaborates with cAMP responsive element binding protein 1 to promote local histone H3 acetylation, thereby counteracting inflammation-induced epigenetic silencing of foxp3. Consequently, Treg-specific deletion of MeCP2 causes spontaneous immune activation in mice and failure in protection against autoimmunity. Furthermore, we demonstrate that Foxp3 expression in MeCP2-deficient Tregs diminishes with time, resulting in their failure to suppress effector T-cell–mediated colitis. Thus, MeCP2 serves as a critical safeguard that confers Tregs with resilience against inflammation. PMID:24958888

  2. Human in vitro induced T regulatory cells and memory T cells share common demethylation of specific FOXP3 promoter region

    OpenAIRE

    Bégin, Philippe; Schulze, Janika; Baron, Udo; Olek, Sven; Rebecca N Bauer; Passerini, Laura; Baccheta, Rosa; Nadeau, Kari C.

    2015-01-01

    Background The FOXP3 gene is the master regulator for T regulatory cells and is under tight DNA methylation control at the Treg specific demethylated region (TSDR) in its first intron. This said, methylation of its promoter region, the significance of which is unknown, has also been associated with various immune-related disease states such as asthma, food allergy, auto-immunity and cancer. Here, we used induced T regulatory cells (iTreg) as a target cell population to identify candidate hypo...

  3. A Regulatory Focus Perspective on Eating Behavior: How Prevention and Promotion Focus Relates to Emotional, External, and Restrained Eating

    Directory of Open Access Journals (Sweden)

    Stefan ePfattheicher

    2014-11-01

    Full Text Available By applying regulatory focus theory (RFT to the context of eating behavior, the present research examines the relations between individual differences in the two motivational orientations as conceptualized in RFT, that is, prevention-focused and promotion-focused self-regulation and emotional, external, and restrained eating. Building on a representative study conducted in the Netherlands (N = 4,230, it is documented that individual differences in prevention focus are positively related to emotional eating whereas negligible associations are found in regards to external and restrained eating. Individual differences in promotion focus are positively related to external eating whereas negligible associations are found in regards to emotional and restrained eating. In relating RFT to different eating styles we were able to document significant relations of basic self-regulatory orientations with regard to essential daily behavior associated with health and well-being. The implications for changing eating styles are discussed.

  4. FANTOM4 EdgeExpressDB: an integrated database of promoters, genes, microRNAs, expression dynamics and regulatory interactions

    OpenAIRE

    Severin, J.; Waterhouse, A. M.; Kawaji, H.; Lassmann, T.; van Nimwegen, E; Balwierz, P. J.; de Hoon, M. J. L.; Hume, D A; Carninci, P.; Hayashizaki, Y.; Suzuki, H.; Daub, C.O.; Forrest, A. R. R.

    2009-01-01

    EdgeExpressDB is a novel database and set of interfaces for interpreting biological networks and comparing large high-throughput expression datasets that requires minimal development for new data types and search patterns. The FANTOM4 EdgeExpress database http://fantom.gsc.riken.jp/4/edgeexpress summarizes gene expression patterns in the context of alternative promoter structures and regulatory transcription factors and microRNAs using intuitive gene-centric and sub-network views. This is an ...

  5. A regulatory focus perspective on eating behavior: how prevention and promotion focus relates to emotional, external, and restrained eating

    OpenAIRE

    Pfattheicher, Stefan; Sassenrath, Claudia

    2014-01-01

    By applying regulatory focus theory (RFT) to the context of eating behavior, the present research examines the relations between individual differences in the two motivational orientations as conceptualized in RFT, that is, prevention-focused and promotion-focused self-regulation and emotional, external, and restrained eating. Building on a representative study conducted in the Netherlands (N = 4,230), it is documented that individual differences in prevention focus are positively related to ...

  6. CD27 Agonism Plus PD-1 Blockade Recapitulates CD4+ T-cell Help in Therapeutic Anticancer Vaccination.

    Science.gov (United States)

    Ahrends, Tomasz; Bąbała, Nikolina; Xiao, Yanling; Yagita, Hideo; van Eenennaam, Hans; Borst, Jannie

    2016-05-15

    While showing promise, vaccination strategies to treat cancer require further optimization. Likely barriers to efficacy involve cancer-associated immunosuppression and peripheral tolerance, which limit the generation of effective vaccine-specific cytotoxic T lymphocytes (CTL). Because CD4(+) T cells improve CTL responsiveness, next-generation vaccines include helper epitopes. Here, we demonstrate in mice how CD4(+) T-cell help optimizes the CTL response to a clinically relevant DNA vaccine engineered to combat human papillomavirus-expressing tumors. Inclusion of tumor-unrelated helper epitopes greatly increased CTL priming, effector, and memory T-cell programming. CD4(+) T-cell help optimized the CTL response in all these aspects via CD27/CD70 costimulation. Notably, administration of an agonistic CD27 antibody could largely replace helper epitopes in promoting primary and memory CTL responses, acting directly on CD8(+) T cells. CD27 agonism improved efficacy of the vaccine without helper epitopes, more so than combined PD-1 and CTLA-4 blockade. Combining CD27 agonism with CTLA-4 blockade improved vaccine-induced CTL priming and tumor infiltration, but only combination with PD-1 blockade was effective at eradicating tumors, thereby fully recapitulating the effect of CD4(+) T-cell help on vaccine efficacy. PD-1 blockade alone did not affect CTL priming or tumor infiltration, so these results implied that it cooperated with CD4(+) T-cell help by alleviating immune suppression against CTL in the tumor. Helper epitope inclusion or CD27 agonism did not stimulate regulatory T cells, and vaccine efficacy was also improved by CD27 agonism in the presence of CD4(+) T-cell help. Our findings provide a preclinical rationale to apply CD27 agonist antibodies, either alone or combined with PD-1 blockade, to improve the therapeutic efficacy of cancer vaccines and immunotherapy generally. Cancer Res; 76(10); 2921-31. ©2016 AACR. PMID:27020860

  7. Prediction of conserved regulatory elements in promoter regions of the cattle genome

    Science.gov (United States)

    Cross-species DNA sequence comparison is the primary approach to discover regulatory elements by identifying highly conserved sequences due to evolutionary constraints. Previously, we reported that a systematic approach, combining position-specific weight matrixes (JASPAR) and phylogenetic footprint...

  8. Systematic identification of conserved regulatory elements in upstream promoter regions of the cattle genome

    Science.gov (United States)

    Cross-species DNA sequence comparison is the primary approach to discover regulatory elements by identifying highly conserved sequences due to evolutionary constraints. Previously, we reported that a systematic approach, combining position-specific weight matrixes (JASPAR) and phylogenetic footprint...

  9. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4⁺ T cells to T-regulatory cells.

    Science.gov (United States)

    Olkhanud, Purevdorj B; Damdinsuren, Bazarragchaa; Bodogai, Monica; Gress, Ronald E; Sen, Ranjan; Wejksza, Katarzyna; Malchinkhuu, Enkhzol; Wersto, Robert P; Biragyn, Arya

    2011-05-15

    Pulmonary metastasis of breast cancer requires recruitment and expansion of T-regulatory cells (Treg) that promote escape from host protective immune cells. However, it remains unclear precisely how tumors recruit Tregs to support metastatic growth. Here we report the mechanistic involvement of a unique and previously undescribed subset of regulatory B cells. These cells, designated tumor-evoked Bregs (tBreg), phenotypically resemble activated but poorly proliferative mature B2 cells (CD19(+) CD25(High) CD69(High)) that express constitutively active Stat3 and B7-H1(High) CD81(High) CD86(High) CD62L(Low) IgM(Int). Our studies with the mouse 4T1 model of breast cancer indicate that the primary role of tBregs in lung metastases is to induce TGF-β-dependent conversion of FoxP3(+) Tregs from resting CD4(+) T cells. In the absence of tBregs, 4T1 tumors cannot metastasize into the lungs efficiently due to poor Treg conversion. Our findings have important clinical implications, as they suggest that tBregs must be controlled to interrupt the initiation of a key cancer-induced immunosuppressive event that is critical to support cancer metastasis. PMID:21444674

  10. Unusual 5'-regulatory structure and regulation of the murine Mlc1 gene: Lack of promoter-specific functional elements

    Directory of Open Access Journals (Sweden)

    Darja Henseler

    2011-10-01

    Full Text Available Normal 0 21 false false false MicrosoftInternetExplorer4 The MLC1 gene is involved in an autosomal recessive neurological disorder, megalencephalic leucoencephalopathy with subcortical cysts (MLC, which is characterized by macrocephaly during the first year of life and swollen white matter (leucoencephaly. Variants of MLC1 have also been associated with psychiatric disorders such as schizophrenia, major depression and bipolar disorder. Currently, little is known about the encoded protein (MLC1. Judging from its similarity to other known proteins, it may serve as a trans-membrane transporter. However, the function of the encoded protein and its gene regulation has not been investigated successfully so far. We investigated the 5’ region of the murine Mlc1 with respect to regulatory elements for gene expression. A promoter search and an in silico analysis were conducted. Luciferase reporter gene constructs with potential promoter regions were created to study promoter activity in vitro. We found two alternative first exons for the murine Mlc1 but were not able to detect any promoter activity for the investigated reporter gene constructs in different cell lines, thus pointing to the presence of essential cis-acting elements far outside of the region. In silico analysis indicated an uncommon promoter structure for Mlc1, with CCAAT-boxes representing the only noticeable elements.

  11. The dynamics of effector T cells and Foxp3+ regulatory T cells in the promotion and regulation of autoimmune encephalitis

    OpenAIRE

    Korn, Thomas; Anderson, Ana C.; Bettelli, Estelle; Oukka, Mohamed

    2007-01-01

    The Th1/Th2 paradigm of T helper cell subsets had to be revised when IL-17 producing T cells (Th17) were identified as a distinct T helper cell lineage. Th17 cells are very efficient inducers of tissue inflammation and crucial initiators of organ specific autoimmunity. Whereas Th17 cells promote autoimmune tissue inflammation, Foxp3+ regulatory T cells (T-reg) are necessary and sufficient to prevent autoimmunity throughout the life span of an individual. Here, we review recent findings of how...

  12. Building promoter aware transcriptional regulatory networks using siRNA perturbation and deepCAGE

    DEFF Research Database (Denmark)

    Vitezic, Morana; Lassmann, Timo; Forrest, Alistair R R;

    2010-01-01

    Perturbation and time-course data sets, in combination with computational approaches, can be used to infer transcriptional regulatory networks which ultimately govern the developmental pathways and responses of cells. Here, we individually knocked down the four transcription factors PU.1, IRF8, MYB...

  13. Functional promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor specific methylation

    International Nuclear Information System (INIS)

    Insulin-like growth factor binding protein (IGFBP)-3 functions as a carrier of insulin-like growth factors (IGFs) in circulation and a mediator of the growth suppression signal in cells. There are two reported p53 regulatory regions in the IGFBP3 gene; one upstream of the promoter and one intronic. We previously reported a hot spot of promoter hypermethylation of IGFBP-3 in human hepatocellular carcinomas and derivative cell lines. As the hot spot locates at the putative upstream p53 consensus sequences, these p53 consensus sequences are really functional is a question to be answered. In this study, we examined the p53 consensus sequences upstream of the IGFBP-3 promoter for the p53 induced expression of IGFBP-3. Deletion, mutagenesis, and methylation constructs of IGFBP-3 promoter were assessed in the human hepatoblastoma cell line HepG2 for promoter activity. Deletions and mutations of these sequences completely abolished the expression of IGFBP-3 in the presence of p53 overexpression. In vitro methylation of these p53 consensus sequences also suppressed IGFBP-3 expression. In contrast, the expression of IGFBP-3 was not affected in the absence of p53 overexpression. Further, we observed by electrophoresis mobility shift assay that p53 binding to the promoter region was diminished when methylated. From these observations, we conclude that four out of eleven p53 consensus sequences upstream of the IGFBP-3 promoter are essential for the p53 induced expression of IGFBP-3, and hypermethylation of these sequences selectively suppresses p53 induced IGFBP-3 expression in HepG2 cells

  14. Functional promoter upstream p53 regulatory sequence of IGFBP3 that is silenced by tumor specific methylation

    Directory of Open Access Journals (Sweden)

    Yumoto Eichiro

    2005-01-01

    Full Text Available Abstract Background Insulin-like growth factor binding protein (IGFBP-3 functions as a carrier of insulin-like growth factors (IGFs in circulation and a mediator of the growth suppression signal in cells. There are two reported p53 regulatory regions in the IGFBP3 gene; one upstream of the promoter and one intronic. We previously reported a hot spot of promoter hypermethylation of IGFBP-3 in human hepatocellular carcinomas and derivative cell lines. As the hot spot locates at the putative upstream p53 consensus sequences, these p53 consensus sequences are really functional is a question to be answered. Methods In this study, we examined the p53 consensus sequences upstream of the IGFBP-3 promoter for the p53 induced expression of IGFBP-3. Deletion, mutagenesis, and methylation constructs of IGFBP-3 promoter were assessed in the human hepatoblastoma cell line HepG2 for promoter activity. Results Deletions and mutations of these sequences completely abolished the expression of IGFBP-3 in the presence of p53 overexpression. In vitro methylation of these p53 consensus sequences also suppressed IGFBP-3 expression. In contrast, the expression of IGFBP-3 was not affected in the absence of p53 overexpression. Further, we observed by electrophoresis mobility shift assay that p53 binding to the promoter region was diminished when methylated. Conclusion From these observations, we conclude that four out of eleven p53 consensus sequences upstream of the IGFBP-3 promoter are essential for the p53 induced expression of IGFBP-3, and hypermethylation of these sequences selectively suppresses p53 induced IGFBP-3 expression in HepG2 cells.

  15. Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy

    OpenAIRE

    Bos, Paula D.; Plitas, George; Rudra, Dipayan; Lee, Sue Y.; Rudensky, Alexander Y.

    2013-01-01

    Rational combinatorial therapeutic strategies have proven beneficial for the management of cancer. Recent success of checkpoint blockade in highly immunogenic tumors has renewed interest in immunotherapy. Regulatory T (T reg) cells densely populate solid tumors, which may promote progression through suppressing anti-tumor immune responses. We investigated the role of T reg cells in murine mammary carcinogenesis using an orthotopic, polyoma middle-T antigen-driven model in Foxp3 DTR knockin mi...

  16. Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance

    OpenAIRE

    Soroosh, Pejman; Doherty, Taylor A.; Duan, Wei; Mehta, Amit Kumar; Choi, Heonsik; Adams, Yan Fei; Mikulski, Zbigniew; Khorram, Naseem; Rosenthal, Peter; Broide, David H.; Croft, Michael

    2013-01-01

    Airway tolerance is the usual outcome of inhalation of harmless antigens. Although T cell deletion and anergy are likely components of tolerogenic mechanisms in the lung, increasing evidence indicates that antigen-specific regulatory T cells (inducible Treg cells [iTreg cells]) that express Foxp3 are also critical. Several lung antigen-presenting cells have been suggested to contribute to tolerance, including alveolar macrophages (MØs), classical dendritic cells (DCs), and plasmacytoid DCs, b...

  17. In vivo promoter analysis on refeeding response of hepatic sterol regulatory element-binding protein-1c expression

    International Nuclear Information System (INIS)

    Sterol regulatory element-binding protein (SREBP)-1c is the master regulator of lipogenic gene expression in liver. The mRNA abundance of SREBP-1c is markedly induced when animals are refed after starvation, although the regulatory mechanism is so far unknown. To investigate the mechanism of refeeding response of SREBP-1c gene expression in vivo, we generated a transgenic mouse model that carries 2.2 kb promoter region fused to the luciferase reporter gene. These transgenic mice exhibited refeeding responses of the reporter in liver and adipose tissues with extents essentially identical to those of endogenous SREBP-1c mRNA. The same results were obtained from experiments using adenovirus-mediated SREBP-1c-promoter-luciferase fusion gene transduction to liver. These data demonstrate that the regulation of SREBP-1c gene expression is at the transcription level, and that the 2.2 kb 5'-flanking region is sufficient for this regulation. Moreover, when these transgenic or adenovirus-infected mice were placed on insulin-depleted state by streptozotocin treatment, the reporter expression was upregulated as strongly as in control mice, demonstrating that this regulation is not dominated by serum insulin level. These mice are the first models to provide the mechanistic insight into the transcriptional regulation of SREBP-1c gene in vivo

  18. The RFA regulatory sequence-binding protein in the promoter of prostate-specific antigen gene

    Institute of Scientific and Technical Information of China (English)

    CHEN; Weiwen; (陈蔚文); ZHANG; Jianye; (张建业); Charles; Y; F; Young; ZHANG; Lianying; (张莲英); CHEN; Liucun; (陈留存); ZHAO; Jian; (赵健)

    2003-01-01

    To assure what sequence associated with the androgen regulation, a 15 bp region at the upstream of the ARE of prostate-specific antigen (PSA) promoter, termed RFA, was found indispensable for androgen receptor (AR)-mediated transactivation of PSA promoter. In transfection and CAT assays, some nucleotides substitution in RFA could significantly decrease the androgen inducibility for PSA promoter. The in vitro DNA binding assay demonstrated that RFA bound specifically with some non-receptor protein factors in prostate cell nucleus, but the mutant type of RFA lost this ability, so RFA might be a novel accessory cis-element. The RFA-binding proteins were isolated and purified by affinity chromatography using RFA probes. SDS-PAGE and preliminary protein identification showed these proteins possessed sequence high homology with multifunctional protein heterogeneous nuclear ribonucleoprotein A1, A2 (hnRNP A1, A2). RFA-binding proteins possibly cooperate with AR-mediated transactivation for PSA promoter as coactivator. The study results will facilitate further understanding the mechanism and tissue specificity of PSA promoter.

  19. Mbd2 Promotes Foxp3 Demethylation and T-Regulatory-Cell Function

    OpenAIRE

    Wang, Liqing; Liu, Yujie; Han, Rongxiang; Ulf H Beier; Thomas, Rajan M.; Wells, Andrew D.; Hancock, Wayne W.

    2013-01-01

    Use of Foxp3-positive (Foxp3+) T-regulatory (Treg) cells as potential cellular therapy in patients with autoimmunity, or post-stem cell or -organ transplantation, requires a sound understanding of the transcriptional regulation of Foxp3. Conserved CpG dinucleotides in the Treg-specific demethylation region (TSDR) upstream of Foxp3 are demethylated only in stable, thymus-derived Foxp3+ Treg cells. Since methyl-binding domain (Mbd) proteins recruit histone-modifying and chromatin-remodeling com...

  20. Regulatory polymorphisms in the bovine Ankyrin 1 gene promoter are associated with tenderness and intramuscular fat content

    Directory of Open Access Journals (Sweden)

    Sweeney Torres

    2010-12-01

    Full Text Available Abstract Background Recent QTL and gene expression studies have highlighted ankyrins as positional and functional candidate genes for meat quality. Our objective was to characterise the promoter region of the bovine ankyrin 1 gene and to test polymorphisms for association with sensory and technological meat quality measures. Results Seven novel promoter SNPs were identified in a 1.11 kb region of the ankyrin 1 promoter in Angus, Charolais and Limousin bulls (n = 15 per breed as well as 141 crossbred beef animals for which meat quality data was available. Eighteen haplotypes were inferred with significant breed variation in haplotype frequencies. The five most frequent SNPs and the four most frequent haplotypes were subsequently tested for association with sensory and technological measures of meat quality in the crossbred population. SNP1, SNP3 and SNP4 (which were subsequently designated regulatory SNPs and SNP5 were associated with traits that contribute to sensorial and technological measurements of tenderness and texture; Haplotype 1 and haplotype 4 were oppositely correlated with traits contributing to tenderness (P Conclusion The conclusion from this study is that alleles defining haplotypes 2 and 4 could usefully contribute to marker SNP panels used to select individuals with improved IMF/juiciness or tenderness in a genome-assisted selection framework.

  1. Regulatory polymorphisms in the bovine Ankyrin 1 gene promoter are associated with tenderness and intra-muscular fat content

    LENUS (Irish Health Repository)

    Aslan, Ozlem

    2010-12-15

    Abstract Background Recent QTL and gene expression studies have highlighted ankyrins as positional and functional candidate genes for meat quality. Our objective was to characterise the promoter region of the bovine ankyrin 1 gene and to test polymorphisms for association with sensory and technological meat quality measures. Results Seven novel promoter SNPs were identified in a 1.11 kb region of the ankyrin 1 promoter in Angus, Charolais and Limousin bulls (n = 15 per breed) as well as 141 crossbred beef animals for which meat quality data was available. Eighteen haplotypes were inferred with significant breed variation in haplotype frequencies. The five most frequent SNPs and the four most frequent haplotypes were subsequently tested for association with sensory and technological measures of meat quality in the crossbred population. SNP1, SNP3 and SNP4 (which were subsequently designated regulatory SNPs) and SNP5 were associated with traits that contribute to sensorial and technological measurements of tenderness and texture; Haplotype 1 and haplotype 4 were oppositely correlated with traits contributing to tenderness (P < 0.05). While no single SNP was associated with intramuscular fat (IMF), a clear association with increased IMF and juiciness was observed for haplotype 2. Conclusion The conclusion from this study is that alleles defining haplotypes 2 and 4 could usefully contribute to marker SNP panels used to select individuals with improved IMF\\/juiciness or tenderness in a genome-assisted selection framework.

  2. A multistep bioinformatic approach detects putative regulatory elements in gene promoters

    OpenAIRE

    Pizzi Cinzia; Bisognin Andrea; Coppe Alessandro; Bortoluzzi Stefania; Danieli Gian

    2005-01-01

    Abstract Background Searching for approximate patterns in large promoter sequences frequently produces an exceedingly high numbers of results. Our aim was to exploit biological knowledge for definition of a sheltered search space and of appropriate search parameters, in order to develop a method for identification of a tractable number of sequence motifs. Results Novel software (COOP) was developed for extraction of sequence motifs, based on clustering of exact or approximate patterns accordi...

  3. Promoter regulatory domain identification of cassava starch synthase IIb gene in transgenic tobacco.

    Science.gov (United States)

    Guan, Zhihui; Chen, Xin; Xie, Hairong; Wang, Wenquan

    2016-05-01

    Soluble starch synthase is a key enzyme in the starch biosynthesis pathway, and its enzyme activity significantly influences starch components in cassava storage root. However, studies on the regulation mechanism of soluble starch synthase gene are rare. In this study, we cloned the 5' flanking sequence of the MeSSIIb gene and predicted the distribution of cis-elements. The region from -453 to -1 was considered the primary core promoter by the quantitative detection of GUS activity in transgenic tobacco plants containing 5' truncated promoters fused with the GUS gene. Analysis results clarified that the region from -531 to -454 significantly repressed promoter activity. The region from -453 to -388 was a repressive domain of ethylene, and some unknown drought responsive cis-elements were located in the region from -387 to -1. These findings will provide useful information on the functional assay and transcriptional regulation mechanisms of the MeSSIIb gene. PMID:26919397

  4. IDO expressing fibroblasts promote the expansion of antigen specific regulatory T cells.

    Science.gov (United States)

    Curran, Terry-Ann; Jalili, Reza Baradar; Farrokhi, Ali; Ghahary, Aziz

    2014-01-01

    Regulatory CD4(+)CD25(+)Foxp3(+) T cells (Tregs) can be induced and expanded by dendritic cells (DCs) in the presence of the enzyme indoleamine 2,3-dioxygenase (IDO). Here we report that a possible alternative to DCs are IDO expressing dermal fibroblasts (DFs), which are easier to isolate and sustain in culture compared to DCs. When mouse splenocytes were co-cultured with IDO expressing DFs, a significant increase in frequency and the number of Tregs was found compared to those of control group (13.16%±1.8 vs. 5.53%±1.2, pa subset of Tregs which can be used to generate antigen-specific immune tolerance. PMID:23891282

  5. Using Patient Avatars to Promote Health Data Sharing Applications: Perspectives and Regulatory Challenges.

    Science.gov (United States)

    Dahi, Alan; Forgó, Nikolaus; Jensen, Sarah; Stauch, Marc

    2016-04-01

    The potential of ICT to address problems in modern healthcare is considerable, and an ICT-driven revolution in healthcare appears imminent. Such developments maybe viewed largely in positive terms. Thus they should result in enhanced treatment and care options, empowering patients--including by permitting greater self-management of illness outside hospital, while offering economic benefits and costs savings over traditional healthcare provision. However, the new possibilities also present manifold risks, such as of data breaches, encroachments on subject autonomy, as well as of other harms. This article considers some of the key regulatory challenges against the background of the progress of the current EU Commission-sponsored 'MyHealthAvatar' project. PMID:27228685

  6. Type-dependent irreversible stochastic spin models for genetic regulatory networks at the level of promotion-inhibition circuitry

    Science.gov (United States)

    Mendonça, J. Ricardo G.; de Oliveira, Mário J.

    2015-12-01

    We describe an approach to model genetic regulatory networks at the level of promotion-inhibition circuitry through a class of stochastic spin models that includes spatial and temporal density fluctuations in a natural way. The formalism can be viewed as an agent-based model formalism with agent behaviour ruled by a classical spin-like pseudo-Hamiltonian playing the role of a local, individual objective function. A particular but otherwise generally applicable choice for the microscopic transition rates of the models also makes them of independent interest. To illustrate the formalism, we investigate (by Monte Carlo simulations) some stationary state properties of the repressilator, a synthetic three-gene network of transcriptional regulators that possesses oscillatory behaviour.

  7. Do regulatory mechanisms promote competition and mitigate market power? Evidence from Spanish electricity market

    International Nuclear Information System (INIS)

    This paper estimates the relationships between bidding quantities, marginal cost and market power measures in the Spanish wholesale electricity market for two different regulatory periods: 2002–2005 and 2006–2007. Using panel econometric techniques we find differences in the impacts on bidding strategies for both periods. Hence, the marginal cost and the market power measures affect bid and net quantities. The market power measures also suggest that the coefficient is consistently positive and highly significant for both periods. Moreover, the market power and marginal costs have mixed effects according to the models proposed for both periods. In addition, our results point to the effectiveness of the different effects of mitigating the market power in the Spanish electricity market. For the 2006–2007 period, the proposed causal relationships are partially validated by the cointegration results, which assumes there is a significant causality between the Lerner Index and the marginal cost. - Highlights: • Competition and regulation in the Spanish electricity market. • Net supplier and net demander behavior in the spot market. • Panel cointegration methods used: FMOLS, PMG, MG, DFE and DOLS. • The price cap regulation is effective in mitigating market power. • Market power and marginal cost have positive effects on bidding strategies

  8. Rewiring drug-activated p53-regulatory network from suppressing to promoting tumorigenesis

    Institute of Scientific and Technical Information of China (English)

    Wei Song; Jiguang Wang; Ying Yang; Naihe Jing; Xiangsun Zhang; Luonan Chen; Jiarui Wu

    2012-01-01

    Many of oncogenes and tumor suppressor genes have been found to exert variable and even opposing roles in different kinds of tumors or at different stages of cancer development.Here we showed that tumorigenic potential of mouse embryonic carcinoma P19 cells cultured in adherent plates (attached-P19-cells) was suppressed by a chemotherapeutic agent,5-aza-2'-deoxycytidine (ZdCyd),whereas the higher pro-tumorigenicity of P19 cells growing in suspension (detached-P19-cells) was generated by the ZdCyd treatment.Surprisingly,p53 activity was highly up-regulated by ZdCyd in both growing conditions.By our developed computational approaches,we revealed that there was a significant enrichment of apoptotic pathways in the ZdCyd-induced p53-dominant gene-regulatory network in attached P19 cells,whereas the pro-survival genes were significantly enriched in the ZdCyd-induced p53 network in detached P19 cells.The protein-protein interaction network of the ZdCyd-treated detached P19 cells was significantly different from that of ZdCyd-treated attached P19 cells.On the other hand,inhibition of pS3 expression by siRNA suppressed the ZdCyd-induced tumorigenesis of detached P19 cells,suggesting that the ZdCyd-activated p53 plays oncogenic function in detached P19 cells.Taken together,these results indicate a context-dependent role for the ZdCyd-activated p53-dominant network in tumorigenesis.

  9. Regulatory T Cells Promote β-Catenin–Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Xiong, Shanshan; Pan, Xiujie; Xu, Long; Yang, Zhihua [Beijing Institute of Radiation Medicine, Beijing (China); Guo, Renfeng [Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan (United States); Gu, Yongqing; Li, Ruoxi; Wang, Qianjun; Xiao, Fengjun; Du, Li; Zhou, Pingkun [Beijing Institute of Radiation Medicine, Beijing (China); Zhu, Maoxiang, E-mail: zhumx@nic.bmi.ac.cn [Beijing Institute of Radiation Medicine, Beijing (China)

    2015-10-01

    Purpose: Radiation-induced pulmonary fibrosis results from thoracic radiation therapy and severely limits radiation therapy approaches. CD4{sup +}CD25{sup +}FoxP3{sup +} regulatory T cells (Tregs) as well as epithelium-to-mesenchyme transition (EMT) cells are involved in pulmonary fibrosis induced by multiple factors. However, the mechanisms of Tregs and EMT cells in irradiation-induced pulmonary fibrosis remain unclear. In the present study, we investigated the influence of Tregs on EMT in radiation-induced pulmonary fibrosis. Methods and Materials: Mice thoraxes were irradiated (20 Gy), and Tregs were depleted by intraperitoneal injection of a monoclonal anti-CD25 antibody 2 hours after irradiation and every 7 days thereafter. Mice were treated on days 3, 7, and 14 and 1, 3, and 6 months post irradiation. The effectiveness of Treg depletion was assayed via flow cytometry. EMT and β-catenin in lung tissues were detected by immunohistochemistry. Tregs isolated from murine spleens were cultured with mouse lung epithelial (MLE) 12 cells, and short interfering RNA (siRNA) knockdown of β-catenin in MLE 12 cells was used to explore the effects of Tregs on EMT and β-catenin via flow cytometry and Western blotting. Results: Anti-CD25 antibody treatment depleted Tregs efficiently, attenuated the process of radiation-induced pulmonary fibrosis, hindered EMT, and reduced β-catenin accumulation in lung epithelial cells in vivo. The coculture of Tregs with irradiated MLE 12 cells showed that Tregs could promote EMT in MLE 12 cells and that the effect of Tregs on EMT was partially abrogated by β-catenin knockdown in vitro. Conclusions: Tregs can promote EMT in accelerating radiation-induced pulmonary fibrosis. This process is partially mediated through β-catenin. Our study suggests a new mechanism for EMT, promoted by Tregs, that accelerates radiation-induced pulmonary fibrosis.

  10. Regulatory T Cells Promote β-Catenin–Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis

    International Nuclear Information System (INIS)

    Purpose: Radiation-induced pulmonary fibrosis results from thoracic radiation therapy and severely limits radiation therapy approaches. CD4+CD25+FoxP3+ regulatory T cells (Tregs) as well as epithelium-to-mesenchyme transition (EMT) cells are involved in pulmonary fibrosis induced by multiple factors. However, the mechanisms of Tregs and EMT cells in irradiation-induced pulmonary fibrosis remain unclear. In the present study, we investigated the influence of Tregs on EMT in radiation-induced pulmonary fibrosis. Methods and Materials: Mice thoraxes were irradiated (20 Gy), and Tregs were depleted by intraperitoneal injection of a monoclonal anti-CD25 antibody 2 hours after irradiation and every 7 days thereafter. Mice were treated on days 3, 7, and 14 and 1, 3, and 6 months post irradiation. The effectiveness of Treg depletion was assayed via flow cytometry. EMT and β-catenin in lung tissues were detected by immunohistochemistry. Tregs isolated from murine spleens were cultured with mouse lung epithelial (MLE) 12 cells, and short interfering RNA (siRNA) knockdown of β-catenin in MLE 12 cells was used to explore the effects of Tregs on EMT and β-catenin via flow cytometry and Western blotting. Results: Anti-CD25 antibody treatment depleted Tregs efficiently, attenuated the process of radiation-induced pulmonary fibrosis, hindered EMT, and reduced β-catenin accumulation in lung epithelial cells in vivo. The coculture of Tregs with irradiated MLE 12 cells showed that Tregs could promote EMT in MLE 12 cells and that the effect of Tregs on EMT was partially abrogated by β-catenin knockdown in vitro. Conclusions: Tregs can promote EMT in accelerating radiation-induced pulmonary fibrosis. This process is partially mediated through β-catenin. Our study suggests a new mechanism for EMT, promoted by Tregs, that accelerates radiation-induced pulmonary fibrosis

  11. PlantPAN: Plant promoter analysis navigator, for identifying combinatorial cis-regulatory elements with distance constraint in plant gene groups

    Directory of Open Access Journals (Sweden)

    Huang Hsien-Da

    2008-11-01

    Full Text Available Abstract Background The elucidation of transcriptional regulation in plant genes is important area of research for plant scientists, following the mapping of various plant genomes, such as A. thaliana, O. sativa and Z. mays. A variety of bioinformatic servers or databases of plant promoters have been established, although most have been focused only on annotating transcription factor binding sites in a single gene and have neglected some important regulatory elements (tandem repeats and CpG/CpNpG islands in promoter regions. Additionally, the combinatorial interaction of transcription factors (TFs is important in regulating the gene group that is associated with the same expression pattern. Therefore, a tool for detecting the co-regulation of transcription factors in a group of gene promoters is required. Results This study develops a database-assisted system, PlantPAN (Plant Promoter Analysis Navigator, for recognizing combinatorial cis-regulatory elements with a distance constraint in sets of plant genes. The system collects the plant transcription factor binding profiles from PLACE, TRANSFAC (public release 7.0, AGRIS, and JASPER databases and allows users to input a group of gene IDs or promoter sequences, enabling the co-occurrence of combinatorial transcription factor binding sites (TFBSs within a defined distance (20 bp to 200 bp to be identified. Furthermore, the new resource enables other regulatory features in a plant promoter, such as CpG/CpNpG islands and tandem repeats, to be displayed. The regulatory elements in the conserved regions of the promoters across homologous genes are detected and presented. Conclusion In addition to providing a user-friendly input/output interface, PlantPAN has numerous advantages in the analysis of a plant promoter. Several case studies have established the effectiveness of PlantPAN. This novel analytical resource is now freely available at http://PlantPAN.mbc.nctu.edu.tw.

  12. Structured Development and Promotion of a Research Field: Hormesis in Biology, Toxicology, and Environmental Regulatory Science.

    Science.gov (United States)

    Mushak, Paul; Elliott, Kevin C

    2015-12-01

    The ability of powerful and well-funded interest groups to steer scientific research in ways that advance their goals has become a significant social concern. This steering ability is increasingly being recognized in the peer-reviewed scientific literature and in findings of deliberative scientific bodies. This paper provides a case study that illustrates some of the major strategies that can be used to structure and advance a controversial research field. It focuses on hormesis, described as a type of dose-response relationship in toxicology and biology showing low-dose stimulation but high-dose inhibition, or the reverse. Hormesis proponents tout its significance, arguing that substances toxic at high doses and beneficial at lower doses should be regulated less stringently. We identify five strategies employed by hormesis proponents to foster its acceptance: (1) creating institutions focused on supporting hormesis; (2) developing terminology, study designs, and data interpretations that cast it in a favorable light; (3) using bibliometric techniques and surveys to attract attention; (4) aggressively advocating for the phenomenon and challenging critics; and (5) working with outside interest groups to apply the hormesis phenomenon in the economic and political spheres. We also suggest a number of oversight strategies that can be implemented to help promote credible and socially responsible research in cases like this one. PMID:26775877

  13. BET-independent MLV-based Vectors Target Away From Promoters and Regulatory Elements

    Science.gov (United States)

    El Ashkar, Sara; De Rijck, Jan; Demeulemeester, Jonas; Vets, Sofie; Madlala, Paradise; Cermakova, Katerina; Debyser, Zeger; Gijsbers, Rik

    2014-01-01

    Stable integration in the host genome renders murine leukemia virus (MLV)-derived vectors attractive tools for gene therapy. Adverse events in otherwise successful clinical trials caused by proto-oncogene activation due to vector integration hamper their application. MLV and MLV-based vectors integrate near strong enhancers, active promoters, and transcription start sites (TSS) through specific interaction of MLV integrase (IN) with the bromodomain and extra-terminal (BET) family of proteins, accounting for insertional mutagenesis. We identified a BET-interaction motif in the C-terminal tail of MLV IN conserved among gammaretroviruses. By deletion of this motif or a single point mutation (INW390A), BET-independent MLV (BinMLV) were engineered. BinMLV vectors carrying INW390A integrate at wild-type efficiency, with an integration profile that no longer correlates with BET chromatin distribution nor with the traditional markers of MLV integration. In particular, BinMLV vector integration associated less with oncogene TSS compared to the MLV vectors currently used in clinical trials. Together, these findings open perspectives to increase the biosafety of gammaretroviral vectors for gene therapy. PMID:25072693

  14. Promotion

    OpenAIRE

    Alam, Hasan B.

    2013-01-01

    This article gives an overview of the promotion process in an academic medical center. A description of different promotional tracks, tenure and endowed chairs, and the process of submitting an application is provided. Finally, some practical advice about developing skills and attributes that can help with academic growth and promotion is dispensed.

  15. Angiopoietin 2 stimulates TIE2-expressing monocytes to suppress T cell activation and to promote regulatory T cell expansion.

    Science.gov (United States)

    Coffelt, Seth B; Chen, Yung-Yi; Muthana, Munitta; Welford, Abigail F; Tal, Andrea O; Scholz, Alexander; Plate, Karl H; Reiss, Yvonne; Murdoch, Craig; De Palma, Michele; Lewis, Claire E

    2011-04-01

    Angiopoietin 2 (ANGPT2) is a proangiogenic cytokine whose expression is often upregulated by endothelial cells in tumors. Expression of its receptor, TIE2, defines a highly proangiogenic subpopulation of myeloid cells in circulation and tumors called TIE2-expressing monocytes/macrophages (TEMs). Genetic depletion of TEMs markedly reduces tumor angiogenesis in various tumor models, emphasizing their essential role in driving tumor progression. Previously, we demonstrated that ANGPT2 augments the expression of various proangiogenic genes, the potent immunosuppressive cytokine, IL-10, and a chemokine for regulatory T cells (Tregs), CCL17 by TEMs in vitro. We now show that TEMs also express higher levels of IL-10 than TIE2(-) macrophages in tumors and that ANGPT2-stimulated release of IL-10 by TEMs suppresses T cell proliferation, increases the ratio of CD4(+) T cells to CD8(+) T cells, and promotes the expansion of CD4(+)CD25(high)FOXP3(+) Tregs. Furthermore, syngeneic murine tumors expressing high levels of ANGPT2 contained not only high numbers of TEMs but also increased numbers of Tregs, whereas genetic depletion of tumor TEMs resulted in a marked reduction in the frequency of Tregs in tumors. Taken together, our data suggest that ANGPT2-stimulated TEMs represent a novel, potent immunosuppressive force in tumors. PMID:21368233

  16. Schisandrin B inhibits Th1/Th17 differentiation and promotes regulatory T cell expansion in mouse lymphocytes.

    Science.gov (United States)

    Chen, Zhaoyang; Guo, Min; Song, Guohua; Gao, Jiping; Zhang, Yinhong; Jing, Zhijie; Liu, Tianfu; Dong, Chuan

    2016-06-01

    Schisandrin B (Sch-B), the most abundant active ingredient of the fruit of Schisandra chinensis, has been proposed to have antioxidant, anti-tumor and anti-inflammatory effects. The present study was undertaken to investigate the effect of Sch-B on differentiation of T helper cells (Th). Using mouse splenic lymphocytes stimulated with concanavalin A (Con A) in vitro and ex vivo as inflammation models, we found that Sch-B significantly inhibited secretion of Th1 and Th17 related cytokines, such as IFN-γ and IL-17. In addition, we found that Sch-B suppressed the differentiation of naive CD4+ T cells into Th1 and Th17 cells, while promoted their differentiation into the regulatory T cells (Treg) in vitro. We further found that Sch-B suppressed transcription of Th1-related T-box transcription factor, T-bet, and Th17-related transcription factor, retinoid related orphan receptor gamma t (RORγt), while enhanced transcription of Treg-related transcription factor forkhead box protein 3 (Foxp3) in naive CD4+ T cells under Th cell polarization conditions. Furthermore, the effect of Sch-B on the T cell differentiation was abrogated by heme oxygenase-1 (HO-1) inhibitor zinc protoporphyrin. Taken together, we conclude that Sch-B can modulate differentiation of naïve CD4+ T cells into specific lineages of effector cells, which may have potential benefits for treatment of autoimmune diseases. PMID:27085037

  17. Regulatory CD4+CD25+ T Cells Dampen Inflammatory Disease in Murine Mycoplasma Pneumonia and Promote IL-17 and IFN-γ Responses

    Science.gov (United States)

    Odeh, Adam N.; Simecka, Jerry W.

    2016-01-01

    Mycoplasmas cause respiratory diseases characterized by persistent infection and chronic airway inflammation. Mycoplasma lung disease is immunopathologic, with CD4+ Th cells determining both disease severity and resistance to infection. Th2 cell responses promote immunopathology, while Th1 cells confer resistance to infection. However, regulatory CD4+ T cells may also have a role in the pathogenesis of mycoplasma respiratory diseases. We hypothesized Treg cells control the severity of the inflammatory lesions and may also promote persistence of infection. To examine this, BALB/c mice were depleted of CD25+ cells, and had increased disease severity due to Mycoplasma pulmonis infection. Increases in mycoplasma antibody responses and lymphocyte infiltration into lungs also occurred after CD25+ cell depletion. CD4+CD25+ regulatory T cells promoted IFN-γ and IL-17 mycoplasma-specific CD4+ T cell responses in vitro and in vivo, while dampening IL-13+ Th responses. Neither IL-10 nor TGF-ß expression was detected in CD4+CD25+ T cells from lymph nodes. Thus, a regulatory T cell population plays an important role in controlling damaging immune responses in mycoplasma respiratory disease but does not contribute to persistence of infection. It appears that a regulatory T cell population preferentially dampens Th2 cell-mediated inflammatory responses to mycoplasma through a mechanism independent of IL-10 or TGF-ß characteristic of “classic” Treg cells. PMID:27175511

  18. Decoding a signature-based model of transcription cofactor recruitment dictated by cardinal cis-regulatory elements in proximal promoter regions.

    Directory of Open Access Journals (Sweden)

    Christopher Benner

    2013-11-01

    Full Text Available Genome-wide maps of DNase I hypersensitive sites (DHSs reveal that most human promoters contain perpetually active cis-regulatory elements between -150 bp and +50 bp (-150/+50 bp relative to the transcription start site (TSS. Transcription factors (TFs recruit cofactors (chromatin remodelers, histone/protein-modifying enzymes, and scaffold proteins to these elements in order to organize the local chromatin structure and coordinate the balance of post-translational modifications nearby, contributing to the overall regulation of transcription. However, the rules of TF-mediated cofactor recruitment to the -150/+50 bp promoter regions remain poorly understood. Here, we provide evidence for a general model in which a series of cis-regulatory elements (here termed 'cardinal' motifs prefer acting individually, rather than in fixed combinations, within the -150/+50 bp regions to recruit TFs that dictate cofactor signatures distinctive of specific promoter subsets. Subsequently, human promoters can be subclassified based on the presence of cardinal elements and their associated cofactor signatures. In this study, furthermore, we have focused on promoters containing the nuclear respiratory factor 1 (NRF1 motif as the cardinal cis-regulatory element and have identified the pervasive association of NRF1 with the cofactor lysine-specific demethylase 1 (LSD1/KDM1A. This signature might be distinctive of promoters regulating nuclear-encoded mitochondrial and other particular genes in at least some cells. Together, we propose that decoding a signature-based, expanded model of control at proximal promoter regions should lead to a better understanding of coordinated regulation of gene transcription.

  19. DHEA promotes osteoblast differentiation by regulating the expression of osteoblast-related genes and Foxp3(+) regulatory T cells.

    Science.gov (United States)

    Qiu, Xuemin; Gui, Yuyan; Xu, Yingping; Li, Dajin; Wang, Ling

    2015-10-01

    Several studies have reported that dehydroepiandrosterone (DHEA) promotes osteoblast proliferation and inhibits osteoblast apoptosis and that DHEA inhibits osteoclast maturation. However, whether DHEA regulates osteoblast differentiation remains unclear. The present study first examined the effect of DHEA on bone morphology in vivo. DHEA was found to increase bone volume (BV), bone mineral density (BMD), and the number of trabeculae in bone (Th.N) and it was found to decrease trabecular spacing in bone (Th.sp) in ovariectomized (OVX) mice. Next, the effect of DHEA on osteoblast differentiation was examined in vitro and osteoblastogenesis-related marker genes, such as Runx2, Osterix, Collagen1, and Osteocalcin, were also detected. DHEA increased osteoblast production in mesenchymal stem cells (MSCs) cultured in osteoblastogenic medium, and DHEA increased the expression of Runx2 and osterix, thereby increasing the expression of osteocalcin and collagen1. Immune cells and bone interact, so changes in immune cells were detected in vivo. DHEA increased the number of Foxp3(+) regulatory T cells (Tregs) in the spleen but it did not affect CTLA-4 or IL-10. When MSCs were treated with DHEA in the presence of Tregs, alkaline phosphatase (ALP) activity increased. Osteoblasts and adipocytes are both generated by MSCs. If osteoblast differentiation increases, adipocyte differentiation will decrease, and the reverse also holds true. DHEA was found to increase the number of adipocytes in osteoblastogenic medium but it had no effect on the number of adipocytes and expression of PPARγ mRNA in adipogenic medium. This finding suggests that osteoblasts may be involved in adipocyte production. In conclusion, the current results suggest that DHEA can improve postmenopausal osteoporosis (PMO) by up-regulating osteoblast differentiation via the up-regulation of the expression of osteoblastogenesis-related genes and via an increase in Foxp3(+) Tregs. PMID:26559023

  20. BAFF promotes regulatory T-cell apoptosis and blocks cytokine production by activating B cells in primary biliary cirrhosis

    International Nuclear Information System (INIS)

    Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology. A number of questions regarding its etiology are unclear. CD4+CD25+ regulatory T cells (Tregs) play a critical role in self-tolerance and, for unknown reasons, their relative number is reduced in PBC patients. B-cell-activating factor (BAFF) is a key survival factor during B-cell maturation and its concentration is increased in peripheral blood of PBC patients. It has been reported that activated B cells inhibit Treg cell proliferation and there are no BAFF receptors on Tregs. Therefore, we speculated that excessive BAFF may result in Treg reduction via B cells. To prove our hypothesis, we isolated Tregs and B cells from PBC and healthy donors. BAFF and IgM concentrations were then analyzed by ELISA and CD40, CD80, CD86, IL-10, and TGF-β expression in B cells and Tregs were measured by flow cytometry. BAFF up-regulated CD40, CD80, CD86, and IgM expression in B cells. However, BAFF had no direct effect on Treg cell apoptosis and cytokine secretion. Nonetheless, we observed that BAFF-activated B cells could induce Treg cell apoptosis and reduce IL-10 and TGF-β expression. We also showed that BAFF-activated CD4+ T cells had no effect on Treg apoptosis. Furthermore, we verified that bezafibrate, a hypolipidemic drug, can inhibit BAFF-induced Treg cell apoptosis. In conclusion, BAFF promotes Treg cell apoptosis and inhibits cytokine production by activating B cells in PBC patients. The results of this study suggest that inhibition of BAFF activation is a strategy for PBC treatment

  1. BAFF promotes regulatory T-cell apoptosis and blocks cytokine production by activating B cells in primary biliary cirrhosis

    Directory of Open Access Journals (Sweden)

    Bo Zhang

    2013-10-01

    Full Text Available Primary biliary cirrhosis (PBC is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology. A number of questions regarding its etiology are unclear. CD4+CD25+ regulatory T cells (Tregs play a critical role in self-tolerance and, for unknown reasons, their relative number is reduced in PBC patients. B-cell-activating factor (BAFF is a key survival factor during B-cell maturation and its concentration is increased in peripheral blood of PBC patients. It has been reported that activated B cells inhibit Treg cell proliferation and there are no BAFF receptors on Tregs. Therefore, we speculated that excessive BAFF may result in Treg reduction via B cells. To prove our hypothesis, we isolated Tregs and B cells from PBC and healthy donors. BAFF and IgM concentrations were then analyzed by ELISA and CD40, CD80, CD86, IL-10, and TGF-β expression in B cells and Tregs were measured by flow cytometry. BAFF up-regulated CD40, CD80, CD86, and IgM expression in B cells. However, BAFF had no direct effect on Treg cell apoptosis and cytokine secretion. Nonetheless, we observed that BAFF-activated B cells could induce Treg cell apoptosis and reduce IL-10 and TGF-β expression. We also showed that BAFF-activated CD4+ T cells had no effect on Treg apoptosis. Furthermore, we verified that bezafibrate, a hypolipidemic drug, can inhibit BAFF-induced Treg cell apoptosis. In conclusion, BAFF promotes Treg cell apoptosis and inhibits cytokine production by activating B cells in PBC patients. The results of this study suggest that inhibition of BAFF activation is a strategy for PBC treatment.

  2. BAFF promotes regulatory T-cell apoptosis and blocks cytokine production by activating B cells in primary biliary cirrhosis

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Bo; Hu, Mintao [Department of Hepatology, Wuxi Infectious Diseases Hospital, Wuxi, Jiangsu (China); Zhang, Peng [Nanjing Medical University, Nanjing, Jiangsu (China); Cao, Hong [Department of Hepatology, Wuxi Infectious Diseases Hospital, Wuxi, Jiangsu (China); Wang, Yongzhen [The Second Hospital of Nanjing, Nanjing, Jiangsu (China); Wang, Zheng; Su, Tingting [Department of Hepatology, Wuxi Infectious Diseases Hospital, Wuxi, Jiangsu (China)

    2013-05-10

    Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology. A number of questions regarding its etiology are unclear. CD4+CD25+ regulatory T cells (Tregs) play a critical role in self-tolerance and, for unknown reasons, their relative number is reduced in PBC patients. B-cell-activating factor (BAFF) is a key survival factor during B-cell maturation and its concentration is increased in peripheral blood of PBC patients. It has been reported that activated B cells inhibit Treg cell proliferation and there are no BAFF receptors on Tregs. Therefore, we speculated that excessive BAFF may result in Treg reduction via B cells. To prove our hypothesis, we isolated Tregs and B cells from PBC and healthy donors. BAFF and IgM concentrations were then analyzed by ELISA and CD40, CD80, CD86, IL-10, and TGF-β expression in B cells and Tregs were measured by flow cytometry. BAFF up-regulated CD40, CD80, CD86, and IgM expression in B cells. However, BAFF had no direct effect on Treg cell apoptosis and cytokine secretion. Nonetheless, we observed that BAFF-activated B cells could induce Treg cell apoptosis and reduce IL-10 and TGF-β expression. We also showed that BAFF-activated CD4+ T cells had no effect on Treg apoptosis. Furthermore, we verified that bezafibrate, a hypolipidemic drug, can inhibit BAFF-induced Treg cell apoptosis. In conclusion, BAFF promotes Treg cell apoptosis and inhibits cytokine production by activating B cells in PBC patients. The results of this study suggest that inhibition of BAFF activation is a strategy for PBC treatment.

  3. BAFF promotes regulatory T-cell apoptosis and blocks cytokine production by activating B cells in primary biliary cirrhosis

    Directory of Open Access Journals (Sweden)

    Bo Zhang

    2013-05-01

    Full Text Available Primary biliary cirrhosis (PBC is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology. A number of questions regarding its etiology are unclear. CD4+CD25+ regulatory T cells (Tregs play a critical role in self-tolerance and, for unknown reasons, their relative number is reduced in PBC patients. B-cell-activating factor (BAFF is a key survival factor during B-cell maturation and its concentration is increased in peripheral blood of PBC patients. It has been reported that activated B cells inhibit Treg cell proliferation and there are no BAFF receptors on Tregs. Therefore, we speculated that excessive BAFF may result in Treg reduction via B cells. To prove our hypothesis, we isolated Tregs and B cells from PBC and healthy donors. BAFF and IgM concentrations were then analyzed by ELISA and CD40, CD80, CD86, IL-10, and TGF-β expression in B cells and Tregs were measured by flow cytometry. BAFF up-regulated CD40, CD80, CD86, and IgM expression in B cells. However, BAFF had no direct effect on Treg cell apoptosis and cytokine secretion. Nonetheless, we observed that BAFF-activated B cells could induce Treg cell apoptosis and reduce IL-10 and TGF-β expression. We also showed that BAFF-activated CD4+ T cells had no effect on Treg apoptosis. Furthermore, we verified that bezafibrate, a hypolipidemic drug, can inhibit BAFF-induced Treg cell apoptosis. In conclusion, BAFF promotes Treg cell apoptosis and inhibits cytokine production by activating B cells in PBC patients. The results of this study suggest that inhibition of BAFF activation is a strategy for PBC treatment.

  4. The human fetal placenta promotes tolerance against the semiallogeneic fetus by inducing regulatory T cells and homeostatic M2 macrophages.

    Science.gov (United States)

    Svensson-Arvelund, Judit; Mehta, Ratnesh B; Lindau, Robert; Mirrasekhian, Elahe; Rodriguez-Martinez, Heriberto; Berg, Göran; Lash, Gendie E; Jenmalm, Maria C; Ernerudh, Jan

    2015-02-15

    A successful pregnancy requires that the maternal immune system is instructed to a state of tolerance to avoid rejection of the semiallogeneic fetal-placental unit. Although increasing evidence supports that decidual (uterine) macrophages and regulatory T cells (Tregs) are key regulators of fetal tolerance, it is not known how these tolerogenic leukocytes are induced. In this article, we show that the human fetal placenta itself, mainly through trophoblast cells, is able to induce homeostatic M2 macrophages and Tregs. Placental-derived M-CSF and IL-10 induced macrophages that shared the CD14(+)CD163(+)CD206(+)CD209(+) phenotype of decidual macrophages and produced IL-10 and CCL18 but not IL-12 or IL-23. Placental tissue also induced the expansion of CD25(high)CD127(low)Foxp3(+) Tregs in parallel with increased IL-10 production, whereas production of IFN-γ (Th1), IL-13 (Th2), and IL-17 (Th17) was not induced. Tregs expressed the suppressive markers CTLA-4 and CD39, were functionally suppressive, and were induced, in part, by IL-10, TGF-β, and TRAIL. Placental-derived factors also limited excessive Th cell activation, as shown by decreased HLA-DR expression and reduced secretion of Th1-, Th2-, and Th17-associated cytokines. Thus, our data indicate that the fetal placenta has a central role in promoting the homeostatic environment necessary for successful pregnancy. These findings have implications for immune-mediated pregnancy complications, as well as for our general understanding of tissue-induced tolerance. PMID:25560409

  5. Promoter analysis reveals cis-regulatory motifs associated with the expression of the WRKY transcription factor CrWRKY1 in Catharanthus roseus.

    Science.gov (United States)

    Yang, Zhirong; Patra, Barunava; Li, Runzhi; Pattanaik, Sitakanta; Yuan, Ling

    2013-12-01

    WRKY transcription factors (TFs) are emerging as an important group of regulators of plant secondary metabolism. However, the cis-regulatory elements associated with their regulation have not been well characterized. We have previously demonstrated that CrWRKY1, a member of subgroup III of the WRKY TF family, regulates biosynthesis of terpenoid indole alkaloids in the ornamental and medicinal plant, Catharanthus roseus. Here, we report the isolation and functional characterization of the CrWRKY1 promoter. In silico analysis of the promoter sequence reveals the presence of several potential TF binding motifs, indicating the involvement of additional TFs in the regulation of the TIA pathway. The CrWRKY1 promoter can drive the expression of a β-glucuronidase (GUS) reporter gene in native (C. roseus protoplasts and transgenic hairy roots) and heterologous (transgenic tobacco seedlings) systems. Analysis of 5'- or 3'-end deletions indicates that the sequence located between positions -140 to -93 bp and -3 to +113 bp, relative to the transcription start site, is critical for promoter activity. Mutation analysis shows that two overlapping as-1 elements and a CT-rich motif contribute significantly to promoter activity. The CrWRKY1 promoter is induced in response to methyl jasmonate (MJ) treatment and the promoter region between -230 and -93 bp contains a putative MJ-responsive element. The CrWRKY1 promoter can potentially be used as a tool to isolate novel TFs involved in the regulation of the TIA pathway. PMID:23979312

  6. Coulomb-Blockade Oscillations in Semiconductor Nanostructures

    OpenAIRE

    Houten, van, H.; Beenakker, C. W. J.; Staring, A.A.M.

    2005-01-01

    I. Introduction (Preface, Basic properties of semiconductor nanostructures). II. Theory of Coulomb-blockade oscillations (Periodicity of the oscillations, Amplitude and lineshape). III. Experiments on Coulomb-blockade oscillations (Quantum dots, Disordered quantum wires, Relation to earlier work on disordered quantum wires). IV. Quantum Hall effect regime (The Aharonov-Bohm effect in a quantum dot, Coulomb blockade of the Aharonov-Bohm effect, Experiments on quantum dots, Experiments on disor...

  7. Potential biomarker for checkpoint blockade immunotherapy and treatment strategy.

    Science.gov (United States)

    Dong, Zhong-Yi; Wu, Si-Pei; Liao, Ri-Qiang; Huang, Shu-Mei; Wu, Yi-Long

    2016-04-01

    Programmed cell death protein-1 (PD-1) and ligand (PD-L1) provide an important escape mechanism from immune attack, and blockade therapy of these proteins show promising clinical benefits in many types of cancer. PD-L1 can be induced by interferon-gamma (IFN-γ), hypoxia, or toll-like receptor (TLR)-mediated pathways that confer adaptive immune resistance, or upregulated by oncogenic signals leading to constitutive expression and resulting in intrinsic immune resistance. The PD-1/PD-L1 checkpoint blockade, which targets regulatory pathways in T cells to overcome immune resistance, is correlated to PD-L1 expression pattern and the presence of tumor-infiltrating lymphocytes (TILs). Meanwhile, immunogenic mutation loads show significant response to checkpoint blockade, which is probably due to PD-1/L1 status and TIL content. Finally, the clinical strategies to design effective checkpoint-targeting immunotherapies are based on the classification of inducible/constitutive expression of PD-L1 and the presence of TILs. PMID:26779629

  8. A cis-regulatory sequence from a short intergenic region gives rise to a strong microbe-associated molecular pattern-responsive synthetic promoter.

    Science.gov (United States)

    Lehmeyer, Mona; Hanko, Erik K R; Roling, Lena; Gonzalez, Lilian; Wehrs, Maren; Hehl, Reinhard

    2016-06-01

    The high gene density in Arabidopsis thaliana leaves only relatively short intergenic regions for potential cis-regulatory sequences. To learn more about the regulation of genes harbouring only very short upstream intergenic regions, this study investigates a recently identified novel microbe-associated molecular pattern (MAMP)-responsive cis-sequence located within the 101 bp long intergenic region upstream of the At1g13990 gene. It is shown that the cis-regulatory sequence is sufficient for MAMP-responsive reporter gene activity in the context of its native promoter. The 3' UTR of the upstream gene has a quantitative effect on gene expression. In context of a synthetic promoter, the cis-sequence is shown to achieve a strong increase in reporter gene activity as a monomer, dimer and tetramer. Mutation analysis of the cis-sequence determined the specific nucleotides required for gene expression activation. In transgenic A. thaliana the synthetic promoter harbouring a tetramer of the cis-sequence not only drives strong pathogen-responsive reporter gene expression but also shows a high background activity. The results of this study contribute to our understanding how genes with very short upstream intergenic regions are regulated and how these regions can serve as a source for MAMP-responsive cis-sequences for synthetic promoter design. PMID:26833485

  9. Perioperative Nerve Blockade: Clues from the Bench

    Directory of Open Access Journals (Sweden)

    M. R. Suter

    2011-01-01

    Full Text Available Peripheral and neuraxial nerve blockades are widely used in the perioperative period. Their values to diminish acute postoperative pain are established but other important outcomes such as chronic postoperative pain, or newly, cancer recurrence, or infections could also be influenced. The long-term effects of perioperative nerve blockade are still controversial. We will review current knowledge of the effects of blocking peripheral electrical activity in different animal models of pain. We will first go over the mechanisms of pain development and evaluate which types of fibers are activated after an injury. In the light of experimental results, we will propose some hypotheses explaining the mitigated results obtained in clinical studies on chronic postoperative pain. Finally, we will discuss three major disadvantages of the current blockade: the absence of blockade of myelinated fibers, the inappropriate duration of blockade, and the existence of activity-independent mechanisms.

  10. The Spinocerebellar Ataxia 12 Gene Product and Protein Phosphatase 2A Regulatory Subunit Bβ2 Antagonizes Neuronal Survival by Promoting Mitochondrial Fission*S⃞

    OpenAIRE

    Dagda, Ruben K.; Merrill, Ronald A.; Cribbs, J. Thomas; Chen, Yucui; Hell, Johannes W; Usachev, Yuriy M.; Strack, Stefan

    2008-01-01

    The neurodegenerative disorder spinocerebellar ataxia 12 (SCA12) is caused by CAG repeat expansion in the non-coding region of the PPP2R2B gene. PPP2R2B encodes Bβ1 and Bβ2, alternatively spliced and neuron-specific regulatory subunits of the protein phosphatase 2A (PP2A) holoenzyme. We show here that in PC12 cells and hippocampal neurons, cell stressors induced a rapid translocation of PP2A/Bβ2 to mitochondria to promote apoptosis. Conversely, silencing of PP2A/Bβ2 pr...

  11. Erythropoietin blockade inhibits the induction of tumor angiogenesis and progression.

    Directory of Open Access Journals (Sweden)

    Matthew E Hardee

    Full Text Available BACKGROUND: The induction of tumor angiogenesis, a pathologic process critical for tumor progression, is mediated by multiple regulatory factors released by tumor and host cells. We investigated the role of the hematopoietic cytokine erythropoietin as an angiogenic factor that modulates tumor progression. METHODOLOGY/PRINCIPAL FINDINGS: Fluorescently-labeled rodent mammary carcinoma cells were injected into dorsal skin-fold window chambers in mice, an angiogenesis model that allows direct, non-invasive, serial visualization and real-time assessment of tumor cells and neovascularization simultaneously using intravital microscopy and computerized image analysis during the initial stages of tumorigenesis. Erythropoietin or its antagonist proteins were co-injected with tumor cells into window chambers. In vivo growth of cells engineered to stably express a constitutively active erythropoietin receptor EPOR-R129C or the erythropoietin antagonist R103A-EPO were analyzed in window chambers and in the mammary fat pads of athymic nude mice. Co-injection of erythropoietin with tumor cells or expression of EPOR-R129C in tumor cells significantly stimulated tumor neovascularization and growth in window chambers. Co-injection of erythropoietin antagonist proteins (soluble EPOR or anti-EPO antibody with tumor cells or stable expression of antagonist R103A-EPO protein secreted from tumor cells inhibited angiogenesis and impaired tumor growth. In orthotopic tumor xenograft studies, EPOR-R129C expression significantly promoted tumor growth associated with increased expression of Ki67 proliferation antigen, enhanced microvessel density, decreased tumor hypoxia, and increased phosphorylation of extracellular-regulated kinases ERK1/2. R103A-EPO antagonist expression in mammary carcinoma cells was associated with near-complete disruption of primary tumor formation in the mammary fat pad. CONCLUSIONS/SIGNIFICANCE: These data indicate that erythropoietin is an

  12. Identification of autoreactive CD4+ and CD8+ T cell subsets resistant to PD-1 pathway blockade#

    OpenAIRE

    Pauken, Kristen E.; Nelson, Christine E; Martinov, Tijana; Spanier, Justin A.; Heffernan, James R; Sahli, Nathanael L; Quarnstrom, Clare F; Osum, Kevin C; Schenkel, Jason M.; Jenkins, Marc K.; Blazar, Bruce R; Vezys, Vaiva; Fife, Brian T.

    2015-01-01

    Programmed Death (PD)-1 promotes T cell tolerance. Despite therapeutically targeting this pathway for chronic infections and tumors, little is known about how different T cell subsets are affected during blockade. We examined PD-1/PD-L1 regulation of self-antigen-specific CD4 and CD8 T cells in autoimmune susceptible models. PD-L1 blockade increased insulin-specific effector CD4 T cells in Type 1 Diabetes. However, anergic islet-specific CD4 T cells were resistant to PD-L1 blockade. Additiona...

  13. Prostaglandin E2 blockade enhances the pulmonary anti-Cryptococcus neoformans immune reaction via the induction of TLR-4.

    Science.gov (United States)

    Shen, Liyun; Liu, Ying

    2015-09-01

    The present study aimed to explore whether the inhibition of prostaglandin E2 enhances pulmonary anti-Cryptococcus neoformans immunity. Lung colony forming unit (CFU) assays demonstrated that the cryptococcal infection was dramatically depressed in mice given EP2 and EP4 or single EP antagonist treatment compared to the untreated wild type mice (pEP4 blockade (pEP4 blockade were strongly M2 polarized, whereas the alveolar macrophages in wild type mice with EP2 and EP4 blockade were M1 polarized. In conclusion, the blockade of EP2 and EP4 promotes mouse survival after cryptococcus infection by promoting the production of cytokines via TLR4, as well as the enhanced M1 polarization of alveolar macrophages. PMID:26122137

  14. The CArG boxes in the promoter of the Arabidopsis floral organ identity gene APETALA3 mediate diverse regulatory effects.

    Science.gov (United States)

    Tilly, J J; Allen, D W; Jack, T

    1998-05-01

    APETALA3 is a MADS box gene required for normal development of the petals and stamens in the Arabidopsis flower. Studies in yeast, mammals and plants demonstrate that MADS domain transcription factors bind with high affinity to a consensus sequence called the CArG box. The APETALA3 promoter contains three close matches to the consensus CArG box sequence. To gain insights into the APETALA3 regulatory circuitry, we have analyzed the APETALA3 promoter using AP3::uidA(GUS) fusions. 496 base pairs of APETALA3 promoter sequence 5' to the transcriptional start directs GUS activity in the same temporal and spatial expression pattern as the APETALA3 RNA and protein in wild-type flowers. A synthetic promoter consisting of three tandem repeats of a 143 base pair sequence directs reporter gene activity exclusively to petals and stamens in the flower. We have analyzed the role of the CArG boxes by site-specific mutagenesis and find that the three CArG boxes mediate discrete regulatory effects. Mutations in CArG1 result in a decrease in reporter expression suggesting that CArG1 is the binding site for a positively acting factor or factors. Mutations in CArG2 result in a decrease in reporter expression in petals, but the expression pattern in stamens is unchanged. By contrast, mutations in CArG3 result in an increase in the level of reporter gene activity during early floral stages suggesting that CArG3 is the binding site for a negatively acting factor. PMID:9521903

  15. An ATF/CREB site is the major regulatory element in the human herpesvirus 6 DNA polymerase promoter.

    OpenAIRE

    Agulnick, A D; Thompson, J R; Ricciardi, R P

    1994-01-01

    Human herpesvirus 6 (HHV-6) is a recently described T-cell pathogen whose medical relevance and molecular biology are just beginning to be addressed. As a first look at the regulation of viral genes, control of the HHV-6 DNA polymerase promoter was examined. Polymerase gene transcription in HHV-6-infected cells was found to initiate from a single site located 115 bases upstream of the translation start codon. A polymerase promoter-chloramphenicol acetyltransferase reporter gene construct fail...

  16. The intrinsic topological information of the wild-type and of up-promoter mutations of the Saccharomyces cerevisiae alcohol dehydrogenase II regulatory region.

    Science.gov (United States)

    Della Seta, F; Camilloni, G; Venditti, S; Di Mauro, E

    1988-11-01

    A 569-base pair fragment encompassing the upstream regulatory region, the RNA initiation sites, and the initial part of the coding region of the Saccharomyces cerevisiae alcohol dehydrogenase II gene has been analyzed for the presence of sites which undergo conformational modification under torsional stress. Fine mapping of P1 and S1 endonuclease-sensitive sites was obtained on single topoisomers produced by in vitro ligation. It was shown that the upstream activator sequence, the TATA sequence, a region directly upstream to the RNA initiation sites, and several positions in the first segment of the transcribed region change conformation as a function of the applied torsional stress in a precisely coordinate fashion. The superhelical density optima for this coordinate modifications have been determined. Analysis of the conformational changes of the promoter sequence in several naturally occurring (Young, E. T., Williamson, V. M., Taguchi, A., Smith, M., Sledziewski, L., Russel, D., Osterman, J., Denis, C., Cox, D., and Beier, D., (1982) in Genetic Engineering of Microorganisms for Chemicals (Hollander, A., De Moss, R. D., Kaplan, S., Konisky, J., Savage, D., and Wolle, R. S., eds) pp. 335-361, Plenum Publishing Corp., New York) up-promoter constitutive mutants was performed. This analysis has shown that the conformation of functionally relevant sites changes as a function of sequence mutations that have taken place elsewhere; this shows that the conformational behavior of the whole promoter region is linked and suggests transmission in cis of topological effects in RNA polymerase II promoters. PMID:3053683

  17. Characterization of the regulatory region of the zebrafish Prep1.1 gene: analogies to the promoter of the human PREP1.

    Directory of Open Access Journals (Sweden)

    Elisa Bernardi

    Full Text Available Prep1 is a developmentally essential TALE class homeodomain transcription factor. In zebrafish and mouse, Prep1 is already ubiquitously expressed at the earliest stages of development, with important tissue-specific peculiarities. The Prep1 gene in mouse is developmentally essential and has haploinsufficient tumor suppressor activity [1]. We have determined the human Prep1 transcription start site (TSS by primer extension analysis and identified, within 20 bp, the transcription start region (TSR of the zebrafish Prep1.1 promoter. The functions of the zebrafish 5' upstream sequences were analyzed both by transient transfections in Hela Cells and by injection in zebrafish embryos. This analysis revealed a complex promoter with regulatory sequences extending up to -1.8, possibly -5.0 Kb, responsible for tissue specific expression. Moreover, the first intron contains a conserved tissue-specific enhancer both in zebrafish and in human cells. Finally, a two nucleotides mutation of an EGR-1 site, conserved in all species including human and zebrafish and located at a short distance from the TSS, destroyed the promoter activity of the -5.0 Kb promoter. A transgenic fish expressing GFP under the -1.8 Kb zebrafish promoter/enhancer co-expressed GFP and endogenous Prep1.1 during embryonic development. In the adult fish, GFP was expressed in hematopoietic regions like the kidney, in agreement with the essential function of Prep1 in mouse hematopoiesis. Sequence comparison showed conservation from man to fish of the sequences around the TSS, within the first intron enhancer. Moreover, about 40% of the sequences spread throughout the 5 Kbof the zebrafish promoter are concentrated in the -3 to -5 Kb of the human upstream region.

  18. 1,25-Dihydroxyvitamin D3 and its analog TX527 promote a stable regulatory T cell phenotype in T cells from type 1 diabetes patients.

    Science.gov (United States)

    Van Belle, Tom L; Vanherwegen, An-Sofie; Feyaerts, Dorien; De Clercq, Pierre; Verstuyf, Annemieke; Korf, Hannelie; Gysemans, Conny; Mathieu, Chantal

    2014-01-01

    The emergence of regulatory T cells (Tregs) as central mediators of peripheral tolerance in the immune system has led to an important area of clinical investigation to target these cells for the treatment of autoimmune diseases such as type 1 diabetes. We have demonstrated earlier that in vitro treatment of T cells from healthy individuals with TX527, a low-calcemic analog of bioactive vitamin D, can promote a CD4+ CD25high CD127low regulatory profile and imprint a migratory signature specific for homing to sites of inflammation. Towards clinical application of vitamin D-induced Tregs in autologous adoptive immunotherapy for type 1 diabetes, we show here that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and TX527 similarly imprint T cells from type 1 diabetes patients with a CD4+ CD25high CD127low regulatory profile, modulate surface expression of skin- and inflammation-homing receptors, and increase expression of CTLA-4 and OX-40. Also, 1,25(OH)2D3 and TX527 treatment inhibit the production of effector cytokines IFN-γ, IL-9, and IL-17. Importantly, 1,25(OH)2D3 and TX527 promote the induction of IL-10-producing CD4+ CD25high CD127low T cells with a stable phenotype and the functional capacity to suppress proliferation of autologous responder T cells in vitro. These findings warrant additional validation of vitamin D-induced Tregs in view of future autologous adoptive immunotherapy in type 1 diabetes. PMID:25279717

  19. 1,25-Dihydroxyvitamin D3 and its analog TX527 promote a stable regulatory T cell phenotype in T cells from type 1 diabetes patients.

    Directory of Open Access Journals (Sweden)

    Tom L Van Belle

    Full Text Available The emergence of regulatory T cells (Tregs as central mediators of peripheral tolerance in the immune system has led to an important area of clinical investigation to target these cells for the treatment of autoimmune diseases such as type 1 diabetes. We have demonstrated earlier that in vitro treatment of T cells from healthy individuals with TX527, a low-calcemic analog of bioactive vitamin D, can promote a CD4+ CD25high CD127low regulatory profile and imprint a migratory signature specific for homing to sites of inflammation. Towards clinical application of vitamin D-induced Tregs in autologous adoptive immunotherapy for type 1 diabetes, we show here that 1,25-dihydroxyvitamin D3 [1,25(OH2D3] and TX527 similarly imprint T cells from type 1 diabetes patients with a CD4+ CD25high CD127low regulatory profile, modulate surface expression of skin- and inflammation-homing receptors, and increase expression of CTLA-4 and OX-40. Also, 1,25(OH2D3 and TX527 treatment inhibit the production of effector cytokines IFN-γ, IL-9, and IL-17. Importantly, 1,25(OH2D3 and TX527 promote the induction of IL-10-producing CD4+ CD25high CD127low T cells with a stable phenotype and the functional capacity to suppress proliferation of autologous responder T cells in vitro. These findings warrant additional validation of vitamin D-induced Tregs in view of future autologous adoptive immunotherapy in type 1 diabetes.

  20. [The practice guideline 'Neuraxis blockade and anticoagulation'].

    Science.gov (United States)

    De Lange, J J; Van Kleef, J W; Van Everdingen, J J E

    2004-07-31

    In a patient with a coagulation disorder, the administration of a local anaesthetic by means of a needle or via the insertion of a catheter into the epidural space or spinal cavity may lead to bleeding and haematoma formation, with a danger of pressure on the spinal cord or nerve roots. Employing the method of the Dutch Institute for Healthcare (CBO) for the development of practice guidelines, a working group of anaesthesiologists, a haematologist and a hospital chemist have drawn up recommendations for neuraxis blockade in combination with anticoagulant therapy. In patients with a clinically acquired tendency toward increased bleeding, the management is highly dependent on the cause of the bleeding tendency. If the patient uses acetylsalicylic acid or clopidogrel, the medication must be withdrawn at least 10 days before neuraxis blockade is started. Therapy with glycoprotein-IIb/IIIa-receptor antagonists is an absolute contra-indication for neuraxis blockade. In patients who are using coumarin derivatives, neuraxis blockade results in an increased risk of a neuraxial haematoma. The coumarin derivative should then be withdrawn and replaced by a different form of anticoagulation. The use of low-molecular-weight heparin at the usual prophylactic dosage is not a contra-indication for neuraxis blockade and the risk of a neuraxial haematoma following neuraxis blockade is also not increased significantly by the subcutaneous administration of unfractionated heparin. PMID:15366721

  1. Regulatory T cell reprogramming towards a Th2 cell-like lineage impairs oral tolerance and promotes food allergy

    OpenAIRE

    Rivas, Magali Noval; Burton, Oliver T.; Wise, Petra; Charbonnier, Louis-Marie; Georgiev, Peter; Oettgen, Hans C.; Rachid, Rima; Chatila, Talal

    2015-01-01

    Oral immunotherapy has had limited success in establishing tolerance in food allergy, reflecting failure to elicit an effective regulatory T (Treg) cell response. We show that disease-susceptible mice (Il4raF709) with enhanced IL-4 receptor (IL-4R) signaling exhibited STAT6-dependent impaired generation and function of mucosal allergen-specific Treg cells. This failure was associated with the acquisition by Treg cells of T helper 2 (Th2) cell-like phenotype, also found in peripheral blood all...

  2. Hormone-mediated promotion of trichome initiation in plants is conserved but utilizes species- and trichome-specific regulatory mechanisms

    OpenAIRE

    Maes, Lies; Goossens, Alain

    2010-01-01

    Plant trichome initiation is steered by diverse developmental and environmental cues, through molecular mechanisms that remain elusive in most plant species. Using a robust experimental method to investigate the molecular mechanisms by which phytohormones modulate leaf trichome formation, we verified the effect of jasmonates, cytokinins and gibberellins in Arabidopsis (Arabidopsis thaliana). All three phytohormones promoted Arabidopsis trichome initiation, but caused divergent effects on tric...

  3. Analysis of the CCR3 promoter reveals a regulatory region in exon 1 that binds GATA-1

    Directory of Open Access Journals (Sweden)

    Koch Laura E

    2005-04-01

    Full Text Available Abstract Background CC Chemokine Receptor 3 (CCR3, the major chemokine receptor expressed on eosinophils, binds promiscuously to several ligands including eotaxins 1, 2, and 3. Even though the only cells that consistently accumulate following eotaxin administration in vivo are myeloid cells (primarily eosinophils, other cell types have recently been shown to express CCR3. It is therefore important to elucidate the molecular mechanisms regulating receptor expression. Results In order to define regions responsible for CCR3 transcription, a DNAse hypersensitive site was identified in the vicinity of exon 1. Coupled with our previous data implicating exon 1 in CCR3 transcription, we hypothesized that transcription factors bind to exon-1. Electrophoretic mobility shift analysis revealed that nuclear proteins in eosinophilic cells bound to exon 1. Furthermore, antibody interference and mutation studies demonstrated GATA-1 binding to exon 1. In order to test the 1.6-kb CCR3 promoter element (that includes exon 1 for in vivo function, this region was used to generate transgenic mice that expressed a reporter protein. Strong transgene expression was achieved, with the pattern of expression suggesting a broad acting promoter. Conclusion The transcription factor GATA-1 binds to CCR3 exon 1. The 1.6-kb CCR3 promoter element, that includes exon 1, is a strong promoter in vivo.

  4. A Promoter Polymorphism in the CD59 Complement Regulatory Protein Gene in Donor Lungs Correlates With a Higher Risk for Chronic Rejection After Lung Transplantation.

    Science.gov (United States)

    Budding, K; van de Graaf, E A; Kardol-Hoefnagel, T; Broen, J C A; Kwakkel-van Erp, J M; Oudijk, E-J D; van Kessel, D A; Hack, C E; Otten, H G

    2016-03-01

    Complement activation leads primarily to membrane attack complex formation and subsequent target cell lysis. Protection against self-damage is regulated by complement regulatory proteins, including CD46, CD55, and CD59. Within their promoter regions, single-nucleotide polymorphisms (SNPs) are present that could influence transcription. We analyzed these SNPs and investigated their influence on protein expression levels. A single SNP configuration in the promoter region of CD59 was found correlating with lower CD59 expression on lung endothelial cells (p = 0.016) and monocytes (p = 0.013). Lung endothelial cells with this SNP configuration secreted more profibrotic cytokine IL-6 (p = 0.047) and fibroblast growth factor β (p = 0.036) on exposure to sublytic complement activation than cells with the opposing configuration, whereas monocytes were more susceptible to antibody-mediated complement lysis (p < 0.0001). Analysis of 137 lung transplant donors indicated that this CD59 SNP configuration correlates with impaired long-term survival (p = 0.094) and a significantly higher incidence of bronchiolitis obliterans syndrome (p = 0.046) in the recipient. These findings support a role for complement in the pathogenesis of this posttransplant complication and are the first to show a deleterious association of a donor CD59 promoter polymorphism in lung transplantation. PMID:26517734

  5. Inferring regulatory elements from a whole genome. An analysis of Helicobacter pylori sigma(80) family of promoter signals.

    Science.gov (United States)

    Vanet, A; Marsan, L; Labigne, A; Sagot, M F

    2000-03-24

    Helicobacter pylori is adapted to life in a unique niche, the gastric epithelium of primates. Its promoters may therefore be different from those of other bacteria. Here, we determine motifs possibly involved in the recognition of such promoter sequences by the RNA polymerase using a new motif identification method. An important feature of this method is that the motifs are sought with the least possible assumptions about what they may look like. The method starts by considering the whole genome of H. pylori and attempts to infer directly from it a description for a family of promoters. Thus, this approach differs from searching for such promoters with a previously established description. The two algorithms are based on the idea of inferring motifs by flexibly comparing words in the sequences with an external object, instead of between themselves. The first algorithm infers single motifs, the second a combination of two motifs separated from one another by strictly defined, sterically constrained distances. Besides independently finding motifs known to be present in other bacteria, such as the Shine-Dalgarno sequence and the TATA-box, this approach suggests the existence in H. pylori of a new, combined motif, TTAAGC, followed optimally 21 bp downstream by TATAAT. Between these two motifs, there is in some cases another, TTTTAA or, less frequently, a repetition of TTAAGC separated optimally from the TATA-box by 12 bp. The combined motif TTAAGCx(21+/-2)TATAAT is present with no errors immediately upstream from the only two copies of the ribosomal 23 S-5 S RNA genes in H. pylori, and with one error upstream from the only two copies of the ribosomal 16 S RNA genes. The operons of both ribosomal RNA molecules are strongly expressed, representing an encouraging sign of the pertinence of the motifs found by the algorithms. In 25 cases out of a possible 30, the combined motif is found with no more than three substitutions immediately upstream from ribosomal proteins, or

  6. Mutational characterization of promoter regions recognized by the Salmonella dublin virulence plasmid regulatory protein SpvR.

    OpenAIRE

    Grob, P; Kahn, D.; Guiney, D G

    1997-01-01

    The virulence plasmid-encoded spv regulon is essential for virulence of Salmonella dublin in mice. The spvR gene product belongs to the LysR family of transcriptional regulator proteins. SpvR induces the expression of the spvABCD operon and positively regulates its own expression. DNase I protection analysis with purified SpvR fusion proteins identified SpvR binding sites within the spvA and spvR promoters (P. Grob and D. G. Guiney, J. Bacteriol. 178:1813-1820, 1996). We have used PCR mutagen...

  7. The Escherichia coli regulatory protein OxyR discriminates between methylated and unmethylated states of the phage Mu mom promoter.

    OpenAIRE

    Bölker, M; Kahmann, R

    1989-01-01

    Expression of the phage Mu mom gene is transcriptionally regulated by DNA methylation. Three GATC sites upstream of the mom promoter have to be methylated by the Escherichia coli deoxyadenosine methylase (Dam) to allow initiation of transcription. An E. coli dam strain was mutagenized with Tn5 in an attempt to isolate mutants which allow mom gene expression. Three independent Tn5 mutants were isolated, each mapped to a gene at 89.6 min which we designate momR. The wildtype gene was cloned and...

  8. Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy.

    Science.gov (United States)

    Noval Rivas, Magali; Burton, Oliver T; Wise, Petra; Charbonnier, Louis-Marie; Georgiev, Peter; Oettgen, Hans C; Rachid, Rima; Chatila, Talal A

    2015-03-17

    Oral immunotherapy has had limited success in establishing tolerance in food allergy, reflecting failure to elicit an effective regulatory T (Treg) cell response. We show that disease-susceptible (Il4ra(F709)) mice with enhanced interleukin-4 receptor (IL-4R) signaling exhibited STAT6-dependent impaired generation and function of mucosal allergen-specific Treg cells. This failure was associated with the acquisition by Treg cells of a T helper 2 (Th2)-cell-like phenotype, also found in peripheral-blood allergen-specific Treg cells of food-allergic children. Selective augmentation of IL-4R signaling in Treg cells induced their reprogramming into Th2-like cells and disease susceptibility, whereas Treg-cell-lineage-specific deletion of Il4 and Il13 was protective. IL-4R signaling impaired the capacity of Treg cells to suppress mast cell activation and expansion, which in turn drove Th2 cell reprogramming of Treg cells. Interruption of Th2 cell reprogramming of Treg cells might thus provide candidate therapeutic strategies in food allergy. PMID:25769611

  9. Cytokine Overproduction, T-Cell Activation, and Defective T-Regulatory Functions Promote Nephritis in Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Marco Tucci

    2010-01-01

    Full Text Available Lupus nephritis (LN occurs in more than one-third of patients with systemic lupus erythematosus. Its pathogenesis is mostly attributable to the glomerular deposition of immune complexes and overproduction of T helper- (Th- 1 cytokines. In this context, the high glomerular expression of IL-12 and IL-18 exerts a major pathogenetic role. These cytokines are locally produced by both macrophages and dendritic cells (DCs which attract other inflammatory cells leading to maintenance of the kidney inflammation. However, other populations including T-cells and B-cells are integral for the development and worsening of renal damage. T-cells include many pathogenetic subsets, and the activation of Th-17 in keeping with defective T-regulatory (Treg cell function regards as further event contributing to the glomerular damage. These populations also activate B-cells to produce nephritogenic auto-antibodies. Thus, LN includes a complex pathogenetic mechanism that involves different players and the evaluation of their activity may provide an effective tool for monitoring the onset of the disease.

  10. HLA Class II Antibody Activation of Endothelial Cells Promotes Th17 and Disrupts Regulatory T Lymphocyte Expansion.

    Science.gov (United States)

    Lion, J; Taflin, C; Cross, A R; Robledo-Sarmiento, M; Mariotto, E; Savenay, A; Carmagnat, M; Suberbielle, C; Charron, D; Haziot, A; Glotz, D; Mooney, N

    2016-05-01

    Kidney transplantation is the most successful treatment option for patients with end-stage renal disease, and chronic antibody-mediated rejection is the principal cause of allograft loss. Predictive factors for chronic rejection include high levels of HLA alloantibodies (particularly HLA class II) and activation of graft endothelial cells (ECs). The mechanistic basis for this association is unresolved. We used an experimental model of HLA-DR antibody stimulation of microvascular ECs to examine the mechanisms underlying the association between HLA class II antibodies, EC activation and allograft damage. Activation of ECs with the F(Ab')2 fragment of HLA-DR antibody led to phosphorylation of Akt, ERK and MEK and increased IL-6 production by ECs cocultured with allogeneic peripheral blood mononuclear cells (PBMCs) in an Akt-dependent manner. We previously showed that HLA-DR-expressing ECs induce polarization of Th17 and FoxP3(bright) regulatory T cell (Treg) subsets. Preactivation of ECs with anti-HLA-DR antibody redirected EC allogenicity toward a proinflammatory response by decreasing amplification of functional Treg and by further increasing IL-6-dependent Th17 expansion. Alloimmunized patient serum containing relevant HLA-DR alloantibodies selectively bound and increased EC secretion of IL-6 in cocultures with PBMCs. These data contribute to understanding of potential mechanisms of antibody-mediated endothelial damage independent of complement activation and FcR-expressing effector cells. PMID:26614587

  11. Regulatory role of the sequences downstream from nodD3 P1 promoter of Rhizobium meliloti

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The 660 bp region between nodD3 P1 promoter and the following coding region of Rhizobium meliloti has been studied.This region is designated "downstream sequences".It consists of two potential open reading frames,ORF1 and ORF2.Studies on the role of the downstream sequences on the activity of nodD3 P1 with nod D3(P1)-lacZ fusion show that deletion of the sequences containing ORF2 causes the increase of the activity of the fusion; on the contrary,addition of extra copies of ORF2 markedly decreases the activity of the fusion.These results indicate that the product of ORF2 plays a negative role in the expression of nod D3.

  12. Transfer of regulatory T cells into abortion-prone mice promotes the expansion of uterine mast cells and normalizes early pregnancy angiogenesis.

    Science.gov (United States)

    Woidacki, Katja; Meyer, Nicole; Schumacher, Anne; Goldschmidt, Alexandra; Maurer, Marcus; Zenclussen, Ana Claudia

    2015-01-01

    Implantation of the fertilized egg depends on the coordinated interplay of cells and molecules that prepare the uterus for this important event. In particular, regulatory T cells (Tregs) are key regulators as their ablation hinders implantation by rendering the uterus hostile for the embryo. In addition, the adoptive transfer of Tregs can avoid early abortion in mouse models. However, it is still not defined which mechanisms underlie Treg function during this early period. Cells of the innate immune system have been reported to support implantation, in part by promoting angiogenesis. In particular, uterine mast cells (uMCs) emerge as novel players at the fetal-maternal interface. Here, we studied whether the positive action of Tregs is based on the expansion of uMCs and the promotion of angiogenesis. We observed that abortion-prone mice have insufficient numbers of uMCs that could be corrected by the adoptive transfer of Tregs. This in turn positively influenced the remodeling of spiral arteries and placenta development as well as the levels of soluble fms-like tyrosine kinase 1 (sFlt-1). Our data suggest an interplay between Tregs and uMCs that is relevant for the changes required at the feto-maternal interface for the normal development of pregnancy. PMID:26355667

  13. Antagonism of airway tolerance by endotoxin/lipopolysaccharide through promoting OX40L and suppressing antigen-specific Foxp3+ T regulatory cells.

    Science.gov (United States)

    Duan, Wei; So, Takanori; Croft, Michael

    2008-12-15

    Respiratory exposure to allergens can lead to airway tolerance. Factors that antagonize tolerance mechanisms in the lung might result in susceptibility to diseases such as asthma. We show that inhalation of endotoxin/LPS with Ag prevented airway tolerance and abolished protection from T cell-driven asthmatic lung inflammation. Under conditions leading to tolerance, adaptive Ag-specific CD4(+)Foxp3(+) T regulatory cells (Treg) were generated following exposure to intranasal Ag and outnumbered IL-4- and IFN-gamma-producing CD4 T cells by 100:1 or greater. Inhaled LPS altered the ratio of Treg to IL-4(+) or IFN-gamma(+) T cells by concomitantly suppressing Treg generation and promoting effector T cell generation. LPS induced OX40L expression on dendritic cells and B cells that resulted in a synergistic activity between TLR4 and OX40 signals, leading to production of IL-4, IFN-gamma, and IL-6, which blocked Treg development. Furthermore, inhibiting OX40/OX40L interactions prevented LPS from suppressing tolerance, and resulted in the generation of greater numbers of adaptive Treg. Thus, cooperation between TLR4 and OX40 controls susceptibility to developing airway disease via modulating the balance between adaptive Treg and IL-4(+) or IFN-gamma(+) T cells. Targeting OX40L then has the potential to improve the efficacy of Ag immunotherapy to promote tolerance. PMID:19050285

  14. The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3.

    Science.gov (United States)

    Chen, Zuojia; Barbi, Joseph; Bu, Shurui; Yang, Huang-Yu; Li, Zhiyuan; Gao, Yayi; Jinasena, Dilini; Fu, Juan; Lin, Fang; Chen, Chen; Zhang, Jing; Yu, Ning; Li, Xiangpei; Shan, Zhao; Nie, Jia; Gao, Zhimei; Tian, Hong; Li, Yangyang; Yao, Zhengju; Zheng, Ying; Park, Benjamin V; Pan, Ziyi; Zhang, Jing; Dang, Eric; Li, Zhiguang; Wang, Honglin; Luo, Weibo; Li, Liwu; Semenza, Gregg L; Zheng, Song-Guo; Loser, Karin; Tsun, Andy; Greene, Mark I; Pardoll, Drew M; Pan, Fan; Li, Bin

    2013-08-22

    Regulatory T (Treg) cells suppress inflammatory immune responses and autoimmunity caused by self-reactive T cells. The key Treg cell transcription factor Foxp3 is downregulated during inflammation to allow for the acquisition of effector T cell-like functions. Here, we demonstrate that stress signals elicited by proinflammatory cytokines and lipopolysaccharides lead to the degradation of Foxp3 through the action of the E3 ubiquitin ligase Stub1. Stub1 interacted with Foxp3 to promote its K48-linked polyubiquitination in an Hsp70-dependent manner. Knockdown of endogenous Stub1 or Hsp70 prevented Foxp3 degradation. Furthermore, the overexpression of Stub1 in Treg cells abrogated their ability to suppress inflammatory immune responses in vitro and in vivo and conferred a T-helper-1-cell-like phenotype. Our results demonstrate the critical role of the stress-activated Stub1-Hsp70 complex in promoting Treg cell inactivation, thus providing a potential therapeutic target for the intervention against autoimmune disease, infection, and cancer. PMID:23973223

  15. Blockade of interferon Beta, but not interferon alpha, signaling controls persistent viral infection.

    Science.gov (United States)

    Ng, Cherie T; Sullivan, Brian M; Teijaro, John R; Lee, Andrew M; Welch, Megan; Rice, Stephanie; Sheehan, Kathleen C F; Schreiber, Robert D; Oldstone, Michael B A

    2015-05-13

    Although type I interferon (IFN-I) is thought to be beneficial against microbial infections, persistent viral infections are characterized by high interferon signatures suggesting that IFN-I signaling may promote disease pathogenesis. During persistent lymphocytic choriomeningitis virus (LCMV) infection, IFNα and IFNβ are highly induced early after infection, and blocking IFN-I receptor (IFNAR) signaling promotes virus clearance. We assessed the specific roles of IFNβ versus IFNα in controlling LCMV infection. While blockade of IFNβ alone does not alter early viral dissemination, it is important in determining lymphoid structure, lymphocyte migration, and anti-viral T cell responses that lead to accelerated virus clearance, approximating what occurs during attenuation of IFNAR signaling. Comparatively, blockade of IFNα was not associated with improved viral control, but with early dissemination of virus. Thus, despite their use of the same receptor, IFNβ and IFNα have unique and distinguishable biologic functions, with IFNβ being mainly responsible for promoting viral persistence. PMID:25974304

  16. Perilipin-mediated lipid droplet formation in adipocytes promotes sterol regulatory element-binding protein-1 processing and triacylglyceride accumulation.

    Directory of Open Access Journals (Sweden)

    Yu Takahashi

    Full Text Available Sterol regulatory element-binding protein-1 (SREBP-1 has been thought to be a critical factor that assists adipogenesis. During adipogenesis SREBP-1 stimulates lipogenic gene expression, and peroxisome proliferator-activated receptor γ (PPARγ enhances perilipin (plin gene expression, resulting in generating lipid droplets (LDs to store triacylglycerol (TAG in adipocytes. Plin coats adipocyte LDs and protects them from lipolysis. Here we show in white adipose tissue (WAT of plin-/- mice that nuclear active SREBP-1 and its target gene expression, but not nuclear SREBP-2, significantly decreased on attenuated LD formation. When plin-/- mouse embryonic fibroblasts (MEFs differentiated into adipocytes, attenuated LDs were formed and nuclear SREBP-1 decreased, but enforced plin expression restored them to their original state. Since LDs are largely derived from the endoplasmic reticulum (ER, alterations in the ER cholesterol content were investigated during adipogenesis of 3T3-L1 cells. The ER cholesterol greatly reduced in differentiated adipocytes. The ER cholesterol level in plin-/- WAT was significantly higher than that of wild-type mice, suggesting that increased LD formation caused a change in ER environment along with a decrease in cholesterol. When GFP-SREBP-1 fusion proteins were exogenously expressed in 3T3-L1 cells, a mutant protein lacking the S1P cleavage site was poorly processed during adipogenesis, providing evidence of the increased canonical pathway for SREBP processing in which SREBP-1 is activated by two cleavage enzymes in the Golgi. Therefore, LD biogenesis may create the ER microenvironment favorable for SREBP-1 activation. We describe the novel interplay between LD formation and SREBP-1 activation through a positive feedback loop.

  17. Atomic Fock State Preparation Using Rydberg Blockade

    CERN Document Server

    Ebert, Matthew; Gibbons, Michael; Zhang, Xianli; Saffman, Mark; Walker, Thad G

    2013-01-01

    We use coherent excitation of 3-16 atom ensembles to demonstrate collective Rabi flopping mediated by Rydberg blockade. Using calibrated atom number measurements, we quantitatively confirm the expected $\\sqrt{N}$ Rabi frequency enhancement to within 4%. The resulting atom number distributions are consistent with essentially perfect blockade. We then use collective Rabi $\\pi$ pulses to produce ${\\cal N}=1,2$ atom number Fock states with fidelities of 62% and 48% respectively. The ${\\cal N}=2$ Fock state shows the collective Rabi frequency enhancement without corruption from atom number fluctuations.

  18. Regulatory Promotion of Waste Wood Reused as an Energy Source and the Environmental Concerns about Ash Residue in the Industrial Sector of Taiwan

    Directory of Open Access Journals (Sweden)

    Wen-Tien Tsai

    2012-11-01

    Full Text Available The objective of this paper was to provide a preliminary analysis of the utilization of energy derived from waste wood in Taiwan, a highly industrialized country with a high dependence (over 99% on imported energy. The discussion focuses on the status of waste wood generation and its management over the past decade. Findings show that the quantities of biomass waste collected for reuse purposes in the industrial sectors of Taiwan has exhibited an increasing trend, from about 4000 tons in 2001 to over 52,000 tons in 2010. Although waste wood can be reused as a fuel and raw material for a variety of applications based on regulatory promotion, the most commonly used end use is to directly utilize it as an auxiliary fuel in industrial utilities (e.g., boilers, heaters and furnaces for the purpose of co-firing with coal/fuel oil. The most progressive measure for promoting biomass-to-power is to introduce the feed-in tariff (FIT mechanism according to the Renewable Energy Development Act passed in June 2009. The financial support for biomass power generation has been increasing over the years from 0.070 US$/kWh in 2010 to 0.094 US$/kWh in 2012. On the other hand, the environmental regulations in Taiwan regarding the hazard identification of wood-combusted ash (especially in filter fly-ash and its options for disposal and utilization are further discussed in the paper, suggesting that waste wood impregnated with chromated copper arsenate (CCA and other copper-based preservatives should be excluded from the wood-to-energy system. Finally, some recommendations for promoting wood-to-energy in the near future of Taiwan are addressed.

  19. Combination Immunotherapy with 4-1BBL and CTLA-4 Blockade for the Treatment of Prostate Cancer

    OpenAIRE

    Kuang Youlin; Zhang Li; Weng Xiaodong; Liu Xiuheng; Zhu Hengchen

    2012-01-01

    Immune regulation has been shown to be involved in the progressive growth of some murine tumours. Interruption of immune regulatory pathways via activation of 4-1BB or cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockade appears to be a promising strategy for cancer immunotherapy. In this study, we examined the effectiveness of 4-1BBL-expressing tumor cell vaccine in combination with CTLA-4 blockade on rejection of murine prostate cancer RM-1. We found that the combination of both a ...

  20. Roles of regulatory T cells in cancer immunity.

    Science.gov (United States)

    Takeuchi, Yoshiko; Nishikawa, Hiroyoshi

    2016-08-01

    CD4(+) regulatory T cells (Tregs) expressing the transcription factor FoxP3 are highly immune suppressive and play central roles in the maintenance of self-tolerance and immune homeostasis, yet in malignant tumors they promote tumor progression by suppressing effective antitumor immunity. Indeed, higher infiltration by Tregs is observed in tumor tissues, and their depletion augments antitumor immune responses in animal models. Additionally, increased numbers of Tregs and, in particular, decreased ratios of CD8(+) T cells to Tregs among tumor-infiltrating lymphocytes are correlated with poor prognosis in various types of human cancers. The recent success of cancer immunotherapy represented by immune checkpoint blockade has provided a new insight in cancer treatment, yet more than half of the treated patients did not experience clinical benefits. Identifying biomarkers that predict clinical responses and developing novel immunotherapies are therefore urgently required. Cancer patients whose tumors contain a large number of neoantigens stemming from gene mutations, which have not been previously recognized by the immune system, provoke strong antitumor T-cell responses associated with clinical responses following immune checkpoint blockade, depending on the resistance to Treg-mediated suppression. Thus, integration of a strategy restricting Treg-mediated immune suppression may expand the therapeutic spectrum of cancer immunotherapy towards patients with a lower number of neoantigens. In this review, we address the current understanding of Treg-mediated immune suppressive mechanisms in cancer, the involvement of Tregs in cancer immunotherapy, and strategies for effective and tolerable Treg-targeted therapy. PMID:27160722

  1. Entanglement of Two Atoms using Rydberg Blockade

    OpenAIRE

    Walker, Thad G.; Saffman, Mark

    2012-01-01

    Over the past few years we have built an apparatus to demonstrate the entanglement of neutral Rb atoms at optically resolvable distances using the strong interactions between Rydberg atoms. Here we review the basic physics involved in this process: loading of single atoms into individual traps, state initialization, state readout, single atom rotations, blockade-mediated manipulation of Rydberg atoms, and demonstration of entanglement.

  2. Metazoan promoters

    DEFF Research Database (Denmark)

    Lenhard, Boris; Sandelin, Albin Gustav; Carninci, Piero

    2012-01-01

    Promoters are crucial for gene regulation. They vary greatly in terms of associated regulatory elements, sequence motifs, the choice of transcription start sites and other features. Several technologies that harness next-generation sequencing have enabled recent advances in identifying promoters ...

  3. Characterization of the bovine pregnancy-associated glycoprotein gene family – analysis of gene sequences, regulatory regions within the promoter and expression of selected genes

    Directory of Open Access Journals (Sweden)

    Walker Angela M

    2009-04-01

    Full Text Available Abstract Background The Pregnancy-associated glycoproteins (PAGs belong to a large family of aspartic peptidases expressed exclusively in the placenta of species in the Artiodactyla order. In cattle, the PAG gene family is comprised of at least 22 transcribed genes, as well as some variants. Phylogenetic analyses have shown that the PAG family segregates into 'ancient' and 'modern' groupings. Along with sequence differences between family members, there are clear distinctions in their spatio-temporal distribution and in their relative level of expression. In this report, 1 we performed an in silico analysis of the bovine genome to further characterize the PAG gene family, 2 we scrutinized proximal promoter sequences of the PAG genes to evaluate the evolution pressures operating on them and to identify putative regulatory regions, 3 we determined relative transcript abundance of selected PAGs during pregnancy and, 4 we performed preliminary characterization of the putative regulatory elements for one of the candidate PAGs, bovine (bo PAG-2. Results From our analysis of the bovine genome, we identified 18 distinct PAG genes and 14 pseudogenes. We observed that the first 500 base pairs upstream of the translational start site contained multiple regions that are conserved among all boPAGs. However, a preponderance of conserved regions, that harbor recognition sites for putative transcriptional factors (TFs, were found to be unique to the modern boPAG grouping, but not the ancient boPAGs. We gathered evidence by means of Q-PCR and screening of EST databases to show that boPAG-2 is the most abundant of all boPAG transcripts. Finally, we provided preliminary evidence for the role of ETS- and DDVL-related TFs in the regulation of the boPAG-2 gene. Conclusion PAGs represent a relatively large gene family in the bovine genome. The proximal promoter regions of these genes display differences in putative TF binding sites, likely contributing to observed

  4. CSF1 Receptor Targeting In Prostate Cancer Reverses Macrophage-Mediated Resistance To Androgen Blockade Therapy

    Science.gov (United States)

    Escamilla, Jemima; Schokrpur, Shiruyeh; Liu, Connie; Priceman, Saul J.; Moughon, Diana; Jiang, Ziyue; Pouliot, Frederic; Magyar, Clara; Sung, James L.; Xu, Jingying; Deng, Gang; West, Brian L.; Bollag, Gideon; Fradet, Yves; Lacombe, Louis; Jung, Michael E.; Huang, Jiaoti; Wu, Lily

    2015-01-01

    Growing evidence suggests that tumor-associated macrophages (TAMs) promote cancer progression and therapeutic resistance by enhancing angiogenesis, matrix-remodeling and immunosuppression. In this study prostate cancer (PCa) under androgen blockade therapy (ABT) was investigated, demonstrating that TAMs contribute to PCa disease recurrence through paracrine signaling processes. ABT induced the tumor cells to express macrophage colony-stimulating factor 1 (M-CSF-1 or CSF-1) and other cytokines that recruit and modulate macrophages, causing a significant increase in TAM infiltration. Inhibitors of CSF-1 signaling through its receptor, CSF-1R, were tested in combination with ABT, demonstrating that blockade of TAM influx in this setting disrupts tumor promotion and sustains a more durable therapeutic response compared to ABT alone. PMID:25736687

  5. In silico analysis, mapping of regulatory elements and corresponding dna-protein interaction in polyphenol oxidase gene promoter from different rice varieties

    International Nuclear Information System (INIS)

    Polyphenol oxidase (PPO) is an important enzyme that has positive impact regarding plant resistance against different biotic and abiotic stresses. In the present study PPO promoter from six different rice varieties was amplified and then analyzed for cis- and trans-acting elements. The study revealed a total of 79 different cis-acting regulatory elements including 11 elements restricted to only one or other variety. Among six varieties Pakhal-Basmati had highest number (5) of these elements, whereas C-622 and Rachna-Basmati have no such sequences. Rachna-Basmati, IR-36-Basmati and Kashmir- Basmati had 1, 2 and 3 unique elements, respectively. Different elementsrelated to pathogen, salt and water stresses were found, which may be helpful in controlling PPO activity according to changing environment. Moreover, HADDOCK was used to understand molecular mechanism of PPO regulation and it was found that DNA-protein interactions are stabilized by many potential hydrogen bonds. Adenine and arginine were the most reactive residues in DNA and proteins respectively.Structural comparison of different protein-DNA complexes show that even a highly conserved transcriptional factor can adopt different conformations when they contact a different DNA binding sequence, however their stable interactions depend on the number of hydrogen bonds formed and distance. (author)

  6. An Interleukin-33-Mast Cell-Interleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers.

    Science.gov (United States)

    Morita, Hideaki; Arae, Ken; Unno, Hirotoshi; Miyauchi, Kousuke; Toyama, Sumika; Nambu, Aya; Oboki, Keisuke; Ohno, Tatsukuni; Motomura, Kenichiro; Matsuda, Akira; Yamaguchi, Sachiko; Narushima, Seiko; Kajiwara, Naoki; Iikura, Motoyasu; Suto, Hajime; McKenzie, Andrew N J; Takahashi, Takao; Karasuyama, Hajime; Okumura, Ko; Azuma, Miyuki; Moro, Kazuyo; Akdis, Cezmi A; Galli, Stephen J; Koyasu, Shigeo; Kubo, Masato; Sudo, Katsuko; Saito, Hirohisa; Matsumoto, Kenji; Nakae, Susumu

    2015-07-21

    House dust mite-derived proteases contribute to allergic disorders in part by disrupting epithelial barrier function. Interleukin-33 (IL-33), produced by lung cells after exposure to protease allergens, can induce innate-type airway eosinophilia by activating natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2), to secrete Th2 type-cytokines. Because IL-33 also can induce mast cells (MCs) to secrete Th2 type-cytokines, MCs are thought to cooperate with NH cells in enhancing protease or IL-33-mediated innate-type airway eosinophilia. However, we found that MC-deficient Kit(W-sh/W-sh) mice exhibited exacerbated protease-induced lung inflammation associated with reduced numbers of regulatory T (Treg) cells. Moreover, IL-2 produced by IL-33-stimulated MCs promoted expansion of numbers of Treg cells, thereby suppressing development of papain- or IL-33-induced airway eosinophilia. We have thus identified a unique anti-inflammatory pathway that can limit induction of innate-type allergic airway inflammation mediated by NH cells. PMID:26200013

  7. Molecular cloning, expression and identification of the promoter regulatory region for the neuropeptide trissin in the nervous system of the silkmoth Bombyx mori.

    Science.gov (United States)

    Roller, Ladislav; Čižmár, Daniel; Gáliková, Zuzana; Bednár, Branislav; Daubnerová, Ivana; Žitňan, Dušan

    2016-06-01

    Trissin has recently been identified as a conserved insect neuropeptide, but its cellular expression and function is unknown. We detected the presence of this neuropeptide in the silkworm Bombyx mori using in silico search and molecular cloning. In situ hybridisation was used to examine trissin expression in the entire central nervous system (CNS) and gut of larvae, pupae and adults. Surprisingly, its expression is restricted to only two pairs of small protocerebral interneurons and four to five large neurons in the frontal ganglion (FG). These neurons were further characterised by subsequent multiple staining with selected antibodies against insect neuropeptides. The brain interneurons innervate edges of the mushroom bodies and co-express trissin with myoinhibitory peptides (MIP) and CRF-like diuretic hormones (CRF-DH). In the FG, one pair of neurons co-express trissin with calcitonin-like diuretic hormone (CT-DH), short neuropeptide F (sNPF) and MIP. These neurons innervate the brain tritocerebrum and musculature of the anterior midgut. The other pair of trissin neurons in the FG co-express sNPF and project axons to the tritocerebrum and midgut. We also used the baculovirus expression system to identify the promoter regulatory region of the trissin gene for targeted expression of various molecular markers in these neurons. Dominant expression of trissin in the FG indicates its possible role in the regulation of foregut-midgut contractions and food intake. PMID:26809512

  8. Combined LFA-1 and costimulatory blockade prevents transplant rejection mediated by heterologous immune memory alloresponses

    Science.gov (United States)

    Kitchens, William H.; Haridas, Divya; Wagener, Maylene E.; Song, Mingqing; Ford, Mandy L.

    2013-01-01

    Background Recent evidence suggests that alloreactive memory T cells are generated by the process of heterologous immunity, whereby memory T cells arising in response to pathogen infection cross-react with donor antigens. Due to their diminished requirements for costimulation during recall, these pathogen-elicited allo-crossreactive memory T cells are of particular clinical importance, especially given the emergence of costimulatory blockade as a transplant immunosuppression strategy. Methods We utilized an established model of heterologous immunity involving sequential infection of a naïve C57BL/6 recipient with lymphocytic choriomeningitis virus and vaccinia virus, followed by combined skin and bone marrow transplant from a BALB/c donor. Results We demonstrate that coupling the integrin antagonist anti-LFA-1 with costimulatory blockade could surmount the barrier posed by heterologous immunity in a fully allogeneic murine transplant system. The combined costimulatory and integrin blockade regimen suppressed proliferation of alloreactive memory T cells and attenuated their cytokine effector responses. This combined blockade regimen also promoted the retention of FoxP3+ Tregs in draining lymph nodes. Finally, we show that in an in vitro mixed lymphocyte reaction system using human T cells, the combination of belatacept and anti-LFA-1 was able to suppress cytokine production by alloreactive memory T cells that was resistant to belatacept alone. Conclusions As an antagonist against human LFA-1 exists and has been used clinically to treat psoriasis, these findings have significant translational potential for future clinical transplant trials. PMID:22475765

  9. Coulomb blockade at almost perfect transmission

    OpenAIRE

    Matveev, K. A.

    1994-01-01

    We study the equilibrium properties of a quantum dot connected to a bulk lead by a single-mode quantum point contact. The ground state energy and other thermodynamic characteristics of the grain show periodic dependence on the gate voltage (Coulomb blockade). We consider the case of almost perfect transmission, and show that the oscillations exist as long as the transmission coefficient of the contact is less than unity. Near the points where the dot charge is half-integer the thermodynamic c...

  10. hERG Blockade by Iboga Alkaloids.

    Science.gov (United States)

    Alper, Kenneth; Bai, Rong; Liu, Nian; Fowler, Steven J; Huang, Xi-Ping; Priori, Silvia G; Ruan, Yanfei

    2016-01-01

    The iboga alkaloids are a class of naturally occurring and synthetic compounds, some of which modify drug self-administration and withdrawal in humans and preclinical models. Ibogaine, the prototypic iboga alkaloid that is utilized clinically to treat addictions, has been associated with QT prolongation, torsades de pointes and fatalities. hERG blockade as IKr was measured using the whole-cell patch clamp technique in HEK 293 cells. This yielded the following IC50 values: ibogaine manufactured by semisynthesis via voacangine (4.09 ± 0.69 µM) or by extraction from T. iboga (3.53 ± 0.16 µM); ibogaine's principal metabolite noribogaine (2.86 ± 0.68 µM); and voacangine (2.25 ± 0.34 µM). In contrast, the IC50 of 18-methoxycoronaridine, a product of rational synthesis and current focus of drug development was >50 µM. hERG blockade was voltage dependent for all of the compounds, consistent with low-affinity blockade. hERG channel binding affinities (K i) for the entire set of compounds, including 18-MC, ranged from 0.71 to 3.89 µM, suggesting that 18-MC binds to the hERG channel with affinity similar to the other compounds, but the interaction produces substantially less hERG blockade. In view of the extended half-life of noribogaine, these results may relate to observations of persistent QT prolongation and cardiac arrhythmia at delayed intervals of days following ibogaine ingestion. The apparent structure-activity relationships regarding positions of substitutions on the ibogamine skeleton suggest that the iboga alkaloids might provide an informative paradigm for investigation of the structural biology of the hERG channel. PMID:25636206

  11. Efficient Multiparticle Entanglement via Asymmetric Rydberg Blockade

    DEFF Research Database (Denmark)

    Saffman, Mark; Mølmer, Klaus

    2009-01-01

    We present an efficient method for producing N particle entangled states using Rydberg blockade interactions. Optical excitation of Rydberg states that interact weakly, yet have a strong coupling to a second control state is used to achieve state dependent qubit rotations in small ensembles. On t...... basis of quantitative calculations, we predict that an entangled quantum superposition state of eight atoms can be produced with a fidelity of 84% in cold Rb atoms....

  12. The photon blockade effect in optomechanical systems

    OpenAIRE

    Rabl, Peter

    2011-01-01

    We analyze the photon statistics of a weakly driven optomechanical system and discuss the effect of photon blockade under single photon strong coupling conditions. We present an intuitive interpretation of this effect in terms of displaced oscillator states and derive analytic expressions for the cavity excitation spectrum and the two photon correlation function $g^{(2)}(0)$. Our results predict the appearance of non-classical photon correlations in the combined strong coupling and sideband r...

  13. Development of targeted therapy for a broad spectrum of cancers (pancreatic cancer, ovarian cancer, glioblastoma and HCC) mediated by a double promoter plasmid expressing diphtheria toxin under the control of H19 and IGF2-P4 regulatory sequences

    Science.gov (United States)

    Amit, Doron; Hochberg, Abraham

    2012-01-01

    Background The human IGF2-P4 and H19 promoters are highly active in a variety of human cancers, while existing at a nearly undetectable level in the surrounding normal tissue. Single promoter vectors expressing diphtheria toxin A-fragment (DTA) under the control regulation of IGF2-P4 or H19 regulatory sequences (IGF2-P4-DTA and H19-DTA) were previously successfully used in cell lines, animal models and recently in human patients with superficial cell carcinoma of the bladder, pancreatic cancer and ovarian cancer (treated with H19-DTA). However this targeted medicine approach may be limited, as not all cancer patients express high levels of H19 and it requires prerequisite diagnostic test for H19. Hence, a double promoter DTA-expressing vector was created, carrying on a single construct two separate genes expressing the diphtheria toxin A-fragment (DTA), from two different regulatory sequences, selected from the cancer-specific promoters H19 and IGF2-P4. Methods H19 and IGF2-P4 gene expression was tested in cell lines of a broad spectrum of different carcinomas (bladder, pancreas, ovary, glioblastoma and HCC), by RT-PCR. The therapeutic potential of the double promoter toxin vector H19-DTA-(IGF2)-P4-DTA was tested in the different cancer cell lines. Results The double promoter vector exhibited superior inhibition activity compared to the single promoter expression vectors, in the different cancer cell lines furthermore, the double promoter vector H19-DTA-P4-DTA exhibited augmented-than-additive anti-cancer activity relative to single promoter expression vectors carrying either DTA sequence alone, when tested in a broad spectrum of tumor cells. Conclusions Our findings show that administration of H19-DTA-P4-DTA has the potential to reach tumor cells, deliver its intracellular toxin without targeting normal tissues, and thus may help reduce tumor burden, improve the quality of life of the patient; and prolong their life span. As H19 and IGF2 were expressed in a broad

  14. Can Airway Tolerance be Promoted Immunopharmacologically with Aspirin in Aspirin-insensitive Allergic Bonchial Asthmatics by T Regulatory Cells (Tregs-directed Immunoregulatory Therapy?

    Directory of Open Access Journals (Sweden)

    Muzammal Hussain

    2012-07-01

    Full Text Available The pathobiology of allergic bronchial asthma is mediated by over-expressed T helper type 2 (Th2-biased immune responses to harmless environmental antigens, leading to airway inflammation and hyper-responsiveness. These Th2 responses are normally suppressed by functional T regulatory cells (Tregs, which maintain the airway tolerance. However, the Tregs activity is conceived to be compromised in allergic asthmatics. The curative therapy to counteract this immune dysregulation is not available so far, and to devise such a remedy is the current research impetus in allergic asthma therapeutics. One of the novel insights is to consider a Tregs-directed immunoregulatory therapy that could harness endogenous Tregs to redress the Th2/Tregs imbalance, thus enhancing the airway tolerance. Aspirin or acetylsalicylic acid (ASA is a prototype non-steroidal anti-inflammatory drug that possesses intriguing immunopharmacological attributes. For example, it can enhance the number or the frequency of functional Tregs, especially natural CD4+ CD25+ FoxP3+ Tregs, either directly or by inducing tolerogenic activity in dendritic cells (DCs. It is also considered to be beneficial for the induction of immunological tolerance in autoimmunity and graft rejection. This raises the question whether ASA, if exploited optimally, may be used to induce and harness endogenous Tregs activity for redressing Th2/Tregs imbalance in allergic asthma. In this paper, we hypothesise that ASA may help to counteract the underlying immune dysregulation in allergic asthma by promoting airway tolerance. Nevertheless, the future research in this regard will selectively need to be targeted to allergic asthma models, which are ASA insensitive, as ASA has some adverse background and is contraindicated in asthmatics who are sensitive to it.

  15. Depletion of CD4+CD25+ regulatory T cells can promote local immunity to suppress tumor growth in benzo[a]pyrene-induced forestomach carcinoma

    Institute of Scientific and Technical Information of China (English)

    Yi-Ling Chen; Jung-Hua Fang; Ming-Derg Lai; Yan-Shen Shan

    2008-01-01

    AIM: To elucidate the distribution of CD4+CD25+ regulatory T cells (Tregs) in different lymphoid tissues and its local enhancement on tumor growth before and after depletion of CD4+CD25+ Tregs.METHODS: Female ICR mice were gavaged with benzo[a]pyrene (BaP) to induce forestomach carcinoma. CD4+CD25+ Tregs were intraperitoneally depleted with monoclonal antibody PC61. These mice were divided into BaP-only, BaP+IgG, BaP+PC61, and control groups. The forestomach of mice was dissected for histological analysis, and tunnel test was performed for apoptosis of tumor cells. CD4+CD25+ Tregs were sorted from different lymphoid tissues and expression of Foxp3, IL-10, and chemokine receptors was analyzed by flow cytometry, semi-quantitative and real-time polymerase chain reaction.RESULTS: The mice gavaged with only BaP showed increased forestomach papilloma and carcinoma at wk 16 and 32. The proportion of CD4+CD25+ Tregs was significantly higher in peri-stomach regional lymph nodes than in other lymphoid tissues. These CD4+CD25+ Tregs in regional lymph nodes expressed higher levels of Foxp3 and IL-10, enriched in the CD62L-subset, and CCR1 and CCR5 chemokine receptors. In mice gavaged with BaP+PC61, the number of tumor nodules and tumor volume decreased significantly with massive infiltrating cells and apoptosis of tumor cells. In the draining regional lymph nodes, the number of CD4+CD25+ Tregs also decreased significantly.CONCLUSION: Inducible and activated CD4+CD25+ Tregs in the draining regional lymph nodes suppress host local immunity during tumor growth. Depletion of CD4+CD25+ Tregs can promote host local immunity to suppress tumor growth.

  16. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma

    OpenAIRE

    Phan, Giao Q.; Yang, James C.; Sherry, Richard M.; Hwu, Patrick; Topalian, Suzanne L.; Schwartzentruber, Douglas J.; Restifo, Nicholas P; Haworth, Leah R.; Seipp, Claudia A.; Freezer, Linda J.; Morton, Kathleen E.; Mavroukakis, Sharon A.; Duray, Paul H.; Steinberg, Seth M.; Allison, James P.

    2003-01-01

    Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical immunoregulatory molecule (expressed on activated T cells and a subset of regulatory T cells) capable of down-regulating T cell activation. Blockade of CTLA-4 has been shown in animal models to improve the effectiveness of cancer immunotherapy. We thus treated 14 patients with metastatic melanoma by using serial i.v. administration of a fully human anti-CTLA-4 antibody (MDX-010) in conjunction with s.c....

  17. Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25.

    Science.gov (United States)

    Hannani, Dalil; Vétizou, Marie; Enot, David; Rusakiewicz, Sylvie; Chaput, Nathalie; Klatzmann, David; Desbois, Melanie; Jacquelot, Nicolas; Vimond, Nadège; Chouaib, Salem; Mateus, Christine; Allison, James P; Ribas, Antoni; Wolchok, Jedd D; Yuan, Jianda; Wong, Philip; Postow, Michael; Mackiewicz, Andrzej; Mackiewicz, Jacek; Schadendorff, Dirk; Jaeger, Dirk; Zörnig, Inka; Hassel, Jessica; Korman, Alan J; Bahjat, Keith; Maio, Michele; Calabro, Luana; Teng, Michele Wl; Smyth, Mark J; Eggermont, Alexander; Robert, Caroline; Kroemer, Guido; Zitvogel, Laurence

    2015-02-01

    The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4(+) T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 blockade, the decoy IL-2 receptor α (IL-2Rα, sCD25) inhibited the anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients receiving ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of overall survival, with high levels predicting resistance to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma. PMID:25582080

  18. In-vitro characterization of novel and functional regulatory SNPs in the promoter region of IL2 and IL2R alpha in a Gabonese population

    OpenAIRE

    Huang Xiangsheng; Kühne Vera; Kun Jürgen F J; Soboslay Peter T; Lell Bertrand; TP, Velavan

    2012-01-01

    Abstract Background The selection pressure imposed by the parasite has a functional consequence on the immune genes, leading to altered immune function in which regulatory T cells (Tregs) induced by parasites during infectious challenges modulate or thwart T effector cell mechanism. Methods We identified and investigated regulatory polymorphisms in the immune gene IL2 and its receptor IL2R alpha (also known as CD25) in Gabonese individuals exposed to plentiful parasitic infections. Results We...

  19. Foxp3-modified bone marrow mesenchymal stem cells promotes liver allograft tolerance through the generation of regulatory T cells in rats

    OpenAIRE

    QI, HAIZHI; Chen, Guangshun; Huang, Yaxun; Si, Zhongzhou; Li, Jiequn

    2015-01-01

    Background The transcription factor forkhead box P3 (Foxp3) is a master regulatory gene necessary for the development and function of CD4+CD25+ regulatory T cells (Tregs). Mesenchymal stem cells (MSC) have recently emerged as promising candidates for cell-based immunosuppression/tolerance induction protocols. Thus, we hypothesized that MSC-based Foxp3 gene therapy would improve immunosuppressive capacity of MSC and induce donor-specific allograft tolerance in rat’s liver allograft model. Meth...

  20. Costimulatory signal blockade in murine relapsing experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Schaub, M; Issazadeh-Navikas, Shohreh; Stadlbauer, T H;

    1999-01-01

    Blockade of the CD28-B7 or CD40L-CD40 T cell costimulatory signals prevents induction of experimental autoimmune encephalomyelitis (EAE). However, the effect of simultaneous blockade of these signals in EAE is unknown. We show that administration of either MR1 (to block CD40L) or CTLA4Ig (to bloc...

  1. Antilocalization of Coulomb Blockade in a Ge-Si Nanowire

    DEFF Research Database (Denmark)

    Higginbotham, Andrew P.; Kuemmeth, Ferdinand; Larsen, Thorvald Wadum;

    2014-01-01

    The distribution of Coulomb blockade peak heights as a function of magnetic field is investigated experimentally in a Ge-Si nanowire quantum dot. Strong spin-orbit coupling in this hole-gas system leads to antilocalization of Coulomb blockade peaks, consistent with theory. In particular, the peak...

  2. Development of targeted therapy for a broad spectrum of solid tumors mediated by a double promoter plasmid expressing diphtheria toxin under the control of IGF2-P4 and IGF2-P3 regulatory sequences

    Science.gov (United States)

    Amit, Doron; Tamir, Sagi; Hochberg, Abraham

    2013-01-01

    Background: The human IGF2-P4 and IGF2-P3 promoters are highly active in a variety of human cancers, while existing at a nearly undetectable level in the surrounding normal tissue. Thus, a double promoter DTA-expressing vector was created, carrying on a single construct two separate genes expressing the diphtheria toxin a-fragment (DTA), from two different regulatory sequences, selected from the cancer-specific promoters IGF2-P4 and IGF2-P3. Methods: The therapeutic potential of the double promoter toxin vector P4-DTA-P3-DTA was tested in different cancer cells (pancreatic cancer, ovarian cancer and HCC). Results: The double promoter vector P4-DTA-P3-DTA exhibited superior inhibition activity in different cancer cell lines, compared to the single promoter expression vectors activity. Conclusions: Our findings suggest that administration of P4-DTA-P3-DTA has the potential to reach and eradicate tumor cells and thus may help reduce tumor burden, improve the quality of life of the patients; and prolong their life span. PMID:23386914

  3. Regulatory unbundling in telecommunications

    OpenAIRE

    Knieps, Günter

    2011-01-01

    Due to its dynamic nature, and the increasing importance of competitive sub-parts, the telecommunications sector provides particularly interesting insights for studying regulatory unbundling. Based on the theory of monopolistic bottle-necks the fallacies of overregulation by undue unbundling obligations are indicated. Neither the promotion of infrastructure competition by mandatory un-bundling of competitive subparts of telecommunications infrastructure, nor regulatory induced network fragmen...

  4. Coulomb blockade of spin-dependent shuttling

    Science.gov (United States)

    Park, Hee Chul; Kadigrobov, Anatoli M.; Shekhter, Robert I.; Jonson, M.

    2013-12-01

    We show that nanomechanical shuttling of single electrons may enable qualitatively new functionality if spin-polarized electrons are injected into a nanoelectromechanical single-electron tunneling (NEM-SET) device. This is due to the combined effects of spin-dependent electron tunneling and Coulomb blockade of tunneling, which are phenomena that occur in certain magnetic NEM-SET devices. Two effects are predicted to occur in such structures. The first is a reentrant shuttle instability, by which we mean the sequential appearance, disappearance and again the appearance of a shuttle instability as the driving voltage is increased (or the mechanical dissipation is diminished). The second effect is an enhanced spin polarization of the nanomechanically assisted current flow.

  5. Anti-CD25 monoclonal antibody Fc variants differentially impact regulatory T cells and immune homeostasis.

    Science.gov (United States)

    Huss, David J; Pellerin, Alex F; Collette, Brian P; Kannan, Arun K; Peng, Liaomin; Datta, Abhishek; Wipke, Brian T; Fontenot, Jason D

    2016-07-01

    Interleukin-2 (IL-2) is a critical regulator of immune homeostasis through its non-redundant role in regulatory T (Treg) cell biology. There is major interest in therapeutic modulation of the IL-2 pathway to promote immune activation in the context of tumour immunotherapy or to enhance immune suppression in the context of transplantation, autoimmunity and inflammatory diseases. Antibody-mediated targeting of the high-affinity IL-2 receptor α chain (IL-2Rα or CD25) offers a direct mechanism to target IL-2 biology and is being actively explored in the clinic. In mouse models, the rat anti-mouse CD25 clone PC61 has been used extensively to investigate the biology of IL-2 and Treg cells; however, there has been controversy and conflicting data on the exact in vivo mechanistic function of PC61. Engineering antibodies to alter Fc/Fc receptor interactions can significantly alter their in vivo function. In this study, we re-engineered the heavy chain constant region of an anti-CD25 monoclonal antibody to generate variants with highly divergent Fc effector function. Using these anti-CD25 Fc variants in multiple mouse models, we investigated the in vivo impact of CD25 blockade versus depletion of CD25(+) Treg cells on immune homeostasis. We report that immune homeostasis can be maintained during CD25 blockade but aberrant T-cell activation prevails when CD25(+) Treg cells are actively depleted. These results clarify the impact of PC61 on Treg cell biology and reveal an important distinction between CD25 blockade and depletion of CD25(+) Treg cells. These findings should inform therapeutic manipulation of the IL-2 pathway by targeting the high-affinity IL-2R. PMID:27012310

  6. Politics of Economic Blockade: A Case of Manipur Experience

    Directory of Open Access Journals (Sweden)

    Hawaibam Herojit Singh

    2013-04-01

    Full Text Available Considering the significance and effects of economic blockade in the region, the paper tries to study various facades of issues surrounding politics of economic blockade in Manipur by highlighting recent example of the economic blockade undertaken by Naga or NSCN (I-M and their cognate groups and Sadar hills Districthood Demand Committee or Kuki-Chin groups on the National High Way no. 2 and 37. The paper tries to argue that economic blockade in Manipur is not to be treated simply as means to pressurize the union and state government as claimed by NSCN and Kuki groups for it has its larger impact on the normal life or against the Right to life of the people in the state particularly the community settling in the valley. It also, however, suggests that the impact of economic blockade extend to all the people of Manipur including the periphery people. The paper also addresses whether the economic blockade is legitimate or not. Therefore economic blockade is not simply an outcome of the policy failures of the state, but also a serious manifestation of ethnic conflicts which have been tormenting Manipur for the last few decades.

  7. Polymorphism in the regulatory region located more than 1.1 kilobases 5' to the start site of transcription, the promoter region, and exon 1 of the HLA-G gene

    DEFF Research Database (Denmark)

    Hviid, T V; Sørensen, Steen; Morling, N

    1999-01-01

    The non-classic Human Leucocyte Antigen class Ib molecule, HLA-G, is expressed on the invasive, extra-villous cytotrophoblast in human placenta. HLA-G protects against natural killer (NK)-cell-mediated lysis and may modulate the secretion of cytokines. Aberrant expression of HLA-G has been reported...... in certain disorders of pregnancy. We have studied the DNA sequences of the putative regulatory region located more than 1.1 kilobases 5' from the start site of transcription (a 244 bp HindIII/EcoRI fragment) of the HLA-G gene and of the promoter region to detect any possible polymorphism. We...

  8. Ionic Coulomb Blockade and Resonant Conduction in Biological Ion Channels

    CERN Document Server

    Kaufman, I Kh; Eisenberg, R S

    2014-01-01

    The conduction and selectivity of calcium/sodium ion channels are described in terms of ionic Coulomb blockade, a phenomenon based on charge discreteness and an electrostatic model of an ion channel. This novel approach provides a unified explanation of numerous observed and modelled conductance and selectivity phenomena, including the anomalous mole fraction effect and discrete conduction bands. Ionic Coulomb blockade and resonant conduction are similar to electronic Coulomb blockade and resonant tunnelling in quantum dots. The model is equally applicable to other nanopores.

  9. Pauli Spin Blockade and the Ultrasmall Magnetic Field Effect

    KAUST Repository

    Danon, Jeroen

    2013-08-06

    Based on the spin-blockade model for organic magnetoresistance, we present an analytic expression for the polaron-bipolaron transition rate, taking into account the effective nuclear fields on the two sites. We reveal the physics behind the qualitatively different magnetoconductance line shapes observed in experiment, as well as the ultrasmall magnetic field effect (USFE). Since our findings agree in detail with recent experiments, they also indirectly provide support for the spin-blockade interpretation of organic magnetoresistance. In addition, we predict the existence of a similar USFE in semiconductor double quantum dots tuned to the spin-blockade regime.

  10. Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism

    OpenAIRE

    Christine eDugovic; Shelton, Jonathan E.; Sujin eYun; Pascal eBonaventure; Shireman, Brock T.; Lovenberg, Timothy W.

    2014-01-01

    In accordance with the prominent role of orexins in the maintenance of wakefulness via activation of orexin-1 (OX1R) and orexin-2 (OX2R) receptors, various dual OX1/2R antagonists have been shown to promote sleep in animals and humans. While selective blockade of OX2R seems to be sufficient to initiate and prolong sleep, the beneficial effect of additional inhibition of OX1R remains controversial. The relative contribution of OX1R and OX2R to the sleep effects induced by a dual OX1/2R antagon...

  11. Human Cancer Immunotherapy with PD-1/PD-L1 Blockade

    OpenAIRE

    Peilin Zheng; Zhiguang Zhou

    2015-01-01

    The ligation of programmed cell death-1 (PD-1) to its ligands PD-L1 and PD-L2 counteracts T-cell activation, which is critical in immune tolerance. The persistent high expression of PD-1 and PD-L1 are also observed on tumor-infiltrating lymphocytes and various tumor cells, maintaining the highly suppressive microenvironment in tumor sites and promoting tumor malignancies. The blockade of PD-1 axis with PD-L2 fusion protein or monoclonal antibodies against either PD-1 or PD-L1 has been clinica...

  12. Angiotensin II (AT1) Receptor Blockade Reduces Vascular Tissue Factor in Angiotensin II-Induced Cardiac Vasculopathy

    OpenAIRE

    Dominik N Müller; Mervaala, Eero M A; Dechend, Ralf; Fiebeler, Anette; Park, Joon-Keun; Schmidt, Folke; Theuer, Jürgen; Breu, Volker; Mackman, Nigel; Luther, Thomas; Schneider, Wolfgang; Gulba, Dietrich; Ganten, Detlev; Haller, Hermann; Luft, Friedrich C.

    2000-01-01

    Tissue factor (TF), a main initiator of clotting, is up-regulated in vasculopathy. We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT1 receptor blockade inhibits TF expression in a model of ANG II-induced cardiac vasculopathy. Furthermore, we explored the mechanisms by examining transcription factor activation and analyzing the TF promoter. Untreated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) feature hypertension and severe left...

  13. Conserved high-affinity NF-kappa B binding site in the interferon regulatory factor-1 promoter is not occupied by NF-kappa B in vivo and is transcriptionally inactive.

    Science.gov (United States)

    Rein, T; Schreck, R; Willenbrink, W; Neubert, W J; Zorbas, H; Bäuerle, P A

    1995-01-01

    The promoter of the interferon regulatory factor-1 (IRF-1) gene contains at position -47 to -38 an evolutionary conserved binding sequence for the inducible transcription factor NF-kappa B. This site is highly homologous to a transcriptionally active site from the MHC class I enhancer. In this study, we show by in vitro assays using purified NF-kappa B that the kappa B motif in the IRF-1 promoter binds the factor specifically and with high affinity, comparable to various other cis-acting kappa B elements. Two copies of the IRF-1 kappa B site fused to the heterologous c-fos promoter conferred induction of a chloramphenicol acetyl transferase (CAT) reported gene in response to stimulation of L929 fibroblasts with various NF-kappa B inducers, such as tumor necrosis factor alpha (TNF alpha) or phorbol 12-myristate 13-acetate (PMA). Mutation of the binding site completely abolished transcriptional inducibility of the heterologous promoter. Surprisingly, the same IRF-1 kappa B motif in context of the homologous IRF-1 promoter was transcriptionally inactive in CAT assays. The very weak induction of the IRF-1 promoter in response to TNF treatment or infection of fibroblasts with Newcastle disease virus (NDV) was barely affected by point mutation of the kappa B site or loss of the site by truncation of the promoter. Analysis of the occupational state of the chromosomal IRF-1 kappa B site by in vivo foot-printing revealed that no footprint was induced over the kappa B motif in the IRF-1 promoter after PMA treatment of L929 fibroblast cells, despite the simultaneous induction of IRF-1 mRNA and NF-kappa B binding activity. Constitutive footprints were detected at a CCAAT and GC-rich region in the promoter. This is the first example of a high-affinity NF-kappa B binding site within a promoter which may not participate in transcriptional regulation under conditions activating NF-kappa B DNA binding and gene expression. PMID:8867671

  14. Promotion of a strong nuclear safety culture: discussion about strengthens and weaknesses of the different regulatory strategies used by nuclear regulators

    International Nuclear Information System (INIS)

    Certain regulatory strategies have been in use since many years ago, but not in a systematic way. Argentinean regulators have used PSA since at least 2 decades ago. But it took more time (beginning in 1990) to licensees to start working on it. Simultaneously, other groups started research and development of different 'tools' like root cause analysis, evaluation of the influence of human behavior in the occurrence of events and some others, which now are part of that so-called 'outcome-based' strategies. However all this approaches were isolated projects. Different groups acted as separated units. Argentinean Nuclear Regulations have changed during the last years because of the need to act dynamically responding to variations in the context, within the regulatory authority policy of continuous improvement. (author)

  15. Daratumumab depletes CD38+ immune-regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma

    DEFF Research Database (Denmark)

    Krejcik, Jakub; Casneuf, Tineke; Nijhof, Inger S;

    2016-01-01

    and at relapse. Regulatory B cells (Bregs) and myeloid-derived suppressor cells (MDSCs), previously shown to express CD38, were evaluated for immunosuppressive activity and daratumumab sensitivity in the myeloma setting. A novel subpopulation of regulatory T cells (Tregs) expressing CD38 was...... identified. These Tregs were more immunosuppressive in vitro than CD38-negative Tregs and were reduced in daratumumab-treated patients. In parallel, daratumumab induced robust increases in helper and cytotoxic T-cell absolute counts. In PB and BM, daratumumab induced significant increases in CD8(+):CD4......(+) and CD8(+):Treg ratios, and increased memory T cells while decreasing naïve T cells. The majority of patients demonstrated these broad T-cell changes, although patients with a partial response or better showed greater maximum effector and helper T cell increases, elevated antiviral and alloreactive...

  16. Effects of sugammadex on incidence of postoperative residual neuromuscular blockade

    DEFF Research Database (Denmark)

    Brueckmann, B; Sasaki, N; Grobara, P; Li, M K; Woo, T; de Bie, J; Maktabi, M; Lee, J; Kwo, J; Pino, R; Sabouri, A S; McGovern, F; Stæhr Rye, Anne Kathrine; Eikermann, M

    2015-01-01

    BACKGROUND: This study aimed to investigate whether reversal of rocuronium-induced neuromuscular blockade with sugammadex reduced the incidence of residual blockade and facilitated operating room discharge readiness. METHODS: Adult patients undergoing abdominal surgery received rocuronium, followed...... residual neuromuscular blockade at PACU admission, defined as a train-of-four (TOF) ratio <0.9, using TOF-Watch® SX. Key secondary endpoint was time between reversal agent administration and operating room discharge-readiness; analysed with analysis of covariance. RESULTS: Of 154 patients randomized, 150...... evidence of partial paralysis. Time between reversal agent administration and operating room discharge-readiness was shorter for sugammadex vs usual care (14.7 vs 18.6 min respectively; P=0.02). CONCLUSIONS: After abdominal surgery, sugammadex reversal eliminated residual neuromuscular blockade in the PACU...

  17. Checkpoint Blockade in Cancer Immunotherapy: Squaring the Circle

    Directory of Open Access Journals (Sweden)

    Maria A.V. Marzolini

    2015-03-01

    Full Text Available Manipulating the complex interaction between the immune system and tumour cells has been the focus of cancer research for many years, but it is only in the past decade that significant progress has been made in the field of cancer immunotherapy resulting in clinically effective treatments. The blockade of co-inhibitory immune checkpoints, essential for maintaining lymphocyte homeostasis and self-tolerance, by immunomodulatory monoclonal antibodies has resulted in the augmentation of anti-tumour responses. The greatest successes so far have been seen with the blockade of cytotoxic T lymphocyte associated antigen-4, which has resulted in the first Phase III clinical trial showing an overall survival benefit in metastatic melanoma, and in the blockade of the programmed cell death protein-1 axis. This concise review will focus on the clinical advances made by the blockade of these two pathways and their role in current cancer treatment strategies.

  18. Dipole blockade in a cold Rydberg atomic sample

    CERN Document Server

    Comparat, Daniel; 10.1364/JOSAB.27.00A208

    2010-01-01

    We review here the studies performed about interactions in an assembly of cold Rydberg atoms. We focus more specially the review on the dipole-dipole interactions and on the effect of the dipole blockade in the laser Rydberg excitation, which offers attractive possibilities for quantum engineering. We present first the various interactions between Rydberg atoms. The laser Rydberg excitation of such an assembly is then described with the introduction of the dipole blockade phenomenon. We report recent experiments performed in this subject by starting with the case of a pair of atoms allowing the entanglement of the wave-functions of the atoms and opening a fascinating way for the realization of quantum bits and quantum gates. We consider then several works on the blockade effect in a large assembly of atoms for three different configurations: blockade through electric-field induced dipole, through F\\"orster resonance and in van der Waals interaction. The properties of coherence and cooperativity are analyzed. ...

  19. Transfer of regulatory T cells into abortion-prone mice promotes the expansion of uterine mast cells and normalizes early pregnancy angiogenesis

    OpenAIRE

    Katja Woidacki; Nicole Meyer; Anne Schumacher; Alexandra Goldschmidt; Marcus Maurer; Ana Claudia Zenclussen

    2015-01-01

    Implantation of the fertilized egg depends on the coordinated interplay of cells and molecules that prepare the uterus for this important event. In particular, regulatory T cells (Tregs) are key regulators as their ablation hinders implantation by rendering the uterus hostile for the embryo. In addition, the adoptive transfer of Tregs can avoid early abortion in mouse models. However, it is still not defined which mechanisms underlie Treg function during this early period. Cells of the innate...

  20. From blockade to transparency: controllable photon transmission through a circuit QED system

    OpenAIRE

    Liu, Yu-xi; Xu, Xun-Wei; Miranowicz, Adam; Nori, Franco

    2012-01-01

    A strong photon-photon nonlinear interaction is a necessary condition for photon blockade. Moreover, this nonlinearity can also result a bistable behavior in the cavity field. We analyze the relation between detecting field and photon blockade in a superconducting circuit QED system, and show that photon blockade cannot occur when the detecting field is in the bistable regime. This photon blockade is the microwave-photonics analog of the Coulomb blockade. We further demonstrate that the photo...

  1. Multi-Manifold Stark Splittings Lift the Rydberg Blockade

    CERN Document Server

    Dumin, Yurii V

    2016-01-01

    The spatial evolution of the Rydberg blockade is studied taking into account Stark-split energy levels across several manifolds. We find that the unexpected restoration of a blockaded Rydberg excitation at small interatomic distances, experimentally observed by P.Schauss, et al. [Nature 491, 87 (2012)], can be explained by the perturbed energy levels from neighboring manifolds that enter the energy window of excitation defined by the bandwidth of the exciting laser.

  2. COULOMB BLOCKADE OSCILLATIONS OF Si SINGLE-ELECTRON TRANSISTORS

    Institute of Scientific and Technical Information of China (English)

    王太宏; 李宏伟; 周均铭

    2001-01-01

    Coulomb blockade oscillations of Si single-electron transistors, which are fabricated completely by the conventional photolithography technique, have been investigated. Most of the single-electron transistors clearly show Coulomb blockade oscillations and these oscillations can be periodic by applying negative voltages to the in-plane gates. A shift of the peak positions is observed at high temperatures. It is also found that the fluctuation of the peak spacing cannot be neglected.

  3. Regulatory Foci and Organizational Commitment

    Science.gov (United States)

    Markovits, Yannis; Ullrich, Johannes; van Dick, Rolf; Davis, Ann J.

    2008-01-01

    We use regulatory focus theory to derive specific predictions regarding the differential relationships between regulatory focus and commitment. We estimated a structural equation model using a sample of 520 private and public sector employees and found in line with our hypotheses that (a) promotion focus related more strongly to affective…

  4. Regulatory activities

    International Nuclear Information System (INIS)

    This publication, compiled in 8 chapters, presents the regulatory system developed by the Nuclear Regulatory Authority (NRA) of the Argentine Republic. The following activities and developed topics in this document describe: the evolution of the nuclear regulatory activity in Argentina; the Argentine regulatory system; the nuclear regulatory laws and standards; the inspection and safeguards of nuclear facilities; the emergency systems; the environmental systems; the environmental monitoring; the analysis laboratories on physical and biological dosimetry, prenatal irradiation, internal irradiation, radiation measurements, detection techniques on nuclear testing, medical program on radiation protection; the institutional relations with national and international organization; the training courses and meeting; the technical information

  5. pcaGoPromoter - An R Package for Biological and Regulatory Interpretation of Principal Components in Genome-Wide Gene Expression Data

    DEFF Research Database (Denmark)

    Hansen, Morten; Gerds, Thomas Alexander; Sedelin, Jacob Benedikt;

    2012-01-01

    Analyzing data obtained from genome-wide gene expression experiments is challenging due to the quantity of variables, the need for multivariate analyses, and the demands of managing large amounts of data. Here we present the R package pcaGoPromoter, which facilitates the interpretation of genome...

  6. Blockade of mast cell activation reduces cutaneous scar formation.

    Science.gov (United States)

    Chen, Lin; Schrementi, Megan E; Ranzer, Matthew J; Wilgus, Traci A; DiPietro, Luisa A

    2014-01-01

    Damage to the skin initiates a cascade of well-orchestrated events that ultimately leads to repair of the wound. The inflammatory response is key to wound healing both through preventing infection and stimulating proliferation and remodeling of the skin. Mast cells within the tissue are one of the first immune cells to respond to trauma, and upon activation they release pro-inflammatory molecules to initiate recruitment of leukocytes and promote a vascular response in the tissue. Additionally, mast cells stimulate collagen synthesis by dermal fibroblasts, suggesting they may also influence scar formation. To examine the contribution of mast cells in tissue repair, we determined the effects the mast cell inhibitor, disodium cromoglycate (DSCG), on several parameters of dermal repair including, inflammation, re-epithelialization, collagen fiber organization, collagen ultrastructure, scar width and wound breaking strength. Mice treated with DSCG had significantly reduced levels of the inflammatory cytokines IL-1α, IL-1β, and CXCL1. Although DSCG treatment reduced the production of inflammatory mediators, the rate of re-epithelialization was not affected. Compared to control, inhibition of mast cell activity caused a significant decrease in scar width along with accelerated collagen re-organization. Despite the reduced scar width, DSCG treatment did not affect the breaking strength of the healed tissue. Tryptase β1 exclusively produced by mast cells was found to increase significantly in the course of wound healing. However, DSCG treatment did not change its level in the wounds. These results indicate that blockade of mast cell activation reduces scar formation and inflammation without further weakening the healed wound. PMID:24465509

  7. Blockade of mast cell activation reduces cutaneous scar formation.

    Directory of Open Access Journals (Sweden)

    Lin Chen

    Full Text Available Damage to the skin initiates a cascade of well-orchestrated events that ultimately leads to repair of the wound. The inflammatory response is key to wound healing both through preventing infection and stimulating proliferation and remodeling of the skin. Mast cells within the tissue are one of the first immune cells to respond to trauma, and upon activation they release pro-inflammatory molecules to initiate recruitment of leukocytes and promote a vascular response in the tissue. Additionally, mast cells stimulate collagen synthesis by dermal fibroblasts, suggesting they may also influence scar formation. To examine the contribution of mast cells in tissue repair, we determined the effects the mast cell inhibitor, disodium cromoglycate (DSCG, on several parameters of dermal repair including, inflammation, re-epithelialization, collagen fiber organization, collagen ultrastructure, scar width and wound breaking strength. Mice treated with DSCG had significantly reduced levels of the inflammatory cytokines IL-1α, IL-1β, and CXCL1. Although DSCG treatment reduced the production of inflammatory mediators, the rate of re-epithelialization was not affected. Compared to control, inhibition of mast cell activity caused a significant decrease in scar width along with accelerated collagen re-organization. Despite the reduced scar width, DSCG treatment did not affect the breaking strength of the healed tissue. Tryptase β1 exclusively produced by mast cells was found to increase significantly in the course of wound healing. However, DSCG treatment did not change its level in the wounds. These results indicate that blockade of mast cell activation reduces scar formation and inflammation without further weakening the healed wound.

  8. Anti-CD20 antibody promotes cancer escape via enrichment of tumor-evoked regulatory B cells expressing low levels of CD20 and CD137L.

    Science.gov (United States)

    Bodogai, Monica; Lee Chang, Catalina; Wejksza, Katarzyna; Lai, Jinping; Merino, Maria; Wersto, Robert P; Gress, Ronald E; Chan, Andrew C; Hesdorffer, Charles; Biragyn, Arya

    2013-04-01

    The possible therapeutic benefits of B-cell depletion in combating tumoral immune escape have been debated. In support of this concept, metastasis of highly aggressive 4T1 breast cancer cells in mice can be abrogated by inactivation of tumor-evoked regulatory B cells (tBreg). Here, we report the unexpected finding that B-cell depletion by CD20 antibody will greatly enhance cancer progression and metastasis. Both murine and human tBregs express low levels of CD20 and, as such, anti-CD20 mostly enriches for these cells. In the 4T1 model of murine breast cancer, this effect of enriching for tBregs suggests that B-cell depletion by anti-CD20 may not be beneficial at all in some cancers. In contrast, we show that in vivo-targeted stimulation of B cells with CXCL13-coupled CpG oligonucleotides (CpG-ODN) can block cancer metastasis by inhibiting CD20(Low) tBregs. Mechanistic investigations suggested that CpG-ODN upregulates low surface levels of 4-1BBL on tBregs to elicit granzyme B-expressing cytolytic CD8(+) T cells, offering some explanative power for the effect. These findings underscore the immunotherapeutic importance of tBreg inactivation as a strategy to enhance cancer therapy by targeting both the regulatory and activating arms of the immune system in vivo. PMID:23365136

  9. Graft-versus-host disease is enhanced by selective CD73 blockade in mice.

    Directory of Open Access Journals (Sweden)

    Long Wang

    Full Text Available CD73 functions as an ecto-5'-nucleotidase to produce extracellular adenosine that has anti-inflammatory and immunosuppressive activity. We here demonstrate that CD73 helps control graft-versus-host disease (GVHD in mouse models. Survival of wild-type (WT recipients of either allogeneic donor naïve CD73 knock-out (KO or WT T cells was similar suggesting that donor naïve T cell CD73 did not contribute to GVHD. By contrast, donor CD73 KO CD4(+CD25(+ regulatory T cells (Treg had significantly impaired ability to mitigate GVHD mortality compared to WT Treg, suggesting that CD73 on Treg is critical for GVHD protection. However, compared to donor CD73, recipient CD73 is more effective in limiting GVHD. Pharmacological blockade of A2A receptor exacerbated GVHD in WT recipients, but not in CD73 KO recipients, suggesting that A2 receptor signaling is primarily implicated in CD73-mediated GVHD protection. Moreover, pharmacological blockade of CD73 enzymatic activity induced stronger alloreactive T cell activity, worsened GVHD and enhanced the graft-versus-leukemia (GVL effect. These findings suggest that both donor and recipient CD73 protects against GVHD but also limits GVL effects. Thus, either enhancing or blocking CD73 activity has great potential clinical application in allogeneic bone marrow transplants.

  10. Integration of Bioinformatics and Synthetic Promoters Leads to the Discovery of Novel Elicitor-Responsive cis-Regulatory Sequences in Arabidopsis1[C][W][OA

    Science.gov (United States)

    Koschmann, Jeannette; Machens, Fabian; Becker, Marlies; Niemeyer, Julia; Schulze, Jutta; Bülow, Lorenz; Stahl, Dietmar J.; Hehl, Reinhard

    2012-01-01

    A combination of bioinformatic tools, high-throughput gene expression profiles, and the use of synthetic promoters is a powerful approach to discover and evaluate novel cis-sequences in response to specific stimuli. With Arabidopsis (Arabidopsis thaliana) microarray data annotated to the PathoPlant database, 732 different queries with a focus on fungal and oomycete pathogens were performed, leading to 510 up-regulated gene groups. Using the binding site estimation suite of tools, BEST, 407 conserved sequence motifs were identified in promoter regions of these coregulated gene sets. Motif similarities were determined with STAMP, classifying the 407 sequence motifs into 37 families. A comparative analysis of these 37 families with the AthaMap, PLACE, and AGRIS databases revealed similarities to known cis-elements but also led to the discovery of cis-sequences not yet implicated in pathogen response. Using a parsley (Petroselinum crispum) protoplast system and a modified reporter gene vector with an internal transformation control, 25 elicitor-responsive cis-sequences from 10 different motif families were identified. Many of the elicitor-responsive cis-sequences also drive reporter gene expression in an Agrobacterium tumefaciens infection assay in Nicotiana benthamiana. This work significantly increases the number of known elicitor-responsive cis-sequences and demonstrates the successful integration of a diverse set of bioinformatic resources combined with synthetic promoter analysis for data mining and functional screening in plant-pathogen interaction. PMID:22744985

  11. Integration of bioinformatics and synthetic promoters leads to the discovery of novel elicitor-responsive cis-regulatory sequences in Arabidopsis.

    Science.gov (United States)

    Koschmann, Jeannette; Machens, Fabian; Becker, Marlies; Niemeyer, Julia; Schulze, Jutta; Bülow, Lorenz; Stahl, Dietmar J; Hehl, Reinhard

    2012-09-01

    A combination of bioinformatic tools, high-throughput gene expression profiles, and the use of synthetic promoters is a powerful approach to discover and evaluate novel cis-sequences in response to specific stimuli. With Arabidopsis (Arabidopsis thaliana) microarray data annotated to the PathoPlant database, 732 different queries with a focus on fungal and oomycete pathogens were performed, leading to 510 up-regulated gene groups. Using the binding site estimation suite of tools, BEST, 407 conserved sequence motifs were identified in promoter regions of these coregulated gene sets. Motif similarities were determined with STAMP, classifying the 407 sequence motifs into 37 families. A comparative analysis of these 37 families with the AthaMap, PLACE, and AGRIS databases revealed similarities to known cis-elements but also led to the discovery of cis-sequences not yet implicated in pathogen response. Using a parsley (Petroselinum crispum) protoplast system and a modified reporter gene vector with an internal transformation control, 25 elicitor-responsive cis-sequences from 10 different motif families were identified. Many of the elicitor-responsive cis-sequences also drive reporter gene expression in an Agrobacterium tumefaciens infection assay in Nicotiana benthamiana. This work significantly increases the number of known elicitor-responsive cis-sequences and demonstrates the successful integration of a diverse set of bioinformatic resources combined with synthetic promoter analysis for data mining and functional screening in plant-pathogen interaction. PMID:22744985

  12. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma.

    Science.gov (United States)

    Krejcik, Jakub; Casneuf, Tineke; Nijhof, Inger S; Verbist, Bie; Bald, Jaime; Plesner, Torben; Syed, Khaja; Liu, Kevin; van de Donk, Niels W C J; Weiss, Brendan M; Ahmadi, Tahamtan; Lokhorst, Henk M; Mutis, Tuna; Sasser, A Kate

    2016-07-21

    Daratumumab targets CD38-expressing myeloma cells through a variety of immune-mediated mechanisms (complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis) and direct apoptosis with crosslinking. These mechanisms may also target nonplasma cells that express CD38, which prompted evaluation of daratumumab's effects on CD38-positive immune subpopulations. Peripheral blood (PB) and bone marrow (BM) from patients with relapsed/refractory myeloma from 2 daratumumab monotherapy studies were analyzed before and during therapy and at relapse. Regulatory B cells and myeloid-derived suppressor cells, previously shown to express CD38, were evaluated for immunosuppressive activity and daratumumab sensitivity in the myeloma setting. A novel subpopulation of regulatory T cells (Tregs) expressing CD38 was identified. These Tregs were more immunosuppressive in vitro than CD38-negative Tregs and were reduced in daratumumab-treated patients. In parallel, daratumumab induced robust increases in helper and cytotoxic T-cell absolute counts. In PB and BM, daratumumab induced significant increases in CD8(+):CD4(+) and CD8(+):Treg ratios, and increased memory T cells while decreasing naïve T cells. The majority of patients demonstrated these broad T-cell changes, although patients with a partial response or better showed greater maximum effector and helper T-cell increases, elevated antiviral and alloreactive functional responses, and significantly greater increases in T-cell clonality as measured by T-cell receptor (TCR) sequencing. Increased TCR clonality positively correlated with increased CD8(+) PB T-cell counts. Depletion of CD38(+) immunosuppressive cells, which is associated with an increase in T-helper cells, cytotoxic T cells, T-cell functional response, and TCR clonality, represents possible additional mechanisms of action for daratumumab and deserves further exploration. PMID:27222480

  13. Rationales for regulatory activity

    Energy Technology Data Exchange (ETDEWEB)

    Perhac, R.M. [Univ. of Tennessee, Knoxville, TN (United States)

    1997-02-01

    The author provides an outline which touches on the types of concerns about risk evaluation which are addressed in the process of establishing regulatory guides. Broadly he says regulatory activity serves three broad constituents: (1) Paternalism (private risk); (2) Promotion of social welfare (public risks); (3) Protection of individual rights (public risks). He then discusses some of the major issues encountered in reaching a decision on what is an acceptable level of risk within each of these areas, and how one establishes such a level.

  14. In silico analysis, mapping of regulatory elements and corresponding protein-DNA interaction in atp-beta gene promoter from different tomato varieties

    International Nuclear Information System (INIS)

    Chloroplast atp-beta gene encodes the beta-subunit of ATP synthase having a function in the synthesis of ATP. ATP synthase is usually present in the mitochondrial and chloroplast membranes as well as in prokaryotes with a highly conserved structure. With the aim to study the functional diversity, atpB gene promoter from Solanum lycopersicum varieties (VCT-1, 127, PETO-86, LBR-16, Continental, LBR-06, CLN-2498D, CLN-2777, LBR-09) was amplified, sequenced and analyzed. BLAST tool analyzed the sequences. Cis acting elements were predicted using Consite tool in the promoter region as these elements have importance in gene regulation and maps of the cis-acting elements were constructed with the help of DOG software for each variety. It was seen from the constructed maps that the distribution pattern of trans-acting elements was quite diverse in the atpB promoter of studied tomato varieties. Various trans-acting elements (HMG-IY, HFH-2, TBP, c-Fos and SOX17) were docked with respective DNA sequence using HADDOCK online software. Main focus was on the analysis of DNA-protein interactions and for this purpose; hydrogen bonds formed with either phosphate backbone or base of DNA were checked. Particularly interactions between amino acid and base pairing were checked. It was revealed that Arginine and Lysine had a greater probability to interact with Thymine and Adenine as compared to other bases and all bonds formed were feasible as their distances were less than 3.5 degree A. During the analysis of interactions, it was also found that Lysine, Arginine, Asparagine and Serine are well capable to bind with Thymine while Glycine and Lysine have made bonds mostly with Adenine. (author)

  15. Insulin-like growth factor-I receptor signaling blockade combined with radiation.

    Science.gov (United States)

    Allen, Gregory W; Saba, Corey; Armstrong, Eric A; Huang, Shyh-Min; Benavente, Sergio; Ludwig, Dale L; Hicklin, Daniel J; Harari, Paul M

    2007-02-01

    Signaling through the insulin-like growth factor-I receptor (IGF-IR) is implicated in cellular proliferation, apoptosis, carcinogenesis, metastasis, and resistance to cytotoxic cancer therapies. Targeted disruption of IGF-IR signaling combined with cytotoxic therapy may therefore yield improved anticancer efficacy over conventional treatments alone. In this study, a fully human anti-IGF-IR monoclonal antibody A12 (ImClone Systems, Inc., New York, NY) is examined as an adjunct to radiation therapy. IGF-IR expression is shown for a diverse cohort of cell lines, whereas targeted IGF-IR blockade by A12 inhibits IGF-IR phosphorylation and activation of the downstream effectors Akt and mitogen-activated protein kinase. Anchorage-dependent proliferation and xenograft growth is inhibited by A12 in a dose-dependent manner, particularly for non-small cell lung cancer lines. Clonogenic radiation survival of H226 and H460 cells grown under anchorage-dependent conditions is impaired by A12, demonstrating a radiation dose-enhancing effect for IGF-IR blockade. Postradiation anchorage-independent colony formation is inhibited by A12 in A549 and H460 cells. In the H460 xenograft model, combining A12 and radiation significantly enhances antitumor efficacy compared with either modality alone. These effects may be mediated by promotion of radiation-induced, double-stranded DNA damage and apoptosis as observed in cell culture. In summary, these results validate IGF-IR signal transduction blockade as a promising strategy to improve radiation therapy efficacy in human tumors, forming a basis for future clinical trials. PMID:17283150

  16. Intrathecal rimantadine induces motor, proprioceptive, and nociceptive blockades in rats.

    Science.gov (United States)

    Tzeng, Jann-Inn; Wang, Jieh-Neng; Wang, Jhi-Joung; Chen, Yu-Wen; Hung, Ching-Hsia

    2016-04-01

    The purpose of the experiment was to evaluate the local anesthetic effect of rimantadine in spinal anesthesia. Rimantadine in a dose-dependent fashion was constructed after intrathecally injecting the rats with four different doses. The potency and duration of rimantadine were compared with that of the local anesthetic lidocaine at producing spinal motor, nociceptive, and proprioceptive blockades. We demonstrated that intrathecal rimantadine dose-dependently produced spinal motor, nociceptive, and proprioceptive blockades. On the 50% effective dose (ED50) basis, the ranks of potencies at inducing spinal motor, nociceptive, and proprioceptive blockades was lidocaine>rimantadine (Pspinal block duration produced by rimantadine was longer than that produced by lidocaine (Pspinal anesthesia when compared with lidocaine. PMID:26949181

  17. Dissection of Arabidopsis NCED9 promoter regulatory regions reveals a role for ABA synthesized in embryos in the regulation of GA-dependent seed germination.

    Science.gov (United States)

    Seo, Mitsunori; Kanno, Yuri; Frey, Anne; North, Helen M; Marion-Poll, Annie

    2016-05-01

    Nine-cis-epoxycarotenoid dioxygenase (NCED) catalyzes the key step of abscisic acid (ABA) biosynthesis. There are five genes encoding NCED in Arabidopsis, which differentially regulate ABA biosynthesis in a spatiotemporal manner in response to endogenous and environmental stimuli. Previous studies have shown that NCED9 is expressed in testa and embryos during seed development. In the present study, we have identified promoter regions required for the expression of NCED9 in testa and embryos, respectively. Electrophoretic mobility shift assays (EMSA) and yeast one-hybrid (Y1H) assays showed that several homeodomain-leucine zipper (HD-Zip) proteins, namely ATHBs, bound to the sequence required for expression of NCED9 in testa, suggesting that they redundantly regulate NCED9 expression. By expressing the NCED9 gene under the control of a deleted NCED9 promoter in an nced9 mutant expression was limited to embryos. Transformants were complemented for the paclobutrazol resistant germination phenotype of the mutant, suggesting that the ABA synthesis mediated by NCED9 in embryos plays an important role in the regulation of gibberellin (GA)-dependent seed germination. PMID:26993239

  18. TLR2 dependent induction of vitamin A metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits TH-17 mediated autoimmunity

    Science.gov (United States)

    Manicassamy, Santhakumar; Ravindran, Rajesh; Deng, Jiusheng; Oluoch, Herold; Denning, Timothy L; Kasturi, Sudhir Pai; Rosenthal, Kristen M.; Evavold, Brian D.; Pulendran, Bali

    2009-01-01

    Immune sensing of a microbe occurs via multiple receptors. How signals from different receptors are coordinated to yield a specific immune response is poorly understood. We demonstrate that the different pathogen recognition receptors, TLR2 and dectin-1, recognizing the same microbial stimulus, stimulate distinct innate and adaptive responses. TLR2 signaling induced splenic dendritic cells (DCs) to express the retinoic acid (RA) metabolizing enzyme Raldh2 and IL-10, and to metabolize vitamin A and stimulate Foxp3+ T regulatory cells (Treg cells). RA acted on DCs to induce Socs3 expression, which suppressed activation of p38 MAPK and pro-inflammatory cytokines. Consistent with this, TLR2 signaling induced Treg cells, and suppressed IL-23 and TH-17/ TH-1 mediated autoimmune responses in vivo. In contrast, dectin-1 signaling mostly induced IL-23 and pro-inflammatory cytokines, and augmented TH-17/ TH-1 mediated autoimmune responses in vivo. These data define a new mechanism for the systemic induction of RA and immune suppression against autoimmunity. PMID:19252500

  19. Toll-like receptor 2-dependent induction of vitamin A-metabolizing enzymes in dendritic cells promotes T regulatory responses and inhibits autoimmunity.

    Science.gov (United States)

    Manicassamy, Santhakumar; Ravindran, Rajesh; Deng, Jiusheng; Oluoch, Herold; Denning, Timothy L; Kasturi, Sudhir Pai; Rosenthal, Kristen M; Evavold, Brian D; Pulendran, Bali

    2009-04-01

    Immune sensing of a microbe occurs via multiple receptors. How signals from different receptors are coordinated to yield a specific immune response is poorly understood. We show that two pathogen recognition receptors, Toll-like receptor 2 (TLR2) and dectin-1, recognizing the same microbial stimulus, stimulate distinct innate and adaptive responses. TLR2 signaling induced splenic dendritic cells (DCs) to express the retinoic acid metabolizing enzyme retinaldehyde dehydrogenase type 2 and interleukin-10 (IL-10) and to metabolize vitamin A and stimulate Foxp3(+) T regulatory cells (T(reg) cells). Retinoic acid acted on DCs to induce suppressor of cytokine signaling-3 expression, which suppressed activation of p38 mitogen-activated protein kinase and proinflammatory cytokines. Consistent with this finding, TLR2 signaling induced T(reg) cells and suppressed IL-23 and T helper type 17 (T(H)17) and T(H)1-mediated autoimmune responses in vivo. In contrast, dectin-1 signaling mostly induced IL-23 and proinflammatory cytokines and augmented T(H)17 and T(H)1-mediated autoimmune responses in vivo. These data define a new mechanism for the systemic induction of retinoic acid and immune suppression against autoimmunity. PMID:19252500

  20. Regulatory foci and the big five

    OpenAIRE

    Bak, Waclaw

    2009-01-01

    The distinction between promotion and prevention focus (Higgins, 1997) have been employed by many researchers dealing with processes of self-regulation. Little is known however about relations between regulatory orientations and more general personality traits. The present paper reports results of the study in which regulatory foci are analyzed in the context of five factor model of personality. To measure personality traits the NEO-FFI was used. Promotion and prevention regulatory foci was a...

  1. Observation of ionic Coulomb blockade in nanopores.

    Science.gov (United States)

    Feng, Jiandong; Liu, Ke; Graf, Michael; Dumcenco, Dumitru; Kis, Andras; Di Ventra, Massimiliano; Radenovic, Aleksandra

    2016-08-01

    Emergent behaviour from electron-transport properties is routinely observed in systems with dimensions approaching the nanoscale. However, analogous mesoscopic behaviour resulting from ionic transport has so far not been observed, most probably because of bottlenecks in the controlled fabrication of subnanometre nanopores for use in nanofluidics. Here, we report measurements of ionic transport through a single subnanometre pore junction, and the observation of ionic Coulomb blockade: the ionic counterpart of the electronic Coulomb blockade observed for quantum dots. Our findings demonstrate that nanoscopic, atomically thin pores allow for the exploration of phenomena in ionic transport, and suggest that nanopores may also further our understanding of transport through biological ion channels. PMID:27019385

  2. Topological matter with collective encoding and Rydberg blockade

    DEFF Research Database (Denmark)

    Nielsen, Anne E. B.; Mølmer, Klaus

    2010-01-01

    We propose to use a permutation symmetric sample of multilevel atoms to simulate the properties of topologically ordered states. The Rydberg blockade interaction is used to prepare states of the sample which are equivalent to resonating valence bond states, Laughlin states, and string-net condens......We propose to use a permutation symmetric sample of multilevel atoms to simulate the properties of topologically ordered states. The Rydberg blockade interaction is used to prepare states of the sample which are equivalent to resonating valence bond states, Laughlin states, and string...

  3. Stellate ganglion blockade for analgesia following upper limb surgery.

    LENUS (Irish Health Repository)

    McDonnell, J G

    2012-01-31

    We report the successful use of a stellate ganglion block as part of a multi-modal postoperative analgesic regimen. Four patients scheduled for orthopaedic surgery following upper limb trauma underwent blockade of the stellate ganglion pre-operatively under ultrasound guidance. Patients reported excellent postoperative analgesia, with postoperative VAS pain scores between 0 and 2, and consumption of morphine in the first 24 h ranging from 0 to 14 mg. While these are preliminary findings, and must be confirmed in a clinical trial, they highlight the potential for stellate ganglion blockade to provide analgesia following major upper limb surgery.

  4. Binding Sites in the EFG1 Promoter for Transcription Factors in a Proposed Regulatory Network: A Functional Analysis in the White and Opaque Phases of Candida albicans

    Science.gov (United States)

    Pujol, Claude; Srikantha, Thyagarajan; Park, Yang-Nim; Daniels, Karla J.; Soll, David R.

    2016-01-01

    In Candida albicans the transcription factor Efg1, which is differentially expressed in the white phase of the white-opaque transition, is essential for expression of the white phenotype. It is one of six transcription factors included in a proposed interactive transcription network regulating white-opaque switching and maintenance of the alternative phenotypes. Ten sites were identified in the EFG1 promoter that differentially bind one or more of the network transcription factors in the white and/or opaque phase. To explore the functionality of these binding sites in the differential expression of EFG1, we generated targeted deletions of each of the 10 binding sites, combinatorial deletions, and regional deletions using a Renilla reniformis luciferase reporter system. Individually targeted deletion of only four of the 10 sites had minor effects consistent with differential expression of EFG1, and only in the opaque phase. Alternative explanations are considered. PMID:27172219

  5. Peptidoglycan recognition protein 1 enhances experimental asthma by promoting Th2 and Th17 and limiting regulatory T cell and plasmacytoid dendritic cell responses.

    Science.gov (United States)

    Park, Shin Yong; Jing, Xuefang; Gupta, Dipika; Dziarski, Roman

    2013-04-01

    Asthma is a common inflammatory disease involving cross-talk between innate and adaptive immunity. We reveal that antibacterial innate immunity protein, peptidoglycan recognition protein (Pglyrp)1, is involved in the development of allergic asthma. Pglyrp1(-/-) mice developed less severe asthma than wild-type (WT) mice following sensitization with house dust mite (allergen) (HDM). HDM-sensitized Pglyrp1(-/-) mice, compared with WT mice, had diminished bronchial hyperresponsiveness (lung airway resistance); numbers of eosinophils, neutrophils, lymphocytes, and macrophages in bronchoalveolar lavage fluid and lungs; inflammatory cell infiltrates in the lungs around bronchi, bronchioles, and pulmonary arteries and veins; lung remodeling (mucin-producing goblet cell hyperplasia and metaplasia and smooth muscle hypertrophy and fibrosis); levels of IgE, eotaxins, IL-4, IL-5, and IL-17 in the lungs; and numbers of Th2 and Th17 cells and expression of their marker genes in the lungs. The mechanism underlying this decreased sensitivity of Pglyrp1(-/-) mice to asthma was increased generation and activation of CD8α(+)β(+) and CD8α(+)β(-) plasmacytoid dendritic cells (pDC) and increased recruitment and activity of regulatory T (Treg) cells in the lungs. In vivo depletion of pDC in HDM-sensitized Pglyrp1(-/-) mice reversed the low responsive asthma phenotype of Pglyrp1(-/-) mice to resemble the more severe WT phenotype. Thus, Pglyrp1(-/-) mice efficiently control allergic asthma by upregulating pDC and Treg cells in the lungs, whereas in WT mice, Pglyrp1 is proinflammatory and decreases pDC and Treg cells and increases proasthmatic Th2 and Th17 responses. Blocking Pglyrp1 or enhancing pDC in the lungs may be beneficial for prevention and treatment of asthma. PMID:23420883

  6. Promoting Implementation of Safety Culture in Nuclear Application for Industrial Facilities; an Important Role of Nuclear Energy Regulatory Agency in Indonesia

    Energy Technology Data Exchange (ETDEWEB)

    Setianingsih, Lilis Susanti [KINS-KAIST Master Degree Program, Daejeon (Korea, Republic of)

    2012-03-15

    Implementation of nuclear energy for industrial purposes has reached its highest peak. BAPETEN, as Nuclear Energy Regulatory Agency of Indonesia has published regulations regarding nuclear energy utilization. As high risk associating such utilization requires direct and thoroughly supervision in order to assure its compliance to safety and security aspect, procedures related to operational activities must by fully applied. Radiation Protection Program as one type of procedures that must be available in nuclear energy utilization operation is intended to provide operators specifically technical guidance to avoid undesired negative effects of incidents or accidents. It is the responsibility of managerial level in a company to provide the procedures and to further supervise their application in the field. Radiation workers, those are all employees working in or within radiation area must understand how to execute the procedures properly. The radiation protection program is intended to protect workers, member of community and property as well as the environment from the negative impacts of nuclear utilization operational due to its radiation exposure. Safety culture, a compound of nature derived from behavior of organization and people within the organization to pay a full attention and give main priority in radiation safety matters, is expected to be achieved by implementing the radiation protection program as safety habits at the work place. It requires a management commitment to ensure that all aspect in safety and, whenever necessary, security are accomplished within the radiation protection program in order to build a safety culture in a radiation work place. Government Regulation No. 33 2007 about Safety for Ionizing Radiation and Security for Radioactive Source and Government Regulation No. 29 2008 regarding Licensing for Utilization of Ionizing Radiation and Nuclear Material present regulation and arrangement related to radiation protection program as a basic

  7. Promoting Implementation of Safety Culture in Nuclear Application for Industrial Facilities; an Important Role of Nuclear Energy Regulatory Agency in Indonesia

    International Nuclear Information System (INIS)

    Implementation of nuclear energy for industrial purposes has reached its highest peak. BAPETEN, as Nuclear Energy Regulatory Agency of Indonesia has published regulations regarding nuclear energy utilization. As high risk associating such utilization requires direct and thoroughly supervision in order to assure its compliance to safety and security aspect, procedures related to operational activities must by fully applied. Radiation Protection Program as one type of procedures that must be available in nuclear energy utilization operation is intended to provide operators specifically technical guidance to avoid undesired negative effects of incidents or accidents. It is the responsibility of managerial level in a company to provide the procedures and to further supervise their application in the field. Radiation workers, those are all employees working in or within radiation area must understand how to execute the procedures properly. The radiation protection program is intended to protect workers, member of community and property as well as the environment from the negative impacts of nuclear utilization operational due to its radiation exposure. Safety culture, a compound of nature derived from behavior of organization and people within the organization to pay a full attention and give main priority in radiation safety matters, is expected to be achieved by implementing the radiation protection program as safety habits at the work place. It requires a management commitment to ensure that all aspect in safety and, whenever necessary, security are accomplished within the radiation protection program in order to build a safety culture in a radiation work place. Government Regulation No. 33 2007 about Safety for Ionizing Radiation and Security for Radioactive Source and Government Regulation No. 29 2008 regarding Licensing for Utilization of Ionizing Radiation and Nuclear Material present regulation and arrangement related to radiation protection program as a basic

  8. PD-1 Blockade Expands Intratumoral Memory T Cells

    DEFF Research Database (Denmark)

    Ribas, Antoni; Shin, Daniel Sanghoon; Zaretsky, Jesse;

    2016-01-01

    Tumor responses to programmed cell death protein 1 (PD-1) blockade therapy are mediated by T cells, which we characterized in 102 tumor biopsies obtained from 53 patients treated with pembrolizumab, an antibody to PD-1. Biopsies were dissociated, and single-cell infiltrates were analyzed by multi...

  9. Axillary Brachial Plexus Blockade for the Reflex Sympathetic Dystrophy Syndrome.

    Science.gov (United States)

    Ribbers, G. M.; Geurts, A. C. H.; Rijken, R. A. J.; Kerkkamp, H. E. M.

    1997-01-01

    Reflex sympathetic dystrophy syndrome (RSD) is a neurogenic pain syndrome characterized by pain, vasomotor and dystrophic changes, and often motor impairments. This study evaluated the effectiveness of brachial plexus blockade with local anaesthetic drugs as a treatment for this condition. Three patients responded well; three did not. (DB)

  10. Humoral immune response induced by an engineered cell-based neuroblastoma vaccine with or without CD25 blockade

    Institute of Scientific and Technical Information of China (English)

    Jin Zheng; Rimas Orentas; Xiaofei Yan; Hongli Liu

    2011-01-01

    Neuroblastoma is the most common extracranial solid cancer in childhood and it can develop in the nerve tissue of the adrenal gland, neck, chest, or spinal cord A number of tumor-associated antigens(TAAs), which can elicit humoral immunity, have been identified in cancer patients. To investigate the humoral immunity during neuroblastoma development, we treated A/J mice with an aggressive clone of neuroblastoma(AGN2a)cells, then vaccinated the mice with cells expressing AGN2a-CD80/CD137L under the condihons with or without regulatory T cell blockade. Strong humoral immunity was induced by AGN2a-CD80/CD137L immunization in the context of regulatory T cell blockade. Sera from treated mice were used to screen an AGN2a cDNA expression library for identifying TAAs by SEREX(serological analysis of recombinant cDNA expression libraries). Clones were identified by sequencing and comparative analysis of gene pools. Further investigation of these gene products revealed that most of them play a role in the neuronal differentiation, cell metabolism, and are highly expressed in other types of malignancy. Asz1(ankyrin repeat, SAM, and basic leucine zipper domaincontaining protein)was found in all tumor-bearing groups. These results implicated that these candidates identified from tumor-bearing mice may be neuroblastoma-associated antigens, which can be used as biomarkers in early diagnosis of neuroblastoma, whereas those identified from vaccinated mice may be the potential therapeutic targets.

  11. Study of regulatory promoter polymorphism (-248 G>A) of Bax gene in patients with gastric cancer in the northern provinces of Iran

    Science.gov (United States)

    Mirmajidi, Seyedeh Habibeh; Najafi, Mojtaba; Mirmajidi, Seyedeh Tahereh; Nasri Nasrabadi, Nafiseh

    2016-01-01

    Aim: The aim of this study is to evaluate the polymorphism in Bax gene and its association with some clinical pathology traits in gastric cancer. Background: Gastric cancer is considered as the fourth most common cancer in the north and northwest of Iran. Bcl2 family has a key role in regulation of apoptosis, and any changes in the expression of Bcl2 lead to cancer. Patients and methods: Blood samples were collected from 100 cases and 89 controls in the northern provinces of Iran to evaluate promoter polymorphism (-248G

  12. USP22 promotes epithelial-mesenchymal transition via the FAK pathway in pancreatic cancer cells.

    Science.gov (United States)

    Ning, Zhen; Wang, Aman; Liang, Jinxiao; Xie, Yunpeng; Liu, Jiwei; Yan, Qiu; Wang, Zhongyu

    2014-10-01

    Epithelial-mesenchymal transition (EMT) contributes to the occurrence and development of tumors, particularly to the promotion of tumor invasion and metastasis. As a newly discovered ubiquitin hydrolase family member, USP22 plays a key role in the malignant transformation of tumors and the regulation of the cell cycle. However, recent studies on USP22 have primarily focused on its role in cell cycle regulation, and the potential mechanism underlying the promotion of tumor invasion and metastasis by abnormal USP22 expression has not been reported. Our studies revealed that the overexpression of USP22 in PANC-1 cells promoted Ezrin redistribution and phosphorylation and cytoskeletal remodeling, upregulated expression of the transcription factors Snail and ZEB1 to promote EMT, and increased cellular invasion and migration. In contrast, blockade of USP22 expression resulted in the opposite effects. In addition, the focal adhesion kinase (FAK) signaling pathway was shown to play a key role in the process of EMT induction in PANC-1 cells by USP22. Thus, the present study suggests that USP22 acts as a regulatory protein for EMT in pancreatic cancer, which may provide a new approach for the targeted therapy of pancreatic cancer. PMID:25070659

  13. The vitamin D analog, TX527, promotes a human CD4+CD25highCD127low regulatory T cell profile and induces a migratory signature specific for homing to sites of inflammation.

    Science.gov (United States)

    Baeke, Femke; Korf, Hannelie; Overbergh, Lut; Verstuyf, Annemieke; Thorrez, Lieven; Van Lommel, Leentje; Waer, Mark; Schuit, Frans; Gysemans, Conny; Mathieu, Chantal

    2011-01-01

    The use of hypocalcemic vitamin D analogs is an appealing strategy to exploit the immunomodulatory actions of active vitamin D in vivo while circumventing its calcemic side effects. The functional modulation of dendritic cells by these molecules is regarded as the key mechanism underlying their ability to regulate T cell reactivity. In this article, we demonstrate the capacity of the vitamin D analog, TX527, to target T cells directly. Microarray analysis of purified human CD3(+) T cells, cultured in the presence of TX527, revealed differential expression of genes involved in T cell activation, proliferation, differentiation, and migratory capacity. Accordingly, functional analysis showed a TX527-mediated suppression of the T cell proliferative capacity and activation status, accompanied by decreased expression of effector cytokines (IFN-γ, IL-4, and IL-17). Furthermore, TX527 triggered the emergence of CD4(+)CD25(high)CD127(low) regulatory T cells featuring elevated levels of IL-10, CTLA-4, and OX40 and the functional capacity to suppress activation and proliferation of effector T cells. Moreover, the vitamin D analog profoundly altered the homing receptor profile of T cells and their migration toward chemokine ligands. Remarkably, TX527 not only modulated skin-homing receptors as illustrated for the parent compound, but also reduced the expression of lymphoid organ-homing receptors (CD62L, CCR7, and CXCR4) and uniquely promoted surface expression of inflammatory homing receptors (CCR5, CXCR3, and CXCR6) on T cells. We conclude that TX527 directly affects human T cell function, thereby inhibiting effector T cell reactivity while inducing regulatory T cell characteristics, and imprints them with a specific homing signature favoring migration to sites of inflammation. PMID:21131424

  14. Hydrogen sulfide promotes cell proliferation of oral cancer through activation of the COX2/AKT/ERK1/2 axis.

    Science.gov (United States)

    Zhang, Shuai; Bian, Huan; Li, Xiaoxu; Wu, Huanhuan; Bi, Qingwei; Yan, Yingbin; Wang, Yixiang

    2016-05-01

    Hydrogen sulfide, the third gaseous transmitter, is one of the main causes of halitosis in the oral cavity. It is generally considered as playing a deleterious role in many oral diseases including oral cancer. However, the regulatory mechanisms involved in the effects of hydrogen sulfide on oral cancer growth remain largely unknown. In the present study, we investigated the underlying mechanisms through CCK-8 assay, EdU incorporation, real-time PCR, western blot and pathway blockade assays. Our results showed that hydrogen sulfide promoted oral cancer cell proliferation through activation of the COX2, AKT and ERK1/2 pathways in a dose-dependent manner. Blocking any of the three above pathways inhibited hydrogen sulfide-induced oral cancer cell proliferation. Meanwhile, blockade of COX2 by niflumic acid downregulated NaHS-induced p-ERK and p-AKT expression. Inactivation of the AKT pathway by GSK690693 significantly decreased NaHS‑induced p-ERK1/2 expression, and inhibition of the ERK1/2 pathway by U0126 markedly increased NaHS-induced p-AKT expression. Either the AKT or ERK1/2 inhibitor did not significantly alter the COX2 expression level. Our data revealed, for the first time, that hydrogen sulfide promotes oral cancer cell proliferation through activation of the COX2/AKT/ERK1/2 axis, suggesting new potential targets to eliminate the effect of hydrogen sulfide on the development of oral cancer. PMID:26987083

  15. A point mutation in the DNA-binding domain of HPV-2 E2 protein increases its DNA-binding capacity and reverses its transcriptional regulatory activity on the viral early promoter

    Directory of Open Access Journals (Sweden)

    Gao Chen

    2012-02-01

    Full Text Available Abstract Background The human papillomavirus (HPV E2 protein is a multifunctional DNA-binding protein. The transcriptional activity of HPV E2 is mediated by binding to its specific binding sites in the upstream regulatory region of the HPV genomes. Previously we reported a HPV-2 variant from a verrucae vulgaris patient with huge extensive clustered cutaneous, which have five point mutations in its E2 ORF, L118S, S235P, Y287H, S293R and A338V. Under the control of HPV-2 LCR, co-expression of the mutated HPV E2 induced an increased activity on the viral early promoter. In the present study, a series of mammalian expression plasmids encoding E2 proteins with one to five amino acid (aa substitutions for these mutations were constructed and transfected into HeLa, C33A and SiHa cells. Results CAT expression assays indicated that the enhanced promoter activity was due to the co-expressions of the E2 constructs containing A338V mutation within the DNA-binding domain. Western blots analysis demonstrated that the transiently transfected E2 expressing plasmids, regardless of prototype or the A338V mutant, were continuously expressed in the cells. To study the effect of E2 mutations on its DNA-binding activity, a serial of recombinant E2 proteins with various lengths were expressed and purified. Electrophoresis mobility shift assays (EMSA showed that the binding affinity of E2 protein with A338V mutation to both an artificial probe with two E2 binding sites or HPV-2 and HPV-16 promoter-proximal LCR sequences were significantly stronger than that of the HPV-2 prototype E2. Furthermore, co-expression of the construct containing A338V mutant exhibited increased activities on heterologous HPV-16 early promoter P97 than that of prototype E2. Conclusions These results suggest that the mutation from Ala to Val at aa 338 is critical for E2 DNA-binding and its transcriptional regulation.

  16. Anti-PD-1 Blockade and Stereotactic Radiation Produce Long-Term Survival in Mice With Intracranial Gliomas

    International Nuclear Information System (INIS)

    Purpose: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model. Methods and Materials: We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen. Results: Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon-γ+/tumor necrosis factor-α+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms. Conclusions: The combination of PD-1 blockade and localized

  17. Anti-PD-1 Blockade and Stereotactic Radiation Produce Long-Term Survival in Mice With Intracranial Gliomas

    Energy Technology Data Exchange (ETDEWEB)

    Zeng, Jing [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); See, Alfred P.; Phallen, Jillian; Jackson, Christopher M.; Belcaid, Zineb; Ruzevick, Jacob [Department of Neurosurgery, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Durham, Nicholas [Department of Immunology, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Meyer, Christian [Department of Oncology, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Harris, Timothy J. [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Albesiano, Emilia; Pradilla, Gustavo [Department of Neurosurgery, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Ford, Eric; Wong, John [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Hammers, Hans-Joerg [Department of Immunology, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Mathios, Dimitris; Tyler, Betty; Brem, Henry [Department of Neurosurgery, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Tran, Phuoc T. [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); Pardoll, Drew; Drake, Charles G. [Department of Immunology, Johns Hopkins Medical Institutes, Baltimore, Maryland (United States); and others

    2013-06-01

    Purpose: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model. Methods and Materials: We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen. Results: Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon-γ+/tumor necrosis factor-α+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms. Conclusions: The combination of PD-1 blockade and localized

  18. Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism

    Directory of Open Access Journals (Sweden)

    Christine eDugovic

    2014-02-01

    Full Text Available In accordance with the prominent role of orexins in the maintenance of wakefulness via activation of orexin-1 (OX1R and orexin-2 (OX2R receptors, various dual OX1/2R antagonists have been shown to promote sleep in animals and humans. While selective blockade of OX2R seems to be sufficient to initiate and prolong sleep, the beneficial effect of additional inhibition of OX1R remains controversial. The relative contribution of OX1R and OX2R to the sleep effects induced by a dual OX1/2R antagonist was further investigated in the rat, and specifically on rapid eye movement (REM sleep since a deficiency of the orexin system is associated with narcolepsy/cataplexy based on clinical and pre-clinical data. As expected, the dual OX1/2R antagonist SB-649868 was effective in promoting non-REM (NREM and REM sleep following oral dosing (10 and 30 mg/kg at the onset of the dark phase. However, a disruption of REM sleep was evidenced by a more pronounced reduction in the onset of REM as compared to NREM sleep, a marked enhancement of the REM/total sleep ratio, and the occurrence of a few episodes of direct wake to REM sleep transitions (REM intrusion. When administered subcutaneously, the OX2R antagonist JNJ-10397049 (10 mg/kg increased NREM duration whereas the OX1R antagonist GSK-1059865 (10 mg/kg did not alter sleep. REM sleep was not affected either by OX2R or OX1R blockade alone, but administration of the OX1R antagonist in combination with the OX2R antagonist induced a significant reduction in REM sleep latency and an increase in REM sleep duration at the expense of the time spent in NREM sleep. These results indicate that additional blockade of OX1R to OX2R antagonism elicits a dysregulation of REM sleep by shifting the balance in favor of REM sleep at the expense of NREM sleep that may increase the risk of adverse events. Translation of this hypothesis remains to be tested in the clinic.

  19. Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism.

    Science.gov (United States)

    Dugovic, Christine; Shelton, Jonathan E; Yun, Sujin; Bonaventure, Pascal; Shireman, Brock T; Lovenberg, Timothy W

    2014-01-01

    In accordance with the prominent role of orexins in the maintenance of wakefulness via activation of orexin-1 (OX1R) and orexin-2 (OX2R) receptors, various dual OX1/2R antagonists have been shown to promote sleep in animals and humans. While selective blockade of OX2R seems to be sufficient to initiate and prolong sleep, the beneficial effect of additional inhibition of OX1R remains controversial. The relative contribution of OX1R and OX2R to the sleep effects induced by a dual OX1/2R antagonist was further investigated in the rat, and specifically on rapid eye movement (REM) sleep since a deficiency of the orexin system is associated with narcolepsy/cataplexy based on clinical and pre-clinical data. As expected, the dual OX1/2R antagonist SB-649868 was effective in promoting non-REM (NREM) and REM sleep following oral dosing (10 and 30 mg/kg) at the onset of the dark phase. However, a disruption of REM sleep was evidenced by a more pronounced reduction in the onset of REM as compared to NREM sleep, a marked enhancement of the REM/total sleep ratio, and the occurrence of a few episodes of direct wake to REM sleep transitions (REM intrusion). When administered subcutaneously, the OX2R antagonist JNJ-10397049 (10 mg/kg) increased NREM duration whereas the OX1R antagonist GSK-1059865 (10 mg/kg) did not alter sleep. REM sleep was not affected either by OX2R or OX1R blockade alone, but administration of the OX1R antagonist in combination with the OX2R antagonist induced a significant reduction in REM sleep latency and an increase in REM sleep duration at the expense of the time spent in NREM sleep. These results indicate that additional blockade of OX1R to OX2R antagonism elicits a dysregulation of REM sleep by shifting the balance in favor of REM sleep at the expense of NREM sleep that may increase the risk of adverse events. Translation of this hypothesis remains to be tested in the clinic. PMID:24592208

  20. Specific blockade by CD54 and MHC II of CD40-mediated signaling for B cell proliferation and survival

    DEFF Research Database (Denmark)

    Doyle, I S; Hollmann, C A; Crispe, I N;

    2001-01-01

    Regulation of B lymphocyte proliferation is critical to maintenance of self-tolerance, and intercellular interactions are likely to signal such regulation. Here, we show that coligation of either the adhesion molecule ICAM-1/CD54 or MHC II with CD40 inhibited cell cycle progression and promoted...... apoptosis of mouse splenic B cells. This resulted from specific blockade of NF-kappa B induction, which normally inhibits apoptosis. LPS- or B cell receptor (BCR)-induced proliferation was not inhibited by these treatments, and mAb-induced association of CD40 with other B cell surface molecules did not have...

  1. Inhibition of calcineurin abrogates while inhibition of mTOR promotes regulatory T cell expansion and graft-versus-host disease protection by IL-2 in allogeneic bone marrow transplantation.

    Directory of Open Access Journals (Sweden)

    Atsushi Satake

    Full Text Available Regulatory T cells (Tregs attenuate excessive immune responses, making their expansion beneficial in immune-mediated diseases including allogeneic bone marrow transplantation (BMT-associated graft-versus-host disease (GVHD. We have recently reported that Treg expansion does not require phospholipase Cγ activation when IL-2 is provided. As such, the combination of IL-2 and a calcineurin inhibitor (Cyclosporine A; CsA expands Tregs while inhibiting Tconv proliferation and protects against a mouse model of multiple sclerosis. However, CsA inhibits Treg proliferation in the presence of a TCR stimulus, suggesting that CsA may negatively impact Treg proliferation when they receive strong allogeneic MHC-mediated TCR signals. In this study, we show that CsA inhibits Treg proliferation and inducible Treg generation in allogeneic but not in syngeneic BMT when IL-2 is provided. In contrast to CsA, the mTOR inhibitor (Rapamycin almost completely suppressed IL-2-mediated Treg proliferation. However, CsA and Rapamycin inhibited Treg proliferation to a similar extent when TCR stimulation was provided. Furthermore, Rapamycin promoted Treg expansion and inducible Treg generation in allogeneic BMT recipients treated with IL-2. Consistent with these observations, CsA abrogated while Rapamycin promoted the protective effect of IL-2 on allogeneic BMT-induced GVHD. These results suggest that while CsA permits IL-2-induced Treg proliferation in the syngeneic setting (absence of strong TCR signals, CsA in combination with IL-2 may be detrimental for Treg proliferation in an allogeneic setting. Thus, in allogeneic settings, an mTOR inhibitor such as Rapamycin is a better choice for adjunct therapy with IL-2 in expansion of Tregs and protection against allogeneic BMT-induced GVHD.

  2. Immunotherapeutic implications of IL-6 blockade for cytokine storm.

    Science.gov (United States)

    Tanaka, Toshio; Narazaki, Masashi; Kishimoto, Tadamitsu

    2016-07-01

    IL-6 contributes to host defense against infections and tissue injuries. However, exaggerated, excessive synthesis of IL-6 while fighting environmental stress leads to an acute severe systemic inflammatory response known as 'cytokine storm', since high levels of IL-6 can activate the coagulation pathway and vascular endothelial cells but inhibit myocardial function. Remarkable beneficial effects of IL-6 blockade therapy using a humanized anti-IL-6 receptor antibody, tocilizumab were recently observed in patients with cytokine release syndrome complicated by T-cell engaged therapy. In this review we propose the possibility that IL-6 blockade may constitute a novel therapeutic strategy for other types of cytokine storm, such as the systemic inflammatory response syndrome including sepsis, macrophage activation syndrome and hemophagocytic lymphohistiocytosis. PMID:27381687

  3. Effect of beta blockade and beta stimulation on stage fright.

    Science.gov (United States)

    Brantigan, C O; Brantigan, T A; Joseph, N

    1982-01-01

    Stage fright, physiologically the "fight or flight" reaction, is a disabling condition to the professional musician. Because it is mediated by the sympathetic nervous system, we have investigated the effects of beta blockade on musical performance with propranolol in a double blind fashion and the effects of beta stimulation using terbutaline. Stage fright symptoms were evaluated in two trials, which included a total of 29 subjects, by questionnaire and by the State Trai Anxiety Inventory. Quality of musical performance was evaluated by experienced music critics. Beta blockade eliminates the physical impediments to performance caused by stage fright and even eliminates the dry mouth so frequently encountered. The quality of musical performance as judged by experienced music critics is significantly improved. This effect is achieved without tranquilization. Beta stimulating drugs increase stage fright problems, and should be used in performing musicians only after consideration of the detrimental effects which they may have on musical performance. PMID:6120650

  4. Dynamical Coulomb blockade and spin-entangled electrons

    OpenAIRE

    Recher, Patrik; Loss, Daniel

    2003-01-01

    We consider the production of mobile and nonlocal pairwise spin-entangled electrons from tunneling of a BCS-superconductor (SC) to two normal Fermi liquid leads. The necessary mechanism to separate the two electrons coming from the same Cooper pair (spin-singlet) is achieved by coupling the SC to leads with a finite resistance. The resulting dynamical Coulomb blockade effect, which we describe phenomenologically in terms of an electromagnetic environment, is shown to be enhanced for tunneling...

  5. Neuromuscular blockade in cardiac surgery: An update for clinicians

    OpenAIRE

    Hemmerling Thomas; Russo Gianluca; Bracco David

    2008-01-01

    There have been great advancements in cardiac surgery over the last two decades; the widespread use of off-pump aortocoronary bypass surgery, minimally invasive cardiac surgery, and robotic surgery have also changed the face of cardiac anaesthesia. The concept of "Fast-track anaesthesia" demands the use of nondepolarising neuromuscular blocking drugs with short duration of action, combining the ability to provide (if necessary) sufficiently profound neuromuscular blockade during surgery and i...

  6. Indirect androgen doping by oestrogen blockade in sports

    OpenAIRE

    Handelsman, D J

    2008-01-01

    Androgens can increase muscular mass and strength and remain the most frequently abused and widely available drugs used in sports doping. Banning the administration of natural or synthetic androgens has led to a variety of strategies to circumvent the ban of the most effective ergogenic agents for power sports. Among these, a variety of indirect androgen doping strategies aiming to produce a sustained rise in endogenous testosterone have been utilized. These include oestrogen blockade by drug...

  7. Input-output theory of the unconventional photon blockade

    OpenAIRE

    Flayac, H.; Savona, V.

    2013-01-01

    We study the unconventional photon blockade, recently proposed for a coupled-cavity system, in the presence of input and output quantum fields. Mixing of the input or output channels still allows strong photon antibunching of the output field, but for optimal values of the system parameters that differ substantially from those that maximize antibunching of the intracavity field. This result shows that the specific input-output geometry in a photonic system determines the optimal design in vie...

  8. Identification of Coulomb blockade and macroscopic quantum tunneling by noise

    OpenAIRE

    Grabert, Hermann; Ingold, Gert-Ludwig

    2002-01-01

    The effects of Macroscopic Quantum Tunneling (MQT) and Coulomb Blockade (CB) in Josephson junctions are of considerable significance both for the manifestations of quantum mechanics on the macroscopic scale and potential technological applications. These two complementary effects are shown to be clearly distinguishable from the associated noise spectra. The current noise is determined exactly and a rather sharp crossover between flux noise in the MQT and charge noise in the CB regions is foun...

  9. H2-receptor blockade and exercise-induced asthma.

    OpenAIRE

    Nogrady, S G; Hahn, A G

    1984-01-01

    While in vitro studies suggest that H2-receptor blockade enhances mediator release from bronchial mast cells and leads to bronchoconstriction, in vivo studies have given conflicting results. Eight asthmatic subjects were given cimetidine 800 mg and placebo double-blind on different days. Baseline values of forced expiratory volume in one second (FEV1) were obtained before an 8 min standardized exercise test using a bicycle ergometer. Subjects inhaled cold, dry air and exercise on cimetidine a...

  10. Regulatory Anatomy

    DEFF Research Database (Denmark)

    Hoeyer, Klaus

    2015-01-01

    This article proposes the term “safety logics” to understand attempts within the European Union (EU) to harmonize member state legislation to ensure a safe and stable supply of human biological material for transplants and transfusions. With safety logics, I refer to assemblages of discourses, le...... arise. In short, I expose the regulatory anatomy of the policy landscape....

  11. Neuromuscular blockade in cardiac surgery: An update for clinicians

    Directory of Open Access Journals (Sweden)

    Hemmerling Thomas

    2008-01-01

    Full Text Available There have been great advancements in cardiac surgery over the last two decades; the widespread use of off-pump aortocoronary bypass surgery, minimally invasive cardiac surgery, and robotic surgery have also changed the face of cardiac anaesthesia. The concept of "Fast-track anaesthesia" demands the use of nondepolarising neuromuscular blocking drugs with short duration of action, combining the ability to provide (if necessary sufficiently profound neuromuscular blockade during surgery and immediate re-establishment of normal neuromuscular transmission at the end of surgery. Postoperative residual muscle paralysis is one of the major hurdles for immediate or early extubation after cardiac surgery. Nondepolarising neuromuscular blocking drugs for cardiac surgery should therefore be easy to titrate, of rapid onset and short duration of action with a pathway of elimination independent from hepatic or renal dysfunction, and should equally not affect haemodynamic stability. The difference between repetitive bolus application and continuous infusion is outlined in this review, with the pharmacodynamic and pharmacokinetic characteristics of vecuronium, pancuronium, rocuronium, and cisatracurium. Kinemyography and acceleromyography are the most important currently used neuromuscular monitoring methods. Whereas monitoring at the adductor pollicis muscle is appropriate at the end of surgery, monitoring of the corrugator supercilii muscle better reflects neuromuscular blockade at more central, profound muscles, such as the diaphragm, larynx, or thoraco-abdominal muscles. In conclusion, cisatracurium or rocuronium is recommended for neuromuscular blockade in modern cardiac surgery.

  12. Blockade of Death Ligand TRAIL Inhibits Renal Ischemia Reperfusion Injury

    International Nuclear Information System (INIS)

    Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI). Many investigators have reported that cell death via apoptosis significantly contributed to the pathophysiology of renal IRI. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, and induces apoptosis and inflammation. However, the role of TRAIL in renal IRI is unclear. Here, we investigated whether TRAIL contributes to renal IRI and whether TRAIL blockade could attenuate renal IRI. AKI was induced by unilateral clamping of the renal pedicle for 60 min in male FVB/N mice. We found that the expression of TRAIL and its receptors were highly upregulated in renal tubular cells in renal IRI. Neutralizing anti-TRAIL antibody or its control IgG was given 24 hr before ischemia and a half-dose booster injection was administered into the peritoneal cavity immediately after reperfusion. We found that TRAIL blockade inhibited tubular apoptosis and reduced the accumulation of neutrophils and macrophages. Furthermore, TRAIL blockade attenuated renal fibrosis and atrophy after IRI. In conclusion, our study suggests that TRAIL is a critical pathogenic factor in renal IRI, and that TRAIL could be a new therapeutic target for the prevention of renal IRI

  13. Dynamical Coulomb blockade of tunnel junctions driven by alternating voltages

    Science.gov (United States)

    Grabert, Hermann

    2015-12-01

    The theory of the dynamical Coulomb blockade is extended to tunneling elements driven by a time-dependent voltage. It is shown that, for standard setups where an external voltage is applied to a tunnel junction via an impedance, time-dependent driving entails an excitation of the modes of the electromagnetic environment by the applied voltage. Previous approaches for ac driven circuits need to be extended to account for the driven bath modes. A unitary transformation involving also the variables of the electromagnetic environment is introduced which allows us to split off the time dependence from the Hamiltonian in the absence of tunneling. This greatly simplifies perturbation-theoretical calculations based on treating the tunneling Hamiltonian as a perturbation. In particular, the average current flowing in the leads of the tunnel junction is studied. Explicit results are given for the case of an applied voltage with a constant dc part and a sinusoidal ac part. The connection with standard dynamical Coulomb blockade theory for constant applied voltage is established. It is shown that an alternating voltage source reveals significant additional effects caused by the electromagnetic environment. The hallmark of the dynamical Coulomb blockade in ac driven devices is a suppression of higher harmonics of the current by the electromagnetic environment. The theory presented basically applies to all tunneling devices driven by alternating voltages.

  14. Sequential RAAS blockade: is it worth the risk?

    Science.gov (United States)

    Persson, Frederik; Rossing, Peter

    2014-03-01

    Soon after the emergence of the renin-angiotensin-aldosterone system (RAAS) blocking treatment as the cornerstone of renoprotective treatment in the prevention and treatment of diabetic and nondiabetic CKD, it was investigated if a higher degree of achievable RAAS blockade by combining more than one compound is feasible and advantageous. Regardless of the benefits from using monotherapy for diabetic kidney disease, there is still much improvement to wish for in terms of kidney prognosis in these populations. A great deal of research has gone into evaluating combinations of the RAAS blocking treatments in different populations and with different drugs and doses. Studies have mostly been short-term and use surrogate endpoints such as albuminuria. Side effects have been well known and expected in terms of increasing potassium levels and hypotension, but to an acceptable extent. With recent disappointing results from major hard endpoint trials using dual RAAS blockade the concept is now under scrutiny. In this review we will discuss the pros and cons of dual RAAS blockade, with facts and findings from smaller studies, endpoint trials, and meta-analyses. PMID:24602465

  15. Assessment of regulatory effectiveness. Peer discussions on regulatory practices

    International Nuclear Information System (INIS)

    This report arises from the seventh series of peer discussions on regulatory practices entitled 'Assessment of Regulatory Effectiveness'. The term 'regulatory effectiveness' covers the quality of the work and level of performance of a regulatory body. In this sense, regulatory effectiveness applies to regulatory body activities aimed at preventing safety degradation and ensuring that an acceptable level of safety is being maintained by the regulated operating organizations. In addition, regulatory effectiveness encompasses the promotion of safety improvements, the timely and cost effective performance of regulatory functions in a manner which ensures the confidence of the operating organizations, the general public and the government, and striving for continuous improvements to performance. Senior regulators from 22 Member States participated in two peer group discussions during March and May 1999. The discussions were focused on the elements of an effective regulatory body, possible indicators of regulatory effectiveness and its assessment. This report presents the outcome of these meetings and recommendations of good practices identified by senior regulators, which do not necessarily reflect those of the governments of the nominating Member States, the organizations they belong to, or the International Atomic Energy Agency. In order to protect people and the environment from hazards associated with nuclear facilities, the main objective of a nuclear regulatory body is to ensure that a high level of safety in the nuclear activities under its jurisdiction is achieved, maintained and within the control of operating organizations. Even if it is possible to directly judge objective safety levels at nuclear facilities, such safety levels would not provide an exclusive indicator of regulatory effectiveness. The way the regulatory body ensures the safety of workers and the public and the way it discharges its responsibilities also determine its effectiveness. Hence the

  16. Putative role of monoamines in the antidepressant-like mechanism induced by striatal MT2 blockade.

    Science.gov (United States)

    Noseda, Ana Carolina D; Rodrigues, Lais S; Targa, Adriano D S; Aurich, Mariana F; Vital, Maria A B F; Da Cunha, Cláudio; Lima, Marcelo M S

    2014-12-15

    It has been observed that the secretion pattern of melatonin is modified in Parkinson's disease (PD). Hence, it is hypothesized that dysregulations of melatonin MT2 receptors may be involved in the installation of depression in PD patients. Together with recent evidence based on the use of the intranigral rotenone model of PD, have led to the hypothesis that modulating the striatal MT2 receptor could provide a more comprehensive understanding of the antidepressant properties triggered. To further investigate this issue, male Wistar rats were infused with intranigral rotenone (12μg/μL) and seven days later subjected to a rapid eye movement sleep deprivation (REMSD) for 24h. After, we injected within the striatum the MT2 selective agonist, 8-M-PDOT (10μg/μL), the MT2 selective antagonist, 4-P-PDOT (5μg/μL) or vehicle. Subsequently, they were tested in the forced swimming test and were allowed to perform the sleep rebound (REB). Then, the rats were re-tested, and the striatum, hippocampus and substantia nigra pars compacta (SNpc) were collected for neurochemical purposes. Results indicated substantial antidepressant effects promoted by the blockade of striatal MT2 receptors that were potentiated by REMSD. MT2 activation increased DA levels in the striatum and hippocampus, while MT2 blockade increase DA in the SNpc. 4-P-PDOT treatment of the rotenone REMSD group generated a decrement in 5-HT levels within the striatum, hippocampus and SNpc. However, increased 5-HT turnover was observed among these structures. Therefore, we demonstrated the neurochemical antidepressant effect induced by striatal MT2 blockage associated with REMSD in the rotenone model of PD. PMID:25218873

  17. Study on Cell Cycle Regulatory Mechanism in Rat Bladder Carcinogenesis Promoted by Terephthalic Acid%对苯二甲酸促进大鼠膀胱癌发生的细胞周期调节机制研究

    Institute of Scientific and Technical Information of China (English)

    石远; 唐建梅

    2011-01-01

    [ Objective ] To study the cell cycle regulatory mechanism in rat bladder carcinogenesis promoted by terephthalic acid (TPA). [ Methods ] A total of 50 male Wister rats were divided into test group (30 rats) and control group (20 rats), respectively intraperitoneally injected with N-methyl-N-nitrosourea (MNU) and citrate buffer twice a week for 4 weeks, and then basal diet containing 5%TPA were given to the test group and basal diet to the control group separately for the next 22 weeks. Major regulatory proteins in Gl cell cycle checkpoint including pl6INK4a, cyclin-dependent kinase 4 (Cdk4), cyclin Dl, and retinoblastoma protein (pRb) were determined during various stages of urinary bladder carcinogenesis by immunohistochemistry. [ Results ] In MNU-5% TPA treated group, the incidences of overexpression of Cdk4, cyclin Dl and pRb in papilloma were significantly higher than those in epithelial simple hyperplasia (P=0.023, .P<0.001 and P< 0.001, respectively) and in papillary or nodular (PN) hyperplasia (P=0.042, ^=0.012 and P=0.002, respectively). The incidence of absent expression of pl61NK4 in papilloma was much higher than that in epithelial simple hyperplasia {P=0.004) and in PN hyperplasia (P=0.02). [ Conclusion ] Our results clearly reveal that the disorder of pl6INK4-cyclin Dl/Cdk4-pRb pathway is associated with bladder carcinogenesis promoted by TPA-stone.%[目的]研究对苯二甲酸(terephthalic acid,TPA)促进膀胱癌发生的细胞周期调节机制.[方法]50只blister大鼠分为实验组(30只)及对照组(20只),每周两次分别腹腔注射甲基亚硝墓脲(MNU)和冰柠檬酸盐缓冲液,持续4周.在随后的22周,分别给大鼠饲以含5%TPA和0%TPA的饲料.利用免疫组织化学方法检查G1细胞周期关卡的主要调节蛋白包括抑癌基因p16(INK4a)蛋白(pl6(INK4a))、周期素依赖性蛋白激酶4(Cdk4)、细胞周期蛋白D1(cyclin Dl)和成视网膜细胞瘤蛋白(pRb)在大鼠膀胱癌发生各

  18. Blockade of Wnt/β-Catenin Pathway Aggravated Silica-Induced Lung Inflammation through Tregs Regulation on Th Immune Responses

    Directory of Open Access Journals (Sweden)

    Wujing Dai

    2016-01-01

    Full Text Available CD4+ T cells play an important role in regulating silica-induced inflammation and fibrosis. Recent studies showed that Wnt/β-catenin pathway could modulate the function and the differentiation of CD4+ T cells. Therefore, Wnt/β-catenin pathway may participate in the development and progress of silicosis. To investigate the role of Wnt/β-catenin pathway, we used lentivirus expressing β-catenin shRNA to block the Wnt/β-catenin pathway by intratracheal instillation to the mice model of silicosis. Treatment of lentivirus could significantly aggravate the silica-induced lung inflammation and attenuated the fibrosis at the late stage. By analyzing CD4+ T cells, we found that blockade of Wnt/β-catenin pathway suppressed regulatory T cells (Tregs. Reciprocally, enhanced Th17 response was responsible for the further accumulation of neutrophils and production of proinflammatory cytokines. In addition, blockade of Wnt/β-catenin pathway delayed the Th1/Th2 polarization by inhibiting Tregs and Th2 response. These results indicated that Wnt/β-catenin pathway could regulate Tregs to modulate Th immune response, which finally altered the pathological character of silicosis. Our study suggested that Wnt/β-catenin pathway might be a potential target to treat the silica-induced inflammation and fibrosis.

  19. Consequences of Zeeman Degeneracy for van der Waals Blockade between Rydberg Atoms

    OpenAIRE

    Walker, Thad G.; Saffman, M.

    2007-01-01

    We analyze the effects of Zeeman degeneracies on the long-range interactions between like Rydberg atoms, with particular emphasis on applications to quantum information processing using van der Waals blockade. We present a general analysis of how degeneracies affect the primary error sources in blockade experiments, emphasizing that blockade errors are sensitive primarily to the weakest possible atom-atom interactions between the degenerate states, not the mean interaction strength. We presen...

  20. International Collaboration on Regulatory Supervision

    International Nuclear Information System (INIS)

    This paper describes the Norwegian Radiation Protection Authority's experience in regulatory cooperation projects in Russia, with special focus on legacy issues. These legacies include large waste sources, such as those used in radioisotope thermoelectric generators, and remediation of former military sites used for storage of spent nuclear fuel and radioactive waste. The objectives of the cooperation programme are to promote effective and efficient regulatory supervision, taking into account international recommendations and good practice in other countries. Specific projects in the program address specific challenges which require practical local interpretation of ICRP recommendations, the IAEA Basic Safety Standards and other IAEA requirements and guidance documents. In some cases, new regulatory documentation has been required, as well as new regulatory procedures. In the long term, the program is intended to lead to an enhanced and enduring safety culture. The positive experience in Russia has encouraged the Norwegian government in 2008 to extend the regulatory collaboration programme to countries in central Asia, using experience gained with Russian regulatory authorities as well as support from Russian Technical Support Organisations. The programmes are evolving into a regional regulatory support group. Noting this experience, the paper includes suggestions and ideas for how such regional groups can be effective in addressing common radiation safety objectives while addressing local differences in technical, geographical, economic and cultural matters in each country. (Author)

  1. CXCR3 blockade protects against Listeria monocytogenes infection-induced fetal wastage.

    Science.gov (United States)

    Chaturvedi, Vandana; Ertelt, James M; Jiang, Tony T; Kinder, Jeremy M; Xin, Lijun; Owens, Kathryn J; Jones, Helen N; Way, Sing Sing

    2015-04-01

    Mammalian pregnancy requires protection against immunological rejection of the developing fetus bearing discordant paternal antigens. Immune evasion in this developmental context entails silenced expression of chemoattractant proteins (chemokines), thereby preventing harmful immune cells from penetrating the maternal-fetal interface. Here, we demonstrate that fetal wastage triggered by prenatal Listeria monocytogenes infection is driven by placental recruitment of CXCL9-producing inflammatory neutrophils and macrophages that promote infiltration of fetal-specific T cells into the decidua. Maternal CD8+ T cells with fetal specificity upregulated expression of the chemokine receptor CXCR3 and, together with neutrophils and macrophages, were essential for L. monocytogenes-induced fetal resorption. Conversely, decidual accumulation of maternal T cells with fetal specificity and fetal wastage were extinguished by CXCR3 blockade or in CXCR3-deficient mice. Remarkably, protection against fetal wastage and in utero L. monocytogenes invasion was maintained even when CXCR3 neutralization was initiated after infection, and this protective effect extended to fetal resorption triggered by partial ablation of immune-suppressive maternal Tregs, which expand during pregnancy to sustain fetal tolerance. Together, our results indicate that functionally overriding chemokine silencing at the maternal-fetal interface promotes the pathogenesis of prenatal infection and suggest that therapeutically reinforcing this pathway represents a universal approach for mitigating immune-mediated pregnancy complications. PMID:25751061

  2. Regulatory aspects on nanomedicines.

    Science.gov (United States)

    Sainz, Vanessa; Conniot, João; Matos, Ana I; Peres, Carina; Zupancic, Eva; Moura, Liane; Silva, Liana C; Florindo, Helena F; Gaspar, Rogério S

    2015-12-18

    Nanomedicines have been in the forefront of pharmaceutical research in the last decades, creating new challenges for research community, industry, and regulators. There is a strong demand for the fast development of scientific and technological tools to address unmet medical needs, thus improving human health care and life quality. Tremendous advances in the biomaterials and nanotechnology fields have prompted their use as promising tools to overcome important drawbacks, mostly associated to the non-specific effects of conventional therapeutic approaches. However, the wide range of application of nanomedicines demands a profound knowledge and characterization of these complex products. Their properties need to be extensively understood to avoid unpredicted effects on patients, such as potential immune reactivity. Research policy and alliances have been bringing together scientists, regulators, industry, and, more frequently in recent years, patient representatives and patient advocacy institutions. In order to successfully enhance the development of new technologies, improved strategies for research-based corporate organizations, more integrated research tools dealing with appropriate translational requirements aiming at clinical development, and proactive regulatory policies are essential in the near future. This review focuses on the most important aspects currently recognized as key factors for the regulation of nanomedicines, discussing the efforts under development by industry and regulatory agencies to promote their translation into the market. Regulatory Science aspects driving a faster and safer development of nanomedicines will be a central issue for the next years. PMID:26260323

  3. Filtering single atoms from Rydberg blockaded mesoscopic ensembles

    CERN Document Server

    Petrosyan, David; Mølmer, Klaus

    2015-01-01

    We propose an efficient method to filter out single atoms from trapped ensembles with unknown number of atoms. The method employs stimulated adiabatic passage to reversibly transfer a single atom to the Rydberg state which blocks subsequent Rydberg excitation of all the other atoms within the ensemble. This triggers the excitation of Rydberg blockaded atoms to short lived intermediate states and their subsequent decay to untrapped states. Using an auxiliary microwave field to carefully engineer the dissipation, we obtain a nearly deterministic single-atom source. Our method is applicable to small atomic ensembles in individual microtraps and in lattice arrays.

  4. COULOMB BLOCKADE EFFECT IN SELF-ASSEMBLED GOLD QUANTUM DOTS

    Institute of Scientific and Technical Information of China (English)

    Shu-Fen Hu; Ru-Ling Yeh; Ru-Shi Liu

    2004-01-01

    Nanometer-scale Au quantum dots have been assembled on SiO2 by controlling the reaction of raw materials to form a citrate Au sol and an aminosilane/dithiol-treated patterned Si wafer. The detailed formation mechanism has been studied. Three gold colloidal particles (~15 nm), aligned in a chain to form a one-dimensional current path, was bridged across an 80-nm gap between source and drain metal electrodes. The device exhibited a Coulomb blockade effect at 33 K.

  5. GP IIb/IIIa Blockade During Peripheral Artery Interventions

    International Nuclear Information System (INIS)

    The activation of the platelet GP IIb/IIIa receptor is the final and common pathway in platelet aggregation. By blocking this receptor, platelet aggregation can be inhibited independently of the stimulus prompted the targeting of this receptor. Several years ago, three drugs have been approved for coronary artery indications. Since that time, there is increasing evidence that GP IIb/IIIa receptor blockade might have also an important role in peripheral arterial intervention. This article summarizes the action and differences of GP Ilb/IIIa receptor inhibitors and its possible indication in peripheral arteries

  6. Optimising abdominal space with deep neuromuscular blockade in gynaecologic laparoscopy

    DEFF Research Database (Denmark)

    Madsen, Matias Vested; Gätke, M R; Springborg, H H;

    2015-01-01

    neuromuscular blockade (NMB) would enlarge surgical space, measured as the distance from the sacral promontory to the trocar in patients undergoing gynaecologic laparoscopy. METHODS: Fourteen patients were randomised in an assessor-blinded crossover design. The distance from the sacral promontory to the trocar...... resulted in significantly better ratings of surgical conditions during suturing of the fascia (P=0.03, Mann-Whitney U-test). CONCLUSION: Deep NMB enlarged surgical space measured as the distance from the sacral promontory to the trocar. The enlargement, however, was minor and the clinical significance is...

  7. Coulomb Blockade in an Ultrathin Ti Nanowire at Room Temperature

    Institute of Scientific and Technical Information of China (English)

    CAIQiyu; YANGTao; CAIBingchu; YINYou; JIANGJianfei

    2003-01-01

    A scanning tunneling microscope operated in ambient air was employed to fabricate a~ 30nm-wide and ~ 700nm-long Ti nanowire connecting the source and drain electrodes on a 3nm-thick Ti film. The ultraflne but nonuniform Ti nanowire was well defined between two ox-idized lines. The gate electrode was capacitively coupled to the nanowire by a ~150nm-wide oxidized line. The electrical properties measured at room temperature of the Ti nanowire showed Coulomb blockade in highly nonlinear Ids-Vds characteristics and Coulomb oscillation in Ids - Vgs characteristics.

  8. Co-receptor and co-stimulation blockade for mixed chimerism and tolerance without myelosuppressive conditioning

    Directory of Open Access Journals (Sweden)

    Fairchild Paul J

    2006-04-01

    Full Text Available Abstract Background A major challenge in the application of marrow transplantation as a route to immunological tolerance of a transplanted organ is to achieve hematopoietic stem cell (HSC engraftment with minimal myelosuppressive treatments. Results We here describe a combined antibody protocol which can achieve long-term engraftment with clinically relevant doses of MHC-mismatched bone marrow, without the need for myelosuppressive drugs. Although not universally applicable in all strains, we achieved reliable engraftment in permissive strains with a two-stage strategy: involving first, treatment with anti-CD8 and anti-CD4 in advance of transplantation; and second, treatment with antibodies targeting CD4, CD8 and CD40L (CD154 at the time of marrow transplantation. Long-term mixed chimerism through co-receptor and co-stimulation blockade facilitated tolerance to donor-type skin grafts, without any evidence of donor-antigen driven regulatory T cells. Conclusion We conclude that antibodies targeting co-receptor and co-stimulatory molecules synergise to enable mixed hematopoietic chimerism and central tolerance, showing that neither cytoreductive conditioning nor 'megadoses' of donor bone marrow are required for donor HSC to engraft in permissive strains.

  9. Combined Anti-CD154/CTLA4Ig Costimulation Blockade-Based Therapy Induces Donor-Specific Tolerance to Vascularized Osteomyocutaneous Allografts.

    Science.gov (United States)

    Lin, C H; Wang, Y L; Anggelia, M R; Chuang, W Y; Cheng, H Y; Mao, Q; Zelken, J A; Lin, C H; Zheng, X X; Lee, W P A; Brandacher, G

    2016-07-01

    Tolerance induction by means of costimulation blockade has been successfully applied in solid organ transplantation; however, its efficacy in vascularized composite allotransplantation, containing a vascularized bone marrow component and thus a constant source of donor-derived stem cells, remains poorly explored. In this study, osteomyocutaneous allografts (alloOMCs) from Balb/c (H2(d) ) mice were transplanted into C57BL/6 (H2(b) ) recipients. Immunosuppression consisted of 1 mg anti-CD154 on day 0, 0.5 mg CTLA4Ig on day 2 and rapamycin (RPM; 3 mg/kg per day from days 0-7, then every other day for 3 weeks). Long-term allograft survival, donor-specific tolerance and donor-recipient cell trafficking were evaluated. Treatment with costimulation blockade plus RPM resulted in long-term graft survival (>120 days) of alloOMC in 12 of 15 recipients compared with untreated controls (median survival time [MST] ≈10.2 ± 0.8 days), RPM alone (MST ≈33 ± 5.5 days) and costimulation blockade alone (MST ≈45.8 ± 7.1 days). Donor-specific hyporesponsiveness in recipients with viable grafts was demonstrated in vitro. Evidence of donor-specific tolerance was further assessed in vivo by secondary donor-specific skin graft survival and third-party graft rejection. A significant increase of Foxp3(+) regulatory T cells was evident in tolerant animals. Donor cells populated peripheral blood, thymus, and both donor and recipient bone marrow. Consequently, combined anti-CD154/CTLA4Ig costimulation blockade-based therapy induces donor-specific tolerance in a stringent murine alloOMC transplant model. PMID:26914847

  10. A flexible regulatory framework

    International Nuclear Information System (INIS)

    Regulatory reform of the Finnish electricity market meant opening up potentially competitive parts of the electricity sector to competition and eliminating all unnecessary forms of regulation covering generation, wholesale supply, retail supply, and foreign trade in electricity. New types of control and regulatory mechanisms and institutions were set up for those parts of the electricity industry that were excluded from competition, such as network operations. Network activities now have to be licensed, whereas no licence is needed for generation or supply. A new sector-specific regulatory authority was established in 1995 to coincide with the implementation of the Electricity Market Act, known as the Electricity Market Authority. This is responsible for regulating network activities and retail supply to captive customers. The core function of the authority, which employs some 14 people, is to promote the smooth operation of the Finnish electricity market and to oversee the implementation of the Electricity Market Act and its provisions. Its most important duties are linked to overseeing the process by which network companies price their electricity. As price regulation no longer exists, all the companies in the electricity sector set their tariffs independently, even network companies. The job of controlling the pricing of network services is handed by the Electricity Market Authority, following the principles of competition control. Pricing control takes place ex post - after a pricing system has been adopted by a company and concentrates on individual cases and companies. There is no ex ante system of setting or approving prices and tariffs by the regulator. The tariffs and pricing of network services can be evaluated, however, by both the Electricity Market Authority and the Finnish Competition Authority, which have overlapping powers as regards the pricing of network activities. The Finnish regulatory framework can be described as a system of light

  11. Assessment of Methods for the Intracellular Blockade of GABAA Receptors.

    Science.gov (United States)

    Atherton, Laura A; Burnell, Erica S; Mellor, Jack R

    2016-01-01

    Selective blockade of inhibitory synaptic transmission onto specific neurons is a useful tool for dissecting the excitatory and inhibitory synaptic components of ongoing network activity. To achieve this, intracellular recording with a patch solution capable of blocking GABAA receptors has advantages over other manipulations, such as pharmacological application of GABAergic antagonists or optogenetic inhibition of populations of interneurones, in that the majority of inhibitory transmission is unaffected and hence the remaining network activity preserved. Here, we assess three previously described methods to block inhibition: intracellular application of the molecules picrotoxin, 4,4'-dinitro-stilbene-2,2'-disulphonic acid (DNDS) and 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS). DNDS and picrotoxin were both found to be ineffective at blocking evoked, monosynaptic inhibitory postsynaptic currents (IPSCs) onto mouse CA1 pyramidal cells. An intracellular solution containing DIDS and caesium fluoride, but lacking nucleotides ATP and GTP, was effective at decreasing the amplitude of IPSCs. However, this effect was found to be independent of DIDS, and the absence of intracellular nucleotides, and was instead due to the presence of fluoride ions in this intracellular solution, which also blocked spontaneously occurring IPSCs during hippocampal sharp waves. Critically, intracellular fluoride ions also caused a decrease in both spontaneous and evoked excitatory synaptic currents and precluded the inclusion of nucleotides in the intracellular solution. Therefore, of the methods tested, only fluoride ions were effective for intracellular blockade of IPSCs but this approach has additional cellular effects reducing its selectivity and utility. PMID:27501143

  12. Our experience on brachial plexus blockade in upper extremity surgery

    Directory of Open Access Journals (Sweden)

    Ömer Uslukaya

    2012-03-01

    Full Text Available Objective: Peripheral nerve blocks are usually used either alone or along with general anesthesia for postoperative analgesia. We also aimed to present the results and experiences.Materials and methods: This retrospective study was conducted to scan the files of patients who underwent orthopedic upper extremity surgery with peripheral nerve block between September 2009 and October 2010. After ethics committee approval was obtained, 114 patients who were ASA physical status I-III, aged 18-70, performed upper extremity surgery in the Orthopedics and Traumatology Clinic were included to study. Patients’ demographic data, clinical diagnoses, premedication status, peripheral block type, local anesthetic dose, stimuplex needle types, hemodynamic parameters at the during surgery, the first postoperative analgesic requirements, complications and patient satisfaction were recorded.Results: Demographic data were similar to each other. Brachial plexus block was commonly performed for the forearm surgery. Infraclavicular block was performed the most frequently to patients. As the classical methods in the supine position were preferred in 98.2% of patients, Stimuplex A needle (B. Braun, Melsungen AG, Germany have been used for blockage in 80.7% of patients. Also, in 54.4% of patients, 30 ml of local anesthetic solution composed of bupivacaine + prilocaine was used for blockade. Blocks applied to patients had provided adequate anesthesia.Conclusion: Since the brachial plexus blockade guided peripheral nerve stimulator for upper extremity surgery provide adequate depth of anesthesia and analgesia, it may be a good alternative to general anesthesia because of unwanted side effects

  13. Effects of VLA-1 Blockade on Experimental Inflammation in Mice.

    Science.gov (United States)

    Totsuka, Ryuichi; Kondo, Takaaki; Matsubara, Shigeki; Hirai, Midori; Kurebayashi, Yoichi

    2016-01-01

    VLA-1 (very late antigen-1) is implicated in recruitment, retention and activation of leukocytes and its blockade has been referred as a potential target of new drug discovery to address unmet medical needs in inflammatory disease area. In the present study, we investigate the effects of an anti-murine CD49a (integrin α subunit of VLA-1) monoclonal antibody (Ha31/8) on various experimental models of inflammatory diseases in mice. Pretreatment with Ha31/8 at an intraperitoneal dose of 250 µg significantly (P<0.01) reduced arthritic symptoms and joint tissue damage in mice with type II collagen-induced arthritis. In addition, Ha31/8 at an intraperitoneal dose of 100 µg significantly (P<0.01) inhibited airway inflammatory cell infiltration induced by repeated exposure to cigarette smoke. In contrast, Ha31/8 failed to inhibit oxazolone-induced chronic dermatitis and OVA-induced airway hyperresponsiveness at an intraperitoneal dose of 100 µg. These results show that VLA-1 is involved, at least partly, in the pathogenesis of type II collagen-induced arthritis and cigarette smoke-induced airway inflammatory cell infiltration in mice, indicating the therapeutic potential of VLA-1 blockade against rheumatoid arthritis and chronic occlusive pulmonary disease. PMID:27578034

  14. Philosophical Intelligence: Letters, Print, and Experiment during Napoleon's Continental Blockade.

    Science.gov (United States)

    Watts, Iain P

    2015-12-01

    This essay investigates scientific exchanges between Britain and France from 1806 to 1814, at the height of the Napoleonic Wars. It argues for a picture of scientific communication that sees letters and printed texts not as separate media worlds, but as interconnected bearers of time-critical information within a single system of intelligence gathering and experimental practice. During this period, Napoleon Bonaparte's Continental System blockade severed most links between Britain and continental Europe, yet scientific communications continued--particularly on electrochemistry, a subject of fierce rivalry between Britain and France. The essay traces these exchanges using the archive of a key go-between, the English man of science Sir Charles Blagden. The first two sections look at Blagden's letter-writing operation, reconstructing how he harnessed connections with neutral American diplomats, merchants, and the State to get scientific intelligence between London and Paris. The third section, following Blagden's words from Britain to France to America, looks at how information in letters cross-fertilized with information in print. The final section considers how letters and print were used together to solve the difficult practical problem of replicating experiments across the blockade. PMID:27024935

  15. A unified architecture of transcriptional regulatory elements

    DEFF Research Database (Denmark)

    Andersson, Robin; Sandelin, Albin Gustav; Danko, Charles G.

    2015-01-01

    Gene expression is precisely controlled in time and space through the integration of signals that act at gene promoters and gene-distal enhancers. Classically, promoters and enhancers are considered separate classes of regulatory elements, often distinguished by histone modifications. However, re...

  16. ICOS Promotes the Function of CD4+ Effector T Cells during Anti-OX40-Mediated Tumor Rejection.

    Science.gov (United States)

    Metzger, Todd C; Long, Hua; Potluri, Shobha; Pertel, Thomas; Bailey-Bucktrout, Samantha L; Lin, John C; Fu, Tihui; Sharma, Padmanee; Allison, James P; Feldman, Reid M R

    2016-07-01

    ICOS is a T-cell coregulatory receptor that provides a costimulatory signal to T cells during antigen-mediated activation. Antitumor immunity can be improved by ICOS-targeting therapies, but their mechanism of action remains unclear. Here, we define the role of ICOS signaling in antitumor immunity using a blocking, nondepleting antibody against ICOS ligand (ICOS-L). ICOS signaling provided critical support for the effector function of CD4(+) Foxp3(-) T cells during anti-OX40-driven tumor immune responses. By itself, ICOS-L blockade reduced accumulation of intratumoral T regulatory cells (Treg), but it was insufficient to substantially inhibit tumor growth. Furthermore, it did not impede antitumor responses mediated by anti-4-1BB-driven CD8(+) T cells. We found that anti-OX40 efficacy, which is based on Treg depletion and to a large degree on CD4(+) effector T cell (Teff) responses, was impaired with ICOS-L blockade. In contrast, the provision of additional ICOS signaling through direct ICOS-L expression by tumor cells enhanced tumor rejection and survival when administered along with anti-OX40 therapy. Taken together, our results showed that ICOS signaling during antitumor responses acts on both Teff and Treg cells, which have opposing roles in promoting immune activation. Thus, effective therapies targeting the ICOS pathway should seek to promote ICOS signaling specifically in effector CD4(+) T cells by combining ICOS agonism and Treg depletion. Cancer Res; 76(13); 3684-9. ©2016 AACR. PMID:27197182

  17. Regulatory Physiology

    Science.gov (United States)

    Lane, Helen W.; Whitson, Peggy A.; Putcha, Lakshmi; Baker, Ellen; Smith, Scott M.; Stewart, Karen; Gretebeck, Randall; Nimmagudda, R. R.; Schoeller, Dale A.; Davis-Street, Janis

    1999-01-01

    As noted elsewhere in this report, a central goal of the Extended Duration Orbiter Medical Project (EDOMP) was to ensure that cardiovascular and muscle function were adequate to perform an emergency egress after 16 days of spaceflight. The goals of the Regulatory Physiology component of the EDOMP were to identify and subsequently ameliorate those biochemical and nutritional factors that deplete physiological reserves or increase risk for disease, and to facilitate the development of effective muscle, exercise, and cardiovascular countermeasures. The component investigations designed to meet these goals focused on biochemical and physiological aspects of nutrition and metabolism, the risk of renal (kidney) stone formation, gastrointestinal function, and sleep in space. Investigations involved both ground-based protocols to validate proposed methods and flight studies to test those methods. Two hardware tests were also completed.

  18. Integrin antagonists prevent costimulatory blockade-resistant transplant rejection by CD8+ memory T cells

    Science.gov (United States)

    Kitchens, W. H.; Haridas, D.; Wagener, M. E.; Song, M.; Kirk, A. D.; Larsen, C. P.; Ford, M. L.

    2012-01-01

    The success of belatacept in late-stage clinical trials inaugurates the arrival of a new class of immunosuppressants based on costimulatory blockade, an immunosuppression strategy that disrupts essential signals required for alloreactive T cell activation. Despite having improved renal function, kidney transplant recipients treated with belatacept experienced increased rates of acute rejection. This finding has renewed focus on costimulatory blockade-resistant rejection and specifically the role of alloreactive memory T cells in mediating this resistance. To study mechanisms of costimulatory blockade-resistant rejection and enhance the clinical efficacy of costimulatory blockade, we developed an experimental transplant system that models a donor-specific memory CD8+ T cell response. After confirming that graft-specific memory T cells mediate costimulatory blockade-resistant rejection, we characterized the role of integrins in this rejection. The resistance of memory T cells to costimulatory blockade was abrogated when costimulatory blockade was coupled with either anti-VLA-4 or anti-LFA-1. Mechanistic studies revealed that in the presence of costimulatory blockade, anti-VLA-4 impaired T cell trafficking to the graft but not memory T cell recall effector function, whereas anti-LFA-1 attenuated both trafficking and memory recall effector function. As antagonists against these integrins are clinically approved, these findings may have significant translational potential for future clinical transplant trials. PMID:21942986

  19. Effects of adductor-canal-blockade on pain and ambulation after total knee arthroplasty

    DEFF Research Database (Denmark)

    Jenstrup, M T; Jæger, P; Lund, J; Fomsgaard, J S; Bache, S; Mathiesen, O; Larsen, T K; Dahl, J B

    2012-01-01

    Total knee arthroplasty (TKA) is associated with intense post-operative pain. Besides providing optimal analgesia, reduction in side effects and enhanced mobilization are important in this elderly population. The adductor-canal-blockade is theoretically an almost pure sensory blockade. We...

  20. Edge-state blockade of transport in quantum dot arrays

    Science.gov (United States)

    Benito, Mónica; Niklas, Michael; Platero, Gloria; Kohler, Sigmund

    2016-03-01

    We propose a transport blockade mechanism in quantum dot arrays and conducting molecules based on an interplay of Coulomb repulsion and the formation of edge states. As a model we employ a dimer chain that exhibits a topological phase transition. The connection to a strongly biased electron source and drain enables transport. We show that the related emergence of edge states is manifest in the shot noise properties as it is accompanied by a crossover from bunched electron transport to a Poissonian process. For both regions we develop a scenario that can be captured by a rate equation. The resulting analytical expressions for the Fano factor agree well with the numerical solution of a full quantum master equation.

  1. Investigation of uncertainty components in Coulomb blockade thermometry

    Energy Technology Data Exchange (ETDEWEB)

    Hahtela, O. M.; Heinonen, M.; Manninen, A. [MIKES Centre for Metrology and Accreditation, Tekniikantie 1, 02150 Espoo (Finland); Meschke, M.; Savin, A.; Pekola, J. P. [Low Temperature Laboratory, Aalto University, Tietotie 3, 02150 Espoo (Finland); Gunnarsson, D.; Prunnila, M. [VTT Technical Research Centre of Finland, Tietotie 3, 02150 Espoo (Finland); Penttilä, J. S.; Roschier, L. [Aivon Oy, Tietotie 3, 02150 Espoo (Finland)

    2013-09-11

    Coulomb blockade thermometry (CBT) has proven to be a feasible method for primary thermometry in every day laboratory use at cryogenic temperatures from ca. 10 mK to a few tens of kelvins. The operation of CBT is based on single electron charging effects in normal metal tunnel junctions. In this paper, we discuss the typical error sources and uncertainty components that limit the present absolute accuracy of the CBT measurements to the level of about 1 % in the optimum temperature range. Identifying the influence of different uncertainty sources is a good starting point for improving the measurement accuracy to the level that would allow the CBT to be more widely used in high-precision low temperature metrological applications and for realizing thermodynamic temperature in accordance to the upcoming new definition of kelvin.

  2. Ultra-high-ohmic microstripline resistors for Coulomb blockade devices.

    Science.gov (United States)

    Lotkhov, Sergey V

    2013-06-14

    In this paper, we report on the fabrication and low-temperature characterization of ultra-high-ohmic microstripline resistors made of a thin film of weakly oxidized titanium. Nearly linear voltage-current characteristics were measured at temperatures down to T ~ 20 mK for films with sheet resistivities as high as ~7 kΩ, i.e. about an order of magnitude higher than our previous findings for weakly oxidized Cr. Our analysis indicates that such an improvement can help to create an advantageous high-impedance environment for different Coulomb blockade devices. Further properties of the Ti film addressed in this work show the promise of low-noise behavior of the resistors when applied in different realizations of the quantum standard of current. PMID:23670293

  3. Cavity polaritons with Rydberg blockade and long-range interactions

    CERN Document Server

    Litinskaya, Marina; Pupillo, Guido

    2016-01-01

    We study interactions between polaritons, arising when photons strongly couple to collective excitations in an array of two-level atoms trapped in an optical lattice inside a cavity. We consider two types of interactions between atoms: Dipolar forces and atomic saturability, which ranges from hard-core repulsion to Rydberg blockade. We show that, in spite of the underlying repulsion in the subsystem of atomic excitations, saturability induces a broadband bunching of photons for two-polariton scattering states. We interpret this bunching as a result of interference, and trace it back to the mismatch of the quantization volumes for atomic excitations and photons. We examine also bound bipolaritonic states: These include states created by dipolar forces, as well as a gap bipolariton, which forms solely due to saturability effects in the atomic transition. Both types of bound states exhibit strong bunching in the photonic component. We discuss the dependence of bunching on experimentally relevant parameters.

  4. Investigation of uncertainty components in Coulomb blockade thermometry

    International Nuclear Information System (INIS)

    Coulomb blockade thermometry (CBT) has proven to be a feasible method for primary thermometry in every day laboratory use at cryogenic temperatures from ca. 10 mK to a few tens of kelvins. The operation of CBT is based on single electron charging effects in normal metal tunnel junctions. In this paper, we discuss the typical error sources and uncertainty components that limit the present absolute accuracy of the CBT measurements to the level of about 1 % in the optimum temperature range. Identifying the influence of different uncertainty sources is a good starting point for improving the measurement accuracy to the level that would allow the CBT to be more widely used in high-precision low temperature metrological applications and for realizing thermodynamic temperature in accordance to the upcoming new definition of kelvin

  5. Effect of on-chip filter on Coulomb blockade thermometer

    International Nuclear Information System (INIS)

    Coulomb Blockade Thermometer (CBT) is a primary thermometer based on electric conductance of normal tunnel junction arrays. One limitation for CBT use at the lowest temperatures has been due to environmental noise heating. To improve on this limitation, we have done measurements on CBT sensors fabricated with different on-chip filtering structures in a dilution refrigerator with a base temperature of 10 mK. The CBT sensors were produced with a wafer scale tunnel junction process. We present how the different on-chip filtering schemes affect the limiting saturation temperatures and show that CBT sensors with proper on-chip filtering work at temperatures below 20 mK and are tolerant to noisy environment.

  6. Thermoelectric properties of Coulomb-blockaded fractional quantum Hall islands

    Directory of Open Access Journals (Sweden)

    Lachezar S. Georgiev

    2015-05-01

    Full Text Available We show that it is possible and rather efficient to compute at non-zero temperature the thermoelectric characteristics of Coulomb blockaded fractional quantum Hall islands, formed by two quantum point contacts inside of a Fabry–Pérot interferometer, using the conformal field theory partition functions for the chiral edge excitations. The oscillations of the thermopower with the variation of the gate voltage as well as the corresponding figure-of-merit and power factors, provide finer spectroscopic tools which are sensitive to the neutral multiplicities in the partition functions and could be used to distinguish experimentally between different universality classes sharing the same electric properties. We also propose a procedure for measuring the ratio r=vn/vc of the Fermi velocities of the neutral and charged edge modes for filling factor νH=5/2 from the power-factor data in the low-temperature limit.

  7. Coulomb blockade in turnstile with multiple tunnel junctions

    CERN Document Server

    Lee, S C; Kang, D S; Kim, D C; Choi, C K; Ryu, J Y

    1999-01-01

    On the basis of the analytic solutions to the electrostatic problem of the multi-grated-small-junction systems, the stable domain for the Coulomb blockade of turnstile with multiple tunnel junctions at zero temperature has been analyzed as a function of the number of tunnel junction, the ratio of the gate capacitance to the junction capacitance, and the asymmetric factor. Our results show that domains form various shaped regions according to the asymmetric factor and their size depends on the number of junction and the ratio of the gate capacitance to the junction capacitance. In particular, it is shown that electrons can be transferred in positive and/or negative bias voltage depending on the asymmetric factor when an appropriate gate cycle is applied. Thus, the asymmetric factor plays an important role in determining the turnstile operation.

  8. Blockade of tolerance to morphine analgesia by cocaine.

    Science.gov (United States)

    Misra, A L; Pontani, R B; Vadlamani, N L

    1989-07-01

    Tolerance to morphine analgesia was induced in male Sprague-Dawley rats by s.c. implantation of a morphine base pellet (75 mg) on the first and second day and determining the magnitude of tolerance 72 h after the first implant by s.c. injection of a test dose of morphine (5 mg/kg). Implantation of a cocaine hydrochloride pellet (25 mg), concurrently with morphine pellets or of a cocaine hydrochloride (50 mg) pellet after the development of tolerance, blocked both the development and expression of morphine analgesic tolerance. In morphine-pelleted animals pretreatment for 3 days with desipramine or zimelidine or phenoxybenzamine but not haloperidol produced no significant morphine tolerance. Pretreatment with a combination of desipramine and zimelidine, however, was as effective as cocaine in blocking morphine tolerance. Alpha-Methyl-p-tyrosine methyl ester counteracted the effect of cocaine in blocking morphine tolerance and potentiated the tolerance development. Blockade of morphine tolerance by cocaine was reinforced and facilitated by pretreatment with fenfluramine or p-chlorophenylalanine ethyl ester and to a lesser extent by clonidine and haloperidol. Acute administration of fenfluramine or zimelidine or a combination of desipramine and zimelidine or alpha-methyl-p-tyrosine methyl ester or p-chlorophenylalanine ethyl ester did not significantly affect morphine analgesia. The study suggests an important role of the concomitant depletion of both central noradrenaline and serotonin in the blockade of morphine tolerance by cocaine and stresses the importance of the counter-balancing functional relationship between these two neurotransmitters in the central nervous system. PMID:2780065

  9. Thyroid blockade in fetuses and infants in a chimpanzee model

    International Nuclear Information System (INIS)

    In the event of a nuclear accident large populations might be exposed to fallout. The main internal radiation dose is received from radioiodine which enters the body with air, food or through the skin. A large fraction of the iodide in the circulation is concentrated by the cells of the thyroid, which have an iodide pump in their cell membrane. Radiation damage will occur mainly in the thyroid. Protection of the thyroid is achieved by preventing ingestion of radioiodine (shielding, food- and water control) and by stopping the thyroid from concentrating circulating radioiodine. Blockade of the thyroidal iodide pump by high levels of circulating iodide is responsible for the reduction of radioiodine uptake by the thyroid. For pregnant women no specific recommendations regarding the administration of stable iodide have been made. For infants younger than one year half the dose is recommended (2,4,5), though data to support this advice do not exist. Fetuses and infants might be more vulnerable to irradiation of the thyroid and therefore require effective protection. Efficiency of thyroid protection with stable iodide, however, was never assessed for these groups in the population. Nineteen infants and thirteen pregnant chimpanzees have been tested. The results demonstrate the efficiency of thyroid blockade with stable iodide in pregnancy and infancy, in chimpanzees. We feel that these data can be safely applied to the human situation. The main risk when fetuses and children are exposed to massive amounts of stable iodide is the induction of hypothyroidism. In the infant chimpanzees this didn't occur. 9 tabs

  10. IL-17 promotes murine lupus.

    Science.gov (United States)

    Amarilyo, Gil; Lourenço, Elaine V; Shi, Fu-Dong; La Cava, Antonio

    2014-07-15

    The proinflammatory activity of IL-17-producing Th17 cells has been associated with the pathogenesis of several autoimmune diseases. In this article, we provide direct evidence for a role of IL-17 in the pathogenesis of systemic lupus erythematosus (SLE). The induction of SLE by pristane in IL-17-sufficient wild-type mice did not occur in IL-17-deficient mice, which were protected from development of lupus autoantibodies and glomerulonephritis. The protection from SLE in IL-17-deficient mice was associated with a reduced frequency of CD3(+)CD4(-)CD8(-) double-negative T cells and an expansion of CD4(+) regulatory T cells, and did not depend on Stat-1 signaling. These data affirm the key role of IL-17 in the pathogenesis of SLE and strengthen the support for IL-17 blockade in the therapy of SLE. PMID:24920843

  11. Long-term Benefit of PD-L1 Blockade in Lung Cancer Associated with JAK3 Activation.

    Science.gov (United States)

    Van Allen, Eliezer M; Golay, Hadrien G; Liu, Yan; Koyama, Shohei; Wong, Karrie; Taylor-Weiner, Amaro; Giannakis, Marios; Harden, Maegan; Rojas-Rudilla, Vanesa; Chevalier, Aaron; Thai, Tran; Lydon, Christine; Mach, Stacy; Avila, Ada G; Wong, Joshua A; Rabin, Alexandra R; Helmkamp, Joshua; Sholl, Lynette; Carter, Scott L; Oxnard, Geoffrey; Janne, Pasi; Getz, Gad; Lindeman, Neal; Hammerman, Peter S; Garraway, Levi A; Hodi, F Stephen; Rodig, Scott J; Dranoff, Glenn; Wong, Kwok-Kin; Barbie, David A

    2015-08-01

    PD-1 immune checkpoint blockade occasionally results in durable clinical responses in advanced metastatic cancers. However, mechanism-based predictors of response to this immunotherapy remain incompletely characterized. We performed comprehensive genomic profiling on a tumor and germline sample from a patient with refractory lung adenocarcinoma who achieved marked long-term clinical benefit from anti-PD-L1 therapy. We discovered activating somatic and germline amino acid variants in JAK3 that promoted PD-L1 induction in lung cancer cells and in the tumor immune microenvironment. These findings suggest that genomic alterations that deregulate cytokine receptor signal transduction could contribute to PD-L1 activation and engagement of the PD-1 immune checkpoint in lung cancer. PMID:26014096

  12. Interleukin-7 receptor blockade suppresses adaptive and innate inflammatory responses in experimental colitis

    Directory of Open Access Journals (Sweden)

    Willis Cynthia R

    2012-10-01

    Full Text Available Abstract Background Interleukin-7 (IL-7 acts primarily on T cells to promote their differentiation, survival, and homeostasis. Under disease conditions, IL-7 mediates inflammation through several mechanisms and cell types. In humans, IL-7 and its receptor (IL-7R are increased in diseases characterized by inflammation such as atherosclerosis, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. In mice, overexpression of IL-7 results in chronic colitis, and T-cell adoptive transfer studies suggest that memory T cells expressing high amounts of IL-7R drive colitis and are maintained and expanded with IL-7. The studies presented here were undertaken to better understand the contribution of IL-7R in inflammatory bowel disease in which colitis was induced with a bacterial trigger rather than with adoptive transfer. Methods We examined the contribution of IL-7R on inflammation and disease development in two models of experimental colitis: Helicobacter bilis (Hb-induced colitis in immune-sufficient Mdr1a−/− mice and in T- and B-cell-deficient Rag2−/− mice. We used pharmacological blockade of IL-7R to understand the mechanisms involved in IL-7R-mediated inflammatory bowel disease by analyzing immune cell profiles, circulating and colon proteins, and colon gene expression. Results Treatment of mice with an anti-IL-7R antibody was effective in reducing colitis in Hb-infected Mdr1a−/− mice by reducing T-cell numbers as well as T-cell function. Down regulation of the innate immune response was also detected in Hb-infected Mdr1a−/− mice treated with an anti-IL-7R antibody. In Rag2−/− mice where colitis was triggered by Hb-infection, treatment with an anti-IL-7R antibody controlled innate inflammatory responses by reducing macrophage and dendritic cell numbers and their activity. Conclusions Results from our studies showed that inhibition of IL-7R successfully ameliorated inflammation and disease development

  13. Effects of alpha-adrenoceptor and of combined sympathetic and parasympathetic blockade on cardiac performance and vascular resistance

    DEFF Research Database (Denmark)

    Kelbaek, H; Frandsen, Henrik Lund; Hilsted, J;

    1992-01-01

    ) blockade. 2. During alpha-adrenoceptor blockade heart rate and cardiac output increased considerably and left ventricular ejection fraction increased because of increased contractility. Systemic vascular resistance fell both during alpha-adrenoceptor blockade alone and during combined blockade. The...... increase in calf blood flow was of the same magnitude after combined blockade and after alpha-adrenoceptor blockade alone, and was considerably higher than the fall in systemic vascular resistance. Plasma catecholamine concentrations increased after phentolamine, but the changes were blunted when...... propranolol and atropine were added. 3. These results indicate that peripheral vasoconstriction especially that exerted by alpha-adrenoceptor nervous tone in skeletal muscle restricts left ventricular emptying of the intact heart. During pharmacologic blockade of the sympathetic and parasympathetic nervous...

  14. Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: Therapeutic implications.

    Science.gov (United States)

    Saavedra, Juan M; Sánchez-Lemus, Enrique; Benicky, Julius

    2011-01-01

    Poor adaptation to stress, alterations in cerebrovascular function and excessive brain inflammation play critical roles in the pathophysiology of many psychiatric and neurological disorders such as major depression, schizophrenia, post traumatic stress disorder, Parkinson's and Alzheimer's diseases and traumatic brain injury. Treatment for these highly prevalent and devastating conditions is at present very limited and many times inefficient, and the search for novel therapeutic options is of major importance. Recently, attention has been focused on the role of a brain regulatory peptide, Angiotensin II, and in the translational value of the blockade of its physiological AT(1) receptors. In addition to its well-known cardiovascular effects, Angiotensin II, through AT(1) receptor stimulation, is a pleiotropic brain modulatory factor involved in the control of the reaction to stress, in the regulation of cerebrovascular flow and the response to inflammation. Excessive brain AT(1) receptor activity is associated with exaggerated sympathetic and hormonal response to stress, vulnerability to cerebrovascular ischemia and brain inflammation, processes leading to neuronal injury. In animal models, inhibition of brain AT(1) receptor activity with systemically administered Angiotensin II receptor blockers is neuroprotective; it reduces exaggerated stress responses and anxiety, prevents stress-induced gastric ulcerations, decreases vulnerability to ischemia and stroke, reverses chronic cerebrovascular inflammation, and reduces acute inflammatory responses produced by bacterial endotoxin. These effects protect neurons from injury and contribute to increase the lifespan. Angiotensin II receptor blockers are compounds with a good margin of safety widely used in the treatment of hypertension and their anti-inflammatory and vascular protective effects contribute to reduce renal and cardiovascular failure. Inhibition of brain AT(1) receptors in humans is also neuroprotective

  15. Regulatory Efforts to Improve Cyber Security

    International Nuclear Information System (INIS)

    The cyber threat has significantly increased over the last decade and continues to evolve. Improving the cyber security at nuclear facilities is critical in today’s environment. The United States Nuclear Regulatory Commission is implementing a number of efforts in rulemaking, licensing and inspection to address and improve cyber security at regulated facilities. The United States Nuclear Regulatory Commission has been working multilaterally with the IAEA and bilaterally with our international partners to promote improvements in cyber security. (author)

  16. Evolution of transcriptional regulatory circuits in bacteria

    OpenAIRE

    Perez, J. Christian; Groisman, Eduardo A.

    2009-01-01

    Related organisms typically respond to a given cue by altering the level or activity of orthologous transcription factors, which, paradoxically, often regulate expression of distinct gene sets. Although promoter rewiring of shared genes is primarily responsible for regulatory differences among related eukaryotic species, in bacteria, species-specific genes are often controlled by ancestral transcription factors and regulatory circuit evolution has been further shaped by horizontal gene transf...

  17. Regulatory challenges

    International Nuclear Information System (INIS)

    The problem for policy makers wanting to liberalize natural gas markets is that its concentrated structure may also be the socially most efficient one. Because of scale economies, more firms operating in the market may incur higher transportation costs unless the market grows sufficiently in each geographic segment. This argument goes for product extension through vertical (or horizontal) integration and the exploitation of economies of scope as well. Thus, the challenge for governments is to intervene in a way that preserves a market structure that has the potential to minimize cost, and at the same lime change its behavior in order to avoid possible lax cost control and exploitation of market power. The existence of scope advantages indicates that liberalization of the market should open for the possibility to bundle services in competition with provision of unbundled services. If operations are unbundled and there exist economies of scope, the gain from increased competition should be weighed against the losses of less efficient operations of each firm. Thus, with the growth in the European market, gradually more arguments support the idea of unbundling. The significant scale economy in trunk pipelines, sunk investments and capital immobility, possible economies of scope in vertical integration and companies' bundling of services influences vertical and horizontal ownership relations and contractual terms in the European gas market. In specific segments of the markets, these relationships may promote efficient investments and pricing without public interference, but the strong concentration of market power indicates that this is rather the exception than the rule. In order to design an efficient and welfare maximizing way of regulating the market one needs a closer identification of the actual goal of the regulation. Microeconomic theory is often used for this purpose. The author discusses the alternatives of laissez-faire, nationalization or regulation for the

  18. Blockaded six- and eight-wave mixing processes tailored by electromagnetically induced transparency scissors

    Science.gov (United States)

    Zheng, H. B.; Yao, X.; Zhang, Z. Y.; Che, J. L.; Zhang, Y. Q.; Zhang, Y. P.; Xiao, M.

    2014-04-01

    We report the first experimental observations of the blockaded six- and eight-wave mixing processes in a collective multi-level Rydberg atomic ensemble tailored by multi-channel scissors and created by three coexisting electromagnetically induced transparency (EIT) windows. The interplay between the dressed-state effect and the Rydberg blockade caused by strong van der Waals interactions is investigated when several parameters in the excitation lasers are changed. Blockaded multi-wave mixing (MWM) signals are obtained when the coupling frequency detuning is changed, which is improved to give multiple channels when the probe detuning is scanned. Such MWM signals tailored by EIT scissors produce a much narrower linewidth and therefore are suitable for application in long-distance quantum communication. The advantages of having multi-channel blockaded MWM signals also makes potential applications in demonstrating multi-channel entanglement possible and improves the performance of quantum computation with Rydberg atoms.

  19. Fano effect dominance over Coulomb blockade in transport properties of parallel coupled quantum dot system

    International Nuclear Information System (INIS)

    Theoretical study of the Coulomb blockade effect on transport properties (Transmission Probability and I-V characteristics) for varied configuration of coupled quantum dot system has been studied by using Non Equilibrium Green Function(NEGF) formalism and Equation of Motion(EOM) method in the presence of magnetic flux. The self consistent approach and intra-dot Coulomb interaction is being taken into account. As the key parameters of the coupled quantum dot system such as dot-lead coupling, inter-dot tunneling and magnetic flux threading through the system can be tuned, the effect of asymmetry parameter and magnetic flux on this tuning is being explored in Coulomb blockade regime. The presence of the Coulomb blockade due to on-dot Coulomb interaction decreases the width of transmission peak at energy level ε + U and by adjusting the magnetic flux the swapping effect in the Fano peaks in asymmetric and symmetric parallel configuration sustains despite strong Coulomb blockade effect

  20. Blockaded six- and eight-wave mixing processes tailored by electromagnetically induced transparency scissors

    International Nuclear Information System (INIS)

    We report the first experimental observations of the blockaded six- and eight-wave mixing processes in a collective multi-level Rydberg atomic ensemble tailored by multi-channel scissors and created by three coexisting electromagnetically induced transparency (EIT) windows. The interplay between the dressed-state effect and the Rydberg blockade caused by strong van der Waals interactions is investigated when several parameters in the excitation lasers are changed. Blockaded multi-wave mixing (MWM) signals are obtained when the coupling frequency detuning is changed, which is improved to give multiple channels when the probe detuning is scanned. Such MWM signals tailored by EIT scissors produce a much narrower linewidth and therefore are suitable for application in long-distance quantum communication. The advantages of having multi-channel blockaded MWM signals also makes potential applications in demonstrating multi-channel entanglement possible and improves the performance of quantum computation with Rydberg atoms. (paper)

  1. Jaynes-Cummings dynamics in mesoscopic ensembles of Rydberg-blockaded atoms

    CERN Document Server

    Beterov, I I; Tretyakov, D B; Entin, V M; Yakshina, E A; Ryabtsev, I I; Bergamini, S

    2014-01-01

    We show that Jaynes-Cummings dynamics can be observed in mesoscopic atomic ensembles interacting with a classical electromagnetic field in the regime of Rydberg blockade, where the time dynamics of the average number of Rydberg excitations in mesoscopic ensembles displays collapses and revivals typical of this model. As the frequency of Rabi oscillations between collective states of Rydberg blockaded ensembles depends on the number of interacting atoms, for randomly loaded optical dipole traps we predict collapses and revivals of Rabi oscillations. We have studied the effects of finite interaction strengths and finite linewidth on the visibility of the revivals. Finally, we considered the interaction of atoms in spatially separated optical dipole traps and demonstrated that partial blockade between ensembles leads to a suppression of the revivals, which can nevertheless be recovered in the regime of perfect blockade between the two ensembles.

  2. Integrin antagonists prevent costimulatory blockade-resistant transplant rejection by CD8+ memory T cells

    OpenAIRE

    Kitchens, W. H.; Haridas, D.; Wagener, M. E.; Song, M.; Kirk, A D; Larsen, C P; Ford, M. L.

    2011-01-01

    The success of belatacept in late-stage clinical trials inaugurates the arrival of a new class of immunosuppressants based on costimulatory blockade, an immunosuppression strategy that disrupts essential signals required for alloreactive T cell activation. Despite having improved renal function, kidney transplant recipients treated with belatacept experienced increased rates of acute rejection. This finding has renewed focus on costimulatory blockade-resistant rejection and specifically the r...

  3. Effect of 5-HT7 receptor blockade on liver regeneration after 60-70% partial hepatectomy

    OpenAIRE

    Tzirogiannis, Konstantinos N; Kourentzi, Kalliopi T; Zyga, Sofia; Papalimneou, Vassiliki; Tsironi, Maria; Grypioti, Agni D; Protopsaltis, Ioannis; Panidis, Dimitrios; Panoutsopoulos, Georgios I

    2014-01-01

    Background Serotonin exhibits a vast repertoire of actions including cell proliferation and differentiation. The effect of serotonin, as an incomplete mitogen, on liver regeneration has recently been unveiled and is mediated through 5-HT2 receptor. The aim of the present study was to investigate the effect of 5-HT7 receptor blockade on liver regeneration after partial hepatectomy. Methods Male Wistar rats were subjected to 60-70% partial hepatectomy. 5-HT7 receptor blockade was applied by int...

  4. Coulomb blockade model of permeation and selectivity in biological ion channels

    OpenAIRE

    Kaufman, Igor Kh.; McClintock, Peter V. E.; Eisenberg, R S

    2015-01-01

    Biological ion channels are protein nanotubes embedded in, and passing through, the bilipid membranes of cells. Physiologically, they are of crucial importance in that they allow ions to pass into and out of cells, fast and efficiently, though in a highly selective way. Here we show that the conduction and selectivity of calcium/sodium ion channels can be described in terms of ionic Coulomb blockade in a simplified electrostatic and Brownian dynamics model of the channel. The Coulomb blockade...

  5. Dual Blockade of the Renin-angiotensin-aldosterone System in Type 2 Diabetic Kidney Disease

    Institute of Scientific and Technical Information of China (English)

    Yan-Huan Feng; Ping Fu

    2016-01-01

    Objective: To examine the efficacy and safety of dual blockade of the renin-angiotensin-aldosterone system (RAAS) among patients with type 2 diabetic kidney disease.Data Sources: We searched the major literature repositories, including the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE, for randomized clinical trials published between January 1990 and October 2015 that compared the efficacy and safety of the use of dual blockade of the RAAS versus the use ofmonotherapy, without applying any language restrictions.Keywords for the searches included "diabetic nephropathy," "chronic kidney disease," "chronic renal insufficiency," "diabetes mellitus," "dual therapy," "combined therapy,""dual blockade," "renin-angiotensin system," "angiotensin-converting enzyme inhibitor," "angiotensin-receptor blocker," "aldosterone blockade," "selective aldosterone blockade," "renin inhibitor," "direct renin inhibitor," "mineralocorticoid receptor blocker," etc.Study Selection: The selected articles were carefully reviewed.We excluded randomized clinical trials in which the kidney damage of patients was related to diseases other than diabetes mellitus.Results: Combination treatment with an angiotensin-converting enzyme inhibitor supplemented by an angiotensin Ⅱ receptor blocking agent is expected to provide a more complete blockade of the RAAS and a better control of hypertension.However, existing literature has presented mixed results, in particular, related to patient safety.In view of this, we conducted a comprehensive literature review in order to explain the rationale for dual blockade of the RAAS, and to discuss the pros and cons.Conclusions: Despite the negative results of some recent large-scale studies, it may be immature to declare that the dual blockade is a failure because of the complex nature of the RAAS surrounding its diversified functions and utility.Further trials are warranted to study the combination therapy as an evidence-based practice.

  6. Transfer of entangled state, entanglement swapping and quantum information processing via the Rydberg blockade

    Science.gov (United States)

    Deng, Li; Chen, Ai-Xi; Zhang, Jian-Song

    2011-11-01

    We provide a scheme with which the transfer of the entangled state and the entanglement swapping can be realized in a system of neutral atoms via the Rydberg blockade. Our idea can be extended to teleport an unknown atomic state. According to the latest theoretical research of the Rydberg excitation and experimental reports of the Rydberg blockade effect in quantum information processing, we discuss the experimental feasibility of our scheme.

  7. Efficacy of regional renal nerve blockade in patients with chronic refractory heart failure

    Institute of Scientific and Technical Information of China (English)

    DAI Qi-ming; FEN Yi; LU Jing; MA Gen-shan

    2013-01-01

    Background Increased renal sympathetic nerve activity can result in diuretic resistance in patients with chronic congestive heart failure.We investigated the effect of regional renal nerve blockade on the patients with chronic refractory heart failure and diuretic resistance.Methods Eighteen patients with chronic refractory heart failure were enrolled (mean age (64±11) years).The patients were randomly divided into two groups (renal nerve blockade group and standard therapy group,n=9 each).Renal nerve blockade was performed by percutaneous injection of local anaesthetic under computed tomographic guidance.Heart rate,mean arterial blood pressure,plasma and urine electrolytes,neurohormones,factional excretion of sodium (FENa),24-hour urine volume were monitored at baseline and the first 24 hours after therapy.Dyspnea and oedema were also evaluated.The major adverse cardiovascular events (MACE),plasma brain natriuretic peptide (BNP) level and left ventricular ejection fraction (LVEF) were compared between the two groups during the 3-12 months follow-up period.Results No complication was observed during the acute phase of renal nerve blockade.After renal nerve blockade,the 24-hour urine volume and FENa were significantly increased,while the level of plasma rennin,angiotensin Ⅱ,aldosterone,BNP and atrial natriuretic peptide as well as dyspnea and oedema were significantly reduced in renal nerve blockade group compared with baseline and standard therapy group.During three to 12 months of follow-up,the rate of MACE and plasma BNP level were significantly lower,while LVEF was significantly higher in renal nerve blockade group than those in standard therapy group.Conclusion Regional renal nerve blockade may be a safe and effective treatment for patients with chronic refractory heart failure.

  8. Dual Blockade of the Renin-angiotensin-aldosterone System in Type 2 Diabetic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Yan-Huan Feng

    2016-01-01

    Full Text Available Objective: To examine the efficacy and safety of dual blockade of the renin-angiotensin-aldosterone system (RAAS among patients with type 2 diabetic kidney disease. Data Sources: We searched the major literature repositories, including the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE, for randomized clinical trials published between January 1990 and October 2015 that compared the efficacy and safety of the use of dual blockade of the RAAS versus the use of monotherapy, without applying any language restrictions. Keywords for the searches included "diabetic nephropathy," "chronic kidney disease," "chronic renal insufficiency," "diabetes mellitus," "dual therapy," "combined therapy," "dual blockade," "renin-angiotensin system," "angiotensin-converting enzyme inhibitor," "angiotensin-receptor blocker," "aldosterone blockade," "selective aldosterone blockade," "renin inhibitor," "direct renin inhibitor," "mineralocorticoid receptor blocker," etc. Study Selection: The selected articles were carefully reviewed. We excluded randomized clinical trials in which the kidney damage of patients was related to diseases other than diabetes mellitus. Results: Combination treatment with an angiotensin-converting enzyme inhibitor supplemented by an angiotensin II receptor blocking agent is expected to provide a more complete blockade of the RAAS and a better control of hypertension. However, existing literature has presented mixed results, in particular, related to patient safety. In view of this, we conducted a comprehensive literature review in order to explain the rationale for dual blockade of the RAAS, and to discuss the pros and cons. Conclusions: Despite the negative results of some recent large-scale studies, it may be immature to declare that the dual blockade is a failure because of the complex nature of the RAAS surrounding its diversified functions and utility. Further trials are warranted to study the combination therapy as an

  9. H2 receptor blockade and bronchial hyperreactivity to histamine in asthma.

    OpenAIRE

    Nogrady, S G; Bevan, C

    1981-01-01

    The role of histamine H1 and H2 receptors in the lung is not clear. H1 receptor blockade results in bronchodilatation and inhibition of histamine induced bronchoconstriction. H2 receptor blockade in vitro prevents the normal negative feedback of histamine on further mediator release in antigen challenge. Bronchospasm in guinea pigs given antigen challenge is enhanced by previous administration of metiamide or burimamide but not of cimetidine. These findings suggest the possible deleterious ef...

  10. Muscle hypertrophy driven by myostatin blockade does not require stem/precursor-cell activity

    OpenAIRE

    Amthor, Helge; Otto, Anthony; Vulin, Adeline; Rochat, Anne; Dumonceaux, Julie; Garcia, Luis; Mouisel, Etienne; Hourdé, Christophe; Macharia, Raymond; Friedrichs, Melanie; Relaix, Frederic; Zammit, Peter S.; Matsakas, Antonios; Patel, Ketan; Partridge, Terence

    2009-01-01

    Myostatin, a member of the TGF-β family, has been identified as a powerful inhibitor of muscle growth. Absence or blockade of myostatin induces massive skeletal muscle hypertrophy that is widely attributed to proliferation of the population of muscle fiber-associated satellite cells that have been identified as the principle source of new muscle tissue during growth and regeneration. Postnatal blockade of myostatin has been proposed as a basis for therapeutic strategies to combat muscle loss ...

  11. ENRICH Forum: Ethical aNd Regulatory Issues in Cancer ResearcH

    Science.gov (United States)

    ENRICH Forum: Ethical aNd Regulatory Issues in Cancer ResearcH, designed to stimulate dialogue on ethical and regulatory issues in cancer research and promote awareness of developing policies and best practices.

  12. To craft or not to craft : The relationships between regulatory focus, job crafting and work outcomes

    NARCIS (Netherlands)

    Brenninkmeijer, Veerle; Hekkert-Koning, Marleen

    2015-01-01

    Purpose – The purpose of this paper is to examine relationships between regulatory focus, job crafting, work engagement and perceived employability. Regulatory focus theory distinguishes between promotion-focused individuals, who strive for growth and development, and preventionfocussed individuals,

  13. Regulação assistencial no recife: possibilidades e limites na promoção do acesso Assistance Regulatory in Recife: possibilities and limits in promoting access

    Directory of Open Access Journals (Sweden)

    Maria do Socorro Veloso de Albuquerque

    2013-03-01

    the point of view of access with equity and integrality. A case study was conducted, having the managers from Municipal Health Department of Recife as its subjects. Content analysis was used in a thematic typology, taking as basis the concepts of government triangle, accessibility and network. It was seen that although the municipality implemented organizational arrangements for care regulation, it has neither invested in the regulation of its own specialized services, nor analyzed the potential capacity of these services. The Consultation and Specialized Exams Regulation Service absorbed only 9.5% of the procedures of medium complexity under municipal management. Moreover, little was invested in the expansion of the solvability of primary care, which contributed to keep a possibly artificial demand for specialized services. The possibility of greater organizational accessibility through the regulation of care was reduced to a process of organizing the existing demand to the capability of supply of SUS' supplementary (private network in Recife. In some cases, this was defined by the interests of the very private sector, over which the regulation implemented by the municipal administration had reduced power of definition. The centralizing action of the Municipal Health Department hindered the creation of a shared regulatory complex between different levels of management. It is concluded that the regulation of care in the sphere of the municipalities can hardly promote full and equal access if it acts only over the services under municipal management, if it does not form regional networks of care and agreements between public entities for continued care and if it acts without subordinating private interests to the welfare needs of the population.

  14. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Brian J. [Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Pollack, Ian F. [Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Okada, Hideho, E-mail: okadah@upmc.edu [Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States)

    2013-11-01

    Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas.

  15. The blockade of immune checkpoints in cancer immunotherapy

    Science.gov (United States)

    Pardoll, Drew M.

    2016-01-01

    Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand–receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses. PMID:22437870

  16. Mevalonate Pathway Blockade, Mitochondrial Dysfunction and Autophagy: A Possible Link

    Directory of Open Access Journals (Sweden)

    Paola Maura Tricarico

    2015-07-01

    Full Text Available The mevalonate pathway, crucial for cholesterol synthesis, plays a key role in multiple cellular processes. Deregulation of this pathway is also correlated with diminished protein prenylation, an important post-translational modification necessary to localize certain proteins, such as small GTPases, to membranes. Mevalonate pathway blockade has been linked to mitochondrial dysfunction: especially involving lower mitochondrial membrane potential and increased release of pro-apoptotic factors in cytosol. Furthermore a severe reduction of protein prenylation has also been associated with defective autophagy, possibly causing inflammasome activation and subsequent cell death. So, it is tempting to hypothesize a mechanism in which defective autophagy fails to remove damaged mitochondria, resulting in increased cell death. This mechanism could play a significant role in Mevalonate Kinase Deficiency, an autoinflammatory disease characterized by a defect in Mevalonate Kinase, a key enzyme of the mevalonate pathway. Patients carrying mutations in the MVK gene, encoding this enzyme, show increased inflammation and lower protein prenylation levels. This review aims at analysing the correlation between mevalonate pathway defects, mitochondrial dysfunction and defective autophagy, as well as inflammation, using Mevalonate Kinase Deficiency as a model to clarify the current pathogenetic hypothesis as the basis of the disease.

  17. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    Directory of Open Access Journals (Sweden)

    Brian J. Ahn

    2013-11-01

    Full Text Available Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas.

  18. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    International Nuclear Information System (INIS)

    Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas

  19. Blockade of MerTK Activation by AMPK Inhibits RPE Cell Phagocytosis.

    Science.gov (United States)

    Qin, Suofu

    2016-01-01

    Timely removal of shed photoreceptor outer segments by retinal pigment epithelial cells (RPE) plays a key role in biological renewal of these highly peroxidizable structures and in maintenance of retina health. How environmental stress cause RPE cell dysfunction is undefined however. AMP-activated protein kinase (AMPK), a heterotrimer of a catalytic α subunit and regulatory β and γ subunits, maintains energy homeostasis by limiting energy utilization and/or promoting energy production when energy supply is compromised. Intriguingly, AMPK has been shown to be important in functions of RPE cells. In this mini-review, the role and mechanisms of AMPK in controlling RPE cell phagocytosis are discussed. PMID:26427488

  20. Regulatory Fit from Stereotype Threat: Enhancing Women’s Leadership Aspirations

    OpenAIRE

    Görzig, Anke

    2008-01-01

    A series of studies investigates the impact of regulatory fit on women’s leadership aspirations. A regulatory fit occurs when an outcome is presented in gain frames under a promotion focus and in loss frames under a prevention focus. Combining research on regulatory focus and research on stereotype threat it is argued that regulatory fit may result from stereotype threat (loss frame) under a prevention focus and from the absence of stereotype threat (gain frame) under a promotion focus. In li...

  1. Development of regulatory policy for SMART-P

    Energy Technology Data Exchange (ETDEWEB)

    Lee, S. H.; Lee, Y. H.; Moo, Philip; Koh, B. J.; Son, M. K.; Han, G. H.; Kim, D. H. [Korea Association for Nuclear Technology, Daejeon (Korea, Republic of)

    2004-06-15

    KAERI promoted the construction of a research reactor, SMART-P, the reduced scale of SMART, with intent to demonstrate the safety and performance of SMART. According to this progress, the development of regulatory process for SMART-P became necessary. The establishment of regulatory policy, based on the current regulatory guidelines as well as technical aspect, became essential matters. Considering the on-going small and medium size reactors in near future, the selection of the appropriate measure in the existing regulatory process to SMART-P is very important. Thus the schematic study for the applicable licensing procedure and regulatory requirements suitable for SMART-P is required.

  2. Development of regulatory policy for SMART-P

    Energy Technology Data Exchange (ETDEWEB)

    Lee, S. H.; Moon, S. H.; Lee, Y. H.; Son, M. K.; Han, K. H.; Kim, D. H. [Korea Association for Nuclear Technology, Taejon (Korea, Republic of)

    2003-06-15

    KAERI promoted the construction of a research reactor, SMART-P, the reduced scale of SMART, with intent to demonstrate the safety and performance of SMART. According to this progress, the development of regulatory process for SMART-P became necessary. The establishment of regulatory policy, based on the current regulatory guidelines as well as technical aspect, became essential matters. Considering the on-going small and medium size reactors m near future, the selection of the appropriate measure in the existing regulatory process to SMART-P is very important. Thus the schematic study for the applicable licensing procedure and regulatory requirements suitable for SMART-P is required.

  3. Development of regulatory policy for SMART-P

    International Nuclear Information System (INIS)

    KAERI promoted the construction of a research reactor, SMART-P, the reduced scale of SMART, with intent to demonstrate the safety and performance of SMART. According to this progress, the development of regulatory process for SMART-P became necessary. The establishment of regulatory policy, based on the current regulatory guidelines as well as technical aspect, became essential matters. Considering the on-going small and medium size reactors m near future, the selection of the appropriate measure in the existing regulatory process to SMART-P is very important. Thus the schematic study for the applicable licensing procedure and regulatory requirements suitable for SMART-P is required

  4. Regulatory requirements for the management of radioactive wastes in Argentina

    International Nuclear Information System (INIS)

    Nuclear activity started in Argentina in the early fifties and since then all the peaceful applications of nuclear energy have been developed including nucleo electricity production. In 1994 the organization in charge of the regulatory control of nuclear activities, now the Nuclear Regulatory Authority (ARN), became independent from the organizations related with nuclear promotion (mainly National Atomic Energy Commission, CNEA). Concerning regulatory activities, the regulatory system applied by ARN in Argentina is based on the IAEA's and ICRP's recommendations, adapted to the needs of the country and its own experience gained through more than thirty years of regulatory activities. Besides, specialists from the regulatory organization from Argentina contributed to the development of the recommendations of such organizations. In order to contribute to the understanding of the application of the nuclear regulatory system in Argentina, an overview of the legal and regulatory framework is provided. (author)

  5. Compliance. Regulatory policy P-211

    International Nuclear Information System (INIS)

    This regulatory policy describes the basic principles and directives for establishing and conducting the Canadian Nuclear Safety Commission (CNSC) Compliance Program. The program is aimed at securing compliance by regulated persons with regulatory requirements made under the Nuclear Safety and Control Act ('the Act'). The policy applies to persons who are regulated by the CNSC through the Act, regulations and licences, as well as by decisions and orders made under the Act. The policy applies to officers and employees of the CNSC, and its authorized representatives or agents, who are involved in developing and carrying out compliance activities. Compliance, in the context of this policy, means conformity by regulated persons with the legally binding requirements of the Act, and the CNSC regulations, licences, decisions, and orders made under the Act. Compliance activities are CNSC measures of promotion, verification and enforcement aimed at securing compliance by regulated person with the applicable legally binding requirements. (author)

  6. Antithrombotic effects of beta2-adrenergic receptor blockade on top of beta1-receptor blockade in patients with acute coronary syndrome or heart failure : a systematic review

    NARCIS (Netherlands)

    De Peuter, O.R.; Lussana, F.; Peters, R.J.; Büller, H.R.; Kamphuisen, P.W.

    2009-01-01

    Background: Non-selective beta1 + 2 blockers may have specific antithrombotic effects not present in eta1-blockers, due to a eta2-specific effect on sympathetic activity. Our aim was to assess the influence of eta2-receptor suppression on top of selective beta1-receptor blockade on the occurrence of

  7. Promoting Competition in the Natural Gas Industry

    OpenAIRE

    OECD

    2002-01-01

    Natural gas is a key source of energy for OECD countries, both in its own right and as an input into the production of electricity. Regulatory reform in this sector shares both important similarities and important differences with regulatory reform in other network industries. Like other network industries, regulatory reform in natural gas involves promoting competition in the competitive segments of the industry (particularly competition between gas producers), the development of a robust re...

  8. Polymorphism in the regulatory region located more than 1.1 kilobases 5' to the start site of transcription, the promoter region, and exon 1 of the HLA-G gene

    DEFF Research Database (Denmark)

    Hviid, T V; Sørensen, Steen; Morling, Niels

    1999-01-01

    The non-classic Human Leucocyte Antigen class Ib molecule, HLA-G, is expressed on the invasive, extra-villous cytotrophoblast in human placenta. HLA-G protects against natural killer (NK)-cell-mediated lysis and may modulate the secretion of cytokines. Aberrant expression of HLA-G has been reported...... can be divided into two groups based on the detected polymorphism. The nucleotide substitutions may have implications for the binding of nuclear factors to the regulatory regions. To our knowledge this is the first study of any polymorphism in the 5'-flanking sequences to the HLA-G gene. Further...

  9. Pharmacological blockade of TRPA1 inhibits mechanical firing in nociceptors

    Directory of Open Access Journals (Sweden)

    Moran Magdalene M

    2009-04-01

    Full Text Available Abstract Background TRPA1 has been implicated in both chemo- and mechanosensation. Recent work demonstrates that inhibiting TRPA1 function reduces mechanical hypersensitivity produced by inflammation. Furthermore, a broad range of chemical irritants require functional TRPA1 to exert their effects. In this study we use the ex-vivo skin-nerve preparation to directly determine the contribution of TRPA1 to mechanical- and chemical-evoked responses at the level of the primary afferent terminal. Results Acute application of HC-030031, a selective TRPA1 antagonist, inhibited all formalin responses in rat C fibers but had no effect on TRPV1 function, assessed by capsaicin responsiveness. Genetic ablation experiments corroborated the pharmacological findings as C fibers from wild type mice responded to both formalin and capsaicin, but fibers from their TRPA1-deficient littermates responded only to capsaicin. HC-030031 markedly reduced the mechanically-evoked action potential firing in rat and wild type mouse C fibers, particularly at high-intensity forces, but had no effect on the mechanical responsiveness of Aδ fiber nociceptors. Furthermore, HC-030031 had no effect on mechanically-evoked firing in C fibers from TRPA1-deficient mice, indicating that HC-030031 inhibits mechanically-evoked firing via a TRPA1-dependent mechanism. Conclusion Our data show that acute pharmacological blockade of TRPA1 at the cutaneous receptive field inhibits formalin-evoked activation and markedly reduces mechanically-evoked action potential firing in C fibers. Thus, functional TRPA1 at sensory afferent terminals in skin is required for their responsiveness to both noxious chemical and mechanical stimuli.

  10. History, synthesis, properties, applications and regulatory issues of prebiotic oligosaccharides

    OpenAIRE

    Tymczyszyn, E. E.; Santos, M. I.; Costa, Maria do Céu; Illanes, A.; Gomez-Zavaglia, A.

    2014-01-01

    In this chapter, the health promoting effects of carbohydrate prebiotics are addressed. A brief description of their synthesis, thermo-physical properties, mechanisms of action, technological applications and current regulatory issues are presented.

  11. Testing Regulatory Consistency

    OpenAIRE

    Robert Breunig; Flavio M. Menezes

    2008-01-01

    We undertake an analysis of regulatory consistency using a database of publicly available regulatory decisions in Australia. We propose a simple exploratory model which allows us to test for regulatory consistency across jurisdictions and industries without detailed knowledge of the regulatory process. We compare two measures using our approach--the weighted average cost of capital and the proportion of firms’ revenue requirement claims disallowed by the regulator. We advocate use of the seco...

  12. Erythropoietin Blockade Inhibits the Induction of Tumor Angiogenesis and Progression

    OpenAIRE

    Hardee, Matthew E.; Cao, Yiting; Fu, Ping; Jiang, Xiaohong; Zhao, Yulin; Rabbani, Zahid N.; Vujaskovic, Zeljko; Dewhirst, Mark W; Arcasoy, Murat O.

    2007-01-01

    Background The induction of tumor angiogenesis, a pathologic process critical for tumor progression, is mediated by multiple regulatory factors released by tumor and host cells. We investigated the role of the hematopoietic cytokine erythropoietin as an angiogenic factor that modulates tumor progression. Methodology/Principal Findings Fluorescently-labeled rodent mammary carcinoma cells were injected into dorsal skin-fold window chambers in mice, an angiogenesis model that allows direct, non-...

  13. Quantum Interference Induced Photon Blockade in a Coupled Single Quantum Dot-Cavity System

    CERN Document Server

    Tang, Jing; Xu, Xiulai

    2015-01-01

    We propose an experimental scheme to implement a strong photon blockade with a single quantum dot coupled to a nanocavity. The photon blockade effect can be tremendously enhanced by driving the cavity and the quantum dot simultaneously with two classical laser fields. This enhancement of photon blockade is ascribed to the quantum interference effect to avoid two-photon excitation of the cavity field. Comparing with Jaynes-Cummings model, the second-order correlation function at zero time delay $g^{(2)}(0)$ in our scheme can be reduced by two orders of magnitude and the system sustains a large intracavity photon number. A red (blue) cavity-light detuning asymmetry for photon quantum statistics with bunching or antibunching characteristics is also observed. The photon blockade effect has a controllable flexibility by tuning the relative phase between the two pumping laser fields and the Rabi coupling strength between the quantum dot and the pumping field. Moreover, the photon blockade scheme based on quantum in...

  14. Effects of beta-adrenergic blockade on ventilation and gas exchange during incremental exercise.

    Science.gov (United States)

    Dodd, S; Powers, S; O'Malley, N; Brooks, E; Sommers, H

    1988-08-01

    Controversy exists concerning the effects of acute beta-adrenergic blockade on ventilation during exercise. Hence, the purpose of this study was to determine the effects of acute beta blockade on ventilation and gas exchange during incremental exercise. Nine male subjects underwent incremental exercise on a cycle ergometer (30 W.min-1) to exhaustion, with one trial being performed 60 min after the subject ingested propranolol hydrochloride (Inderal 1 mg.kg-1 BW) while the second test served as control. The treatment order was counterbalanced to preclude any ordering effect on the results, and 1 week separated the tests. Ventilation and gas exchange were monitored by open circuit techniques. No difference (p greater than 0.05) existed in VE, % Hb sat, VCO2, ventilatory threshold, and VE/VCO2 between treatments at the same exercise stage. VO2max was lowered from 3.82 to 3.26 l.min-1 (p less than 0.05) and HRmax was reduced from 190 to 150 bpm (p less than 0.05) as a result of beta blockade. These data suggested that acute beta blockade had no effect on exercise ventilation, but decreased HRmax at comparable work rates. In addition, VO2max and exercise time to exhaustion were hindered, probably due to beta blockade limitation of HRmax, and, thus, oxygen transport. PMID:3178619

  15. The effect of RAAS blockade on the progression of diabetic nephropathy.

    Science.gov (United States)

    Roscioni, Sara S; Heerspink, Hiddo J Lambers; de Zeeuw, Dick

    2014-02-01

    The renin-angiotensin-aldosterone system (RAAS) has a key role in the regulation of blood pressure, sodium and water balance, and cardiovascular and renal homeostasis. In diabetic nephropathy, excessive activation of the RAAS results in progressive renal damage. RAAS blockade using angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers is the cornerstone of treatment of diabetic renal disease. Alternative RAAS-blockade strategies include renin inhibition and aldosterone blockade. Data from small initial studies of these agents are promising. However, single-agent interventions do not fully block the RAAS and patients treated with these therapies remain at high residual renal risk. Approaches to optimize drug responses include dietary changes and increasing dosages. The theoretically attractive option of combining different RAAS interventions has also been tested in clinical trials but long-term outcomes were disappointing. However, dual RAAS blockade might represent a good therapeutic option for specific patients. A better knowledge of the pathophysiology of the RAAS is crucial to fully understand the mechanisms of action of RAAS blockers and to exploit their renoprotective effects. Moreover, lifestyle interventions or diagnostic tools might be used to optimize RAAS blockade and identify those patients who are most likely to benefit from the therapy. PMID:24296623

  16. Regulatory analysis technical evaluation handbook. Final report

    International Nuclear Information System (INIS)

    The purpose of this Handbook is to provide guidance to the regulatory analyst to promote preparation of quality regulatory analysis documents and to implement the policies of the Regulatory Analysis Guidelines of the US Nuclear Regulatory Commission (NUREG/BR-0058 Rev. 2). This Handbook expands upon policy concepts included in the NRC Guidelines and translates the six steps in preparing regulatory analyses into implementable methodologies for the analyst. It provides standardized methods of preparation and presentation of regulatory analyses, with the inclusion of input that will satisfy all backfit requirements and requirements of NRC's Committee to Review Generic Requirements. Information on the objectives of the safety goal evaluation process and potential data sources for preparing a safety goal evaluation is also included. Consistent application of the methods provided here will result in more directly comparable analyses, thus aiding decision-makers in evaluating and comparing various regulatory actions. The handbook is being issued in loose-leaf format to facilitate revisions. NRC intends to periodically revise the handbook as new and improved guidance, data, and methods become available

  17. Regulatory analysis technical evaluation handbook. Final report

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1997-01-01

    The purpose of this Handbook is to provide guidance to the regulatory analyst to promote preparation of quality regulatory analysis documents and to implement the policies of the Regulatory Analysis Guidelines of the US Nuclear Regulatory Commission (NUREG/BR-0058 Rev. 2). This Handbook expands upon policy concepts included in the NRC Guidelines and translates the six steps in preparing regulatory analyses into implementable methodologies for the analyst. It provides standardized methods of preparation and presentation of regulatory analyses, with the inclusion of input that will satisfy all backfit requirements and requirements of NRC`s Committee to Review Generic Requirements. Information on the objectives of the safety goal evaluation process and potential data sources for preparing a safety goal evaluation is also included. Consistent application of the methods provided here will result in more directly comparable analyses, thus aiding decision-makers in evaluating and comparing various regulatory actions. The handbook is being issued in loose-leaf format to facilitate revisions. NRC intends to periodically revise the handbook as new and improved guidance, data, and methods become available.

  18. Inhibition of β2-adrenergic receptor reduces triple-negative breast cancer brain metastases: The potential benefit of perioperative β-blockade.

    Science.gov (United States)

    Choy, Cecilia; Raytis, John L; Smith, David D; Duenas, Matthew; Neman, Josh; Jandial, Rahul; Lew, Michael W

    2016-06-01

    In response to recent studies, we investigated an association between perioperative β-blockade and breast cancer metastases. First, a retrospective study examining perioperative β-blocker use and cancer recurrence and metastases was conducted on 1,029 patients who underwent breast cancer surgery at the City of Hope Cancer Center between 2000 and 2010. We followed the clinical study and examined proliferation, migration, and invasion in vitro of primary and brain-metastatic breast cancer cells in response to β2-activation and inhibition. We also investigated in vivo the metastatic potential of propranolol-treated metastatic cells. For stage II breast cancer patients, perioperative β-blockade was associated with decreased cancer recurrence using Cox regression analysis (hazard's ratio =0.51; 95% CI: 0.23-0.97; p=0.041). Triple-negative (TN) brain-metastatic cells were found to have increased β2-adrenergic receptor mRNA and protein expression relative to TN primary cells. In response to β2-adrenergic receptor activation, TN brain-metastatic cells also exhibited increased cell proliferation and migration relative to the control. These effects were abrogated by propranolol. Propranolol decreased β2-adrenergic receptor-activated invasion. In vivo, propranolol treatment of TN brain-metastatic cells decreased establishment of brain metastases. Our results suggest that stress and corresponding β2-activation may promote the establishment of brain metastases of TN breast cancer cells. In addition, our data suggest a benefit to perioperative β-blockade during surgery-induced stress with respect to breast cancer recurrence and metastases. PMID:27035124

  19. Propranolol Attenuates Surgical Stress-Induced Elevation of the Regulatory T Cell Response in Patients Undergoing Radical Mastectomy.

    Science.gov (United States)

    Zhou, Lei; Li, Yunli; Li, Xiaoxiao; Chen, Gong; Liang, Huiying; Wu, Yuhui; Tong, Jianbin; Ouyang, Wen

    2016-04-15

    Surgical stress and inflammatory response induce the release of catecholamines and PGs, which may be key factors in facilitating cancer recurrence through immunosuppression. Animal studies have suggested the efficacy of perioperative blockades of catecholamines and PGs in reducing immunosuppression. In this study, to our knowledge, we present the first report of the effects of perioperative propranolol and/or parecoxib on peripheral regulatory T cells (Tregs) in breast cancer patients. Patients were randomly assigned to control, propranolol, parecoxib, and propranolol plus parecoxib groups. We demonstrated that levels of circulating epinephrine, norepinephrine, and PGE2increased in response to surgery. Meanwhile, peripheral FOXP3 mRNA level and Treg frequencies were elevated on postoperative day 7. Propranolol administration, rather than parecoxib, attenuated such elevation of Tregs, indicating the critical roles for catecholamines in surgery-induced promotion of Tregs. Besides, propranolol plus parecoxib treatment demonstrated no additive or synergistic effects. Furthermore, a study of Treg activity on CD4(+)T cell responses to specific tumor Ags was performed in the control and propranolol groups. Propranolol abrogated the increased Treg activity and accompanying suppression of CD4(+)T cell responses after surgery. Finally, we conducted ex vivo experiments on the effects of varying concentrations of epinephrine and/or propranolol on Treg proliferation over PBMCs from breast cancer patients, to provide further direct evidence strengthening our clinical observations. Epinephrine markedly promoted Treg proliferation, whereas propranolol prevented such enhancement effect. In conclusion, our study highlights beneficial roles for propranolol in inhibiting Treg responses in vivo and in vitro, and demonstrates that propranolol could alleviate surgical stress-induced elevation of Tregs in breast cancer patients. PMID:26969754

  20. Two-Atom Rydberg Blockade using a Single-Photon Transition

    CERN Document Server

    Hankin, A M; Parazzoli, L P; Chou, C W; Armstrong, D J; Landahl, A J; Biedermann, G W

    2014-01-01

    We explore a single-photon approach to Rydberg state excitation and Rydberg blockade. Using detailed theoretical models, we show the feasibility of direct excitation, predict the effect of background electric fields, and calculate the required interatomic distance to observe Rydberg blockade. We then measure and control the electric field environment to enable coherent control of Rydberg states. With this coherent control, we demonstrate Rydberg blockade of two atoms separated by 6.6(3) {\\mu}m. When compared with the more common two-photon excitation method, this single-photon approach is advantageous because it eliminates channels for decoherence through photon scattering and AC Stark shifts from the intermediate state while moderately increasing Doppler sensitivity.

  1. Current hot spot in the spin-valley blockade in carbon nanotubes

    Science.gov (United States)

    Széchenyi, Gábor; Pályi, András

    2013-12-01

    We present a theoretical study of the spin-valley blockade transport effect in a double quantum dot defined in a straight carbon nanotube. We find that intervalley scattering due to short-range impurities completely lifts the spin-valley blockade and induces a large leakage current in a certain confined range of the external magnetic field vector. This current hot spot emerges due to different effective magnetic fields acting on the spin-valley qubit states of the two quantum dots. Our predictions are compared to a recent measurement [F. Pei , Nat. Nanotech.1748-338710.1038/nnano.2012.160 7, 630 (2012)]. We discuss the implications for blockade-based schemes for qubit initialization/readout and motion sensing of nanotube-based mechanical resonators.

  2. Water Mediates Recognition of DNA Sequence via Ionic Current Blockade in a Biological Nanopore.

    Science.gov (United States)

    Bhattacharya, Swati; Yoo, Jejoong; Aksimentiev, Aleksei

    2016-04-26

    Electric field-driven translocation of DNA strands through biological nanopores has been shown to produce blockades of the nanopore ionic current that depend on the nucleotide composition of the strands. Coupling a biological nanopore MspA to a DNA processing enzyme has made DNA sequencing via measurement of ionic current blockades possible. Nevertheless, the physical mechanism enabling the DNA sequence readout has remained undetermined. Here, we report the results of all-atom molecular dynamics simulations that elucidated the physical mechanism of ionic current blockades in the biological nanopore MspA. We find that the amount of water displaced from the nanopore by the DNA strand determines the nanopore ionic current, whereas the steric and base-stacking properties of the DNA nucleotides determine the amount of water displaced. Unexpectedly, we find the effective force on DNA in MspA to undergo large fluctuations, which may produce insertion errors in the DNA sequence readout. PMID:27054820

  3. Charge sensed Pauli blockade in a metal-oxide-semiconductor lateral double quantum dot.

    Science.gov (United States)

    Nguyen, Khoi T; Lilly, Michael P; Nielsen, Erik; Bishop, Nathan; Rahman, Rajib; Young, Ralph; Wendt, Joel; Dominguez, Jason; Pluym, Tammy; Stevens, Jeffery; Lu, Tzu-Ming; Muller, Richard; Carroll, Malcolm S

    2013-01-01

    We report Pauli blockade in a multielectron silicon metal-oxide-semiconductor double quantum dot with an integrated charge sensor. The current is rectified up to a blockade energy of 0.18 ± 0.03 meV. The blockade energy is analogous to singlet-triplet splitting in a two electron double quantum dot. Built-in imbalances of tunnel rates in the MOS DQD obfuscate some edges of the bias triangles. A method to extract the bias triangles is described, and a numeric rate-equation simulation is used to understand the effect of tunneling imbalances and finite temperature on charge stability (honeycomb) diagram, in particular the identification of missing and shifting edges. A bound on relaxation time of the triplet-like state is also obtained from this measurement. PMID:24199677

  4. A high fidelity Rydberg blockade entangling gate using shaped, analytic pulses

    CERN Document Server

    Theis, L S; Wilhelm, F K; Saffmann, M

    2016-01-01

    We show that the use of shaped pulses improves the fidelity of a Rydberg blockade two-qubit entangling gate by several orders of magnitude compared to previous protocols based on square pulses or optimal control pulses. Using analytical Derivative Removal by Adiabatic Gate (DRAG) pulses that reduce excitation of primary leakage states and an analytical method of finding the optimal Rydberg blockade we generate Bell states with a fidelity of $F>0.9999$ in a 300 K environment for a gate time of only $50\\;{\\rm ns}$, which is an order of magnitude faster than previous protocols. These results establish the potential of neutral atom qubits with Rydberg blockade gates for scalable quantum computation.

  5. Analgesia, sedation, and neuromuscular blockade during targeted temperature management after cardiac arrest.

    Science.gov (United States)

    Riker, Richard R; Gagnon, David J; May, Teresa; Seder, David B; Fraser, Gilles L

    2015-12-01

    The approach to sedation, analgesia, and neuromuscular blockade during targeted temperature management (TTM) remains largely unstudied, forcing clinicians to adapt previous research from other patient environments. During TTM, very little data guide drug selection, doses, and specific therapeutic goals. Sedation should be deep enough to prevent awareness during neuromuscular blockade, but titration is complex as metabolism and clearance are delayed for almost all drugs during hypothermia. Deeper sedation is associated with prolonged intensive care unit (ICU) and ventilator therapy, increased delirium and infection, and delayed wakening which can confound early critical neurological assessments, potentially resulting in erroneous prognostication and inappropriate withdrawal of life support. We review the potential therapeutic goals for sedation, analgesia, and neuromuscular blockade during TTM; the adverse events associated with that treatment; data suggesting that TTM and organ dysfunction impair drug metabolism; and controversies and potential benefits of specific monitoring. We also highlight the areas needing better research to guide our therapy. PMID:26670815

  6. Does renin-angiotensin system blockade have a role in preventing diabetic retinopathy? A clinical review

    DEFF Research Database (Denmark)

    Sjølie, A K; Dodson, P; Hobbs, F R R

    2011-01-01

    Diabetes management has increasingly focused on the prevention of macrovascular disease, in particular for type 2 diabetes. Diabetic retinopathy, one of the main microvascular complications of diabetes, is also an important public health problem. Much of the care invested in retinopathy relates to...... been identified in the eye and found to be upregulated in retinopathy. This has led to specific interest in the role of RAS blockade in retinopathy prevention. The recent DIRECT programme assessed use of the angiotensin receptor blocker (ARB) candesartan in type 1 and type 2 diabetes. Although the...... primary trial end-points were not met, there was a clear trend to less severe retinopathy with RAS blockade. A smaller trial, RASS, reported reduced retinopathy progression in type 1 diabetes from RAS blockade with both the ARB losartan and the angiotensin converting enzyme (ACE) inhibitor enalapril. The...

  7. [Clonage of the "malA" region of "Escherichia coli" K12: nucleotide sequence of the regulatory region and the promoters, identification and purification of the MalT-activator protein (author's transl)].

    Science.gov (United States)

    Raibaud, O; Débarbouillé, M; Cossart, P

    1982-01-01

    A 5,800-bp (base pair) HindIII-EcoRI DNA fragment containing malT, the positive regulator gene of the maltose regulon, and most of malP, the structural gene for maltodextrin phosphorylase, was cloned into pBR322. A sequence of 802 bp was established in a DNA segment containing the promotor for malPQ and the promoter for malT. A total of 611 bp separates the initiation codons for these two genes, which are transcribed in opposite directions. The malT product was identified as a 94,000 dalton polypeptide. PMID:6462088

  8. Regulatory regime and its influence in the nuclear safety

    International Nuclear Information System (INIS)

    Main elements of nuclear regulatory regime in general is presented. These elements are: national rules and safety regulations, system of nuclear facility licensing, activities of regulatory body. Regulatory body is needed to specify the national safety regulations, review and assess the safety documentation presented to support license application, make inspections to verify fulfilment of safety regulations and license conditions, monitor the quality of work processes of user organization, and to assess whether these processes provide a high safety level, promote high safety culture, promote maintenance and development of national infrastructure relevant to nuclear safety, etc

  9. Dynamical Coulomb blockade of the nonlocal conductance in normalmetal/superconductor hybrid structures

    International Nuclear Information System (INIS)

    In normalmetal/superconductor hybrid structures nonlocal conductance is determined by crossed Andreev reflection (CAR) and elastic cotunneling (EC). This was investigated recently both experimentally and theoretically. Dynamical Coulomb blockade of EC and CAR was predicted theoretically. Here we report on experimental investigations of these effects. We found signatures of dynamical Coulomb blockade in local and nonlocal conductance in the normal state. In the superconducting state, we find s-shaped nonlocal differential conductance curves as a function of bias applied on both contacts. These curves were observed for bias voltages both below and above the gap. We compare our results to theory.

  10. Dynamical Coulomb blockade of the nonlocal conductance in normalmetal/superconductor hybrid structures

    Energy Technology Data Exchange (ETDEWEB)

    Kolenda, Stefan; Wolf, Michael J.; Beckmann, Detlef [Institut fuer Nanotechnologie, KIT, 76021 Karlsruhe (Germany)

    2013-07-01

    In normalmetal/superconductor hybrid structures nonlocal conductance is determined by crossed Andreev reflection (CAR) and elastic cotunneling (EC). This was investigated recently both experimentally and theoretically. Dynamical Coulomb blockade of EC and CAR was predicted theoretically. Here we report on experimental investigations of these effects. We found signatures of dynamical Coulomb blockade in local and nonlocal conductance in the normal state. In the superconducting state, we find s-shaped nonlocal differential conductance curves as a function of bias applied on both contacts. These curves were observed for bias voltages both below and above the gap. We compare our results to theory.

  11. Renal and cardiac function during alpha1-beta-blockade in congestive heart failure

    DEFF Research Database (Denmark)

    Heitmann, M; Davidsen, U; Stokholm, K H;

    2002-01-01

    The kidney and the neurohormonal systems are essential in the pathogenesis of congestive heart failure (CHF) and the physiologic response. Routine treatment of moderate to severe CHF consists of diuretics, angiotensin-converting enzyme (ACE) inhibition and beta-blockade. The need for control of...... renal function during initiation of ACE-inhibition in patients with CHF is well known. The aim of this study was to investigate whether supplementation by a combined alpha1-beta-blockade to diuretics and ACE-inhibition might improve cardiac function without reducing renal function....

  12. Cooperative Lifting of Spin Blockade in a Three-Terminal Triple Quantum Dot

    OpenAIRE

    Kobayashi, Takashi; Ota, Takeshi; Sasaki, Satoshi; Muraki, Koji

    2013-01-01

    We report measurements of multi-path transport through a triple quantum dot (TQD) in the few-electron regime using a GaAs three-terminal device with a separate lead attached to each dot. When two paths reside inside the transport window and are simultaneously spin-blockaded, the leak currents through both paths are significantly enhanced. We suggest that the transport processes in the two paths cooperate to lift the spin blockade. Fine structures in transport spectra indicate that different k...

  13. [Improvement of approach to performance of lumbar sympathetic blockade in patients with tissue ischemia of the lower extremities].

    Science.gov (United States)

    Panov, V M; Fesenko, U A; Kutsyn, V M

    2014-06-01

    New access for performance of sympathic blockade in region of aortal bifurcation, was elaborated, basing on calculations, conducted on 30 spiral computeric tomograms of lumbar and sacral parts of vertebral column. Application of the method permits to escape such complications, as a renal and the main vessels damage, the sympathetic nerves blockade, do not demand roentgenological control. PMID:25252554

  14. Functional characterization of variations on regulatory motifs.

    Directory of Open Access Journals (Sweden)

    Michal Lapidot

    2008-03-01

    Full Text Available Transcription factors (TFs regulate gene expression through specific interactions with short promoter elements. The same regulatory protein may recognize a variety of related sequences. Moreover, once they are detected it is hard to predict whether highly similar sequence motifs will be recognized by the same TF and regulate similar gene expression patterns, or serve as binding sites for distinct regulatory factors. We developed computational measures to assess the functional implications of variations on regulatory motifs and to compare the functions of related sites. We have developed computational means for estimating the functional outcome of substituting a single position within a binding site and applied them to a collection of putative regulatory motifs. We predict the effects of nucleotide variations within motifs on gene expression patterns. In cases where such predictions could be compared to suitable published experimental evidence, we found very good agreement. We further accumulated statistics from multiple substitutions across various binding sites in an attempt to deduce general properties that characterize nucleotide substitutions that are more likely to alter expression. We found that substitutions involving Adenine are more likely to retain the expression pattern and that substitutions involving Guanine are more likely to alter expression compared to the rest of the substitutions. Our results should facilitate the prediction of the expression outcomes of binding site variations. One typical important implication is expected to be the ability to predict the phenotypic effect of variation in regulatory motifs in promoters.

  15. Regulation for continuous improvements - the new regulatory strategy of SKI

    International Nuclear Information System (INIS)

    This paper describes the new regulatory objectives and strategy of the Swedish Nuclear Power Inspectorate. Factors that have influenced the development of the regulatory strategy, including an international peer review, are discussed. In addition to general technical requirements for a defence in depth, the new strategy strongly focuses on the quality of plant safety management processes, to be monitored by process-oriented inspections. Also, quality assurance of regulatory activities is stressed. Experience gained so far shows that the regulatory approach chosen in Sweden promotes utility self assessment, quality of safety management and ownership of safety work within the utility staff. (author)

  16. GD2-specific CAR T Cells Undergo Potent Activation and Deletion Following Antigen Encounter but can be Protected From Activation-induced Cell Death by PD-1 Blockade.

    Science.gov (United States)

    Gargett, Tessa; Yu, Wenbo; Dotti, Gianpietro; Yvon, Eric S; Christo, Susan N; Hayball, John D; Lewis, Ian D; Brenner, Malcolm K; Brown, Michael P

    2016-06-01

    Chimeric antigen receptor (CAR) T cells have shown great promise in the treatment of hematologic malignancies but more variable results in the treatment of solid tumors and the persistence and expansion of CAR T cells within patients has been identified as a key correlate of antitumor efficacy. Lack of immunological "space", functional exhaustion, and deletion have all been proposed as mechanisms that hamper CAR T-cell persistence. Here we describe the events following activation of third-generation CAR T cells specific for GD2. CAR T cells had highly potent immediate effector functions without evidence of functional exhaustion in vitro, although reduced cytokine production reversible by PD-1 blockade was observed after longer-term culture. Significant activation-induced cell death (AICD) of CAR T cells was observed after repeated antigen stimulation, and PD-1 blockade enhanced both CAR T-cell survival and promoted killing of PD-L1(+) tumor cell lines. Finally, we assessed CAR T-cell persistence in patients enrolled in the CARPETS phase 1 clinical trial of GD2-specific CAR T cells in the treatment of metastatic melanoma. Together, these data suggest that deletion also occurs in vivo and that PD-1-targeted combination therapy approaches may be useful to augment CAR T-cell efficacy and persistence in patients. PMID:27019998

  17. Research and regulatory review

    International Nuclear Information System (INIS)

    To enable the regulatory review to be effectively undertaken by the regulatory body, there is a need for it to have ready access to information generated by research activities. Certain advantages have been seen to be gained by the regulatory body itself directly allocating and controlling some portion of these activities. The princial reasons for reaching this conclusion are summarised and a brief description of the Inspectorates directly sponsored programme outlined. (author)

  18. Safety culture from a regulatory perspective

    International Nuclear Information System (INIS)

    The Swedish Nuclear Power Inspectorate, SKI, has in its regulatory approach to the area of management and organization focussed on the process of continuous improvement and have in collaboration with Battelle Human Affairs Research Center, Seattle, developed a conceptual model of the important characteristics of a continuous improvement organization and how to assess it. In this work SKI has also recognized the importance of the regulatory goals and strategies adopted by SKI for promoting an improvement process on the part of the utilities, which will be further discussed below. 15 refs

  19. Blockade of Mast Cell Activation Reduces Cutaneous Scar Formation

    OpenAIRE

    Lin Chen; Megan E Schrementi; Ranzer, Matthew J.; Wilgus, Traci A.; Luisa A DiPietro

    2014-01-01

    Damage to the skin initiates a cascade of well-orchestrated events that ultimately leads to repair of the wound. The inflammatory response is key to wound healing both through preventing infection and stimulating proliferation and remodeling of the skin. Mast cells within the tissue are one of the first immune cells to respond to trauma, and upon activation they release pro-inflammatory molecules to initiate recruitment of leukocytes and promote a vascular response in the tissue. Additionally...

  20. Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation

    International Nuclear Information System (INIS)

    Highlights: → Lysophosphatidic acid (LPA) levels and its receptors LPAR1/3 transcripts were elevated during the development of radiation-induced lung fibrosis. → Lung fibrosis was obviously alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. → VPC12249 administration effectively inhibited radiation-induced fibroblast accumulation in vivo, and suppressed LPA-induced fibroblast proliferation in vitro. → LPA-LPAR1/3 signaling regulated TGFβ1 and CTGF expressions in radiation-challenged lungs, but only influenced CTGF expression in cultured fibroblasts. → LPA-LPAR1/3 signaling induced fibroblast proliferation through a CTGF-dependent pathway, rather than through TGFβ1 activation. -- Abstract: Lung fibrosis is a common and serious complication of radiation therapy for lung cancer, for which there are no efficient treatments. Emerging evidence indicates that lysophosphatidic acid (LPA) and its receptors (LPARs) are involved in the pathogenesis of fibrosis. Here, we reported that thoracic radiation with 16 Gy in mice induced development of radiation lung fibrosis (RLF) accompanied by obvious increases in LPA release and LPAR1 and LPAR3 (LPAR1/3) transcripts. RLF was significantly alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. VPC12249 administration effectively prolonged animal survival, restored lung structure, inhibited fibroblast accumulation and reduced collagen deposition. Moreover, profibrotic cytokines in radiation-challenged lungs obviously decreased following administration of VPC12249, including transforming growth factor β1 (TGFβ1) and connective tissue growth factor (CTGF). In vitro, LPA induced both fibroblast proliferation and CTGF expression in a dose-dependent manner, and both were suppressed by blockade of LPAR1/3. The pro-proliferative activity of LPA on fibroblasts was inhibited by siRNA directed against CTGF. Together, our data suggest that the LPA-LPAR1/3 signaling system is involved in the

  1. Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Gan, Lu [State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Xue, Jian-Xin [Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu (China); Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu (China); Li, Xin [Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu (China); Liu, De-Song [Department of Pediatrics, Sichuan Provincial Hospital of Women and Children, Chengdu (China); Ge, Yan; Ni, Pei-Yan; Deng, Lin [State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Lu, You, E-mail: radyoulu@hotmail.com [State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu (China); Jiang, Wei, E-mail: wcumsjw72@hotmail.com [State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu (China)

    2011-05-27

    Highlights: {yields} Lysophosphatidic acid (LPA) levels and its receptors LPAR1/3 transcripts were elevated during the development of radiation-induced lung fibrosis. {yields} Lung fibrosis was obviously alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. {yields} VPC12249 administration effectively inhibited radiation-induced fibroblast accumulation in vivo, and suppressed LPA-induced fibroblast proliferation in vitro. {yields} LPA-LPAR1/3 signaling regulated TGF{beta}1 and CTGF expressions in radiation-challenged lungs, but only influenced CTGF expression in cultured fibroblasts. {yields} LPA-LPAR1/3 signaling induced fibroblast proliferation through a CTGF-dependent pathway, rather than through TGF{beta}1 activation. -- Abstract: Lung fibrosis is a common and serious complication of radiation therapy for lung cancer, for which there are no efficient treatments. Emerging evidence indicates that lysophosphatidic acid (LPA) and its receptors (LPARs) are involved in the pathogenesis of fibrosis. Here, we reported that thoracic radiation with 16 Gy in mice induced development of radiation lung fibrosis (RLF) accompanied by obvious increases in LPA release and LPAR1 and LPAR3 (LPAR1/3) transcripts. RLF was significantly alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. VPC12249 administration effectively prolonged animal survival, restored lung structure, inhibited fibroblast accumulation and reduced collagen deposition. Moreover, profibrotic cytokines in radiation-challenged lungs obviously decreased following administration of VPC12249, including transforming growth factor {beta}1 (TGF{beta}1) and connective tissue growth factor (CTGF). In vitro, LPA induced both fibroblast proliferation and CTGF expression in a dose-dependent manner, and both were suppressed by blockade of LPAR1/3. The pro-proliferative activity of LPA on fibroblasts was inhibited by siRNA directed against CTGF. Together, our data suggest that the LPA-LPAR1

  2. Differential effects of B7-1 blockade in the rat experimental autoimmune encephalomyelitis model

    DEFF Research Database (Denmark)

    Gallon, L; Chandraker, A; Issazadeh-Navikas, Shohreh;

    1997-01-01

    Blocking the CD28-B7 T cell costimulatory activation pathway protects animals from developing experimental autoimmune encephalomyelitis (EAE). In the mouse EAE model, selective blockade of B7-1 by specific mAbs has been shown to protect animals from EAE. In the Lewis rat model, we have shown that...

  3. Glucose intolerance induced by blockade of central FGF receptors is linked to an acute stress response

    Directory of Open Access Journals (Sweden)

    Jennifer M. Rojas

    2015-08-01

    Conclusions: The effect of acute inhibition of central FGFR signaling to impair glucose tolerance likely involves a stress response associated with pronounced, but transient, sympathoadrenal activation and an associated reduction of insulin secretion. Whether this effect is a true consequence of FGFR blockade or involves an off-target effect of the FGFR inhibitor requires additional study.

  4. Effect of axillary blockade on regional cerebral blood flow during static handgrip

    DEFF Research Database (Denmark)

    Friedman, D B; Friberg, L; Mitchell, J H;

    1991-01-01

    Regional cerebral blood flow (rCBF) was determined at rest and during static handgrip before and after regional blockade with lidocaine. A fast rotating single photon emission computer tomograph system with 133Xe inhalation was used at orbitomeatal plane (OM) +2.5 and +6.5 cm in eight subjects. M...

  5. Effect of spinal sympathetic blockade upon postural changes of blood flow in human peripheral tissues

    DEFF Research Database (Denmark)

    Skagen, K; Haxholdt, O; Henriksen, O;

    1982-01-01

    subcutaneous tissue and skeletal muscle to head-up tilt whereas local blockade was able to prevent the response. Local mechanisms including the local veno-arteriolar reflex appear to play an important role for the observed maintenance of arterial blood pressure in the tilted position during central sympathetic...

  6. Coulomb blockade model of permeation and selectivity in biological ion channels

    Science.gov (United States)

    Kaufman, I. Kh; McClintock, P. V. E.; Eisenberg, R. S.

    2015-08-01

    Biological ion channels are protein nanotubes embedded in, and passing through, the bilipid membranes of cells. Physiologically, they are of crucial importance in that they allow ions to pass into and out of cells, fast and efficiently, though in a highly selective way. Here we show that the conduction and selectivity of calcium/sodium ion channels can be described in terms of ionic Coulomb blockade in a simplified electrostatic and Brownian dynamics model of the channel. The Coulomb blockade phenomenon arises from the discreteness of electrical charge, the strong electrostatic interaction, and an electrostatic exclusion principle. The model predicts a periodic pattern of Ca2+ conduction versus the fixed charge Qf at the selectivity filter (conduction bands) with a period equal to the ionic charge. It thus provides provisional explanations of some observed and modelled conduction and valence selectivity phenomena, including the anomalous mole fraction effect and the calcium conduction bands. Ionic Coulomb blockade and resonant conduction are similar to electronic Coulomb blockade and resonant tunnelling in quantum dots. The same considerations may also be applicable to other kinds of channel, as well as to charged artificial nanopores.

  7. Fascia iliaca compartment blockade for acute pain control in hip fracture patients

    DEFF Research Database (Denmark)

    Foss, Nicolai B; Kristensen, Billy B; Bundgaard, Morten;

    2007-01-01

    Hip fracture patients are in severe pain upon arrival at the emergency department. Pain treatment is traditionally based on systemic opioids. No study has examined the effect of fascia iliaca compartment blockade (FICB) in acute hip fracture pain management within a double-blind, randomized setup....

  8. A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Robert D. Leone

    2015-01-01

    Full Text Available The last several years have witnessed exciting progress in the development of immunotherapy for the treatment of cancer. This has been due in great part to the development of so-called checkpoint blockade. That is, antibodies that block inhibitory receptors such as CTLA-4 and PD-1 and thus unleash antigen-specific immune responses against tumors. It is clear that tumors evade the immune response by usurping pathways that play a role in negatively regulating normal immune responses. In this regard, adenosine in the immune microenvironment leading to the activation of the A2a receptor has been shown to represent one such negative feedback loop. Indeed, the tumor microenvironment has relatively high concentrations of adenosine. To this end, blocking A2a receptor activation has the potential to markedly enhance anti-tumor immunity in mouse models. This review will present data demonstrating the ability of A2a receptor blockade to enhance tumor vaccines, checkpoint blockade and adoptive T cell therapy. Also, as several recent studies have demonstrated that under certain conditions A2a receptor blockade can enhance tumor progression, we will also explore the complexities of adenosine signaling in the immune response. Despite important nuances to the A2a receptor pathway that require further elucidation, studies to date strongly support the development of A2a receptor antagonists (some of which have already been tested in phase III clinical trials for Parkinson Disease as novel modalities in the immunotherapy armamentarium.

  9. Pancreatic Digestive Enzyme Blockade in the Intestine Increases Survival After Experimental Shock

    OpenAIRE

    DeLano, Frank A.; Hoyt, David B.; Schmid-Schönbein, Geert W.

    2013-01-01

    Shock, sepsis, and multiorgan failure are associated with inflammation, morbidity, and high mortality. The underlying pathophysiological mechanism is unknown, but evidence suggests that pancreatic enzymes in the intestinal lumen autodigest the intestine and generate systemic inflammation. Blocking these enzymes in the intestine reduces inflammation and multiorgan dysfunction. We investigated whether enzymatic blockade also reduces mortality after shock. Three rat shock models were used here: ...

  10. Mesoscopic quantum circuit theory to the persistent current and Coulomb blockade

    OpenAIRE

    Li, You-quan

    1997-01-01

    The quantum theory for mesoscopic electric circuit is briefly described. The uncertainty relation for electric charge and current modifies the tranditional Heisenberg uncertainty relation. The mesoscopic ring is regarded as a pure L-design, and the persistent current is obtained explicitly. The Coulomb blockade phenomenon appears when applying to the pure C-design.

  11. The effect of RAAS blockade on markers of renal tubular damage in diabetic nephropathy

    DEFF Research Database (Denmark)

    Nielsen, Stine; Rossing, Kasper; Hess, Georg;

    2012-01-01

    Blockade of the renin-angiotensin-aldosterone system (RAAS) affects both the glomerulus and tubules. We aimed to investigate the effect of irbesartan on the tubular markers: urinary (u) neutrophil gelatinase associated protein (NGAL), Kidney injury molecule 1 (KIM1) and liver-fatty acid......-binding protein (LFABP)....

  12. Effect of epidural blockade and oxygen therapy on changes in subcutaneous oxygen tension after abdominal surgery

    DEFF Research Database (Denmark)

    Rosenberg, J; Pedersen, U; Erichsen, C J; Vibits, H; Moesgaard, F; Kehlet, H

    1994-01-01

    The effect of oxygen therapy (37% by face mask) and epidural local anesthetic blockade (9 ml 0.5% bupivacaine at Th9-11 level) on wound oxygenation was evaluated in eight otherwise healthy patients undergoing elective colorectal resection. The patients were monitored continuously for subcutaneous...

  13. Reversal of prolonged rocuronium neuromuscular blockade with sugammadex in an obstetric patient with transverse myelitis.

    LENUS (Irish Health Repository)

    Weekes, G

    2010-07-01

    A 38-year-old wheelchair-bound primigravida with transverse myelitis presented at 38 weeks of gestation for elective caesarean section. Transverse myelitis, which is characterised by bilateral inflammation of the spinal cord and myelin destruction, is associated with myopathy, autonomic dysreflexia and pulmonary aspiration. Regional anaesthesia was contraindicated in this case as the patient had undergone two previous lumbar spinal fusion procedures. Rocuronium 1.2 mg\\/kg was used to facilitate rapid intubating conditions. The caesarean section proceeded uneventfully, but even after administration of neostigmine the patient exhibited prolonged neuromuscular blockade. After 3 h and 15 min sugammadex was obtained to reverse neuromuscular blockade; the drug was not stocked in our hospital. Sugammadex 4 mg\\/kg resulted in complete reversal of blockade after 2 min. We believe that myopathy associated with transverse myelitis led to the prolonged duration of action of rocuronium. Sugammadex is a relatively new drug with few reported side effects. In this case it was used to reverse neuromuscular blockade and prevented prolonged postoperative ventilatory support.

  14. Reversal of prolonged rocuronium neuromuscular blockade with sugammadex in an obstetric patient with transverse myelitis.

    LENUS (Irish Health Repository)

    Weekes, G

    2012-02-01

    A 38-year-old wheelchair-bound primigravida with transverse myelitis presented at 38 weeks of gestation for elective caesarean section. Transverse myelitis, which is characterised by bilateral inflammation of the spinal cord and myelin destruction, is associated with myopathy, autonomic dysreflexia and pulmonary aspiration. Regional anaesthesia was contraindicated in this case as the patient had undergone two previous lumbar spinal fusion procedures. Rocuronium 1.2 mg\\/kg was used to facilitate rapid intubating conditions. The caesarean section proceeded uneventfully, but even after administration of neostigmine the patient exhibited prolonged neuromuscular blockade. After 3 h and 15 min sugammadex was obtained to reverse neuromuscular blockade; the drug was not stocked in our hospital. Sugammadex 4 mg\\/kg resulted in complete reversal of blockade after 2 min. We believe that myopathy associated with transverse myelitis led to the prolonged duration of action of rocuronium. Sugammadex is a relatively new drug with few reported side effects. In this case it was used to reverse neuromuscular blockade and prevented prolonged postoperative ventilatory support.

  15. A provisional regulatory gene network for specification of endomesoderm in the sea urchin embryo

    Science.gov (United States)

    Davidson, Eric H.; Rast, Jonathan P.; Oliveri, Paola; Ransick, Andrew; Calestani, Cristina; Yuh, Chiou-Hwa; Minokawa, Takuya; Amore, Gabriele; Hinman, Veronica; Arenas-Mena, Cesar; Otim, Ochan; Brown, C. Titus; Livi, Carolina B.; Lee, Pei Yun; Revilla, Roger; Schilstra, Maria J.; Clarke, Peter J C.; Rust, Alistair G.; Pan, Zhengjun; Arnone, Maria I.; Rowen, Lee; Cameron, R. Andrew; McClay, David R.; Hood, Leroy; Bolouri, Hamid

    2002-01-01

    We present the current form of a provisional DNA sequence-based regulatory gene network that explains in outline how endomesodermal specification in the sea urchin embryo is controlled. The model of the network is in a continuous process of revision and growth as new genes are added and new experimental results become available; see http://www.its.caltech.edu/mirsky/endomeso.htm (End-mes Gene Network Update) for the latest version. The network contains over 40 genes at present, many newly uncovered in the course of this work, and most encoding DNA-binding transcriptional regulatory factors. The architecture of the network was approached initially by construction of a logic model that integrated the extensive experimental evidence now available on endomesoderm specification. The internal linkages between genes in the network have been determined functionally, by measurement of the effects of regulatory perturbations on the expression of all relevant genes in the network. Five kinds of perturbation have been applied: (1) use of morpholino antisense oligonucleotides targeted to many of the key regulatory genes in the network; (2) transformation of other regulatory factors into dominant repressors by construction of Engrailed repressor domain fusions; (3) ectopic expression of given regulatory factors, from genetic expression constructs and from injected mRNAs; (4) blockade of the beta-catenin/Tcf pathway by introduction of mRNA encoding the intracellular domain of cadherin; and (5) blockade of the Notch signaling pathway by introduction of mRNA encoding the extracellular domain of the Notch receptor. The network model predicts the cis-regulatory inputs that link each gene into the network. Therefore, its architecture is testable by cis-regulatory analysis. Strongylocentrotus purpuratus and Lytechinus variegatus genomic BAC recombinants that include a large number of the genes in the network have been sequenced and annotated. Tests of the cis-regulatory predictions of

  16. Health Promotion

    DEFF Research Database (Denmark)

    Povlsen, Lene; Borup, I.

    2015-01-01

    In 1953 when the Nordic School of Public Health was founded, the aim of public health programmes was disease prevention more than health promotion. This was not unusual, since at this time health usually was seen as the opposite of disease and illness. However, with the Ottawa Charter of 1986......, the World Health Organization made a crucial change to view health not as a goal in itself but as the means to a full life. In this way, health promotion became a first priority and fundamental action for the modern society. This insight eventually reached NHV and in 2002 - 50 years after the foundation...... - an associate professorship was established with a focus on health promotion. Nevertheless, the concept of health promotion had been integrated with or mentioned in courses run prior to the new post. Subsequently, a wide spectrum of courses in health promotion was introduced, such as Empowerment for Child...

  17. NRC regulatory agenda

    International Nuclear Information System (INIS)

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action or has proposed, or is considering action and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  18. NRC regulatory agenda

    International Nuclear Information System (INIS)

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  19. NRC regulatory agenda

    International Nuclear Information System (INIS)

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has proposed or is considering action and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  20. Nuclear Regulatory legislation

    International Nuclear Information System (INIS)

    This compilation of statutes and material pertaining to nuclear regulatory legislation through the 97th Congress, 2nd Session, has been prepared by the Office of the Executive Legal Director, U.S. Nuclear Regulatory Commission, with the assistance of staff, for use as an internal resource document

  1. NRC Regulatory Agenda

    International Nuclear Information System (INIS)

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  2. NRC Regulatory Agenda

    International Nuclear Information System (INIS)

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action or has proposed, or is considering action and all petitions for rulemaking which have been received by the commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  3. Effect of Neurohormonal Blockade Drug Therapy on Outcomes and Left Ventricular Function and Structure After Left Ventricular Assist Device Implantation.

    Science.gov (United States)

    Grupper, Avishay; Zhao, Yanjun M; Sajgalik, Pavol; Joyce, Lyle D; Park, Soon J; Pereira, Naveen L; Stulak, John M; Burnett, John C; Edwards, Brooks S; Daly, Richard C; Kushwaha, Sudhir S; Schirger, John A

    2016-06-01

    Neurohormonal blockade drug therapy (NHBDT) is the cornerstone therapy in heart failure (HF) management for promoting reverse cardiac remodeling and improving outcomes. It's utility in left ventricular assist device (LVAD) supported patients remains undefined. Sixty-four patients who received continuous flow LVAD at our institution were retrospectively reviewed and divided into 2 groups: no-NHBDT group (n = 33) received LVAD support only and NHBDT group (n = 31) received concurrent NHBDT based on the clinical judgment of the attending physicians. Cardiac remodeling (echocardiographic parameters and biomarkers) and clinical outcome (functional status, HF-related hospital readmissions, and mortality) data were collected. A statistically significant increase in ejection fraction, decrease in LV end-diastolic diameter index and LV mass index, and a sustained reduction in N-terminal pro B-type natriuretic peptide (NTproBNP) were observed in the NHBDT group at 6 months after LVAD implant (p improvement in New York Heart Association functional classification and 6-minute-walk distance throughout the study. The combined end point of cardiovascular death or HF hospitalization was significantly reduced in patients receiving NHBDT (p = 0.013) associated primarily with a 12.1% absolute reduction in HF-related hospitalizations (p = 0.046). In conclusion, NHBDT in LVAD-supported patients is associated with a significant reversal in adverse cardiac remodeling and a reduction in morbidity and mortality compared with LVAD support alone. PMID:27079215

  4. Blockade of KCa3.1 potassium channels protects against cisplatin-induced acute kidney injury.

    Science.gov (United States)

    Chen, Cheng-Lung; Liao, Jiunn-Wang; Hu, Oliver Yoa-Pu; Pao, Li-Heng

    2016-09-01

    Tubular cell apoptosis significantly contributes to cisplatin-induced acute kidney injury (AKI) pathogenesis. Although KCa3.1, a calcium-activated potassium channel, participates in apoptosis, its involvement in cisplatin-induced AKI is unknown. Here, we found that cisplatin treatment triggered an early induction of KCa3.1 expression associated with HK-2 cell apoptosis, the development of renal tubular damage, and apoptosis in mice. Treatment with the highly selective KCa3.1 blocker TRAM-34 suppressed cisplatin-induced HK-2 cell apoptosis. We further assessed whether KCa3.1 mediated cisplatin-induced AKI in genetic knockout and pharmacological blockade mouse models. KCa3.1 deficiency reduced renal function loss, renal tubular damage, and the induction of the apoptotic marker caspase-3 in the kidneys of cisplatin-treated KCa3.1 (-/-) mice. Pharmacological blockade of KCa3.1 by TRAM-34 similarly attenuated cisplatin-induced AKI in mice. Furthermore, we dissected the mechanisms underlying cisplatin-induced apoptosis reduction via KCa3.1 blockade. We found that KCa3.1 blockade attenuated cytochrome c release and the increase in the intrinsic apoptotic mediators Bax, Bak, and caspase-9 after cisplatin treatment. KCa3.1 blocking inhibited the cisplatin-induced activation of the endoplasmic reticulum (ER) stress mediator caspase-12, which is independent of calcium-dependent protease m-calpain activation. Taken together, KCa3.1 blockade protects against cisplatin-induced AKI through the attenuation of apoptosis by interference with intrinsic apoptotic and ER stress-related mediators, providing a potential target for the prevention of cisplatin-induced AKI. PMID:26438401

  5. Analgesic efficacy of the ultrasound-guided blockade of the transversus abdominis plane - a systematic review

    Directory of Open Access Journals (Sweden)

    Javier Ripollés

    2015-08-01

    Full Text Available BACKGROUND: The transverse abdominal plan blockade is a block of abdominal wall that has diffused rapidly in the clinical practice as part of a multimodal analgesia for abdominal surgery. The performance of the ultrasound-guided technique has allowed the lowering of potential complications, as well as new approaches that were carried out according to the descriptions, and the prospective studies would make it possible to utilize the transverse abdominal plan blockade in different surgical interventions; however, the results obtained in randomized clinical trials are inconsistent.OBJECTIVES: To prepare a systematic review aiming to determine the efficacy of the ultrasound-guided transverse abdominal plan blockade for different surgical interventions, as well as the indications according to the approaches and their influences.METHODS: Two research approaches, one manual, and the other in Pubmed returned 28 randomized clinical trials where intervention with ultrasound-guided transverse abdominal plan blockades was performed to compare the analgesic efficacy in contrast to another technique in adults, published between 2007 and October 2013, in English or Spanish, with Jadad score > 1, according to the inclusion criteria for this review. The authors analyzed independently all the randomized clinical trials.CONCLUSIONS: The transverse abdominal plan blockades have been shown to be an effective technique in colorectal surgery, cesarean section, cholecystectomy, hysterectomy, appendectomy, donor nephrectomy, retropubic prostatectomy, and bariatric surgery. However, the data found in randomized clinical trial are not conclusive, and as a result, it is necessary to develop new and well designed randomized clinical trial, with enough statistical power to compare different approaches, drugs, doses, and volumes for the same intervention, aiming to answer the current questions and their effects in the habitual clinical practice.

  6. Identification and Characterization of glnA Promoter and its Corresponding Trans-regulatory Protein GlnR in the Rifamycin SV Producing Actinomycete,Amycolatopsis mediterranei U32

    Institute of Scientific and Technical Information of China (English)

    Hao YU; Wen-Tao PENG; Yang LIU; Ting WU; Yu-Feng YAO; Ming-Xue CUI; Wei-Hong JIANG; Guo-Ping ZHAO

    2006-01-01

    The genetic requirements for the transcription of glnA, encoding the major glutamine synthetase in a rifamycin SV-producing Amycolatopsis mediterranei strain, U32, were investigated. Primer extension experiments showed that the promoter of U32 glnA (pglnA) was likely to have two transcription initiation sites: P1 and P2, located 157 and 45 nucleotides (nt) upstream of the translational start codon, respectively. Gel mobility shift and DNase Ⅰ footprinting analyses revealed a 30 bp cis-element located at 45 to 75 nt downstream of P1, or 38 to 68 nt upstream of P2. The sequence of the cis-element displayed high similarity to the corresponding regions of pglnA from Streptomyces coelicolor and S. roseosporus. With xylE as a reporter gene, the expression levels of U32 pglnA and its deletion derivatives under different nitrogen-source conditions were analyzed by detecting the catechol dioxygenase activities in S. lividans TK54, S. coelicolor J508 and S. coelicolor FS10 (glnR mutant). These in vivo studies showed that the activation of U32 pglnA in S. coelicolor required GlnR, and its binding to the U32 pglnA was further confirmed by the gel mobility shift assay. Cloning and heterologous expression of the U32 glnR allowed us to detect the in vitro interaction between the U32 GlnR and the corresponding pglnA cis-element. Further evidence shown by in vivo glnR inactivation and complementation indicated that GlnR is essential for the active transcription of glnA in U32.

  7. Oximetry-derived perfusion index as an early indicator of CT-guided thoracic sympathetic blockade in palmar hyperhidrosis

    International Nuclear Information System (INIS)

    Aim: To test the hypothesis that the oximetry-derived perfusion index (PI) recorded in the index finger may provide earlier objective evidence for correct positioning of the needle tip during computed tomography (CT)-guided thoracic sympathetic blockade than skin temperature in palmar hyperhidrosis. Materials and methods: Forty-four CT-guided thoracic sympathetic blockades were prospectively performed in both hands of 22 patients. Prior to chemical blockade, PI and skin temperature were recorded at 1 min intervals until 20 min after lidocaine injection. Repeated measures analysis of variance was used to assess the potency of PI and skin temperature over time. Using a 100% increase in the PI as the threshold and symptom relief within 20 min as the reference standard, the sensitivity and specificity for predicting a successful injection were calculated. Results: Thirty-seven (84%) sympathetic blockade procedures were clinically successful. For successful cases, the PI increased as early as 1 min after the blockade of the sympathetic chain (p < 0.05), whereas the skin temperature showed statistical significance 1 min later (p < 0.05). The PI can be used to indicate a successful CT-guided sympathetic blockade with 97% sensitivity and 100% specificity 3 min after lidocaine injection. Conclusion: The PI, a more marked and sensitive indicator than changes in skin temperature, can be used to indicate a successful CT-guided sympathetic blockade with satisfying sensitivity and specificity, 3 min after lidocaine injection in palmar hyperhidrosis

  8. Transcription regulatory networks analysis using CAGE

    KAUST Repository

    Tegnér, Jesper N.

    2009-10-01

    Mapping out cellular networks in general and transcriptional networks in particular has proved to be a bottle-neck hampering our understanding of biological processes. Integrative approaches fusing computational and experimental technologies for decoding transcriptional networks at a high level of resolution is therefore of uttermost importance. Yet, this is challenging since the control of gene expression in eukaryotes is a complex multi-level process influenced by several epigenetic factors and the fine interplay between regulatory proteins and the promoter structure governing the combinatorial regulation of gene expression. In this chapter we review how the CAGE data can be integrated with other measurements such as expression, physical interactions and computational prediction of regulatory motifs, which together can provide a genome-wide picture of eukaryotic transcriptional regulatory networks at a new level of resolution. © 2010 by Pan Stanford Publishing Pte. Ltd. All rights reserved.

  9. Regulatory guidance document

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1994-05-01

    The Office of Civilian Radioactive Waste Management (OCRWM) Program Management System Manual requires preparation of the OCRWM Regulatory Guidance Document (RGD) that addresses licensing, environmental compliance, and safety and health compliance. The document provides: regulatory compliance policy; guidance to OCRWM organizational elements to ensure a consistent approach when complying with regulatory requirements; strategies to achieve policy objectives; organizational responsibilities for regulatory compliance; guidance with regard to Program compliance oversight; and guidance on the contents of a project-level Regulatory Compliance Plan. The scope of the RGD includes site suitability evaluation, licensing, environmental compliance, and safety and health compliance, in accordance with the direction provided by Section 4.6.3 of the PMS Manual. Site suitability evaluation and regulatory compliance during site characterization are significant activities, particularly with regard to the YW MSA. OCRWM`s evaluation of whether the Yucca Mountain site is suitable for repository development must precede its submittal of a license application to the Nuclear Regulatory Commission (NRC). Accordingly, site suitability evaluation is discussed in Chapter 4, and the general statements of policy regarding site suitability evaluation are discussed in Section 2.1. Although much of the data and analyses may initially be similar, the licensing process is discussed separately in Chapter 5. Environmental compliance is discussed in Chapter 6. Safety and Health compliance is discussed in Chapter 7.

  10. Regulatory guidance document

    International Nuclear Information System (INIS)

    The Office of Civilian Radioactive Waste Management (OCRWM) Program Management System Manual requires preparation of the OCRWM Regulatory Guidance Document (RGD) that addresses licensing, environmental compliance, and safety and health compliance. The document provides: regulatory compliance policy; guidance to OCRWM organizational elements to ensure a consistent approach when complying with regulatory requirements; strategies to achieve policy objectives; organizational responsibilities for regulatory compliance; guidance with regard to Program compliance oversight; and guidance on the contents of a project-level Regulatory Compliance Plan. The scope of the RGD includes site suitability evaluation, licensing, environmental compliance, and safety and health compliance, in accordance with the direction provided by Section 4.6.3 of the PMS Manual. Site suitability evaluation and regulatory compliance during site characterization are significant activities, particularly with regard to the YW MSA. OCRWM's evaluation of whether the Yucca Mountain site is suitable for repository development must precede its submittal of a license application to the Nuclear Regulatory Commission (NRC). Accordingly, site suitability evaluation is discussed in Chapter 4, and the general statements of policy regarding site suitability evaluation are discussed in Section 2.1. Although much of the data and analyses may initially be similar, the licensing process is discussed separately in Chapter 5. Environmental compliance is discussed in Chapter 6. Safety and Health compliance is discussed in Chapter 7

  11. Effect of a low-fat diet combined with IGF-1 receptor blockade on 22Rv1 prostate cancer xenografts

    OpenAIRE

    Konijeti, Ramdev; Koyama, Satomi; Gray, Ashley; Barnard, R. James; Said, Jonathan W; Castor, Brandon; Elashoff, David; Wan, Junxiang; Beltran, Pedro J.; Calzone, Frank J; Cohen, Pinchas; Galet, Colette; Aronson, William J.

    2012-01-01

    In pre-clinical models, both dietary fat reduction and IGF-I receptor (IGF-1R) blockade individually inhibit prostate cancer xenograft growth. We hypothesized that a low-fat diet combined with IGF-1R blockade would cause additive inhibition of prostate cancer growth and offset possible untoward metabolic effects of IGF-1R blockade antibody therapy. Fifty SCID mice were injected with 22Rv1 cells subcutaneously. Ten days post-injection, the animals were randomized to four groups: 1) high fat di...

  12. Managing Regulatory Body Competence

    International Nuclear Information System (INIS)

    In 2001, the IAEA published TECDOC 1254, which examined the way in which the recognized functions of a regulatory body for nuclear facilities results in competence needs. Using the systematic approach to training (SAT), TECDOC 1254 provided a framework for regulatory bodies for managing training and developing and their maintaining their competence. It has been successfully used by many regulators. The IAEA has also introduced a methodology and an assessment tool - Guidelines for Systematic Assessment of Regulatory Competence Needs (SARCoN) - which provides practical guidance on analysing the training and development needs of a regulatory body and, through a gap analysis, guidance on establishing competence needs and how to meet them. In 2009, the IAEA established a steering committee (supported by a bureau) with the mission to advise the IAEA on how it could best assist Member States to develop suitable competence management systems for their regulatory bodies. The committee recommended the development of a safety report on managing staff competence as an integral part of a regulatory body's management system. This Safety Report was developed in response to this request. It supersedes TECDOC 1254, broadens its application to regulatory bodies for all facilities and activities, and builds upon the experience gained through the application of TECDOC 1254 and SARCoN and the feedback received from Member States. This Safety Report applies to the management of adequate competence as needs change, and as such is equally applicable to the needs of States 'embarking' on a nuclear power programme. It also deals with the special case of building up the competence of regulatory bodies as part of the overall process of establishing an 'embarking' State's regulatory system

  13. Selective blockade of CD28-mediated T cell costimulation protects rhesus monkeys against acute fatal experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Haanstra, Krista G; Dijkman, Karin; Bashir, Noun; Bauer, Jan; Mary, Caroline; Poirier, Nicolas; Baker, Paul; Crossan, Claire L; Scobie, Linda; 't Hart, Bert A; Vanhove, Bernard

    2015-02-15

    Costimulatory and coinhibitory receptor-ligand pairs on T cells and APC control the immune response. We have investigated whether selective blockade of CD28-CD80/86 costimulatory interactions, which preserves the coinhibitory CTLA4-CD80/86 interactions and the function of regulatory T (Treg) cells, abrogates the induction of experimental autoimmune encephalomyelitis (EAE) in rhesus monkeys. EAE was induced by intracutaneous immunization with recombinant human myelin oligodendrocyte glycoprotein (rhMOG) in CFA on day 0. FR104 is a monovalent, PEGylated-humanized Fab' Ab fragment against human CD28, cross-reactive with rhesus monkey CD28. FR104 or placebo was administered on days 0, 7, 14, and 21. FR104 levels remained high until the end of the study (day 42). Placebo-treated animals all developed clinical EAE between days 12 and 27. FR104-treated animals did not develop clinical EAE and were sacrificed at the end of the study resulting in a significantly prolonged survival. FR104 treatment diminished T and B cell responses against rhMOG, significantly reduced CNS inflammation and prevented demyelination. The inflammatory profile in the cerebrospinal fluid and brain material was also strongly reduced. Recrudescence of latent virus was investigated in blood, spleen, and brain. No differences between groups were observed for the β-herpesvirus CMV and the polyomaviruses SV40 and SA12. Cross-sectional measurement of lymphocryptovirus, the rhesus monkey EBV, demonstrated elevated levels in the blood of FR104-treated animals. Blocking rhesus monkey CD28 with FR104 mitigated autoreactive T and B cell activation and prevented CNS pathology in the rhMOG/CFA EAE model in rhesus monkeys. PMID:25589073

  14. Phylogeny based discovery of regulatory elements

    Directory of Open Access Journals (Sweden)

    Cohen Barak A

    2006-05-01

    Full Text Available Abstract Background Algorithms that locate evolutionarily conserved sequences have become powerful tools for finding functional DNA elements, including transcription factor binding sites; however, most methods do not take advantage of an explicit model for the constrained evolution of functional DNA sequences. Results We developed a probabilistic framework that combines an HKY85 model, which assigns probabilities to different base substitutions between species, and weight matrix models of transcription factor binding sites, which describe the probabilities of observing particular nucleotides at specific positions in the binding site. The method incorporates the phylogenies of the species under consideration and takes into account the position specific variation of transcription factor binding sites. Using our framework we assessed the suitability of alignments of genomic sequences from commonly used species as substrates for comparative genomic approaches to regulatory motif finding. We then applied this technique to Saccharomyces cerevisiae and related species by examining all possible six base pair DNA sequences (hexamers and identifying sequences that are conserved in a significant number of promoters. By combining similar conserved hexamers we reconstructed known cis-regulatory motifs and made predictions of previously unidentified motifs. We tested one prediction experimentally, finding it to be a regulatory element involved in the transcriptional response to glucose. Conclusion The experimental validation of a regulatory element prediction missed by other large-scale motif finding studies demonstrates that our approach is a useful addition to the current suite of tools for finding regulatory motifs.

  15. NRC regulatory agenda

    International Nuclear Information System (INIS)

    The Regulatory Agenda is a quarterly compilation of all rules on which the NRC has recently completed action or has proposed, or is considering action and of all petitions for rulemaking that the NRC has received that are pending disposition

  16. NRC regulatory initiatives

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, T.C. [Nuclear Regulatory Commission (United States)

    1989-11-01

    The US Nuclear Regulatory Commission (NRC) is addressing several low-level waste disposal issues that will be important to waste generators and to States and Compacts developing new disposal capacity. These issues include Greater-Than-Class C (GTCC) waste, mixed waste, below regulatory concern (BRC) waste, and the low-level waste data base. This paper discusses these issues and their current status.

  17. Prospective Randomized Comparison of Ovarian Blockade with Nafarelin Versus Leuprolide During Ovarian Stimulation with Recombinant FSH in an ICSI Program

    OpenAIRE

    Franco Jr, José G; Baruffi, Ricardo L. R.; Mauri, Ana L; Petersen, Claudia G; Chufallo, José E.; Felipe, Valéria; Garbellini, Erika

    2001-01-01

    Purpose: A prospective study was conducted to compare the efficiency of ovarian blockade with nafarelin versus leuprolide in a population whose indication for assisted reproduction was the male factor.

  18. Study of Rydberg blockade mediated optical non-linearity in thermal vapor using optical heterodyne detection technique

    CERN Document Server

    Bhowmick, Arup; Mohapatra, Ashok K

    2016-01-01

    We demonstrate the phenomenon of blockade in two-photon excitations to the Rydberg state in thermal vapor. A technique based on optical heterodyne is used to measure the dispersion of a probe beam far off resonant to the D2 line of rubidium in the presence of a strong laser beam that couples to the Rydberg state via two-photon resonance. Density dependent suppression of the dispersion peak is observed while coupling to the Rydberg state with principal quantum number, n = 60. The experimental observation is explained using the phenomenon of Rydberg blockade. The blockade radius is measured to be about 2.2 {\\mu}m which is consistent with the scaling due to the Doppler width of 2-photon resonance in thermal vapor. Our result promises the realization of single photon source and strong single photon non-linearity based on Rydberg blockade in thermal vapor.

  19. Promoting Models

    Science.gov (United States)

    Li, Qin; Zhao, Yongxin; Wu, Xiaofeng; Liu, Si

    There can be multitudinous models specifying aspects of the same system. Each model has a bias towards one aspect. These models often override in specific aspects though they have different expressions. A specification written in one model can be refined by introducing additional information from other models. The paper proposes a concept of promoting models which is a methodology to obtain refinements with support from cooperating models. It refines a primary model by integrating the information from a secondary model. The promotion principle is not merely an academic point, but also a reliable and robust engineering technique which can be used to develop software and hardware systems. It can also check the consistency between two specifications from different models. A case of modeling a simple online shopping system with the cooperation of the guarded design model and CSP model illustrates the practicability of the promotion principle.

  20. Photon-blockade as protection in photosynthesis Antenna with cyclic structures

    CERN Document Server

    Dong, Hui; Yi, Zhenhuan; Agarwal, Girish S; Scully, Marlan O

    2016-01-01

    Excess energy absorbed by the light-harvesting antennas could be potentially harmful to the photosynthesis complexes. The biological system has developed various mechanisms, e.g. non-photon chemical quenching, to prevent these damages by dissipating energy into the surrounding environment. In additional to this well-known mechanism, we hypothesise a new protection mechanism of suppressing the probability of double excitation in photosynthesis system, where pigment-protein complexes form cyclic structures with dipole-dipole interaction between adjacent chlorophylls. We also demonstrate robustness of the photon blockade against the disorder in the ring structures. The photon blockade can explain the recent observation on the suppression of simultaneous emission of two photons in natural photosynthetic antennas.

  1. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis.

    Science.gov (United States)

    Dubin, Krista; Callahan, Margaret K; Ren, Boyu; Khanin, Raya; Viale, Agnes; Ling, Lilan; No, Daniel; Gobourne, Asia; Littmann, Eric; Huttenhower, Curtis; Pamer, Eric G; Wolchok, Jedd D

    2016-01-01

    The composition of the intestinal microbiota influences the development of inflammatory disorders. However, associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota's composition. Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune-mediated colitis. Here we conduct a prospective study of patients with metastatic melanoma undergoing ipilimumab treatment and correlate the pre-inflammation faecal microbiota and microbiome composition with subsequent colitis development. We demonstrate that increased representation of bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis. Furthermore, a paucity of genetic pathways involved in polyamine transport and B vitamin biosynthesis is associated with an increased risk of colitis. Identification of these biomarkers may enable interventions to reduce the risk of inflammatory complications following cancer immunotherapy. PMID:26837003

  2. Quantum transport through a Coulomb blockaded quantum emitter coupled to a plasmonic dimer.

    Science.gov (United States)

    Goker, A; Aksu, H

    2016-01-21

    We study the electron transmission through a Coulomb blockaded quantum emitter coupled to metal nanoparticles possessing plasmon resonances by employing the time-dependent non-crossing approximation. We find that the coupling of the nanoparticle plasmons with the excitons results in a significant enhancement of the conductance through the discrete state with higher energy beyond the unitarity limit while the other discrete state with lower energy remains Coulomb blockaded. We show that boosting the plasmon-exciton coupling well below the Kondo temperature increases the enhancement adding another quantum of counductance upon saturation. Finite bias and increasing emitter resonance energy tend to reduce this enhancement. We attribute these observations to the opening of an additional transport channel via the plasmon-exciton coupling. PMID:26686761

  3. Split-dose atropine versus glycopyrrolate with neostigmine for reversal of gallamine-induced neuromuscular blockade

    DEFF Research Database (Denmark)

    Wetterslev, J; Jarnvig, I; Jørgensen, L N;

    1991-01-01

    The effects of a split-dose of atropine sulphate versus a single dose of glycopyrrolate given with neostigmine for the reversal of gallamine-induced neuromuscular blockade were studied in 55 patients undergoing gynaecological surgery. The patients were randomized to receive either a single dose of......, whereas none occurred in the glycopyrrolate group (P less than 0.05). It is concluded that a split-dose of atropine has similar chronotropic effects to a single dose of glycopyrrolate for the reversal of gallamine-induced neuromuscular blockade. However, the finding of a higher incidence of cardiac...... arrhythmias in the atropine group suggests that this reversal regime should be reserved for patients without cardiac disease....

  4. Phonon blockade in a nanomechanical resonator resonantly coupled to a qubit

    CERN Document Server

    Xu, Xun-Wei; Liu, Yu-xi

    2016-01-01

    We study phonon statistics in a nanomechanical resonator (NAMR) which is resonantly coupled to a qubit. We find that there are two different mechanisms for phonon blockade in such a resonantly coupled NAMR-qubit system. One is due to the strong anharmonicity of the NAMR-qubit system with large coupling strength; the other one is due to the destructive interference between different paths for two-phonon excitation in the NAMR-qubit system with a moderate coupling strength. In order to enlarge the mean phonon number for strong phonon antibunching with a moderate NAMR-qubit coupling strength, we assume that two external driving fields are applied to the NAMR and qubit, respectively. In this case, we find that the phonon blockades under two mechanisms can appear at the same frequency regime by optimizing the strength ratio and phase difference of the two external driving fields.

  5. Rydberg-Blockade Effects in Autler-Townes Spectra of Ultracold Strontium

    CERN Document Server

    DeSalvo, B J; Gaul, C; Pohl, T; Yoshida, S; Burgdörfer, J; Hazzard, K R A; Dunning, F B; Killian, T C

    2015-01-01

    We present a combined experimental and theoretical study of the effects of Rydberg interactions on Autler-Townes spectra of ultracold gases of atomic strontium. Realizing two-photon Rydberg excitation via a long-lived triplet state allows us to probe the thus far unexplored regime where Rydberg state decay presents the dominant decoherence mechanism. The effects of Rydberg interactions are observed in shifts, asymmetries, and broadening of the measured atom-loss spectra. The experiment is analyzed within a one-body density matrix approach, accounting for interaction-induced level shifts and dephasing through nonlinear terms that approximately incorporate correlations due to the Rydberg blockade. This description yields good agreement with our experimental observations for short excitation times. For longer excitation times, the loss spectrum is altered qualitatively, suggesting additional dephasing mechanisms beyond the standard blockade mechanism based on pure van der Waals interactions.

  6. Intrathecal amantadine for prolonged spinal blockade of sensory and motor functions in rats.

    Science.gov (United States)

    Tzeng, Jann-Inn; Kan, Chung-Dann; Wang, Jieh-Neng; Wang, Jhi-Joung; Lin, Heng-Teng; Hung, Ching-Hsia

    2016-08-01

    We aimed to compare the hypothesized local anesthetic action of amantadine (1-adamantanamine) with that of the known local anesthetic mepivacaine. Motor, proprioceptive, and nociceptive functions were evaluated in rats after intrathecal administration. Amantadine elicited spinal anesthesia in a dose-related fashion and produced a better sensory-selective action over motor blockade (P proprioceptive, and nociceptive block was mepivacaine > amantadine (P proprioception, and nociception. On an equipotent basis (ED25 , ED50 , and ED75 ), the duration of amantadine was longer (P proprioceptive, and nociceptive block. Our preclinical data demonstrated that amantadine was less potent than mepivacaine at producing spinal anesthesia. The spinal block duration produced by amantadine was greater than that produced by mepivacaine. Both amantadine and mepivacaine produced a markedly nociceptive-specific blockade. PMID:27011292

  7. Photonic controlled-phase gates through Rydberg blockade in optical cavities

    Science.gov (United States)

    Das, Sumanta; Grankin, Andrey; Iakoupov, Ivan; Brion, Etienne; Borregaard, Johannes; Boddeda, Rajiv; Usmani, Imam; Ourjoumtsev, Alexei; Grangier, Philippe; Sørensen, Anders S.

    2016-04-01

    We propose a scheme for high-fidelity photonic controlled-phase gates using a Rydberg blockade in an ensemble of atoms in an optical cavity. The gate operation is obtained by first storing a photonic pulse in the ensemble and then scattering a second pulse from the cavity, resulting in a phase change depending on whether the first pulse contained a single photon. We show that the combination of a Rydberg blockade and optical cavities effectively enhances the optical nonlinearity created by the strong Rydberg interaction and makes the gate operation more robust. The resulting gate can be implemented with cavities of moderate finesse, allowing for highly efficient processing of quantum information encoded in photons. As an illustration, we show how the gate can be employed to increase the communication rate of quantum repeaters based on atomic ensembles.

  8. Equivalent benefit of mTORC1 blockade and combined PI3K-mTOR blockade in a mouse model of tuberous sclerosis

    Directory of Open Access Journals (Sweden)

    Pollizzi Kristen

    2009-06-01

    Full Text Available Abstract Background Tuberous sclerosis (TSC is a hamartoma syndrome in which renal and lung tumors cause the greatest morbidity. Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1 and suppression of AKT. Recent studies indicate that inhibition of mTORC1 with RAD001 (everolimus leads to rebound activation of AKT, which could protect tumors from drug-induced cell death. Here we examine the potential benefit of inhibition of both mTOR and AKT signaling in a mouse model of TSC, using a dual pan class I PI3K/mTOR catalytic small molecule inhibitor NVP-BEZ235. Results Using ENU to enhance Tsc2+- kidney tumor development, both RAD001 (10 mg/kg PO 5 d/week and NVP-BEZ235 (45 mg/kg PO QD had equivalent effects in suppressing tumor development during a 4 week treatment period, with a 99% reduction in tumor cell mass. Marked reduction in activation of mTORC1, induction of cell cycle arrest, and absence of apoptotic cell death was seen in mice treated with either drug. However, when either was discontinued, there was prompt recovery of tumor growth, with extensive proliferation. Conclusion Both mTORC1 blockade alone and combined PI3K-mTOR blockade lead to suppression of tumor development but not tumor elimination in this TSC model.

  9. Counting statistics of transport through Coulomb blockade nanostructures: High-order cumulants and non-Markovian effects

    DEFF Research Database (Denmark)

    Flindt, Christian; Novotny, Tomás; Braggio, Alessandro;

    2010-01-01

    Recent experimental progress has made it possible to detect in real-time single electrons tunneling through Coulomb blockade nanostructures, thereby allowing for precise measurements of the statistical distribution of the number of transferred charges, the so-called full counting statistics. These......-Condon blockade, and transport through coherently coupled quantum dots embedded in a dissipative environment. We discuss properties of high-order cumulants as well as possible subtleties associated with non-Markovian dynamics....

  10. Combined androgen blockade in the treatment of advanced prostate cancer--an overview. The Scandinavian Prostatic Cancer Group

    DEFF Research Database (Denmark)

    Iversen, P

    1997-01-01

    The value of combined androgen blockade in the treatment of patients with advanced prostate cancer is still controversial. In this review by the Scandinavian Prostatic Cancer Group, the literature addressing the concept and its clinical use is critically reviewed.......The value of combined androgen blockade in the treatment of patients with advanced prostate cancer is still controversial. In this review by the Scandinavian Prostatic Cancer Group, the literature addressing the concept and its clinical use is critically reviewed....

  11. Magnetic Blockade Mechanism for Quantum Nucleation of Superconducting Vortex-Antivortex Pairs in Zero External Magnetic Field

    OpenAIRE

    Miller Jr, J. H.; Wijesinghe, A. I.

    2011-01-01

    We propose a magnetic dual of the Coulomb blockade effect for quantum nucleation of flux vortex pairs in high-Tc superconducting (HTS) films and grain boundaries in zero applied field. The magnetic blockade instability occurs at {\\theta} = {\\pi}, where {\\theta} is the "vacuum" or theta angle. The {\\theta} term has recently been discussed in the context of several other systems, including charge and spin density waves, topological insulators, the quantum Hall effect, and spontaneous CP violati...

  12. Bayesian variable selection and data integration for biological regulatory networks

    OpenAIRE

    Jensen, Shane T; Chen, Guang; Stoeckert, Jr, Christian J.

    2007-01-01

    A substantial focus of research in molecular biology are gene regulatory networks: the set of transcription factors and target genes which control the involvement of different biological processes in living cells. Previous statistical approaches for identifying gene regulatory networks have used gene expression data, ChIP binding data or promoter sequence data, but each of these resources provides only partial information. We present a Bayesian hierarchical model that integrates all three dat...

  13. Coulomb blockade in monolayer MoS2 single electron transistor

    Science.gov (United States)

    Lee, Kyunghoon; Kulkarni, Girish; Zhong, Zhaohui

    2016-03-01

    Substantial effort has been dedicated to understand the intrinsic electronic properties of molybdenum disulfide (MoS2). However, electron transport study on monolayer MoS2 has been challenging to date, especially at low temperatures due to large metal/semiconductor junction barriers. Herein, we report the fabrication and characterization of the monolayer MoS2 single-electron transistor. High performance devices are obtained through the use of low work function metal (zinc) contact and a rapid thermal annealing step. Coulomb blockade is observed at low temperatures and is attributed to single-electron tunneling via two tunnel junction barriers. The nature of Coulomb blockade is also investigated by temperature-dependent conductance oscillation measurement. Our results hold promise for the study of novel quantum transport phenomena in 2D semiconducting atomic layer crystals.Substantial effort has been dedicated to understand the intrinsic electronic properties of molybdenum disulfide (MoS2). However, electron transport study on monolayer MoS2 has been challenging to date, especially at low temperatures due to large metal/semiconductor junction barriers. Herein, we report the fabrication and characterization of the monolayer MoS2 single-electron transistor. High performance devices are obtained through the use of low work function metal (zinc) contact and a rapid thermal annealing step. Coulomb blockade is observed at low temperatures and is attributed to single-electron tunneling via two tunnel junction barriers. The nature of Coulomb blockade is also investigated by temperature-dependent conductance oscillation measurement. Our results hold promise for the study of novel quantum transport phenomena in 2D semiconducting atomic layer crystals. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr08954a

  14. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis

    OpenAIRE

    Dubin, Krista; Callahan, Margaret K.; Ren, Boyu; Khanin, Raya; Viale, Agnes; Ling, Lilan; No, Daniel; Gobourne, Asia; Littmann, Eric; Huttenhower, Curtis; Pamer, Eric G.; Wolchok, Jedd D.

    2016-01-01

    The composition of the intestinal microbiota influences the development of inflammatory disorders. However, associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota's composition. Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune-med...

  15. Blockade of Wnt signaling inhibits angiogenesis and tumor growth in hepatocellular carcinoma

    OpenAIRE

    J. Hu; Dong, A.; Fernandez-Ruiz, V. (Verónica); Shan, J.; Kawa, M. (Milosz); Martinez-Anso, E. (Eduardo); J. Prieto; Qian, C

    2009-01-01

    Aberrant activation of Wnt signaling plays an important role in hepatocarcinogenesis. In addition to direct effects on tumor cells, Wnt signaling might be involved in the organization of tumor microenvironment. In this study, we have explored whether Wnt signaling blockade by exogenous expression of Wnt antagonists could inhibit tumor angiogenesis and control tumor growth. Human Wnt inhibitory factor 1 (WIF1) and secreted frizzled-related protein 1 (sFRP1) were each fused with Fc fragment of ...

  16. A new method for release of severe mentosternal contractures under central neuraxial blockade

    Directory of Open Access Journals (Sweden)

    Mago Vishal

    2010-10-01

    Full Text Available A new method for release of severe mentosternal contractures has been described in this paper under central neuraxial blockade. The contracture release was performed under thoracic epidural analgesia. This technique can benefit patients with mentosternal contractures to avoid the problems of entubation and it can also assist in postoperative recovery and analgesia. The epidural catheter can be used to extend the height or duration of intraoperative block and is also useful to provide postoperative epidural analgesia.

  17. Cardioprotection conferred by exercise training is blunted by blockade of the opioid system

    OpenAIRE

    Tatiana F.G. Galvão; Matos, Katt C; Brum, Patrícia C; Negrão, Carlos E.; Protásio Lemos da Luz; Chagas, Antônio Carlos P

    2011-01-01

    OBJECTIVES: To investigate the effect of opioid receptor blockade on the myocardial protection conferred by chronic exercise and to compare exercise training with different strategies of myocardial protection (opioid infusion and brief periods of ischemia-reperfusion) preceding irreversible left anterior descending coronary ligation. INTRODUCTION: The acute cardioprotective effects of exercise training are at least partly mediated through opioid receptor-dependent mechanisms in ischemia-reper...

  18. PD-1/PD-L1 blockades in non-small-cell lung cancer therapy

    Directory of Open Access Journals (Sweden)

    Jing W

    2016-01-01

    Full Text Available Wang Jing,1,2,* Miaomiao Li,3,* Yan Zhang,2 Feifei Teng,2 Anqin Han,2 Li Kong,2 Hui Zhu2 1Weifang Medical University, Weifang, Shandong Province, People’s Republic of China; 2Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong Province, People’s Republic of China; 3Shandong Medical College, Jinan, Shandong Province, People’s Republic of China *Both these authors contributed equally to the work Abstract: Lung cancer is the leading cause of cancer death in males and the second leading cause of death in females worldwide. Non-small-cell lung cancer (NSCLC is the main pathological type of lung cancer, and most newly diagnosed NSCLC patients cannot undergo surgery because the disease is already locally advanced or metastatic. Despite chemoradiotherapy and targeted therapy improving clinical outcomes, overall survival remains poor. Immune checkpoint blockade, especially blockade of programmed death-1 (PD-1 receptor and its ligand PD-L1, achieved robust responses and improved survival for patients with locally advanced/metastatic NSCLC in preclinical and clinical studies. However, with regard to PD-1/PD-L1 checkpoint blockade as monotherapy or in combination with other antitumor therapies, such as chemotherapy, radiotherapy (including conventional irradiation and stereotactic body radiotherapy, and target therapy, there are still many unknowns in treating patients with NSCLC. Despite this limited understanding, checkpoint blockade as a novel therapeutic approach may change the treatment paradigm of NSCLC in the future. Here we review the main results from completed and ongoing studies to investigate the feasibility of PD-1/PD-L1 inhibitors, as monotherapy or combinatorial agents in patients with locally advanced and metastatic NSCLC, and explore optimal strategy in such patients. Keywords: immunotherapy, checkpoint, PD-1, PD-L1, NSCLC

  19. Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis

    International Nuclear Information System (INIS)

    Extracellular Ca2+ influx has been suggested to play a role in ethanol-induced hepatocyte apoptosis and necrosis. Previous studies indicated that store-operated Ca2+ entry (SOCE) was involved in liver injury induced by ethanol in HepG2 cells. However, the mechanisms underlying liver injury caused by SOCE remain unclear. We aimed to investigate the effects and mechanism of SOCE inhibition on liver injury induced by ethanol in BRL cells and Sprague–Dawley rats. Our data demonstrated that ethanol (0–400 mM) dose-dependently increased hepatocyte injury and 100 mM ethanol significantly upregulated the mRNA and protein expression of SOC for at least 72 h in BRL cells. Blockade of SOCE by pharmacological inhibitors and sh-RNA knockdown of STIM1 and Orai1 attenuated intracellular Ca2+ overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and inhibited ethanol-induced apoptosis. STIM1 and Orai1 expression was greater in ethanol-treated than control rats, and the SOCE inhibitor corosolic acid ameliorated the histopathological findings and alanine transaminase and aspartate transaminase activity as well as decreased cytochrome C release and inhibited alcohol-induced cell apoptosis. These findings suggest that SOCE blockade could alleviate alcohol-induced hepatotoxicity via inhibiting apoptosis. SOCE might be a useful therapeutic target in alcoholic liver diseases. - Highlights: • Blockade of SOCE alleviated overload of Ca2+ and hepatotoxicity after ethanol application. • Blockade of SOCE inhibited mitochondrial apoptosis after ethanol application. • SOCE might be a useful therapeutic target in alcoholic liver diseases

  20. Grover search algorithm with Rydberg-blockaded atoms: quantum Monte Carlo simulations

    Science.gov (United States)

    Petrosyan, David; Saffman, Mark; Mølmer, Klaus

    2016-05-01

    We consider the Grover search algorithm implementation for a quantum register of size N={2}k using k (or k+1) microwave- and laser-driven Rydberg-blockaded atoms, following the proposal by Mølmer et al (2011 J. Phys. B 44 184016). We suggest some simplifications for the microwave and laser couplings, and analyze the performance of the algorithm for up to k = 4 multilevel atoms under realistic experimental conditions using quantum stochastic (Monte Carlo) wavefunction simulations.

  1. Control of Coulomb blockade in a mesoscopic Josephson junction using single electron tunneling

    OpenAIRE

    Hassel, J.; Seppä, Heikki; Delahaye, Julien; Hakonen, Pertti J.

    2004-01-01

    We study a circuit where a mesoscopic Josephson junction (JJ) is embedded in an environment consisting of a large bias resistor and a normal metal - superconductor tunnel junction (NIS). The effective Coulomb blockade of the JJ can be controlled by the tunneling current through the NIS junction leading to transistor-like characteristics. We show using phase correlation theory and numerical simulations that substantial current gain with low current noise ($i_{n}\\lesssim 1$ fA/$\\sqrt{\\text{Hz}}...

  2. Local adenosine receptor blockade accentuates the sympathetic responses to fatiguing exercise

    OpenAIRE

    Cui, Jian; Leuenberger, Urs A.; Blaha, Cheryl; Yoder, Jonathan; Gao, Zhaohui; Sinoway, Lawrence I.

    2010-01-01

    The role adenosine plays in evoking the exercise pressor reflex in humans remains controversial. We hypothesized that localized forearm adenosine receptor blockade would attenuate muscle sympathetic nerve activity (MSNA) responses to fatiguing handgrip exercise in humans. Blood pressure (Finometer), heart rate, and MSNA from the peroneal nerve were assessed in 11 healthy young volunteers during fatiguing isometric handgrip, postexercise circulatory occlusion (PECO), and passive muscle stretch...

  3. PD-1 blockade in chronically HIV-1-infected humanized mice suppresses viral loads.

    Directory of Open Access Journals (Sweden)

    Edward Seung

    Full Text Available An estimated 34 million people are living with HIV worldwide (UNAIDS, 2012, with the number of infected persons rising every year. Increases in HIV prevalence have resulted not only from new infections, but also from increases in the survival of HIV-infected persons produced by effective anti-retroviral therapies. Augmentation of anti-viral immune responses may be able to further increase the survival of HIV-infected persons. One strategy to augment these responses is to reinvigorate exhausted anti-HIV immune cells present in chronically infected persons. The PD-1-PD-L1 pathway has been implicated in the exhaustion of virus-specific T cells during chronic HIV infection. Inhibition of PD-1 signaling using blocking anti-PD-1 antibodies has been shown to reduce simian immunodeficiency virus (SIV loads in monkeys. We now show that PD-1 blockade can improve control of HIV replication in vivo in an animal model. BLT (Bone marrow-Liver-Thymus humanized mice chronically infected with HIV-1 were treated with an anti-PD-1 antibody over a 10-day period. The PD-1 blockade resulted in a very significant 45-fold reduction in HIV viral loads in humanized mice with high CD8(+ T cell expression of PD-1, compared to controls at 4 weeks post-treatment. The anti-PD-1 antibody treatment also resulted in a significant increase in CD8(+ T cells. PD-1 blockade did not affect T cell expression of other inhibitory receptors co-expressed with PD-1, including CD244, CD160 and LAG-3, and did not appear to affect virus-specific humoral immune responses. These data demonstrate that inhibiting PD-1 signaling can reduce HIV viral loads in vivo in the humanized BLT mouse model, suggesting that blockade of the PD-1-PD-L1 pathway may have therapeutic potential in the treatment of patients already infected with the AIDS virus.

  4. Density functional description of Coulomb blockade: Adiabatic or dynamic exchange-correlation?

    OpenAIRE

    Liu, Zhenfei; Burke, Kieron

    2015-01-01

    Above the Kondo temperature, the Kohn-Sham zero-bias conductance of an Anderson junction has been shown to completely miss the Coulomb blockade. Within a standard model for the spectral function, we deduce a parameterization for both the onsite exchange-correlation potential and the bias drop as a function of the site occupation that applies for all correlation strengths. We use our results to sow doubt on the common interpretation of such corrections as arising from dynamical exchange-correl...

  5. Blockade of pathological retinal ganglion cell hyperactivity improves optogenetically evoked light responses in rd1 mice

    OpenAIRE

    John Martin Barrett; Patrick Degenaar

    2015-01-01

    Retinitis pigmentosa (RP) is a progressive retinal dystrophy that causes visual impairment and eventual blindness. Retinal prostheses are the best currently available vision-restoring treatment for RP, but only restore crude vision. One possible contributing factor to the poor quality of vision achieved with prosthetic devices is the pathological retinal ganglion cell (RGC) hyperactivity that occurs in photoreceptor dystrophic disorders. Gap junction blockade with meclofenamic acid (MFA) was ...

  6. The Effect of Opioid Receptor Blockade on the Neural Processing of Thermal Stimuli

    OpenAIRE

    Eszter D Schoell; Ulrike Bingel; Falk Eippert; Juliana Yacubian; Kerrin Christiansen; Hilke Andresen; Arne May; Christian Buechel

    2010-01-01

    The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore...

  7. Successful Ultrasound-Guided Femoral Nerve Blockade and Catheterization in a Patient with Von Willebrand Disease

    OpenAIRE

    DiStefano, Youmna E.; Lazar, Michael D.

    2015-01-01

    Peripheral nerve blockade (PNB) is superior to neuraxial anesthesia and/or opioid therapy for perioperative analgesia in total knee replacement (TKR). Evidence on the safety of PNB in patients with coagulopathy is lacking. We describe the first documented account of continuous femoral PNB for perioperative analgesia in a patient with Von Willebrand Disease (vWD). Given her history of opioid tolerance and after an informative discussion, a continuous femoral PNB was planned for in this 34-year...

  8. BLOCKADE OF CENTRAL NICOTINE ACETYLCHOLINE RECEPTOR SIGNALING ATTENUATE GHRELIN-INDUCED FOOD INTAKE IN RODENTS

    OpenAIRE

    S.L. Dickson; Hrabovszky, E; Hansson, C.; Jerlhag, E.; Alvarez-Crespo, M.; Skibicka, K. P.; Molnar, C. S.; Liposits, Z; Engel, J. A.; Egecioglu, E.

    2010-01-01

    Here we sought to determine whether ghrelin's central effects on food intake can be interrupted by nicotinic cholinergic receptor (nAChR) blockade. Ghrelin regulates mesolimbic dopamine neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc), partly via cholinergic VTA afferents originating in the laterodorsal tegmental area (LDTg). Given that these cholinergic projections to the VTA have been implicated in natural as well as drug-induced reinforcement, we sou...

  9. Intralipid Therapy for Inadvertent Peripheral Nervous System Blockade Resulting from Local Anesthetic Overdose

    OpenAIRE

    Ihab Kamel; Gaurav Trehan; Rodger Barnette

    2015-01-01

    Although local anesthetics have an acceptable safety profile, significant morbidity and mortality have been associated with their use. Inadvertent intravascular injection of local anesthetics and/or the use of excessive doses have been the most frequent causes of local anesthetic systemic toxicity (LAST). Furthermore, excessive doses of local anesthetics injected locally into the tissues may lead to inadvertent peripheral nerve infiltration and blockade. Successful treatment of LAST with intr...

  10. Effect of {beta}{sub 1} adrenergic receptor blockade on myocardial blood flow and vasodilatory capacity

    Energy Technology Data Exchange (ETDEWEB)

    Boettcher, M.; Czernin, J.; Sun, K. [Univ. of California, Los Angeles, CA (United States)] [and others

    1997-03-01

    The {beta}{sub 1} receptor blockade reduces cardiac work and may thereby lower myocardial blood flow (MBF) at rest. The effect of {beta}{sub 1} receptor blockade on hyperemic MBF is unknown. To evaluate the effect of selective {beta}{sub 1} receptor blockade on MBF at rest and during dipyridamole induced hyperemia, 10 healthy volunteers (8 men, 2 women, mean age 24 {+-} 5 yr) were studied using {sup 13}N-ammonia PET (two-compartment model) under control conditions and again during metoprolol (50 mg orally 12 hr and 1 hr before the study). The resting rate pressure product (6628 {+-} 504 versus 5225 {+-} 807) and heart rate (63 {+-} 6-54 {plus_minus} 5 bpm) declined during metoprolol (p < 0.05). Similarly, heart rate and rate pressure product declined from the baseline dipyridamole study to dipyridamole plus metoprolol (p < 0.05). Resting MBF declined in proportion to cardiac work by approximately 20% from 0.61 {+-} 0.09-0.51 {+-} 0.10 ml/g/min (p < 0.05). In contrast, hyperemic MBF increased when metoprolol was added to dipyridamole (1.86 {plus_minus} 0.27 {+-} 0.45 ml/g/min; p<0.05). The decrease in resting MBF together with the increase in hyperemic MBF resulted in a significant increase in the myocardial flow reserve during metoprolol (3.14 {+-} 0.80-4.61 {+-} 0.68; p<0.01). The {beta}{sub 1} receptor blockade increases coronary vasodilatory capacity and myocardial flow reserve. However, the mechanisms accounting for this finding remain uncertain. 32 refs., 2 figs., 2 tabs.

  11. Quantized current blockade and hydrodynamic correlations in biopolymer translocation through nanopores: evidence from multiscale simulations

    CERN Document Server

    Bernaschi, Massimo; Succi, Sauro; Fyta, Maria; Kaxiras, Efthimios

    2008-01-01

    We present a detailed description of biopolymer translocation through a nanopore in the presence of a solvent, using an innovative multi-scale methodology which treats the biopolymer at the microscopic scale as combined with a self-consistent mesoscopic description for the solvent fluid dynamics. We report evidence for quantized current blockade depending on the folding configuration and offer detailed information on the role of hydrodynamic correlations in speeding-up the translocation process.

  12. Influence of beta adrenergic blockade on effects of physical training in patients with ischaemic heart disease.

    OpenAIRE

    L. Vanhees; Fagard, R.; Amery, A

    1982-01-01

    Reduction in heart rate during submaximal exercise is often used to judge the progress of patients with ischaemic heart disease in the course of a physical training programme. Some patients, however, are treated with beta adrenergic blocking drugs and it remains controversial if chronic beta blockade influences the effects of training and if heart rate remains a useful guide in the evaluation of the state of training of these patients. Male postinfarction patients, 15 treated with and 15 with...

  13. Universal Correlations of Coulomb Blockade Conductance Peaks and the Rotation Scaling in Quantum Dots

    OpenAIRE

    Alhassid, Y.; Attias, H.

    1996-01-01

    We show that the parametric correlations of the conductance peak amplitudes of a chaotic or weakly disordered quantum dot in the Coulomb blockade regime become universal upon an appropriate scaling of the parameter. We compute the universal forms of this correlator for both cases of conserved and broken time reversal symmetry. For a symmetric dot the correlator is independent of the details in each lead such as the number of channels and their correlation. We derive a new scaling, which we ca...

  14. Blockade of N-methyl-d-aspartate receptor activation suppresses learning-induced synaptic elimination

    OpenAIRE

    Bock, Jörg; Braun, Katharina

    1999-01-01

    Auditory filial imprinting in the domestic chicken is accompanied by a dramatic loss of spine synapses in two higher associative forebrain areas, the mediorostral neostriatum/hyperstriatum ventrale (MNH) and the dorsocaudal neostriatum (Ndc). The cellular mechanisms that underlie this learning-induced synaptic reorganization are unclear. We found that local pharmacological blockade of N-methyl-d-aspartate (NMDA) receptors in the MNH, a manipulation that has been shown previously to impair aud...

  15. Angiopoietin-1/Tie-2 activation contributes to vascular survival and tumor growth during VEGF blockade

    OpenAIRE

    Huang, Jianzhong; Bae, Jae-O; Tsai, Judy P.; Kadenhe-Chiweshe, Angela; Papa, Joey; Lee, Alice; Zeng, Shan; Kornfeld, Z. Noah; Ullner, Paivi; Zaghloul, Nibal; Ioffe, Ella; Nandor, Sarah; Burova, Elena; Holash, Jocelyn; Thurston, Gavin

    2009-01-01

    Approval of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab by the FDA in 2004 reflected the success of this vascular targeting strategy in extending survival in patients with advanced cancers. However, consistent with previous reports that experimental tumors can grow or recur during VEGF blockade, it has become clear that many patients treated with VEGF inhibitors will ultimately develop progressive disease. Previous studies have shown that disruption of VEGF signali...

  16. Coulomb Blockade Anisotropic Magnetoresistance Effect in a (Ga,Mn)As Single-Electron Transistor

    Czech Academy of Sciences Publication Activity Database

    Wunderlich, J.; Jungwirth, Tomáš; Kaestner, B.; Irvine, A.C.; Shick, Alexander; Stone, N.; Wang, K. Y.; Rana, U.; Giddings, A.D.; Foxon, C. T.; Campion, R. P.; Williams, D.A.; Gallagher, B. L.

    2006-01-01

    Roč. 97, č. 7 (2006), 077201/1-077201/4. ISSN 0031-9007 R&D Projects: GA ČR GA202/05/0575; GA MŠk LC510 Grant ostatní: EPSRC(GB) GR/S81407/01 Institutional research plan: CEZ:AV0Z10100521 Keywords : anisotropic magnetoresistance * Coulomb blockade * single electron transistor Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 7.072, year: 2006

  17. Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis

    Energy Technology Data Exchange (ETDEWEB)

    Cui, Ruibing [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Lihui [Shandong Normal University, Jinan, Shandong Province 250012 (China); Luo, Zheng; Guo, Xiaolan [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Ming, E-mail: ymylh@163.com [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China)

    2015-08-15

    Extracellular Ca{sup 2+} influx has been suggested to play a role in ethanol-induced hepatocyte apoptosis and necrosis. Previous studies indicated that store-operated Ca{sup 2+} entry (SOCE) was involved in liver injury induced by ethanol in HepG2 cells. However, the mechanisms underlying liver injury caused by SOCE remain unclear. We aimed to investigate the effects and mechanism of SOCE inhibition on liver injury induced by ethanol in BRL cells and Sprague–Dawley rats. Our data demonstrated that ethanol (0–400 mM) dose-dependently increased hepatocyte injury and 100 mM ethanol significantly upregulated the mRNA and protein expression of SOC for at least 72 h in BRL cells. Blockade of SOCE by pharmacological inhibitors and sh-RNA knockdown of STIM1 and Orai1 attenuated intracellular Ca{sup 2+} overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and inhibited ethanol-induced apoptosis. STIM1 and Orai1 expression was greater in ethanol-treated than control rats, and the SOCE inhibitor corosolic acid ameliorated the histopathological findings and alanine transaminase and aspartate transaminase activity as well as decreased cytochrome C release and inhibited alcohol-induced cell apoptosis. These findings suggest that SOCE blockade could alleviate alcohol-induced hepatotoxicity via inhibiting apoptosis. SOCE might be a useful therapeutic target in alcoholic liver diseases. - Highlights: • Blockade of SOCE alleviated overload of Ca{sup 2+} and hepatotoxicity after ethanol application. • Blockade of SOCE inhibited mitochondrial apoptosis after ethanol application. • SOCE might be a useful therapeutic target in alcoholic liver diseases.

  18. System identification of closed-loop cardiovascular control: effects of posture and autonomic blockade

    Science.gov (United States)

    Mullen, T. J.; Appel, M. L.; Mukkamala, R.; Mathias, J. M.; Cohen, R. J.

    1997-01-01

    We applied system identification to the analysis of fluctuations in heart rate (HR), arterial blood pressure (ABP), and instantaneous lung volume (ILV) to characterize quantitatively the physiological mechanisms responsible for the couplings between these variables. We characterized two autonomically mediated coupling mechanisms [the heart rate baroreflex (HR baroreflex) and respiratory sinus arrhythmia (ILV-HR)] and two mechanically mediated coupling mechanisms [the blood pressure wavelet generated with each cardiac contraction (circulatory mechanics) and the direct mechanical effects of respiration on blood pressure (ILV-->ABP)]. We evaluated the method in humans studied in the supine and standing postures under control conditions and under conditions of beta-sympathetic and parasympathetic pharmacological blockades. Combined beta-sympathetic and parasympathetic blockade abolished the autonomically mediated couplings while preserving the mechanically mediated coupling. Selective autonomic blockade and postural changes also altered the couplings in a manner consistent with known physiological mechanisms. System identification is an "inverse-modeling" technique that provides a means for creating a closed-loop model of cardiovascular regulation for an individual subject without altering the underlying physiological control mechanisms.

  19. Blockade of the SNARE protein syntaxin 1 inhibits glioblastoma tumor growth.

    Directory of Open Access Journals (Sweden)

    Fausto Ulloa

    Full Text Available Glioblastoma (GBM is the most prevalent adult brain tumor, with virtually no cure, and with a median overall survival of 15 months from diagnosis despite of the treatment. SNARE proteins mediate membrane fusion events in cells and are essential for many cellular processes including exocytosis and neurotransmission, intracellular trafficking and cell migration. Here we show that the blockade of the SNARE protein Syntaxin 1 (Stx1 function impairs GBM cell proliferation. We show that Stx1 loss-of-function in GBM cells, through ShRNA lentiviral transduction, a Stx1 dominant negative and botulinum toxins, dramatically reduces the growth of GBM after grafting U373 cells into the brain of immune compromised mice. Interestingly, Stx1 role on GBM progression may not be restricted just to cell proliferation since the blockade of Stx1 also reduces in vitro GBM cell invasiveness suggesting a role in several processes relevant for tumor progression. Altogether, our findings indicate that the blockade of SNARE proteins may represent a novel therapeutic tool against GBM.

  20. XcisClique: analysis of regulatory bicliques

    Directory of Open Access Journals (Sweden)

    Grene Ruth

    2006-04-01

    Full Text Available Abstract Background Modeling of cis-elements or regulatory motifs in promoter (upstream regions of genes is a challenging computational problem. In this work, set of regulatory motifs simultaneously present in the promoters of a set of genes is modeled as a biclique in a suitably defined bipartite graph. A biologically meaningful co-occurrence of multiple cis-elements in a gene promoter is assessed by the combined analysis of genomic and gene expression data. Greater statistical significance is associated with a set of genes that shares a common set of regulatory motifs, while simultaneously exhibiting highly correlated gene expression under given experimental conditions. Methods XcisClique, the system developed in this work, is a comprehensive infrastructure that associates annotated genome and gene expression data, models known cis-elements as regular expressions, identifies maximal bicliques in a bipartite gene-motif graph; and ranks bicliques based on their computed statistical significance. Significance is a function of the probability of occurrence of those motifs in a biclique (a hypergeometric distribution, and on the new sum of absolute values statistic (SAV that uses Spearman correlations of gene expression vectors. SAV is a statistic well-suited for this purpose as described in the discussion. Results XcisClique identifies new motif and gene combinations that might indicate as yet unidentified involvement of sets of genes in biological functions and processes. It currently supports Arabidopsis thaliana and can be adapted to other organisms, assuming the existence of annotated genomic sequences, suitable gene expression data, and identified regulatory motifs. A subset of Xcis Clique functionalities, including the motif visualization component MotifSee, source code, and supplementary material are available at https://bioinformatics.cs.vt.edu/xcisclique/.

  1. Development of Regulatory Requirements and Inspection Guides for CANDU Reactors

    Energy Technology Data Exchange (ETDEWEB)

    Kim, M. W.; Kim, K.; Ryu, Y. H. [Korea Institute of Nuclear Safety, Daejeon (Korea, Republic of); Ro, H. Y.; Jin, T. E. [Korea Power Engineering Co., Yongin (Korea, Republic of)

    2009-05-15

    The first domestic CANDU power reactor, Wolsong unit 1, has been operated for about twenty years since commercial operation in 1983, and has been raised common aging issues of CANDU reactors in pressure tubes, calandria tubes, feeder pipes, etc. To solve these aging issues, utility is promoting the refurbishment activities for these major components. Therefore, confirmation and improvement for insufficient requirements considering the CNSC regulatory documents, regulatory principles between regulatory body and utilities related with refurbishment activities are required. These review contents are described herein, and representative review results are presented.

  2. Modeling promoter grammars with evolving hidden Markov models

    DEFF Research Database (Denmark)

    Won, Kyoung-Jae; Sandelin, Albin; Marstrand, Troels Torben;

    2008-01-01

    , we present a method that iteratively evolves an ensemble of regulatory grammars using a hidden Markov Model (HMM) architecture composed of interconnected blocks representing transcription factor binding sites (TFBSs) and background regions of promoter sequences. The ensemble approach reduces the risk......MOTIVATION: Describing and modeling biological features of eukaryotic promoters remains an important and challenging problem within computational biology. The promoters of higher eukaryotes in particular display a wide variation in regulatory features, which are difficult to model. Often several...... factors are involved in the regulation of a set of co-regulated genes. If so, promoters can be modeled with connected regulatory features, where the network of connections is characteristic for a particular mode of regulation. RESULTS: With the goal of automatically deciphering such regulatory structures...

  3. Histamine H2 receptor blockade augments blood pressure responses to acute submaximal exercise in males.

    Science.gov (United States)

    Doh, Hyung-Woo; Stebbins, Charles L; Choi, Hyun-Min; Park, Joonsung; Nho, Hosung; Kim, Jong-Kyung

    2016-06-01

    Histamine is a potent vasodilator that has been found to increase during exercise. We tested the hypothesis that histamine would attenuate blood pressure (BP), cardiac output (CO), and vascular resistance responses to short-term, submaximal dynamic exercise during H2 receptor blockade. Fourteen healthy men (20-29 years of age) were studied. Systolic (SBP), diastolic (DBP), and mean arterial (MAP) BP and heart rate (HR) were assessed at rest and during the last minute of 10 min of submaximal cycling exercise (60% of peak oxygen consumption) in the absence and presence of histamine H2 receptor blockade (ranitidine, 300 mg). Stroke volume (SV) (impedance cardiography) and plasma norepinephrine (NE) were measured, and CO, rate × pressure product (RPP), and total peripheral resistance (TPR) were calculated. Plasma levels of histamine were also measured. H2 blockade had no effects on any variables at rest. During exercise, SBP (184 ± 3 mm Hg vs. 166 ± 2 mm Hg), MAP (121 ± 2 mm Hg vs. 112 ± 5 mm Hg), and RPP (25.9 ± 0.8 × 10(3) mm Hg·beats/min vs. 23.5 ± 0.8 × 10(3) mm Hg/beats·min) were greater during blocked conditions (P < 0.05), and an interaction was observed for TPR. SV, DBP, HR, and NE levels were unaffected by blockade. Plasma histamine increased from 1.83 ± 0.14 ng/mL at rest to 2.33 ± 0.23 ng/mL during exercise (P < 0.05) and was not affected by H2 blockade (1.56 ± 0.23 ng/mL vs. 1.70 ± 0.24 ng/mL). These findings suggest that, during submaximal exercise, histamine attenuates BP, vascular resistance, and the work of the heart via activation of H2 receptors and that these effects occurred primarily in the vasculature and not in the myocardium. PMID:27191340

  4. DNA watermarks in non-coding regulatory sequences

    Directory of Open Access Journals (Sweden)

    Pyka Martin

    2009-07-01

    Full Text Available Abstract Background DNA watermarks can be applied to identify the unauthorized use of genetically modified organisms. It has been shown that coding regions can be used to encrypt information into living organisms by using the DNA-Crypt algorithm. Yet, if the sequence of interest presents a non-coding DNA sequence, either the function of a resulting functional RNA molecule or a regulatory sequence, such as a promoter, could be affected. For our studies we used the small cytoplasmic RNA 1 in yeast and the lac promoter region of Escherichia coli. Findings The lac promoter was deactivated by the integrated watermark. In addition, the RNA molecules displayed altered configurations after introducing a watermark, but surprisingly were functionally intact, which has been verified by analyzing the growth characteristics of both wild type and watermarked scR1 transformed yeast cells. In a third approach we introduced a second overlapping watermark into the lac promoter, which did not affect the promoter activity. Conclusion Even though the watermarked RNA and one of the watermarked promoters did not show any significant differences compared to the wild type RNA and wild type promoter region, respectively, it cannot be generalized that other RNA molecules or regulatory sequences behave accordingly. Therefore, we do not recommend integrating watermark sequences into regulatory regions.

  5. Nuclear Regulatory Legislation

    International Nuclear Information System (INIS)

    This compilation of statutes and material pertaining to nuclear regulatory legislation through the 100th Congress, 2nd Session, has been prepared by the Office of the General Counsel, US Nuclear Regulatory Commission, with the assistance of staff, for use as an internal resource document. Persons using this document are placed on notice that it may not be used as an authoritative citation in lieu of the primary legislative sources. Furthermore, while every effort has been made to ensure the completeness and accuracy of this material, neither the United States Government, the Nuclear Regulatory Commission, nor any of their employees makes any expressed or implied warranty or assumes liability for the accuracy or completeness of the material presented in this compilation

  6. Blockade of transient receptor potential cation channel subfamily V member 1 promotes regeneration after sciatic nerve injury

    OpenAIRE

    Fei Ren; Hong Zhang; Chao Qi; Mei-ling Gao; Hong Wang; Xia-qing Li

    2015-01-01

    The transient receptor potential cation channel subfamily V member 1 (TRPV1) provides the sensation of pain (nociception). However, it remains unknown whether TRPV1 is activated after peripheral nerve injury, or whether activation of TRPV1 affects neural regeneration. In the present study, we established rat models of unilateral sciatic nerve crush injury, with or without pretreatment with AMG517 (300 mg/kg), a TRPV1 antagonist, injected subcutaneously into the ipsilateral paw 60 minutes befo...

  7. Five Measures Promote Opening-Up of Banking Industry

    Institute of Scientific and Technical Information of China (English)

    2004-01-01

    Liu Mingkang, Chairman of China Banking Regulatory Commission(CBRC),stated in a press conference held in last December by the News Office of the State Council, that China Banking Regulatory Commission would successively implement five important measures and continuously guided by the principle of steadily promoting the opening-up of

  8. Balanced Integrated Regulatory Oversight

    International Nuclear Information System (INIS)

    Reactor safety, protecting the public health and safety, and protecting the environment must always be the nuclear regulator's top priorities. Enabling the use of nuclear power for the benefit of society, while protecting the public and the environment requires the regulator to balance many factors. In addition, the regulator is only one part of the overall government that must consider many factors as it carries out its societal responsibilities. Some of the factors that must be balanced and the practical impacts on how the regulator carries out its responsibilities will be addressed. The first International Conference on Effective Regulatory Systems, held in Moscow, Russian Federation, in 2006, focused on safety and security challenges with a goal of improving regulatory effectiveness through cooperation and sharing of information and best practices. The challenge of meeting both safety and security objectives is one example of potentially competing programmes that must be balanced. Other balances that must be evaluated include the benefits of safety improvements compared to the cost of implementation, the use of deterministic and probabilistic approaches, communication openness balanced with the protection of information that could be used for detrimental purposes, and timeliness of regulatory decision making balanced with the need to perform quality work in support of oversight responsibilities. A balanced and integrated approach to regulatory oversight is vital to ensuring that the regulatory body remains effective in its mission to enable the use of nuclear power while protecting the public and the environment. This concept is applicable to nations beginning a nuclear programme as well as established and experienced regulatory bodies. (author)

  9. Corynebacterium glutamicum promoters: a practical approach

    OpenAIRE

    Pátek, M. (Miroslav); Holátko, J. (Jiří); Busche, T.; Kalinowski, J; Nešvera, J. (Jan)

    2013-01-01

    Summary Transcription initiation is the key step in gene expression in bacteria, and it is therefore studied for both theoretical and practical reasons. Promoters, the traffic lights of transcription initiation, are used as construction elements in biotechnological efforts to coordinate ‘green waves’ in the metabolic pathways leading to the desired metabolites. Detailed analyses of Corynebacterium glutamicum promoters have already provided large amounts of data on their structures, regulatory...

  10. Alpha 2-adrenergic receptor turnover in adipose tissue and kidney: irreversible blockade of alpha 2-adrenergic receptors by benextramine

    Energy Technology Data Exchange (ETDEWEB)

    Taouis, M.; Berlan, M.; Lafontan, M.

    1987-01-01

    The recovery of post- and extrasynaptic alpha 2-adrenergic receptor-binding sites was studied in vivo in male golden hamsters after treatment with an irreversible alpha-adrenoceptor antagonist benextramine, a tetramine disulfide that possesses a high affinity for alpha 2-binding sites. The kidney alpha 2-adrenergic receptor number was measured with (/sup 3/H)yohimbine, whereas (/sup 3/H)clonidine was used for fat cell and brain membrane alpha 2-binding site identification. Benextramine treatment of fat cell, kidney, and brain membranes reduced or completely suppressed, in an irreversible manner, (/sup 3/H) clonidine and (/sup 3/H)yohimbine binding without modifying adenosine (A1-receptor) and beta-adrenergic receptor sites. This irreversible binding was also found 1 and 2 hr after intraperitoneal administration of benextramine to the hamsters. Although it bound irreversibly to peripheral and central alpha 2-adrenergic receptors on isolated membranes, benextramine was unable to cross the blood-brain barrier of the hamster at the concentrations used (10-20 mg/kg). After the irreversible blockade, alpha 2-binding sites reappeared in kidney and adipose tissue following a monoexponential time course. Recovery of binding sites was more rapid in kidney than in adipose tissue; the half-lives of the receptor were 31 and 46 hr, respectively in the tissues. The rates of receptor production were 1.5 and 1.8 fmol/mg of protein/hr in kidney and adipose tissue. Reappearance of alpha 2-binding sites was associated with a rapid recovery of function (antilipolytic potencies of alpha 2-agonists) in fat cells inasmuch as occupancy of 15% of (/sup 3/H)clonidine-binding sites was sufficient to promote 40% inhibition of lipolysis. Benextramine is a useful tool to estimate turnover of alpha 2-adrenergic receptors under normal and pathological situations.

  11. SNP@Promoter: a database of human SNPs (Single Nucleotide Polymorphisms) within the putative promoter regions

    OpenAIRE

    Chung Won-Hyong; Park Daeui; Kim Woo-Yeon; Kim Byoung-Chul; Shin Kwang-sik; Bhak Jong

    2008-01-01

    Abstract Background Analysis of single nucleotide polymorphism (SNP) is becoming a key research in genomics fields. Many functional analyses of SNPs have been carried out for coding regions and splicing sites that can alter proteins and mRNA splicing. However, SNPs in non-coding regulatory regions can also influence important biological regulation. Presently, there are few databases for SNPs in non-coding regulatory regions. Description We identified 488,452 human SNPs in the putative promote...

  12. Toxicogenomics in Regulatory Ecotoxicology

    Science.gov (United States)

    The potential utility of toxicogenomics in toxicological research and regulatory activities has been the subject of scientific discussions, and as with any new technology, there is a wide range of opinion. The purpose of this feature article is to consider roles of toxicogenomic...

  13. Comments on regulatory reform

    International Nuclear Information System (INIS)

    Nuclear regulatory reform is divided into two parts. The first part contains all those matters for which new legislation is required. The second part concerns all those matters that are within the power of the Commission under existing statutes. Recommendations are presented

  14. NRC regulatory agenda

    International Nuclear Information System (INIS)

    This document is a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considered action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  15. NRC Regulatory Agenda

    International Nuclear Information System (INIS)

    This document compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rule making which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  16. NRC regulatory agenda

    International Nuclear Information System (INIS)

    This document provides a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  17. Prediction of regulatory elements

    DEFF Research Database (Denmark)

    Sandelin, Albin

    2008-01-01

    -lab methods are time consuming and expensive, it is not realistic to identify TFBS for all uncharacterized genes in the genome by purely experimental means. Computational methods aimed at predicting potential regulatory regions can increase the efficiency of wet-lab experiments significantly. Here, methods...

  18. NRC Regulatory Agenda

    International Nuclear Information System (INIS)

    This document is a compilation of all rules on which the NRC has proposed or is considering action and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter

  19. On regulatory focus and performance in organizational environments

    OpenAIRE

    Beudeker, Dagmar Annemarijn

    2015-01-01

    What motivates people, and when do they perform optimally at work? In this dissertation, a regulatory focus perspective is taken (RFT, Higgins, 1997) to provide answers to these important questions. The results of multiple studies, conducted in complex organizational environments are reported. In many of those environments, there is a clear preference for promotion oriented employees and leaders. Yet, many jobs contain both promotion and prevention tasks. The results show that the use of the ...

  20. Regulatory and operating experience

    International Nuclear Information System (INIS)

    Regulatory and operating experience in the disposal of radioactive waste can be divided into three time periods, World War II and its aftermath, Post World War II till the end of the cold war, and crystal ball gazing into the future. In the first period, there was little regulatory guidance and operating practices, all conducted under wartime secrecy conditions, sometimes were not even up to the norms of the times. Environmental releases resulted in some seriously contaminated sites and high dosages to some offsite populations. Failure to consider even the storage of wastes in a systems context resulted in some stocks that were difficult to recover, treat and dispose of in a final manner. In the second period, increasing civilian uses of nuclear power and isotopes for medical, research, and industrial purposes and military pressure for increased production of Pu-239 resulted in large and more dispersed disposal of radioactive wastes. Regulatory regimes, following growing environmental consciousness, came into existence that minimized exposure to environmental contamination. Practices, in most instances, increasingly conformed to these regulatory demands. The future is unknowable. However, for high level wastes, except for thermodynamically stable forms, no technology can guarantee safety and present methodologies are calculated to produce doses orders of magnitude lower than regulatory limits. Therefore, it is possible that research will be limited to no higher technology than is reasonably achievable. Whereas for low level waste, where proof is practicably possible, as high technology as is reasonably achievable will be best in the long run. (author). 24 refs, 5 figs, 3 tabs

  1. Developing effective consultation programs for regulatory development

    Energy Technology Data Exchange (ETDEWEB)

    Paulson, K.F. [National Energy Board, Ottawa, ON (Canada)

    2003-07-01

    Canada's National Energy Board promotes safety, environmental protection and economic efficiency in the regulation of pipelines, energy development and trade. The Board regulates the design, construction, operation and abandonment of interprovincial and international pipelines within Canada. It also holds regulatory control over tolls and tariffs of interprovincial and international pipelines as well as the export, exploration and development of natural gas and oil resources. Regulatory authorities are required to consult with stakeholders whenever new regulations or amendments to existing regulations are proposed. The Board has launched new initiatives for compliance with Damage Prevention Regulations. Stakeholders were advised through consultative processes such as plain language drafts, open houses, focus meetings and newsletters. The proposed Damage Prevention Regulation will govern activities that have the potential to damage a pipeline. The regulations will apply to pipeline operators, excavators, landowners, municipal planners, emergency responders, and utility companies dealing with federally regulated pipelines. 7 refs., 1 tab.

  2. Promoting industrialisation

    International Nuclear Information System (INIS)

    When the first nuclear power programme is decided upon, automatically the country has to initiate in parallel a programme to modify or add to its current industrial structure and resources. The extent of this new industrialisation depends upon many factors which both, the Government and the Industries have to consider. The Government has a vital role which includes the setting up of the background against which the industrial promotion should take place and in many cases may have also to play an active role all along this programme. Equally, the existing industries have an important role so as to achieve the most efficient participation in the nuclear programme. Invariably the industrial promotional programme will incur a certain degree of transfer of technology, the extent depending on the policies adopted. For this technology transfer to take place efficiently, both the donor and the receiver have to recognise each other's legitimate ambitions and fears. The transfer of technology is a process having a high human content and both donor and receiver have to take this into account. This can be further complicated when there is a difference in culture between them. Technology transfer is carried out within a contractual and organisational framework which will identify the donor (licensor) and the receiver (licensee). This framework may take various forms from a simple cooperative agreement, through a joint-venture organisation right to a standard contract between two separate entities. Each arrangement has its advantages and drawbacks and requires investment of different degrees. One of the keys to a successful industrial promotion is having it carried out in a timely fashion which will be parallel with the nuclear power programme. Experience in some countries has shown the problems when the industrialisation is out of phase with the programme whilst in other cases this industrialisation was at a level and scale unjustified. (author)

  3. Communication planning by the nuclear regulatory body

    International Nuclear Information System (INIS)

    The national regulatory body, whose primary mission is to exercise regulatory control over nuclear facilities and the use of radiation sources, but not to promote their use, may be the most credible source of neutral, balanced and accurate information about issues relating to nuclear and radiation safety. It is therefore important for a regulatory body to establish and exercise an effective communication programme to acquaint the public with its oversight functions, capabilities and effectiveness. If the regulatory body is to maintain credibility and to deal promptly and effectively with nuclear or radiological accidents and any other events that may give rise to significant public concerns, and is to communicate clearly and effectively with the public, it must have adequate resources, including experts in nuclear safety. And if maintaining public confidence in the authorities and avoiding unnecessary concerns are among its principal objectives, it must be able to communicate understandably and truthfully about the known extent of any accident, the actions taken in response to it and its implications. In the past, psychological effects as a result of certain severe nuclear and radiological accidents have been compounded by a lack of candour with the public on the part of the authorities and an absence of an appropriate programme of public information. This publication describes good practices and gives practical examples of how the regulatory body can establish a systematic and structured programme for enhancing effective communication with various parties and under various circumstances. The report presupposes an adequate national infrastructure, including an independent regulatory body with sufficient authority and resources to discharge its responsibilities for the regulation of safety. This Safety Report covers the elements of a regulatory body's programme for communication with various audiences and under the different circumstances that may be encountered

  4. The Limits of Linked Suppression for Regulatory T cells

    Directory of Open Access Journals (Sweden)

    Toshiro eIto

    2016-03-01

    Full Text Available Background: We have previously found that CD4+CD25+ regulatory T cells (T regs can adoptively transfer tolerance after its induction with co-stimulatory blockade in a mouse model of murine cardiac allograft transplantation. In these experiments, we tested an hypothesis with three components: 1 the T regs that transfer tolerance have the capacity for linked suppression, 2 the determinants that stimulate the T regs are expressed by the indirect pathway, and 3 the donor peptides contributing to these indirect determinants are derived from donor MHC antigens. Methods: 1st heart transplants were performed from the indicated donor strain to B10.D2 recipients along with co-stimulatory blockade treatment (250μg i.p. injection of MR1 on day 0 and 250μg i.p. injection of CTLA-4 Ig on day 2. At least 8 weeks later a 2nd heart transplant was performed to a new B10.D2 recipient that had been irradiated with 450 cGy. This recipient was given 40 x 106 naïve B10.D2 spleen cells plus 40 x 106 B10.D2 spleen cells from the first (tolerant recipient. We performed 3 different types of heart transplants with using various donor.Results: 1. T regs suppress the graft rejection in an antigen-specific manner. 2. T regs generated in the face of MHC disparities suppress the rejection of grafts expressing third party MHC along with tolerant MHC. Conclusion:The limits of linkage appear to be quantitative and not universally determined by either the indirect pathway or by peptides of donor MHC antigens.

  5. Measuring Promotion and Prevention Orientations of Secondary School Students: It Is More Than Meets the Eye

    Science.gov (United States)

    Hodis, Flaviu A.; Hattie, John A. C.; Hodis, Georgeta M.

    2016-01-01

    The General Regulatory Focus Measure has been used extensively in psychological research to gauge promotion and prevention orientations. Findings of this research show that for New Zealand secondary school students, the General Regulatory Focus Measure does not measure promotion and prevention as theoretically independent constructs.

  6. Safety culture competition - expectations of a regulatory authority

    International Nuclear Information System (INIS)

    The accident at the Chernobyl nuclear power station on April 26, 1986 influenced the development of reactor safety and promulgated two basic concepts especially in Germany. On the one hand, extensive measures of in-plant accident management have greatly reduced the so-called residual risk. On the other hand, a comprehensive safety approach has been initiated which comprises the nuclear power plant as a system together with people, technology, and organization and also includes safety culture. In a modern regulatory concept based on the dynamic development of safety, the authority's classical regulatory function of controlling is supplemented by the objective of promoting safety. While preserving the division of responsibilities between the regulatory authority and plant operators, the authority uses 'constructive critical dialog' as a tool to enhance safety. Besides the regulatory assessment of safety culture on the basis of indications or indicators, also the continuous promotion of safety culture in a dialog with plant operators is seen as one of the duties of a regulatory authority. Continued efforts are necessary to maintain the high level of safety culture in German nuclear power plants. Operators are expected to establish a safety management which assigns top priority to safety issues, and which pursues the goal of supervising and promoting safety culture. Developments on the deregulated electricity markets must not lead to safety aspects ranking second to economic aspects. Moreover, also under changed boundary conditions, only the safe operation of nuclear power plants ensures economic viability. (orig.)

  7. The effectivity of periprostatic nerve blockade for the pain control during transrectal ultrasound guided prostate biopsy

    Directory of Open Access Journals (Sweden)

    Alper Otunctemur

    2013-06-01

    Full Text Available Aim: Transrectal ultrasound (TRUS guided prostete biopsy is accepted as a standard procedure in the diagnosis of prostate cancer. Many different protocoles are applied to reduce the pain during the process. In this study we aimed to the comparison of two procedure with intrarectal lidocaine gel and periprostatice nerve blockade respective- ly in addition to perianal intrarectal lidocaine gel on the pain control in prostate biop- sy by TRUS. Methods: 473 patients who underwent prostate biopsy guided TRUS between 2008-2012 were included in the study. 10-point linear visual analog pain scale(VAS was used to evaluate the pain during biopsy. The patients were divided into two groups according to anesthesia procedure. In Group 1, there were 159 patients who had perianal-intrarectal lidocaine gel, in Group 2 there were 314 patients who had periprostatic nerve blockade in addition to intrarectal lidocain gel. The pain about probe manipulation was aseesed by VAS-1 and during the biopsy needle entries was evalu- ated by VAS-2. Results were compared with Mann-Whitney U and Pearson chi-square test. Results: Mean VAS-2 scores in Group 1 and Group 2 were 4.54 ± 1.02 and 2.06 ± 0.79 respectively. The pain score was determined significantly lower in the Group 2 (p = 0.001. In both groups there was no significant difference in VAS-1 scores, patient’s age, prostate volume, complication rate and PSA level. Conclusion: The combination of periprostatic nerve blockade and intrarectal lidocain gel provides a more meaningful pain relief compared to group of patients undergoing intrarectal lidocaine gel.

  8. Macroscopic quantum tunneling in Josephson tunnel junctions and Coulomb blockade in single small tunnel junctions

    International Nuclear Information System (INIS)

    Experiments investigating the process of macroscopic quantum tunneling in a moderately-damped, resistively shunted, Josephson junction are described, followed by a discussion of experiments performed on very small capacitance normal-metal tunnel junctions. The experiments on the resistively-shunted Josephson junction were designed to investigate a quantum process, that of the tunneling of the Josephson phase variable under a potential barrier, in a system in which dissipation plays a major role in the dynamics of motion. All the parameters of the junction were measured using the classical phenomena of thermal activation and resonant activation. Theoretical predictions are compared with the experimental results, showing good agreement with no adjustable parameters; the tunneling rate in the moderately damped (Q ∼ 1) junction is seen to be reduced by a factor of 300 from that predicted for an undamped junction. The phase is seen to be a good quantum-mechanical variable. The experiments on small capacitance tunnel junctions extend the measurements on the larger-area Josephson junctions from the region in which the phase variable has a fairly well-defined value, i.e. its wavefunction has a narrow width, to the region where its value is almost completely unknown. The charge on the junction becomes well-defined and is predicted to quantize the current through the junction, giving rise to the Coulomb blockade at low bias. I present the first clear observation of the Coulomb blockade in single junctions. The electrical environment of the tunnel junction, however, strongly affects the behavior of the junction: higher resistance leads are observed to greatly sharpen the Coulomb blockade over that seen with lower resistance leads. I present theoretical descriptions of how the environment influences the junctions; comparisons with the experimental results are in reasonable agreement

  9. Blockade of sonic hedgehog signal pathway enhances antiproliferative effect of EGFR inhibitor in pancreatic cancer cells

    Institute of Scientific and Technical Information of China (English)

    Wei-guo HU; Tao LIU; Jiong-xin XIONG; Chun-you WANG

    2007-01-01

    Aim: To investigate the expression of sonic hedgehog (SHH) and epidermal growth factor receptor (EGFR) signal molecules in pancreatic cancer cells, and to assess the inhibitory effects through the blockade of the SHH and EGFR signaling path- ways by cyclopamine and Iressa, respectively. Methods: The expression of SHH and EGFR in pancreatic cancer cell lines (PANC-1, SUIT-2, and ASPC-1) was de-tected by RT-PCR and Western blot analysis. After treatment with different con-centrations of cyclopamine, alone or in combination with Iressa, the antiproliferative effect on pancreatic cancer cells was analyzed by methyl thiazolyl tetrazolium assays. A flow cytometry analysis was used to detect the cellular cycle distribu-tion and apoptosis of pancreatic cancer cells. Results: All of the 3 pancreatic cancer cell lines expressed SHH, Smoothened (SMO), and EGFR. Cyclopamine could downregulate the expression of EGFR in all cell lines. Cyclopamine or Iressa could induce a growth inhibitory effect in a dose-dependent manner. Moreover,the combined use of 2.5 μmol/L cyclopamine and 1 μmol/L Iressa induced an enhanced inhibitory effect and a greater apoptosis rate than any agent alone. The percentage of the cell population of the G0/G1 and sub-G1 phases was significantly increased along with the increasing dose of cyclopamine and/or Iressa. Conclusion: The blockade of the sonic hedgehog signal pathway enhances the antiproliferative effect of the EGFR inhibitor through the downregulation of its expression in pancreatic cancer cells. The simultaneous blockade of SHH and EGFR signaling represents possible targets of new treatment strategies for pan-creatic carcinoma.

  10. Effect of alpha and beta adrenergic blockade on epinephrine induced pulmonary insufficiency.

    Science.gov (United States)

    Berk, J L; Hagen, J F; Koo, R

    1976-04-01

    Recent studies demonstrated that epinephrine causes significant pulmonary A-V shunting. This study reports the effect of alpha and beta adrenergic blockade on this shunting. Sixty-three anesthetized mongrel dogs were ventilated with a mechanical respirator. Measurements of (1) the pulmonary shunt, (2) cardiac output, (3) mean pulmonary artery, pulmonary capillary wedge and systemic pressures, and (4) pulmonary and systemic vascular resistances were obtained at 5, 15 and 30 minute intervals during the first hour and hourly for 5 hours. Fifteen dogs received no treatment. All others received epinephrine hydrochloride, 2 mug/kg/min for 5 hours. Ten received epinephrine only. Ten were pretreated with propranolol hydrochloride, 250 mug/kg, 12 with phenoxybenzamine, 1 mg/kg, and 16 with phenoxybenzamine and propranolol. Propranolol significantly decreased the epinephrine induced pulmonary shunt at all times and was the most effective drug. Phenoxybenzamine decreased the early shunting, but less than propranolol, and did not decrease the late shunting. Blockade with propranolol and phenoxybenzamine was less effective than propranolol alone. Based on the observed hemodynamic changes it was suggested that beta blockade is effective in reducing epinephrine induced pulmonary insufficiency by favorably altering the flow and distribution of pulmonary blood flow which in turn decreases epinephrine induced ventilation-perfusion inequalities and capillary hypertension both of which result in shunting. Conversely phenoxybenzamine has an unfavorable effect on the pulmonary flow. These studies support previous work in animals and man which showed that beta adrenergic stimulation is important in the pathogenesis of pulmonary insufficiency. Because the amounts of epinephrine used produce blood levels observed in critical illness, these studies add support to a relationship between the increased catecholamine stimulation of critical illness and the associated and often unexplained

  11. The effects of calcium channel blockade on agouti-induced obesity

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jung Han; Moustaid, N.; Zemel, M.B. [Univ. of Tennessee, Knoxville, TN (United States)] [and others

    1996-12-01

    We have previously observed that obese viable yellow (A{sup vy}/a) mice exhibit increased intracellular Ca{sup 2+} ([Ca{sup 2+}]i) and fatty acid synthase (FAS) gene expression; further, recombinant agouti protein increases in cultured adipocytes and these effects are inhibited by Ca{sup 2+} channel blockade. Accordingly, we determined the effect of Ca{sup 2+} channel blockade (nifedipine for 4 wk) on FAS and obesity in transgenic mice expressing the agouti gene in a ubiquitous manner. The transgenic mice initially were significantly heavier (30.5 {+-} 0.6 vs. 27.3 {+-} 0.3 g; P<0.001) and exhibited a 0.81{degrees}C lower initial core temperature (P<0.0005), an approximately twofold increase in fat pad weights (P=0.002), a sevenfold increase in adipose FAS activity (P=0.009), and a twofold increase in plasma insulin level (P<0.05) compared to control mice. Nifedipine treatment resulted in an 18% decrease in fat pad weights (P<0.007) and a 74% decrease in adipose FAS activity (P=0.03), normalized circulating insulin levels and insulin sensitivity (P,0.05), and transiently elevated core temperature in the transgenic mice, but was without effect in the control mice. These data suggest that agouti regulates FAS, fat storage, and possibly thermogenesis, at least partially, via a [Ca{sup 2+}]{sub i}-dependent mechanism, and that Ca{sup 2+} channel blockade may partially attenuate agouti-induced obesity. 42 refs., 4 figs., 1 tab.

  12. Blockade of B-cell-activating factor suppresses lupus-like syndrome in autoimmune BXSB mice

    OpenAIRE

    Ding, Hanlu; Wang, Li; Wu, Xiongfei; Yan, Jun; He, Yani; Ni, Bing; Gao, Wenda; Zhong, Xuemei

    2009-01-01

    Abstract B-cell-activating factor (BAFF), a member of the tumour necrosis factor superfamily, plays a critical role in the maturation, homeostasis and function of B cells. In this study, we demonstrated the biological outcome of BAFF blockade in BXSB murine lupus model, using a soluble fusion protein consisting of human BAFF-R and human mutant IgG4 Fc. Mutation of Leu235 to Glu in IgG4 Fc eliminated antibody-dependent cell cytotoxicity (ADCC) and complement lysis activity, and generated a pro...

  13. Tunable dynamical channel blockade in double-dot Aharonov-Bohm interferometers

    OpenAIRE

    Urban, Daniel; König, Jürgen

    2008-01-01

    We study electronic transport through an Aharonov-Bohm interferometer with single-level quantum dots embedded in the two arms. The full counting statistics in the shot-noise regime is calculated to first order in the tunnel-coupling strength. The interplay of interference and charging energy in the dots leads to a dynamical channel blockade that is tunable by the magnetic flux penetrating the Aharonov-Bohm ring. We find super-Poissonian behavior with diverging second and higher cumulants when...

  14. Blockade of PD-L1 Enhances the Therapeutic Efficacy of Combination Immunotherapy Against Melanoma1

    OpenAIRE

    Pilon-Thomas, Shari; Mackay, Amy; Vohra, Nasreen; Mulé, James J

    2010-01-01

    Inhibition of anti-tumor T cell responses can be mediated by the productive interaction between the programmed death-1 (PD-1) receptor on T cells and its ligand PD-L1. PD-L1 is highly expressed on both murine bone marrow-derived dendritic cells (DC) and B16 melanoma. In this study, in vitro blockade of PD-L1 interaction on DC led to enhanced IFN-gamma production and cytotoxicity by antigen-specific T cells. In vivo, the systemic administration of anti-PD-L1 antibody plus melanoma peptide-puls...

  15. Dopamine blockade and clinical response: Evidence for two biological subgroups of schizophrenia

    International Nuclear Information System (INIS)

    Because CNS neuroleptic concentration cannot be directly measured in patients, the relation between clinical response and extent of dopamine receptor blockade is unknown. This relationship is critical in ascertaining whether nonresponse to neuroleptics is the result merely of inadequate CNS drug levels or of more basic biological differences in pathophysiology. Using [18F]N-methylspiroperidol and positron emission tomography, the authors assessed dopamine receptor occupancy in 10 schizophrenic patients before and after treatment with haloperidol. Responders and nonresponders had virtually identical indices of [18F]N-methylspiroperidol uptake after treatment, indicating that failure to respond clinically was not a function of neuroleptic uptake or binding in the CNS

  16. Ionic interactions of Ba2+ blockades in the MthK K+ channel

    OpenAIRE

    GUO Rui; Zeng, Weizhong; Cui, Hengjun; Chen, Liping; Ye, Sheng

    2014-01-01

    The movement and interaction of multiple ions passing through in single file underlie various fundamental K+ channel properties, from the effective conduction of K+ ions to channel blockade by Ba2+ ions. In this study, we used single-channel electrophysiology and x-ray crystallography to probe the interactions of Ba2+ with permeant ions within the ion conduction pathway of the MthK K+ channel. We found that, as typical of K+ channels, the MthK channel was blocked by Ba2+ at the internal side,...

  17. Microwave probes Dipole Blockade and van der Waals Forces in a Cold Rydberg Gas

    CERN Document Server

    Teixeira, R Celistrino; Nguyen, Thanh Long; Cantat-Moltrecht, T; Raimond, Jean-Michel; Haroche, S; Gleyzes, S; Brune, M

    2015-01-01

    We show that microwave spectroscopy of a dense Rydberg gas trapped on a superconducting atom chip in the dipole blockade regime reveals directly the dipole-dipole many-body interaction energy spectrum. We use this method to investigate the expansion of the Rydberg cloud under the effect of repulsive van der Waals forces and the breakdown of the frozen gas approximation. This study opens a promising route for quantum simulation of many-body systems and quantum information transport in chains of strongly interacting Rydberg atoms.

  18. Quantum Communication and Computing With Atomic Ensembles Using Light-Shift Imbalance Induced Blockade

    OpenAIRE

    Shahriar, M. S.; Pati, G. S.; Salit, K.

    2006-01-01

    Recently, we have shown that for conditions under which the so-called light-shift imbalance induced blockade (LSIIB) occurs, the collective excitation of an ensemble of a multi-level atom can be treated as a closed two level system. In this paper, we describe how such a system can be used as a quantum bit (qubit) for quantum communication and quantum computing. Specifically, we show how to realize a C-NOT gate using the collective qubit and an easily accessible ring cavity, via an extension o...

  19. Cardiovascular and endocrine response to hemorrhage after α1-blockade in lambs and ewes

    International Nuclear Information System (INIS)

    To evaluate the role of the α1-adrenergic system in the response to hemorrhage during development, lambs and adult sheep were chronically catheterized and hemorrhaged after pretreatment with prazosin or vehicle. The adults became markedly more hypotensive after α1-blockade and hemorrhage than after vehicle and hemorrhage, whereas the lambs were no more hypotensive when hemorrhaged after prazosin. In the adults and the lambs hemorrhage produced elevations in plasma renin activity and arginine vasopressin measured by radioimmunoassay. However, after prazosin, the adults had a far greater increase in arginine vasopressin levels than after vehicle treatment

  20. High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons.

    OpenAIRE

    Beurrier, Corinne; Bioulac, Bernard; Audin, Jacques; Hammond, Constance

    2001-01-01

    International audience The effect of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) was analyzed with patch-clamp techniques (whole cell configuration, current- and voltage-clamp modes) in rat STN slices in vitro. A brief tetanus, consisting of 100-micros bipolar stimuli at a frequency of 100--250 Hz during 1 min, produced a full blockade of ongoing STN activity whether it was in the tonic or bursting mode. This HFS-induced silence lasted around 6 min after the end of st...

  1. Transition from Coulomb Blockade to Resonant Transmission in a MoS2 Nanoribbon

    Science.gov (United States)

    Li, Yanjing; Mason, Nadya

    2014-03-01

    We have measured a side-gated nanoribbon of MoS2 at low temperature, and observed the transition from Coulomb blockade to resonant transmission when the Fermi level is tuned with a gate. We show that near the crossover between these regimes, the entire nanoribbon acts as a single quantum dot. Our findings may shed light on quasi-ballistic transport in the material. We also discuss the quantum dot formation in terms of a substrate-induced disorder potential, and consider other possible origins of disorder.

  2. Nuclear Regulatory Commission information digest

    International Nuclear Information System (INIS)

    The Nuclear Regulatory Commission information digest provides summary information regarding the US Nuclear Regulatory Commission, its regulatory responsibilities, and areas licensed by the commission. This is an annual publication for the general use of the NRC Staff and is available to the public. The digest is divided into two parts: the first presents an overview of the US Nuclear Regulatory Commission and the second provides data on NRC commercial nuclear reactor licensees and commercial nuclear power reactors worldwide

  3. Japan's regulatory and safety issues regarding nuclear materials transport

    International Nuclear Information System (INIS)

    This paper focuses on the regulatory and safety issues on nuclear materials transport which the Government of Japan (GOJ) faces and needs to well handle. Background information about the status of nuclear power plants (NPP) and nuclear fuel cycle (NFC) facilities in Japan will promote a better understanding of what this paper addresses

  4. Abrogation of CD40–CD154 Signaling Impedes the Homeostasis of Thymic Resident Regulatory T Cells by Altering the Levels of IL-2, but Does Not Affect Regulatory T Cell Development

    OpenAIRE

    Cuss, Steven M.; Green, E. Allison

    2012-01-01

    Identification of costimulatory signals required for murine regulatory T (Treg) cell development relies on measuring the frequency of total thymic Treg cells. However, the thymus contains both resident and newly developed Treg cells; whether such signals target both populations is unknown. In this study, we show that CD40–CD154 blockade specifically targeted thymic resident Treg cells, but not, as was previously believed, newly developed Treg cells. Unlike CD28–CD80/CD86 signals, CD40–CD154 s...

  5. VISUAL ART AND REGULATORY FIT MESSAGES ON CONSUMER EVALUATIONS

    Directory of Open Access Journals (Sweden)

    Danielle Mantovani

    2016-03-01

    Full Text Available In this study, we demonstrate that the art infusion effect, in which the presence of visual art causes a positive impact on consumers’ perceptions of products and advertising messages, might have a moderation effect on regulatory fit and non-fit messages. We investigate the impact of visual art on advertisement evaluations in regulatory (non- fit conditions. Regulatory focus theory suggests that consumers rely on their motivational focus (prevention vs. promotion for their evaluations and decisions. Usually, consumers prefer products that fit with their personal motivational focus. In the present study, the results of three experiments indicate that using visual art with a promotion or prevention fit message is recommended, while non-art images increase message persuasiveness when non-fit messages are presented. Therefore, not all information compatible with the consumer’s motivational focus are best evaluated. When non-art images are presented, non-fit messages might be more persuasive.

  6. NRC regulatory agenda

    International Nuclear Information System (INIS)

    The NRC Regulatory Agenda is a compilation of all rules on which the NRC has recently completed action, or has proposed action, or is considering action, and all petitions for rulemaking which have been received by the Commission and are pending disposition by the Commission. The Regulatory Agenda is updated and issued each quarter. The rules on which final action has been taken since March 31, 1993 are: Repeal of NRC standards of conduct; Fitness-for-duty requirements for licensees who possess, use, or transport Category I material; Training and qualification of nuclear power plant personnel; Monitoring the effectiveness of maintenance at nuclear power plants; Licensing requirements for land disposal of radioactive wastes; and Licensees' announcements of safeguards inspections

  7. Viral Interferon Regulatory Factors

    OpenAIRE

    Lee, Hye-Ra; Kim, Myung Hee; Lee, Jong-Soo; Liang, Chengyu; Jung, Jae U.

    2009-01-01

    Upon viral infection, the major defensive strategy employed by the host immune system is the activation of the interferon (IFN)-mediated antiviral pathway, which is overseen by IFN regulatory factors (IRFs). In order to complete their life cycles, viruses must find a way to modulate the host IFN-mediated immune response. Kaposi's sarcoma-associated herpesvirus (KSHV), a human tumor-inducing herpesvirus, has developed a unique mechanism for antagonizing cellular IFN-mediated antiviral activity...

  8. Rethinking Regulatory Democracy

    OpenAIRE

    Cuellar, Mariano-Florentino

    2004-01-01

    This Article presents a critique of democratic participation in the modern administrative state, and provides an affirmative proposal for reforming public participation in shaping regulatory policy. According to several different strands of thinking about law and democracy, the legitimacy of the administrative state depends on the claim that it provides opportunities for public engagement as well as a mechanism for expert decisionmaking. A typical rulemaking proceeding lets experts make tec...

  9. The limits of regulatory convergence: globalization and GMO politics in the south

    NARCIS (Netherlands)

    Falkner, R.; Gupta, A.

    2009-01-01

    Is globalization promoting regulatory convergence in agricultural biotechnology policies in the South? This article examines the nature and limits of regulatory convergence in the field of agri-biotechnology and investigates the effects that international forces have on biotechnology and biosafety p

  10. The changing regulatory environment

    International Nuclear Information System (INIS)

    The role and value of regulation in the energy sector was discussed, demonstrating how, despite common perception, regulation is an essential part of Canada's strategy to find and develop new opportunities. The future vision of regulation for industry participants was presented with particular focus on issues related to streamlining the regulatory process. As far as pipelines are concerned, regulatory actions are necessary to facilitate capacity increases and to ensure the line's integrity, safety and environmental record. Furthermore, regulation provides economic solutions where market forces cannot provide them, as for example where business has elements of monopoly. It arbitrates interests of landowners, business, consumers, and environmental groups. It looks for ways to ensure conditions under which competition can flourish. It acts as the guardian of citizens' rights in a democratic society by providing citizens with an opportunity to be heard on the building or expansion of pipelines and associated facilities. As citizens become more and more concerned about their property and the land that surrounds them, citizen involvement in decision making about how industry activity affects their quality of life will become correspondingly more important. Regulatory agencies are committed to facilitate this engagement by flexible hearing procedures and by making use of evolving communication and information technology

  11. Hastening the regulatory process

    International Nuclear Information System (INIS)

    The state of the Canadian oil industry was discussed during this power point presentation with particular emphasis on its production, exports, drilling, industry revenues and capital investment levels. The proposed projects in each of northern Alberta's oil sands deposits, the Athabasca, Peace River and Cold Lake were were announced, along with the inventory of major Alberta projects and the projection of oil sands capital investment. Since 1998, $9 billion has been invested and a further $33 billion has been announced for new or expanded oil sands projects. The year 2000 estimates for Canadian crude oil and natural gas production are 2.3 million barrels per day and 6.3 trillion cubic feet per year respectively. This represented a record year for production of both crude oil and natural gas. In 2000, more than 15,500 wells were drilled in Canada. A graph depicting Canadian crude oil supply forecasted a steady increase in supply from year 2000 to 2010. The Canadian Association of Petroleum Producers (CAPP) completed a review of the Alberta Energy and Utilities Board regulatory and enforcement processes. Both industry and government efforts are focusing on eliminating regulatory overlap and duplication. Some of the main areas of interest for exploration, drilling, production and pipeline facilities include the examination of regulatory processes for environmentally sensitive areas, rural municipalities with planning bylaws, aboriginal lands and additional fees. 8 figs

  12. Boundaries of regulatory fit: Is it the thought that counts?

    DEFF Research Database (Denmark)

    Leikas, S.; Lindeman, M.; Roininen, K.; Lähteenmäki, Liisa

    2009-01-01

    The feeling of regulatory fit is thought to arise from the right kind of goal pursuit, but some studies imply that it may be evoked even by lesser involvement in the right kind of strategies. The present experiment explored the minimum of involvement necessary to evoke regulatory fit. Participants...... (N = 71) first completed a regulatory focus manipulation task and were then led to believe that they would receive either rich or accurate information concerning vegetable sterols, evoking beliefs that they used eager or vigilant information search strategies. In reality, all participants received...... the same information. Participants in promotion focus reported more positive attitudes in the rich information condition, whereas prevention-focused participants reported more positive attitudes in the accurate information condition. The results showed that regulatory fit can be evoked through mere...

  13. Improving nuclear regulation. NEA regulatory guidance booklets volumes 1-14

    International Nuclear Information System (INIS)

    A common theme throughout the series of NEA regulatory guidance reports, or 'green booklets', is the premise that the fundamental objective of all nuclear safety regulatory bodies is to ensure that nuclear facilities are continuously maintained and operated in an acceptably safe manner. In meeting this objective the regulator must bear in mind that it is the operator that has responsibility for safely operating the nuclear facility; the role of the regulator is to assess and to provide assurance regarding the operator's activities in terms of assuming that responsibility. The full series of these reports was brought together in one edition for the first time in 2009 and was widely found to be a useful resource. This second edition comprises 14 volumes, including the latest on The Nuclear Regulator's Role in Assessing Licensee Oversight of Vendor and Other Contracted Services. The reports address various challenges that could apply throughout the lifetime of a nuclear facility, including design, siting, manufacturing, construction, commissioning, operation, maintenance and decommissioning. The compilation is intended to serve as a knowledge management tool both for current regulators and the new nuclear professionals and organisations entering the regulatory field. Contents: Executive Summary; Regulatory Challenges: 1. The Role of the Nuclear Regulator in Promoting and Evaluating Safety Culture; 2. Regulatory Response Strategies for Safety Culture Problems; 3. Nuclear Regulatory Challenges Related to Human Performance; 4. Regulatory Challenges in Using Nuclear Operating Experience; 5. Nuclear Regulatory Review of Licensee Self-assessment (LSA); 6. Nuclear Regulatory Challenges Arising from Competition in Electricity Markets; 7. The Nuclear Regulatory Challenge of Judging Safety Back-fits; 8. The Regulatory Challenges of Decommissioning Nuclear Reactors; 9. The Nuclear Regulator's Role in Assessing Licensee Oversight of Vendor and Other Contracted Services

  14. Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade

    Directory of Open Access Journals (Sweden)

    Elena eNosyreva

    2014-12-01

    Full Text Available Ketamine is a NMDA receptor antagonist that produces rapid antidepressant responses in individuals with major depressive disorder. The antidepressant action of ketamine has been linked to blocking NMDA receptor activation at rest, which inhibits eukaryotic elongation factor2 kinase leading to desuppression of protein synthesis and synaptic potentiation in the CA1 region of the hippocampus. Here, we investigated ketamine mediated antidepressant response and the resulting synaptic potentiation in juvenile animals. We found that ketamine did not produce an antidepressant response in juvenile animals in the novelty suppressed feeding or the forced swim test. In addition ketamine application failed to trigger synaptic potentiation in hippocampal slices obtained from juvenile animals, unlike its action in slices from older animals (6-9 weeks old. The inability of ketamine to trigger an antidepressant response or subsequent synaptic plasticity processes suggests a developmental component to ketamine mediated antidepressant efficacy. We also show that the NMDAR antagonist AP5 triggers synaptic potentiation in mature hippocampus similar to the action of ketamine, demonstrating that global competitive blockade of NMDA receptors is sufficient to trigger this effect. These findings suggest that global blockade of NMDA receptors in developmentally mature hippocampal synapses are required for the antidepressant efficacy of ketamine.

  15. Theory of charge transport in molecular junctions: From Coulomb blockade to coherent tunneling

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Yao-Wen; Jin, Bih-Yaw, E-mail: byjin@ntu.edu.tw [Department of Chemistry and Center for Emerging Material and Advanced Devices and Center for Quantum Science and Engineering, National Taiwan University, Taipei 10617, Taiwan (China)

    2014-08-14

    We study charge transport through molecular junctions in the presence of electron-electron interaction using the nonequilibrium Green's function techniques and the renormalized perturbation theory. In the perturbation treatment, the zeroth-order Hamiltonian of the molecular junction is composed of independent single-impurity Anderson's models, which act as the channels where charges come through or occupy, and the interactions between different channels are treated as the perturbation. Using this scheme, the effects of molecule-lead, electron-electron, and hopping interactions are included nonperturbatively, and the charge transport processes can thus be studied in the intermediate parameter range from the Coulomb blockade to the coherent tunneling regimes. The concept of quasi-particles is introduced to describe the kinetic process of charge transport, and then the electric current can be studied and calculated. As a test study, the Hubbard model is used as the molecular Hamiltonian to simulate dimeric and trimeric molecular junctions. Various nonlinear current-voltage characteristics, including Coulomb blockade, negative differential resistance, rectification, and current hysteresis, are shown in the calculations, and the mechanisms are elucidated.

  16. Theory of charge transport in molecular junctions: From Coulomb blockade to coherent tunneling

    International Nuclear Information System (INIS)

    We study charge transport through molecular junctions in the presence of electron-electron interaction using the nonequilibrium Green's function techniques and the renormalized perturbation theory. In the perturbation treatment, the zeroth-order Hamiltonian of the molecular junction is composed of independent single-impurity Anderson's models, which act as the channels where charges come through or occupy, and the interactions between different channels are treated as the perturbation. Using this scheme, the effects of molecule-lead, electron-electron, and hopping interactions are included nonperturbatively, and the charge transport processes can thus be studied in the intermediate parameter range from the Coulomb blockade to the coherent tunneling regimes. The concept of quasi-particles is introduced to describe the kinetic process of charge transport, and then the electric current can be studied and calculated. As a test study, the Hubbard model is used as the molecular Hamiltonian to simulate dimeric and trimeric molecular junctions. Various nonlinear current-voltage characteristics, including Coulomb blockade, negative differential resistance, rectification, and current hysteresis, are shown in the calculations, and the mechanisms are elucidated

  17. A mean field approach to Coulomb blockade for a disordered assembly of quantum dots

    Indian Academy of Sciences (India)

    Akashdeep Kamra; Praveen Pathak; Vijay A Singh

    2008-02-01

    The Coulomb blockade (CB) in quantum dots (QDs) is by now well documented. It has been used to guide the fabrication of single electron transistors. Even the most sophisticated techniques for synthesizing QDs (e.g. MOCVD/MBE) result in an assembly in which a certain amount of disorder is inevitable. On the other hand, theoretical approaches to CB limit themselves to an analysis of a single QD. In the present work we consider two types of disorders: (i) size disorder; e.g. QDs have a distribution of sizes which could be unimodal or bimodal in nature. (ii) Potential disorder with the confining potential assuming a variety of shapes depending on growth condition and external fields. We assume a Gaussian distribution in disorder in both size and potential and employ a simplified mean field theory. To do this we rely on the scaling laws for the CB (also termed as Hubbard ) obtained for an isolated QD [1]. We analyze the distribution in the Hubbard as a consequence of disorder and observe that Coulomb blockade is partially suppressed by the disorder. Further, the distribution in is a skewed Gaussian with enhanced broadening.

  18. PD-1/PD-L1 blockade in cancer treatment: perspectives and issues.

    Science.gov (United States)

    Hamanishi, Junzo; Mandai, Masaki; Matsumura, Noriomi; Abiko, Kaoru; Baba, Tsukasa; Konishi, Ikuo

    2016-06-01

    Recent studies showed that tumor cells 'edit' host immunity in several ways to evade immune defenses in the tumor microenvironment. This phenomenon is called "cancer immune escape." One of the most important components in this system is an immunosuppressive co-signal (immune checkpoint) mediated by the PD-1 receptor and its ligand, PD-L1. PD-1 is mainly expressed on activated T cells, whereas PD-L1 is expressed on several types of tumor cells. Preclinical studies have shown that inhibition of the interaction between PD-1 and PD-L1 enhances the T-cell response and mediates antitumor activity. Several clinical trials of PD-1/PD-L1 signal-blockade agents have exhibited dramatic antitumor efficacy in patients with certain types of solid or hematological malignancies. In this review, we highlight recent clinical trials using anti-PD-1 or anti-PD-L1 antibodies against several types of malignancies, including a trial conducted in our department, and describe the clinical perspectives and issues regarding the PD-1/PD-L1 blockade in cancer treatment. PMID:26899259

  19. Connexin Hemichannel Blockade Is Neuroprotective after Asphyxia in Preterm Fetal Sheep

    Science.gov (United States)

    Davidson, Joanne O.; Drury, Paul P.; Green, Colin R.; Nicholson, Louise F.; Bennet, Laura; Gunn, Alistair J.

    2014-01-01

    Asphyxia around the time of preterm birth is associated with neurodevelopmental disability. In this study, we tested the hypothesis that blockade of connexin hemichannels would improve recovery of brain activity and reduce cell loss after asphyxia in preterm fetal sheep. Asphyxia was induced by 25 min of complete umbilical cord occlusion in preterm fetal sheep (103–104 d gestational age). Connexin hemichannels were blocked by intracerebroventricular infusion of mimetic peptide starting 90 min after asphyxia at a concentration of 50 µM/h for one hour followed by 50 µM/24 hour for 24 hours (occlusion-peptide group, n = 6) or vehicle infusion for controls (occlusion-vehicle group, n = 7). Peptide infusion was associated with earlier recovery of electroencephalographic power after asphyxia compared to occlusion-vehicle (p<0.05), with reduced neuronal loss in the caudate and putamen (p<0.05), but not in the hippocampus. In the intragyral and periventricular white matter, peptide administration was associated with an increase in total oligodendrocyte numbers (p<0.05) and immature/mature oligodendrocytes compared to occlusion-vehicle (p<0.05), with a significant increase in proliferation (p<0.05). Connexin hemichannel blockade was neuroprotective and reduced oligodendrocyte death and improved recovery of oligodendrocyte maturation in preterm fetuses after asphyxia. PMID:24865217

  20. Connexin hemichannel blockade is neuroprotective after asphyxia in preterm fetal sheep.

    Directory of Open Access Journals (Sweden)

    Joanne O Davidson

    Full Text Available Asphyxia around the time of preterm birth is associated with neurodevelopmental disability. In this study, we tested the hypothesis that blockade of connexin hemichannels would improve recovery of brain activity and reduce cell loss after asphyxia in preterm fetal sheep. Asphyxia was induced by 25 min of complete umbilical cord occlusion in preterm fetal sheep (103-104 d gestational age. Connexin hemichannels were blocked by intracerebroventricular infusion of mimetic peptide starting 90 min after asphyxia at a concentration of 50 µM/h for one hour followed by 50 µM/24 hour for 24 hours (occlusion-peptide group, n = 6 or vehicle infusion for controls (occlusion-vehicle group, n = 7. Peptide infusion was associated with earlier recovery of electroencephalographic power after asphyxia compared to occlusion-vehicle (p<0.05, with reduced neuronal loss in the caudate and putamen (p<0.05, but not in the hippocampus. In the intragyral and periventricular white matter, peptide administration was associated with an increase in total oligodendrocyte numbers (p<0.05 and immature/mature oligodendrocytes compared to occlusion-vehicle (p<0.05, with a significant increase in proliferation (p<0.05. Connexin hemichannel blockade was neuroprotective and reduced oligodendrocyte death and improved recovery of oligodendrocyte maturation in preterm fetuses after asphyxia.

  1. Massachusetts high court supports use of civil rights law to bar blockades.

    Science.gov (United States)

    1994-04-15

    In a 4-3 opinion issued on April 11, the Supreme Judicial Court of the Commonwealth of Massachusetts affirmed a lower court order preventing anti-choice activists from blocking access to a facility providing abortion counseling or services. Granted under the Massachusetts Civil Rights Act, the injunction also prohibits using force against anyone entering, leaving, or working at such a location (see RFN II/22). Several health care providers and pro-choice organizations obtained a preliminary injunction in 1989 against trespassing or blockading at specific clinics. The following year, the Commonwealth of Massachusetts intervened in the case and was granted a similar statewide order by Superior Court Judge Peter Lauriat. Upholding application of the civil rights statute in this context, the Massachusetts Supreme Judicial Court found that the trial court "properly concluded that the defendants' conduct constituted threats, intimidation, and coercion" of women seeking to exercise their constitutional right to choose abortion. Moreover, the state High Court held that the trial court "did not abuse its discretion in denying disclosure of the identities of the women affected by the defendants' conduct." Anti-choice activists had claimed they needed to question patients to show that blockades--not threats, intimidation, or coercion--caused them to delay their abortion procedures. Congratulations to John Henn of Foley, Hoag and Eliot of Boston, who represented plaintiffs in Planned Parenthood League of Massachusetts v. Blake. CRLP's Janet Benshoof, Catherine Albisa, and Priscilla Smith filed an amicus brief in the case (see RFN II/22). PMID:12318701

  2. Light-Shift Imbalance Induced Blockade of Collective Excitations Beyond the Lowest Order

    CERN Document Server

    Shahriar, M S; Pati, G S; Gopal, V; Salit, K

    2006-01-01

    Current proposals focusing on neutral atoms for quantum computing are mostly based on using single atoms as quantum bits (qubits), while using cavity induced coupling or dipole-dipole interaction for two-qubit operations. An alternative approach is to use atomic ensembles as qubits. However, when an atomic ensemble is excited, by a laser beam matched to a two-level transition (or a Raman transition) for example, it leads to a cascade of many states as more and more photons are absorbed^1. In order to make use of an ensemble as a qubit, it is necessary to disrupt this cascade, and restrict the excitation to the absorption (and emission) of a single photon only. Here, we show how this can be achieved by using a new type of blockade mechanism, based on the light-shift imbalance (LSI) in a Raman transition. We describe first a simple example illustrating the concept of light shift imbalanced induced blockade (LSIIB) using a multi-level structure in a single atom, and show verifications of the analytic prediction ...

  3. Effect of alpha 1-adrenergic blockade on myocardial blood flow during exercise after myocardial infarction.

    Science.gov (United States)

    Herzog, C A; Dai, X Z; Bache, R J

    1991-08-01

    The effect of alpha 1-adrenergic blockade with prazosin on myocardial blood flow at rest and during two levels of treadmill exercise was assessed in 16 chronically instrumented dogs 9-14 days after myocardial infarction had been produced by occlusion of the left circumflex coronary artery. During resting conditions prazosin did not alter mean myocardial blood flow or the subendocardial-to-subepicardial flow ratio in either normally perfused or collateral-dependent myocardium. However, during exercise at comparable external work loads and comparable rate-pressure products, prazosin significantly increased blood flow to normally perfused (27% increase at the second level of exercise, P less than 0.001) and collateral-dependent myocardium (35% increase at the second level of exercise, P less than 0.001) compared with control. In addition, prazosin caused a small but significant decrease in the subendocardial-to-subepicardial flow ratio in both normal (1.27 +/- 0.04 to 1.19 +/- 0.04; P less than 0.01) and collateral-dependent myocardium (0.57 +/- 0.11 to 0.52 +/- 0.11; P less than 0.01) compared with control, reflecting a disproportionally greater increase in subepicardial flow in response to alpha 1-adrenergic blockade. These data demonstrate that alpha 1-adrenergic vasoconstriction inhibits coronary vasodilation during exercise, even in areas of collateral-dependent myocardium relatively early after coronary artery occlusion. PMID:1678929

  4. TRANSRECTAL ULTRASOUND GUIDED PROSTATIC NERVE BLOCKADE FOR PAIN CONTROL DURING TRANSRECTAL PROSTATE BIOPSY

    Institute of Scientific and Technical Information of China (English)

    YANG Liu-ping; DENG Jun-hong; ZHONG Hong; HU Jian-bo; WEI Hong-ai; WANG Liang-sheng

    2005-01-01

    Objective: To assess the effect of transrectal ultrasound guided prostatic nerve blockade on the discomfort associated with systematic biopsy of the prostate. Methods: 73 patients receiving systematic 13 cores biopsy of the prostate were randomized into two groups. Group A(37 cases) received an injection of 5 ml 1% lidocaine into the prostatic neurovascular bundles on each side at the base of the prostate under ultrasound guidance and group B(36 cases) received 5 ml saline injection (0.9% sodium chloride) at the same site. Pain during biopsy was assessed by using a 10-point linear visual analog score (VAS) immediately after the biopsy. Results: The mean pain scores during transrectal prostate biopsy were significantly lower in group A than group B(1.1±0.6 versus 5.9±3.1, t=4.81, P<0.01). During this study no patient in either group had any adverse effect from the injection. Conclusion: Transcrectal ultrasound guided prostatic nerve blockade is a safe and efficacious method for providing satisfactory anesthesia in transrectal prostate biopsy. We recommend its routine administration in all patients during this procedure.

  5. Blockade of leukocyte haptokinesis and haptotaxis by ketoprofen, diclofenac and SC-560

    Directory of Open Access Journals (Sweden)

    Paskauskas Saulius

    2011-11-01

    Full Text Available Abstract Background Nonsteroidal anti-inflammatory drugs (NSAID represent a one of the most widely used anti-inflammatory substances. Their anti-inflammatory effects are mainly based on inhibition of cyclooxygenase. The potential direct effect of NSAID on leukocyte migration was poorly investigated. Using time-lapse microscopy and 96-well fluorescence-based assay, we studied the effect of three different NSAID, ketoprofen, diclofenac and SC-560, on leukocyte haptokinesis and haptotaxis in vivo and in vitro. Results NSAID induced an immediate inhibiting effect on leukocyte migration both in vitro and in vivo. This effect was dose-dependent and was not restricted to a specific type of leukocytes. The inhibition of leukocyte migration by NSAID was partially re-stored after removal of inhibiting agent. Only complete blockade of leukocyte migration was accompanied by a strong reduction of [Ca2+]i. Conclusions NSAID strongly supress leukocyte migration. The results of the present study may have important clinical implications since blockade of leukocyte migration can be achieved after topical application of NSAID.

  6. Neurolytic blockade of the obturator nerve in the treatment of idiopatic obturator neuralgia

    Directory of Open Access Journals (Sweden)

    Ćulafić Slobodan

    2008-01-01

    Full Text Available Introduction. Idiopathic obturator neuralgia is a rare chronic pain condition. It consists of pain radiating from the obturator nerve territory to the inner thigh. However, the symptomatic obturator neuralgia is commonly caused by the obturator canal bowel hernia that causes painful compressive neuropathy in more than 85% of the cases. Case report. A 61-year-old female who underwent right femoral amputation due to the occlusion of the aortofemoral vascular graft, complained of the pain characterized by its localization in the inguinal region and anterointernal side of the right inner thigh. Computer tomography and MRI findings excluded obturator canal herniation or lumbar plexopathy. A diagnosis of the obturator neuralgia was confirmed by an analgesic block of the obturator nerve. Thereafter, the neurolitic blockade of the right obturator nerve was done. The complete pain relief was achieved. Pain relief was complete in three-month follow-up period. Conclusion. Neurolitic blockade is an efficacious method in treating chronic pain caused by the idiopathic obturator neuralgia.

  7. Metabolic consequences of beta-adrenergic receptor blockade for the acutely ischemic dog myocardium

    International Nuclear Information System (INIS)

    In an experimental study in 50 dogs the myocardial uptake of free fatty acids (FFAs) after beta-blockade was determined using radioiodinated heptadecanoic acid as a metabolic tracer. All 4 beta-blockers used (metoprolol, timolol, propranolol and pindolol) lowered the uptake of FFAs in the normal canine heart. Uptake of FFAs was also diminished after coronary artery occlusion per se, but administration of beta-blockers exerted little additional influence on the uptake of FFAs. This observation was qualitatively parallelled by the uptake of 201Tl in concomitant experiments. Plasma FFA levels were increased by pindolol (non-selective with intrinsic sympathomimetic activity), not changed by metoprolol (a cardioselective betablocking agent) and lowered by timolol and propranolol (both non-selective compounds). The extent of ischemic tissue, as reflected by uptake of iodoheptadecanoic acid and 201Tl, was diminished by metoprolol but not by other beta-blockers. Regional distribution of both tracers, as shown in the endo-epicardial uptake ratios, was hardly influenced by beta-blockade, except for a small increase of 201Tl uptake in non-occluded endocardium. Uptake of 201Tl as well as of iodoheptadecanoic acid in the ischemic area was increased by metoprolol, timolol and propranolol and decreased by pindolol. We conclude that beta-blocking agents confer different effects on myocardial uptake and metabolism of FFAs which might possibly be related to their different inherent properties. (orig.)

  8. Adrenergic blockade does not abolish elevated glucose turnover during bacterial infection

    International Nuclear Information System (INIS)

    Infusions of adrenergic antagonists were used to investigate the role of catecholamines in infection-induced elevations of glucose kinetics. Infection was produced in conscious catheterized rats by repeated subcutaneous injections of live Escherichia coli over 24 h. Glucose kinetics were measured by the constant intravenous infusion of [6-3H]- and [U-14C]glucose. Compared with noninfected rats, infected animals were hyperthermic and showed increased rates of glucose appearance, clearance, and recycling as well as mild hyperlacticacidemia. Plasma catecholamine concentrations were increased by 50-70% in the infected rats, but there were no differences in plasma glucagon, corticosterone, and insulin levels. Adrenergic blockade was produced by primed constant infusion of both propranolol (β-blocker) and phentolamine (α-blocker). A 2-h administration of adrenergic antagonists did not attenuate the elevated glucose kinetics or plasma lactate concentration in the infected rats, although it abolished the hyperthermia. In a second experiment, animals were infused with propranolol and phentolamine beginning 1 h before the first injection of E. coli and throughout the course of infection. Continuous adrenergic blockade failed to attenuate infection-induced elevations in glucose kinetics and plasma lactate. These results indicate that the adrenergic system does not mediate the elevated glucose metabolism observed in this mild model of infection

  9. CD47 blockade inhibits tumor progression human osteosarcoma in xenograft models

    Science.gov (United States)

    Zhang, Shui-Jun; Zhao, Chen; Qiu, Bin-Song; Gu, Hai-Feng; Hong, Jian-Fei; Cao, Li; Chen, Yu; Xia, Bing; Bi, Qin; Wang, Ya-Ping

    2015-01-01

    Osteosarcoma is the most common bone tumors in children and adolescents. Despite intensive chemotherapy, patients with advanced disease still have a poor prognosis, illustrating the need for alternative therapies. In this study, we explored the use of antibodies that block CD47 with a tumor growth suppressive effect on osteosarcoma. We first found that up-regulation of CD47 mRNA levels in the tumorous tissues from eight patients with osteosarcoma when compared with that in adjacent non-tumorous tissues. Further western-blot (WB) and immunohistochemistry (IHC) demonstrated that CD47 protein level was highly expressed in osteosarcoma compared to normal osteoblastic cells and adjacent non-tumorous tissues. Osteosarcoma cancer stem cell markers staining shown that the majority of CD44+ cells expressed CD47 albeit with different percentages (ranging from 80% to 99%). Furthermore, high CD47 mRNA expression levels were associated with a decreased probability of progression-free and overall survival. In addition, blockade of CD47 by specific Abs suppresses the invasive ability of osteosarcoma tumor cells and further inhibits spontaneous pulmonary metastasis of KRIB osteosarcoma cells in vivo. Finally, CD47 blockade increases macrophage phagocytosis of osteosarcoma tumor cells. In conclusion, our findings demonstrate that CD47 is a critical regulator in the metastasis of osteosarcoma and suggest that targeted inhibition of this antigen by anti-CD47 may be a novel immunotherapeutic approach in the management of this tumor. PMID:26093091

  10. Metabolic consequences of beta-adrenergic receptor blockade for the acutely ischemic dog myocardium

    Energy Technology Data Exchange (ETDEWEB)

    Westera, G.; Hollander, W. den; Wall, E.E. van der; Eenige, M.J. van; Scholtalbers, S.; Visser, F.C.; Roos, J.P.

    1984-02-01

    In an experimental study in 50 dogs the myocardial uptake of free fatty acids (FFAs) after beta-blockade was determined using radioiodinated heptadecanoic acid as a metabolic tracer. All 4 beta-blockers used (metoprolol, timolol, propranolol and pindolol) lowered the uptake of FFAs in the normal canine heart. Uptake of FFAs was also diminished after coronary artery occlusion per se, but administration of beta-blockers exerted little additional influence on the uptake of FFAs. This observation was qualitatively parallelled by the uptake of /sup 201/Tl in concomitant experiments. Plasma FFA levels were increased by pindolol (non-selective with intrinsic sympathomimetic activity), not changed by metoprolol (a cardioselective betablocking agent) and lowered by timolol and propranolol (both non-selective compounds). The extent of ischemic tissue, as reflected by uptake of iodoheptadecanoic acid and /sup 201/Tl, was diminished by metoprolol but not by other beta-blockers. Regional distribution of both tracers, as shown in the endo-epicardial uptake ratios, was hardly influenced by beta-blockade, except for a small increase of /sup 201/Tl uptake in non-occluded endocardium. Uptake of /sup 201/Tl as well as of iodoheptadecanoic acid in the ischemic area was increased by metoprolol, timolol and propranolol and decreased by pindolol. We conclude that beta-blocking agents confer different effects on myocardial uptake and metabolism of FFAs which might possibly be related to their different inherent properties.

  11. A single-copy galK promoter cloning vector suitable for cloning strong promoters

    DEFF Research Database (Denmark)

    Dandanell, Gert; Court, Donald L.; Hammer, Karin

    1986-01-01

    We report the construction of lambda galK promoter cloning vectors for cloning and characterization of strong promoters. This phage, which contains a unique HindIII cloning site, was applied to the cloning and analysis of transcription initiations of the regulatory region of the deo-operon of...

  12. Establishment of independent regulatory authority in Indonesia

    International Nuclear Information System (INIS)

    The Act No. 31 year 1964 on Provision of Atomic Energy stated that National Atomic Energy Agency (Batan) was the prime executive and control agency of atomic energy uses in Indonesia. Some difficulties emerged from that circumstance due to promotional and control function is in one hand. Batan as Promotional Body had duty to develop nuclear technology whereas control function was rather additional job. It meant that development of nuclear technology had high priority and control function had low priority. Consequently, employees recruitment, budget for carrying out control of activity in the use of nuclear energy, radiation safety and inspection equipment, and other concern with the development of controlling was limited. Utilization of nuclear energy had to be controlled strictly in order to avoid detriment to the workers, member of the public, and environment meanwhile the facilities to do the job was minimum so that nuclear energy control was not maximum. Therefore Promotional and Control function is not really able to be in one hand because conflict of interest will occur from time to time. The IAEA recommendation through Basic Safety Standard and Nuclear Safety Convention in 1994 advocates member states to separate promotional and control body. This is the agent of change to separate promotional and control body. But the separation had to change the Act and it was not very easy because it had to be discussed and approved by parliament and before finally signed by President. We spent almost 4 year to change the former Act to the new Act. In 1997 the new Act was issued and the condition changed. Independent Regulatory Body was established in accordance with the Act and main duty of regulatory Body is only to control the utilization of nuclear energy in Indonesia and to do counseling of regulation to the users and member of the public. Making regulations, evaluation of licenses, and doing inspection as well as taking action for law enforcement must be high

  13. Blockades of mitogen-activated protein kinase and calcineurin both change fibre-type markers in skeletal muscle culture

    DEFF Research Database (Denmark)

    Higginson, James; Wackerhage, Henning; Woods, Niall;

    2002-01-01

    and mitogen-activated protein kinase kinase (MEK1/2) blockade with U0126 upon myosin heavy chain (MHC) isoform mRNA levels and activities of metabolic enzymes after 1 day, 3 days and 7 days of treatment in primary cultures of spontaneously twitching rat skeletal muscle. U0126 treatment significantly......Activation of either the calcineurin or the extracellular signal-regulated kinase (ERK1/2) pathway increases the percentage of slow fibres in vivo suggesting that both pathways can regulate fibre phenotypes in skeletal muscle. We investigated the effect of calcineurin blockade with cyclosporin A...

  14. Effects of a New Glutamic Acid Derivative on Myocardial Contractility of Stressed Animals under Conditions of Nitric Oxide Synthesis Blockade.

    Science.gov (United States)

    Tyurenkov, I N; Perfilova, V N; Sadikova, N V; Berestovitskaya, V M; Vasil'eva, O S

    2015-07-01

    Glufimet (glutamic acid derivative) in a dose of 28.7 mg/kg limited the reduction of the cardiac functional reserve in animals subjected to 24-h stress under conditions of nonselective NO synthase blockade with L-NAME (10 mg/kg). Adrenoreactivity and increased afterload tests showed that the increment of myocardial contraction/relaxation rates, left-ventricular pressure, and HR were significantly higher in glufimet-treated stressed animals with NO synthesis blockade than in animals which received no glufimet. The efficiency of glufimet was higher than that of phenibut (the reference drug). PMID:26205724

  15. IL-6 blockade by monoclonal antibodies inhibits apolipoprotein (a) expression and lipoprotein (a) synthesis in humans[S

    OpenAIRE

    Müller, Nike; Schulte, Dominik M.; Türk, Kathrin; Freitag-Wolf, Sandra; Hampe, Jochen; Zeuner, Rainald; Johann O Schröder; Gouni-Berthold, Ioanna; Heiner K Berthold; Krone, Wilhelm; Rose-John, Stefan; Schreiber, Stefan; Laudes, Matthias

    2015-01-01

    Lipoprotein (a) [Lp(a)] is a highly atherogenic lipid particle. Although earlier reports suggested that Lp(a) levels are mostly determined by genetic factors, several recent studies have revealed that Lp(a) induction is also caused by chronic inflammation. Therefore, we aimed to examine whether cytokine blockade by monoclonal antibodies may inhibit Lp(a) metabolism. We found that interleukin 6 (IL-6) blockade by tocilizumab (TCZ) reduced Lp(a) while TNF-α-inhibition by adalimumab in humans ha...

  16. Greater occipital nerve blockade in cervicogenic headache Bloqueio do nervo occipital maior na cefaléia cervicogênica

    OpenAIRE

    Maurice B Vincent; Renato A. Luna; DENISE SCANDIUZZI; Sérgio A. P. Novis

    1998-01-01

    Cervicocogenic headache (CeH) is a relatively common disorder. Although no ideal treatment is available so far, blockades in different structures and nerves may be temporarily effective. We studied the effects of 1-2 mL 0.5% bupivacaine injection at the ipsilateral greater occipital nerve (GON) in 41 CeH patients. The pain is significantly reduced both immediately and as long as 7 days after the blockade. The improvement is less marked during the first two days, a phenomenon we called "tilde ...

  17. Anergic cells induced by the blockade of CD40-CD154 and CD28-B7 costimulatory pathways act as potent immunoregulatory cells in vitro and vivo

    Institute of Scientific and Technical Information of China (English)

    蔡勇; 周佩军; 唐孝达

    2004-01-01

    Background This study was to evaluate whether anergic cells induced by the blockade of CD40-CD154 and CD28-B7 costimulatory pathways can act as potent immunoregulatory cells in vitro and prolong cardiac allograft survival after adoptive transfer.Methods Anergic cells were induced in vitro by the addition of anti-CD154 and anti-CD80 monoclonal antibodies (mAbs) to primary MLR (mixed lymphocyte reaction) consisting of BALB/c as responder and C3H as stimulator. Anergic cells were added to a newly formed MLR in assessing the regulatory capacity and antigen specificity of anergic cells. The ability of anergic cells to respond to antigen and/or exogenous recombinant mouse interleukin-2 (rmIL-2) was tested. For in vivo studies, anergic cells were intravenously injected into 3.0-Gy γ-irradiated BALB/c mice immediately after heterotopic abdominal cardiac transplantation. To prolong allograft survival, recipient mice injected with anergic cells received rapamycin therapy (1 mg·day-1·kg-1).Results Anergic cells strongly suppressed the proliferation of naǐve BALB/c splenocytes against the original (C3H) stimulator in a dose-dependent manner, but they failed to suppress the proliferation of naǐve BALB/c splenocytes against the third-party (C57BL/6J) stimulator. The anergic state was reversed by both original (C3H) stimulator and additional exogenous IL-2. In in vivo studies, untreated irradiated BALB/c mice rejected C3H cardiac allografts with a mean survival time of (8.6±1.1) days, whereas those injected with the anergic cells rejected the allografts with a mean survival time of (11.8±1.9) days, which was slightly longer than that of the untreated mice. The protocol based on anergic cells injection plus rapamycin therapy could prolong allograft survival significantly [(29.6±4.4) days]. Conclusions Anergic cells induced by the blockade of CD40-CD154 and CD28-B7 costimulatory pathways can act as potent immunoregulatory cells in vitro, and prolong cardiac allograft

  18. Association analysis identifies ZNF750 regulatory variants in psoriasis

    Directory of Open Access Journals (Sweden)

    Birnbaum Ramon Y

    2011-12-01

    Full Text Available Abstract Background Mutations in the ZNF750 promoter and coding regions have been previously associated with Mendelian forms of psoriasis and psoriasiform dermatitis. ZNF750 encodes a putative zinc finger transcription factor that is highly expressed in keratinocytes and represents a candidate psoriasis gene. Methods We examined whether ZNF750 variants were associated with psoriasis in a large case-control population. We sequenced the promoter and exon regions of ZNF750 in 716 Caucasian psoriasis cases and 397 Caucasian controls. Results We identified a total of 47 variants, including 38 rare variants of which 35 were novel. Association testing identified two ZNF750 haplotypes associated with psoriasis (p ZNF750 promoter and 5' UTR variants displayed a 35-55% reduction of ZNF750 promoter activity, consistent with the promoter activity reduction seen in a Mendelian psoriasis family with a ZNF750 promoter variant. However, the rare promoter and 5' UTR variants identified in this study did not strictly segregate with the psoriasis phenotype within families. Conclusions Two haplotypes of ZNF750 and rare 5' regulatory variants of ZNF750 were found to be associated with psoriasis. These rare 5' regulatory variants, though not causal, might serve as a genetic modifier of psoriasis.

  19. Schedules for Regulatory Regimes

    International Nuclear Information System (INIS)

    The idea of regulating transporters' terms of operations is that if the market itself does not produce optimal outcomes, then it can be mimicked to do so through regulatory and other public instruments. The first-best solution could be a subsidized (publicly owned) enterprise that sets tariffs according to marginal costs. This has been the tradition in many European countries in the aftermath of WW2. Due to lack of innovative pressure on and x-inefficiency in these companies, this solution is today viewed as inferior to the system of regulating independent (privately owned) firms. When the European gas market becomes liberalized, part of the process in many countries is to (partially) privatise the transport utilities. Privatised or not, in a liberalized market, the transport utilities should face an independent authority that overviews their operations not only in technical, but also in economic terms. Under regulation, a ''visible hand'' is introduced to correct the imperfect market's ''invisible hand''. By regulating the framework and conditions for how firms may operate, public authorities seek to achieve what is considered optimal for the society. The incentives and disincentives given for pricing and production should create mechanisms leading to an efficient allocation of resources and ''acceptable'' distribution of income. As part of intervening into firms' behavior, regulation may be introduced to direct the firm to behave in certain ways. The framework and regulatory mechanisms for the market must then be constructed in a way that companies voluntarily produce an amount at a price that gives maximal profits and simultaneously satisfies social goals. The regulations should lead to consistency between the company's desire to maximize profits and the society's desire for maximizing welfare, as in a perfectly competitive market. This is the core of regulatory economics

  20. International regulatory activities

    International Nuclear Information System (INIS)

    Different international regulatory activities are presented: recommendation on the protection of the public against exposure to radon in drinking water supplies, amendment to the legislation implementing the regulation on imports of agricultural products originating in third countries following the Chernobyl accident, resolution on the commission green paper towards a European strategy for the security of energy supply, declaration of mandatory nature of the international code for the safe carriage of packaged irradiated nuclear fuel, plutonium and high level radioactive wastes on board ships, adoption of action plan against nuclear terrorism. (N.C.)

  1. The Effects of Pharmaceutical Marketing and Promotion on Adverse Drug Events and Regulation

    OpenAIRE

    Guy David; Sara Markowitz; Seth Richards

    2009-01-01

    This paper analyzes the relationship between postmarketing promotional activity and reporting of adverse drug events by modeling the interaction between a welfare maximizing regulator (the FDA) and a profit maximizing firm. In our analysis demand is sensitive to both promotion and regulatory interventions. Promotion-driven market expansions enhance profitability yet may involve the risk that the drug would be prescribed inappropriately, leading to adverse regulatory actions against the firm. ...

  2. Regulatory challenges in using nuclear operating experience

    International Nuclear Information System (INIS)

    The fundamental objective of all nuclear safety regulatory bodies is to ensure that nuclear utilities operate their plants in an acceptably safe manner at all times. Learning from experience has been a key element in meeting this objective. It is therefore very important for nuclear power plant operators to have an active programme for collecting, analysing and acting on the lessons of operating experience that could affect the safety of their plants. NEA experts have noted that almost all of the recent, significant events reported at international meetings have occurred earlier in one form or another. Counteractions are usually well-known, but information does not always seem to reach end users, or corrective action programmes are not always rigorously applied. Thus, one of the challenges that needs to be met in order to maintain good operational safety performance is to ensure that operating experience is promptly reported to established reporting systems, preferably international in order to benefit from a larger base of experience, and that the lessons from operating experience are actually used to promote safety. This report focuses on how regulatory bodies can ensure that operating experience is used effectively to promote the safety of nuclear power plants. While directed at nuclear power plants, the principles in this report may apply to other nuclear facilities as well. (author)

  3. The core to regulatory reform

    International Nuclear Information System (INIS)

    Federal Energy Regulatory Commission (FERC) Orders 436, 500, and 636, the Clean Air Act Amendments of 1990, Public Utility Holding Company Act reform, and the 1992 Energy Policy Act all can have significant effects on an LDC's operations. Such changes in an LDC's environments must be balanced by changes within the utility, its marketplace, and its state regulatory environment. The question is where to start. For Columbia Gas Distribution Cos., based in Columbus, OH, the new operating foundation begins with each employee. Internal strength is critical in designing initiatives that meet the needs of the marketplace and are well-received by regulators. Employees must understand not only the regulatory environment in which the LDC operates, but also how their work contributes to a positive regulatory relationship. To achieve this, Columbia initiated the COntinuing Regulatory Education program, or CORE, in 1991. CORE is a regulatory-focused, information-initiative program coordinated by Columbia's Regulatory Policy, Planning, and Government Affairs Department. The CORE programs can take many forms, such as emerging issue discussions, dialogues with regulators and key parties, updates on regulatory fillings, regulatory policy meetings, and formal training classes. The speakers and discussion facilitators can range from human resource department trainers to senior officers, from regulatory department staff members to external experts, or from state commissioners to executives from other LDCs. The goals of CORE initiatives are to: Support a professional level of regulatory expertise through employee participation in well-developed regulatory programs presented by credible experts. Encourage a constructive state regulatory environment founded on communication and cooperation. CORE achieves these goals via five program levels: introductory basics, advanced learning, professional expertise, crossfunctional dialogues, and external idea exchanges

  4. No Promoter Left Behind (NPLB): learn de novo promoter architectures from genome-wide transcription start sites

    OpenAIRE

    Mitra, Sneha; Narlikar, Leelavati

    2015-01-01

    Summary: Promoters have diverse regulatory architectures and thus activate genes differently. For example, some have a TATA-box, many others do not. Even the ones with it can differ in its position relative to the transcription start site (TSS). No Promoter Left Behind (NPLB) is an efficient, organism-independent method for characterizing such diverse architectures directly from experimentally identified genome-wide TSSs, without relying on known promoter elements. As a test case, we show its...

  5. Direct and indirect effects in the regulation of overlapping promoters.

    Science.gov (United States)

    Bendtsen, Kristian Moss; Erdossy, János; Csiszovszki, Zsolt; Svenningsen, Sine Lo; Sneppen, Kim; Krishna, Sandeep; Semsey, Szabolcs

    2011-09-01

    Optimal response to environmental stimuli often requires activation of certain genes and repression of others. Dual function regulatory proteins play a key role in the differential regulation of gene expression. While repression can be achieved by any DNA binding protein through steric occlusion of RNA polymerase in the promoter region, activation often requires a surface on the regulatory protein to contact RNAP and thus facilitate transcription initiation. RNAP itself is also a DNA binding protein, therefore it can function as a transcriptional repressor. Searching the Escherichia coli promoter database we found that ∼14% of the identified 'forward' promoters overlap with a promoter oriented in the opposite direction. In this article we combine a mathematical model with experimental analysis of synthetic regulatory regions to investigate interference of overlapping promoters. We find that promoter interference depends on the characteristics of overlapping promoters. The model predicts that promoter strength and interference can be regulated separately, which provides unique opportunities for regulation. Our experimental data suggest that in principle any DNA binding protein can be used for both activation and repression of promoter transcription, depending on the context. These findings can be exploited in the construction of synthetic networks. PMID:21609952

  6. The regulatory dynamic

    International Nuclear Information System (INIS)

    An outline of the activities and efforts expanded by the National Energy Board to adjust to the changing natural gas market was provided in this presentation. The author began by defining the role of the National Energy Board in energy markets. It must ensure the adoption of rules and procedures that result in a more competitive and efficient market. Light-handed regulatory techniques are the norm, and the National Energy Board is now committed to facilitating the availability and flow of information so that all parties know where opportunities exist, the terms offered to buy or sell goods and services, their quality and costs. It will specialize in providing new participants with information on the workings of the market, who the players are, the regulatory processes in place, and how, when and where the market can be accessed. The manner in which the Board deals with information was reviewed, providing examples along the way to clarify some points. Some of the documents produced by the National Energy Board are being reviewed with the intent of making them easier to read and understand. Audio streaming over the Internet is another avenue being pursued to ensure individuals can listen in real time to hearings without having to be present in the room. The National Energy Board is also exploring alternative dispute resolution techniques. Consultation with energy market participants represents another facet of these efforts to be more accessible and responsive

  7. Visions of regulatory renewal

    International Nuclear Information System (INIS)

    The economic contribution of the CEPA (Canadian Energy Pipeline Association) member companies to Canada's trade balance was discussed. CEPA member companies transport 95 per cent of the crude oil and natural gas produced in Canada to domestic and export markets. This represents a total of 5.6 Tcf of gas annually. Half of Canada's natural gas and oil production is exported to U.S. markets. All of these exports are transported by pipeline. CEPA member companies operate 90,000 km of pipeline from British Columbia to Quebec. Expansions are needed as a result of a significant increase in demand for natural gas and crude oil since 1990. Several issues exist for regulatory renewal. They include the need to create a level playing field, the overseeing of tolls and contract renewal terms, changing risk/reward trade-offs, the right to confidentiality of information and price discovery mechanism. The drivers for regulatory reform at Westcoast Energy are the need for pricing flexibility, customers desire for toll certainty, decontracting and opposition to rolled-in expansions for gathering and processing. An overview of Westcoast Energy's negotiated toll settlement, its implications, and the components of Westcoast Energy's 'light handed regulation' (LHR) was presented

  8. Status of nuclear regulatory research and its future perspectives

    International Nuclear Information System (INIS)

    A comprehensive investigation of the regulatory research comprising an examination of the research system, its areas and contents, and the goals and financial resources is undertaken. As a result of this study, the future direction of regulatory research and its implementation strategies are suggested to resolve the current issues emerging from this examination. The major issues identified in the study are; (a) an insufficient investment in nuclear regulatory and safety research, (b) an interfacial discrepancy between similar research areas, and (c) a limitation of utilizing research results. To resolve these issues, several measures are proposed : (1) developing a lead project to establish a comprehensive infrastructure for enhancing research cooperation between nuclear organizations including institutes, industry, and universities, with an aim to improve cooperation between projects and to strengthen overall coordination functions among research projects, (2) introducing a certification system on research outcome to promote the proliferation of both research results themselves and their application with a view to enhancing the research quality, (3) strengthening the cooperative system to promote the international cooperative research, and (4) digitalizing all documents and materials relevant to safety and regulatory research to establish KIMS (knowledge and information based management system). It is expected that the aforementioned measures suggested in this study will enhance the efficiency and effectiveness of both nuclear regulatory and safety research, if they are implemented after deliberating with the government and related nuclear industries in the near future

  9. CT-guided injection for ganglion impar blockade: a radiological approach to the management of coccydynia

    International Nuclear Information System (INIS)

    Aim: To evaluate the role of computed tomography (CT) in needle placement for ganglion impar blocks, and to determine the efficacy of CT-guided ganglion impar blocks in the management of coccydynia. Materials and methods: The results of ganglion impar blockade in eight patients with coccydynia secondary to trauma or unknown cause were reviewed. The diagnosis of coccydynia was based on clinical history, location of pain, and response to previous diagnostic and therapeutic procedures. The eight patients were treated with CT-guided ganglion impar blocks to manage their coccyx pain after conservative procedures, including oral medication and cushions, failed to provide relief. All patients were subjected to ganglion impar blocks under a thin-section CT-guided technique for needle placement, using a mixture of bupivacaine and triamcinolone. The patients were followed-up for a period of 6-months. Results: Eight patients were treated in this study with a total of 11 injections. A technical success of 100% was achieved in all cases with accurate needle placement without any complications and all the patients tolerated the procedure well. Out of eight, three patients (37%) had complete relief of pain on the follow-up intervals up to 6 months. Three out of eight patients (37%), had partial relief of symptoms and a second repeat injection was given at the 3 month interval of the follow-up period. At the end of the 6-month follow-up period, six out of eight patients (75%) experienced symptomatic relief (four complete relief and two partial relief) without any additional resort to conventional pain management. Twenty-five percent (two out of eight) did not have any symptomatic improvement. The mean visual analogue score (VAS) pre-procedure was 8 (range 6-10) and had decreased to 2 (range 0-5) in six out of eight patients. Conclusion: CT can be used as an imaging method to identify the ganglion and guide the needle in ganglion impar blockade. The advantages of CT

  10. CT-guided injection for ganglion impar blockade: a radiological approach to the management of coccydynia

    Energy Technology Data Exchange (ETDEWEB)

    Datir, A., E-mail: apdatir@gmail.co [Jackson Memorial Hospital, Miami, FL (United States); Connell, D. [Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex (United Kingdom)

    2010-01-15

    Aim: To evaluate the role of computed tomography (CT) in needle placement for ganglion impar blocks, and to determine the efficacy of CT-guided ganglion impar blocks in the management of coccydynia. Materials and methods: The results of ganglion impar blockade in eight patients with coccydynia secondary to trauma or unknown cause were reviewed. The diagnosis of coccydynia was based on clinical history, location of pain, and response to previous diagnostic and therapeutic procedures. The eight patients were treated with CT-guided ganglion impar blocks to manage their coccyx pain after conservative procedures, including oral medication and cushions, failed to provide relief. All patients were subjected to ganglion impar blocks under a thin-section CT-guided technique for needle placement, using a mixture of bupivacaine and triamcinolone. The patients were followed-up for a period of 6-months. Results: Eight patients were treated in this study with a total of 11 injections. A technical success of 100% was achieved in all cases with accurate needle placement without any complications and all the patients tolerated the procedure well. Out of eight, three patients (37%) had complete relief of pain on the follow-up intervals up to 6 months. Three out of eight patients (37%), had partial relief of symptoms and a second repeat injection was given at the 3 month interval of the follow-up period. At the end of the 6-month follow-up period, six out of eight patients (75%) experienced symptomatic relief (four complete relief and two partial relief) without any additional resort to conventional pain management. Twenty-five percent (two out of eight) did not have any symptomatic improvement. The mean visual analogue score (VAS) pre-procedure was 8 (range 6-10) and had decreased to 2 (range 0-5) in six out of eight patients. Conclusion: CT can be used as an imaging method to identify the ganglion and guide the needle in ganglion impar blockade. The advantages of CT

  11. Muscle-type nicotinic receptor blockade by diethylamine, the hydrophilic moiety of lidocaine

    Directory of Open Access Journals (Sweden)

    Armando eAlberola-Die

    2016-02-01

    Full Text Available Lidocaine bears in its structure both an aromatic ring and a terminal amine, which can be protonated at physiological pH, linked by an amide group. Since lidocaine causes multiple inhibitory actions on nicotinic acetylcholine receptors (nAChRs, this work was aimed to determine the inhibitory effects of diethylamine (DEA, a small molecule resembling the hydrophilic moiety of lidocaine, on Torpedo marmorata nAChRs microtransplanted to Xenopus oocytes. Similarly to lidocaine, DEA reversibly blocked acetylcholine-elicited currents (IACh in a dose-dependent manner (IC50 close to 70 μM, but unlike lidocaine, DEA did not affect IACh desensitization. IACh inhibition by DEA was more pronounced at negative potentials, suggesting an open-channel blockade of nAChRs, although roughly 30% inhibition persisted at positive potentials, indicating additional binding sites outside the pore. DEA block of nAChRs in the resting state (closed channel was confirmed by the enhanced IACh inhibition when pre-applying DEA before its co-application with ACh, as compared with solely DEA and ACh co-application. Virtual docking assays provide a plausible explanation to the experimental observations in terms of the involvement of different sets of drug binding sites. So, at the nAChR transmembrane (TM domain, DEA and lidocaine shared binding sites within the channel pore, giving support to their open-channel blockade; besides, lidocaine, but not DEA, interacted with residues at cavities among the M1, M2, M3 and M4 segments of each subunit and also at intersubunit crevices. At the extracellular (EC domain, DEA and lidocaine binding sites were broadly distributed, which aids to explain the closed channel blockade observed. Interestingly, some DEA clusters were located at the α-γ interphase of the EC domain, in a cavity near the orthosteric binding site pocket; by contrast, lidocaine contacted with all α-subunit loops conforming the ACh binding site, both in α-γ and

  12. Synergistic reversal of type 1 diabetes in NOD mice with anti-CD3 and interleukin-1 blockade

    DEFF Research Database (Denmark)

    Ablamunits, Vitaly; Henegariu, Octavian; Hansen, Jakob Bondo;

    2012-01-01

    Inflammatory cytokines are involved in autoimmune diabetes: among the most prominent is interleukin (IL)-1ß. We postulated that blockade of IL-1ß would modulate the effects of anti-CD3 monoclonal antibody (mAb) in treating diabetes in NOD mice. To test this, we treated hyperglycemic NOD mice with...

  13. Immune checkpoint blockade in cancer treatment: a double-edged sword cross-targeting the host as an "innocent bystander".

    Science.gov (United States)

    Gelao, Lucia; Criscitiello, Carmen; Esposito, Angela; Goldhirsch, Aron; Curigliano, Giuseppe

    2014-03-01

    Targeted immune checkpoint blockade augments anti-tumor immunity and induces durable responses in patients with melanoma and other solid tumors. It also induces specific "immune-related adverse events" (irAEs). IrAEs mainly include gastrointestinal, dermatological, hepatic and endocrinological toxicities. Off-target effects that arise appear to account for much of the toxicity of the immune checkpoint blockade. These unique "innocent bystander" effects are likely a direct result of breaking immune tolerance upon immune check point blockade and require specific treatment guidelines that include symptomatic therapies or systemic corticosteroids. What do we need going forward to limit immune checkpoint blockade-induced toxicity? Most importantly, we need a better understanding of the roles played by these agents in normal tissues, so that we can begin to predict potentially problematic side effects on the basis of their selectivity profile. Second, we need to focus on the predictive factors of the response and toxicity of the host rather than serially focusing on individual agents. Third, rigorous biomarker-driven clinical trials are needed to further elucidate the mechanisms of both the benefit and toxicity. We will summarize the double-edged sword effect of immunotherapeutics in cancer treatment. PMID:24594636

  14. The responses of HT22 cells to the blockade of mitochondrial complexes and potential protective effect of selenium supplementation

    Directory of Open Access Journals (Sweden)

    Jun Panee, Wanyu Liu, Kyoko Nakamura, Marla J. Berry

    2007-01-01

    Full Text Available Mitochondria are the major reactive oxygen species (ROS – generating sites in mammalian cells. Blockade of complexes in the electron transport chain (ETC increases the leakage of single electrons to O2 and therefore increases ROS levels. Complexes I and III have been reported to be the major ROS-generating sites in mitochondria. In this study, using mouse hippocampal HT22 cells as in vitro model, we monitored the change of intracellular ROS level in response to the blockade of ETC at different complex, and measured changes of gene expression of antioxidant enzymes and phase II enzymes, also evaluated potential protective effect of selenium (Se supplementation to the cells under this oxidative stress. In summary, our results showed that complex I was the major ROS-generating site in HT22 cells. Complex I blockade upregulated the mRNA levels of glutamylcysteine synthetase heavy and light chains, glutathione-S-transferases omega1 and alpha 2, hemoxygenase 1, thioredoxin reductase 1, and selenoprotein H. Unexpectedly, the expression of the enzymes that directly scavenge ROS decreased, including superoxide dismutases 1 and 2, glutathione peroxidase 1, and catalase. Se supplementation increased glutathione levels and glutathione peroxidase activity, indicating a potential protective role in oxidative stress caused by ETC blockade.

  15. Sugammadex 4.0 mg kg-1 reversal of deep rocuronium-induced neuromuscular blockade

    DEFF Research Database (Denmark)

    Yu, Buwei; Wang, Xiangrui; Hansen, Søren Helbo;

    2014-01-01

    Objective: Maintenance of deep Neuro Muscular Blockade (NMB) until the end of surgery may be beneficial in some surgical procedures. The selective relaxant binding agent sugammadex rapidly reverses deep levels of rocuronium-induced NMB. The purpose of this study was to evaluate the efficacy and s...

  16. Resolution of diarrhea in an immunocompromised patient with chronic norovirus gastroenteritis correlates with constitution of specific antibody blockade titer.

    Science.gov (United States)

    Knoll, Bettina M; Lindesmith, Lisa C; Yount, Boyd L; Baric, Ralph S; Marty, Francisco M

    2016-08-01

    Norovirus gastroenteritis in immunocompromised hosts can result in a serious and prolonged diarrheal illness. We present a case of chronic norovirus disease during rituximab-bendamustine chemotherapy for non-Hodgkin's lymphoma. We show for the first time a correlation between norovirus strain-specific antibody blockade titers and symptom improvement in an immunocompromised host. PMID:26825307

  17. Relevance of dorsal raphe nucleus firing in serotonin 5-HT2C receptor blockade-induced augmentation of SSRIs effects

    NARCIS (Netherlands)

    Sotty, Florence; Folgering, Joost H. A.; Brennum, Lise T.; Hogg, Sandra; Mork, Arne; Hertel, Peter; Cremers, Thomas I. F. H.

    2009-01-01

    Selective serotonin reuptake inhibitors are the most widely prescribed antidepressant drugs. However, they exhibit a slow onset of action, putatively due to the initial decrease in serotonin cell firing mediated via somato-dendritic autoreceptors. Interestingly, blockade of 5-HT2C receptors signific

  18. Individual titration for maximal blockade of the renin-angiotensin system in proteinuric patients: A feasible strategy?

    NARCIS (Netherlands)

    Vogt, Liffert; Navis, Ger Jan; de Zeeuw, Dick

    2005-01-01

    Agents that interfere with the renin-angiotensin system (RAS) reduce proteinuria and afford renal protection. The combination of different measures that serve maximization of RAS blockade is thought to improve the antiproteinuric efficacy. The feasibility and the efficacy of such a combination strat

  19. Framing of information on the use of public finances, regulatory fit of recipients and tax compliance.

    Science.gov (United States)

    Holler, Marianne; Hoelzl, Erik; Kirchler, Erich; Leder, Susanne; Mannetti, Lucia

    2008-08-01

    Information campaigns to increase tax compliance could be framed in different ways. They can either highlight the potential gains when tax compliance is high, or the potential losses when compliance is low. According to regulatory focus theory, such framing should be most effective when it is congruent with the promotion or prevention focus of its recipients. Two studies confirmed the hypothesized interaction effects between recipients' regulatory focus and framing of information campaigns, with tax compliance being highest under conditions of regulatory fit. To address taxpayers effectively, information campaigns by tax authorities should consider the positive and negative framing of information, and the moderating effect of recipients' regulatory focus. PMID:20495689

  20. Effect of angiotensin II receptor blockade on proximal tubular fluid reabsorption

    DEFF Research Database (Denmark)

    Leyssac, P P; Karlsen, F M; Holstein-Rathlou, N H

    1997-01-01

    The effect of physiological concentrations of angiotensin II on proximal tubular fluid reabsorption remains controversial. To investigate the effect of blockade of intratubular AT1 receptors on tubular reabsorption, losartan (10(-5) M) was administered by microperfusion into an early proximal...... flow rate decreased by 2.0 +/- 0.8 nl/min, and early distal NaCl concentration decreased by 4.3 +/- 0.8 mM (mean +/- SE). No changes were observed after microperfusion with saline. Because the tubuloglomerular feedback mechanism was operating in the closed-loop mode, the decreased NaCl load to the...... early and late proximal convolutions was estimated to be 7.8 nl/min (approximately 36%). It is concluded that a decrease in local luminal angiotensin II levels and/or AT1 receptor activity under free flow conditions increases the rate of proximal tubular fluid reabsorption....