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Sample records for opposing regulatory roles

  1. Opposing roles for interferon regulatory factor-3 (IRF-3 and type I interferon signaling during plague.

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    Ami A Patel

    Full Text Available Type I interferons (IFN-I broadly control innate immunity and are typically transcriptionally induced by Interferon Regulatory Factors (IRFs following stimulation of pattern recognition receptors within the cytosol of host cells. For bacterial infection, IFN-I signaling can result in widely variant responses, in some cases contributing to the pathogenesis of disease while in others contributing to host defense. In this work, we addressed the role of type I IFN during Yersinia pestis infection in a murine model of septicemic plague. Transcription of IFN-β was induced in vitro and in vivo and contributed to pathogenesis. Mice lacking the IFN-I receptor, Ifnar, were less sensitive to disease and harbored more neutrophils in the later stage of infection which correlated with protection from lethality. In contrast, IRF-3, a transcription factor commonly involved in inducing IFN-β following bacterial infection, was not necessary for IFN production but instead contributed to host defense. In vitro, phagocytosis of Y. pestis by macrophages and neutrophils was more effective in the presence of IRF-3 and was not affected by IFN-β signaling. This activity correlated with limited bacterial growth in vivo in the presence of IRF-3. Together the data demonstrate that IRF-3 is able to activate pathways of innate immunity against bacterial infection that extend beyond regulation of IFN-β production.

  2. The cytokines IL-21 and GM-CSF have opposing regulatory roles in the apoptosis of conventional dendritic cells.

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    Wan, Chi-Keung; Oh, Jangsuk; Li, Peng; West, Erin E; Wong, Elizabeth A; Andraski, Allison B; Spolski, Rosanne; Yu, Zu-Xi; He, Jianping; Kelsall, Brian L; Leonard, Warren J

    2013-03-21

    Interleukin-21 (IL-21) has broad actions on T and B cells, but its actions in innate immunity are poorly understood. Here we show that IL-21 induced apoptosis of conventional dendritic cells (cDCs) via STAT3 and Bim, and this was inhibited by granulocyte-macrophage colony-stimulating factor (GM-CSF). ChIP-Seq analysis revealed genome-wide binding competition between GM-CSF-induced STAT5 and IL-21-induced STAT3. Expression of IL-21 in vivo decreased cDC numbers, and this was prevented by GM-CSF. Moreover, repetitive α-galactosylceramide injection of mice induced IL-21 but decreased GM-CSF production by natural killer T (NKT) cells, correlating with decreased cDC numbers. Furthermore, adoptive transfer of wild-type CD4+ T cells caused more severe colitis with increased DCs and interferon-γ (IFN-γ)-producing CD4+ T cells in Il21r(-/-)Rag2(-/-) mice (which lack T cells and have IL-21-unresponsive DCs) than in Rag2(-/-) mice. Thus, IL-21 and GM-CSF exhibit cross-regulatory actions on gene regulation and apoptosis, regulating cDC numbers and thereby the magnitude of the immune response. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. UXT plays dual opposing roles on SARM-induced apoptosis.

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    Sethurathinam, Shalini; Singh, Laishram Pradeepkumar; Panneerselvam, Porkodi; Byrne, Bernadette; Ding, Jeak Ling

    2013-10-11

    Apoptosis is a vital defense mechanism for the clearance of infected cells. Ubiquitously expressed transcript (UXT), which exists in two isoforms (V1 and V2), interact with both apoptotic and cellular proteins. By yeast two-hybrid analysis, we found that UXT interacts with SARM (sterile α and HEAT armadillo motif-containing protein). Since SARM is a TLR adaptor which induces intrinsic apoptosis following immune activation, we were prompted to query whether UXT and SARM might co-regulate apoptosis. We found that the UXT isoforms elicit dual opposing regulatory effects on SARM-induced apoptosis; while UXT V1, co-expressed with SARM, caused a reduction in caspase 8 activity, UXT V2 strongly increased caspase 8 activity and enhanced SARM-induced apoptosis by activating the extrinsic pathway and depolarizing the mitochondria. Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  4. The calpain/calpastatin system has opposing roles in growth and metastatic dissemination of melanoma.

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    Quentin Raimbourg

    Full Text Available Conventional calpains are ubiquitous cysteine proteases whose activity is promoted by calcium signaling and specifically limited by calpastatin. Calpain expression has been shown to be increased in human malignant cells, but the contribution of the calpain/calpastatin system in tumorigenesis remains unclear. It may play an important role in tumor cells themselves (cell growth, migration, and a contrario cell death and/or in tumor niche (tissue infiltration by immune cells, neo-angiogenesis. In this study, we have used a mouse model of melanoma as a tool to gain further understanding of the role of calpains in tumor progression. To determine the respective importance of each target, we overexpressed calpastatin in tumor and/or host in isolation. Our data demonstrate that calpain inhibition in both tumor and host blunts tumor growth, while paradoxically increasing metastatic dissemination to regional lymph nodes. Specifically, calpain inhibition in melanoma cells limits tumor growth in vitro and in vivo but increases dissemination by amplifying cell resistance to apoptosis and accelerating migration process. Meanwhile, calpain inhibition restricted to host cells blunts tumor infiltration by immune cells and angiogenesis required for antitumor immunity, allowing tumor cells to escape tumor niche and disseminate. The development of highly specific calpain inhibitors with potential medical applications in cancer should take into account the opposing roles of the calpain/calpastatin system in initial tumor growth and subsequent metastatic dissemination.

  5. Opposing Roles of Leptin and Ghrelin in the Equine Corpus Luteum Regulation: An In Vitro Study

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    António Galvão

    2014-01-01

    Full Text Available Metabolic hormones have been associated with reproductive function modulation. Thus, the aim of this study was: (i to characterize the immunolocalization, mRNA and protein levels of leptin (LEP, Ghrelin (GHR and respective receptors LEPR and Ghr-R1A, throughout luteal phase; and (ii to evaluate the role of LEP and GHR on progesterone (P4, prostaglandin (PG E2 and PGF2α, nitric oxide (nitrite, tumor necrosis factor-α (TNF; macrophage migration inhibitory factor (MIF secretion, and on angiogenic activity (BAEC proliferation, in equine corpus luteum (CL from early and mid-luteal stages. LEPR expression was decreased in late CL, while GHR/Ghr-R1A system was increased in the same stage. Regarding secretory activity, GHR decreased P4 in early CL, but increased PGF2α, nitrite and TNF in mid CL. Conversely, LEP increased P4, PGE2, angiogenic activity, MIF, TNF and nitrite during early CL, in a dose-dependent manner. The in vitro effect of LEP on secretory activity was reverted by GHR, when both factors acted together. The present results evidence the presence of LEP and GHR systems in the equine CL. Moreover, we suggest that LEP and GHR play opposing roles in equine CL regulation, with LEP supporting luteal establishment and GHR promoting luteal regression. Finally, a dose-dependent luteotrophic effect of LEP was demonstrated.

  6. CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcome

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    Zhang, Qunyuan; Ye, Jian; Wang, Fang; Zhang, Yanping; Hunborg, Pamela; Varvares, Mark A.; Hoft, Daniel F.; Hsueh, Eddy C.; Peng, Guangyong

    2015-01-01

    The Cancer Immunoediting concept has provided critical insights suggesting dual functions of immune system during the cancer initiation and development. However, the dynamics and roles of CD4+ and CD8+ T cells in the pathogenesis of breast cancer remain unclear. Here we utilized two murine breast cancer models (4T1 and E0771) and demonstrated that both CD4+ and CD8+ T cells were increased and involved in immune responses, but with distinct dynamic trends in breast cancer development. In addition to cell number increases, CD4+ T cells changed their dominant subsets from Th1 in the early stages to Treg and Th17 cells in the late stages of the cancer progression. We also analyzed CD4+ and CD8+ T cell infiltration in primary breast cancer tissues from cancer patients. We observed that CD8+ T cells are the key effector cell population mediating effective anti-tumor immunity resulting in better clinical outcomes. In contrast, intra-tumoral CD4+ T cells have negative prognostic effects on breast cancer patient outcomes. These studies indicate that CD4+ and CD8+ T cells have opposing roles in breast cancer progression and outcomes, which provides new insights relevant for the development of effective cancer immunotherapeutic approaches. PMID:25968569

  7. Members of the Penicillium chrysogenum velvet complex play functionally opposing roles in the regulation of penicillin biosynthesis and conidiation.

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    Kopke, Katarina; Hoff, Birgit; Bloemendal, Sandra; Katschorowski, Alexandra; Kamerewerd, Jens; Kück, Ulrich

    2013-02-01

    A velvet multisubunit complex was recently detected in the filamentous fungus Penicillium chrysogenum, the major industrial producer of the β-lactam antibiotic penicillin. Core components of this complex are P. chrysogenum VelA (PcVelA) and PcLaeA, which regulate secondary metabolite production, hyphal morphology, conidiation, and pellet formation. Here we describe the characterization of PcVelB, PcVelC, and PcVosA as novel subunits of this velvet complex. Using yeast two-hybrid analysis and bimolecular fluorescence complementation (BiFC), we demonstrate that all velvet proteins are part of an interaction network. Functional analyses using single- and double-knockout strains clearly indicate that velvet subunits have opposing roles in the regulation of penicillin biosynthesis and light-dependent conidiation. PcVelC, together with PcVelA and PcLaeA, activates penicillin biosynthesis, while PcVelB represses this process. In contrast, PcVelB and PcVosA promote conidiation, while PcVelC has an inhibitory effect. Our genetic analyses further show that light-dependent spore formation depends not only on PcVelA but also on PcVelB and PcVosA. The results provided here contribute to our fundamental understanding of the function of velvet subunits as part of a regulatory network mediating signals responsible for morphology and secondary metabolism and will be instrumental in generating mutants with newly derived properties that are relevant to strain improvement programs.

  8. Opposing roles of TGF-β in prostaglandin production by human follicular dendritic cell-like cells.

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    Choe, Jongseon; Park, Jihoon; Lee, Seungkoo; Kim, Young-Myeong; Jeoung, Dooil

    2016-08-01

    Prostaglandins (PGs) are recognized as important immune regulators. Using human follicular dendritic cell (FDC)-like HK cells, we have investigated the immunoregulatory role of PGs and their production mechanisms. The present study was aimed at determining the role of TGF-β in IL-1β-induced cyclooxygenase-2 (COX-2) expression by immunoblotting. COX-2 is the key enzyme responsible for PG production in HK cells. TGF-β, when added simultaneously with IL-1β, gave rise to an additive effect on COX-2 expression in a dose-dependent manner. However, TGF-β inhibited IL-1β-stimulated COX-2 expression when it was added at least 12h before IL-1β addition. The inhibitory effect of TGF-β was specific to IL-1β-induced COX-2 expression in HK cells. The stimulating and inhibitory effects of TGF-β were reproduced in IL-1β-stimulated PG production. Based on our previous results of the essential requirement of ERK and p38 MAPKs in TGF-β-induced COX-2 expression, we examined whether the differential activation of these MAPKs would underlie the opposing activities of TGF-β. The phosphorylation of ERK and p38 MAPKs was indeed enhanced or suppressed by the simultaneous treatment or pre-treatment, respectively. These results suggest that TGF-β exerts opposing effects on IL-1β-induced COX-2 expression in HK cells by differentially regulating activation of ERK and p38 MAPKs.

  9. HOS2 and HDA1 encode histone deacetylases with opposing roles in Candida albicans morphogenesis.

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    Lucia F Zacchi

    Full Text Available Epigenetic mechanisms regulate the expression of virulence traits in diverse pathogens, including protozoan and fungi. In the human fungal pathogen Candida albicans, virulence traits such as antifungal resistance, white-opaque switching, and adhesion to lung cells are regulated by histone deacetylases (HDACs. However, the role of HDACs in the regulation of the yeast-hyphal morphogenetic transitions, a critical virulence attribute of C. albicans, remains poorly explored. In this study, we wished to determine the relevance of other HDACs on C. albicans morphogenesis. We generated mutants in the HDACs HOS1, HOS2, RPD31, and HDA1 and determined their ability to filament in response to different environmental stimuli. We found that while HOS1 and RPD31 have no or a more limited role in morphogenesis, the HDACs HOS2 and HDA1 have opposite roles in the regulation of hyphal formation. Our results demonstrate an important role for HDACs on the regulation of yeast-hyphal transitions in the human pathogen C. albicans.

  10. Fibroblast growth factor and glutamate: opposing roles in the generation and degeneration of hippocampal neuroarchitecture.

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    Mattson, M P; Murrain, M; Guthrie, P B; Kater, S B

    1989-11-01

    Neuritic regression and cell death (neurodegeneration) are common features of both normal nervous system development and neurodegenerative disorders. Growth factors and excitatory amino acid neurotransmitters have been suggested independently to play roles in neurodegenerative processes. The present study investigated the combined effects of fibroblast growth factor (FGF) and glutamate on the development and degeneration of cultured hippocampal neurons. Consistent with previous data, we found that FGF, but not NGF, promoted neuronal survival and dendritic outgrowth. In contrast, a low level of glutamate (50 microM) caused a reduction in dendritic outgrowth, and high levels (100 microM-1 mM) reduced neuronal survival in a dose-dependent manner. When cultures were maintained in the presence of FGF, there was a striking reduction in neuronal death normally caused by 100-500 microM glutamate. FGF raised the threshold for glutamate neurotoxicity. FGF also antagonized the outgrowth-inhibiting actions of glutamate. Measurements of intracellular calcium levels with fura-2 demonstrated a direct relationship between glutamate-induced rises in intracellular calcium and neurodegeneration. FGF reduced the glutamate-induced increases in intracellular calcium levels. However, when cultures were pretreated with the RNA synthesis inhibitor actinomycin D or with the protein synthesis inhibitor cycloheximide, FGF did not prevent glutamate-induced increases in intracellular calcium or neurodegeneration. Taken together, these results suggest that (1) interactions between growth factors and neurotransmitters may be important in brain development; (2) imbalances in these systems may lead to neurodegeneration; and (3) cellular calcium-regulating systems may be a common focus of growth factor and neurotransmitter actions.

  11. Meditation and Its Regulatory Role on Sleep

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    Nagendra, Ravindra P.; Maruthai, Nirmala; Kutty, Bindu M.

    2012-01-01

    Intense meditation practices help to achieve a harmony between body and mind. Meditation practices influence brain functions, induce various intrinsic neural plasticity events, modulate autonomic, metabolic, endocrine, and immune functions and thus mediate global regulatory changes in various behavioral states including sleep. This brief review focuses on the effect of meditation as a self regulatory phenomenon on sleep.

  12. Meditation and its regulatory role on sleep

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    Ravindra P. Nagendra

    2012-04-01

    Full Text Available Intense meditation practices help to achieve a harmony between body and mind. Meditation practices influence brain functions, induce various intrinsic neural plasticity events, modulate autonomic, metabolic, endocrine and immune functions and thus mediate global regulatory changes in various behavioural states including sleep. This brief review focuses on the effect of meditation as a self regulatory phenomenon on sleep.

  13. Meditation and its regulatory role on sleep.

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    Nagendra, Ravindra P; Maruthai, Nirmala; Kutty, Bindu M

    2012-01-01

    Intense meditation practices help to achieve a harmony between body and mind. Meditation practices influence brain functions, induce various intrinsic neural plasticity events, modulate autonomic, metabolic, endocrine, and immune functions and thus mediate global regulatory changes in various behavioral states including sleep. This brief review focuses on the effect of meditation as a self regulatory phenomenon on sleep.

  14. Opposing roles of Toll-like receptor and cytosolic DNA-STING signaling pathways for Staphylococcus aureus cutaneous host defense

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    Spreafico, Roberto; Modlin, Robert L.; Smale, Stephen T.

    2017-01-01

    Successful host defense against pathogens requires innate immune recognition of the correct pathogen associated molecular patterns (PAMPs) by pathogen recognition receptors (PRRs) to trigger the appropriate gene program tailored to the pathogen. While many PRR pathways contribute to the innate immune response to specific pathogens, the relative importance of each pathway for the complete transcriptional program elicited has not been examined in detail. Herein, we used RNA-sequencing with wildtype and mutant macrophages to delineate the innate immune pathways contributing to the early transcriptional response to Staphylococcus aureus, a ubiquitous microorganism that can activate a wide variety of PRRs. Unexpectedly, two PRR pathways—the Toll-like receptor (TLR) and Stimulator of Interferon Gene (STING) pathways—were identified as dominant regulators of approximately 95% of the genes that were potently induced within the first four hours of macrophage infection with live S. aureus. TLR signaling predominantly activated a pro-inflammatory program while STING signaling activated an antiviral/type I interferon response with live but not killed S. aureus. This STING response was largely dependent on the cytosolic DNA sensor cyclic guanosine-adenosine synthase (cGAS). Using a cutaneous infection model, we found that the TLR and STING pathways played opposite roles in host defense to S. aureus. TLR signaling was required for host defense, with its absence reducing interleukin (IL)-1β production and neutrophil recruitment, resulting in increased bacterial growth. In contrast, absence of STING signaling had the opposite effect, enhancing the ability to restrict the infection. These results provide novel insights into the complex interplay of innate immune signaling pathways triggered by S. aureus and uncover opposing roles of TLR and STING in cutaneous host defense to S. aureus. PMID:28704551

  15. TGF-β1 exerts opposing effects on grass carp leukocytes: implication in teleost immunity, receptor signaling and potential self-regulatory mechanisms.

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    Mu Yang

    Full Text Available In fish immunity, the regulatory role of transforming growth factor-β1 (TGF-β1 has not been fully characterized. Here we examined the immunoregulatory effects of TGF-β1 in grass carp peripheral blood leukocytes (PBL and head kidney leukocytes (HKL. It is interesting that TGF-β1 consistently stimulated the cell viability and the mRNA levels of pro-inflammatory cytokines (Tnfα and Ifnγ and T/B cell markers [Cd4-like (Cd4l, Cd8α, Cd8β and Igμ] in PBL, which contrasted with its inhibitory tone in HKL. Further studies showed that grass carp TGF-β1 type I receptor, activin receptor-like kinase 5 (ALK5, was indispensable for the immunoregulatory effects of TGF-β1 in PBL and HKL. Notably, TGF-β1 persistently attenuated ALK5 expression, whereas immunoneutralization of endogenous grass carp TGF-β1 could increase ALK5 mRNA and protein levels. It is consistent with the observation that TGF-β1 decreased the number of ALK5(+ leukocytes in PBL and HKL, revealing a negative regulation of TGF-β1 signaling at the receptor level. Moreover, transient treatment with TGF-β1 for 24 h was sufficient to induce similar cellular responses compared with the continuous treatment. This indicated a possible mechanism by which TGF-β1 triggered the down-regulation of ALK5 mRNA and protein, leading to the desensitization of grass carp leukocytes toward TGF-β1. Accordingly, our data revealed a dual role of TGF-β1 in teleost immunity in which it can serve as a positive or negative control device and provided additional mechanistic insights as to how TGF-β1 controls its signaling in vertebrate leukocytes.

  16. The role of veterinary medicine regulatory agencies.

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    Smith, M V

    2013-08-01

    An effective animal medicine regulatory programme includes a systematic, evidence-based means of documenting the safety and effectiveness of products before they are produced, marketed or used in a particular country or region. The programme must also include adequate monitoring and controls over the use of these substances. It is clearthat such programmes provide veterinarians, farmers and other animal medicine users with greater assurance that veterinary drugs and biologicals will be safe and effective in preventing and mitigating disease. It is important that these regulatory controls include programmes to ensure that human food obtained from treated animals is safe and that all potential toxicological and microbiological hazards that may be associated with the use of veterinary medicines have been adequately evaluated. There is a great need worldwide for veterinary medicines that provide needed therapies for vast numbers of animals and animal species and, in the case of food-producing animals, for medicinal products that enhance the productivity and efficiency of food production and ensure food safety when they are used in accordance with their approval specifications. The public health mission of regulatory agencies succeeds when they are able to put into the hands of the user an approved, safe and effective, well-manufactured and appropriately labelled medicine, and when there are adequate controls in place to assure proper compliance.

  17. Opposing tissue-specific roles of angiotensin in the pathogenesis of obesity, and implications for obesity-related hypertension.

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    Littlejohn, Nicole K; Grobe, Justin L

    2015-12-15

    Metabolic disease, specifically obesity, has now become the greatest challenge to improving cardiovascular health. The renin-angiotensin system (RAS) exists as both a circulating hormone system and as a local paracrine signaling mechanism within various tissues including the brain, kidney, and adipose, and this system is strongly implicated in cardiovascular health and disease. Growing evidence also implicates the RAS in the control of energy balance, supporting the concept that the RAS may be mechanistically involved in the pathogenesis of obesity and obesity hypertension. Here, we review the involvement of the RAS in the entire spectrum of whole organism energy balance mechanisms, including behaviors (food ingestion and spontaneous physical activity) and biological processes (digestive efficiency and both aerobic and nonaerobic resting metabolic rates). We hypothesize that opposing, tissue-specific effects of the RAS to modulate these various components of energy balance can explain the apparently paradoxical results reported by energy-balance studies that involve stimulating, versus disrupting, the RAS. We propose a model in which such opposing and tissue-specific effects of the RAS can explain the failure of simple, global RAS blockade to result in weight loss in humans, and hypothesize that obesity-mediated uncoupling of endogenous metabolic rate control mechanisms can explain the phenomenon of obesity-related hypertension. Copyright © 2015 the American Physiological Society.

  18. The Contributing Role of the Regulatory Environment

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    1991-04-09

    Sources: Carriers and KJH Comnunicationa (Atlanta) Reproduced in part from " Commuiaions January 1991, p. 102.8 FI THE com ymrnNG ROLE oF HE...were awaiting government approval at the time of publication. - Sources: Carrieo and KJH comnmticatiom (Atlanta) Reproduced in part from " " January 1991. p. 103-4. A’ 4

  19. Regulatory T Cells and Their Role in Animal Disease.

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    Veiga-Parga, T

    2016-07-01

    In humans and mouse models, Foxp3(+) regulatory T cells are known to control all aspects of immune responses. However, only limited information exists on these cells' role in diseases of other animals. In this review, we cover the most important features and different types of regulatory T cells, which include those that are thymus-derived and peripherally induced, the mechanisms by which they control immune responses by targeting effector T cells and antigen-presenting cells, and most important, their role in animal health and diseases including cancer, infections, and other conditions such as hypersensitivities and autoimmunity. Although the literature regarding regulatory T cells in domestic animal species is still limited, multiple articles have recently emerged and are discussed. Moreover, we also discuss the evidence suggesting that regulatory T cells might limit the magnitude of effector responses, which can have either a positive or negative result, depending on the context of animal and human disease. In addition, the issue of plasticity is discussed because plasticity in regulatory T cells can result in the loss of their protective function in some microenvironments during disease. Lastly, the manipulation of regulatory T cells is discussed in assessing the possibility of their use as a treatment in the future. © The Author(s) 2016.

  20. Obesity Hypertension: The Regulatory Role of Leptin

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    Shilpa Kshatriya

    2011-01-01

    Full Text Available Leptin is a 16-kDa-peptide hormone that is primarily synthesized and secreted by adipose tissue. One of the major actions of this hormone is the control of energy balance by binding to receptors in the hypothalamus, leading to reduction in food intake and elevation in temperature and energy expenditure. In addition, increasing evidence suggests that leptin, through both direct and indirect mechanisms, may play an important role in cardiovascular and renal regulation. While the relevance of endogenous leptin needs further clarification, it appears to function as a pressure and volume-regulating factor under conditions of health. However, in abnormal situations characterized by chronic hyperleptinemia such as obesity, it may function pathophysiologically for the development of hypertension and possibly also for direct renal, vascular, and cardiac damage.

  1. The Roles of Regulatory B Cells in Cancer

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    Yan He

    2014-01-01

    Full Text Available Regulatory B cells (Bregs, a newly described subset of B cells, have been proved to play a suppressive role in immune system. Bregs can inhibit other immune cells through cytokines secretion and antigen presentation, which give them the role in the pathogenesis of autoimmune diseases and cancers. There are no clear criteria to identify Bregs; different markers were used in the different experimental conditions. Massive researches had described the functions of immune cells such as regulatory T cells (Tregs, dendritic cells (DCs, and B cells in the autoimmune disorder diseases and cancers. More and more researches focused on the roles of Bregs and the cytokines such as Interleukin-10 (IL-10 and transforming growth factor beta (TGF-β secreted by Bregs. The aim of this review is to summarize the characteristics of Bregs and the roles of Bregs in cancer.

  2. Role of regulatory agencies in translating pharmacogenetics to the clinics

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    Prasad, Krishna

    2009-01-01

    Overall, the regulators (here the term is used in the broad sense including competent authorities, the national departments of health and the European commission) have a significant role in translating pharmacogenomics into clinical practice. The first objective is to establish the role of the genomic information that is available, and this should be data driven. Conduct of robust clinical trials that are sound both scientifically and from a regulatory perspective should be encouraged. Signif...

  3. [The role of regulatory T cells in allergic contact dermatitis].

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    Krecisz, Beata; Chomiczewska, Dorota; Kieć-Swierczyńska, Marta

    2009-01-01

    Regulatory T cells (Treg) play a crucial role in the regulatory mechanisms of immune system. They are responsible for the induction and maintenance of immune tolerance. They are also involved in the pathogenesis of autoimmune and allergic diseases and implicated in transplant rejection and immunopathology of cancers. Treg cells constitute the population of lymphocytes heterogeneous in their phenotype. CD4+CD25+Foxp3+ cells are most important among Treg subsets. Modification of Treg actvity may be useful in the therapy of different diseases, including allergic disorders.

  4. [Role of Academia in Regulatory Science for Global Drug Development].

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    Tsukamoto, Katsura; Takenaka, Toichi

    2016-01-01

    As diseases know no national boundaries, drug development must be designed at a global level. Drugs are highly regulated to maximize the benefits to public health, which is assessed on a regional basis. The complexity and diversity of stakeholders increase dramatically once multiple international regions are involved. Each stakeholder in drug development depends on customized criteria to make decisions for its own benefit. Thus, a huge gap exists among drug discovery researchers, developers, clinicians, patients, and regulatory bodies. With reasonable scientific evidence gathered and analyzed, mutual agreement can be reached. We believe that this important role of regulatory science and academic involvement will create harmony. By practicing diverse, innovative regulatory scientific research, academia has the potential to become the core of communication among various stakeholder groups. Furthermore, another important responsibility of academia, i.e., knowledge, provides additional aspects to the field of drug development. Those who understand regulatory science can contribute to the efficient achievement of innovative, effective, safe drugs. Thus, research and education are essential roles of academia to allow a better understanding of the balance between benefits and risks. Communication and knowledge will promote the prompt delivery of better medical products to patients in need.

  5. The role of research in NRC regulatory programs

    Energy Technology Data Exchange (ETDEWEB)

    Jackson, S.A.

    1996-03-01

    This article is the text of the opening remarks by NRC Chairwoman Shirley Jackson to the Reactor Safety Meeting. In her remarks, Dr. Jackson discusses the role of research in NRC regulatory programs and points out by way of example that many of the research programs provide considerable benefit to the industry as well as to the Commission. She then outlines current activities as well as future plans.

  6. The role of regulatory T cells in cancer immunology

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    Whiteside TL

    2015-01-01

    Theresa L Whiteside University of Pittsburgh Cancer Institute, Pittsburgh, PA, US Abstract: Regulatory T cells (Treg) are generally considered to be significant contributors to tumor escape from the host immune system. Emerging evidence suggests, however, that in some human cancers, Treg are necessary to control chronic inflammation, prevent tissue damage, and limit inflammation-associated cancer development. The dual role of Treg in cancer and underpinnings of Treg diversity are not well und...

  7. Opposing roles of corticotropin-releasing factor and neuropeptide Y within the dorsolateral bed nucleus of the stria terminalis in the negative affective component of pain in rats.

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    Ide, Soichiro; Hara, Taiki; Ohno, Atsushi; Tamano, Ryuta; Koseki, Kana; Naka, Tomonori; Maruyama, Chikashi; Kaneda, Katsuyuki; Yoshioka, Mitsuhiro; Minami, Masabumi

    2013-04-01

    Pain is a complex experience composed of sensory and affective components. Although the neural systems of the sensory component of pain have been studied extensively, those of its affective component remain to be determined. In the present study, we examined the effects of corticotropin-releasing factor (CRF) and neuropeptide Y (NPY) injected into the dorsolateral bed nucleus of the stria terminalis (dlBNST) on pain-induced aversion and nociceptive behaviors in rats to examine the roles of these peptides in affective and sensory components of pain, respectively. In vivo microdialysis showed that formalin-evoked pain enhanced the release of CRF in this brain region. Using a conditioned place aversion (CPA) test, we found that intra-dlBNST injection of a CRF1 or CRF2 receptor antagonist suppressed pain-induced aversion. Intra-dlBNST CRF injection induced CPA even in the absence of pain stimulation. On the other hand, intra-dlBNST NPY injection suppressed pain-induced aversion. Coadministration of NPY inhibited CRF-induced CPA. This inhibitory effect of NPY was blocked by coadministration of a Y1 or Y5 receptor antagonist. Furthermore, whole-cell patch-clamp electrophysiology in dlBNST slices revealed that CRF increased neuronal excitability specifically in type II dlBNST neurons, whereas NPY decreased it in these neurons. Excitatory effects of CRF on type II dlBNST neurons were suppressed by NPY. These results have uncovered some of the neuronal mechanisms underlying the affective component of pain by showing opposing roles of intra-dlBNST CRF and NPY in pain-induced aversion and opposing actions of these peptides on neuronal excitability converging on the same target, type II neurons, within the dlBNST.

  8. Associations of collectivism with relationship commitment, passion, and mate preferences: opposing roles of parental influence and family allocentrism.

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    Kathrine Bejanyan

    Full Text Available In collectivist cultures, families tend to be characterized by respect for parental authority and strong, interdependent ties. Do these aspects of collectivism exert countervailing pressures on mate choices and relationship quality? In the present research, we found that collectivism was associated with greater acceptance of parental influence over mate choice, thereby driving relationship commitment down (Studies 1 and 2, but collectivism was also associated with stronger family ties (referred to as family allocentrism, which drove commitment up (Study 2. Along similar lines, Study 1 found that collectivists' greater acceptance of parental influence on mate choice contributed to their reduced relationship passion, whereas Study 2 found that their greater family allocentrism may have enhanced their passion. Study 2 also revealed that collectivists may have reported a smaller discrepancy between their own preferences for mates high in warmth and trustworthiness and their perception of their parents' preferences for these qualities because of their stronger family allocentrism. However, their higher tolerance of parental influence may have also contributed to a smaller discrepancy in their mate preferences versus their perceptions of their parents' preferences for qualities signifying status and resources. Implications for the roles of collectivism, parental influence, and family allocentrism in relationship quality and mate selection will be discussed.

  9. Associations of collectivism with relationship commitment, passion, and mate preferences: opposing roles of parental influence and family allocentrism.

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    Bejanyan, Kathrine; Marshall, Tara C; Ferenczi, Nelli

    2015-01-01

    In collectivist cultures, families tend to be characterized by respect for parental authority and strong, interdependent ties. Do these aspects of collectivism exert countervailing pressures on mate choices and relationship quality? In the present research, we found that collectivism was associated with greater acceptance of parental influence over mate choice, thereby driving relationship commitment down (Studies 1 and 2), but collectivism was also associated with stronger family ties (referred to as family allocentrism), which drove commitment up (Study 2). Along similar lines, Study 1 found that collectivists' greater acceptance of parental influence on mate choice contributed to their reduced relationship passion, whereas Study 2 found that their greater family allocentrism may have enhanced their passion. Study 2 also revealed that collectivists may have reported a smaller discrepancy between their own preferences for mates high in warmth and trustworthiness and their perception of their parents' preferences for these qualities because of their stronger family allocentrism. However, their higher tolerance of parental influence may have also contributed to a smaller discrepancy in their mate preferences versus their perceptions of their parents' preferences for qualities signifying status and resources. Implications for the roles of collectivism, parental influence, and family allocentrism in relationship quality and mate selection will be discussed.

  10. Opposing roles of the nucleus accumbens and anterior lateral hypothalamic area in the control of sexual behaviour in the male rat.

    Science.gov (United States)

    Kippin, Tod E; Sotiropoulos, Veneta; Badih, Julia; Pfaus, James G

    2004-02-01

    Opposing roles have been implicated for the nucleus accumbens (NAc) and anterior portion of the lateral hypothalamic area (aLHA) in the regulation of sexual behaviour in male rats based on in vivo neurochemical correlates. The present study provides functional evidence supporting this hypothesis by examining the effects of lesions to these structures on copulation, noncontact erection and receptive female preference. Sexually naïve male Long-Evans rats received either bilateral 1.0- micro L injections of NMDA (10 micro g/ micro L/side) or vehicle (shams) into either the aLHA or the NAc. During repeated tests of copulation most of the sham-lesioned males, but few of the aLHA-lesioned and NAc-lesioned males, copulated to ejaculation. Most of the NAc-lesioned males also failed to intromit, whereas the majority of the aLHA-lesioned males intromitted repeatedly. During exposure to an inaccessible receptive female behind a wire-mesh screen, aLHA-lesioned males displayed facilitation of noncontact erections, whereas NAc-lesioned males displayed impaired noncontact erections. Conversely, during simultaneous exposure to inaccessible receptive and nonreceptive females in different compartments, all males spent more time in the proximity of the receptive female. These findings indicate that the aLHA plays an inhibitory role in the regulation of sexual arousal and an excitatory role in the regulation of ejaculation. Conversely, the NAc plays an excitatory role in the regulation in sexual arousal.

  11. Opposing roles of PKA and EPAC in the cAMP-dependent regulation of schwann cell proliferation and differentiation [corrected].

    Directory of Open Access Journals (Sweden)

    Ketty Bacallao

    Full Text Available In Schwann cells (SCs, cyclic adenosine monophosphate (cAMP not only induces differentiation into a myelinating SC-related phenotype, but also synergistically enhances the mitogenic action of growth factors such as neuregulin. To better understand the molecular mechanism by which cAMP exerts these apparently contradictory functions, we investigated the role of the two main effectors of cAMP, protein kinase A (PKA and the exchange protein activated by cAMP (EPAC, on the proliferation and differentiation of both isolated and axon-related SCs. For these studies, a variety of PKA and EPAC agonists and antagonists were used, including pathway-selective analogs of cAMP and pharmacological inhibitors. Our studies indicated that the activity of PKA rather than EPAC was required for the adjuvant effect of cAMP on S-phase entry, whereas the activity of EPAC rather than PKA was required for SC differentiation and myelin formation. Even though selective EPAC activation had an overall anti-proliferative effect in SCs, it failed to drive the expression of Krox-20, a master regulator of myelination, and that of myelin-specific proteins and lipids, suggesting that EPAC activation was insufficient to drive a full differentiating response. Interestingly, inhibition of EPAC activity resulted in a drastic impairment of SC differentiation and myelin formation but not Krox-20 expression, which indicates an independent mechanism of Krox-20 regulation in response to cAMP. In conclusion, our data supports the idea that the outcome of cAMP signaling in SCs depends on the particular set of effectors activated. Whereas the mitogenic action of cAMP relies exclusively on PKA activity, the differentiating action of cAMP requires a PKA-independent (non-canonical cAMP-specific pathway that is partially transduced by EPAC.

  12. Opposing roles of PKA and EPAC in the cAMP-dependent regulation of schwann cell proliferation and differentiation [corrected].

    Science.gov (United States)

    Bacallao, Ketty; Monje, Paula V

    2013-01-01

    In Schwann cells (SCs), cyclic adenosine monophosphate (cAMP) not only induces differentiation into a myelinating SC-related phenotype, but also synergistically enhances the mitogenic action of growth factors such as neuregulin. To better understand the molecular mechanism by which cAMP exerts these apparently contradictory functions, we investigated the role of the two main effectors of cAMP, protein kinase A (PKA) and the exchange protein activated by cAMP (EPAC), on the proliferation and differentiation of both isolated and axon-related SCs. For these studies, a variety of PKA and EPAC agonists and antagonists were used, including pathway-selective analogs of cAMP and pharmacological inhibitors. Our studies indicated that the activity of PKA rather than EPAC was required for the adjuvant effect of cAMP on S-phase entry, whereas the activity of EPAC rather than PKA was required for SC differentiation and myelin formation. Even though selective EPAC activation had an overall anti-proliferative effect in SCs, it failed to drive the expression of Krox-20, a master regulator of myelination, and that of myelin-specific proteins and lipids, suggesting that EPAC activation was insufficient to drive a full differentiating response. Interestingly, inhibition of EPAC activity resulted in a drastic impairment of SC differentiation and myelin formation but not Krox-20 expression, which indicates an independent mechanism of Krox-20 regulation in response to cAMP. In conclusion, our data supports the idea that the outcome of cAMP signaling in SCs depends on the particular set of effectors activated. Whereas the mitogenic action of cAMP relies exclusively on PKA activity, the differentiating action of cAMP requires a PKA-independent (non-canonical) cAMP-specific pathway that is partially transduced by EPAC.

  13. Opposing roles of membrane and soluble forms of the receptor for advanced glycation end products in primary respiratory syncytial virus infection.

    Science.gov (United States)

    Miller, Allison L; Sims, Gary P; Brewah, Yambasu A; Rebelatto, Marlon C; Kearley, Jennifer; Benjamin, Ebony; Keller, Ashley E; Brohawn, Philip; Herbst, Ronald; Coyle, Anthony J; Humbles, Alison A; Kolbeck, Roland

    2012-04-15

    Respiratory syncytial virus (RSV), a common respiratory pathogen in infants and the older population, causes pulmonary inflammation and airway occlusion that leads to impairment of lung function. Here, we have established a role for receptor for advanced glycation end products (RAGE) in RSV infection. RAGE-deficient (ager(-/-)) mice were protected from RSV-induced weight loss and inflammation. This protection correlated with an early increase in type I interferons, later decreases in proinflammatory cytokines, and a reduction in viral load. To assess the contribution of soluble RAGE (sRAGE) to RSV-induced disease, wild-type and ager(-/-) mice were given doses of sRAGE following RSV infection. Of interest, sRAGE treatment prevented RSV-induced weight loss and neutrophilic inflammation to a degree similar to that observed in ager(-/-) mice. Our work further elucidates the roles of RAGE in the pathogenesis of respiratory infections and highlights the opposing roles of membrane and sRAGE in modulating the host response to RSV infection.

  14. The role of regulatory T cells in cancer immunology

    Directory of Open Access Journals (Sweden)

    Whiteside TL

    2015-08-01

    Full Text Available Theresa L Whiteside University of Pittsburgh Cancer Institute, Pittsburgh, PA, US Abstract: Regulatory T cells (Treg are generally considered to be significant contributors to tumor escape from the host immune system. Emerging evidence suggests, however, that in some human cancers, Treg are necessary to control chronic inflammation, prevent tissue damage, and limit inflammation-associated cancer development. The dual role of Treg in cancer and underpinnings of Treg diversity are not well understood. This review attempts to provide insights into the importance of Treg subsets in cancer development and its progression. It also considers the role of Treg as potential biomarkers of clinical outcome in cancer. The strategies for monitoring Treg in cancer patients are discussed as is the need for caution in the use of therapies which indiscriminately ablate Treg. A greater understanding of molecular pathways operating in various tumor microenvironments is necessary for defining the Treg impact on cancer and for selecting immunotherapies targeting Treg. Keywords: cancer, regulatory T cells, tumor microenvironment, immune suppression, anti-Treg therapies

  15. Physiological regulatory networks: ecological roles and evolutionary constraints.

    Science.gov (United States)

    Cohen, Alan A; Martin, Lynn B; Wingfield, John C; McWilliams, Scott R; Dunne, Jennifer A

    2012-08-01

    Ecological and evolutionary physiology has traditionally focused on one aspect of physiology at a time. Here, we discuss the implications of considering physiological regulatory networks (PRNs) as integrated wholes, a perspective that reveals novel roles for physiology in organismal ecology and evolution. For example, evolutionary response to changes in resource abundance might be constrained by the role of dietary micronutrients in immune response regulation, given a particular pathogen environment. Because many physiological components impact more than one process, organismal homeostasis is maintained, individual fitness is determined and evolutionary change is constrained (or facilitated) by interactions within PRNs. We discuss how PRN structure and its system-level properties could determine both individual performance and patterns of physiological evolution.

  16. The role of regulatory T cells in cancer immunology.

    Science.gov (United States)

    Whiteside, Theresa L

    2015-01-01

    Regulatory T cells (Treg) are generally considered to be significant contributors to tumor escape from the host immune system. Emerging evidence suggests, however, that in some human cancers, Treg are necessary to control chronic inflammation, prevent tissue damage, and limit inflammation-associated cancer development. The dual role of Treg in cancer and underpinnings of Treg diversity are not well understood. This review attempts to provide insights into the importance of Treg subsets in cancer development and its progression. It also considers the role of Treg as potential biomarkers of clinical outcome in cancer. The strategies for monitoring Treg in cancer patients are discussed as is the need for caution in the use of therapies which indiscriminately ablate Treg. A greater understanding of molecular pathways operating in various tumor microenvironments is necessary for defining the Treg impact on cancer and for selecting immunotherapies targeting Treg.

  17. Discrimination. Opposing Viewpoints Series.

    Science.gov (United States)

    Williams, Mary E., Ed.

    Books in the Opposing Viewpoints series challenge readers to question their own opinions and assumptions. By reading carefully balanced views, readers confront new ideas on the topic of interest. The Civil Rights Act of 1964, which prohibited job discrimination based on age, race, religion, gender, or national origin, provided the groundwork for…

  18. Opposing roles of TGF-β and EGF in the regulation of TRAIL-induced apoptosis in human breast epithelial cells.

    Science.gov (United States)

    Cano-González, Ana; López-Rivas, Abelardo

    2016-08-01

    Transforming growth factor-beta (TGF-β) induces the epithelial to mesenchymal transition (EMT) in breast epithelial cells and plays an important role in mammary morphogenesis and breast cancer. In non-transformed breast epithelial cells TGF-β antagonizes epidermal growth factor (EGF) action and induces growth inhibition. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to participate in lumen formation during morphogenesis of human breast epithelial cells. Our previous work indicated that sensitivity of human breast epithelial cells to TRAIL can be modulated through the activation of the epidermal growth factor receptor-1 (EGFR). Here, we show that TGF-β opposes EGF-mediated sensitization to TRAIL-induced caspase-8 activation and apoptosis in non-transformed breast epithelial cells. Death-inducing signalling complex (DISC) formation by TRAIL was significantly reduced in cells treated with TGF-β. TGF-β treatment activates cytoprotective autophagy and down-regulates TRAIL-R2 expression at the cell surface by promoting the intracellular accumulation of this receptor. Lastly, we demonstrate that EMT is not involved in the inhibitory effect of TGF-β on apoptosis by TRAIL. Together, the data reveal a fine regulation by EGF and TGF-β of sensitivity of human breast epithelial cells to TRAIL which may be relevant during morphogenesis.

  19. Opposing incentives for collaboration

    DEFF Research Database (Denmark)

    Dorch, Bertil F.; Wien, Charlotte; Larsen, Asger Væring

    The Danish Bibliometric Research Indicator (BFI) is part of the performance-based model for the distribution of a special pool of baseline funding for universities and public research institutions in Denmark. BFI rewards the research publications published in the most recognized scientific journals...... collaboration is associated with a higher number of citations than single authorship which may present the author with two opposing incentives for research collaboration....

  20. Opposing roles of p38 and JNK in a Drosophila model of TDP-43 proteinopathy reveal oxidative stress and innate immunity as pathogenic components of neurodegeneration

    Science.gov (United States)

    Zhan, Lihong; Xie, Qijing; Tibbetts, Randal S.

    2015-01-01

    Pathological aggregation and mutation of the 43-kDa TAR DNA-binding protein (TDP-43) are strongly implicated in the pathogenesis amyotrophic lateral sclerosis and frontotemporal lobar degeneration. TDP-43 neurotoxicity has been extensively modeled in mice, zebrafish, Caenorhabditis elegans and Drosophila, where selective expression of TDP-43 in motoneurons led to paralysis and premature lethality. Through a genetic screen aimed to identify genetic modifiers of TDP-43, we found that the Drosophila dual leucine kinase Wallenda (Wnd) and its downstream kinases JNK and p38 influenced TDP-43 neurotoxicity. Reducing Wnd gene dosage or overexpressing its antagonist highwire partially rescued TDP-43-associated premature lethality. Downstream of Wnd, the JNK and p38 kinases played opposing roles in TDP-43-associated neurodegeneration. LOF alleles of the p38b gene as well as p38 inhibitors diminished TDP-43-associated premature lethality, whereas p38b GOF caused phenotypic worsening. In stark contrast, disruptive alleles of Basket (Bsk), the Drosophila homologue of JNK, exacerbated longevity shortening, whereas overexpression of Bsk extended lifespan. Among possible mechanisms, we found motoneuron-directed expression of TDP-43 elicited oxidative stress and innate immune gene activation that were exacerbated by p38 GOF and Bsk LOF, respectively. A key pathologic role for innate immunity in TDP-43-associated neurodegeneration was further supported by the finding that genetic suppression of the Toll/Dif and Imd/Relish inflammatory pathways dramatically extended lifespan of TDP-43 transgenic flies. We propose that oxidative stress and neuroinflammation are intrinsic components of TDP-43-associated neurodegeneration and that the balance between cytoprotective JNK and cytotoxic p38 signaling dictates phenotypic outcome to TDP-43 expression in Drosophila. PMID:25281658

  1. Institutions, regulatory role and economic growth of national economies

    Directory of Open Access Journals (Sweden)

    Mladen Vedriš

    2008-12-01

    Full Text Available In the present time, characterized by the rapid disturbances in all time more connected global economy, territorially as well as structurally, the role of the state’s influence and responsibility with the adequate institutional addresses and procedures, defined in larger context, becomes the essential point not only of the further growth but also of the existing relations viability. It is simply because the encirclement does not function on the principle of status quo situation any more. Therefore, the role and significance of institutions, adequate regulatory role of these addresses, in the context of demand of permanent and stable economic growth, are of particular interest in the creation of this model. This analysis gains in importance studying the realized accelerated economic growth of states from some parts of the world, notably in the period after WW II. This question turned out to be exceptionally essential during the analysis of national strategies of accelerated economic growth (catch up strategy. On the other side of analysis are the transition period and the processes realized on the territory of the East and Central European states up to 1990 that were under the strong influence of the USSR. The attempts and mistakes in the quest for adequate balance of the market role were initially indoctrinated and led by the predominant conviction that the principles of Washington consensus will lead up to accelerated and efficient change of the entire structure of national economies and new frames for future behaviour. The problems that appeared very soon led to the establishment of significantly more balanced first the understanding and then to establishing significantly, more appropriate concept of balance and complementarity of market development with the permanently present role and responsibility of the state in this process and on this road.

  2. The role of cis regulatory evolution in maize domestication.

    Science.gov (United States)

    Lemmon, Zachary H; Bukowski, Robert; Sun, Qi; Doebley, John F

    2014-11-01

    Gene expression differences between divergent lineages caused by modification of cis regulatory elements are thought to be important in evolution. We assayed genome-wide cis and trans regulatory differences between maize and its wild progenitor, teosinte, using deep RNA sequencing in F1 hybrid and parent inbred lines for three tissue types (ear, leaf and stem). Pervasive regulatory variation was observed with approximately 70% of ∼17,000 genes showing evidence of regulatory divergence between maize and teosinte. However, many fewer genes (1,079 genes) show consistent cis differences with all sampled maize and teosinte lines. For ∼70% of these 1,079 genes, the cis differences are specific to a single tissue. The number of genes with cis regulatory differences is greatest for ear tissue, which underwent a drastic transformation in form during domestication. As expected from the domestication bottleneck, maize possesses less cis regulatory variation than teosinte with this deficit greatest for genes showing maize-teosinte cis regulatory divergence, suggesting selection on cis regulatory differences during domestication. Consistent with selection on cis regulatory elements, genes with cis effects correlated strongly with genes under positive selection during maize domestication and improvement, while genes with trans regulatory effects did not. We observed a directional bias such that genes with cis differences showed higher expression of the maize allele more often than the teosinte allele, suggesting domestication favored up-regulation of gene expression. Finally, this work documents the cis and trans regulatory changes between maize and teosinte in over 17,000 genes for three tissues.

  3. The Role of cis Regulatory Evolution in Maize Domestication

    Science.gov (United States)

    Lemmon, Zachary H.; Bukowski, Robert; Sun, Qi; Doebley, John F.

    2014-01-01

    Gene expression differences between divergent lineages caused by modification of cis regulatory elements are thought to be important in evolution. We assayed genome-wide cis and trans regulatory differences between maize and its wild progenitor, teosinte, using deep RNA sequencing in F1 hybrid and parent inbred lines for three tissue types (ear, leaf and stem). Pervasive regulatory variation was observed with approximately 70% of ∼17,000 genes showing evidence of regulatory divergence between maize and teosinte. However, many fewer genes (1,079 genes) show consistent cis differences with all sampled maize and teosinte lines. For ∼70% of these 1,079 genes, the cis differences are specific to a single tissue. The number of genes with cis regulatory differences is greatest for ear tissue, which underwent a drastic transformation in form during domestication. As expected from the domestication bottleneck, maize possesses less cis regulatory variation than teosinte with this deficit greatest for genes showing maize-teosinte cis regulatory divergence, suggesting selection on cis regulatory differences during domestication. Consistent with selection on cis regulatory elements, genes with cis effects correlated strongly with genes under positive selection during maize domestication and improvement, while genes with trans regulatory effects did not. We observed a directional bias such that genes with cis differences showed higher expression of the maize allele more often than the teosinte allele, suggesting domestication favored up-regulation of gene expression. Finally, this work documents the cis and trans regulatory changes between maize and teosinte in over 17,000 genes for three tissues. PMID:25375861

  4. The role of cis regulatory evolution in maize domestication.

    Directory of Open Access Journals (Sweden)

    Zachary H Lemmon

    2014-11-01

    Full Text Available Gene expression differences between divergent lineages caused by modification of cis regulatory elements are thought to be important in evolution. We assayed genome-wide cis and trans regulatory differences between maize and its wild progenitor, teosinte, using deep RNA sequencing in F1 hybrid and parent inbred lines for three tissue types (ear, leaf and stem. Pervasive regulatory variation was observed with approximately 70% of ∼17,000 genes showing evidence of regulatory divergence between maize and teosinte. However, many fewer genes (1,079 genes show consistent cis differences with all sampled maize and teosinte lines. For ∼70% of these 1,079 genes, the cis differences are specific to a single tissue. The number of genes with cis regulatory differences is greatest for ear tissue, which underwent a drastic transformation in form during domestication. As expected from the domestication bottleneck, maize possesses less cis regulatory variation than teosinte with this deficit greatest for genes showing maize-teosinte cis regulatory divergence, suggesting selection on cis regulatory differences during domestication. Consistent with selection on cis regulatory elements, genes with cis effects correlated strongly with genes under positive selection during maize domestication and improvement, while genes with trans regulatory effects did not. We observed a directional bias such that genes with cis differences showed higher expression of the maize allele more often than the teosinte allele, suggesting domestication favored up-regulation of gene expression. Finally, this work documents the cis and trans regulatory changes between maize and teosinte in over 17,000 genes for three tissues.

  5. The role of cis regulatory evolution in maize domestication.

    Directory of Open Access Journals (Sweden)

    Zachary H Lemmon

    2014-11-01

    Full Text Available Gene expression differences between divergent lineages caused by modification of cis regulatory elements are thought to be important in evolution. We assayed genome-wide cis and trans regulatory differences between maize and its wild progenitor, teosinte, using deep RNA sequencing in F1 hybrid and parent inbred lines for three tissue types (ear, leaf and stem. Pervasive regulatory variation was observed with approximately 70% of ∼17,000 genes showing evidence of regulatory divergence between maize and teosinte. However, many fewer genes (1,079 genes show consistent cis differences with all sampled maize and teosinte lines. For ∼70% of these 1,079 genes, the cis differences are specific to a single tissue. The number of genes with cis regulatory differences is greatest for ear tissue, which underwent a drastic transformation in form during domestication. As expected from the domestication bottleneck, maize possesses less cis regulatory variation than teosinte with this deficit greatest for genes showing maize-teosinte cis regulatory divergence, suggesting selection on cis regulatory differences during domestication. Consistent with selection on cis regulatory elements, genes with cis effects correlated strongly with genes under positive selection during maize domestication and improvement, while genes with trans regulatory effects did not. We observed a directional bias such that genes with cis differences showed higher expression of the maize allele more often than the teosinte allele, suggesting domestication favored up-regulation of gene expression. Finally, this work documents the cis and trans regulatory changes between maize and teosinte in over 17,000 genes for three tissues.

  6. Regulatory roles of microRNAs in human dental tissues.

    Science.gov (United States)

    Sehic, Amer; Tulek, Amela; Khuu, Cuong; Nirvani, Minou; Sand, Lars Peter; Utheim, Tor Paaske

    2017-01-05

    MicroRNAs (miRNAs) are a class of small, non-coding RNAs that provide an efficient pathway for regulation of gene expression at a post-transcriptional level. Tooth development is regulated by a complex network of cell-cell signaling during all steps of organogenesis. Most of the congenital dental defects in humans are caused by mutations in genes involved in developmental regulatory networks. Whereas the developmental morphological stages of the tooth development already are thoroughly documented, the implicated genetic network is still under investigation. The involvement of miRNAs in the regulation of tooth genetic network was suggested for the first time in 2008. MiRNAs regulate tooth morphogenesis by fine-tuning the signaling networks. Unique groups of miRNAs are expressed in dental epithelium compared with mesenchyme, as well as in molars compared with incisors. The present review focuses on the current state of knowledge on the expression and function of miRNAs in human dental tissues, including teeth and the surrounding structures. Herein, we show that miRNAs exhibit specific roles in human dental tissues and are involved in gingival and periodontal disease, tooth movement and eruption, dental pulp physiology including repair and regeneration, differentiation of dental cells, and enamel mineralization. In light of similarities between the tooth development and other organs originating from the epithelium, further understanding of miRNAs` function in dental tissues may have wide biological relevance. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Role of Regulatory Peptide in Pathogenesis of Shock

    Institute of Scientific and Technical Information of China (English)

    董林旺; 常英姿; 佟利家; 汤健; 苏静怡; 唐朝枢

    1994-01-01

    The present study evaluated the pathogenetic roles of three kinds of regulatory peptide. The results showed that (i) plasma endothelin(ET) level elevated significantly in septic shock rats, persistent intravenous drip of low doses ET caused development of shock state in normal rats and the irreversible outcome of light hemorrhagic shock. Furthermore, i. v. administration of specific ET-antiserum was significantly effective to septic shock rats, (Ⅱ) Plasma calcitonin gene-related peptide (CGRP) increased by 260% in septic shock rats, i. v. drip of low doses CGRP both in early and late sepsis were effective to shock rats, (Ⅱi) An-giotensin-Ⅱ (ANG-Ⅱ) contents of heart and aorta increased dramatically both in early and late septic shock, and inhibiting its increase with Captopril in late sepsis significantly improved the shock state, but results were inverse in early sepsis. It could be concluded that ET was one of the most important factors participating in the pathogenesis of shock, CGRP had a compens

  8. Evolutionary dynamics and functional roles of regulatory systems in plants

    NARCIS (Netherlands)

    Berke, L.

    2015-01-01

    Transcription, the process of generating RNA copies of the genetic information stored in the DNA, is crucial for every organism. As with other essential processes in life, correct activation and repression of transcription is governed by complex regulatory mechanisms. These regulatory mechanisms ope

  9. Decoding the role of regulatory element polymorphisms in complex disease.

    Science.gov (United States)

    Vockley, Christopher M; Barrera, Alejandro; Reddy, Timothy E

    2017-04-01

    Genetic variation in gene regulatory elements contributes to diverse human diseases, ranging from rare and severe developmental defects to common and complex diseases such as obesity and diabetes. Early examples of regulatory mechanisms of human diseases involve large chromosomal rearrangements that change the regulatory connections within the genome. Single nucleotide variants in regulatory elements can also contribute to disease, potentially via demonstrated associations with changes in transcription factor binding, enhancer activity, post-translational histone modifications, long-range enhancer-promoter interactions, or RNA polymerase recruitment. Establishing causality between non-coding genetic variants, gene regulation, and disease has recently become more feasible with advances in genome-editing and epigenome-editing technologies. As establishing causal regulatory mechanisms of diseases becomes routine, functional annotation of target genes is likely to emerge as a major bottleneck for translation into patient benefits. In this review, we discuss the history and recent advances in understanding the regulatory mechanisms of human disease, and new challenges likely to be encountered once establishing those mechanisms becomes rote. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Adolescent threat-related interpretive bias and its modification: the moderating role of regulatory control

    NARCIS (Netherlands)

    Salemink, E.; Wiers, R.W.

    2012-01-01

    Dual process models describe psychopathology as the consequence of an imbalance between a fast, impulsive system and a regulatory control system and have recently been applied to anxiety disorders. The aim of the current study was to specifically examine the role of a regulatory control system in re

  11. Sales Growth of New Pharmaceuticals Across the Globe: The Role of Regulatory Regimes

    NARCIS (Netherlands)

    S. Stremersch (Stefan); A. Lemmens (Aurélie)

    2008-01-01

    textabstractPrior marketing literature has overlooked the role of regulatory regimes in explaining international sales growth of new products. This paper addresses this gap in the context of new pharmaceuticals (15 new molecules in 34 countries) and sheds light on the effect regulatory regimes have

  12. Sales Growth of New Pharmaceuticals Across the Globe: The Role of Regulatory Regimes

    NARCIS (Netherlands)

    S. Stremersch (Stefan); A. Lemmens (Aurélie)

    2008-01-01

    textabstractPrior marketing literature has overlooked the role of regulatory regimes in explaining international sales growth of new products. This paper addresses this gap in the context of new pharmaceuticals (15 new molecules in 34 countries) and sheds light on the effect regulatory regimes have

  13. Deciphering Fur transcriptional regulatory network highlights its complex role beyond iron metabolism in Escherichia coli

    DEFF Research Database (Denmark)

    Seo, Sang Woo; Kim, Donghyuk; Latif, Haythem;

    2014-01-01

    The ferric uptake regulator (Fur) plays a critical role in the transcriptional regulation of iron metabolism. However, the full regulatory potential of Fur remains undefined. Here we comprehensively reconstruct the Fur transcriptional regulatory network in Escherichia coli K-12 MG1655 in response...

  14. Improving managerial communication: the role of regulatory fit

    NARCIS (Netherlands)

    Fransen, M.; ter Hoeven, C.

    2011-01-01

    The experiments presented here examine how managers and executives could improve the effectiveness of their (negative) written communications by incorporating the concept of fit into their message framing. By applying regulatory focus theory, the authors suggest that outcome-based fit between the

  15. Competitive mindsets, creativity, and the role of regulatory focus

    NARCIS (Netherlands)

    Bittner, Jenny V.; Heidemeier, Heike

    2013-01-01

    We examined how regulatory focus and intentions to compete rather than cooperate with group members relate to creativity. Study 1 showed that a promotion focus (i.e., a focus on ideals) activated a cooperative mindset, whereas a prevention focus (i.e., a focus on responsibilities) activated a compet

  16. B-type suppression: a role played by "regulatory B cells" or "regulatory plasma cells"?

    Science.gov (United States)

    Ries, Stefanie; Hilgenberg, Ellen; Lampropoulou, Vicky; Shen, Ping; Dang, Van Duc; Wilantri, Siska; Sakwa, Imme; Fillatreau, Simon

    2014-05-01

    B-cell depletion can improve disease in some patients with rheumatoid arthritis or multiple sclerosis, indicating the pathogenic contribution of B cells to autoimmunity. However, studies in mice have demonstrated that B cells have immunosuppressive functions as well, with IL-10 being a critical mediator of B-cell-mediated suppression. IL-10-secreting B cells have been shown to promote disease remission in some mouse models of autoimmune disorders. Human B cells also produce IL-10, and evidence is accumulating that human IL-10-producing B cells might inhibit immunity. There is considerable interest in identifying the phenotype of B cells providing IL-10 in a suppressive manner, which would facilitate the analysis of the molecular mechanisms controlling this B-cell property. Here, we review current knowledge on the B-cell subpopulations found to provide suppressive functions in mice, considering both the pathological context in which they were identified and the signals that control their induction. We discuss the phenotype of B cells that have IL-10-dependent regulatory activities in mice, which leads us to propose that antibody-secreting cells are, in some cases at least, the major source of B-cell-derived regulatory IL-10 in vivo. Anti-inflammatory cytokine production by antibody-secreting cells offers a novel mechanism for the coordination of innate and humoral immune responses.

  17. Role of CD8+ regulatory T cells in organ transplantation

    Directory of Open Access Journals (Sweden)

    Jiyan Su

    2014-01-01

    Full Text Available CD8 + T cells are regulatory T cells (Tregs that suppress both alloimmunity and autoimmunity in many animal models. This class of regulatory cells includes the CD8 + CD28 - , CD8 + CD103 + , CD8 + FoxP3 + and CD8 + CD122 + subsets. The mechanisms of action of these regulatory cells are not fully understood; however, the secretion of immunosuppressive cytokines, such as interleukin (IL-4, IL-10 and transforming growth factor beta (TGF-β as well as the direct killing of target cells via Fas L/Fas and the perforin/granzyme B pathways have been demonstrated in various models. Further studies are necessary to fully understand the mechanisms underlying the suppressive effects of Tregs and to provide experimental support for potential clinical trials. We recently observed that CD8 + CD122 + Tregs more potently suppressed allograft rejection compared to their CD4 + CD25 + counterparts, supporting the hypothesis that CD8 + Tregs may represent a new and promising Treg family that can be targeted to prevent allograft rejection in the clinic. In this review, we summarize the progress in the field during the past 7-10 years and discuss CD8 + Treg phenotypes, mechanisms of action, and their potential clinical applications; particularly in composite tissue transplants in burn and trauma patients.

  18. DMPD: The role of the interferon regulatory factor (IRF) family in dendritic celldevelopment and function. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17702640 The role of the interferon regulatory factor (IRF) family in dendritic cel...b 2007 Aug 16. (.png) (.svg) (.html) (.csml) Show The role of the interferon regulatory factor (IRF) family ...e interferon regulatory factor (IRF) family in dendritic celldevelopment and function. Authors Gabriele L, O

  19. Adolescent threat-related interpretive bias and its modification: the moderating role of regulatory control.

    Science.gov (United States)

    Salemink, Elske; Wiers, Reinout W

    2012-01-01

    Dual process models describe psychopathology as the consequence of an imbalance between a fast, impulsive system and a regulatory control system and have recently been applied to anxiety disorders. The aim of the current study was to specifically examine the role of a regulatory control system in regulating 1) threat-related interpretive bias and 2) the effectiveness of interpretive bias training in adolescents. In total, 67 adolescents participated and followed either a positive Cognitive Bias Modification of Interpretation (CBM-I) training or a placebo-control condition. Results revealed that interpretive bias and the effectiveness of its modification depended on individual differences in regulatory control. That is, low levels of regulatory control in combination with high levels of state anxiety were associated with the strongest threat-related interpretive bias and those individuals benefited the most of the positive interpretation training. The current study provided empirical support for the role of dual processes in adolescent threat-related interpretive bias.

  20. The Role of Regulatory Agencies and Intellectual Property: Part I.

    Science.gov (United States)

    Noonan, Kevin E

    2015-03-16

    The patent and regulatory regimes of different agencies of the federal government are not always in agreement, and although the concept of the "unified executive" holds that the executive branch speaks with one voice, that is not always the case.(1) Some agencies, like the Food and Drug Administration, tend toward cooperation with government patent policies, whereas others, notably the Federal Trade Commission, are often at odds with the Patent Office, the patent system, or both. These skirmishes, when they arise, eventually come before federal courts and ultimately the Supreme Court, where balancing the differing policy objectives, as well as the will of Congress as embodied in its statutes, is subject to the vagaries of the politics of how the issues are framed by the courts, and the judges' and justices' own predilections and prejudices. Examples of these situations were prevalent in 2013 and the circumstances surrounding them illustrative of the tensions inherent between the various federal agencies.

  1. The role of master regulators in gene regulatory networks

    Directory of Open Access Journals (Sweden)

    Enrique Hernández Lemus

    2015-05-01

    Full Text Available Gene regulatory networks present a wide variety of dynamical responses to intrinsic and extrinsic perturbations. Arguably, one of the most important of such coordinated responses is the one of amplification cascades, in which activation of a few key-responsive transcription factors (termed master regulators, MRs lead to a large series of transcriptional activation events. This is so since master regulators are transcription factors controlling the expression of other transcription factor molecules and so on. MRs hold a central position related to transcriptional dynamics and control of gene regulatory networks and are often involved in complex feedback and feedforward loops inducing non-trivial dynamics. Recent studies have pointed out to the myocyte enhancing factor 2C (MEF2C, also known as MADS box transcription enhancer factor 2, polypeptide C as being one of such master regulators involved in the pathogenesis of primary breast cancer. In this work, we perform an integrative genomic analysis of the transcriptional regulation activity of MEF2C and its target genes to evaluate to what extent are these molecules inducing collective responses leading to gene expression deregulation and carcinogenesis. We also analyzed a number of induced dynamic responses, in particular those associated with transcriptional bursts, and nonlinear cascading to evaluate the influence they may have in malignant phenotypes and cancer. Received: 20 Novembre 2014, Accepted: 24 June 2015; Edited by: C. A. Condat, G. J. Sibona; DOI: http://dx.doi.org/10.4279/PIP.070011 Cite as: E Hernández-Lemus, K Baca-López, R Lemus, R García-Herrera, Papers in Physics 7, 070011 (2015

  2. Inferring the role of transcription factors in regulatory networks

    Directory of Open Access Journals (Sweden)

    Le Borgne Michel

    2008-05-01

    Full Text Available Abstract Background Expression profiles obtained from multiple perturbation experiments are increasingly used to reconstruct transcriptional regulatory networks, from well studied, simple organisms up to higher eukaryotes. Admittedly, a key ingredient in developing a reconstruction method is its ability to integrate heterogeneous sources of information, as well as to comply with practical observability issues: measurements can be scarce or noisy. In this work, we show how to combine a network of genetic regulations with a set of expression profiles, in order to infer the functional effect of the regulations, as inducer or repressor. Our approach is based on a consistency rule between a network and the signs of variation given by expression arrays. Results We evaluate our approach in several settings of increasing complexity. First, we generate artificial expression data on a transcriptional network of E. coli extracted from the literature (1529 nodes and 3802 edges, and we estimate that 30% of the regulations can be annotated with about 30 profiles. We additionally prove that at most 40.8% of the network can be inferred using our approach. Second, we use this network in order to validate the predictions obtained with a compendium of real expression profiles. We describe a filtering algorithm that generates particularly reliable predictions. Finally, we apply our inference approach to S. cerevisiae transcriptional network (2419 nodes and 4344 interactions, by combining ChIP-chip data and 15 expression profiles. We are able to detect and isolate inconsistencies between the expression profiles and a significant portion of the model (15% of all the interactions. In addition, we report predictions for 14.5% of all interactions. Conclusion Our approach does not require accurate expression levels nor times series. Nevertheless, we show on both data, real and artificial, that a relatively small number of perturbation experiments are enough to determine

  3. Regulatory Role of Small Nucleolar RNAs in Human Diseases

    Directory of Open Access Journals (Sweden)

    Grigory A. Stepanov

    2015-01-01

    Full Text Available Small nucleolar RNAs (snoRNAs are appreciable players in gene expression regulation in human cells. The canonical function of box C/D and box H/ACA snoRNAs is posttranscriptional modification of ribosomal RNAs (rRNAs, namely, 2′-O-methylation and pseudouridylation, respectively. A series of independent studies demonstrated that snoRNAs, as well as other noncoding RNAs, serve as the source of various short regulatory RNAs. Some snoRNAs and their fragments can also participate in the regulation of alternative splicing and posttranscriptional modification of mRNA. Alterations in snoRNA expression in human cells can affect numerous vital cellular processes. SnoRNA level in human cells, blood serum, and plasma presents a promising target for diagnostics and treatment of human pathologies. Here we discuss the relation between snoRNAs and oncological, neurodegenerative, and viral diseases and also describe changes in snoRNA level in response to artificial stress and some drugs.

  4. Europe's regulatory role in post-crisis global finance

    NARCIS (Netherlands)

    Mügge, D.

    2014-01-01

    Before the crisis, the European Union (EU) had emerged as a major force in global financial governance (GFG). The contributions to this collection examine the different dimensions of the EU's role in GFG and how they have been affected by the recent crisis. Taking a bird's eye view, this introductio

  5. Unexpected Regulatory Role of CCR9 in Regulatory T Cell Development.

    Directory of Open Access Journals (Sweden)

    Heather L Evans-Marin

    Full Text Available T cells reactive to microbiota regulate the pathogenesis of inflammatory bowel disease (IBD. As T cell trafficking to intestines is regulated through interactions between highly specific chemokine-chemokine receptors, efforts have been made to develop intestine-specific immunosuppression based on blocking these key processes. CCR9, a gut-trophic chemokine receptor expressed by lymphocytes and dendritic cells, has been implicated in the regulation of IBD through mediating recruitment of T cells to inflamed sites. However, the role of CCR9 in inducing and sustaining inflammation in the context of IBD is poorly understood. In this study, we demonstrate that CCR9 deficiency in effector T cells and Tregs does not affect the development of colitis in a microbiota antigen-specific, T cell-mediated model. However, Treg cells express higher levels of CCR9 compared to those in effector T cells. Interestingly, CCR9 inhibits Treg cell development, in that CCR9-/- mice demonstrate a high level of Foxp3+ Tregs, and ligation of CCR9 by its ligand CCL25 inhibits Treg cell differentiation in vitro. Collectively, our data indicate that in addition to acting as a gut-homing molecule, CCR9 signaling shapes immune responses by inhibiting Treg cell development.

  6. Role of Regulatory Immune Responses in the Pathogenesis of Schistosomiasis

    Science.gov (United States)

    2008-07-15

    167. Yang, Z., Day, Y.J., Toufektsian, M.C., Xu, Y., Ramos, S.I., Marshall, M.A., French, B.A., and Linden, J. (2006). Myocardial infarct -sparing...O.OOl 3000 P =0.001 P=O.Ol D P=O,OOl P=O.OOl E 蓐 P = om ., g 0 ~ ~ 50 Chapter 2 Role of primed schistosome-specific CD4 + T cells on the growth and

  7. Characterization of the opposing roles of H-NS and TraJ in transcriptional regulation of the F-plasmid tra operon.

    Science.gov (United States)

    Will, William R; Frost, Laura S

    2006-01-01

    The transfer (tra) operon of the conjugative F plasmid of Escherichia coli is a polycistronic 33-kb operon which encodes most of the proteins necessary for F-plasmid transfer. Here, we report that transcription from PY, the tra operon promoter, is repressed by the host nucleoid-associated protein, H-NS. Electrophoretic mobility shift assays indicate that H-NS binds preferentially to the tra promoter region, while Northern blot and transcriptional fusion analyses indicate that transcription of traY, the first gene in the tra operon, is derepressed in an hns mutant throughout growth. The plasmid-encoded regulatory protein TraJ is essential for transcription of the tra operon in wild-type Escherichia coli; however, TraJ is not necessary for plasmid transfer or traY operon transcription in an hns mutant. This indicates that H-NS represses transcription from PY directly and not indirectly via its effects on TraJ levels. These results suggest that TraJ functions to disrupt H-NS silencing at PY, allowing transcription of the tra operon.

  8. Cholesterol: a novel regulatory role in myelin formation.

    Science.gov (United States)

    Saher, Gesine; Quintes, Susanne; Nave, Klaus-Armin

    2011-02-01

    Myelin consists of tightly compacted membranes that form an insulating sheath around axons. The function of myelin for rapid saltatory nerve conduction is dependent on its unique composition, highly enriched in glycosphingolipids and cholesterol. Cholesterol emerged as the only integral myelin component that is essential and rate limiting for the development of CNS and PNS myelin. Experiments with conditional mouse mutants that lack cholesterol biosynthesis in oligodendrocytes revealed that only minimal changes of the CNS myelin lipid composition are tolerated. In Schwann cells of the PNS, protein trafficking and myelin compaction depend on cholesterol. In this review, the authors summarize the role of cholesterol in myelin biogenesis and myelin disease.

  9. Opposing roles for CD34 in B16 melanoma tumor growth alter early stage vasculature and late stage immune cell infiltration.

    Directory of Open Access Journals (Sweden)

    Steven Maltby

    Full Text Available Tumor growth and metastasis are determined by the complex interplay of factors, including those intrinsic to tumor cells and extrinsic factors associated with the tumor microenvironment. Our previous work demonstrated key roles for CD34 in the maintenance of vascular integrity and eosinophil and mast cell homing. Since both of these functions affect tumor development, we characterized the effect of CD34 ablation on tumor growth using the B16F1 melanoma model. Intriguingly, we found that CD34 plays a biphasic role in tumor progression. In early growth, both subcutaneous-injected tumors and intravenous-injected lung metastases grew more slowly in Cd34(-/- mice. This correlated with abnormal vessel morphology and increased vascular permeability in these mice. Bone marrow transplantation experiments confirmed that this reflects a non-hematopoietic function of CD34. At later stages, subcutaneous tumor growth was accelerated in Cd34(-/- mice and surpassed growth in wildtype mice. Bone marrow chimera experiments demonstrated this difference was due to a hematopoietic function for CD34 and, correspondingly we found reduced intra-tumor mast cell numbers in Cd34(-/- mice. In aggregate, our analysis reveals a novel role for CD34 in both early and late tumor growth and provides novel insights into the role of the tumor microenvironment in tumor progression.

  10. Opposing roles of C/EBPbeta and AP-1 in the control of fibroblast proliferation and growth arrest-specific gene expression

    DEFF Research Database (Denmark)

    Gagliardi, Mark; Maynard, Scott; Miyake, Tetsuaki

    2003-01-01

    Chicken embryo fibroblasts (CEF) express several growth arrest-specific (GAS) gene products in G0. In contact-inhibited cells, the expression of the most abundant of these proteins, the p20K lipocalin, is activated at the transcriptional level by C/EBPbeta. In this report, we describe the role of...

  11. Illegal Immigration. Opposing Viewpoints Series.

    Science.gov (United States)

    Cozic, Charles P., Ed.

    Books in the Opposing Viewpoints Series present debates about current issues that can be used to teach critical reading and thinking skills. The variety of opinions expressed in this collection of articles and book excerpts explore many aspects of illegal immigration. Contrary depictions of the aspirations and attitudes of illegal immigrants fuel…

  12. Beyond toxicity: a regulatory role for mitochondrial cyanide.

    Science.gov (United States)

    García, Irene; Gotor, Cecilia; Romero, Luis C

    2014-01-01

    In non-cyanogenic plants, cyanide is a co-product of ethylene and camalexin biosynthesis. To maintain cyanide at non-toxic levels, Arabidopsis plants express the mitochondrial β-cyanoalanine synthase CYS-C1. CYS-C1 knockout leads to an increased level of cyanide in the roots and leaves and a severe defect in root hair morphogenesis, suggesting that cyanide acts as a signaling factor in root development. During compatible and incompatible plant-bacteria interactions, cyanide accumulation and CYS-C1 gene expression are negatively correlated. Moreover, CYS-C1 mutation increases both plant tolerance to biotrophic pathogens and their susceptibility to necrotrophic fungi, indicating that cyanide could stimulate the salicylic acid-dependent signaling pathway of the plant immune system. We hypothesize that CYS-C1 is essential for maintaining non-toxic concentrations of cyanide in the mitochondria to facilitate cyanide's role in signaling.

  13. Opposing Roles of Membrane and Soluble Forms of the Receptor for Advanced Glycation End Products in Primary Respiratory Syncytial Virus Infection

    OpenAIRE

    2012-01-01

    Respiratory syncytial virus (RSV), a common respiratory pathogen in infants and the older population, causes pulmonary inflammation and airway occlusion that leads to impairment of lung function. Here, we have established a role for receptor for advanced glycation end products (RAGE) in RSV infection. RAGE-deficient (ager−/− ) mice were protected from RSV-induced weight loss and inflammation. This protection correlated with an early increase in type I interferons, later decreases in proinflam...

  14. Identification and Role of Regulatory Non-Coding RNAs in Listeria monocytogenes

    Directory of Open Access Journals (Sweden)

    Mobarak Abu Mraheil

    2011-08-01

    Full Text Available Bacterial regulatory non-coding RNAs control numerous mRNA targets that direct a plethora of biological processes, such as the adaption to environmental changes, growth and virulence. Recently developed high-throughput techniques, such as genomic tiling arrays and RNA-Seq have allowed investigating prokaryotic cis- and trans-acting regulatory RNAs, including sRNAs, asRNAs, untranslated regions (UTR and riboswitches. As a result, we obtained a more comprehensive view on the complexity and plasticity of the prokaryotic genome biology. Listeria monocytogenes was utilized as a model system for intracellular pathogenic bacteria in several studies, which revealed the presence of about 180 regulatory RNAs in the listerial genome. A regulatory role of non-coding RNAs in survival, virulence and adaptation mechanisms of L. monocytogenes was confirmed in subsequent experiments, thus, providing insight into a multifaceted modulatory function of RNA/mRNA interference. In this review, we discuss the identification of regulatory RNAs by high-throughput techniques and in their functional role in L. monocytogenes.

  15. Identification and Role of Regulatory Non-Coding RNAs in Listeria monocytogenes

    Science.gov (United States)

    Izar, Benjamin; Mraheil, Mobarak Abu; Hain, Torsten

    2011-01-01

    Bacterial regulatory non-coding RNAs control numerous mRNA targets that direct a plethora of biological processes, such as the adaption to environmental changes, growth and virulence. Recently developed high-throughput techniques, such as genomic tiling arrays and RNA-Seq have allowed investigating prokaryotic cis- and trans-acting regulatory RNAs, including sRNAs, asRNAs, untranslated regions (UTR) and riboswitches. As a result, we obtained a more comprehensive view on the complexity and plasticity of the prokaryotic genome biology. Listeria monocytogenes was utilized as a model system for intracellular pathogenic bacteria in several studies, which revealed the presence of about 180 regulatory RNAs in the listerial genome. A regulatory role of non-coding RNAs in survival, virulence and adaptation mechanisms of L. monocytogenes was confirmed in subsequent experiments, thus, providing insight into a multifaceted modulatory function of RNA/mRNA interference. In this review, we discuss the identification of regulatory RNAs by high-throughput techniques and in their functional role in L. monocytogenes. PMID:21954346

  16. Anorexia in cancer: role of feeding-regulatory peptides.

    Science.gov (United States)

    Perboni, Simona; Inui, Akio

    2006-07-29

    Anorexia is one of the most common symptoms in advanced cancer and is a frequent cause of discomfort for cancer patients and their families. The pathogenesis of cancer anorexia is multi-factorial and involves most of the hypothalamic neuronal signalling pathways modulating energy homeostasis. It is considered to be the result of a failure of usual appetite and satiety signals. Loss of appetite can arise from decreased taste and smell of food, as well as from dysfunctional hypothalamic signalling pathways and cytokine production. Cytokines in particular, appear to play a key role in energy balance through persistent activation of the melanocortin system and inhibition of the neuropeptide Y pathway. The imbalance between anorexigenic and orexigenic peptides leads to suppression of appetite, and increased satiety and satiation associated with marked weight loss and decline in physical performance. High levels of serotonin also appear to contribute to these effects and recent findings implicate corticotropin-releasing factor in the pathogenesis of cancer anorexia as well. Despite significant advances in our understanding of the regulation of food intake and energy expenditure, few effective therapies are available. A better appreciation of the molecular and neuronal mechanisms that control body weight homeostasis may lead to the development of new therapies for improving the survival and quality of life of these patients.

  17. Regulatory role of AINTEGUMENTA in organ initiation and growth

    Energy Technology Data Exchange (ETDEWEB)

    Krizek, Beth Allyn [University of South Carolina; Lebioda, Lukasz [University of South Carolina

    2005-03-01

    Although several members of the plant-specific AP2/ERF family of transcription factors are important developmental regulators, many genes in this large protein family remain uncharacterized. Here, we present a phylogenetic analysis of the18 genes that make up the AP2 subgroup of this family. We report expression analyses of seven Arabidopsis genes most closely related to the floral development gene AINTEGUMENTA and show that all AINTEGUMENTA-like (AIL) genes are transcribed in multiple tissues during development. They are expressed primarily in young actively dividing tissues of a plant and not in mature leaves or stems. The spatial distribution of AIL5, AIL6, and AIL7 mRNA in inflorescences was characterized by in situ hybridization. Each of these genes is expressed in a spatially and temporally distinct pattern within inflorescence meristems and flowers. Ectopic expression of AIL5 resulted in a larger floral organ phenotype, similar to that resulting from ectopic expression of ANT. Our results are consistent with AIL genes having roles in specification of meristematic or division-competent states.

  18. The regulation and regulatory role of collagenase in bone

    Science.gov (United States)

    Partridge, N. C.; Walling, H. W.; Bloch, S. R.; Omura, T. H.; Chan, P. T.; Pearman, A. T.; Chou, W. Y.

    1996-01-01

    Interstitial collagenase plays an important role in both the normal and pathological remodeling of collagenous extracellular matrices, including skeletal tissues. The enzyme is a member of the family of matrix metalloproteinases. Only one rodent interstitial collagenase has been found but there are two human enzymes, human collagenase-1 and -3, the latter being the homologue of the rat enzyme. In developing rat and mouse bone, collagenase is expressed by hypertrophic chondrocytes, osteoblasts, and osteocytes, a situation that is replicated in a fracture callus. Cultured osteoblasts derived from neonatal rat calvariae show greater amounts of collagenase transcripts late in differentiation. These levels can be regulated by parathyroid hormone (PTH), retinoic acid, and insulin-like growth factors, as well as the degree of matrix mineralization. Much of the work on collagenase in bone has been derived from studies on the rat osteosarcoma cell line, UMR 106-01. All bone-resorbing agents stimulate these cells to produce collagenase mRNA and protein, with PTH being the most potent stimulator. Determination of secreted levels of collagenase has been difficult because UMR cells, normal rat osteoblasts, and rat fibroblasts possess a scavenger receptor that removes the enzyme from the extracellular space, internalizes and degrades it, thus imposing another level of control. PTH can also regulate the abundance of the receptor as well as the expression and synthesis of the enzyme. Regulation of the collagenase gene by PTH appears to involve the cAMP pathway as well as a primary response gene, possibly Fos, which then contributes to induction of the collagenase gene. The rat collagenase gene contains an activator protein-1 sequence that is necessary for basal expression, but other promoter regions may also participate in PTH regulation. Thus, there are many levels of regulation of collagenase in bone perhaps constraining what would otherwise be a rampant enzyme.

  19. Negative Regulatory Role of TWIST1 on SNAIL Gene Expression.

    Science.gov (United States)

    Forghanifard, Mohammad Mahdi; Ardalan Khales, Sima; Farshchian, Moein; Rad, Abolfazl; Homayouni-Tabrizi, Masoud; Abbaszadegan, Mohammad Reza

    2017-01-01

    Epithelial-mesenchymal transition (EMT) is crucial for specific morphogenetic movements during embryonic development as well as pathological processes of tumor cell invasion and metastasis. TWIST and SNAIL play vital roles in both developmental and pathological EMT. Our aim in this study was to investigate the functional correlation between TWIST1 and SNAIL in human ESCC cell line (KYSE-30). The packaging cell line GP293T was cotransfected with either control retroviral pruf-IRES-GFP plasmid or pruf-IRES-GFP-hTWIST1 and pGP plasmid. The KYSE-30 ESCC cells were transduced with produced viral particles and examined with inverted fluorescence microscope. DNA was extracted from transduced KYSE-30 cells and analyzed for copy number of integrated retroviral sequences in the target cell genome. The concentration of retroviral particles was determined by Real-time PCR. After RNA extraction and cDNA synthesis, the mRNA expression of TWIST1 and SNAIL was assessed by comparative real-time PCR amplification. Ectopic expression of TWIST1 in KYSE-30, dramatically reduces SNAIL expression. Retroviral transduction enforced TWIST1 overexpression in GFP-hTWIST1 nearly 9 folds in comparison with GFP control cells, and interestingly, this TWIST1 enforced expression caused a - 7 fold decrease of SNAIL mRNA expression in GFP-hTWIST1 compared to GFP control cells. Inverse correlation of TWIST1 and SNAIL mRNA levels may introduce novel molecular gene expression pathway controlling EMT process during ESCC aggressiveness and tumorigenesis. Consequently, these data extend the spectrum of biological activities of TWIST1 and propose that therapeutic repression of TWIST1 may be an effective strategy to inhibit cancer cell invasion and metastasis.

  20. Opposing Roles for Two Molecular Forms of Replication Protein A in Rad51-Rad54-Mediated DNA Recombination in Plasmodium falciparum

    OpenAIRE

    2013-01-01

    ABSTRACT The bacterial RecA protein and its eukaryotic homologue Rad51 play a central role in the homologous DNA strand exchange reaction during recombination and DNA repair. Previously, our lab has shown that PfRad51, the Plasmodium falciparum homologue of Rad51, exhibited ATPase activity and promoted DNA strand exchange in vitro. In this study, we evaluated the catalytic functions of PfRad51 in the presence of putative interacting partners, especially P. falciparum homologues of Rad54 and r...

  1. Lipid mediators in innate immunity against tuberculosis: opposing roles of PGE2 and LXA4 in the induction of macrophage death.

    Science.gov (United States)

    Chen, Minjian; Divangahi, Maziar; Gan, Huixian; Shin, Daniel S J; Hong, Song; Lee, David M; Serhan, Charles N; Behar, Samuel M; Remold, Heinz G

    2008-11-24

    Virulent Mycobacterium tuberculosis (Mtb) induces a maladaptive cytolytic death modality, necrosis, which is advantageous for the pathogen. We report that necrosis of macrophages infected with the virulent Mtb strains H37Rv and Erdmann depends on predominant LXA(4) production that is part of the antiinflammatory and inflammation-resolving action induced by Mtb. Infection of macrophages with the avirulent H37Ra triggers production of high levels of the prostanoid PGE(2), which promotes protection against mitochondrial inner membrane perturbation and necrosis. In contrast to H37Ra infection, PGE(2) production is significantly reduced in H37Rv-infected macrophages. PGE(2) acts by engaging the PGE(2) receptor EP2, which induces cyclic AMP production and protein kinase A activation. To verify a role for PGE(2) in control of bacterial growth, we show that infection of prostaglandin E synthase (PGES)(-/-) macrophages in vitro with H37Rv resulted in significantly higher bacterial burden compared with wild-type macrophages. More importantly, PGES(-/-) mice harbor significantly higher Mtb lung burden 5 wk after low-dose aerosol infection with virulent Mtb. These in vitro and in vivo data indicate that PGE(2) plays a critical role in inhibition of Mtb replication.

  2. Regulatory mechanisms in arterial hypertension: role of microRNA in pathophysiology and therapy.

    Science.gov (United States)

    Klimczak, Dominika; Jazdzewski, Krystian; Kuch, Marek

    2017-02-01

    Multiple factors underlie the pathophysiology of hypertension, involving endothelial dysregulation, vascular smooth muscle dysfunction, increased oxidative stress, sympathetic nervous system activation and altered renin -angiotensin -aldosterone regulatory activity. A class of non-coding RNA called microRNA, consisting of 17-25 nucleotides, exert regulatory function over these processes. This paper summarizes the currently available data from preclinical and clinical studies on miRNA in the development of hypertension as well as the impact of anti-hypertensive treatment on their plasma expression. We present microRNAs' characteristics, their biogenesis and role in the regulation of blood pressure together with their potential diagnostic and therapeutic application in clinical practice.

  3. Opposed turns at signalized intersections

    Energy Technology Data Exchange (ETDEWEB)

    Akcelik, R.

    1989-06-01

    The 1985 Highway Capacity Manual (HCM) brought the U.S. and Australian methodologies for signalized intersections closer together. An important element in this methodology is the techniques used for the estimation of opposed (permissive) turn saturation flows. Although the basic modeling philosophies of the HCM and Australian methods are similar, there are significant differences in the procedures used and therefore in the results from the two methods. In particular, the latest methodology employed in the SIDRA software has eliminated the use of opposed turn adjustment factors for lane groups and adopted an explicit and direct method of modeling individual lanes. The purpose of this paper is to bring these new methods to the attention of the U.S. researchers since it is understood that efforts are being made to improve the 1985 HCM method.

  4. Cbf11 and Cbf12, the fission yeast CSL proteins, play opposing roles in cell adhesion and coordination of cell and nuclear division

    Energy Technology Data Exchange (ETDEWEB)

    Prevorovsky, Martin; Grousl, Tomas; Stanurova, Jana; Rynes, Jan [Department of Cell Biology, Faculty of Science, Charles University in Prague, Vinicna 7, 128 43, Prague 2 (Czech Republic); Nellen, Wolfgang [Department of Genetics, Kassel University, Heinrich Plett Strasse 40, 34132 Kassel (Germany); Puta, Frantisek [Department of Cell Biology, Faculty of Science, Charles University in Prague, Vinicna 7, 128 43, Prague 2 (Czech Republic); Folk, Petr, E-mail: folk@natur.cuni.cz [Department of Cell Biology, Faculty of Science, Charles University in Prague, Vinicna 7, 128 43, Prague 2 (Czech Republic)

    2009-05-01

    The CSL (CBF1/RBP-J{kappa}/Suppressor of Hairless/LAG-1) family is comprised of transcription factors essential for metazoan development, mostly due to their involvement in the Notch receptor signaling pathway. Recently, we identified two novel classes of CSL genes in the genomes of several fungal species, organisms lacking the Notch pathway. In this study, we characterized experimentally cbf11{sup +} and cbf12{sup +}, the two CSL genes of Schizosaccharomyces pombe, in order to elucidate the CSL function in fungi. We provide evidence supporting their identity as genuine CSL genes. Both cbf11{sup +} and cbf12{sup +} are non-essential; they have distinct expression profiles and code for nuclear proteins with transcription activation potential. Significantly, we demonstrated that Cbf11 recognizes specifically the canonical CSL response element GTG{sup A}/{sub G}GAA in vitro. The deletion of cbf11{sup +} is associated with growth phenotypes and altered colony morphology. Furthermore, we found that Cbf11 and Cbf12 play opposite roles in cell adhesion, nuclear and cell division and their coordination. Disturbed balance of the two CSL proteins leads to cell separation defects (sep phenotype), cut phenotype, and high-frequency diploidization in heterothallic strains. Our data show that CSL proteins operate in an organism predating the Notch pathway, which should be of relevance to the understanding of (Notch-independent) CSL functions in metazoans.

  5. [Role of genes and their cis-regulatory elements during animal morphological evolution].

    Science.gov (United States)

    Sun, Boyuan; Tu, Jianbo; Li, Ying; Yang, Mingyao

    2014-06-01

    Cis-regulatory hypothesis is one of the most important theories in evolutionary developmental biology (evo-devo), which claims that evolution of cis-regulatory elements (CREs) plays a key role during evolution of morphology. However, an increasing number of experimental results show that cis-regulatory hypothesis alone is not far enough to explain the complexity of evo-devo processes. Other modifications, including mutations of protein coding, gene and genome duplications, and flexibility of homeodomains and CREs, also cause the morphological changes in animals. In this review, we retrospect the recent results of evolution of CREs and genes associated with CREs and discuss new methods and trends for research in evo-devo.

  6. Introduction: MicroRNAs in human reproduction: small molecules with crucial regulatory roles.

    Science.gov (United States)

    Imbar, Tal; Galliano, Daniela; Pellicer, Antonio; Laufer, Neri

    2014-06-01

    MicroRNAs constitute a large family of approximately 21-nucleotide-long, noncoding RNAs. They emerged more than 20 years ago as key posttranscriptional regulators of gene expression. The regulatory role of these small RNA molecules has recently begun to be explored in the human reproductive system. In this issue's Views and Reviews, the authors present the current knowledge regarding the involvement of microRNAs in several aspects of human reproduction and discuss its future implications for clinical practice.

  7. Regulatory T-cells have a prominent role in the immune modulated vaccine response by specific oligosaccharides

    NARCIS (Netherlands)

    van't Land, Belinda; Schijf, Marcel; van Esch, Betty C. A. M.; van Bergenhenegouwen, Jeroen; Bastiaans, Jacqueline; Schouten, Bastiaan; Boon, Louis; Garssen, Johan

    2010-01-01

    Regulatory T-cells are increasingly important in vaccine strategies. In a Flu-vaccination model the role of CD4(+)CD25(+)Foxp3(+) regulatory T-cells (Tregs) and the immune modulation by orally supplied prebiotic oligosaccharides consisting of scGOS/lcFOS/pAOS, were assessed using anti-CD25 (PC61) me

  8. S¿opposer au Maghreb

    OpenAIRE

    Desrues, Thierry; Hernando de Larramendi, Miguel

    2009-01-01

    Il y a près de vingt ans les États du Maghreb central – Algérie, Maroc et Tunisie – initiaient des réformes politiques qui allaient alors légitimer la problématique du changement. Depuis, la pluralisation du champ politique s’est imposée comme une technique de gouvernement liée à la survie des régimes. Ceux-ci espèrent intégrer leurs opposants dans un jeu politique où le pouvoir n’est pas en jeu. Dans une telle configuration, les oppositions revêtent des formes diverses, qu’elles soient parti...

  9. Bridging research and environmental regulatory processes: the role of knowledge brokers.

    Science.gov (United States)

    Pennell, Kelly G; Thompson, Marcella; Rice, James W; Senier, Laura; Brown, Phil; Suuberg, Eric

    2013-01-01

    Federal funding agencies increasingly require research investigators to ensure that federally sponsored research demonstrates broader societal impact. Specifically, the National Institutes of Environmental Health Sciences (NIEHS) Superfund Research Program (SRP) requires research centers to include research translation and community engagement cores to achieve broader impacts, with special emphasis on improving environmental health policies through better scientific understanding. This paper draws on theoretical insights from the social sciences to show how incorporating knowledge brokers in research centers can facilitate translation of scientific expertise to influence regulatory processes and thus promote public health. Knowledge brokers connect academic researchers with decision-makers, to facilitate the translation of research findings into policies and programs. In this article, we describe the stages of the regulatory process and highlight the role of the knowledge broker and scientific expert at each stage. We illustrate the cooperation of knowledge brokers, scientific experts and policymakers using a case from the Brown University (Brown) SRP. We show how the Brown SRP incorporated knowledge brokers to engage scientific experts with regulatory officials around the emerging public health problem of vapor intrusion (VI). In the Brown SRP, the knowledge broker brought regulatory officials into the research process, to help scientific experts understand the critical nature of this emerging public health threat, and helped scientific experts develop a research agenda that would inform the development of timely measures to protect public health. Our experience shows that knowledge brokers can enhance the impact of environmental research on public health by connecting policy decision-makers with scientific experts at critical points throughout the regulatory process.

  10. The role of learning environment on high school chemistry students' motivation and self-regulatory processes

    Science.gov (United States)

    Judd, Jeffrey S.

    Changes to the global workforce and technological advancements require graduating high school students to be more autonomous, self-directed, and critical in their thinking. To reflect societal changes, current educational reform has focused on developing more problem-based, collaborative, and student-centered classrooms to promote effective self-regulatory learning strategies, with the goal of helping students adapt to future learning situations and become life-long learners. This study identifies key features that may characterize these "powerful learning environments", which I term "high self-regulating learning environments" for ease of discussion, and examine the environment's role on students' motivation and self-regulatory processes. Using direct observation, surveys, and formal and informal interviews, I identified perceptions, motivations, and self-regulatory strategies of 67 students in my high school chemistry classes as they completed academic tasks in both high and low self-regulating learning environments. With social cognitive theory as a theoretical framework, I then examined how students' beliefs and processes changed after they moved from low to a high self-regulating learning environment. Analyses revealed that key features such as task meaning, utility, complexity, and control appeared to play a role in promoting positive changes in students' motivation and self-regulation. As embedded cases, I also included four students identified as high self-regulating, and four students identified as low self-regulating to examine whether the key features of high and low self-regulating learning environments played a similar role in both groups. Analysis of findings indicates that key features did play a significant role in promoting positive changes in both groups, with high self-regulating students' motivation and self-regulatory strategies generally remaining higher than the low self-regulating students; this was the case in both environments. Findings

  11. The regulatory roles of small leucine-rich proteoglycans in extracellular matrix assembly.

    Science.gov (United States)

    Chen, Shoujun; Birk, David E

    2013-05-01

    Small leucine-rich proteoglycans (SLRPs) are involved in a variety of biological and pathological processes. This review focuses on their regulatory roles in matrix assembly. SLRPs have protein cores and hypervariable glycosylation with multivalent binding abilities. During development, differential interactions of SLRPs with other molecules result in tissue-specific spatial and temporal distributions. The changing expression patterns play a critical role in the regulation of tissue-specific matrix assembly and therefore tissue function. SLRPs play significant structural roles within extracellular matrices. In addition, they play regulatory roles in collagen fibril growth, fibril organization and extracellular matrix assembly. Moreover, they are involved in mediating cell-matrix interactions. Abnormal SLRP expression and/or structures result in dysfunctional extracellular matrices and pathophysiology. Altered expression of SLRPs has been found in many disease models, and structural deficiency also causes altered matrix assembly. SLRPs regulate assembly of the extracellular matrix, which defines the microenvironment, modulating both the extracellular matrix and cellular functions, with an impact on tissue function.

  12. Role of CD8 Regulatory T Cells versus Tc1 and Tc17 Cells in the Development of Human Graft-versus-Host Disease

    Science.gov (United States)

    Gutiérrez-Hoya, Adriana; López-Santiago, Rubén; Vela-Ojeda, Jorge; Montiel-Cervantes, Laura; Rodríguez-Cortés, Octavio; Rosales-García, Víctor; Flores-Mejía, Raúl; Sandoval-Borrego, Daniela

    2017-01-01

    CD8+ T cells that secrete proinflammatory cytokines play a central role in exacerbation of inflammation; however, a new subpopulation of CD8 regulatory T cells has recently been characterized. This study analyzes the prominent role of these different subpopulations in the development of graft-versus-host disease (GVHD). Samples from 8 healthy donors mobilized with Filgrastim® (G-CSF) and 18 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) were evaluated by flow cytometry. Mobilization induced an increase in Tc1 (p < 0.01), Th1 (p < 0.001), Tc17 (p < 0.05), and CD8+IL-10+ cells (p < 0.05), showing that G-CSF induces both pro- and anti-inflammatory profiles. Donor-patient correlation revealed a trend (p = 0.06) toward the development of GVHD in patients who receive a high percentage of Tc1 cells. Patients with acute GVHD (aGVHD), either active or controlled, and patients without GVHD were evaluated; patients with active aGVHD had a higher percentage of Tc1 (p < 0.01) and Tc17 (p < 0.05) cells, as opposed to patients without GVHD in whom a higher percentage of CD8 Treg cells (p < 0.01) was found. These findings indicate that the increase in Tc1 and Tc17 cells is associated with GVHD development, while regulatory CD8 T cells might have a protective role in this disease. These tests can be used to monitor and control GVHD. PMID:28164135

  13. Role of CD8 Regulatory T Cells versus Tc1 and Tc17 Cells in the Development of Human Graft-versus-Host Disease

    Directory of Open Access Journals (Sweden)

    Adriana Gutiérrez-Hoya

    2017-01-01

    Full Text Available CD8+ T cells that secrete proinflammatory cytokines play a central role in exacerbation of inflammation; however, a new subpopulation of CD8 regulatory T cells has recently been characterized. This study analyzes the prominent role of these different subpopulations in the development of graft-versus-host disease (GVHD. Samples from 8 healthy donors mobilized with Filgrastim® (G-CSF and 18 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT were evaluated by flow cytometry. Mobilization induced an increase in Tc1 (p<0.01, Th1 (p<0.001, Tc17 (p<0.05, and CD8+IL-10+ cells (p<0.05, showing that G-CSF induces both pro- and anti-inflammatory profiles. Donor-patient correlation revealed a trend (p=0.06 toward the development of GVHD in patients who receive a high percentage of Tc1 cells. Patients with acute GVHD (aGVHD, either active or controlled, and patients without GVHD were evaluated; patients with active aGVHD had a higher percentage of Tc1 (p<0.01 and Tc17 (p<0.05 cells, as opposed to patients without GVHD in whom a higher percentage of CD8 Treg cells (p<0.01 was found. These findings indicate that the increase in Tc1 and Tc17 cells is associated with GVHD development, while regulatory CD8 T cells might have a protective role in this disease. These tests can be used to monitor and control GVHD.

  14. Induction of regulatory T cells: A role for probiotics and prebiotics to suppress autoimmunity.

    Science.gov (United States)

    Dwivedi, Mitesh; Kumar, Prasant; Laddha, Naresh C; Kemp, E Helen

    2016-04-01

    Regulatory T cells (Tregs) are comprised of a heterogeneous population of cells that play a vital role in suppressing inflammation and maintaining immune tolerance. Given the crucial role of Tregs in maintaining immune homeostasis, it is probably not surprising that many microbial species and their metabolites have the potential to induce Tregs. There is now great interest in the therapeutic potential of probiotics and prebiotics based strategies for a range of autoimmune disorders. This review will summarise recent findings concerning the role of probiotics and prebiotics in induction of Tregs to ameliorate the autoimmune conditions. In addition, the article is focused to explain the different mechanisms of Treg induction and function by these probiotics and prebiotics, based on the available studies till date. The article further proposes that induction of Tregs by probiotics and prebiotics could lead to the development of new therapeutic approach towards curbing the autoimmune response and as an alternative to detrimental immunosuppressive drugs.

  15. Adenylyl cyclase plays a regulatory role in development, stress resistance and secondary metabolism in Fusarium fujikuroi.

    Directory of Open Access Journals (Sweden)

    Jorge García-Martínez

    Full Text Available The ascomycete fungus Fusarium fujikuroi (Gibberella fujikuroi MP-C produces secondary metabolites of biotechnological interest, such as gibberellins, bikaverin, and carotenoids. Production of these metabolites is regulated by nitrogen availability and, in a specific manner, by other environmental signals, such as light in the case of the carotenoid pathway. A complex regulatory network controlling these processes is recently emerging from the alterations of metabolite production found through the mutation of different regulatory genes. Here we show the effect of the targeted mutation of the acyA gene of F. fujikuroi, coding for adenylyl cyclase. Mutants lacking the catalytic domain of the AcyA protein showed different phenotypic alterations, including reduced growth, enhanced production of unidentified red pigments, reduced production of gibberellins and partially derepressed carotenoid biosynthesis in the dark. The phenotype differs in some aspects from that of similar mutants of the close relatives F. proliferatum and F. verticillioides: contrary to what was observed in these species, ΔacyA mutants of F. fujikuroi showed enhanced sensitivity to oxidative stress (H(2O(2, but no change in heavy metal resistance or in the ability to colonize tomato tissue, indicating a high versatility in the regulatory roles played by cAMP in this fungal group.

  16. Role of Regulatory T-cells in Different Clinical Expressions of Helicobacter pylori Infection.

    Science.gov (United States)

    Bagheri, Nader; Azadegan-Dehkordi, Fatemeh; Rahimian, Ghorbanali; Rafieian-Kopaei, Mahmoud; Shirzad, Hedayatollah

    2016-05-01

    Helicobacter pylori (H. pylori) colonization induces vigorous innate and specific immune responses; however, the infection does not disappear and a chronic active gastritis continues if left untreated. It has been shown that the topographical pattern and immune response of gastritis are the main reasons for the bacteria persistence and the clinical outcome. Gastritis due to H. pylori is caused by a complicated interaction among a variety of T cell subsets. Regulatory T (Treg) cells suppressing the immune response of antigen-specific T-cells have recently been demonstrated to play a key role in chronic inflammation by immunologic tolerance. Treg cells have been identified as the major regulatory component of the adaptive immune response and being involved in H. pylori-related inflammation and bacterial persistence. There have been many controversies over the role of Treg cells in H. pylori infection. Many studies have shown that the local Treg response protects the gastric mucosa from intensified inflammation and tissue damage, and the risk of H. pylori-associated diseases has an inverse correlation with Treg accumulation, even if the decrease in the inflammatory response is recognized by Treg it causes increase in bacterial density. This paper reviews the role of Treg in different clinical expressions of H. pylori infection.

  17. The role of regulatory T cells in familial Mediterranean fever (FMF).

    Science.gov (United States)

    Rimar, D; Rosner, I; Slobodin, G; Boulman, N; Toubi, E; Kessel, A; Peri, R; Rozenbaum, M

    2012-05-01

    The role of regulatory T cells (T-regs) in familial Mediterranean fever (FMF) was never evaluated. Preliminary studies that we have conducted suggested a rise in the number of regulatory T cells after FMF attacks reaching a maximal level at 7 days. The aim of this study was to evaluate the percentage and activity of regulatory T cells in FMF. Six patients with refractory FMF and six healthy controls were evaluated. The percentage of T-reg cells and forkhead box protein 3 (Foxp3) expression was evaluated and compared between four states: FMF in remission, FMF at the first day of an attack, FMF 7 days after the start of the attack, and healthy controls. Four females and two males were included. All patients had FMF with high severity score, 2.8 ± 0.4 (0-3). The mean age was 31.6 ± 6.2. The mean age at onset was 9.3 ± 9.3. The mean colchicine dose was 2.6 mg ± 0.4. The expression of Foxp3 7 days after the attacks was significantly higher than in FMF at the first day of the attack, FMF in remission, and healthy controls 10.08 ± 2.36 vs. 7.005 ± 0.3 vs. 5.3 ± 1.06 vs. 4.44 ± 1.8; p FMF. Anti-inflammatory cytokines interleukin-10 and TGF-β are known to activate T-regs and have been reported to increase in FMF attacks in line with the present findings. It is suggested that T-regs may have a role in terminating FMF attacks.

  18. The Role of Different Subsets of Regulatory T Cells in Immunopathogenesis of Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Maryam Gol-Ara

    2012-01-01

    Full Text Available Rheumatoid arthritis (RA is a common autoimmune disease and a systemic inflammatory disease which is characterized by chronic joint inflammation and variable degrees of bone and cartilage erosion and hyperplasia of synovial tissues. Considering the role of autoreactive T cells (particularly Th1 and Th17 cells in pathophysiology of RA, it might be assumed that the regulatory T cells (Tregs will be able to control the initiation and progression of disease. The frequency, function, and properties of various subsets of Tregs including natural Tregs (nTregs, IL-10-producing type 1 Tregs (Tr1 cells, TGF-β-producing Th3 cells, CD8+ Tregs, and NKT regulatory cells have been investigated in various studies associated with RA and collagen-induced arthritis (CIA as experimental model of this disease. In this paper, we intend to submit the comprehensive information about the immunobiology of various subsets of Tregs and their roles and function in immunopathophysiology of RA and its animal model, CIA.

  19. Role of complement and complement regulatory proteins in the complications of diabetes.

    Science.gov (United States)

    Ghosh, Pamela; Sahoo, Rupam; Vaidya, Anand; Chorev, Michael; Halperin, Jose A

    2015-06-01

    It is well established that the organ damage that complicates human diabetes is caused by prolonged hyperglycemia, but the cellular and molecular mechanisms by which high levels of glucose cause tissue damage in humans are still not fully understood. The prevalent hypothesis explaining the mechanisms that may underlie the pathogenesis of diabetes complications includes overproduction of reactive oxygen species, increased flux through the polyol pathway, overactivity of the hexosamine pathway causing intracellular formation of advanced glycation end products, and activation of protein kinase C isoforms. In addition, experimental and clinical evidence reported in past decades supports a strong link between the complement system, complement regulatory proteins, and the pathogenesis of diabetes complications. In this article, we summarize the body of evidence that supports a role for the complement system and complement regulatory proteins in the pathogenesis of diabetic vascular complications, with specific emphasis on the role of the membrane attack complex (MAC) and of CD59, an extracellular cell membrane-anchored inhibitor of MAC formation that is inactivated by nonenzymatic glycation. We discuss a pathogenic model of human diabetic complications in which a combination of CD59 inactivation by glycation and hyperglycemia-induced complement activation increases MAC deposition, activates pathways of intracellular signaling, and induces the release of proinflammatory, prothrombotic cytokines and growth factors. Combined, complement-dependent and complement-independent mechanisms induced by high glucose promote inflammation, proliferation, and thrombosis as characteristically seen in the target organs of diabetes complications.

  20. A regulatory role for Staphylococcus aureus toxin-antitoxin system PemIKSa.

    Science.gov (United States)

    Bukowski, Michal; Lyzen, Robert; Helbin, Weronika M; Bonar, Emilia; Szalewska-Palasz, Agnieszka; Wegrzyn, Grzegorz; Dubin, Grzegorz; Dubin, Adam; Wladyka, Benedykt

    2013-01-01

    Toxin-antitoxin systems were shown to be involved in plasmid maintenance when they were initially discovered, but other roles have been demonstrated since. Here we identify and characterize a novel toxin-antitoxin system (pemIKSa) located on Staphylococcus aureus plasmid pCH91. The toxin (PemKSa) is a sequence-specific endoribonuclease recognizing the tetrad sequence U↓AUU, and the antitoxin (PemISa) inhibits toxin activity by physical interaction. Although the toxin-antitoxin system is responsible for stable plasmid maintenance our data suggest the participation of pemIKSa in global regulation of staphylococcal virulence by alteration of the translation of large pools of genes. We propose a common mechanism of reversible activation of toxin-antitoxin systems based on antitoxin transcript resistance to toxin cleavage. Elucidation of this mechanism is particularly interesting because reversible activation is a prerequisite for the proposed general regulatory role of toxin-antitoxin systems.

  1. The role of quantitative safety evaluation in regulatory decision making of drugs.

    Science.gov (United States)

    Chakravarty, Aloka G; Izem, Rima; Keeton, Stephine; Kim, Clara Y; Levenson, Mark S; Soukup, Mat

    2016-01-01

    Evaluation of safety is a critical component of drug review at the US Food and Drug Administration (FDA). Statisticians are playing an increasingly visible role in quantitative safety evaluation and regulatory decision-making. This article reviews the history and the recent events relating to quantitative drug safety evaluation at the FDA. The article then focuses on five active areas of quantitative drug safety evaluation and the role Division of Biometrics VII (DBVII) plays in these areas, namely meta-analysis for safety evaluation, large safety outcome trials, post-marketing requirements (PMRs), the Sentinel Initiative, and the evaluation of risk from extended/long-acting opioids. This article will focus chiefly on developments related to quantitative drug safety evaluation and not on the many additional developments in drug safety in general.

  2. Regulatory T Cells in the Tumor Microenvironment and Cancer Progression: Role and Therapeutic Targeting

    Science.gov (United States)

    Chaudhary, Belal; Elkord, Eyad

    2016-01-01

    Recent years have seen significant efforts in understanding and modulating the immune response in cancer. In this context, immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), have come under intense investigation for their proposed roles in suppressing tumor-specific immune responses and establishing an immunosuppressive tumor microenvironment, thus enabling tumor immune evasion. Additionally, recent evidence indicates that Tregs comprise diverse and heterogeneous subsets; phenotypically and functionally distinct subsets of tumor-infiltrating Tregs could contribute differently to cancer prognosis and clinical outcomes. Understanding Treg biology in the setting of cancer, and specifically the tumor microenvironment, is important for designing effective cancer therapies. In this review, we critically examine the role of Tregs in the tumor microenvironment and in cancer progression focusing on human studies. We also discuss the impact of current therapeutic modalities on Treg biology and the therapeutic opportunities for targeting Tregs to enhance anti-tumor immune responses and clinical benefits. PMID:27509527

  3. General aspects of two-component regulatory circuits in bacteria: Domains, signals and roles.

    Science.gov (United States)

    Padilla-Vaca, Felipe; Mondragón-Jaimes, Verónica; Franco, Bernardo

    2016-08-09

    All living organisms are subject to changing environments, which must be sensed in order to respond swiftly and efficiently. Two-component systems (TCS) are signal transduction regulatory circuits based typically on a membrane bound sensor kinase and a cytoplasmic response regulator, that is activated through a histidine to aspartate phosphorelay reactions. Activated response regulator acts usually as a transcription factor. The best known examples were identified in bacteria, but they are also found in fungi, algae and plants. Thus far, they are not found in mammals. Regulatory circuits coupled to two-component systems exhibit a myriad of responses to environmental stimuli such as: redox potential, pH, specific metabolites, pressure, light and more recently to specific antimicrobial peptides that activate a sensor kinase responsible for expressing virulence factors through the active response regulator. In this review we explore general aspects on two-component systems that ultimately can play a role on virulence regulation, also the intriguing domain properties of the sensor kinases that can be a potential target for antimicrobial compounds. Only a handful of sensor kinases are extensively characterized, the vast majority belong to what we call 'the dark matter of bacterial signal transduction' since no known signal, structure and biochemical properties are available. Regulatory circuits from vertebrate pathogenic organisms can explain virulence in terms of either response to environmental factors or specific niche occupancy. Hopefully, knowledge on these signal transduction systems can lead to identify novel molecules that target two-component systems, since the increase of drug resistant microorganisms is worrisome.

  4. β-arrestins: regulatory role and therapeutic potential in opioid and cannabinoid receptor-mediated analgesia.

    Science.gov (United States)

    Raehal, Kirsten M; Bohn, Laura M

    2014-01-01

    Pain is a complex disorder with neurochemical and psychological components contributing to the severity, the persistence, and the difficulty in adequately treating the condition. Opioid and cannabinoids are two classes of analgesics that have been used to treat pain for centuries and are arguably the oldest of "pharmacological" interventions used by man. Unfortunately, they also produce several adverse side effects that can complicate pain management. Opioids and cannabinoids act at G protein-coupled receptors (GPCRs), and much of their effects are mediated by the mu-opioid receptor (MOR) and cannabinoid CB1 receptor (CB1R), respectively. These receptors couple to intracellular second messengers and regulatory proteins to impart their biological effects. In this chapter, we review the role of the intracellular regulatory proteins, β-arrestins, in modulating MOR and CB1R and how they influence the analgesic and side-effect profiles of opioid and cannabinoid drugs in vivo. This review of the literature suggests that the development of opioid and cannabinoid agonists that bias MOR and CB1R toward G protein signaling cascades and away from β-arrestin interactions may provide a novel mechanism by which to produce analgesia with less severe adverse effects.

  5. The Role and Mechanisms of Double Negative Regulatory T Cells in the Suppression of Immune Responses

    Institute of Scientific and Technical Information of China (English)

    WenhaoChen; MeganS.Ford; KevinJ.Young; LiZhang

    2004-01-01

    Accumulating evidence has demonstrated that regulatory T (Treg) cells play an important role in the maintenance of immunologic self-tolerance and in down-regulating various immune responses. Thus, there has recently been an increasing interest in studying the biology of Treg cells as well as their potential application in treating immune diseases. Many types of Treg cell subsets have been reported in a variety of disease models.Among these subsets, αβ-TCR+CD3+CD4*CD8* double negative (DN) Treg cells are defined by their capability of inhibiting immune responses via directly killing effector T cells in an antigen specific fashion. Furthermore,DN Treg cells have been shown to develop regulatory activity after encountering specific antigens, partially mediated by the acquisition of MHC-peptide complexes from antigen presenting cells (APCs). The presentation of acquired alloantigens on DN T cells allows for the specific interaction between DN Treg cells and alloantigen reactive effector T cells. Once the DN Treg and target cells have come into contact, killing is then mediated by Fas/Fas-ligand interactions, and perhaps through other unidentified pathways. Further characterization of the functions, molecular expression and mechanisms of activation of DN Treg cells will help in the development of novel therapies to induce antigen specific tolerance to self and foreign antigens. Cellular & Molecular Immunology. 2004;1(5):328-335.

  6. The Role and Mechanisms of Double Negative Regulatory T Cells in the Suppression of Immune Responses

    Institute of Scientific and Technical Information of China (English)

    Wenhao Chen; Megan S. Ford; Kevin J. Young; Li Zhang

    2004-01-01

    Accumulating evidence has demonstrated that regulatory T (Treg) cells play an important role in the maintenance of immunologic self-tolerance and in down-regulating various immune responses. Thus, there has recently been an increasing interest in studying the biology of Treg cells as well as their potential application in treating immune diseases. Many types of Treg cell subsets have been reported in a variety of disease models.Among these subsets, αβ-TCR+CD3+CD4-CD8- double negative (DN) Treg cells are defined by their capability of inhibiting immune responses via directly killing effector T cells in an antigen specific fashion. Furthermore,DN Treg cells have been shown to develop regulatory activity after encountering specific antigens, partially mediated by the acquisition of MHC-peptide complexes from antigen presenting cells (APCs). The presentation of acquired alloantigens on DN T cells allows for the specific interaction between DN Treg cells and alloantigen reactive effector T cells. Once the DN Treg and target cells have come into contact, killing is then mediated by Fas/Fas-ligand interactions, and perhaps through other unidentified pathways. Further characterization of the functions, molecular expression and mechanisms of activation of DN Treg cells will help in the development of novel therapies to induce antigen specific tolerance to self and foreign antigens. Cellular & Molecular Immunology. 2004;1(5):328-335.

  7. 49 CFR 236.808 - Signals, opposing.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Signals, opposing. 236.808 Section 236.808..., MAINTENANCE, AND REPAIR OF SIGNAL AND TRAIN CONTROL SYSTEMS, DEVICES, AND APPLIANCES Definitions § 236.808 Signals, opposing. Roadway signals which govern movements in opposite directions on the same track. ...

  8. 49 CFR 236.833 - Train, opposing.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Train, opposing. 236.833 Section 236.833..., MAINTENANCE, AND REPAIR OF SIGNAL AND TRAIN CONTROL SYSTEMS, DEVICES, AND APPLIANCES Definitions § 236.833 Train, opposing. A train, the movement of which is in a direction opposite to and toward another train...

  9. Innate immunity and protective neuroinflammation: new emphasis on the role of neuroimmune regulatory proteins.

    Science.gov (United States)

    Griffiths, M; Neal, J W; Gasque, P

    2007-01-01

    Brain inflammation due to infection, hemorrhage, and aging is associated with activation of the local innate immune system as expressed by infiltrating cells, resident glial cells, and neurons. The innate immune response relies on the detection of "nonself" and "danger-self" ligands behaving as "eat me signals" by a plethora of pattern recognition receptors (PRRs) expressed by professional and amateur phagocytes to promote the clearance of pathogens, toxic cell debris (amyloid fibrils, aggregated synucleins, prions), and apoptotic cells accumulating within the brain parenchyma and the cerebrospinal fluid (CSF). These PRRs (e.g., complement, TLR, CD14, scavenger receptors) are highly conserved between vertebrates and invertebrates and may represent the most ancestral innate scavenging system involved in tissue homeostasis. However, in some diseases, these protective mechanisms lead to neurodegeneration on the ground that several innate immune molecules have neurocytotoxic activities. The response is a "double-edged sword" representing a fine balance between protective and detrimental effects. Several key regulatory mechanisms have now been evidenced in the control of CNS innate immunity, and these could be harnessed to explore novel therapeutic avenues. We will herein provide new emphasis on the role of neuroimmune regulatory proteins (NIRegs), such as CD95L, TNF, CD200, CD47, sialic acids, CD55, CD46, fH, C3a, HMGB1, which are involved in silencing innate immunity at the cellular and molecular levels and suppression of inflammation. For instance, NIRegs may play an important role in controlling lymphocyte/macrophage/microglia hyperinflammatory responses, while sparing host defense and repair mechanisms. Moreover, NIRegs have direct beneficial effects on neurogenesis and contributing to brain tissue remodeling.

  10. The Role of MicroRNAs in Regulatory T Cells and in the Immune Response.

    Science.gov (United States)

    Ha, Tai-You

    2011-02-01

    The discovery of microRNA (miRNA) is one of the major scientific breakthroughs in recent years and has revolutionized current cell biology and medical science. miRNAs are small (19~25nt) noncoding RNA molecules that post-transcriptionally regulate gene expression by targeting the 3' untranslated region (3'UTR) of specific messenger RNAs (mRNAs) for degradation of translation repression. Genetic ablation of the miRNA machinery, as well as loss or degradation of certain individual miRNAs, severely compromises immune development and response, and can lead to immune disorders. Several sophisticated regulatory mechanisms are used to maintain immune homeostasis. Regulatory T (Treg) cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. Recent publications have provided compelling evidence that miRNAs are highly expressed in Treg cells, that the expression of Foxp3 is controlled by miRNAs and that a range of miRNAs are involved in the regulation of immunity. A large number of studies have reported links between alterations of miRNA homeostasis and pathological conditions such as cancer, cardiovascular disease and diabetes, as well as psychiatric and neurological diseases. Although it is still unclear how miRNA controls Treg cell development and function, recent studies certainly indicate that this topic will be the subject of further research. The specific circulating miRNA species may also be useful for the diagnosis, classification, prognosis of diseases and prediction of the therapeutic response. An explosive literature has focussed on the role of miRNA. In this review, I briefly summarize the current studies about the role of miRNAs in Treg cells and in the regulation of the innate and adaptive immune response. I also review the explosive current studies about clinical application of miRNA.

  11. The roles of regulatory focus and medical recommendation avatars' trustworthiness in virtual environment-based e-health.

    Science.gov (United States)

    Jin, Seung-A Annie

    2010-08-01

    This study examined the influence of regulatory focus and medical recommendation avatars' trustworthiness in avatar-based e-health within 3D virtual environments (VEs). Drawing on Higgins's regulatory focus theory and the existing literature on self-construal, a 2 x 2 (regulatory focus: promotion vs. prevention by interdependent self-construal: low vs. high) between-participants factorial design experiment tested the moderating role of health consumers' interdependent self-construal in determining the effects of regulatory focus in VE-based e-health. Results showed an interaction effect of regulatory focus and interdependent self-construal such that VE users with a dominant interdependent self-construal indicated greater issue familiarity and involvement when exposed to a prevention-focused e-health intervention than when exposed to a promotion-focused e-health intervention, whereas the effects of regulatory focus on issue familiarity and involvement among users low in interdependent self-construal demonstrated the opposite pattern. A path analysis further revealed that VE users' evaluation of a medical recommendation avatar's trustworthiness mediated the effects regulatory focus had on their perceived informational and educational values of the health messages. Theoretical contributions and practical implications for VE-based e-health applications are discussed.

  12. The Regulatory Roles of MicroRNAs in Bone Remodeling and Perspectives as Biomarkers in Osteoporosis.

    Science.gov (United States)

    Sun, Mengge; Zhou, Xiaoya; Chen, Lili; Huang, Shishu; Leung, Victor; Wu, Nan; Pan, Haobo; Zhen, Wanxin; Lu, William; Peng, Songlin

    2016-01-01

    MicroRNAs are involved in many cellular and molecular activities and played important roles in many biological and pathological processes, such as tissue formation, cancer development, diabetes, neurodegenerative diseases, and cardiovascular diseases. Recently, it has been reported that microRNAs can modulate the differentiation and activities of osteoblasts and osteoclasts, the key cells that are involved in bone remodeling process. Meanwhile, the results from our and other research groups showed that the expression profiles of microRNAs in the serum and bone tissues are significantly different in postmenopausal women with or without fractures compared to the control. Therefore, it can be postulated that microRNAs might play important roles in bone remodeling and that they are very likely to be involved in the pathological process of postmenopausal osteoporosis. In this review, we will present the updated research on the regulatory roles of microRNAs in osteoblasts and osteoclasts and the expression profiles of microRNAs in osteoporosis and osteoporotic fracture patients. The perspective of serum microRNAs as novel biomarkers in bone loss disorders such as osteoporosis has also been discussed.

  13. Regulatory role of prolactin in paternal behavior in male parents: A narrative review

    Directory of Open Access Journals (Sweden)

    F Hashemian

    2016-01-01

    Full Text Available In all mammalian species, a combination of neuroendocrine and experiential factors contributes to the emergence of remarkable behavioral changes observed in parental behavior. Yet, our understanding of neuroendocrine bases of paternal behavior in humans is still preliminary and more research is needed in this area. In the present review, the authors summarized hormonal bases of paternal behavior in both human and nonhuman mammalian species and focused on studies on the regulatory role of prolactin in occurrence of paternal behavior. All peer-reviewed journal articles published before 2015 for each area discussed (parental brain, hormonal bases of maternal behavior, hormonal bases of paternal behavior and the role of prolactin in regulation of paternal behavior in nonhuman mammalian species, hormonal bases of paternal behavior and the role of prolactin in regulation of paternal behavior in humans were searched by PubMed, Medline, and Scopus for original research and review articles. Publications between 1973 and 2015 were included. Similar to female parents, elevated prolactin levels in new fathers most probably contribute to child-caring behavior and facilitate behavioral and emotional states attributed to child care. Moreover, elevated parental prolactin levels after childbirth decrease the parents′ libidos so that they invest more in parental care than in fertility behavior. According to the available clinical studies, elevation in the amounts of prolactin levels after childbirth in male parents are probably associated with paternal behavior observed in humans.

  14. Regulatory role of prolactin in paternal behavior in male parents: A narrative review.

    Science.gov (United States)

    Hashemian, F; Shafigh, F; Roohi, E

    2016-01-01

    In all mammalian species, a combination of neuroendocrine and experiential factors contributes to the emergence of remarkable behavioral changes observed in parental behavior. Yet, our understanding of neuroendocrine bases of paternal behavior in humans is still preliminary and more research is needed in this area. In the present review, the authors summarized hormonal bases of paternal behavior in both human and nonhuman mammalian species and focused on studies on the regulatory role of prolactin in occurrence of paternal behavior. All peer-reviewed journal articles published before 2015 for each area discussed (parental brain, hormonal bases of maternal behavior, hormonal bases of paternal behavior and the role of prolactin in regulation of paternal behavior in nonhuman mammalian species, hormonal bases of paternal behavior and the role of prolactin in regulation of paternal behavior in humans) were searched by PubMed, Medline, and Scopus for original research and review articles. Publications between 1973 and 2015 were included. Similar to female parents, elevated prolactin levels in new fathers most probably contribute to child-caring behavior and facilitate behavioral and emotional states attributed to child care. Moreover, elevated parental prolactin levels after childbirth decrease the parents' libidos so that they invest more in parental care than in fertility behavior. According to the available clinical studies, elevation in the amounts of prolactin levels after childbirth in male parents are probably associated with paternal behavior observed in humans.

  15. The Regulatory Roles of MicroRNAs in Bone Remodeling and Perspectives as Biomarkers in Osteoporosis

    Directory of Open Access Journals (Sweden)

    Mengge Sun

    2016-01-01

    Full Text Available MicroRNAs are involved in many cellular and molecular activities and played important roles in many biological and pathological processes, such as tissue formation, cancer development, diabetes, neurodegenerative diseases, and cardiovascular diseases. Recently, it has been reported that microRNAs can modulate the differentiation and activities of osteoblasts and osteoclasts, the key cells that are involved in bone remodeling process. Meanwhile, the results from our and other research groups showed that the expression profiles of microRNAs in the serum and bone tissues are significantly different in postmenopausal women with or without fractures compared to the control. Therefore, it can be postulated that microRNAs might play important roles in bone remodeling and that they are very likely to be involved in the pathological process of postmenopausal osteoporosis. In this review, we will present the updated research on the regulatory roles of microRNAs in osteoblasts and osteoclasts and the expression profiles of microRNAs in osteoporosis and osteoporotic fracture patients. The perspective of serum microRNAs as novel biomarkers in bone loss disorders such as osteoporosis has also been discussed.

  16. Mediating role of self-regulatory efficacy on the relationship between punishment certainty, punishment severity and organizational deviance

    Directory of Open Access Journals (Sweden)

    Kabiru Maitama Kura

    2014-04-01

    Full Text Available Employee deviance is prevalent and could have significant consequences to organizations and/or its members. Drawing upon deterrence theory, this study examined the mediating role of self-regulatory efficacy on the relationship between punishment certainty, punishment severity and organizational deviance. The participants were 197 employed postgraduate students who enrolled in the Master of Business Administration programme at two universities located in the north-west geopolitical zone of Nigeria. The model tested suggests that both punishment certainty and punishment severity predict organizational deviance through the influence of self-regulatory efficacy. Results suggest that self-regulatory efficacy partially mediates the relationship between punishment certainty and organizational deviance. Similarly, results suggest that the relationship between punishment severity and organizational deviance was partially mediated by self-regulatory efficacy.

  17. [The role of T-regulatory cells in the pathogenesis of immunological disturbances accompanying obesity and atherosclerosis].

    Science.gov (United States)

    Luczyński, Włodzimierz; Bossowski, Artur; Głowińska-Olszewska, Barbara; Kos, Justyna; Stasiak-Barmuta, Anna

    2010-03-30

    Obesity and atherosclerosis, and their consequences, including cardiovascular disease, are plagues of the 21st century. Chronic inflammation, whose mechanism is not well understood, underlies the pathophysiological bases of both processes. T lymphocytes, macrophages, and the proinflammatory cytokines produced by these cells play key roles in the immunological disturbances accompanying obesity and atherosclerosis. It was recently shown that T-regulatory cells can play a role in these processes. T-regulatory cells are a small subpopulation of T cells which are responsible for inhibition of the immune response. In this review, experiments conducted in mice and human models on the role of diminished number and/or function of T-regulatory lymphocytes in the pathogenesis of immune disturbances accompanying obesity and atherosclerosis are discussed. The results of studies using T-regulatory cells to stabilize and decrease atherosclerotic lesions in blood vessel walls are also summarized. The results of experiments performed so far are encouraging and give some hope for the future use of T-regulatory cells in the therapy of obesity and atherosclerosis.

  18. The role of T-regulatory cells in the pathogenesis of immunological disturbances accompanying obesity and atherosclerosis

    Directory of Open Access Journals (Sweden)

    Włodzimierz Łuczyński

    2010-03-01

    Full Text Available Obesity and atherosclerosis, and their consequences, including cardiovascular disease, are plagues of the 21st century. Chronic inflammation, whose mechanism is not well understood, underlies the pathophysiological bases of both processes. T lymphocytes, macrophages, and the proinflammatory cytokines produced by these cells play key roles in the immunological disturbances accompanying obesity and atherosclerosis. It was recently shown that T-regulatory cells can play a role in these processes. T-regulatory cells are a small subpopulation of T cells which are responsible for inhibition of the immune response. In this review, experiments conducted in mice and human models on the role of diminished number and/or function of T-regulatory lymphocytes in the pathogenesis of immune disturbances accompanying obesity and atherosclerosis are discussed. The results of studies using T-regulatory cells to stabilize and decrease atherosclerotic lesions in blood vessel walls are also summarized. The results of experiments performed so far are encouraging and give some hope for the future use of T-regulatory cells in the therapy of obesity and atherosclerosis.

  19. Regulatory roles of microtubule-associated proteins in neuronal morphogenesis. Involvement of the extracellular matrix

    Directory of Open Access Journals (Sweden)

    Ramírez G.

    1999-01-01

    Full Text Available As a result of recent investigations, the cytoskeleton can be viewed as a cytoplasmic system of interconnected filaments with three major integrative levels: self-assembling macromolecules, filamentous polymers, e.g., microtubules, intermediate filaments and actin filaments, and supramolecular structures formed by bundles of these filaments or networks resulting from cross-bridges between these major cytoskeletal polymers. The organization of this biological structure appears to be sensitive to fine spatially and temporally dependent regulatory signals. In differentiating neurons, regulation of cytoskeleton organization is particularly relevant, and the microtubule-associated protein (MAP tau appears to play roles in the extension of large neuritic processes and axons as well as in the stabilization of microtubular polymers along these processes. Within this context, tau is directly involved in defining neuronal polarity as well as in the generation of neuronal growth cones. There is increasing evidence that elements of the extracellular matrix contribute to the control of cytoskeleton organization in differentiating neurons, and that these regulations could be mediated by changes in MAP activity. In this brief review, we discuss the possible roles of tau in mediating the effects of extracellular matrix components on the internal cytoskeletal arrays and its organization in growing neurons.

  20. Potential gene regulatory role for cyclin D3 in muscle cells

    Indian Academy of Sciences (India)

    Fathima Athar; Veena K Parnaik

    2015-09-01

    Cyclin D3 is important for muscle development and regeneration, and is involved in post-mitotic arrest of muscle cells. Cyclin D3 also has cell-cycle-independent functions such as regulation of specific genes in other tissues. Ectopic expression of cyclin D3 in myoblasts, where it is normally undetectable, promotes muscle gene expression and faster differentiation kinetics upon serum depletion. In the present study, we investigated the mechanistic role of cyclin D3 in muscle gene regulation. We initially showed by mutational analysis that a stable and functional cyclin D3 was required for promoting muscle differentiation. Using chromatin immunoprecipitation assays, we demonstrated that expression of cyclin D3 in undifferentiated myoblasts altered histone epigenetic marks at promoters of muscle-specific genes like MyoD, Pax7, myogenin and muscle creatine kinase but not non-muscle genes. Cyclin D3 expression also reduced the mRNA levels of certain epigenetic modifier genes. Our data suggest that epigenetic modulation of muscle-specific genes in cyclin-D3-expressing myoblasts may be responsible for faster differentiation kinetics upon serum depletion. Our results have implications for a regulatory role for cyclin D3 in muscle-specific gene activation.

  1. Role of Toll-like receptors in regulatory functions of T and B cells

    Institute of Scientific and Technical Information of China (English)

    CHANG ZongLiang

    2008-01-01

    Pathogens can find their ways to most sites in the host. Pathogen sensors, such as Toll-like receptors (TLRs), must be equally and broadly distributed on immune cells to combat them through innate and adaptive immunity. Most classes of TLRs are found in innate immune cells to obtain an immediate re-sponse against pathogens, but recent studies indicate that a number of TLRs are wildly expressed in T and B cells, suggesting TLRs also directly regulate adaptive immune responses. Due to the rapid in-crease of new information on the multiple roles of TLRs, in this paper we aim to review several main properties of TLRs and their direct role in T and B cells. This review consists of 6 parts: (ⅰ) Characteris-tics of Toll-like receptors (TLRs) and signaling; (ⅱ) signalling pathways of TLRs; (ⅲ) TLR expressions on human leukocytes; (ⅳ) TLR expressions and functions in the Th1, CD4+CD45RO+ memory T cells and regulatory/suppressor T as well as B cell populations; (ⅴ) therapeutic potential of TLR agonists; (ⅵ) discussion and perspective. The latest findings and potential therapeutic applications are discussed. There is growing evidence supporting the concept that TLR activation contributes not only to innate immunity but also to adaptive immunity, including direct regulation of both T and B lymphocytes by TLRs.

  2. Dissecting role of regulatory factors in NF-κB pathway with siRNA

    Institute of Scientific and Technical Information of China (English)

    Jun GUO; Yu-cai FU; Carlos R BECERRA

    2005-01-01

    NF-κB, a family of related transcription factors, has been a focus of intense scientific research during the past decade.Multiple stimuli, both extracellular and intracellular, lead to its activation.The NF-κB pathway regulates expression of a diverse array of genes involved in different biological processes.Various pathological states are characterized by the dysregulated NF-κB pathway.Recently,NF-κB activation has been connected with multiple aspects of oncogenesis and serves as an important mechanism to regulate cell survival in response to chemotherapy by activating different genes that inhibit apoptosis.Several methods of inhibiting NF-κB activation, such as antisense oligonucleotides, proteosome inhibitors and RNA interference (RNAi) are currently under investigation.RNAi represents a powerful tool to better define the role of specific genes in different signal transduction pathways and has recently been used to define the function of genes that regulate the NF-κB pathway.This review discusses the emerging role of RNAi to dissect the function of regulatory factors in the NF-κB pathway and its potential use as a targeted therapy.

  3. Multiple Roles of MYC in Integrating Regulatory Networks of Pluripotent Stem Cells

    Science.gov (United States)

    Fagnocchi, Luca; Zippo, Alessio

    2017-01-01

    Pluripotent stem cells (PSCs) are defined by their self-renewal potential, which permits their unlimited propagation, and their pluripotency, being able to generate cell of the three embryonic lineages. These properties render PSCs a valuable tool for both basic and medical research. To induce and stabilize the pluripotent state, complex circuitries involving signaling pathways, transcription regulators and epigenetic mechanisms converge on a core transcriptional regulatory network of PSCs, thus determining their cell identity. Among the transcription factors, MYC represents a central hub, which modulates and integrates multiple mechanisms involved both in the maintenance of pluripotency and in cell reprogramming. Indeed, it instructs the PSC-specific cell cycle, metabolism and epigenetic landscape, contributes to limit exit from pluripotency and modulates signaling cascades affecting the PSC identity. Moreover, MYC extends its regulation on pluripotency by controlling PSC-specific non-coding RNAs. In this report, we review the MYC-controlled networks, which support the pluripotent state and discuss how their perturbation could affect cell identity. We further discuss recent finding demonstrating a central role of MYC in triggering epigenetic memory in PSCs, which depends on the establishment of a WNT-centered self-reinforcing circuit. Finally, we comment on the therapeutic implications of the role of MYC in affecting PSCs. Indeed, PSCs are used for both disease and cancer modeling and to derive cells for regenerative medicine. For these reasons, unraveling the MYC-mediated mechanism in those cells is fundamental to exploit their full potential and to identify therapeutic targets. PMID:28217689

  4. Possible regulatory role of phenylalanine ammonia-lyase in the production of anthocyanins in asparagus (Asparagus officinalis L)

    NARCIS (Netherlands)

    Flores, F.B.; Oosterhaven, J.; Martinez-Madrid, M.C.; Romojaro, F.

    2005-01-01

    The regulatory role of phenylalanine ammonia-lyase (PAL) in the light-induced accumulation of anthocyanins in the epidermis of asparagus spears has been analysed. A correlation between the stimulation of PAL activity and the rise in total anthocyanin content has been observed. Light radiation induce

  5. Induction and measurement of IgE : a study in mice, with emphasis on the regulatory role of lymphokines

    NARCIS (Netherlands)

    H.F.J. Savelkoul (Huub)

    1988-01-01

    textabstractA better understanding of the regulatory mechanisms and cellular interactions of the IgE antibody response is of fundamental interest to allergologists and clinical immunologists because of the role of IgE in the pathogenesis of the immediate type allergic disease. In addition, basic kno

  6. Possible regulatory role of phenylalanine ammonia-lyase in the production of anthocyanins in asparagus (Asparagus officinalis L)

    NARCIS (Netherlands)

    Flores, F.B.; Oosterhaven, J.; Martinez-Madrid, M.C.; Romojaro, F.

    2005-01-01

    The regulatory role of phenylalanine ammonia-lyase (PAL) in the light-induced accumulation of anthocyanins in the epidermis of asparagus spears has been analysed. A correlation between the stimulation of PAL activity and the rise in total anthocyanin content has been observed. Light radiation induce

  7. Possible regulatory role of phenylalanine ammonia-lyase in the production of anthocyanins in asparagus (Asparagus officinalis L)

    NARCIS (Netherlands)

    Flores, F.B.; Oosterhaven, J.; Martinez-Madrid, M.C.; Romojaro, F.

    2005-01-01

    The regulatory role of phenylalanine ammonia-lyase (PAL) in the light-induced accumulation of anthocyanins in the epidermis of asparagus spears has been analysed. A correlation between the stimulation of PAL activity and the rise in total anthocyanin content has been observed. Light radiation

  8. Dual regulatory role for phosphatase and tensin homolog in specification of intestinal endocrine cell subtypes

    Institute of Scientific and Technical Information of China (English)

    Sébastien AB Roy; Marie-Josée Langlois; Julie C Carrier; Fran(c)ois Boudreau; Nathalie Rivard; Nathalie Perreault

    2012-01-01

    AIM:To investigate the impact of phosphatase and tensin homolog (Pten) in the specification of intestinal enteroendocrine subpopulations.METHODS:Using the Cre/IoxP system,a mouse with conditional intestinal epithelial Pten deficiency was generated.Pten mutant mice and controls were sacrificed and small intestines collected for immunofluorescence and quantitative real-time polymerase chain reaction.Blood was collected on 16 h fasted mice by cardiac puncture.Enzyme-linked immunosorbent assay was used to measure blood circulating ghrelin,somatostatin (SST) and glucose-dependent insulinotropic peptide (GIP) levels.RESULTS:Results show an unexpected dual regulatory role for epithelial Pten signalling in the specification/differentiation of enteroendocrine cell subpopulations in the small intestine.Our data indicate that Pten positively regulates chromogranin A (CgA) expressing subpopulations,including cells expressing secretin,ghrelin,gastrin and cholecystokinin (CCK).In contrast,Pten negatively regulates the enteroendocrine subtype specification of non-expressing CgA cells such as GIP and SST expressing cells.CONCLUSION:The present results demonstrate that Pten signalling favours the enteroendocrine progenitor to specify into cells expressing CgA including those producing CCK,gastrin and ghrelin.

  9. The Regulatory Role of MicroRNAs in EMT and Cancer

    Directory of Open Access Journals (Sweden)

    Apostolos Zaravinos

    2015-01-01

    Full Text Available The epithelial to mesenchymal transition (EMT is a powerful process in tumor invasion, metastasis, and tumorigenesis and describes the molecular reprogramming and phenotypic changes that are characterized by a transition from polarized immotile epithelial cells to motile mesenchymal cells. It is now well known that miRNAs are important regulators of malignant transformation and metastasis. The aberrant expression of the miR-200 family in cancer and its involvement in the initiation and progression of malignant transformation has been well demonstrated. The metastasis suppressive role of the miR-200 members is strongly associated with a pathologic EMT. This review describes the most recent advances regarding the influence of miRNAs in EMT and the control they exert in major signaling pathways in various cancers. The ability of the autocrine TGF-β/ZEB/miR-200 signaling regulatory network to control cell plasticity between the epithelial and mesenchymal state is further discussed. Various miRNAs are reported to directly target EMT transcription factors and components of the cell architecture, as well as miRNAs that are able to reverse the EMT process by targeting the Notch and Wnt signaling pathways. The link between cancer stem cells and EMT is also reported and the most recent developments regarding clinical trials that are currently using anti-miRNA constructs are further discussed.

  10. The Role of Regulatory T Cells and TH17 Cells in Multiple Myeloma

    Directory of Open Access Journals (Sweden)

    Walter M. T. Braga

    2012-01-01

    Full Text Available The development of multiple myeloma (MM involves a series of genetic alterations and changes in the bone marrow microenvironment, favoring the growth of the tumor and failure of local immune control. Quantitative and functional alterations in CD4+ and CD8+ T cells have been described in MM. The balance between T regulatory cells (Treg and T helper (Th 17 cells represents one essential prerequisite for maintaining anti-tumor immunity in MM. Tregs play an important role in the preservation of self-tolerance and modulation of overall immune responses against infections and tumor cells. In MM patients, Tregs seem to contribute to myeloma-related immune dysfunction and targeting them could, therefore, help to restore and enhance vital immune responses. Th17 cells protect against fungal and parasitic infections and participate in inflammatory reactions and autoimmunity. The interplay of TGF-β and IL-6, expressed at high levels in the bone marrow of myeloma patients, may affect generation of Th17 cells both directly or via other pro-inflammatory cytokines and thereby modulate antitumor immune responses. A detailed analysis of the balance between Tregs and Th17 cells seems necessary in order to design more effective and less toxic modes of immunotherapy myeloma which still is an uncurable malignancy.

  11. Role of Glucokinase in the Subcellular Localization of Glucokinase Regulatory Protein

    Directory of Open Access Journals (Sweden)

    Ling Jin

    2015-04-01

    Full Text Available Glucokinase (GCK is the rate-limiting enzyme of liver glucose metabolism. Through protein-protein interactions, glucokinase regulatory protein (GCKR post-transcriptionally regulates GCK function in the liver, and causes its nuclear localization. However the role of GCK in regulating GCKR localization is unknown. In the present study, using in vitro and in vivo models, we examined the levels of GCK and GCKR, and their subcellular localization. We found that total cellular levels of GCKR did not vary in the in vivo models, but its subcellular localization did. In animals with normal levels of GCK, GCKR is mainly localized to the nuclei of hepatocytes. In seven-day old rats and liver-specific Gck gene knockout mice (animals that lack or have reduced levels of GCK protein, GCKR was found primarily in the cytoplasm. The interaction of GCK with GCKR was further examined using in vitro models where we varied the levels of GCK and GCKR. Varying the level of GCK protein had no effect on total cellular GCKR protein levels. Taken together, our results indicate that GCK is important for the localization of GCKR to the nucleus and raises the possibility that GCKR may have functions in addition to those regulating GCK activity in the cytoplasm.

  12. Ghrelin, Des-Acyl Ghrelin, and Obestatin: Regulatory Roles on the Gastrointestinal Motility

    Directory of Open Access Journals (Sweden)

    Mineko Fujimiya

    2010-01-01

    Full Text Available Ghrelin, des-acyl ghrelin, and obestatin are derived from a common prohormone, preproghrelin by posttranslational processing, originating from endocrine cells in the stomach. To examine the regulatory roles of these peptides, we applied the manometric measurement of gastrointestinal motility in freely moving conscious rat or mouse model. Ghrelin exerts stimulatory effects on the motility of antrum and duodenum in both fed and fasted state of animals. Des-acyl ghrelin exerts inhibitory effects on the motility of antrum but not on the motility of duodenum in the fasted state of animals. Obestatin exerts inhibitory effects on the motility of antrum and duodenum in the fed state but not in the fasted state of animals. NPY Y2 and Y4 receptors in the brain may mediate the action of ghrelin, CRF type 2 receptor in the brain may mediate the action of des-acyl ghrelin, whereas CRF type 1 and type 2 receptors in the brain may mediate the action of obestatin. Vagal afferent pathways might be involved in the action of ghrelin, but not involved in the action of des-acyl ghrelin, whereas vagal afferent pathways might be partially involved in the action of obestatin.

  13. Spatial proximity statistics suggest a regulatory role of protein phosphorylation on compound binding.

    Science.gov (United States)

    Korkuć, Paula; Walther, Dirk

    2016-05-01

    Phosphorylation is an important post-translational modification that regulates protein function by the attachment of negatively charged phosphate groups to phosphorylatable amino acid residues. As a mode of action, an influence of phosphorylation on the binding of compounds to proteins has been discussed and described for a number of proteins in the literature. However, a systematic statistical survey probing for enriched phosphorylation sites close to compound binding sites in support of this notion and with properly chosen random reference distributions has not been presented yet. Using high-resolution protein structures from the Protein Data Bank including their co-crystallized non-covalently bound compounds and experimentally determined phosphorylation sites, we analyzed the pairwise distance distributions of phosphorylation and compound binding sites on protein surfaces. We found that phosphorylation sites are indeed located at significantly closer distances to compounds than expected by chance holding true specifically also for the subset of compound binding sites serving as catalytic sites of metabolic reactions. This tendency was particularly evident when treating phosphorylation sites as collective sets supporting the relevance of phosphorylation hotspots. Interestingly, phosphorylation sites were found to be closer to negatively charged than to positively charged compounds suggesting a stronger modulation of the binding of negatively charged compounds in dependence on phosphorylation status than on positively charged compounds. The enrichment of phosphorylation sites near compound binding sites confirms a regulatory role of phosphorylation in compound binding and provides a solid statistical basis for the literature-reported selected events.

  14. Role of cytokines in thymus- versus peripherally derived- regulatory T cell differentiation and function

    Directory of Open Access Journals (Sweden)

    jérémie david Goldstein

    2013-06-01

    Full Text Available CD4+CD25+Foxp3+ regulatory T cells (Tregs are essential players in the control of immune responses. Recently, accordingly to their origin, two main subsets of Tregs have been described: thymus-derived Tregs (tTregs and peripherally derived Tregs (pTregs. Numerous signaling pathways including the IL-2/STAT5 or the TGF-β/Smad3 pathways play a crucial role in segregating the two lineages. Here, we review some of the information existing on the distinct requirements of IL-2, TGF-β and TNF-α three major cytokines involved in tTreg and pTreg generation, homeostasis and function. Today it is clear that signaling via the IL-2Rβ chain (CD122 common to IL-2 and IL-15 is required for proper differentiation of tTregs and for tTreg and pTreg survival in the periphery. This notion has led to the development of promising therapeutic strategies based on low-dose IL-2 administration to boost the patients' own Treg compartment and dampen autoimmunity and inflammation. Also, solid evidence points to TGF-β as the master regulator of pTreg differentiation and homeostasis. However, therapeutic administration of TGF-β is difficult to implement due to toxicity and safety issues. Knowledge on the role of TNF-α on the biology of Tregs is fragmentary and inconsistent between mice and humans. Moreover, emerging results from the clinical use of TNF-α inhibitors indicate that part of their anti-inflammatory effect may be dependent on their action on Tregs. Given the profusion of clinical trials testing cytokine administration or blocking to modulate inflammatory diseases, a better knowledge of the effects of cytokines on tTregs and pTregs biology is necessary to improve the efficiency of these immunotherapies.

  15. Enamel wear opposing polished and aged zirconia.

    Science.gov (United States)

    Burgess, J O; Janyavula, S; Lawson, N C; Lucas, T J; Cakir, D

    2014-01-01

    Aging of dental zirconia roughens its surface through low temperature degradation. We hypothesized that age-related roughening of zirconia crowns may cause detrimental wear to the enamel of an opposing tooth. To test our hypothesis, we subjected artificially aged zirconia and reference specimens to simulated mastication in a wear device and measured the wear of an opposing enamel cusp. Additionally, the roughness of the pretest surfaces was measured. The zirconia specimens, artificially aged by autoclave, showed no significant increase in roughness compared to the nonaged specimens. Furthermore, no significant difference in material or opposing enamel wear between the aged and nonaged zirconia was seen. All zirconia specimens showed less material and opposing enamel wear than the enamel to enamel control or veneering porcelain specimens. Scanning electron micrographs showed relatively smooth surfaces of aged and nonaged zirconia following wear testing. The micrographs of the veneering ceramic showed sharp fractured edges and fragments of wear debris. Zirconia may be considered a wear-friendly material for restorations opposing enamel, even after simulated aging.

  16. Wind wave source functions in opposing seas

    KAUST Repository

    Langodan, Sabique

    2015-08-26

    The Red Sea is a challenge for wave modeling because of its unique two opposed wave systems, forced by opposite winds and converging at its center. We investigate the different physical aspects of wave evolution and propagation in the convergence zone. The two opposing wave systems have similar amplitude and frequency, each driven by the action of its own wind. Wave patterns at the centre of the Red Sea, as derived from extensive tests and intercomparison between model and measured data, suggest that the currently available wave model source functions may not properly represent the evolution of the local fields that appear to be characterized by a less effective wind input and an enhanced white-capping. We propose and test a possible simple solution to improve the wave-model simulation under opposing winds and waves condition. This article is protected by copyright. All rights reserved.

  17. Comparative analysis of the ATRX promoter and 5' regulatory region reveals conserved regulatory elements which are linked to roles in neurodevelopment, alpha-globin regulation and testicular function

    Directory of Open Access Journals (Sweden)

    Argentaro Anthony

    2011-06-01

    Full Text Available Abstract Background ATRX is a tightly-regulated multifunctional protein with crucial roles in mammalian development. Mutations in the ATRX gene cause ATR-X syndrome, an X-linked recessive developmental disorder resulting in severe mental retardation and mild alpha-thalassemia with facial, skeletal and genital abnormalities. Although ubiquitously expressed the clinical features of the syndrome indicate that ATRX is not likely to be a global regulator of gene expression but involved in regulating specific target genes. The regulation of ATRX expression is not well understood and this is reflected by the current lack of identified upstream regulators. The availability of genomic data from a range of species and the very highly conserved 5' regulatory regions of the ATRX gene has allowed us to investigate putative transcription factor binding sites (TFBSs in evolutionarily conserved regions of the mammalian ATRX promoter. Results We identified 12 highly conserved TFBSs of key gene regulators involved in biologically relevant processes such as neural and testis development and alpha-globin regulation. Conclusions Our results reveal potentially important regulatory elements in the ATRX gene which may lead to the identification of upstream regulators of ATRX and aid in the understanding of the molecular mechanisms that underlie ATR-X syndrome.

  18. Regulatory roles of serotonin and melatonin in abiotic stress tolerance in plants.

    Science.gov (United States)

    Kaur, Harmeet; Mukherjee, Soumya; Baluska, Frantisek; Bhatla, Satish C

    2015-01-01

    Understanding the physiological and biochemical basis of abiotic stress tolerance in plants has always been one of the major aspects of research aiming to enhance plant productivity in arid and semi-arid cultivated lands all over the world. Growth of stress-tolerant transgenic crops and associated agricultural benefits through increased productivity, and related ethical issues, are also the major concerns of current research in various laboratories. Interesting data on the regulation of abiotic stress tolerance in plants by serotonin and melatonin has accumulated in the recent past. These two indoleamines possess antioxidative and growth-inducing properties, thus proving beneficial for stress acclimatization. Present review shall focus on the modes of serotonin and melatonin-induced regulation of abiotic stress tolerance in plants. Complex molecular interactions of serotonin and auxin-responsive genes have suggested their antagonistic nature. Data from genomic and metabolomic analyses of melatonin-induced abiotic stress signaling have lead to an understanding of the regulation of stress tolerance through the modulation of transcription factors, enzymes and various signaling molecules. Melatonin, nitric oxide (NO) and calmodulin interactions have provided new avenues for research on the molecular aspects of stress physiology in plants. Investigations on the characterization of receptors associated with serotonin and melatonin responses, are yet to be undertaken in plants. Patenting of biotechnological inventions pertaining to serotonin and melatonin formulations (through soil application or foliar spray) are expected to be some of the possible ways to regulate abiotic stress tolerance in plants. The present review, thus, summarizes the regulatory roles of serotonin and melatonin in modulating the signaling events accompanying abiotic stress in plants.

  19. Spatially distinct regulatory roles for gibberellins in the promotion of flowering of Arabidopsis under long photoperiods.

    Science.gov (United States)

    Porri, Aimone; Torti, Stefano; Romera-Branchat, Maida; Coupland, George

    2012-06-01

    The plant growth regulator gibberellin (GA) contributes to many developmental processes, including the transition to flowering. In Arabidopsis, GA promotes this transition most strongly under environmental conditions such as short days (SDs) when other regulatory pathways that promote flowering are not active. Under SDs, GAs activate transcription of SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1) and LEAFY (LFY) at the shoot meristem, two genes encoding transcription factors involved in flowering. Here, the tissues in which GAs act to promote flowering were tested under different environmental conditions. The enzyme GIBBERELLIN 2 OXIDASE 7 (GA2ox7), which catabolizes active GAs, was overexpressed in most tissues from the viral CaMV 35S promoter, specifically in the vascular tissue from the SUCROSE TRANSPORTER 2 (SUC2) promoter or in the shoot apical meristem from the KNAT1 promoter. We find that under inductive long days (LDs), GAs are required in the vascular tissue to increase the levels of FLOWERING LOCUS T (FT) and TWIN SISTER OF FT (TSF) mRNAs, which encode a systemic signal transported from the leaves to the meristem during floral induction. Similarly, impairing GA signalling in the vascular tissue reduces FT and TSF mRNA levels and delays flowering. In the meristem under inductive LDs, GAs are not required to activate SOC1, as reported under SDs, but for subsequent steps in floral induction, including transcription of genes encoding SQUAMOSA PROMOTER BINDING PROMOTER LIKE (SPL) transcription factors. Thus, GA has important roles in promoting transcription of FT, TSF and SPL genes during floral induction in response to LDs, and these functions are spatially separated between the leaves and shoot meristem.

  20. Structural insights on mouse L-threonine dehydrogenase: A regulatory role of Arg180 in catalysis.

    Science.gov (United States)

    He, Chao; Huang, Xianyu; Liu, Yanhong; Li, Fudong; Yang, Yang; Tao, Hongru; Han, Chuanchun; Zhao, Chen; Xiao, Yazhong; Shi, Yunyu

    2015-12-01

    Mouse L-threonine dehydrogenase (mTDH), which belongs to the short-chain dehydrogenase/reductase (SDR) superfamily and mediates threonine catabolism, plays pivotal roles in both powerful biosynthesis and signaling in mouse stem cells and has a regulatory residue Arg180. Here we determined three crystal structures of mTDH: wild-type (WT) in the apo form; in complex with NAD(+) and a substrate analog, glycerol, or with only NAD(+); as well as the R180K variant with NAD(+). This is the first description of a structure for mammalian SDR-type TDH. Structural comparison revealed the structural basis for SDR-type TDH catalysis remains strictly conserved in bacteria and mammals. Kinetic enzyme assays, and isothermal titration calorimetry (ITC) measurements indicated the R180K mutation has little effect on NAD(+) binding affinity, whereas affects the substrate's affinity for the enzyme. The crystal structure of R180K with NAD(+), biochemical and spectroscopic studies suggested that the R180K mutant should bind NAD(+) in a similar way and have a similar folding to the WT. However, the R180K variant may have difficulty adopting the closed form due to reduced interaction of residue 180 with a loop which connects a key position for mTDH switching between the closed and open forms in mTDH catalysis, and thereby exhibited a significantly decreased kcat/Km value toward the substrate, L-Thr. In sum, our results suggest that activity of GalE-like TDH can be regulated by remote interaction, such as hydrogen bonding and hydrophobic interaction around the Arg180 of mTDH.

  1. Building a self-regulatory model of sleep deprivation and deception: the role of caffeine and social influence.

    Science.gov (United States)

    Welsh, David T; Ellis, Aleksander P J; Christian, Michael S; Mai, Ke Michael

    2014-11-01

    Employees are getting less sleep, which has been shown to deplete self-regulatory resources and increase unethical behavior (Barnes, Schaubroeck, Huth, & Ghumman, 2011; Christian & Ellis, 2011). In this study, we extend the original mediated model by examining the role of 2 moderators in the relationship between sleep deprivation, depletion, and deceptive behavior. First, we derive psychological arguments from the psychopharmacology literature to hypothesize that caffeine moderates the relationship between sleep deprivation and depletion by replenishing self-regulatory resources. Second, we draw from recent research in social psychology to hypothesize that social influence moderates the relationship between depletion and deceptive behavior, such that depleted individuals are less able to resist the negative influence of others. Results of a laboratory study provide support for our expanded model combining mediation and moderation, adding to our understanding of the role of sleep deprivation in the incidence of workplace deception. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

  2. Opposed Bellows Would Expel Contents Of Tank

    Science.gov (United States)

    Whitaker, Willie

    1994-01-01

    Proposed storage tank contains two pairs of opposed bellows used to expel its contents. Storage and expulsion volumes of tank same as those of older version of tank equipped with single bellows. Four bellows offer greater stability. Applications include automobile cooling systems and gasoline-powered tools like chain saws and leaf blowers.

  3. A novel in vivo regulatory role of P-glycoprotein in alloimmunity

    Science.gov (United States)

    Izawa, Atsushi; Schatton, Tobias; Frank, Natasha Y.; Ueno, Takuya; Yamaura, Kazuhiro; Pendse, Shona S.; Margaryan, Armen; Grimm, Martin; Gasser, Martin; Waaga-Gasser, Ana Maria; Sayegh, Mohamed H.; Frank, Markus H.

    2013-01-01

    P-glycoprotein (P-gp) is required for adaptive immunity through defined functions in T cell activation and antigen presenting cell (APC) maturation. The potential role of P-gp as an in vivo regulator of alloimmunity is currently unknown. Here we show that P-gp blockade prolongs graft survival in a murine heterotopic cardiac allotransplantation model through in vivo inhibition of the T helper 1 (Th1) cytokine IFN-γ and the Th2 product IL-4, and via downregulation of the APC-expressed positive costimulatory molecule CD80. In vitro, the P-gp antagonist PSC833, a non-calcineurin-inhibitory cyclosporine A analogue, specifically inhibited cellular efflux of the P-gp substrate rhodamine-123 in wild-type CD3+ T cells and MHC class II+ APCs but not their P-gp knockout counterparts that lacked rhodamine-123 efflux capacity. Additionally, P-gp blockade significantly inhibited murine alloimmune T cell activation in a dose-dependent fashion. In vivo, P-gp blockade significantly prolonged graft survival in Balb/c recipients of C57BL/6 cardiac allografts from 8.5±0.5 to 11.7±0.5 days (P<0.01), similar in magnitude to the effects of monotherapy with cyclosporine A. Moreover, P-gp blockade, compared to controls, attenuated intragraft expression of CD3 and CD80, but not CD86, and inhibited IFN-γ and IL-4 production (P<0.05). In the setting of systemic CD86 inhibition, P-gp blockade suppressed IFN-γ and IL-4 production significantly further (to 98%and 89% inhibition, respectively) compared to either P-gp or anti-CD86 blockade alone, and markedly prolonged allograft survival compared to anti-CD86 blockade alone (40.5±4.6 vs. 22.5±2.6 days, respectively, P<0.01). Our findings define a novel in vivo regulatory role of P-gp in alloimmunity and identify P-gp as a potential therapeutic target in allotransplantation. PMID:20230790

  4. Stress spillover in early marriage: the role of self-regulatory depletion.

    Science.gov (United States)

    Buck, April A; Neff, Lisa A

    2012-10-01

    Stressful experiences external to a marriage (e.g., work stress, finances) are often associated with poor relationship functioning and lowered marital satisfaction, a phenomenon called stress spillover. To date, however, little attention has been devoted to understanding the specific mechanisms through which stress may lead to maladaptive relationship patterns. Drawing from theories of self-regulatory depletion, it was predicted that coping with external stress is an effortful process that consumes spouses' regulatory resources, leaving spouses with less energy to effectively respond to their relationship issues. The current study relied on a sample of newly married couples to examine whether self-regulatory depletion may account for the link between external stress and relationship well-being. Couples were asked to complete a 14-day daily diary that assessed their daily stress, their state of self-regulatory depletion, their marital behaviors, and their daily marital appraisals. Within-person analyses revealed that, on average, couples experienced stress spillover, such that on days when their stress was higher than usual they reported enacting more negative behaviors toward their partner and endorsed less positive appraisals of the relationship. Further analyses confirmed that self-regulatory depletion accounted for a majority of these spillover effects. These findings suggest that even happy couples may find it difficult to engage in adaptive relationship processes under conditions of stress.

  5. Digital management and regulatory submission of medical images from clinical trials: role and benefits of the core laboratory

    Science.gov (United States)

    Robbins, William L.; Conklin, James J.

    1995-10-01

    Medical images (angiography, CT, MRI, nuclear medicine, ultrasound, x ray) play an increasingly important role in the clinical development and regulatory review process for pharmaceuticals and medical devices. Since medical images are increasingly acquired and archived digitally, or are readily digitized from film, they can be visualized, processed and analyzed in a variety of ways using digital image processing and display technology. Moreover, with image-based data management and data visualization tools, medical images can be electronically organized and submitted to the U.S. Food and Drug Administration (FDA) for review. The collection, processing, analysis, archival, and submission of medical images in a digital format versus an analog (film-based) format presents both challenges and opportunities for the clinical and regulatory information management specialist. The medical imaging 'core laboratory' is an important resource for clinical trials and regulatory submissions involving medical imaging data. Use of digital imaging technology within a core laboratory can increase efficiency and decrease overall costs in the image data management and regulatory review process.

  6. Targeted resequencing of regulatory regions at schizophrenia risk loci: Role of rare functional variants at chromatin repressive states.

    Science.gov (United States)

    González-Peñas, Javier; Amigo, Jorge; Santomé, Luis; Sobrino, Beatriz; Brenlla, Julio; Agra, Santiago; Paz, Eduardo; Páramo, Mario; Carracedo, Ángel; Arrojo, Manuel; Costas, Javier

    2016-07-01

    There is mounting evidence that regulatory variation plays an important role in genetic risk for schizophrenia. Here, we specifically search for regulatory variants at risk by sequencing promoter regions of twenty-three genes implied in schizophrenia by copy number variant or genome-wide association studies. After strict quality control, a total of 55,206bp per sample were analyzed in 526 schizophrenia cases and 516 controls from Galicia, NW Spain, using the Applied Biosystems SOLiD System. Variants were filtered based on frequency from public databases, chromatin states from the RoadMap Epigenomics Consortium at tissues relevant for schizophrenia, such as fetal brain, mid-frontal lobe, and angular gyrus, and prediction of functionality from RegulomeDB. The proportion of rare variants at polycomb repressive chromatin state at relevant tissues was higher in cases than in controls. The proportion of rare variants with predicted regulatory role was significantly higher in cases than in controls (P=0.0028, OR=1.93, 95% C.I.=1.23-3.04). Combination of information from both sources led to the identification of an excess of carriers of rare variants with predicted regulatory role located at polycomb repressive chromatin state at relevant tissues in cases versus controls (P=0.0016, OR=19.34, 95% C.I.=2.45-2495.26). The variants are located at two genes affected by the 17q12 copy number variant, LHX1 and HNF1B. These data strongly suggest that a specific epigenetic mechanism, chromatin remodeling by histone modification during early development, may be impaired in a subset of schizophrenia patients, in agreement with previous data.

  7. The pleasures and pains of distinct self-construals: the role of interdependence in regulatory focus.

    Science.gov (United States)

    Lee, A Y; Aaker, J L; Gardner, W L

    2000-06-01

    Regulatory focus theory distinguishes between self-regulatory processes that focus on promotion and prevention strategies for goal pursuit. Five studies provide support for the hypothesis that these strategies differ for individuals with distinct self-construals. Specifically, individuals with a dominant independent self-construal were predicted to place more emphasis on promotion-focused information, and those with a dominant interdependent self-construal on prevention-focused information. Support for this hypothesis was obtained for participants who scored high versus low on the Self-Construal Scale, participants who were presented with an independent versus interdependent situation, and participants from a Western versus Eastern culture. The influence of interdependence on regulatory focus was observed in both importance ratings of information and affective responses consistent with promotion or prevention focus.

  8. Role of Regulatory T cell in Clinical Outcome of Traumatic Brain Injury

    Institute of Scientific and Technical Information of China (English)

    Min Li; Yun-Peng Lin; Jie-Li Chen; Hong Li; Rong-Cai Jiang; Jian-Ning Zhang

    2015-01-01

    Background:Traumatic brain injury (TBI) is a life-threatening disease worldwide.Regulatory T cells (Treg cells) were involved in the immunological system in central nervous system.It is defined as a subpopulation of CD4+ cells that express CD25 and transcription factor forkhead box P3.The level of circulating Treg cells increases in a variety of pathologic conditions.The purpose of this study was to uncover the role of circulating Treg cells in TBI.Methods:A clinical study was conducted in two neurosurgical intensive care units of Tianjin Medical University General Hospital and Second Hospital of Tianjin Medical University (Tianjin,China).Forty patients and 30 healthy controls were recruited from August 2013 to November 2013.Circulating Treg cells was detected on the follow-up period of 1,4,7,14,and 21 days after TBI.Blood sample (1 ml)was withdrawn in the morning and processed within 2 h.Results:There was no significant difference in the level of circulating Treg cells between TBI patients and normal controls during follow-up.TBI patients exhibited higher circulating Treg level than normal controls on the 1 st day after TBI.Treg level was decreased on the 4th day,climbed up on the 7th day and peaked on 14th day after TBI.Treg cells declined to the normal level on 21th day after TBI.The level of circulating Treg cells was significantly higher in survival TBI patients when compared to nonsurvival TBI patients.TBI patients with improved conditions exhibited significantly higher circulating Treg level when compared to those with deteriorated conditions.The circulating Treg level was correlated with neurologic recovery after TBI.A better neural recovery and lower hospital mortality were found in TBI patients with circulating Treg cells more than 4.91% in total CD4+ mononuclear cells as compared to those with circulating Treg cells less than 4.91% in total CD4+ mononuclear cells in the first 14 days.Conclusions:The level of circulating Treg cells is positively

  9. Regulation and regulatory role of WNT signaling in potentiating FSH action during bovine dominant follicle selection.

    Directory of Open Access Journals (Sweden)

    P S P Gupta

    Full Text Available Follicular development occurs in wave like patterns in monotocous species such as cattle and humans and is regulated by a complex interaction of gonadotropins with local intrafollicular regulatory molecules. To further elucidate potential mechanisms controlling dominant follicle selection, granulosa cell RNA harvested from F1 (largest and F2 (second largest follicles isolated at predeviation (PD and onset of diameter deviation (OD stages of the first follicular wave was subjected to preliminary RNA transcriptome analysis. Expression of numerous WNT system components was observed. Hence experiments were performed to test the hypothesis that WNT signaling modulates FSH action on granulosa cells during follicular waves. Abundance of mRNA for WNT pathway members was evaluated in granulosa cells harvested from follicles at emergence (EM, PD, OD and early dominance (ED stages of the first follicular wave. In F1 follicles, abundance of CTNNB1 and DVL1 mRNAs was higher and AXIN2 mRNA was lower at ED versus EM stages and DVL1 and FZD6 mRNAs were higher and AXIN2 mRNA was lower in F1 versus F2 follicle at the ED stage. Bovine granulosa cells were treated in vitro with increasing doses of the WNT inhibitor IWR-1+/- maximal stimulatory dose of FSH. IWR-1 treatment blocked the FSH-induced increase in granulosa cell numbers and reduced the FSH-induced increase in estradiol. Granulosa cells were also cultured in the presence or absence of FSH +/- IWR-1 and hormonal regulation of mRNA for WNT pathway members and known FSH targets determined. FSH treatment increased CYP19A1, CCND2, CTNNB1, AXIN2 and FZD6 mRNAs and the stimulatory effect on CYP19A1 mRNA was reduced by IWR-1. In contrast, FSH reduced CARTPT mRNA and IWR-1 partially reversed the inhibitory effect of FSH. Results support temporal and hormonal regulation and a potential role for WNT signaling in potentiating FSH action during dominant follicle selection.

  10. Matching the message: the role of regulatory fit in negative managerial communication

    NARCIS (Netherlands)

    Fransen, M.L.; ter Hoeven, C.L.

    2013-01-01

    The experiments presented here examine how managers and executives can improve the effectiveness of their negative written communications (i.e., refusal of employees’ requests) by incorporating the concept of fit into their message framing. By applying regulatory focus theory, the authors suggest th

  11. Reducing the Effect of Stereotype Threat: The Role of Coaction Contexts and Regulatory Fit

    Science.gov (United States)

    Wen, Fangfang; Zuo, Bin; Wu, Yang; Dong, Xuanhao; Wang, Wei

    2016-01-01

    Two experiments examined the effects of competition and cooperation contexts, as well as regulatory fit, on reducing the negative influence of stereotype threat. Experiment 1 demonstrated that in high stereotype threat conditions, participants in the cooperation context scored significantly higher on a math test than those in the competition…

  12. Matching the message: the role of regulatory fit in negative managerial communication

    NARCIS (Netherlands)

    Fransen, M.L.; ter Hoeven, C.L.

    2013-01-01

    The experiments presented here examine how managers and executives can improve the effectiveness of their negative written communications (i.e., refusal of employees’ requests) by incorporating the concept of fit into their message framing. By applying regulatory focus theory, the authors suggest

  13. Role of regulatory T-cells in immunization strategies involving a recombinant alphavirus vector system

    NARCIS (Netherlands)

    Walczak, Mateusz; Regts, Joke; van Oosterhout, Antoon J. M.; Boon, Louis; Wilschut, Jan; Nijman, Hans W.; Daemen, Toos

    2011-01-01

    Background: Regulatory T-cells (Treg) hamper immune responses elicited by cancer vaccines. Therefore, depletion of Treg is being used to improve the outcome of vaccinations. Methods: We studied whether an alphavirus vector-based immunotherapeutic vaccine changes the number and/or activity of Treg an

  14. Frequencies and role of regulatory T cells in patients with (pre)malignant cervical neoplasia

    NARCIS (Netherlands)

    Visser, J.; Nijman, H. W.; Hoogenboom, B.-N.; Jager, P.; van Baarle, D.; Schuuring, E.; Abdulahad, W.; Miedema, F.; van der Zee, A. G.; Daemen, T.

    2007-01-01

    Oncogenic human papillomavirus (HPV)-infection is crucial for developing cervical cancer and its precursor lesions [cervical intraepithelial neoplasia (CIN)]. Regulatory T cells (T-regs) might be involved in the failure of the immune system to control the development of HPV-induced cancer. We

  15. A Proteome-wide, Quantitative Survey of In Vivo Ubiquitylation Sites Reveals Widespread Regulatory Roles

    DEFF Research Database (Denmark)

    Wagner, Sebastian Alexander; Beli, Petra; Weinert, Brian Tate;

    2011-01-01

    Post-translational modification of proteins by ubiquitin is a fundamentally important regulatory mechanism. However, proteome-wide analysis of endogenous ubiquitylation remains a challenging task, and almost always has relied on cells expressing affinity tagged ubiquitin. Here we combine single-s...

  16. Frequencies and role of regulatory T cells in patients with (pre)malignant cervical neoplasia

    NARCIS (Netherlands)

    Visser, J.; Nijman, H. W.; Hoogenboom, B.-N.; Jager, P.; van Baarle, D.; Schuuring, E.; Abdulahad, W.; Miedema, F.; van der Zee, A. G.; Daemen, T.

    2007-01-01

    Oncogenic human papillomavirus (HPV)-infection is crucial for developing cervical cancer and its precursor lesions [cervical intraepithelial neoplasia (CIN)]. Regulatory T cells (T-regs) might be involved in the failure of the immune system to control the development of HPV-induced cancer. We invest

  17. Frequencies and role of regulatory T cells in patients with (pre)malignant cervical neoplasia

    NARCIS (Netherlands)

    Visser, J.; Nijman, H. W.; Hoogenboom, B.-N.; Jager, P.; van Baarle, D.; Schuuring, E.; Abdulahad, W.; Miedema, F.; van der Zee, A. G.; Daemen, T.

    2007-01-01

    Oncogenic human papillomavirus (HPV)-infection is crucial for developing cervical cancer and its precursor lesions [cervical intraepithelial neoplasia (CIN)]. Regulatory T cells (T-regs) might be involved in the failure of the immune system to control the development of HPV-induced cancer. We invest

  18. Role of the Pi3k Regulatory Subunit in the Control of Actin Organization and Cell Migration

    Science.gov (United States)

    Jiménez, Concepción; Portela, Rosario Armas; Mellado, Mario; Rodríguez-Frade, Jose Miguel; Collard, John; Serrano, Antonio; Martínez-A, Carlos; Avila, Jesus; Carrera, Ana C.

    2000-01-01

    Cell migration represents an important cellular response that utilizes cytoskeletal reorganization as its driving force. Here, we describe a new signaling cascade linking PDGF receptor stimulation to actin rearrangements and cell migration. We demonstrate that PDGF activates Cdc42 and its downstream effector N-WASP to mediate filopodia formation, actin stress fiber disassembly, and a reduction in focal adhesion complexes. Induction of the Cdc42 pathway is independent of phosphoinositide 3-kinase (PI3K) enzymatic activity, but it is dependent on the p85α regulatory subunit of PI3K. Finally, data are provided showing that activation of this pathway is required for PDGF-induced cell migration on collagen. These observations show the essential role of the PI3K regulatory subunit p85α in controlling PDGF receptor–induced cytoskeletal changes and cell migration, illustrating a novel signaling pathway that links receptor stimulation at the cell membrane with actin dynamics. PMID:11038173

  19. RNA-Sequencing Analysis Reveals a Regulatory Role for Transcription Factor Fezf2 in the Mature Motor Cortex

    Directory of Open Access Journals (Sweden)

    Alison J. Clare

    2017-09-01

    Full Text Available Forebrain embryonic zinc finger (Fezf2 encodes a transcription factor essential for the specification of layer 5 projection neurons (PNs in the developing cerebral cortex. As with many developmental transcription factors, Fezf2 continues to be expressed into adulthood, suggesting it remains crucial to the maintenance of neuronal phenotypes. Despite the continued expression, a function has yet to be explored for Fezf2 in the PNs of the developed cortex. Here, we investigated the role of Fezf2 in mature neurons, using lentiviral-mediated delivery of a shRNA to conditionally knockdown the expression of Fezf2 in the mouse primary motor cortex (M1. RNA-sequencing analysis of Fezf2-reduced M1 revealed significant changes to the transcriptome, identifying a regulatory role for Fezf2 in the mature M1. Kyoto Encyclopedia Genes and Genomes (KEGG pathway analyses of Fezf2-regulated genes indicated a role in neuronal signaling and plasticity, with significant enrichment of neuroactive ligand-receptor interaction, cell adhesion molecules and calcium signaling pathways. Gene Ontology analysis supported a functional role for Fezf2-regulated genes in neuronal transmission and additionally indicated an importance in the regulation of behavior. Using the mammalian phenotype ontology database, we identified a significant overrepresentation of Fezf2-regulated genes associated with specific behavior phenotypes, including associative learning, social interaction, locomotor activation and hyperactivity. These roles were distinct from that of Fezf2-regulated genes identified in development, indicating a dynamic transition in Fezf2 function. Together our findings demonstrate a regulatory role for Fezf2 in the mature brain, with Fezf2-regulated genes having functional roles in sustaining normal neuronal and behavioral phenotypes. These results support the hypothesis that developmental transcription factors are important for maintaining neuron transcriptomes and that

  20. The Role of Regulatory Pressure in Banks’ Capital and Risk Decisions

    Directory of Open Access Journals (Sweden)

    Alessandra Tanda

    2015-06-01

    Full Text Available Capital regulation represents the core of prudential regulation in banking. Despite the aim of the regulators to have a safer and more robust banking industry, the effects of capital regulation on banks’ capital and risk decisions appear ambiguous. The paper analyses the relationship between capital and risk changes and the impact of regulatory pressure for a sample of European banks during the period 2006–2010, which encompasses the start of the latest financial crisis. Results highlight that banks tend to adopt a different behaviour depending on the capital ratio considered, supporting the so-called ‘gamble for resurrection’ hypothesis. Evidence supports the rethinking of the regulatory framework, especially with reference to higher and stricter capital requirements.

  1. Transcriptional control of yeast ribosome biogenesis: A multifaceted role for general regulatory factors.

    Science.gov (United States)

    Bosio, Maria Cristina; Fermi, Beatrice; Dieci, Giorgio

    2017-08-08

    In Saccharomyces cerevisiae, a group of more than 200 co-regulated genes (Ribi genes) is involved in ribosome biogenesis. This regulon has recently been shown to rely on a small set of transcriptional regulators (mainly Abf1, but also Reb1, Tbf1 and Rap1) previously referred to as general regulatory factors (GRFs) because of their widespread binding and action at many promoters and other specialized genomic regions. Intriguingly, Abf1 binding to Ribi genes is differentially modulated in response to distinct nutrition signaling pathways. Such a dynamic promoter association has the potential to orchestrate both activation and repression of Ribi genes in synergy with neighboring regulatory sites and through the functional interplay of histone acetyltransferases and deacetylases.

  2. The role of pregnancy-associated hormones in the development and function of regulatory B cells.

    Science.gov (United States)

    Muzzio, Damián; Zygmunt, Marek; Jensen, Federico

    2014-01-01

    During mammalian pregnancy, highly specialized mechanisms of immune tolerance are triggered in order to allow the semi-allogeneic fetus to grow within the maternal uterus in harmony with the maternal immune system. Among other mechanisms, changes in the endocrine status have been proposed to be at least part of the machinery responsible for the induction of immune tolerance during pregnancy. Indeed, pregnancy-associated hormones, estradiol, progesterone, and human chorionic gonadotropin are known to confer immune suppressive capacity to innate as well as adaptive immune cells. Regulatory B cells, a subpopulation of B lymphocytes with strong immunosuppressive functions, were shown to expand during pregnancy. Furthermore, it is well-known that some women suffering from multiple sclerosis, significantly improve their symptoms during pregnancy and this was attributed to the effect of female sex hormones. Accordingly, estradiol protects mice from developing experimental autoimmune encephalomyelitis by triggering the expansion and activation of regulatory B cells. In this review, we discuss different mechanisms associated with the development, activation, and function of regulatory B cells with a special focus on those involving pregnancy-associated hormones.

  3. The moderating role of regulatory focus on the social modeling of food intake.

    Science.gov (United States)

    Florack, Arnd; Palcu, Johanna; Friese, Malte

    2013-10-01

    Regulatory focus theory proposes two distinct modi of self-regulation, a promotion focus and a prevention focus. According to this theory, individuals in a prevention focus apply behavioral strategies to successfully avoid unpleasant outcomes and maintain a safe and secure state. By contrast, individuals in a promotion focus apply behavioral strategies to realize pleasant outcomes and to advance the current state. Applied to the context of eating behavior, regulatory focus theory suggests that individuals in a prevention focus should be especially sensitive to avoid socially inappropriate eating behavior. A way to ensure socially appropriate eating behavior is to follow social models. In the present research, we therefore tested the assumption that a prevention focus leads to stronger modeling effects in eating behavior than a promotion focus. In two studies, we manipulated individual's self-regulation states by putting individuals in a state of reflection about their hopes and aspirations (promotion focus) vs. a state of reflection about their duties and responsibilities (prevention focus). Participants then observed the consumption behavior of a second participant who either consumed or did not consume offered food (Study 1) or received incidental information about the amount of food an ostensible previous participant had consumed (Study 2). Across both studies, participants in a prevention focus matched their food consumption more closely to that of a present (Study 1) and not-present social model (Study 2), compared to participants in a promotion focus. The results advance our understanding of modeling effects in food intake by showing the importance of regulatory orientations.

  4. The Role of Crowding Forces in Juxtaposing β-Globin Gene Domain Remote Regulatory Elements in Mouse Erythroid Cells.

    Directory of Open Access Journals (Sweden)

    Arkadiy K Golov

    Full Text Available The extremely high concentration of macromolecules in a eukaryotic cell nucleus indicates that the nucleoplasm is a crowded macromolecular solution in which large objects tend to gather together due to crowding forces. It has been shown experimentally that crowding forces support the integrity of various nuclear compartments. However, little is known about their role in control of chromatin dynamics in vivo. Here, we experimentally addressed the possible role of crowding forces in spatial organization of the eukaryotic genome. Using the mouse β-globin domain as a model, we demonstrated that spatial juxtaposition of the remote regulatory elements of this domain in globin-expressing cells may be lost and restored by manipulation of the level of macromolecular crowding. In addition to proving the role of crowding forces in shaping interphase chromatin, our results suggest that the folding of the chromatin fiber is a major determinant in juxtaposing remote genomic elements.

  5. Regulatory underpinnings of Global Health security: FDA's roles in preventing, detecting, and responding to global health threats.

    Science.gov (United States)

    Courtney, Brooke; Bond, Katherine C; Maher, Carmen

    2014-01-01

    In February 2014, health officials from around the world announced the Global Health Security Agenda, a critical effort to strengthen national and global systems to prevent, detect, and respond to infectious disease threats and to foster stronger collaboration across borders. With its increasing global roles and broad range of regulatory responsibilities in ensuring the availability, safety, and security of medical and food products, the US Food and Drug Administration (FDA) is engaged in a range of efforts in support of global health security. This article provides an overview of FDA's global health security roles, focusing on its responsibilities related to the development and use of medical countermeasures (MCMs) for preventing, detecting, and responding to global infectious disease and other public health emergency threats. The article also discusses several areas-antimicrobial resistance, food safety, and supply chain integrity-in which FDA's global health security roles continue to evolve and extend beyond MCMs and, in some cases, beyond traditional infectious disease threats.

  6. An essential regulatory role of downstream of kinase-1 in the ovalbumin-induced murine model of asthma.

    Directory of Open Access Journals (Sweden)

    Chang-Min Lee

    Full Text Available The downstream of kinase (DOK-1 is involved in the protein tyrosine kinase (PTK pathway in mast cells, but the role of DOK-1 in the pathogenesis of asthma has not been defined. In this study, we have demonstrated a novel regulatory role of DOK-1 in airway inflammation and physiologic responses in a murine model of asthma using lentiviral vector containing DOK-1 cDNA or DOK-1-specific ShRNA. The OVA-induced inflammatory cells, airway hyperresponsiveness, Th2 cytokine expression, and mucus response were significantly reduced in DOK-1 overexpressing mice compared to OVA-challenged control mice. The transgenic introduction of DOK-1 significantly stimulated the activation and expression of STAT-4 and T-bet, while impressively inhibiting the activation and expression of STAT-6 and GATA-3 in airway epithelial cells. On the other hand, DOK-1 knockdown mice enhanced STAT-6 expression and its nuclear translocation compared to OVA-challenged control mice. When viewed in combination, our studies demonstrate DOK-1 regulates allergen-induced Th2 immune responses by selective stimulation and inhibition of STAT-4 and STAT-6 signaling pathways, respectively. These studies provide a novel insight on the regulatory role of DOK-1 in allergen-induced Th2 inflammation and airway responses, which has therapeutic potential for asthma and other allergic diseases.

  7. The costly benefits of opposing agricultural biotechnology.

    Science.gov (United States)

    Apel, Andrew

    2010-11-30

    Rigorous application of a simple definition of what constitutes opposition to agricultural biotechnology readily encompasses a wide array of key players in national and international systems of food production, distribution and governance. Even though the sum of political and financial benefits of opposing agricultural biotechnology appears vastly to outweigh the benefits which accrue to providers of agricultural biotechnology, technology providers actually benefit from this opposition. If these barriers to biotechnology were removed, subsistence farmers still would not represent a lucrative market for improved seed. The sum of all interests involved ensures that subsistence farmers are systematically denied access to agricultural biotechnology. Copyright © 2010 Elsevier B.V. All rights reserved.

  8. Reflections on the role of the pharmacy regulatory authority in enhancing quality related event reporting in community pharmacies.

    Science.gov (United States)

    Boyle, Todd A; Bishop, Andrea C; Mahaffey, Thomas; Mackinnon, Neil J; Ashcroft, Darren M; Zwicker, Bev; Reid, Carolyn

    2014-01-01

    Given the demanding nature of providing pharmacy services, coupled with the expanded scope of practice of the professions in jurisdictions around the world, greater commitment to continuous quality improvement through adoption of quality-related event (QRE) reporting is necessary to ensure patient safety. Pharmacy regulatory authorities (PRAs) are in a unique position to enhance QRE reporting and learning through the standardization of expected practice. This study was aimed to gain a better understanding of the perceived roles of PRAs in enhancing QRE reporting and learning in community pharmacies, and identifying regulatory best practices to execute such roles. A purposive case sampling approach was used to identify PRA staff members from two groups (Deputy registrars and pharmacy inspectors) in 10 Canadian jurisdictions to participate in focus groups in the fall of 2011. Focus groups were used to explore perceptions of the role of PRAs in enhancing and promoting QRE reporting and learning, and perceived barriers to effective implementation in practice. Thematic analysis was used to analyze the qualitative data. Two focus groups were conducted, one with seven Deputy registrars/Practice managers, and one with nine pharmacy inspectors. Five themes were identified, including (1) defining QRE reporting and compliance, (2) navigating role conflict, (3) educating for enhanced QRE reporting and learning, (4) promoting the positive/removing the fear of QREs, and (5) tailoring QRE reporting and learning consistency. Overall, participants perceived a strong role for PRAs in enhancing QRE reporting and learning and providing education for pharmacies to support their compliance with reporting standards. However, PRAs must navigate the conflict inherent in both educating and promoting a process for achieving a standard while simultaneously inspecting compliance to that standard. Ensuring pharmacies have autonomy in operationalizing standards may help to mitigate this conflict

  9. REFLECTIONS ON THE ROLE OF THE PHARMACY REGULATORY AUTHORITY IN ENHANCING QUALITY RELATED EVENT REPORTING IN COMMUNITY PHARMACIESi

    Science.gov (United States)

    Boyle, Todd A.; Bishop, Andrea C.; Mahaffey, Thomas; MacKinnon, Neil J.; Ashcroft, Darren; Zwicker, Bev; Reid, Carolyn

    2016-01-01

    Background Given the demanding nature of providing pharmacy services, coupled with the expanded scope of practice of the professions in jurisdictions around the world, greater commitment to continuous quality improvement through adoption of quality related event (QRE) reporting is necessary to ensure patient safety. Pharmacy regulatory authorities (PRAs) are in a unique position to enhance QRE reporting and learning through the standardization of expected practice Objective This study aims to better understand the perceived roles of PRAs in enhancing QRE reporting and learning in community pharmacies and identifying regulatory best practices to execute such roles. Methods A purposive case sampling approach was used to identify PRA staff members from two groups (deputy registrars and pharmacy inspectors) in 10 Canadian jurisdictions to participate in focus groups in the fall of 2011. Focus groups were used to explore perceptions of the role of PRAs in enhancing and promoting QRE reporting and learning, and perceived barriers to effective implementation in practice. Thematic analysis was used to analyze the qualitative data. Results Two focus groups were conducted, one with seven deputy registrars/practice managers and one with nine pharmacy inspectors. Five themes were identified, including (1) defining QRE reporting and compliance, (2) navigating role conflict, (3) educating for enhanced QRE reporting and learning, (4) promoting the positive/removing the fear of QREs, and (5) tailoring QRE reporting and learning consistency. Conclusions Overall, participants perceived a strong role for PRAs in enhancing QRE reporting and learning and providing education for pharmacies to support their compliance with reporting standards. However, PRAs must navigate the conflict inherent in both educating and promoting a process for achieving a standard while simultaneously inspecting compliance to that standard. Ensuring pharmacies have autonomy in operationalizing standards may

  10. Balancing Opposing Views to Reduce Controversy

    CERN Document Server

    Garimella, Kiran; Gionis, Aristides; Mathioudakis, Michael

    2016-01-01

    Society is often polarized by controversial issues, that split the population into groups of opposing views. When such issues emerge on social media, we often observe the creation of 'echo chambers', i.e., situations where like-minded people reinforce each other's opinion, but do not get exposed to the views of the opposing side. In this paper we study algorithmic techniques for bridging these chambers, and thus, reducing controversy. Specifically, we represent the discussion on a controversial issue with an endorsement graph, and cast our problem as an edge-recommendation problem on this graph. The goal of the recommendation is to reduce the controversy score of the graph, which is measured by a recently-developed metric based on random walks. At the same time, we take into account the acceptance probability of the recommended edge, which represents how likely the edge is to materialize in the endorsement graph. We propose a simple model based on a recently-developed user-level controversy score, that is com...

  11. CD4 T cells mediate both positive and negative regulation of the immune response to HIV infection: complex role of T follicular helper cells and Regulatory T cells in pathogenesis

    Directory of Open Access Journals (Sweden)

    Chansavath ePhetsouphanh

    2015-01-01

    Full Text Available HIV-1 infection results in chronic activation of cells in lymphoid tissue, including T cells, B cells and myeloid lineage cells. The resulting characteristic hyperplasia is an amalgam of proliferating host immune cells in the adaptive response, increased concentrations of innate response mediators due to viral and bacterial products, and homeostatic responses to inflammation. While it is generally thought that CD4 T cells are greatly depleted, in fact, two types of CD4 T cells appear to be increased, namely regulatory T cells (Tregs and T follicular helper cells (Tfh. These cells have opposing roles, but may both be important in the pathogenic process. Whether Tregs are failing in their role to limit lymphocyte activation is unclear, but there is no doubt now that Tfh are associated with B cell hyperplasia and increased germinal centre activity. Antiretroviral therapy (ART may reduce the lymphocyte activation, but not completely, and therefore there is a need for interventions that selectively enhance normal CD4 function without exacerbating Tfh, B cell or Treg dysfunction.

  12. Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-β.

    Science.gov (United States)

    Palomares, O; Martín-Fontecha, M; Lauener, R; Traidl-Hoffmann, C; Cavkaytar, O; Akdis, M; Akdis, C A

    2014-12-01

    The prevalence of allergic diseases has significantly increased in industrialized countries. Allergen-specific immunotherapy (AIT) remains as the only curative treatment. The knowledge about the mechanisms underlying healthy immune responses to allergens, the development of allergic reactions and restoration of appropriate immune responses to allergens has significantly improved over the last decades. It is now well-accepted that the generation and maintenance of functional allergen-specific regulatory T (Treg) cells and regulatory B (Breg) cells are essential for healthy immune responses to environmental proteins and successful AIT. Treg cells comprise different subsets of T cells with suppressive capacity, which control the development and maintenance of allergic diseases by various ways of action. Molecular mechanisms of generation of Treg cells, the identification of novel immunological organs, where this might occur in vivo, such as tonsils, and related epigenetic mechanisms are starting to be deciphered. The key role played by the suppressor cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β produced by functional Treg cells during the generation of immune tolerance to allergens is now well established. Treg and Breg cells together have a role in suppression of IgE and induction of IgG4 isotype allergen-specific antibodies particularly mediated by IL-10. Other cell types such as subsets of dendritic cells, NK-T cells and natural killer cells producing high levels of IL-10 may also contribute to the generation of healthy immune responses to allergens. In conclusion, better understanding of the immune regulatory mechanisms operating at different stages of allergic diseases will significantly help the development of better diagnostic and predictive biomarkers and therapeutic interventions.

  13. Opposing actions of dibutyryl cyclic AMP and GMP on temperature in conscious guinea-pigs

    Science.gov (United States)

    Kandasamy, S. B.; Williaes, B. A.

    1983-01-01

    It is shown that the intracerebroventricular administration of dibutyryl cyclic AMP (Db-cAMP) induced hyperthermia in guinea pigs which was not mediated through prostaglandins or norepinephrine since a prostaglandin synthesis inhibitor and an alpha-adrenergic receptor blocking agent did not antagonize the hyperthermia. However, the hyperthermic response to Db-cAMP was attenuated by the central administration of a beta-adrenergic receptor antagonist, which indicates that cAMP may be involved, through beta-adrenergic receptors, in the central regulation of heat production and conservation. The central administration of Db-cGMP produced hypothermia which was not mediated via histamine H1 or H2 receptors and serotonin. The antagonism of hypothermia induced by Db-cGMP and acetylcholine + physostigmine by central administration of a cholinergic muscarine receptor antagonist and not by a cholinergic nicotinic receptor antagonist suggests that cholinoceptive neurons and endogenous cGMP may regulate heat loss through cholinergic muscarine receptors. It is concluded that these results indicate a regulatory role in thermoregulation provided by a balance between opposing actions of cAMP and cGMP in guinea pigs.

  14. Regulatory roles of LINE-1-encoded reverse transcriptase in cancer onset and progression.

    Science.gov (United States)

    Sciamanna, Ilaria; Gualtieri, Alberto; Piazza, Pier Francesco; Spadafora, Corrado

    2014-09-30

    LINE-1 retrotransposons encode the reverse transcriptase (RT) enzyme, required for their own mobility, the expression of which is inhibited in differentiated tissues while being active in tumors. Experimental evidence indicate that the inhibition of LINE-1-derived RT restores differentiation in cancer cells, inhibits tumor progression and yields globally reprogrammed transcription profiles. Newly emerging data suggest that LINE-1-encoded RT modulates the biogenesis of miRNAs, by governing the balance between the production of regulatory double-stranded RNAs and RNA:DNA hybrid molecules, with a direct impact on global gene expression. Abnormally high RT activity unbalances the transcriptome in cancer cells, while RT inhibition restores "normal" miRNA profiles and their regulatory networks. This RT-dependent mechanism can target the myriad of transcripts - both coding and non-coding, sense and antisense - in eukaryotic transcriptomes, with a profound impact on cell fates. LINE-1-encoded RT emerges therefore as a key regulator of a previously unrecognized mechanism in tumorigenesis.

  15. Regulatory Mode and Risk-Taking: The Mediating Role of Anticipated Regret.

    Science.gov (United States)

    Panno, Angelo; Lauriola, Marco; Pierro, Antonio

    2015-01-01

    We propose that decision maker's regulatory mode affects risk-taking through anticipated regret. In the Study 1 either a locomotion or an assessment orientation were experimentally induced, and in the Studies 2 and 3 these different orientations were assessed as chronic individual differences. To assess risk-taking we used two behavioral measures of risk: BART and hot-CCT. The results show that experimentally induced assessment orientation--compared to locomotion--leads to decreased risk-taking through increased anticipated regret (Study 1). People chronically predisposed to be in the assessment state take less risk through increased anticipated regret (Study 2 and Study 3). Study 2 results also show a marginally non-significant indirect effect of chronic locomotion mode on BART through anticipated regret. Differently, Study 3 shows that people chronically predisposed to be in the locomotion state take greater risk through decreased anticipated regret, when play a dynamic risk task triggering stronger emotional arousal. Through all three studies, the average effect size for the relationship of assessment with anticipated regret was in the moderate-large range, whereas for risk-taking was in the moderate range. The average effect size for the relationship of locomotion with anticipated regret was in the moderate range, whereas for risk-taking was in the small-moderate range. These results increase our understanding of human behavior under conditions of risk obtaining novel insights into regulatory mode theory and decision science.

  16. Regulatory roles of LINE-1-encoded reverse transcriptase in cancer onset and progression

    Science.gov (United States)

    Sciamanna, Ilaria; Gualtieri, Alberto; Piazza, Pier Vincenzo; Spadafora, Corrado

    2014-01-01

    LINE-1 retrotransposons encode the reverse transcriptase (RT) enzyme, required for their own mobility, the expression of which is inhibited in differentiated tissues while being active in tumors. Experimental evidence indicate that the inhibition of LINE-1-derived RT restores differentiation in cancer cells, inhibits tumor progression and yields globally reprogrammed transcription profiles. Newly emerging data suggest that LINE-1-encoded RT modulates the biogenesis of miRNAs, by governing the balance between the production of regulatory double-stranded RNAs and RNA:DNA hybrid molecules, with a direct impact on global gene expression. Abnormally high RT activity unbalances the transcriptome in cancer cells, while RT inhibition restores ‘normal’ miRNA profiles and their regulatory networks. This RT-dependent mechanism can target the myriad of transcripts - both coding and non-coding, sense and antisense - in eukaryotic transcriptomes, with a profound impact on cell fates. LINE-1-encoded RT emerges therefore as a key regulator of a previously unrecognized mechanism in tumorigenesis PMID:25478632

  17. Regulatory Mode and Risk-Taking: The Mediating Role of Anticipated Regret.

    Directory of Open Access Journals (Sweden)

    Angelo Panno

    Full Text Available We propose that decision maker's regulatory mode affects risk-taking through anticipated regret. In the Study 1 either a locomotion or an assessment orientation were experimentally induced, and in the Studies 2 and 3 these different orientations were assessed as chronic individual differences. To assess risk-taking we used two behavioral measures of risk: BART and hot-CCT. The results show that experimentally induced assessment orientation--compared to locomotion--leads to decreased risk-taking through increased anticipated regret (Study 1. People chronically predisposed to be in the assessment state take less risk through increased anticipated regret (Study 2 and Study 3. Study 2 results also show a marginally non-significant indirect effect of chronic locomotion mode on BART through anticipated regret. Differently, Study 3 shows that people chronically predisposed to be in the locomotion state take greater risk through decreased anticipated regret, when play a dynamic risk task triggering stronger emotional arousal. Through all three studies, the average effect size for the relationship of assessment with anticipated regret was in the moderate-large range, whereas for risk-taking was in the moderate range. The average effect size for the relationship of locomotion with anticipated regret was in the moderate range, whereas for risk-taking was in the small-moderate range. These results increase our understanding of human behavior under conditions of risk obtaining novel insights into regulatory mode theory and decision science.

  18. Role of bundle helices in a regulatory crosstalk in the trimeric betaine transporter BetP.

    Science.gov (United States)

    Gärtner, Rebecca M; Perez, Camilo; Koshy, Caroline; Ziegler, Christine

    2011-12-02

    The Na(+)-coupled betaine symporter BetP regulates transport activity in response to hyperosmotic stress only in its trimeric state, suggesting a regulatory crosstalk between individual protomers. BetP shares the overall fold of two inverted structurally related five-transmembrane (TM) helix repeats with the sequence-unrelated Na(+)-coupled symporters LeuT, vSGLT, and Mhp1, which are neither trimeric nor regulated in transport activity. Conformational changes characteristic for this transporter fold involve the two first helices of each repeat, which form a four-TM-helix bundle. Here, we identify two ionic networks in BetP located on both sides of the membrane that might be responsible for BetP's unique regulatory behavior by restricting the conformational flexibility of the four-TM-helix bundle. The cytoplasmic ionic interaction network links both first helices of each repeat in one protomer to the osmosensing C-terminal domain of the adjacent protomer. Moreover, the periplasmic ionic interaction network conformationally locks the four-TM-helix bundle between the same neighbor protomers. By a combination of site-directed mutagenesis, cross-linking, and betaine uptake measurements, we demonstrate how conformational changes in individual bundle helices are transduced to the entire bundle by specific inter-helical interactions. We suggest that one purpose of bundle networking is to assist crosstalk between protomers during transport regulation by specifically modulating the transition from outward-facing to inward-facing state.

  19. Rethinking the role of the rTPJ in attention and social cognition in light of the opposing domains hypothesis: findings from an ALE-based meta-analysis and resting-state functional connectivity.

    Science.gov (United States)

    Kubit, Benjamin; Jack, Anthony I

    2013-01-01

    The right temporo-parietal junction (rTPJ) has been associated with two apparently disparate functional roles: in attention and in social cognition. According to one account, the rTPJ initiates a "circuit-breaking" signal that interrupts ongoing attentional processes, effectively reorienting attention. It is argued this primary function of the rTPJ has been extended beyond attention, through a process of evolutionarily cooption, to play a role in social cognition. We propose an alternative account, according to which the capacity for social cognition depends on a network which is both distinct from and in tension with brain areas involved in focused attention and target detection: the default mode network (DMN). Theory characterizing the rTPJ based on the area's purported role in reorienting may be falsely guided by the co-occurrence of two distinct effects in contiguous regions: activation of the supramarginal gyrus (SMG), associated with its functional role in target detection; and the transient release, during spatial reorienting, of suppression of the angular gyrus (AG) associated with focused attention. Findings based on meta-analysis and resting functional connectivity are presented which support this alternative account. We find distinct regions, possessing anti-correlated patterns of resting connectivity, associated with social reasoning (AG) and target detection (SMG) at the rTPJ. The locus for reorienting was spatially intermediate between the AG and SMG and showed a pattern of connectivity with similarities to social reasoning and target detection seeds. These findings highlight a general methodological concern for brain imaging. Given evidence that certain tasks not only activate some areas but also suppress activity in other areas, it is suggested that researchers need to distinguish two distinct putative mechanisms, either of which may produce an increase in activity in a brain area: functional engagement in the task vs. release of suppression.

  20. Rethinking the role of the rTPJ in attention and social cognition in light of the opposing domains hypothesis: findings from an ALE-based meta-analysis and resting-state functional connectivity.

    Directory of Open Access Journals (Sweden)

    Benjamin eKubit

    2013-07-01

    Full Text Available The right temporo-parietal junction (rTPJ has been associated with two apparently disparate functional roles: in attention and in social cognition. According to one account, the rTPJ initiates a circuit-breaking signal that interrupts ongoing attentional processes, effectively reorienting attention. It is argued this primary function of the rTPJ has been extended beyond attention, through a process of evolutionarily cooption, to play a role in social cognition. We propose an alternative account, according to which the capacity for social cognition depends on a network which is both distinct from and in tension with brain areas involved in focused attention and target detection: the default mode network. Theory characterizing the rTPJ based on the area’s purported role in reorienting may be falsely guided by the co-occurrence of two distinct effects in contiguous regions: activation of the supramarginal gyrus (SMG, associated with its functional role in target detection; and the transient release, during spatial reorienting, of suppression of the angular gyrus (AG associated with focused attention. Findings based on meta-analysis and resting functional connectivity are presented which support this alternative account. We find distinct regions, possessing anti-correlated patterns of resting connectivity, associated with social reasoning (AG and target detection (SMG at the rTPJ. The locus for reorienting was spatially intermediate between the AG and SMG and showed a pattern of connectivity with similarities to social reasoning and target detection seeds. These findings highlight a general methodological concern for brain imaging. Given evidence that certain tasks not only activate some areas but also suppress activity in other areas, it is suggested that researchers need to distinguish two distinct putative mechanisms, either of which may produce an increase in activity in a brain area: functional engagement in the task versus release of

  1. The regulatory role of c-MYC on HDAC2 and PcG expression in human multipotent stem cells

    Science.gov (United States)

    Bhandari, Dilli Ram; Seo, Kwang-Won; Jung, Ji-Won; Kim, Hyung-Sik; Yang, Se-Ran; Kang, Kyung-Sun

    2011-01-01

    Abstract Myelocytomatosis oncogene (c-MYC) is a well-known nuclear oncoprotein having multiple functions in cell proliferation, apoptosis and cellular transformation. Chromosomal modification is also important to the differentiation and growth of stem cells. Histone deacethylase (HDAC) and polycomb group (PcG) family genes are well-known chromosomal modification genes. The aim of this study was to elucidate the role of c-MYC in the expression of chromosomal modification via the HDAC family genes in human mesenchymal stem cells (hMSCs). To achieve this goal, c-MYC expression was modified by gene knockdown and overexpression via lentivirus vector. Using the modified c-MYC expression, our study was focused on cell proliferation, differentiation and cell cycle. Furthermore, the relationship of c-MYC with HDAC2 and PcG genes was also examined. The cell proliferation and differentiation were checked and shown to be dramatically decreased in c-MYC knocked-down human umbilical cord blood-derived MSCs, whereas they were increased in c-MYC overexpressing cells. Similarly, RT-PCR and Western blotting results revealed that HDAC2 expression was decreased in c-MYC knocked-down and increased in c-MYC overexpressing hMSCs. Database indicates presence of c-MYC binding motif in HDAC2 promoter region, which was confirmed by chromatin immunoprecipitation assay. The influence of c-MYC and HDAC2 on PcG expression was confirmed. This might indicate the regulatory role of c-MYC over HDAC2 and PcG genes. c-MYCs’ regulatory role over HDAC2 was also confirmed in human adipose tissue-derived MSCs and bone-marrow derived MSCs. From this finding, it can be concluded that c-MYC plays a vital role in cell proliferation and differentiation via chromosomal modification. PMID:20716118

  2. Endogenous opioids: The downside of opposing stress

    Directory of Open Access Journals (Sweden)

    Rita J. Valentino

    2015-01-01

    Full Text Available Our dynamic environment regularly exposes us to potentially life-threatening challenges or stressors. To answer these challenges and maintain homeostasis, the stress response, an innate coordinated engagement of central and peripheral neural systems is initiated. Although essential for survival, the inappropriate initiation of the stress response or its continuation after the stressor is terminated has pathological consequences that have been linked to diverse neuropsychiatric and medical diseases. Substantial individual variability exists in the pathological consequences of stressors. A theme of this Special Issue is that elucidating the basis of individual differences in resilience or its flipside, vulnerability, will greatly advance our ability to prevent and treat stress-related diseases. This can be approached by studying individual differences in “pro-stress” mediators such as corticosteroids or the hypothalamic orchestrator of the stress response, corticotropin-releasing factor. More recently, the recognition of endogenous neuromodulators with “anti-stress” activity that have opposing actions or that restrain stress-response systems suggests additional bases for individual differences in stress pathology. These “anti-stress” neuromodulators offer alternative strategies for manipulating the stress response and its pathological consequences. This review uses the major brain norepinephrine system as a model stress-response system to demonstrate how co-regulation by opposing pro-stress (corticotropin-releasing factor and anti-stress (enkephalin neuromodulators must be fine-tuned to produce an adaptive response to stress. The clinical consequences of tipping this fine-tuned balance in the direction of either the pro- or anti-stress systems are emphasized. Finally, that each system provides multiple points at which individual differences could confer stress vulnerability or resilience is discussed.

  3. Role of the lncRNA-p53 regulatory network in cancer.

    Science.gov (United States)

    Zhang, Ali; Xu, Min; Mo, Yin-Yuan

    2014-06-01

    Advances in functional genomics have led to discovery of a large group of previous uncharacterized long non-coding RNAs (lncRNAs). Emerging evidence indicates that lncRNAs may serve as master gene regulators through various mechanisms. Dysregulation of lncRNAs is often associated with a variety of human diseases including cancer. Of significant interest, recent studies suggest that lncRNAs participate in the p53 tumor suppressor regulatory network. In this review, we discuss how lncRNAs serve as p53 regulators or p53 effectors. Further characterization of these p53-associated lncRNAs in cancer will provide a better understanding of lncRNA-mediated gene regulation in the p53 pathway. As a result, lncRNAs may prove to be valuable biomarkers for cancer diagnosis or potential targets for cancer therapy.

  4. Role of Non-coding Regulatory RNA in the Virulence of Human Pathogenic Vibrios

    Science.gov (United States)

    Pérez-Reytor, Diliana; Plaza, Nicolás; Espejo, Romilio T.; Navarrete, Paola; Bastías, Roberto; Garcia, Katherine

    2017-01-01

    In recent decades, the identification of small non-coding RNAs in bacteria has revealed an important regulatory mechanism of gene expression involved in the response to environmental signals and to the control of virulence. In the family Vibrionaceae, which includes several human and animal pathogens, small non-coding RNAs (sRNAs) are closely related to important processes including metabolism, quorum sensing, virulence, and fitness. Studies conducted in silico and experiments using microarrays and high-throughput RNA sequencing have led to the discovery of an unexpected number of sRNAs in Vibrios. The present review discusses the most relevant reports regarding the mechanisms of action of sRNAs and their implications in the virulence of the main human pathogens in the family Vibrionaceae: Vibrio parahaemolyticus, V. vulnificus and V. cholerae. PMID:28123382

  5. The dual effects of leading for safety: The mediating role of employee regulatory focus.

    Science.gov (United States)

    Kark, Ronit; Katz-Navon, Tal; Delegach, Marianna

    2015-09-01

    This study examined the underlying mechanisms through which transformational and transactional leadership influence employee safety behaviors. Linking leadership theory with self-regulatory focus (SRF) theory, we examined a model of dual effects of leadership on safety initiative and safety compliance behaviors as mediated by promotion and prevention self-regulations. We conducted an experimental study (N = 107), an online study (N = 99) and a field study (N = 798 employees and 49 managers). Results demonstrated that followers' situational promotion focus mediated the positive relationship between transformational leadership and safety initiative behaviors. Through all 3 studies, transactional active leadership was positively associated with followers' situational prevention focus, however, the association between followers' prevention focus and safety compliance behaviors was inconsistent, showing the expected mediation relationships in the experimental setting, but not in the online and field studies. We discuss theoretical and practical implications of the findings. (c) 2015 APA, all rights reserved).

  6. Understanding the Role of Housekeeping and Stress-Related Genes in Transcription-Regulatory Networks

    Science.gov (United States)

    Heath, Allison; Kavraki, Lydia; Balázsi, Gábor

    2008-03-01

    Despite the increasing number of completely sequenced genomes, much remains to be learned about how living cells process environmental information and respond to changes in their surroundings. Accumulating evidence indicates that eukaryotic and prokaryotic genes can be classified in two distinct categories that we will call class I and class II. Class I genes are housekeeping genes, often characterized by stable, noise resistant expression levels. In contrast, class II genes are stress-related genes and often have noisy, unstable expression levels. In this work we analyze the large scale transcription-regulatory networks (TRN) of E. coli and S. cerevisiae and preliminary data on H. sapien. We find that stable, housekeeping genes (class I) are preferentially utilized as transcriptional inputs while stress related, unstable genes (class II) are utilized as transcriptional integrators. This might be the result of convergent evolution that placed the appropriate genes in the appropriate locations within transcriptional networks according to some fundamental principles that govern cellular information processing.

  7. The role of CTCF binding sites in the 3' immunoglobulin heavy chain regulatory region.

    Science.gov (United States)

    Birshtein, Barbara K

    2012-01-01

    The immunoglobulin heavy chain locus undergoes a series of DNA rearrangements and modifications to achieve the construction and expression of individual antibody heavy chain genes in B cells. These events affect variable regions, through VDJ joining and subsequent somatic hypermutation, and constant regions through class switch recombination (CSR). Levels of IgH expression are also regulated during B cell development, resulting in high levels of secreted antibodies from fully differentiated plasma cells. Regulation of these events has been attributed primarily to two cis-elements that work from long distances on their target sequences, i.e., an ∼1 kb intronic enhancer, Eμ, located between the V region segments and the most 5' constant region gene, Cμ; and an ∼40 kb 3' regulatory region (3' RR) that is located downstream of the most 3' C(H) gene, Cα. The 3' RR is a candidate for an "end" of B cell-specific regulation of the Igh locus. The 3' RR contains several B cell-specific enhancers associated with DNase I hypersensitive sites (hs1-4), which are essential for CSR and for high levels of IgH expression in plasma cells. Downstream of this enhancer-containing region is a region of high-density CTCF binding sites, which extends through hs5, 6, and 7 and further downstream. CTCF, with its enhancer-blocking activities, has been associated with all mammalian insulators and implicated in multiple chromosomal interactions. Here we address the 3' RR CTCF-binding region as a potential insulator of the Igh locus, an independent regulatory element and a predicted modulator of the activity of 3' RR enhancers. Using chromosome conformation capture technology, chromatin immunoprecipitation, and genetic approaches, we have found that the 3' RR with its CTCF-binding region interacts with target sequences in the V(H), Eμ, and C(H) regions through DNA looping as regulated by protein binding. This region impacts on B cell-specific Igh processes at different stages of B cell

  8. The role of CTCF binding sites in the 3’ immunoglobulin heavy chain regulatory region

    Directory of Open Access Journals (Sweden)

    Barbara K Birshtein

    2012-11-01

    Full Text Available The immunoglobulin heavy chain locus undergoes a series of DNA rearrangements and modifications to achieve the construction and expression of individual antibody heavy chain genes in B cells. These events affect variable regions, through VDJ joining and subsequent somatic hypermutation, and constant regions through class switch recombination. Levels of IgH expression are also regulated during B cell development, resulting in high levels of secreted antibodies from fully-differentiated plasma cells. Regulation of these events has been attributed primarily to two cis-elements that work from long distances on their target sequences, i.e., an ~1 kb intronic enhancer, Eμ, located between the V region segments and the most 5′ constant region gene, Cμ; and an ~40 kb 3′ regulatory region (3′ RR that is located downstream of the most 3′ CH gene, Cα. The 3′ RR is a candidate for an end of B cell-specific regulation of the Igh locus. The 3′ RR contains several B cell-specific enhancers associated with DNase I hypersensitive sites (hs1-4, which are essential for class switch recombination and for high levels of IgH expression in plasma cells. Downstream of this enhancer-containing region is a region of high-density CTCF binding sites, which extends through hs5, 6, and 7 and further downstream. CTCF, with its enhancer-blocking activities, has been associated with all mammalian insulators and implicated in multiple chromosomal interactions. Here we address the 3′ RR CTCF-binding region as a potential insulator of the Igh locus, an independent regulatory element and a predicted modulator of the activity of 3’ RR enhancers. Using chromosome conformation capture technology, chromatin immunoprecipitation and genetic approaches, we have found that the 3’ RR with its CTCF binding region interacts with target sequences in the VH, Eμ and CH regions through DNA looping as regulated by protein binding. This region impacts on B cell-specific Igh

  9. Essential role of BAF complex interacting with Pax6 in establishment of a core cross-regulatory neurogenic network

    Science.gov (United States)

    Ninkovic, Jovica; Steiner-Mezzadri, Andrea; Jawerka, Melanie; Akinci, Umut; Masserdotti, Giacomo; Petricca, Stefania; Fischer, Judith; von Holst, Alexander; Beckers, Johanes; Lie, Chichung D.; Petrik, David; Miller, Erik; Tang, Jiong; Wu, Jiang; Lefebvre, Veronique; Demmers, Jeroen; Eisch, Amelia; Metzger, Daniel; Crabtree, Gerald; Irmler, Martin; Poot, Raymond; Götz, Magdalena

    2014-01-01

    The molecular mechanisms of neurogenic fate determination are of particular importance in light of the need to regenerate neurons. Here we define the mechanisms of installing neurogenic fate by the transcription factor Pax6 acting together with the Brg1-containing BAF chromatin remodeling complex. We show that Pax6 physically interacts with Brg1-containing BAF complex and genetic deletion of either Pax6 or Brg1, in the neural stem cells in the adult mouse subependymal zone results in a strikingly similar fate conversion from neuronal progenitors to glia. The Pax6-BAF complex drives neurogenesis by directly activating transcription factors Sox11, Nfib and Pou3f4, which form a cross-regulatory network that maintains neurogenic fate downstream of the Pax6-BAF complex in neuroblasts. Our work identifies a novel concept of stratification in neural fate commitment with a strikingly specific role of the Pax6-BAF complex in initiating a cross-regulatory network essential for maintenance of the neurogenic lineage in the adult brain. PMID:23933087

  10. Role of Regulatory T Cells in Pathogenesis and Biological Therapy of Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Milan Buc

    2013-01-01

    Full Text Available Multiple sclerosis (MS is an inflammatory disease in which the myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms. It is caused by an autoimmune response to self-antigens in a genetically susceptible individual induced by unknown environmental factors. Principal cells of the immune system that drive the immunopathological processes are T cells, especially of TH1 and TH17 subsets. However, in recent years, it was disclosed that regulatory T cells took part in, too. Subsequently, there was endeavour to develop ways how to re-establish their physiological functions. In this review, we describe known mechanisms of action, efficacy, and side-effects of contemporary and emerging MS immunotherapeutical agents on Treg cells and other cells of the immune system involved in the immunopathogenesis of the disease. Furthermore, we discuss how laboratory immunology can offer physicians its help in the diagnosis process and decisions what kind of biological therapy should be used.

  11. Regulatory roles of conserved intergenic domains in vertebrate Dlx bigene clusters.

    Science.gov (United States)

    Ghanem, Noël; Jarinova, Olga; Amores, Angel; Long, Qiaoming; Hatch, Gary; Park, Byung Keon; Rubenstein, John L R; Ekker, Marc

    2003-04-01

    Dlx homeobox genes of vertebrates are generally arranged as three bigene clusters on distinct chromosomes. The Dlx1/Dlx2, Dlx5/Dlx6, and Dlx3/Dlx7 clusters likely originate from duplications of an ancestral Dlx gene pair. Overlaps in expression are often observed between genes from the different clusters. To determine if the overlaps are a result of the conservation of enhancer sequences between paralogous clusters, we compared the Dlx1/2 and the Dlx5/Dlx6 intergenic regions from human, mouse, zebrafish, and from two pufferfish, Spheroides nephelus and Takifugu rubripes. Conservation between all five vertebrates is limited to four sequences, two in Dlx1/Dlx2 and two in Dlx5/Dlx6. These noncoding sequences are >75% identical over a few hundred base pairs, even in distant vertebrates. However, when compared to each other, the four intergenic sequences show a much more limited similarity. Each intergenic sequence acts as an enhancer when tested in transgenic animals. Three of them are active in the forebrain with overlapping patterns despite their limited sequence similarity. The lack of sequence similarity between paralogous intergenic regions and the high degree of sequence conservation of orthologous enhancers suggest a rapid divergence of Dlx intergenic regions early in chordate/vertebrate evolution followed by fixation of cis-acting regulatory elements.

  12. The role of quality of life in functional gastrointestinal disorders: regulatory issues.

    Science.gov (United States)

    Bergmann, J F; Chassany, O

    1998-01-01

    Generic questionnaire such as SF36 and functional gastrointestinal disorder (FGD)-specific questionnaires (i.e. IBSQOL or FGDQL) are now available for the evaluation of new drugs for the treatment of irritable bowel syndrome or functional dyspepsia. For regulatory issues it is necessary to describe in detail the scale of the QOL questionnaire, its psychometric properties and reason for its choice, as well as validation studies, populations concerned, means of administration and methods for analysis. Preselection of few dimensions of the QOL questionnaire, if necessary, has to be explained. QOL results have to be compared with symptom scores. Trials have to be double-blind placebo- controlled studies with a sample size calculation taking account of the high placebo-response. No official guidelines are available in FGD and more validation studies are needed to help in the choice of the specific QOL questionnaire, in the metrologic analysis and in the interpretation of QOL changes during FGD treatment. Then QOL questionnaires could become a primary end point in clinical trials if efficient drugs for FGD treatment are developed.

  13. Role of regulatory T cells in pathogenesis and biological therapy of multiple sclerosis.

    Science.gov (United States)

    Buc, Milan

    2013-01-01

    Multiple sclerosis (MS) is an inflammatory disease in which the myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms. It is caused by an autoimmune response to self-antigens in a genetically susceptible individual induced by unknown environmental factors. Principal cells of the immune system that drive the immunopathological processes are T cells, especially of TH1 and TH17 subsets. However, in recent years, it was disclosed that regulatory T cells took part in, too. Subsequently, there was endeavour to develop ways how to re-establish their physiological functions. In this review, we describe known mechanisms of action, efficacy, and side-effects of contemporary and emerging MS immunotherapeutical agents on Treg cells and other cells of the immune system involved in the immunopathogenesis of the disease. Furthermore, we discuss how laboratory immunology can offer physicians its help in the diagnosis process and decisions what kind of biological therapy should be used.

  14. The Essential Role of Circulating Thyroglobulin in Maintaining Dominance of Natural Regulatory T Cell Function to Prevent Autoimmune Thyroiditis.

    Science.gov (United States)

    Kong, Y M; Brown, N K; Morris, G P; Flynn, J C

    2015-09-01

    Several key findings from the late 1960s to mid-1970s regarding thyroid hormone metabolism and circulating thyroglobulin composition converged with studies pertaining to the role of T lymphocytes in autoimmune thyroiditis. These studies cemented the foundation for subsequent investigations into the existence and antigenic specificity of thymus-derived natural regulatory T cells (nTregs). These nTregs prevented the development of autoimmune thyroiditis, despite the ever-present genetic predisposition, autoantigen (thyroglobulin), and thyroglobulin-reactive T cells. Guided by the hypothalamus-pituitary-thyroid axis as a fixed set-point regulator in thyroid hormone metabolism, we used a murine model and compared at key junctures the capacity of circulating thyroglobulin level (raised by thyroid-stimulating hormone or exogenous thyroglobulin administration) to strengthen self-tolerance and resist autoimmune thyroiditis. The findings clearly demonstrated an essential role for raised circulating thyroglobulin levels in maintaining the dominance of nTreg function and inhibiting thyroid autoimmunity. Subsequent identification of thyroglobulin-specific nTregs as CD4(+)CD25(+)Foxp3(+) in the early 2000s enabled the examination of probable mechanisms of nTreg function. We observed that whenever nTreg function was perturbed by immunotherapeutic measures, opportunistic autoimmune disorders invariably surfaced. This review highlights the step-wise progression of applying insights from endocrinologic and immunologic studies to advance our understanding of the clonal balance between natural regulatory and autoreactive T cells. Moreover, we focus on how tilting the balance in favor of maintaining peripheral tolerance could be achieved. Thus, murine autoimmune thyroiditis has served as a unique model capable of closely simulating natural physiologic conditions.

  15. A regulatory role of androgen in ovarian steroidogenesis by rat granulosa cells.

    Science.gov (United States)

    Hasegawa, Toru; Kamada, Yasuhiko; Hosoya, Takeshi; Fujita, Shiho; Nishiyama, Yuki; Iwata, Nahoko; Hiramatsu, Yuji; Otsuka, Fumio

    2017-09-01

    Excess androgen and insulin-like growth factor (IGF)-I in the ovarian follicle has been suggested to be involved in the pathophysiology of polycystic ovary syndrome (PCOS). Here we investigated the impact of androgen and IGF-I on the regulatory mechanism of ovarian steroidogenesis using rat primary granulosa cells. It was revealed that androgen treatment with dihydrotestosterone (DHT) amplified progesterone synthesis in the presence of FSH and IGF-I, whereas it had no significant effect on estrogen synthesis by rat granulosa cells. In accordance with the effects of androgen on steroidogenesis, DHT enhanced the expression of progesterogenic factors and enzymes, including StAR, P450scc and 3βHSD, and cellular cAMP synthesis induced by FSH and IGF-I. Of note, treatment with DHT and IGF-I suppressed Smad1/5/8 phosphorylation and transcription of the BMP target gene Id-1, suggesting that androgen and IGF-I counteract BMP signaling that inhibits FSH-induced progesterone synthesis in rat granulosa cells. DHT was revealed to suppress the expression of BMP-6 receptors, consisting of ALK-2, ALK-6 and ActRII, while it increased the expression of inhibitory Smads in rat granulosa cells. In addition, IGF-I treatment upregulated androgen receptor (AR) expression and DHT treatment suppressed IGF-I receptor expression on rat granulosa cells. Collectively, the results indicate that androgen and IGF-I mutually interact and accelerate progesterone production, at least in part, by regulating endogenous BMP signaling in rat granulosa cells. Cooperative effects of androgen and IGF-I counteract endogenous BMP-6 activity in rat granulosa cells, which is likely to be functionally linked to the steroidogenic property shown in the PCOS ovary. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Deep transcriptome profiling of mammalian stem cells supports a regulatory role for retrotransposons in pluripotency maintenance

    DEFF Research Database (Denmark)

    Fort, Alexandre; Hashimoto, Kosuke; Yamada, Daisuke

    2014-01-01

    The importance of microRNAs and long noncoding RNAs in the regulation of pluripotency has been documented; however, the noncoding components of stem cell gene networks remain largely unknown. Here we investigate the role of noncoding RNAs in the pluripotent state, with particular emphasis on nucl...

  17. The Bright side of hematopoiesis: Regulatory roles of ARID3a/Bright in human and mouse hematopoiesis.

    Directory of Open Access Journals (Sweden)

    Michelle L. Ratliff

    2014-03-01

    Full Text Available ARID3a/Bright is a DNA binding protein that was originally discovered for its ability to increase immunoglobulin transcription in antigen-activated B cells. It interacts with DNA as a dimer through its ARID, or A/T-rich interacting domain. In association with other proteins, ARID3a increased transcription of the immunoglobulin heavy chain and led to improved chromatin accessibility of the heavy chain enhancer. Constitutive expression of ARID3a in B lineage cells resulted in autoantibody production, suggesting its regulation is important. Abnormal ARID3a expression has also been associated with increased proliferative capacity and malignancy. Roles for ARID3a in addition to interactions with the immunoglobulin locus were suggested by transgenic and knockout mouse models. Over-expression of ARID3a resulted in skewing of mature B cell subsets and altered gene expression patterns of follicular B cells, whereas loss of function resulted in loss of B1 lineage B cells and defects in hematopoiesis. More recent studies showed that loss of ARID3a in adult somatic cells promoted developmental plasticity, alterations in gene expression patterns, and lineage fate decisions. Together, these data suggest new regulatory roles for ARID3a. The genes influenced by ARID3a are likely to play pivotal roles in lineage decisions, highlighting the importance of this understudied transcription factor.

  18. The Bright Side of Hematopoiesis: Regulatory Roles of ARID3a/Bright in Human and Mouse Hematopoiesis.

    Science.gov (United States)

    Ratliff, Michelle L; Templeton, Troy D; Ward, Julie M; Webb, Carol F

    2014-01-01

    ARID3a/Bright is a DNA-binding protein that was originally discovered for its ability to increase immunoglobulin transcription in antigen-activated B cells. It interacts with DNA as a dimer through its ARID, or A/T-rich interacting domain. In association with other proteins, ARID3a increased transcription of the immunoglobulin heavy chain and led to improved chromatin accessibility of the heavy chain enhancer. Constitutive expression of ARID3a in B lineage cells resulted in autoantibody production, suggesting its regulation is important. Abnormal ARID3a expression has also been associated with increased proliferative capacity and malignancy. Roles for ARID3a in addition to interactions with the immunoglobulin locus were suggested by transgenic and knockout mouse models. Over-expression of ARID3a resulted in skewing of mature B cell subsets and altered gene expression patterns of follicular B cells, whereas loss of function resulted in loss of B1 lineage B cells and defects in hematopoiesis. More recent studies showed that loss of ARID3a in adult somatic cells promoted developmental plasticity, alterations in gene expression patterns, and lineage fate decisions. Together, these data suggest new regulatory roles for ARID3a. The genes influenced by ARID3a are likely to play pivotal roles in lineage decisions, highlighting the importance of this understudied transcription factor.

  19. A role for tolerogenic dendritic cell-induced B-regulatory cells in type 1 diabetes mellitus.

    Science.gov (United States)

    Giannoukakis, Nick; Trucco, Massimo

    2012-08-01

    To review the important recent findings on the nature, characteristics and function of novel populations of immunosuppressive B-lymphocytes (Bregs) and their possible role as a regulatory cell population, potentially responsive to dendritic cells, in preventing and possibly controlling type 1 diabetes mellitus. Although almost all of the experimental work in immunosuppressive B-lymphocyte biology has focused on their role in arthritis and experimental inflammatory bowel disease, only recently has a role for Bregs in the regulation of type 1 diabetes been looked at more extensively. IL-10-producing Bregs are of significant interest, more so because of their potential modulation by tolerogenic dendritic cells. Additionally, novel populations have been discovered that could also be relevant in the regulation of diabetes autoimmunity. The unexpected discovery of a novel population of Bregs, whose frequency was upregulated in our phase I clinical trial of tolerogenic autologous dendritic cell administration in humans, opens a new frontier for basic and translational research into these novel cell populations. Bregs are a recently rediscovered population of suppressive lymphocytes whose activation, differentiation and function could be sensitive to tolerogenic dendritic cell networks. Modulation of these dendritic cell networks, or the Bregs directly, offers novel options to attenuate and reverse type 1 diabetes autoimmunity as a possible cure for the disease.

  20. Regulatory role of PBAN in sex pheromone biosynthesis of heliothine moths

    Directory of Open Access Journals (Sweden)

    Russell eJurenka

    2011-10-01

    Full Text Available Both males and females of heliothine moths utilize sex pheromones during the mating process. Females produce and release a sex pheromone for the long-range attraction of males for mating. Production of sex pheromone in females is controlled by the peptide hormone PBAN (pheromone biosynthesis activating neuropeptide. This review will highlight what is known about the role PBAN plays in controlling pheromone production in female moths. Male moths produce compounds associated with a hair-pencil structure associated with the aedaegus that are used as short-range aphrodisiacs during the mating process. We will discuss the role that PBAN plays in regulating male production of hair-pencil pheromones.

  1. Lamins, laminopathies and disease mechanisms: Possible role for proteasomal degradation of key regulatory proteins

    Indian Academy of Sciences (India)

    Veena K Parnaik; Pankaj Chaturvedi; B H Muralikrishna

    2011-08-01

    Lamins are major structural proteins of the nucleus and are essential for nuclear integrity and organization of nuclear functions. Mutations in the human lamin genes lead to highly degenerative genetic diseases that affect a number of different tissues such as muscle, adipose or neuronal tissues, or cause premature ageing syndromes. New findings on the role of lamins in cellular signalling pathways, as well as in ubiquitin-mediated proteasomal degradation, have given important insights into possible mechanisms of pathogenesis.

  2. The GTPase Rho has a critical regulatory role in thymus development.

    OpenAIRE

    Henning, S W; Galandrini, R; Hall, A; Cantrell, D A

    1997-01-01

    The present study employs a genetic approach to explore the role of Rho GTPases in murine thymic development. Inactivation of Rho function in the thymus was achieved by thymic targeting of a transgene encoding C3 transferase from Clostridium botulinum which selectively ADP-ribosylates Rho within its effector domain and thereby abolishes its biological function. Thymi lacking functional Rho isolated from C3 transgenic mice were strikingly smaller and showed a marked (90%) decrease in cellulari...

  3. Bridging structure with function: structural, regulatory, and developmental role of laminins.

    Science.gov (United States)

    Tzu, Julia; Marinkovich, M Peter

    2008-01-01

    The basement membrane is a highly intricate and organized portion of the extracellular matrix that interfaces with a variety of cell types including epithelial, endothelial, muscle, nerve, and fat cells. The laminin family of glycoproteins is a major constituent of the basement membrane. The 16 known laminin isoforms are formed from combinations of alpha, beta, and gamma chains, with each chain containing specific domains capable of interacting with cellular receptors such as integrins and other extracellular ligands. In addition to its role in the assembly and architectural integrity of the basement membrane, laminins interact with cells to influence proliferation, differentiation, adhesion, and migration, processes activated in normal and pathologic states. In vitro these functions are regulated by the post-translational modifications of the individual laminin chains. In vivo laminin knockout mouse studies have been particularly instructive in defining the function of specific laminins in mammalian development and have also highlighted its role as a key component of the basement membrane. In this review, we will define how laminin structure complements function and explore its role in both normal and pathologic processes.

  4. The GTPase Rho has a critical regulatory role in thymus development.

    Science.gov (United States)

    Henning, S W; Galandrini, R; Hall, A; Cantrell, D A

    1997-05-01

    The present study employs a genetic approach to explore the role of Rho GTPases in murine thymic development. Inactivation of Rho function in the thymus was achieved by thymic targeting of a transgene encoding C3 transferase from Clostridium botulinum which selectively ADP-ribosylates Rho within its effector domain and thereby abolishes its biological function. Thymi lacking functional Rho isolated from C3 transgenic mice were strikingly smaller and showed a marked (90%) decrease in cellularity compared with their normal litter mates. We also observed a similar decrease in levels of peripheral T cells in C3 transgenic mice. Analysis of the maturation status of thymocytes indicated that differentiation of progenitor cells to mature T cells can occur in the absence of Rho function, and both positive and negative selection of T cells appear to be intact. However, transgenic mice that lack Rho function in the thymus show maturational, proliferative and cell survival defects during T-cell development that severely impair the generation of normal numbers of thymocytes and mature peripheral T cells. The present study thus identifies a role for Rho-dependent signalling pathways in thymocyte development. The data show that the function of Rho GTPases is critical for the proliferative expansion of thymocytes. This defines a selective role for the GTPase Rho in early thymic development as a critical integrator of proliferation and cell survival signals.

  5. The role of alternative oxidase in tomato fruit ripening and its regulatory interaction with ethylene.

    Science.gov (United States)

    Xu, Fei; Yuan, Shu; Zhang, Da-Wei; Lv, Xin; Lin, Hong-Hui

    2012-09-01

    Although the alternative oxidase (AOX) has been proposed to play a role in fruit development, the function of AOX in fruit ripening is unclear. To gain further insight into the role of AOX in tomato fruit ripening, transgenic tomato plants 35S-AOX1a and 35S-AOX-RNAi were generated. Tomato plants with reduced LeAOX levels exhibited retarded ripening; reduced carotenoids, respiration, and ethylene production; and the down-regulation of ripening-associated genes. Moreover, no apparent respiratory climacteric occurred in the AOX-reduced tomato fruit, indicating that AOX might play an important role in climacteric respiration. In contrast, the fruit that overexpressed LeAOX1a accumulated more lycopene, though they displayed a similar pattern of ripening to wild-type fruit. Ethylene application promoted fruit ripening and anticipated ethylene production and respiration, including the alternative pathway respiration. Interestingly, the transgenic plants with reduced LeAOX levels failed to ripen after 1-methylcyclopropene (1-MCP) treatment, while such inhibition was notably less effective in 35S-AOX1a fruit. These findings indicate that AOX is involved in respiratory climacteric and ethylene-mediated fruit ripening of tomato.

  6. Distinct Wnt signaling pathways have opposing roles in appendage regeneration.

    Science.gov (United States)

    Stoick-Cooper, Cristi L; Weidinger, Gilbert; Riehle, Kimberly J; Hubbert, Charlotte; Major, Michael B; Fausto, Nelson; Moon, Randall T

    2007-02-01

    In contrast to mammals, lower vertebrates have a remarkable capacity to regenerate complex structures damaged by injury or disease. This process, termed epimorphic regeneration, involves progenitor cells created through the reprogramming of differentiated cells or through the activation of resident stem cells. Wnt/beta-catenin signaling regulates progenitor cell fate and proliferation during embryonic development and stem cell function in adults, but its functional involvement in epimorphic regeneration has not been addressed. Using transgenic fish lines, we show that Wnt/beta-catenin signaling is activated in the regenerating zebrafish tail fin and is required for formation and subsequent proliferation of the progenitor cells of the blastema. Wnt/beta-catenin signaling appears to act upstream of FGF signaling, which has recently been found to be essential for fin regeneration. Intriguingly, increased Wnt/beta-catenin signaling is sufficient to augment regeneration, as tail fins regenerate faster in fish heterozygous for a loss-of-function mutation in axin1, a negative regulator of the pathway. Likewise, activation of Wnt/beta-catenin signaling by overexpression of wnt8 increases proliferation of progenitor cells in the regenerating fin. By contrast, overexpression of wnt5b (pipetail) reduces expression of Wnt/beta-catenin target genes, impairs proliferation of progenitors and inhibits fin regeneration. Importantly, fin regeneration is accelerated in wnt5b mutant fish. These data suggest that Wnt/beta-catenin signaling promotes regeneration, whereas a distinct pathway activated by wnt5b acts in a negative-feedback loop to limit regeneration.

  7. Heat Shock Protein A2 (HSPA2): Regulatory Roles in Germ Cell Development and Sperm Function.

    Science.gov (United States)

    Nixon, Brett; Bromfield, Elizabeth G; Cui, Jinwei; De Iuliis, Geoffry N

    2017-01-01

    Among the numerous families of heat shock protein (HSP) that have been implicated in the regulation of reproductive system development and function, those belonging to the 70 kDa HSP family have emerged as being indispensable for male fertility. In particular, the testis-enriched heat shock 70 kDa protein 2 (HSPA2) has been shown to be critical for the progression of germ cell differentiation during spermatogenesis in the mouse model. Beyond this developmentally important window, mounting evidence has also implicated HSPA2 in the functional transformation of the human sperm cell during their ascent of the female reproductive tract. Specifically, HSPA2 appears to coordinate the remodelling of specialised sperm domains overlying the anterior region of the sperm head compatible with their principle role in oocyte recognition. The fact that levels of the HSPA2 protein in mature spermatozoa tightly correlate with the efficacy of oocyte binding highlight its utility as a powerful prognostic biomarker of male fertility. In this chapter, we consider the unique structural and biochemical characteristics of HSPA2 that enable this heat shock protein to fulfil its prominent roles in orchestrating the morphological differentiation of male germ cells during spermatogenesis as well as their functional transformation during post-testicular sperm maturation.

  8. Evidence for a regulatory role of diatom silicon transporters in cellular silicon responses.

    Science.gov (United States)

    Shrestha, Roshan P; Hildebrand, Mark

    2015-01-01

    The utilization of silicon by diatoms has both global and small-scale implications, from oceanic primary productivity to nanotechnological applications of their silica cell walls. The sensing and transport of silicic acid are key aspects of understanding diatom silicon utilization. At low silicic acid concentrations (silicon starvation. SIT1 and SIT2 were localized in the plasma membrane, and protein levels were generally inversely correlated with cellular silicon needs, with a distinct response being found when the two SITs were compared. We developed highly effective approaches for RNA interference and antisense knockdowns, the first such approaches developed for a centric diatom. SIT knockdown differentially affected the uptake of silicon and the incorporation of silicic acid and resulted in the induction of lipid accumulation under silicon starvation conditions far earlier than in the wild-type cells, suggesting that the cells were artificially sensing silicon limitation. The data suggest that the transport role of the SITs is relatively minor under conditions with sufficient silicic acid. Their primary role is to sense silicic acid levels to evaluate whether the cell can proceed with its cell wall formation and division processes.

  9. The mitochondrial PPR protein LOVASTATIN INSENSITIVE 1 plays regulatory roles in cytosolic and plastidial isoprenoid biosynthesis through RNA editing.

    Science.gov (United States)

    Tang, Jianwei; Kobayashi, Keiko; Suzuki, Masashi; Matsumoto, Shogo; Muranaka, Toshiya

    2010-02-01

    Unlike animals, plants synthesize isoprenoids via two pathways, the cytosolic mevalonate (MVA) pathway and the plastidial 2-C-methyl-d-erythritol-4-phosphate (MEP) pathway. Little information is known about the mechanisms that regulate these complex biosynthetic networks over multiple organelles. To understand such regulatory mechanisms of the biosynthesis of isoprenoids in plants, we previously characterized the Arabidopsis mutant, lovastatin insensitive 1 (loi1), which is resistant to lovastatin and clomazone, specific inhibitors of the MVA and MEP pathways, respectively. LOI1 encodes a pentatricopeptide repeat (PPR) protein localized in mitochondria that is thought to have RNA binding ability and function in post-transcriptional regulation of mitochondrial gene expression. LOI1 belongs to the DYW subclass of PPR proteins, which is hypothesized to be correlated with RNA editing. As a result of analysis of RNA editing of mitochondrial genes in loi1, a defect in RNA editing of three genes, nad4, ccb203 and cox3, was identified in loi1. These genes are related to the respiratory chain. Wild type (WT) treated with some respiration inhibitors mimicked the loi1 phenotype. Interestingly, HMG-CoA reductase activity of WT treated with lovastatin combined with antimycin A, an inhibitor of complex III in the respiratory chain, was higher than that of WT treated with only lovastatin, despite the lack of alteration of transcript or protein levels of HMGR. These results suggest that HMGR enzyme activity is regulated through the respiratory cytochrome pathway. Although various mechanisms exist for isoprenoid biosynthesis, our studies demonstrate the novel possibility that mitochondrial respiration plays potentially regulatory roles in isoprenoid biosynthesis.

  10. Revisiting the regulatory roles of the TGF-β family of cytokines.

    Science.gov (United States)

    Fujio, Keshi; Komai, Toshihiko; Inoue, Mariko; Morita, Kaoru; Okamura, Tomohisa; Yamamoto, Kauzhiko

    2016-09-01

    TGF-β family members are multipotent cytokines that are involved in many cellular processes, including cell differentiation, organ development, wound healing and immune regulation. TGF-β has pleiotropic effects on adaptive immunity, especially in the regulation of CD4(+) T cell and B cell responses. Furthermore, identification of CD4(+) T cell subsets that produce TGF-β3 revealed unexpected roles of TGF-β3 in the control of adaptive immunity. In contrast to TGF-β1, which induces extensive fibrosis, TGF-β3 induces non-scarring wound healing and counteracts tissue fibrosis. Recent progress in the understanding of the activation mechanism of TGF-β may enable us to develop novel biologic therapies based on advanced protein engineering.

  11. Why do so many Americans oppose the Affordable Care Act?

    Science.gov (United States)

    Dalen, James E; Waterbrook, Keith; Alpert, Joseph S

    2015-08-01

    The Patient Protection and Affordable Care Act (ACA) was passed by a Democratic Congress and signed into law by a Democratic president in 2010. Republican congressmen, governors, and Republican candidates have consistently opposed the ACA and have vowed to repeal it. Polls have consistently shown that it is supported by care. Yet Medicare, a mandatory insurance for seniors administered by the federal government since 1965, is overwhelmingly approved by the American public. The opposition to a government role in health care is based on the fact that that the vast majority of our citizens do not trust their government. Republicans are much less trusting of the federal government and much less supportive of a government role in health care than Democrats. The overwhelmingly negative TV ads against the ACA by the Republican candidates in the elections of 2012 and 2014 have had a major impact on Americans' views of the ACA. More than 60% of Americans have stated that most of what they know about the ACA came from watching TV. Opposition to a government role in health care and to mandatory health insurance makes it unlikely that the US will be able to insure that all of its citizens have ongoing access to health care in the near future.

  12. The Regulatory Role of Signaling Crosstalk in Hypertrophy of MSCs and Human Articular Chondrocytes.

    Science.gov (United States)

    Zhong, Leilei; Huang, Xiaobin; Karperien, Marcel; Post, Janine N

    2015-08-14

    Hypertrophic differentiation of chondrocytes is a main barrier in application of mesenchymal stem cells (MSCs) for cartilage repair. In addition, hypertrophy occurs occasionally in osteoarthritis (OA). Here we provide a comprehensive review on recent literature describing signal pathways in the hypertrophy of MSCs-derived in vitro differentiated chondrocytes and chondrocytes, with an emphasis on the crosstalk between these pathways. Insight into the exact regulation of hypertrophy by the signaling network is necessary for the efficient application of MSCs for articular cartilage repair and for developing novel strategies for curing OA. We focus on articles describing the role of the main signaling pathways in regulating chondrocyte hypertrophy-like changes. Most studies report hypertrophic differentiation in chondrogenesis of MSCs, in both human OA and experimental OA. Chondrocyte hypertrophy is not under the strict control of a single pathway but appears to be regulated by an intricately regulated network of multiple signaling pathways, such as WNT, Bone morphogenetic protein (BMP)/Transforming growth factor-β (TGFβ), Parathyroid hormone-related peptide (PTHrP), Indian hedgehog (IHH), Fibroblast growth factor (FGF), Insulin like growth factor (IGF) and Hypoxia-inducible factor (HIF). This comprehensive review describes how this intricate signaling network influences tissue-engineering applications of MSCs in articular cartilage (AC) repair, and improves understanding of the disease stages and cellular responses within an OA articular joint.

  13. The Regulatory Role of Signaling Crosstalk in Hypertrophy of MSCs and Human Articular Chondrocytes

    Directory of Open Access Journals (Sweden)

    Leilei Zhong

    2015-08-01

    Full Text Available Hypertrophic differentiation of chondrocytes is a main barrier in application of mesenchymal stem cells (MSCs for cartilage repair. In addition, hypertrophy occurs occasionally in osteoarthritis (OA. Here we provide a comprehensive review on recent literature describing signal pathways in the hypertrophy of MSCs-derived in vitro differentiated chondrocytes and chondrocytes, with an emphasis on the crosstalk between these pathways. Insight into the exact regulation of hypertrophy by the signaling network is necessary for the efficient application of MSCs for articular cartilage repair and for developing novel strategies for curing OA. We focus on articles describing the role of the main signaling pathways in regulating chondrocyte hypertrophy-like changes. Most studies report hypertrophic differentiation in chondrogenesis of MSCs, in both human OA and experimental OA. Chondrocyte hypertrophy is not under the strict control of a single pathway but appears to be regulated by an intricately regulated network of multiple signaling pathways, such as WNT, Bone morphogenetic protein (BMP/Transforming growth factor-β (TGFβ, Parathyroid hormone-related peptide (PTHrP, Indian hedgehog (IHH, Fibroblast growth factor (FGF, Insulin like growth factor (IGF and Hypoxia-inducible factor (HIF. This comprehensive review describes how this intricate signaling network influences tissue-engineering applications of MSCs in articular cartilage (AC repair, and improves understanding of the disease stages and cellular responses within an OA articular joint.

  14. Hyperinsulinism/hyperammonemia syndrome: insights into the regulatory role of glutamate dehydrogenase in ammonia metabolism.

    Science.gov (United States)

    Stanley, Charles A

    2004-04-01

    The second most common form of congenital hyperinsulinism, the hyperinsulinism/hyperammonemia syndrome (HI/HA), is associated with dominantly expressed missense mutations of the mitochondrial matrix enzyme, glutamate dehydrogenase (GDH). GDH catalyzes the oxidative deamination of glutamate to alpha-ketoglutarate plus ammonia, using NAD or NADP as co-factor. HI/HA mutations impair GDH sensitivity to its allosteric inhibitor, GTP, resulting in a gain of enzyme function and increased sensitivity to its allosteric activator, leucine. The phenotype is dominated by hypoglycemia with post-prandial hypoglycemia following protein meals, as well as fasting hypoglycemia. Plasma ammonia levels are increased 3-5 times normal due to expression of mutant GDH in liver, probably reflecting increased ammonia release from glutamate as well as impaired synthesis of NAG, due to reduction of hepatic glutamate pools. Ammonia levels are unaffected by feeding or fasting and appear to cause no symptoms, perhaps due to a protective effect of increased GDH activity in brain. The clinical consequences of the HI/HA mutations imply that GDH plays a central role in overall control of amino acid catabolism and ammonia metabolism integrating responses to changes in intracellular energy potential and amino acid levels.

  15. Obligatory role of membrane events in the regulatory effect of metformin on the respiratory chain function.

    Science.gov (United States)

    Detaille, Dominique; Guigas, Bruno; Leverve, Xavier; Wiernsperger, Nicolas; Devos, Pierre

    2002-04-01

    From recent findings about the indirect effect of metformin (MET) targeted on the respiratory chain complex I, we reconsidered this question and tried to determine the causality of any alteration at this enzymatic level using Xenopus laevis oocytes. Addition of MET (50 microM) reduced by 40% the rotenone-sensitive activity of complex I only in incubating intact oocytes but not in mitochondria isolated by differential centrifugation. The drug prior injected inside these cells had also no measurable effect. In spite of this and the weak binding of MET to the mitochondrial fraction, there was a fairly good correlation between the marked inhibitory action of MET on complex I and its progressive appearance within the oocyte cytoplasm. The intriguing observation that MET as a liposomal form was again able to exert its role when added directly to isolated mitochondria is in accordance with a membrane-mediated uptake and vesicular routing of MET. Furthermore, a temperature-dependent effect was clearly shown. At 4 degrees, oocytes failed to take up efficiently MET and accordingly its subsequent action on respiration was therefore lost. Likewise, MET transport was hindered and inhibition of complex I totally disappeared when a structural analog, asymmetrical dimethylarginine (ADMA), was placed together with MET either at an identical concentration or in excess. These data strongly support the view that MET may recognise some specific membranous sites, likely belonging to effector systems, before penetrating the cell in a bound state via an obscure endocytotic event which still has to be identified.

  16. A Regulatory Role of NAD Redox Status on Flavin Cofactor Homeostasis in S. cerevisiae Mitochondria

    Directory of Open Access Journals (Sweden)

    Teresa Anna Giancaspero

    2013-01-01

    Full Text Available Flavin adenine dinucleotide (FAD and nicotinamide adenine dinucleotide (NAD are two redox cofactors of pivotal importance for mitochondrial functionality and cellular redox balance. Despite their relevance, the mechanism by which intramitochondrial NAD(H and FAD levels are maintained remains quite unclear in Saccharomyces cerevisiae. We investigated here the ability of isolated mitochondria to degrade externally added FAD and NAD (in both its reduced and oxidized forms. A set of kinetic experiments demonstrated that mitochondrial FAD and NAD(H destroying enzymes are different from each other and from the already characterized NUDIX hydrolases. We studied here, in some detail, FAD pyrophosphatase (EC 3.6.1.18, which is inhibited by NAD+ and NADH according to a noncompetitive inhibition, with Ki values that differ from each other by an order of magnitude. These findings, together with the ability of mitochondrial FAD pyrophosphatase to metabolize endogenous FAD, presumably deriving from mitochondrial holoflavoproteins destined to degradation, allow for proposing a novel possible role of mitochondrial NAD redox status in regulating FAD homeostasis and/or flavoprotein degradation in S. cerevisiae.

  17. Identification of a negative regulatory role for spi-C in the murine B cell lineage.

    Science.gov (United States)

    Li, Stephen K H; Solomon, Lauren A; Fulkerson, Patricia C; DeKoter, Rodney P

    2015-04-15

    Spi-C is an E26 transformation-specific family transcription factor that is highly related to PU.1 and Spi-B. Spi-C is expressed in developing B cells, but its function in B cell development and function is not well characterized. To determine whether Spi-C functions as a negative regulator of Spi-B (encoded by Spib), mice were generated that were germline knockout for Spib and heterozygous for Spic (Spib(-/-)Spic(+/-)). Interestingly, loss of one Spic allele substantially rescued B cell frequencies and absolute numbers in Spib(-/-) mouse spleens. Spib(-/-)Spic(+/-) B cells had restored proliferation compared with Spib(-/-) B cells in response to anti-IgM or LPS stimulation. Investigation of a potential mechanism for the Spib(-/-)Spic(+/-) phenotype revealed that steady-state levels of Nfkb1, encoding p50, were elevated in Spib(-/-)Spic(+/-) B cells compared with Spib(-/-) B cells. Spi-B was shown to directly activate the Nfkb1 gene, whereas Spi-C was shown to repress this gene. These results indicate a novel role for Spi-C as a negative regulator of B cell development and function.

  18. Regulatory roles of 24-epibrassinolide in tolerance of Acacia gerrardii Benth to salt stress.

    Science.gov (United States)

    Abd Allah, Elsayed Fathi; Alqarawi, A A; Hashem, Abeer; Wirth, Stephan; Egamberdieva, Dilfuza

    2017-07-11

    This experiment aimed to investigate the role of 24-epibrassinolide (EBL) against NaCl-induced salinity stress in Acacia gerrardii Benth. NaCl (200 mM) imparted deleterious effects on the growth and chlorophyll contents of A. gerrardii, but foliar application of EBL (1.0 mg/l; each plant received 2.5 ml) mitigated the negative effect considerably. NaCl reduced chlorophyll content but this was significantly ameliorated by the application of EBL. EBL reduced significantly NaCl-induced oxidative stress hence protect membranes and also improved the relative water content significantly by 6.6% as compared with control. Nitrate reductase activity declined after NaCl treatment but EBL application sustained its activity under normal and stressed conditions. Exogenous application of EBL significantly improved the activity of superoxide dismutase, catalase and the enzymes of the ascorbate-glutathione pathway thereby protecting the photosynthetic electron transport chain and other metabolic processes in A. gerrardii from NaCl-induced oxidative stress.

  19. A regulatory role for NBS1 in strand-specific mutagenesis during somatic hypermutation.

    Directory of Open Access Journals (Sweden)

    Likun Du

    Full Text Available Activation-induced cytidine deaminase (AID is believed to initiate somatic hypermutation (SHM by deamination of deoxycytidines to deoxyuridines within the immunoglobulin variable regions genes. The deaminated bases can subsequently be replicated over, processed by base excision repair or mismatch repair, leading to introduction of different types of point mutations (G/C transitions, G/C transversions and A/T mutations. It is evident that the base excision repair pathway is largely dependent on uracil-DNA glycosylase (UNG through its uracil excision activity. It is not known, however, which endonuclease acts in the step immediately downstream of UNG, i.e. that cleaves at the abasic sites generated by the latter. Two candidates have been proposed, an apurinic/apyrimidinic endonuclease (APE and the Mre11-Rad50-NBS1 complex. The latter is intriguing as this might explain how the mutagenic pathway is primed during SHM. We have investigated the latter possibility by studying the in vivo SHM pattern in B cells from ataxia-telangiectasia-like disorder (Mre11 deficient and Nijmegen breakage syndrome (NBS1 deficient patients. Our results show that, although the pattern of mutations in the variable heavy chain (V(H genes was altered in NBS1 deficient patients, with a significantly increased number of G (but not C transversions occurring in the SHM and/or AID targeting hotspots, the general pattern of mutations in the V(H genes in Mre11 deficient patients was only slightly altered, with an increased frequency of A to C transversions. The Mre11-Rad50-NBS1 complex is thus unlikely to be the major nuclease involved in cleavage of the abasic sites during SHM, whereas NBS1 might have a specific role in regulating the strand-biased repair during phase Ib mutagenesis.

  20. EXPRESSION OF HYPOXIA INDUCIBLE FACTOR-1α AND ITS REGULATORY ROLE IN DEVELOPING VERTEBRAE

    Institute of Scientific and Technical Information of China (English)

    ZHU Xun-bing; DENG Lian-fu; XIAO Yu-zhou

    2009-01-01

    Objective To explore the expression pattern and possible role of hypoxia inducible factor-1α(HIF-1α) in fetal vertebrae development of mouse.Methods The developmental stages of mice fetal vertebrae were observed from embryonic days 13.5 to 18.5 (E13.5 to E18.5) by stereoscopic and light microscopes respectively, and the expressions of HIF-1α at various times were also detected at levels of mRNA and protein by using methods of RT-PCR and Western blotting. Distribution of HIF-1α in the vertebrae was examined by immunohistochemical assay. Vascular endothelia growth factor (VEGF) mRNA and other chondro-osteoblast marker genes as type Ⅱ collagen a1 (Coll2a1) and osteocalcin (OCN) were detected by RT-PCR too.Results The cartilaginous spine column began to form at E13.5, followed by the arising of the primary ossification center in vertebrae at E15.5, then the osteogenesis expanded and extended to both sides of the vertebrae. HIF-1α mRNA began to express at E13.5, and showed significantly higher level at E14.5 (P<0.05), then declined to a low level. VEGF mRNA expressed coincidently with HIF-1α. While HIF-1α protein expression was observed at E14.5 and lasted at low level till to birth. The expression pattern of Coll2a1 and OCN elucidated the cell evolution from chondrocyte to osteoblast.Conclusion The developmental pattern of vertebrae appears to be an endochondral osteogenesis process. Existed hypoxia microenviroment in the vertebrae may increase HIF-1α mRNA and protein contents thus activate VEGF expression, as may be related to the activation of other downstream genes of hypoxia inducible factor-1α and initiate the cascade of endochondral osteogenesis.

  1. Regulatory roles of bone morphogenetic proteins and glucocorticoids in catecholamine production by rat pheochromocytoma cells.

    Science.gov (United States)

    Kano, Yoshihiro; Otsuka, Fumio; Takeda, Masaya; Suzuki, Jiro; Inagaki, Kenichi; Miyoshi, Tomoko; Miyamoto, Manabu; Otani, Hiroyuki; Ogura, Toshio; Makino, Hirofumi

    2005-12-01

    We here report a new physiological system that governs catecholamine synthesis involving bone morphogenetic proteins (BMPs) and activin in the rat pheochromocytoma cell line, PC12. BMP type I receptors, including activin receptor-like kinase-2 (ALK-2) (also referred to as ActRIA) and ALK-3 (BMPRIA), both type II receptors, ActRII and BMPRII, as well as the ligands BMP-2, -4, and -7 and inhibin/activin subunits were expressed in PC12 cells. PC12 cells predominantly secrete dopamine, whereas noradrenaline and adrenaline production is negligible. BMP-2, -4, -6, and -7 and activin A each suppressed dopamine and cAMP synthesis in a dose-dependent fashion. The BMP ligands also decreased 3,4-dihydroxyphenylalanine decarboxylase mRNA expression, whereas activin suppressed tyrosine hydroxylase expression. BMPs induced both Smad1/5/8 phosphorylation and Tlx2-Luc activation, whereas activin stimulated 3TP-Luc activity and p38 MAPK phosphorylation. ERK signaling was not affected by BMPs or activin. Dexamethasone enhanced catecholamine synthesis, accompanying increases in tyrosine hydroxylase and 3,4-dihydroxyphenylalanine decarboxylase transcription without cAMP accumulation. In the presence of dexamethasone, BMPs and activin failed to reduce dopamine as well as cAMP production. In addition, dexamethasone modulated mitotic suppression of PC12 induced by BMPs in a ligand-dependent manner. Furthermore, intracellular BMP signaling was markedly suppressed by dexamethasone treatment and the expression of ALK-2, ALK-3, and BMPRII was significantly inhibited by dexamethasone. Collectively, the endogenous BMP/activin system plays a key role in the regulation of catecholamine production. Controlling activity of the BMP system may be critical for glucocorticoid-induced catecholamine synthesis by adrenomedullar cells.

  2. Cancer Dormancy: A Regulatory Role for Endogenous Immunity in Establishing and Maintaining the Tumor Dormant State

    Directory of Open Access Journals (Sweden)

    Constantin N. Baxevanis

    2015-07-01

    Full Text Available The significant contribution of host immunity in early tumorigenesis has been recently recognized as a result of our better understanding of the molecular pathways regulating tumor cell biology and tumor-lymphocyte interactions. Emerging evidence suggests that disseminated dormant tumor cells derived from primary tumors before or after immune surveillance, are responsible for subsequent metastases. Recent trends from the field of onco-immunology suggest that efficiently stimulating endogenous anticancer immunity is a prerequisite for the successful outcome of conventional cancer therapies. Harnessing the immune system to achieve clinical efficacy is realistic in the context of conventional therapies resulting in immunogenic cell death and/or immunostimulatory side effects. Targeted therapies designed to target oncogenic pathways in tumor cells can also positively regulate the endogenous immune response and tumor microenvironment. Identification of T cell inhibitory signals has prompted the development of immune checkpoint inhibitors, which specifically hinder immune effector inhibition, reinvigorating and potentially expanding the preexisting anticancer immune response. This anticancer immunity can be amplified in the setting of immunotherapies, mostly in the form of vaccines, which boost naturally occurring T cell clones specifically recognizing tumor antigens. Thus, a promising anticancer therapy will aim to activate patients’ naturally occurring anticancer immunity either to eliminate residual tumor cells or to prolong dormancy in disseminated tumor cells. Such an endogenous anticancer immunity plays a significant role for controlling the balance between dormant tumor cells and tumor escape, and restraining metastases. In this review, we mean to suggest that anticancer therapies aiming to stimulate the endogenous antitumor responses provide the concept of the therapeutic management of cancer.

  3. The regulatory role of Streptomyces coelicolor TamR in central metabolism.

    Science.gov (United States)

    Huang, Hao; Sivapragasam, Smitha; Grove, Anne

    2015-03-01

    Trans-aconitate methyltransferase regulator (TamR) is a member of the ligand-responsive multiple antibiotic resistance regulator (MarR) family of transcription factors. In Streptomyces coelicolor, TamR regulates transcription of tamR (encoding TamR), tam (encoding trans-aconitate methyltransferase) and sacA (encoding aconitase); up-regulation of these genes promotes metabolic flux through the citric acid cycle. DNA binding by TamR is attenuated and transcriptional derepression is achieved on binding of ligands such as citrate and trans-aconitate to TamR. In the present study, we show that three additional genes are regulated by S. coelicolor TamR. Genes encoding malate synthase (aceB1; SCO6243), malate dehydrogenase (mdh; SCO4827) and isocitrate dehydrogenase (idh; SCO7000) are up-regulated in vivo when citrate and trans-aconitate accumulate, and TamR binds the corresponding gene promoters in vitro, a DNA binding that is attenuated by cognate ligands. Mutations to the TamR binding site attenuate DNA binding in vitro and result in constitutive promoter activity in vivo. The predicted TamR binding sites are highly conserved in the promoters of these genes in Streptomyces species that encode divergent tam-tamR gene pairs, suggesting evolutionary conservation. Like aconitase and trans-aconitate methyltransferase, malate dehydrogenase, isocitrate dehydrogenase and malate synthase are closely related to the citric acid cycle, either catalysing individual reaction steps or, in the case of malate synthase, participating in the glyoxylate cycle to produce malate that enters the citric acid cycle to replenish the intermediate pool. Taken together, our data suggest that TamR plays an important and conserved role in promoting metabolic flux through the citric acid cycle.

  4. Investigation of thermal protection system by forward-facing cavity and opposing jet combinatorial configuration

    Institute of Scientific and Technical Information of China (English)

    Lu Haibo; Liu Weiqiang

    2013-01-01

    This paper focuses on the usage of the forward-facing cavity and opposing jet combinatorial configuration as the thermal protection system (TPS) for hypersonic vehicles.A hemispherecone nose-tip with the combinatorial configuration is investigated numerically in hypersonic free stream.Some numerical results are validated by experiments.The flow field parameters,aerodynamic force and surface heat flux distribution are obtained.The influence of the opposing jet stagnation pressure on cooling efficiency of the combinatorial TPS is discussed.The detailed numerical results show that the aerodynamic heating is reduced remarkably by the combinatorial system.The recirculation region plays a pivotal role for the reduction of heat flux.The larger the stagnation pressure of opposing jet is,the more the heating reduction is.This kind of combinatorial system is suitable to be the TPS for the high-speed vehicles which need long-range and long time flight.

  5. The role of inflammatory, anti-inflammatory, and regulatory cytokines in patients infected with cutaneous leishmaniasis in Amazonas State, Brazil.

    Science.gov (United States)

    Espir, Thaís Tibery; Figueira, Luanda de Paula; Naiff, Maricleide de Farias; da Costa, Allyson Guimarães; Ramalho-Ortigão, Marcelo; Malheiro, Adriana; Franco, Antonia Maria Ramos

    2014-01-01

    The authors discuss in this paper the role of inflammatory, anti-inflammatory, and regulatory cytokines in patients infected with different species of Leishmania in Amazonas State, Brazil. A comparative analysis was made of serum concentrations of these cytokines in the peripheral blood of 33 patients infected with cutaneous leishmaniasis. The isolates were identified as Leishmania guyanensis, L. naiffi, and L. amazonensis. Most (64%) of the patients were male ranging in age from 18 to 58 years. Protein expression profiles of IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α, and IL-17 cytokines were shown to vary significantly between infected and noninfected (control group) individuals and according to the Leishmania species. Infection caused by L. guyanensis accounted for 73% of the cases and patients with this parasite also showed higher concentrations of IL-2, IFN-γ, IL-4, and IL-17 when compared to infection by L. amazonensis. Patients with infection caused by L. naiffi showed higher concentration of the cytokines analyzed when compared to uninfected patients; however, there was no statistically significant difference with the other species analyzed.

  6. Genetic polymorphism in FOXP3 gene: imbalance in regulatory T-cell role and development of human diseases

    Indian Academy of Sciences (India)

    Julie Massayo Maeda Oda; Bruna Karina Banin Hirata; Roberta Losi Guembarovski; Maria Angelica Ehara Watanabe

    2013-04-01

    The FOXP3 gene encodes a transcription factor thought to be important for the development and function of regulatory T cells (Treg cells). These cells are involved in the regulation of T cell activation and therefore are essential for normal immune homeostasis. Signals from microenvironment have a profound influence on the maintenance or progression of diseases. Thus, Tregs have an important marker protein, FOXP3, though it does not necessarily confer a Treg phenotype when expressed. FOXP3 polymorphisms that occur with high frequency in the general populations have been studied in common multifactorial human diseases. Dysfunction of FOXP3 gene product could result in lack of Treg cells and subsequently chronically activated CD4+ T cells which express increased levels of several activation markers and cytokines, resulting in some autoimmune diseases. In contrast, high Treg levels have been reported in peripheral blood, lymph nodes, and tumour specimens from patients with different types of cancer. The present study discusses the polymorphisms located in intron, exon and promoter regions of FOXP3 which have already been investigated by many researchers. FOXP3 has received considerable attention in attempts to understand the molecular aspect of Treg cells. Therefore, in the present study, the relationship between genetic polymorphism of FOXP3 in Treg-cell role and in disease development are reviewed considering the interactive effect of genetic factors.

  7. The Role of Inflammatory, Anti-Inflammatory, and Regulatory Cytokines in Patients Infected with Cutaneous Leishmaniasis in Amazonas State, Brazil

    Directory of Open Access Journals (Sweden)

    Thaís Tibery Espir

    2014-01-01

    Full Text Available The authors discuss in this paper the role of inflammatory, anti-inflammatory, and regulatory cytokines in patients infected with different species of Leishmania in Amazonas State, Brazil. A comparative analysis was made of serum concentrations of these cytokines in the peripheral blood of 33 patients infected with cutaneous leishmaniasis. The isolates were identified as Leishmania guyanensis, L. naiffi, and L. amazonensis. Most (64% of the patients were male ranging in age from 18 to 58 years. Protein expression profiles of IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α, and IL-17 cytokines were shown to vary significantly between infected and noninfected (control group individuals and according to the Leishmania species. Infection caused by L. guyanensis accounted for 73% of the cases and patients with this parasite also showed higher concentrations of IL-2, IFN-γ, IL-4, and IL-17 when compared to infection by L. amazonensis. Patients with infection caused by L. naiffi showed higher concentration of the cytokines analyzed when compared to uninfected patients; however, there was no statistically significant difference with the other species analyzed.

  8. Comparative analysis of regulatory roles of P38 signaling pathway in 8 types liver cell during liver regeneration.

    Science.gov (United States)

    Yang, Xianguang; Zhu, Lin; Zhao, Weiming; Shi, Yaohuang; He, Chuncui; Xu, Cunshuan

    2016-12-05

    P38MAPK signaling pathway was closely related to cell proliferation, apoptosis, cell differentiation, cell survival, cell death, and so on. However, the regulatory mechanism of P38MAPK signaling pathway in liver regeneration (LR) was unclear. In order to further reveal the roles of P38MAPK signaling pathway in rat liver regeneration, Ingenuity Pathway Analysis (IPA) software and related data sites were used to construct P38MAPK signaling pathway, and the pathway was confirmed by relevant documents literature. The expression changes of P38MAPK signaling pathway-related gene in eight type cells were further analyzed by Rat Genome 230 2.0 Array, and the results showed that 95 genes in P38MAPK signaling pathway had significant changes. H-cluster analysis showed that hepatocyte cell (HC), pit cell (PC), oval cell (OC) and biliary epithelial cell (BEC) are clustered together; and the same as Kupffer cell (KC), sinusoidal endothelial cell (SEC), dendritic cell (DC) and hepatic stellate cell (HSC). IPA software and expression analysis systematic explorer (EASE) were applied to functional enrichment analysis, and the results showed that P38MAPK signaling pathway was mainly involved in apoptosis, cell death, cell proliferation, cell survival, cell viability, activation, cell cycle progression, necrosis, synthesis of DNA and other physical activity during LR. In conclusion, P38MAPK signaling pathway regulated various physiological activities of LR through multiple signaling pathways.

  9. The Roles of T Helper 1, T Helper 17 and Regulatory T Cells in the Pathogenesis of Sarcoidosis

    Directory of Open Access Journals (Sweden)

    Esmaeil Mortaz

    2016-08-01

    Full Text Available Sarcoidosis is a systemic granulomatous disorder of unidentified etiology, with a heterogeneous clinical presentation. It is characterized by a reduced delayed-type hypersensitivity to tuberculin and common antigens. The balance between Th1, Th17 and Regulatory T(Treg cells controls T-cell proliferation and activation.The Th17/Treg ratio in the peripheral blood and bronchoalveolar lavage fluidis increased in patients with active sarcoidosis. Amplified IL-17A expression in granulomas and the presence of IL-17A+, IL-17A+IL-4+ and IL-17A+IFN-γ+ memory T helper cells in the circulation and BAL indicate Th17 cell involvement in granuloma induction and/or maintenance in sarcoidosis. Sarcoidosis should therefore be considered as a Th1/Th17 multisystem disorder and anti-IL-17/Th17 approaches that control and reduce IL-17Amay be an option, therefore, for the treatment of sarcoidosis.Here we provide a short overview as to the role of Th17 cells as critical cells in the pathogenesis of sarcoidosis.

  10. RNA sequencing and functional analysis implicate the regulatory role of long non-coding RNAs in tomato fruit ripening.

    Science.gov (United States)

    Zhu, Benzhong; Yang, Yongfang; Li, Ran; Fu, Daqi; Wen, Liwei; Luo, Yunbo; Zhu, Hongliang

    2015-08-01

    Recently, long non-coding RNAs (lncRNAs) have been shown to play critical regulatory roles in model plants, such as Arabidopsis, rice, and maize. However, the presence of lncRNAs and how they function in fleshy fruit ripening are still largely unknown because fleshy fruit ripening is not present in the above model plants. Tomato is the model system for fruit ripening studies due to its dramatic ripening process. To investigate further the role of lncRNAs in fruit ripening, it is necessary and urgent to discover and identify novel lncRNAs and understand the function of lncRNAs in tomato fruit ripening. Here it is reported that 3679 lncRNAs were discovered from wild-type tomato and ripening mutant fruit. The lncRNAs are transcribed from all tomato chromosomes, 85.1% of which came from intergenic regions. Tomato lncRNAs are shorter and have fewer exons than protein-coding genes, a situation reminiscent of lncRNAs from other model plants. It was also observed that 490 lncRNAs were significantly up-regulated in ripening mutant fruits, and 187 lncRNAs were down-regulated, indicating that lncRNAs could be involved in the regulation of fruit ripening. In line with this, silencing of two novel tomato intergenic lncRNAs, lncRNA1459 and lncRNA1840, resulted in an obvious delay of ripening of wild-type fruit. Overall, the results indicated that lncRNAs might be essential regulators of tomato fruit ripening, which sheds new light on the regulation of fruit ripening.

  11. Taking back your turf: understanding the role of law in medical decision making in opioid management (Part II--putting legal/regulatory materials to work for you).

    Science.gov (United States)

    Bolen, Jennifer

    2005-01-01

    In Part I of this series, I discussed the basic role of the law in the decision-making process for opioid management. I set out three basic rules: 1) read and learn applicable federal and state legal/regulatory materials on using controlled substances to treat pain, 2) stay current on accepted clinical standards of care, and 3) use a compliance program to minimize the potential for abuse and diversion of controlled substances. Here in Part II, I focus on the third rule and offer a few suggestions on developing and maintaining a compliance program. I also discuss using language from legal/regulatory materials in your practice forms in a manner that, once again, allows you to "take back your turf" and prescribe opioids without fear of legal/regulatory sanction (see Disclaimer). Take a minute to review the self-audit questions that follow and see where you stand on your knowledge and use of legal/regulatory matters in your daily practice. More "yes" answers indicate better knowledge of key compliance and documentation issues. More "no" and "I don't know" answers indicate that more work should be done to minimize potential legal/regulatory compliance problems in your practice.

  12. The incorporation of epigenetics in artificial gene regulatory networks.

    Science.gov (United States)

    Turner, Alexander P; Lones, Michael A; Fuente, Luis A; Stepney, Susan; Caves, Leo S D; Tyrrell, Andy M

    2013-05-01

    Artificial gene regulatory networks are computational models that draw inspiration from biological networks of gene regulation. Since their inception they have been used to infer knowledge about gene regulation and as methods of computation. These computational models have been shown to possess properties typically found in the biological world, such as robustness and self organisation. Recently, it has become apparent that epigenetic mechanisms play an important role in gene regulation. This paper describes a new model, the Artificial Epigenetic Regulatory Network (AERN) which builds upon existing models by adding an epigenetic control layer. Our results demonstrate that AERNs are more adept at controlling multiple opposing trajectories when applied to a chaos control task within a conservative dynamical system, suggesting that AERNs are an interesting area for further investigation.

  13. Regulatory agencies and regulatory risk

    OpenAIRE

    Knieps, Günter; Weiß, Hans-Jörg

    2007-01-01

    The aim of this paper is to show that regulatory risk is due to the discretionary behaviour of regulatory agencies, caused by a too extensive regulatory mandate provided by the legislator. The normative point of reference and a behavioural model of regulatory agencies based on the positive theory of regulation are presented. Regulatory risk with regard to the future behaviour of regulatory agencies is modelled as the consequence of the ex ante uncertainty about the relative influence of inter...

  14. MicroRNA profiling analysis throughout tomato fruit development and ripening reveals potential regulatory role of RIN on microRNAs accumulation.

    Science.gov (United States)

    Gao, Chao; Ju, Zheng; Cao, Dongyan; Zhai, Baiqiang; Qin, Guozheng; Zhu, Hongliang; Fu, Daqi; Luo, Yunbo; Zhu, Benzhong

    2015-04-01

    The development and ripening of tomato fruit are complex processes involving many gene regulatory pathways at the transcriptional and post-transcriptional level. Ripening inhibitor (RIN) is a vital transcription factor, which targets numerous ripening-related genes at the transcriptional level during tomato fruit ripening. MicroRNAs (miRNAs) are a class of short noncoding RNAs that play important roles in post-transcriptional gene regulation. To elucidate the potential regulatory relationship between rin and miRNAs during fruit development and ripening, we identified known miRNAs and profiled their expression in wild-type tomato and rin mutant using a deep sequencing approach combined with quantitative RT-PCR. A total of 33 known miRNA families were identified, of which 14 miRNA families were differently accumulated. Subsequent promoter analysis showed that possible RIN-binding motifs (CArG-box) tended to occur frequently in the promoter regions of partial differently expressed miRNAs. In addition, ethylene may participate in the regulation of miRNAs accumulation during tomato fruit ripening. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay confirmed the direct binding of RIN to the promoter of MIR172a. Collectively, these results showed a close correlation between miRNA expression and RIN as well as ethylene, which further elucidated the regulatory roles of miRNAs during fruit development and ripening and enriched the regulatory network of RIN in tomato fruit.

  15. Analysis of Cold Flowfield of Multi—Annular Opposed Jets

    Institute of Scientific and Technical Information of China (English)

    H.F.Zhao; G.C.Benelli

    1992-01-01

    The technique of the use of multi-annular opposed jets as different from using swirl and bluff body creates an excellent recirculation zone with desired size in a large space.The size of ecirculation,the magnitude of reverse velocity and turbulence intensity are much greater than those formed by bluff body.Factors affecting the flowfield include the velocity ration of the opposed jets to the primary air J.the diameter and construction of the opposed jet ring,secondary air velocity and configuration,and confined or unconfined flow condition and so on.This method is a promising way for flame stabilization in combustion technology.

  16. Obligatory role in GTP hydrolysis for the amide carbonyl oxygen of the Mg(2+)-coordinating Thr of regulatory GTPases.

    Science.gov (United States)

    Zurita, Adolfo; Zhang, Yinghao; Pedersen, Lee; Darden, Tom; Birnbaumer, Lutz

    2010-05-25

    When G-protein alpha subunits binds GTP and Mg(2+), they transition from their inactive to their active conformation. This transition is accompanied by completion of the coordination shell of Mg(2+) with electrons from six oxygens: two water molecules, the ss and gamma phosphoryls of GTP, a helix-alpha1 Ser, and a switch I domain (SWI) Thr, and the repositioning of SWI and SWII domains. SWII binds and regulates effector enzymes and facilitates GTP hydrolysis by repositioning the gamma-carbonyl of a Gln. Mutating the Ser generates regulatory GTPases that cannot lock Mg(2+) into its place and are locked in their inactive state with dominant negative properties. Curiously, mutating the Thr appears to reduce GTP hydrolysis. The reason for this difference is not known because it is also not known why removal of the Thr should affect the overall GTPase cycle differently than removal of the Ser. Working with recombinant Gsalpha, we report that mutating its SWI-Thr to either Ala, Glu, Gln, or Asp results not only in diminished GTPase activity but also in spontaneous activation of the SWII domain. Upon close examination of existing alpha subunit crystals, we noted the oxygen of the backbone carbonyl of SWI-Thr and of the gamma-carbonyl of SWII Gln to be roughly equidistant from the oxygen of the hydrolytic H(2)O. Our observations indicate that the Gln and Thr carbonyls play equihierarchical roles in the GTPase process and provide the mechanism that explains why mutating the Thr mimics mutating the Gln and not that of the Ser.

  17. The influence of regulatory fit on evaluation and intentions to buy genetically modified foods: The mediating role of social identification

    NARCIS (Netherlands)

    Fransen, M.L.; Reinders, M.J.; Bartels, J.; Maassen, R.L.

    2010-01-01

    The present study examines how communicated messages could be effective in affecting consumers' attitudes and behavioural intentions regarding genetically modified (GM) foods. Based on Regulatory Focus Theory, it was hypothesized that exposure to a communication message matching a consumer's regulat

  18. Opposing effects of reward and punishment on human vigor

    Science.gov (United States)

    Griffiths, Benjamin; Beierholm, Ulrik R.

    2017-01-01

    The vigor with which humans and animals engage in a task is often a determinant of the likelihood of the task’s success. An influential theoretical model suggests that the speed and rate at which responses are made should depend on the availability of rewards and punishments. While vigor facilitates the gathering of rewards in a bountiful environment, there is an incentive to slow down when punishments are forthcoming so as to decrease the rate of punishments, in conflict with the urge to perform fast to escape punishment. Previous experiments confirmed the former, leaving the latter unanswered. We tested the influence of punishment in an experiment involving economic incentives and contrasted this with reward related behavior on the same task. We found that behavior corresponded with the theoretical model; while instantaneous threat of punishment caused subjects to increase the vigor of their response, subjects’ response times would slow as the overall rate of punishment increased. We quantitatively show that this is in direct contrast to increases in vigor in the face of increased overall reward rates. These results highlight the opposed effects of rewards and punishments and provide further evidence for their roles in the variety of types of human decisions. PMID:28205567

  19. Revealing genome-scale transcriptional regulatory landscape of OmpR highlights its expanded regulatory roles under osmotic stress in Escherichia coli K-12 MG1655

    DEFF Research Database (Denmark)

    Seo, Sang Woo; Gao, Ye; Kim, Donghyuk

    2017-01-01

    A transcription factor (TF), OmpR, plays a critical role in transcriptional regulation of the osmotic stress response in bacteria. Here, we reveal a genome-scale OmpR regulon in Escherichia coli K-12 MG1655. Integrative data analysis reveals that a total of 37 genes in 24 transcription units (TUs...

  20. Enhancing Tissue Engineering and Regenerative Medicine Product Commercialization: The Role of Science in Regulatory Decision-Making for the TE/RM Product Development.

    Science.gov (United States)

    Bertram, Timothy A; Johnson, Peter C; Tawil, Bill J; Van Dyke, Mark; Hellman, Kiki B

    2015-10-01

    TERMIS-AM Industry Committee (TERMIS-AM/IC), in collaboration with the TERMIS-Europe (EU)/IC, conducted a symposium involving the European Medicines Agency and the U.S. Food and Drug Administration (FDA) toward building an understanding of the rational basis for regulatory decision-making and providing a framework for decisions made during the evaluation of safety and efficacy of TE/RM technologies. This symposium was held in August 2012 during the TERMIS-WC in Vienna, Austria. Emerging from this international initiative by the European Union and the United States, representatives from the respective agencies demonstrated that there are ongoing interagency efforts for developing common national practices toward harmonization of regulatory requirements for the TE/RM products. To extend a broad-based understanding of the role of science in regulatory decision-making, TERMIS-AM/IC, in cooperation with the FDA, organized a symposium at the 2014 TERMIS-AM Annual Meeting, which was held in Washington, DC. This event provided insights from leaders in the FDA and TERMIS on the current status of regulatory approaches for the approved TE/RM products, the use of science in making regulatory decisions, and TE/RM technologies that are in the development pipeline to address unmet medical needs. A far-ranging discussion with FDA representatives, industrialists, physicians, regenerative medicine biologists, and tissue engineers considered the gaps in today's scientific and regulatory understanding of TE/RM technologies. The identified gaps represent significant opportunities to advance TE/RM technologies toward commercialization.

  1. Comparative analysis of the ATRX promoter and 5' regulatory region reveals conserved regulatory elements which are linked to roles in neurodevelopment, alpha-globin regulation and testicular function

    OpenAIRE

    Tang, Paisu; Frankenberg, Stephen; Argentaro, Anthony; Graves, Jennifer M; Familari, Mary

    2011-01-01

    Background ATRX is a tightly-regulated multifunctional protein with crucial roles in mammalian development. Mutations in the ATRX gene cause ATR-X syndrome, an X-linked recessive developmental disorder resulting in severe mental retardation and mild alpha-thalassemia with facial, skeletal and genital abnormalities. Although ubiquitously expressed the clinical features of the syndrome indicate that ATRX is not likely to be a global regulator of gene expression but involved in regulating specif...

  2. In vivo FRET imaging revealed a regulatory role of RanGTP in kinetochore-microtubule attachments via Aurora B kinase.

    Science.gov (United States)

    Lee, Yoke-Peng; Wong, Chi-Hang; Chan, Kheng-Sze; Lai, Soak-Kuan; Koh, Cheng-Gee; Li, Hoi-Yeung

    2012-01-01

    Under the fluctuating circumstances provided by the innate dynamics of microtubules and opposing tensions resulted from microtubule-associated motors, it is vital to ensure stable kinetochore-microtubule attachments for accurate segregation. However, a comprehensive understanding of how this regulation is mechanistically achieved remains elusive. Using our newly designed live cell FRET time-lapse imaging, we found that post-metaphase RanGTP is crucial in the maintenance of stable kinetochore-microtubule attachments by regulating Aurora B kinase via the NES-bearing Mst1. More importantly, our study demonstrates that by ensuring stable alignment of metaphase chromosomes prior to segregation, RanGTP is indispensible in governing the genomic integrity and the fidelity of cell cycle progression. Our findings suggest an additional role of RanGTP beyond its known function in mitotic spindle assembly during the prometaphase-metaphase transition.

  3. In vivo FRET imaging revealed a regulatory role of RanGTP in kinetochore-microtubule attachments via Aurora B kinase.

    Directory of Open Access Journals (Sweden)

    Yoke-Peng Lee

    Full Text Available Under the fluctuating circumstances provided by the innate dynamics of microtubules and opposing tensions resulted from microtubule-associated motors, it is vital to ensure stable kinetochore-microtubule attachments for accurate segregation. However, a comprehensive understanding of how this regulation is mechanistically achieved remains elusive. Using our newly designed live cell FRET time-lapse imaging, we found that post-metaphase RanGTP is crucial in the maintenance of stable kinetochore-microtubule attachments by regulating Aurora B kinase via the NES-bearing Mst1. More importantly, our study demonstrates that by ensuring stable alignment of metaphase chromosomes prior to segregation, RanGTP is indispensible in governing the genomic integrity and the fidelity of cell cycle progression. Our findings suggest an additional role of RanGTP beyond its known function in mitotic spindle assembly during the prometaphase-metaphase transition.

  4. Uncertainty and innovation: Understanding the role of cell-based manufacturing facilities in shaping regulatory and commercialization environments.

    Science.gov (United States)

    Isasi, Rosario; Rahimzadeh, Vasiliki; Charlebois, Kathleen

    2016-12-01

    The purpose of this qualitative study is to elucidate stakeholder perceptions of, and institutional practices related to cell-based therapies and products (CTP) regulation and commercialization in Canada. The development of reproducible, safe and effective CTPs is predicated on regulatory and commercialization environments that enable innovation. Manufacturing processes constitute a critical step for CTP development in this regard. The road from CTP manufacturing to translation in the clinic, however, has yet to be paved. This study aims to fill an empirical gap in the literature by exploring how CTP manufacturing facilities navigate Canadian regulatory and commercialization environments, which together drive the translation of novel CTPs from bench to bedside. Using the multi-level model of practice-driven institutional change proposed by Smets et al., we demonstrate how CTP manufacturing practices are governed by established standards, yet meaningfully shape higher-order regulatory and commercial norms in CTP research and development. We identify four key themes that undergird such processes of innovation: 1) managing regulatory uncertainty, which stems from an inability to classify CTPs within existing regulatory categories for approval and commercialization purposes; 2) building a 'business case' whereby a CTP's market potential is determined in large part by proving its safety and effectiveness; 3) standardizing manufacturing procedures that mobilize CTPs from a research and development phase to a commercialization one; and 4) networking between researchers and regulators to develop responsible commercialization processes that reflect the uniqueness of CTPs as distinct from other biologics and medical devices.

  5. Messenger RNA Fluctuations and Regulatory RNAs Shape the Dynamics of Negative Feedback Loop

    CERN Document Server

    Martínez, María Rodríguez; Tlusty, Tsvi; Pilpel, Yitzhak; Furman, Itay; 10.1103/PhysRevE.81.031924

    2010-01-01

    Single cell experiments of simple regulatory networks can markedly differ from cell population experiments. Such differences arise from stochastic events in individual cells that are averaged out in cell populations. For instance, while individual cells may show sustained oscillations in the concentrations of some proteins, such oscillations may appear damped in the population average. In this paper we investigate the role of RNA stochastic fluctuations as a leading force to produce a sustained excitatory behavior at the single cell level. Opposed to some previous models, we build a fully stochastic model of a negative feedback loop that explicitly takes into account the RNA stochastic dynamics. We find that messenger RNA random fluctuations can be amplified during translation and produce sustained pulses of protein expression. Motivated by the recent appreciation of the importance of non--coding regulatory RNAs in post--transcription regulation, we also consider the possibility that a regulatory RNA transcri...

  6. Role of tumor endothelium in CD4+ CD25+ regulatory T cell infiltration of human pancreatic carcinoma.

    Science.gov (United States)

    Nummer, Daniel; Suri-Payer, Elisabeth; Schmitz-Winnenthal, Hubertus; Bonertz, Andreas; Galindo, Luis; Antolovich, Dalibor; Koch, Moritz; Büchler, Markus; Weitz, Jürgen; Schirrmacher, Volker; Beckhove, Philipp

    2007-08-01

    Regulatory T (Treg) cells have been detected in human carcinomas and may play a role in preventing the rejection of malignant cells. We quantified Treg cells and the expression of the addressins and the respective ligands that attract them in blood and in human pancreatic tumors and adjacent nonmalignant tissues from 47 patients. The capacity of Treg cells to adhere to and transmigrate through autologous endothelial cells was tested in vitro using spheroid adhesion assays and in vivo using a xenotransplant NOD/SCID model and in the presence and absence of antibodies to addressins. All statistical tests were two-sided. More Treg cells infiltrated pancreatic carcinomas than adjacent nonmalignant pancreatic tissues (120 cells per mm2 versus 80 cells per mm2, difference = 40 cells per mm2, 95% confidence interval [CI] = 21.2 cells per mm2 to 52.1 cells per mm2; P<.001). In contrast to conventional CD4+ T cells, more blood-derived Treg cells adhered to (1.0% versus 5.2%, difference = 4.2%, 95% CI = 2.7% to 5.6%; P<.001) and transmigrated through (3332 cells versus 4976 cells, difference = 1644 cells, 95% CI = 708 cells to 2580 cells; P = .008) autologous tumor-derived endothelial cells in vitro and in vivo (458 cells versus 605 cells, difference = 147 cells, 95% CI = 50.8 to 237.2 cells; P = .04). Tumor-derived endothelial cells expressed higher levels of addressins--including mucosal adressin cell adhesion molecule-1 (MAdCAM-1), vascular cell adhesion molecule-1 (VCAM-1), CD62-E, and CD166--than endothelial cells from normal tissue. Experiments using antibodies to addressins showed that transmigration was mediated by interactions of addressins, including MAdCAM-1, VCAM-1, CD62-E, and CD166 with their respective ligands, beta7 integrin, CD62L, and CD166, which were expressed specifically on Treg cells. Tumor-induced expression of addressins on the surface of endothelial cells allows a selective transmigration of Treg cells from peripheral blood to tumor tissues.

  7. Mutually opposing forces during locomotion can eliminate the tradeoff between maneuverability and stability

    Science.gov (United States)

    Cowan, Noah; Sefati, Shahin; Neveln, Izaak; Roth, Eatai; Mitchell, Terence; Snyder, James; Maciver, Malcolm; Fortune, Eric

    A surprising feature of animal locomotion is that organisms typically produce substantial forces in directions other than what is necessary to move the animal through its environment, such as perpendicular to, or counter to, the direction of travel. The effect of these forces has been difficult to observe because they are often mutually opposing and therefore cancel out. Using a combination of robotic physical modeling, computational modeling, and biological experiments, we discovered that these forces serve an important role: to simplify and enhance the control of locomotion. Specifically, we examined a well-suited model system, the glass knifefish Eigenmannia virescens, which produces mutually opposing forces during a hovering behavior. By systematically varying the locomotor parameters of our biomimetic robot, and measuring the resulting forces and kinematics, we demonstrated that the production and differential control of mutually opposing forces is a strategy that generates passive stabilization while simultaneously enhancing maneuverability. Mutually opposing forces during locomotion are widespread across animal taxa, and these results indicate that such forces can eliminate the tradeoff between stability and maneuverability, thereby simplifying robotic and neural control.

  8. Cell-intrinsic role for NF-kappa B-inducing kinase in peripheral maintenance but not thymic development of Foxp3+ regulatory T cells in mice.

    Directory of Open Access Journals (Sweden)

    Susan E Murray

    Full Text Available NF-κB inducing kinase (NIK, MAP3K14 is a key signaling molecule in non-canonical NF-κB activation, and NIK deficient mice have been instrumental in deciphering the immunologic role of this pathway. Global ablation of NIK prevents lymph node development, impairs thymic stromal development, and drastically reduces B cells. Despite altered thymic selection, T cell numbers are near normal in NIK deficient mice. The exception is CD4(+ regulatory T cells (Tregs, which are reduced in the thymus and periphery. Defects in thymic stroma are known to contribute to impaired Treg generation, but whether NIK also plays a cell intrinsic role in Tregs is unknown. Here, we compared intact mice with single and mixed BM chimeric mice to assess the intrinsic role of NIK in Treg generation and maintenance. We found that while NIK expression in stromal cells suffices for normal thymic Treg development, NIK is required cell-intrinsically to maintain peripheral Tregs. In addition, we unexpectedly discovered a cell-intrinsic role for NIK in memory phenotype conventional T cells that is masked in intact mice, but revealed in BM chimeras. These results demonstrate a novel role for NIK in peripheral regulatory and memory phenotype T cell homeostasis.

  9. IL-10-Producing CD1dhiCD5+ Regulatory B Cells May Play a Critical Role in Modulating Immune Homeostasis in Silicosis Patients

    Science.gov (United States)

    Chen, Ying; Li, Chao; Lu, Yiping; Zhuang, Huiying; Gu, Weijia; Liu, Bo; Liu, Fangwei; Sun, Jinkai; Yan, Bo; Weng, Dong; Chen, Jie

    2017-01-01

    Silicosis is characterized by chronic lung inflammation and fibrosis, which are extremely harmful to human health. The pathogenesis of silicosis involves uncontrolled immune processes. Evidence supports that regulatory B cells (Bregs) produce negative regulatory cytokines, such as IL-10, which can negatively regulate immune responses in inflammation and autoimmune diseases. Our previous study found that IL-10-producing B cells were involved in the development of silica-induced lung inflammation and fibrosis of mice. However, little is known about the role of Bregs in silicosis patients (SP). In this study, we found that serum concentrations of IL-10 were significantly increased in SP by using protein array screening. We further determined that the frequency of IL-10-producing CD1dhiCD5+ Bregs, not IL-10-producing non-B lymphocytes, was significantly higher in SP compared to subjects under surveillance (SS) and healthy workers (HW) by flow cytometry. We also found that regulatory T cells (Tregs) and Th2 cytokines (IL-4, IL-5, and IL-13) were significantly increased in SP. Th1 cytokines (IFN-γ, IL-2, and IL-12) and inflammatory cytokines (IL-1β, IL-6, and TNF-α) were not significantly different between SP, SS, and HW. Our study indicated that IL-10-producing CD1dhiCD5+ Bregs might maintain Tregs and regulate Th1/Th2 polarization in SP, suggesting that IL-10-producing Bregs may play a critical role in modulating immune homeostasis in SP.

  10. Where we stand, where we are moving: Surveying computational techniques for identifying miRNA genes and uncovering their regulatory role

    KAUST Repository

    Kleftogiannis, Dimitrios A.

    2013-06-01

    Traditional biology was forced to restate some of its principles when the microRNA (miRNA) genes and their regulatory role were firstly discovered. Typically, miRNAs are small non-coding RNA molecules which have the ability to bind to the 3\\'untraslated region (UTR) of their mRNA target genes for cleavage or translational repression. Existing experimental techniques for their identification and the prediction of the target genes share some important limitations such as low coverage, time consuming experiments and high cost reagents. Hence, many computational methods have been proposed for these tasks to overcome these limitations. Recently, many researchers emphasized on the development of computational approaches to predict the participation of miRNA genes in regulatory networks and to analyze their transcription mechanisms. All these approaches have certain advantages and disadvantages which are going to be described in the present survey. Our work is differentiated from existing review papers by updating the methodologies list and emphasizing on the computational issues that arise from the miRNA data analysis. Furthermore, in the present survey, the various miRNA data analysis steps are treated as an integrated procedure whose aims and scope is to uncover the regulatory role and mechanisms of the miRNA genes. This integrated view of the miRNA data analysis steps may be extremely useful for all researchers even if they work on just a single step. © 2013 Elsevier Inc.

  11. Evidence for the role of transposons in the recruitment of cis-regulatory motifs during the evolution of C4 photosynthesis.

    Science.gov (United States)

    Cao, Chensi; Xu, Jiajia; Zheng, Guangyong; Zhu, Xin-Guang

    2016-03-08

    C4 photosynthesis evolved from C3 photosynthesis and has higher light, water, and nitrogen use efficiencies. Several C4 photosynthesis genes show cell-specific expression patterns, which are required for these high resource-use efficiencies. However, the mechanisms underlying the evolution of cis-regulatory elements that control these cell-specific expression patterns remain elusive. In the present study, we tested the hypothesis that the cis-regulatory motifs related to C4 photosynthesis genes were recruited from non-photosynthetic genes and further examined potential mechanisms facilitating this recruitment. We examined 65 predicted bundle sheath cell-specific motifs, 17 experimentally validated cell-specific cis-regulatory elements, and 1,034 motifs derived from gene regulatory networks. Approximately 7, 5, and 1,000 of these three categories of motifs, respectively, were apparently recruited during the evolution of C4 photosynthesis. In addition, we checked 1) the distance between the acceptors and the donors of potentially recruited motifs in a chromosome, and 2) whether the potentially recruited motifs reside within the overlapping region of transposable elements and the promoter of donor genes. The results showed that 7, 4, and 658 of the potentially recruited motifs might have moved via the transposable elements. Furthermore, the potentially recruited motifs showed higher binding affinity to transcription factors compared to randomly generated sequences of the same length as the motifs. This study provides molecular evidence supporting the hypothesis that transposon-driven recruitment of pre-existing cis-regulatory elements from non-photosynthetic genes into photosynthetic genes plays an important role during C4 evolution. The findings of the present study coincide with the observed repetitive emergence of C4 during evolution.

  12. Drosophila Smad2 Opposes Mad Signaling during Wing Vein Development

    Science.gov (United States)

    Sander, Veronika; Eivers, Edward; Choi, Renee H.; De Robertis, Edward M.

    2010-01-01

    In the vertebrates, the BMP/Smad1 and TGF-β/Smad2 signaling pathways execute antagonistic functions in different contexts of development. The differentiation of specific structures results from the balance between these two pathways. For example, the gastrula organizer/node of the vertebrates requires a region of low Smad1 and high Smad2 signaling. In Drosophila, Mad regulates tissue determination and growth in the wing, but the function of dSmad2 in wing patterning is largely unknown. In this study, we used an RNAi loss-of-function approach to investigate dSmad2 signaling during wing development. RNAi-mediated knockdown of dSmad2 caused formation of extra vein tissue, with phenotypes similar to those seen in Dpp/Mad gain-of-function. Clonal analyses revealed that the normal function of dSmad2 is to inhibit the response of wing intervein cells to the extracellular Dpp morphogen gradient that specifies vein formation, as measured by expression of the activated phospho-Mad protein. The effect of dSmad2 depletion in promoting vein differentiation was dependent on Medea, the co-factor shared by Mad and dSmad2. Furthermore, double RNAi experiments showed that Mad is epistatic to dSmad2. In other words, depletion of Smad2 had no effect in Mad-deficient wings. Our results demonstrate a novel role for dSmad2 in opposing Mad-mediated vein formation in the wing. We propose that the main function of dActivin/dSmad2 in Drosophila wing development is to antagonize Dpp/Mad signaling. Possible molecular mechanisms for the opposition between dSmad2 and Mad signaling are discussed. PMID:20442782

  13. Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation

    NARCIS (Netherlands)

    Morikawa, Hiromasa; Ohkura, Naganari; Vandenbon, Alexis; Itoh, Masayoshi; Nagao-Sato, Sayaka; Kawaji, Hideya; Lassmann, Timo; Carninci, Piero; Hayashizaki, Yoshihide; Forrest, Alistair R R; Standley, Daron M; Date, Hiroshi; Sakaguchi, Shimon; Clevers, Hans

    2014-01-01

    Naturally occurring regulatory T (Treg) cells, which specifically express the transcription factor forkhead box P3 (Foxp3), are engaged in the maintenance of immunological self-tolerance and homeostasis. By transcriptional start site cluster analysis, we assessed here how genome-wide patterns of DNA

  14. The roles of T helper 1, T helper 17 and regulatory T cells in the pathogenesis of sarcoidosis

    NARCIS (Netherlands)

    Mortaz, Esmaeil|info:eu-repo/dai/nl/29141320X; Rezayat, Fatemeh; Amani, Davar; Kiani, Arda; Garssen, Johan|info:eu-repo/dai/nl/086369962; Adocock, Ian M.; Velayati, Aliakbar

    2016-01-01

    Sarcoidosis is a systemic granulomatous disorder of unidentified etiology, with a heterogeneous clinical presentation. It is characterized by a reduced delayed- Type hypersensitivity to tuberculin and common antigens. The balance between Th1, Th17 and Regulatory T(Treg) cells controls T-cell

  15. Physical Activity in the Transition to University: The Role of Past Behavior and Concurrent Self-Regulatory Efficacy

    Science.gov (United States)

    Crozier, Alyson J.; Gierc, Madelaine S. H.; Locke, Sean R.; Brawley, Lawrence R.

    2015-01-01

    Objective: Two studies were conducted to examine the relationship between past physical activity, concurrent self-regulatory efficacy (CSRE), and current physical activity during the transition to university. Participants: Study 1 included 110 first-year undergraduate students recruited during October/November of 2012. Study 2 involved 86…

  16. ‘Fit for charity’: the moderating role of private self-focus in the persuasiveness of regulatory fit

    NARCIS (Netherlands)

    M.L. Fransen; B.M. Fennis; K.D. Vohs; A.T.H. Pruyn

    2009-01-01

    The present research extends work on the ‘the value from fit’ principle by showing that regulatory fit effects on charitable behavior are stronger for consumers high in private self-focus. Based on previous research showing that individuals high in private self-focus are more affected by external in

  17. The association between regulatory focus and distress in patients with a chronic disease : The moderating role of partner support

    NARCIS (Netherlands)

    Schokker, Marike C.; Links, Thera P.; Luttik, Marie Louise; Hagedoorn, Mariet

    2010-01-01

    Objectives. To determine the association between two regulatory foci (i.e. promotion and prevention focus) and distress in patients with chronic disease requiring self-management, and to determine whether these associations were moderated by partner support. Design and method. Four hundred and seven

  18. Physical Activity in the Transition to University: The Role of Past Behavior and Concurrent Self-Regulatory Efficacy

    Science.gov (United States)

    Crozier, Alyson J.; Gierc, Madelaine S. H.; Locke, Sean R.; Brawley, Lawrence R.

    2015-01-01

    Objective: Two studies were conducted to examine the relationship between past physical activity, concurrent self-regulatory efficacy (CSRE), and current physical activity during the transition to university. Participants: Study 1 included 110 first-year undergraduate students recruited during October/November of 2012. Study 2 involved 86…

  19. The role of Smad Ubiquitin Regulatory Factor-1: SMURF1 in the differentiation 3T3-L1

    OpenAIRE

    Muñiz Diego, María del Carmen

    2013-01-01

    The Smad Ubiquitin Regulatory Factor-1: SMURF1 is an E3 ligase. This E3 ligase has been linked to several important biological pathways, including the bone morphogenetic protein pathway, the non-canonical Wnt pathway and the mitogen-activated protein kinase pathway. Multiple functions of Smurf1 have been discovered in cell growth and morphogenesis, cell migration, cell polarity and autophagy. Previous studies, in 2003, have demonstrated that overexpression of Smurf1 induces proteasomal degrad...

  20. A Highly Coupled Network of Tertiary Interactions in the SAM-I Riboswitch and Their Role in Regulatory Tuning.

    Science.gov (United States)

    Wostenberg, Christopher; Ceres, Pablo; Polaski, Jacob T; Batey, Robert T

    2015-11-06

    RNA folding in vivo is significantly influenced by transcription, which is not necessarily recapitulated by Mg(2+)-induced folding of the corresponding full-length RNA in vitro. Riboswitches that regulate gene expression at the transcriptional level are an ideal system for investigating this aspect of RNA folding as ligand-dependent termination is obligatorily co-transcriptional, providing a clear readout of the folding outcome. The folding of representative members of the SAM-I family of riboswitches has been extensively analyzed using approaches focusing almost exclusively upon Mg(2+) and/or S-adenosylmethionine (SAM)-induced folding of full-length transcripts of the ligand binding domain. To relate these findings to co-transcriptional regulatory activity, we have investigated a set of structure-guided mutations of conserved tertiary architectural elements of the ligand binding domain using an in vitro single-turnover transcriptional termination assay, complemented with phylogenetic analysis and isothermal titration calorimetry data. This analysis revealed a conserved internal loop adjacent to the SAM binding site that significantly affects ligand binding and regulatory activity. Conversely, most single point mutations throughout key conserved features in peripheral tertiary architecture supporting the SAM binding pocket have relatively little impact on riboswitch activity. Instead, a secondary structural element in the peripheral subdomain appears to be the key determinant in observed differences in regulatory properties across the SAM-I family. These data reveal a highly coupled network of tertiary interactions that promote high-fidelity co-transcriptional folding of the riboswitch but are only indirectly linked to regulatory tuning.

  1. Negative Correlation between Circulating CD4(+)FOXP3(+)CD127(-) Regulatory T Cells and Subsequent Antibody Responses to Infant Measles Vaccine but Not Diphtheria-Tetanus-Pertussis Vaccine Implies a Regulatory Role.

    Science.gov (United States)

    Ndure, Jorjoh; Noho-Konteh, Fatou; Adetifa, Jane U; Cox, Momodou; Barker, Francis; Le, My Thanh; Sanyang, Lady C; Drammeh, Adboulie; Whittle, Hilton C; Clarke, Ed; Plebanski, Magdalena; Rowland-Jones, Sarah L; Flanagan, Katie L

    2017-01-01

    Regulatory T cells (Tregs) play a key homeostatic role by suppressing immune responses. They have been targeted in mouse and human cancer studies to improve vaccine immunogenicity and tumor clearance. A number of commercially available drugs and experimental vaccine adjuvants have been shown to target Tregs. Infants have high numbers of Tregs and often have poor responses to vaccination, yet the role Tregs play in controlling vaccine immunogenicity has not been explored in this age group. Herein, we explore the role of CD4(+)FOXP3(+)CD127(-) Tregs in controlling immunity in infant males and females to vaccination with diphtheria-tetanus-whole cell pertussis (DTP) and/or measles vaccine (MV). We find correlative evidence that circulating Tregs at the time of vaccination suppress antibody responses to MV but not DTP; and Tregs 4 weeks after DTP vaccination may suppress vaccine-specific cellular immunity. This opens the exciting possibility that Tregs may provide a future target for improved vaccine responses in early life, including reducing the number of doses of vaccine required. Such an approach would need to be safe and the benefits outweigh the risks, thus further research in this area is required.

  2. Negative Correlation between Circulating CD4+FOXP3+CD127− Regulatory T Cells and Subsequent Antibody Responses to Infant Measles Vaccine but Not Diphtheria–Tetanus–Pertussis Vaccine Implies a Regulatory Role

    Directory of Open Access Journals (Sweden)

    Jorjoh Ndure

    2017-08-01

    Full Text Available Regulatory T cells (Tregs play a key homeostatic role by suppressing immune responses. They have been targeted in mouse and human cancer studies to improve vaccine immunogenicity and tumor clearance. A number of commercially available drugs and experimental vaccine adjuvants have been shown to target Tregs. Infants have high numbers of Tregs and often have poor responses to vaccination, yet the role Tregs play in controlling vaccine immunogenicity has not been explored in this age group. Herein, we explore the role of CD4+FOXP3+CD127− Tregs in controlling immunity in infant males and females to vaccination with diphtheria–tetanus–whole cell pertussis (DTP and/or measles vaccine (MV. We find correlative evidence that circulating Tregs at the time of vaccination suppress antibody responses to MV but not DTP; and Tregs 4 weeks after DTP vaccination may suppress vaccine-specific cellular immunity. This opens the exciting possibility that Tregs may provide a future target for improved vaccine responses in early life, including reducing the number of doses of vaccine required. Such an approach would need to be safe and the benefits outweigh the risks, thus further research in this area is required.

  3. Interrelationship of dendritic cells, type 1 interferon system, regulatory T cells and toll-like receptors and their role in lichen planus and lupus erythematosus -- a literature review.

    Science.gov (United States)

    Trucci, Victoria Martina; Salum, Fernanda Gonçalves; Figueiredo, Maria Antonia; Cherubini, Karen

    2013-10-01

    There is evidence that the activation of some receptors of the toll-like family (TLRs) of the innate immune system, and also changes in expression levels of forkhead box p3 (Foxp3) protein, which is found in regulatory T cells (Tregs), could be involved in the development of autoimmunity. We present here a literature review focusing on the interrelationship of dendritic cells, TLRs, Tregs and type 1 interferon in autoimmune diseases, with special interest in lichen planus and lupus erythematosus. Understanding the specific role of each of these factors would help elucidate the obscure aetiology of such diseases and open new perspectives for their management and treatment.

  4. Regulatory Role of the MisR/S Two-Component System in Hemoglobin Utilization in Neisseria meningitidis▿ †

    OpenAIRE

    2009-01-01

    Outer membrane iron receptors are some of the major surface entities that are critical for meningococcal pathogenesis. The gene encoding the meningococcal hemoglobin receptor, HmbR, is both independently transcribed and transcriptionally linked to the upstream gene hemO, which encodes a heme oxygenase. The MisR/S two-component system was previously determined to regulate hmbR transcription, and its hemO and hmbR regulatory mechanisms were characterized further here. The expression of hemO and...

  5. Novel two-component regulatory systems play a role in biofilm formation of Lactobacillus reuteri rodent isolate 100-23.

    Science.gov (United States)

    Su, Marcia Shu-Wei; Gänzle, Michael G

    2014-04-01

    This study characterized the two-component regulatory systems encoded by bfrKRT and cemAKR, and assessed their influence on biofilm formation by Lactobacillus reuteri 100-23. A method for deletion of multiple genes was employed to disrupt the genetic loci of two-component systems. The operons bfrKRT and cemAKR showed complementary organization. Genes bfrKRT encode a histidine kinase, a response regulator and an ATP-binding cassette-type transporter with a bacteriocin-processing peptidase domain, respectively. Genes cemAKR code for a signal peptide, a histidine kinase and a response regulator, respectively. Deletion of single or multiple genes in the operons bfrKRT and cemAKR did not affect cell morphology, growth or the sensitivity to various stressors. However, gene disruption affected biofilm formation; this effect was dependent on the carbon source. Deletion of bfrK or cemA increased sucrose-dependent biofilm formation in vitro. Glucose-dependent biofilm formation was particularly increased by deletion of cemK. The expression of cemK and cemR was altered by deletion of bfrK, indicating cross-talk between these two regulatory systems. These results may contribute to our understanding of the genetic factors related to the biofilm formation and competitiveness of L. reuteri in intestinal ecosystems.

  6. Assimilation and contrast effects: the role of self-construal and regulatory focus as moderators in collectivistic cultures of honour.

    Science.gov (United States)

    Puente-Díaz, Rogelio

    2014-06-01

    Human judgments are context dependent. When answering a question about one's overall satisfaction with life, a previous question about one's romantic life might pose redundancy problems influencing one's judgment of life satisfaction, something known as item order effects. However, in order to detect such redundancy, one needs to pay attention to the context of the conversation. Any variable that influences the amount of attention given the context of the conversation can determine whether the presumed redundancy is detected or not. In three studies, two experiments and one correlational study, we tested the influence of induced self-construal (study 1) and self-regulatory focus (study 2) and self-regulatory focus measured as an individual difference variable (study 3) as moderators of context effects among college students from Mexico. In study 1, participants induced to have an independent mindset were less likely to detect the redundancy posed by two questions, resulting, as predicted, in a contrast effect. In study 3, participants with lower levels of prevention focus were less likely to detect the redundancy posed by the same two questions as study 1, resulting, as predicted, in an assimilation effect. The implications of the results were discussed within the framework of the inclusion/exclusion model.

  7. Motivated response styles: the role of cultural values, regulatory focus, and self-consciousness in socially desirable responding.

    Science.gov (United States)

    Lalwani, Ashok K; Shrum, L J; Chiu, Chi-Yue

    2009-04-01

    Three studies investigated the relations between cultural values and socially desirable responding, the processes that underlie them, and factors that influence the strength of the relations. Results indicated that individualism was associated with self-deceptive enhancement but not impression management, whereas collectivism was associated with impression management but not self-deceptive enhancement. Regulatory focus was found to mediate these relations. A promotion focus mediated the relation between individualism and self-deceptive enhancement, whereas a prevention focus mediated the relation between collectivism and impression management. This mediation pattern held regardless of whether individualism and collectivism were determined at the group level (Study 1) or measured at the individual level (Studies 2-3), whether socially desirable responding was operationalized as a scale measure (Studies 1-3) or as reactions to behavioral scenarios (Study 2), and across different measures of regulatory focus. This general mediation pattern was found to be moderated by type of self-consciousness (Study 3): The promotion focus mediation was stronger for participants low (vs. high) in private self-consciousness, and the prevention focus mediation was stronger for participants high (vs. low) in public self-consciousness.

  8. 微小RNA在神经发生中的调控作用%The regulatory roles of microRNAs in neurogenesis

    Institute of Scientific and Technical Information of China (English)

    潘长福; 汪泱; 邓志锋

    2010-01-01

    神经发生是指神经干细胞自我增殖和分化成为新的神经元,并整合入神经网络的生物学过程,包括胚胎时期神经发牛和成体时期的神经发生.研究表明,微小RNA在神经发生中发挥着重要的调控作用.文章就近年来微小RNA在胚胎和成体神经发生调控中的分子机制以及脑缺血后神经发生过程中微小RNA的可能调控作用进行了综述.%Neurogenesis refers to a biological process of neural stem cells self-proliferate and differentiate into new neurons, and are integrated into the neural networks, including the embryonic neurogenesis and adult neurogenesis. Studies have suggested that microRNAs (miRNAs) play vital regulatory roles in neurogenesis. This article reviews the molecular mechanisms of miRNAs in the regulation of embryonic and adult neurogenesis as well as the possible regulatory roles of miRNAs in the process of neurogenesis after cerebral ischemia.

  9. Mindfulness and mind-wandering: finding convergence through opposing constructs.

    Science.gov (United States)

    Mrazek, Michael D; Smallwood, Jonathan; Schooler, Jonathan W

    2012-06-01

    Research into both mindfulness and mind-wandering has grown rapidly, yet clarification of the relationship between these two seemingly opposing constructs is still absent. A first study addresses the relationship between a dispositional measure of mindfulness (Mindful Attention and Awareness Scale, MAAS) and converging measures of both self-reported and indirect markers of mind-wandering. Negative correlations between dispositional mindfulness and 4 measures of mind-wandering confirm the opposing relationship between the 2 constructs and further validate the use of the MAAS as a dispositional measure of mindfulness. A second study demonstrated that 8 minutes of mindful breathing reduces behavioral indicators of mind-wandering during a Sustained Attention to Response Task compared with both passive relaxation and reading. Together these studies clarify the opposition between the constructs of mindfulness and mind-wandering and so should lead to greater convergence between what have been predominately separate, yet mutually relevant, lines of research.

  10. Opposing flow in square porous annulus: Influence of Dufour effect

    Science.gov (United States)

    Athani, Abdulgaphur; Al-Rashed, Abdullah A. A. A.; Khaleed, H. M. T.

    2016-06-01

    Heat and mass transfer in porous medium is very important area of research which is also termed as double diffusive convection or thermo-solutal convection. The buoyancy ratio which is the ratio of thermal to concentration buoyancy can have negative values thus leading to opposing flow. This article is aimed to study the influence of Dufour effect on the opposing flow in a square porous annulus. The partial differential equations that govern the heat and mass transfer behavior inside porous medium are solved using finite element method. A three node triangular element is used to divide the porous domain into smaller elements. Results are presented with respect to geometric and physical parameters such as duct diameter ratio, Rayleigh number, radiation parameter etc. It is found that the heat transfer increase with increase in Rayleigh number and radiation parameter. It is observed that Dufour coefficient has more influence on velocity profile.

  11. Proinflammatory cytokines oppose opioid induced acute and chronic analgesia

    OpenAIRE

    Hutchinson, Mark R.; Coats, Benjamen D; Lewis, Susannah S.; Zhang, Yingning; Sprunger, David B.; Rezvani, Niloofar; Baker, Eric M.; Jekich, Brian M.; Wieseler, Julie L.; Somogyi, Andrew A; Martin, David; Poole, Stephen; Judd, Charles M.; Steven F. Maier; Watkins, Linda R.

    2008-01-01

    Spinal proinflammatory cytokines are powerful pain-enhancing signals that contribute to pain following peripheral nerve injury (neuropathic pain). Recently, one proinflammatory cytokine, interleukin-1, was also implicated in the loss of analgesia upon repeated morphine exposure (tolerance). In contrast to prior literature, we demonstrate that the action of several spinal proinflammatory cytokines oppose systemic and intrathecal opioid analgesia, causing reduced pain suppression. In vitro morp...

  12. A pivotal role of vitamin B9 in the maintenance of regulatory T cells in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Jun Kunisawa

    Full Text Available Dietary factors regulate immunological function, but the underlying mechanisms remain elusive. Here we show that vitamin B9 is a survival factor for regulatory T (Treg cells expressing high levels of vitamin B9 receptor (folate receptor 4. In vitamin B9-reduced condition in vitro, Treg cells could be differentiated from naïve T cells but failed to survive. The impaired survival of Treg cells was associated with decreased expression of anti-apoptotic Bcl2 and independent of IL-2. In vivo depletion of dietary vitamin B9 resulted in the reduction of Treg cells in the small intestine, a site for the absorption of dietary vitamin B9. These findings provide a new link between diet and the immune system, which could maintain the immunological homeostasis in the intestine.

  13. Opposing selection and environmental variation modify optimal timing of breeding.

    Science.gov (United States)

    Tarwater, Corey E; Beissinger, Steven R

    2013-09-17

    Studies of evolution in wild populations often find that the heritable phenotypic traits of individuals producing the most offspring do not increase proportionally in the population. This paradox may arise when phenotypic traits influence both fecundity and viability and when there is a tradeoff between these fitness components, leading to opposing selection. Such tradeoffs are the foundation of life history theory, but they are rarely investigated in selection studies. Timing of breeding is a classic example of a heritable trait under directional selection that does not result in an evolutionary response. Using a 22-y study of a tropical parrot, we show that opposing viability and fecundity selection on the timing of breeding is common and affects optimal breeding date, defined by maximization of fitness. After accounting for sampling error, the directions of viability (positive) and fecundity (negative) selection were consistent, but the magnitude of selection fluctuated among years. Environmental conditions (rainfall and breeding density) primarily and breeding experience secondarily modified selection, shifting optimal timing among individuals and years. In contrast to other studies, viability selection was as strong as fecundity selection, late-born juveniles had greater survival than early-born juveniles, and breeding later in the year increased fitness under opposing selection. Our findings provide support for life history tradeoffs influencing selection on phenotypic traits, highlight the need to unify selection and life history theory, and illustrate the importance of monitoring survival as well as reproduction for understanding phenological responses to climate change.

  14. Transport synthetic acceleration with opposing reflecting boundary conditions

    Energy Technology Data Exchange (ETDEWEB)

    Zika, M.R.; Adams, M.L.

    2000-02-01

    The transport synthetic acceleration (TSA) scheme is extended to problems with opposing reflecting boundary conditions. This synthetic method employs a simplified transport operator as its low-order approximation. A procedure is developed that allows the use of the conjugate gradient (CG) method to solve the resulting low-order system of equations. Several well-known transport iteration algorithms are cast in a linear algebraic form to show their equivalence to standard iterative techniques. Source iteration in the presence of opposing reflecting boundary conditions is shown to be equivalent to a (poorly) preconditioned stationary Richardson iteration, with the preconditioner defined by the method of iterating on the incident fluxes on the reflecting boundaries. The TSA method (and any synthetic method) amounts to a further preconditioning of the Richardson iteration. The presence of opposing reflecting boundary conditions requires special consideration when developing a procedure to realize the CG method for the proposed system of equations. The CG iteration may be applied only to symmetric positive definite matrices; this condition requires the algebraic elimination of the boundary angular corrections from the low-order equations. As a consequence of this elimination, evaluating the action of the resulting matrix on an arbitrary vector involves two transport sweeps and a transmission iteration. Results of applying the acceleration scheme to a simple test problem are presented.

  15. Testosterone replacement effectively inhibits the development of experimental autoimmune orchitis in rats: evidence for a direct role of testosterone on regulatory T cell expansion.

    Science.gov (United States)

    Fijak, Monika; Schneider, Eva; Klug, Jörg; Bhushan, Sudhanshu; Hackstein, Holger; Schuler, Gerhard; Wygrecka, Malgorzata; Gromoll, Jörg; Meinhardt, Andreas

    2011-05-01

    Despite the immune-privileged status of the male genital tract, infection and inflammation of the male genital tract are important etiological factors in male infertility. A common observation in clinical and experimental orchitis as well as in systemic infection and inflammation are decreased levels of testosterone. Emerging data point to an immunosuppressive role of testosterone. In our study, we substituted testosterone levels in experimental autoimmune orchitis (EAO) in rat by s.c. testosterone implants. EAO development was reduced to 17% when animals were treated with low-dose testosterone implants (3 cm long, EAO+T3) and to 33% when rats were supplied with high-dose testosterone implants (24 cm, EAO+T24) compared with 80% of animals developing disease in the EAO control group. In the testis, testosterone replacement in EAO animals prevented the accumulation of macrophages and significantly reduced the number of CD4(+) T cells with a strong concomitant increase in the number of regulatory T cells (CD4(+)CD25(+)Foxp3(+)) compared with EAO control. In vitro testosterone treatment of naive T cells led to an expansion of the regulatory T cell subset with suppressive activity and ameliorated MCP-1-stimulated chemotaxis of T lymphocytes in a Transwell assay. Moreover, expression of proinflammatory mediators such as MCP-1, TNF-α, and IL-6 in the testis and secretion of Th1 cytokines such as IFN-γ and IL-2 by mononuclear cells isolated from testicular draining lymph nodes were decreased in the EAO+T3 and EAO+T24 groups. Thus, our study shows an immunomodulatory and protective effect of testosterone substitution in the pathogenesis of EAO and suggests androgens as a new factor in the differentiation of regulatory T cells.

  16. Rol de las células T regulatorias en esclerosis múltiple Role of T-regulatory cells in multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Juan Ignacio Rojas

    2010-02-01

    Full Text Available La esclerosis múltiple (EM es una enfermedad inflamatoria autoinmune desmielinizante del sistema nervioso central (SNC. La mayoría de las enfermedades autoinmunes se originan por la activación anormal de la respuesta inflamatoria contra auto-antígenos (la mayoría de ellos desconocidos a la fecha como consecuencia de la pérdida de la tolerancia periférica. Las células T-regulatorias constituyen un grupo esencial de linfocitos T encargados del mantenimiento de la tolerancia periférica, la prevención de enfermedades autoinmunes y la limitación de enfermedades inflamatorias crónicas. Teniendo en cuenta la importancia de la tolerancia periférica, las células T-regulatorias serían componentes cruciales en el escenario fisiopatológico de los procesos autoinmunes, incluyendo la EM. El presente trabajo recopila los conocimientos actuales sobre la función de las células T-regulatorias en la EM, la enfermedad autoinmune desmielinizante del SNC más prevalente en los seres humanos.Multiple sclerosis (MS is an autoimmune inflammatory demyelinating disease of the central nervous system (CNS. Most of autoimmune diseases arise by an abnormal activation of the inflammatory response against self-antigens (most of them unknown up to date as a consequence of dysfunction in peripheral tolerance. Regulatory T-cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory conditions. Based on that knowledge, T-regulatory cells have emerged as a key component of the physiopathology of autoimmune diseases including MS. This review compiles the current knowledge on the role and function of T-regulatory cells in MS, the most prevalent CNS autoimmune disease in humans.

  17. Analysis of Two Putative Candida albicans Phosphopantothenoylcysteine Decarboxylase / Protein Phosphatase Z Regulatory Subunits Reveals an Unexpected Distribution of Functional Roles

    Science.gov (United States)

    Petrényi, Katalin; Molero, Cristina; Kónya, Zoltán; Erdődi, Ferenc; Ariño, Joaquin; Dombrádi, Viktor

    2016-01-01

    Protein phosphatase Z (Ppz) is a fungus specific enzyme that regulates cell wall integrity, cation homeostasis and oxidative stress response. Work on Saccharomyces cerevisiae has shown that the enzyme is inhibited by Hal3/Vhs3 moonlighting proteins that together with Cab3 constitute the essential phosphopantothenoylcysteine decarboxylase (PPCDC) enzyme. In Candida albicans CaPpz1 is also involved in the morphological changes and infectiveness of this opportunistic human pathogen. To reveal the CaPpz1 regulatory context we searched the C. albicans database and identified two genes that, based on the structure of their S. cerevisiae counterparts, were termed CaHal3 and CaCab3. By pull down analysis and phosphatase assays we demonstrated that both of the bacterially expressed recombinant proteins were able to bind and inhibit CaPpz1 as well as its C-terminal catalytic domain (CaPpz1-Cter) with comparable efficiency. The binding and inhibition were always more pronounced with CaPpz1-Cter, indicating a protective effect against inhibition by the N-terminal domain in the full length protein. The functions of the C. albicans proteins were tested by their overexpression in S. cerevisiae. Contrary to expectations we found that only CaCab3 and not CaHal3 rescued the phenotypic traits that are related to phosphatase inhibition by ScHal3, such as tolerance to LiCl or hygromycin B, requirement for external K+ concentrations, or growth in a MAP kinase deficient slt2 background. On the other hand, both of the Candida proteins turned out to be essential PPCDC components and behaved as their S. cerevisiae counterparts: expression of CaCab3 and CaHal3 rescued the cab3 and hal3 vhs3 S. cerevisiae mutations, respectively. Thus, both CaHal3 and CaCab3 retained the PPCDC related functions and have the potential for CaPpz1 inhibition in vitro. The fact that only CaCab3 exhibits its phosphatase regulatory potential in vivo suggests that in C. albicans CaCab3, but not CaHal3, acts as a

  18. Delayed functional maturation of natural regulatory T cells in the medulla of postnatal thymus: role of TSLP

    Directory of Open Access Journals (Sweden)

    Knudsen Geoffry

    2006-04-01

    Full Text Available Abstract Background Generation of functional CD4+CD8-CD25+ regulatory T cells (Treg in the murine thymus depends on FoxP3. Removal of the thymus from neonatal mice has been shown to result in a multiple organ autoimmune disease phenotype that can be prevented by introducing the FoxP3+ Treg population to the animal. It has therefore, been proposed that functional FoxP3+ Treg cells are not made in the neonatal thymus; however, it remains unclear when and where functional FoxP3+CD4+CD8-CD25+ thymocytes are generated in postnatal thymus. Results We report that neither FoxP3 mRNA nor protein is expressed in CD4+CD8-CD25+, or CD4+CD8-CD25- thymocytes until 3–4 days post birth, despite the presence of mature CD4+CD8-CD25+/- thymocytes in the thymus by 1–2 days after birth. FoxP3-CD4+CD8-CD25+ thymocytes from day 2 newborn mice show no Treg activity. Interestingly, we are able to detect low numbers of FoxP3+ thymocytes dispersed throughout the medullary region of the thymus as early as 3–4 days post birth. Expression of FoxP3 is induced in embryonic day 17 fetal thymus organ culture (FTOC after 4–6 days of in vitro culture. Treatment of FTOCs with thymic stromal derived lymphopoietin (TSLP enhanced expression of FoxP3, and blocking the TSLP receptor reduces FoxP3 expression in FTOC. Furthermore, TSLP stimulates FoxP3 expression in purified CD4+CD8- thymocytes, but not in CD4+CD8+, CD4-CD8+ and CD4-CD8- thymocytes. Conclusion Expression of FoxP3 or Treg maturation is ontogenically distinct and kinetically delayed from the generation of CD4+CD8-CD25+ or CD4+CD8-CD25- thymocytes in the postnatal thymus. TSLP produced from medullary thymic epithelia cells (mTEC contributes to the expression of FoxP3 and the maturation of natural regulatory T cells. Overall, these results suggest that the development of Treg cells requires paracrine signaling during late stages of thymocyte maturation that is distinct from signaling during positive or negative

  19. Reconstruction of the gene regulatory network involved in the sonic hedgehog pathway with a potential role in early development of the mouse brain.

    Directory of Open Access Journals (Sweden)

    Jinhua Liu

    2014-10-01

    Full Text Available The Sonic hedgehog (Shh signaling pathway is crucial for pattern formation in early central nervous system development. By systematically analyzing high-throughput in situ hybridization data of E11.5 mouse brain, we found that Shh and its receptor Ptch1 define two adjacent mutually exclusive gene expression domains: Shh+Ptch1- and Shh-Ptch1+. These two domains are associated respectively with Foxa2 and Gata3, two transcription factors that play key roles in specifying them. Gata3 ChIP-seq experiments and RNA-seq assays on Gata3-knockdown cells revealed that Gata3 up-regulates the genes that are enriched in the Shh-Ptch1+ domain. Important Gata3 targets include Slit2 and Slit3, which are involved in the process of axon guidance, as well as Slc18a1, Th and Qdpr, which are associated with neurotransmitter synthesis and release. By contrast, Foxa2 both up-regulates the genes expressed in the Shh+Ptch1- domain and down-regulates the genes characteristic of the Shh-Ptch1+ domain. From these and other data, we were able to reconstruct a gene regulatory network governing both domains. Our work provides the first genome-wide characterization of the gene regulatory network involved in the Shh pathway that underlies pattern formation in the early mouse brain.

  20. Perifornical hypothalamic pathway to the adrenal gland: Role for glutamatergic transmission in the glucose counter-regulatory response.

    Science.gov (United States)

    Sabetghadam, A; Korim, W S; Verberne, A J M

    2017-03-01

    Adrenaline is an important counter-regulatory hormone that helps restore glucose homeostasis during hypoglycaemia. However, the neurocircuitry that connects the brain glucose sensors and the adrenal sympathetic outflow to the chromaffin cells is poorly understood. We used electrical microstimulation of the perifornical hypothalamus (PeH) and the rostral ventrolateral medulla (RVLM) combined with adrenal sympathetic nerve activity (ASNA) recording to examine the relationship between the RVLM, the PeH and ASNA. In urethane-anaesthetised male Sprague-Dawley rats, intermittent single pulse electrical stimulation of the rostroventrolateral medulla (RVLM) elicited an evoked ASNA response that consisted of early (60±3ms) and late peaks (135±4ms) of preganglionic and postganglionic activity. In contrast, RVLM stimulation evoked responses in lumbar sympathetic nerve activity that were almost entirely postganglionic. PeH stimulation also produced an evoked excitatory response consisting of both preganglionic and postganglionic excitatory peaks in ASNA. Both peaks in ASNA following RVLM stimulation were reduced by intrathecal kynurenic acid (KYN) injection. In addition, the ASNA response to systemic neuroglucoprivation induced by 2-deoxy-d-glucose was abolished by bilateral microinjection of KYN into the RVLM. This suggests that a glutamatergic pathway from the perifornical hypothalamus (PeH) relays in the RVLM to activate the adrenal SPN and so modulate ASNA. The main findings of this study are that (i) adrenal premotor neurons in the RVLM may be, at least in part, glutamatergic and (ii) that the input to these neurons that is activated during neuroglucoprivation is also glutamatergic.

  1. Circulating Regulatory T-Cells in Monoclonal Gammopathies of Uncertain Significance and Multiple Myeloma: In Search of a Role

    Directory of Open Access Journals (Sweden)

    Giovanni D’Arena

    2016-01-01

    Full Text Available The frequency and function of regulatory T-cells (Tregs in multiple myeloma (MM are still matter of debate. The percentage and absolute number of circulating Tregs (CD4+CD25+high  densityCD127-/low  density from 39 patients with untreated MM and 44 patients with monoclonal gammopathies of uncertain significance (MGUS were tested and compared with 20 healthy subjects as controls. The mean percentage number of circulating Tregs was 2.1%  ± 1.0 (range 0.75–6.1% in MM patients; 2.1%  ± 0.9 (range 0.3–4.4% in MGUS; and 1.5%  ± 0.4 (range 0.9–2.1% in controls (p ns. Mean absolute number of Tregs was 36.3/μL ± 23.7 (range 6.7–149/μL in MM; 38.8/μL ± 19.1 (range 4.3–87/μL in MGUS; and 39.4/μL ± 12.5 (range 18–63/μL in controls (p ns. After a median follow-up of 38 months, 5 MGUS and 2 smoldering MM (SMM transformed into overt MM; however Tregs number did not predict this evolution. With respect to MM patients and after a median follow-up of 33 months, Tregs did not show any significant correlation with main clinical and laboratory characteristics. Finally, from a functional point of view, Tregs displayed an effective suppressor function, irrespective of disease status. This study indicates that the number of circulating Tregs does not differ in different monoclonal gammopathies and normal subjects and do not correlate with clinical features of MM.

  2. Circulating Regulatory T-Cells in Monoclonal Gammopathies of Uncertain Significance and Multiple Myeloma: In Search of a Role.

    Science.gov (United States)

    D'Arena, Giovanni; Rossi, Giovanni; Laurenti, Luca; Statuto, Teodora; D'Auria, Fiorella; Valvano, Luciana; Simeon, Vittorio; Giudice, Aldo; Innocenti, Idanna; De Feo, Vincenzo; Filosa, Rosanna; Musto, Pellegrino

    2016-01-01

    The frequency and function of regulatory T-cells (Tregs) in multiple myeloma (MM) are still matter of debate. The percentage and absolute number of circulating Tregs (CD4(+)CD25(+high  density)CD127(-/low  density)) from 39 patients with untreated MM and 44 patients with monoclonal gammopathies of uncertain significance (MGUS) were tested and compared with 20 healthy subjects as controls. The mean percentage number of circulating Tregs was 2.1%  ± 1.0 (range 0.75-6.1%) in MM patients; 2.1%  ± 0.9 (range 0.3-4.4%) in MGUS; and 1.5%  ± 0.4 (range 0.9-2.1%) in controls (p ns). Mean absolute number of Tregs was 36.3/μL ± 23.7 (range 6.7-149/μL) in MM; 38.8/μL ± 19.1 (range 4.3-87/μL) in MGUS; and 39.4/μL ± 12.5 (range 18-63/μL) in controls (p ns). After a median follow-up of 38 months, 5 MGUS and 2 smoldering MM (SMM) transformed into overt MM; however Tregs number did not predict this evolution. With respect to MM patients and after a median follow-up of 33 months, Tregs did not show any significant correlation with main clinical and laboratory characteristics. Finally, from a functional point of view, Tregs displayed an effective suppressor function, irrespective of disease status. This study indicates that the number of circulating Tregs does not differ in different monoclonal gammopathies and normal subjects and do not correlate with clinical features of MM.

  3. Role of the SaeRS two-component regulatory system in Staphylococcus epidermidis autolysis and biofilm formation

    Directory of Open Access Journals (Sweden)

    Francois Patrice

    2011-06-01

    Full Text Available Abstract Background Staphylococcus epidermidis (SE has emerged as one of the most important causes of nosocomial infections. The SaeRS two-component signal transduction system (TCS influences virulence and biofilm formation in Staphylococcus aureus. The deletion of saeR in S. epidermidis results in impaired anaerobic growth and decreased nitrate utilization. However, the regulatory function of SaeRS on biofilm formation and autolysis in S. epidermidis remains unclear. Results The saeRS genes of SE1457 were deleted by homologous recombination. The saeRS deletion mutant, SE1457ΔsaeRS, exhibited increased biofilm formation that was disturbed more severely (a 4-fold reduction by DNase I treatment compared to SE1457 and the complementation strain SE1457saec. Compared to SE1457 and SE1457saec, SE1457ΔsaeRS showed increased Triton X-100-induced autolysis (approximately 3-fold and decreased cell viability in planktonic/biofilm states; further, SE1457ΔsaeRS also released more extracellular DNA (eDNA in the biofilms. Correlated with the increased autolysis phenotype, the transcription of autolysis-related genes, such as atlE and aae, was increased in SE1457ΔsaeRS. Whereas the expression of accumulation-associated protein was up-regulated by 1.8-fold in 1457ΔsaeRS, the expression of an N-acetylglucosaminyl transferase enzyme (encoded by icaA critical for polysaccharide intercellular adhesin (PIA synthesis was not affected by the deletion of saeRS. Conclusions Deletion of saeRS in S. epidermidis resulted in an increase in biofilm-forming ability, which was associated with increased eDNA release and up-regulated Aap expression. The increased eDNA release from SE1457ΔsaeRS was associated with increased bacterial autolysis and decreased bacterial cell viability in the planktonic/biofilm states.

  4. Circulating Regulatory T-Cells in Monoclonal Gammopathies of Uncertain Significance and Multiple Myeloma: In Search of a Role

    Science.gov (United States)

    Rossi, Giovanni; Laurenti, Luca; Statuto, Teodora; D'Auria, Fiorella; Valvano, Luciana; Simeon, Vittorio; Giudice, Aldo; Innocenti, Idanna; De Feo, Vincenzo; Filosa, Rosanna; Musto, Pellegrino

    2016-01-01

    The frequency and function of regulatory T-cells (Tregs) in multiple myeloma (MM) are still matter of debate. The percentage and absolute number of circulating Tregs (CD4+CD25+high  densityCD127−/low  density) from 39 patients with untreated MM and 44 patients with monoclonal gammopathies of uncertain significance (MGUS) were tested and compared with 20 healthy subjects as controls. The mean percentage number of circulating Tregs was 2.1%  ± 1.0 (range 0.75–6.1%) in MM patients; 2.1%  ± 0.9 (range 0.3–4.4%) in MGUS; and 1.5%  ± 0.4 (range 0.9–2.1%) in controls (p ns). Mean absolute number of Tregs was 36.3/μL ± 23.7 (range 6.7–149/μL) in MM; 38.8/μL ± 19.1 (range 4.3–87/μL) in MGUS; and 39.4/μL ± 12.5 (range 18–63/μL) in controls (p ns). After a median follow-up of 38 months, 5 MGUS and 2 smoldering MM (SMM) transformed into overt MM; however Tregs number did not predict this evolution. With respect to MM patients and after a median follow-up of 33 months, Tregs did not show any significant correlation with main clinical and laboratory characteristics. Finally, from a functional point of view, Tregs displayed an effective suppressor function, irrespective of disease status. This study indicates that the number of circulating Tregs does not differ in different monoclonal gammopathies and normal subjects and do not correlate with clinical features of MM. PMID:27493974

  5. The role of genome and gene regulatory network canalization in the evolution of multi-trait polymorphisms and sympatric speciation

    Directory of Open Access Journals (Sweden)

    Hogeweg Paulien

    2009-07-01

    Full Text Available Abstract Background Sexual reproduction has classically been considered as a barrier to the buildup of discrete phenotypic differentiation. This notion has been confirmed by models of sympatric speciation in which a fixed genetic architecture and a linear genotype phenotype mapping were assumed. In this paper we study the influence of a flexible genetic architecture and non-linear genotype phenotype map on differentiation under sexual reproduction. We use an individual based model in which organisms have a genome containing genes and transcription factor binding sites. Mutations involve single genes or binding sites or stretches of genome. The genome codes for a regulatory network that determines the gene expression pattern and hence the phenotype of the organism, resulting in a non-linear genotype phenotype map. The organisms compete in a multi-niche environment, imposing selection for phenotypic differentiation. Results We find as a generic outcome the evolution of discrete clusters of organisms adapted to different niches, despite random mating. Organisms from different clusters are distinct on the genotypic, the network and the phenotypic level. However, the genome and network differences are constrained to a subset of the genome locations, a process we call genotypic canalization. We demonstrate how this canalization leads to an increased robustness to recombination and increasing hybrid fitness. Finally, in case of assortative mating, we explain how this canalization increases the effectiveness of assortativeness. Conclusion We conclude that in case of a flexible genetic architecture and a non-linear genotype phenotype mapping, sexual reproduction does not constrain phenotypic differentiation, but instead constrains the genotypic differences underlying it. We hypothesize that, as genotypic canalization enables differentiation despite random mating and increases the effectiveness of assortative mating, sympatric speciation is more likely

  6. AQP2 exocytosis in the renal collecting duct -- involvement of SNARE isoforms and the regulatory role of Munc18b.

    NARCIS (Netherlands)

    Procino, G.; Barbieri, C.; Tamma, G.; Benedictis, L De; Pessin, J.E.; Svelto, M.; Valenti, G.

    2008-01-01

    Vasopressin regulates the fusion of the water channel aquaporin 2 (AQP2) to the apical membrane of the renal collecting-duct principal cells and several lines of evidence indicate that SNARE proteins mediate this process. In this work MCD4 renal cells were used to investigate the functional role of

  7. Rho kinase's role in myosin recruitment to the equatorial cortex of mitotic Drosophila S2 cells is for myosin regulatory light chain phosphorylation.

    Directory of Open Access Journals (Sweden)

    Sara O Dean

    Full Text Available BACKGROUND: Myosin II recruitment to the equatorial cortex is one of the earliest events in establishment of the cytokinetic contractile ring. In Drosophila S2 cells, we previously showed that myosin II is recruited to the furrow independently of F-actin, and that Rho1 and Rok are essential for this recruitment [1]. Rok phosphorylates several cellular proteins, including the myosin regulatory light chain (RLC. METHODOLOGY/PRINCIPAL FINDINGS: Here we express phosphorylation state mimic constructs of the RLC in S2 cells to examine the role of RLC phosphorylation involving Rok in the localization of myosin. Phosphorylation of the RLC is required for myosin localization to the equatorial cortex during mitosis, and the essential role of Rok in this localization and for cytokinesis is to maintain phosphorylation of the RLC. The ability to regulate the RLC phosphorylation state spatio-temporally is not essential for the myosin localization. Furthermore, the essential role of Citron in cytokinesis is not phosphorylation of the RLC. CONCLUSIONS/SIGNIFICANCE: We conclude that the Rho1 pathway leading to myosin localization to the future cytokinetic furrow is relatively straightforward, where only Rok is needed, and it is only needed to maintain phosphorylation of the myosin RLC.

  8. 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.

  9. Two Opposed Ideas As Immature Ambivalence In The Greatk Gatsby

    Institute of Scientific and Technical Information of China (English)

    HuZhu

    1999-01-01

    The Great Gatsby narrates a symbolist tragedy in a transitional era.It's ambivalent characterization and themes find justifications in the writer's own ideology of two opposed ideas,and in his efforts to define and judge subjects of social problems.The ambivalent characterization concerns the writer's dual response to the protagonist's corruption and innocence respectively.Ultimately the writer is convinced that both the corruption and mnocence are justifiable in the morality of his protagonist.Whereas the ambivalent themes dealing with the American dream attach importance to the social class perspectives and the vision of history.undoubtedly the writer slides into a compromise with his themes:repudation and approval.Because of the equally strong interplay of two opposed ideas,the writer fails to locate a definite position and scale,which results in his immature control in the art of the work.The writer's characteristic code and achievement are significant because they genuinely reveal human being's fundamental dilemma in social life.

  10. Differential roles of regulatory light chain and myosin binding protein-C phosphorylations in the modulation of cardiac force development

    Energy Technology Data Exchange (ETDEWEB)

    Colson, Brett A.; Locher, Matthew R.; Bekyarova, Tanya; Patel, Jitandrakumar R.; Fitzsimons, Daniel P.; Irving, Thomas C.; Moss, Richard L. (IIT); (UW-MED)

    2010-05-25

    Phosphorylation of myosin regulatory light chain (RLC) by myosin light chain kinase (MLCK) and myosin binding protein-C (cMyBP-C) by protein kinase A (PKA) independently accelerate the kinetics of force development in ventricular myocardium. However, while MLCK treatment has been shown to increase the Ca{sup 2+} sensitivity of force (pCa{sub 50}), PKA treatment has been shown to decrease pCa{sub 50}, presumably due to cardiac troponin I phosphorylation. Further, MLCK treatment increases Ca{sup 2+}-independent force and maximum Ca{sup 2+}-activated force, whereas PKA treatment has no effect on either force. To investigate the structural basis underlying the kinase-specific differential effects on steady-state force, we used synchrotron low-angle X-ray diffraction to compare equatorial intensity ratios (I{sub 1,1}/I{sub 1,0}) to assess the proximity of myosin cross-bridge mass relative to actin and to compare lattice spacings (d{sub 1,0}) to assess the inter-thick filament spacing in skinned myocardium following treatment with either MLCK or PKA. As we showed previously, PKA phosphorylation of cMyBP-C increases I{sub 1,1}/I{sub 1,0} and, as hypothesized, treatment with MLCK also increased I{sub 1,1}/I{sub 1,0}, which can explain the accelerated rates of force development during activation. Importantly, interfilament spacing was reduced by {approx}2 nm ({Delta} 3.5%) with MLCK treatment, but did not change with PKA treatment. Thus, RLC or cMyBP-C phosphorylation increases the proximity of cross-bridges to actin, but only RLC phosphorylation affects lattice spacing, which suggests that RLC and cMyBP-C modulate the kinetics of force development by similar structural mechanisms; however, the effect of RLC phosphorylation to increase the Ca{sup 2+} sensitivity of force is mediated by a distinct mechanism, most probably involving changes in interfilament spacing.

  11. Advancing regulatory science to bring novel medical devices for use in emergency care to market: the role of the Food and Drug Administration.

    Science.gov (United States)

    Scully, Christopher G; Forrest, Shawn; Galeotti, Loriano; Schwartz, Suzanne B; Strauss, David G

    2015-04-01

    The Food and Drug Administration (FDA) performs regulatory science to provide science-based medical product regulatory decisions. This article describes the types of scientific research the FDA's Center for Devices and Radiological Health performs and highlights specific projects related to medical devices for emergency medicine. In addition, this article discusses how results from regulatory science are used by the FDA to support the regulatory process as well as how the results are communicated to the public. Regulatory science supports the FDA's mission to assure safe, effective, and high-quality medical products are available to patients.

  12. Histone H2B ubiquitylation represses gametogenesis by opposing RSC-dependent chromatin remodeling at the ste11 master regulator locus.

    Science.gov (United States)

    Materne, Philippe; Vázquez, Enrique; Sánchez, Mar; Yague-Sanz, Carlo; Anandhakumar, Jayamani; Migeot, Valerie; Antequera, Francisco; Hermand, Damien

    2016-01-01

    In fission yeast, the ste11 gene encodes the master regulator initiating the switch from vegetative growth to gametogenesis. In a previous paper, we showed that the methylation of H3K4 and consequent promoter nucleosome deacetylation repress ste11 induction and cell differentiation (Materne et al., 2015) but the regulatory steps remain poorly understood. Here we report a genetic screen that highlighted H2B deubiquitylation and the RSC remodeling complex as activators of ste11 expression. Mechanistic analyses revealed more complex, opposite roles of H2Bubi at the promoter where it represses expression, and over the transcribed region where it sustains it. By promoting H3K4 methylation at the promoter, H2Bubi initiates the deacetylation process, which decreases chromatin remodeling by RSC. Upon induction, this process is reversed and efficient NDR (nucleosome depleted region) formation leads to high expression. Therefore, H2Bubi represses gametogenesis by opposing the recruitment of RSC at the promoter of the master regulator ste11 gene.

  13. Pref-1 in brown adipose tissue: specific involvement in brown adipocyte differentiation and regulatory role of C/EBPδ.

    Science.gov (United States)

    Armengol, Jordi; Villena, Josep A; Hondares, Elayne; Carmona, María C; Sul, Hei Sook; Iglesias, Roser; Giralt, Marta; Villarroya, Francesc

    2012-05-01

    Pref-1 (pre-adipocyte factor-1) is known to play a central role in regulating white adipocyte differentiation, but the role of Pref-1 in BAT (brown adipose tissue) has not been analysed. In the present study we found that Pref-1 expression is high in fetal BAT and declines progressively after birth. However, Pref-1-null mice showed unaltered fetal development of BAT, but exhibited signs of over-activation of BAT thermogenesis in the post-natal period. In C/EBP (CCAAT/enhancer-binding protein) α-null mice, a rodent model of impaired fetal BAT differentiation, Pref-1 was dramatically overexpressed, in association with reduced expression of the Ucp1 (uncoupling protein 1) gene, a BAT-specific marker of thermogenic differentiation. In brown adipocyte cell culture models, Pref-1 was mostly expressed in pre-adipocytes and declined with brown adipocyte differentiation. The transcription factor C/EBPδ activated the Pref-1 gene transcription in brown adipocytes, through binding to the proximal promoter region. Accordingly, siRNA (small interfering RNA)-induced C/EBPδ knockdown led to reduced Pref-1 gene expression. This effect is consistent with the observed overexpression of C/EBPδ in C/EBPα-null BAT and high expression of C/EBPδ in brown pre-adipocytes. Dexamethasone treatment of brown pre-adipocytes suppressed Pref-1 down-regulation occurring throughout the brown adipocyte differentiation process, increased the expression of C/EBPδ and strongly impaired expression of the thermogenic markers UCP1 and PGC-1α [PPARγ (peroxisome-proliferator-activated receptor γ) co-activator-α]. However, it did not alter normal fat accumulation or expression of non-BAT-specific genes. Collectively, these results specifically implicate Pref-1 in controlling the thermogenic gene expression program in BAT, and identify C/EBPδ as a novel transcriptional regulator of Pref-1 gene expression that may be related to the specific role of glucocorticoids in BAT differentiation.

  14. Reconstruction of the yeast Snf1 kinase regulatory network reveals its role as a global energy regulator

    DEFF Research Database (Denmark)

    Usaite, Renata; Jewett, Michael Christopher; Soberano de Oliveira, Ana Paula

    2009-01-01

    identified Snf1's global regulation on gene and protein expression levels, and showed that yeast Snf1 has a far more extensive function in controlling energy metabolism than reported earlier. Additionally, we identified complementary roles of Snf1 and Snf4. Similar to the function of AMPK in humans, our...... findings showed that Snf1 is a low-energy checkpoint and that yeast can be used more extensively as a model system for studying the molecular mechanisms underlying the global regulation of AMPK in mammals, failure of which leads to metabolic diseases....

  15. The role of regulatory proteins and S-nitrosylation of endothelial nitric oxide synthase in the human clitoris: implications for female sexual function.

    Science.gov (United States)

    Oliver, Janine L; Kavoussi, Parviz K; Smith, Ryan P; Woodson, Robin I; Corbett, Sean T; Costabile, Raymond A; Palmer, Lisa A; Lysiak, Jeffrey J

    2014-08-01

    During female sexual arousal, clitoral blood flow is controlled by endothelial nitric oxide synthase (eNOS) and its product, nitric oxide (NO). The mechanisms regulating eNOS activity and NO bioavailability in the clitoris are largely unknown. To identify proteins involved in regulation of eNOS activity within the clitoris and to evaluate the effects of S-nitrosoglutathione reductase (GSNO-R) and eNOS nitrosylation/denitrosylation on clitoral blood flow. Immunohistochemistry for eNOS, caveolin-1 (Cav1), heat shock protein-90 (Hsp90), phosphodiesterase type 5 (PDE5), GSNO-R, and soluble guanylate cyclase (sGC) was performed on human and murine clitoral tissue. Western blot analysis was performed for eNOS, phosphorylated eNOS (phospho-eNOS, Ser1177), Cav1, Hsp90, sGC, PDE5, phosphoinositide 3-kinase (PI3K), Akt (protein kinase B), and GSNO-R on protein from human clitoral tissue. A biotin switch assay was used to analyze the S-nitrosylation of eNOS, nNOS, and GSNO-R. Clitoral blood flow was measured in wild-type and GSNO-R(-/-) mice at baseline and during cavernous nerve electrical stimulation (CNES). Localization of eNOS regulatory proteins and clitoral blood flow. eNOS and GSNO-R co-localized to the vascular endothelium and sinusoids of human clitoral tissue. Immunohistochemistry also localized Cav1 and Hsp90 to the endothelium and PDE5 and sGC to the trabecular smooth muscle. Expression of S-nitrosylated (SNO)-eNOS and SNO-GSNO-R was detected by biotin switch assays. Wild-type control mice exhibited increased clitoral blood flow with CNES whereas GSNO-R(-/-) animals failed to show an increase in blood flow. Several key eNOS regulatory proteins are present in the clitoral tissue in a cellular specific pattern. S-nitrosylation of eNOS may also represent a key regulatory mechanism governing eNOS activation/deactivation since mice deficient in GSNO-R failed to increase clitoral blood flow. Additional studies are necessary to define the role of S-nitrosylation in the

  16. Infant, maternal, and familial predictors and correlates of regulatory problems in early infancy: The differential role of infant temperament and maternal anxiety and depression.

    Science.gov (United States)

    Martini, Julia; Petzoldt, Johanna; Knappe, Susanne; Garthus-Niegel, Susan; Asselmann, Eva; Wittchen, Hans-Ulrich

    2017-09-01

    Excessive infant crying, feeding and sleeping problems are likely to emerge from the complex interplay of various factors. To investigate the role of infant (e.g., temperament), maternal (e.g., anxiety and depressive disorders), and familial (e.g., social support) factors as potential precursors of infant regulatory problems. Prospective-longitudinal study. 286 mother-infant dyads were investigated from early pregnancy until 16 months postpartum via questionnaires and interviews. Regulatory problems at 2, 4 and 16 months postpartum assessed by standardized diagnostic interviews. Fussy infant temperament and maternal anxiety disorders were associated with excessive infant crying (OR=1.16, 95%CI:1.05-1.29, OR=3.28, 95%CI:1.16-9.26) and feeding problems (OR=1.05, 95%CI:1.01-1.11, OR=2.27, 95%CI:1.36-3.80) whereas maternal depressive disorders were associated with infant sleeping problems (OR=2.55, 95%CI:1.06-6.11). Moreover, high maternal age (OR=0.86, 95%CI:0.75-0.98) was associated with a lower risk for excessive crying and being a single mother (OR=0.16, 95%CI:0.03-0.73) and cognitive reappraisal to regulate emotions (OR: 0.59, 95%CI:0.36-0.96) was associated with a lower risk for sleeping problems. Excessive infant crying and feeding problems may be related to interactional deficits of anxious mothers who perceive their infants as "difficult" during soothing or feeding situations. Sleeping problems may be transmitted already during pregnancy by an altered sleep-wake-rhythm of mothers with a history of depression or by a genetic predisposition. Therapeutic interventions should focus on maternal anxiety and depression, behavior management techniques to cope with difficult situations with "fussy" infants and potential protective factors (e.g. favorable maternal emotion regulation) to address crying, feeding and sleeping problems. Copyright © 2017. Published by Elsevier B.V.

  17. Role played by CD4+FOXP3+ regulatory T Cells in suppression of host responses to Haemophilus ducreyi during experimental infection of human volunteers.

    Science.gov (United States)

    Li, Wei; Tenner-Racz, Klara; Racz, Paul; Janowicz, Diane M; Fortney, Kate R; Katz, Barry P; Spinola, Stanley M

    2010-06-15

    Haemophilus ducreyi causes chancroid, a genital ulcer disease. Among human volunteers, the majority of experimentally infected individuals fail to clear the infection and form pustules. Here, we investigated the role played by CD4(+)FOXP3(+) regulatory T (T(reg)) cells in the formation of pustules. In pustules, there was a significant enrichment of CD4(+)FOXP3(+) T cells, compared with that in peripheral blood. The majority of lesional FOXP3(+) T cells were CD4(+), CD25(+), CD127(lo/-), and CTLA-4(+). FOXP3(+) T cells were found throughout pustules but were most abundant at their base. Significantly fewer lesional CD4(+)FOXP3(+) T cells expressed interferon gamma, compared with lesional CD4(+)FOXP3(-) effector T cells. Depletion of CD4(+)CD25(+) T cells from the peripheral blood of infected and uninfected volunteers significantly enhanced proliferation of H. ducreyi-reactive CD4(+) T cells. Our results indicate that the population of CD4(+)CD25(+)CD127(lo/-)FOXP3(+) T(reg) cells are expanded at H. ducreyi-infected sites and that these cells may play a role in suppressing the host immune response to the bacterium.

  18. The Regulatory Role of Rolipram on Inflammatory Mediators and Cholinergic/Adrenergic Stimulation-Induced Signals in Isolated Primary Mouse Submandibular Gland Cells

    Directory of Open Access Journals (Sweden)

    Dong Un Lee

    2016-01-01

    Full Text Available Exposure to bacterial lipopolysaccharides (LPS induces inflammatory signals in salivary glands. We investigated the regulatory role of phosphodiesterase 4 (PDE4 inhibitor rolipram on inflammatory mediators and cholinergic/adrenergic stimulation-induced intracellular Ca2+ signaling in salivary acinar and ductal cells. Submandibular gland (SMG expressed PDE4A through 4D mRNA and PDE4 was localized in the luminal membrane of SMG. LPS induced Ca2+ signaling and ROS production in SMG. Treatment with rolipram blocked LPS-induced Ca2+ increase and ROS production. The application of histamine evoked Ca2+ signals and ROS production, which were attenuated by rolipram in SMG cells. Moreover, LPS-induced NLRP3 inflammasome and cleaved caspase-1 were inhibited by rolipram. The inhibitory role of rolipram in ROS-induced Ca2+ signaling was mainly observed in acinar cells and not in ductal cells. Rolipram also protected SMG acinar but not ductal cells from LPS-induced cell membrane damage. In the case of cholinergic/adrenergic stimulation, carbachol/isoproterenol-induced Ca2+ signals were upregulated by the treatment of rolipram in SMG. In the case of cAMP-dependent ductal bicarbonate secretion by rolipram, no effect was observed on the modulation of ductal chloride/bicarbonate exchange activity. Rolipram could suppress the inflammatory signals and could be a potential therapeutic strategy against LPS-induced inflammation to protect the salivary gland cells.

  19. The Regulatory Role of Rolipram on Inflammatory Mediators and Cholinergic/Adrenergic Stimulation-Induced Signals in Isolated Primary Mouse Submandibular Gland Cells

    Science.gov (United States)

    Lee, Dong Un; Shin, Dong Min; Hong, Jeong Hee

    2016-01-01

    Exposure to bacterial lipopolysaccharides (LPS) induces inflammatory signals in salivary glands. We investigated the regulatory role of phosphodiesterase 4 (PDE4) inhibitor rolipram on inflammatory mediators and cholinergic/adrenergic stimulation-induced intracellular Ca2+ signaling in salivary acinar and ductal cells. Submandibular gland (SMG) expressed PDE4A through 4D mRNA and PDE4 was localized in the luminal membrane of SMG. LPS induced Ca2+ signaling and ROS production in SMG. Treatment with rolipram blocked LPS-induced Ca2+ increase and ROS production. The application of histamine evoked Ca2+ signals and ROS production, which were attenuated by rolipram in SMG cells. Moreover, LPS-induced NLRP3 inflammasome and cleaved caspase-1 were inhibited by rolipram. The inhibitory role of rolipram in ROS-induced Ca2+ signaling was mainly observed in acinar cells and not in ductal cells. Rolipram also protected SMG acinar but not ductal cells from LPS-induced cell membrane damage. In the case of cholinergic/adrenergic stimulation, carbachol/isoproterenol-induced Ca2+ signals were upregulated by the treatment of rolipram in SMG. In the case of cAMP-dependent ductal bicarbonate secretion by rolipram, no effect was observed on the modulation of ductal chloride/bicarbonate exchange activity. Rolipram could suppress the inflammatory signals and could be a potential therapeutic strategy against LPS-induced inflammation to protect the salivary gland cells. PMID:27143817

  20. Strength training and testosterone treatment have opposing effects on migration inhibitor factor levels in ageing men

    DEFF Research Database (Denmark)

    Glintborg, D.; Christensen, L. L.; Kvorning, T.;

    2013-01-01

    Strength Training and Testosterone Treatment Have Opposing Effects on Migration Inhibitor Factor Levels in Ageing Men......Strength Training and Testosterone Treatment Have Opposing Effects on Migration Inhibitor Factor Levels in Ageing Men...

  1. Final disposal of spent nuclear fuel - regulatory system and roles of different actors during the decision process

    Energy Technology Data Exchange (ETDEWEB)

    2009-03-15

    In November 2006 Swedish Nuclear Fuels Co. applied for a license to build a plant for encapsulation of spent nuclear fuels at Oskarshamn, Sweden. The company also have plans to apply, in 2009, for a license to construct a underground repository for spent nuclear fuels. KASAM arranged a seminar in November 2006 in order to describe and discuss the licensing rules and regulations and the roles of different parties in the decision making. Another objective of the seminar was to point out possible ambiguities in this process. Another interesting question under discussion was in what ways the basic data for the decision should be produced. The seminar covered the part of the process beginning with the application for a license and ending with the government approval/rejection of the application. Most time was spent on the legal aspects of the process

  2. Homeobox genes and melatonin synthesis: regulatory roles of the cone-rod homeobox transcription factor in the rodent pineal gland.

    Science.gov (United States)

    Rohde, Kristian; Møller, Morten; Rath, Martin Fredensborg

    2014-01-01

    Nocturnal synthesis of melatonin in the pineal gland is controlled by a circadian rhythm in arylalkylamine N-acetyltransferase (AANAT) enzyme activity. In the rodent, Aanat gene expression displays a marked circadian rhythm; release of norepinephrine in the gland at night causes a cAMP-based induction of Aanat transcription. However, additional transcriptional control mechanisms exist. Homeobox genes, which are generally known to encode transcription factors controlling developmental processes, are also expressed in the mature rodent pineal gland. Among these, the cone-rod homeobox (CRX) transcription factor is believed to control pineal-specific Aanat expression. Based on recent advances in our understanding of Crx in the rodent pineal gland, we here suggest that homeobox genes play a role in adult pineal physiology both by ensuring pineal-specific Aanat expression and by facilitating cAMP response element-based circadian melatonin production.

  3. Homeobox Genes and Melatonin Synthesis: Regulatory Roles of the Cone-Rod Homeobox Transcription Factor in the Rodent Pineal Gland

    Directory of Open Access Journals (Sweden)

    Kristian Rohde

    2014-01-01

    Full Text Available Nocturnal synthesis of melatonin in the pineal gland is controlled by a circadian rhythm in arylalkylamine N-acetyltransferase (AANAT enzyme activity. In the rodent, Aanat gene expression displays a marked circadian rhythm; release of norepinephrine in the gland at night causes a cAMP-based induction of Aanat transcription. However, additional transcriptional control mechanisms exist. Homeobox genes, which are generally known to encode transcription factors controlling developmental processes, are also expressed in the mature rodent pineal gland. Among these, the cone-rod homeobox (CRX transcription factor is believed to control pineal-specific Aanat expression. Based on recent advances in our understanding of Crx in the rodent pineal gland, we here suggest that homeobox genes play a role in adult pineal physiology both by ensuring pineal-specific Aanat expression and by facilitating cAMP response element-based circadian melatonin production.

  4. Role of AtCDC48 & the AtCDC48 Regulatory Protein Family, PUX, in Plant Cell Morphogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Bednarek, Sebastian, Y.

    2009-11-08

    The long-term objective of this work is to understand the molecular events and mechanisms involved in secretory membrane trafficking and organelle biogenesis, which are crucial for normal plant growth and development. Our studies have suggested a vital role for the cytosolic chaperone Cdc48p/p97 during cytokinesis and cell expansion which are highly dependent upon secretory membrane trafficking. Localization studies have shown that the plant Cdc48p/p97, AtCDC48, and the Arabidopsis ortholog of the ER- and Golgi-associated SNARE, syntaxin 5, (referred to as SYP31) are targeted to the division plane during cytokinesis. In addition, AtCDC48 and SYP31 were shown to interact in vitro and in vivo. To characterize further the function of AtCDC48 and SYP31 we have utilized affinity chromatography and MALDI-MS to identify several plant-specific proteins that interact with SYP31 and/or modulate the activity of AtCDC48 including two UBX (i.e. ubiquitin-like) domain containing proteins, PUX1 and PUX2 (Proteins containing UBX domain). These proteins define a plant protein family consisting of 15 uncharacterized members that we postulate interact with AtCDC48. Biochemical studies have demonstrated that PUX2 is a novel membrane adapter for AtCDC48 that mediates AtCDC48/SYP31 interaction and is likely to control AtCDC48-dependent membrane fusion. In contrast, PUX1 negatively regulates AtCDC48 by inhibiting its ATPase activity and by promoting the disassembly of the active hexamer. These findings provide the first evidence that the assembly and disassembly of the CDC48/p97complex is actually a dynamic process. This new unexpected level of regulation for CDC48/p97 was demonstrated to be critical in vivo as pux1 loss-of-function mutants grow faster than wild-type plants. These studies suggest a role for AtCDC48 in plant cell cycle progression including cytokinesis and/or cell expansion. The proposed studies are designed to: 1) characterize further the localization and function of At

  5. Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy.

    Science.gov (United States)

    van der Most, Robbert G; Currie, Andrew J; Mahendran, Sathish; Prosser, Amy; Darabi, Anna; Robinson, Bruce W S; Nowak, Anna K; Lake, Richard A

    2009-08-01

    Tumor cell death potentially engages with the immune system. However, the efficacy of anti-tumor chemotherapy may be limited by tumor-driven immunosuppression, e.g., through CD25+ regulatory T cells. We addressed this question in a mouse model of mesothelioma by depleting or reconstituting CD25+ regulatory T cells in combination with two different chemotherapeutic drugs. We found that the efficacy of cyclophosphamide to eradicate established tumors, which has been linked to regulatory T cell depletion, was negated by adoptive transfer of CD25+ regulatory T cells. Analysis of post-chemotherapy regulatory T cell populations revealed that cyclophosphamide depleted cycling (Ki-67(hi)) T cells, including foxp3+ regulatory CD4+ T cells. Ki-67(hi) CD4+ T cells expressed increased levels of two markers, TNFR2 and ICOS, that have been associated with a maximally suppressive phenotype according to recently published studies. This suggest that cyclophosphamide depletes a population of maximally suppressive regulatory T cells, which may explain its superior anti-tumor efficacy in our model. Our data suggest that regulatory T cell depletion could be used to improve the efficacy of anti-cancer chemotherapy regimens. Indeed, we observed that the drug gemcitabine, which does not deplete cycling regulatory T cells, eradicates established tumors in mice only when CD25+ CD4+ T cells are concurrently depleted. Cyclophosphamide could be used to achieve regulatory T cell depletion in combination with chemotherapy.

  6. 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...... they arise. In short, I expose the regulatory anatomy of the policy landscape....

  7. Regulatory role of kit ligand-c-kit interaction and oocyte factors in steroidogenesis by rat granulosa cells.

    Science.gov (United States)

    Miyoshi, Tomoko; Otsuka, Fumio; Nakamura, Eri; Inagaki, Kenichi; Ogura-Ochi, Kanako; Tsukamoto, Naoko; Takeda, Masaya; Makino, Hirofumi

    2012-07-06

    Although kit ligand (KL)-c-kit interaction is known to be critical for oogenesis and folliculogenesis, its role in ovarian steroidogenesis has yet to be elucidated. We studied the impact of KL-c-kit interaction in regulation of steroidogenesis using rat oocyte/granulosa cell co-culture. In the presence of oocytes, soluble KL suppressed FSH-induced estradiol production and aromatase mRNA expression without affecting FSH-induced progesterone production. The KL effect on steroidogenesis was interrupted by an anti-c-kit neutralizing antibody, suggesting that KL-c-kit interaction is involved in suppression of estrogen by granulosa cells through oocyte c-kit action. The cAMP-PKA pathway activity was not directly involved in the estrogen regulation by KL-c-kit action. It was of note that KL treatment increased the expression levels of oocyte-derived FGF-8, GDF-9 and BMP-6, while it reduced the expression levels of oocyte-derived BMP-15 in the oocyte-granulosa cell co-culture. Given the findings that FGF-8, but not GDF-9, BMP-6 or -15, suppressed FSH-induced estrogen production by granulosa cells, oocyte-derived FGF-8 is linked to suppression of FSH-induced estrogen production through the KL-c-kit interaction. Furthermore, the suppression of FSH-induced estrogen production by KL in the co-culture was reversed by a FGF receptor kinase inhibitor and the effect of the inhibitor was enhanced in combination with extracellular-domain protein of BMPRII, which interferes with BMP-15 and GDF-9 activities. Thus, the actions of endogenous oocyte factors including FGF-8 and BMP-15/GDF-9 were involved in the KL activity that inhibited FSH-induced estradiol production. Collectively, the results indicate that KL-c-kit interaction plays a role in estrogenic regulation through oocyte-granulosa cell communication.

  8. Active diffusion and microtubule-based transport oppose myosin forces to position organelles in cells

    Science.gov (United States)

    Lin, Congping; Schuster, Martin; Guimaraes, Sofia Cunha; Ashwin, Peter; Schrader, Michael; Metz, Jeremy; Hacker, Christian; Gurr, Sarah Jane; Steinberg, Gero

    2016-06-01

    Even distribution of peroxisomes (POs) and lipid droplets (LDs) is critical to their role in lipid and reactive oxygen species homeostasis. How even distribution is achieved remains elusive, but diffusive motion and directed motility may play a role. Here we show that in the fungus Ustilago maydis ~95% of POs and LDs undergo diffusive motions. These movements require ATP and involve bidirectional early endosome motility, indicating that microtubule-associated membrane trafficking enhances diffusion of organelles. When early endosome transport is abolished, POs and LDs drift slowly towards the growing cell end. This pole-ward drift is facilitated by anterograde delivery of secretory cargo to the cell tip by myosin-5. Modelling reveals that microtubule-based directed transport and active diffusion support distribution, mobility and mixing of POs. In mammalian COS-7 cells, microtubules and F-actin also counteract each other to distribute POs. This highlights the importance of opposing cytoskeletal forces in organelle positioning in eukaryotes.

  9. Active diffusion and microtubule-based transport oppose myosin forces to position organelles in cells

    Science.gov (United States)

    Lin, Congping; Schuster, Martin; Guimaraes, Sofia Cunha; Ashwin, Peter; Schrader, Michael; Metz, Jeremy; Hacker, Christian; Gurr, Sarah Jane; Steinberg, Gero

    2016-01-01

    Even distribution of peroxisomes (POs) and lipid droplets (LDs) is critical to their role in lipid and reactive oxygen species homeostasis. How even distribution is achieved remains elusive, but diffusive motion and directed motility may play a role. Here we show that in the fungus Ustilago maydis ∼95% of POs and LDs undergo diffusive motions. These movements require ATP and involve bidirectional early endosome motility, indicating that microtubule-associated membrane trafficking enhances diffusion of organelles. When early endosome transport is abolished, POs and LDs drift slowly towards the growing cell end. This pole-ward drift is facilitated by anterograde delivery of secretory cargo to the cell tip by myosin-5. Modelling reveals that microtubule-based directed transport and active diffusion support distribution, mobility and mixing of POs. In mammalian COS-7 cells, microtubules and F-actin also counteract each other to distribute POs. This highlights the importance of opposing cytoskeletal forces in organelle positioning in eukaryotes. PMID:27251117

  10. Structure of a poly(ethylene) opposed flow diffusion flame

    Energy Technology Data Exchange (ETDEWEB)

    Pitz, W.J.; Brown, N.J.; Sawyer, R.F.

    1980-08-01

    Structural measurements were obtained and compared with other investigations of diffusion flames. Departures from the commonly assumed collapsed flame model of laminar diffusion flames were observed in terms of excessive CO concentrations and oxygen penetration into the fuel side of the flame. An upper bound on the importance of oxygen diffusion to the fuel surface and subsequent surface oxidation was placed at 20% of the energy required for fuel pyrolysis, with the remainder of the energy being delivered to the surface from the flame through heat transfer processes. As the oxygen concentration in the oxidizer flow was decreased and extinction conditions approached, the CO/CO/sub 2/ ratio at the flame increased slightly, the oxygen concentration at the luminous flame zone decreased, the flame stand-off distance decreased, and the flame temperature decreased. Radial similarity in the composition and temperature profiles was established experimentally which confirms predictions and greatly simplifies the modeling of the opposed flow diffusion flame.

  11. Islam, Islamophobia and the West: Opposing Views and Social Reality

    Directory of Open Access Journals (Sweden)

    Adila Pavelić

    2015-12-01

    Full Text Available Through reviewing different and often opposing views on the relationship between Islam and the West, the paper aims to offer a better understanding of this relationship, and of Islamophobia as an old, yet increasingly actual and in many respects relevant social problem. A short historical overview of the understanding of the relationship between Islam and the West, and various definitions of Islamophobia, are followed by examination of some recent works that from different perspectives deal with the issue. Firstly, is given insight into the works written by Western theorists who describe the relationship between Islam and the West within the framework of the idea of the clash of civilizations while, at the same time, labeling Islam often as a non-modern religion and culture whose members reject Western values such as democracy, freedom and gender equality. In contrast to them are introduced the authors whose argumentation opposes stereotypical views of Islam; among them are also those that critically address Islamophobia in today’s Western society, either by presenting results of their research on Islamophobia or by documenting the dominant media image of Islam, which has been perpetuating stereotypes, especially in the aftermath of the terrorist attacks on New York in 2001. Lastly, it is concluded that, regardless of the origin of works dealing with the relationship between Islam and the West or of the type of their arguments, they more often than not interpret Islam and the West primarily as two separate, self-contained and in itself incompatible worlds. In doing so, the authors here argue, they employ an essentialist and reductionist approach not only to Islam – as it might be assumed – but also to the West, while the relationship between Islam and the West is simplified and schematized.

  12. CD4+CD25+CD127 regulatory cells play multiple roles in maintaining HIV-1 p24 production in patients on long-term treatment: HIV-1 p24-producing cells and suppression of anti-HIV immunity

    Directory of Open Access Journals (Sweden)

    Yan-Mei Jiao

    2015-08-01

    Conclusions: CD4+CD25+CD127 regulatory cells play multiple roles in maintaining HIV-1 p24 production in long-term ART patients. Treg cells may be a target for eliminating the latent HIV reservoir after effective long-term ART.

  13. AQP2 exocytosis in the renal collecting duct -- involvement of SNARE isoforms and the regulatory role of Munc18b.

    Science.gov (United States)

    Procino, Giuseppe; Barbieri, Claudia; Tamma, Grazia; De Benedictis, Leonarda; Pessin, Jeffrey E; Svelto, Maria; Valenti, Giovanna

    2008-06-15

    Vasopressin regulates the fusion of the water channel aquaporin 2 (AQP2) to the apical membrane of the renal collecting-duct principal cells and several lines of evidence indicate that SNARE proteins mediate this process. In this work MCD4 renal cells were used to investigate the functional role of a set of Q- and R-SNAREs, together with that of Munc18b as a negative regulator of the formation of the SNARE complex. Both VAMP2 and VAMP3 were associated with immunoisolated AQP2 vesicles, whereas syntaxin 3 (Stx3), SNAP23 and Munc18 were associated with the apical plasma membrane. Co-immunoprecipitation experiments indicated that Stx3 forms complexes with VAMP2, VAMP3, SNAP23 and Munc18b. Protein knockdown coupled to apical surface biotinylation demonstrated that reduced levels of the R-SNAREs VAMP2 and VAMP3, and the Q-SNAREs Stx3 and SNAP23 strongly inhibited AQP2 fusion at the apical membrane. In addition, knockdown of Munc18b promoted a sevenfold increase of AQP2 fused at the plasma membrane without forskolin stimulation. Taken together these findings propose VAMP2, VAMP3, Stx3 and SNAP23 as the complementary set of SNAREs responsible for AQP2-vesicle fusion into the apical membrane, and Munc18b as a negative regulator of SNARE-complex formation in renal collecting-duct principal cells.

  14. A regulatory role for the cohesin loader NIPBL in nonhomologous end joining during immunoglobulin class switch recombination.

    Science.gov (United States)

    Enervald, Elin; Du, Likun; Visnes, Torkild; Björkman, Andrea; Lindgren, Emma; Wincent, Josephine; Borck, Guntram; Colleaux, Laurence; Cormier-Daire, Valerie; van Gent, Dik C; Pie, Juan; Puisac, Beatriz; de Miranda, Noel Fcc; Kracker, Sven; Hammarström, Lennart; de Villartay, Jean-Pierre; Durandy, Anne; Schoumans, Jacqueline; Ström, Lena; Pan-Hammarström, Qiang

    2013-11-18

    DNA double strand breaks (DSBs) are mainly repaired via homologous recombination (HR) or nonhomologous end joining (NHEJ). These breaks pose severe threats to genome integrity but can also be necessary intermediates of normal cellular processes such as immunoglobulin class switch recombination (CSR). During CSR, DSBs are produced in the G1 phase of the cell cycle and are repaired by the classical NHEJ machinery. By studying B lymphocytes derived from patients with Cornelia de Lange Syndrome, we observed a strong correlation between heterozygous loss-of-function mutations in the gene encoding the cohesin loading protein NIPBL and a shift toward the use of an alternative, microhomology-based end joining during CSR. Furthermore, the early recruitment of 53BP1 to DSBs was reduced in the NIPBL-deficient patient cells. Association of NIPBL deficiency and impaired NHEJ was also observed in a plasmid-based end-joining assay and a yeast model system. Our results suggest that NIPBL plays an important and evolutionarily conserved role in NHEJ, in addition to its canonical function in sister chromatid cohesion and its recently suggested function in HR.

  15. Oncogenic potential of histone-variant H2A.Z.1 and its regulatory role in cell cycle and epithelial-mesenchymal transition in liver cancer

    Science.gov (United States)

    Eun, Jung Woo; Shen, Qingyu; Kim, Hyung Seok; Shin, Woo Chan; Ahn, Young Min; Park, Won Sang; Lee, Jung Young; Nam, Suk Woo

    2016-01-01

    H2A.Z is a highly conserved H2A variant, and two distinct H2A.Z isoforms, H2A.Z.1 and H2A.Z.2, have been identified as products of two non-allelic genes, H2AFZ and H2AFV. H2A.Z has been reported to be overexpressed in breast, prostate and bladder cancers, but most studies did not clearly distinguish between isoforms. One recent study reported a unique role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma. Here we first report that H2A.Z.1 plays a pivotal role in the liver tumorigenesis by selectively regulating key molecules in cell cycle and epithelial-mesenchymal transition (EMT). H2AFZ expression was significantly overexpressed in a large cohort of hepatocellular carcinoma (HCC) patients, and high expression of H2AFZ was significantly associated with their poor prognosis. H2A.Z.1 overexpression was demonstrated in a subset of human HCC and cell lines. H2A.Z.1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins and caused apoptotic cell death of HCC cells. We also observed that H2A.Z.1 knockdown reduced the metastatic potential of HCC cells by selectively modulating epithelial-mesenchymal transition regulatory proteins such as E-cadherin and fibronectin. In addition, H2A.Z.1 knockdown reduced the in vivo tumor growth rate in a mouse xenograft model. In conclusion, our findings suggest the oncogenic potential of H2A.Z.1 in liver tumorigenesis and that it plays established role in accelerating cell cycle transition and EMT during hepatocarcinogenesis. This makes H2A.Z.1 a promising target in liver cancer therapy. PMID:26863632

  16. Oncogenic potential of histone-variant H2A.Z.1 and its regulatory role in cell cycle and epithelial-mesenchymal transition in liver cancer.

    Science.gov (United States)

    Yang, Hee Doo; Kim, Pum-Joon; Eun, Jung Woo; Shen, Qingyu; Kim, Hyung Seok; Shin, Woo Chan; Ahn, Young Min; Park, Won Sang; Lee, Jung Young; Nam, Suk Woo

    2016-03-08

    H2A.Z is a highly conserved H2A variant, and two distinct H2A.Z isoforms, H2A.Z.1 and H2A.Z.2, have been identified as products of two non-allelic genes, H2AFZ and H2AFV. H2A.Z has been reported to be overexpressed in breast, prostate and bladder cancers, but most studies did not clearly distinguish between isoforms. One recent study reported a unique role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma. Here we first report that H2A.Z.1 plays a pivotal role in the liver tumorigenesis by selectively regulating key molecules in cell cycle and epithelial-mesenchymal transition (EMT). H2AFZ expression was significantly overexpressed in a large cohort of hepatocellular carcinoma (HCC) patients, and high expression of H2AFZ was significantly associated with their poor prognosis. H2A.Z.1 overexpression was demonstrated in a subset of human HCC and cell lines. H2A.Z.1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins and caused apoptotic cell death of HCC cells. We also observed that H2A.Z.1 knockdown reduced the metastatic potential of HCC cells by selectively modulating epithelial-mesenchymal transition regulatory proteins such as E-cadherin and fibronectin. In addition, H2A.Z.1 knockdown reduced the in vivo tumor growth rate in a mouse xenograft model. In conclusion, our findings suggest the oncogenic potential of H2A.Z.1 in liver tumorigenesis and that it plays established role in accelerating cell cycle transition and EMT during hepatocarcinogenesis. This makes H2A.Z.1 a promising target in liver cancer therapy.

  17. Papel das células T reguladoras no desenvolvimento de dermatoses Role of regulatory T cells in the development of skin diseases

    Directory of Open Access Journals (Sweden)

    Hermênio Cavalcante Lima

    2006-06-01

    Full Text Available Células T, em particular as células T CD4+, têm sido associadas a muitos aspectos das doenças de pele. A evidência atual sugere, porém, que o papel dos linfócitos T CD4+ no desenvolvimento de inflamação cutânea excede o de ativador pró-inflamatório das células T de ação que dirigem a resposta imune. Subtipos de células T com capacidade reguladora, tais como Tregs CD4+CD25+high, têm sido identificadas. Observações recentes sugerem que em algumas doenças da pele a função dessas células está modificada. Portanto, o desenvolvimento e a função de Tregs na dermatologia são atualmente um tópico atraente devido a sua importância no controle da resposta do sistema imune contra tumores e doenças infecciosas, bem como inibindo o desenvolvimento de auto-imunidade e alergia. Assim, mecanismos reguladores defeituosos podem permitir a quebra da tolerância imune periférica seguida por inflamação crônica e doença. Detalham-se as anormalidades funcionais e a contribuição de diferentes subtipos de células T reguladoras no desenvolvimento de doenças dermatológicas nesta revisão. Acentuam-se os possíveis alvos terapêuticos e as modificações dos T reguladores causados por imunomoduladores usados no campo da dermatologia.T cells, particularly CD4+ T cells, have been associated with many aspects of skin disease. Current evidence suggests, however, that the role of CD4+ T lymphocytes in the development of cutaneous inflammation surpasses that of pro-inflammatory activation of effector T cells that direct the immune response. T cell subtypes with regulatory capacity, such as CD4+CD25+high Tregs, have been identified. Recent observations suggest that in some skin diseases the function of these cells is modified. Therefore, the development and function of Treg cells in Dermatology are currently attractive topics because of their importance in controlling the immune system response against tumors and infectious diseases, as well

  18. Expression Pattern and Regulatory Role of microRNA-23a in Conjugated Linoleic Acids-Induced Apoptosis of Adipocytes

    Directory of Open Access Journals (Sweden)

    Renli Qi

    2016-11-01

    Full Text Available Background/Aims: Conjugated linoleic acids (CLAs are known to induce apoptosis in adipocytes; however, the cellular mechanisms involved remained illdefined. We explored the different apoptotic induction effects of two CLA isomers on adipocytes and then investigated the expression and function of microRNAs (miRNAs related to the apoptosis. Methods: TUNEL and FCM assays were used to detect CLAs-induced adipocyte apoptosis. Microarrays were used to compare the differential expression of miRNAs. MiR-23a, a miRNA that showed significant changes in expression in the CLA-treated cells, was selected for the subsequent functional studies via over-expression and knock down in in vivo and in vitro experiments. Results: C9, t11-CLA exhibited a stronger induction of apoptosis in the differentiated 3T3-L1 adipocytes than t10, c12-CLA. However, t10, c12-CLA could rapidly activate NF-κB, which may have caused their different apoptotic effects. MiR-23a was markedly down-regulated by the CLAs treatment and miR-23a over-expression attenuated CLA-induced apoptosis. Apoptosis protease-activating factor 1 (APAF1 was identified as a target gene of miR-23a. In an in vivo experiment endogenous miR-23a was down-regulated in mice fed with a mixture of both CLAs. The mice also exhibited less fat deposition and more apoptotic fat cells in adipose tissue. Moreover, endogenous miR-23a was suppressed in mice via intravenous injection with an antagomir which resulted in decreased body weight, increased number of apoptotic fat cells and increased APAF1 expression in adipose tissue. Conclusion: Taken together, our results suggest that miR-23a plays a critical role in CLA-induced apoptosis in adipocytes via controlling APAF1 expression.

  19. The regulatory mechanism of Hsp90{alpha} secretion from endothelial cells and its role in angiogenesis during wound healing

    Energy Technology Data Exchange (ETDEWEB)

    Song, Xiaomin [National Engineering Laboratory for Anti-tumor Protein Therapeutics, Tsinghua University, Beijing 100084 (China); Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084 (China); Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084 (China); Luo, Yongzhang, E-mail: yluo@tsinghua.edu.cn [National Engineering Laboratory for Anti-tumor Protein Therapeutics, Tsinghua University, Beijing 100084 (China); Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084 (China); Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084 (China)

    2010-07-16

    Research highlights: {yields} Growth factors such as bFGF, VEGF, PDGF and SDF-1 stimulate Hsp90{alpha} secretion from endothelial cells. {yields} Secreted Hsp90{alpha} localizes on the leading edge of activated endothelial cells. {yields} Secreted Hsp90{alpha} promotes angiogenesis in wound healing. -- Abstract: Heat shock protein 90{alpha} (Hsp90{alpha}) is a ubiquitously expressed molecular chaperone, which is essential for the maintenance of eukaryote homeostasis. Hsp90{alpha} can also be secreted extracellularly and is associated with several physiological and pathological processes including wound healing, cancer, infectious diseases and diabetes. Angiogenesis, defined as the sprouting of new blood vessels from pre-existing capillaries via endothelial cell proliferation and migration, commonly occurs in and contributes to the above mentioned processes. However, the secretion of Hsp90{alpha} from endothelial cells and also its function in angiogenesis are still unclear. Here we investigated the role of extracellular Hsp90{alpha} in angiogenesis using dermal endothelial cells in vitro and a wound healing model in vivo. We find that the secretion of Hsp90{alpha} but not Hsp90{beta} is increased in activated endothelial cells with the induction of angiogenic factors and matrix proteins. Secreted Hsp90{alpha} localizes on the leading edge of endothelial cells and promotes their angiogenic activities, whereas Hsp90{alpha} neutralizing antibodies reverse the effect. Furthermore, using a mouse skin wound healing model in vivo, we demonstrate that extracellular Hsp90{alpha} localizes on blood vessels in granulation tissues of wounded skin and promotes angiogenesis during wound healing. Taken together, our study reveals that Hsp90{alpha} can be secreted by activated endothelial cells and is a positive regulator of angiogenesis, suggesting the potential application of Hsp90{alpha} as a stimulator for wound repair.

  20. Opposed-phase MR imaging of lipid storage myopathy in a case of Chanarin-Dorfman disease

    Energy Technology Data Exchange (ETDEWEB)

    Gaeta, Michele; Celona, Antonio; Racchiusa, Sergio; Mazziotti, Silvio [University of Messina, Department of Radiological Sciences, Messina (Italy); Minutoli, Fabio [University of Messina, Department of Radiological Sciences, Messina (Italy); A.O.U. ' ' Policlinico G. Martino' ' , Dipartimento di Scienze Radiologiche, Messina (Italy); Toscano, Antonio; Musumeci, Olimpia [University of Messina, Department of Neurosciences, Psychiatry and Anaesthesiology, Messina (Italy)

    2008-11-15

    Chanarin-Dorfman disease (CDD) is a rare genetic disorder characterized by ichthyosis, myopathy, central nervous system disturbances, and intracellular lipid storage in muscle fibers, hepatocytes, and granulocytes. We describe skeletal muscle magnetic resonance imaging findings in a case of CDD, outlining the potential role of GE T1-weighted opposed-phase sequence (chemical shift imaging) in the evaluation of lipid storage myopathies. (orig.)

  1. Cytosolic purine 5'-nucleotidases of rat liver and human red blood cells: regulatory properties and role in AMP dephosphorylation.

    Science.gov (United States)

    Van den Berghe, G; Bontemps, F; Vincent, M F

    1988-01-01

    Of the various species of cellular 5'-nucleotidases, membranous, lysosomal and cytosolic, only the latter are likely to play a role in the physiologic dephosphorylation of the 5'-nucleoside monophosphates present in the cytoplasm. The necessity to preserve cellular ATP renders a strict control of the dephosphorylation as well as of the deamination of AMP mandatory, because both nucleotides are maintained in equilibrium by adenylate kinase. Our studies of cytosolic purine 5'-nucleotidases purified from rat liver and from human erythrocytes, reviewed in this presentation, have shown that both display complex kinetic properties. Both enzymes have markedly higher affinities for IMP and for GMP than for AMP. In addition, they are stimulated by nucleoside triphosphates, among them ATP and GTP, and inhibited by Pi. The erythrocytic purine 5'-nucleotidase is also stimulated by glycerate 2,3-bisphosphate. It could thus be expected that under conditions of ATP and GTP breakdown, particularly when accompanied by an increase in Pi, the dephosphorylation of AMP would be curtailed. To verify this hypothesis, experiments were performed with isolated rat hepatocytes and with human red blood cells. The rate of dephosphorylation of AMP was measured by following time-wise the production of adenosine in the presence of coformycin (or deoxycoformycin) and 5-iodotubercidin. The coformycins inhibit the deamination of adenosine into inosine by adenosine deaminase, and 5-iodotubercidin inhibits the recycling of adenosine into AMP by adenosine kinase. Upon induction of ATP catabolism by the addition of fructose to isolated rat hepatocytes, the dephosphorylation of AMP was nearly completely suppressed. In accordance with these results, the activity of the rat liver cytosolic 5'-nucleotidase, assayed in the presence of concentrations of substrate and effectors mimicking those measured in intact cells following the addition of fructose, was decreased as compared to control conditions. In

  2. Critical role of intestinal interleukin-4 modulating regulatory T cells for desensitization, tolerance, and inflammation of food allergy

    Science.gov (United States)

    Fujimura, Yoko; Takeyama, Jun; Hiraide, Erika; Kikuchi, Akira; Murakami, Hitoshi; Hosono, Akira; Nochi, Tomonori; Wakatsuki, Yoshio; Shimojo, Naoki; Kaminogawa, Shuichi; Sato, Ryuichiro; Kiyono, Hiroshi; Hachimura, Satoshi

    2017-01-01

    Background and objective The mechanism inducing either inflammation or tolerance to orally administered food allergens remains unclear. To investigate this we analyzed mouse models of food allergy (OVA23-3) and tolerance (DO11.10 [D10]), both of which express ovalbumin (OVA)-specific T-cell receptors. Methods OVA23-3, recombination activating gene (RAG)-2-deficient OVA23-3 (R23-3), D10, and RAG-2-deficient D10 (RD10) mice consumed a diet containing egg white (EW diet) for 2–28 days. Interleukin (IL)-4 production by CD4+ T cells was measured as a causative factor of enteropathy, and anti-IL-4 antibody was used to reveal the role of Foxp3+ OVA-specific Tregs (aiTreg) in this process. Results Unlike OVA23-3 and R23-3 mice, D10 and RD10 mice did not develop enteropathy and weight loss on the EW diet. On days 7–10, in EW-fed D10 and RD10 mice, splenic CD4+ T cells produced significantly more IL-4 than did those in the mesenteric lymph nodes (MLNs); this is in contrast to the excessive IL-4 response in the MLNs of EW-fed OVA23-3 and R23-3 mice. EW-fed R23-3 mice had few aiTregs, whereas EW-fed RD10 mice had them in both tissues. Intravenous injections of anti-IL-4 antibody recovered the percentage of aiTregs in the MLNs of R23-3 mice. On day 28, in EW-fed OVA23-3 and R23-3 mice, expression of Foxp3 on CD4+ T cells corresponded with recovery from inflammation, but recurrence of weight loss was observed on restarting the EW diet after receiving the control-diet for 1 month. No recurrence developed in D10 mice. Conclusions Excessive IL-4 levels in the MLNs directly inhibited the induction of aiTregs and caused enteropathy. The aiTregs generated in the attenuation of T cell-dependent food allergic enteropathy may function differently than aiTregs induced in a tolerance model. Comparing the two models enables to investigate their aiTreg functions and to clarify differences between inflammation with subsequent desensitization versus tolerance. PMID:28234975

  3. Cell-autonomous role of TGFβ and IL-2 receptors in CD4+ and CD8+ inducible regulatory T-cell generation during GVHD.

    Science.gov (United States)

    Sawamukai, Norifumi; Satake, Atsushi; Schmidt, Amanda M; Lamborn, Ian T; Ojha, Priti; Tanaka, Yoshiya; Kambayashi, Taku

    2012-06-01

    FoxP3(+) regulatory T cells (Tregs) suppress GVHD while preserving graft-versus-tumor effects, making them an attractive target for GVHD therapy. The donor-derived Treg pool can potentially be derived from the expansion of preexisting natural Tregs (nTregs) or from de novo generation of inducible Tregs (iTregs) from donor Tconvs in the transplantation recipient. Using an MHC-mismatched model of acute GVHD, in the present study we found that the Treg pool was comprised equally of donor-derived nTregs and iTregs. Experiments using various combinations of T cells from wild-type and FoxP3-deficient mice suggested that both preexisting donor nTregs and the generation of iTregs in the recipient mice contribute to protection against GVHD. Surprisingly, CD8(+)FoxP3(+) T cells represented approximately 70% of the iTreg pool. These CD8(+)FoxP3(+) T cells shared phenotypic markers with their CD4(+) counterparts and displayed suppressive activity, suggesting that they were bona fide iTregs. Both CD4(+) and CD8(+) Tregs appeared to be protective against GVHD-induced lethality and required IL-2 and TGFβ receptor expression for their generation. These data illustrate the complex makeup of the donor-derived FoxP3(+) Treg pool in allogeneic recipients and their potential role in protection against GVHD.

  4. Molecular simulations illuminate the role of regulatory components of the RNA polymerase from the hepatitis C virus in influencing protein structure and dynamics.

    Science.gov (United States)

    Davis, Brittny C; Thorpe, Ian F

    2013-07-02

    The RNA polymerase (gene product NS5B) from the hepatitis C virus is responsible for replication of the viral genome and is a validated drug target for new therapeutic agents. NS5B has a structure resembling an open right hand (containing the fingers, palm, and thumb subdomains), a hydrophobic C-terminal region, and two magnesium ions coordinated in the palm domain. Biochemical data suggest that the magnesium ions provide structural stability and are directly involved in catalysis, while the C-terminus plays a regulatory role in NS5B function. Nevertheless, the molecular mechanisms by which these two features regulate polymerase activity remain unclear. To answer this question, we performed molecular dynamics simulations of NS5B variants with different C-terminal lengths in the presence or absence of magnesium ions to determine the impact on enzyme properties. We observed that metal binding increases both the magnitude and the degree of correlated enzyme motions. In contrast, we observed that the C-terminus restricts enzyme dynamics. Under certain conditions, our simulations revealed a fully closed conformation of NS5B that may facilitate de novo initiation of RNA replication. This knowledge is important because it fosters the development of a comprehensive description of RNA replication by NS5B and is relevant to understanding the functional properties of a broad class of related RNA polymerases such as 3D-pol from poliovirus. Ultimately, this information may also be pertinent to designing novel NS5B therapeutics.

  5. Single-cell analyses of regulatory network perturbations using enhancer-targeting TALEs suggest novel roles for PU.1 during haematopoietic specification.

    Science.gov (United States)

    Wilkinson, Adam C; Kawata, Viviane K S; Schütte, Judith; Gao, Xuefei; Antoniou, Stella; Baumann, Claudia; Woodhouse, Steven; Hannah, Rebecca; Tanaka, Yosuke; Swiers, Gemma; Moignard, Victoria; Fisher, Jasmin; Hidetoshi, Shimauchi; Tijssen, Marloes R; de Bruijn, Marella F T R; Liu, Pentao; Göttgens, Berthold

    2014-10-01

    Transcription factors (TFs) act within wider regulatory networks to control cell identity and fate. Numerous TFs, including Scl (Tal1) and PU.1 (Spi1), are known regulators of developmental and adult haematopoiesis, but how they act within wider TF networks is still poorly understood. Transcription activator-like effectors (TALEs) are a novel class of genetic tool based on the modular DNA-binding domains of Xanthomonas TAL proteins, which enable DNA sequence-specific targeting and the manipulation of endogenous gene expression. Here, we report TALEs engineered to target the PU.1-14kb and Scl+40kb transcriptional enhancers as efficient new tools to perturb the expression of these key haematopoietic TFs. We confirmed the efficiency of these TALEs at the single-cell level using high-throughput RT-qPCR, which also allowed us to assess the consequences of both PU.1 activation and repression on wider TF networks during developmental haematopoiesis. Combined with comprehensive cellular assays, these experiments uncovered novel roles for PU.1 during early haematopoietic specification. Finally, transgenic mouse studies confirmed that the PU.1-14kb element is active at sites of definitive haematopoiesis in vivo and PU.1 is detectable in haemogenic endothelium and early committing blood cells. We therefore establish TALEs as powerful new tools to study the functionality of transcriptional networks that control developmental processes such as early haematopoiesis.

  6. Messenger RNA fluctuations and regulatory RNAs shape the dynamics of a negative feedback loop

    Science.gov (United States)

    Rodríguez Martínez, María; Soriano, Jordi; Tlusty, Tsvi; Pilpel, Yitzhak; Furman, Itay

    2010-03-01

    Single-cell experiments of simple regulatory networks can markedly differ from cell population experiments. Such differences arise from stochastic events in individual cells that are averaged out in cell populations. For instance, while individual cells may show sustained oscillations in the concentrations of some proteins, such oscillations may appear damped in the population average. In this paper we investigate the role of RNA stochastic fluctuations as a leading force to produce a sustained excitatory behavior at the single-cell level. As opposed to some previous models, we build a fully stochastic model of a negative feedback loop that explicitly takes into account the RNA stochastic dynamics. We find that messenger RNA random fluctuations can be amplified during translation and produce sustained pulses of protein expression. Motivated by the recent appreciation of the importance of noncoding regulatory RNAs in post-transcription regulation, we also consider the possibility that a regulatory RNA transcript could bind to the messenger RNA and repress translation. Our findings show that the regulatory transcript helps reducing gene expression variability both at the single-cell level and at the cell population level.

  7. 精子发生过程中调控性非编码RNAs的功能%The role of regulatory non-coding RNAs during spermatogenesis

    Institute of Scientific and Technical Information of China (English)

    王燕; 郭文龙; 耿德海; 王波; 张建立; 张艳敏; 刘淑卓

    2014-01-01

    Global rise in male infertility as a result of falling sperm count and quality has been pointed out by many investigations. Therefore, it is essential to understand the molecular mechanism of spermatogenesis and its regulation. Spermatogenesis is characterized by three phases: mitosis, meiosis and spermiogenesiss, which are strictly regulated by phase-speciifc gene expression that is controlled by myriads of regulatory non-coding RNAs. Rapid advancement in genome mining technologies has identiifed role of regulatory non-coding RNAs including microRNA(miRNA), small-interfering RNA(siRNA), PIWI-interacting RNA(piRNA) and long non-coding RNA(lncRNA) as controllers of gene expression at transcriptional as well as post-transcriptional level in different biological context and disease processes. Here, we discuss the recent advances in our understanding about the involvement of these transcripts in spermatogenesis. In addition, we review here the relationship between their abnormal experssion and associated diseases.%精子数量下降和质量减低是全球范围内男性不育疾病增加的主要原因。因此理解精子发生及其调控的分子机制是非常必要的。精子发生主要分为有丝分裂、减数分裂和精子形成三个阶段,这些过程被阶段特异性的基因表达严格调控,而众多的调控性非编码RNAs则是基因表达的重要调控因子。飞速发展的基因组检测技术已经证实,调控性非编码RNAs在不同生物演化和疾病进程中基因表达的转录和转录后水平上发挥重要的调控作用,其包括微小RNA(miRNA)、小干扰RNA(siRNA)、与PIWI蛋白相互作用的RNAs(piRNA)和长链非编码RNA(lncRNA)。讨论这些转录本在精子发生中的功能作用,并综述其异常表达与相关疾病的关系。

  8. The role of the Staphylococcal VraTSR regulatory system on vancomycin resistance and vanA operon expression in vancomycin-resistant Staphylococcus aureus.

    Science.gov (United States)

    Qureshi, Nadia K; Yin, Shaohui; Boyle-Vavra, Susan

    2014-01-01

    Vancomycin is often the preferred treatment for invasive methicillin-resistant Staphylococcus aureus (MRSA) infection. With the increase in incidence of MRSA infections, the use of vancomycin has increased and, as feared, isolates of vancomycin-resistant Staphylococcus aureus (VRSA) have emerged. VRSA isolates have acquired the entercoccal vanA operon contained on transposon (Tn) 1546 residing on a conjugal plasmid. VraTSR is a vancomycin and β-lactam-inducible three-component regulatory system encoded on the S. aureus chromosome that modulates the cell-wall stress response to cell-wall acting antibiotics. Mutation in vraTSR has shown to increase susceptibility to β-lactams and vancomycin in clinical VISA strains and in recombinant strain COLVA-200 which expresses a plasmid borne vanA operon. To date, the role of VraTSR in vanA operon expression in VRSA has not been demonstrated. In this study, the vraTSR operon was deleted from the first clinical VRSA strain (VRS1) by transduction with phage harvested from a USA300 vraTSR operon deletion strain. The absence of the vraTSR operon and presence of the vanA operon were confirmed in the transductant (VRS1Δvra) by PCR. Broth MIC determinations, demonstrated that the vancomycin MIC of VRS1Δvra (64 µg/ml) decreased by 16-fold compared with VRS1 (1024 µg/ml). The effect of the vraTSR operon deletion on expression of the van gene cluster (vanA, vanX and vanR) was examined by quantitative RT-PCR using relative quantification. A 2-5-fold decreased expression of the vanA operon genes occured in strain VRS1Δvra at stationary growth phase compared with the parent strain, VRS1. Both vancomycin resistance and vancomycin-induced expression of vanA and vanR were restored by complementation with a plasmid harboring the vraTSR operon. These findings demonstrate that expression in S. aureus of the horizontally acquired enterococcal vanA gene cluster is enhanced by the staphylococcal three-component cell wall stress regulatory

  9. Storm track processes and the opposing influences of climate change

    Science.gov (United States)

    Shaw, T. A.; Baldwin, M.; Barnes, E. A.; Caballero, R.; Garfinkel, C. I.; Hwang, Y.-T.; Li, C.; O'Gorman, P. A.; Rivière, G.; Simpson, I. R.; Voigt, A.

    2016-09-01

    Extratropical cyclones are storm systems that are observed to travel preferentially within confined regions known as storm tracks. They contribute to precipitation, wind and temperature extremes in mid-latitudes. Cyclones tend to form where surface temperature gradients are large, and the jet stream influences their speed and direction of travel. Storm tracks shape the global climate through transport of energy and momentum. The intensity and location of storm tracks varies seasonally, and in response to other natural variations, such as changes in tropical sea surface temperature. A hierarchy of numerical models of the atmosphere-ocean system -- from highly idealized to comprehensive -- has been used to study and predict responses of storm tracks to anthropogenic climate change. The future position and intensity of storm tracks depend on processes that alter temperature gradients. However, different processes can have opposing influences on temperature gradients, which leads to a tug of war on storm track responses and makes future projections more difficult. For example, as climate warms, surface shortwave cloud radiative changes increase the Equator-to-pole temperature gradient, but at the same time, longwave cloud radiative changes reduce this gradient. Future progress depends on understanding and accurately quantifying the relative influence of such processes on the storm tracks.

  10. Regulatory role of acupuncture and moxibustion in immunosenescence and epigenetic mechanisms%针灸调节免疫衰老及其表观遗传机制

    Institute of Scientific and Technical Information of China (English)

    沈文宾; 周次利; 吴焕淦; 黄艳; 赵琛; 崔云华

    2015-01-01

    BACKGROUND:The acupuncture and moxibustion is an effective method to regulate the immunosenescence. The epigenetic modification has become a focus in the research of immunosenescence regulation. OBJECTIVE: To summarize the relationship between epigenetic regulation and the regulatory role of acupuncture and moxibustion on immunosenescence, and to explore the relevant mechanisms. METHODS: We searched CNKI, VIP, WANFANG DATA, SinoMed, Ebsco Medline, Springer, ScienceDirect and Embase by computer for relevant articles published from January 1999 to August 2014. The keywords were “acupuncture”, “moxibustion”, “aging”, “immunosenescence” and “epigenetic” in Chinese and English. Al databases were cross-searched to minimize missing data. We excluded documents based on inclusion and exclusion criteria thereby checking the title and abstract. RESULTS AND CONCLUSION:Finaly 64 articles were included, including 8 Chinese publications and 56 English publications. The innate immune system and the adaptive immune system can vary with aging, which is the most obvious feature in immunosenescence. The acupuncture and moxibustion can improve immunosenescence overal. The epigenetic modification plays an important role in immunosenescence. The acupuncture and moxibustion can affect the epigenetic modification directly. However, the epigenetic mechanism underlying the regulatory role of acupuncture and moxibustion in immunosenescence needs further studies.%背景:针灸可有效调节免疫衰老,运用表观遗传修饰手段研究免疫衰老成为了近年来国内外研究的热点之一。目的:归纳总结针灸对免疫衰老的调节作用及与表观遗传调控的关系,探讨其作用机制。方法:通过计算机检索中国知网(CNKI)、维普期刊资源整合服务平台(VIP)、万方数据知识服务平台(WANFANG DATA)、中国生物医学文献服务系统(SinoMed)、PubMed、Ebsco Medline、Springer、ScienceDirect和Embase,所有

  11. Annexin 2-mediated enhancement of cytomegalovirus infection opposes inhibition by annexin 1 or annexin 5.

    Science.gov (United States)

    Derry, Mélanie C; Sutherland, Michael R; Restall, Christina M; Waisman, David M; Pryzdial, Edward L G

    2007-01-01

    Biochemical studies have suggested that annexin 2 (A2) may participate in cytomegalovirus (CMV) infection. In the current work, effects of A2 monomer (p36) and heterotetramer (A2t; p36(2)p11(2)) were investigated. Demonstrating a role for endogenous A2, the four stages of infection that were followed were each inhibited by anti-p36 or anti-p11 at 37 degrees C. Immuno-inhibition was attenuated when the virus and cells were pre-incubated at 4 degrees C to coordinate virus entry initiated afterwards at 37 degrees C, reconciling controversy in the literature. As an explanation, CMV-induced phosphorylation of p36 was prevented by the 4 degrees C treatment. Supporting these immuno-inhibition data, purified A2t or p11 increased CMV infectious-progeny generation and CMV gene expression. A specific role for A2t was indicated by purified p36 having no effect. Unlike other steps, primary plaque formation was not enhanced by purified A2t or p11, possibly because of undetectable phosphorylation. As annexins 1 (A1) and 5 (A5) interact with A2, their effect on CMV was also tested. Both purified proteins inhibited CMV infection. In each experiment, the concentration of A1 required for half-maximal inhibition was five- to 10-fold lower than that of A5. Addition of A2 opposed A1- or A5-mediated inhibition of CMV, as did certain A2-specific antibodies that had no effect in the absence of added A1 or A5. Transfection of the p36-deficient cell line HepG2 increased CMV infection and was required for inhibition by the other annexins. These data suggest that CMV exploits A2t at physiological temperature to oppose the protection of cells conferred by A1 or A5.

  12. Immune regulatory effects of simvastatin on regulatory T cell-mediated tumour immune tolerance.

    Science.gov (United States)

    Lee, K J; Moon, J Y; Choi, H K; Kim, H O; Hur, G Y; Jung, K H; Lee, S Y; Kim, J H; Shin, C; Shim, J J; In, K H; Yoo, S H; Kang, K H; Lee, S Y

    2010-08-01

    Statins are potent inhibitors of hydroxyl-3-methylglutaryl co-enzyme A (HMG-CoA) reductase, and have emerged as potential anti-cancer agents based on preclinical evidence. In particular, compelling evidence suggests that statins have a wide range of immunomodulatory properties. However, little is known about the role of statins in tumour immune tolerance. Tumour immune tolerance involves the production of immunosuppressive molecules, such as interleukin (IL)-10, transforming growth factor (TGF)-beta and indoleamine-2,3-dioxygenase (IDO) by tumours, which induce a regulatory T cell (T(reg)) response. In this study, we investigated the effect of simvastatin on the production of IL-10, TGF-beta and IDO production and the proliferation of T(regs) using several cancer cell lines, and Lewis lung cancer (3LL) cells-inoculated mouse tumour model. Simvastatin treatment resulted in a decrease in the number of cancer cells (3LL, A549 and NCI-H292). The production of the immune regulatory markers IL-10, TGF-beta in 3LL and NCI-H292 cells increased after treatment with simvastatin. The expression of IDO and forkhead box P3 (FoxP3) transcription factor was also increased in the presence of simvastatin. In a murine 3LL model, there were no significant differences in tumour growth rate between untreated and simvastatin-treated mice groups. Therefore, while simvastatin had an anti-proliferative effect, it also exhibited immune tolerance-promoting properties during tumour development. Thus, due to these opposing actions, simvastatin had no net effect on tumour growth.

  13. Healthcare regulatory concepts in Brazil.

    Science.gov (United States)

    Oliveira, Robson Rocha de; Elias, Paulo Eduardo Mangeon

    2012-06-01

    The healthcare regulatory concepts used in Brazilian scientific publications on healthcare management were reviewed. A typo-logical classification for regulatory concepts was developed from the most current ideas in five disciplines: life sciences, law, economics, sociology and political science. Four ideas stood out: control, balance, adaptation and direction, with greatest emphasis on the technical nature of regulation. The political nature of regulation was secondary. It was considered that dis-cussion of healthcare regulatory concepts was connected with comprehension of the role that the state plays in this sector. De-finition of the forms of state intervention is the key convergence point between the different ways of conceptualizing healthcare regulation.

  14. Opposing environmental gradients govern vegetation zonation in an intermountain playa

    Science.gov (United States)

    Sanderson, J.S.; Kotliar, N.B.; Steingraeber, D.A.

    2008-01-01

    Vegetation zonation was investigated at an intermountain playa wetland (Mishak Lakes) in the San Luis Valley (SLV) of southern Colorado. Plant composition and abiotic conditions were quantified in six vegetation zones. Reciprocal transplants were performed to test the importance of abiotic factors in governing zonation. Abiotic conditions differed among several vegetation zones. Prolonged inundation led to anaerobic soils in the Eleocharis palustris and the submerged aquatics zones, on the low end of the site's 1.25 m elevation gradient. On the high end of the gradient, soil salinity and sodicity (a measure of exchangeable sodium) were high in the Distichlis spicata zone (electrical conductivity, EC = 5.3 dS/m, sodium absorption ratio, SAR = 44.0) and extreme in the Sarcobatus vermiculatus zone (EC = 21 dS/m, SAR = 274). Transplanted species produced maximum biomass in the zone where they originated, not in any other higher or lower vegetation zone. The greatest overall transplant effect occurred for E. palustris, which experienced a ??? 77% decline in productivity when transplanted to other zones. This study provides evidence that physical factors are a major determinant of vegetation zone composition and distribution across the entire elevation gradient at Mishak Lakes. Patterns at Mishak Lakes arise from counter-directional stress gradients: a gradient from anaerobic to well-oxygenated from basin bottom to upland and a gradient from extremely high salinity to low salinity in the opposing direction. Because abiotic conditions dominate vegetation zonation, restoration of the altered hydrologic regime of this wetland to a natural hydrologic regime may be sufficient to re-establish many of the natural biodiversity functions provided by these wetlands. ?? 2008 The Society of Wetland Scientists.

  15. Subcomponents of psychopathy have opposing correlations with punishment judgments.

    Science.gov (United States)

    Schaich Borg, Jana; Kahn, Rachel E; Sinnott-Armstrong, Walter; Kurzban, Robert; Robinson, Paul H; Kiehl, Kent A

    2013-10-01

    Psychopathy research is plagued by an enigma: Psychopaths reliably act immorally, but they also accurately report whether an action is morally wrong. The current study revealed that cooperative suppressor effects and conflicting subsets of personality traits within the construct of psychopathy might help explain this conundrum. Among a sample of adult male offenders (N = 100) who ranked deserved punishment of crimes, Psychopathy Checklist-Revised (PCL-R) total scores were not linearly correlated with deserved punishment task performance. However, these null results masked significant opposing associations between task performance and factors of psychopathy: the PCL-R Interpersonal/Affective (i.e., manipulative and callous) factor was positively associated with task performance, while the PCL-R Social Deviance (i.e., impulsive and antisocial) factor was simultaneously negatively associated with task performance. These relationships were qualified by a significant interaction where the Interpersonal/Affective traits were positively associated with task performance when Social Deviance traits were high, but Social Deviance traits were negatively associated with task performance when Interpersonal/Affective traits were low. This interaction helped reveal a significant nonlinear relationship between PCL-R total scores and task performance such that individuals with very low or very high PCL-R total scores performed better than those with middle-range PCL-R total scores. These results may explain the enigma of why individuals with very high psychopathic traits, but not other groups of antisocial individuals, usually have normal moral judgment in laboratory settings, but still behave immorally, especially in contexts where social deviance traits have strong influence.

  16. Oncogenic potential of CK2α and its regulatory role in EGF-induced HDAC2 expression in human liver cancer.

    Science.gov (United States)

    Kim, Hyung S; Chang, Young G; Bae, Hyun J; Eun, Jung W; Shen, Qingyu; Park, Se J; Shin, Woo C; Lee, Eun K; Park, Soha; Ahn, Young M; Park, Won S; Lee, Jung Y; Nam, Suk W

    2014-02-01

    Histone deacetylase 2 (HDAC2) is aberrantly regulated and plays a pivotal role in the development of hepatocellular carcinoma (HCC) through regulation of cell-cycle components at the transcriptional level, but the underlying mechanism leading to oncogenic HDAC2 remains unknown. In this study, we show that expression of CK2α (casein kinase II α subunit) was up-regulated in a large cohort of human HCC patients, and that high expression of CK2α was significantly associated with poor prognosis of HCC patients in terms of five-year overall survival. It was also found that CK2α over-expression positively correlated with HDAC2 over-expression in a subset of HCCs. We observed that treatment with epidermal growth factor (EGF) elicited an increase in CK2α expression and Akt phosphorylation, causing induction of HDAC2 expression in liver cancer cells. It was also observed that ectopic expression of dominant-negative CK2α blocked EGF-induced HDAC2 expression, and that ectopic CK2α expression attenuated the suppressive effect of Akt knockdown on HDAC2 expression in liver cancer cells. Targeted disruption of CK2α influenced the cell cycle, causing a significant increase in the number of liver cancer cells remaining in G₂/M phase, and suppressed growth via repression of Cdc25c and cyclin B in liver cancer cells. Taken together, our findings suggest the oncogenic potential of CK2α in liver tumorigenesis. Furthermore, a regulatory mechanism for HDAC2 expression is proposed whereby EGF induces transcriptional activation of HDAC2 by CK2α/Akt activation in liver cancer cells. Therefore, this makes CK2α a promising target in cancer therapy.

  17. Genetic evidence of the regulatory role of parathyroid hormone-related protein in articular chondrocyte maintenance in an experimental mouse model.

    Science.gov (United States)

    Macica, Carolyn; Liang, Guoying; Nasiri, Ali; Broadus, Arthur E

    2011-11-01

    Parathyroid hormone-related protein (PTHrP) regulates the rate of differentiation of growth chondrocytes and is also expressed in articular chondrocytes. This study tested the hypothesis that PTHrP might have a regulatory role in articular chondrocyte maintenance. Control sequences of growth differentiation factor 5 were used to delete PTHrP from articular chondrocytes in the mid-region of mouse articular cartilage. Mice with conditional deletion of PTHrP (knockout [KO]) and littermate control mice were evaluated for degenerative changes using both a time-course design and destabilization of the medial meniscus (DMM) technique. A total histologic score of degenerative changes was determined for the femoral and tibial articular surfaces (total maximum score of 60). The time-course study revealed degenerative changes in only a minority of the KO mice. In the DMM model, male KO mice were highly susceptible to DMM-induced degenerative changes (mean ± SEM total histologic score 45 ± 2.7 in KO mice versus 23 ± 1.4 in controls; P PTHrP normally functions in a feedback loop with Indian hedgehog (IHH), in which a reduction in one signaling partner induces a compensatory increase in the other. A number of phenotypic and functional markers were documented in KO mice to suggest that the IHH-PTHrP axis is capable of compensating in response to a partial Cre-driven PTHrP deletion, a finding that underscores the need to subject the mouse articular cartilage to a destabilizing challenge in order to elicit frankly degenerative findings. PTHrP may regulate articular chondrocyte maintenance in mice. Copyright © 2011 by the American College of Rheumatology.

  18. Important role of interferon regulatory factor (IRF)-3 in the interferon response of mouse macrophages upon infection by Newcastle disease virus.

    Science.gov (United States)

    Wilden, Holger; Schirrmacher, Volker; Fournier, Philippe

    2011-08-01

    Newcastle disease virus (NDV) is an interesting agent for activating innate immune activity in macrophages including secretion of TNF-α and IFN-α, upregulation of TRAIL and activation of NF-κB and iNOS. However, the molecular mechanism of such cellular activities remains largely unknown. Tumor selectivity of replication of NDV has been described to be linked to deviations in tumor cells of the type I interferon response. We therefore focused on the interferon response to NDV of macrophages as part of innate anti-viral and anti-tumor activity. In particular, we investigated the functional significance of the interferon regulatory factor genes (IRF)-3 and IRF-7. Deletion of the IRF-3 or IRF-7 gene was found to increase susceptibility of mouse macrophages to virus infection. Surprisingly, NDV replicated better in IRF-3 KO than in IRF-7 KO macrophages. Further analysis showed that IRF-3 KO macrophages have a lower basal and NDV-induced RIG-I expression in comparison to IRF-7 KO macrophages. This might explain why, in IRF-3 KO macrophages, the secretion of type I interferons after NDV infection is delayed, when compared to IRF-7 KO and wild-type macrophages. In addition, IRF-3 KO cells showed reduced NDV-induced levels of IRF-7. This effect could be prevented by priming the cells first by interferon-α. Further results indicated that an early production of type I interferon rather than high maximal levels at later time points are important for resistance to infection by NDV. In conclusion, these results demonstrate an important role of IRF-3 for the innate anti-viral response to NDV of mouse macrophages.

  19. The Transcription Factor Interferon Regulatory Factor-1 (IRF1) Plays a Key Role in the Terminal Effector Pathways of Human Preterm Labor.

    Science.gov (United States)

    Lim, Ratana; Tran, Ha Thi; Liong, Stella; Barker, Gillian; Lappas, Martha

    2016-02-01

    Preterm birth is the largest single cause of neonatal death and morbidity. By activating cytokine- and Toll-like receptor (TLR)-signaling pathways, infection and/or inflammation are strongly associated with preterm delivery. Interferon regulatory factor-1 (IRF1) is an important regulator of the inflammatory response. The aims of this study were to establish the effect of 1) labor on IRF1 expression in human fetal membranes and myometrium, 2) prolabor mediators on IRF1 expression and activity, and 3) IRF1 small interfering RNA on the expression of prolabor mediators. IRF1 expression was higher in fetal membranes and myometrium after spontaneous term labor and in preterm fetal membranes with infection. The proinflammatory cytokine IL1B, the bacterial product fsl-1, and viral analog polyinosinic:polycytidylic acid (poly [I:C]) significantly increased IRF1 mRNA expression and transcriptional activity in human primary myometrial cells. In addition, IL1B increased IRF1 activity in primary amnion cells. IRF1 silencing in myometrial cells decreased IL1B-, fsl-1-, and poly (I:C)-induced cytokine (IL6, TNF, IL1B) and chemokine (CXCL8, CCL2) mRNA expression and IL6, CXCL8, and CCL2 release. IL1B-, fsl-1-, and poly (I:C)-induced PTGS2 mRNA expression and IL1B-induced prostaglandin release was also decreased by IRF1 silencing. In conclusion, IRF1 upregulation in fetal membranes and myometrium after term labor indicates a proinflammatory role for IRF1 in human parturition. IRF1 is involved in TLR- and cytokine-mediated signaling in human myometrium. These data provide new insights into the mechanisms associated with inflammation- and infection-associated preterm birth. IRF1 inhibitors as therapeutics for the management of spontaneous preterm birth warrants further investigation. © 2016 by the Society for the Study of Reproduction, Inc.

  20. Seasonal variation in pectoralis muscle and heart myostatin and tolloid-like proteinases in small birds: a regulatory role for seasonal phenotypic flexibility?

    Science.gov (United States)

    Swanson, David L; King, Marisa O; Harmon, Erin

    2014-02-01

    Seasonally variable environments produce seasonal phenotypes in small birds such that winter birds have higher thermogenic capacities and pectoralis and heart masses. One potential regulator of these seasonal phenotypes is myostatin, a muscle growth inhibitor, which may be downregulated under conditions promoting increased energy demand. We examined summer-to-winter variation in skeletal muscle and heart masses and used qPCR and Western blots to measure levels of myostatin and its metalloproteinase activators TLL-1 and TLL-2 for two small temperate-zone resident birds, American goldfinches (Spinus tristis) and black-capped chickadees (Poecile atricapillus). Winter pectoralis and heart masses were significantly greater than in summer for American goldfinches. Neither myostatin expression nor protein levels differed significantly between seasons for goldfinch pectoralis. However, myostatin levels in goldfinch heart were significantly greater in summer than in winter, although heart myostatin expression was seasonally stable. In addition, expression of both metalloproteinase activators was greater in summer than in winter goldfinches for both pectoralis and heart, significantly so except for heart TLL-2 (P = 0.083). Black-capped chickadees showed no significant seasonal variation in muscle or heart masses. Seasonal patterns of pectoralis and heart expression and/or protein levels for myostatin and its metalloproteinase activators in chickadees showed no consistent seasonal trends, which may help explain the absence of significant seasonal variation in muscle or heart masses for chickadees in this study. These data are partially consistent with a regulatory role for myostatin, and especially myostatin processing capacity, in mediating seasonal metabolic phenotypes of small birds.

  1. Abundant intergenic TAACTGA direct repeats and putative alternate RNA polymerase β´ subunits in marine Beggiatoaceae genomes: possible regulatory roles and origins

    Directory of Open Access Journals (Sweden)

    Barbara J. MacGregor

    2015-12-01

    Full Text Available The genome sequences of several giant marine sulfur-oxidizing bacteria present evidence of a possible post-transcriptional regulatory network that may have been transmitted to or from two distantly related bacteria lineages. The draft genome of a Cand. Maribeggiatoa filament from the Guaymas Basin (Gulf of California, Mexico seafloor contains 169 sets of TAACTGA direct repeats and one indirect repeat, with two to six copies per set. Related heptamers are rarely or never found as direct repeats. TAACTGA direct repeats are also found in some other Beggiatoaceae, Thiocystis violascens, a range of Cyanobacteria, and five Bacteroidetes. This phylogenetic distribution suggests they may have been transmitted horizontally, but no mechanism is evident. There is no correlation between total TAACTGA occurrences and repeats per genome. In most species the repeat units are relatively short, but longer arrays of up to 43 copies are found in several Bacteroidetes and Cyanobacteria. The majority of TAACTGA repeats in the Cand. Maribeggiatoa Orange Guaymas (BOGUAY genome are within several nucleotides upstream of a putative start codon, suggesting they may be binding sites for a post-transcriptional regulator. Candidates include members of the ribosomal protein S1, Csp (cold shock protein, and Csr (carbon storage regulator families. No pattern was evident in the predicted functions of the open reading frames (ORFs downstream of repeats, but some encode presumably essential products such as ribosomal proteins. Among these is an ORF encoding a possible alternate or modified RNA polymerase beta prime subunit, predicted to have the expected subunit interaction domains but lacking most catalytic residues. A similar ORF was found in the Thioploca ingrica draft genome, but in no others. In both species they are immediately upstream of putative sensor kinase genes with nearly identical domain structures. In the marine Beggiatoaceae, a role for the TAACTGA repeats in

  2. A role for DNA-dependent activator of interferon regulatory factor in the recognition of herpes simplex virus type 1 by glial cells

    Directory of Open Access Journals (Sweden)

    Furr Samantha R

    2011-08-01

    Full Text Available Abstract Background The rapid onset of potentially lethal neuroinflammation is a defining feature of viral encephalitis. Microglia and astrocytes are likely to play a significant role in viral encephalitis pathophysiology as they are ideally positioned to respond to invading central nervous system (CNS pathogens by producing key inflammatory mediators. Recently, DNA-dependent activator of IFN regulatory factor (DAI has been reported to function as an intracellular sensor for DNA viruses. To date, the expression and functional role of DAI in the inflammatory responses of resident CNS cells to neurotropic DNA viruses has not been reported. Methods Expression of DAI and its downstream effector molecules was determined in C57BL/6-derived microglia and astrocytes, either at rest or following exposure to herpes simplex virus type 1 (HSV-1 and/or murine gammaherpesvirus-68 (MHV-68, by immunoblot analysis. In addition, such expression was studied in ex vivo microglia/macrophages and astrocytes from uninfected animals or mice infected with HSV-1. Inflammatory cytokine production by glial cultures following transfection with a DAI specific ligand (B-DNA, or following HSV-1 challenge in the absence or presence of siRNA directed against DAI, was assessed by specific capture ELISA. The production of soluble neurotoxic mediators by HSV-1 infected glia following DAI knockdown was assessed by analysis of the susceptibility of neuron-like cells to conditioned glial media. Results We show that isolated microglia and astrocytes constitutively express DAI and its effector molecules, and show that such expression is upregulated following DNA virus challenge. We demonstrate that these resident CNS cells express DAI in situ, and show that its expression is similarly elevated in a murine model of HSV-1 encephalitis. Importantly, we show B-DNA transfection can elicit inflammatory cytokine production by isolated glial cells and DAI knockdown can significantly reduce

  3. Role of the two-component regulatory system arlRS in ica operon and aap positive but non-biofilm-forming Staphylococcus epidermidis isolates from hospitalized patients.

    Science.gov (United States)

    Wu, Yang; Liu, Jingran; Jiang, Juan; Hu, Jian; Xu, Tao; Wang, Jiaxue; Qu, Di

    2014-11-01

    The ica operon and aap gene are important factors for Staphylococcus epidermidis biofilm formation. However, we found 15 out of 101 S. epidermidis strains isolated from patients had both the ica operon and the aap gene in the genome but could not form biofilms (ica(+)aap(+)/BF(-) isolates). Compared with standard strain RP62A, the 15 ica(+)aap(+)/BF(-) isolates had similar growth curves and initial attachment abilities, but had much lower apparent transcription levels of the icaA gene and significantly less production of polysaccharide intercellular adhesion (PIA). Furthermore, the expression of accumulation-associated protein in ica(+)aap(+)/BF(-) isolates was much weaker than in RP62A. The mRNA levels of icaADBC transcription-related regulatory genes, including icaR, sarA, rsbU, srrA, arlRS and luxS, were measured in the 15 ica(+)aap(+)/BF(-) clinical isolates. The mRNA levels of arlR and rsbU in all of the ica(+)aap(+)/BF(-) isolates were lower than in RP62A at 4 h. At 10 h, 14/15 of the isolates showed lower mRNA levels of arlR and rsbU than shown by RP62A. However, expression of sarA, luxS, srrA and icaR varied in different ica(+)aap(+)/BF(-) isolates. To further investigate the role of arlRS in biofilm formation, we analyzed icaA, sarA and rsbU transcription, PIA synthesis, Aap expression and biofilm formation in an arlRS deletion mutant of S. epidermidis strain 1457 and all were much less than in the wild type strain. This is consistent with the hypothesis that ArlRS may play an important role in regulating biofilm formation by the ica(+)aap(+)/BF(-)S. epidermidis clinical isolates and operate via both ica-dependent and Aap-dependent pathways.

  4. Sequence and Expression Analysis of Interferon Regulatory Factor 10 (IRF10 in Three Diverse Teleost Fish Reveals Its Role in Antiviral Defense.

    Directory of Open Access Journals (Sweden)

    Qiaoqing Xu

    Full Text Available Interferon regulatory factor (IRF 10 was first found in birds and is present in the genome of other tetrapods (but not humans and mice, as well as in teleost fish. The functional role of IRF10 in vertebrate immunity is relatively unknown compared to IRF1-9. The target of this research was to clone and characterize the IRF10 genes in three economically important fish species that will facilitate future evaluation of this molecule in fish innate and adaptive immunity.In the present study, a single IRF10 gene was cloned in grass carp Ctenopharyngodon idella and Asian swamp eel Monopterus albus, and two, named IRF10a and IRF10b, in rainbow trout Oncorhynchus mykiss. The fish IRF10 molecules share highest identities to other vertebrate IRF10s, and have a well conserved DNA binding domain, IRF-associated domain, and an 8 exon/7 intron structure with conserved intron phase. The presence of an upstream ATG or open reading frame (ORF in the 5'-untranslated region of different fish IRF10 cDNA sequences suggests potential regulation at the translational level, and this has been verified by in vitro transcription/translation experiments of the trout IRF10a cDNA, but would still need to be validated in fish cells.Both trout IRF10 paralogues are highly expressed in thymus, blood and spleen but are relatively low in head kidney and caudal kidney. Trout IRF10b expression is significantly higher than IRF10a in integumentary tissues i.e. gills, scales, skin, intestine, adipose fin and tail fins, suggesting that IRF10b may be more important in mucosal immunity. The expression of both trout IRF10 paralogues is up-regulated by recombinant IFN-γ. The expression of the IRF10 genes is highly induced by Poly I:C in vitro and in vivo, and by viral infection, but is less responsive to peptidoglycan and bacterial infection, suggesting an important role of fish IRF10 in antiviral defense.

  5. Scavenge flow analysis of opposed-piston two-stroke engine based on dynamic characteristics

    Directory of Open Access Journals (Sweden)

    Fu-kang Ma

    2015-04-01

    Full Text Available Opposed-piston two-stroke engine has been proposed by Beijing Institute of Technology to improve power density and complete machine balance relative to conventional engines. In order to study opposed-piston two-stroke engine scavenging flow, a scavenging system was configured using a three-dimensional computational fluid dynamics model effectively coupled to experiments. The boundary conditions are obtained through one-dimensional working process simulation results and experiments. As the opposed-piston relative dynamic characteristics of opposed-piston two-stroke engine depend on different design and operating parameters including the opposed-piston motion phase difference and crank-connecting rod ratio, a numerical simulation program was built using MATLAB/Simulink to define opposed-piston motion profiles based on equivalent crank angle of opposed crank-connecting rod mechanism. The opposed-piston motion phase difference only affects scavenging timing while crank-connecting rod ratio affects scavenging timing and duration. Scavenging timing and duration are the main factors which affect scavenging performance. The results indicate that a match of opposed-piston motion phase difference and crank-connecting rod ratio has the potential to achieve high scavenging and trapping efficiency with a right flow in cylinder.

  6. Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling

    Energy Technology Data Exchange (ETDEWEB)

    Frampton, Gabriel; Coufal, Monique [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Li, Huang [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Department of Hepatobiliary Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou (China); Ramirez, Jonathan [Digestive Disease Research Center, Scott and White Hospital, Temple, TX (United States); DeMorrow, Sharon, E-mail: demorrow@medicine.tamhsc.edu [Department of Internal Medicine, Texas A and M Health Science Center College of Medicine, Temple, TX (United States); Digestive Disease Research Center, Scott and White Hospital, Temple, TX (United States)

    2010-05-15

    The endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) have opposing effects on cholangiocarcinoma growth. Implicated in cancer, Notch signaling requires the {gamma}-secretase complex for activation. The aims of this study were to determine if the opposing effects of endocannabinoids depend on the differential activation of the Notch receptors and to demonstrate that the differential activation of these receptors are due to presenilin 1 containing- and presenilin 2 containing-{gamma}-secretase complexes. Mz-ChA-1 cells were treated with AEA or 2-AG. Notch receptor expression, activation, and nuclear translocation were determined. Specific roles for Notch 1 and 2 on cannabinoid-induced effects were determined by transient transfection of Notch 1 or 2 shRNA vectors before stimulation with AEA or 2-AG. Expression of presenilin 1 and 2 was determined after AEA or 2-AG treatment, and the involvement of presenilin 1 and 2 in the cannabinoid-induced effects was demonstrated in cell lines with low presenilin 1 or 2 expression. Antiproliferative effects of AEA required increased Notch 1 mRNA, activation, and nuclear translocation, whereas the growth-promoting effects induced by 2-AG required increased Notch 2 mRNA expression, activation, and nuclear translocation. AEA increased presenilin 1 expression and recruitment into the {gamma}-secretase complex, whereas 2-AG increased expression and recruitment of presenilin 2. The development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for cholangiocarcinoma management.

  7. Opposing Biological Functions of Tryptophan Catabolizing Enzymes During Intracellular Infection

    Science.gov (United States)

    Divanovic, Senad; Sawtell, Nancy M.; Trompette, Aurelien; Warning, Jamie I.; Dias, Alexandra; Cooper, Andrea M.; Yap, George S.; Arditi, Moshe; Shimada, Kenichi; DuHadaway, James B.; Prendergast, George C.; Basaraba, Randall J.; Mellor, Andrew L.; Munn, David H.; Aliberti, Julio

    2012-01-01

    Recent studies have underscored physiological and pathophysiological roles for the tryptophan-degrading enzyme indolamine 2,3-dioxygenase (IDO) in immune counterregulation. However, IDO was first recognized as an antimicrobial effector, restricting tryptophan availability to Toxoplasma gondii and other pathogens in vitro. The biological relevance of these findings came under question when infectious phenotypes were not forthcoming in IDO-deficient mice. The recent discovery of an IDO homolog, IDO-2, suggested that the issue deserved reexamination. IDO inhibition during murine toxoplasmosis led to 100% mortality, with increased parasite burdens and no evident effects on the immune response. Similar studies revealed a counterregulatory role for IDO during leishmaniasis (restraining effector immune responses and parasite clearance), and no evident role for IDO in herpes simplex virus type 1 (HSV-1) infection. Thus, IDO plays biologically important roles in the host response to diverse intracellular infections, but the dominant nature of this role—antimicrobial or immunoregulatory—is pathogen-specific. PMID:21990421

  8. Circadian timed wakefulness at dawn opposes compensatory sleep responses after sleep deprivation in Octodon degus

    NARCIS (Netherlands)

    Kas, M J; Edgar, D M

    1999-01-01

    The circadian timing system in mammals is thought to promote wakefulness and oppose sleep drive that accumulates across the activity phase in diurnal and nocturnal species. Whether the circadian system actively opposes compensatory sleep responses in mammals with episodes of alertness consolidated a

  9. Contrasting Roles For All-Trans Retinoic Acid in TGF-ß-mediated Induction of Foxp3 and Il10 Genes in Developing Regulatory T Cells

    Science.gov (United States)

    Extrathymic induction of regulatory T cells (Treg) is essential to the regulation of effector T cell responses in the periphery. TGF-ß has been shown to induce Foxp3-expressing Tregs both in vitro and in vivo. More recently, the vitamin A metabolite, all-trans retinoic acid (at-RA), has been found t...

  10. From city marketing to museum marketing and opposed

    OpenAIRE

    Metaxas, Theodore

    2013-01-01

    European cities today need to confront the challenges of the current socio economic changes. In this framework the role of city marketing becomes essential especially during the socio economic crisis. City marketing is important because it is related to procedures connected with city global competition, tourist attraction, urban management, urban government and the special identity of cities (city branding). Many European cities take initiatives either creative or innovative to improve their ...

  11. Regulatory Snapshots: integrative mining of regulatory modules from expression time series and regulatory networks.

    Directory of Open Access Journals (Sweden)

    Joana P Gonçalves

    Full Text Available Explaining regulatory mechanisms is crucial to understand complex cellular responses leading to system perturbations. Some strategies reverse engineer regulatory interactions from experimental data, while others identify functional regulatory units (modules under the assumption that biological systems yield a modular organization. Most modular studies focus on network structure and static properties, ignoring that gene regulation is largely driven by stimulus-response behavior. Expression time series are key to gain insight into dynamics, but have been insufficiently explored by current methods, which often (1 apply generic algorithms unsuited for expression analysis over time, due to inability to maintain the chronology of events or incorporate time dependency; (2 ignore local patterns, abundant in most interesting cases of transcriptional activity; (3 neglect physical binding or lack automatic association of regulators, focusing mainly on expression patterns; or (4 limit the discovery to a predefined number of modules. We propose Regulatory Snapshots, an integrative mining approach to identify regulatory modules over time by combining transcriptional control with response, while overcoming the above challenges. Temporal biclustering is first used to reveal transcriptional modules composed of genes showing coherent expression profiles over time. Personalized ranking is then applied to prioritize prominent regulators targeting the modules at each time point using a network of documented regulatory associations and the expression data. Custom graphics are finally depicted to expose the regulatory activity in a module at consecutive time points (snapshots. Regulatory Snapshots successfully unraveled modules underlying yeast response to heat shock and human epithelial-to-mesenchymal transition, based on regulations documented in the YEASTRACT and JASPAR databases, respectively, and available expression data. Regulatory players involved in

  12. Regulatory Expectations for Safety Culture

    Energy Technology Data Exchange (ETDEWEB)

    Jung, Su Jin; Oh, Jang Jin; Choi, Young Sung [Korea Institute of Nuclear Safety, Daejeon (Korea, Republic of)

    2014-05-15

    The oversight of licensee's safety culture becomes an important issue that attracts great public and political concerns recently in Korea. Beginning from the intended violation of rules, a series of corruptions, documents forgery and disclosure of wrong-doings made the public think that the whole mindset of nuclear workers has been inadequate. Thus, they are demanding that safety culture shall be improved and that regulatory body shall play more roles and responsibilities for the improvements and oversight for them. This paper introduces, as an effort of regulatory side, recent changes in the role of regulators in safety culture, regulatory expectations on the desired status of licensee's safety culture, the pilot inspection program for safety culture and research activity for the development of oversight system. After the Fukushima accident in Japan 2011, many critics has searched for cultural factors that caused the unacceptable negligence pervaded in Japan nuclear society and the renewed emphasis has been placed on rebuilding safety culture by operators, regulators, and relevant institutions globally. Significant progress has been made in how to approach safety culture and led to a new perspective different from the existing normative assessment method both in operators and regulatory side. Regulatory expectations and oversight of them are based on such a new holistic concept for human, organizational and cultural elements to maintain and strengthen the integrity of defense in depth and consequently nuclear safety.

  13. Cytotoxic T Lymphocyte–Associated Antigen 4 Plays an Essential Role in the Function of Cd25+Cd4+ Regulatory Cells That Control Intestinal Inflammation

    OpenAIRE

    Read, Simon; Malmström, Vivianne; Powrie, Fiona

    2000-01-01

    It is now clear that functionally specialized regulatory T (Treg) cells exist as part of the normal immune repertoire, preventing the development of pathogenic responses to both self- and intestinal antigens. Here, we report that the Treg cells that control intestinal inflammation express the same phenotype (CD25+CD45RBlowCD4+) as those that control autoimmunity. Previous studies have failed to identify how CD25+ Treg cells function in vivo. Our studies reveal that the immune-suppressive func...

  14. The role of the Crc/Hfq/CrcZ-CrcY global regulatory system on the regulation of metabolic and cellular processes in Pseudomonas putida

    OpenAIRE

    La Rosa, Ruggero

    2015-01-01

    Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 28-09-2015 Metabolically versatile bacteria have evolved diverse strategies to adapt and to colonize different environments and niches. This ensures high fitness and the ability to withstand changing surrounding conditions and diverse kinds of stresses. These abilities rely on a varied genetic repertoire and on complex regulatory networks t...

  15. Regulatory MicroRNA Networks: Complex Patterns of Target Pathways for Disease-related and Housekeeping MicroRNAs

    Directory of Open Access Journals (Sweden)

    Sachli Zafari

    2015-06-01

    Full Text Available Blood-based microRNA (miRNA signatures as biomarkers have been reported for various pathologies, including cancer, neurological disorders, cardiovascular diseases, and also infections. The regulatory mechanism behind respective miRNA patterns is only partially understood. Moreover, “preserved” miRNAs, i.e., miRNAs that are not dysregulated in any disease, and their biological impact have been explored to a very limited extent. We set out to systematically determine their role in regulatory networks by defining groups of highly-dysregulated miRNAs that contribute to a disease signature as opposed to preserved housekeeping miRNAs. We further determined preferential targets and pathways of both dysregulated and preserved miRNAs by computing multi-layer networks, which were compared between housekeeping and dysregulated miRNAs. Of 848 miRNAs examined across 1049 blood samples, 8 potential housekeepers showed very limited expression variations, while 20 miRNAs showed highly-dysregulated expression throughout the investigated blood samples. Our approach provides important insights into miRNAs and their role in regulatory networks. The methodology can be applied to systematically investigate the differences in target genes and pathways of arbitrary miRNA sets.

  16. Parvalbumin-Positive Inhibitory Interneurons Oppose Propagation But Favor Generation of Focal Epileptiform Activity.

    Science.gov (United States)

    Sessolo, Michele; Marcon, Iacopo; Bovetti, Serena; Losi, Gabriele; Cammarota, Mario; Ratto, Gian Michele; Fellin, Tommaso; Carmignoto, Giorgio

    2015-07-01

    Parvalbumin (Pv)-positive inhibitory interneurons effectively control network excitability, and their optogenetic activation has been reported to block epileptic seizures. An intense activity in GABAergic interneurons, including Pv interneurons, before seizures has been described in different experimental models of epilepsy, raising the hypothesis that an increased GABAergic inhibitory signal may, under certain conditions, initiate seizures. It is therefore unclear whether the activity of Pv interneurons enhances or opposes epileptiform activities. Here we use a mouse cortical slice model of focal epilepsy in which the epileptogenic focus can be identified and the role of Pv interneurons in the generation and propagation of seizure-like ictal events is accurately analyzed by a combination of optogenetic, electrophysiological, and imaging techniques. We found that a selective activation of Pv interneurons at the focus failed to block ictal generation and induced postinhibitory rebound spiking in pyramidal neurons, enhancing neuronal synchrony and promoting ictal generation. In contrast, a selective activation of Pv interneurons distant from the focus blocked ictal propagation and shortened ictal duration at the focus. We revealed that the reduced ictal duration was a direct consequence of the ictal propagation block, probably by preventing newly generated afterdischarges to travel backwards to the original focus of ictal initiation. Similar results were obtained upon individual Pv interneuron activation by intracellular depolarizing current pulses. The functional dichotomy of Pv interneurons here described opens new perspectives to our understanding of how local inhibitory circuits govern generation and spread of focal epileptiform activities.

  17. Opposing Shh and Fgf signals initiate nasotemporal patterning of the zebrafish retina

    Science.gov (United States)

    Hernández-Bejarano, María; Gestri, Gaia; Spawls, Lana; Nieto-López, Francisco; Picker, Alexander; Tada, Masazumi; Brand, Michael; Bovolenta, Paola; Wilson, Stephen W.; Cavodeassi, Florencia

    2015-01-01

    The earliest known determinants of retinal nasotemporal identity are the transcriptional regulators Foxg1, which is expressed in the prospective nasal optic vesicle, and Foxd1, which is expressed in the prospective temporal optic vesicle. Previous work has shown that, in zebrafish, Fgf signals from the dorsal forebrain and olfactory primordia are required to specify nasal identity in the dorsal, prospective nasal, optic vesicle. Here, we show that Hh signalling from the ventral forebrain is required for specification of temporal identity in the ventral optic vesicle and is sufficient to induce temporal character when activated in the prospective nasal retina. Consequently, the evaginating optic vesicles become partitioned into prospective nasal and temporal domains by the opposing actions of Fgfs and Shh emanating from dorsal and ventral domains of the forebrain primordium. In absence of Fgf activity, foxd1 expression is established irrespective of levels of Hh signalling, indicating that the role of Shh in promoting foxd1 expression is only required in the presence of Fgf activity. Once the spatially complementary expression of foxd1 and foxg1 is established, the boundary between expression domains is maintained by mutual repression between Foxd1 and Foxg1. PMID:26428010

  18. The core regulatory network in human cells.

    Science.gov (United States)

    Kim, Man-Sun; Kim, Dongsan; Kang, Nam Sook; Kim, Jeong-Rae

    2017-03-04

    In order to discover the common characteristics of various cell types in the human body, many researches have been conducted to find the set of genes commonly expressed in various cell types and tissues. However, the functional characteristics of a cell is determined by the complex regulatory relationships among the genes rather than by expressed genes themselves. Therefore, it is more important to identify and analyze a core regulatory network where all regulatory relationship between genes are active across all cell types to uncover the common features of various cell types. Here, based on hundreds of tissue-specific gene regulatory networks constructed by recent genome-wide experimental data, we constructed the core regulatory network. Interestingly, we found that the core regulatory network is organized by simple cascade and has few complex regulations such as feedback or feed-forward loops. Moreover, we discovered that the regulatory links from genes in the core regulatory network to genes in the peripheral regulatory network are much more abundant than the reverse direction links. These results suggest that the core regulatory network locates at the top of regulatory network and plays a role as a 'hub' in terms of information flow, and the information that is common to all cells can be modified to achieve the tissue-specific characteristics through various types of feedback and feed-forward loops in the peripheral regulatory networks. We also found that the genes in the core regulatory network are evolutionary conserved, essential and non-disease, non-druggable genes compared to the peripheral genes. Overall, our study provides an insight into how all human cells share a common function and generate tissue-specific functional traits by transmitting and processing information through regulatory network.

  19. Utility of opposed-phase magnetic resonance imaging in differentiating sarcoma from benign bone lesions

    Directory of Open Access Journals (Sweden)

    Barry E. Kenneally

    2015-12-01

    Conclusion: Opposed-phase imaging is helpful in differentiating benign from malignant lesions in bone. Confidence in diagnosis rose for both the attending and the resident as result of the inclusion of OP sequences.

  20. Multiple opposing constraints govern chromosome interactions during meiosis.

    Directory of Open Access Journals (Sweden)

    Doris Y Lui

    Full Text Available Homolog pairing and crossing over during meiosis I prophase is required for accurate chromosome segregation to form euploid gametes. The repair of Spo11-induced double-strand breaks (DSB using a homologous chromosome template is a major driver of pairing in many species, including fungi, plants, and mammals. Inappropriate pairing and crossing over at ectopic loci can lead to chromosome rearrangements and aneuploidy. How (or if inappropriate ectopic interactions are disrupted in favor of allelic interactions is not clear. Here we used an in vivo "collision" assay in budding yeast to test the contributions of cohesion and the organization and motion of chromosomes in the nucleus on promoting or antagonizing interactions between allelic and ectopic loci at interstitial chromosome sites. We found that deletion of the cohesin subunit Rec8, but not other chromosome axis proteins (e.g. Red1, Hop1, or Mek1, caused an increase in homolog-nonspecific chromosome interaction, even in the absence of Spo11. This effect was partially suppressed by expression of the mitotic cohesin paralog Scc1/Mdc1, implicating Rec8's role in cohesion rather than axis integrity in preventing nonspecific chromosome interactions. Disruption of telomere-led motion by treating cells with the actin polymerization inhibitor Latrunculin B (Lat B elevated nonspecific collisions in rec8Δ spo11Δ. Next, using a visual homolog-pairing assay, we found that the delay in homolog pairing in mutants defective for telomere-led chromosome motion (ndj1Δ or csm4Δ is enhanced in Lat B-treated cells, implicating actin in more than one process promoting homolog juxtaposition. We suggest that multiple, independent contributions of actin, cohesin, and telomere function are integrated to promote stable homolog-specific interactions and to destabilize weak nonspecific interactions by modulating the elastic spring-like properties of chromosomes.

  1. Regulatory aspects

    Science.gov (United States)

    Stern, Arthur M.

    1986-07-01

    At this time, there is no US legislation that is specifically aimed at regulating the environmental release of genetically engineered organisms or their modified components, either during the research and development stage or during application. There are some statutes, administered by several federal agencies, whose language is broad enough to allow the extension of intended coverage to include certain aspects of biotechnology. The one possible exception is FIFRA, which has already brought about the registration of several natural microbial pesticides but which also has provision for requiring the registration of “strain improved” microbial pesticides. Nevertheless, there may be gaps in coverage even if all pertinent statutes were to be actively applied to the control of environmental release of genetically modified substances. The decision to regulate biotechnology under TSCA was justified, in part, on the basis of its intended role as a gap-filling piece of environmental legislation. The advantage of regulating biotechnology under TSCA is that this statute, unlike others, is concerned with all media of exposure (air, water, soil, sediment, biota) that may pose health and environmental hazards. Experience may show that extending existing legislation to regulate biotechnology is a poor compromise compared to the promulgation of new legislation specifically designed for this purpose. It appears that many other countries are ultimately going to take the latter course to regulate biotechnology.

  2. Opposing roles for RhoH GTPase during T-cell migration and activation

    DEFF Research Database (Denmark)

    Baker, Christina M; Comrie, William A; Hyun, Young-Min

    2012-01-01

    T cells spend the majority of their time perusing lymphoid organs in search of cognate antigen presented by antigen presenting cells (APCs) and then quickly recirculate through the bloodstream to another lymph node. Therefore, regulation of a T-cell response is dependent upon the ability of cells...... to arrive in the correct location following chemokine gradients ("go" signal) as well as to receive appropriate T-cell receptor (TCR) activation signals upon cognate antigen recognition ("stop" signal). However, the mechanisms by which T cells regulate these go and stop signals remain unclear. We found...... that overexpression of the hematopoietic-specific RhoH protein in the presence of chemokine signals resulted in decreased Rap1-GTP and LFA-1 adhesiveness to ICAM-1, thus impairing T-cell chemotaxis; while in the presence of TCR signals, there were enhanced and sustained Rap1-GTP and LFA-1 activation as well...

  3. Opposing Roles of JNK and p38 in Lymphangiogenesis in Melanoma.

    Science.gov (United States)

    Puujalka, Emmi; Heinz, Magdalena; Hoesel, Bastian; Friedl, Peter; Schweighofer, Bernhard; Wenzina, Judith; Pirker, Christine; Schmid, Johannes A; Loewe, Robert; Wagner, Erwin F; Berger, Walter; Petzelbauer, Peter

    2016-05-01

    In primary melanoma, the amount of vascular endothelial growth factor C (VEGF-C) expression and lymphangiogenesis predicts the probability of metastasis to sentinel nodes, but conditions boosting VEGF-C expression in melanoma are poorly characterized. By comparative mRNA expression analysis of a set of 22 human melanoma cell lines, we found a striking negative correlation between VEGF-C and microphthalmia-associated transcription factor (MITF) expression, which was confirmed by data mining in GEO databases of human melanoma Affymetrix arrays. Moreover, in human patients, high VEGF-C and low MITF levels in primary melanoma significantly correlated with the chance of metastasis. Pathway analysis disclosed the respective c-Jun N-terminal kinase and p38/mitogen-activated protein kinase activities as being responsible for the inverse regulation of VEGF-C and MITF. Predominant c-Jun N-terminal kinase signaling results in a VEGF-C(low)/MITF(high) phenotype; these melanoma cells are highly proliferative, show low mobility, and are poorly lymphangiogenic. Predominant p38 signaling results in a VEGF-C(high)/MITF(low) phenotype, corresponding to a slowly cycling, highly mobile, lymphangiogenic, and metastatic melanoma. In conclusion, the relative c-Jun N-terminal kinase and p38 activities determine the biological behavior of melanoma. VEGF-C and MITF levels serve as surrogate markers for the respective c-Jun N-terminal kinase and p38 activities and may be used to predict the risk of metastasis in primary melanoma.

  4. Transcriptional dynamics of two seed compartments with opposing roles in Arabidopsis seed germination

    NARCIS (Netherlands)

    Dekkers, S.J.W.; Pearce, S.; Bolderen-Veldkamp, R.P.; Marshall, A.; Widera, P.; Gilbert, J.; Drost, H.G.; Bassel, G.; Muller, K.; King, J.R.; Wood, A.; Grosse, I.; Bentsink, L.

    2013-01-01

    Seed germination is a critical stage in the plant life cycle and the first step toward successful plant establishment. Therefore, understanding germination is of important ecological and agronomical relevance. Previous research revealed that different seed compartments (testa, endosperm, and embryo)

  5. The Opposing Roles of Nucleophosmin and the ARF Tumor Suppressor in Breast Cancer

    Science.gov (United States)

    2007-04-01

    Roussel, M.F.; Sherr, C.J. Mol. Cell, 2003, 11 , 415.[48] Palmero, I.; Pantoja , C.; Serrano, M. Nature, 1998, 395, 125. [49] Momand, J.; Jung, D...Medicinal Chemistry, 2007, Vol. 14, No. 17 Saporita et al. [114] Gutierrez , M.I.; Siraj, A.K.; Khaled, H.; Koon, N.; El-Rifai, W.; Bhatia, K. Mod...Chromosomes Cancer, 2002, 33 , 322.[115] Gonzalez-Gomez, P.; Bello, M.J.; Alonso, M.E.; Aminoso, C.; Lopez- Marin, I.; De Campos, J.M.; Isla, A.; Gutierrez , M

  6. Reelin and stk25 have opposing roles in neuronal polarization and dendritic Golgi deployment.

    Science.gov (United States)

    Matsuki, Tohru; Matthews, Russell T; Cooper, Jonathan A; van der Brug, Marcel P; Cookson, Mark R; Hardy, John A; Olson, Eric C; Howell, Brian W

    2010-11-24

    The Reelin ligand regulates a Dab1-dependent signaling pathway required for brain lamination and normal dendritogenesis, but the specific mechanisms underlying these actions remain unclear. We find that Stk25, a modifier of Reelin-Dab1 signaling, regulates Golgi morphology and neuronal polarization as part of an LKB1-Stk25-Golgi matrix protein 130 (GM130) signaling pathway. Overexpression of Stk25 induces Golgi condensation and multiple axons, both of which are rescued by Reelin treatment. Reelin stimulation of cultured neurons induces the extension of the Golgi into dendrites, which is suppressed by Stk25 overexpression. In vivo, Reelin and Dab1 are required for the normal extension of the Golgi apparatus into the apical dendrites of hippocampal and neocortical pyramidal neurons. This demonstrates that the balance between Reelin-Dab1 signaling and LKB1-Stk25-GM130 regulates Golgi dispersion, axon specification, and dendrite growth and provides insights into the importance of the Golgi apparatus for cell polarization.

  7. Aurora B kinase and protein phosphatase 1 have opposing roles in modulating kinetochore assembly.

    Science.gov (United States)

    Emanuele, Michael J; Lan, Weijie; Jwa, Miri; Miller, Stephanie A; Chan, Clarence S M; Stukenberg, P Todd

    2008-04-21

    The outer kinetochore binds microtubules to control chromosome movement. Outer kinetochore assembly is restricted to mitosis, whereas the inner kinetochore remains tethered to centromeres throughout the cell cycle. The cues that regulate this transient assembly are unknown. We find that inhibition of Aurora B kinase significantly reduces outer kinetochore assembly in Xenopus laevis and human tissue culture cells, frog egg extracts, and budding yeast. In X. leavis M phase extracts, preassembled kinetochores disassemble after inhibiting Aurora B activity with either drugs or antibodies. Kinetochore disassembly, induced by Aurora B inhibition, is rescued by restraining protein phosphatase 1 (PP1) activity. PP1 is necessary for kinetochores to disassemble at the exit from M phase, and purified enzyme is sufficient to cause disassembly on isolated mitotic nuclei. These data demonstrate that Aurora B activity is required for kinetochore maintenance and that PP1 is necessary and sufficient to disassemble kinetochores. We suggest that Aurora B and PP1 coordinate cell cycle-dependent changes in kinetochore assembly though phosphorylation of kinetochore substrates.

  8. Low-ω3 Fatty Acid and Soy Protein Attenuate Alcohol-Induced Fatty Liver and Injury by Regulating the Opposing Lipid Oxidation and Lipogenic Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Karina Reyes-Gordillo

    2016-01-01

    Full Text Available Chronic ethanol-induced downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1β affect hepatic lipid oxidation and lipogenesis, respectively, leading to fatty liver injury. Low-ω3 fatty acid (Low-ω3FA that primarily regulates PGC1α and soy protein (SP that seems to have its major regulatory effect on PGC1β were evaluated for their protective effects against ethanol-induced hepatosteatosis in rats fed with Lieber-deCarli control or ethanol liquid diets with high or low ω3FA fish oil and soy protein. Low-ω3FA and SP opposed the actions of chronic ethanol by reducing serum and liver lipids with concomitant decreased fatty liver. They also prevented the downregulation of hepatic Sirtuin 1 (SIRT1 and PGC1α and their target fatty acid oxidation pathway genes and attenuated the upregulation of hepatic PGC1β and sterol regulatory element-binding protein 1c (SREBP1c and their target lipogenic pathway genes via the phosphorylation of 5′ adenosine monophosphate-activated protein kinase (AMPK. Thus, these two novel modulators attenuate ethanol-induced hepatosteatosis and consequent liver injury potentially by regulating the two opposing lipid oxidation and lipogenic pathways.

  9. The Political Communication of Independent Regulatory Agencies

    National Research Council Canada - National Science Library

    Puppis, Manuel; Maggetti, Martino; Gilardi, Fabrizio; Biela, Jan; Papadopoulos, Yannis

    2014-01-01

    .... In this context, public communication plays an important role. On the one hand, regulatory agencies might try to use communication to raise their accountability and thereby to mitigate their democratic deficit...

  10. Modernizing the Regulatory System for Biotechnology Products

    Science.gov (United States)

    This Web page describes the continuing effort to modernize the federal regulatory system for biotechnology products as well as clarify various roles of EPA, FDA and USDA in evaluating new biotechnology products.

  11. Clinical research: regulatory issues.

    Science.gov (United States)

    Wermeling, D P

    1999-02-01

    The regulatory issues faced by institutions performing clinical research are described. Many institutions do not have on staff an expert who understands the regulatory issues involved in managing investigational new drug research and who knows the institution's obligations under the federal rules. Because pharmacists understand the FDA regulations that apply to the management of drugs in clinical research, institutions are asking pharmacists to expand their role and manage clinical research offices. Many authorities govern various aspects of investigational drug research. FDA has published regulations for good clinical practice (GCP), and the International Conference on Harmonisation is developing an international standard for the proper management of clinical trials. The guidelines published by the Joint Commission on Accreditation of Healthcare Organizations aim to protect patients who are in the institution to receive health care and also participate in clinical trials. The Social Security Administration Acts specifically state that only items and services that are reasonable and necessary for the diagnosis and treatment of injury or disease can be billed to the government; research-related billings are excluded from coverage. Proper management of drug research is crucial to the success of a research program that is integrated with patient care.

  12. Toxicogenomics in regulatory ecotoxicology

    Science.gov (United States)

    Ankley, Gerald T.; Daston, George P.; Degitz, Sigmund J.; Denslow, Nancy D.; Hoke, Robert A.; Kennedy, Sean W.; Miracle, Ann L.; Perkins, Edward J.; Snape, Jason; Tillitt, Donald E.; Tyler, Charles R.; Versteeg, Donald

    2006-01-01

    Recently, we have witnessed an explosion of different genomic approaches that, through a combination of advanced biological, instrumental, and bioinformatic techniques, can yield a previously unparalleled amount of data concerning the molecular and biochemical status of organisms. Fueled partially by large, well-publicized efforts such as the Human Genome Project, genomic research has become a rapidly growing topical area in multiple biological disciplines. Since 1999, when the term “toxicogenomics” was coined to describe the application of genomics to toxicology (1), a rapid increase in publications on the topic has occurred (Figure 1). The potential utility of toxicogenomics in toxicological research and regulatory activities has been the subject of scientific discussions and, as with any new technology, has evoked a wide range of opinion (2–6). VIEWPOINT © 2006 american chemical Society july 1, 2006 / EnvironmEntal SciEncE & tEchnology n 4055 The purpose of this feature article is to consider the roles of toxicogenomics in the field of regulatory ecotoxicology, explore current limitations in the science and practice of genomics, and propose possible avenues to approach and resolve some of the major challenges. A significant amount of input to our analysis came from a workshop sponsored by the Society of Environmental Toxicology and Chemistry (SETAC) in Pellston, Mich., in September 2005. A complete list of names and affiliations of the experts participating in that workshop is provided online in Table 1 of the Supporting Information for this paper.

  13. Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands.

    Science.gov (United States)

    Knoechel, Thorsten R; Tucker, Alec D; Robinson, Colin M; Phillips, Chris; Taylor, Wendy; Bungay, Peter J; Kasten, Shane A; Roche, Thomas E; Brown, David G

    2006-01-17

    Pyruvate dehydrogenase kinase (PDHK) regulates the activity of the pyruvate dehydrogenase multienzyme complex. PDHK inhibition provides a route for therapeutic intervention in diabetes and cardiovascular disorders. We report crystal structures of human PDHK isozyme 2 complexed with physiological and synthetic ligands. Several of the PDHK2 structures disclosed have C-terminal cross arms that span a large trough region between the N-terminal regulatory (R) domains of the PDHK2 dimers. The structures containing bound ATP and ADP demonstrate variation in the conformation of the active site lid, residues 316-321, which enclose the nucleotide beta and gamma phosphates at the active site in the C-terminal catalytic domain. We have identified three novel ligand binding sites located in the R domain of PDHK2. Dichloroacetate (DCA) binds at the pyruvate binding site in the center of the R domain, which together with ADP, induces significant changes at the active site. Nov3r and AZ12 inhibitors bind at the lipoamide binding site that is located at one end of the R domain. Pfz3 (an allosteric inhibitor) binds in an extended site at the other end of the R domain. We conclude that the N-terminal domain of PDHK has a key regulatory function and propose that the different inhibitor classes act by discrete mechanisms. The structures we describe provide insights that can be used for structure-based design of PDHK inhibitors.

  14. The role of Personal Self-Regulation and Regulatory Teaching to predict motivational-affective variables, achievement and satisfaction: A structural model

    Directory of Open Access Journals (Sweden)

    Jesus ede la Fuente

    2015-04-01

    Full Text Available The present investigation examines how personal self-regulation (presage variable and regulatory teaching (process variable of teaching relate to learning approaches, strategies for coping with stress, and self-regulated learning (process variables of learning and, finally, how they relate to performance and satisfaction with the learning process (product variables. The objective was to clarify the associative and predictive relations between these variables, as contextualized in two different models that use the presage-process-product paradigm (the Biggs and DEDEPRO models. A total of 1101 university students participated in the study. The design was cross-sectional and retrospective with attributional (or selection variables, using correlations and structural analysis. The results provide consistent and significant empirical evidence for the relationships hypothesized, incorporating variables that are part of and influence the teaching-learning process in Higher Education. Findings confirm the importance of interactive relationships within the teaching-learning process, where personal self-regulation is assumed to take place in connection with regulatory teaching. Variables that are involved in the relationships validated here reinforce the idea that both personal factors and teaching and learning factors should be taken into consideration when dealing with a formal teaching-learning context at university.

  15. 调节性T细胞在慢性阻塞性肺疾病发病机制中的作用%The role of regulatory T cells in the pathogenesis of chronic obstructive pulmonary disease

    Institute of Scientific and Technical Information of China (English)

    赵考昌; 陈国忠

    2015-01-01

    COPD是一种复杂的慢性气道炎症性疾病,其发病机制仍不明确,最新理论认为COPD是一种具有自身免疫反应特征性的疾病,调节性T细胞通过其免疫调节作用参与自身免疫耐受.因此调节性T细胞在COPD发病中的作用引起诸多学者的关注.%Chronic obstructive pulmonary disease (COPD) is a complex,chronic airway inflammatory disease.The pathogenesis of COPD remains unclear.According to the latest theory,autoimmune reaction plays an important role in the pathogenesis of COPD.It has been shown that regulatory T cells are important in the control of autoimmunity by immunoregulation.So the role of regulatory T cells in the pathogenesis of COPD attracts the attention of many scholars.

  16. Global mapping of cell type-specific open chromatin by FAIRE-seq reveals the regulatory role of the NFI family in adipocyte differentiation.

    Directory of Open Access Journals (Sweden)

    Hironori Waki

    2011-10-01

    Full Text Available Identification of regulatory elements within the genome is crucial for understanding the mechanisms that govern cell type-specific gene expression. We generated genome-wide maps of open chromatin sites in 3T3-L1 adipocytes (on day 0 and day 8 of differentiation and NIH-3T3 fibroblasts using formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIRE-seq. FAIRE peaks at the promoter were associated with active transcription and histone modifications of H3K4me3 and H3K27ac. Non-promoter FAIRE peaks were characterized by H3K4me1+/me3-, the signature of enhancers, and were largely located in distal regions. The non-promoter FAIRE peaks showed dynamic change during differentiation, while the promoter FAIRE peaks were relatively constant. Functionally, the adipocyte- and preadipocyte-specific non-promoter FAIRE peaks were, respectively, associated with genes up-regulated and down-regulated by differentiation. Genes highly up-regulated during differentiation were associated with multiple clustered adipocyte-specific FAIRE peaks. Among the adipocyte-specific FAIRE peaks, 45.3% and 11.7% overlapped binding sites for, respectively, PPARγ and C/EBPα, the master regulators of adipocyte differentiation. Computational motif analyses of the adipocyte-specific FAIRE peaks revealed enrichment of a binding motif for nuclear family I (NFI transcription factors. Indeed, ChIP assay showed that NFI occupy the adipocyte-specific FAIRE peaks and/or the PPARγ binding sites near PPARγ, C/EBPα, and aP2 genes. Overexpression of NFIA in 3T3-L1 cells resulted in robust induction of these genes and lipid droplet formation without differentiation stimulus. Overexpression of dominant-negative NFIA or siRNA-mediated knockdown of NFIA or NFIB significantly suppressed both induction of genes and lipid accumulation during differentiation, suggesting a physiological function of these factors in the adipogenic program. Together, our

  17. Opposing regulation of histamine-induced calcium signaling by sodium selenite and ebselen via alterations of thiol redox status.

    Science.gov (United States)

    Zhang, Huihui; Zhong, Liangwei

    2010-01-25

    Elevated blood histamine plays a role in the pathogenesis of atherosclerosis. Calcium signaling mediates histamine action in endothelial cells. Selenium (Se) is a dietary essential trace element for humans. Se compounds in different oxidation states were found to exhibit an opposing effect on the histamine-induced calcium signaling in the ECV304 cell line. When Se in the form of sodium selenite was added in the cell culture, the reactivity of the histamine H(1)-receptor was increased as reported in our previous paper. We here show that as a culture supplement, sodium selenite enhanced the activity of selenoprotein thioredoxin reductase (TrxR) and the calcium response to histamine stimulation, which were reversed by treating the cells with gold thioglucose, a nucleophilic drug that selectively modifies thiolate/selenolate groups. Sodium selenite most likely caused a reductive shift in the thiol/disulfide redox balance through increasing TrxR activity. In contrast, when the cells were treated with Se in the form of ebselen, a thiol oxidant with peroxidase-like activity, histamine-induced calcium release and calcium entry were significantly suppressed. This effect appeared related to the thiol-directed modification rather than the peroxidase-like activity of ebselen, because this inhibitory effect was not replicated by increasing cellular peroxidase activity. Thus, the opposing effects of sodium selenite and ebselen on histamine-induced calcium signaling are achieved, at least in part, through their opposite actions in modulating the thiol/disulfide redox state.

  18. Legal principles of regulatory administration and nuclear safety regulation

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Kyeong Hui; Cheong, Sang Kee [Hannam Univ., Taejon (Korea, Republic of)

    2000-12-15

    This research presents a critical analysis and evaluation of principles of administrative laws in order to provide framework of structural reform on the nuclear safety regulation system. The focus of this analysis and evaluation is centered around the area of origin of regulatory administrative laws; authorities of regulation; procedures of regulatory actions; regulatory enforcement; and administrative relief system. In chapter 2 the concept of regulatory administration is analysed. Chapter 3 identifies the origin of regulatory administration and the principles of administration laws. It also examines legal nature of the nuclear safety standard. In relation to regulatory authorities. Chapter 4 identifies role and responsibility of administration authorities and institutions. It also examines fundamental principles of delegation of power. Then the chapter discusses the nuclear safety regulation authorities and their roles and responsibilities. Chapter 5 classifies and examines regulatory administration actions. Chapter 6 evaluates enforcement measure for effectiveness of regulation. Finally, chapter 7 discusses the administrative relief system for reviewing unreasonable regulatory acts.

  19. Genomics in the land of regulatory science.

    Science.gov (United States)

    Tong, Weida; Ostroff, Stephen; Blais, Burton; Silva, Primal; Dubuc, Martine; Healy, Marion; Slikker, William

    2015-06-01

    Genomics science has played a major role in the generation of new knowledge in the basic research arena, and currently question arises as to its potential to support regulatory processes. However, the integration of genomics in the regulatory decision-making process requires rigorous assessment and would benefit from consensus amongst international partners and research communities. To that end, the Global Coalition for Regulatory Science Research (GCRSR) hosted the fourth Global Summit on Regulatory Science (GSRS2014) to discuss the role of genomics in regulatory decision making, with a specific emphasis on applications in food safety and medical product development. Challenges and issues were discussed in the context of developing an international consensus for objective criteria in the analysis, interpretation and reporting of genomics data with an emphasis on transparency, traceability and "fitness for purpose" for the intended application. It was recognized that there is a need for a global path in the establishment of a regulatory bioinformatics framework for the development of transparent, reliable, reproducible and auditable processes in the management of food and medical product safety risks. It was also recognized that training is an important mechanism in achieving internationally consistent outcomes. GSRS2014 provided an effective venue for regulators andresearchers to meet, discuss common issues, and develop collaborations to address the challenges posed by the application of genomics to regulatory science, with the ultimate goal of wisely integrating novel technical innovations into regulatory decision-making.

  20. The role of research-article writing motivation and self-regulatory strategies in explaining research-article abstract writing ability.

    Science.gov (United States)

    Lin, Ming-Chia; Cheng, Yuh-Show; Lin, Sieh-Hwa; Hsieh, Pei-Jung

    2015-04-01

    The purpose of the study was to investigate the effects of research-article writing motivation and use of self-regulatory writing strategies in explaining second language (L2) research-article abstract writing ability, alongside the L2 literacy effect. Four measures were administered: a L2 literacy test, a research abstract performance assessment, and inventories of writing motivation and strategy. Participants were L2 graduate students in Taiwan (N=185; M age=25.8 yr., SD=4.5, range=22-53). Results of structural equation modeling showed a direct effect of motivation on research-article writing ability, but no direct effect of strategy or indirect effect of motivation via strategy on research-article writing ability, with L2 literacy controlled. The findings suggest research-article writing instruction should address writing motivation, besides L2 literacy.

  1. The potential role of functional inhibition of T regulatory cells by anti-TGFβ antibody in photodynamic therapy of renal cancer

    Science.gov (United States)

    Mroz, Pawel; Hamblin, Michael R.

    2011-03-01

    Photodynamic therapy (PDT) has been shown to be an effective locally ablative anti-cancer treatment that has the additional advantage of inducing tumor-directed immune response. We hypothesized that PDT could be combined with anti-transforming growth factor (TGF) beta antibody that does not significantly affect the population of cytotoxic T lymphocytes (CTL) but at the same time, has the potential to decrease the immunosuppressive effects of regulatory T-cells (Treg) mediated by TGF beta. This hypothesis was tested with aTGF-beta antibody combined with BPD-mediated PDT in a BALB/c renal cell carcinoma model. Evidence of positive benefits of the combination therapy over individual treatments alone was obtained.

  2. IL-2 and IL-15 Exhibit Opposing Effects on Fas Mediated Apoptosis

    Institute of Scientific and Technical Information of China (English)

    Gulcin Demirci; Xian Chang Li

    2004-01-01

    It has been shown that IL-2 and IL-15 can have opposing effects on life and death of T cells. However, the role of IL-2 and IL-15 in regulating the fate of other cell types is less clear. In the present study, we examined the impact of IL-2 and IL-15 on life and death of pre-B cells using the BAF-B03 line. We showed that BAF-B03 cells constitutively expressed the private IL-2Rα chain and IL-15Rα chain, and the shared IL-2Rβ chain and γc chain. Stimulation of BAF-B03 cells in vitro with IL-2 and IL-15 induced vigorous cell proliferation in a dose-dependent fashion. Titration of IL-2 and IL-15 in the assay showed that the mitotic effects of IL-2 and IL-15 were remarkably similar, Howerer, the sensitivities of BAF-B03 cells to Fas mediated apoptosis after IL-2 and IL-15 stimulation were strikingly different. Cells cultured in IL-2 readily underwent apoptotic cell deathupon cross-linking of the Fas receptor whereas cells cultured in IL-15 were extremely resistant to Fas triggered cell death. The anti-apoptotic effect of IL-15 in this model was associated with increased expression of Bcl-xL. FLIP expression, however, was comparable between IL-2 and IL-15 stimulated cells. We conclude that IL-2 and IL-15 have diametrically opposite effect on the fate of BAF-B03 cells, although both cytokines share similar receptor structure and exhibitsimilarmitoticactivities.

  3. Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative stress in acetaminophen-induced hepato-renal injury.

    Science.gov (United States)

    Naguib, Yahya M; Azmy, Rania M; Samaka, Rehab M; Salem, Mohamed F

    2014-12-15

    Acetaminophen (APAP)-induced toxicity is a predominant cause of acute hepatic and renal failure. In both humans and rodents toxicity begins with a reactive metabolite that binds to proteins. This leads to mitochondrial dysfunction and nuclear DNA fragmentation resulting in necrotic cell death. Pleurotus ostreatus (an edible oyster mushroom) is well recognized as a flavourful food, as well as a medicinal supplement. In the present study, we evaluated the role of Pleurotus ostreatus in the protection against APAP-induced hepato-renal toxicity. We also explored the mechanism by which Pleurotus ostreatus exerts its effects. Ninety adult male Swiss albino mice were divided into three groups (30 mice/group). Mice were offered normal diet (control and APAP groups), or diet supplemented with 10% Pleurotus ostreatus (APAP + Pleurotus ostreatus) for 10 days. Mice were either treated with vehicle (control group, single intra-peritoneal injection.), or APAP (APAP and APAP + Pleurotus ostreatus groups, single intra-peritoneal injection, 500 mg/kg), 24 hours after the last meal. APAP increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) glutamate dehydrogenase (GDH), creatinine, blood urea nitrogen (BUN), urinary kidney injury molecule-1 (KIM-1), and hepatic and renal malondialdehyde (MDA) content. APAP decreased hepatic and renal glutathione (GSH) content, as well as glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. Supplementation with Pleurotus ostreatus significantly reduced APAP-induced elevated levels of ALT, AST, GDH, creatinine, BUN, KIM-1and MDA, while GSH level, and GSH-Px and SOD activities were significantly increased. Our findings were further validated by histopathology; treatment with Pleurotus ostreatus significantly decreased APAP-induced cell necrosis in liver and kidney tissues. We report here that the antioxidant effect of Pleurotus ostreatus opposes mitochondrial dysfunction and oxidative

  4. Unintended hand movements after abrupt cessation of variable and constant opposing forces.

    Science.gov (United States)

    Rapp, K; Heuer, H

    2013-04-16

    Humans are highly efficient in moving in a world of variable resistive forces which result, e.g., from different masses of objects or different directions of movements relative to gravity. However, the underlying mechanisms are challenged when an opposing force is suddenly removed. The resulting involuntary movements are known as accident risks in everyday life. We studied their characteristics upon abrupt cessations of opposing forces of 1, 2, and 4N which were presented in a series of variable or constant forces. The characteristics of the involuntary hand movements are largely determined by the mechanical impedance of the limb. The involuntary movements are oscillatory in nature, and their amplitude increases with stronger opposing force. Limb impedance is modulated both in a reactive and in an anticipatory manner. The reactive modulation occurs during each involuntary movement as a consequence of the neural responses elicited by the rapid limb acceleration consequent upon the cessation of the opposing force. Anticipatory modulation of limb impedance may serve to produce similar involuntary movements in spite of different opposing forces. The modulation is thus stronger with variable forces, where differences between resulting involuntary movements can be experienced more easily, than with constant forces.

  5. Regulatory T cell suppressive potency dictates the balance between bacterial proliferation and clearance during persistent Salmonella infection.

    Directory of Open Access Journals (Sweden)

    Tanner M Johanns

    Full Text Available The pathogenesis of persistent infection is dictated by the balance between opposing immune activation and suppression signals. Herein, virulent Salmonella was used to explore the role and potential importance of Foxp3-expressing regulatory T cells in dictating the natural progression of persistent bacterial infection. Two distinct phases of persistent Salmonella infection are identified. In the first 3-4 weeks after infection, progressively increasing bacterial burden was associated with delayed effector T cell activation. Reciprocally, at later time points after infection, reductions in bacterial burden were associated with robust effector T cell activation. Using Foxp3(GFP reporter mice for ex vivo isolation of regulatory T cells, we demonstrate that the dichotomy in infection tempo between early and late time points is directly paralleled by drastic changes in Foxp3(+ Treg suppressive potency. In complementary experiments using Foxp3(DTR mice, the significance of these shifts in Treg suppressive potency on infection outcome was verified by enumerating the relative impacts of regulatory T cell ablation on bacterial burden and effector T cell activation at early and late time points during persistent Salmonella infection. Moreover, Treg expression of CTLA-4 directly paralleled changes in suppressive potency, and the relative effects of Treg ablation could be largely recapitulated by CTLA-4 in vivo blockade. Together, these results demonstrate that dynamic regulation of Treg suppressive potency dictates the course of persistent bacterial infection.

  6. Opposing effects of 5,7-DHT infusions into the orbitofrontal cortex and amygdala on flexible responding.

    Science.gov (United States)

    Man, M S; Dalley, J W; Roberts, A C

    2010-07-01

    Central serotonin is implicated in a variety of emotional and behavioral control processes. Serotonin depletion can lead to exaggerated aversive processing and deficient response inhibition, effects that have been linked to serotonin's actions in the amygdala and orbitofrontal cortex (OFC), respectively. However, a direct comparison of serotonin manipulations within the OFC and amygdala in the same experimental context has not been undertaken. This study compared the effects of infusing the serotonin neurotoxin, 5,7-dihydroxytryptamine into the OFC and amygdala of marmosets performing an appetitive test of response inhibition. Marmosets had to learn to inhibit a prepotent response tendency to choose a box containing high-incentive food and instead choose a box containing low-incentive food, to obtain reward. OFC infusions caused long-lasting reductions in serotonin tissue levels, as revealed at postmortem, and exaggerated prepotent responses. In contrast, the significantly reduced prepotent responses following amygdala infusions occurred at a time when serotonin tissue levels had undergone considerable recovery, but there remained residual reductions in extracellular serotonin, in vivo. These opposing behavioral effects of serotonin manipulations in the same experimental context may be understood in terms of the top-down regulatory control of the amygdala by the OFC.

  7. Regulatory T Cells and Parasites

    Directory of Open Access Journals (Sweden)

    TP. Velavan

    2011-01-01

    Full Text Available Human host encounters a wide array of parasites; however, the crucial aspect is the failure of the host immune system to clear these parasites despite antigen recognition. In the recent past, a new immunological concept has emerged, which provides a framework to better understand several aspects of host susceptibility to parasitic infection. It is widely believed that parasites are able to modulate the magnitude of effector responses by inducing regulatory T cell (Tregs population and several studies have investigated whether this cell population plays a role in balancing protective immunity and pathogenesis during parasite infection. This review discusses the several mechanism of Treg-mediated immunosuppression in the human host and focuses on the functional role of Tregs and regulatory gene polymorphisms in infectious diseases.

  8. Mixed Convection Opposing Flow in a Vertical Porous Annulus-Two Temperature Model

    Science.gov (United States)

    Al-Rashed, Abdullah A. AA; J, Salman Ahmed N.; Khaleed, H. M. T.; Yunus Khan, T. M.; NazimAhamed, K. S.

    2016-09-01

    The opposing flow in a porous medium refers to a condition when the forcing velocity flows in opposite direction to thermal buoyancy obstructing the buoyant force. The present research refers to the effect of opposing flow in a vertical porous annulus embedded with fluid saturated porous medium. The thermal non-equilibrium approach with Darcy modal is considered. The boundary conditions are such that the inner radius is heated with constant temperature Tw the outer radius is maintained at constant temperature Tc. The coupled nonlinear partial differential equations such as momentum equation, energy equation for fluid and energy equation for solid are solved using the finite element method. The opposing flow variation of average Nusselt number with respect to radius ratio Rr, Aspect ratioAr and Radiation parameter Rd for different values of Peclet number Pe are investigated. It is found that the flow behavior is quite different from that of aiding flow.

  9. Malignant mixed Mullerian tumors of the uterus: histopathological evaluation of cell cycle and apoptotic regulatory proteins

    Directory of Open Access Journals (Sweden)

    Senger Jenna-Lynn B

    2010-07-01

    Full Text Available Abstract Aim The aim of our study was to evaluate survival outcomes in malignant mixed Mullerian tumors (MMMT of the uterus with respect to the role of cell cycle and apoptotic regulatory proteins in the carcinomatous and sarcomatous components. Methods 23 cases of uterine MMMT identified from the Saskatchewan Cancer Agency (1970-1999 were evaluated. Immunohistochemical expression of Bad, Mcl-1, bcl-x, bak, mdm2, bax, p16, p21, p53, p27, EMA, Bcl-2, Ki67 and PCNA was correlated with clinico-pathological data including survival outcomes. Results Histopathological examination confirmed malignant epithelial component with homologous (12 cases and heterologous (11 cases sarcomatous elements. P53 was strongly expressed (70-95% in 15 cases and negative in 5 cases. The average survival in the p53+ve cases was 3.56 years as opposed to 8.94 years in p53-ve cases. Overexpression of p16 and Mcl-1 were observed in patients with longer survival outcomes (> 2 years. P16 and p21 were overexpressed in the carcinomatous and sarcomatous elements respectively. Cyclin-D1 was focally expressed only in the carcinomatous elements. Conclusions Our study supports that a cell cycle and apoptotic regulatory protein dysregulation is an important pathway for tumorigenesis and b p53 is an important immunoprognostic marker in MMMT of the uterus.

  10. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation.

    Science.gov (United States)

    Read, S; Malmström, V; Powrie, F

    2000-07-17

    It is now clear that functionally specialized regulatory T (Treg) cells exist as part of the normal immune repertoire, preventing the development of pathogenic responses to both self- and intestinal antigens. Here, we report that the Treg cells that control intestinal inflammation express the same phenotype (CD25(+)CD45RB(low)CD4(+)) as those that control autoimmunity. Previous studies have failed to identify how CD25(+) Treg cells function in vivo. Our studies reveal that the immune-suppressive function of these cells in vivo is dependent on signaling via the negative regulator of T cell activation cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), as well as secretion of the immune-suppressive cytokine transforming growth factor beta. Strikingly, constitutive expression of CTLA-4 among CD4(+) cells was restricted primarily to Treg cells, suggesting that CTLA-4 expression by these cells is involved in their immune-suppressive function. These findings raise the possibility that Treg cell function contributes to the immune suppression characteristic of CTLA-4 signaling. Identification of costimulatory molecules involved in the function of Treg cells may facilitate further characterization of these cells and development of new therapeutic strategies for the treatment of inflammatory diseases.

  11. Expanded roles of leucine-responsive regulatory protein in transcription regulation of the Escherichia coli genome: Genomic SELEX screening of the regulation targets

    Science.gov (United States)

    Saito, Natsumi; Maeda, Michihisa; Tanaka, Kan; Ishihama, Akira

    2015-01-01

    Leucine-responsive regulatory protein (Lrp) is a transcriptional regulator for the genes involved in transport, biosynthesis and catabolism of amino acids in Escherichia coli. In order to identify the whole set of genes under the direct control of Lrp, we performed Genomic SELEX screening and identified a total of 314 Lrp-binding sites on the E. coli genome. As a result, the regulation target of Lrp was predicted to expand from the hitherto identified genes for amino acid metabolism to a set of novel target genes for utilization of amino acids for protein synthesis, including tRNAs, aminoacyl-tRNA synthases and rRNAs. Northern blot analysis indicated alteration of mRNA levels for at least some novel targets, including the aminoacyl-tRNA synthetase genes. Phenotype MicroArray of the lrp mutant indicated significant alteration in utilization of amino acids and peptides, whilst metabolome analysis showed variations in the concentration of amino acids in the lrp mutant. From these two datasets we realized a reverse correlation between amino acid levels and cell growth rate: fast-growing cells contain low-level amino acids, whilst a high level of amino acids exists in slow-growing cells. Taken together, we propose that Lrp is a global regulator of transcription of a large number of the genes involved in not only amino acid transport and metabolism, but also amino acid utilization. PMID:28348809

  12. Stable Suppression of Lactate Dehydrogenase Activity during Anoxia in the Foot Muscle of Littorina littorea and the Potential Role of Acetylation as a Novel Posttranslational Regulatory Mechanism.

    Science.gov (United States)

    Shahriari, Ali; Dawson, Neal J; Bell, Ryan A V; Storey, Kenneth B

    2013-01-01

    The intertidal marine snail, Littorina littorea, has evolved to withstand extended bouts of oxygen deprivation brought about by changing tides or other potentially harmful environmental conditions. Survival is dependent on a strong suppression of its metabolic rate and a drastic reorganization of its cellular biochemistry in order to maintain energy balance under fixed fuel reserves. Lactate dehydrogenase (LDH) is a crucial enzyme of anaerobic metabolism as it is typically responsible for the regeneration of NAD(+), which allows for the continued functioning of glycolysis in the absence of oxygen. This study compared the kinetic and structural characteristics of the D-lactate specific LDH (E.C. 1.1.1.28) from foot muscle of aerobic control versus 24 h anoxia-exposed L. littorea. Anoxic LDH displayed a near 50% decrease in V max (pyruvate-reducing direction) as compared to control LDH. These kinetic differences suggest that there may be a stable modification and regulation of LDH during anoxia, and indeed, subsequent dot-blot analyses identified anoxic LDH as being significantly less acetylated than the corresponding control enzyme. Therefore, acetylation may be the regulatory mechanism that is responsible for the suppression of LDH activity during anoxia, which could allow for the production of alternative glycolytic end products that in turn would increase the ATP yield under fixed fuel reserves.

  13. Stable Suppression of Lactate Dehydrogenase Activity during Anoxia in the Foot Muscle of Littorina littorea and the Potential Role of Acetylation as a Novel Posttranslational Regulatory Mechanism

    Directory of Open Access Journals (Sweden)

    Ali Shahriari

    2013-01-01

    Full Text Available The intertidal marine snail, Littorina littorea, has evolved to withstand extended bouts of oxygen deprivation brought about by changing tides or other potentially harmful environmental conditions. Survival is dependent on a strong suppression of its metabolic rate and a drastic reorganization of its cellular biochemistry in order to maintain energy balance under fixed fuel reserves. Lactate dehydrogenase (LDH is a crucial enzyme of anaerobic metabolism as it is typically responsible for the regeneration of NAD+, which allows for the continued functioning of glycolysis in the absence of oxygen. This study compared the kinetic and structural characteristics of the D-lactate specific LDH (E.C. 1.1.1.28 from foot muscle of aerobic control versus 24 h anoxia-exposed L. littorea. Anoxic LDH displayed a near 50% decrease in Vmax (pyruvate-reducing direction as compared to control LDH. These kinetic differences suggest that there may be a stable modification and regulation of LDH during anoxia, and indeed, subsequent dot-blot analyses identified anoxic LDH as being significantly less acetylated than the corresponding control enzyme. Therefore, acetylation may be the regulatory mechanism that is responsible for the suppression of LDH activity during anoxia, which could allow for the production of alternative glycolytic end products that in turn would increase the ATP yield under fixed fuel reserves.

  14. Mining the LIPG allelic spectrum reveals the contribution of rare and common regulatory variants to HDL cholesterol.

    Directory of Open Access Journals (Sweden)

    Sumeet A Khetarpal

    2011-12-01

    Full Text Available Genome-wide association studies (GWAS have successfully identified loci associated with quantitative traits, such as blood lipids. Deep resequencing studies are being utilized to catalogue the allelic spectrum at GWAS loci. The goal of these studies is to identify causative variants and missing heritability, including heritability due to low frequency and rare alleles with large phenotypic impact. Whereas rare variant efforts have primarily focused on nonsynonymous coding variants, we hypothesized that noncoding variants in these loci are also functionally important. Using the HDL-C gene LIPG as an example, we explored the effect of regulatory variants identified through resequencing of subjects at HDL-C extremes on gene expression, protein levels, and phenotype. Resequencing a portion of the LIPG promoter and 5' UTR in human subjects with extreme HDL-C, we identified several rare variants in individuals from both extremes. Luciferase reporter assays were used to measure the effect of these rare variants on LIPG expression. Variants conferring opposing effects on gene expression were enriched in opposite extremes of the phenotypic distribution. Minor alleles of a common regulatory haplotype and noncoding GWAS SNPs were associated with reduced plasma levels of the LIPG gene product endothelial lipase (EL, consistent with its role in HDL-C catabolism. Additionally, we found that a common nonfunctional coding variant associated with HDL-C (rs2000813 is in linkage disequilibrium with a 5' UTR variant (rs34474737 that decreases LIPG promoter activity. We attribute the gene regulatory role of rs34474737 to the observed association of the coding variant with plasma EL levels and HDL-C. Taken together, the findings show that both rare and common noncoding regulatory variants are important contributors to the allelic spectrum in complex trait loci.

  15. Regulating regulatory T cells.

    Science.gov (United States)

    Le, N T; Chao, N

    2007-01-01

    Regulatory T cells (Tregs) are a specialized subpopulation of T cells that act to suppress activation of other immune cells and thereby maintain immune system homeostasis, self-tolerance as well as control excessive response to foreign antigens. The mere concept of Tregs was the subject of significant controversy among immunologists for many years owing to the paucity of reliable markers for defining these cells and the ambiguity of the nature and molecular basis of suppressive phenomena. However, recent advances in the molecular characterization of this cell population have firmly established their existence and their vital role in the vertebrate immune system. Of interest, accumulating evidence from both humans and experimental animal models has implicated the involvement of Tregs in the development of graft-versus-host disease (GVHD). The demonstration that Tregs could separate GVHD from graft-versus-tumor (GVT) activity suggests that their immunosuppressive potential could be manipulated to reduce GVHD without detrimental consequence on GVT effect. Although a variety of T lymphocytes with suppressive capabilities have been reported, the two best-characterized subsets are the naturally arising, intrathymic-generated Tregs (natural Tregs) and the peripherally generated, inducible Tregs (inducible Tregs). This review summarizes our current knowledge of the generation, function and regulation of these two populations of Tregs during an immune response. Their role in the development of GVHD and their therapeutic potential for the prevention and treatment of GVHD will also be described.

  16. Spreadsheet Calculations for Jets in Crossflow: Opposed Rows of Inline and Staggered Holes and Single and Opposed Rows with Alternating Hole Sizes

    Science.gov (United States)

    Holdeman, James D.; Clisset, James R.; Moder, Jeffrey P.

    2010-01-01

    The primary purpose of this jet-in-crossflow study was to calculate expected results for two configurations for which limited or no experimental results have been published: (1) cases of opposed rows of closely-spaced jets from inline and staggered round holes and (2) rows of jets from alternating large and small round holes. Simulations of these configurations were performed using an Excel (Microsoft Corporation) spreadsheet implementation of a NASA-developed empirical model which had been shown in previous publications to give excellent representations of mean experimental scalar results suggesting that the NASA empirical model for the scalar field could confidently be used to investigate these configurations. The supplemental Excel spreadsheet is posted with the current report on the NASA Glenn Technical Reports Server (http://gltrs.grc.nasa.gov) and can be accessed from the Supplementary Notes section as TM-2010-216100-SUPPL1.xls. Calculations for cases of opposed rows of jets with the orifices on one side shifted show that staggering can improve the mixing, particularly for cases where jets would overpenetrate slightly if the orifices were in an aligned configuration. The jets from the larger holes dominate the mixture fraction for configurations with a row of large holes opposite a row of smaller ones although the jet penetration was about the same. For single and opposed rows with mixed hole sizes, jets from the larger holes penetrated farther. For all cases investigated, the dimensionless variance of the mixture fraction decreased significantly with increasing downstream distance. However, at a given downstream distance, the variation between cases was small.

  17. Progress on Regulatory Role of miRNA in Complete Metamorphosis Insects Development%miRNA对完全变态昆虫发育的调控作用研究进展

    Institute of Scientific and Technical Information of China (English)

    柴连琴; 王乐; 苗迎春

    2015-01-01

    昆虫尤其是完全变态昆虫的发育过程是一个复杂的网络调控过程,仍有很多问题尚待解决。miRNA是近年来发现的在真核生物中普遍存在的一类19~25 nt微小RNA分子,在转录后水平上发挥重要作用,广泛参与多种重要生物学过程。综述了近年来miRNA在调控完全变态昆虫(果蝇、家蚕、伊蚊、按蚊等)胚胎发育、组织分化以及变态发育等方面的研究进展,以期为深化理解昆虫变态发育机制、发现新的生物防控靶标分子奠定基础。%There are still many issues to be studied about the development of insects,especially complete metamorphosis insects,which is a complex network of regulatory processes. miRNA is present in eukaryotic cells and is a class of natural small regulatory RNA. Its size is 19—25 nucleotides. miRNAs play an important role in post-transcriptional gene regulation,and they can control hundreds of gene targets and regulate diverse biological processes. Here, we review recent developments of the roles of miRNAs in embryogenesis, tissue differentiation and metamorphosis of complete metamorphosis insects, such as drosophila,silkworm,aedes and anopheles,etc,in order to lay the foundation for profoundly reveal the metamorphosis developmental mechanism of insects and discover new molecular targets for prevention and control of insect pests.

  18. 植物类Caspase及其调控细胞程序性死亡的研究进展%Progress in Caspase-Like Proteases and Their Regulatory Roles in Programmed Cell Death in Plants

    Institute of Scientific and Technical Information of China (English)

    詹洁; 何虎翼; 李文; 何龙飞

    2012-01-01

    Programmed cell death (PCD) plays an important role in the development and adaptation of plants under different environmental stresses. Cysteine-aspartic acid proteases (caspase) are responsible for initiating, executing and signal transduction of animal PCD. The existence of caspase-like proteases has been also demonstrated experimentally in plants by the applications of artificial synthesized substrates and inhibitors of caspase. Caspase-like proteases can be divided into three classes including metacaspases, vacuolar processing enzymes (VPEs) and saspases. In the paper, the progresses of the types, structures, locations, functions of caspase-like proteases and their regulatory roles in plant PCD are reviewed. Subsequently, a regulatory pathway of caspase-like proteases in plant PCD is also suggested. It can support a new insight into further study of caspase-like proteases and their effects in plant PCD.%植物细胞程序性死亡(PCD)在植物生长发育和逆境适应中发挥重要作用.半胱氨酸蛋白酶(caspase)调控动物PCD的启动、执行及信号转导.通过人工合成底物、动物caspase抑制剂等方法已证实在植物中存在类caspase,可分为metacas-pases、VPEs (vacuolar processing enzymes)和saspases等.本文综述了植物类caspase的种类、结构、定位、功能及其调控PCD的研究进展,提出植物PCD中类caspase作用的调控途径,为深入研究植物PCD提供参考.

  19. The ζ isoform of diacylglycerol kinase plays a predominant role in regulatory T cell development and TCR-mediated ras signaling.

    Science.gov (United States)

    Joshi, Rohan P; Schmidt, Amanda M; Das, Jayajit; Pytel, Dariusz; Riese, Matthew J; Lester, Melissa; Diehl, J Alan; Behrens, Edward M; Kambayashi, Taku; Koretzky, Gary A

    2013-11-26

    Diacylglycerol (DAG) is a critical second messenger that mediates T cell receptor (TCR)-stimulated signaling. The abundance of DAG is reduced by the diacylglycerol kinases (DGKs), which catalyze the conversion of DAG to phosphatidic acid (PA) and thus inhibit DAG-mediated signaling. In T cells, the predominant DGK isoforms are DGKα and DGKζ, and deletion of the genes encoding either isoform enhances DAG-mediated signaling. We found that DGKζ, but not DGKα, suppressed the development of natural regulatory T (T(reg)) cells and predominantly mediated Ras and Akt signaling downstream of the TCR. The differential functions of DGKα and DGKζ were not attributable to differences in protein abundance in T cells or in their localization to the contact sites between T cells and antigen-presenting cells. RasGRP1, a key DAG-mediated activator of Ras signaling, associated to a greater extent with DGKζ than with DGKα; however, in silico modeling of TCR-stimulated Ras activation suggested that a difference in RasGRP1 binding affinity was not sufficient to cause differences in the functions of each DGK isoform. Rather, the model suggested that a greater catalytic rate for DGKζ than for DGKα might lead to DGKζ exhibiting increased suppression of Ras-mediated signals compared to DGKα. Consistent with this notion, experimental studies demonstrated that DGKζ was more effective than DGKα at catalyzing the metabolism of DAG to PA after TCR stimulation. The enhanced effective enzymatic production of PA by DGKζ is therefore one possible mechanism underlying the dominant functions of DGKζ in modulating T(reg) cell development.

  20. Mechanisms of action of hormone-sensitive lipase in mouse Leydig cells: its role in the regulation of the steroidogenic acute regulatory protein.

    Science.gov (United States)

    Manna, Pulak R; Cohen-Tannoudji, Joëlle; Counis, Raymond; Garner, Charles W; Huhtaniemi, Ilpo; Kraemer, Fredric B; Stocco, Douglas M

    2013-03-22

    Hormone-sensitive lipase (HSL) catalyzes the hydrolysis of cholesteryl esters in steroidogenic tissues and, thus, facilitates cholesterol availability for steroidogenesis. The steroidogenic acute regulatory protein (StAR) controls the rate-limiting step in steroid biosynthesis. However, the modes of action of HSL in the regulation of StAR expression remain obscure. We demonstrate in MA-10 mouse Leydig cells that activation of the protein kinase A (PKA) pathway, by a cAMP analog Bt2cAMP, enhanced expression of HSL and its phosphorylation (P) at Ser-660 and Ser-563, but not at Ser-565, concomitant with increased HSL activity. Phosphorylation and activation of HSL coincided with increases in StAR, P-StAR (Ser-194), and progesterone levels. Inhibition of HSL activity by CAY10499 effectively suppressed Bt2cAMP-induced StAR expression and progesterone synthesis. Targeted silencing of endogenous HSL, with siRNAs, resulted in increased cholesteryl ester levels and decreased cholesterol content in MA-10 cells. Depletion of HSL affected lipoprotein-derived cellular cholesterol influx, diminished the supply of cholesterol to the mitochondria, and resulted in the repression of StAR and P-StAR levels. Cells overexpressing HSL increased the efficacy of liver X receptor (LXR) ligands on StAR expression and steroid synthesis, suggesting HSL-mediated steroidogenesis entails enhanced oxysterol production. Conversely, cells deficient in LXRs exhibited decreased HSL responsiveness. Furthermore, an increase in HSL was correlated with the LXR target genes, steroid receptor element-binding protein 1c and ATP binding cassette transporter A1, demonstrating HSL-dependent regulation of steroidogenesis predominantly involves LXR signaling. LXRs interact/cooperate with RXRs and result in the activation of StAR gene transcription. These findings provide novel insight and demonstrate the molecular events by which HSL acts to drive cAMP/PKA-mediated regulation of StAR expression and

  1. Characterization and expression analysis of EF hand domain-containing calcium-regulatory gene from disk abalone: calcium homeostasis and its role in immunity.

    Science.gov (United States)

    Nikapitiya, Chamilani; De Zoysa, Mahanama; Whang, Ilson; Kim, Se-Jae; Choi, Cheol Young; Lee, Jae-Seong; Lee, Jehee

    2010-08-01

    The complete amino acid sequence of a calcium-regulatory gene (denoted as Ab-CaReg I) was identified from the disk abalone Haliotis discus discus cDNA library. The Ab-CaReg I is composed of 176 amino acids and the calculated molecular mass and isoelectric point were 20 and 4.2, respectively. The sequence homology of Ab-CaReg I was 28-30 and 18-27% of known calmodulin and troponin C, respectively. Four characteristic calcium-binding EF hand motifs with some modifications at conserved positions of known homologous calmodulin genes were observed in the sequence. The tissue-specific transcription analysis and variation of mRNA transcription level of Ab-CaReg I in gills and mantle after animals were immersed in seawater containing 2000 ppm CaCl(2) was quantified by SYBR Green real-time PCR analysis. Transcription variation of Ab-CaReg I in hemocytes and gills followed by bacteria challenge (Vibrio alginolyticus, Vibrio parahaemolyticus and Listeria monocytogenes) was used to investigate Ab-CaReg I in immune responses. Transcripts of Ab-CaReg I mRNA were mainly detected in hemocytes, mantle, muscle, gills, digestive tract and hepatopancreas with highest expression in hemocytes. The CaCl(2) immersion significantly altered the Ab-CaReg I mRNA transcription level by 3 h, compared to animals in normal seawater (control). The mRNA expression of Ab-CaReg I in gills and hemocytes was upregulated significantly to 11-fold and 4-fold in 3 h compared to control (uninfected), respectively, in bacteria-challenged abalones. The results suggest that Ab-CaReg I could be effectively induced to maintain internal Ca(2+) homeostasis of the animal due to influx of Ca(2+) in the cells by external stimuli such as a high dose of Ca(2+) and pathogens like bacteria.

  2. SURFACE MODIFICATION OF NANOPARTICLES TO OPPOSE UPTAKE BY THE MONONUCLEAR PHAGOCYTE SYSTEM

    NARCIS (Netherlands)

    STORM, G; BELLIOT, SO; DAEMEN, T; LASIC, DD

    1995-01-01

    An overview of recent advances in the surface modification of colloidal particles to oppose uptake by the mononuclear phagocyte system (MPS) is presented. First, we describe the colloidal particles and hydrophilic coating materials investigated, with particular focus on the literature concerning par

  3. Polyvinyl siloxane template aids in recontouring natural teeth opposing single dentures.

    Science.gov (United States)

    Javid, N; Esquivel, J F

    1996-09-01

    This article describes a procedure that provides proper reduction of natural teeth opposing complete dentures. By use of a polyvinyl siloxane prosthetic template, natural dentition can be reduced to a more favorable plane, which will facilitate denture construction. This procedure will eliminate the risk of arbitrary grinding and will minimize guesswork through guided intraoral reduction.

  4. Circumcision of the Female Intellect: 19th Century Women Who Opposed Scholarly Education

    Science.gov (United States)

    Holmes, Marbeth

    2009-01-01

    In 19th century America, some women decried the opportunity for scholarly education as rebellion against religion and predicted a grim decline in the quality of life, home, and hearth for American families and for American culture and politics. In particular, women who opposed scholarly education argued that God had not created men and women…

  5. Assessment of a dual regulatory role for NO in liver regeneration after partial hepatectomy: protection against apoptosis and retardation of hepatocyte proliferation.

    Science.gov (United States)

    Zeini, Miriam; Hortelano, Sonsoles; Través, Paqui G; Gómez-Valadés, Alicia G; Pujol, Anna; Perales, José C; Bartrons, Ramón; Boscá, Lisardo

    2005-06-01

    The role of hepatic nitric oxide (NO) in liver regeneration after partial hepatectomy (PH) was studied in animals carrying a nitric oxide synthase-2 transgene under the control of the phospho(enol)pyruvate carboxykinase promoter. These mice expressed NOS-2 in liver cells under fasting conditions. Liver mass recovery and molecular parameters related to cell proliferation were determined after PH. Preexisting hepatic NO synthesis, as well as NO delivery by NO-donors, impaired early signaling (for example, attenuated NF-kappaB activation and TNF-alpha and IL-6 release). The regenerative process was also impaired as a result of an insufficient proliferative response, but mouse survival after surgery was not compromised. However, NO exerted a protective role against apoptosis in transgenic hepatectomized mice. Local production of NO in liver cells, achieved by hydrodynamic-based transfection with a NOS-2-encoding plasmid, also resulted in delayed liver recovery after PH and also protected against Fas-mediated apoptosis. These data show that sustained presence of NO after PH exerts a dual role: attenuating liver regeneration while efficiently protecting against liver apoptosis.

  6. Phosphorylated TDP-43 becomes resistant to cleavage by calpain: A regulatory role for phosphorylation in TDP-43 pathology of ALS/FTLD.

    Science.gov (United States)

    Yamashita, Takenari; Teramoto, Sayaka; Kwak, Shin

    2016-06-01

    TAR DNA-binding protein-43 (TDP-43) pathology, which includes the presence of abnormal TDP-43-containing inclusions with a loss of nuclear TDP-43 in affected neurons, is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and/or frontotemporal lobar degeneration (FTLD). TDP-43 in the pathological brains and spinal cords of ALS/FTLD patients is abnormally fragmented and phosphorylated. It is believed that the generation of aggregation-prone TDP-43 fragments initiates TDP-43 pathology, and we previously reported that calpain has an important role in the generation of such aggregation-prone TDP-43 fragments. However, the role of phosphorylation in TDP-43 pathology has not been largely elucidated, despite previous observations that several kinases and their kinases are involved in TDP-43 phosphorylation. Here, we investigated the role of TDP-43 phosphorylation in the calpain-dependent cleavage of TDP-43 and found that phosphorylated, full-length TDP-43 and calpain-dependent TDP-43 fragments were more resistant to cleavage by calpain than endogenous full-length TDP-43 was. These results suggest that both phosphorylated and calpain-cleaved TDP-43 fragments persist intracellularly for a length of time that is sufficient for self-aggregation, thereby serving as seeds for inclusions. Copyright © 2015 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  7. Zooming in on regulatory intermediaries: The impact of non-state regulators on sustainable construction practice

    NARCIS (Netherlands)

    van der Heijden, J.

    2014-01-01

    Levi-Faur and Starobin (2013) have recently drawn our attention to the important role of regulatory intermediates in contemporary regulatory regimes. Among others they argue that regulatory intermediaries come in a wide variety of appearances, and that these can influence the outcomes of regulatory

  8. Properdin and Factor H: Opposing players on the alternative complement pathway see-saw

    Directory of Open Access Journals (Sweden)

    Lubna eKouser

    2013-04-01

    Full Text Available Properdin and factor H are two key regulatory proteins having opposite functions in the alternative complement pathway. Properdin up-regulates the alternative pathway by stabilising the C3bBb complex, whereas factor H down-regulates the pathway by promoting proteolytic degradation of C3b. While factor H is mainly produced in the liver, there are several extrahepatic sources. In addition to the liver, factor H is also synthesized in fetal tubuli, keratinocytes, skin fibroblasts, ocular tissue, adipose tissue, brain, lungs, heart, spleen, pancreas, kidney, muscle, and placenta. Neutrophils are the major source of properdin, and it is also produced by monocytes, T cells and bone marrow progenitor cell line. Properdin is released by neutrophils from intracellular stores following stimulation by N-formyl-methionine-leucine-phenylalanine and tumour necrosis factor alpha. The HEP G2 cells derived from human liver has been found to produce functional properdin. Endothelial cells also produce properdin when induced by shear stress, thus is a physiological source for plasma properdin.. The diverse range of extrahepatic sites for synthesis of these two complement regulators suggests the importance and need for local availability of the proteins. Here, we discuss the significance of the local synthesis of properdin and factor H. This assumes greater importance in view of recently identified unexpected and novel roles of properdin and factor H that are potentially independent of their involvement in the complement regulation.

  9. Opposing Functions of the N-terminal Acetyltransferases Naa50 and NatA in Sister-chromatid Cohesion.

    Science.gov (United States)

    Rong, Ziye; Ouyang, Zhuqing; Magin, Robert S; Marmorstein, Ronen; Yu, Hongtao

    2016-09-02

    During the cell cycle, sister-chromatid cohesion tethers sister chromatids together from S phase to the metaphase-anaphase transition and ensures accurate segregation of chromatids into daughter cells. N-terminal acetylation is one of the most prevalent protein covalent modifications in eukaryotes and is mediated by a family of N-terminal acetyltransferases (NAT). Naa50 (also called San) has previously been shown to play a role in sister-chromatid cohesion in metazoans. The mechanism by which Naa50 contributes to cohesion is not understood however. Here, we show that depletion of Naa50 in HeLa cells weakens the interaction between cohesin and its positive regulator sororin and causes cohesion defects in S phase, consistent with a role of Naa50 in cohesion establishment. Strikingly, co-depletion of NatA, a heterodimeric NAT complex that physically interacts with Naa50, rescues the sister-chromatid cohesion defects and the resulting mitotic arrest caused by Naa50 depletion, indicating that NatA and Naa50 play antagonistic roles in cohesion. Purified recombinant NatA and Naa50 do not affect each other's NAT activity in vitro Because NatA and Naa50 exhibit distinct substrate specificity, we propose that they modify different effectors and regulate sister-chromatid cohesion in opposing ways.

  10. Two group A streptococcal peptide pheromones act through opposing Rgg regulators to control biofilm development.

    Science.gov (United States)

    Chang, Jennifer C; LaSarre, Breah; Jimenez, Juan C; Aggarwal, Chaitanya; Federle, Michael J

    2011-08-01

    Streptococcus pyogenes (Group A Streptococcus, GAS) is an important human commensal that occasionally causes localized infections and less frequently causes severe invasive disease with high mortality rates. How GAS regulates expression of factors used to colonize the host and avoid immune responses remains poorly understood. Intercellular communication is an important means by which bacteria coordinate gene expression to defend against host assaults and competing bacteria, yet no conserved cell-to-cell signaling system has been elucidated in GAS. Encoded within the GAS genome are four rgg-like genes, two of which (rgg2 and rgg3) have no previously described function. We tested the hypothesis that rgg2 or rgg3 rely on extracellular peptides to control target-gene regulation. We found that Rgg2 and Rgg3 together tightly regulate two linked genes encoding new peptide pheromones. Rgg2 activates transcription of and is required for full induction of the pheromone genes, while Rgg3 plays an antagonistic role and represses pheromone expression. The active pheromone signals, termed SHP2 and SHP3, are short and hydrophobic (DI[I/L]IIVGG), and, though highly similar in sequence, their ability to disrupt Rgg3-DNA complexes were observed to be different, indicating that specificity and differential activation of promoters are characteristics of the Rgg2/3 regulatory circuit. SHP-pheromone signaling requires an intact oligopeptide permease (opp) and a metalloprotease (eep), supporting the model that pro-peptides are secreted, processed to the mature form, and subsequently imported to the cytoplasm to interact directly with the Rgg receptors. At least one consequence of pheromone stimulation of the Rgg2/3 pathway is increased biogenesis of biofilms, which counteracts negative regulation of biofilms by RopB (Rgg1). These data provide the first demonstration that Rgg-dependent quorum sensing functions in GAS and substantiate the role that Rggs play as peptide receptors across the

  11. Two group A streptococcal peptide pheromones act through opposing Rgg regulators to control biofilm development.

    Directory of Open Access Journals (Sweden)

    Jennifer C Chang

    2011-08-01

    Full Text Available Streptococcus pyogenes (Group A Streptococcus, GAS is an important human commensal that occasionally causes localized infections and less frequently causes severe invasive disease with high mortality rates. How GAS regulates expression of factors used to colonize the host and avoid immune responses remains poorly understood. Intercellular communication is an important means by which bacteria coordinate gene expression to defend against host assaults and competing bacteria, yet no conserved cell-to-cell signaling system has been elucidated in GAS. Encoded within the GAS genome are four rgg-like genes, two of which (rgg2 and rgg3 have no previously described function. We tested the hypothesis that rgg2 or rgg3 rely on extracellular peptides to control target-gene regulation. We found that Rgg2 and Rgg3 together tightly regulate two linked genes encoding new peptide pheromones. Rgg2 activates transcription of and is required for full induction of the pheromone genes, while Rgg3 plays an antagonistic role and represses pheromone expression. The active pheromone signals, termed SHP2 and SHP3, are short and hydrophobic (DI[I/L]IIVGG, and, though highly similar in sequence, their ability to disrupt Rgg3-DNA complexes were observed to be different, indicating that specificity and differential activation of promoters are characteristics of the Rgg2/3 regulatory circuit. SHP-pheromone signaling requires an intact oligopeptide permease (opp and a metalloprotease (eep, supporting the model that pro-peptides are secreted, processed to the mature form, and subsequently imported to the cytoplasm to interact directly with the Rgg receptors. At least one consequence of pheromone stimulation of the Rgg2/3 pathway is increased biogenesis of biofilms, which counteracts negative regulation of biofilms by RopB (Rgg1. These data provide the first demonstration that Rgg-dependent quorum sensing functions in GAS and substantiate the role that Rggs play as peptide

  12. Evidence for a positive regulatory role of strawberry (Fragaria x ananassa) Fa WRKY1 and Arabidopsis At WRKY75 proteins in resistance.

    Science.gov (United States)

    Encinas-Villarejo, Sonia; Maldonado, Ana M; Amil-Ruiz, Francisco; de los Santos, Berta; Romero, Fernando; Pliego-Alfaro, Fernando; Muñoz-Blanco, Juan; Caballero, José L

    2009-01-01

    Knowledge of the molecular basis of plant resistance to pathogens in species other than Arabidopsis is limited. The function of Fa WRKY1, the first WRKY gene isolated from strawberry (Fragaria x ananassa), an important agronomical fruit crop, has been investigated here. Fa WRKY1 encodes a IIc WRKY transcription factor and is up-regulated in strawberry following Colletotrichum acutatum infection, treatments with elicitors, and wounding. Its Arabidopsis sequence homologue, At WRKY75, has been described as playing a role in regulating phosphate starvation responses. However, using T-DNA insertion mutants, a role for the At WRKY75 and Fa WRKY1 in the activation of basal and R-mediated resistance in Arabidopsis is demonstrated. At wrky75 mutants are more susceptible to virulent and avirulent isolates of Pseudomonas syringae. Overexpression of Fa WRKY1 in At wrky75 mutant and wild type reverts the enhanced susceptible phenotype of the mutant, and even increases resistance to avirulent strains of P. syringae. The resistance phenotype is uncoupled to PATHOGENESIS-RELATED (PR) gene expression, but it is associated with a strong oxidative burst and glutathione-S-transferase (GST) induction. Taken together, these results indicate that At WRKY75 and Fa WRKY1 act as positive regulators of defence during compatible and incompatible interactions in Arabidopsis and, very likely, Fa WRKY1 is an important element mediating defence responses to C. acutatum in strawberry. Moreover, these results provide evidence that Arabidopsis can be a useful model for functional studies in Rosacea species like strawberry.

  13. The transcription factor Ste12 mediates the regulatory role of the Tmk1 MAP kinase in mycoparasitism and vegetative hyphal fusion in the filamentous fungus Trichoderma atroviride.

    Science.gov (United States)

    Gruber, Sabine; Zeilinger, Susanne

    2014-01-01

    Mycoparasitic species of the fungal genus Trichoderma are potent antagonists able to combat plant pathogenic fungi by direct parasitism. An essential step in this mycoparasitic fungus-fungus interaction is the detection of the fungal host followed by activation of molecular weapons in the mycoparasite by host-derived signals. The Trichoderma atroviride MAP kinase Tmk1, a homolog of yeast Fus3/Kss1, plays an essential role in regulating the mycoparasitic host attack, aerial hyphae formation and conidiation. However, the transcription factors acting downstream of Tmk1 are hitherto unknown. Here we analyzed the functions of the T. atroviride Ste12 transcription factor whose orthologue in yeast is targeted by the Fus3 and Kss1 MAP kinases. Deletion of the ste12 gene in T. atroviride not only resulted in reduced mycoparasitic overgrowth and lysis of host fungi but also led to loss of hyphal avoidance in the colony periphery and a severe reduction in conidial anastomosis tube formation and vegetative hyphal fusion events. The transcription of several orthologues of Neurospora crassa hyphal fusion genes was reduced upon ste12 deletion; however, the Δste12 mutant showed enhanced expression of mycoparasitism-relevant chitinolytic and proteolytic enzymes and of the cell wall integrity MAP kinase Tmk2. Based on the comparative analyses of Δste12 and Δtmk1 mutants, an essential role of the Ste12 transcriptional regulator in mediating outcomes of the Tmk1 MAPK pathway such as regulation of the mycoparasitic activity, hyphal fusion and carbon source-dependent vegetative growth is suggested. Aerial hyphae formation and conidiation, in contrast, were found to be independent of Ste12.

  14. Mass spectrometric analysis of the interactions between CP12, a chloroplast protein, and metal ions: a possible regulatory role within a PRK/GAPDH/CP12 complex.

    Science.gov (United States)

    Delobel, Arnaud; Graciet, Emmanuelle; Andreescu, Simona; Gontero, Brigitte; Halgand, Frédéric; Laprévote, Olivier

    2005-01-01

    The small chloroplast protein CP12 plays the role of a protein linker in the assembly process of a PRK/GAPDH/CP12 complex that is involved in CO2 assimilation in photosynthetic organisms. The redox state of CP12 regulates its role as a protein linker. Only the oxidized protein, with two disulfide bonds, is active in complex formation. Several observations indicating that CP12 might bind a metal ion led us to screen the binding of different metal ions on oxidized or reduced CP12 using non-covalent electrospray ionization mass spectrometry (ESI-MS) experiments. The oxidized protein bound specifically Cu2+ and Ni2+ (Kd of 26+/-1 microM and 11+/-1 microM, respectively); other cations such as Fe2+ and Zn2+ did not bind, while cations such as Cd2+ formed non-specific adducts to CP12. Similar results were obtained for metal ions on screening with the reduced CP12. Interestingly, the present results suggest that Cu2+ catalyzes the re-formation of the disulfide bonds of the reduced CP12, leading to recovery of the fully oxidized CP12 that is then able to bind a Cu2+ ion. Finally the high similarity between CP12 and copper chaperones from Arabidopsis thaliana, as judged by hydrophobic cluster analysis, provides additional evidence for the relevance of metal binding for the in vivo situation. The findings that CP12 is able to bind a metal ion, and that Cu2+ catalyzes the oxidation of the thiol groups of CP12, are new characteristics of this protein that may prove to be important in the regulation of the assembly process of the PRK/GAPDH/CP12 complex.

  15. The transcription factor Ste12 mediates the regulatory role of the Tmk1 MAP kinase in mycoparasitism and vegetative hyphal fusion in the filamentous fungus Trichoderma atroviride.

    Directory of Open Access Journals (Sweden)

    Sabine Gruber

    Full Text Available Mycoparasitic species of the fungal genus Trichoderma are potent antagonists able to combat plant pathogenic fungi by direct parasitism. An essential step in this mycoparasitic fungus-fungus interaction is the detection of the fungal host followed by activation of molecular weapons in the mycoparasite by host-derived signals. The Trichoderma atroviride MAP kinase Tmk1, a homolog of yeast Fus3/Kss1, plays an essential role in regulating the mycoparasitic host attack, aerial hyphae formation and conidiation. However, the transcription factors acting downstream of Tmk1 are hitherto unknown. Here we analyzed the functions of the T. atroviride Ste12 transcription factor whose orthologue in yeast is targeted by the Fus3 and Kss1 MAP kinases. Deletion of the ste12 gene in T. atroviride not only resulted in reduced mycoparasitic overgrowth and lysis of host fungi but also led to loss of hyphal avoidance in the colony periphery and a severe reduction in conidial anastomosis tube formation and vegetative hyphal fusion events. The transcription of several orthologues of Neurospora crassa hyphal fusion genes was reduced upon ste12 deletion; however, the Δste12 mutant showed enhanced expression of mycoparasitism-relevant chitinolytic and proteolytic enzymes and of the cell wall integrity MAP kinase Tmk2. Based on the comparative analyses of Δste12 and Δtmk1 mutants, an essential role of the Ste12 transcriptional regulator in mediating outcomes of the Tmk1 MAPK pathway such as regulation of the mycoparasitic activity, hyphal fusion and carbon source-dependent vegetative growth is suggested. Aerial hyphae formation and conidiation, in contrast, were found to be independent of Ste12.

  16. Mutational Analysis of the QRRQ Motif in the Yeast Hig1-type 2 Protein, Rcf1, Reveals a Regulatory Role for the Cytochrome c Oxidase Complex.

    Science.gov (United States)

    Garlich, Joshua; Strecker, Valentina; Wittig, Ilka; Stuart, Rosemary A

    2017-02-06

    The yeast Rcf1 protein is a member of the conserved family of proteins termed the hypoxia induced gene (domain) 1 (Hig1 or HIGD1) family. Rcf1 interacts with components of the mitochondrial oxidative phosphorylation system in particular the cytochrome bc1 (complex III)-cytochrome c oxidase (complex IV) supercomplex (termed III-IV) and the ADP/ATP carrier proteins (AAC). Rcf1 plays a role in the assembly and modulation of the activity of complex IV, however, the molecular basis for how Rcf1 influences the activity of complex IV is currently unknown. Hig1-type 2 isoforms, which include the Rcf1 protein, are characterized in part by the presence of a conserved motif, (Q/I)-X3-(R/H)-X-R-X3-Q, termed here the QRRQ motif. We show that mutation of conserved residues within the Rcf1 QRRQ motif alters the interactions between Rcf1 and partner proteins and results in the destabilization of complex IV and an alteration of its enzymatic properties. Our findings indicate that Rcf1 does not serve as a stoichiometric component, i.e. as a subunit of complex IV, to support its activity. Rather, we propose that Rcf1 serves to dynamically interact with complex IV during its assembly process and in doing so regulates a late maturation step of complex IV. We speculate that the Rcf1/Hig1 proteins play a role in the incorporation and/or remodeling of lipids, in particular cardiolipin, into complex IV and possibly other mitochondrial proteins, such as AAC.

  17. RNA Sequencing and Bioinformatics Analysis Implicate the Regulatory Role of a Long Noncoding RNA-mRNA Network in Hepatic Stellate Cell Activation.

    Science.gov (United States)

    Guo, Can-Jie; Xiao, Xiao; Sheng, Li; Chen, Lili; Zhong, Wei; Li, Hai; Hua, Jing; Ma, Xiong

    2017-08-11

    To analyze the long noncoding (lncRNA)-mRNA expression network and potential roles in rat hepatic stellate cells (HSCs) during activation. LncRNA expression was analyzed in quiescent and culture-activated HSCs by RNA sequencing, and differentially expressed lncRNAs verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR) were subjected to bioinformatics analysis. In vivo analyses of differential lncRNA-mRNA expression were performed on a rat model of liver fibrosis. We identified upregulation of 12 lncRNAs and 155 mRNAs and downregulation of 12 lncRNAs and 374 mRNAs in activated HSCs. Additionally, we identified the differential expression of upregulated lncRNAs (NONRATT012636.2, NONRATT016788.2, and NONRATT021402.2) and downregulated lncRNAs (NONRATT007863.2, NONRATT019720.2, and NONRATT024061.2) in activated HSCs relative to levels observed in quiescent HSCs, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that changes in lncRNAs associated with HSC activation revealed 11 significantly enriched pathways according to their predicted targets. Moreover, based on the predicted co-expression network, the relative dynamic levels of NONRATT013819.2 and lysyl oxidase (Lox) were compared during HSC activation both in vitro and in vivo. Our results confirmed the upregulation of lncRNA NONRATT013819.2 and Lox mRNA associated with the extracellular matrix (ECM)-related signaling pathway in HSCs and fibrotic livers. Our results detailing a dysregulated lncRNA-mRNA network might provide new treatment strategies for hepatic fibrosis based on findings indicating potentially critical roles for NONRATT013819.2 and Lox in ECM remodeling during HSC activation. © 2017 The Author(s). Published by S. Karger AG, Basel.

  18. RNA Sequencing and Bioinformatics Analysis Implicate the Regulatory Role of a Long Noncoding RNA-mRNA Network in Hepatic Stellate Cell Activation

    Directory of Open Access Journals (Sweden)

    Can-Jie Guo

    2017-08-01

    Full Text Available Background/Aims: To analyze the long noncoding (lncRNA-mRNA expression network and potential roles in rat hepatic stellate cells (HSCs during activation. Methods: LncRNA expression was analyzed in quiescent and culture-activated HSCs by RNA sequencing, and differentially expressed lncRNAs verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR were subjected to bioinformatics analysis. In vivo analyses of differential lncRNA-mRNA expression were performed on a rat model of liver fibrosis. Results: We identified upregulation of 12 lncRNAs and 155 mRNAs and downregulation of 12 lncRNAs and 374 mRNAs in activated HSCs. Additionally, we identified the differential expression of upregulated lncRNAs (NONRATT012636.2, NONRATT016788.2, and NONRATT021402.2 and downregulated lncRNAs (NONRATT007863.2, NONRATT019720.2, and NONRATT024061.2 in activated HSCs relative to levels observed in quiescent HSCs, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that changes in lncRNAs associated with HSC activation revealed 11 significantly enriched pathways according to their predicted targets. Moreover, based on the predicted co-expression network, the relative dynamic levels of NONRATT013819.2 and lysyl oxidase (Lox were compared during HSC activation both in vitro and in vivo. Our results confirmed the upregulation of lncRNA NONRATT013819.2 and Lox mRNA associated with the extracellular matrix (ECM-related signaling pathway in HSCs and fibrotic livers. Conclusion: Our results detailing a dysregulated lncRNA-mRNA network might provide new treatment strategies for hepatic fibrosis based on findings indicating potentially critical roles for NONRATT013819.2 and Lox in ECM remodeling during HSC activation.

  19. Tug-of-war between opposing molecular motors explains chromosomal oscillation during mitosis.

    Science.gov (United States)

    Sutradhar, S; Paul, R

    2014-03-07

    Chromosomes move towards and away from the centrosomes during the mitosis. This oscillation is observed when the kinetochore, a specific protein structure on the chromosome is captured by centrosome-nucleated polymer called microtubules. We present a computational model, incorporating activities of various molecular motors and microtubule dynamics, to demonstrate the observed oscillation. The model is robust and is not restricted to any particular cell type. Quantifying the average velocity, amplitude and periodicity of the chromosomal oscillation, we compare numerical results with the available experimental data. Our analysis supports a tug-of-war like mechanism between opposing motors that changes the course of chromosomal oscillation. It turns out that, various modes of oscillation can be fully understood by assembling the dynamics of molecular motors. Near the stall regime, when opposing motors are engaged in a tug-of-war, sufficiently large kinetochore-microtubule generated force may prolong the stall durations.

  20. Opposable spines facilitate fine and gross object manipulation in fire ants

    Science.gov (United States)

    Cassill, Deby; Greco, Anthony; Silwal, Rajesh; Wang, Xuefeng

    2007-04-01

    Ants inhabit diverse terrestrial biomes from the Sahara Desert to the Arctic tundra. One factor contributing to the ants’ successful colonization of diverse geographical regions is their ability to manipulate objects when excavating nests, capturing, transporting and rendering prey or grooming, feeding and transporting helpless brood. This paper is the first to report the form and function of opposable spines on the foretarsi of queens and workers used during fine motor and gross motor object manipulation in the fire ant, Solenopsis invicta. In conjunction with their mandibles, queens and workers used their foretarsi to grasp and rotate eggs, push or pull thread-like objects out of their way or push excavated soil pellets behind them for disposal by other workers. Opposable spines were found on the foretarsi of workers from seven of eight other ant species suggesting that they might be a common feature in the Formicidae.

  1. A closer look at opposing models for the T cell response to pathogens

    Science.gov (United States)

    Hanson, Shalla

    2016-06-01

    The problem of understanding the mechanisms of differentiation, activation, and interconversion of phenotypes of CD8+ T cells is one of crucial importance in cancer therapy, owing to both the anti-tumor efficacy of CD8+ T cells as well as the severe toxicity that results from excess expansion of this population. Several opposing theories exist which describe potential pathways for the development of the CD8+ T cell repertoire; however, the accuracy of each remains controversial. Here we review the current hypotheses, provide a critical overview of pivotal biological data from which these theories are derived, and discuss principle population-level implications. Finally, we offer a novel hypothesis which maintains consistency with each of the experimental studies and seeks to unify the currently opposing but not so disparate theories.

  2. The Path of Ambivalence: Tracing the Pull of Opposing Evaluations using Mouse Trajectories

    Directory of Open Access Journals (Sweden)

    Iris K. Schneider

    2015-07-01

    Full Text Available Ambivalence refers to a psychological conflict between opposing evaluations, often experienced as being torn between alternatives. This dynamic aspect of ambivalence is hard to capture with outcome-focused measures, such as response times or self-report. To gain more insight into ambivalence as it unfolds, the current work uses an embodied measure of pull, drawing on research in dynamic systems. In three studies, using different materials, we tracked people’s mouse movements as they chose between negative and positive evaluations of attitude objects. When participants evaluated ambivalent attitude objects, their mouse trajectories showed more pull of the non-chosen evaluative option than when they evaluated univalent attitude objects, revealing that participants were literally torn between the two opposing evaluations. We address the relationship of this dynamic measure to response time and self-reports of ambivalence and discuss implications and avenues for future research.

  3. The path of ambivalence: tracing the pull of opposing evaluations using mouse trajectories

    Science.gov (United States)

    Schneider, Iris K.; van Harreveld, Frenk; Rotteveel, Mark; Topolinski, Sascha; van der Pligt, Joop; Schwarz, Norbert; Koole, Sander L.

    2015-01-01

    Ambivalence refers to a psychological conflict between opposing evaluations, often experienced as being torn between alternatives. This dynamic aspect of ambivalence is hard to capture with outcome-focused measures, such as response times or self-report. To gain more insight into ambivalence as it unfolds, the current work uses an embodied measure of pull, drawing on research in dynamic systems. In three studies, using different materials, we tracked people’s mouse movements as they chose between negative and positive evaluations of attitude objects. When participants evaluated ambivalent attitude objects, their mouse trajectories showed more pull of the non-chosen evaluative option than when they evaluated univalent attitude objects, revealing that participants were literally torn between the two opposing evaluations. We address the relationship of this dynamic measure to response time and self-reports of ambivalence and discuss implications and avenues for future research. PMID:26236267

  4. On the influence of the gas velocity profile on the theoretically predicted opposed flow flame spread

    Energy Technology Data Exchange (ETDEWEB)

    DiBlasi, C.; Crescitelli, S.; Russo, G. (Dipartimento di Ingegneria Chimica, Universita de Napoli, Piazzale v Tecchio, Naples (IT)); FernandezPello, A.C. (California Univ., Berkeley, CA (USA). Dept. of Mechanical Engineering)

    1989-01-01

    A numerical analysis is presented of the effect on the predicted flame spread rate and flame structure of a prescribed gas velocity field opposing the direction of flame propagation. The calculations are made for two limiting cases of oxygen mass fraction and with Oseen and Hagen-Poiseuille velocity profiles. It is shown that the selected gas velocity profile has a significant influence on the flame spread predictions.

  5. OGlcNAcylation and phosphorylation have opposing structural effects in tau: phosphothreonine induces particular conformational order.

    Science.gov (United States)

    Brister, Michael A; Pandey, Anil K; Bielska, Agata A; Zondlo, Neal J

    2014-03-12

    Phosphorylation and OGlcNAcylation are dynamic intracellular protein post-translational modifications that frequently are alternatively observed on the same serine and threonine residues. Phosphorylation and OGlcNAcylation commonly occur in natively disordered regions of proteins, and often have opposing functional effects. In the microtubule-associated protein tau, hyperphosphorylation is associated with protein misfolding and aggregation as the neurofibrillary tangles of Alzheimer's disease, whereas OGlcNAcylation stabilizes the soluble form of tau. A series of peptides derived from the proline-rich domain (residues 174-251) of tau was synthesized, with free Ser/Thr hydroxyls, phosphorylated Ser/Thr (pSer/pThr), OGlcNAcylated Ser/Thr, and diethylphosphorylated Ser/Thr. Phosphorylation and OGlcNAcylation were found by CD and NMR to have opposing structural effects on polyproline helix (PPII) formation, with phosphorylation favoring PPII, OGlcNAcylation opposing PPII, and the free hydroxyls intermediate in structure, and with phosphorylation structural effects greater than OGlcNAcylation. For tau196-209, phosphorylation and OGlcNAcylation had similar structural effects, opposing a nascent α-helix. Phosphomimic Glu exhibited PPII-favoring structural effects. Structural changes due to Thr phosphorylation were greater than those of Ser phosphorylation or Glu, with particular conformational restriction as the dianion, with mean (3)JαN = 3.5 Hz (pThr) versus 5.4 Hz (pSer), compared to 7.2, 6.8, and 6.2 Hz for Thr, Ser, and Glu, respectively, values that correlate with the backbone torsion angle ϕ. Dianionic phosphothreonine induced strong phosphothreonine amide protection and downfield amide chemical shifts (δmean = 9.63 ppm), consistent with formation of a stable phosphate-amide hydrogen bond. These data suggest potentially greater structural importance of threonine phosphorylation than serine phosphorylation due to larger induced structural effects.

  6. Who Opposes Immigrants' Integration into the Labor Market? The Swiss Case

    OpenAIRE

    Mueller, Tobias; Tai, Silvio H. T.

    2010-01-01

    First, we spell out a political-economy model, based on segmented labor markets, which explains why a guest-worker system is preferred to a non-discriminatory immigration regime and why measures to improve the integration of low-skill immigrants tend to be opposed subsequently. The model also predicts that attitudes towards the integration of immigrants are positively related to education. Second, we examine the empirical evidence on attitudes towards the integration of immigrants. Our findin...

  7. [Clinical efficacy on peripheral facial paralysis at acute stage treated with opposing needling technique].

    Science.gov (United States)

    Li, Ying; Zhang, Zhongyi; Chen, Yuelai; Zong, Lei; Li, Jing; Tao, Ying; Zeng, Liang; Hou, Wenguang

    2015-01-01

    To compare the differences in clinical efficacy on peripheral facial paralysis at acute stage between the opposing needling technique and routine acupuncture at the affected side so as to provide the evidence on the acupuncture treatment for peripheral facial paralysis at acute stage. Forty patients were rando- mized into an opposing needling technique group (19 cases) and an affected side needling technique group (21 cases). The basic medication was same in the two groups. The acupoints were Fengchi (GB 20), Yangbai (GB 14) to Yuyao (EX-HN 4) (penetrating needling method), Jingming (BL 1), Chengqi (ST 1), Xiaguan (ST 7), Jiache (ST 6) to Dicang (ST 4), Hegu (LI 4) and Zusanli (ST 36). In supplementation, in the opposing needling technique group, the acupoints were stimulated on the face of healthy side. In the affected side needling technique group, the acupoints were stimulated on the face of the affected side. The treatment was given three times a week, for 4 weeks. House-Brackmann (H-B) facial nerve function assessment was used to evaluate facial nerve function before and after treatment in the patients of the two groups. The efficacy was compared between the two groups. The facial nerve function was recovered in the two groups and the total effective rate was 100.0% in the two groups (P>0.05). The curative rate was 68.4% (13/19) in the opposing needling technique group and better than 47.6% (10/21) in the affected side needling technique group (Pfacial nerve function in peripheral facial paralysis at acute stage and apparently shortens the curative time. The efficacy is better than that in acupuncture on the affect- ed side of the face.

  8. Two different approaches for creating a prescribed opposed-flow velocity field for flame spread experiments

    Directory of Open Access Journals (Sweden)

    Carmignani Luca

    2015-01-01

    Full Text Available Opposed-flow flame spread over solid fuels is a fundamental area of research in fire science. Typically combustion wind tunnels are used to generate the opposing flow of oxidizer against which a laminar flame spread occurs along the fuel samples. The spreading flame is generally embedded in a laminar boundary layer, which interacts with the strong buoyancy-induced flow to affect the mechanism of flame spread. In this work, two different approaches for creating the opposed-flow are compared. In the first approach, a vertical combustion tunnel is used where a thin fuel sample, thin acrylic or ashless filter paper, is held vertically along the axis of the test-section with the airflow controlled by controlling the duty cycles of four fans. As the sample is ignited, a flame spreads downward in a steady manner along a developing boundary layer. In the second approach, the sample is held in a movable cart placed in an eight-meter tall vertical chamber filled with air. As the sample is ignited, the cart is moved downward (through a remote-controlled mechanism at a prescribed velocity. The results from the two approaches are compared to establish the boundary layer effect on flame spread over thin fuels.

  9. To open or to close: species-specific stomatal responses to simultaneously applied opposing environmental factors.

    Science.gov (United States)

    Merilo, Ebe; Jõesaar, Indrek; Brosché, Mikael; Kollist, Hannes

    2014-04-01

    Plant stomatal responses to single environmental factors are well studied; however, responses to a change in two (or more) factors - a common situation in nature - have been less frequently addressed. We studied the stomatal responses to a simultaneous application of opposing environmental factors in six evolutionarily distant mono- and dicotyledonous herbs representing different life strategies (ruderals, competitors and stress-tolerators) to clarify whether the crosstalk between opening- and closure-inducing pathways leading to stomatal response is universal or species-specific. Custom-made gas exchange devices were used to study the stomatal responses to a simultaneous application of two opposing factors: decreased/increased CO2 concentration and light availability or reduced air humidity. The studied species responded similarly to changes in single environmental factors, but showed species-specific and nonadditive responses to two simultaneously applied opposing factors. The stomata of the ruderals Arabidopsis thaliana and Thellungiella salsuginea (previously Thellungiella halophila) always opened, whereas those of competitor-ruderals either closed in all two-factor combinations (Triticum aestivum), remained relatively unchanged (Nicotiana tabacum) or showed a response dominated by reduced air humidity (Hordeum vulgare). Our results, indicating that in changing environmental conditions species-specific stomatal responses are evident that cannot be predicted from studying one factor at a time, might be interesting for stomatal modellers, too.

  10. Two different approaches for creating a prescribed opposed-flow velocity field for flame spread experiments

    Science.gov (United States)

    Carmignani, Luca; Celniker, Greg; Bussett, Kyle; Paolini, Christopher; Bhattacharjee, Subrata

    2015-05-01

    Opposed-flow flame spread over solid fuels is a fundamental area of research in fire science. Typically combustion wind tunnels are used to generate the opposing flow of oxidizer against which a laminar flame spread occurs along the fuel samples. The spreading flame is generally embedded in a laminar boundary layer, which interacts with the strong buoyancy-induced flow to affect the mechanism of flame spread. In this work, two different approaches for creating the opposed-flow are compared. In the first approach, a vertical combustion tunnel is used where a thin fuel sample, thin acrylic or ashless filter paper, is held vertically along the axis of the test-section with the airflow controlled by controlling the duty cycles of four fans. As the sample is ignited, a flame spreads downward in a steady manner along a developing boundary layer. In the second approach, the sample is held in a movable cart placed in an eight-meter tall vertical chamber filled with air. As the sample is ignited, the cart is moved downward (through a remote-controlled mechanism) at a prescribed velocity. The results from the two approaches are compared to establish the boundary layer effect on flame spread over thin fuels.

  11. Major regulatory factors in the evolution of development: the roles of goosecoid and Msx in the evolution of the direct-developing sea urchin Heliocidaris erythrogramma.

    Science.gov (United States)

    Wilson, Keen A; Andrews, Mary E; Rudolf Turner, F; Raff, Rudolf A

    2005-01-01

    The transcription factors Gsc and Msx are expressed in the oral ectoderm of the indirect-developing sea urchin Heliocidaris tuberculata. Their patterns of expression are highly modified in the direct developer Heliocidaris erythrogramma, which lacks an oral ectoderm. We here test the hypothesis that they are large effect genes responsible for the loss of the oral ectoderm module in the direct-developing larva of H. erythrogramma as well as for the restoration of an overt oral ectoderm in H.e. xH.t. hybrids. We undertook misexpression/overexpression and knockdown assays in the two species and in hybrids by mRNA injection. The results indicate that dramatic changes of function of these transcription factors has occurred. One of these genes, Gsc, has the ability when misexpressed to partially restore oral ectoderm in H. erythrogramma. On the other hand, Msx has lost any oral function and instead has a role in mesoderm proliferation and patterning. In addition, we found that the H. tuberculataGsc is up regulated in H.e. xH.t. hybrids, showing a preferential use of the indirect developing parental gene in the development of the hybrid. We suggest that Gsc qualifies as a gene of large evolutionary effect and is partially responsible for the evolution of direct development of H. erythrogramma. We discuss these results in light of modularity and genetic networks in development, as well as in their implications for the rapid evolution of large morphological changes in development.

  12. Regulatory role of TNF-α in the pathogenesis of IBD%TNF-α在IBD发病机制中的调节

    Institute of Scientific and Technical Information of China (English)

    郑海涵

    2011-01-01

    炎症性肠病(inflammatory bowel disease,IBD)是一种病因不明的肠道非特异性炎症性疾病,包括溃疡性结肠炎和克罗恩病,它们有各自的临床特征,内镜表现和组织学可区分;有学者认为它们是同一疾病的两个不同的阶段.在免疫应答中,TNF-α(TNF核心家族成员之一)作为细胞增殖和凋亡的主要促炎因子,在IBD的发病机制中起重要的调节作用.%Inflammatory bowel disease (IBD), which includes Crohn' s disease (CD) and ulcerative colitis (UC),is a uncontrolled inflammatory of the gastrointestinal tract. The etiology is not clear yet. CD and UC have respective clinical features, they could be distinguished with endoscopy and histology. Some studies consider that CD and UC are different stages of development in IBD. In the immune response, TNF-α, as the main pro-inflammatory cytokines of cell proliferation and apoptosis, plays an important role in the regulation of the pathogenesis of IBD.

  13. AQP2 exocytosis in the renal collecting duct – involvement of SNARE isoforms and the regulatory role of Munc18b

    Science.gov (United States)

    Procino, Giuseppe; Barbieri, Claudia; Tamma, Grazia; De Benedictis, Leonarda; Pessin, Jeffrey E.; Svelto, Maria; Valenti, Giovanna

    2015-01-01

    Summary Vasopressin regulates the fusion of the water channel aquaporin 2 (AQP2) to the apical membrane of the renal collecting-duct principal cells and several lines of evidence indicate that SNARE proteins mediate this process. In this work MCD4 renal cells were used to investigate the functional role of a set of Q- and R-SNAREs, together with that of Munc18b as a negative regulator of the formation of the SNARE complex. Both VAMP2 and VAMP3 were associated with immunoisolated AQP2 vesicles, whereas syntaxin 3 (Stx3), SNAP23 and Munc18 were associated with the apical plasma membrane. Co-immunoprecipitation experiments indicated that Stx3 forms complexes with VAMP2, VAMP3, SNAP23 and Munc18b. Protein knockdown coupled to apical surface biotinylation demonstrated that reduced levels of the R-SNAREs VAMP2 and VAMP3, and the Q-SNAREs Stx3 and SNAP23 strongly inhibited AQP2 fusion at the apical membrane. In addition, knockdown of Munc18b promoted a sevenfold increase of AQP2 fused at the plasma membrane without forskolin stimulation. Taken together these findings propose VAMP2, VAMP3, Stx3 and SNAP23 as the complementary set of SNAREs responsible for AQP2-vesicle fusion into the apical membrane, and Munc18b as a negative regulator of SNARE-complex formation in renal collecting-duct principal cells. PMID:18505797

  14. Expression and Subcellular Localization of Retinoic Acid Receptor-α (RARα) in Healthy and Varicocele Human Spermatozoa: Its Possible Regulatory Role in Capacitation and Survival.

    Science.gov (United States)

    Perrotta, Ida; Perri, Mariarita; Santoro, Marta; Panza, Salvatore; Caroleo, Maria C; Guido, Carmela; Mete, Annamaria; Cione, Erika; Aquila, Saveria

    2015-01-01

    Varicocele, an abnormal tortuosity and dilation of veins of the pampiniform plexus, is the most common identifiable and correctable cause of male infertility. It is now becoming apparent that signaling through vitamin A metabolites, such as all-trans retinoic acid (ATRA), is indispensable for spermatogenesis and disruption of retinoic acid receptor-α (RARα) function may result in male sterility and aberrant spermatogenesis. Herein, we investigated by Western blot and immunogold electron microscopy the expression profiles and subcellular localization of RARα in healthy and varicocele human sperm; in addition, we analyzed the effects of ATRA on cholesterol efflux and sperm survival utilizing enzymatic colorimetric CHOD-PAP method and Eosin Y technique, respectively. In varicocele samples, a strong reduction of RARα expression was observed. Immunogold labeling evidenced cellular location of RARα also confirming its reduced expression in "varicocele" samples. Sperm responsiveness to ATRA treatment was reduced in varicocele sperm. Our study showed that RARα is expressed in human sperm probably with a dual role in promoting both cholesterol efflux and survival. RARα might be involved in the pathogenesis of varicocele as its expression is reduced in pathologic samples. Thus, ATRA administration in procedures for artificial insemination or dietary vitamin A supplementation might represent a promising therapeutic approach for the management of male infertility.

  15. Single-base resolution maps of cultivated and wild rice methylomes and regulatory roles of DNA methylation in plant gene expression

    Directory of Open Access Journals (Sweden)

    Li Xin

    2012-07-01

    Full Text Available Abstract Background DNA methylation plays important biological roles in plants and animals. To examine the rice genomic methylation landscape and assess its functional significance, we generated single-base resolution DNA methylome maps for Asian cultivated rice Oryza sativa ssp. japonica, indica and their wild relatives, Oryza rufipogon and Oryza nivara. Results The overall methylation level of rice genomes is four times higher than that of Arabidopsis. Consistent with the results reported for Arabidopsis, methylation in promoters represses gene expression while gene-body methylation generally appears to be positively associated with gene expression. Interestingly, we discovered that methylation in gene transcriptional termination regions (TTRs can significantly repress gene expression, and the effect is even stronger than that of promoter methylation. Through integrated analysis of genomic, DNA methylomic and transcriptomic differences between cultivated and wild rice, we found that primary DNA sequence divergence is the major determinant of methylational differences at the whole genome level, but DNA methylational difference alone can only account for limited gene expression variation between the cultivated and wild rice. Furthermore, we identified a number of genes with significant difference in methylation level between the wild and cultivated rice. Conclusions The single-base resolution methylomes of rice obtained in this study have not only broadened our understanding of the mechanism and function of DNA methylation in plant genomes, but also provided valuable data for future studies of rice epigenetics and the epigenetic differentiation between wild and cultivated rice.

  16. Identification of a malonyl CoA-acyl carrier protein transacylase and its regulatory role in fatty acid biosynthesis in oleaginous microalga Nannochloropsis oceanica.

    Science.gov (United States)

    Chen, Jia-Wen; Liu, Wan-Jun; Hu, Dong-Xiong; Wang, Xiang; Balamurugan, Srinivasan; Alimujiang, Adili; Yang, Wei-Dong; Liu, Jie-Sheng; Li, Hong-Ye

    2016-08-30

    Oleaginous microalgae hold great promises for biofuel production. However, commercialization of microalgal biofuels remains impracticable due to lack of suitable industrial strain with high growth rate and lipid productivity. Engineering of metabolic pathways is a potential strategy for the improvement of microalgal strains for the production of lipids and also value-added products in microalgae. Malonyl CoA-acyl carrier protein transacylase (MCAT) has been reported to be involved in fatty acid biosynthesis. Here, we identified a putative MCAT in the oleaginous marine microalga Nannochloropsis oceanica. NoMCAT-overexpressing N. oceanica showed higher growth rate and photosynthetic efficiency. The neutral lipid content of engineered lines showed a significant increase by up to 31% compared to wild type. GC-MS analysis revealed that NoMCAT overexpression significantly altered the fatty acid composition. The composition of EPA (C20:5) increased by 8%, which is a polyunsaturated fatty acid necessary for animal nutrition. These results demonstrate the role of MCAT in enhancing fatty acid biosynthesis and growth in microalgae, and also provide an insight into metabolic engineering of microalgae with high industrial potential. This article is protected by copyright. All rights reserved.

  17. Novel positive regulatory role for the SPL6 transcription factor in the N TIR-NB-LRR receptor-mediated plant innate immunity.

    Directory of Open Access Journals (Sweden)

    Meenu S Padmanabhan

    2013-03-01

    Full Text Available Following the recognition of pathogen-encoded effectors, plant TIR-NB-LRR immune receptors induce defense signaling by a largely unknown mechanism. We identify a novel and conserved role for the SQUAMOSA PROMOTER BINDING PROTEIN (SBP-domain transcription factor SPL6 in enabling the activation of the defense transcriptome following its association with a nuclear-localized immune receptor. During an active immune response, the Nicotiana TIR-NB-LRR N immune receptor associates with NbSPL6 within distinct nuclear compartments. NbSPL6 is essential for the N-mediated resistance to Tobacco mosaic virus. Similarly, the presumed Arabidopsis ortholog AtSPL6 is required for the resistance mediated by the TIR-NB-LRR RPS4 against Pseudomonas syringae carrying the avrRps4 effector. Transcriptome analysis indicates that AtSPL6 positively regulates a subset of defense genes. A pathogen-activated nuclear-localized TIR-NB-LRR like N can therefore regulate defense genes through SPL6 in a mechanism analogous to the induction of MHC genes by mammalian immune receptors like CIITA and NLRC5.

  18. 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.

  19. Bacterial lipoprotein delays apoptosis in human neutrophils through inhibition of caspase-3 activity: regulatory roles for CD14 and TLR-2.

    LENUS (Irish Health Repository)

    Power, Colm P

    2012-02-03

    The human sepsis syndrome resulting from bacterial infection continues to account for a significant proportion of hospital mortality. Neutralizing strategies aimed at individual bacterial wall products (such as LPS) have enjoyed limited success in this arena. Bacterial lipoprotein (BLP) is a major constituent of the wall of diverse bacterial forms and profoundly influences cellular function in vivo and in vitro, and has been implicated in the etiology of human sepsis. Delayed polymorphonuclear cell (PMN) apoptosis is a characteristic feature of human sepsis arising from Gram-negative or Gram-positive bacterial infection. Bacterial wall product ligation and subsequent receptor-mediated events upstream of caspase inhibition in neutrophils remain incompletely understood. BLP has been shown to exert its cellular effects primarily through TLR-2, and it is now widely accepted that lateral associations with the TLRs represent the means by which CD14 communicates intracellular messages. In this study, we demonstrate that BLP inhibits neutrophil mitochondrial membrane depolarization with a subsequent reduction in caspase-3 processing, ultimately leading to a significant delay in PMN apoptosis. Pretreatment of PMNs with an anti-TLR-2 mAb or anti-CD14 mAb prevented BLP from delaying PMN apoptosis to such a marked degree. Combination blockade using both mAbs completely prevented the effects of BLP (in 1 and 10 ng\\/ml concentrations) on PMN apoptosis. At higher concentrations of BLP, the antiapoptotic effects were observed, but were not as pronounced. Our findings therefore provide the first evidence of a crucial role for both CD14 and TLR-2 in delayed PMN apoptosis arising from bacterial infection.

  20. A marker-derived gene network reveals the regulatory role of PPARGC1A, HNF4G, and FOXP3 in intramuscular fat deposition of beef cattle.

    Science.gov (United States)

    Ramayo-Caldas, Y; Fortes, M R S; Hudson, N J; Porto-Neto, L R; Bolormaa, S; Barendse, W; Kelly, M; Moore, S S; Goddard, M E; Lehnert, S A; Reverter, A

    2014-07-01

    High intramuscular fat (IMF) awards price premiums to beef producers and is associated with meat quality and flavor. Studying gene interactions and pathways that affect IMF might unveil causative physiological mechanisms and inform genomic selection, leading to increased accuracy of predictions of breeding value. To study gene interactions and pathways, a gene network was derived from genetic markers associated with direct measures of IMF, other fat phenotypes, feedlot performance, and a number of meat quality traits relating to body conformation, development, and metabolism that might be plausibly expected to interact with IMF biology. Marker associations were inferred from genomewide association studies (GWAS) based on high density genotypes and 29 traits measured on 10,181 beef cattle animals from 3 breed types. For the network inference, SNP pairs were assessed according to the strength of the correlation between their additive association effects across the 29 traits. The co-association inferred network was formed by 2,434 genes connected by 28,283 edges. Topological network parameters suggested a highly cohesive network, in which the genes are strongly functionally interconnected. Pathway and network analyses pointed towards a trio of transcription factors (TF) as key regulators of carcass IMF: PPARGC1A, HNF4G, and FOXP3. Importantly, none of these genes would have been deemed as significantly associated with IMF from the GWAS. Instead, a total of 313 network genes show significant co-association with the 3 TF. These genes belong to a wide variety of biological functions, canonical pathways, and genetic networks linked to IMF-related phenotypes. In summary, our GWAS and network predictions are supported by the current literature and suggest a cooperative role for the 3 TF and other interacting genes including CAPN6, STC2, MAP2K4, EYA1, COPS5, XKR4, NR2E1, TOX, ATF1, ASPH, TGS1, and TTPA as modulators of carcass and meat quality traits in beef cattle.

  1. The knockdown of chloroplastic ascorbate peroxidases reveals its regulatory role in the photosynthesis and protection under photo-oxidative stress in rice.

    Science.gov (United States)

    Caverzan, Andréia; Bonifacio, Aurenivia; Carvalho, Fabricio E L; Andrade, Claudia M B; Passaia, Gisele; Schünemann, Mariana; Maraschin, Felipe Dos Santos; Martins, Marcio O; Teixeira, Felipe K; Rauber, Rafael; Margis, Rogério; Silveira, Joaquim Albenisio Gomes; Margis-Pinheiro, Márcia

    2014-01-01

    The inactivation of the chloroplast ascorbate peroxidases (chlAPXs) has been thought to limit the efficiency of the water-water cycle and photo-oxidative protection under stress conditions. In this study, we have generated double knockdown rice (Oryza sativa L.) plants in both OsAPX7 (sAPX) and OsAPX8 (tAPX) genes, which encode chloroplastic APXs (chlAPXs). By employing an integrated approach involving gene expression, proteomics, biochemical and physiological analyses of photosynthesis, we have assessed the role of chlAPXs in the regulation of the protection of the photosystem II (PSII) activity and CO2 assimilation in rice plants exposed to high light (HL) and methyl violagen (MV). The chlAPX knockdown plants were affected more severely than the non-transformed (NT) plants in the activity and structure of PSII and CO2 assimilation in the presence of MV. Although MV induced significant increases in pigment content in the knockdown plants, the increases were apparently not sufficient for protection. Treatment with HL also caused generalized damage in PSII in both types of plants. The knockdown and NT plants exhibited differences in photosynthetic parameters related to efficiency of utilization of light and CO2. The knockdown plants overexpressed other antioxidant enzymes in response to the stresses and increased the GPX activity in the chloroplast-enriched fraction. Our data suggest that a partial deficiency of chlAPX expression modulate the PSII activity and integrity, reflecting the overall photosynthesis when rice plants are subjected to acute oxidative stress. However, under normal growth conditions, the knockdown plants exhibit normal phenotype, biochemical and physiological performance.

  2. Maize and Arabidopsis ARGOS Proteins Interact with Ethylene Receptor Signaling Complex, Supporting a Regulatory Role for ARGOS in Ethylene Signal Transduction[OPEN

    Science.gov (United States)

    Shi, Jinrui; Wang, Hongyu; Habben, Jeffrey E.

    2016-01-01

    The phytohormone ethylene regulates plant growth and development as well as plant response to environmental cues. ARGOS genes reduce plant sensitivity to ethylene when overexpressed in transgenic Arabidopsis (Arabidopsis thaliana) and maize (Zea mays). A previous genetic study suggested that the endoplasmic reticulum and Golgi-localized maize ARGOS1 targets the ethylene signal transduction components at or upstream of CONSTITUTIVE TRIPLE RESPONSE1, but the mechanism of ARGOS modulating ethylene signaling is unknown. Here, we demonstrate in Arabidopsis that ZmARGOS1, as well as the Arabidopsis ARGOS homolog ORGAN SIZE RELATED1, physically interacts with Arabidopsis REVERSION-TO-ETHYLENE SENSITIVITY1 (RTE1), an ethylene receptor interacting protein that regulates the activity of ETHYLENE RESPONSE1. The protein-protein interaction was also detected with the yeast split-ubiquitin two-hybrid system. Using the same yeast assay, we found that maize RTE1 homolog REVERSION-TO-ETHYLENE SENSITIVITY1 LIKE4 (ZmRTL4) and ZmRTL2 also interact with maize and Arabidopsis ARGOS proteins. Like AtRTE1 in Arabidopsis, ZmRTL4 and ZmRTL2 reduce ethylene responses when overexpressed in maize, indicating a similar mechanism for ARGOS regulating ethylene signaling in maize. A polypeptide fragment derived from ZmARGOS8, consisting of a Pro-rich motif flanked by two transmembrane helices that are conserved among members of the ARGOS family, can interact with AtRTE1 and maize RTL proteins in Arabidopsis. The conserved domain is necessary and sufficient to reduce ethylene sensitivity in Arabidopsis and maize. Overall, these results suggest a physical association between ARGOS and the ethylene receptor signaling complex via AtRTE1 and maize RTL proteins, supporting a role for ARGOS in regulating ethylene perception and the early steps of signal transduction in Arabidopsis and maize. PMID:27268962

  3. Molecular cloning, expression pattern analysis of porcine Rb1 gene and its regulatory roles during primary dedifferentiated fat cells adipogenic differentiation.

    Science.gov (United States)

    Hu, Xiaoming; Luo, Pei; Peng, Xuewu; Song, Tongxing; Zhou, Yuanfei; Wei, Hongkui; Peng, Jian; Jiang, Siwen

    2015-04-01

    Adipocytes are the main constituent of adipose tissue and are considered to be a corner stone in the homeostatic control of whole body metabolism. Recent reports evidenced that retinoblastoma 1 (Rb1) gene plays an important role in fat development and adipogenesis in mice. Here, we cloned the partial cDNA sequences of the porcine Rb1 gene which contains the complete coding sequences (CDS) of 2820bp encoding a protein of 939 amino acids. Bioinformatic analysis revealed that the CDS of porcine Rb1 was highly identical with those of cattle, human and mice. The porcine Rb1 has three typical conserved structural domains, including Rb-A pocket domain, CYCLIN domain and C-terminus domain, and the phylogenetic tree indicates a closer genetic relationship with cattle and human. Tissue distribution analysis showed that Rb1 expression appeared to be ubiquitously in various tissues, being higher in heart, liver, muscle, and stomach. Furthermore, significant downregulation of Rb1 was found at the initial stage of dedifferentiated fat (DFAT) cells adipogenic differentiation. With the knockdown of the Rb1 expression by siRNA, the number of DFAT cells recruited to white rather than brown adipogenesis was promoted, and mRNA levels of adipogenic markers, such as PPARγ, aP2, LPL and adiponectin and protein expression of PPARγ and adiponectin were increased after hormone stimulation. The underlying mechanisms may be that knockdown of Rb1 promotes the mitotic clonal expansion and PPARγ expression by derepressing the transcriptional activity of E2F so as to facilitate the first steps of adipogenesis. In summary, we cloned and characterized an important negative regulator in adipogenic commitment of porcine DFAT cells.

  4. CD73在弓型体感染中的作用%The regulatory roles of CD73 in Toxoplasma gondii infection

    Institute of Scientific and Technical Information of China (English)

    汪咏梅

    2012-01-01

    胞外-5'-核苷酸酶(ecto-5'-nucleotidase,CD73)和由CD73催化产生的腺苷,作为一种内源性的嘌呤核苷在弓形虫感染宿主的过程中起着重要的调节作用,如作为弓形虫的主要营养、能量来源,有利于弓形虫入侵宿主,有利于弓形虫在宿主细胞内的胞内繁殖,有利于弓形虫的免疫逃逸和其胞内免疫屏蔽.抑制CD73的生物活性或控制其基因表达将会成为新型的弓形虫感染生物治疗方法.%Ecto-5'-nucleotidase (CD73) and adenosine (its generation is catalyzed by CD73) as endogenous signaling molecules play an important role in regulation of Toxoplasma gondii infection. Adenosine may be the main and direct sources for nutrition and energy; It promotes the Toxoplasma gondii attachment, invasion, metabolism and replication in the host cells and is helpful in Toxoplasma gondii immuno-shadow and dodge in the host cells by regulating the host immuno-cells and cytokines. Inhibition of CD73 biological and physiological function and CD73 gene expression would be the new biological therapeutical methods for toxoplasma gondii infection.

  5. Quantification of hTERT Splice Variants in Melanoma by SYBR Green Real-time Polymerase Chain Reaction Indicates a Negative Regulatory Role for the β Deletion Variant

    Directory of Open Access Journals (Sweden)

    Lisa F. Lincz

    2008-10-01

    Full Text Available Telomerase activity is primarily determined by transcriptional regulation of the catalytic subunit, human telomerase reverse transcriptase (hTERT. Several mRNA splice variants for hTERT have been identified, but it is not clear if telomerase activity is determined by the absolute or relative levels of full-length (functional and variant hTERT transcripts. We have developed an SYBR green-based reverse transcription-quantitative polymerase chain reaction assay for the enumeration of the four common hTERT mRNA variants and correlated these with telomerase activity and telomere length in 24 human melanoma cell lines. All except five of the lines expressed four hTERT transcripts, with an overall significant level of co-occurrence between absolute mRNA levels of full-length α+/β+ hTERT and the three splice variants α-/β+, α+/β-, and α-/β-. On average, α+/β+ made up the majority (48.1% of transcripts, followed by α+/β- (44.6%, α-/β- (4.4%, and α-/β+ (2.9%. Telomerase activity ranged from 1 to 247 relative telomerase activity and correlated most strongly with the absolute amount of α+/β+ (R = 0.791, P = .000004 and the relative amount of α+/β- (R = -0.465, P = .022. This study shows that telomerase activity in melanoma cells is best determined by the absolute expression of full-length hTERT mRNA and indicates a role for the hTERT β deletion variant in the negative regulation of enzyme activity.

  6. Regulatory role of PI3K-protein kinase B on the release of interleukin-1β in peritoneal macrophages from the ascites of cirrhotic patients.

    Science.gov (United States)

    Tapia-Abellán, A; Ruiz-Alcaraz, A J; Antón, G; Miras-López, M; Francés, R; Such, J; Martínez-Esparza, M; García-Peñarrubia, P

    2014-12-01

    Great effort has been paid to identify novel targets for pharmaceutical intervention to control inflammation associated with different diseases. We have studied the effect of signalling inhibitors in the secretion of the proinflammatory and profibrogenic cytokine interleukin (IL)-1β in monocyte-derived macrophages (M-DM) obtained from the ascites of cirrhotic patients and compared with those obtained from the blood of healthy donors. Peritoneal M-DM were isolated from non-infected ascites of cirrhotic patients and stimulated in vitro with lipopolysaccharide (LPS) and heat-killed Candida albicans in the presence or absence of inhibitors for c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase 1 (MEK1), p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). The IL1B and CASP1 gene expression were evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The expression of IL-1β and caspase-1 were determined by Western blot. IL-1β was also assayed by enzyme-linked immunosorbent assay (ELISA) in cell culture supernatants. Results revealed that MEK1 and JNK inhibition significantly reduced the basal and stimulated IL-1β secretion, while the p38 MAPK inhibitor had no effect on IL-1β levels. On the contrary, inhibition of PI3K increased the secretion of IL-1β from stimulated M-DM. The activating effect of PI3K inhibitor on IL-1β release was mediated mainly by the enhancement of the intracellular IL-1β and caspase-1 content release to the extracellular medium and not by increasing the corresponding mRNA and protein expression levels. These data point towards the role of MEK1 and JNK inhibitors, in contrast to the PI3K-protein kinase B inhibitors, as potential therapeutic tools for pharmaceutical intervention to diminish hepatic damage by reducing the inflammatory response mediated by IL-1β associated with liver failure.

  7. Regulatory nodD1 and nodD2 genes of Rhizobium tropici strain CIAT 899 and their roles in the early stages of molecular signaling and host-legume nodulation.

    Science.gov (United States)

    del Cerro, Pablo; Rolla-Santos, Amanda Alves Paiva; Gomes, Douglas Fabiano; Marks, Bettina Berquó; Pérez-Montaño, Francisco; Rodríguez-Carvajal, Miguel Ángel; Nakatani, André Shigueyoshi; Gil-Serrano, Antonio; Megías, Manuel; Ollero, Francisco Javier; Hungria, Mariangela

    2015-03-28

    Nodulation and symbiotic nitrogen fixation are mediated by several genes, both of the host legume and of the bacterium. The rhizobial regulatory nodD gene plays a critical role, orchestrating the transcription of the other nodulation genes. Rhizobium tropici strain CIAT 899 is an effective symbiont of several legumes-with an emphasis on common bean (Phaseolus vulgaris)-and is unusual in carrying multiple copies of nodD, the roles of which remain to be elucidated. Phenotypes, Nod factors and gene expression of nodD1 and nodD2 mutants of CIAT 899 were compared with those of the wild type strain, both in the presence and in the absence of the nod-gene-inducing molecules apigenin and salt (NaCl). Differences between the wild type and mutants were observed in swimming motility and IAA (indole acetic acid) synthesis. In the presence of both apigenin and salt, large numbers of Nod factors were detected in CIAT 899, with fewer detected in the mutants. nodC expression was lower in both mutants; differences in nodD1 and nodD2 expression were observed between the wild type and the mutants, with variation according to the inducing molecule, and with a major role of apigenin with nodD1 and of salt with nodD2. In the nodD1 mutant, nodulation was markedly reduced in common bean and abolished in leucaena (Leucaena leucocephala) and siratro (Macroptilium atropurpureum), whereas a mutation in nodD2 reduced nodulation in common bean, but not in the other two legumes. Our proposed model considers that full nodulation of common bean by R. tropici requires both nodD1 and nodD2, whereas, in other legume species that might represent the original host, nodD1 plays the major role. In general, nodD2 is an activator of nod-gene transcription, but, in specific conditions, it can slightly repress nodD1. nodD1 and nodD2 play other roles beyond nodulation, such as swimming motility and IAA synthesis.

  8. Regulatory T cell memory

    Science.gov (United States)

    Rosenblum, Michael D.; Way, Sing Sing; Abbas, Abul K.

    2016-01-01

    Memory for antigen is a defining feature of adaptive immunity. Antigen-specific lymphocyte populations show an increase in number and function after antigen encounter and more rapidly re-expand upon subsequent antigen exposure. Studies of immune memory have primarily focused on effector B cells and T cells with microbial specificity, using prime challenge models of infection. However, recent work has also identified persistently expanded populations of antigen-specific regulatory T cells that protect against aberrant immune responses. In this Review, we consider the parallels between memory effector T cells and memory regulatory T cells, along with the functional implications of regulatory memory in autoimmunity, antimicrobial host defence and maternal fetal tolerance. In addition, we discuss emerging evidence for regulatory T cell memory in humans and key unanswered questions in this rapidly evolving field. PMID:26688349

  9. N-methyl-d-aspartate-evoked release of [{sup 3}H]acetylcholine in striatal compartments of the rat: regulatory roles of dopamine and GABA

    Energy Technology Data Exchange (ETDEWEB)

    Glowinski, J.; Perez, S.; Desban, M.; Gauchy, C.; Kemel, M.L.; Blanchet, F. [Chaire de Neuropharmacologie, INSERM U114, College de France, 11 place Marcelin Berthelot, 75231 Paris (France)

    1997-08-26

    } receptors can either reduce (striosomes) or enhance (matrix) this response, since in the latter case the effect induced by the combined application of the D{sub 1} and D{sub 2} receptor antagonists was smaller than that observed with the D{sub 2} receptor antagonist alone.Indicating that released GABA facilitates N-methyl-d-aspartate responses, the blockade of GABA{sub A} receptors with bicuculline (5 {mu}M) reduced the 50 {mu}M N-methyl-d-aspartate-evoked release of [{sup 3}H]acetylcholine in both striatal compartments and the 1 mM N-methyl-d-aspartate + d-serine response in the matrix. These effects result from an inhibition by GABA of the evoked release of dopamine, since the reducing effects of bicuculline on N-methyl-d-aspartate responses were not observed under the complete blockade of dopaminergic transmission by the D{sub 1} and D{sub 2} receptor antagonists. Further demonstrating a facilitatory role of GABA in the control of N-methyl-d-aspartate-evoked release of [{sup 3}H]acetylcholine, in the presence of bicuculline, (-)-sulpiride and SCH23390 alone or in combination enhanced, in both compartments, the responses induced not only by 1 mM N-methyl-d-aspartate + d-serine, but also by 50 {mu}M N-methyl-d-aspartate. (Copyright (c) 1997 Elsevier Science B.V., Amsterdam. All rights reserved.)

  10. 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.

  11. Oleanolic Acid Diminishes Liquid Fructose-Induced Fatty Liver in Rats: Role of Modulation of Hepatic Sterol Regulatory Element-Binding Protein-1c-Mediated Expression of Genes Responsible for De Novo Fatty Acid Synthesis

    Directory of Open Access Journals (Sweden)

    Changjin Liu

    2013-01-01

    Full Text Available Oleanolic acid (OA, contained in more than 1620 plants and as an aglycone precursor for naturally occurred and synthesized triterpenoid saponins, is used in China for liver disorders in humans. However, the underlying liver-protecting mechanisms remain largely unknown. Here, we found that treatment of rats with OA (25 mg/kg/day, gavage, once daily over 10 weeks diminished liquid fructose-induced excess hepatic triglyceride accumulation without effect on total energy intake. Attenuation of the increased vacuolization and Oil Red O staining area was evident on histological examination of liver in OA-treated rats. Hepatic gene expression profile demonstrated that OA suppressed fructose-stimulated overexpression of sterol regulatory element-binding protein-(SREBP- 1/1c mRNA and nuclear protein. In accord, overexpression of SREBP-1c-responsive genes responsible for fatty acid synthesis was also downregulated. In contrast, overexpressed nuclear protein of carbohydrate response element-binding protein and its target genes liver pyruvate kinase and microsomal triglyceride transfer protein were not altered. Additionally, OA did not affect expression of peroxisome proliferator-activated receptor-gamma- and -alpha and their target genes. It is concluded that modulation of hepatic SREBP-1c-mediated expression of the genes responsible for de novo fatty acid synthesis plays a pivotal role in OA-elicited diminishment of fructose-induced fatty liver in rats.

  12. Flame Spread and Extinction Over a Thick Solid Fuel in Low-Velocity Opposed and Concurrent Flows

    Science.gov (United States)

    Zhu, Feng; Lu, Zhanbin; Wang, Shuangfeng

    2016-05-01

    Flame spread and extinction phenomena over a thick PMMA in purely opposed and concurrent flows are investigated by conducting systematical experiments in a narrow channel apparatus. The present tests focus on low-velocity flow regime and hence complement experimental data previously reported for high and moderate velocity regimes. In the flow velocity range tested, the opposed flame is found to spread much faster than the concurrent flame at a given flow velocity. The measured spread rates for opposed and concurrent flames can be correlated by corresponding theoretical models of flame spread, indicating that existing models capture the main mechanisms controlling the flame spread. In low-velocity gas flows, however, the experimental results are observed to deviate from theoretical predictions. This may be attributed to the neglect of radiative heat loss in the theoretical models, whereas radiation becomes important for low-intensity flame spread. Flammability limits using oxygen concentration and flow velocity as coordinates are presented for both opposed and concurrent flame spread configurations. It is found that concurrent spread has a wider flammable range than opposed case. Beyond the flammability boundary of opposed spread, there is an additional flammable area for concurrent spread, where the spreading flame is sustainable in concurrent mode only. The lowest oxygen concentration allowing concurrent flame spread in forced flow is estimated to be approximately 14 % O2, substantially below that for opposed spread (18.5 % O2).

  13. Feasibility of monitoring patient motion with opposed stereo infrared cameras during supine medical imaging

    Science.gov (United States)

    Beach, Richard D.; McNamara, Joseph E.; Terlecki, George; King, Michael A.

    2006-10-01

    Patient motion during single photon emission computed tomographic (SPECT) acquisition causes inconsistent projection data and reconstruction artifacts which can significantly affect diagnostic accuracy. We have investigated use of the Polaris stereo infrared motion-tracking system to track 6-Degrees-of-Freedom (6-DOF) motion of spherical reflectors (markers) on stretchy bands about the patient's chest and abdomen during cardiac SPECT imaging. The marker position information, obtained by opposed stereo infrared-camera systems, requires processing to correctly record tracked markers, and map Polaris co-ordinate data into the SPECT co-ordinate system. One stereo camera views the markers from the patient's head direction, and the other from the patient's foot direction. The need for opposed cameras is to overcome anatomical and geometrical limitations which sometimes prevent all markers from being seen by a single stereo camera. Both sets of marker data are required to compute rotational and translational 6-DOF motion of the patient which ultimately will be used for SPECT patient-motion corrections. The processing utilizes an algorithm involving least-squares fitting, to each other, of two 3-D point sets using singular value decomposition (SVD) resulting in the rotation matrix and translation of the rigid body centroid. We have previously demonstrated the ability to monitor multiple markers for twelve patients viewing from the foot end, and employed a neural network to separate the periodic respiratory motion component of marker motion from aperiodic body motion. We plan to initiate routine 6-DOF tracking of patient motion during SPECT imaging in the future, and are herein evaluating the feasibility of employing opposed stereo cameras.

  14. Rigid motion correction of dual opposed planar projections in single photon imaging

    Science.gov (United States)

    Angelis, G. I.; Ryder, W. J.; Gillam, J. E.; Boisson, F.; Kyme, A. Z.; Fulton, R. R.; Meikle, S. R.; Kench, P. L.

    2017-05-01

    Awake and/or freely moving small animal single photon emission imaging allows the continuous study of molecules exhibiting slow kinetics without the need to restrain or anaesthetise the animals. Estimating motion free projections in freely moving small animal planar imaging can be considered as a limited angle tomography problem, except that we wish to estimate the 2D planar projections rather than the 3D volume, where the angular sampling in all three axes depends on the rotational motion of the animal. In this study, we hypothesise that the motion corrected planar projections estimated by reconstructing an estimate of the 3D volume using an iterative motion compensating reconstruction algorithm and integrating it along the projection path, will closely match the true, motion-less, planar distribution regardless of the object motion. We tested this hypothesis for the case of rigid motion using Monte-Carlo simulations and experimental phantom data based on a dual opposed detector system, where object motion was modelled with 6 degrees of freedom. In addition, we investigated the quantitative accuracy of the regional activity extracted from the geometric mean of opposing motion corrected planar projections. Results showed that it is feasible to estimate qualitatively accurate motion-corrected projections for a wide range of motions around all 3 axes. Errors in the geometric mean estimates of regional activity were relatively small and within 10% of expected true values. In addition, quantitative regional errors were dependent on the observed motion, as well as on the surrounding activity of overlapping organs. We conclude that both qualitatively and quantitatively accurate motion-free projections of the tracer distribution in a rigidly moving object can be estimated from dual opposed detectors using a correction approach within an iterative reconstruction framework and we expect this approach can be extended to the case of non-rigid motion.

  15. Reconsidering examining cannabis subtypes together due to opposing effects on brain, cognition and behavior

    DEFF Research Database (Denmark)

    Thomsen, Kristine Rømer; Callesen, Mette Buhl; Ewing, Sarah W. Feeldstein

    examinations of cannabis have historically consolidated all types of cannabis collectively. However, this approach misses a fundamental fact about how different cannabinoids operate. Here we address the contrasting properties of tetrahydrocannabinol (THC) and cannabidiol (CBD) and their opposing effects...... on a wide array of health function. In addition, we address the increase in cannabis potency throughout the past two decades and how that impacts generalizability of early data on current public health. We put forth the urgent need for future research to disaggregate examination of THC from CBD, along...

  16. Temperature Measurements in an Ethylene-Air-Opposed Flow Diffusion Flame

    Science.gov (United States)

    2012-01-01

    loss of efficiency, it is also a health concern. Precursors to soot, such as C6H6 pose many health risks ( Glass et al., 2003; IARC, 1987; Rinsky et...sensor, a Schott KG3 IR cutoff filter was placed between the lens and flame. Phantom v5.1c  Camera Opposed Flow Burner Nikon Lens IR cutoff filter... Glass , D.; Gray, C.; Jolley, D.; Gibbons, C.; Sim, M.; Fritschi, L.; Adams, G.; Bisby, J.; Manuell, R. Leukemia Risk Associated With Low-Level Benzene

  17. Homosexuality: representing the devil or a spiritual gift? Two opposing views in the same Marian devotion.

    Science.gov (United States)

    Samson, Judith; Notermans, Catrien; Jansen, Willy

    2013-01-01

    This article analyzes opposing discourses on homosexuality forwarded by two different Catholic social actors. These are linked to the messages of the Lady of All Nations, a Marian apparition site in Amsterdam. These different actors are understood as competing moral communities ( Hunt, 2009 ), especially about the issue of what constitute European values. Both discourses can be seen as examples of the minoritizing yet universalizing view on homosexuality ( Kosofsky Sedgwick, 1990 , p. 85). The devotion to the Lady of All Nations serves as a site for promoting competing discourses ( Hermkens, Jansen, & Notermans, 2009 ).

  18. Overall Effects of China's Recent Macroeconomic Regulatory Policies

    Institute of Scientific and Technical Information of China (English)

    LiJianwei,; ZhuShida; DavidKelly

    2004-01-01

    China's economic regulatory policies in the last few years have played an important role in curbing the slide of its consistent growth drive. In terms of overall effects, the macroeconomic regulatory policies of each fiscal year have attained their targets. In some years, however,

  19. Regulatory Evolution and Theoretical Arguments in Evolutionary Biology

    Science.gov (United States)

    Ioannidis, Stavros

    2013-01-01

    The "cis"-regulatory hypothesis is one of the most important claims of evolutionary developmental biology. In this paper I examine the theoretical argument for "cis"-regulatory evolution and its role within evolutionary theorizing. I show that, although the argument has some weaknesses, it acts as a useful example for the importance of current…

  20. PAPEL DE LAS PROTEÍNAS REGULADORAS Y ACCESORIAS DEL VIH-1 EN LA PATOGÉNESIS DE ESA INFECCIÓN Role of the regulatory and accesory proteins of HIV- 1 in its pathogenisis

    Directory of Open Access Journals (Sweden)

    XIOMARA úSUGA

    in the development of new antiretrovirals and their impact in the quality and life expectancy of infected individuals, the current therapy does not allow a complete immune reconstitution and is also associated with deleterious side effects and the appearance of viral resistance. Therefore the search for new therapeutic targets is required to face this pandemic. The role of the accessory and regulatory proteins of the HIV- 1 in the replication cycle and in the pathogenesis of the infection has been ignored for several years now; however, recent studies indicated that these proteins play essential roles in the replication cycle, being responsible for several processes associated to viral pathogenesis. These findings have underlined the importance of these proteins as promissory targets in the development of new therapeutic agents. In this review, we detailed the role of each one of the HIV-1’s regulatory and accessory proteins in the replicative cycle and in the pathogenesis of this infection.

  1. Reconciling the IPC and Two-Hit Models: Dissecting the Underlying Cellular and Molecular Mechanisms of Two Seemingly Opposing Frameworks.

    Science.gov (United States)

    Morris, Carlos F M; Tahir, Muhammad; Arshid, Samina; Castro, Mariana S; Fontes, Wagner

    2015-01-01

    Inflammatory cascades and mechanisms are ubiquitous during host responses to various types of insult. Biological models and interventional strategies have been devised as an effort to better understand and modulate inflammation-driven injuries. Amongst those the two-hit model stands as a plausible and intuitive framework that explains some of the most frequent clinical outcomes seen in injuries like trauma and sepsis. This model states that a first hit serves as a priming event upon which sequential insults can build on, culminating on maladaptive inflammatory responses. On a different front, ischemic preconditioning (IPC) has risen to light as a readily applicable tool for modulating the inflammatory response to ischemia and reperfusion. The idea is that mild ischemic insults, either remote or local, can cause organs and tissues to be more resilient to further ischemic insults. This seemingly contradictory role that the two models attribute to a first inflammatory hit, as priming in the former and protective in the latter, has set these two theories on opposing corners of the literature. The present review tries to reconcile both models by showing that, rather than debunking each other, each framework offers unique insights in understanding and modulating inflammation-related injuries.

  2. Coordination of opposing sex-specific and core muscle groups regulates male tail posture during Caenorhabditis elegans male mating behavior

    Directory of Open Access Journals (Sweden)

    Sternberg Paul W

    2009-06-01

    Full Text Available Abstract Background To survive and reproduce, animals must be able to modify their motor behavior in response to changes in the environment. We studied a complex behavior of Caenorhabditis elegans, male mating behavior, which provided a model for understanding motor behaviors at the genetic, molecular as well as circuit level. C. elegans male mating behavior consists of a series of six sub-steps: response to contact, backing, turning, vulva location, spicule insertion, and sperm transfer. The male tail contains most of the sensory structures required for mating, in addition to the copulatory structures, and thus to carry out the steps of mating behavior, the male must keep his tail in contact with the hermaphrodite. However, because the hermaphrodite does not play an active role in mating and continues moving, the male must modify his tail posture to maintain contact. We provide a better understanding of the molecular and neuro-muscular pathways that regulate male tail posture during mating. Results Genetic and laser ablation analysis, in conjunction with behavioral assays were used to determine neurotransmitters, receptors, neurons and muscles required for the regulation of male tail posture. We showed that proper male tail posture is maintained by the coordinated activity of opposing muscle groups that curl the tail ventrally and dorsally. Specifically, acetylcholine regulates both ventral and dorsal curling of the male tail, partially through anthelmintic levamisole-sensitive, nicotinic receptor subunits. Male-specific muscles are required for acetylcholine-driven ventral curling of the male tail but dorsal curling requires the dorsal body wall muscles shared by males and hermaphrodites. Gamma-aminobutyric acid activity is required for both dorsal and ventral acetylcholine-induced curling of the male tail and an inhibitory gamma-aminobutyric acid receptor, UNC-49, prevents over-curling of the male tail during mating, suggesting that cross

  3. CFD modelling of buoyancy-driven natural ventilation opposed by wind

    Energy Technology Data Exchange (ETDEWEB)

    Cook, M.; Ji, Y. [De Montfort Univ., Leceister (United Kingdom). Inst. of Energy and Sustainable Development; Hunt, G. [Imperial College of London, London (United Kingdom). Dept. of Civil and Environmental Engineering

    2005-07-01

    This study formed the basis for generating guidelines on how to use computational fluid dynamics (CFD) to model natural ventilation in low-energy building designs. Previous studies have investigated steady natural displacement ventilation in a single space driven by buoyancy alone. The simulations used an external flow domain which allowed airflow through inlets and outlets to be modelled without the need for boundary conditions at these locations. CFD methods were used successfully to model buoyancy-driven displacement ventilation in which wind forces oppose the flow. Simulations were then conducted for a wind assisted buoyancy-driven displacement ventilation flow. The use of boundary conditions was the basic differences in the way these simulations were modelled. It was emphasized that the simulations are for natural displacement ventilation in which wind forces oppose buoyancy. Results of analytical predictions and experimental measurements were found to be in good agreement. The small discrepancies in the interface height separating the warm stratified air from the cooler ambient layer below can be attributed to differences in the plume behaviour and performance of the gauze used for inhibiting horizontal momentum. The under-prediction in the reduced gravity of the upper layer may also be due to the small differences in plume structure. 12 refs., 1 tab., 11 figs.

  4. The Physiological Role of Mitophagy: New Insights into Phosphorylation Events

    Directory of Open Access Journals (Sweden)

    Yuko Hirota

    2012-01-01

    Full Text Available Mitochondria play an essential role in oxidative phosphorylation, fatty acid oxidation, and the regulation of apoptosis. However, this organelle also produces reactive oxygen species (ROS that continually inflict oxidative damage on mitochondrial DNA, proteins, and lipids, which causes further production of ROS. To oppose this oxidative stress, mitochondria possess quality control systems that include antioxidant enzymes and the repair or degradation of damaged mitochondrial DNA and proteins. If the oxidative stress exceeds the capacity of the mitochondrial quality control system, it seems that autophagy degrades the damaged mitochondria to maintain cellular homeostasis. Indeed, recent evidence from yeast to mammals indicates that the autophagy-dependent degradation of mitochondria (mitophagy contributes to eliminate dysfunctional, aged, or excess mitochondria. In this paper, we describe the molecular processes and regulatory mechanisms of mitophagy in yeast and mammalian cells.

  5. 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.

  6. Do Organic Consumers Oppose Genetically Modified Food Stronger than Others? Results of a Consumer Research in Germany

    OpenAIRE

    Wirthgen, Antje

    2007-01-01

    The majority of consumers, in particular European consumers oppose genetic modifi-cation of food. Although consumers oppose strongly genetic modification of food, genetically modified food production increases world wide. The co-existence of both, genetically modified food production and food production free of genetic modification cannot be ensured. There is always a risk that non-genetically modified food gets contaminated despite safety regulations. Thus, even organic production, which is ...

  7. Regulatory T-cells and autoimmunity.

    LENUS (Irish Health Repository)

    Ni Choileain, Niamh

    2012-02-03

    Approximately 20% of the population is affected by autoimmune or inflammatory diseases mediated by an abnormal immune response. A characteristic feature of autoimmune disease is the selective targeting of a single cell type, organ or tissue by certain populations of autoreactive T-cells. Examples of such diseases include rheumatoid arthritis, insulin-dependent diabetes mellitus, and systemic lupus erythematosus (SLE), all of which are characterized by chronic inflammation, tissue destruction and target organ malfunction. Although strong evidence links most autoimmune diseases to specific genes, considerable controversy prevails regarding the role of regulatory T-cell populations in the disease process. These cells are now also believed to play a key role in mediating transplantation tolerance and inhibiting the induction of tumor immunity. Though the concept of therapeutic immune regulation aimed at treating autoimmune pathology has been validated in many animal models, the development of strategies for the treatment of human autoimmune disorders remains in its infancy. The main obstacles to this include the conflicting findings of different model systems, as well as the contrasting functions of regulatory T-cells and cytokines involved in the development of such disorders. This review examines the role of regulatory T-cells in the pathogenesis of autoimmunity and describes the therapeutic potential of these cells for the prevention of immune-mediated pathologies in the future. Although much remains to be learned about such pathologies, a clearer understanding of the mechanisms by which regulatory T-cells function will undoubtedly lead to exciting new possibilities for immunotherapeutics.

  8. Prediction of regulatory elements

    DEFF Research Database (Denmark)

    Sandelin, Albin

    2008-01-01

    Finding the regulatory mechanisms responsible for gene expression remains one of the most important challenges for biomedical research. A major focus in cellular biology is to find functional transcription factor binding sites (TFBS) responsible for the regulation of a downstream gene. As wet-lab...

  9. Regulatory Issues Surrounding Merchant Interconnection

    Energy Technology Data Exchange (ETDEWEB)

    Kuijlaars, Kees-Jan; Zwart, Gijsbert [Office for Energy Regulation (DTe), The Hague (Netherlands)

    2003-11-01

    We discussed various issues concerning the regulatory perspective on private investment in interconnectors. One might claim that leaving investment in transmission infrastructure to competing market parties is more efficient than relying on regulated investment only (especially in the case of long (DC) lines connecting previously unconnected parts of the grids, so that externalities from e.g. loop flows do not play a significant role). We considered that some aspects of interconnection might reduce these market benefits. In particular, the large fixed costs of interconnection construction may lead to significant under investment (due to both first mover monopoly power and the fact that part of generation cost efficiencies realised by interconnection are not captured by the investor itself, and remain external to the investment decision). Second, merchant ownership restricts future opportunities for adaptation of regulation, as would be required e.g. for introduction of potentially more sophisticated methods of congestion management or market splitting. Some of the disadvantages of merchant investment may be mitigated however by a suitable regulatory framework, and we discussed some views in this direction. The issues we discussed are not intended to give a complete framework, and detailed regulation will certainly involve many more specific requirements. Areas we did not touch upon include e.g. the treatment of deep connection costs, rules for operation and maintenance of the line, and impact on availability of capacity on other interconnections.

  10. Opposing Shear-Induced Forces Dominate Inertial Focusing in Curved Channels and High Reynolds Numbers

    CERN Document Server

    Keinan, Eliezer; Nahmias, Yaakov

    2015-01-01

    Inertial focusing is the migration of particles in fluid toward equilibrium, where current theory predicts that shear-induced and wall-induced lift forces are balanced. First reported in 1961, this Segre-Silberberg effect is particularly useful for microfluidic isolation of cells and particles. Interestingly, recent work demonstrated particle focusing at high Reynolds numbers that cannot be explained by current theory. In this work, we show that non-monotonous velocity profiles, such as those developed in curved channels, create peripheral velocity maxima around which opposing shear-induced forces dominate over wall effects. Similarly, entry effects amplified in high Reynolds flow produce an equivalent trapping mechanism in short, straight channels. This new focusing mechanism in the developing flow regime enables a 10-fold miniaturization of inertial focusing devices, while our model corrects long-standing misconceptions about the nature of mechanical forces governing inertial focusing in curved channels.

  11. Velocity anti-correlation of diametrically opposed galaxy satellites in the low-redshift Universe.

    Science.gov (United States)

    Ibata, Neil G; Ibata, Rodrigo A; Famaey, Benoit; Lewis, Geraint F

    2014-07-31

    Recent work has shown that the Milky Way and the Andromeda galaxies both possess the unexpected property that their dwarf satellite galaxies are aligned in thin and kinematically coherent planar structures. It is interesting to evaluate the incidence of such planar structures in the larger galactic population, because the Local Group may not be a representative environment. Here we report measurements of the velocities of pairs of diametrically opposed satellite galaxies. In the local Universe (redshift z 7σ confidence). This may indicate that planes of co-rotating satellites, similar to those seen around the Andromeda galaxy, are ubiquitous, and their coherent motion suggests that they represent a substantial repository of angular momentum on scales of about 100 kiloparsecs.

  12. Levitation Performance of Two Opposed Permanent Magnet Pole-Pair Separated Conical Bearingless Motors

    Science.gov (United States)

    Kascak, Peter; Jansen, Ralph; Dever, Timothy; Nagorny, Aleksandr; Loparo, Kenneth

    2013-01-01

    In standard motor applications, rotor suspension with traditional mechanical bearings represents the most economical solution. However, in certain high performance applications, rotor suspension without contacting bearings is either required or highly beneficial. Examples include applications requiring very high speed or extreme environment operation, or with limited access for maintenance. This paper expands upon a novel bearingless motor concept, in which two motors with opposing conical air-gaps are used to achieve full five-axis levitation and rotation of the rotor. Force in this motor is created by deliberately leaving the motor s pole-pairs unconnected, which allows the creation of different d-axis flux in each pole pair. This flux imbalance is used to create lateral force. This approach is different than previous bearingless motor designs, which require separate windings for levitation and rotation. This paper examines the predicted and achieved suspension performance of a fully levitated prototype bearingless system.

  13. Numerical simulation of NOx formation in a cyclone-opposed coal-fired utility boiler

    Institute of Scientific and Technical Information of China (English)

    LI Fang-qin; REN Jian-xing; WEI Dun-song

    2005-01-01

    In this paper, FLUENT software was used to simulate the burning process in a utility boiler. Chose the kinetics/diffusion-limited as combustion model, two-compet-ingrates as devolatjlization model, RNG k-εmodel as viscous model, and PDF model as combustion turbulent flow model. Numerical calculation of NOx formation in a 330 MW cyclone-opposed coal-fired utility boiler with 32 double air registers was done. The distribution characteristics of temperature, NOx and oxygen concentration in furnace were studied. They were symmetrically distributed in furnace. In the combustion area, temperature and NOx concentration are high, while oxygen concentration is low. Temperature and NOx concentration are declined gradually along with furnace height, while oxygen concentration is raised. The higher the temperature is and the greater the excess air coefficient is, the more NOx formation.

  14. Proglacial vs postglacial depostional environments, the opposing processes that filled the southern North Sea tunnel valleys

    DEFF Research Database (Denmark)

    Moreau, Julien; Huuse, Mads

    prograding north in opposing direction to the former ice flows whose south­ward flowing meltwater excavated the valleys. The first hypothesis, by analogy with some small eskers introduced the concept of backfilling where the eroded sediments upstream is deposited directly below the ice margin, in a conveyor...... observed south­dipping clinoforms and postglacial for the north­dipping clinoforms onlapping the latter. The north­dipping clinoforms are interpreted to be formed within a large deltaic system associated with the Rhine­Meuse river(s). The delta was probably infilling a large lake system containing...... were not in equilibrium during that postglacial time, and the ice might have been occasionally present in the lacustrine basin so that the lake levels may have been very variable and difficult to tie to the present­day topographic configuration. This system of competition between one of the biggest...

  15. Responses of Escherichia coli bacteria to two opposing chemoattractant gradients depend on the chemoreceptor ratio.

    Science.gov (United States)

    Kalinin, Yevgeniy; Neumann, Silke; Sourjik, Victor; Wu, Mingming

    2010-04-01

    Escherichia coli chemotaxis has long served as a simple model of environmental signal processing, and bacterial responses to single chemical gradients are relatively well understood. Less is known about the chemotactic behavior of E. coli in multiple chemical gradients. In their native environment, cells are often exposed to multiple chemical stimuli. Using a recently developed microfluidic chemotaxis device, we exposed E. coli cells to two opposing but equally potent gradients of major attractants, methyl-aspartate and serine. The responses of E. coli cells demonstrated that chemotactic decisions depended on the ratio of the respective receptor number of Tar/Tsr. In addition, the ratio of Tar to Tsr was found to vary with cells' growth conditions, whereby it depended on the culture density but not on the growth duration. These results provide biological insights into the decision-making processes of chemotactic bacteria that are subjected to multiple chemical stimuli and demonstrate the importance of the cellular microenvironment in determining phenotypic behavior.

  16. Velocity anti-correlation of diametrically opposed galaxy satellites in the low redshift universe

    CERN Document Server

    Ibata, Neil G; Famaey, Benoit; Lewis, Geraint F

    2014-01-01

    Recent work has shown that both the Milky Way and the Andromeda galaxies possess the unexpected property that their dwarf satellite galaxies are aligned in thin and kinematically coherent planar structures. It is now important to evaluate the incidence of such planar structures in the larger galactic population, since the Local Group may not be a sufficiently representative environment. Here we report that the measurement of the velocity of pairs of diametrically opposed galaxy satellites provides a means to determine statistically the prevalence of kinematically coherent planar alignments. In the local universe (redshift $z7\\sigma$ confidence). Our finding may indicate that co-rotating planes of satellites, similar to that seen around the Andromeda galaxy, are ubiquitous in nature, while their coherent motion also suggests that they are a significant repository of angular momentum on $\\sim 100$ kpc scales.

  17. Simulation of fluid flow induced by opposing ac magnetic fields in a continuous casting mold

    Energy Technology Data Exchange (ETDEWEB)

    Chang, F.C.; Hull, J.R. [Argonne National Lab., IL (United States); Beitelman, L. [J. Mulcahy Enterprises, Whitby, ON (Canada)

    1995-07-01

    A numerical simulation was performed for a novel electromagnetic stirring system employing two rotating magnetic fields. The system controls stirring flow in the meniscus region of a continuous casting mold independently from the stirring induced within the remaining volume of the mold by a main electromagnetic stirrer (M-EMS). This control is achieved by applying to the meniscus region an auxiliary electromagnetic field whose direction of rotation is opposite to that of the main magnetic field produced by the M-EMS. The model computes values and spatial distributions of electromagnetic parameters and fluid flow in the stirred pools of mercury in cylindrical and square geometries. Also predicted are the relationships between electromagnetics and fluid flows pertinent to a dynamic equilibrium of the opposing stirring swirls in the meniscus region. Results of the numerical simulation compared well with measurements obtained from experiments with mercury pools.

  18. Chemical kinetic modeling of a methane opposed flow diffusion flame and comparison to experiments

    Energy Technology Data Exchange (ETDEWEB)

    Marinov, N.M., Pitz, W.J.; Westbrook, C.K. [Lawrence Livermore National Lab., CA (United States); Vincitore, A.M.; Senka, S.M. [Univ. of California, Los Angeles, CA (United States); Lutz, A.E. [Sandia National Labs., Livermore, CA (United States)

    1998-01-01

    The chemical structure of an opposed flow, methane diffusion flame is studied using a chemical kinetic model and the results are compared to experimental measurements. The chemical kinetic paths leading to aromatics and polycyclic aromatics hydrocarbons (PAHs) in the diffusion flame are identified. These paths all involve resonantly stabilized radicals which include propargyl, allyl, cyclopentadienyl, and benzyl radicals. The modeling results show reasonable agreement with the experimental measurements for the large hydrocarbon aliphatic compounds, aromatics, and PAHs. the benzene was predicted to be formed primarily by the reaction sequence of Allyl plus Propargyl equals Fulvene plus H plus H followed by fulvene isomerization to benzene. Naphthalene was modeled using the reaction of benzyl with propargyl, while the combination of cyclopentadienyl radicals were shown to be a minor contributor in the diffusion flame. The agreement between the model and experiment for the four-ring PAHs was poor.

  19. Snapping shrimp prefer natural as opposed to artificial materials as their habitat in laboratory conditions

    Science.gov (United States)

    Sim, Lai Kean; Ghazali, Shahriman M.

    2014-09-01

    This study analyzed the habitat selection behavior of the snapping shrimp, Alpheus spp., comparing natural shelters (Rocks with oysters attached on the surface Sh; rocks with smooth surface, Ro and coral rubble, Co with plastic bottle. Controlled laboratory experiments were conducted to assess the habitat preference, effect of photoperiod and shrimp orientation at shelter. The current study indicated that snapping shrimp preferred natural materials but rejected plastic bottle as their shelter. Among the natural shelters, coral rubble was the most preferred habitat followed by shell and rock. Photoperiod showed minimum effect on the shrimp where they spend most of the time inside and underneath the shelters. In conclusion the current study showed that snapping shrimp preferred coral rubble as opposed to other natural material and plastic bottle. The result also suggested that plastic debris in the marine environment is not an alternative habitat for snapping shrimp.

  20. A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis.

    Science.gov (United States)

    Adorno, Maddalena; Cordenonsi, Michelangelo; Montagner, Marco; Dupont, Sirio; Wong, Christine; Hann, Byron; Solari, Aldo; Bobisse, Sara; Rondina, Maria Beatrice; Guzzardo, Vincenza; Parenti, Anna R; Rosato, Antonio; Bicciato, Silvio; Balmain, Allan; Piccolo, Stefano

    2009-04-03

    TGFbeta ligands act as tumor suppressors in early stage tumors but are paradoxically diverted into potent prometastatic factors in advanced cancers. The molecular nature of this switch remains enigmatic. Here, we show that TGFbeta-dependent cell migration, invasion and metastasis are empowered by mutant-p53 and opposed by p63. Mechanistically, TGFbeta acts in concert with oncogenic Ras and mutant-p53 to induce the assembly of a mutant-p53/p63 protein complex in which Smads serve as essential platforms. Within this ternary complex, p63 functions are antagonized. Downstream of p63, we identified two candidate metastasis suppressor genes associated with metastasis risk in a large cohort of breast cancer patients. Thus, two common oncogenic lesions, mutant-p53 and Ras, selected in early neoplasms to promote growth and survival, also prefigure a cellular set-up with particular metastasis proclivity by TGFbeta-dependent inhibition of p63 function.

  1. Chemical Kinetic Modeling of Dimethyl Carbonate in an Opposed-Flow Diffusion Flame

    Energy Technology Data Exchange (ETDEWEB)

    Glaude, P A; Pitz, W J; Thomson, M J

    2003-12-08

    Dimethyl carbonate (DMC) has been of interest as an oxygenate additive to diesel fuel because of its high oxygen content. In this study, a chemical kinetic mechanism for DMC was developed for the first time and used to understand its combustion under conditions in an opposed flow diffusion flame. Computed results were compared to experimental results from an opposed flow diffusion flame. It was found that the decomposition rate DMC {yields} H{sub 3}COC(=O)O. + CH{sub 3} in the flame was much slower than originally thought because resonance stabilization in the H{sub 3}COC(=O)O. radical was less than expected. Also, a new molecular elimination path for DMC is proposed and its rate calculated by quantum chemical methods. In the simulations of DMC in the flame, it was determined that much of the oxygen in dimethyl carbonate goes directly to CO{sub 2}. This characteristic indicates that DMC would not be an effective oxygenate additive for reducing soot emissions from diesel engines. In an ideal oxygenate additive for diesel fuel, each oxygen atom stays bonded to one carbon atom in the products thereby preventing the formation of carbon-carbon bonds that can lead to soot. When CO2 is formed directly, two oxygen atoms are bonded to one carbon atom thereby wasting one oxygen atom in the oxygenate additive. To determine how much CO{sub 2} is formed directly, the branching ratio of the key reaction, CH{sub 3}OC.=O going to the products CH{sub 3} + CO{sub 2} or CH{sub 3}O + CO was determined by ab initio methods. The A-factors of the rate constant of this reaction were found to be about 20 times higher than previous factors estimates. The new reaction rate constants obtained can be used as reaction rate rules for all oxygenates that contain the ester moiety including biodiesel.

  2. Wear resistance of a pressable low-fusing ceramic opposed by dental alloys.

    Science.gov (United States)

    Faria, Adriana Cláudia Lapria; de Oliveira, André Almeida; Alves Gomes, Erica; Silveira Rodrigues, Renata Cristina; Faria Ribeiro, Ricardo

    2014-04-01

    Dental alloys have increasingly replaced by dental ceramics in dentistry because of aesthetics. As both dental alloys and ceramics can be present in the oral cavity, the evaluation of the wear resistance of ceramics opposed by dental alloys is important. The aim of the present study was to evaluate wear resistance of a pressable low-fusing ceramic opposed by dental alloys as well as the microhardness of the alloys and the possible correlation of wear and antagonist microhardness. Fifteen stylus tips samples of pressable low-fusing ceramic were obtained, polished and glazed. Samples were divided into three groups according to the disk of alloy/metal to be used as antagonist: Nickel-Chromium (Ni-Cr), Cobalt-Chromium (Co-Cr) and commercially pure titanium (cp Ti). Vickers microhardness of antagonist disks was evaluated before wear tests. Then, antagonist disks were sandblasted until surface roughness was adjusted to 0.75μm. Wear tests were performed at a speed of 60 cycles/min and distance of 10mm, in a total of 300,000 cycles. Before and after wear tests, samples were weighted and had their profile designed in an optical comparator to evaluate weight and height loss, respectively. Ni-Cr and cp Ti caused greater wear than Co-Cr, presenting greater weight (p=.009) and height (p=.002) loss. Cp Ti microhardness was lower than Ni-Cr and Co-Cr (p<.05). There is a positive correlation between weight and height loss (p<.05), but weight (p=.204) and height (p=.05) loss are not correlated to microhardness. The results suggest that pressable low-fusing ceramic presents different wear according to the dental alloy used as antagonist and the wear is not affected by antagonist microhardness.

  3. Do hedonic motives moderate regulatory focus motives? Evidence from the framing of persuasive messages.

    Science.gov (United States)

    Malaviya, Prashant; Brendl, C Miguel

    2014-01-01

    Research on regulatory focus has established a regulatory matching effect: The persuasiveness of a message is enhanced when regulatory orientations of message and perceiver match (i.e., both are promotion or both are prevention). We report evidence that varying the hedonic outcome reverses this effect. We manipulated hedonic outcome by explicitly stating pleasurable versus painful outcomes as part of the message frame as well as by priming perceivers to focus on either pleasurable or painful outcomes. When both message and perceiver were focused on pleasurable outcomes, we replicated the regulatory matching effect. However, the matching effect reversed when the hedonic outcome of the message was opposed to that of the perceiver (i.e., one was pleasurable and the other painful). Under these conditions, messages that mismatched the perceivers' regulatory orientation were more persuasive (i.e., promotion message for a prevention oriented perceiver or vice versa). We also examined the persuasion effects when both message and perceiver were focused on painful outcomes and found that the regulatory matching effect re-emerged. The reversal of the regulatory matching effect by hedonic outcome strongly suggests that hedonic motives (approach of pleasure vs. avoidance of pain) and regulatory focus motives are distinct constructs. This is important because contrary to theoretical statements these constructs have often been confounded.

  4. Nuclear Regulatory Commission information digest

    Energy Technology Data Exchange (ETDEWEB)

    None,

    1990-03-01

    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.

  5. 2012 Global Summit on Regulatory Science (GSRS-2012)--modernizing toxicology.

    Science.gov (United States)

    Miller, Margaret A; Tong, Weida; Fan, Xiaohui; Slikker, William

    2013-01-01

    Regulatory science encompasses the tools, models, techniques, and studies needed to assess and evaluate product safety, efficacy, quality, and performance. Several recent publications have emphasized the role of regulatory science in improving global health, supporting economic development and fostering innovation. As for other scientific disciplines, research in regulatory science is the critical element underpinning the development and advancement of regulatory science as a modern scientific discipline. As a regulatory agency in the 21st century, the Food and Drug Administration (FDA) has an international component that underpins its domestic mission; foods, drugs, and devices are developed and imported to the United States from across the world. The Global Summit on Regulatory Science, an international conference for discussing innovative technologies, approaches, and partnerships that enhance the translation of basic science into regulatory applications, is providing leadership for the advancement of regulatory sciences within the global context. Held annually, this international conference provides a platform where regulators, policy makers, and bench scientists from various countries can exchange views on how to develop, apply, and implement innovative methodologies into regulatory assessments in their respective countries, as well as developing a harmonized strategy to improve global public health through global collaboration.

  6. P19ARF and RasV¹² offer opposing regulation of DHX33 translation to dictate tumor cell fate.

    Science.gov (United States)

    Zhang, Yandong; Saporita, Anthony J; Weber, Jason D

    2013-04-01

    DHX33 is a pivotal DEAH-box RNA helicase in the multistep process of RNA polymerase I-directed transcription of the ribosomal DNA locus. We explored the regulation of DHX33 expression by Ras(V12) and ARF to determine DHX33's role in sensing these opposing signals to regulate ribosome biogenesis. In wild-type primary fibroblasts, Ras(V12) infection induced a transient increase in DHX33 protein level, as well as an rRNA transcriptional rate that was eventually suppressed by a delayed activation of the ARF/p53 pathway. DHX33 expression was exclusively controlled at the level of translation. ARF caused a dramatic reduction in polysome-associated DHX33 mRNAs, while Ras(V12) led to a complete shift of existing DHX33 mRNAs to actively translating polysomes. The translation of DHX33 by Ras(V12) was sensitive to inhibitors of phosphatidylinositol 3-kinase, mTOR, and mitogen-activated protein and was pivotal for enhanced rRNA transcription and enhanced overall cellular protein translation. In addition, DHX33 knockdown abolished Ras(V12)-induced rRNA transcription and protein translation and prevented both the in vitro and in vivo transforming properties of oncogenic Ras(V12). Our results directly implicate DHX33 as a crucial player in establishing rRNA synthesis rates in the face of Ras(V12) or ARF signals, adjusting ribosome biogenesis to match the appropriate growth or antigrowth signals.

  7. Opposing effects of low molecular weight heparins on the release of inflammatory cytokines from peripheral blood mononuclear cells of asthmatics.

    Directory of Open Access Journals (Sweden)

    Madhur D Shastri

    Full Text Available T-cell-mediated inflammatory cytokines, such as interleukin (IL-4, IL-5, IL-13 and tumor necrosis factor-alpha (TNF-α, play an important role in the initiation and progression of inflammatory airways diseases. Low-molecular-weight heparins (LMWHs, widely used anticoagulants, possess anti-inflammatory properties making them potential treatment options for inflammatory diseases, including asthma. In the current study, we investigated the modulating effects of two LMWHs (enoxaparin and dalteparin on the release of cytokines from stimulated peripheral blood mononuclear cells (PBMCs of asthmatic subjects to identify the specific components responsible for the effects.PBMCs from asthmatic subjects (consist of ~75% of T-cells were isolated from blood taken from ten asthmatic subjects. The PBMCs were pre-treated in the presence or absence of different concentrations of LMWHs, and were then stimulated by phytohaemagglutinin for the release of IL-4, IL-5, IL-13 and TNF-α. LMWHs were completely or selectively desulfated and their anticoagulant effect, as well as the ability to modulate cytokine release, was determined. LMWHs were chromatographically fractionated and each fraction was tested for molecular weight determination along with an assessment of anticoagulant potency and effect on cytokine release.Enoxaparin inhibited cytokine release by more than 48%, whereas dalteparin increased their release by more than 25%. The observed anti-inflammatory effects of enoxaparin were independent of their anticoagulant activities. Smaller fractions, in particular dp4 (four saccharide units, were responsible for the inhibitory effect of enoxaparin. Whereas, the larger fractions, in particular dp22 (twenty two saccharide units, were associated with the stimulatory effect of dalteparin.Enoxaparin and dalteparin demonstrated opposing effects on inflammatory markers. These observed effects could be due to the presence of structurally different components in the two

  8. Role of CD4 + CD25 + regulatory T cells in the patients with ulcerative colitis%CD4+CD25+T细胞在溃疡性结肠炎患者中的表达及意义

    Institute of Scientific and Technical Information of China (English)

    宋振梅; 王晓娣

    2010-01-01

    目的 研究溃疡性结肠炎(UC)患者外周血CD4+CD25+调节性T细胞和其特异性标志物Foxp3的表达及其在UC不同病期的变化,探讨其在UC发病机制中的意义.方法 研究纳入2007年2月至2008年12月在我院就诊的UC患者40例,其中活动期23例,缓解期17例;同时选择33例肠易激综合征(IBS)患者及32名健康者作为对照.用流式细胞仪检测UC患者、IBS患者和正常对照者的外周血CD4+CD25+T细胞阳性率,用RT-PCR检测外周血单个核细胞(PBMC)中Foxp3 mRNA的表达,用酶联免疫吸附实验检测血清中白细胞介素-10(IL-10)和转化生长因子-β(TGF-β)的浓度.结果 活动期和缓解期UC患者、IBS患者、正常对照者外周血CD4+T细胞总数相比差异无统计学意义(P=0.126).CD4+CD25+T细胞在CD4+T细胞中所占比例在活动期和缓解期UC患者中均明显低于IBS患者和正常对照组(P均<0.01),活动期患者较缓解期患者更低(P<0.001),并且与疾病活动指数(r=-0.660,P<0.001)及红细胞沉降率(r=-0.572,P=0.001)均呈显著负相关,而IBS患者和正常对照者间差异没有统计学意义(P=0.343).PBMC中Foxp3 mRNA的表达在活动期和缓解期UC患者均明显低于IBS患者和正常对照组(P均<0.001).而血清IL-10和TGF-β的浓度在活动期和缓解期UC患者、IBS患者和正常对照者4组间无明显差异(P均>0.05).结论 活动期UC患者外周血CD4+CD25+调节性T细胞明显降低,缓解期UC患者的表达有所升高,并且与临床疾病活动相关,提示这类细胞可能参与了UC疾病的发生发展,Foxp3表达降低可能是导致CD4+CD25+T细胞发育障碍的重要因素.%Objective To investigate the levels of CD4 + CD25 + regulatory T cells and the Foxp3 in the peripheral blood of patients with ulcerative colitis ( UC), and analyze its role in the pathogenesis of UC. Methods From February 2007 to December 2008, 40 UC patients (23 active and 17 remissive), 33 irritable bowel syndrome (IBS

  9. Slit2 and Robo1 induce opposing effects on metastasis of hepatocellular carcinoma Sk-hep-1 cells.

    Science.gov (United States)

    Yuan, Mingjing; Guo, Hui; Li, Jing; Sui, Chengzhi; Qin, Ying; Wang, Jingjing; Khan, Yasir Hayat; Ye, Liying; Xie, Fuan; Wang, Heng; Yuan, Li; Ye, Jun

    2016-07-01

    The neural guidance molecular, Slit2, and its cognate receptor, Robo1, play critical roles in the development of the nervous system, nevertheless, their functions are not limited to this system. Numerous studies have shown decreased Slit2 expression in a wide variety of cancers, highlighting its potential as a tumor suppressor. However, the Slit2/Robo1 signaling axis was reported to induce either suppressive or stimulatory effects on tumor growth and metastasis, depending on cellular context. There is a paucity of information on the effects of the Slit2/Robo1 signaling axis on the growth and metastasis of human hepatocellular carcinoma (HCC). Large-scale data mining of the Oncomine database has revealed heterogeneous expression of Slit2 in HCC. We screened the Sk-hep-1, a cell line showing a relatively high level of Slit2, and low level of Robo1 expression. After Slit2 knockdown and Robo1 overexpression in these cells, we found Slit2 and Robo1 exerted opposing effects on tumor growth and metastasis both in in vitro and in vivo models. Slit2 knockdown and Robo1 overexpression in Sk-hep-1 cells promoted tumor growth and metastasis, suggesting a negative and positive role for Slit2 and Robo1, respectively, in tumor progression. Robo1 overexpression upregulated matrix metalloproteinase (MMP)2, -9 and membrane-type1 MMP (MT1-MMP) expression, stimulated MMP2, but not MMP9 activation, and downregulated expression of TIMP1 and 2. The PI3K/Akt signaling pathway is of importance in regulating MMP2 expression in Sk-hep-1 cells, since Robo1 overexpression stimulated phosphorylation of Akt while the PI3K inhibitor LY294002, significantly inhibited the upregulation of MMP2 and also the enhanced cell invasion induced by Robo1 overexpression. We postulate that Robo1 promotes tumor invasion partly by the upregulation of MMP2 after activation of PI3K/Akt signaling pathway. Notably, Slit2 knockdown caused the upregulation of Robo1 expression both at the mRNA and protein levels

  10. Hastening the regulatory process

    Energy Technology Data Exchange (ETDEWEB)

    Stringham, G. [Canadian Association of Petroleum Producers, Calgary, AB (Canada)

    2001-07-01

    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.

  11. Opposed-Flow Flame Spread in a Narrow Channel Apparatus over Thin PMMA Sheets

    Science.gov (United States)

    Bornand, G. R.; Olson, Sandra L.; Miller, F. J.; Pepper, J. M.; Wichman, I. S.

    2013-01-01

    Flame spread tests have been conducted over polymethylmethacrylate (PMMA) samples in San Diego State University's Narrow Channel Apparatus (SDSU NCA). The Narrow Channel Apparatus (NCA) has the ability to suppress buoyant flow in horizontally spreading flames, and is currently being investigated as a possible replacement or complement to NASA's current material flammability test standard for non-metallic solids, NASA-STD-(I)-6001B Test 1. The buoyant suppression achieved with a NCA allows for tests to be conducted in a simulated microgravity atmosphere-a characteristic that Test 1 lacks since flames present in Test 1 are buoyantly driven. The SDSU NCA allows for flame spread tests to be conducted with varying opposed flow oxidizer velocities, oxygen percent by volume, and total pressure. Also, since the test sample is placed symmetrically between two confining plates so that there is a gap above and below the sample, this gap can be adjusted. This gap height adjustment allows for a compromise between heat loss from the flame to the confining boundaries and buoyancy suppression achieved by those boundaries. This article explores the effect gap height has on the flame spread rate for 75 µm thick PMMA at 1 atm pressure and 21% oxygen concentration by volume in the SDSU NCA. Flame spread results from the SDSU NCA for thin cellulose fuels have previously been compared to results from tests in actual microgravity at various test conditions with the same sample materials and were found to be in good agreement. This article also presents results from the SDSU NCA for PMMA at 1 atm pressure, opposed oxidizer velocity ranging from 3 to 35 cm/s, oxygen concentration by volume at 21%, 30 %, and 50% and fuel thicknesses of 50 and 75 µm. These results are compared to results obtained in actual microgravity for PMMA obtained at the 4.5s drop tower of MGLAB in Gifu, Japan, and the 5.2s drop tower at NASA's Zero-Gravity Research Facility in Cleveland, OH. This comparison confirms

  12. Wear of human enamel opposing monolithic zirconia, glass ceramic, and composite resin: an in vitro study.

    Science.gov (United States)

    Sripetchdanond, Jeerapa; Leevailoj, Chalermpol

    2014-11-01

    Demand is increasing for ceramic and composite resin posterior restorations. However, ceramics are recognized for their high abrasiveness to opposing dental structure. The purpose of this study was to investigate the wear of enamel as opposed to dental ceramics and composite resin. Twenty-four test specimens (antagonists), 6 each of monolithic zirconia, glass ceramic, composite resin, and enamel, were prepared into cylindrical rods. Enamel specimens were prepared from 24 extracted human permanent molar teeth. Enamel specimens were abraded against each type of antagonist with a pin-on-disk wear tester under a constant load of 25 N at 20 rpm for 4800 cycles. The maximum depth of wear (Dmax), mean depth of wear (Da), and mean surface roughness (Ra) of the enamel specimens were measured with a profilometer. All data were statistically analyzed by 1-way ANOVA, followed by the Tukey test (α=.05). A paired t test was used to compare the Ra of enamel at baseline and after testing. The wear of both the enamel and antagonists was evaluated qualitatively with scanning electron microscopic images. No significant differences were found in enamel wear depth (Dmax, Da) between monolithic zirconia (2.17 ±0.80, 1.83 ±0.75 μm) and composite resin (1.70 ±0.92, 1.37 ±0.81 μm) or between glass ceramic (8.54 ±2.31, 7.32 ±2.06 μm) and enamel (10.72 ±6.31, 8.81 ±5.16 μm). Significant differences were found when the enamel wear depth caused by monolithic zirconia and composite resin was compared with that of glass ceramic and enamel (Pcomposite resin resulted in less wear depth to human enamel compared with glass ceramic and enamel. All test materials except composite resin similarly increased the enamel surface roughness after wear testing. Copyright © 2014 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.

  13. Influence of Length of Opposing bi-Au Cone-Tips and Different Environment on Field Enhancement in Feed Gap

    Institute of Scientific and Technical Information of China (English)

    LI Xu-Feng; WU Shi-Fa

    2007-01-01

    Electric field enhancement distributions encountered in feed gap of opposing bi-Au cone-tips is studied using a frequency-domain three-dimensional finite element method to solve Maxwell's equations of electric field distributions. Both the influences of cone-tip length and surrounding medium on electric field enhancement are investigated. The maximal