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Sample records for adprt1 akr1b1 rage

  1. RAGE splicing variants in mammals.

    Science.gov (United States)

    Sterenczak, Katharina Anna; Nolte, Ingo; Murua Escobar, Hugo

    2013-01-01

    The receptor for advanced glycation end products (RAGE) is a multiligand receptor of environmental stressors which plays key roles in pathophysiological processes, including immune/inflammatory disorders, Alzheimer's disease, diabetic arteriosclerosis, tumorigenesis, and metastasis. Besides the full-length RAGE protein in humans nearly 20 natural occurring RAGE splicing variants were described on mRNA and protein level. These naturally occurring isoforms are characterized by either N-terminally or C-terminally truncations and are discussed as possible regulators of the full-length RAGE receptor either by competitive ligand binding or by displacing the full-length protein in the membrane. Accordingly, expression deregulations of the naturally occurring isoforms were supposed to have significant effect on RAGE-mediated disorders. Thereby the soluble C-truncated RAGE isoforms present in plasma and tissues are the mostly focused isoforms in research and clinics. Deregulations of the circulating levels of soluble RAGE forms were reported in several RAGE-associated pathological disorders including for example atherosclerosis, diabetes, renal failure, Alzheimer's disease, and several cancer types. Regarding other mammalian species, the canine RAGE gene showed high similarities to the corresponding human structures indicating RAGE to be evolutionary highly conserved between both species. Similar to humans the canine RAGE showed a complex and extensive splicing activity leading to a manifold pattern of RAGE isoforms. Due to the similarities seen in several canine and human diseases-including cancer-comparative structural and functional analyses allow the development of RAGE and ligand-specific therapeutic approaches beneficial for human and veterinary medicine.

  2. RAGE and TLRs: relatives, friends or neighbours?

    Science.gov (United States)

    Ibrahim, Zaridatul Aini; Armour, Carol L; Phipps, Simon; Sukkar, Maria B

    2013-12-01

    The innate immune system forms the first line of protection against infectious and non-infectious tissue injury. Cells of the innate immune system detect pathogen-associated molecular patterns or endogenous molecules released as a result of tissue injury or inflammation through various innate immune receptors, collectively termed pattern-recognition receptors. Members of the Toll-like receptor (TLR) family of pattern-recognition receptors have well established roles in the host immune response to infection, while the receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor predominantly involved in the recognition of endogenous molecules released in the context of infection, physiological stress or chronic inflammation. RAGE and TLRs share common ligands and signaling pathways, and accumulating evidence points towards their co-operative interaction in the host immune response. At present however, little is known about the mechanisms that result in TLR versus RAGE signalling or RAGE-TLR cross-talk in response to their shared ligands. Here we review what is known in relation to the physicochemical basis of ligand interactions between TLRs and RAGE, focusing on three shared ligands of these receptors: HMGB1, S100A8/A9 and LPS. Our aim is to discuss what is known about differential ligand interactions with RAGE and TLRs and to highlight important areas for further investigation so that we may better understand the role of these receptors and their relationship in host defense. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. The receptor RAGE: Bridging inflammation and cancer

    Directory of Open Access Journals (Sweden)

    Hess Jochen

    2009-05-01

    Full Text Available Abstract The receptor for advanced glycation end products (RAGE is a single transmembrane receptor of the immunoglobulin superfamily that is mainly expressed on immune cells, neurons, activated endothelial and vascular smooth muscle cells, bone forming cells, and a variety of cancer cells. RAGE is a multifunctional receptor that binds a broad repertoire of ligands and mediates responses to cell damage and stress conditions. It activates programs responsible for acute and chronic inflammation, and is implicated in a number of pathological diseases, including diabetic complications, stroke, atheriosclerosis, arthritis, and neurodegenerative disorders. The availability of Rage knockout mice has not only advanced our knowledge on signalling pathways within these pathophysiological conditions, but also on the functional importance of the receptor in processes of cancer. Here, we will summarize molecular mechanisms through which RAGE signalling contributes to the establishment of a pro-tumourigenic microenvironment. Moreover, we will review recent findings that provide genetic evidence for an important role of RAGE in bridging inflammation and cancer.

  4. AGEs, RAGEs and s-RAGE; friend or foe for cancer.

    Science.gov (United States)

    Ahmad, Saheem; Khan, Hamda; Siddiqui, Zeba; Khan, Mohd Yasir; Rehman, Shahnawaz; Shahab, Uzma; Godovikova, Tatyana; Silnikov, Vladimir; Moinuddin

    2018-04-01

    Impaired awareness of glycation biology in cancer initiation and progression is one of the fundamental reasons for its meticulous investigation of the molecules involved in signalling pathway. Glycation of biological macromolecules results in the progression of advanced glycation end-products (AGEs) that proliferates the process of carcinogenesis by activation of transcription factors and release of cytokines. The receptor for advanced glycation end-products (RAGEs) with the binding of its different ligands like; AGEs, HMGB1 and S100 activate the signalling arrays. The activation of downstream signalling pathway ultimately leads to the pathophysiological conditions of diabetes, ageing, neurological disorders and cancers as well as a result of the activation of transcription factors which is discussed in the main body text of this review. However, there might be a likelihood of the positive effect of the HMGB1 and S100 proteins in cancer. Still, some untouched mechanisms might be responsible for the establishment of the function of AGE-RAGE or AGE-sRAGE axis activation that leads to the friend-foe association with the cancers. The levels of RAGE and s-RAGE may be a useful biomarker of ligand-RAGE pathway activation and cancer. Thus, the possibility of providing a potential complement to carcinogenesis is very high which might be an interesting target for therapeutic interventions. This article is an insightful assessment on AGE, RAGE and s-RAGE for its possible role in cancer onset and progression. The novel therapeutic targets for cancer prevention or inhibition are also explained in brief in relation to AGE and RAGE. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. RAGE, receptor of advanced glycation endoproducts, negatively regulates chondrocytes differentiation.

    Directory of Open Access Journals (Sweden)

    Tatsuya Kosaka

    Full Text Available RAGE, receptor for advanced glycation endoproducts (AGE, has been characterized as an activator of osteoclastgenesis. However, whether RAGE directly regulates chondrocyte proliferation and differentiation is unclear. Here, we show that RAGE has an inhibitory role in chondrocyte differentiation. RAGE expression was observed in chondrocytes from the prehypertrophic to hypertrophic regions. In cultured cells, overexpression of RAGE or dominant-negative-RAGE (DN-RAGE demonstrated that RAGE inhibited cartilaginous matrix production, while DN-RAGE promoted production. Additionally, RAGE regulated Ihh and Col10a1 negatively but upregulated PTHrP receptor. Ihh promoter analysis and real-time PCR analysis suggested that downregulation of Cdxs was the key for RAGE-induced inhibition of chondrocyte differentiation. Overexpression of the NF-κB inhibitor I-κB-SR inhibited RAGE-induced NF-κB activation, but did not influence inhibition of cartilaginous matrix production by RAGE. The inhibitory action of RAGE was restored by the Rho family GTPases inhibitor Toxin B. Furthermore, inhibitory action on Ihh, Col10a1 and Cdxs was reproduced by constitutively active forms, L63RhoA, L61Rac, and L61Cdc42, but not by I-κB-SR. Cdx1 induced Ihh and Col10a1 expressions and directly interacted with Ihh promoter. Retinoic acid (RA partially rescued the inhibitory action of RAGE. These data combined suggests that RAGE negatively regulates chondrocyte differentiation at the prehypertrophic stage by modulating NF-κB-independent and Rho family GTPases-dependent mechanisms.

  6. "Uproar, bulk, rage, suffocation, effort unceasing, frenzied and vain": Beckett's Transports of Rage.

    Science.gov (United States)

    Smith, Russell

    2016-06-01

    In a 1961 interview, Beckett warded off philosophical interpretations of his work: 'I'm no intellectual. All I am is feeling'. Despite the emotional intensity of Beckett's post-war writing, Beckett criticism has tended to ignore this claim, preferring the kinds of philosophical readings that Beckett here rejects. In particular, Beckett criticism underestimates the element of rage in his work. This paper argues that Beckett's post-war breakthrough is enabled by a radical reconsideration of the nature of feeling and of rage in particular. It involves the rejection of the idea of rage as pathological and the embrace of a positive conception of rage as drive or compulsion, a locus of energy and even pleasure.This paper reads the 'Moran' section of Molloy as a kind of 'rage fable', drawing on the ancient Greek concept of thymos, of anger as a virtue. It draws on Alfred Adler's theory of the 'masculine protest', with which Beckett was familiar from his extensive note-taking on Adler in 1934-5, and Sianne Ngai's discussion of the distinction between irritation and rage. According to this reading, Moran's report charts a narrative of thymotic liberation from the irritations of servitude, prefiguring the Unnamable's abandonment to impersonal affective intensities. It ends by suggesting that the prose of the Trilogy might be better understood, not as a 'syntax of weakness' but as a 'syntax of rage', a stylistic correlative of the imperious drive of thymos. We might then begin to understand the Trilogy as the epic of a heroic, impersonal, implacable and liberated rage.

  7. xRage Equation of State

    Energy Technology Data Exchange (ETDEWEB)

    Grove, John W. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-08-16

    The xRage code supports a variety of hydrodynamic equation of state (EOS) models. In practice these are generally accessed in the executing code via a pressure-temperature based table look up. This document will describe the various models supported by these codes and provide details on the algorithms used to evaluate the equation of state.

  8. Women's experience of rage: a critical feminist analysis.

    Science.gov (United States)

    Flemke, Kimberly; Allen, Katherine R

    2008-01-01

    We conducted in-depth interviews with 37 incarcerated women on their experience of rage towards their intimate partner. Participants used specific criteria to distinguish their experience of rage from anger. Rage is described as an overwhelming experience with particular physiological and cognitive changes that takes control of a woman's emotions and actions. In contrast, anger is described as a controllable emotion with a specific termination point. Motivations for acting violently in rage with an intimate partner are described and discussed. Findings suggest a primary trigger for experiencing rage is feeling threatened and feeling emotionally overwhelmed.

  9. Protection against RAGE-mediated neuronal cell death by sRAGE-secreting human mesenchymal stem cells in 5xFAD transgenic mouse model.

    Science.gov (United States)

    Son, Myeongjoo; Oh, Seyeon; Park, Hyunjin; Ahn, Hyosang; Choi, Junwon; Kim, Hyungho; Lee, Hye Sun; Lee, Sojung; Park, Hye-Jeong; Kim, Seung U; Lee, Bonghee; Byun, Kyunghee

    2017-11-01

    Alzheimer's disease (AD), which is the most commonly encountered neurodegenerative disease, causes synaptic dysfunction and neuronal loss due to various pathological processes that include tau abnormality and amyloid beta (Aβ) accumulation. Aβ stimulates the secretion and the synthesis of Receptor for Advanced Glycation End products (RAGE) ligand by activating microglial cells, and has been reported to cause neuronal cell death in Aβ 1-42 treated rats and in mice with neurotoxin-induced Parkinson's disease. The soluble form of RAGE (sRAGE) is known to reduce inflammation, and to decrease microglial cell activation and Aβ deposition, and thus, it protects from neuronal cell death in AD. However, sRAGE protein has too a short half-life for therapeutic purposes. We developed sRAGE-secreting umbilical cord derived mesenchymal stem cells (sRAGE-MSCs) to enhance the inhibitory effects of sRAGE on Aβ deposition and to reduce the secretion and synthesis of RAGE ligands in 5xFAD mice. In addition, these cells improved the viability of injected MSCs, and enhanced the protective effects of sRAGE by inhibiting the binding of RAGE and RAGE ligands in 5xFAD mice. These findings suggest sRAGE protein from sRAGE-MSCs has better protection against neuronal cell death than sRAGE protein or single MSC treatment by inhibiting the RAGE cell death cascade and RAGE-induce inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. RAGE: a new frontier in chronic airways disease

    Science.gov (United States)

    Sukkar, Maria B; Ullah, Md Ashik; Gan, Wan Jun; Wark, Peter AB; Chung, Kian Fan; Hughes, J Margaret; Armour, Carol L; Phipps, Simon

    2012-01-01

    Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand–RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions. PMID:22506507

  11. The RAGE radiation-hydrodynamic code

    Energy Technology Data Exchange (ETDEWEB)

    Gittings, Michael; Clover, Michael; Betlach, Thomas; Byrne, Nelson; Ranta, Dale [Science Applications International Corp. MS A-1, 10260 Campus Point Drive, San Diego, CA 92121 (United States); Weaver, Robert; Coker, Robert; Dendy, Edward; Hueckstaedt, Robert; New, Kim; Oakes, W Rob [Los Alamos National Laboratory, MS T087, PO Box 1663, Los Alamos, NM 87545 (United States); Stefan, Ryan [TaylorMade-adidas Golf, 5545 Fermi Court, Carlsbad, CA 92008-7324 (United States)], E-mail: michael.r.clover@saic.com

    2008-10-01

    We describe RAGE, the 'radiation adaptive grid Eulerian' radiation-hydrodynamics code, including its data structures, its parallelization strategy and performance, its hydrodynamic algorithm(s), its (gray) radiation diffusion algorithm, and some of the considerable amount of verification and validation efforts. The hydrodynamics is a basic Godunov solver, to which we have made significant improvements to increase the advection algorithm's robustness and to converge stiffnesses in the equation of state. Similarly, the radiation transport is a basic gray diffusion, but our treatment of the radiation-material coupling, wherein we converge nonlinearities in a novel manner to allow larger timesteps and more robust behavior, can be applied to any multi-group transport algorithm.

  12. The RAGE radiation-hydrodynamic code

    International Nuclear Information System (INIS)

    Gittings, Michael; Clover, Michael; Betlach, Thomas; Byrne, Nelson; Ranta, Dale; Weaver, Robert; Coker, Robert; Dendy, Edward; Hueckstaedt, Robert; New, Kim; Oakes, W Rob; Stefan, Ryan

    2008-01-01

    We describe RAGE, the 'radiation adaptive grid Eulerian' radiation-hydrodynamics code, including its data structures, its parallelization strategy and performance, its hydrodynamic algorithm(s), its (gray) radiation diffusion algorithm, and some of the considerable amount of verification and validation efforts. The hydrodynamics is a basic Godunov solver, to which we have made significant improvements to increase the advection algorithm's robustness and to converge stiffnesses in the equation of state. Similarly, the radiation transport is a basic gray diffusion, but our treatment of the radiation-material coupling, wherein we converge nonlinearities in a novel manner to allow larger timesteps and more robust behavior, can be applied to any multi-group transport algorithm

  13. RAGE receptor and its soluble isoforms in diabetes mellitus complications

    Directory of Open Access Journals (Sweden)

    Mauren Isfer Anghebem Oliveira

    2013-04-01

    Full Text Available Chronic hyperglycemia, which is present in all types of diabetes, increases the formation of advanced glycation end-products (AGEs. The interaction of AGEs with receptor of advanced glycation end-products (RAGE initiates a cascade of pro-inflammatory and pro-coagulant processes that result in oxidative stress, stimulating the formation and accumulation of more AGE molecules. This cyclic process, denominated metabolic memory, may explain the persistency of diabetic vascular complications in patients with satisfactory glycemic control. The RAGE found in several cell membranes is also present in soluble isoforms (esRAGE and cRAGE, which are generated by alternative deoxyribonucleic acid splicing or by proteolytic cleavage. This review focuses on new research into these mediators as potential biomarkers for vascular complications in diabetes.

  14. RAGE: a new frontier in chronic airways disease.

    Science.gov (United States)

    Sukkar, Maria B; Ullah, Md Ashik; Gan, Wan Jun; Wark, Peter A B; Chung, Kian Fan; Hughes, J Margaret; Armour, Carol L; Phipps, Simon

    2012-11-01

    Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand-RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  15. Structure function relationship of recombinant sRAGE

    OpenAIRE

    Premaratne, Dinamithra Gedara Sujeewani Rasika

    2017-01-01

    The receptor for advanced glycation end-products (RAGE) is a member of the immunoglobulin super family of cell surface receptors. It acts as the direct mediator of physiological and pathological responses such as inflammation, chemotaxis, neurite outgrowth, angiogenesis, apoptosis and proliferation. RAGE is known to bind with structurally and functionally diverse ligands, such as advanced glycation end-products (AGEs), high mobility group family proteins including HMGB-1/amphoterin, matrix pr...

  16. Pentamidine blocks the interaction between mutant S100A5 and RAGE V domain and inhibits the RAGE signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Ching Chang, E-mail: ccjwo@yahoo.com.tw [Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan (China); Chou, Ruey Hwang, E-mail: rhchou@mail.cmu.edu.tw [Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung 40402, Taiwan (China); Yu, Chin, E-mail: cyu.nthu@gmail.com [Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan (China)

    2016-08-19

    The human S100 protein family contains small, dimeric and acidic proteins that contain two EF-hand motifs and bind calcium. When S100A5 binds calcium, its conformation changes and promotes interaction with the target protein. The extracellular domain of RAGE (Receptor of Advanced Glycation End products) contain three domains: C1, C2 and V. The RAGE V domain is the target protein of S100A5 that promotes cell survival, growth and differentiation by activating several signaling pathways. Pentamidine is an apoptotic and antiparasitic drug that is used to treat or prevent pneumonia. Here, we found that pentamidine interacts with S100A5 using HSQC titration. We elucidated the interactions of S100A5 with RAGE V domain and pentamidine using fluorescence and NMR spectroscopy. We generated two binary models—the S100A5-RAGE V domain and S100A5-Pentamidine complex—and then observed that the pentamidine and RAGE V domain share a similar binding region in mS100A5. We also used the WST-1 assay to investigate the bioactivity of S100A5, RAGE V domain and pentamidine. These results indicated that pentamidine blocks the binding between S100A5 and RAGE V domain. This finding is useful for the development of new anti-proliferation drugs. - Highlights: • The interaction between mS100A5–RAGE V was investigated by fluorescence spectroscopy. • The interfacial residues on mS100A5–RAGE V and mS100A5–pentamidine contact surface were mapped by {sup 1}H-{sup 15}N HSQC experiments. • mS100A5–RAGE V and mS100A5–pentamidine complex models were generated from NMR restraints using HADDOCK program. • The bioactivity of the mS100A5–RAGE V and mS100A5–pentamidine complex was studied using WST-1 assay.

  17. Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose-tolerant individuals and are associated with the development of type 2 diabetes

    DEFF Research Database (Denmark)

    Miranda, Edwin R; Somal, Vikram S; Mey, Jacob T

    2017-01-01

    The soluble receptor for advanced glycation end products (sRAGE) may be protective against inflammation associated with obesity and type 2 diabetes (T2DM). The aim of this study was to determine the distribution of sRAGE isoforms and whether sRAGE isoforms are associated with risk of T2DM...... development in subjects spanning the glucose tolerance continuum. In this retrospective analysis, circulating total sRAGE and endogenous secretory RAGE (esRAGE) were quantified via ELISA, and cleaved RAGE (cRAGE) was calculated in 274 individuals stratified by glucose tolerance status (GTS) and obesity. Group......RAGE, and esRAGE were all lower with IGT and T2DM, while the ratio of cRAGE to esRAGE (cRAGE:esRAGE) was only lower (P obesity, cRAGE:esRAGE was higher with obesity and lower with IGT (P

  18. Inner Milky Way Raging with Star Formation

    Science.gov (United States)

    2008-01-01

    More than 444,580 frames from NASA's Spitzer Space Telescope were stitched together to create this portrait of the raging star-formation occurring in the inner Milky Way. As inhabitants of a flat galactic disk, Earth and its solar system have an edge-on view of their host galaxy, like looking a glass dish from its edge. From our perspective, most of the galaxy is condensed into a blurry narrow band of light that stretches completely around the sky, also known as the galactic plane. In this mosaic the galactic plane is broken up into five components: the far-left side of the plane (top image); the area just left of the galactic center (second to top); galactic center (middle); the area to the right of galactic center (second to bottom); and the far-right side of the plane (bottom). Together, these panels represent more than 50 percent of our entire Milky Way galaxy. The red haze that permeates the picture comes from organic molecules called polycyclic aromatic hydrocarbons, which are illuminated by light from massive baby stars. On Earth, these molecules are found in automobile exhaust, or charred barbeque grills anywhere carbon molecules are burned incompletely. The patches of black are dense, obscuring dust clouds impenetrable by even Spitzer's super-sensitive infrared eyes. Bright arcs of white throughout the image are massive stellar incubators. The bluish-white haze that hovers heavily in the middle panel is starlight from the older stellar population towards the center of the galaxy. This picture was taken with Spitzer's infrared array camera, as part of the Galactic Legacy Infrared Mid-Plane Survey Extraordinaire (GLIMPSE) project. This is a four-color composite where blue is 3.6-micron light, green is 4.5 microns, orange is 5.8 microns and red is 8.0 microns.

  19. AGE-RAGE Stress, Stressors, and Antistressors in Health and Disease.

    Science.gov (United States)

    Prasad, Kailash; Mishra, Manish

    2018-03-01

    Adverse effects of advanced glycation end-products (AGEs) on the tissues are through nonreceptor- and receptor-mediated mechanisms. In the receptor-mediated mechanism, interaction of AGEs with its cell-bound receptor of AGE (RAGE) increases generation of oxygen radicals, activates nuclear factor-kappa B, and increases expression and release of pro-inflammatory cytokines resulting in the cellular damage. The deleterious effects of AGE and AGE-RAGE interaction are coined as "AGE-RAGE stress." The body is equipped with defense mechanisms to counteract the adverse effects of AGE and RAGE through endogenous enzymatic (glyoxalase 1, glyoxalase 2) and AGE receptor-mediated (AGER1, AGER2) degradation of AGE, and through elevation of soluble receptor of AGE (sRAGE). Exogenous defense mechanisms include reduction in consumption of AGE, prevention of AGE formation, and downregulation of RAGE expression. We have coined AGE and RAGE as "stressors" and the defense mechanisms as "anti-stressors." AGE-RAGE stress is defined as a shift in the balance between stressors and antistressors in the favor of stressors. Measurements of stressors or antistressors alone would not assess AGE-RAGE stress. For true assessment of AGE-RAGE stress, the equation should include all the stressors and antistressors. The equation for AGE-RAGE stress, therefore, would be the ratio of AGE + RAGE/sRAGE + glyoxalase1 + glyoxalase 2 + AGER1 +AGER2. This is, however, not practical in patients. AGE-RAGE stress may be assessed simply by the ratio of AGE/sRAGE. A high ratio of AGE/sRAGE indicates a relative shift in stressors from antistressors, suggesting the presence of AGE-RAGE stress, resulting in tissue damage, initiation, and progression of the diseases and their complications.

  20. Receptor for advanced glycation endproducts (RAGE maintains pulmonary structure and regulates the response to cigarette smoke.

    Directory of Open Access Journals (Sweden)

    Lisa Wolf

    Full Text Available The receptor for advanced glycation endproducts (RAGE is highly expressed in the lung but its physiological functions in this organ is still not completely understood. To determine the contribution of RAGE to physiological functions of the lung, we analyzed pulmonary mechanics and structure of wildtype and RAGE deficient (RAGE-/- mice. RAGE deficiency spontaneously resulted in a loss of lung structure shown by an increased mean chord length, increased respiratory system compliance, decreased respiratory system elastance and increased concentrations of serum protein albumin in bronchoalveolar lavage fluids. Pulmonary expression of RAGE was mainly localized on alveolar epithelial cells and alveolar macrophages. Primary murine alveolar epithelial cells isolated from RAGE-/- mice revealed an altered differentiation and defective barrier formation under in vitro conditions. Stimulation of interferone-y (IFNy-activated alveolar macrophages deficient for RAGE with Toll-like receptor (TLR ligands resulted in significantly decreased release of proinflammatory cytokines and chemokines. Exposure to chronic cigarette smoke did not affect emphysema-like changes in lung parenchyma in RAGE-/- mice. Acute cigarette smoke exposure revealed a modified inflammatory response in RAGE-/- mice that was characterized by an influx of macrophages and a decreased keratinocyte-derived chemokine (KC release. Our data suggest that RAGE regulates the differentiation of alveolar epithelial cells and impacts on the development and maintenance of pulmonary structure. In cigarette smoke-induced lung pathology, RAGE mediates inflammation that contributes to lung damage.

  1. RAGE Architecture for Reusable Serious Gaming Technology Components

    Directory of Open Access Journals (Sweden)

    Wim van der Vegt

    2016-01-01

    Full Text Available For seizing the potential of serious games, the RAGE project—funded by the Horizon-2020 Programme of the European Commission—will make available an interoperable set of advanced technology components (software assets that support game studios at serious game development. This paper describes the overall software architecture and design conditions that are needed for the easy integration and reuse of such software assets in existing game platforms. Based on the component-based software engineering paradigm the RAGE architecture takes into account the portability of assets to different operating systems, different programming languages, and different game engines. It avoids dependencies on external software frameworks and minimises code that may hinder integration with game engine code. Furthermore it relies on a limited set of standard software patterns and well-established coding practices. The RAGE architecture has been successfully validated by implementing and testing basic software assets in four major programming languages (C#, C++, Java, and TypeScript/JavaScript, resp.. Demonstrator implementation of asset integration with an existing game engine was created and validated. The presented RAGE architecture paves the way for large scale development and application of cross-engine reusable software assets for enhancing the quality and diversity of serious gaming.

  2. RAGE Architecture for Reusable Serious Gaming Technology Components

    NARCIS (Netherlands)

    Van der Vegt, Wim; Westera, Wim; Nyamsuren, Enkhbold; Georgiev, Atanas; Martinez Ortiz, Ivan

    2016-01-01

    For seizing the potential of serious games, the RAGE project - funded by the Horizon-2020 Programme of the European Commission - will make available an interoperable set of advanced technology components (software assets) that support game studios at serious game development. This paper describes

  3. The RAGE Software Asset Model and Metadata Model

    NARCIS (Netherlands)

    Georgiev, Atanas; Grigorov, Alexander; Bontchev, Boyan; Boytchev, Pavel; Stefanov, Krassen; Bahreini, Kiavash; Nyamsuren, Enkhbold; Van der Vegt, Wim; Westera, Wim; Prada, Rui; Hollins, Paul; Moreno, Pablo

    2016-01-01

    Software assets are key output of the RAGE project and they can be used by applied game developers to enhance the pedagogical and educational value of their games. These software assets cover a broad spectrum of functionalities – from player analytics including emotion detection to intelligent

  4. RAGE polymorphisms and oxidative stress levels in Hashimoto's thyroiditis.

    Science.gov (United States)

    Giannakou, Maria; Saltiki, Katerina; Mantzou, Emily; Loukari, Eleni; Philippou, Georgios; Terzidis, Konstantinos; Lili, Kiriaki; Stavrianos, Charalampos; Kyprianou, Miltiades; Alevizaki, Maria

    2017-05-01

    Polymorphisms of the receptor for advanced glycation end products (RAGE) gene have been studied in various autoimmune disorders, but not in Hashimoto's thyroiditis. Also, increased oxidative stress has been described in patients with Hashimoto's thyroiditis. The aim of this study was to investigate the possible role of two common RAGE polymorphisms (-429T>C, -374T>A) in Hashimoto's thyroiditis; in parallel, we studied oxidative stress levels. A total of 300 consecutive euthyroid women were examined and classified into three groups: Hashimoto's thyroiditis with treatment (n = 96), Hashimoto's thyroiditis without treatment (n = 109) and controls (n = 95). For a rough evaluation of oxidative stress, total lipid peroxide levels in serum were measured. The -429T>C AluI and -374T>A MfeI polymorphisms of RAGE were studied in genomic DNA. Significant association of the RAGE system with Hashimoto's thyroiditis was found only with regard to the prevalence of the -429T>C, but not with -374T>A polymorphism. The levels of oxidative stress were significantly elevated in Hashimoto's thyroiditis patients under treatment. Further analysis demonstrated that an oxidative stress cut-off value of 590 μmol/L is associated with an increased risk of progression of Hashimoto's thyroiditis from euthyroidism to hypothyroidism; this risk is further increased in carriers of the RAGE -429T>C polymorphism. Our findings indicate that both examined risk factors may be implicated in the occurrence of Hashimoto's thyroiditis, but this covers only a fraction of the pathophysiology of the disease. © 2017 Stichting European Society for Clinical Investigation Journal Foundation.

  5. Radical Roles for RAGE in the Pathogenesis of Oxidative Stress in Cardiovascular Diseases and Beyond

    Directory of Open Access Journals (Sweden)

    Radha Ananthakrishnan

    2013-10-01

    Full Text Available Oxidative stress is a central mechanism by which the receptor for advanced glycation endproducts (RAGE mediates its pathological effects. Multiple experimental inquiries in RAGE-expressing cultured cells have demonstrated that ligand-RAGE interaction mediates generation of reactive oxygen species (ROS and consequent downstream signal transduction and regulation of gene expression. The primary mechanism by which RAGE generates oxidative stress is via activation of NADPH oxidase; amplification mechanisms in the mitochondria may further drive ROS production. Recent studies indicating that the cytoplasmic domain of RAGE binds to the formin mDia1 provide further support for the critical roles of this pathway in oxidative stress; mDia1 was required for activation of rac1 and NADPH oxidase in primary murine aortic smooth muscle cells treated with RAGE ligand S100B. In vivo, in multiple distinct disease models in animals, RAGE action generates oxidative stress and modulates cellular/tissue fate in range of disorders, such as in myocardial ischemia, atherosclerosis, and aneurysm formation. Blockade or genetic deletion of RAGE was shown to be protective in these settings. Indeed, beyond cardiovascular disease, evidence is accruing in human subjects linking levels of RAGE ligands and soluble RAGE to oxidative stress in disorders such as doxorubicin toxicity, acetaminophen toxicity, neurodegeneration, hyperlipidemia, diabetes, preeclampsia, rheumatoid arthritis and pulmonary fibrosis. Blockade of RAGE signal transduction may be a key strategy for the prevention of the deleterious consequences of oxidative stress, particularly in chronic disease.

  6. Incidence, clinical correlates and treatment effect of rage in anxious children.

    Science.gov (United States)

    Johnco, Carly; Salloum, Alison; De Nadai, Alessandro S; McBride, Nicole; Crawford, Erika A; Lewin, Adam B; Storch, Eric A

    2015-09-30

    Episodic rage represents an important and underappreciated clinical feature in pediatric anxiety. This study examined the incidence and clinical correlates of rage in children with anxiety disorders. Change in rage during treatment for anxiety was also examined. Participants consisted of 107 children diagnosed with an anxiety disorder and their parents. Participants completed structured clinical interviews and questionnaire measures to assess rage, anxiety, functional impairment, family accommodation and caregiver strain, as well as the quality of the child's relationship with family and peers. Rage was a common feature amongst children with anxiety disorders. Rage was associated with a more severe clinical profile, including increased anxiety severity, functional impairment, family accommodation and caregiver strain, as well as poorer relationships with parents, siblings, extended family and peers. Rage was more common in children with separation anxiety, comorbid anxiety, attention deficit/hyperactivity disorder and behavioral disorders, but not depressive symptoms. Rage predicted higher levels of functional impairment, beyond the effect of anxiety severity. Rage severity reduced over treatment in line with changes in anxiety symptoms. Findings suggest that rage is a marker of greater psychopathology in anxious youth. Standard cognitive behavioral treatment for anxiety appears to reduce rage without adjunctive treatment. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Targeting receptor for advanced glycation end products (RAGE) expression induces apoptosis and inhibits prostate tumor growth

    International Nuclear Information System (INIS)

    Elangovan, Indira; Thirugnanam, Sivasakthivel; Chen, Aoshuang; Zheng, Guoxing; Bosland, Maarten C.; Kajdacsy-Balla, André; Gnanasekar, Munirathinam

    2012-01-01

    Highlights: ► Targeting RAGE by RNAi induces apoptosis in prostate cancer cells. ► Silencing RAGE expression abrogates rHMGB1 mediated cell proliferation. ► Down regulation of RAGE by RNAi inhibits PSA secretion of prostate cancer cells. ► Knock down of RAGE abrogates prostate tumor growth in vivo. ► Disruption of RAGE expression in prostate tumor activates death receptors. -- Abstract: Expression of receptor for advanced glycation end products (RAGE) plays a key role in the progression of prostate cancer. However, the therapeutic potential of targeting RAGE expression in prostate cancer is not yet evaluated. Therefore in this study, we have investigated the effects of silencing the expression of RAGE by RNAi approach both in vitro and in vivo. The results of this study showed that down regulation of RAGE expression by RNAi inhibited the cell proliferation of androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells. Furthermore, targeting RAGE expression resulted in apoptotic elimination of these prostate cancer cells by activation of caspase-8 and caspase-3 death signaling. Of note, the levels of prostate specific antigen (PSA) were also reduced in LNCaP cells transfected with RAGE RNAi constructs. Importantly, the RAGE RNAi constructs when administered in nude mice bearing prostate tumors, inhibited the tumor growth by targeting the expression of RAGE, and its physiological ligand, HMGB1 and by up regulating death receptors DR4 and DR5 expression. Collectively, the results of this study for the first time show that targeting RAGE by RNAi may be a promising alternative therapeutic strategy for treating prostate cancer.

  8. Acute secondhand smoke-induced pulmonary inflammation is diminished in RAGE knockout mice.

    Science.gov (United States)

    Wood, Tyler T; Winden, Duane R; Marlor, Derek R; Wright, Alex J; Jones, Cameron M; Chavarria, Michael; Rogers, Geraldine D; Reynolds, Paul R

    2014-11-15

    The receptor for advanced glycation end-products (RAGE) has increasingly been demonstrated to be an important modulator of inflammation in cases of pulmonary disease. Published reports involving tobacco smoke exposure have demonstrated increased expression of RAGE, its participation in proinflammatory signaling, and its role in irreversible pulmonary remodeling. The current research evaluated the in vivo effects of short-term secondhand smoke (SHS) exposure in RAGE knockout and control mice compared with identical animals exposed to room air only. Quantitative PCR, immunoblotting, and immunohistochemistry revealed elevated RAGE expression in controls after 4 wk of SHS exposure and an anticipated absence of RAGE expression in RAGE knockout mice regardless of smoke exposure. Ras activation, NF-κB activity, and cytokine elaboration were assessed to characterize the molecular basis of SHS-induced inflammation in the mouse lung. Furthermore, bronchoalveolar lavage fluid was procured from RAGE knockout and control animals for the assessment of inflammatory cells and molecules. As a general theme, inflammation coincident with leukocyte recruitment was induced by SHS exposure and significantly influenced by the availability of RAGE. These data reveal captivating information suggesting a role for RAGE signaling in lungs exposed to SHS. However, ongoing research is still warranted to fully explain roles for RAGE and other receptors in cells coping with involuntary smoke exposure for prolonged periods of time. Copyright © 2014 the American Physiological Society.

  9. [The Habit of Rage in a United States Ghetto.

    Science.gov (United States)

    Bourgois, Philippe; Castrillo, Fernando Montero; Hart, Laurie; Karandinos, George

    2013-04-01

    For five years, the open air drug sales block where the authors resided and conducted participant-observation fieldwork in the Puerto Rican corner of inner-city Philadelphia was subject to a routinized whirlwind of shootings, stabbings and assaults. The narcotics industry filled the void left by deindustrialization, turning the city's former factory district into an open-air narcotics supermarket staffed at the entry level by young Puerto Ricans serving primarily poor white injectors. A capacity to mobilize rage ensures success in the drug economy, protection in prison, and minimal income for the no-longer-worthy poor who are diagnosed as cognitively disabled. Many residents seek alliances in social networks that oblige them to participate in solidary exchanges of assistive violence. A dynamic of embodied, primitive accumulation kills, maims, disables or incarcerates most of this industry's entry-level employees and customers. Artificially high profit margins depend on violence and coercion. A rage-filled habitus propels street-level sellers into violently defending the micro-monopoly power of their bosses in the underground economy as if it were fun. They rush to enforce commercial transactions in the absence of protective legal sanctions in an environment of scarcity that is flooded by streams of cash, addictive drugs and automatic weapons. With the end of welfare entitlements, the left hand of the state, in the form of social services, attempts to continue subsidies for vulnerable individuals by diagnosing scarred bodies and brains as proof of permanent cognitive disability in need of heavy pharmaceutical medication. Periodic outbursts of interpersonal or of self-inflicted rage-filled violence emerge as the best way to ensure the continuity of that fragile public subsidy. Simultaneously, within the bowels of the right hand of the state, in overcrowded, hostilely-supervised violent prisons, rage becomes a valuable physical self-protection strategy for inmates. In

  10. Low-molecular weight fractions of Japanese soy sauce act as a RAGE antagonist via inhibition of RAGE trafficking to lipid rafts.

    Science.gov (United States)

    Munesue, Seiichi; Yamamoto, Yasuhiko; Urushihara, Ryouta; Inomata, Kouhei; Saito, Hidehito; Motoyoshi, So; Watanabe, Takuo; Yonekura, Hideto; Yamamoto, Hiroshi

    2013-12-01

    Advanced glycation end-products (AGE) have been implicated in aging and the pathogenesis of diabetic complications, inflammation, Alzheimer's disease, and cancer. AGE engage the cell surface receptor for AGE (RAGE), which in turn elicits intracellular signaling, leading to activation of NF-κB to cause deterioration of tissue homeostasis. AGE are not only formed within our bodies but are also derived from foods, endowing them with flavor. In the present study, we assessed the agonistic/antagonistic effects of food-derived AGE on RAGE signaling in a reporter assay system and found that low-molecular weight AGE can antagonize the action of AGE-BSA. Foods tested were Japanese soy sauce, coffee, cola, and red wine, all of which showed fluorescence characteristics of AGE. Soy sauce and coffee contained N(ε)-carboxymethyl-lysine (CML). Soy sauce, coffee, and red wine inhibited the RAGE ligand-induced activation of NF-κB, whereas cola had no effect on the ligand induction of NF-κB. The liquids were then fractionated into high-molecular weight (HMW) fractions and low-molecular weight (LMW) fractions. Soy sauce-, coffee-, and red wine-derived LMW fractions consistently inhibited the RAGE ligand induction of NF-κB, whereas the HMW fractions of these foods activated RAGE signaling. Using the LMW fraction of soy sauce as a model food-derived RAGE antagonist, we performed a plate-binding assay and found that the soy sauce LMW fractions competitively inhibited AGE-RAGE association. Further, this fraction significantly reduced AGE-dependent monocyte chemoattractant protein-1 (MCP-1) secretion from murine peritoneal macrophages. The LMF from soy sauce suppressed the AGE-induced RAGE trafficking to lipid rafts. These results indicate that small components in some, if not all, foods antagonize RAGE signaling and could exhibit beneficial effects on RAGE-related diseases.

  11. Local and systemic RAGE axis changes in pulmonary hypertension: CTEPH and iPAH.

    Directory of Open Access Journals (Sweden)

    Bernhard Moser

    Full Text Available OBJECTIVE: The molecular determinants of chronic thromboembolic pulmonary hypertension (CTEPH and idiopathic pulmonary arterial hypertension (iPAH remain poorly understood. The receptor for advanced glycation endproducts (RAGE and its ligands: HMGB1 and S100A9 are involved in inflammatory disorders. We sought to investigate the role of the RAGE axis in patients with CTEPH undergoing pulmonary endarterectomy (PEA, iPAH undergoing lung transplantation (LuTX. The high pulmonary vascular resistance in CTEPH/iPAH results in pressure overload of the right ventricle. We compared sRAGE measurements to that of patients with aortic valve stenosis (AVS - pressure overload of the left ventricle. METHODS: We enrolled patients with CTEPH(26, iPAH(15, AVS(15 and volunteers(33. Immunohistochemistry with antibodies to RAGE and HMGB1 was performed on PEA specimens and lung tissues. We employed enzyme-linked immunosorbent assays to determine the concentrations of sRAGE, esRAGE, HMGB1 and S100A9 in serum of volunteers and patients with CTEPH, iPAH, AVS before and after PEA, LuTX and aortic valve replacement (AVR. RESULTS: In endarterectomised tissues from patients with CTEPH RAGE and HMGB1 were identified in myofibroblasts (α-SMA+vimentin+CD34-, recanalizing vessel-like structures of distal myofibrotic tissues and endothelium of neointima. RAGE was differentially expressed in prototypical Heath Edwards lesions in iPAH. We found significantly increased serum concentrations of sRAGE, esRAGE and HMGB1 in CTEPH. In iPAH, sRAGE and esRAGE were significantly higher than in controls. Serum concentrations of sRAGE were significantly elevated in iPAH(p<0.001 and CTEPH(p = 0.001 compared to AVS. Serum sRAGE was significantly higher in iPAH compared to CTEPH(p = 0.042 and significantly reduced in AVS compared to controls(p = 0.001. There were no significant differences in sRAGE serum concentrations before and after surgical therapy for CTEPH, iPAH or AVS. CONCLUSIONS: Our

  12. In vitro anticancer effects of a RAGE inhibitor discovered using a structure-based drug design system

    Science.gov (United States)

    El-Far, Ali Hafez Ali Mohammed; Munesue, Seiichi; Harashima, Ai; Sato, Akira; Shindo, Mika; Nakajima, Shingo; Inada, Mana; Tanaka, Mariko; Takeuchi, Akihiko; Tsuchiya, Hiroyuki; Yamamoto, Hiroshi; Shaheen, Hazem M.E.; El-Sayed, Yasser S.; Kawano, Shuhei; Tanuma, Sei-Ichi; Yamamoto, Yasuhiko

    2018-01-01

    Receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in the pathogenesis of certain types of cancer. In the present study, papaverine was identified as a RAGE inhibitor using the conversion to small molecules through optimized-peptide strategy drug design system. Papaverine significantly inhibited RAGE-dependent nuclear factor κ-B activation driven by high mobility group box-1, a RAGE ligand. Using RAGE- or dominant-negative RAGE-expressing HT1080 human fibrosarcoma cells, the present study revealed that papaverine suppressed RAGE-dependent cell proliferation and migration dose-dependently. Furthermore, papaverine significantly inhibited cell invasion. The results of the present study suggested that papaverine could inhibit RAGE, and provided novel insights into the field of RAGE biology, particularly anticancer therapies. PMID:29541234

  13. Total soluble and endogenous secretory receptor for advanced glycation endproducts (RAGE) in IBD.

    Science.gov (United States)

    Meijer, Berrie; Hoskin, Teagan; Ashcroft, Anna; Burgess, Laura; Keenan, Jacqueline I; Falvey, James; Gearry, Richard B; Day, Andrew S

    2014-06-01

    Recruitment and activation of neutrophils, with release of specific proteins such as S100 proteins, is a feature of inflammatory bowel disease (IBD). Soluble forms of the receptor for advanced glycation endproducts (sRAGE), and variants such as endogenous secretory (esRAGE), can act as decoy receptors by binding ligands, including S100A12. The aims of this study were to determine total sRAGE and esRAGE concentrations in patients with IBD and correlate these with C-reactive protein (CRP), endoscopic scores and clinical disease activity scores. EDTA-plasma was collected from patients undergoing colonoscopy including those with Crohn's disease (CD: n=125), ulcerative colitis (UC: n=79) and control patients without endoscopic signs of inflammation (non-IBD: n=156). Concentrations of sRAGE and esRAGE were determined by enzyme-linked immunosorbent assay and plasma CRP concentrations measured. Standard clinical disease activity and endoscopic severity scores were defined for all subjects. Plasma sRAGE concentrations were lower in UC (but not CD) than non-IBD subjects (pdefine the significance of sRAGE and esRAGE in IBD. Copyright © 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

  14. Dynamic changes in sRAGE levels and relationship with cardiac function in STEMI patients

    DEFF Research Database (Denmark)

    Jensen, Louise J N; Lindberg, Søren; Hoffmann, Søren

    2015-01-01

    the dynamic changes in sRAGE levels during AMI and relationship with cardiac dysfunction. DESIGN AND METHODS: We prospectively included 80 patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). sRAGE concentrations were measured before p...... in the early phase of AMI; sRAGE levels significantly increased after pPCI compared with sRAGE before pPCI (median ratio: 1.25, 95% CI: 1.15-1.35, P...phase rather than in the days after AMI and pPCI. The increase...

  15. Correlation between follicular fluid levels of sRAGE and vitamin D in women with PCOS.

    Science.gov (United States)

    Garg, Deepika; Grazi, Richard; Lambert-Messerlian, Geralyn M; Merhi, Zaher

    2017-11-01

    The pro-inflammatory advanced glycation end products (AGEs) and their anti-inflammatory soluble receptors, sRAGE, play a role in the pathogenesis of PCOS. There is a correlation between vitamin D (vit D) and sRAGE in the serum, whereby vit D replacement increases serum sRAGE levels in women with PCOS, thus incurring a protective anti-inflammatory role. This study aims to compare levels of sRAGE, N-carboxymethyl-lysine (CML; one of the AGEs), and 25-hydroxy-vit D in the follicular fluid (FF) of women with or without PCOS, and to evaluate the correlation between sRAGE and 25-hydroxy-vit D in the FF. Women with (n = 12) or without (n = 13) PCOS who underwent IVF were prospectively enrolled. Women with PCOS had significantly higher anti-Mullerian hormone levels, higher number of total retrieved and mature oocytes, and higher number of day 3 and day 5 embryos formed. Compared to women without PCOS, women with PCOS had significantly lower FF sRAGE levels. In women with PCOS, in women without PCOS, and in all participants together, there was a significant positive correlation between sRAGE and 25-hydroxy-vit D. sRAGE positively correlated with CML in women without PCOS but not in women with PCOS. In women with PCOS, the low ovarian levels of the anti-inflammatory sRAGE suggest that sRAGE could represent a biomarker and a potential therapeutic target for ovarian dysfunction in PCOS. Whether there is a direct causal relationship between sRAGE and vit D in the ovaries remains to be determined.

  16. Images en mouvement stockage, repérage, indexation

    CERN Document Server

    Turner, James

    1998-01-01

    L'avènement puis la fusion des nouveaux modes de communication que sont l'informatique, les télécommunications et l'audiovisuel ont mis à la portée de tous une grande quantité d'images fixes et en mouvement dont la conservation et le repérage risquent de prendre des proportions démesurées. Le présent ouvrage veut offrir aux responsables de collection des repères pour aborder la problématique de l'indexation des images et faciliter l'accès des usagers à ces images.

  17. AGE and their receptor RAGE in systemic autoimmune diseases : An inflammation propagating factor contributing to accelerated atherosclerosis

    NARCIS (Netherlands)

    Nienhuis, Hans L. A.; Westra, Johanna; Smit, Andries J.; Limburg, Pieter C.; Kallenberg, Cees G. M.; Bijl, Marc

    2009-01-01

    Systemic autoimmune diseases are associated with inflammation, and oxidative stress favouring the formation of advanced glycation endproducts (AGE), able to modulate cellular functions by activation of receptor for advanced glycation endproducts (RAGE). As RAGE expression is increased in an

  18. Discovering Small Molecule Inhibitors Targeted to Ligand-Stimulated RAGE-DIAPH1 Signaling Transduction

    Science.gov (United States)

    Pan, Jinhong

    The receptor of advanced glycation end product (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules, which plays an important role in immune responses. Full-length RAGE includes three extracellular immunoglobulin domains, a transmembrane domain and an intracellular domain. It is a pattern recognition receptor that can bind diverse ligands. NMR spectroscopy and x-ray crystallization studies of the extracellular domains of RAGE indicate that RAGE ligands bind by distinct charge- and hydrophobicity-dependent mechanisms. It is found that calgranulin binding to the C1C2 domain or AGEs binding to the V domain activates extracellular signaling, which triggers interactions of the RAGE cytoplasmic tail (ctRAGE) with intracellular effector, such as diaphanous 1 (DIAPH1), to initiate signal transduction cascades. ctRAGE is essential for RAGE-ligand-mediated signal transduction and consequent modulation of gene expression and cellular properties. RAGE is over-expressed in diseased tissues of most RAGE-associated pathogenic conditions, such as complications of Alzheimer's diseases, diabetes, vascular diseases, inflammation, cancers and neurodegeneration. They are the major diseases affecting a large population worldwide. RAGE can function as a biomarker or drug target for these diseases. The cytoplasmic tail of RAGE can be used as a drug target to inhibit RAGE-induced intracellular signaling by small molecule inhibitors to treat RAGE-associated diseases. We developed a high throughput screening assay with which we probed a small molecule library of 58,000 compounds to find that 777 small molecules displayed 50% inhibition and 97 compounds demonstrated dose-dependent inhibition of the binding of ctRAGE-DIAPH1. Eventually, there were 13 compounds which displayed dose-dependent inhibition of ctRAGE binding to DIAPH1 and direct binding to ctRAGE analyzed by 15N HSQC-NMR and native tryptophan fluorescence titration experiments; thus, they were

  19. Review: Joschka Philipps, Ambivalent Rage: Youth Gangs and Urban Protest in Conakry, Guinea (2013)

    OpenAIRE

    Ineke van Kessel; Afrika-Studiecentrum Leiden

    2014-01-01

    Review of the Monograph:Joschka Philipps, Ambivalent Rage: Youth Gangs and Urban Protest in Conakry, Guinea, Paris: L’Harmattan, 2013, ISBN 978-2-343-01577-4, 238 pp. Besprechung der Monographie:Joschka Philipps, Ambivalent Rage: Youth Gangs and Urban Protest in Conakry, Guinea, Paris: L’Harmattan, 2013, ISBN 978-2-343-01577-4, 238 Seiten

  20. Total soluble and endogenous secretory receptor for advanced glycation endproducts (RAGE) in IBD

    NARCIS (Netherlands)

    Meijer, Berrie; Hoskin, Teagan; Ashcroft, Anna; Burgess, Laura; Keenan, Jacqueline I.; Falvey, James; Gearry, Richard B.; Day, Andrew S.

    2014-01-01

    Recruitment and activation of neutrophils, with release of specific proteins such as S100 proteins, is a feature of inflammatory bowel disease (IBD). Soluble forms of the receptor for advanced glycation endproducts (sRAGE), and variants such as endogenous secretory (esRAGE), can act as decoy

  1. Expression of receptor for advanced glycation end-products (RAGE) in thymus from myasthenia patients.

    Science.gov (United States)

    Bouchikh, M; Zouaidia, F; Benhaddou, E H A; Mahassini, N; Achir, A; El Malki, H O

    2017-06-01

    The receptor for advanced glycation end-products (RAGE) is a membranous immunoglobulin involved in the pathogenesis of numerous autoimmune diseases and tumors. The aim of this study was to investigate the possible involvement of RAGE in the pathogenesis of myasthenia gravis. This prospective study included 41 cases of myasthenia gravis treated at our institution between 2010 and 2015. There were 18 men and 23 women, with an average age of 36.44±14.47 years. The majority of patients (24.4%) were classified as IIb, according to MGFA scoring, and 21 of them required corticosteroid and/or immunosuppressive treatment. Assessment of RAGE in thymus specimens was done by immunohistochemistry using RAGE antibody (C-term). RAGE expression was assessed according to various clinical, paraclinical and pathological parameters. Histopathological studies found 18 thymomas, 17 hyperplasias and six other types of pathology. Expression of RAGE was negative/weak in 19 cases and moderate/strong in 22 cases. It was more important in thymoma type B2 (Pmyasthenia was short (P=0.04), and was not significantly related to either myasthenia clinical severity or preoperative treatment. Our results suggest that the RAGE pathway is involved in myasthenia gravis pathophysiology, especially at disease onset, and in forms with thymomas. Further studies would be indispensable to explore other aspects of this signaling pathway, especially the potential role of different ligands and soluble forms of RAGE. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  2. The RAGE Advanced Game Technologies Repository for Supporting Applied Game Development

    NARCIS (Netherlands)

    Georgiev, Atanas; Grigorov, Alexander; Bontchev, Boyan; Boytchev, Pavel; Stefanov, Krassen; Westera, Wim; Prada, Rui; Hollins, Paul; Moreno Ger, Pablo

    2016-01-01

    This paper describes the structural architecture of the RAGE repository, which is a unique and dedicated infrastructure that provides access to a wide variety of advanced technologies (RAGE software assets) for applied game development. These software assets are reusable across a wide diversity of

  3. RAGE mediates the inactivation of nAChRs in sympathetic neurons under high glucose conditions.

    Science.gov (United States)

    Chandna, Andrew R; Nair, Manoj; Chang, Christine; Pennington, Paul R; Yamamoto, Yasuhiko; Mousseau, Darrell D; Campanucci, Verónica A

    2015-02-01

    Autonomic dysfunction is a serious complication of diabetes and can lead to cardiovascular abnormalities and premature death. It was recently proposed that autonomic dysfunction is triggered by oxidation-mediated inactivation of neuronal nicotinic acetylcholine receptors (nAChRs), impairing synaptic transmission in sympathetic ganglia and resulting in autonomic failure. We investigated whether the receptor for advanced glycation end products (RAGE) and its role in the generation of reactive oxygen species (ROS) could be contributing to the events that initiate sympathetic malfunction under high glucose conditions. Using biochemical, live imaging and electrophysiological tools we demonstrated that exposure of sympathetic neurons to high glucose increases RAGE expression and oxidative markers, and that incubation with RAGE ligands (e.g. AGEs, S100 and HMGB1) mimics both ROS elevation and nAChR inactivation. In contrast, co-treatment with either antioxidants or an anti-RAGE IgG prevented the inactivation of nAChRs. Lastly, a role for RAGE in this context was corroborated by the lack of sensitivity of sympathetic neurons from RAGE knock-out mice to high glucose. These data define a pivotal role for RAGE in initiating the events associated with exposure of sympathetic neurons to high glucose, and strongly support RAGE signaling as a potential therapeutic target in the autonomic complications associated with diabetes. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  4. A Molecular Dynamics Study on RAGE-Aβ42 Interaction and the Influence of G82S RAGE Polymorphism on Aβ Interaction

    Directory of Open Access Journals (Sweden)

    Sreeram Krishnan

    2015-12-01

    Full Text Available Interaction of amyloid peptides (Aβ with receptor for advanced glycation end products (RAGE elicits an inflammatory response and augments Alzheimer's disease (AD pathology. The present study was aimed to analyse the interactions of different forms of Aβ42 peptide with ligand binding domain of normal and G82S RAGE and their possible consequences in AD pathology. The structures of RAGE ectodomain (3CJJ, monomeric forms of Aβ42 - 1IYT (apolar and 1Z0Q (polar and fibrillar (2BEG were obtained from PDB. The structure of G82 and S82 RAGE was generated using SWISS MODEL. SIFT and PolyPhen analysis was performed to predict the phenotypic and functional effect of the amino acid substitution. The G82 and S82 variant structures were simulated in GROMACS and the 10 lowest energy structures were docked with different forms of Aβ42 using CLUSPRO in antibody mode. The lowest energy docked structure was further simulated for 5 ns. The structures corresponding to 0-5 ns were taken and the amino acid interactions were generated using PDBSUM. SIFT analysis indicated that G82S SNP had a tolerating effect on the structure of protein but polyphen predicted a probable damaging effect. Highest binding score was obtained with 2BEG docked with both G82 RAGE (-375.84 ± 7.425 Kcal/mol and G82S variant (-391.09 ± 13.391 Kcal/mol indicating that the fibrillar form showed better interaction. Compared to G82 RAGE, the S82 variant showed better interaction to all three forms of Aβ42. The results of study indicate that RAGE interacted better with fibrillar form of Aβ42 peptide and G82S mutation enhanced the binding affinity of RAGE towards amyloid peptides leading to enhanced inflammatory response.

  5. The receptor for advanced glycation end products (RAGE) and the lung.

    LENUS (Irish Health Repository)

    Buckley, Stephen T

    2010-01-01

    The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules. As a pattern-recognition receptor capable of binding a diverse range of ligands, it is typically expressed at low levels under normal physiological conditions in the majority of tissues. In contrast, the lung exhibits high basal level expression of RAGE localised primarily in alveolar type I (ATI) cells, suggesting a potentially important role for the receptor in maintaining lung homeostasis. Indeed, disruption of RAGE levels has been implicated in the pathogenesis of a variety of pulmonary disorders including cancer and fibrosis. Furthermore, its soluble isoforms, sRAGE, which act as decoy receptors, have been shown to be a useful marker of ATI cell injury. Whilst RAGE undoubtedly plays an important role in the biology of the lung, it remains unclear as to the exact nature of this contribution under both physiological and pathological conditions.

  6. The receptor for advanced glycation end products (RAGE contributes to the progression of emphysema in mice.

    Directory of Open Access Journals (Sweden)

    Nisha Sambamurthy

    Full Text Available Several recent clinical studies have implied a role for the receptor for advanced glycation end products (RAGE and its variants in chronic obstructive pulmonary disease (COPD. In this study we have defined a role for RAGE in the pathogenesis of emphysema in mice. RAGE deficient mice (RAGE-/- exposed to chronic cigarette smoke were significantly protected from smoke induced emphysema as determined by airspace enlargement and had no significant reduction in lung tissue elastance when compared to their air exposed controls contrary to their wild type littermates. The progression of emphysema has been largely attributed to an increased inflammatory cell-mediated elastolysis. Acute cigarette smoke exposure in RAGE-/- mice revealed an impaired early recruitment of neutrophils, approximately a 6-fold decrease compared to wild type mice. Hence, impaired neutrophil recruitment with continued cigarette smoke exposure reduces elastolysis and consequent emphysema.

  7. Oligomerization interface of RAGE receptor revealed by MS-monitored hydrogen deuterium exchange.

    Directory of Open Access Journals (Sweden)

    Ewa Sitkiewicz

    Full Text Available Activation of the receptor for advanced glycation end products (RAGE leads to a chronic proinflammatory signal, affecting patients with a variety of diseases. Potentially beneficial modification of RAGE activity requires understanding the signal transduction mechanism at the molecular level. The ligand binding domain is structurally uncoupled from the cytoplasmic domain, suggesting receptor oligomerization is a requirement for receptor activation. In this study, we used hydrogen-deuterium exchange and mass spectrometry to map structural differences between the monomeric and oligomeric forms of RAGE. Our results indicated the presence of a region shielded from exchange in the oligomeric form of RAGE and led to the identification of a new oligomerization interface localized at the linker region between domains C1 and C2. Based on this finding, a model of a RAGE dimer and higher oligomeric state was constructed.

  8. Expression of RAGE and HMGB1 in thymic epithelial tumors, thymic hyperplasia and regular thymic morphology.

    Science.gov (United States)

    Moser, Bernhard; Janik, Stefan; Schiefer, Ana-Iris; Müllauer, Leonhard; Bekos, Christine; Scharrer, Anke; Mildner, Michael; Rényi-Vámos, Ferenc; Klepetko, Walter; Ankersmit, Hendrik Jan

    2014-01-01

    Recently, a role of the receptor for advanced glycation endproducts (RAGE) in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1) play key roles in autoimmunity and cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (pB3>thymic carcinoma (pepithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall's corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay): serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008); and in invasive tumors (p = 0.008). Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003), HMGB1 was only elevated in malignancies (p = 0.036). Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-)physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer.

  9. Receptor for Advanced Glycation End Products (RAGE and Its Ligands: Focus on Spinal Cord Injury

    Directory of Open Access Journals (Sweden)

    Juhyun Song

    2014-07-01

    Full Text Available Spinal cord injury (SCI results in neuronal and glial death and the loss of axons at the injury site. Inflammation after SCI leads to the inhibition of tissue regeneration and reduced neuronal survival. In addition, the loss of axons after SCI results in functional loss below the site of injury accompanied by neuronal cell body’s damage. Consequently, reducing inflammation and promoting axonal regeneration after SCI is a worthy therapeutic goal. The receptor for advanced glycation end products (RAGE is a transmembrane protein and receptor of the immunoglobulin superfamily. RAGE is implicated in inflammation and neurodegeneration. Several recent studies demonstrated an association between RAGE and central nervous system disorders through various mechanisms. However, the relationship between RAGE and SCI has not been shown. It is imperative to elucidate the association between RAGE and SCI, considering that RAGE relates to inflammation and axonal degeneration following SCI. Hence, the present review highlights recent research regarding RAGE as a compelling target for the treatment of SCI.

  10. Decreased levels of sRAGE in follicular fluid from patients with PCOS.

    Science.gov (United States)

    Wang, BiJun; Li, Jing; Yang, QingLing; Zhang, FuLi; Hao, MengMeng; Guo, YiHong

    2017-03-01

    This study aimed to explore the association between soluble receptor for advanced glycation end products (sRAGE) levels in follicular fluid and the number of oocytes retrieved and to evaluate the effect of sRAGE on vascular endothelial growth factor (VEGF) in granulosa cells in patients with polycystic ovarian syndrome (PCOS). Two sets of experiments were performed in this study. In part one, sRAGE and VEGF protein levels in follicular fluid samples from 39 patients with PCOS and 35 non-PCOS patients were measured by ELISA. In part two, ovarian granulosa cells were isolated from an additional 10 patients with PCOS and cultured. VEGF and SP1 mRNA and protein levels, as well as pAKT levels, were detected by real-time PCR and Western blotting after cultured cells were treated with different concentrations of sRAGE. Compared with the non-PCOS patients, patients with PCOS had lower sRAGE levels in follicular fluid. Multi-adjusted regression analysis showed that high sRAGE levels in follicular fluid predicted a lower Gn dose, more oocytes retrieved, and a better IVF outcome in the non-PCOS group. Logistic regression analysis showed that higher sRAGE levels predicted favorably IVF outcomes in the non-PCOS group. Multi-adjusted regression analysis also showed that high sRAGE levels in follicular fluid predicted a lower Gn dose in the PCOS group. Treating granulosa cells isolated from patients with PCOS with recombinant sRAGE decreased VEGF and SP1 mRNA and protein expression and pAKT levels in a dose-dependent manner. © 2017 Society for Reproduction and Fertility.

  11. Decreased Neointimal Extracellular Matrix Formation in RAGE-Knockout Mice After Microvascular Denudation

    Energy Technology Data Exchange (ETDEWEB)

    Groezinger, Gerd, E-mail: gerd.groezinger@med.uni-tuebingen.de; Schmehl, Joerg, E-mail: joerg.schmehl@med.uni-tuebingen.de; Bantleon, Ruediger, E-mail: ruediger.bantleon@med.uni-tuebingen.de; Kehlbach, Rainer, E-mail: rainer.kehlbach@uni-tuebingen.de [University of Tuebingen, Department of Diagnostic and Interventional Radiology (Germany); Mehra, Tarun, E-mail: tarun.mehra@med.uni-tuebingen.de [University of Tuebingen, Department of Dermatology (Germany); Claussen, Claus, E-mail: gerd.groezinger@med.uni-tuebingen.de; Wiesinger, Benjamin, E-mail: benjamin.wiesinger@med.uni-tuebingen.de [University of Tuebingen, Department of Diagnostic and Interventional Radiology (Germany)

    2012-12-15

    Purpose: To evaluate in vivo the role of RAGE (receptor for advanced glycated end products) in the development of restenosis and neointimal proliferation in RAGE-deficient knockout (KO) mice compared with wild-type (WT) mice in an animal model. Materials and Methods: Sixteen WT and 15 RAGE-deficient mice underwent microvascular denudation of the common femoral artery under general anaesthesia. Contralateral arteries underwent a sham operation and served as controls. Four weeks after the intervention, all animals were killed, and paraformaldehyde-fixed specimens of the femoral artery were analysed with different stains (hematoxylin and eosin and Elastica van Gieson) and several different types of immunostaining (proliferating cell nuclear antigen, {alpha}-actin, collagen, von Willebrand factor, RAGE). Luminal area, area of the neointima, and area of the media were measured in all specimens. In addition, colony-formation assays were performed, and collagen production by WT smooth muscle cells (SMCs) and RAGE-KO SMCs was determined. For statistical analysis, P < 0.05 was considered statistically significant. Results: Four weeks after denudation, WT mice showed a 49.6% loss of luminal area compared with 14.9% loss of luminal area in RAGE-deficient mice (sham = 0% loss) (P < 0.001). The neointima was 18.2 (*1000 {mu}m{sup 2} [n = 15) in the WT group compared with only 8.4 (*1000 {mu}m{sup 2} [n = 16]) in the RAGE-KO group. RAGE-KO SMCs showed significantly decreased proliferation activity and production of extracellular matrix protein. Conclusion: RAGE may be shown to play a considerable role in the formation of neointima leading to restenosis after vascular injury.

  12. MR imaging in epilepsy with use of 3D MP-RAGE

    International Nuclear Information System (INIS)

    Tanaka, Akio; Ohno, Sigeru; Sei, Tetsuro; Kanazawa, Susumu; Yasui, Koutaro; Kuroda, Masahiro; Hiraki, Yoshio; Oka, Eiji

    1996-01-01

    The patients were 40 males and 33 females; their ages ranged from 1 month to 39 years (mean: 15.7 years). The patients underwent MR imaging, including spin-echo T 1 -weighted, turbo spin-echo proton density/T 2 -weighted, and 3D magnetization-prepared rapid gradient-echo (3D MP-RAGE) images. These examinations disclosed 39 focal abnormalities. On visual evaluation, the boundary of abnormal gray matter in the neuronal migration disorder (NMD) cases was most clealy shown on 3D MP-RAGE images as compared to the other images. This is considered to be due to the higher spatial resolution and the better contrast of the 3D MP-RAGE images than those of the other techniques. The relative contrast difference between abnormal gray matter and the adjacent white matter was also assessed. The results revealed that the contrast differences on the 3D MP-RAGE images were larger than those on the other images; this was statistically significant. Although the sensitivity of 3D MP-RAGE for NMD was not specifically evaluated in this study, the possibility of this disorder, in cases suspected on other images, could be ruled out. Thus, it appears that the specificity with respect to NMD was at least increased with us of 3D MP-RAGE. 3D MP-RAGE also enabled us to build three-dimensional surface models that were helpful in understanding the three-dimensional anatomy. Furthermore. 3D MP-RAGE was considered to be the best technique for evaluating hippocampus atrophy in patients with MTS. On the other hand, the sensitivity in the signal change of the hippocampus was higher on T 2 -weighted images. In addition, demonstration of cortical tubers of tuberous sclerosis in neurocutaneous syndrome was superior on T 2 -weighted images than on 3D MP-RAGE images. (K.H.)

  13. Blockade of RAGE in Zucker obese rats with experimental periodontitis

    DEFF Research Database (Denmark)

    Grauballe, M B; Østergaard, J A; Schou, S

    2017-01-01

    BACKGROUND AND OBJECTIVE: Periodontitis and type 2 diabetes mellitus (T2D) are two interrelated chronic diseases. Periodontitis is more prevalent in patients with T2D than in healthy subjects, and studies indicate that periodontitis impacts the metabolic control of patients with T2D. Hyperglycemia...... on the interrelationship between periodontitis and T2D in a rat model of both diseases. MATERIAL AND METHODS: Zucker obese rats (HsdHlr:ZUCKER-Lepr (fa/fa) ) and their lean littermates were divided into five treatment groups, with and without periodontitis. Monoclonal anti-RAGE IgG3 were injected into the rats three times...... evaluated in plasma. Kidney complications were evaluated by quantitative real-time PCR, the creatinine clearance rate, the albumin excretion rate and kidney hypertrophy. Periodontitis was evaluated by morphometric registration of alveolar bone loss and radiographic recording of bone support. RESULTS...

  14. Thalamus segmentation from MP2RAGE: a comparative study

    DEFF Research Database (Denmark)

    Eskildsen, Simon Fristed; Næss-Schmidt, Erhard; Blicher, Jakob

    RAGE sequence on a Siemens Magnetom Skyra 3T MRI system with a 32 channel head coil. Parameters were TR=5 s, TI1=0.7 s, TI2=2.5 s, α1=4°, α2=5° and acquired at a nominal, isotropic, resolution of 1mm (acquisition matrix: 240x256, 176 sagittal slices). An experienced neuro-radiologist manually traced......, increasing the number of training images in the library of SNIPE improves segmentation accuracy (Figure 4). Even though the DSI seems to plateau around a library size of 10-11 images, increasing the library may improve the accuracy even further. Conclusions: Widely used atlas based segmentation methods...

  15. Expression of RAGE and HMGB1 in thymic epithelial tumors, thymic hyperplasia and regular thymic morphology.

    Directory of Open Access Journals (Sweden)

    Bernhard Moser

    Full Text Available Recently, a role of the receptor for advanced glycation endproducts (RAGE in myasthenia gravis was described. RAGE and its ligand high mobility group box 1 (HMGB1 play key roles in autoimmunity and cancer. To test whether these molecules are involved in patients with thymic abnormalities we applied immunohistochemical analysis in 33 cases of thymic epithelial tumors, comprising 27 thymomas and 6 thymic carcinomas, and 21 nonneoplastic thymuses. Both molecules were detected in neoplastic epithelial cells: RAGE staining was most intense in WHO type B2 thymomas and thymic carcinomas (pB3>thymic carcinoma (p<0.001. Conversely, HMGB1 cytoplasmic staining intensities were as follows: A and AB (none, B1 (strong, B2 (moderate, B3 and thymic carcinoma (weak; (p<0.001. Fetal thymic tissue showed a distinct expression of RAGE and HMGB1 in subcapsular cortical epithelial cells which was found in 50% of myasthenic patients. Furthermore RAGE and HMGB1 were expressed in thymocytes, macrophages, Hassall's corpuscles, thymic medulla, and germinal center cells in myasthenic patients. Immunohistochemistry results were complemented by systemic measurements (immunosorbent assay: serum levels of soluble RAGE were significantly reduced in patients with epithelial tumors (p = 0.008; and in invasive tumors (p = 0.008. Whereas RAGE was equally reduced in thymic hyperplasia and epithelial tumors (p = 0.003, HMGB1 was only elevated in malignancies (p = 0.036. Results were most pronounced in thymic carcinomas. Thus, RAGE and HMGB1 are involved in the (patho-physiology of thymus, as evidenced by differentiated thymic and systemic expression patterns that may act as diagnostic or therapeutic targets in autoimmune disease and cancer.

  16. The association between the RAGE G82S polymorphism, sRAGE and chronic periodontitis in Taiwanese individuals with and without diabetes.

    Science.gov (United States)

    Wu, T-L; Tsai, C-C; Wang, Y-Y; Ho, K-Y; Wu, Y-M; Hung, H-C; Lin, Y-C

    2015-12-01

    The present study investigated the association between the RAGE G82S polymorphism, the plasma levels of sRAGE and chronic periodontitis in subjects with and without diabetes mellitus (DM). A total of 230 patients with DM and 264 non-DM participants were recruited for this study. Genotyping of the RAGE G82S polymorphism was accomplished using polymerase chain reaction-restriction fragment length polymorphism, and associations were analyzed with the chi-squared test and logistic regression analysis. In the non-DM group, the chi-squared test showed that the frequency distributions of the G82S polymorphism were significantly different between chronic periodontitis and non-chronic periodontitis subjects (χ(2) = 8.39, p = 0.02). A multivariate logistic regression model showed that the (G82S + S82S) genotypes were associated with a significantly increased risk of chronic periodontitis development compared to the G82G genotype (adjusted odds ratio = 2.06, 95% confidence interval: 1.08-4.07). In the DM group, there was no association between the G82S polymorphism and chronic periodontitis development when a multivariate logistic regression was performed. Plasma levels of sRAGE were significantly higher in subjects with the G82G genotype compared to those with the (G82S + S82S) genotypes in both the non-DM (856.6 ± 332.0 vs. 720.4 ± 311.4 pg/mL, p = 0.003) and DM groups (915.3 ± 497.1 vs. 603.5 ± 298.3 pg/mL, p chronic periodontitis and non-chronic periodontitis subjects in both the DM and non-DM groups. Moreover, when the subjects were further sub-divided by the G82S polymorphism, the difference in plasma levels of sRAGE between chronic periodontitis and non-chronic periodontitis subjects in the DM and non-DM groups remained statistically insignificant. The present study revealed that the RAGE G82S polymorphism was associated with chronic periodontitis in the non-DM group but not in the DM group. Our results also showed that the plasma levels of sRAGE were

  17. The RAGE Game Software Components Repository for Supporting Applied Game Development

    Directory of Open Access Journals (Sweden)

    Krassen Stefanov

    2017-09-01

    Full Text Available This paper presents the architecture of the RAGE repository, which is a unique and dedicated infrastructure that provides access to a wide variety of advanced technology components for applied game development. The RAGE project, which is the principal Horizon2020 research and innovation project on applied gaming, develops up to three dozens of software components (RAGE software assets that are reusable across a wide diversity of game engines, game platforms and programming languages. The RAGE repository provides storage space for assets and their artefacts and is designed as an asset life-cycle management system for defining, publishing, updating, searching and packaging for distribution of these assets. It will be embedded in a social platform for asset developers and other users. A dedicated Asset Repository Manager provides the main functionality of the repository and its integration with other systems. Tools supporting the Asset Manager are presented and discussed. When the RAGE repository is in full operation, applied game developers will be able to easily enhance the quality of their games by including selected advanced game software assets. Making available the RAGE repository system and its variety of software assets aims to enhance the coherence and decisiveness of the applied game industry.

  18. Narcissistic rage: The Achilles’ heel of the patient with chronic physical illness

    Science.gov (United States)

    Hyphantis, Thomas; Almyroudi, Augustina; Paika, Vassiliki; Goulia, Panagiota; Arvanitakis, Konstantinos

    2009-01-01

    Based on the psychoanalytic reading of Homer’s Iliad whose principal theme is “Achilles’ rage” (the semi-mortal hero invulnerable in all of his body except for his heel, hence “Achilles’ heel” has come to mean a person’s principal weakness), we aimed to assess whether “narcissistic rage” has an impact on several psychosocial variables in patients with severe physical illness across time. In 878 patients with cancer, rheumatological diseases, multiple sclerosis, inflammatory bowel disease, and glaucoma, we assessed psychological distress (SCL-90 and GHQ-28), quality of life (WHOQOL-BREF), interpersonal difficulties (IIP-40), hostility (HDHQ), and defense styles (DSQ). Narcissistic rage comprised DSQ “omnipotence” and HDHQ “extraverted hostility”. Hierarchical multiple regressions analyses were performed. We showed that, in patients with disease duration less than one year, narcissistic rage had a minor impact on psychosocial variables studied, indicating that the rage was rather part of a “normal” mourning process. On the contrary, in patients with longer disease duration, increased rates of narcissistic rage had a great impact on all outcome variables, and the opposite was true for patients with low rates of narcissistic rage, indicating that narcissistic rage constitutes actually an “Achilles’ Heel” for patients with long-term physical illness. These findings may have important clinical implications. PMID:19936167

  19. Differential effects of ethanol on feline rage and predatory attack behavior: an underlying neural mechanism.

    Science.gov (United States)

    Schubert, K; Shaikh, M B; Han, Y; Poherecky, L; Siegel, A

    1996-08-01

    Previous studies have shown that, at certain dose levels, ethanol can exert a powerful, facilitatory effect on aggressive behavior in both animals and humans. In the cat, however, it was discovered that ethanol differentially alters two forms of aggression that are common to this species. Defensive rage behavior is significantly enhanced, whereas predatory attack behavior is suppressed by ethanol administration. One possible mechanism governing alcohol's potentiation of defensive rage behavior is that it acts on the descending pathway from the medial hypothalamus to the midbrain periaqueductal gray (PAG)-an essential pathway for the expression of defensive rage behavior that uses excitatory amino acids as a neurotransmitter. This hypothesis is supported by the finding that the excitatory effects of alcohol on defensive rage behavior are blocked by administration of the N-methyl-D-aspartate antagonist alpha-2-amino-7-phosphoheptanoic acid (AP-7) when microinjected into the periaqueductal gray, a primary neuronal target of descending fibers from the medial hypothalamus that mediate the expression of defensive rage behavior. Thus, the present study establishes for the first time a specific component of the neural circuit for defensive rage behavior over which the potentiating effects of ethanol are mediated.

  20. Advanced glycation endproduct (AGE) accumulation and AGE receptor (RAGE) up‐regulation contribute to the onset of diabetic cardiomyopathy

    Science.gov (United States)

    Ma, Heng; Li, Shi‐Yan; Xu, Peisheng; Babcock, Sara A.; Dolence, E. Kurt; Brownlee, Michael; Li, Ji

    2008-01-01

    Abstract Diabetic cardiomyopathy is manifested by compromised systolic and diastolic function. This study was designed to examine the role of advanced glycation endproduct (AGE) and AGE receptor (RAGE) in diabetic cardiomyopathy. Heart function was assessed in isolated control and streptozotocin‐induced diabetic hearts following in vivo RAGE gene knockdown using RNA interference. Cardiomyocyte mechanical properties were evaluated including peak shortening (PS), time‐to‐PS (TPS) and time‐to‐90% relengthening (TR90). RAGE was assayed by RT‐PCR and immunoblot. Diabetes significantly enhanced cardiac MG, AGE and RAGE levels accompanied with colocalization of AGE and RAGE in cardiomyocytes. Diabetes‐elicited increase in RAGE was inhibited by in vivo siRNA interference. The AGE formation inhibitor benfotiamine significantly attenuated diabetes‐induced elevation in MG, AGE, RAGE and collagen cross‐linking without affecting hypertriglyceridaemia and hypercholesterolaemia in diabetes. Diabetes markedly decreased LV contractility, as evidenced by reduced ±dP/dt and LV developed pressure (LVDP), which were protected by RAGE gene knockdown. In addition, MG‐derived AGE (MG‐AGE) up‐regulated cardiac RAGE mRNA and triggered cardiomyocyte contractile dysfunction reminiscent of diabetic cardiomyopathy. The MG‐AGE‐elicited prolongation of TPS and TR90 was ablated by an anti‐RAGE antibody in cardiomyocytes. Interestingly, MG‐AGE‐induced cardiomyocyte dysfunction was associated with mitochondrial membrane potential (MMP) depolarization and reduced GSK‐3β inactivation in control cardiomyocytes, similar to those from in vivo diabetes. Treatment with siRNA‐RAGE ablated diabetes‐induced MMP depolarization and GSK‐3β inactivation. Collectively, our result implicated a role of AGE‐RAGE in the pathogenesis of diabetic cardiomyopathy. PMID:19602045

  1. The AGE-RAGE axis in an Arab population: The United Arab Emirates Healthy Futures (UAEHFS pilot study

    Directory of Open Access Journals (Sweden)

    Claire K. Inman

    2017-12-01

    Full Text Available Aims: The transformation of the United Arab Emirates (UAE from a semi-nomadic to a high income society has been accompanied by increasing rates of obesity and Type 2 diabetes mellitus. We examined if the AGE-RAGE (receptor for advanced glycation endproducts axis is associated with obesity and diabetes mellitus in the pilot phase of the UAE Healthy Futures Study (UAEHFS. Methods: 517 Emirati subjects were enrolled and plasma/serum levels of AGE, carboxy methyl lysine (CML-AGE, soluble (sRAGE and endogenous secretory (esRAGE were measured along with weight, height, waist and hip circumference (WC/HC, blood pressure, HbA1c, Vitamin D levels and routine chemistries. The relationship between the AGE-RAGE axis and obesity and diabetes mellitus was tested using proportional odds models and linear regression. Results: After covariate adjustment, AGE levels were significantly associated with diabetes status. Levels of sRAGE and esRAGE were associated with BMI and levels of sRAGE were associated with WC/HC. Conclusions: The AGE-RAGE axis is associated with diabetes status and obesity in this Arab population. Prospective serial analysis of this axis may identify predictive biomarkers of obesity and cardiometabolic dysfunction in the UAEHFS. Keywords: Advanced glycation endproducts (AGEs, Receptor for AGE (RAGE, Cohort study, Diabetes mellitus, Obesity

  2. Protocatechuic aldehyde ameliorates experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway

    International Nuclear Information System (INIS)

    Zhang, Liang; Ji, Yunxia; Kang, Zechun; Lv, Changjun; Jiang, Wanglin

    2015-01-01

    An abnormal high mobility group box 1 (HMGB1) activation and a decrease in receptor for advanced glycation end-product (RAGE) play a key role in the pathogenesis of pulmonary fibrosis. Protocatechuic aldehyde (PA) is a naturally occurring compound, which is extracted from the degradation of phenolic acids. However, whether PA has anti-fibrotic functions is unknown. In this study, the effects of PA on the transforming growth factor-β1 (TGF-β1)-mediated epithelial–mesenchymal transition (EMT) in A549 cells, on the apoptosis of human type I alveolar epithelial cells (AT I), on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis in vivo were investigated. PA treatment resulted in a reduction of EMT in A549 cells with a decrease in vimentin and HMGB, an increase of E-cadherin and RAGE, a reduction of HLF-1 proliferation with a decrease of fibroblast growth factor 2 (FGF-2) and platelet-derived growth factor (PDGF). Apoptosis of AT I was attenuated with an increase of RAGE. PA ameliorated BLM-induced pulmonary fibrosis in rats with a reduction of histopathological scores and collagen deposition, and a lower FGF-2, PDGF, α-smooth muscle actin (α-SMA) and HMGB1 expression, whereas higher RAGE was found in BLM-instilled lungs. Through the decrease of HGMB1 and the regulation of RAGE, PA reversed the EMT, inhibited HLF-1 proliferation as well as reduced apoptosis in AT I, and prevented pulmonary fibrosis in vivo. Collectively, our results demonstrate that PA prevents experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway. - Highlights: • PA prevents EMT, reduces the apoptosis of AT1 in vitro. • PA decreases proliferation of HLF-1, reduces PDGF and FGF expression in vitro. • PA prevents experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway

  3. Protocatechuic aldehyde ameliorates experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Liang, E-mail: countryspring@sina.com; Ji, Yunxia, E-mail: 413499057@qq.com; Kang, Zechun, E-mail: davidjiangwl@163.com; Lv, Changjun, E-mail: Lucky_lcj@sina.com; Jiang, Wanglin, E-mail: jwl518@163.com

    2015-02-15

    An abnormal high mobility group box 1 (HMGB1) activation and a decrease in receptor for advanced glycation end-product (RAGE) play a key role in the pathogenesis of pulmonary fibrosis. Protocatechuic aldehyde (PA) is a naturally occurring compound, which is extracted from the degradation of phenolic acids. However, whether PA has anti-fibrotic functions is unknown. In this study, the effects of PA on the transforming growth factor-β1 (TGF-β1)-mediated epithelial–mesenchymal transition (EMT) in A549 cells, on the apoptosis of human type I alveolar epithelial cells (AT I), on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on bleomycin (BLM)-induced pulmonary fibrosis in vivo were investigated. PA treatment resulted in a reduction of EMT in A549 cells with a decrease in vimentin and HMGB, an increase of E-cadherin and RAGE, a reduction of HLF-1 proliferation with a decrease of fibroblast growth factor 2 (FGF-2) and platelet-derived growth factor (PDGF). Apoptosis of AT I was attenuated with an increase of RAGE. PA ameliorated BLM-induced pulmonary fibrosis in rats with a reduction of histopathological scores and collagen deposition, and a lower FGF-2, PDGF, α-smooth muscle actin (α-SMA) and HMGB1 expression, whereas higher RAGE was found in BLM-instilled lungs. Through the decrease of HGMB1 and the regulation of RAGE, PA reversed the EMT, inhibited HLF-1 proliferation as well as reduced apoptosis in AT I, and prevented pulmonary fibrosis in vivo. Collectively, our results demonstrate that PA prevents experimental pulmonary fibrosis by modulating HMGB1/RAGE pathway. - Highlights: • PA prevents EMT, reduces the apoptosis of AT1 in vitro. • PA decreases proliferation of HLF-1, reduces PDGF and FGF expression in vitro. • PA prevents experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway.

  4. The AGE-RAGE Axis: Implications for Age-Associated Arterial Diseases

    Directory of Open Access Journals (Sweden)

    Laura M. Senatus

    2017-12-01

    Full Text Available The process of advanced glycation leads to the generation and accumulation of an heterogeneous class of molecules called advanced glycation endproducts, or AGEs. AGEs are produced to accelerated degrees in disorders such as diabetes, renal failure, inflammation, neurodegeneration, and in aging. Further, AGEs are present in foods and in tobacco products. Hence, through both endogenous production and exogenous consumption, AGEs perturb vascular homeostasis by a number of means; in the first case, AGEs can cause cross-linking of long-lived molecules in the basement membranes such as collagens, thereby leading to “vascular stiffening” and processes that lead to hyperpermeability and loss of structural integrity. Second, AGEs interaction with their major cell surface signal transduction receptor for AGE or RAGE sets off a cascade of events leading to modulation of gene expression and loss of vascular and tissue homeostasis, processes that contribute to cardiovascular disease. In addition, it has been shown that an enzyme, which plays key roles in the detoxification of pre-AGE species, glyoxalase 1 (GLO1, is reduced in aged and diabetic tissues. In the diabetic kidney devoid of Ager (gene encoding RAGE, higher levels of Glo1 mRNA and GLO1 protein and activity were observed, suggesting that in conditions of high AGE accumulation, natural defenses may be mitigated, at least in part through RAGE. AGEs are a marker of arterial aging and may be detected by both biochemical means, as well as measurement of “skin autofluorescence.” In this review, we will detail the pathobiology of the AGE-RAGE axis and the consequences of its activation in the vasculature and conclude with potential avenues for therapeutic interruption of the AGE-RAGE ligand-RAGE pathways as means to forestall the deleterious consequences of AGE accumulation and signaling via RAGE.

  5. Peripheral and central mediators of lipopolysaccharide induced suppression of defensive rage behavior in the cat.

    Science.gov (United States)

    Bhatt, S; Bhatt, R S; Zalcman, S S; Siegel, A

    2009-11-10

    Based upon recent findings in our laboratory that cytokines microinjected into the medial hypothalamus or periaqueductal gray (PAG) powerfully modulate defensive rage behavior in cat, the present study determined the effects of peripherally released cytokines following lipopolysaccharide (LPS) challenge upon defensive rage. The study involved initial identification of the effects of peripheral administration of LPS upon defensive rage by electrical stimulation from PAG and subsequent determination of the peripheral and central mechanisms governing this process. The results revealed significant elevation in response latencies for defensive rage from 60 to 300 min, post LPS injection, with no detectable signs of sickness behavior present at 60 min. In contrast, head turning behavior elicited by stimulation of adjoining midbrain sites was not affected by LPS administration, suggesting a specificity of the effects of LPS upon defensive rage. Direct administration of LPS into the medial hypothalamus had no effect on defensive rage, suggesting that the effects of LPS were mediated by peripheral cytokines rather than by any direct actions upon hypothalamic neurons. Complete blockade of the suppressive effects of LPS by peripheral pretreatment with an Anti-tumor necrosis factor-alpha (TNFalpha) antibody but not with an anti- interleukin-1 (IL-1) antibody demonstrated that the effects of LPS were mediated through TNF-alpha rather than through an IL-1 mechanism. A determination of the central mechanisms governing LPS suppression revealed that pretreatment of the medial hypothalamus with PGE(2) or 5-HT(1A) receptor antagonists each completely blocked the suppressive effects of LPS, while microinjections of a TNF-alpha antibody into the medial hypothalamus were ineffective. Microinjections of -Iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) benzamide monohydrochloride (p-MPPI) into lateral hypothalamus (to test for anatomical specificity) had no effect upon

  6. Interaction between tumor cell surface receptor RAGE and proteinase 3 mediates prostate cancer metastasis to bone

    Science.gov (United States)

    Kolonin, Mikhail G.; Sergeeva, Anna; Staquicini, Daniela I.; Smith, Tracey L.; Tarleton, Christy A.; Molldrem, Jeffrey J.; Sidman, Richard L.; Marchiò, Serena; Pasqualini, Renata; Arap, Wadih

    2017-01-01

    Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that RAGE-PR3 interaction mediates homing of prostate cancer cells to the bone marrow. PR3 bound to RAGE on the surface of prostate cancer cells in vitro, inducing tumor cell motility through a non-proteolytic signal transduction cascade involving activation and phosphorylation of ERK1/2 and JNK1. In preclinical models of experimental metastasis, ectopic expression of RAGE on human prostate cancer cells was sufficient to promote bone marrow homing within a short time frame. Our findings demonstrate how RAGE-PR3 interactions between human prostate cancer cells and the bone marrow microenvironment mediate bone metastasis during prostate cancer progression, with potential implications for prognosis and therapeutic intervention. PMID:28428279

  7. The Spectacle of Redemption: Guilt and Violence in Martin Scorsese’s Raging Bull

    Directory of Open Access Journals (Sweden)

    Arturo Serrano

    2015-06-01

    Full Text Available Of all the characters that undertake a search for redemption in Martin Scorsese’s films, perhaps it is the story of Jake La Motta in Raging Bull that for many reasons presents the greatest challenge to understanding redemption’s role in the narratives of his films. Is Jake La Motta a redeemed character at the end of Raging Bull? I argue that Scorsese uses Raging Bull to criticize a ritualistic view of redemption by portraying the beginning of Jake’s search as a futile attempt to submit himself to a public spectacle of ritual violence in the boxing ring while visually relating this to the Catholic sacraments and the crucifixion. It will only be later—in the loneliness of a jail cell, estranged from his family and without having to have had gone through a rite—that Jake achieves the self-awareness redemption requires.

  8. The AGE-RAGE axis in an Arab population: The United Arab Emirates Healthy Futures (UAEHFS) pilot study.

    Science.gov (United States)

    Inman, Claire K; Aljunaibi, Abdullah; Koh, Hyunwook; Abdulle, Abdishakur; Ali, Raghib; Alnaeemi, Abdullah; Al Zaabi, Eiman; Oumeziane, Naima; Al Bastaki, Marina; Al-Houqani, Mohammed; Al-Maskari, Fatma; Al Dhaheri, Ayesha; Shah, Syed M; Abdel Wareth, Laila; Al Mahmeed, Wael; Alsafar, Habiba; Al Anouti, Fatme; Al Hosani, Ayesha; Haji, Muna; Galani, Divya; O'Connor, Matthew J; Ahn, Jiyoung; Kirchhoff, Tomas; Sherman, Scott; Hayes, Richard B; Li, Huilin; Ramasamy, Ravichandran; Schmidt, Ann Marie

    2017-12-01

    The transformation of the United Arab Emirates (UAE) from a semi-nomadic to a high income society has been accompanied by increasing rates of obesity and Type 2 diabetes mellitus. We examined if the AGE-RAGE (receptor for advanced glycation endproducts) axis is associated with obesity and diabetes mellitus in the pilot phase of the UAE Healthy Futures Study (UAEHFS). 517 Emirati subjects were enrolled and plasma/serum levels of AGE, carboxy methyl lysine (CML)-AGE, soluble (s)RAGE and endogenous secretory (es)RAGE were measured along with weight, height, waist and hip circumference (WC/HC), blood pressure, HbA1c, Vitamin D levels and routine chemistries. The relationship between the AGE-RAGE axis and obesity and diabetes mellitus was tested using proportional odds models and linear regression. After covariate adjustment, AGE levels were significantly associated with diabetes status. Levels of sRAGE and esRAGE were associated with BMI and levels of sRAGE were associated with WC/HC. The AGE-RAGE axis is associated with diabetes status and obesity in this Arab population. Prospective serial analysis of this axis may identify predictive biomarkers of obesity and cardiometabolic dysfunction in the UAEHFS.

  9. Structural insights into calcium-bound S100P and the V domain of the RAGE complex.

    Directory of Open Access Journals (Sweden)

    Srinivasa R Penumutchu

    Full Text Available The S100P protein is a member of the S100 family of calcium-binding proteins and possesses both intracellular and extracellular functions. Extracellular S100P binds to the cell surface receptor for advanced glycation end products (RAGE and activates its downstream signaling cascade to meditate tumor growth, drug resistance and metastasis. Preventing the formation of this S100P-RAGE complex is an effective strategy to treat various disease conditions. Despite its importance, the detailed structural characterization of the S100P-RAGE complex has not yet been reported. In this study, we report that S100P preferentially binds to the V domain of RAGE. Furthermore, we characterized the interactions between the RAGE V domain and Ca(2+-bound S100P using various biophysical techniques, including isothermal titration calorimetry (ITC, fluorescence spectroscopy, multidimensional NMR spectroscopy, functional assays and site-directed mutagenesis. The entropy-driven binding between the V domain of RAGE and Ca(+2-bound S100P was found to lie in the micromolar range (Kd of ∼ 6 µM. NMR data-driven HADDOCK modeling revealed the putative sites that interact to yield a proposed heterotetrameric model of the S100P-RAGE V domain complex. Our study on the spatial structural information of the proposed protein-protein complex has pharmaceutical relevance and will significantly contribute toward drug development for the prevention of RAGE-related multifarious diseases.

  10. Cloning, characterisation, and comparative quantitative expression analyses of receptor for advanced glycation end products (RAGE) transcript forms.

    Science.gov (United States)

    Sterenczak, Katharina A; Willenbrock, Saskia; Barann, Matthias; Klemke, Markus; Soller, Jan T; Eberle, Nina; Nolte, Ingo; Bullerdiek, Jörn; Murua Escobar, Hugo

    2009-04-01

    RAGE is a member of the immunoglobulin superfamily of cell surface molecules playing key roles in pathophysiological processes, e.g. immune/inflammatory disorders, Alzheimer's disease, diabetic arteriosclerosis and tumourigenesis. In humans 19 naturally occurring RAGE splicing variants resulting in either N-terminally or C-terminally truncated proteins were identified and are lately discussed as mechanisms for receptor regulation. Accordingly, deregulation of sRAGE levels has been associated with several diseases e.g. Alzheimer's disease, Type 1 diabetes, and rheumatoid arthritis. Administration of recombinant sRAGE to animal models of cancer blocked tumour growth successfully. In spite of its obvious relationship to cancer and metastasis data focusing sRAGE deregulation and tumours is rare. In this study we screened a set of tumours, healthy tissues and various cancer cell lines for RAGE splicing variants and analysed their structure. Additionally, we analysed the ratio of the mainly found transcript variants using quantitative Real-Time PCR. In total we characterised 24 previously not described canine and 4 human RAGE splicing variants, analysed their structure, classified their characteristics, and derived their respective protein forms. Interestingly, the healthy and the neoplastic tissue samples showed in majority RAGE transcripts coding for the complete receptor and transcripts showing insertions of intron 1.

  11. Narcissistic rage: The Achilles’ heel of the patient with chronic physical illness

    Directory of Open Access Journals (Sweden)

    Thomas Hyphantis

    2009-08-01

    Full Text Available Thomas Hyphantis1, Augustina Almyroudi1, Vassiliki Paika1, Panagiota Goulia1, Konstantinos Arvanitakis2,31Department of Psychiatry, Medical School, University of Ioannina, Ioannina, Greece; 2Canadian Institute of Psychoanalysis, Mcgill University, Montreal, Canada; 3Departments of Philosophy and Psychiatry, Mcgill University Health Centre, Montreal, CanadaAbstract: Based on the psychoanalytic reading of Homer’s Iliad whose principal theme is “Achilles’ rage” (the semi-mortal hero invulnerable in all of his body except for his heel, hence “Achilles’ heel” has come to mean a person’s principal weakness, we aimed to assess whether “narcissistic rage” has an impact on several psychosocial variables in patients with severe physical illness across time. In 878 patients with cancer, rheumatological diseases, multiple sclerosis, inflammatory bowel disease, and glaucoma, we assessed psychological distress (SCL-90 and GHQ-28, quality of life (WHOQOL-BREF, interpersonal difficulties (IIP-40, hostility (HDHQ, and defense styles (DSQ. Narcissistic rage comprised DSQ “omnipotence” and HDHQ “extraverted hostility”. Hierarchical multiple regressions analyses were performed. We showed that, in patients with disease duration less than one year, narcissistic rage had a minor impact on psychosocial variables studied, indicating that the rage was rather part of a “normal” mourning process. On the contrary, in patients with longer disease duration, increased rates of narcissistic rage had a great impact on all outcome variables, and the opposite was true for patients with low rates of narcissistic rage, indicating that narcissistic rage constitutes actually an “Achilles’ Heel” for patients with long-term physical illness. These findings may have important clinical implications.Keywords: consultation-liaison psychiatry, psychosomatics, narcissism, physical illness, quality of life, psychological distress, personality

  12. Experiments at Scale with In-Situ Visualization Using ParaView/Catalyst in RAGE

    Energy Technology Data Exchange (ETDEWEB)

    Kares, Robert John [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2014-10-31

    In this paper I describe some numerical experiments performed using the ParaView/Catalyst in-situ visualization infrastructure deployed in the Los Alamos RAGE radiation-hydrodynamics code to produce images from a running large scale 3D ICF simulation on the Cielo supercomputer at Los Alamos. The detailed procedures for the creation of the visualizations using ParaView/Catalyst are discussed and several images sequences from the ICF simulation problem produced with the in-situ method are presented. My impressions and conclusions concerning the use of the in-situ visualization method in RAGE are discussed.

  13. Advanced glycation end products (AGEs) and their receptor (RAGE) induce apoptosis of periodontal ligament fibroblasts

    International Nuclear Information System (INIS)

    Li, D.X.; Deng, T.Z.; Lv, J.; Ke, J.

    2014-01-01

    Diabetics have an increased prevalence of periodontitis, and diabetes is one of the causative factors of severe periodontitis. Apoptosis is thought to be involved in this pathogenic relationship. The aim of this study was to investigate apoptosis in human periodontal ligament (PDL) fibroblasts induced by advanced glycation end products (AGEs) and their receptor (RAGE). We examined the roles of apoptosis, AGEs, and RAGE during periodontitis in diabetes mellitus using cultured PDL fibroblasts that were treated by AGE-modified bovine serum albumin (AGE-BSA), bovine serum albumin (BSA) alone, or given no treatment (control). Microscopy and real-time quantitative PCR indicated that PDL fibroblasts treated with AGE-BSA were deformed and expressed higher levels of RAGE and caspase 3. Cell viability assays and flow cytometry indicated that AGE-BSA reduced cell viability (69.80±5.50%, P<0.01) and increased apoptosis (11.31±1.73%, P<0.05). Hoechst 33258 staining and terminal-deoxynucleotidyl transferase-mediated nick-end labeling revealed that AGE-BSA significantly increased apoptosis of PDL fibroblasts. The results showed that the changes in PDL fibroblasts induced by AGE-BSA may explain how AGE-RAGE participates in and exacerbates periodontium destruction

  14. Thinking through Moments of Sexual Refusal in "Looking for Alibrandi" and "The Rage in Placid Lake"

    Science.gov (United States)

    Clarke, Kyra

    2016-01-01

    This paper explores two scenarios in which young women refuse the sexual advances of young men in the films "Looking for Alibrandi" and "The Rage in Placid Lake." The paper highlights the heteronormative nature of education around refusing sex, which reinstates gendered stereotypes of masculine as active and feminine as…

  15. RAGE Reusable Game Software Components and Their Integration into Serious Game Engines

    NARCIS (Netherlands)

    Van der Vegt, Wim; Nyamsuren, Enkhbold; Westera, Wim

    2016-01-01

    This paper presents and validates a methodology for integrating reusable software components in diverse game engines. While conforming to the RAGE com-ponent-based architecture described elsewhere, the paper explains how the interac-tions and data exchange processes between a reusable software

  16. T1 mapping of the mouse brain following fractionated manganese administration using MP2RAGE.

    Science.gov (United States)

    Driencourt, Luc; Romero, Carola Jacqueline; Lepore, Mario; Eggenschwiler, Florent; Reynaud, Olivier; Just, Nathalie

    2017-01-01

    With the increasing development of transgenic mouse models of neurodegenerative diseases allowing improved understanding of the underlying mechanisms of these disorders, robust quantitative mapping techniques are also needed in rodents. MP2RAGE has shown great potential for structural imaging in humans at high fields. In the present work, MP2RAGE was successfully implemented at 9.4T and 14.1T. Following fractionated injections of MnCl 2 , MP2RAGE images were acquired allowing simultaneous depiction and T 1 mapping of structures in the mouse brain at both fields. In addition, T 1 maps demonstrated significant T 1 shortenings in different structures of the mouse brain (p < 0.0008 at 9.4T, p < 0.000001 at 14.1T). T 1 values recovered to the levels of saline-injected animals 1 month after the last injection except in the pituitary gland. We believe that MP2RAGE represents an important prospective translational tool for further structural MRI.

  17. Plausible Roles for RAGE in Conditions Exacerbated by Direct and Indirect (Secondhand) Smoke Exposure.

    Science.gov (United States)

    Lewis, Joshua B; Hirschi, Kelsey M; Arroyo, Juan A; Bikman, Benjamin T; Kooyman, David L; Reynolds, Paul R

    2017-03-17

    Approximately 1 billion people smoke worldwide, and the burden placed on society by primary and secondhand smokers is expected to increase. Smoking is the leading risk factor for myriad health complications stemming from diverse pathogenic programs. First- and second-hand cigarette smoke contains thousands of constituents, including several carcinogens and cytotoxic chemicals that orchestrate chronic inflammatory responses and destructive remodeling events. In the current review, we outline details related to compromised pulmonary and systemic conditions related to smoke exposure. Specifically, data are discussed relative to impaired lung physiology, cancer mechanisms, maternal-fetal complications, cardiometabolic, and joint disorders in the context of smoke exposure exacerbations. As a general unifying mechanism, the receptor for advanced glycation end-products (RAGE) and its signaling axis is increasingly considered central to smoke-related pathogenesis. RAGE is a multi-ligand cell surface receptor whose expression increases following cigarette smoke exposure. RAGE signaling participates in the underpinning of inflammatory mechanisms mediated by requisite cytokines, chemokines, and remodeling enzymes. Understanding the biological contributions of RAGE during cigarette smoke-induced inflammation may provide critically important insight into the pathology of lung disease and systemic complications that combine during the demise of those exposed.

  18. Soluble receptor for advanced glycation end products (sRAGE) and ...

    African Journals Online (AJOL)

    Egyptian Journal of Medical Human Genetics ... Patients with disease duration less than 5 years, connective tissue disease, liver dysfunction, or apparent cardiovascular disease and those on lipid lowering ... Laboratory investigations included; HbA1c%, urinary albumin excretion (UAE), fasting lipid profile and sRAGE.

  19. Advanced glycation end products (AGEs) and their receptor (RAGE) induce apoptosis of periodontal ligament fibroblasts

    Energy Technology Data Exchange (ETDEWEB)

    Li, D.X.; Deng, T.Z.; Lv, J.; Ke, J. [Department of Stomatology, Air Force General Hospital PLA, Haidian District, Beijing (China)

    2014-09-19

    Diabetics have an increased prevalence of periodontitis, and diabetes is one of the causative factors of severe periodontitis. Apoptosis is thought to be involved in this pathogenic relationship. The aim of this study was to investigate apoptosis in human periodontal ligament (PDL) fibroblasts induced by advanced glycation end products (AGEs) and their receptor (RAGE). We examined the roles of apoptosis, AGEs, and RAGE during periodontitis in diabetes mellitus using cultured PDL fibroblasts that were treated by AGE-modified bovine serum albumin (AGE-BSA), bovine serum albumin (BSA) alone, or given no treatment (control). Microscopy and real-time quantitative PCR indicated that PDL fibroblasts treated with AGE-BSA were deformed and expressed higher levels of RAGE and caspase 3. Cell viability assays and flow cytometry indicated that AGE-BSA reduced cell viability (69.80±5.50%, P<0.01) and increased apoptosis (11.31±1.73%, P<0.05). Hoechst 33258 staining and terminal-deoxynucleotidyl transferase-mediated nick-end labeling revealed that AGE-BSA significantly increased apoptosis of PDL fibroblasts. The results showed that the changes in PDL fibroblasts induced by AGE-BSA may explain how AGE-RAGE participates in and exacerbates periodontium destruction.

  20. Book review: The Wilderness Debate Rages On: Continuing the Great New Wilderness Debate

    Science.gov (United States)

    Peter Landres

    2009-01-01

    The Wilderness Debate Rages On is a collection of mostly previously published papers about the meaning, value, and role of wilderness and continues the discussion that was propelled by the editors' previous book The Great New Wilderness Debate (also a collection of papers) published in 1998. The editors state that this sequel to their previous book is mandated...

  1. Activation of the HMGB1-RAGE axis upregulates TH expression in dopaminergic neurons via JNK phosphorylation.

    Science.gov (United States)

    Kim, Soo Jeong; Ryu, Min Jeong; Han, Jeongsu; Jang, Yunseon; Kim, Jungim; Lee, Min Joung; Ryu, Ilhwan; Ju, Xianshu; Oh, Eungseok; Chung, Woosuk; Kweon, Gi Ryang; Heo, Jun Young

    2017-11-04

    The derangement of tyrosine hydroxylase (TH) activity reduces dopamine synthesis and is implicated in the pathogenesis of Parkinson's disease. However, the extracellular modulator and intracellular regulatory mechanisms of TH have yet to be identified. Recently, high-mobility group box 1 (HMGB1) was reported to be actively secreted from glial cells and is regarded as a mediator of dopaminergic neuronal loss. However, the mechanism for how HMGB1 affects TH expression, particularly through the receptor for advanced glycation endproducts (RAGE), has not yet been investigated. We found that recombinant HMGB1 (rHMGB1) upregulates TH mRNA expression via simultaneous activation of JNK phosphorylation, and this induction of TH expression is blocked by inhibitors of RAGE and JNK. To investigate how TH expression levels change through the HMGB1-RAGE axis as a result of MPP + toxicity, we co-treated SN4741 dopaminergic cells with MPP + and rHMGB1. rHMGB1 blocked the reduction of TH mRNA following MPP + treatment without altering cell survival rates. Our results suggest that HMGB1 upregulates TH expression to maintain dopaminergic neuronal function via activating RAGE, which is dependent on JNK phosphorylation. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Soluble receptor for advanced glycation end products (sRAGE) and ...

    African Journals Online (AJOL)

    Eman M. Sherif

    2014-07-10

    Jul 10, 2014 ... other metabolites such as methylglyoxal. AGEs formation in ... Patients were further subdivided into two groups according to the presence of microvascular complications; Group I: ... variables using independent t-test in cases of two independent .... between sRAGE and SBP were only detected in controls.

  3. French version of the Rating Scale for Aggressive Behaviour in the Elderly (F-RAGE: Psychometric properties and diagnostic accuracy

    Directory of Open Access Journals (Sweden)

    Barry Adama

    Full Text Available ABSTRACT Aggressive behaviour is the most disturbing and distressing behaviour displayed by elderly people. The prevalence of aggressive behaviour is around 50% among psychogeriatric patients. Objective: This study sought to analyze the psychometric properties and diagnostic accuracy of the French version of the Rating Scale for Aggressive Behaviour in the Elderly (F-RAGE. Methods: The F-RAGE was administered to 79 patients hospitalized in a geriatric psychiatry department. A psychiatrist, who was blind to the subjects' RAGE scores, performed the diagnosis for aggressivity based on global clinical impression. The F-RAGE and MMSE were applied by a trained researcher blind to subjects' clinical diagnoses while the Cohen-Mansfield Agitation Inventory and Neuropsychiatric Inventory were administered by medical and nursing staff. Internal consistency, reliability, cut-off points, sensitivity and specificity for F-RAGE were estimated. Results: F-RAGE showed satisfactory validity and reliability measurements. Regarding reliability, Cronbach's a coefficient was satisfactory with a value of 0.758. For diagnostic accuracy, a cut-off point of 8 points (sensitivity=74.19%; specificity=97.98% and area under curve of 0.960 were estimated to distinguish between aggressive patients and control subjects. Discussion: F-RAGE showed acceptable psychometric properties, supported by evidence of validity and reliability for its use in the diagnosis of aggressive behaviour in elderly.

  4. N(epsilon)-carboxymethyllysine-modified proteins are unable to bind to RAGE and activate an inflammatory response.

    Science.gov (United States)

    Buetler, Timo M; Leclerc, Estelle; Baumeyer, Alexandra; Latado, Helia; Newell, John; Adolfsson, Oskar; Parisod, Véronique; Richoz, Janique; Maurer, Sarah; Foata, Francis; Piguet, Dominique; Junod, Sylviane; Heizmann, Claus W; Delatour, Thierry

    2008-03-01

    Advanced glycation endproducts (AGEs) containing carboxymethyllysine (CML) modifications are generally thought to be ligands of the receptor for AGEs, RAGEs. It has been argued that this results in the activation of pro-inflammatory pathways and diseases. However, it has not been shown conclusively that a CML-modified protein can interact directly with RAGE. Here, we have analyzed whether beta-lactoglobulin (bLG) or human serum albumin (HSA) modified chemically to contain only CML (10-40% lysine modification) can (i) interact with RAGE in vitro and (ii) interact with and activate RAGE in lung epithelial cells. Our results show that CML-modified bLG or HSA are unable to bind to RAGE in a cell-free assay system (Biacore). Furthermore, they are unable to activate pro-inflammatory signaling in the cellular system. Thus, CML probably does not form the necessary structure(s) to interact with RAGE and activate an inflammatory signaling cascade in RAGE-expressing cells.

  5. Explaining seemingly paradoxical consumer experiences: conjoining weekly road rage and church attendance.

    Science.gov (United States)

    Gau, Li-Shiue; Woodside, Arch G; Martin, Drew

    2015-02-01

    The purposes of the current study are threefold: Provide evidence that an extreme paradoxical group exists-people frequently attending church and exhibiting road rage, profile this group, and frame possible explanations for the seemingly paradoxical behaviors. This study employs data from a national (USA) lifestyle survey conducted by Market Facts with 3,350 American respondents. The major questions asked about church participation and road-rage behavior ("giving a finger" and "flashing headlights"). Nomologically, relevant activities include 3 items for church goers and 3 items for road-rage givers. Additionally, 14 items profiled the lifestyles of the unique paradoxical behavior segment. Utilizing cross-tabulation tables, property space analyses identify the double extreme (XX) group (18 people) and other 6 groups with a significant chi-square test, confirming the extreme group exists. Analyses of variance test results show that comparing nomologically relevant activities among the seven groups is all statistically significant, indicating the nomological validity is met. Overall, the XX group tends to have more males, be younger, and have a higher proportion of people working in sales. The profile of lifestyle analyses shows the XX group members have both high ambitions and expectations, might be very frustrated individuals, and equip with the adventurous and masculine traits related to aggression. The XX behavior group's demographic and psychographic characteristics portray similar lifestyles that differ from other groups. Case-based analyses provide further contextual information of nuances to XX segment individuals. The limited energy theory, the Eagleman's theory of unconscious mind, and justification theory help to explain why people conjointly go to church and commit road rage. Addressing chronic paradoxical behaviors provides implications for social de-marketing to reduce aggressive anti-social behavior such as road rage. Frequent church attendance may

  6. An Ultra-High Field Study of Cerebellar Pathology in Early Relapsing-Remitting Multiple Sclerosis Using MP2RAGE.

    Science.gov (United States)

    Fartaria, Mário João; OʼBrien, Kieran; Şorega, Alexandra; Bonnier, Guillaume; Roche, Alexis; Falkovskiy, Pavel; Krueger, Gunnar; Kober, Tobias; Bach Cuadra, Meritxell; Granziera, Cristina

    2017-05-01

    The aim of this study was to study focal cerebellar pathology in early stages of multiple sclerosis (MS) using ultra-high-field magnetization-prepared 2 inversion-contrast rapid gradient-echo (7T MP2RAGE). Twenty early-stage relapsing-remitting MS patients underwent an MP2RAGE acquisition at 7 T magnetic resonance imaging (MRI) (images acquired at 2 different resolutions: 0.58 × 0.58 × 0.58 mm, 7T_0.58, and 0.75 × 0.75 × 0.90 mm, 7T_0.75) and 3 T MRI (1.0 × 1.0 × 1.2 mm, 3T_1.0). Total cerebellar lesion load and volume and mean cerebellar lesion volume were compared across images using a Wilcoxon signed-rank test. Mean T1 relaxation times in lesions and normal-appearing tissue as well as contrast-to-noise ratio (CNR) measurements were also compared using a Wilcoxon signed-rank test. A multivariate analysis was applied to assess the contribution of MRI metrics to clinical performance in MS patients. Both 7T_0.58 and 7T_0.75 MP2RAGE showed significantly higher lesion load compared with 3T_1.0 MP2RAGE (P < 0.001). Plaques that were judged as leukocortical in 7T_0.75 and 3T_1.0 MP2RAGEs were instead identified as WM lesions in 7T_0.58 MP2RAGE. Cortical lesion CNR was significantly higher in MP2RAGEs at 7 T than at 3 T. Total lesion load as well as total and mean lesion volume obtained at both 7 T and 3 T MP2RAGE significantly predicted attention (P < 0.05, adjusted R = 0.5), verbal fluency (P < 0.01, adjusted R = 0.6), and motor performance (P = 0.01, adjusted R = 0.7). This study demonstrates the value of 7 T MP2RAGE to study the cerebellum in early MS patients. 7T_0.58 MP2RAGE provides a more accurate anatomical description of white and gray matter pathology compared with 7T_0.75 and 3T_1.0 MP2RAGE, likely due to the improved spatial resolution, lower partial volume effects, and higher CNR.

  7. Clinical and Biological Predictors of Plasma Levels of Soluble RAGE in Critically Ill Patients: Secondary Analysis of a Prospective Multicenter Observational Study

    Directory of Open Access Journals (Sweden)

    Thibaut Pranal

    2018-01-01

    Full Text Available Rationale. Although soluble forms of the receptor for advanced glycation end products (RAGE have been recently proposed as biomarkers in multiple acute or chronic diseases, few studies evaluated the influence of usual clinical and biological parameters, or of patient characteristics and comorbidities, on circulating levels of soluble RAGE in the intensive care unit (ICU setting. Objectives. To determine, among clinical and biological parameters that are usually recorded upon ICU admission, which variables, if any, could be associated with plasma levels of soluble RAGE. Methods. Data for this ancillary study were prospectively obtained from adult patients with at least one ARDS risk factor upon ICU admission enrolled in a large multicenter observational study. At ICU admission, plasma levels of total soluble RAGE (sRAGE and endogenous secretory (esRAGE were measured by duplicate ELISA and baseline patient characteristics, comorbidities, and usual clinical and biological indices were recorded. After univariate analyses, significant variables were used in multivariate, multidimensional analyses. Measurements and Main Results. 294 patients were included in this ancillary study, among whom 62% were admitted for medical reasons, including septic shock (11%, coma (11%, and pneumonia (6%. Although some variables were associated with plasma levels of RAGE soluble forms in univariate analysis, multidimensional analyses showed no significant association between admission parameters and baseline plasma sRAGE or esRAGE. Conclusions. We found no obvious association between circulating levels of soluble RAGE and clinical and biological indices that are usually recorded upon ICU admission. This trial is registered with NCT02070536.

  8. RAGE-dependent activation of gene expression of superoxide dismutase and vanins by AGE-rich extracts in mice cardiac tissue and murine cardiac fibroblasts.

    Science.gov (United States)

    Leuner, Beatrice; Ruhs, Stefanie; Brömme, Hans-Jürgen; Bierhaus, Angelika; Sel, Saadettin; Silber, Rolf-Edgar; Somoza, Veronika; Simm, Andreas; Nass, Norbert

    2012-10-01

    Advanced glycation end products (AGEs) are stable compounds formed from initial Maillard reaction products. They are considered as markers for ageing and often associated with age-related, degenerative diseases. Bread crust represents an established model for nutritional compounds rich in AGEs and is able to induce antioxidative defense genes such as superoxide dismutases and vanins in cardiac cells. The aim of this study was to investigate to what extend the receptor for AGEs (RAGE) contributes to this response. Signal transduction in response to bread crust extract was analysed in cardiac fibroblasts derived from C57/B6-NCrl (RAGE +/+) and the corresponding RAGE-knock out C57/B6-NCrl mouse strain (RAGE -/-). Activation of superoxide dismutases in animals was then analysed upon bread crust feeding in these two mice strains. Cardiac fibroblasts from RAGE -/- mice did not express RAGE, but the expression of AGER-1 and AGER-3 was up-regulated, whereas the expression of SR-B1 was down-regulated. RAGE -/- cells were less sensitive to BCE in terms of MAP-kinase phosphorylation and NF-κB reporter gene activation. Bread crust extract induced mRNA levels of MnSOD and Vnn-1 were also reduced in RAGE -/- cells, whereas Vnn-3 mRNA accumulation seemed to be RAGE receptor independent. In bread crust feeding experiments, RAGE -/- mice did not exhibit an activation of MnSOD-mRNA and -protein accumulation as observed for the RAGE +/+ animals. In conclusion, RAGE was clearly a major factor for the induction of antioxidant defense signals derived from bread crust in cardiac fibroblast and mice. Nevertheless higher doses of bread crust extract could overcome the RAGE dependency in cell cultures, indicating that additional mechanisms are involved in BCE-mediated activation of SOD and vanin expression.

  9. Nuclear DAMP complex-mediated RAGE-dependent macrophage cell death

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Ruochan [Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Department of Infectious Diseases and State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Fu, Sha; Fan, Xue-Gong [Department of Infectious Diseases and State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Lotze, Michael T.; Zeh, Herbert J. [Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Tang, Daolin, E-mail: tangd2@upmc.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 (United States); Kang, Rui, E-mail: kangr@upmc.edu [Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213 (United States)

    2015-03-13

    High mobility group box 1 (HMGB1), histone, and DNA are essential nuclear components involved in the regulation of chromosome structure and function. In addition to their nuclear function, these molecules act as damage-associated molecular patterns (DAMPs) alone or together when released extracellularly. The synergistic effect of these nuclear DNA-HMGB1-histone complexes as DAMP complexes (nDCs) on immune cells remains largely unexplored. Here, we demonstrate that nDCs limit survival of macrophages (e.g., RAW264.7 and peritoneal macrophages) but not cancer cells (e.g., HCT116, HepG2 and Hepa1-6). nDCs promote production of inflammatory tumor necrosis factor α (TNFα) release, triggering reactive oxygen species-dependent apoptosis and necrosis. Moreover, the receptor for advanced glycation end products (RAGE), but not toll-like receptor (TLR)-4 and TLR-2, was required for Akt-dependent TNFα release and subsequent cell death following treatment with nDCs. Genetic depletion of RAGE by RNAi, antioxidant N-Acetyl-L-cysteine, and TNFα neutralizing antibody significantly attenuated nDC-induced cell death. These findings provide evidence supporting novel signaling mechanisms linking nDCs and inflammation in macrophage cell death. - Highlights: • Nuclear DAMP complexes (nDCs) selectively induce cell death in macrophages, but not cancer cells. • TNFα-mediated oxidative stress is required for nDC-induced death. • RAGE-mediated Akt activation is required for nDC-induced TNFα release. • Blocking RAGE and TNFα inhibits nDC-induced macrophage cell death.

  10. Evaluating anorexia-related brain atrophy using MP2RAGE-based morphometry

    Energy Technology Data Exchange (ETDEWEB)

    Boto, Jose; Loevblad, Karl-Olof; Vargas, Maria Isabel [Geneva University Hospital (Switzerland). Div. of Neuroradiology and Faculty of Medicine of Geneva; Gkinis, Georgios; Ortiz, Nadia [Geneva University Hospital (Switzerland). Dept. of Mental Health and Psychiatry; Roche, Alexis; Kober, Tobias; Marechal, Benedicte [Siemens Healthcare HC CEMEA SUI DI BM PI, Lausanne (Switzerland). Siemens ACIT, Advanced Clinical Imaging Technology; University Hospital (CHUV), Lausanne (Switzerland). Dept. of Radiology; Ecole Polytechnique Federale de Lausanne (Switzerland). LTS5; Lazeyras, Francois [Geneva University Hospital (Switzerland). Div. of Radiology and Faculty of Medicine of Geneva

    2017-12-15

    To evaluate brain atrophy in anorexic patients by automated cerebral segmentation with the magnetization-prepared 2 rapid acquisition gradient echo (MP2RAGE) MRI sequence. Twenty patients (female; mean age, 27.9 years), presenting consecutively for brain MRI between August 2014-December 2016 with clinical suspicion of anorexia nervosa and BMI<18.5 kg/m{sup 2} were included. Controls were ten healthy females (mean age, 26.5 years). Automated brain morphometry was performed based on MP2RAGE. Means of morphometric results in the two groups were compared and correlation with BMI was analysed. Significantly lower volumes of total brain, grey matter (GM), white matter (WM), cerebellum and insula were found in anorexic patients. Anorexics had higher volumes of CSF, ventricles, lateral ventricles and third ventricle. When adjusted means for weight and height were compared, the volume of WM and cerebellum were not significantly different. However, volume of WM was significantly affected by weight and positively correlated with BMI. Significant positive correlations were found between BMI and volumes of total brain, GM, cortical GM and WM. BMI was negatively correlated with volumes of CSF and third ventricle. Brain atrophy was demonstrated in anorexic patients with MP2RAGE-based automated segmentation, which seems to reliably estimate brain volume. (orig.)

  11. Evaluating anorexia-related brain atrophy using MP2RAGE-based morphometry

    International Nuclear Information System (INIS)

    Boto, Jose; Loevblad, Karl-Olof; Vargas, Maria Isabel; Gkinis, Georgios; Ortiz, Nadia; Roche, Alexis; Kober, Tobias; Marechal, Benedicte; University Hospital; Ecole Polytechnique Federale de Lausanne; Lazeyras, Francois

    2017-01-01

    To evaluate brain atrophy in anorexic patients by automated cerebral segmentation with the magnetization-prepared 2 rapid acquisition gradient echo (MP2RAGE) MRI sequence. Twenty patients (female; mean age, 27.9 years), presenting consecutively for brain MRI between August 2014-December 2016 with clinical suspicion of anorexia nervosa and BMI<18.5 kg/m 2 were included. Controls were ten healthy females (mean age, 26.5 years). Automated brain morphometry was performed based on MP2RAGE. Means of morphometric results in the two groups were compared and correlation with BMI was analysed. Significantly lower volumes of total brain, grey matter (GM), white matter (WM), cerebellum and insula were found in anorexic patients. Anorexics had higher volumes of CSF, ventricles, lateral ventricles and third ventricle. When adjusted means for weight and height were compared, the volume of WM and cerebellum were not significantly different. However, volume of WM was significantly affected by weight and positively correlated with BMI. Significant positive correlations were found between BMI and volumes of total brain, GM, cortical GM and WM. BMI was negatively correlated with volumes of CSF and third ventricle. Brain atrophy was demonstrated in anorexic patients with MP2RAGE-based automated segmentation, which seems to reliably estimate brain volume. (orig.)

  12. Optimizing the magnetization-prepared rapid gradient-echo (MP-RAGE sequence.

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    Jinghua Wang

    Full Text Available The three-dimension (3D magnetization-prepared rapid gradient-echo (MP-RAGE sequence is one of the most popular sequences for structural brain imaging in clinical and research settings. The sequence captures high tissue contrast and provides high spatial resolution with whole brain coverage in a short scan time. In this paper, we first computed the optimal k-space sampling by optimizing the contrast of simulated images acquired with the MP-RAGE sequence at 3.0 Tesla using computer simulations. Because the software of our scanner has only limited settings for k-space sampling, we then determined the optimal k-space sampling for settings that can be realized on our scanner. Subsequently we optimized several major imaging parameters to maximize normal brain tissue contrasts under the optimal k-space sampling. The optimal parameters are flip angle of 12°, effective inversion time within 900 to 1100 ms, and delay time of 0 ms. In vivo experiments showed that the quality of images acquired with our optimal protocol was significantly higher than that of images obtained using recommended protocols in prior publications. The optimization of k-spacing sampling and imaging parameters significantly improved the quality and detection sensitivity of brain images acquired with MP-RAGE.

  13. Road rage and road traffic accidents among commercial vehicle drivers in Lahore, Pakistan.

    Science.gov (United States)

    Shaikh, M A; Shaikh, I A; Siddiqui, Z

    2012-04-01

    Road rage and road traffic accidents increase the burden of morbidity and mortality in a population. A cross-sectional survey with convenience sampling was conducted among commercial vehicle drivers in Lahore, Pakistan (n = 901) to record their behaviours/experiences regarding road rage and road traffic accidents. Respondents were asked about incidents of shouting/cursing/rude gestures or threats to physically hurt the person/vehicle, by others or themselves, in the previous 24 hours or 3 months, and their involvement in road traffic accidents in the previous 12 months. Auto-rickshaw drivers were significantly more likely to report various road rage experiences/behaviours and involvement in accidents compared with bus and wagon drivers. A total of 112 respondents (12.4%) reported being involved in a road traffic accident in the previous 12 months but traffic police did not record the accident in 52.7% of cases. The results of this study underline the need to improve road safety in Pakistan.

  14. Soluble Receptor for Advanced Glycation End Products (sRAGE is Up-Regulated in Multiple Sclerosis Patients Treated with Interferon β-1a

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    Mahnoosh Rahimi

    2018-03-01

    Full Text Available Background/Aims: Multiple sclerosis (MS is a chronic inflammatory disorder of the central nervous system. Considering the role of immune system in its pathogenesis, researchers have focused on evaluation of the expression of immune-related genes or proteins in MS patients. Among proteins whose participation in inflammatory process has been documented is the receptor for advanced glycation end products (RAGE. Methods: In the present study, we compared RAGE transcript levels by means of quantitative real-time PCR as well as the serum level of soluble RAGE (sRAGE by means of enzyme- linked immunosorbent assay (ELISA in 50 IFNβ-1a responsive relapsing-remitting MS patients when compared with age and sex-matched healthy subjects. Results: Elevated expression of RAGE as well as higher levels of sRAGE were detected in IFN-β responsive MS patients compared with the controls. A significant inverse correlation between sRAGE plasma concentrations and the expanded disability status scale (EDSS was also detected in which each unit of increase in sRAGE level resulted in a 0.308 unit decrease in EDSS. Conclusion: Considering the stable clinical state of the MS patients in this study and their response to IFNβ-1a, the elevated levels of sRAGE in patients compared with healthy subjects could be related to the effects of this kind of treatment.

  15. RAGE-Specific Inhibitor FPS-ZM1 Attenuates AGEs-Induced Neuroinflammation and Oxidative Stress in Rat Primary Microglia.

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    Shen, Chao; Ma, Yingjuan; Zeng, Ziling; Yin, Qingqing; Hong, Yan; Hou, Xunyao; Liu, Xueping

    2017-10-01

    Advanced glycation end products (AGEs) enhance microglial activation and intensify the inflammatory response and oxidative stress in the brain. This process may occur due to direct cytotoxicity or interacting with AGEs receptors (RAGE), which are expressed on the surface of microglia. FPS-ZM1 is a high-affinity but nontoxic RAGE-specific inhibitor that has been recently shown to attenuate the Aβ-induced inflammatory response by blocking the ligation of Aβ to RAGE. In this study, we further investigated the effect of FPS-ZM1 on the AGEs/RAGE interaction and downstream elevation of neuroinflammation and oxidative stress in primary microglia cells. The results suggested that FPS-ZM1 significantly suppressed AGEs-induced RAGE overexpression, RAGE-dependent microglial activation, nuclear translocation of nuclear factor kappaB p65 (NF-κB p65), and the expression of downstream inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) and inducible nitric oxide synthase (iNOS)/nitric oxide (NO). Furthermore, FPS-ZM1 attenuated AGEs-stimulated NADPH oxidase (NOX) activation and reactive oxygen species (ROS) expression. Finally, FPS-ZM1 elevated the levels of transcription factors nuclear-factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1), as well as decreased antioxidant capacity and increased production of oxidative species. Our results suggest that FPS-ZM1 may be neuroprotective through attenuating microglial activation, oxidative stress and inflammation by blocking RAGE.

  16. HMGB1/RAGE Signaling and Pro-Inflammatory Cytokine Responses in Non-HIV Adults with Active Pulmonary Tuberculosis.

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    Grace Lui

    Full Text Available We aimed to study the pathogenic roles of High-Mobility Group Box 1 (HMGB1 / Receptor-for-Advanced-Glycation-End-products (RAGE signaling and pro-inflammatory cytokines in patients with active pulmonary tuberculosis (PTB.A prospective study was conducted among non-HIV adults newly-diagnosed with active PTB at two acute-care hospitals (n = 80; age-and-sex matched asymptomatic individuals (tested for latent TB were used for comparison (n = 45. Plasma concentrations of 8 cytokines/chemokines, HMGB1, soluble-RAGE, and transmembrane-RAGE expressed on monocytes/dendritic cells, were measured. Gene expression (mRNA of HMGB1, RAGE, and inflammasome-NALP3 was quantified. Patients' PBMCs were stimulated with recombinant-HMGB1 and MTB-antigen (lipoarabinomannan for cytokine induction ex vivo.In active PTB, plasma IL-8/CXCL8 [median(IQR, 6.0(3.6-15.1 vs 3.6(3.6-3.6 pg/ml, P<0.001] and IL-6 were elevated, which significantly correlated with mycobacterial load, extent of lung consolidation (rs +0.509, P<0.001, severity-score (rs +0.317, P = 0.004, and fever and hospitalization durations (rs +0.407, P<0.001. IL-18 and sTNFR1 also increased. Plasma IL-8/CXCL8 (adjusted OR 1.12, 95%CI 1.02-1.23 per unit increase, P = 0.021 and HMGB1 (adjusted OR 1.42 per unit increase, 95%CI 1.08-1.87, P = 0.012 concentrations were independent predictors for respiratory failure, as well as for ICU admission/death. Gene expression of HMGB1, RAGE, and inflammasome-NALP3 were upregulated (1.2-2.8 fold. Transmembrane-RAGE was increased, whereas the decoy soluble-RAGE was significantly depleted. RAGE and HMGB1 gene expressions positively correlated with cytokine levels (IL-8/CXCL8, IL-6, sTNFR1 and clinico-/radiographical severity (e.g. extent of consolidation rs +0.240, P = 0.034. Ex vivo, recombinant-HMGB1 potentiated cytokine release (e.g. TNF-α when combined with lipoarabinomannan.In patients with active PTB, HMGB1/RAGE signaling and pro-inflammatory cytokines may play important

  17. Sleep Now in The Fire: An Analysis of A Song by Rage Against The Machine Using Marxism

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    Abdul Azis Turhan Kariko

    2011-10-01

    Full Text Available Rage against the Machine is known for their politics as well as their music, which the later helped creating an aggressive-heavy rock-rap genre. Article presents a song by Rage against the Machine band related to ideological movement in America, titled Sleep Now in the Fire. This effort brings an understanding of ideology that is embraced by the band. The method is through literature study. Presentation begins with a short biography of the band, theoretical concepts, and analysis of the song as well its music video. It is concluded that the song represents ideological criticism toward capitalism using Marxism. Both of these lyric and music video represents Marxism as it shares the same movement to fight capitalism—which in this case, Rage against the Machine is using their music, lyric, and video to fight the crime against humanity and cultural imperialism. 

  18. Quantitative PCR and immunohistochemical analyses of HMGB1 and RAGE expression in canine disseminated histiocytic sarcoma (malignant histiocytosis).

    Science.gov (United States)

    Sterenczak, Katharina A; Kleinschmidt, Sven; Wefstaedt, Patrick; Eberle, Nina; Hewicker-Trautwein, Marion; Bullerdiek, Jörn; Nolte, Ingo; Murua Escobar, Hugo

    2011-05-01

    Disorders of histiocytic origin affecting humans and dogs share various similarities. Canine disseminated histiocytic sarcoma (DHS) (formerly known as malignant histiocytosis) is an aggressive neoplasm of interstitial dendritic cells (DCs). The receptor for glycation end products (RAGE) and the high mobility group box1 protein (HMGB1) have been shown to be required for the maturation and migration of DCs. Thus, deregulation of the expression of these genes could have a major effect on the progression of histiocytic disorders. Neoplastic canine DHS samples and non-neoplastic control samples were analysed immunohistochemically and via real-time PCR. Significant down-regulation of RAGE in the lung tumour samples and down-regulation of HMGB1 in the lung, lymph node and spleen tumour samples were detected compared to their non-neoplastic counterparts. RAGE and HMGB1 expression down-regulation in canine DHS points to a role in the progression of histiocytic disorders.

  19. A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease

    Science.gov (United States)

    Deane, Rashid; Singh, Itender; Sagare, Abhay P.; Bell, Robert D.; Ross, Nathan T.; LaRue, Barbra; Love, Rachal; Perry, Sheldon; Paquette, Nicole; Deane, Richard J.; Thiyagarajan, Meenakshisundaram; Zarcone, Troy; Fritz, Gunter; Friedman, Alan E.; Miller, Benjamin L.; Zlokovic, Berislav V.

    2012-01-01

    In Alzheimer disease (AD), amyloid β peptide (Aβ) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aβ binding to the V domain of RAGE and inhibited Aβ40- and Aβ42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo. FPS-ZM1 was nontoxic to mice and readily crossed the blood-brain barrier (BBB). In aged APPsw/0 mice overexpressing human Aβ-precursor protein, a transgenic mouse model of AD with established Aβ pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Aβ40 and Aβ42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited β-secretase activity and Aβ production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Aβ40 and Aβ42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APPsw/0 mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Aβ-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD. PMID:22406537

  20. Persistent Increase in Microglial RAGE Contributes to Chronic Stress-Induced Priming of Depressive-like Behavior.

    Science.gov (United States)

    Franklin, Tina C; Wohleb, Eric S; Zhang, Yi; Fogaça, Manoela; Hare, Brendan; Duman, Ronald S

    2018-01-01

    Chronic stress-induced inflammatory responses occur in part via danger-associated molecular pattern (DAMP) molecules, such as high mobility group box 1 protein (HMGB1), but the receptor(s) underlying DAMP signaling have not been identified. Microglia morphology and DAMP signaling in enriched rat hippocampal microglia were examined during the development and expression of chronic unpredictable stress (CUS)-induced behavioral deficits, including long-term, persistent changes after CUS. The results show that CUS promotes significant morphological changes and causes robust upregulation of HMGB1 messenger RNA in enriched hippocampal microglia, an effect that persists for up to 6 weeks after CUS exposure. This coincides with robust and persistent upregulation of receptor for advanced glycation end products (RAGE) messenger RNA, but not toll-like receptor 4 in hippocampal microglia. CUS also increased surface expression of RAGE protein on hippocampal microglia as determined by flow cytometry and returned to basal levels 5 weeks after CUS. Importantly, exposure to short-term stress was sufficient to increase RAGE surface expression as well as anhedonic behavior, reflecting a primed state that results from a persistent increase in RAGE messenger RNA expression. Further evidence for DAMP signaling in behavioral responses is provided by evidence that HMGB1 infusion into the hippocampus was sufficient to cause anhedonic behavior and by evidence that RAGE knockout mice were resilient to stress-induced anhedonia. Together, the results provide evidence of persistent microglial HMGB1-RAGE expression that increases vulnerability to depressive-like behaviors long after chronic stress exposure. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  1. High-mobility group B1 (HMGB1) and receptor for advanced glycation end-products (RAGE) expression in canine lymphoma.

    Science.gov (United States)

    Sterenczak, Katharina A; Joetzke, Alexa E; Willenbrock, Saskia; Eberle, Nina; Lange, Sandra; Junghanss, Christian; Nolte, Ingo; Bullerdiek, Jörn; Simon, Daniela; Murua Escobar, Hugo

    2010-12-01

    Canine lymphoma is a commonly occurring, spontaneously developing neoplasia similar to human non-Hodgkin's lymphoma and, thus, is used as a valuable model for human malignancy. HMGB1 and RAGE are strongly associated with tumour progression and vascularisation. Consequently, deregulated RAGE and HMGB1 may play an important role in the mechanisms involved in lymphoma progression. Expression patterns of HMGB1 and RAGE were analysed in 22 canine lymphoma and three canine non-neoplastic control samples via real time PCR and canine beta-glucuronidase gene (GUSB) as endogenous control. HMGB1 was up-regulated in the neoplastic samples, while RAGE expression remained inconspicuous. This study demonstrated similar mechanisms in lymphoma progression in humans and dogs due to overexpression of HMGB1, which was described in human lymphomas. RAGE remained stable in terms of expression indicating that the extracellular HMGB1-induced effects are regulated by HMGB1 itself.

  2. RAGE and TGF-β1 Cross-Talk Regulate Extracellular Matrix Turnover and Cytokine Synthesis in AGEs Exposed Fibroblast Cells.

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    Andreea Iren Serban

    Full Text Available AGEs accumulation in the skin affects extracellular matrix (ECM turnover and triggers diabetes associated skin conditions and accelerated skin aging. The receptor of AGEs (RAGE has an essential contribution to cellular dysfunction driven by chronic inflammatory responses while TGF-β1 is critical in both dermal homeostasis and inflammation. We investigated the contribution of RAGE and TGF-β1 to the modulation of inflammatory response and ECM turnover in AGEs milieu, using a normal fibroblast cell line. RAGE, TGF-β1, collagen I and III gene and protein expression were upregulated after exposure to AGEs-BSA, and MMP-2 was activated. AGEs-RAGE was pivotal in NF-κB dependent collagen I expression and joined with TGF-β1 to stimulate collagen III expression, probably via ERK1/2 signaling. AGEs-RAGE axis induced upregulation of TGF-β1, TNF-α and IL-8 cytokines. TNF-α and IL-8 were subjected to TGF-β1 negative regulation. RAGE's proinflammatory signaling also antagonized AGEs-TGF-β1 induced fibroblast contraction, suggesting the existence of an inhibitory cross-talk mechanism between TGF-β1 and RAGE signaling. RAGE and TGF-β1 stimulated anti-inflammatory cytokines IL-2 and IL-4 expression. GM-CSF and IL-6 expression appeared to be dependent only on TGF-β1 signaling. Our data also indicated that IFN-γ upregulated in AGEs-BSA milieu in a RAGE and TGF-β1 independent mechanism. Our findings raise the possibility that RAGE and TGF-β1 are both involved in fibrosis development in a complex cross-talk mechanism, while also acting on their own individual targets. This study contributes to the understanding of impaired wound healing associated with diabetes complications.

  3. Reviving Rage

    Science.gov (United States)

    West, Isaac

    2012-01-01

    As people commemorate ACT UP and examine its memory in public cultures, the 2011 revival of "The Normal Heart" (TNH) and the rhetorical labor undertaken to evoke political emotionalities inside and outside of the theater provides one site for analyzing how direct action politics, both past and present, are imagined as a kairotic response to…

  4. La rage

    OpenAIRE

    Ribadeau-Dumas , Florence; Dacheux , Laurent; Bourhy , Hervé

    2013-01-01

    International audience; Rabies virus, a neurotropic lyssavirus responsible for unavoidable fatal encephalitis, is transmitted by saliva of infected animals through bite, scratch or licking of broken skin or a mucous membrane. Infection can be prevented by timely prevention (wash for several minutes, antisepsis and vaccination completed by antirabies immunoglobulins [Ig] according to the severity of exposure). The 55,000 human deaths estimated annually worldwide result mainly from uncontrolled...

  5. Receptor for advanced glycation end products (RAGE) functions as receptor for specific sulfated glycosaminoglycans, and anti-RAGE antibody or sulfated glycosaminoglycans delivered in vivo inhibit pulmonary metastasis of tumor cells.

    Science.gov (United States)

    Mizumoto, Shuji; Takahashi, Jun; Sugahara, Kazuyuki

    2012-06-01

    Altered expression of chondroitin sulfate (CS) and heparan sulfate (HS) at the surfaces of tumor cells plays a key role in malignant transformation and tumor metastasis. Previously we demonstrated that a Lewis lung carcinoma (LLC)-derived tumor cell line with high metastatic potential had a higher proportion of E-disaccharide units, GlcUA-GalNAc(4,6-O-disulfate), in CS chains than low metastatic LLC cells and that such CS chains are involved in the metastatic process. The metastasis was markedly inhibited by the pre-administration of CS-E from squid cartilage rich in E units or by preincubation with a phage display antibody specific for CS-E. However, the molecular mechanism of the inhibition remains to be investigated. In this study the receptor molecule for CS chains containing E-disaccharides expressed on LLC cells was revealed to be receptor for advanced glycation end products (RAGE), which is a member of the immunoglobulin superfamily predominantly expressed in the lung. Interestingly, RAGE bound strongly to not only E-disaccharide, but also HS-expressing LLC cells. Furthermore, the colonization of the lungs by LLC cells was effectively inhibited by the blocking of CS or HS chains at the tumor cell surface with an anti-RAGE antibody through intravenous injections in a dose-dependent manner. These results provide the clear evidence that RAGE is at least one of the critical receptors for CS and HS chains expressed at the tumor cell surface and involved in experimental lung metastasis and that CS/HS and RAGE are potential molecular targets in the treatment of pulmonary metastasis.

  6. The S100P/RAGE signaling pathway regulates expression of microRNA-21 in colon cancer cells.

    Science.gov (United States)

    Mercado-Pimentel, Melania E; Onyeagucha, Benjamin C; Li, Qing; Pimentel, Angel C; Jandova, Jana; Nelson, Mark A

    2015-08-19

    S100P signaling through the receptor for advanced glycation end-products (RAGE) contributes to colon cancer invasion and metastasis, but the mechanistic features of this process are obscure. Here, we investigate whether activation of S100P/RAGE signaling regulates oncogenic microRNA-21 (miR-21). We show that exogenous S100P up-regulates miR-21 levels in human colon cancer cells, whereas knockdown of S100P results in a decrease of miR-21. Furthermore, blockage of RAGE with anti-RAGE antibody suppresses S100P induction of miR-21. In addition, we found that S100P induction of miR-21 expression involves ERK and is suppressed by the MEK inhibitor U0126. Also, S100P treatment stimulates the enrichment of c-Fos, and AP-1 family members, at the miR-21 gene promoter. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  7. Relationship of Soluble RAGE with Insulin Resistance and Beta Cell Function during Development of Type 2 Diabetes Mellitus

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    Subrata Kumar Biswas

    2015-01-01

    Full Text Available This study examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE alter in prediabetes and correlate with insulin resistance (IR and beta cell function in prediabetes and newly diagnosed type 2 diabetes mellitus (T2DM. Subjects without previous history of diabetes were recruited and grouped as control, prediabetes, and newly diagnosed T2DM. The control subjects (n=40 and people with prediabetes (n=52 and diabetes (n=66 were similar in terms of age, sex, BMI, systolic and diastolic BP, and fasting insulin level. HOMA-IR was found significantly higher in people with diabetes than control subjects (p<0.001 and people with prediabetes (p=0.005; and HOMA-%B was found significantly deteriorated in people with diabetes (p<0.001 compared to control subjects and people with prediabetes. However, serum sRAGE levels did not show any significant alteration in people with prediabetes compared to control subjects. Moreover, univariate and multivariate analyses did not identify any significant correlation and statistical association of sRAGE with HOMA-IR and HOMA-%B in people with prediabetes and newly diagnosed T2DM. Our data suggest that serum sRAGE levels do not alter in people with prediabetes compared to control subjects and do not correlate or associate with IR and beta cell function during development of T2DM.

  8. Clinical significance of AGE-RAGE axis in colorectal cancer: associations with glyoxalase-I, adiponectin receptor expression and prognosis

    International Nuclear Information System (INIS)

    Sakellariou, Stratigoula; Fragkou, Paraskevi; Levidou, Georgia; Gargalionis, Antonios N.; Piperi, Christina; Dalagiorgou, Georgia; Adamopoulos, Christos; Saetta, Angelica; Agrogiannis, George; Theohari, Irini; Sougioultzis, Stavros; Tsioli, Panagiota; Karavokyros, Ioannis; Tsavaris, Nikolaos; Kostakis, Ioannis D.; Zizi-Serbetzoglou, Adamantia; Vandoros, Gerasimos P.; Patsouris, Efstratios; Korkolopoulou, Penelope

    2016-01-01

    Advanced glycation end products (AGEs) and their receptor RAGE emerge as important pathogenic contributors in colorectal carcinogenesis. However, their relationship to the detoxification enzyme Glyoxalase (GLO)-I and Adiponectin receptors (AdipoR1, AdipoR2) in colorectal carcinoma (CRC) is currently understudied. In the present study, we investigated the expression levels of the above molecules in CRC compared to adjacent non-tumoral tissue and their potential correlation with clinicopathological characteristics and patients’ survival. We analyzed the immunohistochemical expression of AGE, RAGE, GLO-1, AdipoR1 and AdipoR2 in 133 primary CRC cases, focusing on GLO-I. The tumour MSI status was further assessed in mucinous carcinomas. Western immunoblotting was employed for validation of immunohistochemical data in normal and tumoral tissues as well in three CRC cell lines. An independent set of 55 patients was also used to validate the results of univariate survival analysis regarding GLO-I. CRC tissue showed higher intensity of both AGE and RAGE expression compared with normal colonic mucosa which was negative for GLO-I in most cases (78 %). Western immunoblotting confirmed AGE, RAGE and GLO-I overexpression in tumoral tissue. GLO-I expression was directly related to RAGE and inversely related to AGE immunolabeling. There was a trend towards higher expression of all markers (except for RAGE) in the subgroup of mucinous carcinomas which, although of borderline significance, seemed to be more prominent for AdipoR1 and AGE. Additionally, AGE, AdipoR1 and Adipo R2 expression was related to tumor grade, whereas GLO-1 and AdipoR1 to T-category. In survival analysis, AdipoR2 and GLO-I overexpression predicted shortened survival in the entire cohort and in early stage cases, an effect which for GLO-I was reproduced in the validation cohort. Moreover, GLO-I emerged as an independent prognosticator of adverse significance in the patients’ cohort. We herein provide novel

  9. Serum Levels of sRAGE Are Associated with Body Measurements, but Not Glycemic Parameters in Patients with Prediabetes.

    Science.gov (United States)

    Guclu, Metin; Ali, Asuman; Eroglu, Derya Ustun; Büyükuysal, Sema Oral; Cander, Soner; Ocak, Nihal

    2016-02-01

    Our aim was to assess serum levels of the soluble receptor for advanced glycation end products (sRAGE) and to examine their association with anthropometric and metabolic parameters in patients with prediabetes and obese controls. The two study groups were composed of 42 patients with prediabetes and diabetic neuropathy and 42 age-, gender-, body weight (BW)-, and body mass index (BMI)-matched obese adults as the control group. Prediabetes was diagnosed by the following criteria issued by the American Diabetes Association: impaired fasting glucose [fasting plasma glucose (FPG) level of 100-125 mg/dL], impaired glucose tolerance (2 hr plasma glucose level of 140-199 mg/dL after a 75 grams oral glucose challenge), or a glycated hemoglobin (HbA1C) level of 5.7%-6.4%. There were no differences between the groups in terms of age, gender distribution, BW, or BMI. Despite these similarities, patients with prediabetes had higher FPG, HbA1c, and 2-hr postchallenge glucose levels, higher systolic and diastolic blood pressure, and larger waist and hip circumferences compared with the obese controls. Lipid measurements, complete blood counts, kidney and liver function tests, high-sensitivity C-reactive protein, and sRAGE levels were similar between the two groups. We found significant negative correlations between sRAGE levels and BW, BMI, waist and hip circumferences, waist-to-hip ratios, and low-density lipoprotein (LDL) cholesterol levels. There were no significant correlations with other parameters, including demographic, metabolic, and blood pressure measurements. In contrast to glycemic parameters, serum levels of sRAGE were negatively correlated with body measurements indicative of obesity in the prediabetic state. In addition, the negative correlation with LDL cholesterol levels suggests that sRAGE has a more robust association with metabolic syndrome than with prediabetes.

  10. HMGB1 induces an inflammatory response in endothelial cells via the RAGE-dependent endoplasmic reticulum stress pathway

    International Nuclear Information System (INIS)

    Luo, Ying; Li, Shu-Jun; Yang, Jian; Qiu, Yuan-Zhen; Chen, Fang-Ping

    2013-01-01

    Highlights: •Mechanisms of inflammatory response induced by HMGB1 are incompletely understood. •We found that endoplasmic reticulum stress mediate the inflammatory response induced by HMGB1. •RAGE-mediated ERS pathways are involved in those processes. •We reported a new mechanism for HMGB1 induced inflammatory response. -- Abstract: The high mobility group 1B protein (HMGB1) mediates chronic inflammatory responses in endothelial cells, which play a critical role in atherosclerosis. However, the underlying mechanism is unknown. The goal of our study was to identify the effects of HMGB1 on the RAGE-induced inflammatory response in endothelial cells and test the possible involvement of the endoplasmic reticulum stress pathway. Our results showed that incubation of endothelial cells with HMGB1 (0.01–1 μg/ml) for 24 h induced a dose-dependent activation of endoplasmic reticulum stress transducers, as assessed by PERK and IRE1 protein expression. Moreover, HMGB1 also promoted nuclear translocation of ATF6. HMGB1-mediated ICAM-1 and P-selectin production was dramatically suppressed by PERK siRNA or IRE1 siRNA. However, non-targeting siRNA had no such effects. HMGB1-induced increases in ICAM-1 and P-selectin expression were also inhibited by a specific eIF2α inhibitor (salubrinal) and a specific JNK inhibitor (SP600125). Importantly, a blocking antibody specifically targeted against RAGE (anti-RAGE antibody) decreased ICAM-1, P-selectin and endoplasmic reticulum stress molecule (PERK, eIF2α, IRE1 and JNK) protein expression levels. Collectively, these novel findings suggest that HMGB1 promotes an inflammatory response by inducing the expression of ICAM-1 and P-selectin via RAGE-mediated stimulation of the endoplasmic reticulum stress pathway

  11. Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation.

    Science.gov (United States)

    Ramasamy, Ravichandran; Vannucci, Susan J; Yan, Shirley Shi Du; Herold, Kevan; Yan, Shi Fang; Schmidt, Ann Marie

    2005-07-01

    The products of nonenzymatic glycation and oxidation of proteins and lipids, the advanced glycation end products (AGEs), accumulate in a wide variety of environments. AGEs may be generated rapidly or over long times stimulated by a range of distinct triggering mechanisms, thereby accounting for their roles in multiple settings and disease states. A critical property of AGEs is their ability to activate receptor for advanced glycation end products (RAGE), a signal transduction receptor of the immunoglobulin superfamily. It is our hypothesis that due to such interaction, AGEs impart a potent impact in tissues, stimulating processes linked to inflammation and its consequences. We hypothesize that AGEs cause perturbation in a diverse group of diseases, such as diabetes, inflammation, neurodegeneration, and aging. Thus, we propose that targeting this pathway may represent a logical step in the prevention/treatment of the sequelae of these disorders.

  12. Robust T1-weighted structural brain imaging and morphometry at 7T using MP2RAGE.

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    Kieran R O'Brien

    Full Text Available PURPOSE: To suppress the noise, by sacrificing some of the signal homogeneity for numerical stability, in uniform T1 weighted (T1w images obtained with the magnetization prepared 2 rapid gradient echoes sequence (MP2RAGE and to compare the clinical utility of these robust T1w images against the uniform T1w images. MATERIALS AND METHODS: 8 healthy subjects (29.0 ± 4.1 years; 6 Male, who provided written consent, underwent two scan sessions within a 24 hour period on a 7T head-only scanner. The uniform and robust T1w image volumes were calculated inline on the scanner. Two experienced radiologists qualitatively rated the images for: general image quality; 7T specific artefacts; and, local structure definition. Voxel-based and volume-based morphometry packages were used to compare the segmentation quality between the uniform and robust images. Statistical differences were evaluated by using a positive sided Wilcoxon rank test. RESULTS: The robust image suppresses background noise inside and outside the skull. The inhomogeneity introduced was ranked as mild. The robust image was significantly ranked higher than the uniform image for both observers (observer 1/2, p-value = 0.0006/0.0004. In particular, an improved delineation of the pituitary gland, cerebellar lobes was observed in the robust versus uniform T1w image. The reproducibility of the segmentation results between repeat scans improved (p-value = 0.0004 from an average volumetric difference across structures of ≈ 6.6% to ≈ 2.4% for the uniform image and robust T1w image respectively. CONCLUSIONS: The robust T1w image enables MP2RAGE to produce, clinically familiar T1w images, in addition to T1 maps, which can be readily used in uniform morphometry packages.

  13. RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose.

    Science.gov (United States)

    Lam, Doris; Momeni, Zeinab; Theaker, Michael; Jagadeeshan, Santosh; Yamamoto, Yasuhiko; Ianowski, Juan P; Campanucci, Verónica A

    2018-01-01

    Diabetes mellitus is associated with sensory abnormalities, including exacerbated responses to painful (hyperalgesia) or non-painful (allodynia) stimuli. These abnormalities are symptoms of diabetic peripheral neuropathy (DPN), which is the most common complication that affects approximately 50% of diabetic patients. Yet, the underlying mechanisms linking hyperglycemia and symptoms of DPN remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in such sensory abnormalities and shows elevated expression levels in animal models of diabetes. Here, we investigated the function of TRPV1 channels in sensory neurons cultured from the dorsal root ganglion (DRG) of neonatal mice, under control (5mM) and high glucose (25mM) conditions. After maintaining DRG neurons in high glucose for 1 week, we observed a significant increase in capsaicin (CAP)-evoked currents and CAP-evoked depolarizations, independent of TRPV1 channel expression. These functional changes were largely dependent on the expression of the receptor for Advanced Glycation End-products (RAGE), calcium influx, cytoplasmic ROS accumulation, PKC, and Src kinase activity. Like cultured neurons from neonates, mature neurons from adult mice also displayed a similar potentiation of CAP-evoked currents in the high glucose condition. Taken together, our data demonstrate that under the diabetic condition, DRG neurons are directly affected by elevated levels of glucose, independent of vascular or glial signals, and dependent on RAGE expression. These early cellular and molecular changes to sensory neurons in vitro are potential mechanisms that might contribute to sensory abnormalities that can occur in the very early stages of diabetes.

  14. Systemic levels of the anti-inflammatory decoy receptor soluble RAGE (receptor for advanced glycation end products) are decreased in dogs with inflammatory bowel disease.

    Science.gov (United States)

    Heilmann, Romy M; Otoni, Cristiane C; Jergens, Albert E; Grützner, Niels; Suchodolski, Jan S; Steiner, Jörg M

    2014-10-15

    Inflammatory bowel disease (IBD) is a common condition in dogs, and a dysregulated innate immunity is believed to play a major role in its pathogenesis. S100A12 is an endogenous damage-associated molecular pattern molecule, which is involved in phagocyte activation and is increased in serum/fecal samples from dogs with IBD. S100A12 binds to the receptor of advanced glycation end products (RAGE), a pattern-recognition receptor, and results of studies in human patients with IBD and other conditions suggest a role of RAGE in chronic inflammation. Soluble RAGE (sRAGE), a decoy receptor for inflammatory proteins (e.g., S100A12) that appears to function as an anti-inflammatory molecule, was shown to be decreased in human IBD patients. This study aimed to evaluate serum sRAGE and serum/fecal S100A12 concentrations in dogs with IBD. Serum and fecal samples were collected from 20 dogs with IBD before and after initiation of medical treatment and from 15 healthy control dogs. Serum sRAGE and serum and fecal S100A12 concentrations were measured by ELISA, and were compared between dogs with IBD and healthy controls, and between dogs with a positive outcome (i.e., clinical remission, n=13) and those that were euthanized (n=6). The relationship of serum sRAGE concentrations with clinical disease activity (using the CIBDAI scoring system), serum and fecal S100A12 concentrations, and histologic disease severity (using a 4-point semi-quantitative grading system) was tested. Serum sRAGE concentrations were significantly lower in dogs with IBD than in healthy controls (p=0.0003), but were not correlated with the severity of histologic lesions (p=0.4241), the CIBDAI score before (p=0.0967) or after treatment (p=0.1067), the serum S100A12 concentration before (p=0.9214) and after treatment (p=0.4411), or with the individual outcome (p=0.4066). Clinical remission and the change in serum sRAGE concentration after treatment were not significantly associated (p=0.5727); however, serum sRAGE

  15. Implication of advanced glycation end products (Ages) and their receptor (Rage) on myocardial contractile and mitochondrial functions.

    Science.gov (United States)

    Neviere, Remi; Yu, Yichi; Wang, Lei; Tessier, Frederic; Boulanger, Eric

    2016-08-01

    Advanced glycation end products (AGEs) play an important role for the development and/or progression of cardiovascular diseases, mainly through induction of oxidative stress and inflammation. AGEs are a heterogeneous group of molecules formed by non-enzymatic reaction of reducing sugars with amino acids of proteins, lipids and nucleic acids. AGEs are mainly formed endogenously, while recent studies suggest that diet constitutes an important exogenous source of AGEs. The presence and accumulation of AGEs in various cardiac cell types affect extracellular and intracellular structure and function. AGEs contribute to a variety of microvascular and macrovascular complications through the formation of cross-links between molecules in the basement membrane of the extracellular matrix and by engaging the receptor for advanced glycation end products (RAGE). Activation of RAGE by AGEs causes up regulation of the transcription factor nuclear factor-κB and its target genes. of the RAGE engagement stimulates oxidative stress, evokes inflammatory and fibrotic reactions, which all contribute to the development and progression of devastating cardiovascular disorders. This review discusses potential targets of glycation in cardiac cells, and underlying mechanisms that lead to heart failure with special interest on AGE-induced mitochondrial dysfunction in the myocardium.

  16. In-Situ Visualization Experiments with ParaView Cinema in RAGE

    Energy Technology Data Exchange (ETDEWEB)

    Kares, Robert John [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2015-10-15

    A previous paper described some numerical experiments performed using the ParaView/Catalyst in-situ visualization infrastructure deployed in the Los Alamos RAGE radiation-hydrodynamics code to produce images from a running large scale 3D ICF simulation. One challenge of the in-situ approach apparent in these experiments was the difficulty of choosing parameters likes isosurface values for the visualizations to be produced from the running simulation without the benefit of prior knowledge of the simulation results and the resultant cost of recomputing in-situ generated images when parameters are chosen suboptimally. A proposed method of addressing this difficulty is to simply render multiple images at runtime with a range of possible parameter values to produce a large database of images and to provide the user with a tool for managing the resulting database of imagery. Recently, ParaView/Catalyst has been extended to include such a capability via the so-called Cinema framework. Here I describe some initial experiments with the first delivery of Cinema and make some recommendations for future extensions of Cinema’s capabilities.

  17. Verification test of the SURF and SURFplus models in xRage

    Energy Technology Data Exchange (ETDEWEB)

    Menikoff, Ralph [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2016-05-18

    As a verification test of the SURF and SURFplus models in the xRage code we use a propagating underdriven detonation wave in 1-D. This is about the only test cases for which an accurate solution can be determined based on the theoretical structure of the solution. The solution consists of a steady ZND reaction zone profile joined with a scale invariant rarefaction or Taylor wave and followed by a constant state. The end of the reaction profile and the head of the rarefaction coincide with the sonic CJ state of the detonation wave. The constant state is required to match a rigid wall boundary condition. For a test case, we use PBX 9502 with the same EOS and burn rate as previously used to test the shock detector algorithm utilized by the SURF model. The detonation wave is propagated for 10 μs (slightly under 80mm). As expected, the pointwise errors are largest in the neighborhood of discontinuities; pressure discontinuity at the lead shock front and pressure derivative discontinuities at the head and tail of the rarefaction. As a quantitative measure of the overall accuracy, the L2 norm of the difference of the numerical pressure and the exact solution is used. Results are presented for simulations using both a uniform grid and an adaptive grid that refines the reaction zone.

  18. Association of the receptor for advanced glycation end-products (RAGE gene polymorphisms in Malaysian patients with chronic kidney disease

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    Foo Nian Wong

    2016-04-01

    Full Text Available Background: Chronic kidney disease (CKD is a condition associated with progressive loss of kidney function and kidney damage. The two common causes of CKD are diabetes mellitus and hypertension. Other causes of CKD also include polycystic kidney disease, obstructive uropathy and primary glomerulonephritis. The receptor for advanced glycation end-products (RAGE is a multi-ligand cell surface receptor of the immunoglobulin superfamily and it has been associated with kidney disease in both non-diabetic and diabetic patients. Presently, data on the association between RAGE polymorphisms and CKD in the Malaysian population is limited, while numerous studies have reported associations of RAGE polymorphisms with diabetic complications in other populations. The present study aims to explore the possibility of using RAGE polymorphisms as candidate markers of CKD in Malaysian population by using association analysis. Methods: A total of 102 non-diabetic CKD patients, 204 diabetic CKD patients and 345 healthy controls were enrolled in the study. DNA isolated from blood samples were subjected to genotyping of RAGE G82S, −374T/A, −429T/C, 1704G/T and 2184A/G polymorphisms using real-time polymerase chain reaction (PCR. The 63-bp deletion, a polymorphism in the RAGE gene promoter, was genotyped using conventional PCR method and visualized using agarose gel electrophoresis. The collective frequencies of genotypes with at least one copy of the minor alleles of the four polymorphisms were compared between the non-diabetic CKD patients, diabetic CKD patients and healthy controls. Results: After adjustment of age, gender and ethnic groups in binary logistic regression analysis, the G82S CT + TT genotypes were associated with non-diabetic CKD patients when compared with diabetic CKD patients (p = 0.015, OR = 1.896, 95% CI = 1.132–3.176. After further adjustment of CKD comorbidities, the G82S CT + TT genotypes were still associated with non-diabetic CKD

  19. The proinflammatory RAGE/NF-κB pathway is involved in neuronal damage and reactive gliosis in a model of sleep apnea by intermittent hypoxia.

    Science.gov (United States)

    Angelo, Maria Florencia; Aguirre, Alejandra; Avilés Reyes, Rolando X; Villarreal, Alejandro; Lukin, Jerónimo; Melendez, Matías; Vanasco, Virginia; Barker, Phil; Alvarez, Silvia; Epstein, Alberto; Jerusalinsky, Diana; Ramos, Alberto Javier

    2014-01-01

    Sleep apnea (SA) causes long-lasting changes in neuronal circuitry, which persist even in patients successfully treated for the acute effects of the disease. Evidence obtained from the intermittent hypoxia (IH) experimental model of SA has shown neuronal death, impairment in learning and memory and reactive gliosis that may account for cognitive and structural alterations observed in human patients. However, little is known about the mechanism controlling these deleterious effects that may be useful as therapeutic targets in SA. The Receptor for Advanced Glycation End products (RAGE) and its downstream effector Nuclear Factor Kappa B (NF-κB) have been related to neuronal death and astroglial conversion to the pro-inflammatory neurodegenerative phenotype. RAGE expression and its ligand S100B were shown to be increased in experimental models of SA. We here used dissociated mixed hippocampal cell cultures and male Wistar rats exposed to IH cycles and observed that NF-κB is activated in glial cells and neurons after IH. To disclose the relative contribution of the S100B/RAGE/NF-κB pathway to neuronal damage and reactive gliosis after IH we performed sequential loss of function studies using RAGE or S100B neutralizing antibodies, a herpes simplex virus (HSV)-derived amplicon vector that induces the expression of RAGEΔcyto (dominant negative RAGE) and a chemical blocker of NF-κB. Our results show that NF-κB activation peaks 3 days after IH exposure, and that RAGE or NF-κB blockage during this critical period significantly improves neuronal survival and reduces reactive gliosis. Both in vitro and in vivo, S100B blockage altered reactive gliosis but did not have significant effects on neuronal survival. We conclude that both RAGE and downstream NF-κB signaling are centrally involved in the neuronal alterations found in SA models, and that blockage of these pathways is a tempting strategy for preventing neuronal degeneration and reactive gliosis in SA.

  20. Role of IL-1 beta and 5-HT2 receptors in midbrain periaqueductal gray (PAG) in potentiating defensive rage behavior in cat.

    Science.gov (United States)

    Bhatt, Suresh; Bhatt, Rekha; Zalcman, Steven S; Siegel, Allan

    2008-02-01

    Feline defensive rage, a form of aggressive behavior that occurs in response to a threat can be elicited by electrical stimulation of the medial hypothalamus or midbrain periaqueductal gray (PAG). Our laboratory has recently begun a systematic examination of the role of cytokines in the regulation of rage and aggressive behavior. It was shown that the cytokine, interleukin-2 (IL-2), differentially modulates defensive rage when microinjected into the medial hypothalamus and PAG by acting through separate neurotransmitter systems. The present study sought to determine whether a similar relationship exists with respect to interleukin 1-beta (IL-1 beta), whose receptor activation in the medial hypothalamus potentiates defensive rage. Thus, the present study identified the effects of administration of IL-1 beta into the PAG upon defensive rage elicited from the medial hypothalamus. Microinjections of IL-1 beta into the dorsal PAG significantly facilitated defensive rage behavior elicited from the medial hypothalamus in a dose and time dependent manner. In addition, the facilitative effects of IL-1 beta were blocked by pre-treatment with anti-IL-1 beta receptor antibody, while IL-1 beta administration into the PAG had no effect upon predatory attack elicited from the lateral hypothalamus. The findings further demonstrated that IL-1 beta's effects were mediated through 5-HT(2) receptors since pretreatment with a 5-HT(2C) receptors antagonist blocked the facilitating effects of IL-1 beta. An extensive pattern of labeling of IL-1 beta and 5-HT(2C) receptors in the dorsal PAG supported these findings. The present study demonstrates that IL-beta in the dorsal PAG, similar to the medial hypothalamus, potentiates defensive rage behavior and is mediated through a 5-HT(2C) receptor mechanism.

  1. Microalbuminuria and sRAGE in High-Risk Hypertensive Patients Treated with Nifedipine/Telmisartan Combination Treatment: A Substudy of TALENT

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    Colomba Falcone

    2012-01-01

    Full Text Available Some antihypertensive drugs have also renoprotective and anti-inflammatory properties that go beyond their effect on blood pressure. It has been suggested that microalbuminuria and glomerular filtration rate (GFR are associated with circulating levels of the soluble form of the receptor, sRAGE (soluble receptor for advanced glycation ends-products. In the present analysis, we used data from the TALENT study to evaluate soluble receptor for advanced glycation end-products (sRAGE plasma levels in patients with hypertension and high-cardiovascular risk-treated nifedipine and telmisartan in combination. Treatment with nifedipine-telmisartan significantly decreased mean systolic and diastolic ambulatory blood pressure and resulted in a significant increase in sRAGE plasma concentrations after 24 weeks of therapy. We concluded that in hypertensive patients with early-stage renal disease, sRAGE concentrations are not influenced by either microalbuminuria or GFR. Long-term treatment with a combination of nifedipine-telmisartan may have a beneficial effect increasing sRAGE plasma levels, thus exerting an atheroprotective and anti-inflammatory activity.

  2. Effects of RAGE-Specific Inhibitor FPS-ZM1 on Amyloid-β Metabolism and AGEs-Induced Inflammation and Oxidative Stress in Rat Hippocampus.

    Science.gov (United States)

    Hong, Yan; Shen, Chao; Yin, Qingqing; Sun, Menghan; Ma, Yingjuan; Liu, Xueping

    2016-05-01

    An increased level of advanced glycation end products (AGEs) is observed in brains of patients with Alzheimer's disease (AD). AGEs and receptor for AGEs (RAGE) play important roles in the pathogenesis of AD. FPS-ZM1 is a high-affinity RAGE-specific blocker that inhibits amyloid-β binding to RAGE, neurological damage and inflammation in the APP(sw/0) transgenic mouse model of AD. FPS-ZM1 is not toxic to mice and can easily cross the blood-brain barrier. In this study, an AGEs-RAGE-activated rat model were established by intrahippocampal injection of AGEs, then these rats were treated with intraperitoneal administration of FPS-ZM1 and the possible neuroprotective effects were investigated. We found that AGEs administration induced an-regulation of Abeta production, inflammation, and oxidative stress, and an increased escape latency of rats in the Morris water maze test, all of these are significantly reduced by FPS-ZM1 treatment. Our results suggest that the AGEs-RAGE pathway is responsible for cognitive deficits, and therefore may be a potential treatment target. FPS-ZM1 might be a novel therapeutic agent to treat AD patients.

  3. Manejo da irrigação na cultura do crisântemo em vaso, cultivar rage, cultivado em ambiente protegido Irrigation schedule in pot chrysanthemum, cultivar rage, grown in greenhouse

    Directory of Open Access Journals (Sweden)

    Maryzélia F. de Farias

    2004-04-01

    Full Text Available Dentre as dificuldades que os produtores têm encontrado ao adotarem o cultivo em ambiente protegido, destaca-se a falta de dados específicos sobre o uso racional da água e o desconhecimento da quantidade e do momento de irrigar. Esta pesquisa foi desenvolvida na propriedade de um produtor, no Distrito de Holambra II, região de Paranapanema - SP, em cultivos rotineiramente desenvolvidos pelo produtor, buscando melhor representatividade dos dados obtidos. O objetivo principal deste experimento foi identificar a tensão de água no solo que pudesse resultar em melhor qualidade comercial da cultivar de crisântemo "Rage", cultivado em vaso e mantido em ambiente protegido. O delineamento experimental foi o inteiramente casualizado, com duas repetições. Os tratamentos foram definidos por seis níveis de tensão de água: -2; -3; -4; -6; -10 e -30 kPa. Para cada tensão, foram calculadas a altura correspondente na coluna de mercúrio do tensiômetro, as lâminas e o tempo de irrigação. Os resultados obtidos demonstraram que a cultivar Rage obteve a maior porcentagem de vasos de alta qualidade (A1 no tratamento irrigado com a tensão de -4 kPa. O tratamento irrigado, quando atingia -30 kPa, resultou na menor porcentagem de vasos A1.The most important difficulty that the producers have been found to adopt the cultivation in plastic greenhouses is the lack of specific data on the rational use of the water and informations about when and how much water apply. This research was developed in a farm in Paranapanema - SP, Brazil, with tradition in pot chrysanthemum grow. The main objective was to identify the soil water tension that could result in better commercial quality of chrysanthemum Rage, cultivated in pot and maintained in greenhouse. The treatments were defined for six levels of substrate water tension: -2; -3; -4; -6; -10 and -30 kPa. The irrigation time was defined for each tension and also the equivalent height int the mercury column of

  4. Edaravone Protected Human Brain Microvascular Endothelial Cells from Methylglyoxal-Induced Injury by Inhibiting AGEs/RAGE/Oxidative Stress

    Science.gov (United States)

    Li, Wenlu; Xu, Hongjiao; Hu, Yangmin; He, Ping; Ni, Zhenzhen; Xu, Huimin; Zhang, Zhongmiao; Dai, Haibin

    2013-01-01

    Subjects with diabetes experience an increased risk of cerebrovascular disease and stroke compared with nondiabetic age-matched individuals. Increased formation of reactive physiological dicarbonyl compound methylglyoxal (MGO) seems to be implicated in the development of diabetic vascular complication due to its protein glycation and oxidative stress effect. Edaravone, a novel radical scavenger, has been reported to display the advantageous effects on ischemic stroke both in animals and clinical trials; however, little is known about whether edaravone has protective effects on diabetic cerebrovascular injury. Using cultured human brain microvascular endothelial cells (HBMEC), protective effects of edaravone on MGO and MGO enhancing oxygen-glucose deprivation (OGD) induced injury were investigated. Cell injury was measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) formation, cell account, lactate dehydrogenase (LDH) release and Rhodamine 123 staining. Advanced glycation end-products (AGEs) formation and receptor for advanced glycation end-products (RAGE) expression were measured by western blotting. Cellular oxidative stress was measured by reactive oxygen species (ROS) release. Treatment of MGO for 24 h significantly induced HBMEC injury, which was inhibited by pretreatment of edaravone from 10–100 µmol/l. What’s more, treatment of MGO enhanced AGEs accumulation, RAGE expression and ROS release in the cultured HBMEC, which were inhibited by 100 µmol/l edaravone. Finally, treatment of MGO for 24 h and then followed by 3 h OGD insult significantly enhanced cell injury when compared with OGD insult only, which was also protected by 100 µmol/l edaravone. Thus, edaravone protected HBMEC from MGO and MGO enhancing OGD-induced injury by inhibiting AGEs/RAGE/oxidative stress. PMID:24098758

  5. Edaravone protected human brain microvascular endothelial cells from methylglyoxal-induced injury by inhibiting AGEs/RAGE/oxidative stress.

    Directory of Open Access Journals (Sweden)

    Wenlu Li

    Full Text Available Subjects with diabetes experience an increased risk of cerebrovascular disease and stroke compared with nondiabetic age-matched individuals. Increased formation of reactive physiological dicarbonyl compound methylglyoxal (MGO seems to be implicated in the development of diabetic vascular complication due to its protein glycation and oxidative stress effect. Edaravone, a novel radical scavenger, has been reported to display the advantageous effects on ischemic stroke both in animals and clinical trials; however, little is known about whether edaravone has protective effects on diabetic cerebrovascular injury. Using cultured human brain microvascular endothelial cells (HBMEC, protective effects of edaravone on MGO and MGO enhancing oxygen-glucose deprivation (OGD induced injury were investigated. Cell injury was measured by 3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT formation, cell account, lactate dehydrogenase (LDH release and Rhodamine 123 staining. Advanced glycation end-products (AGEs formation and receptor for advanced glycation end-products (RAGE expression were measured by western blotting. Cellular oxidative stress was measured by reactive oxygen species (ROS release. Treatment of MGO for 24 h significantly induced HBMEC injury, which was inhibited by pretreatment of edaravone from 10-100 µmol/l. What's more, treatment of MGO enhanced AGEs accumulation, RAGE expression and ROS release in the cultured HBMEC, which were inhibited by 100 µmol/l edaravone. Finally, treatment of MGO for 24 h and then followed by 3 h OGD insult significantly enhanced cell injury when compared with OGD insult only, which was also protected by 100 µmol/l edaravone. Thus, edaravone protected HBMEC from MGO and MGO enhancing OGD-induced injury by inhibiting AGEs/RAGE/oxidative stress.

  6. Whole brain MP2RAGE-based mapping of the longitudinal relaxation time at 9.4T.

    Science.gov (United States)

    Hagberg, G E; Bause, J; Ethofer, T; Ehses, P; Dresler, T; Herbert, C; Pohmann, R; Shajan, G; Fallgatter, A; Pavlova, M A; Scheffler, K

    2017-01-01

    Mapping of the longitudinal relaxation time (T 1 ) with high accuracy and precision is central for neuroscientific and clinical research, since it opens up the possibility to obtain accurate brain tissue segmentation and gain myelin-related information. An ideal, quantitative method should enable whole brain coverage within a limited scan time yet allow for detailed sampling with sub-millimeter voxel sizes. The use of ultra-high magnetic fields is well suited for this purpose, however the inhomogeneous transmit field potentially hampers its use. In the present work, we conducted whole brain T 1 mapping based on the MP2RAGE sequence at 9.4T and explored potential pitfalls for automated tissue classification compared with 3T. Data accuracy and T 2 -dependent variation of the adiabatic inversion efficiency were investigated by single slice T 1 mapping with inversion recovery EPI measurements, quantitative T 2 mapping using multi-echo techniques and simulations of the Bloch equations. We found that the prominent spatial variation of the transmit field at 9.4T (yielding flip angles between 20% and 180% of nominal values) profoundly affected the result of image segmentation and T 1 mapping. These effects could be mitigated by correcting for both flip angle and inversion efficiency deviations. Based on the corrected T 1 maps, new, 'flattened', MP2RAGE contrast images were generated, that were no longer affected by variations of the transmit field. Unlike the uncorrected MP2RAGE contrast images acquired at 9.4T, these flattened images yielded image segmentations comparable to 3T, making bias-field correction prior to image segmentation and tissue classification unnecessary. In terms of the T 1 estimates at high field, the proposed correction methods resulted in an improved precision, with test-retest variability below 1% and a coefficient-of-variation across 25 subjects below 3%. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. HMGB1-RAGE pathway drives peroxynitrite signaling-induced IBD-like inflammation in murine nonalcoholic fatty liver disease

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    Varun Chandrashekaran

    2017-10-01

    Full Text Available Recent clinical studies found a strong association of colonic inflammation and Inflammatory bowel disease (IBD-like phenotype with NonAlcoholic Fatty liver Disease (NAFLD yet the mechanisms remain unknown. The present study identifies high mobility group box 1 (HMGB1 as a key mediator of intestinal inflammation in NAFLD and outlines a detailed redox signaling mechanism for such a pathway. NAFLD mice showed liver damage and release of elevated HMGB1 in systemic circulation and increased intestinal tyrosine nitration that was dependent on NADPH oxidase. Intestines from NAFLD mice showed higher Toll like receptor 4 (TLR4 activation and proinflammatory cytokine release, an outcome strongly dependent on the existence of NAFLD pathology and NADPH oxidase. Mechanistically intestinal epithelial cells showed the HMGB1 activation of TLR-4 was both NADPH oxidase and peroxynitrite dependent with the latter being formed by the activation of NADPH oxidase. Proinflammatory cytokine production was significantly blocked by the specific peroxynitrite scavenger phenyl boronic acid (FBA, AKT inhibition and NADPH oxidase inhibitor Apocynin suggesting NADPH oxidase-dependent peroxynitrite is a key mediator in TLR-4 activation and cytokine release via an AKT dependent pathway. Studies to ascertain the mechanism of HMGB1-mediated NADPH oxidase activation showed a distinct role of Receptor for advanced glycation end products (RAGE as the use of inhibitors targeted against RAGE or use of deformed HMGB1 protein prevented NADPH oxidase activation, peroxynitrite formation, TLR4 activation and finally cytokine release. Thus, in conclusion the present study identifies a novel role of HMGB1 mediated inflammatory pathway that is RAGE and redox signaling dependent and helps promote ectopic intestinal inflammation in NAFLD.

  8. EARLY AFFECT-CONFUSION: THE BORDERLINE BETWEEN DESPAIR AND RAGE - PART 1 OF A CASE STUDY TRILOGY

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    Richard G. Erskine

    2012-12-01

    Full Text Available This three part case study illustrates the principles, theoretical concepts, and relational methods of Integrative Psychotherapy in the treatment of a client who continually experienced early affect-confusion and lived on a “borderline” between intense neediness and rage, despair and self-reliance, impulsivity and manipulation. Part 1 describes the behavioral dynamics of a 38 year old female client who required a two-part treatment approach that emphasized an inter-subjective relationship, consistency, and respect while helping her to acknowledge and value her relational-needs and to engage in a relationally contactful form of anger.

  9. Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection by N-Acetyl-L-Cysteine

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    Chun-tao Yang

    2017-02-01

    Full Text Available Background/Aim: Accumulation of advanced glycation end products (AGEs is a major cause of diabetes mellitus (DM skin complications. Methylglyoxal (MGO, a reactive dicarbonyl compound, is a crucial intermediate of AGEs generation. N-acetyl-L-cysteine (NAC, an active ingredient of some medicines, can induce endogenous GSH and hydrogen sulfide generation, and set off a condensation reaction with MGO. However, there is rare evidence to show NAC can alleviate DM-induced skin injury through inhibition of AGEs generation or toxicity. The present study aimed to observe the effects of NAC on MGO-induced inflammatory injury and investigate the roles of AGEs and its receptor (RAGE in NAC’s dermal protection in human HaCaT keratinocytes. Methods: The cells were exposed to MGO to simulate a high MGO status in diabetic blood or tissues. The content of AGEs in serum or cell medium was measured with ELISA. The protective effects of NAC against MGO-induce injury were evaluated by administration before MGO one hour, in virtue of cell viability, mitochondrial membrane potential, inflammation reaction, nuclear factor (NF-κB activation, matrix metalloproteinase (MMP-9 expression, as well as cellular behavioral function. Results: We found the AGEs levels of patients with DM were elevated comparing with healthy volunteers. The in vitro AGEs generation was also able to be enhanced by the exposure of HaCaT cells to MGO, which reduced dose-dependently cellular viability, damaged mitochondrial function, triggered secretion of interleukin (IL-6 and IL-8, activated NF-κB and upregulated MMP-9 expression. Furthermore, the exposure caused cellular adhesion and migration dysfunction, as well as collagen type I inhibition. Importantly, before the exposure to MGO, the preconditioning with NAC significantly attenuated MGO-induced AGEs generation, improved cellular viability and mitochondrial function, partially reversed the overexpression of proinflammatory factors and MMP-9

  10. The association of low muscle mass with soluble receptor for advanced glycation end products (sRAGE): The Korean Sarcopenic Obesity Study (KSOS).

    Science.gov (United States)

    Kim, Tae Nyun; Park, Man Sik; Lee, Eun Joo; Chung, Hye Soo; Yoo, Hye Jin; Kang, Hyun Joo; Song, Wook; Baik, Sei Hyun; Choi, Kyung Mook

    2018-03-01

    Advanced glycation end products (AGEs) are accumulated with aging in various tissues of humans. The soluble receptor for AGEs (sRAGE) exerts a protective role against the development of aging-related chronic disorders by neutralizing the action of AGEs. We investigated the implication of sRAGE on low muscle mass in Asian men and women. This cross-sectional study included a 390-participant, nondiabetic subcohort recruited within the framework of the Korean Sarcopenic Obesity Study, an ongoing prospective cohort study. Low muscle mass was defined based on the distribution of appendicular skeletal muscle mass divided by body mass index, as proposed by the Foundation for the National Institutes Sarcopenia Project. Serum sRAGE levels were significantly lower in participants with low muscle mass than in participants without low muscle mass (0.76 [0.60-1.00] ng/mL vs 0.87 [0.67-1.15] ng/mL, P = .005). In age- and sex-adjusted correlation analyses, appendicular skeletal muscle mass divided by body mass index was associated with sRAGE (r = 0.109, P = .037). Furthermore, decreased circulating levels of sRAGE are independently associated with low muscle mass (odds ratio = 0.254, P = .002) after adjusting for confounding factors, including insulin resistance and inflammatory markers. The present study shows that a low circulating level of sRAGE may be an independent risk factor for the presence of low muscle mass. Copyright © 2017 John Wiley & Sons, Ltd.

  11. Nifedipine inhibits advanced glycation end products (AGEs) and their receptor (RAGE) interaction-mediated proximal tubular cell injury via peroxisome proliferator-activated receptor-gamma activation

    International Nuclear Information System (INIS)

    Matsui, Takanori; Yamagishi, Sho-ichi; Takeuchi, Masayoshi; Ueda, Seiji; Fukami, Kei; Okuda, Seiya

    2010-01-01

    Research highlights: → Nifedipine inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ. → GW9662 treatment alone increased RAGE mRNA levels in tubular cells. → Nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-κB activation and increases in intercellular adhesion molecule-1 and transforming growth factor-β gene expression in tubular cells, all of which were blocked by GW9662. -- Abstract: There is a growing body of evidence that advanced glycation end products (AGEs) and their receptor (RAGE) interaction evokes oxidative stress generation and subsequently elicits inflammatory and fibrogenic reactions, thereby contributing to the development and progression of diabetic nephropathy. We have previously found that nifedipine, a calcium-channel blocker (CCB), inhibits the AGE-induced mesangial cell damage in vitro. However, effects of nifedipine on proximal tubular cell injury remain unknown. We examined here whether and how nifedipine blocked the AGE-induced tubular cell damage. Nifedipine, but not amlodipine, a control CCB, inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ (PPARγ). GW9662 treatment alone was found to increase RAGE mRNA levels in tubular cells. Further, nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-κB activation and increases in intercellular adhesion molecule-1 and transforming growth factor-beta gene expression in tubular cells, all of which were blocked by GW9662. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-oxidative and anti-inflammatory agent against AGEs in tubular cells by suppressing RAGE expression via PPARγ activation.

  12. Reduced soluble receptor for advanced glycation end-products (sRAGE) scavenger capacity precedes pre-eclampsia in Type 1 diabetes

    Science.gov (United States)

    Yu, Y; Hanssen, KF; Kalyanaraman, V; Chirindel, A; Jenkins, AJ; Nankervis, AJ; Torjesen, PA; Scholz, H; Henriksen, T; Lorentzen, B; Garg, SK; Menard, MK; Hammad, SM; Scardo, JA; Stanley, JR; Wu, M; Basu, A; Aston, CE; Lyons, TJ

    2014-01-01

    Objective Increased advanced glycation end-products (AGEs) and their soluble receptors (sRAGE) have been implicated in the pathogenesis of pre-eclampsia (PE). However, this association has not been elucidated in pregnancies complicated by diabetes. We aimed to investigate the serum levels of these factors in pregnant women with Type 1 diabetes mellitus (T1DM), a condition associated with a four-fold increase in PE. Design Prospective study in women with T1DM at 12.2 ± 1.9, 21.6 ± 1.5 and 31.5 ± 1.7 weeks of gestation [mean ± standard deviation (SD); no overlap] before PE onset. Setting Antenatal clinics. Population Pregnant women with T1DM (n = 118; 26 developed PE) and healthy nondiabetic pregnant controls (n = 21). Methods Maternal serum levels of sRAGE (total circulating pool), Nε-(carboxymethyl)lysine (CML), hydroimidazolone (methylglyoxal-modified proteins) and total AGEs were measured by immunoassays. Main outcome measures Serum sRAGE and AGEs in pregnant women with T1DM who subsequently developed PE (DM PE+) versus those who remained normotensive (DM PE–). Results In DM PE+ versus DM PE–, sRAGE was significantly lower in the first and second trimesters, prior to the clinical manifestation of PE (P diabetes, parity and mean arterial pressure as covariates. Conclusions In the early stages of pregnancy, lower circulating sRAGE levels, and the ratio of sRAGE to AGEs, may be associated with the subsequent development of PE in women with T1DM. PMID:22900949

  13. Nifedipine inhibits advanced glycation end products (AGEs) and their receptor (RAGE) interaction-mediated proximal tubular cell injury via peroxisome proliferator-activated receptor-gamma activation

    Energy Technology Data Exchange (ETDEWEB)

    Matsui, Takanori [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume (Japan); Yamagishi, Sho-ichi, E-mail: shoichi@med.kurume-u.ac.jp [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume (Japan); Takeuchi, Masayoshi [Department of Pathophysiological Science, Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa (Japan); Ueda, Seiji; Fukami, Kei; Okuda, Seiya [Department of Medicine, Kurume University School of Medicine, Kurume (Japan)

    2010-07-23

    Research highlights: {yields} Nifedipine inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma}. {yields} GW9662 treatment alone increased RAGE mRNA levels in tubular cells. {yields} Nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-{kappa}B activation and increases in intercellular adhesion molecule-1 and transforming growth factor-{beta} gene expression in tubular cells, all of which were blocked by GW9662. -- Abstract: There is a growing body of evidence that advanced glycation end products (AGEs) and their receptor (RAGE) interaction evokes oxidative stress generation and subsequently elicits inflammatory and fibrogenic reactions, thereby contributing to the development and progression of diabetic nephropathy. We have previously found that nifedipine, a calcium-channel blocker (CCB), inhibits the AGE-induced mesangial cell damage in vitro. However, effects of nifedipine on proximal tubular cell injury remain unknown. We examined here whether and how nifedipine blocked the AGE-induced tubular cell damage. Nifedipine, but not amlodipine, a control CCB, inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}). GW9662 treatment alone was found to increase RAGE mRNA levels in tubular cells. Further, nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-{kappa}B activation and increases in intercellular adhesion molecule-1 and transforming growth factor-beta gene expression in tubular cells, all of which were blocked by GW9662. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-oxidative and anti-inflammatory agent against AGEs in tubular cells by suppressing RAGE expression

  14. Association between the RAGE (receptor for advanced glycation end-products -374T/A gene polymorphism and diabetic retinopathy in T2DM

    Directory of Open Access Journals (Sweden)

    Dan Tao

    Full Text Available Summary Objective: Interaction between advanced glycation end-products (AGEs and receptor for AGEs (RAGE in cells could affect both extracellular and intracellular structure and function, which plays a pivotal role in diabetic microvascular complications. The results from previous epidemiological studies on the association between RAGE gene -374T/A polymorphism and diabetic retinopathy (DR risk were inconsistent. Thus, we conducted this meta-analysis to summarize the possible association between RAGE -374T/A polymorphism and DR risk. Method: We searched all relevant articles on the association between RAGE -374T/A polymorphism and DR risk from PubMed, Cochrane Library, ScienceDirect, Wanfang, VIP and Chinese National Knowledge Infrastructure (CNKI web databases up to August 2016. Odds ratio (OR with 95% confidence interval (CI were calculated to assess those associations. All analyses were performed using the Review Manager software. Results: Nine case-control studies, including 1,705 DR cases and 2,236 controls were enrolled, and the results showed that the A allele of RAGE -374T/A polymorphism was significantly associated with increased DR risk in dominant model (TA/AA vs. TT: OR=1.22, 95CI 1.05-1.41, p=0.006 and heterozygote model (TA vs. TT: OR=1.26, 95CI 1.07-1.47, p=0.005. The subgroup analysis by ethnicity showed that significantly increased DR risk was found in both Asian and Caucasian populations. Conclusion: This meta-analysis reveals that the A allele of RAGE -374T/A polymorphism probably increase DR risk.

  15. Higher plasma soluble Receptor for Advanced Glycation End Products (sRAGE) levels are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes

    DEFF Research Database (Denmark)

    Nin, Johanna W M; Jorsal, Anders; Ferreira, Isabel

    2010-01-01

    To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunct......To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal...

  16. Diffusion-weighted imaging of the rat pelvis using 3D water-excitation MP-RAGE MR sequence

    International Nuclear Information System (INIS)

    Numano, Tomokazu; Homma, Kazuhiro; Hyodo, Koji; Nitta, Naotaka; Iwasaki, Nobuaki

    2008-01-01

    We developed a novel technique for fat-saturated, 3-dimensional (3D) diffusion-weighted (DW) magnetic resonance (MR) imaging sequencing based upon the 3D magnetization-prepared, rapid gradient-echo (3D-MP-RAGE) method. We saturated fat using 2 techniques, chemical shift selective (CHESS; FatSat)-3D-DWI sequence versus water excitation (WE)-3D-DWI method, then compared the 2 sequences in terms of degree of fat suppression. In preparing the FatSat-3D-DWI sequence, we used a ''CHESS-90deg radiofrequency (RF)-motion probing gradient (MPG)-180deg RFMPG-90deg RF'' pulse-train, to sensitize the magnetization to fat-saturated diffusion. In contrast, in the WE-3D-DWI sequence, we selected a RAGE-excitation pulse with a binominal-pulse 1-1 or 1-2-1 for water-excited (fat-saturated) diffusion imaging. Experimental results in a phantom confirmed the effects of diffusion weighting and of fat saturation. Fat saturation was much better in the WE-3D-DWI sequence than the CHESS-3D-DWI sequence. From results from animal (rat pelvis) experiments using WE-3D-DWI, we obtained fat-saturated DWI. This sequence was useful for in vivo imaging. (author)

  17. Water temperature profiles for reaches of the Raging River during summer baseflow, King County, western Washington, July 2015

    Science.gov (United States)

    Gendaszek, Andrew S.; Opatz, Chad C.

    2016-03-22

    Re-introducing wood into rivers where it was historically removed is one approach to improving habitat conditions in rivers of the Pacific Northwest. The Raging River drainage basin, which flows into the Snoqualmie River at Fall City, western Washington, was largely logged during the 20th century and wood was removed from its channel. To improve habitat conditions for several species of anadromous salmonids that spawn and rear in the Raging River, King County Department of Transportation placed untethered log jams in a 250-meter reach where wood was historically removed. The U.S. Geological Survey measured longitudinal profiles of near-streambed temperature during summer baseflow along 1,026 meters of channel upstream, downstream, and within the area of wood placements. These measurements were part of an effort by King County to monitor the geomorphic and biological responses to these wood placements. Near-streambed temperatures averaged over about 1-meter intervals were measured with a fiber‑optic distributed temperature sensor every 30 minutes for 7 days between July 7 and 13, 2015. Vertical temperature profiles were measured coincident with the longitudinal temperature profile at four locations at 0 centimeters (cm) (at the streambed), and 35 and 70 cm beneath the streambed to document thermal dynamics of the hyporheic zone and surface water in the study reach.

  18. Morphological Changes and Immunohistochemical Expression of RAGE and its Ligands in the Sciatic Nerve of Hyperglycemic Pig (Sus Scrofa

    Directory of Open Access Journals (Sweden)

    Judyta K. Juranek

    2010-09-01

    Full Text Available The aim of our project was to study the effect of streptozotocin (STZ—induced hyperglycemia on sciatic nerve morphology, blood plasma markers and immunohistochemical expression of RAGE (the Receptor for Advanced Glycation End-products, and its ligands—S100B and Carboxymethyl Lysine (CML-advanced glycation endproduct (AGE in the laboratory pig. Six months after STZ—injections, blood plasma measurements, morphometric analysis of sciatic nerve fiber density, immunofluorescent distribution of potential molecular neuropathy contributors, ELISA measurement of plasma AGE level and HPLC analysis of sciatic nerve levels of one of the pre-AGE and the glycolysis intermediate products—methyl-glyoxal (MG were performed. The results of our study revealed that STZ—injected animals displayed elevated levels of plasma glucose, gamma glutamyl transferase (GGT and triglycerides. The sciatic nerve of STZ-injected pigs revealed significantly lower numbers of small-diameter myelinated fibers, higher immunoreactivity for RAGE and S100B and increased levels of MG as compared to control animals. Our results correspond to clinical findings in human patients with hyperglycemia/diabetes-evoked peripheral neuropathy and suggest that the domestic pig may be a suitable large animal model for the study of mechanisms underlying hyperglycemia-induced neurological complications in the peripheral nerve and may serve as a relevant model for the pre-clinical assessment of candidate drugs in neuropathy.

  19. Morphological Changes and Immunohistochemical Expression of RAGE and its Ligands in the Sciatic Nerve of Hyperglycemic Pig (Sus Scrofa

    Directory of Open Access Journals (Sweden)

    Judyta K. Juranek

    2010-01-01

    Full Text Available The aim of our project was to study the effect of streptozotocin (STZ–-induced hyperglycemia on sciatic nerve morphology, blood plasma markers and immunohistochemical expression of RAGE (the Receptor for Advanced Glycation End-products, and its ligands–-S100B and Carboxymethyl Lysine (CML-advanced glycation endproduct (AGE in the laboratory pig. Six months after STZ–-injections, blood plasma measurements, morphometric analysis of sciatic nerve fiber density, immunofluorescent distribution of potential molecular neuropathy contributors, ELISA measurement of plasma AGE level and HPLC analysis of sciatic nerve levels of one of the pre-AGE and the glycolysis intermediate products–-methylglyoxal (MG were performed. The results of our study revealed that STZ–-injected animals displayed elevated levels of plasma glucose, gamma glutamyl transferase (GGT and triglycerides. The sciatic nerve of STZ-injected pigs revealed significantly lower numbers of small-diameter myelinated fibers, higher immunoreactivity for RAGE and S100B and increased levels of MG as compared to control animals. Our results correspond to clinical findings in human patients with hyperglycemia/diabetes-evoked peripheral neuropathy and suggest that the domestic pig may be a suitable large animal model for the study of mechanisms underlying hyperglycemia-induced neurological complications in the peripheral nerve and may serve as a relevant model for the pre-clinical assessment of candidate drugs in neuropathy.

  20. Rage in a Time of Millennial Raving: Rage Against the Machine’s Critical Disruption of Y2K Excitement Rage Against the Machine, ou la critique raisonnée de la frénésie millénariste

    Directory of Open Access Journals (Sweden)

    Phillip Serrato

    2009-11-01

    Full Text Available Nous étudierons l’intrusion brillante et salutaire du groupe Rage Against the Machine, avec son album The Battle of Los Angeles (1999, dans la frénésie euphorique du passage au deuxième millénaire à la fin de l’année 1999. Les genres musicaux les plus populaires de l’époque – dance music et pop « bubble gum » – reflètent un intérêt décroissant pour le politique, notamment sur les questions ethniques et le problème de l’immigration. Face à la popularité d’artistes latinos comme Jennifer Lopez et Marc Anthony semblant annoncer une ère d’où aurait disparu toute discrimination raciale, le disque de Rage Against the Machine détonne singulièrement, de par son insistance à défendre des positions politiques tranchées. Au vu de la place prépondérante des questions d’immigration au début de l’an 2000, l’album de ce groupe engagé peut être envisagé comme un avertissement aux allures prophétiques contre la tentation de l’étourdissement dans une euphorie millénariste.

  1. A multicenter matched case-control analysis on seven polymorphisms from HMGB1 and RAGE genes in predicting hepatocellular carcinoma risk.

    Science.gov (United States)

    Wang, Dan; Qi, Xiaoying; Liu, Fang; Yang, Chuanhua; Jiang, Wenguo; Wei, Xiaodan; Li, Xuri; Mi, Jia; Tian, Geng

    2017-07-25

    Based on 540 hepatocellular carcinoma patients and 540 age- and gender-matched controls, we tested the hypothesis that high mobility group protein box1 (HMGB1) and the receptor for advanced glycation end products (RAGE) genes are two potential candidate susceptibility genes for hepatocellular carcinoma in a multicenter hospital-based case-control analysis. The genotypes of seven widely-studied polymorphisms were determined, and their distributions respected the Hardy-Weinberg equilibrium. The mutant alleles of two polymorphisms, rs1045411 in HMGB1 gene and rs2070600 in RAGE gene, had significantly higher frequencies in patients than in controls (P hepatocellular carcinoma significantly, particularly for rs2070600 under the additive (odds ratio [OR] = 1.77; 95% confidence interval [CI]: 1.34-2.32; P hepatocellular carcinoma compared with the commonest C-C-T haplotype after adjustment. In RAGE gene, the T-T-A-G (rs1800625-rs1800624-rs2070600-rs184003) (adjusted OR; 95% CI; P: 1.75; 1.02-3.03; 0.045) and T-T-A-T (adjusted OR; 95% CI; P: 1.95; 1.01-3.76; 0.048) haplotypes were associated with a marginally increased risk of hepatocellular carcinoma compared with the commonest T-T-G-G haplotype. In summary, we identified two risk-associated polymorphisms (rs1045411 and rs2070600), and more importantly a joint impact of seven polymorphisms from the HMGB1/RAGE axis in susceptibility to hepatocellular carcinoma.

  2. A Novel, Multi-Target Natural Drug Candidate, Matrine, Improves Cognitive Deficits in Alzheimer's Disease Transgenic Mice by Inhibiting Aβ Aggregation and Blocking the RAGE/Aβ Axis.

    Science.gov (United States)

    Cui, Lili; Cai, Yujie; Cheng, Wanwen; Liu, Gen; Zhao, Jianghao; Cao, Hao; Tao, Hua; Wang, Yan; Yin, Mingkang; Liu, Tingting; Liu, Yu; Huang, Pengru; Liu, Zhou; Li, Keshen; Zhao, Bin

    2017-04-01

    The treatment of AD is a topic that has puzzled researchers for many years. Current mainstream theories still consider Aβ to be the most important target for the cure of AD. In this study, we attempted to explore multiple targets for AD treatments with the aim of identifying a qualified compound that could both inhibit the aggregation of Aβ and block the RAGE/Aβ axis. We believed that a compound that targets both Aβ and RAGE may be a feasible strategy for AD treatment. A novel and small natural compound, Matrine (Mat), was identified by high-throughput screening of the main components of traditional Chinese herbs used to treat dementia. Various experimental techniques were used to evaluate the effect of Mat on these two targets both in vitro and in AD mouse model. Mat could inhibit Aβ42-induced cytotoxicity and suppress the Aβ/RAGE signaling pathway in vitro. Additionally, the results of in vivo evaluations of the effects of Mat on the two targets were consistent with the results of our in vitro studies. Furthermore, Mat reduced proinflammatory cytokines and Aβ deposition and attenuated the memory deficits of AD transgenic mice. We believe that this novel, multi-target strategy to inhibit both Aβ and RAGE, is worthy of further exploration. Therefore, our future studies will focus on identifying even more effective multi-target compounds for the treatment of AD based on the molecular structure of Mat.

  3. The proinflammatory RAGE/NF-κB pathway is involved in neuronal damage and reactive gliosis in a model of sleep apnea by intermittent hypoxia.

    Directory of Open Access Journals (Sweden)

    Maria Florencia Angelo

    Full Text Available Sleep apnea (SA causes long-lasting changes in neuronal circuitry, which persist even in patients successfully treated for the acute effects of the disease. Evidence obtained from the intermittent hypoxia (IH experimental model of SA has shown neuronal death, impairment in learning and memory and reactive gliosis that may account for cognitive and structural alterations observed in human patients. However, little is known about the mechanism controlling these deleterious effects that may be useful as therapeutic targets in SA. The Receptor for Advanced Glycation End products (RAGE and its downstream effector Nuclear Factor Kappa B (NF-κB have been related to neuronal death and astroglial conversion to the pro-inflammatory neurodegenerative phenotype. RAGE expression and its ligand S100B were shown to be increased in experimental models of SA. We here used dissociated mixed hippocampal cell cultures and male Wistar rats exposed to IH cycles and observed that NF-κB is activated in glial cells and neurons after IH. To disclose the relative contribution of the S100B/RAGE/NF-κB pathway to neuronal damage and reactive gliosis after IH we performed sequential loss of function studies using RAGE or S100B neutralizing antibodies, a herpes simplex virus (HSV-derived amplicon vector that induces the expression of RAGEΔcyto (dominant negative RAGE and a chemical blocker of NF-κB. Our results show that NF-κB activation peaks 3 days after IH exposure, and that RAGE or NF-κB blockage during this critical period significantly improves neuronal survival and reduces reactive gliosis. Both in vitro and in vivo, S100B blockage altered reactive gliosis but did not have significant effects on neuronal survival. We conclude that both RAGE and downstream NF-κB signaling are centrally involved in the neuronal alterations found in SA models, and that blockage of these pathways is a tempting strategy for preventing neuronal degeneration and reactive gliosis in SA.

  4. A Correlational Study of How Airline Customer Service and Consumer Perception of Airline Customer Service Affect the Air Rage Phenomenon

    Science.gov (United States)

    Hunter, Joyce A.

    2007-01-01

    Between 1995 and 2000, customer service declined throughout the airline industry, as reported in February 2001 by the U.S. Department of Transportation (2001). One of the biggest problems today within the airline industry is the constant complaining from customers regarding the deterioraton of service (McCollough, Berry, & Yadav, 2000). Since 1995, unfortunately no airline has been immune from service deterioration, as reported by the Airline Quality Rating, an annual report by two airline industry experts who analyzed Department of Transportation statistics (Harrison & Kleinsasser, 1999). The airline' refusal to recognize the issue of customer service has perpetuated an environment that has become dangerous and detrimental to the traveling public as well as to airline employees, which in turn has fueled a new phenomenon, now referred to as "air rage".

  5. Repérage d’Images Ordinaires : Analyse des Requêtes des Chercheurs d’Images

    Directory of Open Access Journals (Sweden)

    Elaine Ménard

    2009-06-01

    also emphasizes the pressing necessity to optimize the methods used for image processing, in order to facilitate image retrieval and dissemination in multilingual environments. Résumé Depuis quelques années, le web est devenu un média incontournable pour la diffusion de ressources multilingues. Cependant, les différences linguistiques constituent souvent un obstacle majeur aux échanges de documents scientifiques, culturels, pédagogiques et commerciaux. En plus de cette diversité linguistique, on constate le développement croissant de bases de données et de collections composées de différents types de documents textuels ou multimédias, ce qui complexifie également le processus de repérage documentaire. Par exemple, les collections d’images numériques sont aussi nombreuses que diversifiées. Le besoin de repérer une image spécifique dans diverses collections est devenu une préoccupation partagée par plusieurs communautés. La croissance du web a mis en relief le besoin pressant de se doter d’outils propres à la description des images dans le but de faciliter leur repérage, puisque l’on retrouve celles-ci dans la plupart des ressources disponibles. Cette recherche compare le repérage d’images dans deux contextes linguistiques différents : un contexte monolingue, c’est-à-dire que la langue de la requête (français est la même que la langue d’indexation (français; et un contexte multilingue où la langue de la requête (français est différente de la langue d’indexation (anglais. Cet article présente les résultats de l’analyse des requêtes formulées par les participants pour repérer un ensemble d’images ordinaires représentant des objets de la vie quotidienne, en contexte de repérage multilingue. L’examen des termes contenus dans les requêtes des chercheurs d’images révèle les tendances observées sur le plan terminologique, perceptuel et structurel. Les participants emploient généralement des requêtes simples

  6. Ligature-associated bacterial profiles are linked to type 2 diabetes mellitus in a rat model and influenced by antibody treatment against TNF-α or RAGE

    DEFF Research Database (Denmark)

    Grauballe, M B; Belstrøm, D; Østergaard, J A

    2017-01-01

    on oral bacterial profiles. Therefore, we aimed to evaluate the influence of T2D on the ligature-associated bacterial profile in a diabetic rat model with PD and investigated the impact of blocking inflammatory pathways with antibodies targeting either Tumor Necrosis Factor α (TNF-α) or the receptor......There is a bidirectional relationship between periodontal disease (PD) and type 2 diabetes mellitus (T2D). T2D may lead to ecological perturbations in the oral environment, which may facilitate an altered microbiota. However, previous studies have been inconclusive in determining the effect of T2D...... of advanced glycation end-products (RAGE). A total of 62 Zucker obese rats (45 T2D) and 17 lean (non-T2D) were divided into 4 treatment groups; lean with PD, obese with PD, obese with PD and anti-TNF-α treatment, and obese with PD with anti-RAGE treatment. Periodontal disease was ligature induced. Ligature...

  7. Advanced glycation end products impair the functions of saphenous vein but not thoracic artery smooth muscle cells through RAGE/MAPK signalling pathway in diabetes.

    Science.gov (United States)

    Sun, Yongxin; Kang, Le; Li, Jun; Liu, Huan; Wang, Yulin; Wang, Chunsheng; Zou, Yunzeng

    2016-10-01

    Saphenous vein (SV) and internal thoracic artery (ITA) are commonly used bypass conduits. However, graft failure occurs in SV rather than in ITA, especially in diabetes (DM). The mechanism for this difference has not been fully understood. Accumulation of advanced glycation end products (AGEs) and activation of AGEs receptor (RAGE) could accelerate smooth muscle cells (SMC) proliferation in DM, we thus asked whether AGEs-RAGE could mediate the differences between SMC from SV (SMCV ) and from ITA (SMCA ). Twenty-five patients with DM and other 25 patients without DM were enclosed in DM and control group, respectively. AGEs (100 μg/ml) were added to cultured SMCA and SMCV obtained at coronary artery bypass graft (CABG) and proliferative rates were determined. Transcript expression, phosphorylation or protein expression levels of MAP kinase family (ERK, p38 and JNK), matrix metalloproteinases (MMP)-2 and MMP-9 were analysed by real-time PCR, Western-blot or immunofluorescence staining, respectively. Compared with paired SMCA , SMCV showed significantly increased proliferation rate, MAP kinase family phosphorylation, and MMP-2/9 expression in both groups, especially in DM group. The responses of SMCV induced by AGEs were significantly larger in DM than in control group, which could be suppressed by inhibition of RAGE and ERK. However, all the cellular events of SMCV were not found in paired SMCA . This study suggests that AGEs-RAGE could induce the proliferation of SMCV but not SMCA via MAP kinase pathway in DM. It is the intrinsic 'inactive' tendency of SMCA that contributes to the different rates of graft disease between SV and ITA after CABG. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  8. Regulatory landscape of AGE-RAGE-oxidative stress axis and its modulation by PPARγ activation in high fructose diet-induced metabolic syndrome.

    Science.gov (United States)

    Cannizzaro, Luca; Rossoni, Giuseppe; Savi, Federica; Altomare, Alessandra; Marinello, Cristina; Saethang, Thammakorn; Carini, Marina; Payne, D Michael; Pisitkun, Trairak; Aldini, Giancarlo; Leelahavanichkul, Asada

    2017-01-01

    The AGE-RAGE-oxidative stress (AROS) axis is involved in the onset and progression of metabolic syndrome induced by a high-fructose diet (HFD). PPARγ activation is known to modulate metabolic syndrome; however a systems-level investigation looking at the protective effects of PPARγ activation as related to the AROS axis has not been performed. The aim of this work is to simultaneously characterize multiple molecular parameters within the AROS axis, using samples taken from different body fluids and tissues of a rat model of HFD-induced metabolic syndrome, in the presence or absence of a PPARγ agonist, Rosiglitazone (RGZ). Rats were fed with 60% HFD for the first half of the treatment duration (21 days) then continued with either HFD alone or HFD plus RGZ for the second half. Rats receiving HFD alone showed metabolic syndrome manifestations including hypertension, dyslipidemia, increased glucose levels and insulin resistance, as well as abnormal kidney and inflammatory parameters. Systolic blood pressure, plasma triglyceride and glucose levels, plasma creatinine, and albuminuria were significantly improved in the presence of RGZ. The following molecular parameters of the AROS axis were significantly upregulated in our rat model: carboxymethyl lysine (CML) in urine and liver; carboxyethyl lysine (CEL) in urine; advanced glycation end products (AGEs) in plasma; receptor for advanced glycation end products (RAGE) in liver and kidney; advanced oxidation protein products (AOPP) in plasma; and 4-hydroxynonenal (HNE) in plasma, liver, and kidney. Conversely, with RGZ administration, the upregulation of AOPP and AGEs in plasma, CML and CEL in urine, RAGE in liver as well as HNE in plasma and liver was significantly counteracted/prevented. Our data demonstrate (i) the systems-level regulatory landscape of HFD-induced metabolic syndrome involving multiple molecular parameters, including HNE, AGEs and their receptor RAGE, and (ii) attenuation of metabolic syndrome by

  9. Structural and quantitative characterisation of canine RAGE gene transcripts and evaluation of canine HMG genes and proteins for the establishment of therapeutic strategies

    OpenAIRE

    Sterenczak, Katharina

    2011-01-01

    Cancer is the leading cause of death in economic strong countries and a large number of in vivo and in vitro models of human cancer were established until today. Thereby the dog has attracted scientific interest as neoplasias seen in dogs share many characteristics with their human counterparts. The aim of this thesis was the analysis of the molecular structure and/or expression pattern of cancer associated genes and proteins in canine neoplasias including the receptor RAGE and members of the...

  10. Ethyl pyruvate inhibits proliferation and induces apoptosis of hepatocellular carcinoma via regulation of the HMGB1–RAGE and AKT pathways

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Ping; Dai, Weiqi; Wang, Fan; Lu, Jie; Shen, Miao; Chen, Kan; Li, Jingjing; Zhang, Yan; Wang, Chengfen; Yang, Jing; Zhu, Rong; Zhang, Huawei; Zheng, Yuanyuan; Guo, Chuan-Yong, E-mail: guochuanyong@hotmail.com; Xu, Ling, E-mail: xuling606@sina.com

    2014-01-24

    Highlights: • Ethyl pyruvate inhibits liver cancer. • Promotes apoptosis. • Decreased the expression of HMGB1, p-Akt. - Abstract: Ethyl pyruvate (EP) was recently identified as a stable lipophilic derivative of pyruvic acid with significant antineoplastic activities. The high mobility group box-B1 (HMGB1)–receptor for advanced glycation end-products (RAGE) and the protein kinase B (Akt) pathways play a crucial role in tumorigenesis and development of many malignant tumors. We tried to observe the effects of ethyl pyruvate on liver cancer growth and explored its effects in hepatocellular carcinoma model. In this study, three hepatocellular carcinoma cell lines were treated with ethyl pyruvate. An MTT colorimetric assay was used to assess the effects of EP on cell proliferation. Flow cytometry and TUNEL assays were used to analyze apoptosis. Real-time PCR, Western blotting and immunofluorescence demonstrated ethyl pyruvate reduced the HMGB1–RAGE and AKT pathways. The results of hepatoma orthotopic tumor model verified the antitumor effects of ethyl pyruvate in vivo. EP could induce apoptosis and slow the growth of liver cancer. Moreover, EP decreased the expression of HMGB1, RAGE, p-AKT and matrix metallopeptidase-9 (MMP9) and increased the Bax/Bcl-2 ratio. In conclusion, this study demonstrates that ethyl pyruvate induces apoptosis and cell-cycle arrest in G phase in hepatocellular carcinoma cells, plays a critical role in the treatment of cancer.

  11. Methylglyoxal and carboxyethyllysine reduce glutamate uptake and S100B secretion in the hippocampus independently of RAGE activation.

    Science.gov (United States)

    Hansen, Fernanda; Battú, Cíntia Eickhoff; Dutra, Márcio Ferreira; Galland, Fabiana; Lirio, Franciane; Broetto, Núbia; Nardin, Patrícia; Gonçalves, Carlos-Alberto

    2016-02-01

    Diabetes is a metabolic disease characterized by high fasting-glucose levels. Diabetic complications have been associated with hyperglycemia and high levels of reactive compounds, such as methylglyoxal (MG) and advanced glycation endproducts (AGEs) formation derived from glucose. Diabetic patients have a higher risk of developing neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease. Herein, we examined the effect of high glucose, MG and carboxyethyllysine (CEL), a MG-derived AGE of lysine, on oxidative, metabolic and astrocyte-specific parameters in acute hippocampal slices, and investigated some of the mechanisms that could mediate these effects. Glucose, MG and CEL did not alter reactive oxygen species (ROS) formation, glucose uptake or glutamine synthetase activity. However, glutamate uptake and S100B secretion were decreased after MG and CEL exposure. RAGE activation and glycation reactions, examined by aminoguanidine and L-lysine co-incubation, did not mediate these changes. Acute MG and CEL exposure, but not glucose, were able to induce similar effects on hippocampal slices, suggesting that conditions of high glucose concentrations are primarily toxic by elevating the rates of these glycation compounds, such as MG, and by generation of protein cross-links. Alterations in the secretion of S100B and the glutamatergic activity mediated by MG and AGEs can contribute to the brain dysfunction observed in diabetic patients.

  12. Hemorrhagic Stroke in a Young Healthy Male Following Use of Pre-Workout Supplement Animal Rage XL.

    Science.gov (United States)

    Harris, Brandon F; Winn, Coty; Ableman, Thomas B

    2017-09-01

    So-called "pre-workout" supplements are substances marketed as natural dietary supplements with claims of helping athletes achieve more focused and intense workouts. The use of such products remains popular among American youth as a whole, but is especially high among active duty service members. Supplements are minimally regulated by the Food and Drug Administration (FDA), and unlike pharmaceuticals, supplements are often brought to market without any testing to show neither efficacy nor safety. Several case reports have documented serious adverse events and raise the question of whether supplement use was a causative factor. Reported events occurring after use of pre-workout supplements include, among others, ischemic stroke, hemorrhagic stroke, myocardial infarction, hepatitis, and death. Here, we present the case of a healthy 25-year-old active duty male who experienced a bilateral cerebellar hemorrhagic stroke occurring shortly after taking a supplement named Animal Rage XL. Hemorrhagic stroke occurring in a healthy 25-year-old male with no risk factors is exceedingly rare. This is the first known case of stroke temporally associated with this particular supplement, which is currently available for purchase at military exchanges. Additionally, several of the active ingredients in this supplement have been shown to cause hypertension, tachycardia, and vasospasm. All of these effects could increase the likelihood and severity of a hemorrhagic stroke. The investigated ingredients in this abstract include β-phenethylamine, creatine-monophosphate, and caffeine. Reprint & Copyright © 2017 Association of Military Surgeons of the U.S.

  13. De la rage à l'enthousiasme : le parcours d'un jeune électeur saoudien

    Directory of Open Access Journals (Sweden)

    Pascal Ménoret

    2004-12-01

    Full Text Available Comment apprend-on le métier d'électeur dans une société autoritairement dépolitisée ? Cet entretien approfondi, réalisé avec un jeune électeur saoudien au lendemain de la victoire du courant religieux modéré aux élections municipale de février 2005 à Riyad, permet d'avancer quelques éléments de réponse. On verra ainsi que des dispositions politiques susceptibles d'être réinvesties dans l'activisme électoral ont pu être puisées par les plus fervents partisans du processus électoral dans les schèmes de pensée et d'acion propres aux groupes islamiques des écoles, aux cercles coraniques des mosquées et aux centres d'été du ministère des Affaires islamiques. L'activisme islamique n'est pas foncièrement incompatible avec un processus de démocratisation ; encore faut-il que la « rage » contractée au spectacle de la dictature et des injustices occidentales puisse se transformer en « enthousiasme » politique et électoral.

  14. Inhibition of the receptor for advanced glycation end-products (RAGE) protects from secondhand smoke (SHS)-induced intrauterine growth restriction IUGR in mice.

    Science.gov (United States)

    Lewis, Joshua B; Mejia, Camilo; Jordan, Clinton; Monson, Troy D; Bodine, Jared S; Dunaway, Todd M; Egbert, Kaleb M; Lewis, Adam L; Wright, Tanner J; Ogden, K Connor; Broberg, Dallin S; Hall, Parker D; Nelson, Shawn M; Hirschi, Kelsey M; Reynolds, Paul R; Arroyo, Juan A

    2017-12-01

    Intrauterine growth restriction (IUGR) is a disease affecting 10% of all pregnancies. IUGR is associated with maternal, fetal, or placental abnormalities. Studies investigating the effects of secondhand smoke (SHS) exposure and IUGR are limited. The receptor for advanced glycation end-products (RAGE) is a pro-inflammatory transmembrane receptor increased by SHS in the placenta. We tested the hypothesis that inhibition of RAGE during SHS exposure protects from smoke-induced IUGR. C57BL/6 mice were exposed to SHS or SHS + semi-synthetic glycosaminoglycan ethers (SAGEs) known to inhibit RAGE signaling. Trophoblast cells were treated with cigarette smoke extract (CSE) with or without SAGEs in order to address the effects of RAGE inhibition during trophoblast invasion in vitro. SHS-treated mice demonstrated a significant reduction in fetal weight (7.35-fold, P ≤ 0.0001) and placental weight (1.13-fold, P ≤ 0.0001) compared with controls. Mice co-treated with SHS and SAGEs were protected from SHS-induced fetal weights decreases. SHS treatment of C57BL/6 mice activated placental extracellular signal-regulated kinase (ERK) (3.0-fold, P ≤ 0.05), JNK (2.4-fold, P ≤ 0.05) and p38 (2.1-fold, P ≤ 0.05) and the expression of inflammatory mediators including TNF-α (1.34-fold, P ≤ 0.05) and IL-1β (1.03-fold, P ≤ 0.05). SHS-mediated activation of these molecules was reduced to basal levels when SAGE was co-administered. Invasion of trophoblast cells decreased 92% (P < 0.002) when treated with CSE and CSE-mediated invasion was completely reversed by SAGEs. We conclude that RAGE inhibition protects against fetal weight loss during SHS-induced IUGR. These studies provide insight into tobacco-mediated IUGR development and clarify avenues that may be helpful in the alleviation of placental complications.

  15. Neuroprotective effects of vildagliptin in rat rotenone Parkinson's disease model: role of RAGE-NFκB and Nrf2-antioxidant signaling pathways.

    Science.gov (United States)

    Abdelsalam, Rania M; Safar, Marwa M

    2015-06-01

    Gliptins have been recently shown to conquer neuronal degeneration in cell cultures via modulating glucagon-like peptide (GLP)-1. This peptide produced in the gut not only crosses the blood-brain barrier but is also synthesized in the brain and acts on GLP-1R exerting central anti-inflammatory and antiapoptotic effects, thus impeding neuronal damage. This study investigated the antiparkinsonian effect of vildagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor in a rat rotenone model targeting mainly the RAGE-NFκB/Nrf2-signaling pathways, to judge the potential anti-inflammatory/antioxidant effects of the drug. Vildagliptin markedly improved the motor performance in the open field and rotarod tests, effects that were emphasized by the accompanied reduction in striatal dopamine content. It modified the striatal energy level (ADP/ATP) associated with partial antagonism of body weight reduction. This incretin enhancer suppressed nuclear factor (NF)κB and, consequently, the downstream inflammatory mediator tumor necrosis factor-α. Normalization of receptor for advanced glycated end product (RAGE) is a main finding which justifies the anti-inflammatory effects of vildagliptin, together with hampering striatal inducible nitric oxide synthase, intracellular adhesion molecule-1 as well as myeloperoxidase. The antioxidant potential of vildagliptin was depicted as entailing reduction in thiobarbituric acid-reactive substances and the transcriptional factor Nrf-2 level. Vildagliptin guarded against neuronal demise through an antiapoptotic effect as reflected by the reduction in the mitochondrial matrix component cytochrome c and the key downstream executioner caspase-3. In conclusion, vildagliptin is endowed with various neuroprotective effects and thus can be a promising candidate for the management of Parkinson's disease. In the rat rotenone model of Parkinson's disease (PD), striatal RAGE/NFκB signaling was up-regulated associated with elevated levels of inflammatory

  16. Chronic sustained inflammation links to left ventricular hypertrophy and aortic valve sclerosis: a new link between S100/RAGE and FGF23.

    Science.gov (United States)

    Yan, Ling; Bowman, Marion A Hofmann

    Cardiovascular disease including left ventricular hypertrophy, diastolic dysfunction and ectopic valvular calcification are common in patients with chronic kidney disease (CKD). Both S100A12 and fibroblast growth factor 23 (FGF23) have been identified as biomarkers of cardiovascular morbidity and mortality in patients with CKD. We tested the hypothesis that human S100/calgranulin would accelerate cardiovascular disease in mice subjected to CKD. This review paper focuses on S100 proteins and their receptor for advanced glycation end products (RAGE) and summarizes recent findings obtained in novel developed transgenic hBAC-S100 mice that express S100A12 and S100A8/9 proteins. A bacterial artificial chromosome of the human S100/calgranulin gene cluster containing the genes and regulatory elements for S100A8, S100A9 and S100A12 was expressed in C57BL/6J mice (hBAC-S100). CKD was induced by ureteral ligation, and hBAC-S100 mice and WT mice were studied after 10 weeks of chronic uremia. hBAC-S100 mice with CKD showed increased FGF23 in the heart, left ventricular hypertrophy (LVH), diastolic dysfunction, focal cartilaginous metaplasia and calcification of the mitral and aortic valve annulus together with aortic valve sclerosis. This phenotype was not observed in WT mice with CKD or in hBAC-S100 mice lacking RAGE with CKD, suggesting that the inflammatory milieu mediated by S100/RAGE promotes pathological cardiac hypertrophy in CKD. In vitro, inflammatory stimuli including IL-6, TNFα, LPS, or serum from hBAC-S100 mice up regulated FGF23 mRNA and protein in primary murine neonatal and adult cardiac fibroblasts. Taken together, our study shows that myeloid-derived human S100/calgranulin is associated with the development of cardiac hypertrophy and ectopic cardiac calcification in a RAGE dependent manner in a mouse model of CKD. We speculate that FGF23 produced by cardiac fibroblasts in response to cytokines may act in a paracrine manner to accelerate LVH and diastolic

  17. Pioglitazone Confers Neuroprotection Against Ischemia-Induced Pyroptosis due to its Inhibitory Effects on HMGB-1/RAGE and Rac1/ROS Pathway by Activating PPAR-ɤ

    Directory of Open Access Journals (Sweden)

    Pingping Xia

    2018-03-01

    Full Text Available Background/Aims: Recent researches highlighted the protective potential of pioglitazone, a PPAR-γ agonist, in the progression of cerebral ischemia-reperfusion injury. However, there has been no study on the application of pioglitazone in treating ischemic stroke through mechanisms involving pyroptosis. Methods: The cerebral injury was established by middle cerebral artery occlusion (MCAO. in vitro ischemia in primary cultured astrocytes was induced by the oxygen-glucose deprivation (OGD. ELISA and Western Blot analysis were employed to the levels of PPAR-γ, pyroptosis-related biomarkers and cytoplasmic translocation of HMGB-1 and RAGE expression as well as Rac1 activity, respectively. Results: We demonstrated that repeated intraperitoneal administration of pioglitazone remarkably reduced the infarct volume, improved neurological deficits and suppressed the Rac1 activity with significant reduction of excessive ROS in rat model of middle cerebral artery occlusion (MCAO. Moreover, pioglitazone alleviated the up-regulation of pyroptosis-related biomarkers and the increased cytoplasmic translocation of HMGB-1 and RAGE expression in cerebral penumbra cortex. Similarly, the protective effects of pioglitazone on cultured astrocytes were characterized by reduced Rac1 activity, pyroptosis related protein expressions and lactate dehydrogenase (LDH release. However, these protective effects of pioglitazone were neutralized with the use of GW9662, a PPAR-γ inhibitor. Interestingly, Rac1 knockdown in lentivirus with the Rac1 small hair RNA (shRNA could inhibit the OGD-induced pyroptosis of primary cultured astrocytes. Furthermore, the combination of Rac1-shRNA and pioglitazone can further strengthen the inhibitory effects on pyroptosis induced by OGD. Conclusion: The neuroprotection of pioglitazone was attributable to the alleviated ischemia/hypoxia-induced pyroptosis and was also associated with the PPARγ-mediated suppression of HGMB-1/RAGE signaling

  18. Cross-sectional analysis of obesity and serum analytes in males identifies sRAGE as a novel biomarker inversely associated with diverticulosis.

    Directory of Open Access Journals (Sweden)

    Sarah S Comstock

    Full Text Available Diverticulosis can lead to diverticulitis, a colon condition involving inflammation and other complications. Diverticulosis can result from biological, behavioral, or genetic causes. However, the etiology of diverticulosis is unknown. Although diet is associated with diverticulosis, recent studies suggest other factors influence risk. We sought to identify anthropometric or serum markers that were associated with the presence of diverticulosis. To determine these associations, 126 asymptomatic men (48-65 yr were recruited at the time of preventative screening colonoscopy. Anthropometric measures were taken, and blood was collected for serum protein analysis. Data were analyzed by logistic regression and factor analysis. Obese individuals (BMI >30 were 7.8 (CI: 2.3-26.3 times more likely than normal weight (BMI 45 inches were 8.1 (CI: 2.8-23.8 times more likely to have diverticulosis than those with a waist circumference <38 inches. Leptin was also positively associated with diverticulosis (OR = 5.5, CI: 2.0-14.7. Both low molecular weight adiponectin (LMW, OR = 0.50; CI: 0.3-0.8 and the soluble receptor for advanced glycation end products (sRAGE, OR = 0.4, CI: 0.3-0.7 were inversely related to the presence of diverticulosis. sRAGE levels were not correlated with leptin or C-peptide concentrations. The pattern of high BMI, waist circumference, leptin and C-peptide increased the odds of diverticulosis while the pattern of high levels of sRAGE and LMW adiponectin decreased the odds of diverticulosis. Associations between diverticulosis and anthropometric or serum markers may elucidate the origins of diverticulosis and may enable physicians to identify individuals at risk for diverticulitis.

  19. Optimization of parameter values for complex pulse sequences by simulated annealing: application to 3D MP-RAGE imaging of the brain.

    Science.gov (United States)

    Epstein, F H; Mugler, J P; Brookeman, J R

    1994-02-01

    A number of pulse sequence techniques, including magnetization-prepared gradient echo (MP-GRE), segmented GRE, and hybrid RARE, employ a relatively large number of variable pulse sequence parameters and acquire the image data during a transient signal evolution. These sequences have recently been proposed and/or used for clinical applications in the brain, spine, liver, and coronary arteries. Thus, the need for a method of deriving optimal pulse sequence parameter values for this class of sequences now exists. Due to the complexity of these sequences, conventional optimization approaches, such as applying differential calculus to signal difference equations, are inadequate. We have developed a general framework for adapting the simulated annealing algorithm to pulse sequence parameter value optimization, and applied this framework to the specific case of optimizing the white matter-gray matter signal difference for a T1-weighted variable flip angle 3D MP-RAGE sequence. Using our algorithm, the values of 35 sequence parameters, including the magnetization-preparation RF pulse flip angle and delay time, 32 flip angles in the variable flip angle gradient-echo acquisition sequence, and the magnetization recovery time, were derived. Optimized 3D MP-RAGE achieved up to a 130% increase in white matter-gray matter signal difference compared with optimized 3D RF-spoiled FLASH with the same total acquisition time. The simulated annealing approach was effective at deriving optimal parameter values for a specific 3D MP-RAGE imaging objective, and may be useful for other imaging objectives and sequences in this general class.

  20. Pioglitazone Confers Neuroprotection Against Ischemia-Induced Pyroptosis due to its Inhibitory Effects on HMGB-1/RAGE and Rac1/ROS Pathway by Activating PPAR-ɤ.

    Science.gov (United States)

    Xia, Pingping; Pan, Yundan; Zhang, Fan; Wang, Na; Wang, E; Guo, Qulian; Ye, Zhi

    2018-01-01

    Recent researches highlighted the protective potential of pioglitazone, a PPAR-γ agonist, in the progression of cerebral ischemia-reperfusion injury. However, there has been no study on the application of pioglitazone in treating ischemic stroke through mechanisms involving pyroptosis. The cerebral injury was established by middle cerebral artery occlusion (MCAO). in vitro ischemia in primary cultured astrocytes was induced by the oxygen-glucose deprivation (OGD). ELISA and Western Blot analysis were employed to the levels of PPAR-γ, pyroptosis-related biomarkers and cytoplasmic translocation of HMGB-1 and RAGE expression as well as Rac1 activity, respectively. We demonstrated that repeated intraperitoneal administration of pioglitazone remarkably reduced the infarct volume, improved neurological deficits and suppressed the Rac1 activity with significant reduction of excessive ROS in rat model of middle cerebral artery occlusion (MCAO). Moreover, pioglitazone alleviated the up-regulation of pyroptosis-related biomarkers and the increased cytoplasmic translocation of HMGB-1 and RAGE expression in cerebral penumbra cortex. Similarly, the protective effects of pioglitazone on cultured astrocytes were characterized by reduced Rac1 activity, pyroptosis related protein expressions and lactate dehydrogenase (LDH) release. However, these protective effects of pioglitazone were neutralized with the use of GW9662, a PPAR-γ inhibitor. Interestingly, Rac1 knockdown in lentivirus with the Rac1 small hair RNA (shRNA) could inhibit the OGD-induced pyroptosis of primary cultured astrocytes. Furthermore, the combination of Rac1-shRNA and pioglitazone can further strengthen the inhibitory effects on pyroptosis induced by OGD. The neuroprotection of pioglitazone was attributable to the alleviated ischemia/hypoxia-induced pyroptosis and was also associated with the PPARγ-mediated suppression of HGMB-1/RAGE signaling pathway. Moreover, the inhibition of Rac1 promoted this function

  1. Evaluation des Connaissances-Attitudes-Pratiques des populations des districts sanitaires de Benoye, Laoukassy, Moundou et N?Djam?na Sud sur la rage canine au Tchad

    OpenAIRE

    Mindekem, Rolande; Lechenne, Monique; Alfaroukh, Idriss Oumar; Moto, Daugla Doumagoum; Zinsstag, Jakob; Ouedraogo, Laurent Tinoaga; Salifou, Sahidou

    2017-01-01

    Introduction La rage canine demeure une pr?occupation en Afrique comme au Tchad. La pr?sente ?tude vise ? ?valuer les Connaissances-Attitudes-Pratiques des populations pour la prise en charge appropri?e des personnes expos?es et une lutte efficace. M?thodes C??tait une ?tude transversale descriptive r?alis?e en juillet et septembre dans quatre districts sanitaires au Tchad en 2015. Les donn?es ont ?t? collect?es ? l?aide d?un questionnaire aupr?s des m?nages recrut?s suivant un sondage al?ato...

  2. Hyperoside Downregulates the Receptor for Advanced Glycation End Products (RAGE and Promotes Proliferation in ECV304 Cells via the c-Jun N-Terminal Kinases (JNK Pathway Following Stimulation by Advanced Glycation End-Products In Vitro

    Directory of Open Access Journals (Sweden)

    Zhengyu Zhang

    2013-11-01

    Full Text Available Hyperoside is a major active constituent in many medicinal plants which are traditionally used in Chinese medicines for their neuroprotective, anti-inflammatory and antioxidative effects. The molecular mechanisms underlying these effects are unknown. In this study, quiescent ECV304 cells were treated in vitro with advanced glycation end products (AGEs in the presence or absence of hyperoside. The results demonstrated that AGEs induced c-Jun N-terminal kinases (JNK activation and apoptosis in ECV304 cells. Hyperoside inhibited these effects and promoted ECV304 cell proliferation. Furthermore, hyperoside significantly inhibited RAGE expression in AGE-stimulated ECV304 cells, whereas knockdown of RAGE inhibited AGE-induced JNK activation. These results suggested that AGEs may promote JNK activation, leading to viability inhibition of ECV304 cells via the RAGE signaling pathway. These effects could be inhibited by hyperoside. Our findings suggest a novel role for hyperoside in the treatment and prevention of diabetes.

  3. Higher plasma soluble Receptor for Advanced Glycation End Products (sRAGE) levels are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes: a 12-year follow-up study

    DEFF Research Database (Denmark)

    Nin, Johanna W M; Jorsal, Anders; Merces Ferreira, Isabel Maria

    2010-01-01

    To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal dysfunct......To investigate the associations of plasma levels of soluble receptor for advanced glycation end products (sRAGE) with incident cardiovascular disease (CVD) and all-cause mortality in type 1 diabetes and the extent to which any such associations could be explained by endothelial and renal...

  4. Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models

    Directory of Open Access Journals (Sweden)

    Rahul Jandial

    2018-01-01

    Full Text Available Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1 to detoxify the toxic glycolytic byproduct methylglyoxal (MG and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs. Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM, the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA approaches. Inhibition of GLO1 with S-(p-bromobenzyl glutathione dicyclopentyl ester (p-BrBzGSH(Cp2 increased levels of the DNA-AGE N2-1-(carboxyethyl-2′-deoxyguanosine (CEdG, a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE; and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p-BrBzGSH(Cp2 exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.

  5. Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models.

    Science.gov (United States)

    Jandial, Rahul; Neman, Josh; Lim, Punnajit P; Tamae, Daniel; Kowolik, Claudia M; Wuenschell, Gerald E; Shuck, Sarah C; Ciminera, Alexandra K; De Jesus, Luis R; Ouyang, Ching; Chen, Mike Y; Termini, John

    2018-01-30

    Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S -( p -bromobenzyl) glutathione dicyclopentyl ester ( p- BrBzGSH(Cp)₂) increased levels of the DNA-AGE N ²-1-(carboxyethyl)-2'-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p -BrBzGSH(Cp)₂ exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.

  6. A ternary-complex of a suicide gene, a RAGE-binding peptide, and polyethylenimine as a gene delivery system with anti-tumor and anti-angiogenic dual effects in glioblastoma.

    Science.gov (United States)

    Choi, Eunji; Oh, Jungju; Lee, Dahee; Lee, Jaewon; Tan, Xiaonan; Kim, Minkyung; Kim, Gyeungyun; Piao, Chunxian; Lee, Minhyung

    2018-04-13

    The receptor for advanced glycation end-products (RAGE) is involved in tumor angiogenesis. Inhibition of RAGE might be an effective anti-angiogenic therapy for cancer. In this study, a cationic RAGE-binding peptide (RBP) was produced as an antagonist of RAGE, and a ternary-complex consisting of RBP, polyethylenimine (2 kDa, PEI2k), and a suicide gene (pHSVtk) was developed as a gene delivery system with dual functions: the anti-tumor effect of pHSVtk and anti-angiogenic effect of RBP. As an antagonist of RAGE, RBP decreased the secretion of vascular-endothelial growth factor (VEGF) in activated macrophages and reduced the tube-formation of endothelial cells in vitro. In in vitro transfection assays, the RBP/PEI2k/plasmid DNA (pDNA) ternary-complex had higher transfection efficiency than the PEI2k/pDNA binary-complex. In an intracranial glioblastoma animal model, the RBP/PEI2k/pHSVtk ternary-complex reduced α-smooth muscle actin expression, suggesting that the complex has an anti-angiogenic effect. In addition, the ternary-complex had higher pHSVtk delivery efficiency than the PEI2k/pHSVtk and PEI25k/pHSVtk binary-complexes in an animal model. As a result, the ternary-complex induced apoptosis and reduced tumor volume more effectively than the PEI2k/pHSVtk and PEI25k/pHSVtk binary-complexes. In conclusion, due to its dual anti-tumor and anti-angiogenesis effects, the RBP/PEI2k/pHSVtk ternary-complex might be an efficient gene delivery system for the treatment of glioblastoma. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Gadolinium-Enhanced Three-Dimensional Magnetization - Prepared Rapid Gradient-Echo (3D MP-RAGE) Imaging is Superior to Spin-Echo Imaging in Delineating Brain Metastases

    International Nuclear Information System (INIS)

    Takeda, T.; Takeda, A.; Nagaoka, T.; Kunieda, E.; Takemasa, K.; Watanabe, M.; Hatou, T.; Oguro, S.; Katayama, M.

    2008-01-01

    Background: Precisely defining the number and location of brain metastases is very important for establishing a treatment strategy for malignancies. Although magnetic resonance imaging (MRI) is now considered the best modality, various improvements in sequences are still being made. Purpose: To prospectively compare the diagnostic ability of three-dimensional, magnetization-prepared rapid gradient-echo (3D MP-RAGE) imaging in detecting metastatic brain tumors, with that of two-dimensional spin-echo (2D SE) T1-weighted imaging. Material and Methods: A total of 123 examinations were included in this study, and 119 examinations from 88 patients with known malignancies were analyzed. All patients underwent T1- and T2-weighted 2D SE transverse imaging, followed by gadolinium-enhanced T1-weighted transverse and coronal 2D SE imaging and 3D MP-RAGE transverse imaging. Four radiologists interpreted the images to compare the accuracy and the time required for interpretation for each imaging. Results: 3D MP-RAGE imaging was significantly better than 2D SE imaging for detecting metastatic brain lesions, regardless of the readers' experience. The sensitivities of the 3D MP-RAGE and 2D SE imaging for all observers were 0.81 vs. 0.80 (P>0.05), specificities were 0.93 vs. 0.87 (P 0.05), and accuracies were 0.84 vs. 0.78 (P<0.05), respectively. There was no significant difference in the time required for image interpretation between the two modalities (15.6±4.0 vs. 15.4±4.1 min). Conclusion: 3D MP-RAGE imaging proved superior to 2D SE imaging in the detection of brain metastases

  8. Evaluation des Connaissances-Attitudes-Pratiques des populations des districts sanitaires de Benoye, Laoukassy, Moundou et N’Djaména Sud sur la rage canine au Tchad

    Science.gov (United States)

    Mindekem, Rolande; Lechenne, Monique; Alfaroukh, Idriss Oumar; Moto, Daugla Doumagoum; Zinsstag, Jakob; Ouedraogo, Laurent Tinoaga; Salifou, Sahidou

    2017-01-01

    Introduction La rage canine demeure une préoccupation en Afrique comme au Tchad. La présente étude vise à évaluer les Connaissances-Attitudes-Pratiques des populations pour la prise en charge appropriée des personnes exposées et une lutte efficace. Méthodes C’était une étude transversale descriptive réalisée en juillet et septembre dans quatre districts sanitaires au Tchad en 2015. Les données ont été collectées à l’aide d’un questionnaire auprès des ménages recrutés suivant un sondage aléatoire à 3 degrés. Résultats C’était 2428 personnes enquêtées avec un niveau maximum primaire (54,12%). L’âge moyen était de 36 ± 13,50 ans. Ils étaient cultivateurs (35,17%), commerçants (18,04%), ménagères (12,81%). La rage était définie comme une maladie transmise du chien à l’homme (41,43%), une altération du cerveau (41,27%), une sous-alimentation (10,26%). Le chat était faiblement connu réservoir (13,84%) et vecteur (19,77%) ainsi que la griffure comme moyen de transmission (4,61%) et la vaccination du chat comme mesure préventive (0,49%). Les premiers soins en cas de morsure à domicile étaient les pratiques traditionnelles (47,69%), le lavage des plaies (19,48%) ou aucune action entreprise (20,43%). Les ménages consultaient la santé humaine (78,50%), la santé animale (5,35%) et les guérisseurs traditionnels (27%). Conclusion La communication en rapport avec des premiers soins à la maison en cas de morsure, la connaissance du chat comme réservoir et vecteur, celle de la griffure comme moyen de transmission et la promotion de la consultation des services vétérinaires en cas de morsure sont nécessaires. PMID:28761600

  9. Nifedipine, a calcium channel blocker, inhibits advanced glycation end product (AGE)-elicited mesangial cell damage by suppressing AGE receptor (RAGE) expression via peroxisome proliferator-activated receptor-gamma activation

    International Nuclear Information System (INIS)

    Matsui, Takanori; Yamagishi, Sho-ichi; Takeuchi, Masayoshi; Ueda, Seiji; Fukami, Kei; Okuda, Seiya

    2009-01-01

    The interaction between advanced glycation end products (AGE) and their receptor RAGE mediates the progressive alteration in renal architecture and loss of renal function in diabetic nephropathy. Oxidative stress generation and inflammation also play a central role in diabetic nephropathy. This study investigated whether and how nifedipine, a calcium channel blocker (CCB), blocked the AGE-elicited mesangial cell damage in vitro. Nifedipine, but not amlodipine, a control CCB, down-regulated RAGE mRNA levels and subsequently reduced reactive oxygen species (ROS) generation in AGE-exposed mesangial cells. AGE increased mRNA levels of vascular cell adhesion molecule-1 (VCAM-1) and induced monocyte chemoattractant protein-1 (MCP-1) production in mesangial cells, both of which were prevented by the treatment with nifedipine, but not amlodipine. The beneficial effects of nifedipine on AGE-exposed mesangial cells were blocked by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ (PPAR-γ). Although nifedipine did not affect expression levels of PPAR-γ, it increased the PPAR-γ transcriptional activity in mesangial cells. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-inflammatory agent against AGE by suppressing RAGE expression in cultured mesangial cells via PPAR-γ activation.

  10. The ''2T'' ion-electron semi-analytic shock solution for code-comparison with xRAGE: A report for FY16

    International Nuclear Information System (INIS)

    Ferguson, Jim Michael

    2016-01-01

    This report documents an effort to generate the semi-analytic '2T' ion-electron shock solution developed in the paper by Masser, Wohlbier, and Lowrie, and the initial attempts to understand how to use this solution as a code-verification tool for one of LANL's ASC codes, xRAGE. Most of the work so far has gone into generating the semi-analytic solution. Considerable effort will go into understanding how to write the xRAGE input deck that both matches the boundary conditions imposed by the solution, and also what physics models must be implemented within the semi-analytic solution itself to match the model assumptions inherit within xRAGE. Therefore, most of this report focuses on deriving the equations for the semi-analytic 1D-planar time-independent '2T' ion-electron shock solution, and is written in a style that is intended to provide clear guidance for anyone writing their own solver.

  11. High-Mobility Group Box 1 Mediates Fibroblast Activity via RAGE-MAPK and NF-κB Signaling in Keloid Scar Formation.

    Science.gov (United States)

    Kim, Jihee; Park, Jong-Chul; Lee, Mi Hee; Yang, Chae Eun; Lee, Ju Hee; Lee, Won Jai

    2017-12-28

    Emerging studies have revealed the involvement of high-mobility group box 1 (HMGB1) in systemic fibrotic diseases, yet its role in the cutaneous scarring process has not yet been investigated. We hypothesized that HMGB1 may promote fibroblast activity to cause abnormal cutaneous scarring. In vitro wound healing assay with normal and keloid fibroblasts demonstrated that HMGB1 administration promoted the migration of both fibroblasts with increased speed and a greater traveling distance. Treatment of the HMGB1 inhibitor glycyrrhizic acid (GA) showed an opposing effect on both activities. To analyze the downstream mechanism, the protein levels of extracellular signal-regulated kinase (ERK) 1/2, protein kinase B (AKT), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were measured by western blot analysis. HMGB1 increased the expression levels of ERK1/2, AKT, and NF-κB compared to the control, which was suppressed by GA. HMGB1 promoted both normal and keloid fibroblasts migration to a degree equivalent to that achieved with TGF-β. We concluded that HMGB1 activates fibroblasts via the receptor for advanced glycation end product (RAGE)-mitogen-activated protein kinases (MAPK) and NF-κB interaction signaling pathways. Further knowledge of the relationship of HMGB1 with skin fibrosis may lead to a promising clinical approach to manage abnormal scarring.

  12. The Extract of Aster Koraiensis Prevents Retinal Pericyte Apoptosis in Diabetic Rats and Its Active Compound, Chlorogenic Acid Inhibits AGE Formation and AGE/RAGE Interaction

    Directory of Open Access Journals (Sweden)

    Junghyun Kim

    2016-09-01

    Full Text Available Retinal capillary cell loss is a hallmark of early diabetic retinal changes. Advanced glycation end products (AGEs are believed to contribute to retinal microvascular cell loss in diabetic retinopathy. In this study, the protective effects of Aster koraiensis extract (AKE against damage to retinal vascular cells were investigated in streptozotocin (STZ-induced diabetic rats. To examine this issue further, AGE accumulation, nuclear factor-kappaB (NF-κB and inducible nitric oxide synthase (iNOS were investigated using retinal trypsin digests from streptozotocin-induced diabetic rats. In the diabetic rats, TUNEL (Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling-positive retinal microvascular cells were markedly increased. Immunohistochemical studies revealed that AGEs were accumulated within the retinal microvascular cells, and this accumulation paralleled the activation of NF-κB and the expression of iNOS in the diabetic rats. However, AKE prevented retinal microvascular cell apoptosis through the inhibition of AGE accumulation and NF-κB activation. Moreover, to determine the active compounds of AKE, two major compounds, chlorogenic acid and 3,5-di-O-caffeoylquinic acid, were tested in an in vitro assay. Among these compounds, chlorogenic acid significantly reduced AGE formation as well as AGE/RAGE (receptor for AGEs binding activity. These results suggest that AKE, particularly chlorogenic acid, is useful in inhibiting AGE accumulation in retinal vessels and exerts a preventive effect against the injuries of diabetic retinal vascular cells.

  13. Three-year follow-up comparing metabolic surgery versus medical weight management in patients with type 2 diabetes and BMI 30-35. The role of sRAGE biomarker as predictor of satisfactory outcomes.

    Science.gov (United States)

    Horwitz, Daniel; Saunders, John K; Ude-Welcome, Aku; Marie Schmidt, Ann; Dunn, Van; Leon Pachter, H; Parikh, Manish

    2016-08-01

    Patients with type 2 diabetes (T2D) and body mass index (BMI)<35 may benefit from metabolic surgery. The soluble form of the receptor for advanced glycation end products (sRAGE) may identify patients at greater chance for T2D remission. To study long-term outcomes of patients with T2D and BMI 30-35 treated with metabolic surgery or medical weight management (MWM) and search for predictors of T2D remission. University METHODS: Retrospective review of the original cohort, including patients who crossed over from MWM to surgery. Repeated-measures linear models were used to model weight loss (%WL), change in glycated hemoglobin (HbA1C) and association with baseline sRAGE. Fifty-seven patients with T2D and BMI 30-35 were originally randomly assigned to metabolic surgery versus MWM. Mean BMI and HbA1C was 32.6% and 7.8%, respectively. A total of 30 patients underwent surgery (19 sleeves, 8 bypasses, 3 bands). Three-year follow-up in the surgery group and MWM group was 75% and 86%, respectively. Surgery resulted in higher T2D remission (63% versus 0%; P<.001) and lower HbA1C (6.9% versus 8.4%; P<.001) for up to 3 years. There was no difference in %WL in those with versus those without T2D remission (21.7% versus 20.6%, P = .771), suggesting that additional mechanisms other than %WL play an important role for the studied outcome. Higher baseline sRAGE was associated with greater change in HbA1C and greater %WL after surgery (P< .001). Metabolic surgery was effective in promoting remission of T2D in 63% of patients with BMI 30-35; higher baseline sRAGE predicted T2D remission with surgery. Larger-scale randomly assigned trials are needed in this patient population. Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

  14. Exorcising the demons of collectivism in art history’: Branko Mitrović, Rage and Denials. Collectivist Philosophy, Politics, and Art Historiography, 1890-1947, University Park, Pennsylvania University Press 2015

    Directory of Open Access Journals (Sweden)

    Ladislav Kesner

    2016-12-01

    Full Text Available Branko Mitrović´s Rage and Denials. Collectivist Philosophy, Politics, and Art Historiography, 1890-1947 traces the history of collectivist approaches in (art historiography and debates between the individualist and collectivist positions, with the dominant focus on German-speaking scholarship. Author further suggests that denials and false appropriations and other forms of bizzare and irrational claims inherent in many of these collectivist historiographies originated in the failures of self-esteem regulation of their authors. The review then critically examines some problematic claims and assumptions which constitute the theoretical and conceptual backbone of the historical survey.

  15. Road Rage Menace: A Cross-sectional Study to Assess Driver Anger Level in Public Motor Vehicle Drivers in a City in Central India

    Directory of Open Access Journals (Sweden)

    Sanjay Dixit

    2011-07-01

    Full Text Available Introduction: Road rage and aggressive driving is a prevalent condition in today’s society due to motorists’ frustrations during heavy traffic volumes. Objective: This study was done to assess the level of anger amongst the drivers of public transport vehicles in Indore, using Driving Anger Scale (DAS by Deffenbacher et. al. and various factors affecting it. Material and Methods: A cross-sectional study was conducted among 135 drivers of Public transport vehicle drivers (Star bus, City-van and star cab drivers in Indore to assess their anger level using Driving Anger Scale. The participants were required to record the amount of anger they would experience in response to each item in the scale (1=not at all angry, 2=a little angry, 3=some anger, 4=much anger, 5=very much angry. Results: The mean DAS score in Indore was found to be 3.013 and in the three organizations namely Star bus drivers, City van drivers and Star cab drivers was 2.92, 3.08 and 3.04 respectively. The DAS score of drivers with respect to the 6 sub-scales were: hostile gestures (Star bus -3.42,City van -3.67,Star cab -3.38, slow driving (Star bus -2.73,City van driv-2.78,Star cab-3.17, traffic obstructions (Star bus-2.85,City van -3.25,Star cab-3.18, discourtesy (Star bus -3.23,City van-3.33,Star cab -3.25and police presence (Star bus -2.15,City van -1.99,Star cab -2.78, illegal driving (Star bus -3.04,City van -3.14,Star cab -2.89. The DAS scores of the drivers did not vary significantly with age group, experience, and educational qualification. Conclusion: Though DAS scores did not vary between the three groups of drivers, however average level anger for various given circumstances commonly found in the Indian traffic scenario was on the higher side.

  16. Repérages bibliographiques

    Directory of Open Access Journals (Sweden)

    Sabrina Mommolin

    2015-10-01

    Full Text Available Commerce électronique - E-commerce AYDIN, E., SAVRUL, B. K. (2014, "The Relationship between Globalization and E-commerce: Turkish Case", Procedia - Social and Behavioral Sciences, vol. 150, pp. 1267-1276. BASTARD, I., BOURREAU, M., MOREAU, F. (2014, "L’impact du piratage sur l’achat et le téléchargement légal: Une comparaison de quatre filières culturelles", Revue économique, vol. 65, n°3, pp. 573-599. FEIZOLLAHI, S., SHIRMOHAMMADI, A., KAHREH, Z. S., et al. (2014, "Investigation the Effe...

  17. Repérages bibliographiques

    Directory of Open Access Journals (Sweden)

    Sabrina Mommolin

    2016-05-01

    Full Text Available Développement durable – Sustainable development APAK S., ATAY E. (2015, “Global Competitiveness in the EU through Green Innovation Technologies and Knowledge Production”, Procedia - Social and Behavioral Sciences, vol. 181, pp. 207-217. BORSDORF A., BENDER O., BRAUN F., HALLER A. (2015, Web-based instruments for strengthening sustainable regional development in the Alps, Geografski Zbornik / Acta Geographica Slovenica, vol. 55, N° 1, pp. 174-182. SIRSIKAR S.V., KAREMORE P. (2015, Design an...

  18. Repérages bibliographiques

    Directory of Open Access Journals (Sweden)

    Sabrina Mommolin

    2013-04-01

    Full Text Available Gouvernance – Governance AYANSO A., CHATTERJEE D., CHO D. I. (2011, “E-Government readiness index: A methodology and analysis”, Government Information Quarterly, vol. 28, n° 4, pp. 522-532. CHEN Y.-C., CHU P.-Y. (2011, Electronic Governance and Cross-Boundary Collaboration: Innovations and Advancing Tools, Hershey, PA: IGI Global, 422 p. ISBN: 9781609607548 CONCHA G., ASTUDILLO H., PORRÚA M. (et al. (2011, “E-Government procurement observatory, maturity model and early measurements”, Gove...

  19. Association analysis of nine candidate gene polymorphisms in Indian patients with type 2 diabetic retinopathy

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    Govindarajan Gowthaman

    2010-11-01

    Full Text Available Abstract Background Diabetic retinopathy (DR is classically defined as a microvasculopathy that primarily affects the small blood vessels of the inner retina as a complication of diabetes mellitus (DM.It is a multifactorial disease with a strong genetic component. The aim of this study is to investigate the association of a set of nine candidate genes with the development of diabetic retinopathy in a South Indian cohort who have type 2 diabetes mellitus (T2DM. Methods Seven candidate genes (RAGE, PEDF, AKR1B1, EPO, HTRA1, ICAM and HFE were chosen based on reported association with DR in the literature. Two more, CFH and ARMS2, were chosen based on their roles in biological pathways previously implicated in DR. Fourteen single nucleotide polymorphisms (SNPs and one dinucleotide repeat polymorphism, previously reported to show association with DR or other related diseases, were genotyped in 345 DR and 356 diabetic patients without retinopathy (DNR. The genes which showed positive association in this screening set were tested further in additional sets of 100 DR and 90 DNR additional patients from the Aravind Eye Hospital. Those which showed association in the secondary screen were subjected to a combined analysis with the 100 DR and 100 DNR subjects previously recruited and genotyped through the Sankara Nethralaya Hospital, India. Genotypes were evaluated using a combination of direct sequencing, TaqMan SNP genotyping, RFLP analysis, and SNaPshot PCR assays. Chi-square and Fisher exact tests were used to analyze the genotype and allele frequencies. Results Among the nine loci (15 polymorphisms screened, SNP rs2070600 (G82S in the RAGE gene, showed significant association with DR (allelic P = 0.016, dominant model P = 0.012, compared to DNR. SNP rs2070600 further showed significant association with DR in the confirmation cohort (P = 0.035, dominant model P = 0.032. Combining the two cohorts gave an allelic P HTRA1, rs11200638 (G>A, showed marginal

  20. GHB acid: A rage or reprive

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    Prakhar Kapoor

    2013-01-01

    Full Text Available Gamma-hydroxybutyric acid (GHB is a naturally occurring analog of gamma-aminobutyric acid (GABA that has been used in research and clinical medicine for many years. GHB was used clinically as an anesthetic in the 1960s but was withdrawn due to side effects that included seizures and coma. GHB has been implicated in a number of crime types; most notably in drug-facilitated sexual assault. GHB is abused by three main groups of users: Body builders who use the substance believing that it stimulated the release of growth hormone; sexual predators who covertly administer the drug for its sedative and amnesic effects and club-goers (rave parties who take the drug for its euphoric effects. The short-lived hypnotic effects, relative safety and widespread availability of the drug have made it particularly well suited to this role. The drug has an addictive potential if used for long term. The primary effects of GHB use are those of a CNS depressant and therefore range from relaxation, to euphoria, confusion, amnesia, hallucinations, and coma. Despite the increased regulation, GHB remains widely available through the Internet where one can easily purchase the necessary reagents as well as recipes for home production. There are reports of patients being unresponsive to painful stimuli and cases of oral self-mutilations linked to the abuse of GHB, though quiet rare. Such cases should remind odontologists that intra-oral lesions may be the result of self-mutilation either due to mental illness or altered states caused by the use of prescription or non-prescription drugs.

  1. The Roots of Muslim Rage Revisited

    Science.gov (United States)

    2013-03-01

    freedom of speech , our freedom to vote and assemble and disagree with each other” 24, and therefore “This is not […] just America’s fight, and what is at...widespread belief that Islam and western concepts such as democracy, freedom of speech and women’s rights are incompatible. In the aftermath of 9/11, the...Turkey, Indonesia, and Malaysia, which work fairly well.45 Furthermore, many in the Muslim world agree that political freedom, liberty, and freedom of speech , is

  2. Drug: D03807 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D03807 Drug Zenarestat (USAN/INN) ... C17H11BrClFN2O4 D03807.gif ... Antidiabetic agen...t ... DG01882 ... Aldose reductase inhibitor ... Treatment of diabetic neuropathy AKR1B1 [HSA:231] [KO:K00011] ... CA

  3. Thymoquinone-rich fraction nanoemulsion (TQRFNE) decreases Aβ40 and Aβ42 levels by modulating APP processing, up-regulating IDE and LRP1, and down-regulating BACE1 and RAGE in response to high fat/cholesterol diet-induced rats.

    Science.gov (United States)

    Ismail, Norsharina; Ismail, Maznah; Azmi, Nur Hanisah; Bakar, Muhammad Firdaus Abu; Yida, Zhang; Abdullah, Maizaton Atmadini; Basri, Hamidon

    2017-11-01

    Though the causes of Alzheimer's disease (AD) are yet to be understood, much evidence has suggested that excessive amyloid-β (Aβ) accumulation due to abnormal amyloid-β precursor protein (APP) processing and Aβ metabolism are crucial processes towards AD pathogenesis. Hence, approaches aiming at APP processing and Aβ metabolism are currently being actively pursued for the management of AD. Studies suggest that high cholesterol and a high fat diet have harmful effects on cognitive function and may instigate the commencement of AD pathogenesis. Despite the neuropharmacological attributes of black cumin seed (Nigella sativa) extracts and its main active compound, thymoquinone (TQ), limited records are available in relation to AD research. Nanoemulsion (NE) is exploited as drug delivery systems due to their capacity of solubilising non-polar active compounds and is widely examined for brain targeting. Herewith, the effects of thymoquinone-rich fraction nanoemulsion (TQRFNE), thymoquinone nanoemulsion (TQNE) and their counterparts' conventional emulsion in response to high fat/cholesterol diet (HFCD)-induced rats were investigated. Particularly, the Aβ generation; APP processing, β-secretase 1 (BACE1), γ-secretases of presenilin 1 (PSEN1) and presenilin 2 (PSEN2), Aβ degradation; insulin degrading enzyme (IDE), Aβ transportation; low density lipoprotein receptor-related protein 1 (LRP1) and receptor for advanced glycation end products (RAGE) were measured in brain tissues. TQRFNE reduced the brain Aβ fragment length 1-40 and 1-42 (Aβ40 and Aβ42) levels, which would attenuate the AD pathogenesis. This reduction could be due to the modulation of β- and γ-secretase enzyme activity, and the Aβ degradation and transportation in/out of the brain. The findings show the mechanistic actions of TQRFNE in response to high fat and high cholesterol diet associated to Aβ generation, degradation and transportation in the rat's brain tissue. Copyright © 2017 Elsevier

  4. Engineering of blood vessel patterns by angio-morphogens [angiotropins]: non-mitogenic copper-ribonucleoprotein cytokins [CuRNP ribokines] with their metalloregulated constituents of RAGE-binding S100-EF-hand proteins and extracellular RNA bioaptamers in vascular remodeling of tissue and angiogenesis in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Wissler, J.H. [ARCONS Applied Research, Bad Nauheim (Germany)

    2001-12-01

    Tissue vascularization is requisite to successful cell-based therapies, biomaterial design and implant integration. Thus, known problems in ossointegration of avascular implants in connection with the generation of bone tissue reflect arrays of general problems of socio-economic relevance existing in reparative medicine still waiting for to be solved. For this purpose, morphogenesis and remodeling of endothelial angio-architectures in tissue and in vitro by isolated non-mitogenic angio-morphogens [angiotropins] are considered in terms of their structure, function and action mechanisms. Extracellular angiotropins are secreted by activated leukocytes/monocytes/macrophages. They are a family of cytokines with morphogen bioactivity selectively directed to endothelial cells. Their structure was deciphered as metalloregulated copper-ribonucleoproteins [CuRNP ribokines]. They are built up of angiotropin-related S100-EF-hand protein [ARP] and highly modified and edited 5'end-phosphorylated RNA [ARNA], complexed together by copper ions. Oxidant-sensitive ARNA and their precursors represent novel types in a RNA world: They are the first isolated and sequenced forms of extracellular RNA [eRNA], may act as cytokine and bioaptamer, contain isoguanosine [crotonoside] as modified nucleoside and show up copper as RNA-structuring transition metal ion. By metalloregulated bioaptamer functions, ARNA impart novel biofunctions to RAGE-binding S100-EF-hand proteins. Angiotropin morphogens were shown suitable for neointiation and remodeling of blood vessel patterns in different, adult, embryonal and artificial tissues. These neovascular patterns manifest regulated hemodynamics for preventing tissue necrosis, supporting tissue functions and promoting wound healing. As evaluated in skin and muscle vascularization, the neovascular patterns are integrated into homeostatic control mechanisms of tissue. Thus, the morphogens show up beneficial perspectives and are suggested useful tools

  5. Fructose Synthesis and Transport at the Uterine-Placental Interface of Pigs: Cell-Specific Localization of SLC2A5, SLC2A8, and Components of the Polyol Pathway.

    Science.gov (United States)

    Steinhauser, Chelsie B; Landers, McKinsey; Myatt, Louise; Burghardt, Robert C; Vallet, Jeffrey L; Bazer, Fuller W; Johnson, Greg A

    2016-11-01

    The fetal fluids and uterine flushings of pigs contain higher concentrations of fructose than glucose, but fructose is not detected in maternal blood. Fructose can be synthesized from glucose via enzymes of the polyol pathway, aldose reductase (AKR1B1) and sorbitol dehydrogenase (SORD), transported across cell membranes by solute carriers SLC2A5 and SLC2A8, and converted to fructose-1-phosphate by ketohexokinase (KHK). SLC2A8, SLC2A5, AKR1B1, SORD, and KHK mRNAs and proteins were analyzed using quantitative PCR and immunohistochemistry or in situ hybridization in endometria and placentae of cyclic and pregnant gilts, cyclic gilts injected with estrogen, and ovariectomized gilts injected with progesterone. Progesterone up-regulated SLC2A8 protein in uterine luminal (LE) and glandular epithelia during the peri-implantation period, and expression became exclusively placental, chorion and blood vessels, after Day 30. P4 up-regulated SLC2A5 mRNA in uterine LE and glandular epithelia after implantation, and the chorion expressed SLC2A5 between Days 30 and 85. AKR1B1 and SORD proteins localized to uterine LE during the peri-implantation period, but expression switched to chorion by Day 20 and was maintained through Day 85. Uterine expression of AKR1B1 mRNA was down-regulated by estrogen. KHK protein localized to trophectoderm/chorion throughout gestation. These results provide evidence that components for the conversion of glucose to fructose and for fructose transport are present at the uterine-placental interface of pigs. The shift in expression from LE to chorion during pregnancy suggests free-floating conceptuses are supported by fructose synthesized by the uterus, but after implantation, the chorion becomes self-sufficient for fructose synthesis and transport. © 2016 by the Society for the Study of Reproduction, Inc.

  6. Design, Synthesis and in Combo Antidiabetic Bioevaluation of Multitarget Phenylpropanoic Acids

    Directory of Open Access Journals (Sweden)

    Blanca Colín-Lozano

    2018-02-01

    Full Text Available We have synthesized a small series of five 3-[4-arylmethoxyphenyl]propanoic acids employing an easy and short synthetic pathway. The compounds were tested in vitro against a set of four protein targets identified as key elements in diabetes: G protein-coupled receptor 40 (GPR40, aldose reductase (AKR1B1, peroxisome proliferator-activated receptor gama (PPARγ and solute carrier family 2 (facilitated glucose transporter, member 4 (GLUT-4. Compound 1 displayed an EC50 value of 0.075 μM against GPR40 and was an AKR1B1 inhibitor, showing IC50 = 7.4 μM. Compounds 2 and 3 act as slightly AKR1B1 inhibitors, potent GPR40 agonists and showed an increase of 2 to 4-times in the mRNA expression of PPARγ, as well as the GLUT-4 levels. Docking studies were conducted in order to explain the polypharmacological mode of action and the interaction binding mode of the most active molecules on these targets, showing several coincidences with co-crystal ligands. Compounds 1–3 were tested in vivo at an explorative 100 mg/kg dose, being 2 and 3 orally actives, reducing glucose levels in a non-insulin-dependent diabetes mice model. Compounds 2 and 3 displayed robust in vitro potency and in vivo efficacy, and could be considered as promising multitarget antidiabetic candidates. This is the first report of a single molecule with these four polypharmacological target action.

  7. Ritual, rage and revenge in 2 Maccabees 6 and 7

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    Pierre J. Jordaan

    2012-10-01

    Full Text Available The martyrs in 2 Maccabees 6 and 7 have been explored in various ways. In their commentaries on 2 Maccabees, Jan Willem van Henten and Daniel Schwartz proposed that the deaths of the martyrs should be seen as human sacrifices to please the deity. This idea has either been challenged or supported by scholars. This article supported the idea of human sacrifice, and applied the view of Richard DeMaris of the martyr’s deaths as exit rite to the above-mentioned texts. In essence this amounts to ritual critique. The results were surprising, and proved the model of DeMaris as a useful tool to examine rituals. The conclusion was reached that 2 Maccabees 6 and 7 is indeed an exit rite.

  8. From Rage to Rap and Prison to Print:

    Directory of Open Access Journals (Sweden)

    Josephine Metcalf

    2009-11-01

    Full Text Available 1. IntroductionBy the late 1980s, while thousands of former gang members were either dead or incarcerated, their legacy and the gang subculture was being celebrated and commodified through gangsta rap music and videos, film and fashion. In the early 1990s this lucrative cultural trend sparked interest from potential authors and publishers. Such literary attention was partially fuelled by a public fascination with life in the ghettos following the 1992 Los Angeles (LA riots, resulting in a ne...

  9. New Rage on Campus: E-Commerce Degrees.

    Science.gov (United States)

    Dobbs, Kevin

    1999-01-01

    As electronic commerce expands, higher education attempts to keep up with the demand for instruction. Some universities have added a concentration in e-commerce to their master of business administration program and others are adding majors, certifications, or degrees. (JOW)

  10. Peru v. Yale: A Battle Rages over Machu Picchu

    Science.gov (United States)

    Glenn, David

    2009-01-01

    In early 1916, the legendary Yale University archaeologist Hiram Bingham III completed his third and final expedition in southern Peru. He shipped home 74 boxes of artifacts from Machu Picchu, a spectacular site in the Andes that is believed to have been the last major settlement of the Inca empire. Those boxes were supposed to be on temporary…

  11. Reducing Adolescent Rage Bullies: Study on Behavior Management Training Intervention

    Directory of Open Access Journals (Sweden)

    M Beirami

    2016-12-01

    Full Text Available Background and aim: Adverse effects inner anger and interpersonal relationships will follow on from the other parent behavior management training and promoting and improving relations between parent-child.در این راستا هدف پژوهش حاضر بررسی اثربخشی آموزش مدیریت رفتار براساس مدل بارکلی در کاهش خشم دانش آموزان دختر و پسر قلدر دوره اول متوسطه بود. Methods: The present Experimental research used a pretest– posttest and a control group. جامعه آماری شامل دانش آموزان دختر و پسر دوره اول متوسطه شهر تبریز که در سال تحصیلی 93-1392 مشغول به تحصیل بودند. The population consisted of male and female junior high school students in Tabriz who were enrolled in the 2012-2013 school year. به منظور اجرای پژوهش پس از انجام سرند توسط معلمان و اجرای پرسشنامه قلدر/قربانی الویوس، 30نفر از کودکانی که براساس نمرات کسب شده در پرسشنامه الویوس، به عنوان قلدر طبقه بندی شده بودند به صورت تصادفی در دو گروه 15 نفری آزمایش و کنترل جایگزین شدند؛ و پس از تکمیل پرسشنامه خشم نیلسون(2000 توسط دانش آموزان قلدر؛ والدین گروه آزمایش به مدت 9جلسه (45 دقیقه ای در برنامه آموزش مدیریت رفتار قرارگرفتند، ولی گروه کنترل هیچگونه آموزشی دریافت نکرد.Therefore, after screening by the teachers and the Nelson anger questionnaire, 30 children who, according to scores on the questionnaire were bullies, were classified randomly into two groups of 15 cases and controls were replaced and after completing the questionnaire anger Nilsson (2000 bullying by students, parents groups for 9 sessions (45 minutes each were treated in a management training program, while the control group received no training. آزمودنی ها پس پایان جلسات آموزش مدیریت رفتار والدین ، مورد بررسی مجدد قرار گرفتند. Parent Management Training participants after the end of the session, were reviewed and followed a month later. داده ها با استفاده از نرم افزار آماری18 SPSS و با استفاده از شاخص های توصیفی و آزمون تحلیل کوواریانس چند متغیری مورد تجزیه وتحلیل قرار گرفتند. نتایج حاکی از اثربخشی آموزش مدیریت رفتاری والدین بر کاهش خشم نوجوانان قلدر (05/0 P< بود. Data were analyzed by the SPSS version 18 statistical software using descriptive indicators and multivariate analysis. Results: The results indicated the effectiveness of Parent Management Training to Reduce Anger of the teen bullies (P <0.05, respectively.فقط در مولفه های ناکامی و پرخاشگری بدنی تفاوت معنی داری نبود و در مقایسه اثربخشی آموزش مدیریت رفتار به دختران و پسران گروه آزمایش، نتایج نشان داد که در بین دختران و پسران گروه آزمایش تفاوت معناداری وجود ندارد این نشانگر این است که آموزش مدیریت رفتار به والدین درکاهش خشم نوجوانان قلدر، هردوگروه تاثیر مثبت داشته است. . نتایج درمرحله پیگیری نیز تفاوت معناداری (05/0 P< را بین گروه آزمایش وکنترل نشان داد. The results of the follow-up phase difference (P <0.05 between the test and control groups, respectively. Conclusion: The findings revealed that the behavioral management training had been effective in reducing anger bullying teenagers that might have been due to the effect of education on their daily relations. کلید واژه‌ها: آموزش مدیریت رفتار، بهزیستی روانشناختی، قلدری Keywords: Anger, Bulling, Behavior management training

  12. Surveillance épidémiologique de la rage humaine dans un contexte d’endémie de rage canine en Cote d’Ivoire

    OpenAIRE

    Tiembré , I.; Dagnan , S; Douba , A; Adjogoua , E V; Bourhy , Hervé; Dacheux , L; Kouassi , L; Dosso , M; Odehouri-Koudou , P; Tiembré , P

    2010-01-01

    International audience; The objective of this study was to analyze the epidemiologic monitoring of human rabies in the rabies medical center of Abidjan.; A cross-sectional study was undertaken based on files of patients having consulted in the rabies center after exposure and suspicion of human rabies between January 2001 and June 2009.; Twenty-six cases of human rabies were reported in 10,706,136 inhabitants (annual incidence of 0.028 cases per 100,000). The number of detected cases increase...

  13. Fighting Rage with Fear: The “Faces of Muhammad” and the Limits of Secular Rationality

    Directory of Open Access Journals (Sweden)

    Shirin S. Deylami

    2018-03-01

    Full Text Available In recent years, a number of incidents have pitted Islam against secularism and liberal democracy. This essay examines the Danish publication of the Prophet Muhammad cartoons in order to examine the deployment of rationality as a litmus test for political membership. It argues that Western media and political analysis of the protests surrounding the cartoons constructed Muslims as anti-rational and thus unfit for democratic citizenship. Such a deployment of rationality inhibits the possibility of and demands for political pluralism. The essay then looks to two disparate theorists of affective reason, Abdulkarim Soroush and William Connolly, to offer an alternative model of reason that encourages pluralist political engagement.

  14. Raging Against the Machine: Network Gatekeeping and Collective Action on Social Media Platforms

    Directory of Open Access Journals (Sweden)

    Sarah Myers West

    2017-09-01

    Full Text Available Social media platforms act as networked gatekeepers—by ranking, channeling, promoting, censoring, and deleting content they hold power to facilitate or hinder information flows. One of the mechanisms they use is content moderation, or the enforcement of which content is allowed or disallowed on the platform. Though content moderation relies on users’ labor to identify content to delete, users have little capacity to influence content policies or enforcement. Despite this, some social media users are turning to collective action campaigns, redirecting information flows by subverting the activities of moderators, raising the visibility of otherwise hidden moderation practices, and organizing constituencies in opposition to content policies. Drawing on the example of the campaign to change Facebook’s nudity policy, this paper examines the strategies and tactics of users turning to collective action, considering which factors are most influential in determining the success or failure of a campaign. It finds that network gatekeeping salience is a good model for assessing which collective action efforts are most likely to be effective in achieving individual user goals. This indicates that the users who are already most able to harness the attention economy of social media platforms are more likely to successfully navigate the content moderation process. The analysis concludes by attending to what users might learn from the dynamics of network gatekeeping as they seek to resist the asymmetrical power relations of platforms.

  15. Central Asia's raging waters the prospects of water conflict in Central Asia

    OpenAIRE

    Hartman, William B.

    2007-01-01

    This thesis examines the prospects of conflict caused by water scarcity in Central Asia. The thesis analyzes the three most recent political eras of Central Asia, Tsarist Russia, the Soviet Union and independence, utilizing indicators of water tensions including: water quality, water quantity, the management of water for multiple uses, the political divisions and geopolitical setting, state institutions and national water ethos. Although water is not likely to be the sole cause of a majo...

  16. NutrimiRAging: Micromanaging Nutrient Sensing Pathways through Nutrition to Promote Healthy Aging.

    Science.gov (United States)

    Micó, Víctor; Berninches, Laura; Tapia, Javier; Daimiel, Lidia

    2017-04-26

    Current sociodemographic predictions point to a demographic shift in developed and developing countries that will result in an unprecedented increase of the elderly population. This will be accompanied by an increase in age-related conditions that will strongly impair human health and quality of life. For this reason, aging is a major concern worldwide. Healthy aging depends on a combination of individual genetic factors and external environmental factors. Diet has been proved to be a powerful tool to modulate aging and caloric restriction has emerged as a valuable intervention in this regard. However, many questions about how a controlled caloric restriction intervention affects aging-related processes are still unanswered. Nutrient sensing pathways become deregulated with age and lose effectiveness with age. These pathways are a link between diet and aging. Thus, fully understanding this link is a mandatory step before bringing caloric restriction into practice. MicroRNAs have emerged as important regulators of cellular functions and can be modified by diet. Some microRNAs target genes encoding proteins and enzymes belonging to the nutrient sensing pathways and, therefore, may play key roles in the modulation of the aging process. In this review, we aimed to show the relationship between diet, nutrient sensing pathways and microRNAs in the context of aging.

  17. Rage against the machine? Google's self-driving cars versus human drivers.

    Science.gov (United States)

    Teoh, Eric R; Kidd, David G

    2017-12-01

    Automated driving represents both challenges and opportunities in highway safety. Google has been developing self-driving cars and testing them under employee supervision on public roads since 2009. These vehicles have been involved in several crashes, and it is of interest how this testing program compares to human drivers in terms of safety. Google car crashes were coded by type and severity based on narratives released by Google. Crash rates per million vehicle miles traveled (VMT) were computed for crashes deemed severe enough to be reportable to police. These were compared with police-reported crash rates for human drivers. Crash types also were compared. Google cars had a much lower rate of police-reportable crashes per million VMT than human drivers in Mountain View, Calif., during 2009-2015 (2.19 vs 6.06), but the difference was not statistically significant. The most common type of collision involving Google cars was when they got rear-ended by another (human-driven) vehicle. Google cars shared responsibility for only one crash. These results suggest Google self-driving cars, while a test program, are safer than conventional human-driven passenger vehicles; however, currently there is insufficient information to fully examine the extent to which disengagements affected these results. Results suggest that highly-automated vehicles can perform more safely than human drivers in certain conditions, but will continue to be involved in crashes with conventionally-driven vehicles. Copyright © 2017. Published by Elsevier Ltd.

  18. Fat-saturated diffusion-weighted imaging with three-dimensional MP-RAGE sequence

    International Nuclear Information System (INIS)

    Numano, Tomokazu; Homma, Kazuhiro; Takahashi, Nobuyuki; Hirose, Takeshi

    2005-01-01

    Image misrepresentation due to chemical shifts can create image artifacts on MR images. Distinguishing the organization and affected area can be difficult due to the chemical shift artifacts. Chemical shift selective (CHESS) is a method of decreasing chemical shift artifacts. In this study we have developed a new sequence for fat-saturated three-dimensional diffusion weighted MR imaging. This imaging was done during in vivo studies using an animal experiment MR imaging system at 2.0 T. In this sequence a preparation phase with a ''CHESS-90 deg RF-Motion Proving Gradient (MPG-180 deg RF-MPG-90 deg RF pulse train) was used to sensitize the magnetization to fat-saturated diffusion. Centric k-space acquisition order is necessary to minimize saturation effects from tissues with short relaxation times. From experimental results obtained with a phantom, the effect of the diffusion weighting and the effect of the fat-saturation were confirmed. From rat experimental results, fat-saturated diffusion weighted image data (0.55 x 0.55 x 0.55 mm 3 : voxel size) were obtained. This sequence was useful for in vivo imaging. (author)

  19. Rage against the Machine: Vincenzo Agnetti’s Critique of Industrial Alienation

    Directory of Open Access Journals (Sweden)

    Laura Moure Cecchini

    2012-12-01

    Full Text Available This essay analyzes the work of the Milanese artist Vincenzo Agnetti (1926-1981, in particular his pieces La macchina drogata (1968 and NEG (1970. Like other Italian artists and intellectuals of the 1960s and 1970s, Agnetti was concerned about the alienation caused by industrial development and consumer society, manifested in carefully designed objects of everyday use. To counteract the automatism of perception and thought that he considered the sign of alienated experience, Agnetti’s artworks employed several strategies that obliged the public to attend to its thinking processes. Thus, Agnetti put in practice forms of aesthetic estrangement similar to those evoked in the same period by Gillo Dorfles and Umberto Eco to counteract the widespread loss of awareness.

  20. Energy efficiency - The struggle for load management is raging. The French Riviera redoubles savings

    International Nuclear Information System (INIS)

    Moragues, Manuel; Barla, Jean-Christophe

    2014-01-01

    A first article discusses the debate initiated by a decree on load management associated with the French Brottes law on energy. Load management is the possibility for consumers to reduce their consumption at peak hours. Electricity producers and suppliers are of course against, whereas new actors (load managers or aggregators) are for. The issue is then to determine who will pay this managed (and not consumed) energy. The article also evokes a controversy about the Brottes law which creates a bonus to subsidy load management, and comments the development of this load management market and its legal framework. A second article describes actions undertaken by industries of the French Riviera to manage their energy consumption

  1. Relatively Conscious: The Enduring Rage of Baldwin and the Education of a White Southern Baptist Queer

    Directory of Open Access Journals (Sweden)

    Jon-Marc McDonald

    2016-12-01

    Full Text Available Delivered in Paris at the 2016 International James Baldwin Conference just two weeks before the killing of 49 individuals at a LGBT nightclub in Orlando, Florida on 26 June 2016, “Relatively Conscious” explores, through the eyes of an LGBT American and the words of James Baldwin, how separate and unequal life remains for so many within the United States. Written in the tradition of memoir, it recounts how, just as Paris saved Baldwin from himself, the writer’s life was transformedupon the discovery of Baldwin.

  2. RAGE and activation of chondrocytes and fibroblast-like synoviocytes in joint diseases

    NARCIS (Netherlands)

    Steenvoorden, Marjan Maria Claziena

    2007-01-01

    This dissertation describes a new model in which cartilage degradation can be studied. New cartilage is formed by bovine chondrocytes obtained from the slaughterhouse and cocultured with synovial cells from rheumatoid arthritis (RA) patients to study the interaction between the chondrocytes and

  3. Rest rages between physical execise under the influence of cardivascular sistem

    OpenAIRE

    Jurevičiūtė, Eglė

    2005-01-01

    SUMMARY Peculiarities of organizm to adaptation physical strain are very relevant problem to sport and its range. Relative narrow and particular purpose is raised in the solution of this problem: to estimate conception of professionals working in athletic club and those who goes in for sports there – abaut the importance of rest intervals in training for seeking result during the physical exercising also to ascertain the influence of rest intervals between physical strains to pe...

  4. GRAPPA reconstructed wave-CAIPI MP-RAGE at 7 Tesla.

    Science.gov (United States)

    Schwarz, Jolanda M; Pracht, Eberhard D; Brenner, Daniel; Reuter, Martin; Stöcker, Tony

    2018-04-16

    The aim of this project was to develop a GRAPPA-based reconstruction for wave-CAIPI data. Wave-CAIPI fully exploits the 3D coil sensitivity variations by combining corkscrew k-space trajectories with CAIPIRINHA sampling. It reduces artifacts and limits reconstruction induced spatially varying noise enhancement. The GRAPPA-based wave-CAIPI method is robust and does not depend on the accuracy of coil sensitivity estimations. We developed a GRAPPA-based, noniterative wave-CAIPI reconstruction algorithm utilizing multiple GRAPPA kernels. For data acquisition, we implemented a fast 3D magnetization-prepared rapid gradient-echo wave-CAIPI sequence tailored for ultra-high field application. The imaging results were evaluated by comparing the g-factor and the root mean square error to Cartesian CAIPIRINHA acquisitions. Additionally, to assess the performance of subcortical segmentations (calculated by FreeSurfer), the data were analyzed across five subjects. Sixteen-fold accelerated whole brain magnetization-prepared rapid gradient-echo data (1 mm isotropic resolution) were acquired in 40 seconds at 7T. A clear improvement in image quality compared to Cartesian CAIPIRINHA sampling was observed. For the chosen imaging protocol, the results of 16-fold accelerated wave-CAIPI acquisitions were comparable to results of 12-fold accelerated Cartesian CAIPIRINHA. In comparison to the originally proposed SENSitivity Encoding reconstruction of Wave-CAIPI data, the GRAPPA approach provided similar image quality. High-quality, wave-CAIPI magnetization-prepared rapid gradient-echo images can be reconstructed by means of a GRAPPA-based reconstruction algorithm. Even for high acceleration factors, the noniterative reconstruction is robust and does not require coil sensitivity estimations. By altering the aliasing pattern, ultra-fast whole-brain structural imaging becomes feasible. © 2018 International Society for Magnetic Resonance in Medicine.

  5. NutrimiRAging: Micromanaging Nutrient Sensing Pathways through Nutrition to Promote Healthy Aging

    Directory of Open Access Journals (Sweden)

    Víctor Micó

    2017-04-01

    Full Text Available Current sociodemographic predictions point to a demographic shift in developed and developing countries that will result in an unprecedented increase of the elderly population. This will be accompanied by an increase in age-related conditions that will strongly impair human health and quality of life. For this reason, aging is a major concern worldwide. Healthy aging depends on a combination of individual genetic factors and external environmental factors. Diet has been proved to be a powerful tool to modulate aging and caloric restriction has emerged as a valuable intervention in this regard. However, many questions about how a controlled caloric restriction intervention affects aging-related processes are still unanswered. Nutrient sensing pathways become deregulated with age and lose effectiveness with age. These pathways are a link between diet and aging. Thus, fully understanding this link is a mandatory step before bringing caloric restriction into practice. MicroRNAs have emerged as important regulators of cellular functions and can be modified by diet. Some microRNAs target genes encoding proteins and enzymes belonging to the nutrient sensing pathways and, therefore, may play key roles in the modulation of the aging process. In this review, we aimed to show the relationship between diet, nutrient sensing pathways and microRNAs in the context of aging.

  6. Central Asia's Raging Waters: The Prospects of Water Conflict in Central Asia

    National Research Council Canada - National Science Library

    Hartman, William B

    2007-01-01

    .... The thesis analyzes these three political eras of Central Asian history using indicators of water conflict, including water quality, water quantity, water management for multiple uses, political...

  7. Road rage: an exploratory study on aggressive driving experience on Indian roads.

    Science.gov (United States)

    Sagar, Rajesh; Mehta, Manju; Chugh, Geetanjali

    2013-06-01

    Driving on Indian roads is a stressful experience. A lacuna of research on aggressive driving experiences in the Indian set-up highlights the need to address this growing concern for individuals, society and mental health professionals. To explore and compare driving-related anger triggers and anger expression among high- and low-angry Indian drivers. Two hundred randomly chosen drivers from the city of Delhi were administered a semi-structured questionnaire intended to understand driving-related aggression. Honking, overtaking from the wrong side, loud music in other cars and hot and humid climate significantly increased the risk of experiencing anger among high-angry drivers. High-angry drivers were significantly more likely to engage in direct and aggressive expression of anger, including overtaking, verbal abuse, yelling and arguing, not giving space to other drivers, fighting, and hitting and bumping other cars in protest. Passive anger expressions such as holding grudges against other drivers and eating or drinking something to cool down were significantly more likely to be used by low-angry drivers. Drivers who are high on anger have a significantly higher risk of experiencing anger triggered by a variety of individual and environmental factors on Indian roads and are more susceptible to engage in aggressive driving behaviour.

  8. The impact of B1+ correction on MP2RAGE cortical T1 and apparent cortical thickness at 7T

    NARCIS (Netherlands)

    Haast, Roy A M; Ivanov, Dimo; Uludağ, Kâmil

    2018-01-01

    Determination of cortical thickness using MRI has often been criticized due to the presence of various error sources. Specifically, anatomical MRI relying on T1 contrast may be unreliable due to spatially variable image contrast between gray matter (GM), white matter (WM) and cerebrospinal fluid

  9. Receptor for Advanced Glycation End Products (RAGE) as a Novel Target for Inhibiting Breast Cancer Bone Metastasis

    Science.gov (United States)

    2013-04-01

    obtained from these three or four experiments. The statistical significance was determined by the Student’s t test and value of p \\ 0.05 was...Table S1. Statistical analysis Student t test was used to compare different experimental groups. P < 0.05 was considered to be statistically...We analyzed the effect of hS100A7 secreted into the conditioned media on chemotaxis of the differentiated monocytic cell line THP -1. hS100A7

  10. How to Rage Against the Dying of the Light? A Critique of Ritzer's McDonaldization Thesis.

    NARCIS (Netherlands)

    A. Peper (Bram)

    1996-01-01

    textabstractRitzer presents his 'The McDonalization of Society' as a social critique on the nationalization of modern society. In this article I will analyze the underlying assumptions of his critique. By means of a meta-theoretical analysis, I examine Ritzer's views on modernity and rationality.

  11. Gartley and Pesavento’s harmonic patterns: the corner of stability in the rage sea of technical analysis

    Directory of Open Access Journals (Sweden)

    Ruslan R. Rakhmangulov

    2013-01-01

    Full Text Available Rapid development of financial sector has been attracting many people who want to try themselves as investors during last decades. As statistics says, 9 out of 10 traders lose their money. They fly by the seat of their pants and this is the main reason of failures. Trading system, described in this work, promotes to order investment process and to make it profitable.

  12. Enzymes of the AKR1B and AKR1C subfamilies and uterine diseases

    Directory of Open Access Journals (Sweden)

    Tea eLanisnik Rizner

    2012-03-01

    Full Text Available Endometrial and cervical cancers, uterine myoma, and endometriosis are very common uterine diseases. Worldwide, more than 800,000 women are affected annually by gynecological cancers, as a result of which, more than 360,000 die. During their reproductive age, about 70% of women develop uterine myomas, 10% to 15% suffer from endometriosis, and 35% to 50% from infertility associated with endometriosis. Uterine diseases are associated with aberrant inflammatory responses and concomitant increased production of prostaglandins (PG. They are also related to decreased differentiation, due to low levels of protective progesterone and retinoic acid, and to enhanced proliferation, due to high local concentrations of estrogens. The pathogenesis of these diseases can thus be attributed to disturbed PG, estrogen and retinoid metabolism and actions. Five human members of the aldo-keto reductase 1B (AKR1B and 1C (AKR1C superfamilies, i.e., AKR1B1, AKR1B10, AKR1C1, AKR1C2 and AKR1C3, have roles in these processes and can thus be implicated in uterine diseases. AKR1B1 and AKR1C3 catalyze the formation of PGF2alpha which stimulates cell proliferation. AKR1C3 converts PGD2 to 9alpha,11beta-PGF2, and thus counteracts the formation of 15deoxy-PGJ2, which can activate pro-apoptotic peroxisome-proliferator-activated receptor beta. AKR1B10 catalyzes the reduction of retinal to retinol, and in thus lessens the formation of retinoic acid, with potential pro-differentiating actions. The AKR1C1-AKR1C3 enzymes also act as 17-keto- and 20-ketosteroid reductases to varying extents, and are implicated in increased estradiol and decreased progesterone levels. This review comprises a short introduction to uterine diseases, followed by an overview of the current literature on the AKR1B and AKR1C expression in the uterus and in uterine diseases. The potential implications of the AKR1B and AKR1C enzymes and their pathophysiologies are then discussed, followed by conclusions and

  13. Advanced glycation end products (AGEs) and its receptors in the pathogenesis of hyperthyroidism.

    Science.gov (United States)

    Caspar-Bell, Gudrun; Dhar, Indu; Prasad, Kailash

    2016-03-01

    Oxidative stress has been implicated in the pathogenesis of hyperthyroidism and its complications. Interaction of advanced glycation end products (AGEs) with receptor RAGE (receptor for AGEs) generates reactive oxygen species. Soluble receptor for AGEs (sRAGE) competes with RAGE for binding with AGEs and attenuates the generation of ROS. Low levels sRAGE and high levels AGEs would generate more ROS leading to hyperthyroidism and its complications. The objectives are to determine if levels of serum sRAGE are low and the levels of AGEs and AGEs/sRAGE are high in patients with hyperthyroidism. The study subjects comprised of 33 patients with hyperthyroidism and 20 controls. Levels of serum sRAGE were lower, while that of AGEs and AGEs/sRAGE were higher in patients compared to controls, being significant only for sRAGE and AGEs/sRAGE. When the levels of sRAGE, AGEs, and AGEs/sRAGE were assessed for hyperthyroidism associated with different diseases, the levels of sRAGE were lower in Hashimoto disease, and levels of AGEs were higher in patients with Graves' disease compared to control. The levels of AGEs/sRAGE were elevated in an all except patients with Hashimoto disease. The levels of AGEs, sRAGE, or AGEs/RAGE were not correlated with age, weight, and blood pressures except systolic pressure which was inversely correlated with sRAGE. The levels of sRAGE were negatively correlated with AGEs and AGEs/sRAGE. The levels of AGEs/sRAGE were positively correlated with AGEs. In conclusion, low levels of sRAGE, and high levels of AGEs and AGEs/sRAGE are risk biomarkers in the pathogenesis hyperthyroidism and its complications.

  14. Sulodexide prevents activation of the PLA2/COX-2/VEGF inflammatory pathway in human retinal endothelial cells by blocking the effect of AGE/RAGE.

    Science.gov (United States)

    Giurdanella, Giovanni; Lazzara, Francesca; Caporarello, Nunzia; Lupo, Gabriella; Anfuso, Carmelina Daniela; Eandi, Chiara M; Leggio, Gian Marco; Drago, Filippo; Bucolo, Claudio; Salomone, Salvatore

    2017-10-15

    Diabetic retinopathy is characterized by the breakdown of endothelial blood-retinal barrier. We tested the hypothesis that sulodexide (SDX), a highly purified glycosaminoglycan composed of 80% iduronylglycosaminoglycan sulfate and 20% dermatan sulfate, protects human retinal endothelial cells (HREC) from high glucose (HG)-induced damage, through the suppression of inflammatory ERK/cPLA2/COX-2/PGE 2 pathway, by blocking the effect of advanced glycation end-products (AGEs). HREC were treated with HG (25mM) or AGEs (glycated-BSA, 2mg/ml) for 48h, with or without SDX (60μg/ml) or aflibercept (AFL, 40μg/ml), a VEGF-trap. SDX protected HREC from HG-induced damage (MTT and LDH release) and preserved their blood-retinal barrier-like properties (Trans Endothelial Electrical Resistance and junction proteins, claudin-5, VE-cadherin and occludin, immunofluorescence and immunoblot) as well as their angiogenic potential (Tube Formation Assay). Both HG and AGEs increased phosphoERK and phospho-cPLA 2 , an effect counteracted by SDX and, less efficiently, by AFL. Both HG and exogenous VEGF (80ng/ml) increased PGE 2 release, an effect partially reverted by SDX for HG and by AFL for VEGF. Analysis of NFκB activity revealed that HG increased the abundance of p65 in the nuclear fraction (nuclear translocation), an effect entirely reverted by SDX, but only partially by AFL. SDX, AFL and SDX+AFL protected HREC even when added 24h after HG. These data show that SDX protects HREC from HG damage and suggest that it counteracts the activation of ERK/cPLA2/COX-2/PGE 2 pathway by reducing AGE-related signaling and downstream NFκB activity. This mechanism, partially distinct from VEGF blockade, may contribute to the therapeutic effect of SDX. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Cross-Sectional Analysis of Obesity and Serum Analytes in Males Identifies sRAGE as a Novel Biomarker Inversely Associated with Diverticulosis

    OpenAIRE

    Comstock, Sarah S.; Lewis, Markita M.; Pathak, Dorothy R.; Hortos, Kari; Kovan, Bruce; Fenton, Jenifer I.

    2014-01-01

    Diverticulosis can lead to diverticulitis, a colon condition involving inflammation and other complications. Diverticulosis can result from biological, behavioral, or genetic causes. However, the etiology of diverticulosis is unknown. Although diet is associated with diverticulosis, recent studies suggest other factors influence risk. We sought to identify anthropometric or serum markers that were associated with the presence of diverticulosis. To determine these associations, 126 asymptomati...

  16. High-Mobility Group Box 1 Mediates Fibroblast Activity via RAGE-MAPK and NF-κB Signaling in Keloid Scar Formation

    Directory of Open Access Journals (Sweden)

    Jihee Kim

    2017-12-01

    Full Text Available Emerging studies have revealed the involvement of high-mobility group box 1 (HMGB1 in systemic fibrotic diseases, yet its role in the cutaneous scarring process has not yet been investigated. We hypothesized that HMGB1 may promote fibroblast activity to cause abnormal cutaneous scarring. In vitro wound healing assay with normal and keloid fibroblasts demonstrated that HMGB1 administration promoted the migration of both fibroblasts with increased speed and a greater traveling distance. Treatment of the HMGB1 inhibitor glycyrrhizic acid (GA showed an opposing effect on both activities. To analyze the downstream mechanism, the protein levels of extracellular signal-regulated kinase (ERK 1/2, protein kinase B (AKT, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB were measured by western blot analysis. HMGB1 increased the expression levels of ERK1/2, AKT, and NF-κB compared to the control, which was suppressed by GA. HMGB1 promoted both normal and keloid fibroblasts migration to a degree equivalent to that achieved with TGF-β. We concluded that HMGB1 activates fibroblasts via the receptor for advanced glycation end product (RAGE—mitogen-activated protein kinases (MAPK and NF-κB interaction signaling pathways. Further knowledge of the relationship of HMGB1 with skin fibrosis may lead to a promising clinical approach to manage abnormal scarring.

  17. Long-Term Intake of Uncaria rhynchophylla Reduces S100B and RAGE Protein Levels in Kainic Acid-Induced Epileptic Seizures Rats

    Directory of Open Access Journals (Sweden)

    Nou-Ying Tang

    2017-01-01

    Full Text Available Epileptic seizures are crucial clinical manifestations of recurrent neuronal discharges in the brain. An imbalance between the excitatory and inhibitory neuronal discharges causes brain damage and cell loss. Herbal medicines offer alternative treatment options for epilepsy because of their low cost and few side effects. We established a rat epilepsy model by injecting kainic acid (KA, 12 mg/kg, i.p. and subsequently investigated the effect of Uncaria rhynchophylla (UR and its underlying mechanisms. Electroencephalogram and epileptic behaviors revealed that the KA injection induced epileptic seizures. Following KA injection, S100B levels increased in the hippocampus. This phenomenon was attenuated by the oral administration of UR and valproic acid (VA, 250 mg/kg. Both drugs significantly reversed receptor potentiation for advanced glycation end product proteins. Rats with KA-induced epilepsy exhibited no increase in the expression of metabotropic glutamate receptor 3, monocyte chemoattractant protein 1, and chemokine receptor type 2, which play a role in inflammation. Our results provide novel and detailed mechanisms, explaining the role of UR in KA-induced epileptic seizures in hippocampal CA1 neurons.

  18. Long-Term Intake of Uncaria rhynchophylla Reduces S100B and RAGE Protein Levels in Kainic Acid-Induced Epileptic Seizures Rats

    OpenAIRE

    Tang, Nou-Ying; Lin, Yi-Wen; Ho, Tin-Yun; Cheng, Chin-Yi; Chen, Chao-Hsiang; Hsieh, Ching-Liang

    2017-01-01

    Epileptic seizures are crucial clinical manifestations of recurrent neuronal discharges in the brain. An imbalance between the excitatory and inhibitory neuronal discharges causes brain damage and cell loss. Herbal medicines offer alternative treatment options for epilepsy because of their low cost and few side effects. We established a rat epilepsy model by injecting kainic acid (KA, 12?mg/kg, i.p.) and subsequently investigated the effect of Uncaria rhynchophylla (UR) and its underlying mec...

  19. Long-Term Intake of Uncaria rhynchophylla Reduces S100B and RAGE Protein Levels in Kainic Acid-Induced Epileptic Seizures Rats.

    Science.gov (United States)

    Tang, Nou-Ying; Lin, Yi-Wen; Ho, Tin-Yun; Cheng, Chin-Yi; Chen, Chao-Hsiang; Hsieh, Ching-Liang

    2017-01-01

    Epileptic seizures are crucial clinical manifestations of recurrent neuronal discharges in the brain. An imbalance between the excitatory and inhibitory neuronal discharges causes brain damage and cell loss. Herbal medicines offer alternative treatment options for epilepsy because of their low cost and few side effects. We established a rat epilepsy model by injecting kainic acid (KA, 12 mg/kg, i.p.) and subsequently investigated the effect of Uncaria rhynchophylla (UR) and its underlying mechanisms. Electroencephalogram and epileptic behaviors revealed that the KA injection induced epileptic seizures. Following KA injection, S100B levels increased in the hippocampus. This phenomenon was attenuated by the oral administration of UR and valproic acid (VA, 250 mg/kg). Both drugs significantly reversed receptor potentiation for advanced glycation end product proteins. Rats with KA-induced epilepsy exhibited no increase in the expression of metabotropic glutamate receptor 3, monocyte chemoattractant protein 1, and chemokine receptor type 2, which play a role in inflammation. Our results provide novel and detailed mechanisms, explaining the role of UR in KA-induced epileptic seizures in hippocampal CA1 neurons.

  20. Receptor for advanced glycation end products inhibits proliferation in osteoblast through suppression of Wnt, PI3K and ERK signaling

    International Nuclear Information System (INIS)

    Li, Guofeng; Xu, Jingren; Li, Zengchun

    2012-01-01

    Highlights: ► RAGE overexpression suppresses cell proliferation in MC3T3-E1 cells. ► RAGE overexpression decreases Wnt/β-catenin signaling. ► RAGE overexpression decreases ERK and PI3K signaling. ► Inhibition of Wnt signaling abolishes PI3K signaling restored by RAGE blockade. ► Inhibition of Wnt signaling abolishes ERK signaling restored by RAGE blockade. -- Abstract: Expression of receptor for advanced glycation end products (RAGE) plays a crucial role in bone metabolism. However, the role of RAGE in the control of osteoblast proliferation is not yet evaluated. In the present study, we demonstrate that RAGE overexpression inhibits osteoblast proliferation in vitro. The negative regulation of RAGE on cell proliferation results from suppression of Wnt, PI3K and ERK signaling, and is restored by RAGE neutralizing antibody. Prevention of Wnt signaling using Sfrp1 or DKK1 rescues RAGE-decreased PI3K and ERK signaling and cell proliferation, indicating that the altered cell growth in RAGE overexpressing cells is in part secondary to alterations in Wnt signaling. Consistently, RAGE overexpression inhibits the expression of Wnt targets cyclin D1 and c-myc, which is partially reversed by RAGE blockade. Overall, these results suggest that RAGE inhibits osteoblast proliferation via suppression of Wnt, PI3K and ERK signaling, which provides novel mechanisms by which RAGE regulates osteoblast growth.

  1. Receptor for advanced glycation end products inhibits proliferation in osteoblast through suppression of Wnt, PI3K and ERK signaling

    Energy Technology Data Exchange (ETDEWEB)

    Li, Guofeng [Department of Emergency Surgery, East Hospital, Tongji University School of Medicine, Shanghai 200120 (China); Xu, Jingren [Department of Traditional Chinese Orthopaedics, East Hospital, Tongji University School of Medicine, Shanghai 200120 (China); Li, Zengchun, E-mail: lizc.2007@yahoo.com.cn [Department of Emergency Surgery, East Hospital, Tongji University School of Medicine, Shanghai 200120 (China)

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer RAGE overexpression suppresses cell proliferation in MC3T3-E1 cells. Black-Right-Pointing-Pointer RAGE overexpression decreases Wnt/{beta}-catenin signaling. Black-Right-Pointing-Pointer RAGE overexpression decreases ERK and PI3K signaling. Black-Right-Pointing-Pointer Inhibition of Wnt signaling abolishes PI3K signaling restored by RAGE blockade. Black-Right-Pointing-Pointer Inhibition of Wnt signaling abolishes ERK signaling restored by RAGE blockade. -- Abstract: Expression of receptor for advanced glycation end products (RAGE) plays a crucial role in bone metabolism. However, the role of RAGE in the control of osteoblast proliferation is not yet evaluated. In the present study, we demonstrate that RAGE overexpression inhibits osteoblast proliferation in vitro. The negative regulation of RAGE on cell proliferation results from suppression of Wnt, PI3K and ERK signaling, and is restored by RAGE neutralizing antibody. Prevention of Wnt signaling using Sfrp1 or DKK1 rescues RAGE-decreased PI3K and ERK signaling and cell proliferation, indicating that the altered cell growth in RAGE overexpressing cells is in part secondary to alterations in Wnt signaling. Consistently, RAGE overexpression inhibits the expression of Wnt targets cyclin D1 and c-myc, which is partially reversed by RAGE blockade. Overall, these results suggest that RAGE inhibits osteoblast proliferation via suppression of Wnt, PI3K and ERK signaling, which provides novel mechanisms by which RAGE regulates osteoblast growth.

  2. Receptor for Advanced Glycation End Products Facilitates Host Defense during Escherichia coli-Induced Abdominal Sepsis in Mice

    NARCIS (Netherlands)

    van Zoelen, Marieke A. D.; Schmidt, Ann-Marie; Florquin, Sandrine; Meijers, Joost C.; de Beer, Regina; de Vos, Alex F.; Nawroth, Peter P.; Bierhaus, Angelika; van der Poll, Tom

    2009-01-01

    Background. The receptor for advanced glycation end products (RAGE) mediates a variety of inflammatory responses. Methods. To determine the role of RAGE in the innate immune response to abdominal sepsis caused by Escherichia coli, RAGE-deficient (RAGE(-/-)) and normal wild-type mice were

  3. Soluble Receptor for Advanced Glycation End Product Ameliorates Chronic Intermittent Hypoxia Induced Renal Injury, Inflammation, and Apoptosis via P38/JNK Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Xu Wu

    2016-01-01

    Full Text Available Obstructive sleep apnea (OSA associated chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH triggered tissue damage. Receptor for advanced glycation end product (RAGE and its ligand high mobility group box 1 (HMGB1 are expressed on renal cells and mediate inflammatory responses in OSA-related diseases. To determine their roles in CIH-induced renal injury, soluble RAGE (sRAGE, the RAGE neutralizing antibody, was intravenously administered in a CIH model. We also evaluated the effect of sRAGE on inflammation and apoptosis. Rats were divided into four groups: (1 normal air (NA, (2 CIH, (3 CIH+sRAGE, and (4 NA+sRAGE. Our results showed that CIH accelerated renal histological injury and upregulated RAGE-HMGB1 levels involving inflammatory (NF-κB, TNF-α, and IL-6, apoptotic (Bcl-2/Bax, and mitogen-activated protein kinases (phosphorylation of P38, ERK, and JNK signal transduction pathways, which were abolished by sRAGE but p-ERK. Furthermore, sRAGE ameliorated renal dysfunction by attenuating tubular endothelial apoptosis determined by immunofluorescence staining of CD31 and TUNEL. These findings suggested that RAGE-HMGB1 activated chronic inflammatory transduction cascades that contributed to the pathogenesis of the CIH-induced renal injury. Inhibition of RAGE ligand interaction by sRAGE provided a therapeutic potential for CIH-induced renal injury, inflammation, and apoptosis through P38 and JNK pathways.

  4. Vessel Ultrasound Sonographic Assessment of Soluble Receptor for Advanced Glycation End Products Efficacy in a Rat Balloon Injury Model

    Directory of Open Access Journals (Sweden)

    Hyun-Jin Tae, DVM, PhD

    2014-12-01

    Conclusions: Sonograph results are consistent with those obtained from histology; that is, sRAGE produced in Chinese hamster ovary cells has significantly higher efficacy than insect cell-originated sRAGE cells.

  5. Soluble Receptor for Advanced Glycation End Product: A Biomarker for Acute Coronary Syndrome

    Directory of Open Access Journals (Sweden)

    Louise J. N. Jensen

    2015-01-01

    Full Text Available The receptor of advanced glycation end products (RAGE and its ligands are linked to the pathogenesis of coronary artery disease (CAD, and circulating soluble receptor of advanced glycation end products (sRAGE, reflecting the RAGE activity, is suggested as a potential biomarker. Elevated sRAGE levels are reported in relation to acute ischemia and this review focuses on the role of sRAGE as a biomarker for the acute coronary syndrome (ACS. The current studies demonstrated that sRAGE levels are elevated in relation to ACS, however during a very narrow time period, indicating that the time of sampling needs attention. Interestingly, activation of RAGE may influence the pathogenesis and reflection in sRAGE levels in acute and stable CAD differently.

  6. Transient and Prolonged Response of Chicken Cecum Mucosa to Colonization with Different Gut Microbiota

    Science.gov (United States)

    Volf, Jiri; Polansky, Ondrej; Varmuzova, Karolina; Gerzova, Lenka; Sekelova, Zuzana; Faldynova, Marcela; Babak, Vladimir; Medvecky, Matej; Smith, Adrian L.; Kaspers, Bernd; Velge, Philippe; Rychlik, Ivan

    2016-01-01

    In this study we determined protein and gene expression in the caeca of newly hatched chickens inoculated with cecal contents sourced from hens of different ages. Over 250 proteins exhibited modified expression levels in response to microbiota inoculation. The most significant inductions were observed for ISG12-2, OASL, ES1, LYG2, DMBT1-L, CDD, ANGPTL6, B2M, CUZD1, IgM and Ig lambda chain. Of these, ISG12-2, ES1 and both immunoglobulins were expressed at lower levels in germ-free chickens compared to conventional chickens. In contrast, CELA2A, BRT-2, ALDH1A1, ADH1C, AKR1B1L, HEXB, ALDH2, ALDOB, CALB1 and TTR were expressed at lower levels following inoculation of microbiota. When chicks were given microbiota preparations from different age donors, the recipients mounted differential responses to the inoculation which also differed from the response profile in naturally colonised birds. For example, B2M, CUZD1 and CELA2A responded differently to the inoculation with microbiota of 4- or 40-week-old hens. The increased or decreased gene expression could be recorded 6 weeks after the inoculation of newly hatched chickens. To characterise the proteins that may directly interact with the microbiota we characterised chicken proteins that co-purified with the microbiota and identified a range of host proteins including CDD, ANGPTL6, DMBT1-L, MEP1A and Ig lambda. We propose that induction of ISG12-2 results in reduced apoptosis of host cells exposed to the colonizing commensal microbiota and that CDD, ANGPTL6, DMBT1-L, MEP1A and Ig lambda reduce contact of luminal microbiota with the gut epithelium thereby reducing the inflammatory response. PMID:27685470

  7. Effect of embryo density on in vitro development and gene expression in bovine in vitro-fertilized embryos cultured in a microwell system.

    Science.gov (United States)

    Sugimura, Satoshi; Akai, Tomonori; Hashiyada, Yutaka; Aikawa, Yoshio; Ohtake, Masaki; Matsuda, Hideo; Kobayashi, Shuji; Kobayashi, Eiji; Konishi, Kazuyuki; Imai, Kei

    2013-01-01

    To identify embryos individually during in vitro development, we previously developed the well-of-the-well (WOW) dish, which contains 25 microwells. Here we investigated the effect of embryo density (the number of embryos per volume of medium) on in vitro development and gene expression of bovine in vitro-fertilized embryos cultured in WOW dishes. Using both conventional droplet and WOW culture formats, 5, 15, and 25 bovine embryos were cultured in 125 μl medium for 168 h. The blastocysts at Day 7 were analyzed for number of cells and expression of ten genes (CDX2, IFN-tau, PLAC8, NANOG, OCT4, SOX2, AKR1B1, ATP5A1, GLUT1 and IGF2R). In droplet culture, the rates of formation of >4-cell cleavage embryos and blastocysts were significantly lower in embryos cultured at 5 embryos per droplet than in those cultured at 15 or 25 embryos per droplet, but not in WOW culture. In both droplet and WOW culture, developmental kinetics and blastocyst cell numbers did not differ among any groups. IFN-tau expression in embryos cultured at 25 embryos per droplet was significantly higher than in those cultured at 15 embryos per droplet and in artificial insemination (AI)-derived blastocysts. Moreover, IGF2R expression was significantly lower in the 25-embryo group than in the 5-embryo group and in AI-derived blastocysts. In WOW culture, these expressions were not affected by embryo density and were similar to those in AI-derived blastocysts. These results suggest that, as compared with conventional droplet culture, in vitro development and expression of IFN-tau and IGF2R in the microwell system may be insensitive to embryo density.

  8. Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population

    Science.gov (United States)

    Arenas, I. A.; Tremblay, J.; Deslauriers, B.; Sandoval, J.; Šeda, O.; Gaudet, D.; Merlo, E.; Kotchen, T.; Cowley, A. W.

    2013-01-01

    Blood pressure (BP) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions. Standing upright is a recent evolutionary trait, and genetic factors that influence postural adaptations may contribute to BP variability. We studied the effect of posture on the genetics of BP and intermediate BP phenotypes. We included 384 sib-pairs in 64 sib-ships from families ascertained by early-onset hypertension and dyslipidemia. Blood pressure, three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright. The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees. Linkage was conducted on 196 candidate genes by sib-pair analyses, and empirical estimates of significance were obtained. A permutation algorithm was implemented to study the postural effect on linkage. ADRA1A, APO, CAST, CORIN, CRHR1, EDNRB, FGF2, GC, GJA1, KCNB2, MMP3, NPY, NR3C2, PLN, TGFBR2, TNFRSF6, and TRHR showed evidence of linkage with any phenotype in the supine position and not upon standing, whereas AKR1B1, CD36, EDNRA, F5, MMP9, PKD2, PON1, PPARG, PPARGC1A, PRKCA, and RET were specifically linked to standing phenotypes. Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture. When investigators perform genetic studies exclusively on a single posture, important genetic components of BP are missed. Supine and standing BPs have distinct genetic signatures. Standardized maneuvers influence the results of genetic investigations into BP, thus reflecting its dynamic regulation. PMID:23269701

  9. Receptor for advanced glycation end product polymorphisms and type 2 diabetes: the CODAM study

    NARCIS (Netherlands)

    Gaens, K.H.; Kallen, C.J.; Greevenboek, van M.M.; Feskens, E.J.M.; Stehouwer, C.D.; Schalkwijk, C.G.

    2008-01-01

    Genetic variation in the receptor for advanced glycation end products (RAGE) gene may alter the expression and function of RAGE and affect disease development and outcome. We investigated whether single nucleotide polymorphisms (SNPs) in RAGE were associated with diabetes and parameters of glucose

  10. Correlation of human S100A12 (EN-RAGE) and high-sensitivity C-reactive protein as gingival crevicular fluid and serum markers of inflammation in chronic periodontitis and type 2 diabetes.

    Science.gov (United States)

    Pradeep, A R; Martande, Santosh S; Singh, Sonender Pal; Suke, Deepak Kumar; Raju, Arjun P; Naik, Savitha B

    2014-04-01

    The aim of the present study was to evaluate the levels and correlation of human S100A12 and high-sensitivity C-reactive protein (hs-CRP) in gingival crevicular fluid (GCF) and serum in chronic periodontitis (CP) subjects with and without type 2 diabetes mellitus (DM). A total of 44 subjects were divided into three groups: group 1 had 10 periodontally healthy subjects, group 2 consisted of 17 CP subjects and group 3 had 17 type 2 DM subjects with CP. GCF and serum levels of human S100A12 and hs-CRP were quantified using enzyme-linked immunosorbent assay and immunoturbidimetric analysis, respectively. The clinical outcomes evaluated were gingival index, probing depth and clinical attachment level and the correlations of the two inflammatory mediators with clinical parameters were evaluated. Both human S100A12 and hs-CRP levels increased from group 1 to group 2 to group 3. The GCF and serum values of both these inflammatory mediators correlated positively with each other and with the periodontal parameters evaluated (p < 0.05). Human S100A12 and hs-CRP can be considered as possible GCF and serum markers of inflammatory activity in CP and DM.

  11. The decrease in the IgG-binding capacity of intensively dry heated whey proteins is associatead with intense Maillard reaction, structural changes of the proteins and formation of RAGE-ligands

    NARCIS (Netherlands)

    Liu, F.; Teodorowicz, M.; Boekel, van M.A.J.S.; Wichers, H.J.; Hettinga, K.A.

    2016-01-01

    Heat treatment is the most common way of milk processing, inducing structural changes as well as chemical modifications in milk proteins. These modifications influence the immune-reactivity and allergenicity of milk proteins. This study shows the influence of dry heating on the solubility, particle

  12. Generation of Soluble Advanced Glycation End Products Receptor (sRAGE)-Binding Ligands during Extensive Heat Treatment of Whey Protein/Lactose Mixtures Is Dependent on Glycation and Aggregation

    NARCIS (Netherlands)

    Liu, Fahui; Teodorowicz, Gosia; Wichers, Harry J.; Boekel, van Tiny; Hettinga, Kasper A.

    2016-01-01

    Heating of protein- and sugar-containing materials is considered the primary factor affecting the formation of advanced glycation end products (AGEs). This study aimed to investigate the influence of heating conditions, digestion, and aggregation on the binding capacity of AGEs to the soluble AGE

  13. Correction: Kikuchi, K., et al., Potential of the Angiotensin Receptor Blockers (ARBs Telmisartan, Irbesartan, and Candesartan for Inhibiting the HMGB1/RAGE Axis in Prevention and Acute Treatment of Stroke. Int. J. Mol. Sci. 2013, 14, 18899–18924.

    Directory of Open Access Journals (Sweden)

    Kiyoshi Kikuchi

    2014-03-01

    Full Text Available The original version of the paper [1] reports that “This ACTIVE I study was supported by Pfizer” (Page 18905. However, the sponsors of the ACTIVE I study were actually Bristol-Myers Squibb and Sanofi-Aventis rather than Pfizer.

  14. Signal Diversity of Receptor for Advanced Glycation End Products.

    Science.gov (United States)

    Sakaguchi, Masakiyo; Kinoshita, Rie; Putranto, Endy Widya; Ruma, I Made Winarsa; Sumardika, I Wayan; Youyi, Chen; Tomonobu, Naoko; Yamamoto, Ken-Ichi; Murata, Hitoshi

    2017-12-01

    The receptor for advanced glycation end products (RAGE) is involved in inflammatory pathogenesis. It functions as a receptor to multiple ligands such as AGEs, HMGB1 and S100 proteins, activating multiple intracellular signaling pathways with each ligand binding. The molecular events by which ligand-activated RAGE controls diverse signaling are not well understood, but some progress was made recently. Accumulating evidence revealed that RAGE has multiple binding partners within the cytoplasm and on the plasma membrane. It was first pointed out in 2008 that RAGE's cytoplasmic tail is able to recruit Diaphanous-1 (Dia-1), resulting in the acquisition of increased cellular motility through Rac1/Cdc42 activation. We also observed that within the cytosol, RAGE's cytoplasmic tail behaves similarly to a Toll-like receptor (TLR4)-TIR domain, interacting with TIRAP and MyD88 adaptor molecules that in turn activate multiple downstream signals. Subsequent studies demonstrated the presence of an alternative adaptor molecule, DAP10, on the plasma membrane. The coupling of RAGE with DAP10 is critical for enhancing the RAGE-mediated survival signal. Interestingly, RAGE interaction on the membrane was not restricted to DAP10 alone. The chemotactic G-protein-coupled receptors (GPCRs) formyl peptide receptors1 and 2 (FPR1 and FPR2) also interacted with RAGE on the plasma membrane. Binding interaction between leukotriene B4 receptor 1 (BLT1) and RAGE was also demonstrated. All of the interactions affected the RAGE signal polarity. These findings indicate that functional interactions between RAGE and various molecules within the cytoplasmic area or on the membrane area coordinately regulate multiple ligand-mediated RAGE responses, leading to typical cellular phenotypes in several pathological settings. Here we review RAGE's signaling diversity, to contribute to the understanding of the elaborate functions of RAGE in physiological and pathological contexts.

  15. Lower serum endogenous secretory receptor for advanced glycation end product level as a risk factor of metabolic syndrome among Japanese adult men: a 2-year longitudinal study.

    Science.gov (United States)

    Momma, Haruki; Niu, Kaijun; Kobayashi, Yoritoshi; Huang, Cong; Chujo, Masahiko; Otomo, Atsushi; Tadaura, Hiroko; Miyata, Toshio; Nagatomi, Ryoichi

    2014-02-01

    Receptor for advanced glycation end products (RAGE) activation by its ligands is implicated in obesity-related metabolic disease and accelerated atherothrombosis. Circulating soluble (sRAGE) and/or endogenous secretory RAGE (esRAGE) may counteract the detrimental effects of RAGE. This study aimed at determining the relationship between circulating RAGE and metabolic syndrome (MetS) incidence among Japanese adult men. This 2-year longitudinal study included 426 Japanese men aged 30-83 years who had no MetS at baseline. Serum esRAGE and sRAGE were assayed by ELISA at baseline. Incident metabolic syndrome, defined according to the Asian cutoff based on the 2009 criteria of the American Heart Association Scientific Statements, was evaluated after the 2-year follow-up. During the follow-up period, 55 participants (12.9%) had newly diagnosed MetS. In the multiple logistic models comparing MetS risk in the lowest with that in the highest tertile of baseline esRAGE, a high serum esRAGE level was found to be significantly associated with a low risk of MetS [odds ratios (95% confidence interval), 0.37 (0.14-0.95); P for trend = 0.038] after adjusting for lifestyle and sociodemographic factors, serum high-sensitivity C-reactive protein level, estimated glomerular filtration rate, and MetS components at baseline. Although sRAGE and esRAGE were strongly correlated (r(s) = 0.88), the sRAGE level was not associated with MetS incidence. A high circulating esRAGE level, but not sRAGE level, was associated with a low MetS incidence among Japanese adult men.

  16. Clearance kinetics and matrix binding partners of the receptor for advanced glycation end products.

    Directory of Open Access Journals (Sweden)

    Pavle S Milutinovic

    Full Text Available Elucidating the sites and mechanisms of sRAGE action in the healthy state is vital to better understand the biological importance of the receptor for advanced glycation end products (RAGE. Previous studies in animal models of disease have demonstrated that exogenous sRAGE has an anti-inflammatory effect, which has been reasoned to arise from sequestration of pro-inflammatory ligands away from membrane-bound RAGE isoforms. We show here that sRAGE exhibits in vitro binding with high affinity and reversibly to extracellular matrix components collagen I, collagen IV, and laminin. Soluble RAGE administered intratracheally, intravenously, or intraperitoneally, does not distribute in a specific fashion to any healthy mouse tissue, suggesting against the existence of accessible sRAGE sinks and receptors in the healthy mouse. Intratracheal administration is the only effective means of delivering exogenous sRAGE to the lung, the organ in which RAGE is most highly expressed; clearance of sRAGE from lung does not differ appreciably from that of albumin.

  17. The distribution of advanced glycation end products and their receptor in the gastrointestinal tract in the rats

    DEFF Research Database (Denmark)

    Chen, Pengmin; Zhao, Jingbo; Gregersen, Hans

    2012-01-01

    To investigate the distribution of advanced glycation end products (AGEs) and their receptor (RAGE) in the gastrointestinal (GI) tract to provide a basis for further study of the association between AGE/RAGE and diabetic GI dysfunction. METHODS: The distribution of AGEs [N epsilon-(carboxymethyl)......To investigate the distribution of advanced glycation end products (AGEs) and their receptor (RAGE) in the gastrointestinal (GI) tract to provide a basis for further study of the association between AGE/RAGE and diabetic GI dysfunction. METHODS: The distribution of AGEs [N epsilon......-(carboxymethyl) lysine and N epsilon-(carboxyethyl) lysine] and RAGE were detected in the esopha-geal, gastric, duodenal, jejunal, ileal, colonic and rectal tissues of normal adult Wistar rats using immunohistochemistry. RESULTS: In the esophagus, AGEs and RAGE were mainly distributed in striated muscle cells...

  18. Receptor for advanced glycation end products and its ligand high-mobility group box-1 mediate allergic airway sensitization and airway inflammation.

    Science.gov (United States)

    Ullah, Md Ashik; Loh, Zhixuan; Gan, Wan Jun; Zhang, Vivian; Yang, Huan; Li, Jian Hua; Yamamoto, Yasuhiko; Schmidt, Ann Marie; Armour, Carol L; Hughes, J Margaret; Phipps, Simon; Sukkar, Maria B

    2014-08-01

    The receptor for advanced glycation end products (RAGE) shares common ligands and signaling pathways with TLR4, a key mediator of house dust mite (Dermatophagoides pteronyssinus) (HDM) sensitization. We hypothesized that RAGE and its ligand high-mobility group box-1 (HMGB1) cooperate with TLR4 to mediate HDM sensitization. To determine the requirement for HMGB1 and RAGE, and their relationship with TLR4, in airway sensitization. TLR4(-/-), RAGE(-/-), and RAGE-TLR4(-/-) mice were intranasally exposed to HDM or cockroach (Blatella germanica) extracts, and features of allergic inflammation were measured during the sensitization or challenge phase. Anti-HMGB1 antibody and the IL-1 receptor antagonist Anakinra were used to inhibit HMGB1 and the IL-1 receptor, respectively. The magnitude of allergic airway inflammation in response to either HDM or cockroach sensitization and/or challenge was significantly reduced in the absence of RAGE but not further diminished in the absence of both RAGE and TLR4. HDM sensitization induced the release of HMGB1 from the airway epithelium in a biphasic manner, which corresponded to the sequential activation of TLR4 then RAGE. Release of HMGB1 in response to cockroach sensitization also was RAGE dependent. Significantly, HMGB1 release occurred downstream of TLR4-induced IL-1α, and upstream of IL-25 and IL-33 production. Adoptive transfer of HDM-pulsed RAGE(+/+)dendritic cells to RAGE(-/-) mice recapitulated the allergic responses after HDM challenge. Immunoneutralization of HMGB1 attenuated HDM-induced allergic airway inflammation. The HMGB1-RAGE axis mediates allergic airway sensitization and airway inflammation. Activation of this axis in response to different allergens acts to amplify the allergic inflammatory response, which exposes it as an attractive target for therapeutic intervention. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  19. Differential Receptor for Advanced Glycation End Products Expression in Preeclamptic, Intrauterine Growth Restricted, and Gestational Diabetic Placentas.

    Science.gov (United States)

    Alexander, Kristen L; Mejia, Camilo A; Jordan, Clinton; Nelson, Michael B; Howell, Brian M; Jones, Cameron M; Reynolds, Paul R; Arroyo, Juan A

    2016-02-01

    Receptor for advanced glycation end products (RAGE) is a receptor implicated in the modulation of inflammation. Inflammation has been associated with pregnancy pathologies including preeclampsia (PE), intrauterine growth restriction (IUGR), and gestational diabetes mellitus (GDM). Our objective was to examine placental RAGE expression in PE, IUGR, and GDM complications. Human placental tissues were obtained for RAGE determination using Q-PCR, immunohistochemistry, and Western blot. Invasive trophoblast cells were cultured and treated with AGES for RAGE activation studies. Compared to control placenta, we observed: (i) decreased RAGE gene expression during GDM, (ii) increased RAGE protein in the PE placenta, and (iii) decreased RAGE protein in the IUGR placenta. In trophoblast cells exposed AGEs, we observed: (i) decreased trophoblast invasion, (ii) increased c-Jun N-terminal kinases (JNK) and Extracellular signal-regulated kinases (ERK), and (iii) increased TNF-α and IL-1β secretion. We conclude that placental RAGE is activated during PE and that RAGE-mediated inflammation in the trophoblast involves increased pro-inflammatory cytokine secretion. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Protective mechanisms against oxidative stress and angiopathy in young patients with diabetes type 1 (DM1).

    Science.gov (United States)

    Koutroumani, Nikolitsa; Partsalaki, Ioanna; Lamari, Fotini; Dettoraki, Athina; Gil, Andrea Paola Rojas; Karvela, Alexia; Kostopoulou, Eirini; Spiliotis, Bessie E

    2013-01-01

    Advanced glycation end-products (AGEs) via their receptor, RAGE, are involved in diabetic angiopathy. Soluble RAGE, an inhibitor of this axis, is formed by enzymatic catalysis (sRAGE) or alternative splicing (esRAGE). Malondialdehyde (MDA) is an oxidative stress marker, and ferric reducing ability of plasma (FRAP) is an anti-oxidant capacity marker. In isolated mononuclear blood cells from 110 DM1-patients (P) and 124 controls (C) (4-29 years) RAGE mRNA (g) and protein expression (pe) were measured by RT-PCR and Western immunoblotting, respectively. Plasma levels of CML (AGEs) and sRAGE were measured by ELISA, MDA by flurometry and FRAP according to 'Benzie and Strain'. P showed: (i) higher g of RAGE, especially in p>13 years of age and >5 years DM1, (ii) increased pe of esRAGE in DM1>5 years and (iii) increased FRAP and MDA. The increased esRAGE and FRAP with increased levels of CML and MDA possibly reflects a protective response against the formation of diabetic complications in these young diabetic patients.

  1. Pop / Tõnis Kahu

    Index Scriptorium Estoniae

    Kahu, Tõnis, 1962-

    2008-01-01

    Heliplaatidest: Chemical Brothers "Brotherhood", Plutonium 74 "Peittoalueen ulkopuolella", Disturbed "Indestructible", Thomas Feiner & Anywhen "The Opiates Revised", DefRage "Save Us from Religion", Kago "Mopskassi maja"

  2. TNF-α promotes nuclear enrichment of the transcription factor TonEBP/NFAT5 to selectively control inflammatory but not osmoregulatory responses in nucleus pulposus cells.

    Science.gov (United States)

    Johnson, Zariel I; Doolittle, Alexandra C; Snuggs, Joseph W; Shapiro, Irving M; Le Maitre, Christine L; Risbud, Makarand V

    2017-10-20

    Intervertebral disc degeneration (IDD) causes chronic back pain and is linked to production of proinflammatory molecules by nucleus pulposus (NP) and other disc cells. Activation of tonicity-responsive enhancer-binding protein (TonEBP)/NFAT5 by non-osmotic stimuli, including proinflammatory molecules, occurs in cells involved in immune response. However, whether inflammatory stimuli activate TonEBP in NP cells and whether TonEBP controls inflammation during IDD is unknown. We show that TNF-α, but not IL-1β or LPS, promoted nuclear enrichment of TonEBP protein. However, TNF-α-mediated activation of TonEBP did not cause induction of osmoregulatory genes. RNA sequencing showed that 8.5% of TNF-α transcriptional responses were TonEBP-dependent and identified genes regulated by both TNF-α and TonEBP. These genes were over-enriched in pathways and diseases related to inflammatory response and inhibition of matrix metalloproteases. Based on RNA-sequencing results, we further investigated regulation of novel TonEBP targets CXCL1 , CXCL2 , and CXCL3 TonEBP acted synergistically with TNF-α and LPS to induce CXCL1 -proximal promoter activity. Interestingly, this regulation required a highly conserved NF-κB-binding site but not a predicted TonE, suggesting cross-talk between these two members of the Rel family. Finally, analysis of human NP tissue showed that TonEBP expression correlated with canonical osmoregulatory targets TauT/SLC6A6 , SMIT/SLC5A3 , and AR/AKR1B1 , supporting in vitro findings that the inflammatory milieu during IDD does not interfere with TonEBP osmoregulation. In summary, whereas TonEBP participates in the proinflammatory response to TNF-α, therapeutic strategies targeting this transcription factor for treatment of disc disease must spare osmoprotective, prosurvival, and matrix homeostatic activities. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Genetics of Plasma Soluble Receptor for Advanced Glycation End-Products and Cardiovascular Outcomes in a Community-based Population: Results from the Atherosclerosis Risk in Communities Study.

    Directory of Open Access Journals (Sweden)

    Nisa M Maruthur

    Full Text Available Plasma soluble Receptor for Advanced Glycation End-products (sRAGE is a strong marker of vascular outcomes although evidence on the direction of association is mixed. Compared to whites, blacks have lower levels of sRAGE. We hypothesized that genetic determinants of sRAGE would help clarify the causal role of sRAGE and the black-white difference in sRAGE levels. We conducted a genome-wide analysis of sRAGE in whites and blacks from the Atherosclerosis Risk in Communities Study. Median plasma sRAGE levels were lower in blacks than whites (728 vs. 1067 pg/ml; P<0.0001. The T (vs. C allele of rs2070600, a missense variant in AGER, the gene encoding RAGE, was associated with approximately 50% lower sRAGE levels in both whites (N = 1,737; P = 7.26x10-16; minor allele frequency (MAF = 0.04 and blacks (N = 581; P = 0.02; MAF = 0.01. In blacks, the T (vs. C allele of rs2071288, intronic to AGER, was associated with 43% lower sRAGE levels (P = 2.22x10-8; MAF = 0.10 and was nearly absent in whites. These AGER SNPs explained 21.5% and 26% of the variation in sRAGE in blacks and whites, respectively, but did not explain the black-white difference in sRAGE. These SNPs were not significantly associated with incident death, coronary heart disease, diabetes, heart failure, or chronic kidney disease in whites (N = 8,130-9,017 or blacks (N = 2,293-2,871 (median follow up ~20 years. We identified strong genetic determinants of sRAGE that did not explain the large black-white difference in sRAGE levels or clearly influence risk of clinical outcomes, suggesting that sRAGE may not be a causal factor in development of these outcomes.

  4. The Receptor for Advanced Glycation End Products Impairs Host Defense in Pneumococcal Pneumonia

    NARCIS (Netherlands)

    van Zoelen, Marieke A. D.; Schouten, Marcel; de Vos, Alex F.; Florquin, Sandrine; Meijers, Joost C. M.; Nawroth, Peter P.; Bierhaus, Angelika; van der Poll, Tom

    2009-01-01

    Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that is expressed ubiquitously in the lungs. Engagement of RAGE leads to activation of multiple intracellular signaling pathways,

  5. Sputum–plasma ratio of soluble receptor for advanced glycation end-products in patients with chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Essam Gouda Hassanein

    2016-07-01

    Conclusions: sRAGE level either in induced sputum, plasma or sputum plasma ratio is not significantly different between stable COPD patients, smokers and healthy controls. Thus, sRAGE cannot be considered as a marker of either diagnosis or severity of COPD.

  6. Soluble receptor for advanced glycation end-product levels are related to albuminuria and arterial stiffness in essential hypertension.

    Science.gov (United States)

    Dimitriadis, K; Tsioufis, C; Kasiakogias, A; Miliou, A; Poulakis, M; Kintis, K; Bafakis, I; Benardis, E; Tousoulis, D; Stefanadis, C

    2013-04-01

    Emerging evidence suggests that the soluble receptor for advanced glycation end-products (sRAGE) is implicated in the development of vascular disease. We investigated the interrelationships of sRAGE with albumin to creatinine ratio (ACR) and arterial stiffness in essential hypertension. In 309 untreated non-diabetic hypertensives, ACR values were determined as the mean of three non-consecutive morning spot urine samples and aortic stiffness was evaluated on the basis of carotid to femoral pulse wave velocity (c-f PWV). In all subjects, venous blood sampling was performed for the estimation of sRAGE levels. Patients with low (n = 155) compared to those with high sRAGE values (n = 154) had greater 24-h systolic BP (140 ± 8 vs. 134 ± 7 mmHg, p involvement of sRAGE in the progression of hypertensive vascular damage. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. Spatial and temporal dynamics of receptor for advanced glycation endproducts, integrins, and actin cytoskeleton as probed with fluorescence-based imaging techniques

    Energy Technology Data Exchange (ETDEWEB)

    Syed, Aleem [Iowa State Univ., Ames, IA (United States)

    2016-01-01

    Systematic spatial and temporal fluctuations are a fundamental part of any biological process. For example, lateral diffusion of membrane proteins is one of the key mechanisms in their cellular function. Lateral diffusion governs how membrane proteins interact with intracellular, transmembrane, and extracellular components to achieve their function. Herein, fluorescence-based techniques are used to elucidate the dynamics of receptor for advanced glycation end-products (RAGE) and integrin membrane proteins. RAGE is a transmembrane protein that is being used as a biomarker for various diseases. RAGE dependent signaling in numerous pathological conditions is well studied. However, RAGE lateral diffusion in the cell membrane is poorly understood. For this purpose, effect of cholesterol, cytoskeleton dynamics, and presence of ligand on RAGE lateral diffusion is investigated.

  8. RAGE阻断剂FPS-ZM1减轻异氟醚麻醉诱发老龄大鼠认知功能障碍%RAGE inhibitor FPS-ZM1 reduces isoflurane anesthesia induced cognitive dysfunction in aged rats

    Institute of Scientific and Technical Information of China (English)

    史成梅; 易端; 李正迁; 郭向阳

    2016-01-01

    目的 探讨RAGE阻断剂FPS-ZM1对异氟醚麻醉诱发老龄大鼠认知功能障碍的影响.方法 将老龄大鼠60只,随机分为4组(n=15):NS+ O2组、NS+ ISO组、FPS-ZM1+ ISO组及FPS-ZM1+ O2组.NS+ O2组及NS+ ISO组,侧脑室注射无菌0.9%氯化钠溶液10 μL,FPS-ZM1+ISO及FPS-ZM1+O2组,侧脑室注射FPS-ZM1 10 μL(5 g/L).侧脑室注射后24 h,NS+ O2及FPS-ZM1+ O2组吸人含有30%氧气的空氧混合气体4h,FPS-ZM1+ ISO及FPS-ZM1+ ISO组吸入2%异氟醚+100%氧气4h.用Morris水迷宫评测大鼠学习和记忆功能,用免疫组织化学技术观察海马CA1区RAGE及Aβ的表达.结果 与NS+ O2组相比,NS+ ISO组第1~4天逃避潜伏期延长、探索时间缩短、海马CA1区RAGE表达上调、Aβ表达上调.与NS+ ISO组相比,FPS-ZM1+ ISO组第1~4天逃避潜伏期缩短,探索时间延长,RAGE表达下调、Aβ表达下调.结论 RAGE阻断剂FPS-ZM1可改善异氟醚麻醉诱发老年大鼠认知功能障碍,其机制可能与其抑制海马CA1区Aβ沉积有关.

  9. Serum level of soluble receptor for advanced glycation end products in asthmatic children and its correlation to severity and pulmonary functions.

    Science.gov (United States)

    El-Seify, Magda Y Hussein; Fouda, Eman Mahmoud; Nabih, Enas Samir

    2014-01-01

    Soluble receptor for advanced glycation end products (sRAGE) acts as a decoy receptor for RAGE which has several distinct pro-inflammatory ligands in the extracellular compartment, and is believed to afford protection against inflammation and cell injury. This study was conducted to measure serum sRAGE in asthmatic children and to assess its correlation with clinical and functional severity and to asthma phenotype according to sputum cytology. The study was conducted on 60 asthmatic children from the Pediatric Chest Clinic, Children's Hospital, Ain Shams University. The patients were divided according to asthma control and severity. sRAGE showed statistically significant lower levels in asthmatic patients (899.1 +/- 399.8 pg/mL) compared to the control group (1406.7 +/- 474.3 pg/mL, p = 0.000), with a cut off value of asthma diagnosis of 1080.4 pg/mL with a sensitivity and specificity of 77% and 75%, respectively. Uncontrolled and severe asthmatic subgroups showed lower levels of sRAGE, cut off value of sRAGE for the severity of asthma was 829 pg/mL with 89% sensitivity and 81% specificity. Asthmatic patients stratified according to sputum cytology revealed that those with > 2% eosinophils and > or = 40% neutrophils showed lower levels of sRAGE (710 +/- 258 pg/mL) compared to those with > 2% eosinophils and functionally. It may be a target of future therapeutic interventions.

  10. Overexpression of Receptor for Advanced Glycation End Products and High-Mobility Group Box 1 in Human Dental Pulp Inflammation

    Directory of Open Access Journals (Sweden)

    Salunya Tancharoen

    2014-01-01

    Full Text Available High mobility group box 1 (HMGB1, a nonhistone DNA-binding protein, is released into the extracellular space and promotes inflammation. HMGB1 binds to related cell signaling transduction receptors, including receptor for advanced glycation end products (RAGE, which actively participate in vascular and inflammatory diseases. The aim of this study was to examine whether RAGE and HMGB1 are involved in the pathogenesis of pulpitis and investigate the effect of Prevotella intermedia (P. intermedia lipopolysaccharide (LPS on RAGE and HMGB1 expression in odontoblast-like cells (OLC-1. RAGE and HMGB1 expression levels in clinically inflamed dental pulp were higher than those in healthy dental pulp. Upregulated expression of RAGE was observed in odontoblasts, stromal pulp fibroblasts-like cells, and endothelial-like cell lining human pulpitis tissue. Strong cytoplasmic HMGB1 immunoreactivity was noted in odontoblasts, whereas nuclear HMGB1 immunoreactivity was seen in stromal pulp fibroblasts-like cells in human pulpitis tissue. LPS stimulated OLC-1 cells produced HMGB1 in a dose-dependent manner through RAGE. HMGB1 translocation towards the cytoplasm and secretion from OLC-1 in response to LPS was inhibited by TPCA-1, an inhibitor of NF-κB activation. These findings suggest that RAGE and HMGB1 play an important role in the pulpal immune response to oral bacterial infection.

  11. Association of high mobility group BOX-1 and receptor for advanced glycation endproducts with clinicopathological features of haematological malignancies: a systematic review

    Directory of Open Access Journals (Sweden)

    Austin H. Nguyen

    2017-01-01

    Full Text Available High-mobility group box 1 (HMGB1 is a versatile protein with nuclear and extracellular functions. In the extracellular milieu, HMGB1 binds to several receptors, notably the receptor for advanced glycation end-products (RAGE. The expressions of HMGB1 and RAGE have been described in a variety of cancers. However, the clinical values of HMGB1 and RAGE in haematological malignancies have yet to be evaluated. A systematic search through PubMed and the Web of Science for articles discussing the role of HMGB1 and RAGE in haematological malignancies produced 15 articles. Overexpression of HMGB1 was reported to be associated with malignancy and, in certain studies, poor prognosis and tumour aggressiveness. Only one included study investigated the clinical value of RAGE, in which no significant difference was found between expression of RAGE in CLL neoplastic cells and nonmalignant controls. The discussed associations of HMGB1 and RAGE with clinicopathological characteristics of patients with haematological malignancies warrants further investigation into the prognostic and diagnostic value of both of these molecules.

  12. Soluble and Endogenous Secretory Receptors for Advanced Glycation End Products in Threatened Preterm Labor and Preterm Premature Rupture of Fetal Membranes

    Directory of Open Access Journals (Sweden)

    Rafał Rzepka

    2015-01-01

    Full Text Available The aim of the study was to compare sRAGE and esRAGE plasma levels in pregnant women with (A threatened premature labor (n=41, (B preterm premature rupture of membranes (n=49, and (C preterm rupture of membranes at term (n=48. The relationship between these and classic intrauterine infection markers and the latent time from symptoms up to delivery depending on RAGE’s concentration were investigated. In groups A and B, a positive correlation was found between plasma sRAGE and latent time (r = 0,422; p = 0,001; r = 0,413, p = 0,004, resp.. High prognostic values were found in both groups for plasma sRAGE concentration and the latent time from symptoms up to delivery. Groups B and C presented higher levels of esRAGE than group A (526,315 ± 129,453 pg/mL and 576,212 ± 136,237 pg/mL versus 485,918 ± 133,127 pg/mL, p< 0,05. The conclusion is that sRAGE concentration can be a favorable prognostic factor in the presence of symptoms of threatened premature labor. Higher esRAGE plasma level in case of the rupture of membranes in mature and premature pregnancy suggests its participation in fetal membranes destruction.

  13. Soluble and Endogenous Secretory Receptors for Advanced Glycation End Products in Threatened Preterm Labor and Preterm Premature Rupture of Fetal Membranes

    Science.gov (United States)

    Dołegowska, Barbara; Kwiatkowski, Sebastian; Sałata, Daria; Budkowska, Marta; Domański, Leszek; Mikołajek-Bedner, Wioletta; Torbé, Andrzej

    2015-01-01

    The aim of the study was to compare sRAGE and esRAGE plasma levels in pregnant women with (A) threatened premature labor (n = 41), (B) preterm premature rupture of membranes (n = 49), and (C) preterm rupture of membranes at term (n = 48). The relationship between these and classic intrauterine infection markers and the latent time from symptoms up to delivery depending on RAGE's concentration were investigated. In groups A and B, a positive correlation was found between plasma sRAGE and latent time (r = 0,422; p = 0,001; r = 0,413, p = 0,004, resp.). High prognostic values were found in both groups for plasma sRAGE concentration and the latent time from symptoms up to delivery. Groups B and C presented higher levels of esRAGE than group A (526,315 ± 129,453 pg/mL and 576,212 ± 136,237 pg/mL versus 485,918 ± 133,127 pg/mL, ppremature labor. Higher esRAGE plasma level in case of the rupture of membranes in mature and premature pregnancy suggests its participation in fetal membranes destruction. PMID:26413536

  14. Soluble Receptor for Advanced Glycation End-Products Predicts Impaired Alveolar Fluid Clearance in Acute Respiratory Distress Syndrome.

    Science.gov (United States)

    Jabaudon, Matthieu; Blondonnet, Raiko; Roszyk, Laurence; Bouvier, Damien; Audard, Jules; Clairefond, Gael; Fournier, Mathilde; Marceau, Geoffroy; Déchelotte, Pierre; Pereira, Bruno; Sapin, Vincent; Constantin, Jean-Michel

    2015-07-15

    Levels of the soluble form of the receptor for advanced glycation end-products (sRAGE) are elevated during acute respiratory distress syndrome (ARDS) and correlate with severity and prognosis. Alveolar fluid clearance (AFC) is necessary for the resolution of lung edema but is impaired in most patients with ARDS. No reliable marker of this process has been investigated to date. To verify whether sRAGE could predict AFC during ARDS. Anesthetized CD-1 mice underwent orotracheal instillation of hydrochloric acid. At specified time points, lung injury was assessed by analysis of blood gases, alveolar permeability, lung histology, AFC, and plasma/bronchoalveolar fluid measurements of proinflammatory cytokines and sRAGE. Plasma sRAGE and AFC rates were also prospectively assessed in 30 patients with ARDS. The rate of AFC was inversely correlated with sRAGE levels in the plasma and the bronchoalveolar fluid of acid-injured mice (Spearman's ρ = -0.73 and -0.69, respectively; P < 10(-3)), and plasma sRAGE correlated with AFC in patients with ARDS (Spearman's ρ = -0.59; P < 10(-3)). Similarly, sRAGE levels were significantly associated with lung injury severity, and decreased over time in mice, whereas AFC was restored and lung injury resolved. Our results indicate that sRAGE levels could be a reliable predictor of impaired AFC during ARDS, and should stimulate further studies on the pathophysiologic implications of RAGE axis in the mechanisms leading to edema resolution. Clinical trial registered with www.clinicaltrials.gov (NCT 00811629).

  15. 糖基化终末产物及其受体在糖尿病大鼠胃组织中的分布 (Distribution of advanced glycation end products and their receptor in the stomach of diabetic rats)

    DEFF Research Database (Denmark)

    Tian, Jia Xing; Zhao, Jingbo; Li, Min

    2015-01-01

    AIM: To observe the distribution of advanced glycation end products (AGEs) and their receptor (RAGE) in the stomach of diabetic rats. METHODS: Diabetes mellitus (DM) and control (CON) rats were reared for eight weeks. Fasting plasma glucose (FPG), glycated serum protein (GSP) and gastric layer...... with the CON group (P stomach was significantly higher in the DM group than in the CON group (P ...: The expression of AGEs and RAGE is up-regulated in the stomach of diabetic rats. The increased levels of AGE and RAGE in gastric tissue may contribute to diabetic gastrointestinal dysfunction. © 2015 Baishideng Publishing Group Inc. All rights reserved. Key Words: Diabetes mellitus; Stomach; Advanced glycation...

  16. Fandango and the Rhetoric of Resistance in Flamenco

    Directory of Open Access Journals (Sweden)

    Tony Dumas

    2015-01-01

    socioeconómico. Como dice una de las bailaoras des Flo6x8,flamenco captures perfectly how we feel about the crisis. You can use it to express desperation, rage, pain, and the desire to change things.

  17. Depression in Teens

    Science.gov (United States)

    ... Sadness and hopelessness Lack of enthusiasm, energy or motivation Anger and rage Overreaction to criticism Feelings of ... Monthly Gift Legacy Gift Clifford Beers Society In Memory In Honor Other Ways to Give Policy Current ...

  18. Fulltext PDF

    Indian Academy of Sciences (India)

    the beginning of this century when a great debate raged in biology on the mechanism of adaptive evolution. Darwin's original theory of evolution by natural selection had left open ... Of course this event -like life, history and even the universe.

  19. Revisions in Need of Revising: What Went Wrong in the Iraq War

    National Research Council Canada - National Science Library

    Hendrickson, David C; Tucker, Robert W

    2005-01-01

    ... and its American occupiers -- criminal anarchy and lawlessness, a raging insurgency, and a society divided into rival and antagonistic groups -- were virtually inevitable consequences that flowed from the act of war itself...

  20. Political Christianity in Renaissance Drama

    Science.gov (United States)

    Al-Joulan, Nayef Ali

    2017-01-01

    Examining the following selected Renaissance dramas: Marlowe's "The Jew of Malta" (1585), Shakespeare's "The Merchant of Venice" (1596), Massinger's "The Renegado" (1624), Daborne's "A Christian Turn'd Turk" (1612), and Goffe's "The Raging Turk" (1656), this research investigates Renaissance…

  1. Coping with Feelings

    Medline Plus

    Full Text Available ... resources that can help you with home care, transportation and social needs. Think about why you feel ... and oxygen to the heart. Anger is a problem when you often: Lose your temper. Feel rage ...

  2. A very brief history of relativity

    Science.gov (United States)

    O'Raifeartaigh, Cormac

    2015-08-01

    On 25 November 1915, as devastating war raged throughout Europe, Albert Einstein presented the paper Die Feldgleichungen der Gravitation (“The field equations of gravitation”) to the Prussian Academy of Sciences.

  3. Correlation of expressions of S100A8 and S100A9 and its ...

    African Journals Online (AJOL)

    (S100A9) in nasopharyngeal carcinoma (NPC) tissues and their correlation with clinical pathological characteristics and ..... receptor (RAGE), a process which also activates .... S100A8 and S100A9 between Prostate Cancer and. BPH.

  4. Intermittent Explosive Disorder

    Science.gov (United States)

    ... explosive disorder involves repeated, sudden episodes of impulsive, aggressive, violent behavior or angry verbal outbursts in which you react grossly out of proportion to the situation. Road rage, domestic abuse, throwing or breaking objects, or other temper tantrums ...

  5. Effect of tomato cultivars, honey finisher and processing methods on ...

    African Journals Online (AJOL)

    use

    2011-12-14

    Dec 14, 2011 ... microbiological and sensory quality of tomato ketchup that was prepared using low-cost ... The color of tomato ketchup samples were measured by comparing it with standard color chart .... multiple rage tests. RESULTS AND ...

  6. Foreign remedies: what the experience of other nations can tell us about next steps in reforming U.S. health care

    National Research Council Canada - National Science Library

    Rochefort, David A; Donnelly, Kevin P

    2012-01-01

    "The Patient Protection and Affordable Care Act marked a watershed in U.S. health policy, but controversy over its passage rages on, and much uncertainty surrounds the law's transformation from blueprint into operational program...

  7. Water policy: Science versus political realities

    Science.gov (United States)

    Ryan, Mark A.

    2017-11-01

    Debate rages over which water bodies in the US are protected under federal law by the Clean Water Act. Science shows that isolated wetlands and headwater systems provide essential downstream services, but convincing politicians is another matter.

  8. Uusi plaate / Marko T. Lepp

    Index Scriptorium Estoniae

    Lepp, Marko T.

    1999-01-01

    Uutest plaatidest Enrique Iglesias "Enrique", Will Smith "Willennium", Celine Dion "All The Way... A Decade Of Song". Korn "Issues", Rage Agains The Machine "The Battle Of Los Angeles", Sevendust "Home"

  9. Subcontracting in electronics : from contract manufacturers to providers of electronic manufacturing services (EMS)

    OpenAIRE

    Liemt van, Gijsbert

    2007-01-01

    Discusses how the top contract manufacturers in the electronics industry try to become providers of electronic manufacturing services by deepening and broadening the rage of services that they offer and by diversifying into markets other than computing and telecommunications.

  10. Clinical significance of RECK and MMP-9 expression in ... - AJOL

    African Journals Online (AJOL)

    DR. NJ TONUKARI

    2012-04-17

    Apr 17, 2012 ... RECK [mouse anti-human monoclonal (MMP-9) or rabbit anti- human polyclonal ..... Li R, Deng Y (2010). Expression of RECK, RAGE and MMP-9 in ... Matrix metalloproteinase-2 and -9 involvement in canine tumors. Vet.

  11. The Experience of Violence by Male Juvenile Offenders Convicted ...

    African Journals Online (AJOL)

    Christopher R Stones

    psychological, personal and social dimensions. ... mostly emotional in nature and included emotions such as anger, rage and fury. ... police statistics do not differentiate between age .... and adolescents have perceptual tendencies that are.

  12. Theological reflections on empire | Boesak | HTS Teologiese ...

    African Journals Online (AJOL)

    2004), and the adoption of the Accra Declaration, a debate has been raging in the churches about globalisation, socio-economic justice, ecological responsibility, political and cultural domination and globalised war. Central to this debate is the ...

  13. ORIGINAL ARTICLES Homicidal violence during foreign military ...

    African Journals Online (AJOL)

    2003-11-12

    Nov 12, 2003 ... explosive rage with little or no warning and may be associated with substance use ... reported to the Regimental Aid Post complaining of fatigue, restlessness and ... European country by hitting him on the head. Although the.

  14. The Trinity River Greenway: A Prototype

    Science.gov (United States)

    1972-06-01

    study have gone into the formulation of a multipurpose plan of management designed to tame the raging waters of the Trinity, subdue its flooding crests...TABLE 6 MAMMALS OF THE STUDY AREA Shorttail Shrew (Blarina brevicauda) Beaver (Castor canadensis) Least Shrew (Crytotis parva) Armadillo (Dasypjs...property resulted. The Trinity became an J :enemy, a raging torrent to be tamed and eventually subdued. Meanwhile, thoughful men began to realize that

  15. Receptor for advanced glycation end products mediates sepsis-triggered amyloid-β accumulation, Tau phosphorylation, and cognitive impairment.

    Science.gov (United States)

    Gasparotto, Juciano; Girardi, Carolina S; Somensi, Nauana; Ribeiro, Camila T; Moreira, José C F; Michels, Monique; Sonai, Beatriz; Rocha, Mariane; Steckert, Amanda V; Barichello, Tatiana; Quevedo, João; Dal-Pizzol, Felipe; Gelain, Daniel P

    2018-01-05

    Patients recovering from sepsis have higher rates of CNS morbidities associated with long-lasting impairment of cognitive functions, including neurodegenerative diseases. However, the molecular etiology of these sepsis-induced impairments is unclear. Here, we investigated the role of the receptor for advanced glycation end products (RAGE) in neuroinflammation, neurodegeneration-associated changes, and cognitive dysfunction arising after sepsis recovery. Adult Wistar rats underwent cecal ligation and perforation (CLP), and serum and brain (hippocampus and prefrontal cortex) samples were obtained at days 1, 15, and 30 after the CLP. We examined these samples for systemic and brain inflammation; amyloid-β peptide (Aβ) and Ser-202-phosphorylated Tau (p-Tau Ser-202 ) levels; and RAGE, RAGE ligands, and RAGE intracellular signaling. Serum markers associated with the acute proinflammatory phase of sepsis (TNFα, IL-1β, and IL-6) rapidly increased and then progressively decreased during the 30-day period post-CLP, concomitant with a progressive increase in RAGE ligands (S100B, N ϵ-[carboxymethyl]lysine, HSP70, and HMGB1). In the brain, levels of RAGE and Toll-like receptor 4, glial fibrillary acidic protein and neuronal nitric-oxide synthase, and Aβ and p-Tau Ser-202 also increased during that time. Of note, intracerebral injection of RAGE antibody into the hippocampus at days 15, 17, and 19 post-CLP reduced Aβ and p-Tau Ser-202 accumulation, Akt/mechanistic target of rapamycin signaling, levels of ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein, and behavioral deficits associated with cognitive decline. These results indicate that brain RAGE is an essential factor in the pathogenesis of neurological disorders following acute systemic inflammation. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Prairie du Chien: A Historical Study,

    Science.gov (United States)

    1976-10-01

    of the mounds excavated had grave goods in them, typical Hopewell copper beads, breastplates, silver beads, bear canine teeth, and pottery vessels...Chien area. During this period, from 1753-1763, the French and Indian War (Seven Year War in Europe) raged through the wilder- ness from the Mississippi...appears to have spread through this village. Unlike the 1781 version which merely states that a type of disease had recently raged through this village

  17. Cardiomyocyte mitochondrial respiration is reduced by receptor for advanced glycation end-product signaling in a ceramide-dependent manner.

    Science.gov (United States)

    Nelson, Michael B; Swensen, Adam C; Winden, Duane R; Bodine, Jared S; Bikman, Benjamin T; Reynolds, Paul R

    2015-07-01

    Cigarette smoke exposure is associated with an increased risk of cardiovascular complications. The role of advanced glycation end products (AGEs) is already well established in numerous comorbidities, including cardiomyopathy. Given the role of AGEs and their receptor, RAGE, in activating inflammatory pathways, we sought to determine whether ceramides could be a mediator of RAGE-induced altered heart mitochondrial function. Using an in vitro model, we treated H9C2 cardiomyocytes with the AGE carboxy-methyllysine before mitochondrial respiration assessment. We discovered that mitochondrial respiration was significantly impaired in AGE-treated cells, but not when cotreated with myriocin, an inhibitor of de novo ceramide biosynthesis. Moreover, we exposed wild-type and RAGE knockout mice to secondhand cigarette smoke and found reduced mitochondrial respiration in the left ventricular myocardium from wild-type mice, but RAGE knockout mice were protected from this effect. Finally, conditional overexpression of RAGE in the lungs of transgenic mice elicited a robust increase in left ventricular ceramides in the absence of smoke exposure. Taken together, these findings suggest a RAGE-ceramide axis as an important contributor to AGE-mediated disrupted cardiomyocyte mitochondrial function. Copyright © 2015 the American Physiological Society.

  18. Advanced glycation end products impair function of late endothelial progenitor cells through effects on protein kinase Akt and cyclooxygenase-2

    International Nuclear Information System (INIS)

    Chen Qin; Dong Li; Wang Lian; Kang Lina; Xu Biao

    2009-01-01

    Endothelial progenitor cells (EPCs) exhibit impaired function in the context of diabetes, and advanced glycation end products (AGEs), which accumulate in diabetes, may contribute to this. In the present study, we investigated the mechanism by which AGEs impair late EPC function. EPCs from human umbilical cord blood were isolated, and incubated with AGE-modified albumin (AGE-albumin) at different concentrations found physiologically in plasma. Apoptosis, migration, and tube formation assays were used to evaluate EPC function including capacity for vasculogenesis, and expression of the receptor for AGEs (RAGE), Akt, endothelial nitric oxide synthase (eNOS), and cycloxygenase-2 (COX-2) were determined. Anti-RAGE antibody was used to block RAGE function. AGE-albumin concentration-dependently enhanced apoptosis and depressed migration and tube formation, but did not affect proliferation, of late EPCs. High AGE-albumin increased RAGE mRNA and protein expression, and decreased Akt and COX-2 protein expression, whilst having no effect on eNOS mRNA or protein in these cells. These effects were inhibited by co-incubation with anti-RAGE antibody. These results suggest that RAGE mediates the AGE-induced impairment of late EPC function, through down-regulation of Akt and COX-2 in these cells.

  19. Elevated Serum Level of HMGB1 in Patients with the Antiphospholipid Syndrome

    Directory of Open Access Journals (Sweden)

    Valeria Manganelli

    2017-01-01

    Full Text Available Pregnancy problems are common in patients with rheumatic disease; indeed, autoimmune disorders and autoantibodies can affect pregnancy progress and lead to maternal complications. Recent studies have highlighted a close association between HMGB1, chronic inflammation, and autoimmune diseases. Thus, in this investigation, we analyzed serum levels of HMGB1, an alarmin which plays a pivotal role in inducing and enhancing immune cell function. Sera from 30 patients with antiphospholipid syndrome (11 primary and 19 secondary APS, 35 subjects with pregnancy morbidity, and 30 healthy women were analysed for HMGB1 and its putative receptor RAGE (sRAGE by Western blot and for TNF-α by ELISA. Results revealed that APS patients showed significantly increased serum levels of HMGB1, sRAGE, and the proinflammatory cytokine TNF-α, as compared to healthy women. However, also, the pregnancy morbidity subjects showed significantly increased levels of HMGB1 and sRAGE as well as TNF-α compared to healthy women. Our findings suggest that in subjects with pregnancy morbidity, including obstetric APS, elevated levels of HMGB1/sRAGE may represent an alarm signal, indicating an increase of proinflammatory triggers. Further studies are needed to evaluate the role of HMGB1/sRAGE as a possible tool to evaluate the risk stratification of adverse pregnancy outcomes.

  20. Receptor for advanced glycation end-products is a marker of type I lung alveolar cells.

    Science.gov (United States)

    Shirasawa, Madoka; Fujiwara, Naoyuki; Hirabayashi, Susumu; Ohno, Hideki; Iida, Junko; Makita, Koshi; Hata, Yutaka

    2004-02-01

    Lung alveolar epithelial cells are comprised of type I (ATI) and type II (ATII) cells. ATI cells are polarized, although they have very flat morphology. The identification of marker proteins for apical and basolateral membranes of ATI cells is important to investigate into the differentiation of ATI cells. In this paper, we characterized receptor for advanced glycation end-products (RAGE) as a marker for ATI cells. RAGE was localized on basolateral membranes of ATI cells in the immunoelectron microscopy and its expression was enhanced in a parallel manner to the differentiation of ATI cells in vivo and in primary cultures of ATII cells. RAGE and T1 alpha, a well-known ATI marker protein, were targeted to basolateral and apical membranes, respectively, when expressed in polarized Madine Darby canine kidney cells. Moreover, RAGE was expressed in ATI cells after T1 alpha in vivo and in ex in vivo organ cultures. In conclusion, RAGE is a marker for basolateral membranes of well-differentiated ATI cells. ATI cells require some signal provided by the in vivo environment to express RAGE.

  1. Brain structures and neurotransmitters regulating aggression in cats: implications for human aggression.

    Science.gov (United States)

    Gregg, T R; Siegel, A

    2001-01-01

    1. Violence and aggression are major public health problems. 2. The authors have used techniques of electrical brain stimulation, anatomical-immunohistochemical techniques, and behavioral pharmacology to investigate the neural systems and circuits underlying aggressive behavior in the cat. 3. The medial hypothalamus and midbrain periaqueductal gray are the most important structures mediating defensive rage behavior, and the perifornical lateral hypothalamus clearly mediates predatory attack behavior. The hippocampus, amygdala, bed nucleus of the stria terminalis, septal area, cingulate gyrus, and prefrontal cortex project to these structures directly or indirectly and thus can modulate the intensity of attack and rage. 4. Evidence suggests that several neurotransmitters facilitate defensive rage within the PAG and medial hypothalamus, including glutamate, Substance P, and cholecystokinin, and that opioid peptides suppress it; these effects usually depend on the subtype of receptor that is activated. 5. A key recent discovery was a GABAergic projection that may underlie the often-observed reciprocally inhibitory relationship between these two forms of aggression. 6. Recently, Substance P has come under scrutiny as a possible key neurotransmitter involved in defensive rage, and the mechanism by which it plays a role in aggression and rage is under investigation. 7. It is hoped that this line of research will provide a better understanding of the neural mechanisms and substrates regulating aggression and rage and thus establish a rational basis for treatment of disorders associated with these forms of aggression.

  2. Receptor for advanced glycation end-products and World Trade Center particulate induced lung function loss: A case-cohort study and murine model of acute particulate exposure.

    Science.gov (United States)

    Caraher, Erin J; Kwon, Sophia; Haider, Syed H; Crowley, George; Lee, Audrey; Ebrahim, Minah; Zhang, Liqun; Chen, Lung-Chi; Gordon, Terry; Liu, Mengling; Prezant, David J; Schmidt, Ann Marie; Nolan, Anna

    2017-01-01

    World Trade Center-particulate matter(WTC-PM) exposure and metabolic-risk are associated with WTC-Lung Injury(WTC-LI). The receptor for advanced glycation end-products (RAGE) is most highly expressed in the lung, mediates metabolic risk, and single-nucleotide polymorphisms at the AGER-locus predict forced expiratory volume(FEV). Our objectives were to test the hypotheses that RAGE is a biomarker of WTC-LI in the FDNY-cohort and that loss of RAGE in a murine model would protect against acute PM-induced lung disease. We know from previous work that early intense exposure at the time of the WTC collapse was most predictive of WTC-LI therefore we utilized a murine model of intense acute PM-exposure to determine if loss of RAGE is protective and to identify signaling/cytokine intermediates. This study builds on a continuing effort to identify serum biomarkers that predict the development of WTC-LI. A case-cohort design was used to analyze a focused cohort of male never-smokers with normal pre-9/11 lung function. Odds of developing WTC-LI increased by 1.2, 1.8 and 1.0 in firefighters with soluble RAGE (sRAGE)≥97pg/mL, CRP≥2.4mg/L, and MMP-9≤397ng/mL, respectively, assessed in a multivariate logistic regression model (ROCAUC of 0.72). Wild type(WT) and RAGE-deficient(Ager-/-) mice were exposed to PM or PBS-control by oropharyngeal aspiration. Lung function, airway hyperreactivity, bronchoalveolar lavage, histology, transcription factors and plasma/BAL cytokines were quantified. WT-PM mice had decreased FEV and compliance, and increased airway resistance and methacholine reactivity after 24-hours. Decreased IFN-γ and increased LPA were observed in WT-PM mice; similar findings have been reported for firefighters who eventually develop WTC-LI. In the murine model, lack of RAGE was protective from loss of lung function and airway hyperreactivity and was associated with modulation of MAP kinases. We conclude that in a multivariate adjusted model increased sRAGE is

  3. Concentration of Endogenous Secretory Receptor for Advanced Glycation End Products and Matrix Gla Protein in Controlled and Uncontrolled Type 2 Diabetes Mellitus Patients

    Directory of Open Access Journals (Sweden)

    Dwi Yuniati Daulay

    2013-04-01

    Full Text Available BACKGROUND: Advanced glycation end products (AGE and their receptor (RAGE system play an important role in the development of diabetic vascular complications. Recently, an endogenous secretory RAGE (esRAGE has been identified as a novel splice variant, which lacks the transmembrane domain and is secreted in human sera. Interestingly, it was reported that esRAGE binds AGE ligands and neutralizes AGE actions. Many studies have reported that diabetes mellitus correlates with vascular calcification event and increases progressively in uncontrolled diabetes. Matrix Gla Protein (MGP is known to act as an inhibitor in vascular calcification. The aim of this study was to observe progress of vascular calcification in uncontrolled diabetes patient by biochemical markers MGP as inhibitor in vascular calcification, via mechanism of AGEs. METHODS: This study was an observational study with cross sectional design on adult type 2 diabetic male patients who were defined by the 2011 Indonesian diabetes mellitus consensus criteria. RESULTS: The results of this study showed that there was a positive significant correlation between esRAGE and HbA1C (r=0.651, p=0.009, and negative correlation between MGP and HbA1C (r=-0.465, p=0.081 in controlled diabetes group. In uncontrolled diabetes group there was a positive significant correlation between MGP and HbA1C (r=0.350, p=0.023, despite the fact esRAGE showed no significant correlation with HbA1C. There was no significant difference in level of esRAGE and MGP in controlled and uncontrolled diabetes group, but MGP showed lower level in uncontrolled diabetes group, contrary to esRAGE that had higher concentration. CONCLUSIONS: In diabetes condition, complications of vascular calcification are caused by the mechanism of increased AGE formation represented by esRAGE. In diabetes control it is very important to keep the blood vessels from complications caused by vascular calcification. KEYWORDS: type 2 diabetes mellitus

  4. Receptor for advanced glycation end-products and World Trade Center particulate induced lung function loss: A case-cohort study and murine model of acute particulate exposure.

    Directory of Open Access Journals (Sweden)

    Erin J Caraher

    Full Text Available World Trade Center-particulate matter(WTC-PM exposure and metabolic-risk are associated with WTC-Lung Injury(WTC-LI. The receptor for advanced glycation end-products (RAGE is most highly expressed in the lung, mediates metabolic risk, and single-nucleotide polymorphisms at the AGER-locus predict forced expiratory volume(FEV. Our objectives were to test the hypotheses that RAGE is a biomarker of WTC-LI in the FDNY-cohort and that loss of RAGE in a murine model would protect against acute PM-induced lung disease. We know from previous work that early intense exposure at the time of the WTC collapse was most predictive of WTC-LI therefore we utilized a murine model of intense acute PM-exposure to determine if loss of RAGE is protective and to identify signaling/cytokine intermediates. This study builds on a continuing effort to identify serum biomarkers that predict the development of WTC-LI. A case-cohort design was used to analyze a focused cohort of male never-smokers with normal pre-9/11 lung function. Odds of developing WTC-LI increased by 1.2, 1.8 and 1.0 in firefighters with soluble RAGE (sRAGE≥97pg/mL, CRP≥2.4mg/L, and MMP-9≤397ng/mL, respectively, assessed in a multivariate logistic regression model (ROCAUC of 0.72. Wild type(WT and RAGE-deficient(Ager-/- mice were exposed to PM or PBS-control by oropharyngeal aspiration. Lung function, airway hyperreactivity, bronchoalveolar lavage, histology, transcription factors and plasma/BAL cytokines were quantified. WT-PM mice had decreased FEV and compliance, and increased airway resistance and methacholine reactivity after 24-hours. Decreased IFN-γ and increased LPA were observed in WT-PM mice; similar findings have been reported for firefighters who eventually develop WTC-LI. In the murine model, lack of RAGE was protective from loss of lung function and airway hyperreactivity and was associated with modulation of MAP kinases. We conclude that in a multivariate adjusted model increased sRAGE

  5. Soluble receptor for advanced glycation end products as a potential biomarker to predict weight loss and improvement of insulin sensitivity by a very low calorie diet of obese human subjects.

    Science.gov (United States)

    Hagen, Imke; Schulte, Dominik M; Müller, Nike; Martinsen, Jessica; Türk, Kathrin; Hedderich, Jürgen; Schreiber, Stefan; Laudes, Matthias

    2015-06-01

    Obesity is associated with low-grade systemic inflammation which is thought to trigger the development of comorbidities such as type 2 diabetes. The soluble receptor for advanced glycation end products (sRAGE) belongs to the innate immune system and has been linked to obesity, recently. The aim of the present study was to examine whether serum sRAGE concentrations are related to the grade of weight loss and improvement of insulin resistance due to a very low calorie diet (VLCD). 22 severe obese subjects (Median Body Mass Index (BMI): 44.5kg/m(2)) were included in a dietary intervention study of 6month, consisting of a very low calorie formula diet phase (VLCD: 800kcal/d) for 12 weeks and a following 12 week weight maintenance phase. Fasting glucose, fasting insulin, adiponectin, leptin and sRAGE were determined from sera. Insulin sensitivity was estimated by Homeostasis Model Assessment (HOMA) index and leptin-to-adiponectin-ratio (LAR). Mean body weight reduction by VLCD accounted to 21.7kg with a significant improvement of insulin resistance. At baseline, sRAGE serum levels were significantly inversely related to BMI (rS=-0.642, p=0.001) and HOMA (rS=-0.419, p=0.041). Of interest, sRAGE serum levels at baseline were significantly lower in study subjects with greater reduction of BMI (p=0.017). In addition, a significantly greater HOMA reduction was observed in subjects with lower sRAGE serum levels at baseline (p=0.006). Finally, correlation analysis revealed, that changes of sRAGE serum levels were significantly correlated to changes of BMI (rS=-0.650, p=0.022) during intervention. Anti-inflammatory sRAGE might be a potential future biomarker to predict weight loss and improvement of insulin resistance by a VLCD whereby lower baseline sRAGE serum levels indicate a better outcome of the dietary intervention. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Hypertension induces brain β-amyloid accumulation, cognitive impairment, and memory deterioration through activation of receptor for advanced glycation end products in brain vasculature.

    Science.gov (United States)

    Carnevale, Daniela; Mascio, Giada; D'Andrea, Ivana; Fardella, Valentina; Bell, Robert D; Branchi, Igor; Pallante, Fabio; Zlokovic, Berislav; Yan, Shirley Shidu; Lembo, Giuseppe

    2012-07-01

    Although epidemiological data associate hypertension with a strong predisposition to develop Alzheimer disease, no mechanistic explanation exists so far. We developed a model of hypertension, obtained by transverse aortic constriction, leading to alterations typical of Alzheimer disease, such as amyloid plaques, neuroinflammation, blood-brain barrier dysfunction, and cognitive impairment, shown here for the first time. The aim of this work was to investigate the mechanisms involved in Alzheimer disease of hypertensive mice. We focused on receptor for advanced glycation end products (RAGE) that critically regulates Aβ transport at the blood-brain barrier and could be influenced by vascular factors. The hypertensive challenge had an early and sustained effect on RAGE upregulation in brain vessels of the cortex and hippocampus. Interestingly, RAGE inhibition protected from hypertension-induced Alzheimer pathology, as showed by rescue from cognitive impairment and parenchymal Aβ deposition. The increased RAGE expression in transverse aortic coarctation mice was induced by increased circulating advanced glycation end products and sustained by their later deposition in brain vessels. Interestingly, a daily treatment with an advanced glycation end product inhibitor or antioxidant prevented the development of Alzheimer traits. So far, Alzheimer pathology in experimental animal models has been recognized using only transgenic mice overexpressing amyloid precursor. This is the first study demonstrating that a chronic vascular insult can activate brain vascular RAGE, favoring parenchymal Aβ deposition and the onset of cognitive deterioration. Overall we demonstrate that RAGE activation in brain vessels is a crucial pathogenetic event in hypertension-induced Alzheimer disease, suggesting that inhibiting this target can limit the onset of vascular-related Alzheimer disease.

  7. Skin Autofluorescence Relates to Soluble Receptor for Advanced Glycation End-Products and Albuminuria in Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    J. Škrha

    2013-01-01

    Full Text Available The aim of this study was to compare skin autofluorescence caused by advanced glycation end-products (AGEs with biochemical markers of endothelial dysfunction and soluble receptor for AGEs (sRAGE in patients with diabetes. Skin autofluorescence (AF assessed by AGE-Reader was evaluated with sRAGE and other biochemical parameters in 88 patients with diabetes (47 Type 1/T1DM/ and 41 Type 2/T2DM/ and 20 controls. Skin AF was significantly higher in T1DM and T2DM in comparison to controls (2.39 ± 0.54, 2.63 ± 0.73 versus 1.96 ± 0.33 AU; P<0.0001. Positive correlation of AF with sRAGE was detected in T1DM and T2DM (r=0.37, P<0.02 and r=0.60, P<0.0001, but not in controls. Significantly higher AF values were found in patients with positive albuminuria as compared to those with normal albuminuria. Similarly, higher AF was detected in patients with endothelial dysfunction expressed by vWF, ICAM-1, and VCAM-1. Multiple regression analysis revealed independent association of skin AF with age, sRAGE, and albumin-creatinine ratio in patients with diabetes (R2=0.38. Our study confirms that AF is elevated in patients with diabetes, especially with positive albuminuria and endothelial dysfunction. The strong and independent relationship between AF and sRAGE supports the idea that AF may reflect AGEs/RAGE interactions. The exact mechanism remains to be established.

  8. The advanced glycation end-product Nϵ -carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes-associated risk and its prevention.

    Science.gov (United States)

    Menini, Stefano; Iacobini, Carla; de Latouliere, Luisa; Manni, Isabella; Ionta, Vittoria; Blasetti Fantauzzi, Claudia; Pesce, Carlo; Cappello, Paola; Novelli, Francesco; Piaggio, Giulia; Pugliese, Giuseppe

    2018-03-13

    Diabetes is an established risk factor for pancreatic cancer (PaC), together with obesity, a Western diet, and tobacco smoking. The common mechanistic link might be the accumulation of advanced glycation end-products (AGEs), which characterizes all of the above disease conditions and unhealthy habits. Surprisingly, however, the role of AGEs in PaC has not been examined yet, despite the evidence of a tumour-promoting role of receptor for advanced glycation end-products (RAGE), the receptor for AGEs. Here, we tested the hypothesis that AGEs promote PaC through RAGE activation. To this end, we investigated the effects of the AGE N ϵ -carboxymethyllysine (CML) in human pancreatic ductal adenocarcinoma (PDA) cell lines and in a mouse model of Kras-driven PaC interbred with a bioluminescent model of proliferation. Tumour growth was monitored in vivo by bioluminescence imaging and confirmed by histology. CML promoted PDA cell growth and RAGE expression, in a concentration-dependent and time-dependent manner, and activated downstream tumourigenic signalling pathways. These effects were counteracted by RAGE antagonist peptide (RAP). Exogenous AGE administration to PaC-prone mice induced RAGE upregulation in pancreatic intraepithelial neoplasias (PanINs) and markedly accelerated progression to invasive PaC. At 11 weeks of age (6 weeks of CML treatment), PaC was observed in eight of 11 (72.7%) CML-treated versus one of 11 (9.1%) vehicle-treated [control (Ctr)] mice. RAP delayed PanIN development in Ctr mice but failed to prevent PaC promotion in CML-treated mice, probably because of competition with soluble RAGE for binding to AGEs and/or compensatory upregulation of the RAGE homologue CD166/ activated leukocyte cell adhesion molecule, which also favoured tumour spread. These findings indicate that AGEs modulate the development and progression of PaC through receptor-mediated mechanisms, and might be responsible for the additional risk conferred by diabetes and other

  9. National Program for Inspection of Non-Federal Dams. Shenipsit Dam (CT 00482), Thames River Basin, Stafford, Connecticut. Phase I Inspection Report.

    Science.gov (United States)

    1980-09-01

    calculatec by the Soil Loss Formula (0.1 ton/ac/yr. y±cld). The dosianed heiGht of the structures vill provide st rage for a 50 year sediment...As shown in the above listing the design meet, the c:rr,1 ,ia established in all instances. L B-13 rage -,- n We have discussed with the S. C.S...WALTHAM,* MASS rMdlRie INSPECTION OF Stafford, CT CANIN ENGINEERS INC. WALLINGFORD, CON.NF. DAS CE# 27 785 KC EWNGINEER NO-FD AS DATE Set𔃺 PAGE C-4 S S U

  10. Women in the Infantry - The Effect on the Moral Domain

    Science.gov (United States)

    1992-12-12

    psychological toll on the infantrymen. Okinawa’s mud drove us to a state of frustration and exasperation bordering on rage . It can be appreciated only by...waited to move out. The cursing and outbursts of rage didn’t seem to help, although ,no one was above it when goaded to the point of desperation and...of the canines , chest thumping, display of the ruff, and so forth).69 The authors believed that the similarity of soldier language to the primates

  11. Evaluation of advanced glycation end-products in diabetic and inherited canine cataracts.

    Science.gov (United States)

    Bras, I Dineli; Colitz, Carmen M H; Kusewitt, Donna F; Chandler, Heather; Lu, Ping; Gemensky-Metzler, Anne J; Wilkie, David A

    2007-02-01

    The receptor for advanced glycation end-products (RAGE) increases in the human cataract and should correlate with increased DNA damage and proliferation of lens epithelial cells (LECs). The purpose of this study was to measure and immunolocalize RAGE in normal and cataractous canine LECs, and to determine whether there was a correlation between RAGE and DNA damage (gadd45), cell-cycle regulation (p21), and LEC proliferation (proliferating cell nuclear antigen, PCNA). Thirty-two anterior lens capsules from 22 dogs that underwent cataract surgery and 10 lenses from dogs with normal eyes were evaluated. Eleven of the cataractous lenses were from diabetic patients (n=16), and eleven were from patients with inherited cataracts (n=16). Standard immunohistochemical staining was performed using antibodies against RAGE, gadd45, p21, PCNA, alpha-smooth muscle actin, and TGF-beta. Immunostaining intensity for each antibody was given a score of 0-4+. Standard Western blot analysis on normal and cataractous lens capsules was performed using the same antibodies as in the immunohistochemical staining. Comparisons were also made based on age and sex. Real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed for RAGE. There was an increase in RAGE expression with age in normal LECs, but no significant difference was seen when normal adult LECs were compared to cataractous LECs. The stage of the cataract and the presence of LIU were not associated with a significant increase in RAGE expression. There was no age-dependent difference in the normal lenses for gadd45, p21, or PCNA. Significant up-regulation of p21 (P RAGE and PCNA expression did not increase with cataractogenesis, possibly due to overexpression associated with normal aging and constant exposure to oxidative stress from sunlight-related ultraviolet irradiation, respectively. However, p21 and PCNA increased in diabetic cataractogenesis suggesting cell cycle and proliferation dysregulation. This may

  12. The political theology of violence in contemporary India

    NARCIS (Netherlands)

    Hansen, T.B.

    2008-01-01

    What are we to make of the fact that most violence in India rarely has any visible or clear actors? Why is most violence represented as 'pure events' without identifiable actors - but as 'mobs', as spontaneous combustion, as spontaneous rage that arises from perceived collective grievances and

  13. Is ATAR Useful for Predicting the Success of Australian Students in Initial Teacher Education?

    Science.gov (United States)

    Wright, Vince J.

    2015-01-01

    Quality teaching is the most significant systemic factor contributing to student achievement. Attracting, developing and retaining effective teachers are important goals for Australia as they are for all nations. Debate rages currently about criteria for selection of students into Initial Teacher Education (ITE). The Australian Tertiary Admission…

  14. Tourette's disease with impulse control disorder

    OpenAIRE

    Raj, Rajnish; Sidhu, Balwant Singh

    2011-01-01

    We report a case of Tourette's disease (TD) with impulse control disorder which is rare;these type of patients are prone to rage attack and explosive outbursts in the childhood and adolescence which can be detrimental. Hence, a case is reported to understand the phenomenology of its co-morbidity in TD.

  15. Girl's Schooling in War-Torn Somalia

    Science.gov (United States)

    Moyi, Peter

    2012-01-01

    A civil war has raged in Somalia since 1991. The civil war was the final blow to an already collapsed education system. Somalia has received little research and policy attention yet children, especially girls, are very vulnerable during times of conflict. The different gender roles, activities, and status in society create gender differentiated…

  16. Petrol war in Nijmegen, Netherlands

    International Nuclear Information System (INIS)

    De Jong, E.; Kramer, I.

    2000-01-01

    Since April 2000 a petrol war rages in Nijmegen and surroundings (Netherlands) whereby considerable discounts are given to the national retail prices. The cause of the war is a new unmanned petrol station of the enterprise Tango. In this article the development and the consequences of the discount at petrol stations in Nijmegen and surroundings are analyzed 3 refs

  17. Radiologic evidence for absence of the facial nerve in Mobius syndrome.

    NARCIS (Netherlands)

    Verzijl, H.T.F.M.; Valk, J.; Vries, R. de; Padberg, G.W.A.M.

    2005-01-01

    OBJECTIVE: To detail the radiologic findings in Mobius syndrome, in order to clarify its pathogenetic mechanisms. METHODS: High resolution three-dimensional T1 (MP rage) and T2 (CISS) weighted MRI were used to study the cisternal and canalicular portion of the seventh cranial nerve in six Mobius

  18. The Acceptance of Exceptionality: A Three Dimensional Model.

    Science.gov (United States)

    Martin, Larry L.; Nivens, Maryruth K.

    A model extrapolates from E. Kubler-Ross' conception of the stages of grief to apply to parent and family reactions when an exceptionality is identified. A chart lists possible parent feelings and reactions, possible school reactions to the parent in grief, and the child's reactions during each of five stages: denial, rage and anger, bargaining,…

  19. Massive Open Online Librarianship: Emerging Practices in Response to MOOCs

    Science.gov (United States)

    Mune, Christina

    2015-01-01

    Massive Open Online Courses, or MOOCs, have recently emerged as a disruptive pedagogy gaining rapid momentum in higher education. In some states, proposed legislations would accredit MOOCs to provide college-credit courses in the name of cost saving, efficiency and access. While debates rage regarding the place of MOOCs in higher education, some…

  20. Anthony Trollope’s Barsetshire Heroes

    Science.gov (United States)

    1990-01-01

    tapped the rich lode of Greek mythology and the epic heroes to obtain sources for poems, essays, and stories. In The Heroea, for example, Kingsley’s 1856...and the defiant Prometheus of Greek mythology exhibit the rage and unyielding independence that attracted the later Romantic poets. In Shelley’s

  1. The Positivity Imperative: A Critical Look at the "New" Youth Development Movement

    Science.gov (United States)

    Sukarieh, Mayssoun; Tannock, Stuart

    2011-01-01

    The field of youth development, long given over to discussions of youth as a time of storm and stress, raging hormones and problem behavior, has increasingly turned to look at the "sunny side" of youth--at their agency, insights, capabilities and contributions. Youth, we are now regularly told, are not problems but resources and assets. In this…

  2. Experimental and clinical studies of fast three-dimensional MR imaging of the heart

    International Nuclear Information System (INIS)

    Sato, Shuhei

    1999-01-01

    MRI has been utilized since its inception to study the anatomy and physiology of the heart. However, the sensitivity of MRI to motion has always posed a major challenge in imaging this organ. The purpose of this study was to develop a 3D MP-RAGE technique for the heart, and to apply it clinically. In the experimental study, data acquisition timing was discussed by normal volunteers. Changes in magnetization recovery time affected imaging contrast very little in the phantom study. Fourteen adults and 21 children were examined. In the adults, MP-RAGE images were rated as high in quality in the visual estimation. In the quantitative estimation, the images provided almost the same anatomical information as those of cine MRI. In the children, MP-RAGE was useful for cases of partial anomalous pulmonary venous drainage, particularly in the evaluation of abnormal pulmonary veins. The 3D MP-RAGE technique was useful in imaging the heart because it was possible to obtain continuous views in the same cardiac cycle and to reconstruct views from any direction after the examination. (author)

  3. In the eye of the hurricane

    DEFF Research Database (Denmark)

    Henriksen, Kristoffer

    “In the eye of a hurricane” was a metaphor used by a sailor during the 2016 Olympic Games. It described her intention to remain calm, present-moment focused and aware of her values, while at the same time a storm of media attention, results speculation, and social invitations was raging all around...

  4. Liberia's difficult reconstruction

    OpenAIRE

    Blume, Till

    2008-01-01

    For more than 14 years, one of the worst civil wars in Africa raged in Liberia. The fighting ended in August 2003. Since then, Liberia has enjoyed peace. But while many things have improved in the country, the political situation is anything but stable. The article gives an outlook on the situation in Liberia in 2007.

  5. Neurofeedback, Affect Regulation and Attachment: A Case Study and Analysis of Anti-Social Personality

    Science.gov (United States)

    Fisher, Sebern F.

    2007-01-01

    This case study examines the effects of neurofeedback (EEG biofeedback) training on affect regulation in a fifty-five year-old man with a history marked by fear, rage, alcoholism, chronic unemployment and multiple failed treatments. He had been diagnosed with ADHD and attachment disorder and met criteria for anti-social personality disorder. The…

  6. How Should the Financial Crisis Change How We Teach Economics?

    Science.gov (United States)

    Shiller, Robert J.

    2010-01-01

    Student dissatisfaction with teaching of economics--particularly with macroeconomics--during the current financial crisis mirrors dissatisfaction that was expressed during the last big crisis, the Great Depression. Then and now, a good number of students have felt that their lectures bear little relation to the economic crisis raging outside the…

  7. U.S. - UK - Canada Trilateral Symposium

    Science.gov (United States)

    2009-10-02

    e . 4. Procedures for intra-community arms transfers simplified. 5 Retransfer controls disco raged b t m st be. u u u complied with. Li d...IRIS – T • Airbus A310 refueller 10 FUTURE OF TRANSATLANTIC ARMAMENTS COOPERATION 1996 VISION – “I believe that national security – ours and that

  8. Factors associated to populations' behaviour towards cholera in ...

    African Journals Online (AJOL)

    A disease related to hygiene, cholera is an affection which rages for centuries in the endemic states with epidemic hatchings worldwide. Benin, in particular in its littoral region, is not spared by the disease. The objective of this study was to determine the behavioural factors of the bad hygiene practice of the populations from ...

  9. 3 CFR 8463 - Proclamation 8463 of December 4, 2009. National Pearl Harbor Remembrance Day, 2009

    Science.gov (United States)

    2010-01-01

    ... who selflessly served our Nation at home and abroad during World War II. On a tranquil Sunday morning, as war raged around the globe, the attack on Pearl Harbor effectively ended American isolation... have hereunto set my hand this fourth day of December, in the year of our Lord two thousand nine, and...

  10. "If I Knew Where the Enemy, or Even Germany Was, We Could Have Fired in that Direction": Bion's Experience of War

    Science.gov (United States)

    Likierman, Meira

    2012-01-01

    During the First World War, Bion fought in three major battles over a period of two years. He left ample writings both honest and soul searching. Travelling to The Front under raging pressure from his father, he enlisted in a state of mind, which fluctuated wildly between wanting to be a "hero" and sudden fears that made him join the…

  11. [The development of an oral biomechanical testing instrument].

    Science.gov (United States)

    Zhang, X H; Sun, X D; Lin, Z

    2000-03-01

    An oral biomechanical testing instrument, which is portable, powered with batteries and controlled by single chip microcomputer, was described. The instrument was characterized by its multichannel, high accuracy, low power dissipation, wide rage of force measurement and stable performance. It can be used for acquisiting, displaying and storing data. And it may be expected to be an ideal instrument for oral biomechanical measurements.

  12. Misophonia: physiological investigations and case descriptions

    NARCIS (Netherlands)

    Edelstein, M.; Brang, D.; Rouw, R.; Ramachandran, V.S.

    2013-01-01

    Misophonia is a relatively unexplored chronic condition in which a person experiences autonomic arousal (analogous to an involuntary "fight-or-flight" response) to certain innocuous or repetitive sounds such as chewing, pen clicking, and lip smacking. Misophonics report anxiety, panic, and rage when

  13. Effect of Creative Drama-Based Group Guidance on Male-Adolescents' Conflict Resolution Skills

    Science.gov (United States)

    Yavuzer, Yasemin

    2012-01-01

    Problem Statement: This study assumes that conflict itself is not constructive or destructive, whereas the path chosen to resolve the conflict is what leads to constructive or destructive results. When individuals resolve conflicts in a destructive manner, they instill feelings of anger, rage, hostility and violence in the people involved. On the…

  14. Access and Quality in Education in Resettlement Schools: The Case Study of Zvivingwi Secondary School in Gutu District, Masvingo Province in Zimbabwe

    Science.gov (United States)

    Jenjekwa, Vincent

    2013-01-01

    In Zimbabwe, the discourse on access and quality in education has been a raging one since the colonial days of bottlenecks and outright discrimination against black Zimbabweans in education. The doors to education were declared open to all at independence in 1980 with the new Zimbabwe government's enunciated policy of education for all. It is an…

  15. High mobility group box 1 levels are not associated with subclinical carotid atherosclerosis in patients with granulomatosis with polyangiitis but are reduced by glucocorticoids and statins

    NARCIS (Netherlands)

    Silva de Souza, Alexandre; De Leeuw, Karina; Westra, Johanna; Smit, Andries J.; Van Der Graaf, Anne Marijn; Nienhuis, Hans L.A.; Bijzet, Johan; Limburg, Pieter C.; Stegeman, Coen A.; Bijl, Marc; Kallenberg, Cees G.M.

    2012-01-01

    Background/Purpose: High mobility group box 1 (HMGB1) is a non-histone DNA binding protein that is passively released by dying cells or actively secreted by immunocompetent cells and the receptor for advanced glycation end-products (RAGE) is one of its receptors. Higher levels of HMGB1 have been

  16. Teens Will Be Teens: The Latest Brain Research Has a Lot to Say about Adolescent Behavior

    Science.gov (United States)

    Jones, Jami

    2005-01-01

    Most adults are challenged when it comes to understanding teens' motives. "What were they thinking of?" is an all-too-common response. Without a doubt, no developmental period in life is more confounding and baffling than adolescence. Until recently, erratic teen behavior was blamed on raging hormones, but scientific research in the last decade…

  17. Hard Facts and Soft Skills

    Science.gov (United States)

    Terego, Alex

    2009-01-01

    The argument now raging in academic circles pits those who espouse teaching 21st century skills against those who believe that schools should be teaching explicit and well-sequenced content. This debate has largely been framed as an either-or proposition. In this author's view, portraying this debate as one between two mutually exclusive sides…

  18. Distribution and Characteristics of Non Carious Cervical lesions in ...

    African Journals Online (AJOL)

    Background: Controversies rages in the literature as to the characteristics of non carious cervical lesions (NCCLs) in terms of the location and its severity. Objective: The study is to investigate the characteristics of NCCLs in adult patients who had a high incidence in them and to see if there are any association with the ...

  19. The First Amendment and the Web: The Internet Porn Panic and Restricting Indecency in Cyberspace.

    Science.gov (United States)

    Mullin, Dorothy Imrich

    In the wake of the Communications Decency Act of 1996, discussions have raged both online and in the press about free speech, online pornography, and the protection of children. This paper discusses the legal and social science issues surrounding content regulation of the World Wide Web and the Internet as a whole, with an emphasis on the…

  20. George Washington and the Establishment of Civil-Military Relations in Relation to the Declaration of Independence

    Science.gov (United States)

    2015-06-12

    sending their men to fight the British or to die trying. Like the rage militaire that spurred men to surround the city of Boston, public support for...those around him “with vast ease and dignity , and dispens[ed] happiness around him.”263 Washington also consulted with and advised the Continental

  1. The Course of Skin and Serum Biomarkers of Advanced Glycation Endproducts and Its Association with Oxidative Stress, Inflammation, Disease Severity, and Mortality during ICU Admission in Critically Ill Patients : Results from a Prospective Pilot Study

    NARCIS (Netherlands)

    Meertens, John H.; Nienhuis, Hans L; Lefrandt, Joop D; Schalkwijk, Casper G; Nyyssönen, Kristiina; Ligtenberg, Jack J M; Smit, Andries J; Zijlstra, Jan G; Mulder, Douwe J.

    2016-01-01

    Background Advanced glycation end products (AGEs) have been implicated in multiple organ failure, predominantly via their cellular receptor (RAGE) in preclinical studies. Little is known about the time course and prognostic relevance of AGEs in critically ill human patients, including those with

  2. Spatial atmospheric ALD of functional layers for CIGS Solar Cells

    NARCIS (Netherlands)

    Illiberi, A.; Frijters, C.; Balder, J.E.; Poodt, P.W.G.; Roozeboom, F.

    2015-01-01

    Spatial Atmosperic Atomic Layer Depositon combines the advantages of temporal ALD, i.e. excellent control of film composition and uniformity over large area substrates, with high growth rages (up tot nm/s). In this paper we present a short overview of our research acctivity carried out on S-ALD of

  3. Between green and grey

    NARCIS (Netherlands)

    Jeanet Kullberg

    2016-01-01

    Original title: Tussen groen en grijs Taking cuttings is cool. Growing vegetables is all the rage. Green oases can now be found scattered throughout Dutch towns and cities: community gardens and roof gardens where residents can go to relax and enjoy themselves, improve the appearance of their

  4. Academic Superheroes? A Critical Analysis of Academic Job Descriptions

    Science.gov (United States)

    Pitt, Rachael; Mewburn, Inger

    2016-01-01

    For over a decade, debate has raged about the nature and purpose of the PhD, including its role as preparation for working in academia. Academic work has changed a great deal in the last 60 years, yet our doctoral curriculum has remained relatively static. While there is increasing interest in matching PhD programmes to "real world"…

  5. Computer Game-based Learning: Applied Game Development Made Simpler

    NARCIS (Netherlands)

    Nyamsuren, Enkhbold

    2018-01-01

    The RAGE project (Realising an Applied Gaming Ecosystem, http://rageproject.eu/) is an ongoing initiative that aims to offer an ecosystem to support serious games’ development and use. Its two main objectives are to provide technologies for computer game-based pedagogy and learning and to establish

  6. Prophets at loggerheads. Accusations of adultery in Jeremiah 23:9-15

    African Journals Online (AJOL)

    The focus of this article is on one aspect of the raging conflict between the prophetic parties addressed in Jeremiah 23:9-15. In this section the aspect of disloyalty to Yahweh is raised as hampering factor for being a true prophet. The research investigates the relationship between doing evil (cf. words such as adultery and ...

  7. Fulltext PDF

    Indian Academy of Sciences (India)

    The study of history, including history of science, is fraught with dangers of misinterpretations of facts. Often national pride and racial prejudice tend to add flavours to the otherwise mundane facts of history. The current debate raging in our country over some aspects of ancient Indian history is a case in poin t. As practitioners ...

  8. Open access: the changing face of scientific publishing.

    Science.gov (United States)

    Chatterjee, Pranab; Biswas, Tamoghna; Mishra, Vishala

    2013-04-01

    The debate on open access to scientific literature that has been raging in scholarly circles for quite some time now has been fueled further by the recent developments in the realm of the open access movement. This article is a short commentary on the current scenario, challenges, and the future of the open access movement.

  9. Putting Politics Where It Belongs: In the Classroom

    Science.gov (United States)

    Hess, Diana; Gatti, Lauren

    2010-01-01

    Throughout the last 50 years, the debate over engaging politics in the college classroom has raged on, sparked in part by the belief that liberal biases saturate scholarship and teaching in universities, which in turn lays the bedrock for the left-wing indoctrination of students. Polarizing and vitriolic debates abound regarding if, when, and how…

  10. 109 Speaking for the Voiceless: Yvonne Vera's Characters and ...

    African Journals Online (AJOL)

    Ike Odimegwu

    women and the men constitute the voiceless members of ... on the move in search of employment and a better future. Because of the raging ... Pointedly, her action is hinged on the fact that the child will bind her to ..... Their extreme reactions.

  11. The Feud over Food: The Truth about the School Lunch Wars

    Science.gov (United States)

    Johns, Stephanie

    2010-01-01

    Serving meals and snacks at school is fraught with politics and pitfalls. While the battle rages in school cafeterias over menu choices, beverage sales, vending foods, and outright bans on what students can buy or even bring to school, there is some good news. More school districts are reducing the number of fried foods, increasing the levels of…

  12. Soft-tissue wound healing by anti-advanced glycation end-products agents.

    Science.gov (United States)

    Chang, P-C; Tsai, S-C; Jheng, Y-H; Lin, Y-F; Chen, C-C

    2014-04-01

    The blocking of advanced glycation end-products (AGE) has been shown to reduce diabetic complications and control periodontitis. This study investigated the pattern of palatal wound-healing after graft harvesting under the administration of aminoguanidine (AG), an AGE inhibitor, or N-phenacylthiazolium bromide (PTB), a glycated cross-link breaker. Full-thickness palatal excisional wounds (5.0 x 1.5 mm(2)) were created in 72 Sprague-Dawley rats. The rats received daily intraperitoneal injections of normal saline (control), AG, or PTB and were euthanized after 4 to 28 days. The wound-healing pattern was assessed by histology, histochemistry for collagen matrix deposition, immunohistochemistry for AGE and the AGE receptor (RAGE), and the expression of RAGE, as well as inflammation- and recovery-associated genes. In the first 14 days following AG or PTB treatments, wound closure, re-epithelialization, and collagen matrix deposition were accelerated, whereas AGE deposition, RAGE-positive cells, and inflammation were reduced. RAGE and tumor necrosis factor-alpha were significantly down-regulated at day 7, and heme oxygenase-1 was persistently down-regulated until day 14. The levels of vascular endothelial growth factor, periostin, type I collagen, and fibronectin were all increased at day 14. In conclusion, anti-AGE agents appeared to facilitate palatal wound-healing by reducing AGE-associated inflammation and promoting the recovery process.

  13. Feminist Pedagogy Meets Feminist Therapy: Teaching Feminist Therapy in Women's Studies

    Science.gov (United States)

    Magnet, Shoshana; Diamond, Shaindl

    2010-01-01

    The affective realm--including sorrow, pain, ecstasy, vulnerability, joy, and rage--is a central component of feminist teaching and learning. Feminist classrooms are spaces where strong feelings are raised, paradigms shift, and ruptures are created. Coming to feminist consciousness may involve grief, anger, and sadness for students. Speaking about…

  14. Deprivation, HIV and AIDS in Northern Uganda

    African Journals Online (AJOL)

    2007-09-28

    physical aggression, deprivation, hunger and family separation, among others, for over twenty years. ... by various types of sexual crimes of rape (including marital rape), defilement and child .... insecurity and civil strife raged in northern Uganda mainly between the government ...... The Daily Monitor of September 28, 2007.

  15. A Mediating Model of Relational Aggression, Narcissistic Orientations, Guilt Feelings, and Perceived Classroom Norms

    Science.gov (United States)

    Onishi, Ayako; Kawabata, Yoshito; Kurokawa, Masayuki; Yoshida, Toshikazu

    2012-01-01

    The purpose of the present study was to examine the relation between narcissistic orientations (grandiose sense of self-importance, interpersonal exploitation, and narcissistic rage) and relational aggression (self-satisfactory and punishment type) and the mediating effects of guilt feelings toward and perceived classroom norms against relational…

  16. A Delinquent Discipline: The Rise and Fall of Criminology

    Science.gov (United States)

    Adams, Mike S.

    2009-01-01

    What is the cause of crime? One can find answers in many places: in Genesis, in the plays of Sophocles and Shakespeare, in Dostoyevsky's "Crime and Punishment" and "Brothers Karamazov." The many answers include impiety, appetite, rage, and even the lure of transgression itself. For many, religious and poetic insights still offer the most…

  17. Poverty and Brain Development in Children: Implications for Learning

    Science.gov (United States)

    Dike, Victor E.

    2017-01-01

    Debates on the effect of poverty on brain development in children and its implications for learning have been raging for decades. Research suggests that poverty affects brain development in children and that the implications for learning are more compelling today given the attention the issue has attracted. For instance, studies in the fields of…

  18. Beyond Socioeconomic Status: The Impact of Principal Leadership in Urban and High-Poverty Turnaround Schools

    Science.gov (United States)

    Adejumo, Mojisola

    2017-01-01

    The quest to transform failing urban and high-poverty schools in America has been a slippery uphill battle since the banner of war was raised against the many schools serving impoverished children. As battle rages, a few are schools leading their students, teachers, parents, and community to victory by turning their once-failing schools into…

  19. Oriana Fallaci viha ja raev / Urmas Kiil

    Index Scriptorium Estoniae

    Kiil, Urmas

    2006-01-01

    Ajakirjanik ja kirjanik Oriana Fallaci, kelle artikkel New Yorgis toimunud terrorirünnaku muljetest avaldati 29. sept. 2001. a. Itaalia juhtivas ajalehes Corriere della sera, avaldas peagi raamatu "Raev ja uhkus" (The Rage and Pride). Raamatus mõistab ta islamimaailma mööndusteta tervikuna hukka

  20. Peace Education in Societies Involved in Intractable Conflicts: Direct and Indirect Models

    Science.gov (United States)

    Bar-Tal, Daniel; Rosen, Yigal

    2009-01-01

    The present article deals with the crucial question: Can peace education facilitate change in the sociopsychological infrastructure that feeds continued intractable conflict and then how the change can be carried? Intractable conflicts still rage in various parts of the globe, and they not only cause local misery and suffering but also threaten…

  1. Dispositional and Situational Autonomy as Moderators of Mood and Creativity

    Science.gov (United States)

    Xiao, Fengqiu; Wang, Ling; Chen, Yinghe; Zheng, Zhiwei; Chen, Wenjun

    2015-01-01

    Although previous research suggests that mood can influence creativity, the controversy about the effects of positive and negative moods has raged for years. This study investigated how the relationship between induced mood and creativity is moderated by dispositional and situational autonomy. It contrasted the different moderating effects of the…

  2. Justice for Sexual Crimes Committed by IS : Exploring Accountability and Compliance Mechanisms

    NARCIS (Netherlands)

    Ryngaert, C.M.J.; Hora Siccama, D.

    2016-01-01

    The civil war in Syria has been raging for over almost six years now. Since 2011, several armed groups have been fighting government forces and each other for control over portions of Syrian territory. The most well-known of these groups proclaimed itself as the ‘Islamic State’ (IS). Under the

  3. Evidence from the Gukurahundi violence in Zimbabwe

    African Journals Online (AJOL)

    the trauma' and as a result, 'the children are compelled to deal with the shame, rage ... during Gukurahundi', and 'It has an effect when our parents narrate how .... So, when the desire for revenge remains on the level of fantasy, it serves.

  4. Optimal Rather than Mandatory EU Company Law

    NARCIS (Netherlands)

    Hertig, G.; McCahery, J.A.

    2006-01-01

    A significant debate rages within the EU about whether to give firms the choice to opt in or out of corporate law provisions. Both sides agree that more flexibility and adaptability of legal rules to business needs is crucial. Nevertheless, and not surprisingly, many still view EU mandatory

  5. Freedom, Revolt and "Citizenship": Three Pillars of Identity for Youngsters Living on the Streets of Rio de Janeiro

    Science.gov (United States)

    Butler, Udi Mandel

    2009-01-01

    This article investigates the experiences, identities and aspirations of children and adolescents living on the streets of Rio de Janeiro, formed as they are around the conditions of exclusion, violence and discrimination. Significant here are experiences of "revolta"--revolt or rage--the aspiration for freedom through life on the street…

  6. A Military Hospice Model

    Science.gov (United States)

    1983-05-06

    the medical director of the hospice might find necessary in the manangement of an individual case. If, for instance, the patient required speech...patients to go through the classical five stages of death: denial, rage or 40 anger, bargaining, depression and finally acceptance. In this task the social

  7. "I Asked My Parents Why a Wall Was so Important": Teaching about the GDR and Post-Reunification Germany

    Science.gov (United States)

    Streitwieser, Bernhard; Lys, Franziska

    2008-01-01

    Fifteen years after the "peaceful revolutions" brought about the collapse of communism and the reunification of East and West Germany, a heated debate rages over the legacy of communism and the continuing impact of 1989. This paper describes a new course that explores the contentious issues in this debate through the innovative use of…

  8. Coping with Feelings

    Medline Plus

    Full Text Available ... also causes angina (chest pain) because vessels constrict (narrow), reducing blood and oxygen to the heart. Anger is a problem when you often: Lose your temper. Feel rage at people who are in your way in daily situations, ...

  9. The Math Wars: Tensions in the Development of School Mathematics Curricula

    Science.gov (United States)

    Wright, Pete

    2012-01-01

    The Math Wars have been raging since the 1990's in the United States, where the world of mathematics education has become polarised into two camps: the reformers and the traditionalists. In this article I explore the background to the Math Wars, with specific reference to conflicting ideologies of mathematics education. I draw parallels with…

  10. The Origins of Creationism in the Netherlands: The Evolution Debate Among Twentieth-Century Dutch Neo-Calvinists

    NARCIS (Netherlands)

    Flipse, A.C.

    2012-01-01

    The Netherlands is, besides the United States, one of the few countries where debates about creationism have been raging for decades. Strict creationism has become deeply rooted in traditional Reformed (Calvinist) circles, which is all the more remarkable as it stemmed from a very different culture

  11. The role of wildfire in the establishment and range expansion of nonnative plant species into natural areas: A review of current literature

    Science.gov (United States)

    Mara Johnson; Lisa J. Rew; Bruce D. Maxwell; Steve Sutherland

    2006-01-01

    Nonnative invasive plants are one of the greatest threats to natural ecosystems worldwide (Vitousek et al. 1996). In fact, their spread has been described as "a raging biological wildfire" (Dewey et al. 1995). Disturbances tend to create conditions that are favorable for germination and establishment of plant species. Nonnative plant species are often...

  12. Restoring the Unwritten Alliance in Brazil -- United States Relations

    Science.gov (United States)

    2012-03-23

    has had difficulty with indigenous minority groups. For example, it is constantly challenged to persuade the Amazon aboriginals the benefits of...and oil installations. Tribes and smugglers rule desert areas south of the capital. Clashes among various militias for turf and political power rage

  13. Establishing Law and Order After Conflict

    Science.gov (United States)

    2005-01-01

    capable of responding to high-risk circumstances. One specific special police unit is a canine unit composed of 35 men and 25 dogs. In 2003, about one... raged out of control for a period. ORHA and the CPA responded by rapidly recalling Iraqi police personnel to assist with basic law and order, with mixed

  14. National Strategy for Combating Terrorism: Prospects and Implications

    Science.gov (United States)

    2003-12-01

    their canine explosives detection programs. Customs increased searches of passengers, baggage, and cargo leaving the US. Finally, the ATF was...77 Bernard Lewis, “The Roots of Muslim Rage ,” in Kegley, 198-200. 78 Wilfred Thesiger, Arabian Sands (Green, UK

  15. Improving the Efficiency and Efficacy of Glibenclamide in Limiting Progressive Hemorrhagic Necrosis Following Traumatic Spinal Cord Injury

    Science.gov (United States)

    2015-02-01

    microvasculature in the canine spinal cord. Anat. Rec. 200, 102–113.Kilbourne, M., Kuehn, R., Tosun, C., Caridi, J., Keledjian, K., Bochicchio, G...acquisition gradient echo (MP- RAGE ) images were acquired in the axial plane with adequate coverage of the injury using 64 slices over a field of view

  16. Receptor for advanced glycation end products involved in lung ischemia reperfusion injury in cardiopulmonary bypass attenuated by controlled oxygen reperfusion in a canine model.

    Science.gov (United States)

    Rong, Jian; Ye, Sheng; Liang, Meng-ya; Chen, Guang-xian; Liu, Hai; Zhang, Jin-Xin; Wu, Zhong-kai

    2013-01-01

    Controlled oxygen reperfusion could protect the lung against ischemia-reperfusion injury in cardiopulmonary bypass (CPB) by downregulating high mobility group box 1 (HMGB1), a high affinity receptor of HMGB1. This study investigated the effect of controlled oxygen reperfusion on receptor for advanced glycation end products (RAGE) expression and its downstream effects on lung ischemia-reperfusion injury. Fourteen canines received CPB with 60 minutes of aortic clamping and cardioplegic arrest followed by 90 minutes of reperfusion. Animals were randomized to receive 80% FiO2 during the entire procedure (control group) or to a test group receiving a controlled oxygen reperfusion protocol. Pathologic changes in lung tissues, RAGE expression, serum interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were evaluated. The lung pathologic scores after 25 and 90 minutes of reperfusion were significantly lower in the test group compared with the control group (p RAGE expression, TNF-α, and IL-6 were downregulated by controlled oxygen treatment (p RAGE might be involved in the lung ischemia-reperfusion injury in canine model of CPB, which was downregulated by controlled oxygen reperfusion.

  17. Joint Force Quarterly. Number 7, Spring 1995

    Science.gov (United States)

    1995-02-01

    agencies which use canines . The Air Force also operates a law enforcement school at Lackland for Navy and Air Force “cops.” In ad- dition, English...were not moving as quickly as marines. This incident caused a debate that rages to this day. On Guam, however, the Army (77th Di- vision) and the

  18. A Case Study of a "Collaborative Organizational Innovation" Intervention, Combining Action Research and Design-Thinking Methodologies

    Science.gov (United States)

    Wetzler, Jeffrey Richard

    2013-01-01

    For decades, debates have raged about performance management in education. While it is essential to understand the degree of student learning and the nature of teacher impact in education systems, when attempts at managing outcomes go wrong, the consequences can be problematic. National Education Organization (a pseudonym for the organization…

  19. Putting Big Data to Work: Community Colleges Use Detailed Reports to Design Smarter Workforce Training and Education Programs

    Science.gov (United States)

    Woods, Bob

    2013-01-01

    In this article, Bob Woods reports that "Big data" is all the rage on college campuses, and it makes sense that administrators would use what they know to boost student outcomes. Woods points out that community colleges around the country are using the data: (1) to guide the systematic expansion of its curriculum, providing targeted…

  20. ADEC - The Astrophysics Data Centers Executive Council

    Science.gov (United States)

    Gay Bears | RawGayBears | Gay Bears Porno | GayBearsPorno | Seductive 18 | Seductive18 | Raging | MotherFuckerXXX | X Groupsex Mobile | XGroupsexMobile | Gay Bears Porno Mobile | GayBearsPornoMobile | Evil Angel Older Younger | LesbianOlderYounger | Ebony BBW Porno | EbonyBBWPorno | Ass Teen Mouth | AssTeenMouth

  1. Beyond the Bravado: Sex Roles and the Exploitive Male.

    Science.gov (United States)

    Taubman, Stan

    1986-01-01

    Examines the tendency of men to engage in domestic violence and sexual exploitation and presents male sex-role acquisition as a process of psychosocial violence against young boys, which creates a sense of shame, powerlessness, self-alienation, isolation from others, and retaliatory rage and inhibits capacities for intimacy and mutuality.…

  2. Undocumented to Hyperdocumented: A "Jornada" of Protection, Papers, and PhD Status

    Science.gov (United States)

    Chang, Aurora

    2011-01-01

    In this personal essay, Aurora Chang describes her experience of "hyperdocumentation"--the effort to accrue awards, accolades, and eventually academic degrees to compensate for her undocumented status. In spite of her visible successes and naturalization, Chang still confronts the rage and intolerance of American "commonsense" beliefs about…

  3. The significance of the second cave episode in Jerome's Vita Malchi

    African Journals Online (AJOL)

    2014-05-16

    May 16, 2014 ... (2005/2006:5) states that the reason why caves had excited ... rejection of sexual union is followed by living together for the rest of their lives for .... raging famine drives him) he gnaws and drags / at the tender flock mute with ...

  4. Polymorphism screening of four genes encoding advanced glycation end-product putative receptors. Association study with nephropathy in type 1 diabetic patients

    DEFF Research Database (Denmark)

    Poirier, Odette; Nicaud, Viviane; Vionnet, N

    2001-01-01

    Advanced glycation end-products (AGEs) may play an important role in the pathogenesis and progression of cardiovascular and renal complications of diabetes. Four putative AGE receptors (RAGEs), AGE-R1, AGE-R2, and AGE-R3 have been described. In this study, we scanned the sequence of the genes enc...

  5. Negative Experiences as Learning Trigger: A Play Experience Empirical Research on a Game for Social Change Case Study

    Science.gov (United States)

    Mariani, Ilaria; Gandolfi, Enrico

    2016-01-01

    This study shows the results gathered from 141 subjects playing the persuasive urban game "A Hostile World" via a post-game-experience quantitative questionnaire. The aim is to problematize and deepen the role of negative emotions (e.g., frustration, rage)--explicitly fostered by "A Hostile World" to increase empathy toward…

  6. Robust and Fault Tolerant Control of CD-players

    DEFF Research Database (Denmark)

    Vidal, Enrique Sanchez

    Several new standards have emerged recently in the area of portable optical data sto-rage media and more are on their way. In addition to the well known Compact Disc(CD), portable optical media now also feature media for video storage (DVDs) and ge-neral data storage media for computer purposes (CD...

  7. Experimental and clinical studies of fast three-dimensional MR imaging of the heart

    Energy Technology Data Exchange (ETDEWEB)

    Sato, Shuhei [Okayama Univ. (Japan). School of Medicine

    1999-07-01

    MRI has been utilized since its inception to study the anatomy and physiology of the heart. However, the sensitivity of MRI to motion has always posed a major challenge in imaging this organ. The purpose of this study was to develop a 3D MP-RAGE technique for the heart, and to apply it clinically. In the experimental study, data acquisition timing was discussed by normal volunteers. Changes in magnetization recovery time affected imaging contrast very little in the phantom study. Fourteen adults and 21 children were examined. In the adults, MP-RAGE images were rated as high in quality in the visual estimation. In the quantitative estimation, the images provided almost the same anatomical information as those of cine MRI. In the children, MP-RAGE was useful for cases of partial anomalous pulmonary venous drainage, particularly in the evaluation of abnormal pulmonary veins. The 3D MP-RAGE technique was useful in imaging the heart because it was possible to obtain continuous views in the same cardiac cycle and to reconstruct views from any direction after the examination. (author)

  8. An overview of the Los Alamos Crestone Project : uses for astrophysical problems

    Energy Technology Data Exchange (ETDEWEB)

    Weaver, R. P. (Robert P.); Gittings, M. L. (Michael L.); Gisler, Galen R.; Coker, R. F. (Robert F.); New, K. C. (Kimberly C.); Hueckstaedt, R. M. (Robert M.)

    2004-01-01

    The Los Alamos Crestone Project is part of the Department of Energy's (DoE) Advanced Simulation and Computing (ASC) program. The main goal of this project is to investigate the use of continuous adaptive mesh refinement (CAMR) techniques for application to problems of interest to the Laboratory. An overview of the astrophysical simulations performed with the SAGE/RAGE codes will be shown here, including asteroid impacts in the deep-ocean, asteroid impacts on the continental shelf (e.g. - Chicxulub - the dinosaur killer), calculations of massive black holes at the galactic center, and calculations of supernova explosions. Examples of these simulations will be shown. We have shown that the SAGE and RAGE codes of the Crestone Project have been very successful products of the DoE's Advanced Simulation and Computing program. It is clear to those performing massively-parallel computations, that the use of thousands of processors in parallel is fundamentally changing the way we think about computer simulations. The Crestone Project codes are fully utilizing each new ASC supercomputer as they become available. The SAGE and RAGE codes are sophisticated Continuous Adaptive Mesh Refinement hydrodynamics codes for large parallel simulations. SAGE and RAGE are becoming useful tools for astrophysical applications. Further research is starting in a wider variety of areas, including cosmological studies with Mike Norman's group at UCSD.

  9. Dublini festival II : Külalised. Muust / Jaak Rähesoo

    Index Scriptorium Estoniae

    Rähesoo, Jaak, 1941-

    2002-01-01

    Ka Kopenhaageni Betty Nanseni Teatri näidatud Robert Wilsoni tehtud Georg Büchneri "Woyzecki" tõlgenduse ning noore inglise trupi näidatud Edward Halli lavastatud William Shakespeare "Rose Rage" ("Henry VI") etenduse lavakujundusest ja -kostüümidest.

  10. The Middle School Mess: If You Love Bungee Jumping, You're the Middle School Type

    Science.gov (United States)

    Meyer, Peter

    2011-01-01

    Suspended "between childhood and the adult world, pre-teens have been called the toughest to teach." Indeed, one can't touch middle school without hearing about "raging hormones." By all accounts, middle schools are a weak link in the chain of public education. Is it the churn of ill-conceived attempts at reform that's causing all the problems? Is…

  11. Follow the Leaders? An Analysis of Convergence and Innovation of Faculty Recruiting Practices in US Business Schools

    Science.gov (United States)

    Finch, David; Deephouse, David L.; O'Reilly, Norm; Massie, Tyler; Hillenbrand, Carola

    2016-01-01

    The debate associated with the qualifications of business school faculty has raged since the 1959 release of the Gordon-Howell and Pierson reports, which encouraged business schools in the USA to enhance their legitimacy by increasing their faculties' doctoral qualifications and scholarly rigor. Today, the legitimacy of specific faculty…

  12. Age-related accumulation of advanced glycation end-products-albumin, S100β, and the expressions of advanced glycation end product receptor differ in visceral and subcutaneous fat

    International Nuclear Information System (INIS)

    Son, Kuk Hui; Son, Myeongjoo; Ahn, Hyosang; Oh, Seyeon; Yum, Yoonji; Choi, Chang Hu; Park, Kook Yang; Byun, Kyunghee

    2016-01-01

    Visceral fat induces more inflammation by activating macrophages than subcutaneous fat, and inflammation is an underlying feature of the pathogeneses of various diseases, including cardiovascular disease and diabetes. Advanced glycation end products (AGEs), S100β, and their receptors, the receptor for advanced glycation end products (RAGE), lead to macrophage activation. However, little information is available regarding the differential accumulations of AGE-albumin (serum albumin modified by AGEs), S100β, or expressions of RAGE in different adipocyte types in fat tissues. In this study, the authors investigated whether age-related AGE-albumin accumulations S100β level, and RAGE expressions differ in subcutaneous and visceral fat tissues. Subcutaneous and visceral fat were harvested from 3- and 28-week-old rats. Macrophage activation was confirmed by Iba1 staining, and AGE-albumin accumulations and RAGE expressions were assessed by confocal microscopy. S100β were analyzed by immunoblotting. It was found that activated macrophage infiltration, AGE-albumin accumulation, and S100β in visceral fat was significantly greater in 28-week-old rats than in 3-week-old rats, but similar in subcutaneous fat. The expression of RAGE in visceral fat was much greater in 28-week-old rats, but its expression in subcutaneous fat was similar in 3- and 28-week-old rats. Furthermore, inflammatory signal pathways (NFκB, TNF-α) and proliferation pathways (FAK) in visceral fat were more activated in 28-week-old rats. These results imply that age-related AGE-albumin accumulation, S100β, and RAGE expression are more prominent in visceral than in subcutaneous fat, suggesting that visceral fat is involved in the pathogenesis of inflammation-induced diseases in the elderly. - Highlights: • The age-related AGE-albumin accumulation and S100β were more prominent in visceral than subcutaneous fat. • The age-related RAGE expression were more prominent in visceral than subcutaneous fat.

  13. Age-related accumulation of advanced glycation end-products-albumin, S100β, and the expressions of advanced glycation end product receptor differ in visceral and subcutaneous fat

    Energy Technology Data Exchange (ETDEWEB)

    Son, Kuk Hui [Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon (Korea, Republic of); Son, Myeongjoo [Department of Anatomy and Cell Biology, Gachon University Graduate School of Medicine, Incheon (Korea, Republic of); Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon (Korea, Republic of); Ahn, Hyosang; Oh, Seyeon; Yum, Yoonji [Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon (Korea, Republic of); Choi, Chang Hu [Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon (Korea, Republic of); Park, Kook Yang, E-mail: kkyypark@ghil.com [Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon (Korea, Republic of); Byun, Kyunghee, E-mail: khbyun1@gachon.ac.kr [Department of Anatomy and Cell Biology, Gachon University Graduate School of Medicine, Incheon (Korea, Republic of); Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon (Korea, Republic of)

    2016-08-19

    Visceral fat induces more inflammation by activating macrophages than subcutaneous fat, and inflammation is an underlying feature of the pathogeneses of various diseases, including cardiovascular disease and diabetes. Advanced glycation end products (AGEs), S100β, and their receptors, the receptor for advanced glycation end products (RAGE), lead to macrophage activation. However, little information is available regarding the differential accumulations of AGE-albumin (serum albumin modified by AGEs), S100β, or expressions of RAGE in different adipocyte types in fat tissues. In this study, the authors investigated whether age-related AGE-albumin accumulations S100β level, and RAGE expressions differ in subcutaneous and visceral fat tissues. Subcutaneous and visceral fat were harvested from 3- and 28-week-old rats. Macrophage activation was confirmed by Iba1 staining, and AGE-albumin accumulations and RAGE expressions were assessed by confocal microscopy. S100β were analyzed by immunoblotting. It was found that activated macrophage infiltration, AGE-albumin accumulation, and S100β in visceral fat was significantly greater in 28-week-old rats than in 3-week-old rats, but similar in subcutaneous fat. The expression of RAGE in visceral fat was much greater in 28-week-old rats, but its expression in subcutaneous fat was similar in 3- and 28-week-old rats. Furthermore, inflammatory signal pathways (NFκB, TNF-α) and proliferation pathways (FAK) in visceral fat were more activated in 28-week-old rats. These results imply that age-related AGE-albumin accumulation, S100β, and RAGE expression are more prominent in visceral than in subcutaneous fat, suggesting that visceral fat is involved in the pathogenesis of inflammation-induced diseases in the elderly. - Highlights: • The age-related AGE-albumin accumulation and S100β were more prominent in visceral than subcutaneous fat. • The age-related RAGE expression were more prominent in visceral than subcutaneous fat.

  14. Generation of cell lines for drug discovery through random activation of gene expression: application to the human histamine H3 receptor.

    Science.gov (United States)

    Song, J; Doucette, C; Hanniford, D; Hunady, K; Wang, N; Sherf, B; Harrington, J J; Brunden, K R; Stricker-Krongrad, A

    2005-06-01

    Target-based high-throughput screening (HTS) plays an integral role in drug discovery. The implementation of HTS assays generally requires high expression levels of the target protein, and this is typically accomplished using recombinant cDNA methodologies. However, the isolated gene sequences to many drug targets have intellectual property claims that restrict the ability to implement drug discovery programs. The present study describes the pharmacological characterization of the human histamine H3 receptor that was expressed using random activation of gene expression (RAGE), a technology that over-expresses proteins by up-regulating endogenous genes rather than introducing cDNA expression vectors into the cell. Saturation binding analysis using [125I]iodoproxyfan and RAGE-H3 membranes revealed a single class of binding sites with a K(D) value of 0.77 nM and a B(max) equal to 756 fmol/mg of protein. Competition binding studies showed that the rank order of potency for H3 agonists was N(alpha)-methylhistamine approximately (R)-alpha- methylhistamine > histamine and that the rank order of potency for H3 antagonists was clobenpropit > iodophenpropit > thioperamide. The same rank order of potency for H3 agonists and antagonists was observed in the functional assays as in the binding assays. The Fluorometic Imaging Plate Reader assays in RAGE-H3 cells gave high Z' values for agonist and antagonist screening, respectively. These results reveal that the human H3 receptor expressed with the RAGE technology is pharmacologically comparable to that expressed through recombinant methods. Moreover, the level of expression of the H3 receptor in the RAGE-H3 cells is suitable for HTS and secondary assays.

  15. HbA1c Identifies Subjects With Prediabetes and Subclinical Left Ventricular Diastolic Dysfunction.

    Science.gov (United States)

    Di Pino, Antonino; Mangiafico, Sarah; Urbano, Francesca; Scicali, Roberto; Scandura, Salvatore; D'Agate, Veronica; Piro, Salvatore; Tamburino, Corrado; Purrello, Francesco; Rabuazzo, Agata Maria

    2017-10-01

    Prediabetes is associated with subclinical cardiac changes associated with heart failure development. We investigated diastolic function and its association with markers of glycation and inflammation related to cardiovascular disease in patients with prediabetes. We focused on individuals with prediabetes identified only by glycated hemoglobin A1c [HbA1c; 5.7% to 6.4% and normal fasting glucose (NFG) and normal glucose tolerance (NGT) after an oral glucose tolerance test (OGTT)]. Cross-sectional study. Departments of Clinical and Experimental Medicine and Cardiology, University of Catania, Catania, Italy. HbA1c, OGTT, Doppler echocardiography, soluble receptor for advanced glycation end products (sRAGEs), and endogenous secretory RAGE (esRAGE) were evaluated. We recruited 167 subjects with NFG/NGT who were stratified according to HbA1c level: controls (HbA1c prediabetes (HbA1c 5.7% to 6.4%). Patients with HbA1c prediabetes (n = 106) showed a lower peak mitral inflow in early diastole (E wave) to late diastolic atrial filling velocity (A wave) ratio (E/A ratio) than controls (n = 61) (1.10 ± 0.24 vs 1.18 ± 0.23; P prediabetes exhibited subclinical cardiac alterations associated with sRAGE, esRAGE, and HbA1c. These subjects would not have been classified as having prediabetes on the basis of fasting glycemia or post-OGTT values. Copyright © 2017 Endocrine Society

  16. Glomerular cell death and inflammation with high-protein diet and diabetes.

    Science.gov (United States)

    Meek, Rick L; LeBoeuf, Renee C; Saha, Sandeep A; Alpers, Charles E; Hudkins, Kelly L; Cooney, Sheryl K; Anderberg, Robert J; Tuttle, Katherine R

    2013-07-01

    Overfeeding amino acids (AAs) increases cellular exposure to advanced glycation end-products (AGEs), a mechanism for protein intake to worsen diabetic kidney disease (DKD). This study assessed receptor for AGE (RAGE)-mediated apoptosis and inflammation in glomerular cells exposed to metabolic stressors characteristic of high-protein diets and/or diabetes in vitro with proof-of-concept appraisal in vivo. Mouse podocytes and mesangial cells were cultured under control and metabolic stressor conditions: (i) no addition; (ii) increased AAs (4-6-fold>control); (iii) high glucose (HG, 30.5 mM); (iv) AA/HG combination; (v) AGE-bovine serum albumin (AGE-BSA, 300 µg/mL); (vi) BSA (300 µg/mL). RAGE was inhibited by blocking antibody. Diabetic (streptozotocin) and nondiabetic mice (C57BL/6J) consumed diets with protein calories of 20 or 40% (high) for 20 weeks. People with DKD and controls provided 24-h urine samples. In podocytes and mesangial cells, apoptosis (caspase 3/7 activity and TUNEL) increased in all metabolic stressor conditions. Both inflammatory mediator expression (real-time reverse transcriptase-polymerase chain reaction: serum amyloid A, caspase-4, inducible nitric oxide synthase, and monocyte chemotactic protein-1) and RAGE (immunostaining) also increased. RAGE inhibition prevented apoptosis and inflammation in podocytes. Among mice fed high protein, podocyte number (WT-1 immunostaining) decreased in the diabetic group, and only these diabetic mice developed albuminuria. Protein intake (urea nitrogen) correlated with AGE excretion (carboxymethyllysine) in people with DKD and controls. High-protein diet and/or diabetes-like conditions increased glomerular cell death and inflammation, responses mediated by RAGEs in podocytes. The concept that high-protein diets exacerbate early indicators of DKD is supported by data from mice and people.

  17. Benazepril, an angiotensin-converting enzyme inhibitor, alleviates renal injury in spontaneously hypertensive rats by inhibiting advanced glycation end-product-mediated pathways.

    Science.gov (United States)

    Liu, Xue-Ping; Pang, Yue-Jiu; Zhu, Wei-Wei; Zhao, Ting-Ting; Zheng, Min; Wang, Yi-Bing; Sun, Zhi-Jian; Sun, Siao-Jing

    2009-03-01

    1. Advanced glycation end-products (AGE) and their receptors (RAGE) have been implicated in renal damage in diabetes. The aim of the present study was to investigate the effects of benazepril, an angiotensin-converting enzyme inhibitor (ACEI), on the formation of AGE, the expression RAGE and other associated components in the oxidative stress pathway in spontaneously hypertensive rats (SHR). 2. Groups of SHR were treated with or without 10 mg/kg per day benazepril for 12 weeks. Systolic blood pressure (SBP) and angiotensin (Ang) II levels were evaluated in SHR and control Wistar-Kyoto (WKY) rats. Renal function was investigated by determining levels of proteinuria and glomerulosclerosis. Furthermore, reactive oxygen species (ROS) in the rat renal cortex were analysed using an H(2)O(2)-based hydroxyl radical-detection assay and the renal content of AGE, RAGE, NADPH oxidase p47phox, nuclear factor (NF)-kappaB p65, phosphorylated (p-) NF-kappaB p65, vascular cell adhesion molecule (VCAM)-1 and transforming growth factor (TGF)-beta1 was determined by immunohistochemistry, quantitative real-time polymerase chain reaction and western blot analysis. 3. Treatment with benazepril inhibited the formation of AngII, reduced SBP and alleviated renal lesions in SHR compared with both untreated SHR and control WKY rats. Benazepril treatment significantly suppressed the accumulation of AGE and expression of RAGE in the kidney of SHR. In addition, benazepril treatment reduced the upregulation of NADPH oxidase p47phox, ROS generation and NF-kappaB p65, p-NF-kappaB p65, VCAM-1 and TGF-beta1 expression in the kidney of SHR compared with both untreated SHR and control WKY rats. 4. The results of the present study provide new insights into the regulation by the renin-angiotensin system of AGE-RAGE, oxidative stress and nephropathy, increasing our understanding of the role of the RAS in nephropathy.

  18. A Rickettsia Genome Overrun by Mobile Genetic Elements Provides Insight into the Acquisition of Genes Characteristic of an Obligate Intracellular Lifestyle

    Science.gov (United States)

    Joardar, Vinita; Williams, Kelly P.; Driscoll, Timothy; Hostetler, Jessica B.; Nordberg, Eric; Shukla, Maulik; Walenz, Brian; Hill, Catherine A.; Nene, Vishvanath M.; Azad, Abdu F.; Sobral, Bruno W.; Caler, Elisabet

    2012-01-01

    We present the draft genome for the Rickettsia endosymbiont of Ixodes scapularis (REIS), a symbiont of the deer tick vector of Lyme disease in North America. Among Rickettsia species (Alphaproteobacteria: Rickettsiales), REIS has the largest genome sequenced to date (>2 Mb) and contains 2,309 genes across the chromosome and four plasmids (pREIS1 to pREIS4). The most remarkable finding within the REIS genome is the extraordinary proliferation of mobile genetic elements (MGEs), which contributes to a limited synteny with other Rickettsia genomes. In particular, an integrative conjugative element named RAGE (for Rickettsiales amplified genetic element), previously identified in scrub typhus rickettsiae (Orientia tsutsugamushi) genomes, is present on both the REIS chromosome and plasmids. Unlike the pseudogene-laden RAGEs of O. tsutsugamushi, REIS encodes nine conserved RAGEs that include F-like type IV secretion systems similar to that of the tra genes encoded in the Rickettsia bellii and R. massiliae genomes. An unparalleled abundance of encoded transposases (>650) relative to genome size, together with the RAGEs and other MGEs, comprise ∼35% of the total genome, making REIS one of the most plastic and repetitive bacterial genomes sequenced to date. We present evidence that conserved rickettsial genes associated with an intracellular lifestyle were acquired via MGEs, especially the RAGE, through a continuum of genomic invasions. Robust phylogeny estimation suggests REIS is ancestral to the virulent spotted fever group of rickettsiae. As REIS is not known to invade vertebrate cells and has no known pathogenic effects on I. scapularis, its genome sequence provides insight on the origin of mechanisms of rickettsial pathogenicity. PMID:22056929

  19. Aggressive Behaviour in Huntington’s Disease: A Cross-Sectional Study in a Nursing Home Population

    Directory of Open Access Journals (Sweden)

    R. S. Shiwach

    1993-01-01

    Full Text Available We describe a cross-sectional study of aggressive behaviour in a sample of patients suffering from Huntington's disease in a residential nursing home. Data were obtained using the RAGE, a behaviourally oriented rating scale for measuring aggressive behaviour in cognitively impaired patients. Nursing staff rated 27 patients after a 3 day observation period. A third of the sample were rated to be at least mildly aggressive; the frequencies of some specific types of aggressive behaviour were high. In contrast, the frequency of injuries sustained and the use of restraints and medication for aggressive behaviour were low. Aggressive behaviour was found to be significantly related to the degree of functional impairment. These data are compared with those reported in a study using the RAGE to assess aggressive behaviour in a sample of elderly patients with dementia.

  20. Psychohistory and Family Among Antebellum Slaveholders.

    Science.gov (United States)

    Adams, Kenneth Alan

    2016-01-01

    This article examines the macroscopic reasons for maternal rage and its injection into slaveholder children in the antebellum South. It is argued that the misogyny that infected antebellum life metastasized in southern mistresses and affected the way they felt about themselves and their children. As mothers, they were casual parents, concerned with molding the character of their charges, rearing warriors and proper ladies, but uninterested in caring for them and helping them realize their own aspirations. It is argued that the misanthropic rage that they injected into their children constituted the poison that each generation of slaveholders had to ventilate into poison containers, slaves, as a homeostatic means of psycho-emotional survival. This intergenerational process of poison injection--from father to mother, from mother to child, from child to slave, constituted the process that insured the perpetuation of the psychic structure necessary for the continuation of slavery from generation to generation.

  1. Targeted reduction of advanced glycation improves renal function in obesity

    DEFF Research Database (Denmark)

    Harcourt, Brooke E; Sourris, Karly C; Coughlan, Melinda T

    2011-01-01

    -lowering pharmaceutical, alagebrium, and mice in which the receptor for AGE (RAGE) was deleted. Obesity, resulting from a diet high in both fat and AGE, caused renal impairment; however, treatment of the RAGE knockout mice with alagebrium improved urinary albumin excretion, creatinine clearance, the inflammatory profile...... if treatments that lower tissue AGE burden in patients and mice would improve obesity-related renal dysfunction. Overweight and obese individuals (body mass index (BMI) 26-39¿kg/m(2)) were recruited to a randomized, crossover clinical trial involving 2 weeks each on a low- and a high-AGE-containing diet. Renal......, and renal oxidative stress. Alagebrium treatment, however, resulted in decreased weight gain and improved glycemic control compared with wild-type mice on a high-fat Western diet. Thus, targeted reduction of the advanced glycation pathway improved renal function in obesity....

  2. On the Significance of New Biochemical Markers for the Diagnosis of Premature Labour

    Directory of Open Access Journals (Sweden)

    Rafał Rzepka

    2014-01-01

    Full Text Available Preterm labour is defined as a birth taking place between 22nd and 37th weeks of gestation. Despite numerous studies on the aetiology and pathogenesis of preterm labour, its very cause still remains unclear. The importance of the cytokines and acute inflammation in preterm labour aetiology is nowadays well-proven. However, chronic inflammation as an element of the pathogenesis of premature labour is still unclear. This paper presents a literature review on the damage-associated molecular patterns (DAMPs, receptors for advanced glycation end products (RAGE, negative soluble isoforms of RAGE, chemokine-stromal cell-derived factor-1 (SDF-1 and one of the adipokines, resistin, in the pathogenesis of preterm labour. We conclude that the chronic inflammatory response can play a much more important role in the pathogenesis of preterm delivery than the acute one.

  3. Advanced glycation end-product expression is upregulated in the gastrointestinal tract of type 2 diabetic rats

    DEFF Research Database (Denmark)

    Chen, Peng-Min; Gregersen, Hans; Zhao, Jingbo

    2015-01-01

    AIM: To investigate changes in advanced glycation end products (AGEs) and their receptor (RAGE) expression in the gastrointestinal (GI) tract in type 2 diabetic rats. METHODS: Eight inherited type 2 diabetic rats Goto-Kakizak (GK) and ten age-matched normal rats were used in the study. From 18 wk...... and five micron sections were cut. The layer thickness was measured in Hematoxylin and Eosin-stained slides. AGE [N epsilon-(carboxymethyl) lysine and N epsilon-(carboxyethyl)lysine] and RAGE were detected by immunohistochemistry staining and image analysis was done using Sigmascan Pro 4.0 image analysis...... strongest in the diabetes group. Significant difference for AGE was found in the epithelial cells of villi and crypt in duodenum (immuno-positive area/total measuring area %: 13.37 ± 3.51 vs 37.48 ± 8.43, P

  4. A Psychoanalytic Study of Sylvia Plath.

    Science.gov (United States)

    Feirstein, Frederick

    2016-02-01

    Sylvia Plath's rage at her abandoning husband and at her late beloved father was partly a displacement of anger toward her loving but smothering mother. Her schizoid pathology resulting from the symbiosis (along with her bipolarity) helped prompt her suicide. At the same time her rage at the men represented a struggle to prevent it. The focus of this paper is to explore in the context of her life how the style as well as the content of her last book, Ariel, made for one long suicide note-albeit a beautifully written work of art. In the most accessible of her poems, such as "Daddy," "Lady Lazarus," and "Edge," her health overcomes her pathology. In others her pathology dominates. In Ariel Plath attempted and succeeded in turning herself into a tragic, mythic heroine, eventually drowning herself in a gas oven as she would have in the ocean-a key metaphor for her mother.

  5. Simulation and Analysis of Converging Shock Wave Test Problems

    Energy Technology Data Exchange (ETDEWEB)

    Ramsey, Scott D. [Los Alamos National Laboratory; Shashkov, Mikhail J. [Los Alamos National Laboratory

    2012-06-21

    Results and analysis pertaining to the simulation of the Guderley converging shock wave test problem (and associated code verification hydrodynamics test problems involving converging shock waves) in the LANL ASC radiation-hydrodynamics code xRAGE are presented. One-dimensional (1D) spherical and two-dimensional (2D) axi-symmetric geometric setups are utilized and evaluated in this study, as is an instantiation of the xRAGE adaptive mesh refinement capability. For the 2D simulations, a 'Surrogate Guderley' test problem is developed and used to obviate subtleties inherent to the true Guderley solution's initialization on a square grid, while still maintaining a high degree of fidelity to the original problem, and minimally straining the general credibility of associated analysis and conclusions.

  6. Glucagon-like peptide 1: A potential anti-inflammatory pathway in obesity-related asthma.

    Science.gov (United States)

    Nguyen, Dan-Vinh; Linderholm, Angela; Haczku, Angela; Kenyon, Nicholas

    2017-12-01

    Alterations in arginine metabolism and accelerated formation of advanced glycation end-products (AGEs), crucial mechanisms in obesity-related asthma, can be modulated by glucagon-like peptide 1 (GLP-1). l-arginine dysregulation in obesity promotes inflammation and bronchoconstriction. Prolonged hyperglycemia, dyslipidemia, and oxidative stress leads to production of AGEs, that bind to their receptor (RAGE) further potentiating inflammation. By binding to its widely distributed receptor, GLP-1 blunts the effects of RAGE activation and arginine dysregulation. The GLP-1 pathway, while comprehensively studied in the endocrine and cardiovascular literature, is under-recognized in pulmonary research. Insights into GLP-1 and the lung may lead to novel treatments for obesity-related asthma. Published by Elsevier Inc.

  7. Feruidus Ille Canis: the Lore and Poetry of the Dog Star in Antiquity

    Science.gov (United States)

    Ceragioli, Roger Charles

    1992-01-01

    The Dog Star, Sirius, appears in many important works of classical poetry. It also appears in numerous myths and several religious rituals. A complex body of folklore surrounds it and it had a paramount importance in agriculture. Yet no one has attempted a systematic analysis of Sirius' place in Greco-Roman art and thought. This thesis begins that analysis. The introductory chapter discusses the methodology and approach that the thesis takes to the evidence, and supplies essential background information on Sirius' place among the constellations and its relation to the physical environment of the Mediterranean. Chapter one explores Sirius' role in ancient warrior traditions. Sirius embodied the principle of cosmic heat, and through heat it was thought to cause rabies in dogs. The Greek word for rabies is lussa. But lussa also named the madness of warriors such as Achilles in the Iliad. Etymologically, lussa meant "wolfishness." Rabid dogs, wolves, and raging warriors all exhibit fiery heat as an integral part of their natures. It is argued that raging warriors, wolves, and rabid dogs were largely interchangeable entities for the Greeks. Thus when Hector and Achilles in their raging are compared to Sirius, the comparison reflects more than the likeness of their surface brilliance. Chapter two explores Sirius' connection to erotic themes in ancient poetry. Because erotic experience could be represented as a conflagration that might burn the lover into a frenzy, the fiery raging Dog Star was an appropriate symbolic accompaniment. Sirius itself experienced erotic frenzy when it became passionate for Opora (the ripe fruits of summer). Chapter three turns to Sirius' involvement in viticulture. Sirius was said to ripen the grapes, but was also conceived to have once been the faithful dog of Icarius, who first introduced wine-drinking among humans. The chapter explores Sirius' role in the myth of Icarius, and the relation of that myth to the erotic and martial sides of

  8. Design and Calibration of a Flowfield Survey Rake for Inlet Flight Research

    Science.gov (United States)

    Flynn, Darin C.; Ratnayake, Nalin A.; Frederick, Michael

    2009-01-01

    Flowfield rake was designed to quantify the flowfield for inlet research underneath NASA DFRC s F-15B airplane. Detailed loads and stress analysis performed using CFD and empirical methods to assure structural integrity. Calibration data were generated through wind tunnel testing of the rake. Calibration algorithm was developed to determine the local Mach and flow angularity at each probe. RAGE was flown November, 2008. Data is currently being analyzed.

  9. Multistakeholder Initiatives in Corporate Social Responsibility: The OECD Guidance and Conflict Minerals

    OpenAIRE

    Johns, Matthew

    2010-01-01

    In recent years, war has raged in the Democratic Republic of Congo between various military bodies, bringing death and devastation to millions of innocent civilians. The conflict has been fuelled by the country‟s abundant mineral wealth, with factions exploiting state weakness and taking control of a large proportion of the mining sector. One of the largest purchasers of the Congo‟s minerals is the global electronics industry. NGOs and civil society have subsequently accused electronics compa...

  10. Protective roles of pulmonary rehabilitation mixture in experimental pulmonary fibrosis in vitro and in vivo

    International Nuclear Information System (INIS)

    Zhang, L.; Ji, Y.X.; Jiang, W.L.; Lv, C.J.

    2015-01-01

    Abnormal high mobility group protein B1 (HMGB1) activation is involved in the pathogenesis of pulmonary fibrosis. Pulmonary rehabilitation mixture (PRM), which combines extracts from eight traditional Chinese medicines, has very good lung protection in clinical use. However, it is not known if PRM has anti-fibrotic activity. In this study, we investigated the effects of PRM on transforming growth factor-β1 (TGF-β1)-mediated and bleomycin (BLM)-induced pulmonary fibrosis in vitro and in vivo. The effects of PRM on TGF-β1-mediated epithelial-mesenchymal transition (EMT) in A549 cells, on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on BLM-induced pulmonary fibrosis in vivo were investigated. PRM treatment resulted in a reduction of EMT in A549 cells that was associated with attenuating an increase of vimentin and a decrease of E-cadherin. PRM inhibited the proliferation of HLF-1 at an IC 50 of 0.51 µg/mL. PRM ameliorated BLM-induced pulmonary fibrosis in rats, with reduction of histopathological scores and collagen deposition, and a decrease in α-smooth muscle actin (α-SMA) and HMGB1 expression. An increase in receptor for advanced glycation end-product (RAGE) expression was found in BLM-instilled lungs. PRM significantly decreased EMT and prevented pulmonary fibrosis through decreasing HMGB1 and regulating RAGE in vitro and in vivo. PRM inhibited TGF-β1-induced EMT via decreased HMGB1 and vimentin and increased RAGE and E-cadherin levels. In summary, PRM prevented experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway

  11. Ivan IV, el Terrible, ¿padeció de un síndrome del lóbulo temporal?

    OpenAIRE

    Espinoza G, Ricardo; Benavides S, Evelyn

    2006-01-01

    Ivan IV "The Terrible" was the first Tsar of all Russias and was crowned in 1547. He extended Russian territories and opened the route to Siberia in successful campaigns against Tartars. He increased his personal power to the point of generating an autocracy that isolated him progressively from the council of Boyars. He had a complex personality and his acts were impregnated by a profound religiousness, episodes of rage, mood changes and a sense of "personal fate". All these traits configure ...

  12. Protective roles of pulmonary rehabilitation mixture in experimental pulmonary fibrosis in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, L.; Ji, Y.X.; Jiang, W.L.; Lv, C.J. [School of Pharmaceutical Sciences, Binzhou Medical University, Yantai (China)

    2015-05-08

    Abnormal high mobility group protein B1 (HMGB1) activation is involved in the pathogenesis of pulmonary fibrosis. Pulmonary rehabilitation mixture (PRM), which combines extracts from eight traditional Chinese medicines, has very good lung protection in clinical use. However, it is not known if PRM has anti-fibrotic activity. In this study, we investigated the effects of PRM on transforming growth factor-β1 (TGF-β1)-mediated and bleomycin (BLM)-induced pulmonary fibrosis in vitro and in vivo. The effects of PRM on TGF-β1-mediated epithelial-mesenchymal transition (EMT) in A549 cells, on the proliferation of human lung fibroblasts (HLF-1) in vitro, and on BLM-induced pulmonary fibrosis in vivo were investigated. PRM treatment resulted in a reduction of EMT in A549 cells that was associated with attenuating an increase of vimentin and a decrease of E-cadherin. PRM inhibited the proliferation of HLF-1 at an IC{sub 50} of 0.51 µg/mL. PRM ameliorated BLM-induced pulmonary fibrosis in rats, with reduction of histopathological scores and collagen deposition, and a decrease in α-smooth muscle actin (α-SMA) and HMGB1 expression. An increase in receptor for advanced glycation end-product (RAGE) expression was found in BLM-instilled lungs. PRM significantly decreased EMT and prevented pulmonary fibrosis through decreasing HMGB1 and regulating RAGE in vitro and in vivo. PRM inhibited TGF-β1-induced EMT via decreased HMGB1 and vimentin and increased RAGE and E-cadherin levels. In summary, PRM prevented experimental pulmonary fibrosis by modulating the HMGB1/RAGE pathway.

  13. Simultaneous involvement of third and sixth cranial nerve in a patient with Lyme disease

    Energy Technology Data Exchange (ETDEWEB)

    Lell, M.; Schmid, A.; Tomandl, B.F. [Division of Neuroradiology, Department of Neurosurgery, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen (Germany); Stemper, B.; Maihoefner, C.; Heckmann, J.G. [Department of Neurosurgery, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen (Germany)

    2003-02-01

    We report a 57-year-old woman with neuroborreliosis presenting with headache, shoulder muscle pain and double vision. MRI demonstrated enhancement of the right third and sixth cranial nerves. A 3D MP-RAGE sequence was used to perform multiplanar reformations to show this more graphically. The patient was free of symptoms 1 month after completion of therapy, when thickening and contrast enhancement of the nerves were less pronounced. (orig.)

  14. Fourth Generation Warfare and the Cultural Divide

    Science.gov (United States)

    2006-04-01

    her own socio-political agenda. While the West exports its brand of democracy, Islamists concurrently export their incompatible ideology to the West...who espouse “progressive” ideas feel that America is a victim of her own socio-political agenda. While the West exports its brand of democracy...culture relationships. In newspapers and on television around the globe, an emotionally explosive war rages: the underdog status quo of civility, mutual

  15. Misbehaving macrophages in the pathogenesis of psoriasis

    OpenAIRE

    Clark, Rachael A.; Kupper, Thomas S.

    2006-01-01

    Psoriasis is a chronic inflammatory skin disease unique to humans. In this issue of the JCI, 2 studies of very different mouse models of psoriasis both report that macrophages play a key role in inducing psoriasis-like skin disease. Psoriasis is clearly a polygenic, inherited disease of uncontrolled cutaneous inflammation. The debate that currently rages in the field is whether psoriasis is a disease of autoreactive T cells or whether it reflects an intrinsic defect within the skin — or both....

  16. Approved wind energy sites - Kern County, CA (Tehachapi Mountains)

    Energy Technology Data Exchange (ETDEWEB)

    1984-01-01

    Rising out of the California desert near Mojave, California, are the Tehachapi Mountains - a rugged chain of wind swept hills. Up until 1981, this land was used almost exclusively by local ranchers for grazing beef cattle. But, in a raging December blizzard, a dedicated band of men and women threw the switch and fed the first wind-generated electrical power into Southern California Edison's grid. That single event drastically changed land use patterns in the Tehachapi's.

  17. Genome-wide RNAi screen reveals the E3 SUMO-protein ligase gene SIZ1 as a novel determinant of furfural tolerance in Saccharomyces cerevisiae

    OpenAIRE

    Xiao, Han; Zhao, Huimin

    2014-01-01

    Background Furfural is a major growth inhibitor in lignocellulosic hydrolysates and improving furfural tolerance of microorganisms is critical for rapid and efficient fermentation of lignocellulosic biomass. In this study, we used the RNAi-Assisted Genome Evolution (RAGE) method to select for furfural resistant mutants of Saccharomyces cerevisiae, and identified a new determinant of furfural tolerance. Results By using a genome-wide RNAi (RNA-interference) screen in S. cerevisiae for genes in...

  18. Spin, Unit Climate, and Aggression: Near Term, Long Term, and Reciprocal Predictors of Violence Among Workers in Military Settings

    Science.gov (United States)

    2017-08-01

    bullying, harassment, intimate partner violence) as well as physical health and mental health outcomes often associated with exposure to aggression (e.g... physical aggression, witnessing aggression in the workplace can have negative consequences for unit performance, physical health , and mental health . An...constructs (e.g., physical assault, verbal aggression, anger / rage, bullying, harassment, intimate partner violence) as well as physical health and

  19. GLOBAL WARMING, CLIMATE CHANGE AND TOURISM: A REVIEW OF LITERATURE

    OpenAIRE

    Ramasamy, Rajesh; Swamy, Anjaneya

    2015-01-01

    Global warming, climate change and tourism of late, have taken the centre stage of academic research. A raging debate is on apart from the popular writings and research articles published on the theme. According to the Intergovernmental Panel on Climate Change “Warming of the climate system is unequivocal as is now evident from observations of increases in global average air and ocean temperatures, widespread melting of snow and ice since the mid 20th century”. This conceptual paper discussed...

  20. Proprietary software versus Open Source Software for Education

    OpenAIRE

    N. Pankaja

    2013-01-01

    The Internet has brought learning "online" and offers many advantages. It is convenient, available at any time of the day, and can be accessed nearly anywhere in the world. Recently, Cloud computing is all the rage. E-Learning offers tremendous potential to increase the availability and convenience of education. Today, online content is varied and can include: text on a website, digital audio, digital video, animated images, and virtual reality environments. This content can be created in a v...

  1. S100A4 and BMP-2 Co-Dependently Induce Vascular Smooth Muscle Cell Migration via pERK and Chloride Intracellular Channel 4 (CLIC4)

    Science.gov (United States)

    Spiekerkoetter, Edda; Guignabert, Christophe; de Jesus Perez, Vinicio; Alastalo, Tero-Pekka; Powers, Janine M; Wang, Lingli; Lawrie, Allan; Ambartsumian, Noona; Schmidt, Ann-Marie; Berryman, Mark; Ashley, Richard H; Rabinovitch, Marlene

    2009-01-01

    Rationale S100A4/Mts1 is implicated in motility of human pulmonary artery smooth muscle cells (hPASMC), through an interaction with the receptor for advanced glycation end products (RAGE). Objective We hypothesized that S100A4/Mts1-mediated hPASMC motility might be enhanced by loss of function of bone morphogenetic protein (BMP) receptor (R) II, observed in pulmonary arterial hypertension (PAH). Methods and Results Both S100A4/Mts1 (500ng/ml) and BMP-2 (10ng/ml) induce migration of hPASMCS in a novel co-dependent manner, in that the response to either ligand is lost with anti-RAGE or BMPRII siRNA. Phosphorylation of ERK is induced by both ligands and is required for motility by inducing MMP2 activity, but phosphoERK1/2 is blocked by anti-RAGE and not by BMPRII siRNA. In contrast, BMPRII siRNA, but not anti-RAGE, reduces expression of intracellular chloride channel 4 (CLIC4), a scaffolding molecule necessary for motility in response to S100A4/Mts1 or BMP-2. Reduced CLIC4 expression does not interfere with S100A4/Mts1 internalization or its interaction with myosin heavy chain IIA (MHCIIA), but does alter alignment of MHCIIA and actin filaments creating the appearance of vacuoles. This abnormality is associated with reduced peripheral distribution and/or delayed activation of RhoA and Rac1, small GTPases required for retraction and extension of lamellipodiae in motile cells. Conclusions Our studies demonstrate how a single ligand (BMP-2 or S100A4/Mts1) can recruit multiple cell surface receptors to relay signals that coordinate events culminating in a functional response, i.e., cell motility. We speculate that this carefully controlled process limits signals from multiple ligands, but could be subverted in disease. PMID:19713532

  2. A Brief Survey of Democracy Promotion in U.S. Foreign Policy

    Science.gov (United States)

    2014-03-01

    highlight that economic and security concerns both pre-dated active democracy promotion efforts. 2 For its first centennial , the United States was...the troubles of the world. The 1930s brought the Great Depression and the perception that democracy and capitalism might not be such good ideas after...peacetime foreign policy on democracy was somewhat constrained by the Great Depression and World War II. As World War II raged, FDR eloquently

  3. Turkey and Copyleft Music Production : Reflectionson Bandista

    OpenAIRE

    Mehrabov, Ilkin

    2013-01-01

    This article focuses on copyleft music production in Turkey through a case study on Bandista, amusic collective with strong oppositional stance formed in 2006 in Istanbul. Describing itsmusical performances as "situationist experiment of rage and rapture" Bandista becameimmensely popular in the Turkish political music scenery after releasing its debut album De tefabula narratur in 2009 under the copyleft scheme. The article tries to look at the copyleft withthe notion of 'music as performance...

  4. Aggressive behaviour in children and adolescents as a possible symptom of different mental disorders

    OpenAIRE

    Hojka Gregorič Kumperščak

    2015-01-01

    Causes of aggressive behaviour in children and adolescents are manifold with exogenous and endogenous factors such as personality traits, temperament, family, socio-cultural, economic and financial factors closely intertwined. Aggressive behaviour, however, can also be associated with mental disorders and this is the topic discussed by the present article. Isolated and occasional outbursts of anger, aggressiveness and rage in children and adolescents can often be confused with conduct disorde...

  5. America’s Army: The Strength of the Nation. 2010 Army Posture Statement

    Science.gov (United States)

    2010-02-19

    that the Army Soldier is the best equipped and most re- spected combatant in the world. In order to ex- ecute Army Modernization and ensure the con...Force Traumatic Brain Injury ( TBI ) Unaccompanied Personnel Housing (UPH) Unmanned Aircraft, Raven Small System Unmanned Aircraft, Shadow System Unmanned...Services TBI Traumatic Brain Injury 30 LoyaLty | Duty | Respect | seLfLess seRvice | HonoR | integRity | peRsonaL couRage 2010 Army

  6. Development and Investigation of an Optical Power Meter Front End

    Directory of Open Access Journals (Sweden)

    Edgaras Korsakas

    2015-07-01

    Full Text Available Circuit of the classical transimpedance amplifier (TIA is revised and improved circuit is developed. Analytical solutions for the classical and improved circuits are derived. Both circuits were built and their parameters were measured. An experiment results showed that improved TIA achieves 4.5 dB greater dynamic rage than the classical TIA at +50 °C and 12 dB greater at –10 °C.

  7. Three’s Company: The Efficacy of Third-Party Intervention in Support of Counterinsurgency

    Science.gov (United States)

    2009-10-26

    counterinsurgency is an appreciation for the unique role of the third-party intervener. Because these studies primarily examine conflicts 2 Thomas X...insurgency as a novel “technology of military conflict.”5 In a related study, Jason Lyall and Isaiah Wilson study conflict outcome and insurgencies...D. Fearon and David D. Laitin, "Ethnicity, Insurgency, and Civil War," 75 6 Jason Lyall and Isaiah Wilson, "Rage Against the Machines: Explaining

  8. Current studies of biological materials using instrumental and radiochemical neutron activation analysis

    International Nuclear Information System (INIS)

    Fardy, J.J.; McOrist, G.D.; Farrar, Y.J.

    1985-01-01

    Instrumental neutron activation analysis still remains the preferred option when analysing the trace element distribution in a wide rage of materials by neutron activation analysis. However, when lower limits of detection are required or major interferences reduce the effectiveness of this technique, radiochemical neutron activation analysis is applied. This paper examines the current use of both methods and the development of rapid radiochemical techniques for analysis of the biological materials, hair, cow's milk, human's milk, milk powder, blood and blood serum

  9. Unfractionated Heparin Alleviates Human Lung Endothelial Barrier Dysfunction Induced by High Mobility Group Box 1 Through Regulation of P38–GSK3β–Snail Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Zhenggang Luan

    2018-04-01

    Full Text Available Background/Aims: The high mobility group box 1 (HMGB1 has been regarded as an important inflammatory mediator. Previous studies showed the involvement of HMGB1 protein in the dysfunction of endothelial barrier function during acute lung injury. However, the molecular mechanism remains unclear. Methods: In this study, we used recombinant human HMGB1 (rhHMGB1 and HMGB1 plasmid to treat human pulmonary microvascular endothelial cell (HPMECs. We examined endothelial permeability by measuring TEER value and HRP flux. Western blot and real-time PCR were used to examined change of endothelial-to-mesenchymal transition (EndoMT markers and related pathways. Immunofluorescence was used to examine localization and expression of ZO-1 and VE-cadherin. SB203580.was used to block p38 pathway. Unfractionated heparin (UFH and RAGE siRNA were also used to antagonize the effect of HMGB1. Results: We showed that HMGB1 induced EndoMT with downregulation of ZO-1 and VE-cadherin at both mRNA and protein levels in HPMECs. We also demonstrated that HMGB1 upregulated endothelial permeability by measuring TEER value and HRP flux. Moreover, HMGB1 activated p38/GSK3β/Snail signaling pathway and treatment with p38 inhibitor SB203580 abolished its biological effects. In addition, we found that UFH was able to reverse the effect of HMGB1 on EndoMT and endothelial permeability through inhibition of p38 signaling in a dose-dependent manner. We discovered that RAGE, a membrane receptor of HMGB1, transduced p38/Snail pathway to EndoMT. RAGE siRNA inhibited the effect of HMGB1 induced EndoMT in HPMECs. Conclusion: The present study demonstrated that HMGB1 induced EndoMT through RAGE receptor and p38/GSK3β/Snail pathway. While UFH antagonized HMGB1 and maintained the integrity of the endothelial barrier through p38 inhibition.

  10. Simultaneous involvement of third and sixth cranial nerve in a patient with Lyme disease

    International Nuclear Information System (INIS)

    Lell, M.; Schmid, A.; Tomandl, B.F.; Stemper, B.; Maihoefner, C.; Heckmann, J.G.

    2003-01-01

    We report a 57-year-old woman with neuroborreliosis presenting with headache, shoulder muscle pain and double vision. MRI demonstrated enhancement of the right third and sixth cranial nerves. A 3D MP-RAGE sequence was used to perform multiplanar reformations to show this more graphically. The patient was free of symptoms 1 month after completion of therapy, when thickening and contrast enhancement of the nerves were less pronounced. (orig.)

  11. Properties of epitaxial films of indium phosphides alloyed with erbium in strong electric fields

    International Nuclear Information System (INIS)

    Borisov, V.I.; Dvoryankin, V.F.; Korobkin, V.A.; Kudryashov, A.A.; Lopatin, V.V.; Lyubchenko, V.E.; Telegin, A.A.

    1986-01-01

    Temperature dependences of specific resistance and free charge-carrier mobility at low temperatures for indium phosphide films grown by liquid-phase epitaxial method with erbium additions (0.01-0.1 mass%). The main mechanisms of scattering for different temperature regions: scattering on ionized impurities in the rage from 20 to 40 K and lattice scattering at the temperature above 90 K are determined. The current density dependences on applied electric field strength are presented

  12. TREATMENT PLANNING, PACING, AND COUNTERTRANSFERENCE: PERSPECTIVES ON THE PSYCHOTHERAPY OF EARLY AFFECT-CONFUSION

    Directory of Open Access Journals (Sweden)

    Richard G. Erskine

    2012-12-01

    Full Text Available This article is a rejoinder and elaboration on the article “Early Affect-Confusion: The ‘Borderline’ Between Despair and Rage: Part 1 of a Case Study Trilogy” and addresses the distinction between personality style, pattern, and disorder. It describes the pacing of a time-limited psychotherapy, the use of phenomenological inquiry in resolving transferential enactments, and the psychological function of idealization.

  13. Responding to Catastrophe via Law Enforcement Deployment Teams: A Policy Analysis

    Science.gov (United States)

    2008-12-01

    emergency medicine, canine -handling, firefighting, law enforcement, hazardous material handling, communications and logistics.128 The team’s purpose...were unavailable due to vacation, injury or other reasons. Maintenance of records, training and availability of canines were also problems.153 The...federalism is maintained under this approach, debate has raged as to its continued effectiveness. Kettl points out that while Arlington and New York

  14. RABIES IN NIGERIA: A REVIEW OF LITERATURE

    African Journals Online (AJOL)

    boaz

    Elle est causée par le virus de la rage (RABV), une forme de balle, virus enveloppé à ARN,45 – 100nm de diamètre et 100 – 430 nm en longueur avec des saillies et des nucléocapsidehélicoïdale, l'un des virus encéphalite mieux connu de la famille. Rhabdoviridae et le genre Lyssavirus type 1. C'est unproblème majeur ...

  15. Nye patologier i selvdannelsens tidsalder

    DEFF Research Database (Denmark)

    Hammershøj, Lars Geer

    2004-01-01

    The aim of this article is to inquire into today's social pathologies, i.e. the negative consequences of the developmental processes of society. In a dialogue with Axel Honneth, the article asserts that a shift has occurred in individualization, a shift that implies a fundamental change in social...... in self-Bildung', which is conceived as a ‘refusal to transcend oneself into sociality', and offers interpretations of present pathologies such as depression, anorexia, populist freedom of speech, and demonic rage....

  16. An FPGA-based reconfigurable DDC algorithm

    Science.gov (United States)

    Juszczyk, B.; Kasprowicz, G.

    2016-09-01

    This paper describes implementation of reconfigurable digital down converter in an FPGA structure. System is designed to work with quadrature signals. One of the main criteria of the project was to provied wide range of reconfiguration in order to fulfill various application rage. Potential applications include: software defined radio receiver, passive noise radars and measurement data compression. This document contains general system overview, short description of hardware used in the project and gateware implementation.

  17. Alone of all her sex? The Dutch Jeanne Merkus and the hitherto hidden other viragos in the Balkans during the great eastern crisis (1875-1878)

    OpenAIRE

    Grémaux René

    2017-01-01

    This paper deals with the question as to whether the well-reported Dutch volunteer warrior Jeanne Merkus was indeed the sole female fighter at the time of the anti-Ottoman rebellions and the wars in the Balkan Peninsula from 1875 to 1878, when the Great Eastern Crisis raged. While this rich outlandish lady - who has only recently earned her official biography - attracted much attention from the contemporary press, and later often surfaced in memoirs of sort...

  18. Archaeological Reconnaissance of the Lower Ohio River Navigation Area, Illinois and Kentucky

    Science.gov (United States)

    1981-01-01

    Pulaski Counties, Illinois. O.L. Baskins and Company, Historical Publishers: Chicago, IL. Robbins , Chandles S., Bertel Brunn, and Herbert S. Zim 196b...woodpecker (Campephllus principalis) ( Robbins et^ al . 1966). Faunal resources available from the Ohio River, the levee flank lakes, and the backwater...the area, occasional raids occurred (Müller and Davy 1977:31). These Indian raids were often bloody and cruel ( Baskin 1883:536-537) as rage and

  19. Air Base Defense: Different Times Call for Different Methods

    Science.gov (United States)

    2006-12-01

    small explosives in an attempt to drive U.S. forces from their territories. Many of these attacks were successful, resulting in the loss of human ...value.27 As the war rages on in Iraq, Matthew Levitt argues that the U.S. cannot afford to be distracted by the situation there, as terrorists may...serious and more difficult to defend.101 Air bases typically employ infrared and thermal imagers, security sentries, canine patrols and motion-tracking

  20. The Economic Impact of the Homeland Security Advisory System: The Cost of Heightened Border Security

    Science.gov (United States)

    2008-12-01

    Protection’s office responsible for securing the United States’ land border in the Detroit area. PoD provides a wide rage of cargo processing functions...a wide range of threats. Improper trademark labeling, tariffs, import quotas, agricultural issues, narcotics, human trafficking, and terrorism are...unloaded a truck, CBP agents search through the cargo. They open boxes, use hand-held radiation detectors, canines , and x-ray machines to inspect the

  1. Verification of dosimetry cross sections above 10 MeV based on measurement of activation reaction rates in fission neutron field

    International Nuclear Information System (INIS)

    Odano, Naoteru; Miura, Toshimasa; Yamaji, Akio.

    1996-01-01

    To validate the dosimetry cross sections in fast neutron energy range, activation reaction rates were measured for 5 types of dosimetry cross sections which have sensitivity in the energy rage above 10 MeV utilizing JRR-4 reactor of JAERI. The measured reaction rates were compared with the calculations reaction rates by a continuous energy monte carlo code MVP. The calculated reaction rates were based on two dosimetry files, JENDL Dosimetry File and IRDF-90.2. (author)

  2. Caffeic acid attenuates the inflammatory stress induced by glycated LDL in human endothelial cells by mechanisms involving inhibition of AGE-receptor, oxidative, and endoplasmic reticulum stress.

    Science.gov (United States)

    Toma, Laura; Sanda, Gabriela M; Niculescu, Loredan S; Deleanu, Mariana; Stancu, Camelia S; Sima, Anca V

    2017-09-10

    Type 2 diabetes mellitus is a worldwide epidemic and its atherosclerotic complications determine the high morbidity and mortality of diabetic patients. Caffeic acid (CAF), a phenolic acid present in normal diets, is known for its antioxidant properties. The aim of this study was to investigate CAF's anti-inflammatory properties and its mechanism of action, using cultured human endothelial cells (HEC) incubated with glycated low-density lipoproteins (gLDL). Levels of the receptor for advanced glycation end-products (RAGE), inflammatory stress markers (C reactive protein, CRP; vascular cell adhesion molecule-1, VCAM-1; monocyte chemoattractant protein-1, MCP-1), and oxidative stress and endoplasmic reticulum stress (ERS) markers were evaluated in gLDL-exposed HEC, in the presence/absence of CAF. RAGE silencing or blocking, specific inhibitors for oxidative stress (apocynin, N-acetyl-cysteine), and ERS (salubrinal) were used. The results showed that: (i) gLDL induced CRP synthesis and secretion through mechanisms involving NADPH oxidase-dependent oxidative stress and ERS in HEC; (ii) gLDL-RAGE interaction, oxidative stress, and ERS stimulated the secretion of VCAM-1 and MCP-1 in HEC; and (iii) CAF reduced the secretion of CRP, VCAM-1, and MCP-1 in gLDL-exposed HEC by inhibiting RAGE expression, oxidative stress, and ERS. In conclusion, CAF might be a promising alternative to ameliorate a wide spectrum of disorders due to its complex mechanisms of action resulting in anti-inflammatory and antioxidative properties. © 2017 BioFactors, 43(5):685-697, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

  3. Impulsive Action, Psychological Stress, and Behavioral Sensitization to Nicotine in a Rat Model of lmpulsivity

    Science.gov (United States)

    2010-06-30

    Bodily changes in pain, hunger , fear, and rage. New York: Harper and Row. Cannon, W. B. (1932). The wisdom ofthe body. New York: Norton. Camp, D. M...Report (Vol. 58, pp. 1227-1232). Clark L., Cools R., & Robbins T.W. (2004). The neuropsychology of ventral prefrontal cortex: Decision-making and...R, McFarland, B., Hitzemann, RJ., & Mitchell, S.H. (2006). Neuropsychological function and delay discounting in methamphetamine-dependent

  4. High Intensity Focused Ultrasound: A Novel Model of Mild Traumatic Brain Injury

    Science.gov (United States)

    2013-11-07

    and depression-related phenomena. Rationale. Changes in neurological functioning are measurable in humans using neuropsychological assessment... hunger , fear and rage. 20. Cernak I. 2005. Animal models of head trauma. NeuroRx 2:410-22 21. Chandran R, Sharma A, Barry ES, Balakathiresan NS...the Wechsler Test of Adult Reading (WTAR). Journal of Clinical and Experimental Neuropsychology 30:163-72 43. Grunberg NE. 1982. The effects of

  5. Lower concentrations of receptor for advanced glycation end products and epiregulin in amniotic fluid correlate to chemically induced cleft palate in mice.

    Science.gov (United States)

    Wang, Xinhuan; Zhu, Jingjing; Fang, Yanjun; Bian, Zhuan; Meng, Liuyan

    2017-04-01

    This study investigated the correlation between differentially expressed proteins in amniotic fluid (AF) and cleft palate induced by all-trans retinoic acid (atRA), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice. Seven proteins were differentially expressed at embryonic day (E) 16.5 in atRA and control groups as revealed by label-based mouse antibody array. Enzyme-linked immunosorbent assay was further used to detect the expression levels of these proteins in AF from E13.5 to E16.5 in atRA, TCDD, and control groups. The cleft palate groups showed lower concentrations of receptor for advanced glycation end products (RAGE) and epiregulin at E16.5. RAGE immunostaining obviously decreased in palatal tissue sections obtained from E14.5 to E16.5 in the cleft palate groups as revealed by immunohistochemistry. These findings indicate that reduced levels of RAGE and epiregulin in AF are correlated to chemically induced cleft palate in mice. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Oriented Immobilization of His-Tagged Protein on a Redox Active Thiol Derivative of DPTA-Cu(II Layer Deposited on a Gold Electrode—The Base of Electrochemical Biosensors

    Directory of Open Access Journals (Sweden)

    Hanna Radecka

    2013-09-01

    Full Text Available This paper concerns the development of an electrochemical biosensor for the determination of Aβ16–23' and Aβ1–40 peptides. The His-tagged V and VC1 domains of Receptor for Advanced Glycation end Products (RAGE immobilized on a gold electrode surface were used as analytically active molecules. The immobilization of His6–RAGE domains consists of: (i formation of a mixed layer of N-acetylcysteamine (NAC and the thiol derivative of pentetic acid (DPTA; (ii complexation of Cu(II by DPTA; (iii oriented immobilization of His6–RAGE domains via coordination bonds between Cu(II sites from DPTA–Cu(II complex and imidazole nitrogen atoms of a histidine tag. Each modification step was controlled by cyclic voltammetry (CV, Osteryoung square-wave voltammetry (OSWV, and atomic force microscopy (AFM. The applicability of the proposed biosensor was tested in the presence of human plasma, which had no influence on its performance. The detection limits for Aβ1–40 determination were 1.06 nM and 0.80 nM, in the presence of buffer and human plasma, respectively. These values reach the concentration level of Aβ1–40 which is relevant for determination of its soluble form in human plasma, as well as in brain. This indicates the promising future application of biosensor presented for early diagnosis of neurodegenerative diseases.

  7. MR imaging of cranial nerve lesions using six different high-resolution T1- and T2(*)-weighted 3D and 2D sequences

    Energy Technology Data Exchange (ETDEWEB)

    Seitz, J.; Held, P.; Strotzer, M.; Voelk, M.; Nitz, W.R.; Dorenbeck, U.; Feuerbach, S. [Univ. Hospital of Regensburg (Germany). Dept. of Diagnostic Radiology; Stamato, S. [Univ. of California, San Diego, CA (United States). Dept. of Radiology

    2002-07-01

    Purpose: To find a suitable high-resolution MR protocol for the visualization of lesions of all 12 cranial nerves. Material and Methods: Thirty-eight pathologically changed cranial nerves (17 patients) were studied with MR imaging at 1.5T using 3D T2*-weighted CISS, T1-weighted 3D MP-RAGE (without and with i.v. contrast medium), T2-weighted 3D TSE, T2-weighted 2D TSE and T1-weighted fat saturation 2D TSE sequences. Visibility of the 38 lesions of the 12 cranial nerves in each sequence was evaluated by consensus of two radiologists using an evaluation scale from 1 (excellently visible) to 4 (not visible). Results: The 3D CISS sequence provided the best resolution of the cranial nerves and their lesions when surrounded by CSF. In nerves which were not surrounded by CSF, the 2D T1-weighted contrast-enhanced fat suppression technique was the best sequence. Conclusions: A combination of 3D CISS, the 2D T1-weighted fat suppressed sequence and a 3D contrast-enhanced MP-RAGE proved to be the most useful sequence to visualize all lesions of the cranial nerves. For the determination of enhancement, an additional 3D MP-RAGE sequence without contrast medium is required. This sequence is also very sensitive for the detection of hemorrhage.

  8. Advanced oxidation protein products induce chondrocyte apoptosis via receptor for advanced glycation end products-mediated, redox-dependent intrinsic apoptosis pathway.

    Science.gov (United States)

    Wu, Qian; Zhong, Zhao-Ming; Zhu, Si-Yuan; Liao, Cong-Rui; Pan, Ying; Zeng, Ji-Huan; Zheng, Shuai; Ding, Ruo-Ting; Lin, Qing-Song; Ye, Qing; Ye, Wen-Bin; Li, Wei; Chen, Jian-Ting

    2016-01-01

    Pro-inflammatory cytokine-induced chondrocyte apoptosis is a primary cause of cartilage destruction in the progression of rheumatoid arthritis (RA). Advanced oxidation protein products (AOPPs), a novel pro-inflammatory mediator, have been confirmed to accumulate in patients with RA. However, the effect of AOPPs accumulation on chondrocyte apoptosis and the associated cellular mechanisms remains unclear. The present study demonstrated that the plasma formation of AOPPs was enhanced in RA rats compared with normal. Then, chondrocyte were treated with AOPPs-modified rat serum albumin (AOPPs-RSA) in vitro. Exposure of chondrocyte to AOPPs activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and increased expression of NADPH oxidase subunits, which was mediated by receptor for advanced glycation end products (RAGE), but not scavenger receptor CD36. Moreover, AOPPs challenge triggered NADPH oxidase-dependent ROS generation which induced mitochondrial dysfunction and endoplasmic reticulum stress resulted in activation of caspase family that eventually lead to apoptosis. Lastly, blockade of RAGE, instead of CD36, largely attenuated these signals. Our study demonstrated first time that AOPPs induce chondrocyte apoptosis via RAGE-mediated and redox-dependent intrinsic apoptosis pathway in vitro. These data implicates that AOPPs may represent a novel pathogenic factor that contributes to RA progression. Targeting AOPPs-triggered cellular mechanisms might emerge as a promising therapeutic option for patients with RA.

  9. Expression of high mobility group box 1 in inflamed dental pulp and its chemotactic effect on dental pulp cells

    International Nuclear Information System (INIS)

    Zhang, Xufang; Jiang, Hongwei; Gong, Qimei; Fan, Chen; Huang, Yihua; Ling, Junqi

    2014-01-01

    Highlights: • HMGB1 translocated from nucleus to cytoplasm during dental pulp inflammation. • HMGB1and its receptor RAGE were up-regulated in hDPCs under LPS stimulation. • HMGB1 enhanced hDPCs migration and induces cytoskeleton reorganization. • HMGB1 may play a critical role in dental pulp repair during inflamed state. - Abstract: High mobility group box 1 protein (HMGB1) is a chromatin protein which can be released extracellularly, eliciting a pro-inflammatory response and promoting tissue repair process. This study aimed to examine the expression and distribution of HMGB1 and its receptor RAGE in inflamed dental pulp tissues, and to assess its effects on proliferation, migration and cytoskeleton of cultured human dental pulp cells (DPCs). Our data demonstrated that cytoplasmic expression of HMGB1 was observed in inflamed pulp tissues, while HMGB1 expression was confined in the nuclei in healthy dental pulp. The mRNA expression of HMGB1 and RAGE were significantly increased in inflamed pulps. In in vitro cultured DPCs, expression of HMGB1 in both protein and mRNA level was up-regulated after treated with lipopolysaccharide (LPS). Exogenous HMGB1 enhanced DPCs migration in a dose-dependent manner and induced the reorganization of f-actin in DPCs. Our results suggests that HMGB1 are not only involved in the process of dental pulp inflammation, but also play an important role in the recruitment of dental pulp stem cells, promoting pulp repair and regeneration

  10. Expression of high mobility group box 1 in inflamed dental pulp and its chemotactic effect on dental pulp cells

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Xufang, E-mail: xufang.zhang@student.qut.edu.au [Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Guangdong Province Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055 (China); Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059 (Australia); Jiang, Hongwei, E-mail: jianghw@163.com [Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Guangdong Province Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055 (China); Gong, Qimei, E-mail: gongqmei@gmail.com [Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Guangdong Province Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055 (China); Fan, Chen, E-mail: c3.fan@student.qut.edu.au [Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD 4059 (Australia); Huang, Yihua, E-mail: enu0701@163.com [Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Guangdong Province Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055 (China); Ling, Junqi, E-mail: lingjq@mail.sysu.edu.cn [Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Guangdong Province Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou 510055 (China)

    2014-08-08

    Highlights: • HMGB1 translocated from nucleus to cytoplasm during dental pulp inflammation. • HMGB1and its receptor RAGE were up-regulated in hDPCs under LPS stimulation. • HMGB1 enhanced hDPCs migration and induces cytoskeleton reorganization. • HMGB1 may play a critical role in dental pulp repair during inflamed state. - Abstract: High mobility group box 1 protein (HMGB1) is a chromatin protein which can be released extracellularly, eliciting a pro-inflammatory response and promoting tissue repair process. This study aimed to examine the expression and distribution of HMGB1 and its receptor RAGE in inflamed dental pulp tissues, and to assess its effects on proliferation, migration and cytoskeleton of cultured human dental pulp cells (DPCs). Our data demonstrated that cytoplasmic expression of HMGB1 was observed in inflamed pulp tissues, while HMGB1 expression was confined in the nuclei in healthy dental pulp. The mRNA expression of HMGB1 and RAGE were significantly increased in inflamed pulps. In in vitro cultured DPCs, expression of HMGB1 in both protein and mRNA level was up-regulated after treated with lipopolysaccharide (LPS). Exogenous HMGB1 enhanced DPCs migration in a dose-dependent manner and induced the reorganization of f-actin in DPCs. Our results suggests that HMGB1 are not only involved in the process of dental pulp inflammation, but also play an important role in the recruitment of dental pulp stem cells, promoting pulp repair and regeneration.

  11. Advanced glycation end products delay corneal epithelial wound healing through reactive oxygen species generation.

    Science.gov (United States)

    Shi, Long; Chen, Hongmei; Yu, Xiaoming; Wu, Xinyi

    2013-11-01

    Delayed healing of corneal epithelial wounds is a serious complication in diabetes. Advanced glycation end products (AGEs) are intimately associated with the diabetic complications and are deleterious to the wound healing process. However, the effect of AGEs on corneal epithelial wound healing has not yet been evaluated. In the present study, we investigated the effect of AGE-modified bovine serum albumin (BSA) on corneal epithelial wound healing and its underlying mechanisms. Our data showed that AGE-BSA significantly increased the generation of intracellular ROS in telomerase-immortalized human corneal epithelial cells. However, the generation of intracellular ROS was completely inhibited by antioxidant N-acetylcysteine (NAC), anti-receptor of AGEs (RAGE) antibodies, or the inhibitor of NADPH oxidase. Moreover, AGE-BSA increased NADPH oxidase activity and protein expression of NADPH oxidase subunits, p22phox and Nox4, but anti-RAGE antibodies eliminated these effects. Furthermore, prevention of intracellular ROS generation using NAC or anti-RAGE antibodies rescued AGE-BSA-delayed epithelial wound healing in porcine corneal organ culture. In conclusion, our results demonstrated that AGE-BSA impaired corneal epithelial wound healing ex vivo. AGE-BSA increased intracellular ROS generation through NADPH oxidase activation, which accounted for the delayed corneal epithelial wound healing. These results may provide better insights for understanding the mechanism of delayed healing of corneal epithelial wounds in diabetes.

  12. Contrast-enhanced MR imaging of metastatic brain tumor at 3 Tesla. Utility of T1-weighted SPACE compared with 2D spin echo and 3D gradient echo sequence

    International Nuclear Information System (INIS)

    Komada, Tomohiro; Naganawa, Shinji; Ogawa, Hiroshi

    2008-01-01

    We evaluated the newly developed whole-brain, isotropic, 3-dimensional turbo spin-echo imaging with variable flip angle echo train (SPACE) for contrast-enhanced T 1 -weighted imaging in detecting brain metastases at 3 tesla (T). Twenty-two patients with suspected brain metastases underwent postcontrast study with SPACE, magnetization-prepared rapid gradient-echo (MP-RAGE), and 2-dimensional T 1 -weighted spin echo (2D-SE) imaging at 3 T. We quantitatively compared SPACE, MP-RAGE, and 2D-SE images by using signal-to-noise ratios (SNRs) for gray matter (GM) and white matter (WM) and contrast-to-noise ratios (CNRs) for GM-to-WM, lesion-to-GM, and lesion-to-WM. Two blinded radiologists evaluated the detection of brain metastases by segment-by-segment analysis and continuously-distributed test. The CNR between GM and WM was significantly higher on MP-RAGE images than on SPACE images (P 1 -weighted imaging. (author)

  13. The role of high mobility group box 1 (HMGB-1) in the diabetic retinopathy inflammation and apoptosis.

    Science.gov (United States)

    Yu, Yao; Yang, Lu; Lv, Jinlei; Huang, Xu; Yi, Jinglin; Pei, Chonggang; Shao, Yi

    2015-01-01

    Diabetic Retinopathy (DR) is one of the most common complications of the late phase diabetes, and also a common cause of blindness. High mobility group box 1 (HMGB-1) is considered to be an inflammatory mediator in the late phase that promotes inflammation and neovascularization in diabetes. Therefore, this paper discussed the role of HMGB-1 in diabetic retinopathy inflammation and neovascularization. 96 adult SD rats were randomly divided into control and diabetes group. The diabetic rat model was established by intraperitoneal injection of streptomycin (0.1 mol/L). Western blot was applied to determine HMGB-1 and its receptor RAGE and TLR2 protein expression in the serum. TUNEL was used to detect retinal apoptosis. Immunofluorescence was performed to test HMGB1 protein expression in retina. HBGM-1 and RAGE expression in diabetic rat retina was significantly higher than the control (P detection showed that diabetic rat retinal cells presented obviously higher apoptosis rate (P diabetic rat retinal cells (P diabetic retinopathy by binding with RAGE receptor to accelerate rat retinal cells apoptosis.

  14. Primary emotional traits in patients with personality disorders.

    Science.gov (United States)

    Karterud, Sigmund; Pedersen, Geir; Johansen, Merete; Wilberg, Theresa; Davis, Ken; Panksepp, Jaak

    2016-11-01

    There is a longstanding tradition that connects temperament pathology and personality disorders. Emotions are the major constituents of temperament. In mammals, seven primary emotions have been identified: SEEKING, FEAR, CARE, RAGE, SADNESS/PANIC, LUST and PLAY. The study aimed at exploring the relationship between primary emotions and personality disorders (PDs). Five hundred forty-six patients with different degrees and qualities of personality pathology, admitted to treatment in specialized PD services, were diagnosed according to Structured Clinical Interview for DSM-IV Axis II Personality Disorders, and their primary emotional profiles were assessed by the Affective Neuroscience Personality Scales. The Affective Neuroscience Personality Scales explained 19% of the variance in borderline and avoidant criteria. The DSM-IV PD categories displayed different patterns of association to the primary emotions, e.g. the borderline PD profile suggested low thresholds for RAGE and SADNESS, but on the positive side a propensity for SEEKING. In contrast, the dependent PD profile suggested a low threshold for SADNESS but a high threshold for RAGE and SEEKING. The results are promising for a more coherent and evolution-based overall theory of PDs, and the correlations found in this study indicate testable causal pathways to PDs. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  15. Effects of monascin on anti-inflammation mediated by Nrf2 activation in advanced glycation end product-treated THP-1 monocytes and methylglyoxal-treated wistar rats.

    Science.gov (United States)

    Lee, Bao-Hong; Hsu, Wei-Hsuan; Huang, Tao; Chang, Yu-Ying; Hsu, Ya-Wen; Pan, Tzu-Ming

    2013-02-13

    Hyperglycemia is associated with advanced glycation end products (AGEs). This study was designed to evaluate the inhibitory effects of monascin on receptor for advanced glycation end product (RAGE) signal and THP-1 monocyte inflammation after treatment with S100b, a specific ligand of RAGE. Monascin inhibited cytokine production by S100b-treated THP-1 monocytes via up-regulation of nuclear factor-erythroid 2-related factor-2 (Nrf2) and alleviated p47phox translocation to the membrane. Methylglyoxal (MG, 600 mg/kg bw) was used to induce diabetes in Wistar rats. Inhibitions of RAGE and p47phox by monascin were confirmed by peripheral blood mononuclear cells (PBMCs) of MG-induced rats. Silymarin (SM) was used as a positive control group. It was found that monascin promoted heme oxygenase-1 (HO-1) expression mediated by Nrf2. Suppressions of AGEs, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-β) in serum of MG-induced rats were attenuated in the monascin administration group treated with retinoic acid (RA). RA treatment resulted in Nrf2 inactivation by increasing RA receptor-α (RARα) activity, suggesting that RA acts as an inhibitor of Nrf2. The results showed that monascin exerted anti-inflammatory and antioxidative effects mediated by Nrf2 to prevent the development of diseases such as type 2 diabetes caused by inflammation.

  16. Advanced glycation end-product (AGE)-albumin from activated macrophage is critical in human mesenchymal stem cells survival and post-ischemic reperfusion injury.

    Science.gov (United States)

    Son, Myeongjoo; Kang, Woong Chol; Oh, Seyeon; Bayarsaikhan, Delger; Ahn, Hyosang; Lee, Jaesuk; Park, Hyunjin; Lee, Sojung; Choi, Junwon; Lee, Hye Sun; Yang, Phillip C; Byun, Kyunghee; Lee, Bonghee

    2017-09-14

    Post-ischemic reperfusion injury (PIRI) triggers an intense inflammatory response which is essential for repair but is also implicated in pathogenesis of post-ischemic remodeling in several organs in human. Stem cell therapy has recently emerged as a promising method for treatment of PIRI in human. However, satisfactory results have not been reported due to severe loss of injected stem cells in PIRI including critical limb ischemia (CLI). For investigating the advanced glycation end-product-albumin (AGE-albumin) from activated macrophages is critical in both muscle cell and stem cell death, we evaluated the recovery of PIRI-CLI by injection of human bone marrow derived mesenchymal stem cells (hBD-MSCs) with or without soluble receptor for AGEs (sRAGE). Our results showed that activated M1 macrophages synthesize and secrete AGE-albumin, which induced the skeletal muscle cell death and injected hBD-MSCs in PIRI-CLI through RAGE increase. Combined injection of sRAGE and hBD-MSCs resulted in enhanced survival of hBD-MSCs and angiogenesis in PIRI-CLI mice. Taken together, AGE-albumin from activated macrophages is critical for both skeletal muscle cell and hBD-MSCs death in PIRI-CLI. Therefore, the inhibition of AGE-albumin from activated macrophages could be a successful therapeutic strategy for treatment of PIRI including CLI with or without stem cell therapy.

  17. MR imaging of cranial nerve lesions using six different high-resolution T1- and T2(*)-weighted 3D and 2D sequences

    International Nuclear Information System (INIS)

    Seitz, J.; Held, P.; Strotzer, M.; Voelk, M.; Nitz, W.R.; Dorenbeck, U.; Feuerbach, S.; Stamato, S.

    2002-01-01

    Purpose: To find a suitable high-resolution MR protocol for the visualization of lesions of all 12 cranial nerves. Material and Methods: Thirty-eight pathologically changed cranial nerves (17 patients) were studied with MR imaging at 1.5T using 3D T2*-weighted CISS, T1-weighted 3D MP-RAGE (without and with i.v. contrast medium), T2-weighted 3D TSE, T2-weighted 2D TSE and T1-weighted fat saturation 2D TSE sequences. Visibility of the 38 lesions of the 12 cranial nerves in each sequence was evaluated by consensus of two radiologists using an evaluation scale from 1 (excellently visible) to 4 (not visible). Results: The 3D CISS sequence provided the best resolution of the cranial nerves and their lesions when surrounded by CSF. In nerves which were not surrounded by CSF, the 2D T1-weighted contrast-enhanced fat suppression technique was the best sequence. Conclusions: A combination of 3D CISS, the 2D T1-weighted fat suppressed sequence and a 3D contrast-enhanced MP-RAGE proved to be the most useful sequence to visualize all lesions of the cranial nerves. For the determination of enhancement, an additional 3D MP-RAGE sequence without contrast medium is required. This sequence is also very sensitive for the detection of hemorrhage

  18. Pattern-recognition receptors: signaling pathways and dysregulation in canine chronic enteropathies-brief review.

    Science.gov (United States)

    Heilmann, Romy M; Allenspach, Karin

    2017-11-01

    Pattern-recognition receptors (PRRs) are expressed by innate immune cells and recognize pathogen-associated molecular patterns (PAMPs) as well as endogenous damage-associated molecular pattern (DAMP) molecules. With a large potential for synergism or convergence between their signaling pathways, PRRs orchestrate a complex interplay of cellular mediators and transcription factors, and thus play a central role in homeostasis and host defense. Aberrant activation of PRR signaling, mutations of the receptors and/or their downstream signaling molecules, and/or DAMP/PAMP complex-mediated receptor signaling can potentially lead to chronic auto-inflammatory diseases or development of cancer. PRR signaling pathways appear to also present an interesting new avenue for the modulation of inflammatory responses and to serve as potential novel therapeutic targets. Evidence for a dysregulation of the PRR toll-like receptor (TLR)2, TLR4, TLR5, and TLR9, nucleotide-binding oligomerization domain-containing protein (NOD)2, and the receptor of advanced glycation end products (RAGE) exists in dogs with chronic enteropathies. We describe the TLR, NOD2, and RAGE signaling pathways and evaluate the current veterinary literature-in comparison to human medicine-to determine the role of TLRs, NOD2, and RAGE in canine chronic enteropathies.

  19. Cloning and characterization of the canine receptor for advanced glycation end products.

    Science.gov (United States)

    Murua Escobar, Hugo; Soller, Jan T; Sterenczak, Katharina A; Sperveslage, Jan D; Schlueter, Claudia; Burchardt, Birgit; Eberle, Nina; Fork, Melanie; Nimzyk, Rolf; Winkler, Susanne; Nolte, Ingo; Bullerdiek, Jörn

    2006-03-15

    Metastasis is one of the major problems when dealing with malignant neoplasias. Accordingly, the finding of molecular targets, which can be addressed to reduce tumour metastasising, will have significant impact on the development of new therapeutic approaches. Recently, the receptor for advanced glycation end products (RAGE)-high mobility group B1 (HMGB1) protein complex has been shown to have significant influence on invasiveness, growth and motility of tumour cells, which are essential characteristics required for metastatic behaviour. A set of in vitro and in vivo approaches showed that blocking of this complex resulted in drastic suppression of tumour cell growth. Due to the similarities of human and canine cancer the dog has joined the common rodent animal model for therapeutic and preclinical studies. However, complete characterisation of the protein complex is a precondition to a therapeutic approach based on the blocking of the RAGE-HMGB1 complex to spontaneously occurring tumours in dogs. We recently characterised the canine HMGB1 gene and protein completely. Here we present the complete characterisation of the canine RAGE gene including its 1384 bp mRNA, the 1215 bp protein coding sequence, the 2835 bp genomic structure, chromosomal localisation, gene expression pattern, and its 404 amino acid protein. Furthermore we compared the CDS of six different canine breeds and screened them for single nucleotide polymorphisms.

  20. Identification and characterization of the direct interaction between methotrexate (MTX and high-mobility group box 1 (HMGB1 protein.

    Directory of Open Access Journals (Sweden)

    Yuki Kuroiwa

    Full Text Available BACKGROUND: Methotrexate (MTX is an agent used in chemotherapy of tumors and autoimmune disease including rheumatoid arthritis (RA. In addition, MTX has some anti-inflammatory activity. Although dihydrofolate reductase (DHFR is a well-known target for the anti-tumor effect of MTX, the mode of action for the anti-inflammatory activity of MTX is not fully understood. METHODOLOGY/RESULT: Here, we performed a screening of MTX-binding proteins using T7 phage display with a synthetic biotinylated MTX derivative. We then characterized the interactions using surface plasmon resonance (SPR analysis and electrophoretic mobility shift assay (EMSA. Using a T7 phage display screen, we identified T7 phages that displayed part of high-mobility group box 1 (HMGB1 protein (K86-V175. Binding affinities as well as likely binding sites were characterized using genetically engineered truncated versions of HMGB1 protein (Al G1-K87, Bj: F88-K181, indicating that MTX binds to HMGB1 via two independent sites with a dissociation constants (KD of 0.50±0.03 µM for Al and 0.24 ± 0.01 µM for Bj. Although MTX did not inhibit the binding of HMGB1 to DNA via these domains, HMGB1/RAGE association was impeded in the presence of MTX. These data suggested that binding of MTX to part of the RAGE-binding region (K149-V175 in HMGB1 might be significant for the anti-inflammatory effect of MTX. Indeed, in murine macrophage-like cells (RAW 264.7, TNF-α release and mitogenic activity elicited by specific RAGE stimulation with a truncated monomeric HMGB1 were inhibited in the presence of MTX. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that HMGB1 is a direct binding protein of MTX. Moreover, binding of MTX to RAGE-binding region in HMGB1 inhibited the HMGB1/RAGE interaction at the molecular and cellular levels. These data might explain the molecular basis underlying the mechanism of action for the anti-inflammatory effect of MTX.

  1. Advancements in web-database applications for rabies surveillance

    Directory of Open Access Journals (Sweden)

    Bélanger Denise

    2011-08-01

    Full Text Available Abstract Background Protection of public health from rabies is informed by the analysis of surveillance data from human and animal populations. In Canada, public health, agricultural and wildlife agencies at the provincial and federal level are responsible for rabies disease control, and this has led to multiple agency-specific data repositories. Aggregation of agency-specific data into one database application would enable more comprehensive data analyses and effective communication among participating agencies. In Québec, RageDB was developed to house surveillance data for the raccoon rabies variant, representing the next generation in web-based database applications that provide a key resource for the protection of public health. Results RageDB incorporates data from, and grants access to, all agencies responsible for the surveillance of raccoon rabies in Québec. Technological advancements of RageDB to rabies surveillance databases include 1 automatic integration of multi-agency data and diagnostic results on a daily basis; 2 a web-based data editing interface that enables authorized users to add, edit and extract data; and 3 an interactive dashboard to help visualize data simply and efficiently, in table, chart, and cartographic formats. Furthermore, RageDB stores data from citizens who voluntarily report sightings of rabies suspect animals. We also discuss how sightings data can indicate public perception to the risk of racoon rabies and thus aid in directing the allocation of disease control resources for protecting public health. Conclusions RageDB provides an example in the evolution of spatio-temporal database applications for the storage, analysis and communication of disease surveillance data. The database was fast and inexpensive to develop by using open-source technologies, simple and efficient design strategies, and shared web hosting. The database increases communication among agencies collaborating to protect human health from

  2. Effect of glycyrrhizin on traumatic brain injury in rats and its mechanism

    Directory of Open Access Journals (Sweden)

    Gu Xiangjin

    2014-02-01

    Full Text Available 【Abstract】Objective: To investigate the neuroprotective effects of glycyrrhizin (Gly as well as its effect on expression of high-mobility group box 1 (HMGB1 in rats after traumatic brain injury (TBI. Methods: Male Sprague-Dawley rats were randomly divided into three groups: sham group, TBI group, and TBI+Gly group (n=36 per group. Rat TBI model was made by using the modified Feeney’s method. In TBI+Gly group, Gly was administered intravenously at a dosage of 10 mg/kg 30 min after TBI. At 24 h after TBI, motor function and brain water content were evaluated. Meanwhile, HMGB1/HMGB1 receptors including toll-like receptor 4 (TLR4 and receptor for advanced glycation end products (RAGE/nuclear factor- κB(NF- κB signaling pathway and inflammatory cytokines in the injured brain tissues were detected using quantitative real-time polymerase chain reaction, western blot, electrophoretic mobility shift assay and enzyme-linked immunosorbent assay. Furthermore, HMGB1, RAGE and TLR4 immunohistochemistry and apoptosis were analyzed. Results: Beam walking performance impairment and brain edema were significantly reduced in TBI+Gly group compared with TBI group; meanwhile, the over-expressions of HMGB1/HMGB1 receptors (TLR4 and RAGE/NF-κB DNA-binding activity and inflammatory cytokines were inhibited. The percentages of HMGB1, RAGE and TLR4- positive cells and apoptotic cells were respectively 58.37%±5.06%, 54.15%±4.65%, 65.50%± 4.83%, 52.02%± 4.63% in TBI group and 39.99%±4.99%, 34.87%±5.02%, 43.33%±4.54%, 37.84%±5.16% in TBI+Gly group (all P<0.01 compared with TBI group. Conclusion: Gly can reduce secondary brain injury and improve outcomes in rat following TBI by down-regulation of HMGB1/HMGB1 receptors (TLR4 and RAGE/NF-κB - mediated inflammatory responses in the injured rat brain.

  3. Switching to multiple daily injection therapy with glulisine improves glycaemic control, vascular damage and treatment satisfaction in basal insulin glargine-injected diabetic patients.

    Science.gov (United States)

    Yanagisawa, Katsuyuki; Ashihara, Junya; Obara, Shinji; Wada, Norio; Takeuchi, Masayoshi; Nishino, Yuri; Maeda, Sayaka; Ishibashi, Yuji; Yamagishi, Sho-ichi

    2014-11-01

    Basal and bolus insulin therapy is required for strict blood control in diabetic patients, which could lead to prevention of vascular complications in diabetes. However, the optimal combination regimen is not well established. Fifty-nine diabetic patients (49 type 1 and 10 type 2; 52.9 ± 13.3 years old) whose blood glucose levels were uncontrolled (HbA1c  > 6.2%) by combination treatment of basal insulin glargine with multiple daily pre-meal injections of bolus short-acting insulin [aspart (n = 19), lispro (n = 37) and regular human insulin (n = 3)] for at least 8 weeks were enrolled in this study. We examined whether glycaemic control and vascular injury were improved by replacement of short-acting insulin with glulisine. Patient satisfaction was assessed with Diabetes Treatment Satisfaction Questionnaire. Although bolus and basal insulin doses were almost unchanged before and after replacement therapy, switching to glulisine insulin for 24 weeks significantly decreased level of HbA1c , advanced glycation end products (AGEs), soluble receptor for AGEs (sRAGE), monocyte chemoattractant protein-1 (MCP-1) and urinary albumin excretion. In multiple stepwise regression analysis, change in MCP-1 values from baseline (ΔMCP-1) was a sole determinant of log urinary albumin excretion. ΔAGEs and ΔsRAGE were independently correlated with each other. The relationship between ΔMCP-1 and ΔsRAGE was marginally significant (p = 0.05). Replacement of short-acting insulin by glulisine significantly increased Diabetes Treatment Satisfaction Questionnaire scores. Our present study suggests that combination therapy of glargine with multiple daily pre-meal injections of glulisine might show superior efficacy in controlling blood glucose, preventing vascular damage and improving treatment satisfaction in diabetic patients. Copyright © 2014 John Wiley & Sons, Ltd.

  4. Advanced glycation endproducts alter functions and promote apoptosis in endothelial progenitor cells through receptor for advanced glycation endproducts mediate overpression of cell oxidant stress.

    Science.gov (United States)

    Chen, Jianfei; Song, Minbao; Yu, Shiyong; Gao, Pan; Yu, Yang; Wang, Hong; Huang, Lan

    2010-02-01

    Endothelial progenitor cells (EPCs) play an important role in preventing atherosclerosis. The factors that regulate the function of EPCs are not completely clear. Increased formation of advanced glycation endproducts (AGEs) is generally regarded as one of the main mechanisms responsible for vascular damage in patients with diabetes and atherosclerosis. AGEs lead to the generation of reactive oxygen species (ROS) and part of the regenerative capacity of EPCs seems to be due to their low baseline ROS levels and reduced sensitivity to ROS-induced cell apoptosis. Therefore, we tested the hypothesis that AGEs can alter functions and promote apoptosis in EPCs through overpress cell oxidant stress. EPCs, isolated from bone marrow, were cultured in the absence or presence of AGEs (50, 100, and 200 microg/ml). A modified Boyden's chamber was used to assess the migration of EPCs and the number of recultured EPCs was counted to measure the adhesiveness function. MTT assay was used to determine the proliferation function. ROS were analyzed using the ROS assay kit. A spectrophotometer was used to assess superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activity, and PCR was used to test mRNA expression of SOD and GSH-PX. SiRNA was used to block receptor for advanced glycation endproducts (RAGEs) expression. Apoptosis was evaluated by Annexin V immunostaining and TUNEL staining. Co-culturing with AGEs increases ROS production, decreases anti-oxidant defenses, overpresses oxidant stress, inhibits the proliferation, migration, and adhesion of EPCs, and induces EPCs apoptosis. In addition, these effects were attenuated during block RAGE protein expression by siRNA. AGEs may serve to impair EPCs functions through RAGE-mediate oxidant stress, and promote EPCs sensitivity toward oxidative-stress-mediated apoptosis, which indicates a new pathophysiological mechanism of disturbed vascular adaptation in atherosclerosis and suggests that lower levels of AGEs might improve the

  5. High-resolution anatomy of the human brain stem using 7-T MRI: improved detection of inner structures and nerves?

    Energy Technology Data Exchange (ETDEWEB)

    Gizewski, Elke R. [Medical University Innsbruck, Department of Neuroradiology, Innsbruck (Austria); Maderwald, Stefan [University Duisburg-Essen, Erwin L. Hahn Institute for Magnetic Resonance Imaging, Essen (Germany); Linn, Jennifer; Bochmann, Katja [LMU Munich, Department of Neuroradiology, Munich (Germany); Dassinger, Benjamin [Medical University Innsbruck, Department of Neuroradiology, Innsbruck (Austria); Justus-Liebig-University Giessen, Department of Neuroradiology, Giessen (Germany); Forsting, Michael [University Hospital, University Duisburg-Essen, Departments of Diagnostic and Interventional Radiology and Neuroradiology, Essen (Germany); Ladd, Mark E. [University Duisburg-Essen, Erwin L. Hahn Institute for Magnetic Resonance Imaging, Essen (Germany); University Hospital, University Duisburg-Essen, Departments of Diagnostic and Interventional Radiology and Neuroradiology, Essen (Germany)

    2014-03-15

    The purpose of this paper is to assess the value of 7 Tesla (7 T) MRI for the depiction of brain stem and cranial nerve (CN) anatomy. Six volunteers were examined at 7 T using high-resolution SWI, MPRAGE, MP2RAGE, 3D SPACE T2, T2, and PD images to establish scanning parameters targeted at optimizing spatial resolution. Direct comparisons between 3 and 7 T were performed in two additional subjects using the finalized sequences (3 T: T2, PD, MPRAGE, SWAN; 7 T: 3D T2, MPRAGE, SWI, MP2RAGE). Artifacts and the depiction of structures were evaluated by two neuroradiologists using a standardized score sheet. Sequences could be established for high-resolution 7 T imaging even in caudal cranial areas. High in-plane resolution T2, PD, and SWI images provided depiction of inner brain stem structures such as pons fibers, raphe, reticular formation, nerve roots, and periaqueductal gray. MPRAGE and MP2RAGE provided clear depiction of the CNs. 3D T2 images improved depiction of inner brain structure in comparison to T2 images at 3 T. Although the 7-T SWI sequence provided improved contrast to some inner structures, extended areas were influenced by artifacts due to image disturbances from susceptibility differences. Seven-tesla imaging of basal brain areas is feasible and might have significant impact on detection and diagnosis in patients with specific diseases, e.g., trigeminal pain related to affection of the nerve root. Some inner brain stem structures can be depicted at 3 T, but certain sequences at 7 T, in particular 3D SPACE T2, are superior in producing anatomical in vivo images of deep brain stem structures. (orig.)

  6. High ASMA+ Fibroblasts and Low Cytoplasmic HMGB1+ Breast Cancer Cells Predict Poor Prognosis.

    Science.gov (United States)

    Amornsupak, Kamolporn; Jamjuntra, Pranisa; Warnnissorn, Malee; O-Charoenrat, Pornchai; Sa-Nguanraksa, Doonyapat; Thuwajit, Peti; Eccles, Suzanne A; Thuwajit, Chanitra

    2017-10-01

    The influence of cancer-associated fibroblasts (CAFs) and high mobility group box 1 (HMGB1) has been recognized in several cancers, although their roles in breast cancer are unclear. The present study aimed to determine the levels and prognostic significance of α-smooth muscle actin-positive (ASMA + ) CAFs, plus HMGB1 and receptor for advanced glycation end products (RAGE) in cancer cells. A total of 127 breast samples, including 96 malignant and 31 benign, were examined for ASMA, HMGB1, and RAGE by immunohistochemistry. The χ 2 test and Fisher's exact test were used to test the association of each protein with clinicopathologic parameters. The Kaplan-Meier method or log-rank test and Cox regression were used for survival analysis. ASMA + fibroblast infiltration was significantly increased in the tumor stroma compared with that in benign breast tissue. The levels of cytoplasmic HMGB1 and RAGE were significantly greater in the breast cancer tissue than in the benign breast tissues. High ASMA expression correlated significantly with large tumor size, clinical stage III-IV, and angiolymphatic and perinodal invasion. In contrast, increased cytoplasmic HMGB1 correlated significantly with small tumor size, pT stage, early clinical stage, luminal subtype (but not triple-negative subtype), and estrogen receptor and progesterone receptor expression. The levels of ASMA (hazard ratio, 14.162; P = .010) and tumor cytoplasmic HMGB1 (hazard ratio, 0.221; P = .005) could serve as independent prognostic markers for metastatic relapse in breast cancer patients. The ASMA-high/HMGB1-low profile provided the most reliable prediction of metastatic relapse. We present for the first time, to the best of our knowledge, the potential clinical implications of the combined assessment of ASMA + fibroblasts and cytoplasmic HMGB1 in breast cancer. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Impact of type 2 diabetes and the metabolic syndrome on myocardial structure and microvasculature of men with coronary artery disease

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    Yii Michael

    2011-09-01

    Full Text Available Abstract Background Type 2 diabetes and the metabolic syndrome are associated with impaired diastolic function and increased heart failure risk. Animal models and autopsy studies of diabetic patients implicate myocardial fibrosis, cardiomyocyte hypertrophy, altered myocardial microvascular structure and advanced glycation end-products (AGEs in the pathogenesis of diabetic cardiomyopathy. We investigated whether type 2 diabetes and the metabolic syndrome are associated with altered myocardial structure, microvasculature, and expression of AGEs and receptor for AGEs (RAGE in men with coronary artery disease. Methods We performed histological analysis of left ventricular biopsies from 13 control, 10 diabetic and 23 metabolic syndrome men undergoing coronary artery bypass graft surgery who did not have heart failure or atrial fibrillation, had not received loop diuretic therapy, and did not have evidence of previous myocardial infarction. Results All three patient groups had similar extent of coronary artery disease and clinical characteristics, apart from differences in metabolic parameters. Diabetic and metabolic syndrome patients had higher pulmonary capillary wedge pressure than controls, and diabetic patients had reduced mitral diastolic peak velocity of the septal mitral annulus (E', consistent with impaired diastolic function. Neither diabetic nor metabolic syndrome patients had increased myocardial interstitial fibrosis (picrosirius red, or increased immunostaining for collagen I and III, the AGE Nε-(carboxymethyllysine, or RAGE. Cardiomyocyte width, capillary length density, diffusion radius, and arteriolar dimensions did not differ between the three patient groups, whereas diabetic and metabolic syndrome patients had reduced perivascular fibrosis. Conclusions Impaired diastolic function of type 2 diabetic and metabolic syndrome patients was not dependent on increased myocardial fibrosis, cardiomyocyte hypertrophy, alteration of the

  8. The outpatient psychotherapy of the borderline patient.

    Science.gov (United States)

    Chessick, R D

    1993-01-01

    This paper discussed common problems in the outpatient psychotherapy of borderline patients, especially their rage, seductiveness, and abrupt negative shifts. The definition of "borderline" is not settled. Even DSM-III-R mixes it up with other personality disorders. There are no pathognomonic symptoms, no specific personality constellations, and no compelling evidence for a definitive stage in infant development when this disorder is fixed; all stages are involved, from faulty foundational to oedipal periods. It is a descriptive diagnosis and typical presentations of such patients are reviewed. In the psychotherapeutic approach, limits must be set first, but these must be flexible and reasonable. Medications are used rarely and with care. We attempt to form an alliance by (a) getting the patient to join us in a study of himself or herself, especially a study of when rage and maladaptive behavior emerges, and (b) providing a consistent and reasonable ambience. The ultimate aim is uncovering and interpreting when the patient is ready for it, more and more approximating psychoanalytic treatment as the patient's pathology permits. The special phenomena of the self-object (Kohut), transitional object (Modell), and disruptive extreme erotic or raging (Kernberg) transferences were reviewed, as well as the pitfalls of therapist anxiety and impatience in dealing with them. While archaic transferences predominate, we serve as an auxiliary microscopic ego and appeal to the rational adult part of the patient's ego in a phenomenological investigation. We interpret early only if we cannot get the patient to examine what has led to the explosions and when distortions or projection without insight continues to predominate. The dangers of early transference interpretations are discussed. Therapy is long, tedious, and requires the willingness to patiently catalyze the patient's resumed development and endure the periodic disruptions. Countertransference problems and what to do about

  9. Glucagon-like peptide-1 counteracts the detrimental effects of Advanced Glycation End-Products in the pancreatic beta cell line HIT-T 15

    International Nuclear Information System (INIS)

    Puddu, A.; Storace, D.; Durante, A.; Odetti, P.; Viviani, G.L.

    2010-01-01

    Research highlights: → GLP-1 prevents AGEs-induced cell death. → GLP-1 prevents AGEs-induced oxidative stress. → GLP-1 ameliorated AGEs-induced cell dysfunction. → GLP-1 attenuates AGEs-induced RAGE increment. → GLP-1 counteracts AGEs-induced pancreatic cell death and dysfunction. -- Abstract: Advanced Glycation End-Products (AGEs), a group of compounds resulting from the non-enzymatic reaction of reducing sugars with the free amino group of proteins, are implicated in diabetic complications. We previously demonstrated that exposure of the pancreatic islet cell line HIT-T 15 to high concentrations of AGEs significantly decreases cell proliferation and insulin secretion, and affects transcription factors regulating insulin gene transcription. The glucagon-like peptide-1 (GLP-1) is an incretin hormone that increases proinsulin biosynthesis, stimulates insulin secretion, and improves pancreatic beta-cell viability. The aim of this work was to investigate the effects of GLP-1 on the function and viability of HIT-T 15 cells cultured with AGEs. HIT-T 15 cells were cultured for 5 days in presence of AGEs alone, or supplemented with 10 nmol/l GLP-1. Cell viability, insulin secretion, redox balance, and expression of the AGEs receptor (RAGE) were then determined. The results showed that GLP-1 protected beta cell against AGEs-induced cell death preventing both apoptosis and necrosis. Moreover, addition of GLP-1 to the AGEs culture medium restored the redox balance, improved the responsiveness to glucose, and attenuated AGEs-induced RAGE expression. These findings provide evidence that GLP-1 protects beta cells from the dangerous effects of AGEs.

  10. Hepatic microvascular dysfunction and increased advanced glycation end products are components of non-alcoholic fatty liver disease.

    Science.gov (United States)

    Pereira, Evelyn Nunes Goulart da Silva; Silvares, Raquel Rangel; Flores, Edgar Eduardo Ilaquita; Rodrigues, Karine Lino; Ramos, Isalira Peroba; da Silva, Igor José; Machado, Marcelo Pelajo; Miranda, Rosiane Aparecida; Pazos-Moura, Carmen Cabanelas; Gonçalves-de-Albuquerque, Cassiano F; Faria-Neto, Hugo Caire de Castro; Tibiriça, Eduardo; Daliry, Anissa

    2017-01-01

    This study aimed to investigate the pathophysiology of hepatic microcirculatory dysfunction in non-alcoholic fatty liver disease (NAFLD). In Wistar rats, NAFLD model was induced by 20 weeks of high-fat diet (HFD) feeding. Rolling and adhesion of leukocytes and tissue perfusion in hepatic microcirculation were examined using in vivo microscopic and laser speckle contrast imaging (LSCI), respectively. Oxidative stress and inflamatory parameters were analysed by TBARs, catalase enzyme activity, RT-PCR and ELISA. The participation of advanced glycation end-products (AGE) and its receptor RAGE was evaluated by the measurement of gene and protein expression of RAGE by RT-PCR and Western-blot, respectively and by liver and serum quantification of fluorescent AGEs. Wistar rats fed high-fat diet (HFD) showed increase in epididymal and abdominal fat content, systolic arterial blood pressure, fasting blood glucose levels, hepatic triglycerides and cholesterol, and impairment of glucose and insulin metabolisms. Liver histology confirmed the presence of steatosis and ultrasound analysis revealed increased liver size and parenchymal echogenicity in HFD-fed rats. HFD causes significant increases in leukocyte rolling and adhesion on hepatic microcirculation and decrease in liver microvascular blood flow. Liver tissue presented increase in oxidative stress and inflammtion. At 20 weeks, there was a significantly increase in AGE content in the liver and serum of HFD-fed rats and an increase in RAGE gene expression in the liver. The increase in liver AGE levels and microcirculatory disturbances could play a role in the pathogenesis of liver injury and are key components of NAFLD.

  11. Tumor necrosis factor receptor 2 as a possible marker of COPD in smokers and ex-smokers.

    Science.gov (United States)

    Caram, Laura Miranda de Oliveira; Ferrari, R; Nogueira, D L; Oliveira, Mrm; Francisqueti, F V; Tanni, S E; Corrêa, C R; Godoy, I

    2017-01-01

    Oxidative stress and systemic inflammation are higher in smokers and patients with COPD; however, markers that may help differentiate between smokers and patients with COPD have not yet been identified. We hypothesized that tumor necrosis factor-alpha receptor (TNFR) and soluble form of the receptor for advanced glycation end products (sRAGE) can be indicators of COPD in asymptomatic patients. We evaluated 32 smokers (smoking history >10 pack-years), 32 patients with mild/moderate COPD (smokers and ex-smokers), and 32 never smokers. Concentrations of C-reactive protein (CRP), interleukin (IL)-6, TNFR1 and TNFR2, advanced glycation end products (AGEs), and the sRAGE were measured in serum. There were higher CRP and AGEs concentrations in smokers and in patients with COPD ( P smokers and patients with COPD. Concentrations of sRAGE, IL-6, and TNFR1 did not differ between study groups. TNFR2 was significantly higher in patients with COPD than in smokers ( P =0.004) and controls ( P =0.004), and the presence of COPD ( P =0.02) and CRP ( P =0.001) showed a positive association with TNFR2. Positive associations for smoking ( P =0.04), CRP ( P =0.03), and IL-6 ( P =0.03) with AGEs were also found. The interaction variable (smoking × COPD) showed a positive association with IL-6. Our data suggest that TNFR2 may be a possible marker of COPD in asymptomatic smokers and ex-smokers. Although smokers and patients with early COPD presented other increased systemic inflammation markers (eg, CRP) and oxidative stress (measured by AGEs), they did not differentiate smokers from COPD.

  12. Involvement of high mobility group box 1 in the development and maintenance of chemotherapy-induced peripheral neuropathy in rats

    International Nuclear Information System (INIS)

    Nishida, Takeshi; Tsubota, Maho; Kawaishi, Yudai; Yamanishi, Hiroki; Kamitani, Natsuki; Sekiguchi, Fumiko; Ishikura, Hiroyasu; Liu, Keyue; Nishibori, Masahiro; Kawabata, Atsufumi

    2016-01-01

    Given that high mobility group box 1 (HMGB1), a nuclear protein, once released to the extracellular space, promotes nociception, we asked if inactivation of HMGB1 prevents or reverses chemotherapy-induced painful neuropathy in rats and also examined possible involvement of Toll-like receptor 4 (TLR4) and the receptor for advanced glycation endproduct (RAGE), known as targets for HMGB1. Painful neuropathy was produced by repeated i.p. administration of paclitaxel or vincristine in rats. Nociceptive threshold was determined by the paw pressure method and/or von Frey test in the hindpaw. Tissue protein levels were determined by immunoblotting. Repeated i.p. administration of the anti-HMGB1-neutralizing antibody or recombinant human soluble thrombomodulin (rhsTM), known to inactivate HMGB1, prevented the development of hyperalgesia and/or allodynia induced by paclitaxel or vincristine in rats. A single i.p. or intraplantar (i.pl.) administration of the antibody or rhsTM reversed the chemotherapy-induced neuropathy. A single i.pl. administration of a TLR4 antagonist or low molecular weight heparin, known to inhibit RAGE, attenuated the hyperalgesia caused by i.pl. HMGB1 and also the chemotherapy-induced painful neuropathy. Paclitaxel or vincristine treatment significantly decreased protein levels of HMGB1 in the dorsal root ganglia, but not sciatic nerves. HMGB1 thus participates in both development and maintenance of chemotherapy-induced painful neuropathy, in part through RAGE and TLR4. HMGB1 inactivation is considered useful to prevent and treat the chemotherapy-induced painful neuropathy.

  13. Association of peripheral neuropathy with circulating advanced glycation end products, soluble receptor for advanced glycation end products and other risk factors in patients with type 2 diabetes.

    Science.gov (United States)

    Aubert, C E; Michel, P-L; Gillery, P; Jaisson, S; Fonfrede, M; Morel, F; Hartemann, A; Bourron, O

    2014-11-01

    The pathogenesis of diabetic peripheral neuropathy remains uncertain and nonenzymatic glycoxidation is one of the contributing mechanisms. The aim of this study was to assess the respective relationship of diabetic peripheral neuropathy with glycoxidation, compared with other identified risk factors, in patients with type 2 diabetes. We included 198 patients with type 2 diabetes and high risk for vascular complications. Circulating concentrations of three advanced glycation end products (carboxymethyllysine, methyl-glyoxal-hydroimidazolone-1, pentosidine) and of their soluble receptor (sRAGE) were measured. Peripheral neuropathy was assessed by the neuropathy disability score and by the monofilament test and defined as either an abnormal monofilament test and/or a neuropathy disability score ≥6. Multivariate regression analyses were performed adjusting for potential confounding factors for neuropathy: age, gender, diabetes duration, current smoking, systolic blood pressure, waist circumference, height, peripheral arterial occlusive disease, glycated haemoglobin, estimated glomerular filtration rate and lipid profile. Prevalence of peripheral neuropathy was 20.7%. sRAGE and carboxymethyllysine were independently and positively associated with the presence of peripheral neuropathy. No significant association was found between peripheral neuropathy and methyl-glyoxal-hydroimidazolone-1 or pentosidine. Waist circumference, height and peripheral arterial occlusive disease were independently associated with peripheral neuropathy. Carboxymethyllysine and sRAGE were independently associated with peripheral neuropathy in patients with type 2 diabetes. Although the conclusions are limited by the absence of a healthy control population, this study confirms the relationship between advanced glycoxidation and diabetic peripheral neuropathy, independently of other risk factors. Copyright © 2014 John Wiley & Sons, Ltd.

  14. High-resolution anatomy of the human brain stem using 7-T MRI: improved detection of inner structures and nerves?

    International Nuclear Information System (INIS)

    Gizewski, Elke R.; Maderwald, Stefan; Linn, Jennifer; Bochmann, Katja; Dassinger, Benjamin; Forsting, Michael; Ladd, Mark E.

    2014-01-01

    The purpose of this paper is to assess the value of 7 Tesla (7 T) MRI for the depiction of brain stem and cranial nerve (CN) anatomy. Six volunteers were examined at 7 T using high-resolution SWI, MPRAGE, MP2RAGE, 3D SPACE T2, T2, and PD images to establish scanning parameters targeted at optimizing spatial resolution. Direct comparisons between 3 and 7 T were performed in two additional subjects using the finalized sequences (3 T: T2, PD, MPRAGE, SWAN; 7 T: 3D T2, MPRAGE, SWI, MP2RAGE). Artifacts and the depiction of structures were evaluated by two neuroradiologists using a standardized score sheet. Sequences could be established for high-resolution 7 T imaging even in caudal cranial areas. High in-plane resolution T2, PD, and SWI images provided depiction of inner brain stem structures such as pons fibers, raphe, reticular formation, nerve roots, and periaqueductal gray. MPRAGE and MP2RAGE provided clear depiction of the CNs. 3D T2 images improved depiction of inner brain structure in comparison to T2 images at 3 T. Although the 7-T SWI sequence provided improved contrast to some inner structures, extended areas were influenced by artifacts due to image disturbances from susceptibility differences. Seven-tesla imaging of basal brain areas is feasible and might have significant impact on detection and diagnosis in patients with specific diseases, e.g., trigeminal pain related to affection of the nerve root. Some inner brain stem structures can be depicted at 3 T, but certain sequences at 7 T, in particular 3D SPACE T2, are superior in producing anatomical in vivo images of deep brain stem structures. (orig.)

  15. Interaction between S100P and the anti-allergy drug cromolyn

    International Nuclear Information System (INIS)

    Penumutchu, Srinivasa R.; Chou, Ruey-Hwang; Yu, Chin

    2014-01-01

    Highlights: • The interaction between S100P–cromolyn was investigated by fluorescence spectroscopy. • The interfacial residues on S100P and cromolyn contact surface were mapped by 1 H- 15 N HSQC experiments. • S100P–cromolyn complex model was generated from NMR restraints using HADDOCK program. • The stability of the S100P–cromolyn complex was studied using molecular dynamics simulations. - Abstract: The S100P protein has been known to mediate cell proliferation by binding the receptor for advanced glycation end products (RAGE) to activate signaling pathways, such as the extracellular regulated kinase (ERK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. S100P/RAGE signaling is involved in a variety of diseases, such as cancer, metastasis, and diabetes. Cromolyn is an anti-allergy drug that binds S100P to block the interaction between S100P and RAGE. In the present study, we characterized the properties of the binding between cromolyn and calcium-bound S100P using various biophysical techniques. The binding affinity for S100P and cromolyn was measured to be in the millimolar range by fluorescence spectroscopy. NMR-HSQC titration experiments and HADDOCK modeling was employed to determine the spatial structure of the proposed heterotetramer model of the S100P–cromolyn complex. Additional MD simulation results revealed the important properties in the complex stability and conformational flexibility of the S100P–cromolyn complex. This proposed model has provided an understanding of the molecular level interactions of S100P–cromolyn complex

  16. Interaction between S100P and the anti-allergy drug cromolyn

    Energy Technology Data Exchange (ETDEWEB)

    Penumutchu, Srinivasa R. [Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan (China); Chou, Ruey-Hwang [Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan (China); Department of Biotechnology, Asia University, Taichung 413, Taiwan (China); Yu, Chin, E-mail: cyu.nthu@gmail.com [Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan (China); The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005 (China)

    2014-11-21

    Highlights: • The interaction between S100P–cromolyn was investigated by fluorescence spectroscopy. • The interfacial residues on S100P and cromolyn contact surface were mapped by {sup 1}H-{sup 15}N HSQC experiments. • S100P–cromolyn complex model was generated from NMR restraints using HADDOCK program. • The stability of the S100P–cromolyn complex was studied using molecular dynamics simulations. - Abstract: The S100P protein has been known to mediate cell proliferation by binding the receptor for advanced glycation end products (RAGE) to activate signaling pathways, such as the extracellular regulated kinase (ERK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. S100P/RAGE signaling is involved in a variety of diseases, such as cancer, metastasis, and diabetes. Cromolyn is an anti-allergy drug that binds S100P to block the interaction between S100P and RAGE. In the present study, we characterized the properties of the binding between cromolyn and calcium-bound S100P using various biophysical techniques. The binding affinity for S100P and cromolyn was measured to be in the millimolar range by fluorescence spectroscopy. NMR-HSQC titration experiments and HADDOCK modeling was employed to determine the spatial structure of the proposed heterotetramer model of the S100P–cromolyn complex. Additional MD simulation results revealed the important properties in the complex stability and conformational flexibility of the S100P–cromolyn complex. This proposed model has provided an understanding of the molecular level interactions of S100P–cromolyn complex.

  17. The answers are within me. An evaluation of a person centred counselling service for men at HMP Doncaster who have had experience of domestic violence 2005-2007

    OpenAIRE

    Hamilton, P.; Wilkinson, K.; Meadows, L.; Cadet, N.

    2008-01-01

    This report is the second year evaluation of the person centred counselling service for male victims and perpetrators of domestic violence at HMP Doncaster in 2006/7. This report follows on from the previous year's evaluation, Raging Anger Within Me, which evaluated this project in 2005/6. Initiated by the Doncaster Rape and Sexual Abuse Counselling Centre (DRSACC), the second year of counselling service delivery was also funded by Lloyds TSB and the Tudor Trust.\\ud The report provides a back...

  18. TMD: it's our responsibility.

    Science.gov (United States)

    Dale, R

    1999-01-01

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

  19. Collaboration de chercheurs québécois et béninois contre le sida ...

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

    12 oct. 2010 ... Au Bénin, il y a 20 ans, l'épidémie de VIH/sida faisait rage, et le pays manquait de tout pour l'endiguer. Aujourd'hui, la guerre au sida n'est pas encore terminée, mais de nombreux combats ont été gagnés. Et cela, entre autres, grâce à la ténacité de chercheurs comme Michel Alary, rattaché au Centre ...

  20. Turbine Engine Testing.

    Science.gov (United States)

    1981-01-01

    English climate. (c) Functional Testing Functional testing is a ’catch all’ title for the multitude of tests required to examine and confirm or correct the...rage I I I , I ’s slot envs Atar ONK propulsent les Miraiges IV de la levce A~rientic Strat~giqiie l-vanlaisc, tanilis tilit leg mcters Atar 91K50 sent...moignent. Irtuwi Atar 9 ~K50 est tine version MANv~ du motenr Atar 9K proptilsant le hirdaceur vi1 *c ~Ik (lttur 11 et dest in 5 6qtiiper I ’avion polyvalent

  1. Architecting the cloud design decisions for cloud computing service models (SaaS, PaaS, and IaaS)

    CERN Document Server

    Kavis, Michael J

    2014-01-01

    An expert guide to selecting the right cloud service model for your business Cloud computing is all the rage, allowing for the delivery of computing and storage capacity to a diverse community of end-recipients. However, before you can decide on a cloud model, you need to determine what the ideal cloud service model is for your business. Helping you cut through all the haze, Architecting the Cloud is vendor neutral and guides you in making one of the most critical technology decisions that you will face: selecting the right cloud service model(s) based on a combination of both business and tec

  2. Influence of Samsung Marketing Tools to Smartphone Purchase Intention of Manado Youth People

    OpenAIRE

    Manoa, Giovanny Guruh

    2014-01-01

    Smartphone has been quite a phenomenon especially in Manado city when finding people own more than one is easy. There are so many company involves in Smartphone market one of them is Samsung a Korean company who has been selling many Smartphone despite of a raging battle of competitions, this has become a questions for many people. The purpose of this research is to find out how Samsung influence the purchase intentions of a young people the most fertile segment in gadget market through their...

  3. Nuclear war would cause total destruction

    International Nuclear Information System (INIS)

    Caldicott, H.

    1985-01-01

    In this paper, the author urges everyone to become better informed about the nuclear hazard humanity faces and challenges the reader to take action to ensure human survival on Earth. The author explains what would happen in the event of a nuclear war. Population centers would be smashed flat. Firestorms would rage over millions of acres. People near the center of the blast would die immediately. Those who survived would reenter a totally devastated world, lacking the life-support systems on which the human species depends. Epidemics would be rampant. Only if we abolish nuclear weapons and permanently halt the nuclear power industry can we hope to survive

  4. Hitler: a neurohistorical formulation.

    Science.gov (United States)

    Martindale, C; Hasenfus, N; Hines, D

    1976-01-01

    It is hypothesized that Adolf Hitler suffered from a constitutional left-side weakness that allowed his cerebral hemisphere to exert a strong influence on his thought and behavior. Physical characteristics such as trembling of the left extremities, lack of a left testicle, and tendency to exhibit leftward eye movements are interpreted as supportive of the hypothesis. Right hemisphere dominance is consistent with a number of Hitler's personal traits such as praise of the irrational, automatic speech, auditory hallucinations, hypochondriasis, uncontrolled rages, and spatial and musical interests. Right hemisphere dominated thought may also have formed a basis for his two basic political policies: Lebensraum and anti-Semitism.

  5. Disease mongering in psychiatry: fact or fiction?

    Directory of Open Access Journals (Sweden)

    S Saddichha

    2010-12-01

    Full Text Available Disease mongering starts at the top of recent accusations being hurled at psychiatry. It is used to refer to the attempts by pharmaceutical companies or others who have similar interests, to enlarge the market for a treatment by convincing people that they are sick and need medical intervention. This paper critically analyses the 'for' and 'against' arguments of disease mongering in psychiatric disorders, both new and old, such as Bipolar disorders, attention deficit hyperactivity disorder, Restless legs syndrome, Premenstrual dysphoric disorder, female sexual dysfunction, social phobia, metabolic syndrome and road rage disorder. Keywords: disease mongeringpharmaceutical companies, psychiatry.

  6. Recognition and management of Shaken Baby Syndrome

    LENUS (Irish Health Repository)

    Nicholson, Alf

    2016-04-01

    Abusive head trauma (previously referred to as Shaken Baby Syndrome) consists of a triad of findings which included subdural haemorrhage, retinal haemorrhages and encephalopathy after receiving a shake injury or blunt trauma to the head. Debate rages regarding the exact mechanism. Previously published reports on abusive head trauma (AHT) highlight the young age of the victims (median 4 months of age), the significant preponderance of male infants (3:1 in most series), the high rate of probable male perpetrators (just over 50%), and relatively high rates of mortality and morbidity

  7. Characterization of Static/Dynamic Topological Routing For Grid Networks

    DEFF Research Database (Denmark)

    Gutierrez Lopez, Jose Manuel; Cuevas, Ruben; Riaz, M. Tahir

    2009-01-01

    Grid or 2D Mesh structures are becoming one of the most attractive network topologies to study. They can be used in many different fields raging from future broadband networks to multiprocessors structures. In addition, the high requirements of future services and applications demand more flexible...... and adaptive networks. Topological routing in grid networks is a simple and efficient alternative to traditional routing techniques, e.g. routing tables, and the paper extends this kind of routing providing a "Dynamic" attribute. This new property attempts to improve the overall network performance for future...

  8. Privacy and Big Data

    CERN Document Server

    Craig, Terence

    2011-01-01

    Much of what constitutes Big Data is information about us. Through our online activities, we leave an easy-to-follow trail of digital footprints that reveal who we are, what we buy, where we go, and much more. This eye-opening book explores the raging privacy debate over the use of personal data, with one undeniable conclusion: once data's been collected, we have absolutely no control over who uses it or how it is used. Personal data is the hottest commodity on the market today-truly more valuable than gold. We are the asset that every company, industry, non-profit, and government wants. Pri

  9. О НАВОДНЕНИИ В ПОЭМЕ "МЕДНЫЙ ВСАДНИК"

    OpenAIRE

    杉野, ゆり; Юри, СУГИНО; 大阪外国語大学; Осакский инст. иностранных языков

    1990-01-01

    The Bronze Horseman was completed by Pushkin in Boldino in the autumn of 1833. The central incident of this poem is the flood which struck St. Petersburg in November of 1824. In the present paper it will be shown that Pushkin associated the flood of "The Bronze Horseman" with the rebellions of the 1770's and 1830's. In "The Bronze Horseman" three figures related to beasts play an important role: the flood, Evgeny, and a marble lion. The raging flood is metaphorically likened to a beast. The l...

  10. An ancient harbour at Dwarka: Study based on the recent underwater explorations

    Digital Repository Service at National Institute of Oceanography (India)

    Gaur, A.S.; Sundaresh; Tripati, S.

    vegetation were rarely n o ticed. A number of artifacts were discovered du r ing offshore ex - plo rations between 3 and 16 m water depths. Broadly, these artifacts can be d i vi ded into the following two categories. (A) Structures : Underwater... of underwater struc tures at Dwarka. A 19th century map of the area indicates that shoreline has advanced land - ward by 550 m du r ing the last 130 years 24 with an ave - rage of 4 m/yr. The pr e sent offshore explorations have indi - cated that most...

  11. Basilar artery aneurysm case presented with neck pain

    Directory of Open Access Journals (Sweden)

    Uygar Utku

    2013-04-01

    Full Text Available Neck pain related with disorders of the brain and neck vascular structures is not rare but importance was attached to a condition that is often overlooked. Tension as a sudden onset, radiating to the nape, the neck pain becomes unbearable and within seconds the raging 51-year-old female patient with aneurysm at the distal end of basilar artery was found. Case, the only sign of neck pain with unruptured basilar artery aneurysm is presented in terms of raising awareness on the subject.

  12. ONR Tokyo Scientific Bulletin. Volume 2, Number 2. April-June 1977,

    Science.gov (United States)

    1977-01-01

    expression (now it is not pound s overweight but blood levels ) . Thin l)eoPle still live longer , on the ave rage , than fat people. The~’ will...l i - t y s usctl in the exp en im em -its a re . of course ’, se l ec ted t i c s i m p l i f y t he cx peru r u ue m u t~t l p ro h i lc tu t

  13. Numerical simulation of Cr2N age-precipitation in high nitrogen stainless steels

    International Nuclear Information System (INIS)

    Dai, Q.X.; Yuan, Z.Z.; Luo, X.M.; Cheng, X.N.

    2004-01-01

    At the temperature raging from 700 to 950 deg. C, the Cr 2 N age-precipitation in high nitrogen austenitic stainless steels Fe24Mn18Cr3Ni0.62N was investigated in this paper. A qualitative mathematical model of Cr 2 N age-precipitation, ln t S = f (Me,1/T), was established based on the thermodynamics and kinetics and phase transformation theories. Satisfactory results were obtained by means of the test of artificial neural network. This mathematical model can be applied to the calculation design and predication of Cr 2 N age-precipitation in high nitrogen stainless steels

  14. Institutional dynamic of the call center industry in Denmark and France

    DEFF Research Database (Denmark)

    Sørensen, Ole H.; Beraud, Mathieu; Colin, Thierry

    2005-01-01

    The call centre development is substantially increasing in the most part of industrialized countries. Coming to the fore and seeking for staff, this sector is still looking for benchmarks, especially in terms of employment. Currently it can be said that the sector is under construction since its ...... to the specific micro and meso dynamic of this emerging industry. We base on a part of the first results obtained in a research on low wage initiated by the Russell Rage Foundation. More precisely we use the results from sectoral survey....

  15. A designated centre for people with disabilities operated by Nua Healthcare Services, Tipperary

    LENUS (Irish Health Repository)

    Nicholson, Alf

    2016-04-01

    Abusive head trauma (previously referred to as Shaken Baby Syndrome) consists of a triad of findings which included subdural haemorrhage, retinal haemorrhages and encephalopathy after receiving a shake injury or blunt trauma to the head. Debate rages regarding the exact mechanism. Previously published reports on abusive head trauma (AHT) highlight the young age of the victims (median 4 months of age), the significant preponderance of male infants (3:1 in most series), the high rate of probable male perpetrators (just over 50%), and relatively high rates of mortality and morbidity

  16. The conservation and dissemination of information - A democratic issue

    International Nuclear Information System (INIS)

    Torbacke, J.

    1996-01-01

    The societal function of the historians are pointed out, to describe and explain, in cooperation with the archives, the chain of political, economic, social and cultural events that has shaped the country's history. The lessons of the past, whether pleasant or unpleasant, should be passed on to the posterity. Open information is an important element in a democratic society and is normally one of the criteria that distinguishes democracy from autocracy. In the closed and controlled information society all that is hushed up and covered up leads to bitterness and rage among the citizens

  17. EFFECTS OF DIFFERENT NUMERICAL INTERFACE METHODS ON HYDRODYNAMICS INSTABILITY

    Energy Technology Data Exchange (ETDEWEB)

    FRANCOIS, MARIANNE M. [Los Alamos National Laboratory; DENDY, EDWARD D. [Los Alamos National Laboratory; LOWRIE, ROBERT B. [Los Alamos National Laboratory; LIVESCU, DANIEL [Los Alamos National Laboratory; STEINKAMP, MICHAEL J. [Los Alamos National Laboratory

    2007-01-11

    The authors compare the effects of different numerical schemes for the advection and material interface treatments on the single-mode Rayleigh-Taylor instability, using the RAGE hydro-code. The interface growth and its surface density (interfacial area) versus time are investigated. The surface density metric shows to be better suited to characterize the difference in the flow, than the conventional interface growth metric. They have found that Van Leer's limiter combined to no interface treatment leads to the largest surface area. Finally, to quantify the difference between the numerical methods they have estimated the numerical viscosity in the linear-regime at different scales.

  18. Criteria for the recognition of pedogenic/supergene and nonpedogenic/hypogene deposits and their relationship to the origin of calcite/opal deposits at Yucca Mountain. Special report No. 14

    International Nuclear Information System (INIS)

    Hill, C.A.; Schluter, C.M.; Monger, H.C.

    1993-10-01

    This study is part of the research program of the Yucca Mountain Project intended to provide the State of Nevada with a detailed assessment of the geology and geochemistry of Yucca Mountain and adjacent regions. The purpose of this report is to try and establish criteria for the recognition of pedogenic/supergene deposits of calcite/opal versus non-pedogenic/hypogene deposits of calcite/opal. Far from being of esoteric concern, this subject is of paramount importance to the pedogenic-hypogene debate which rages around the suitability of Yucca Mountain as a high-level radioactive waste repository site

  19. Who calls the tune?

    Directory of Open Access Journals (Sweden)

    Claude Chastagner

    2011-04-01

    Full Text Available The real action was taking place behind the scenes.Irwin Pincus, music publisherA couple of weeks ago, while researching for this paper, I decided to read again Chronicles, Bob Dylan’s autobiography. Chapter 4 deals with the recording in a rented New Orleans mansion of Oh Mercy, the 1989 album produced by Daniel Lanois, unanimously hailed as Dylan’s resurrection. Dylan insists on the significant impact Lanois had on his own artistry. Through conversations, flashes of rage and frustration, and...

  20. [History of oyster as drug from the origin to the 21st century].

    Science.gov (United States)

    Bonnemain, Bruno

    2015-06-01

    Since Antiquity, oyster is a subject of interest and medical use, as indicated by Oribiase and Galien. From the 17th century, this unique drug was proposed by physicians for various diseases, and more often for (la rage). One could think that that drug disappeared at the 20th and 21st centuries. But we can observe that it was still recommended by several authors as drug. Still today, companies offer oyster under various forms for allopathic and homeopathic treatments, as well as for food supplement. Research are ongoing to discover active substances within oyster and their potential medical interests.

  1. Nuclear industry review

    International Nuclear Information System (INIS)

    1982-01-01

    This review examines the consequences of projected excess electrical generating capacity for the maintenance of an independent nuclear power capability in Canada. Although consumption of electricity will continue to grow at rages well below historical averages, significant additions to capacity will be required in all parts of Canada in the 1990s. CANDU reactors are an attractive option for meeting load growth, particularly east of Manitoba. However, the absence of domestic orders in the 1980s may threaten the maintenance of this option. Even the most optimistic projections indicate that only one supplier of each component will remain in the nuclear business in the 1990s

  2. African Women in the Entrepreneurial Landscape: reconsidering the formal and informal sectors

    OpenAIRE

    Spring, Anita

    2006-01-01

    Informal and formal can be seen as «dual economies» of African countries. Governments oTen concern themselves with the formal, while development agencies oTen support the informal. This paper discusses the full landscape of entrepreneurship, considering both sectors, and the range from small to large within each. It queries whether or not there can be movement within and between sectors, and if the «rages to riches» upward movement, as seen in developed countries, is possible i...

  3. Lung inflammation biomarkers and lung function in children chronically exposed to arsenic

    Energy Technology Data Exchange (ETDEWEB)

    Olivas-Calderón, Edgar, E-mail: edgar_olivascalderon@hotmail.com [Department of Environmental Health, Biomedical Research Center, School of Medicine, University of Coahuila, Torreon, Coahuila (Mexico); School of Medicine, University Juarez of Durango, Gomez Palacio, Durango (Mexico); Recio-Vega, Rogelio, E-mail: rrecio@yahoo.com [Department of Environmental Health, Biomedical Research Center, School of Medicine, University of Coahuila, Torreon, Coahuila (Mexico); Gandolfi, A. Jay, E-mail: gandolfi@pharmacy.arizona.edu [Southwest Environmental Health Science Center, University of Arizona, Tucson, AZ (United States); Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ (United States); Lantz, R. Clark, E-mail: lantz@email.arizona.edu [Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ (United States); Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ (United States); González-Cortes, Tania, E-mail: taniagc2201@hotmail.com [Department of Environmental Health, Biomedical Research Center, School of Medicine, University of Coahuila, Torreon, Coahuila (Mexico); Gonzalez-De Alba, Cesar, E-mail: cesargonzalezalba@hotmail.com [Department of Environmental Health, Biomedical Research Center, School of Medicine, University of Coahuila, Torreon, Coahuila (Mexico); Froines, John R., E-mail: jfroines@ucla.edu [Center for Environmental and Occupational Health, School of Public Health, University of California at Los Angeles, Los Angeles, CA (United States); Espinosa-Fematt, Jorge A., E-mail: dr.jorge.espinosa@gmail.com [School of Medicine, University Juarez of Durango, Gomez Palacio, Durango (Mexico)

    2015-09-01

    Evidence suggests that exposure to arsenic in drinking water during early childhood or in utero has been associated with an increase in respiratory symptoms or diseases in the adulthood, however only a few studies have been carried out during those sensitive windows of exposure. Recently our group demonstrated that the exposure to arsenic during early childhood or in utero in children was associated with impairment in the lung function and suggested that this adverse effect could be due to a chronic inflammation response to the metalloid. Therefore, we designed this cross-sectional study in a cohort of children associating lung inflammatory biomarkers and lung function with urinary As levels. A total of 275 healthy children were partitioned into four study groups according with their arsenic urinary levels. Inflammation biomarkers were measured in sputum by ELISA and the lung function was evaluated by spirometry. Fifty eight percent of the studied children were found to have a restrictive spirometric pattern. In the two highest exposed groups, the soluble receptor for advanced glycation end products' (sRAGE) sputum level was significantly lower and matrix metalloproteinase-9 (MMP-9) concentration was higher. When the biomarkers were correlated to the urinary arsenic species, negative associations were found between dimethylarsinic (DMA), monomethylarsonic percentage (%MMA) and dimethylarsinic percentage (%DMA) with sRAGE and positive associations between %DMA with MMP-9 and with the MMP-9/tissue inhibitor of metalloproteinase (TIMP-1) ratio. In conclusion, chronic arsenic exposure of children negatively correlates with sRAGE, and positively correlated with MMP-9 and MMP-9/TIMP-1 levels, and increases the frequency of an abnormal spirometric pattern. Arsenic-induced alterations in inflammatory biomarkers may contribute to the development of restrictive lung diseases. - Highlights: • First study in children evaluating lung inflammatory biomarkers and As levels

  4. Eleonora Pasotti, Political branding in cities. The decline of machine politics in Bogotá, Naples, and Chicago

    Directory of Open Access Journals (Sweden)

    Gilles Pinson

    2011-11-01

    Full Text Available Au travers de cet ouvrage, Eleonora Pasotti, professeure de science politique à l’Université de Californie à Santa Cruz, renoue avec la grande tradition nord-américaine des travaux de science politique qui aborde la grande ville comme lieu d’invention et de repérage des nouvelles formes d’échange politique et de lien entre gouvernants et gouvernés. Le livre articule une analyse des nouveaux comportements électoraux et des nouvelles logiques de mobilisation électorale, d’une part, et une analy...

  5. Trials of Command: General John D. Lavelle and the Seventh Air Force in Vietnam

    Science.gov (United States)

    2011-04-07

    Lavelle related that Ryan accused Lavelle ofgoing behind his back td the Secretary and undermining his decision on the Lockheed plan. In Lavelle’s...however, after meeting with his immediate supervisor and officer in charge received a direct order td comply with the . reporting requirement.· The...PrRs oN 1 r1AY 19?2• ~, llJ ) pUBLIC A.FfHRS GIJ!DANCE, MO i"USUc A.f•.!NOl:JNCEHeNT Op r<Ny .- !(.HiD WILL SE HAD:; !~JTH REG;!,RO rAGE 1 DE

  6. Strategic alliances fit pattern of industry innovation

    International Nuclear Information System (INIS)

    Crump, J.G.

    1997-01-01

    The strategic alliance, vitally important as an isolated practice in the oil and gas business, also fits a broad pattern of innovation by which the industry is redefining itself for prosperity in a new energy age. The industry is experiencing a renaissance in almost every aspect, from technological breakthroughs to innovative business practices to new products and markets. An inevitable outgrowth of such rapid and fundamental change is an evolution in business relationships. The strategic alliance is at the forefront of this trend. Development of new relationships capitalizes on, and partly results from, enormous advances in technology and finance. The paper discusses new relationships, the outsourcing rage, integrating work flows, and technological advances

  7. A Persistent Threat: The Evolution of al Qa’ida and Other Salafi Jihadists

    Science.gov (United States)

    2014-01-01

    Thomas Joscelyn at the Founda- tion for Defense of Democracies, and William McCants at the Brook- ings Institution. Numerous individuals in the U.S...4, November 2010, pp. 1459–1510. 29 Abrahms, “Why Terrorism Does Not Work,” 2006, pp. 52–56; Jason Lyall and Isaiah Wilson, “Rage Against the...Set, accessed December 16, 2013. 58 Ibid. 59 Thomas Hegghammer, “The Recruiter’s Dilemma: Signaling and Rebel Recruitment Tac- tics,” Journal of

  8. Modeling of laser-driven hydrodynamics experiments

    Science.gov (United States)

    di Stefano, Carlos; Doss, Forrest; Rasmus, Alex; Flippo, Kirk; Desjardins, Tiffany; Merritt, Elizabeth; Kline, John; Hager, Jon; Bradley, Paul

    2017-10-01

    Correct interpretation of hydrodynamics experiments driven by a laser-produced shock depends strongly on an understanding of the time-dependent effect of the irradiation conditions on the flow. In this talk, we discuss the modeling of such experiments using the RAGE radiation-hydrodynamics code. The focus is an instability experiment consisting of a period of relatively-steady shock conditions in which the Richtmyer-Meshkov process dominates, followed by a period of decaying flow conditions, in which the dominant growth process changes to Rayleigh-Taylor instability. The use of a laser model is essential for capturing the transition. also University of Michigan.

  9. Molecular Pathways Involved in the Amelioration of Myocardial Injury in Diabetic Rats by Kaempferol.

    Science.gov (United States)

    Suchal, Kapil; Malik, Salma; Khan, Sana Irfan; Malhotra, Rajiv Kumar; Goyal, Sameer N; Bhatia, Jagriti; Ojha, Shreesh; Arya, Dharamvir Singh

    2017-05-15

    There is growing evidence that chronic hyperglycemia leads to the formation of advanced glycation end products (AGEs) which exerts its effect via interaction with the receptor for advanced glycation end products (RAGE). AGE-RAGE activation results in oxidative stress and inflammation. It is well known that this mechanism is involved in the pathogenesis of cardiovascular disease in diabetes. Kaempferol, a dietary flavonoid, is known to possess antioxidant, anti-apoptotic, and anti-inflammatory activities. However, little is known about the effect of kaempferol on myocardial ischemia-reperfusion (IR) injury in diabetic rats. Diabetes was induced in male albino Wistar rats using streptozotocin (70 mg/kg; i.p.), and rats with glucose level >250 mg/dL were considered as diabetic. Diabetic rats were treated with vehicle (2 mL/kg; i.p.) and kaempferol (20 mg/kg; i.p.) daily for a period of 28 days and on the 28th day, ischemia was produced by one-stage ligation of the left anterior descending coronary artery for 45 min followed by reperfusion for 60 min. After completion of surgery, rats were sacrificed and the heart tissue was processed for biochemical, morphological, and molecular studies. Kaempferol pretreatment significantly reduced hyperglycemia, maintained hemodynamic function, suppressed AGE-RAGE axis activation, normalized oxidative stress, and preserved morphological alterations. In addition, there was decreased level of inflammatory markers (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and NF-κB), inhibition of active c-Jun N-terminal kinase (JNK) and p38 proteins, and activation of Extracellular signal regulated kinase 1/2 (ERK1/2) a prosurvival kinase. Furthermore, it also attenuated apoptosis by reducing the expression of pro-apoptotic proteins (Bax and Caspase-3), Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells, and increasing the level of anti-apoptotic protein (Bcl-2). In conclusion, kaempferol attenuated

  10. Continuing after Chernobyl

    International Nuclear Information System (INIS)

    Beckurts, K.H.

    1986-01-01

    The serious reactor accident in the Soviet Union has caused anxiety and fear. Nobody giving nuclear energy a serious thought can be left unconcerned. In West Germany, there was, and still is, more uneasiness than anywhere else in the world. The nuclear controversy, which raged heavily already in the seventies, has revived again. There is an increasing trend towards ''getting out''. Still, we should beware of making an emotional decision on the spur of the moment which may endanger West Germany's future as an industrialized nation. (orig.) [de

  11. The Influence of Brand Image, Advertising,perceived Price Toward Consumer Purchase Intention at Samsung Smartphone

    OpenAIRE

    Rumokoy, Farlane; Pangemanan, Sifrid S.; Manorek, Sutria Langling

    2015-01-01

    Smartphone has been quite a phenomenon especially in Manado city when finding people own more than one is easy. There are so many company involves in Smartphone market one of them is Samsung a Korean company who has been selling many Smartphone despite of a raging battle of competitions, this has become a questions for many people. Marketing is needed for the process of buying and selling a product or service , marketing as a liaison to the process or it can be regarded as a market that meet ...

  12. Theological reflections on empire

    Directory of Open Access Journals (Sweden)

    Allan A. Boesak

    2009-11-01

    Full Text Available Since the meeting of the World Alliance of Reformed Churches in Accra, Ghana (2004, and the adoption of the Accra Declaration, a debate has been raging in the churches about globalisation, socio-economic justice, ecological responsibility, political and cultural domination and globalised war. Central to this debate is the concept of empire and the way the United States is increasingly becoming its embodiment. Is the United States a global empire? This article argues that the United States has indeed become the expression of a modern empire and that this reality has considerable consequences, not just for global economics and politics but for theological refl ection as well.

  13. Be steadily on the progress, be in pursuit of brilliance. For deep understanding the development tendency of quality management in nuclear geologic exploration

    International Nuclear Information System (INIS)

    Zhang Qiuying

    2006-01-01

    A new knowledge economy era driven by brings forth new ideas in science-technology and marked by quality innovation as an important element has come. At present, a great upsurge of quality management represented by outstanding quality management models such as Liuxigma management, outstanding achievement-effect evaluation and quality management system etc. are spreading throughout the world like a raging fire. Enterprises of nuclear geological exploration must be steadily on the progress, to strengthen quality management, to guarantee the successful fulfillment of tasks in uranium resources exploration by outstanding achievements. (authors)

  14. African-American English i direkt anföring : Etta James självbiografi översatt till svenska – att anpassa översättningen efter en varietet som inte har någon motsvarighet på svenska

    OpenAIRE

    Anteryd, Linn

    2015-01-01

    Detta examensarbete är indelat i tre delar. Examensarbetet består av en översättning av tre kapitel ur Etta James självbiografi Rage to survive: the Etta James story skriven av James och spökförfattaren David Ritz, samt ett kapitel om vilka textspecifika översättningsproblem som uppstod vid översättningen. Den tredje delen består av en djupanalys av hur varieteten African-American English (AAE) översatts i två andra verk, nämligen I know why the caged bird sings av Maya Angelou och The bluest...

  15. The (APolitical Economy of Bitcoin

    Directory of Open Access Journals (Sweden)

    Vasilis Kostakis

    2014-06-01

    Full Text Available The still raging financial crisis of 2007–2008 has enabled the emergence of several alternative practices concerning the production, circulation and use of money. This essay explores the political economy of the Bitcoin ecosystem. Specifically, we examine the context in which this digital currency is emerging as well as its nature, dynamics, advantages, and disadvantages. We conclude that Bitcoin, a truly interesting experiment, exemplifies "distributed capitalism" and should be mostly seen as a technological innovation. Rather than providing pragmatic answers and solutions to the current views on the financial crisis, Bitcoin provides some useful and timely questions about the principles and bases of the dominant political economy.

  16. Strategic Assessment 1999. Priorities for a Turbulent World.

    Science.gov (United States)

    1999-01-01

    1995, the av - erage annual return on U.S. direct investment in Africa was 30 percent. Major legislation to pro- mote U.S. t rade with Africa, the...economies per formed reason- ably well. The UN Economic Commiss ion for Latin America and the Caribbean (ECLAC) re- por t s an ave rage g r o w t h...1990), 21-22. 2 guls Cation, El Patrdn: Vida Y Muerte de Pablo Es- cobar (Bogot~i: Planeta Colombiana Editorial S.A, 1994). 3 "World Crime Trends and

  17. Elemental magic, v.2 the technique of special effects animation

    CERN Document Server

    Gilland, Joseph

    2012-01-01

    Design beautiful, professional-level animated effects with these detailed step-by-step tutorials from former Disney animator and animated effects expert Joseph Gilland. Filled with beautiful, full-color artwork, Elemental Magic, Volume II, breaks down the animated effect process from beginning to end-including booming explosions, gusting winds, magical incantations, and raging fires. He also breaks down the process of effects ""clean-up,"" as well as timing and frame rates. The companion website includes real-time footage of the author lecturing as he animates the drawings from the

  18. University-industry coupling: exaggerated expectations

    Energy Technology Data Exchange (ETDEWEB)

    Roy, R.

    This coupling, formally disdainful to university presidents and leading scientists, is now all the rage, according to the author. The presidents' enthusiasm is sparked apparently by hopes of making killings on patents and gaining equity participation in the Silicon Valleys of the future, he notes. The reality of the situation, the cautions, is that all ventures are highly speculative; further, the performance of most universities in knowledge transfer is mixed. He supports research interactions between universities and industries where natural and effective, but warms against the public's grossly exaggerated expectations. 6 references

  19. War of Words : Dutch Pro-Boer Propaganda and the South African War (1899-1902)

    OpenAIRE

    Kuitenbrouwer, Vincent

    2012-01-01

    Between 1899 and 1902 the Dutch public was captivated by the war raging in South Africa between the Boer republics and the British Empire. Dutch popular opinion was on the side of the Boers: these descendants of the seventeenth-century Dutch settlers were perceived as kinsmen, the most tangible result of which was a flood of propaganda material intended as a counterweight to the British coverage of the war. The author creates a fascinating account of the Dutch pro-Boer movement from its origi...

  20. Penile Replantation After Five Hours of Warm Ischemia

    Directory of Open Access Journals (Sweden)

    Fernando N. Facio Jr.

    2015-05-01

    Full Text Available Although a rare occurrence, this event may occur as a result of self-mutilation among individuals with psychiatric disturbances or due to work-related accidents, iatrogenic injuries or the actions of individuals motivated by jealously, rage and feelings of betrayal. In western societies, most penile amputations are the result of self-aggression during a psychotic episode, the treatment of victims involves resuscitation, stabilization and immediate psychiatric support. The amputated tissue must be preserved under hypothermic conditions. Micro-surgery is currently the most widely employed method for penile replantation. This paper describes a successful case of penile replantation following 5 hours of warm ischemia.