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Sample records for models il-22 induces

  1. IL22/IL-22R pathway induces cell survival in human glioblastoma cells.

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    Hussein Akil

    Full Text Available Interleukin-22 (IL-22 is a member of the IL-10 cytokine family that binds to a heterodimeric receptor consisting of IL-22 receptor 1 (IL-22R1 and IL-10R2. IL-22R expression was initially characterized on epithelial cells, and plays an essential role in a number of inflammatory diseases. Recently, a functional receptor was detected on cancer cells such as hepatocarcinoma and lung carcinoma, but its presence was not reported in glioblastoma (GBM. Two GBM cell lines and 10 primary cell lines established from patients undergoing surgery for malignant GBM were used to investigate the expression of IL-22 and IL-22R by using quantitative RT-PCR, western blotting and confocal microscopy studies. The role of IL-22 in proliferation and survival of GBM cell lines was investigated in vitro by BrdU and ELISA cell death assays. We report herein that the two subunits of the IL-22R complex are expressed on human GBM cells. Their activation, depending on exogenous IL-22, induced antiapoptotic effect and cell proliferation. IL-22 treatment of GBM cells resulted in increased levels of phosphorylated Akt, STAT3 signaling protein and its downstream antiapoptotic protein Bcl-xL and decreased level of phosphorylated ERK1/2. In addition, IL-22R subunits were expressed in all the 10 tested primary cell lines established from GBM tumors. Our results showed that IL-22R is expressed on GBM established and primary cell lines. Depending on STAT3, ERK1/2 and PI3K/Akt pathways, IL-22 induced GBM cell survival. These data are consistent with a potential role of IL-22R in tumorigenesis of GBM. Since endogenous IL-22 was not detected in all studied GBM cells, we hypothesize that IL-22R could be activated by immune microenvironmental IL-22 producing cells.

  2. IL-22/STAT3-Induced Increases in SLURP1 Expression within Psoriatic Lesions Exerts Antimicrobial Effects against Staphylococcus aureus.

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    Yasuhiro Moriwaki

    Full Text Available SLURP1 is the causal gene for Mal de Meleda (MDM, an autosomal recessive skin disorder characterized by diffuse palmoplantar keratoderma and transgressive keratosis. Moreover, although SLURP1 likely serves as an important proliferation/differentiation factor in keratinocytes, the possible relation between SLURP1 and other skin diseases, such as psoriasis and atopic dermatitis, has not been studied, and the pathophysiological control of SLURP1 expression in keratinocytes is largely unknown.Our aim was to examine the involvement of SLURP1 in the pathophysiology of psoriasis using an imiquimod (IMQ-induced psoriasis model mice and normal human epidermal keratinocytes (NHEKs.SLURP1 expression was up-regulated in the skin of IMQ-induced psoriasis model mice. In NHEKs stimulated with the inflammatory cytokines IL-17, IL-22 and TNF-α, which are reportedly expressed in psoriatic lesions, SLURP1 mRNA expression was significantly up-regulated by IL-22 but not the other two cytokines. The stimulatory effect of IL-22 was completely suppressed in NHEKs treated with a STAT3 inhibitor or transfected with siRNA targeting STAT3. Because IL-22 induces production of antimicrobial proteins in epithelial cells, the antibacterial activity of SLURP1 was assessed against Staphylococcus aureus (S. aureus, which is known to be associated with disease severity in psoriasis. SLURP1 significantly suppressed the growth of S. aureus.These results indicate SLURP1 participates in pathophysiology of psoriasis by regulating keratinocyte proliferation and differentiation, and by suppressing the growth of S. aureus.

  3. Structure of IL-22 Bound to Its High-Affinity IL-22R1 Chain

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    Jones, B.C.; Logsdon, N.J.; Walter, M.R. (UAB)

    2008-09-29

    IL-22 is an IL-10 family cytokine that initiates innate immune responses against bacterial pathogens and contributes to immune disease. IL-22 biological activity is initiated by binding to a cell-surface complex composed of IL-22R1 and IL-10R2 receptor chains and further regulated by interactions with a soluble binding protein, IL-22BP, which shares sequence similarity with an extracellular region of IL-22R1 (sIL-22R1). IL-22R1 also pairs with the IL-20R2 chain to induce IL-20 and IL-24 signaling. To define the molecular basis of these diverse interactions, we have determined the structure of the IL-22/sIL-22R1 complex. The structure, combined with homology modeling and surface plasmon resonance studies, defines the molecular basis for the distinct affinities and specificities of IL-22 and IL-10 receptor chains that regulate cellular targeting and signal transduction to elicit effective immune responses.

  4. IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation.

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    Ma, Hak-Ling; Liang, Spencer; Li, Jing; Napierata, Lee; Brown, Tom; Benoit, Stephen; Senices, Mayra; Gill, Davinder; Dunussi-Joannopoulos, Kyriaki; Collins, Mary; Nickerson-Nutter, Cheryl; Fouser, Lynette A; Young, Deborah A

    2008-02-01

    Psoriasis is a chronic skin disease resulting from the dysregulated interplay between keratinocytes and infiltrating immune cells. We report on a psoriasis-like disease model, which is induced by the transfer of CD4(+)CD45RB(hi)CD25(-) cells to pathogen-free scid/scid mice. Psoriasis-like lesions had elevated levels of antimicrobial peptide and proinflammatory cytokine mRNA. Also, similar to psoriasis, disease progression in this model was dependent on the p40 common to IL-12 and IL-23. To investigate the role of IL-22, a Th17 cytokine, in disease progression, mice were treated with IL-22-neutralizing antibodies. Neutralization of IL-22 prevented the development of disease, reducing acanthosis (thickening of the skin), inflammatory infiltrates, and expression of Th17 cytokines. Direct administration of IL-22 into the skin of normal mice induced both antimicrobial peptide and proinflammatory cytokine gene expression. Our data suggest that IL-22, which acts on keratinocytes and other nonhematopoietic cells, is required for development of the autoreactive Th17 cell-dependent disease in this model of skin inflammation. We propose that IL-22 antagonism might be a promising therapy for the treatment of human psoriasis.

  5. IL-22 is required for Th17 cell–mediated pathology in a mouse model of psoriasis-like skin inflammation

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    Ma, Hak-Ling; Liang, Spencer; Li, Jing; Napierata, Lee; Brown, Tom; Benoit, Stephen; Senices, Mayra; Gill, Davinder; Dunussi-Joannopoulos, Kyriaki; Collins, Mary; Nickerson-Nutter, Cheryl; Fouser, Lynette A.; Young, Deborah A.

    2008-01-01

    Psoriasis is a chronic skin disease resulting from the dysregulated interplay between keratinocytes and infiltrating immune cells. We report on a psoriasis-like disease model, which is induced by the transfer of CD4+CD45RBhiCD25– cells to pathogen-free scid/scid mice. Psoriasis-like lesions had elevated levels of antimicrobial peptide and proinflammatory cytokine mRNA. Also, similar to psoriasis, disease progression in this model was dependent on the p40 common to IL-12 and IL-23. To investigate the role of IL-22, a Th17 cytokine, in disease progression, mice were treated with IL-22–neutralizing antibodies. Neutralization of IL-22 prevented the development of disease, reducing acanthosis (thickening of the skin), inflammatory infiltrates, and expression of Th17 cytokines. Direct administration of IL-22 into the skin of normal mice induced both antimicrobial peptide and proinflammatory cytokine gene expression. Our data suggest that IL-22, which acts on keratinocytes and other nonhematopoietic cells, is required for development of the autoreactive Th17 cell–dependent disease in this model of skin inflammation. We propose that IL-22 antagonism might be a promising therapy for the treatment of human psoriasis. PMID:18202747

  6. IL-17a and IL-22 Induce Expression of Antimicrobials in Gastrointestinal Epithelial Cells and May Contribute to Epithelial Cell Defense against Helicobacter pylori.

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    Beverly R E A Dixon

    Full Text Available Helicobacter pylori colonization of the human stomach can lead to adverse clinical outcomes including gastritis, peptic ulcers, or gastric cancer. Current data suggest that in addition to bacterial virulence factors, the magnitude and types of immune responses influence the outcome of colonization. Specifically, CD4+ T cell responses impact the pathology elicited in response to H. pylori. Because gastritis is believed to be the initiating host response to more detrimental pathological outcomes, there has been a significant interest in pro-inflammatory T cell cytokines, including the cytokines produced by T helper 17 cells. Th17 cells produce IL-17A, IL-17F, IL-21 and IL-22. While these cytokines have been linked to inflammation, IL-17A and IL-22 are also associated with anti-microbial responses and control of bacterial colonization. The goal of this research was to determine the role of IL-22 in activation of antimicrobial responses in models of H. pylori infection using human gastric epithelial cell lines and the mouse model of H. pylori infection. Our data indicate that IL-17A and IL-22 work synergistically to induce antimicrobials and chemokines such as IL-8, components of calprotectin (CP, lipocalin (LCN and some β-defensins in both human and primary mouse gastric epithelial cells (GEC and gastroids. Moreover, IL-22 and IL-17A-activated GECs were capable of inhibiting growth of H. pylori in vitro. While antimicrobials were activated by IL-17A and IL-22 in vitro, using a mouse model of H. pylori infection, the data herein indicate that IL-22 deficiency alone does not render mice more susceptible to infection, change their antimicrobial gene transcription, or significantly change their inflammatory response.

  7. Though active on RINm5F insulinoma cells and cultured pancreatic islets, recombinant IL-22 fails to modulate cytotoxicity and disease in a protocol of streptozotocin-induced experimental diabetes.

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    Anika eBerner

    2016-01-01

    Full Text Available Interleukin (IL-22 is a cytokine displaying tissue protective and pro-regenerative functions in various preclinical disease models. Anti-bacterial, pro-proliferative, and anti-apoptotic properties mediated by activation of the transcription factor signal transducer and activator of transcription (STAT-3 are key to biological functions of this IL-10 family member. Herein, we introduce RINm5F insulinoma cells as rat ß-cell line that, under the influence of IL-22, displays activation of STAT3 with induction of its downstream gene targets Socs3, Bcl3, and Reg3ß. In addition, IL-22 also activates STAT1 in this cell type. To refine those observations, IL-22 biological activity was evaluated using ex vivo cultivated murine pancreatic islets. In accord with data on RINm5F cells, islet exposure to IL-22 activated STAT3 and upregulation of STAT3-inducible Socs3, Bcl3, and STEAP4 was evident under those conditions. As these observations supported the hypothesis that IL-22 may exert protective functions in toxic ß-cell injury, application of IL-22 was investigated in murine multiple-low-dose streptozotocin (STZ-induced diabetes. For that purpose, recombinant IL-22 was administered thrice either immediately before and at disease onset (at d4, d6, d8 or closely thereafter (at d8, d10, d12. These two IL-22-treatment periods coincide with two early peaks of ß-cell injury detectable in this model. Notably, none of the two IL-22-treatment strategies affected diabetes incidence or blood glucose levels in STZ-treated mice. Moreover, pathological changes in islet morphology analyzed 28 days after disease induction were not ameliorated by IL-22 administration. Taken together, despite being active on rat RINm5F insulinoma cells and murine pancreatic islets, recombinant IL-22 fails to protect pancreatic ß-cells in the tested protocols from toxic effects of STZ and thus is unable to ameliorate disease in the widely used model of STZ-induced diabetes.

  8. Fiber-Mediated Nourishment of Gut Microbiota Protects against Diet-Induced Obesity by Restoring IL-22-Mediated Colonic Health.

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    Zou, Jun; Chassaing, Benoit; Singh, Vishal; Pellizzon, Michael; Ricci, Matthew; Fythe, Michael D; Kumar, Matam Vijay; Gewirtz, Andrew T

    2018-01-10

    Dietary supplementation with fermentable fiber suppresses adiposity and the associated parameters of metabolic syndrome. Microbiota-generated fiber-derived short-chain fatty acids (SCFAs) and free fatty acid receptors including GPR43 are thought to mediate these effects. We find that while fermentable (inulin), but not insoluble (cellulose), fiber markedly protected mice against high-fat diet (HFD)-induced metabolic syndrome, the effect was not significantly impaired by either inhibiting SCFA production or genetic ablation of GPR43. Rather, HFD decimates gut microbiota, resulting in loss of enterocyte proliferation, leading to microbiota encroachment, low-grade inflammation (LGI), and metabolic syndrome. Enriching HFD with inulin restored microbiota loads, interleukin-22 (IL-22) production, enterocyte proliferation, and antimicrobial gene expression in a microbiota-dependent manner, as assessed by antibiotic and germ-free approaches. Inulin-induced IL-22 expression, which required innate lymphoid cells, prevented microbiota encroachment and protected against LGI and metabolic syndrome. Thus, fermentable fiber protects against metabolic syndrome by nourishing microbiota to restore IL-22-mediated enterocyte function. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. IL-22R Ligands IL-20, IL-22, and IL-24 Promote Wound Healing in Diabetic db/db Mice.

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    Kolumam, Ganesh; Wu, Xiumin; Lee, Wyne P; Hackney, Jason A; Zavala-Solorio, Jose; Gandham, Vineela; Danilenko, Dimitry M; Arora, Puneet; Wang, Xiaoting; Ouyang, Wenjun

    2017-01-01

    Diabetic foot ulcers (DFU) are one of the major complications in type II diabetes patients and can result in amputation and morbidity. Although multiple approaches are used clinically to help wound closure, many patients still lack adequate treatment. Here we show that IL-20 subfamily cytokines are upregulated during normal wound healing. While there is a redundant role for each individual cytokine in this subfamily in wound healing, mice deficient in IL-22R, the common receptor chain for IL-20, IL-22, and IL-24, display a significant delay in wound healing. Furthermore, IL-20, IL-22 and IL-24 are all able to promote wound healing in type II diabetic db/db mice. Mechanistically, when compared to other growth factors such as VEGF and PDGF that accelerate wound healing in this model, IL-22 uniquely induced genes involved in reepithelialization, tissue remodeling and innate host defense mechanisms from wounded skin. Interestingly, IL-22 treatment showed superior efficacy compared to PDGF or VEGF in an infectious diabetic wound model. Taken together, our data suggest that IL-20 subfamily cytokines, particularly IL-20, IL-22, and IL-24, might provide therapeutic benefit for patients with DFU.

  10. Intestinal Epithelial Cell Tyrosine Kinase 2 Transduces IL-22 Signals To Protect from Acute Colitis.

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    Hainzl, Eva; Stockinger, Silvia; Rauch, Isabella; Heider, Susanne; Berry, David; Lassnig, Caroline; Schwab, Clarissa; Rosebrock, Felix; Milinovich, Gabriel; Schlederer, Michaela; Wagner, Michael; Schleper, Christa; Loy, Alexander; Urich, Tim; Kenner, Lukas; Han, Xiaonan; Decker, Thomas; Strobl, Birgit; Müller, Mathias

    2015-11-15

    In the intestinal tract, IL-22 activates STAT3 to promote intestinal epithelial cell (IEC) homeostasis and tissue healing. The mechanism has remained obscure, but we demonstrate that IL-22 acts via tyrosine kinase 2 (Tyk2), a member of the Jak family. Using a mouse model for colitis, we show that Tyk2 deficiency is associated with an altered composition of the gut microbiota and exacerbates inflammatory bowel disease. Colitic Tyk2(-/-) mice have less p-STAT3 in colon tissue and their IECs proliferate less efficiently. Tyk2-deficient primary IECs show reduced p-STAT3 in response to IL-22 stimulation, and expression of IL-22-STAT3 target genes is reduced in IECs from healthy and colitic Tyk2(-/-) mice. Experiments with conditional Tyk2(-/-) mice reveal that IEC-specific depletion of Tyk2 aggravates colitis. Disease symptoms can be alleviated by administering high doses of rIL-22-Fc, indicating that Tyk2 deficiency can be rescued via the IL-22 receptor complex. The pivotal function of Tyk2 in IL-22-dependent colitis was confirmed in Citrobacter rodentium-induced disease. Thus, Tyk2 protects against acute colitis in part by amplifying inflammation-induced epithelial IL-22 signaling to STAT3. Copyright © 2015 by The American Association of Immunologists, Inc.

  11. Interleukin (IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17

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    Muñoz, Melba; Heimesaat, Markus M; Danker, Kerstin

    2009-01-01

    Peroral infection with Toxoplasma gondii leads to the development of small intestinal inflammation dependent on Th1 cytokines. The role of Th17 cells in ileitis is unknown. We report interleukin (IL)-23-mediated gelatinase A (matrixmetalloproteinase [MMP]-2) up-regulation in the ileum of infected...... mice. MMP-2 deficiency as well as therapeutic or prophylactic selective gelatinase blockage protected mice from the development of T. gondii-induced immunopathology. Moreover, IL-23-dependent up-regulation of IL-22 was essential for the development of ileitis, whereas IL-17 was down...

  12. Endogenous IL-22 Plays a Dual Role in Arthritis: Regulation of Established Arthritis via IFN-γ Responses

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    Justa, Shivali; Zhou, Xiaoqun; Sarkar, Sujata

    2014-01-01

    Objective IL-22 is elevated in patients with inflammatory arthritis and correlates with disease activity. IL-22 deficient mice have reduced incidence of arthritis. Recombinant IL-22 restrains progression of arthritis via increase in IL-10 responses when administered prior to onset of arthritis. These findings imply a possible dual role of IL-22 in inflammatory arthritis depending on the phase of arthritis. Experiments outlined here were designed to elucidate the contribution of endogenous IL-22 before and after the onset of arthritis. Methods Collagen induced arthritis (CIA) was induced in DBA1 or IFN-γ deficient mice following immunization with collagen and complete Freund's adjuvant. Anti-IL-22 antibody or isotype control were administered prior to or after onset of arthritis and disease progression assessed by clinical scoring and histopathology. IL-22, IL-17 and IFN-γ responses were measured by ELISA and flowcytometry. Anti-collagen antibody responses were analyzed by ELISA. Expression of IL-22R1 in CD4+ cells was elucidated by flowcytometry and real time PCR. Results Collagen specific IL-22 responses were expanded during arthritis and IL-22 producing cells were discrete from IL-17 or IFN-γ producing cells. Neutralization of IL-22 after onset of arthritis resulted in significant increase in Th1 responses and significantly reduced severity of arthritis. CD4+ cells from arthritic mice showed increased surface expression of IL-22R1. In vitro, CD4+T cells cultured with antigen presenting cells in the presence or absence of IL-22 suppressed or induced IFN-γ, respectively. The protective effect of anti-IL-22 was reversed in IFN-γ deficient mice. Moreover, administration of anti-IL-22 prior to onset of arthritis augmented arthritis severity. Conclusion We show for the first time that IL-22 plays a dual role: protective prior to the onset of arthritis and pathogenic after onset of arthritis. The pathogenic effect of IL-22 is dependent on suppression of IFN

  13. Lacrimal gland-derived IL-22 regulates IL-17-mediated ocular mucosal inflammation

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    Ji, Yong Woo; Mittal, Sharad K.; Hwang, Ho Sik; Chang, Eun-Ju; Lee, Joon H.; Seo, Yuri; Yeo, Areum; Noh, Hyemi; Lee, Hye Sun; Chauhan, Sunil K.; Lee, Hyung Keun

    2016-01-01

    Inflammatory damage of mucosal surface of the eye is a hallmark of dry eye disease (DED), and in severe cases can lead to significant discomfort, visual impairment, and blindness. DED is a multifactorial autoimmune disorder with a largely unknown pathogenesis. Using a cross-sectional patient study and a well-characterized murine model of DED, herein we investigated the immunoregulatory function of interleukin-22 (IL-22) in the pathogenesis of DED. We found that IL-22 levels were elevated in lacrimal fluids of DED patients and inversely correlated with severity of disease. Acinar cells of the lacrimal glands, not inflammatory immune cells, are the primary source of IL-22, which suppresses inflammation in ocular surface epithelial cells upon desiccating stress. Moreover, loss of function analyses using IL-22 knock-out mice demonstrated that IL-22 is essential for suppression of ocular surface infiltration of Th17 cells and inhibition of DED induction. Our novel findings elucidate immunoregulatory function of lacrimal gland-derived IL-22 in inhibiting IL-17-mediated ocular surface epitheliopathy in DED thus making IL-22 a new relevant therapeutic target. PMID:28051088

  14. IL-22: An Evolutionary Missing-Link Authenticating the Role of the Immune System in Tissue Regeneration

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    Pawan Kumar, Kamalakannan Rajasekaran, Jeanne M Palmer, Monica S Thakar, Subramaniam Malarkannan

    2013-01-01

    Full Text Available Tissue regeneration is a critical component of organ maintenance. The ability of lymphocytes to kill pathogen-infected cells has been well-studied. However, the necessity for lymphocytes to participate in reconstruction of destroyed tissues has not been explored until recently. Interleukin (IL-22, a newly defined cytokine exclusively produced by subsets of lymphocytes, provides the strongest proof yet for the tissue regenerative potentials of the immune system. IL-22 plays an obligatory role in epithelial homeostasis in the gut, liver and lung. The receptor for IL-22 (IL-22R1 and IL-10R2 is predominantly expressed by epithelial cells. While the pro-inflammatory effect is questioned, the pro-constructive potential of IL-22 is well established. It is evident from the response to IL-22, that epithelial cells not only produce anti-microbial peptides but also actively proliferate. Aryl hydrocarbon receptor (AhR and retinoic acid-related orphan receptor (RORγt transcription factor are required for IL-22 generation from Lymphoid Tissue inducer cells LTi, Th22 and NK-like cells. However, IL-22 production from conventional NK cells is independent of AhR and RORγt. In this review, we present a case for a paradigm shift in how we define the function of the immune system. This would include tissue regeneration as a legitimate immune function.

  15. Differentiation, distribution and gammadelta T cell-driven regulation of IL-22-producing T cells in tuberculosis.

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    Shuyu Yao

    2010-02-01

    Full Text Available Differentiation, distribution and immune regulation of human IL-22-producing T cells in infections remain unknown. Here, we demonstrated in a nonhuman primate model that M. tuberculosis infection resulted in apparent increases in numbers of T cells capable of producing IL-22 de novo without in vitro Ag stimulation, and drove distribution of these cells more dramatically in lungs than in blood and lymphoid tissues. Consistently, IL-22-producing T cells were visualized in situ in lung tuberculosis (TB granulomas by confocal microscopy and immunohistochemistry, indicating that mature IL-22-producing T cells were present in TB granuloma. Surprisingly, phosphoantigen HMBPP activation of Vgamma2Vdelta2 T cells down-regulated the capability of T cells to produce IL-22 de novo in lymphocytes from blood, lung/BAL fluid, spleen and lymph node. Up-regulation of IFNgamma-producing Vgamma2Vdelta2 T effector cells after HMBPP stimulation coincided with the down-regulated capacity of these T cells to produce IL-22 de novo. Importantly, anti-IFNgamma neutralizing Ab treatment reversed the HMBPP-mediated down-regulation effect on IL-22-producing T cells, suggesting that Vgamma2Vdelta2 T-cell-driven IFNgamma-networking function was the mechanism underlying the HMBPP-mediated down-regulation of the capability of T cells to produce IL-22. These novel findings raise the possibility to ultimately investigate the function of IL-22 producing T cells and to target Vgamma2Vdelta2 T cells for balancing potentially hyper-activating IL-22-producing T cells in severe TB.

  16. TL1A increases expression of CD25, LFA-1, CD134 and CD154, and induces IL-22 and GM-CSF production from effector CD4 T-cells

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    Reichwald, Kirsten; Jørgensen, Tina Z.; Skov, Søren

    2014-01-01

    Elevated levels of the cytokine TL1A is associated with several autoimmune diseases e.g. rheumatoid arthritis and inflammatory bowel disease. However, the exact role of TL1A remains elusive. In this study, we investigated the function of TL1A in a pro-inflammatory setting. We show that TL1A toget...... of CD25 (IL-2Rα) and CD11a (α-chain of LFA-1) on CD4 T-cells, likely governing increased IL-2/IL-15 sensitivity and cell-cell contact. Along with this, TL1A co-stimulation caused a specific induction of IL-22 and GM-CSF from the activated T-cells. These results substantially contribute...

  17. Polycyclic aromatic hydrocarbons reciprocally regulate IL-22 and IL-17 cytokines in peripheral blood mononuclear cells from both healthy and asthmatic subjects.

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    Coline Plé

    Full Text Available Pollution, including polycyclic aromatic hydrocarbons (PAH, may contribute to increased prevalence of asthma. PAH can bind to the Aryl hydrocarbon Receptor (AhR, a transcription factor involved in Th17/Th22 type polarization. These cells produce IL17A and IL-22, which allow neutrophil recruitment, airway smooth muscle proliferation and tissue repair and remodeling. Increased IL-17 and IL-22 productions have been associated with asthma. We hypothesized that PAH might affect, through their effects on AhR, IL-17 and IL-22 production in allergic asthmatics. Activated peripheral blood mononuclear cells (PBMCs from 16 nonallergic nonasthmatic (NA and 16 intermittent allergic asthmatic (AA subjects were incubated with PAH, and IL-17 and IL-22 productions were assessed. At baseline, activated PBMCs from AA exhibited an increased IL-17/IL-22 profile compared with NA subjects. Diesel exhaust particle (DEP-PAH and Benzo[a]Pyrene (B[a]P stimulation further increased IL-22 but decreased IL-17A production in both groups. The PAH-induced IL-22 levels in asthmatic patients were significantly higher than in healthy subjects. Among PBMCs, PAH-induced IL-22 expression originated principally from single IL-22- but not from IL-17- expressing CD4 T cells. The Th17 transcription factors RORA and RORC were down regulated, whereas AhR target gene CYP1A1 was upregulated. IL-22 induction by DEP-PAH was mainly dependent upon AhR whereas IL-22 induction by B[a]P was dependent upon activation of PI3K and JNK. Altogether, these data suggest that DEP-PAH and B[a]P may contribute to increased IL22 production in both healthy and asthmatic subjects through mechanisms involving both AhR -dependent and -independent pathways.

  18. SOCS3 inhibits the pathological effects of IL-22 in non-melanoma skin tumor-derived keratinocytes.

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    Madonna, Stefania; Scarponi, Claudia; Morelli, Martina; Sestito, Rosanna; Scognamiglio, Pasqualina Liana; Marasco, Daniela; Albanesi, Cristina

    2017-04-11

    Basal cell carcinomas (BCC) and squamous-cell carcinomas (SCC) are common malignancies in humans, caused by neoplastic transformation of keratinocytes of the basal or suprabasal layers of epidermis, respectively. Tumor-infiltrating lymphocytes (TILs) are frequently found in BCC and SCC, and functionally promote epithelial carcinogenesis. TILs secreting IL-22, in particular, participate to BCC and SCC growth by inducing keratinocyte proliferation and migration, as well as the expression of inflammatory, anti-apoptotic and pro-angiogenic genes.In this study, we identified SOCS3 as a valid candidate to be manipulated for suppressing tumorigenic functions in BCC and SCC. We found that SOCS3 and SOCS1 expression was reduced in vivo, in tumor lesions of BCC and SCC, as compared to other skin inflammatory conditions such as psoriasis, despite the high number of IL-22-secreting TILs. Moreover, IL-22 was not able to induce in vitro the transcriptional expression of SOCS3 in BCC-or SCC-derived keratinocytes, contrarily to healthy cells. Aimed at rescuing SOCS3 activity in these tumor contexts, a SOCS3-derived peptide, named KIR-ESS, was synthesized, and its ability in suppressing IL-22-induced responses was evaluated in healthy and transformed keratinocytes. We found that KIR-ESS peptide efficiently suppressed the IL-22 molecular signaling in keratinocytes, by acting on STAT3 and Erk1/2 cascade, as well as on the expression of STAT3-dependent downstream genes. Interestingly, after treatment with peptide, both healthy and transformed keratinocytes could no longer aberrantly proliferate and migrate in response to IL-22. Finally, treatment of athymic nude mice bearing SCC xenografts with KIR-ESS peptide concomitantly reduced tumor growth and activated STAT3 levels. As a whole, these data provides the rationale for the use in BCC and SCC skin tumors of SOCS3 mimetics, being able to inhibit the deleterious effects of IL-22 in these contexts.

  19. Gene expression profiling of the Notch-AhR-IL22 axis at homeostasis and in response to tissue injury.

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    Weidenbusch, Marc; Rodler, Severin; Song, Shangqing; Romoli, Simone; Marschner, Julian A; Kraft, Franziska; Holderied, Alexander; Kumar, Santosh; Mulay, Shrikant R; Honarpisheh, Mohsen; Kumar Devarapu, Satish; Lech, Maciej; Anders, Hans-Joachim

    2017-12-22

    Notch and interleukin-22 (IL-22) signaling are known to regulate tissue homeostasis and respond to injury in humans and mice, and the induction of endogenous aryl hydrocarbon receptor (Ahr) ligands through Notch links the two pathways in a hierarchical fashion. However in adults, the species-, organ- and injury-specific gene expression of the Notch-AhR-IL22 axis components is unknown. We therefore performed gene expression profiling of DLL1, DLL3, DLL4, DLK1, DLK2, JAG1, JAG2, Notch1, Notch2, Notch3, Notch4, ADAM17/TNF-α ADAM metalloprotease converting enzyme (TACE), PSEN1, basigin (BSG)/CD147, RBP-J, HES1, HES5, HEY1, HEYL, AHR, ARNT, ARNT2, CYP1A1, CYP24A1, IL-22, IL22RA1, IL22RA2, IL10RB, and STAT3 under homeostatic conditions in ten mature murine and human organs. Additionally, the expression of these genes was assessed in murine models of acute sterile inflammation and progressive fibrosis. We show that there are organ-specific gene expression profiles of the Notch-AhR-IL22 axis in humans and mice. Although there is an overall interspecies congruency, specific differences between human and murine expression signatures do exist. In murine tissues with AHR/ARNT expression CYP1A1 and IL-22 were correlated with HES5 and HEYL expression, while in human tissues no such correlation was found. Notch and AhR signaling are involved in renal inflammation and fibrosis with specific gene expression changes in each model. Despite the presence of all Notch pathway molecules in the kidney and a model-specific induction of Notch ligands, IL-22 was only up-regulated in acute inflammation, but rapidly down-regulated during regeneration. This implies that for targeting injury responses, e.g. via IL-22, species-specific differences, injury type and time points have to be considered. © 2017 The Author(s).

  20. IL-22 Upregulates Epithelial Claudin-2 to Drive Diarrhea and Enteric Pathogen Clearance.

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    Tsai, Pei-Yun; Zhang, Bingkun; He, Wei-Qi; Zha, Juan-Min; Odenwald, Matthew A; Singh, Gurminder; Tamura, Atsushi; Shen, Le; Sailer, Anne; Yeruva, Sunil; Kuo, Wei-Ting; Fu, Yang-Xin; Tsukita, Sachiko; Turner, Jerrold R

    2017-06-14

    Diarrhea is a host response to enteric pathogens, but its impact on pathogenesis remains poorly defined. By infecting mice with the attaching and effacing bacteria Citrobacter rodentium, we defined the mechanisms and contributions of diarrhea and intestinal barrier loss to host defense. Increased permeability occurred within 2 days of infection and coincided with IL-22-dependent upregulation of the epithelial tight junction protein claudin-2. Permeability increases were limited to small molecules, as expected for the paracellular water and Na + channel formed by claudin-2. Relative to wild-type, claudin-2-deficient mice experienced severe disease, including increased mucosal colonization by C. rodentium, prolonged pathogen shedding, exaggerated cytokine responses, and greater tissue injury. Conversely, transgenic claudin-2 overexpression reduced disease severity. Chemically induced osmotic diarrhea reduced colitis severity and C. rodentium burden in claudin-2-deficient, but not transgenic, mice, demonstrating that claudin-2-mediated protection is the result of enhanced water efflux. Thus, IL-22-induced claudin-2 upregulation drives diarrhea and pathogen clearance. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Interleukin-22 (IL-22) Gingival Gene Expression and GCF Concentration in Periodontal Health and Disease

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    Amini Behbahani A; Sattari M; Mofid R; Ganji A

    2014-01-01

    IL-22 is a cytokine that is assumed to improve anti-microbial defense of epidermal and epithelial cells and the cells of gastrointestinal and respiratory systems. With respect to absence of enough relevant articles in this regard the aim of this study was to evaluate the correlation between IL-22 gene expression in gingival tissues as well as its concentration in GCF and periodontal diseases. Gingival samples obtained from 60 patients of three different groups (healthy, gingivitis and chronic...

  2. The Secretion of IL-22 from Mucosal NKp44+ NK Cells Is Associated with Microbial Translocation and Virus Infection in SIV/SHIV-Infected Chinese Macaques

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    Wei Wang

    2014-01-01

    Full Text Available Microbial translocation (MT causes systemic immune activation in chronic human immunodeficiency virus (HIV infection. The role of a novel subtype of innate lymphoid cells, the NKp44+ NK cells, in HIV/simian immunodeficiency virus- (SIV- induced MT remains unknown. In this study, 12 simian-human immunodeficiency virus- (SHIV- infected macaques were chosen and split into two groups based on the MT level. Blood and Peripheral lymphoid tissue were sampled for flow cytometric analysis, viral load detection, and interleukin testing. Then, six naive Chinese macaques were used to determine the dynamics of cytokine secretion from mucosal NKp44+ NK cells in different phases of SIV infection. As a result, the degranulation capacity and IL-22 production of mucosal NKp44+ NK cells were associated with the MT level in the SHIV-infected macaques. And the number of mucosal NKp44+ NK cells and IL-22 secretion by these cells were lower in the chronic phase than in the early acute phase of SIV infection. The number of mucosal NKp44+ NK cells and interleukin-22 (IL-22 secretion by these cells increased before MT occurred. Therefore, we conclude that a decline in IL-22 production from mucosal NKp44+ NK cells induced by virus infection may be one of the causes of microbial translocation in HIV/SIV infection.

  3. Pro-inflammatory signaling by IL-10 and IL-22: bad habit stirred up by interferons ?

    Directory of Open Access Journals (Sweden)

    Heiko eMühl

    2013-02-01

    Full Text Available Interleukin (IL-10 and IL-22 are key members of the IL-10 cytokine family that share characteristic properties such as defined structural features, usage of IL-10R2 as one receptor chain, and activation of signal transducer and activator of transcription (STAT-3 as dominant signaling mode. IL-10, formerly known as cytokine synthesis inhibitory factor, is key to deactivation of monocytes/macrophages and dendritic cells. Accordingly, pre-clinical studies document its anti-inflammatory capacity. However, the outcome of clinical trials assessing the therapeutic potential of IL-10 in prototypic inflammatory disorders has been disappointing. In contrast to IL-10, IL-22 acts primarily on non-leukocytic cells, in particular epithelial cells of intestine, skin, liver, and lung. STAT3-driven proliferation, anti-apoptosis, and anti-microbial tissue protection is regarded a principal function of IL-22 at host/environment interfaces. In this hypothesis article, hidden/underappreciated pro-inflammatory characteristics of IL-10 and IL-22 are outlined and related to cellular priming by type I interferon. It is tempting to speculate that an inherent inflammatory potential of IL-10 and IL-22 confines their usage in tissue protective therapy and beyond that determines in some patients efficacy of type I interferon treatment.

  4. IL-22 Defect During Streptococcus pneumoniae Infection Triggers Exacerbation of Chronic Obstructive Pulmonary Disease

    Directory of Open Access Journals (Sweden)

    Muriel Pichavant

    2015-11-01

    Full Text Available Progression of chronic obstructive pulmonary disease (COPD is linked to episodes of exacerbations caused by bacterial infections due to Streptococcus pneumoniae. Our objective was to identify during COPD, factors of susceptibility to bacterial infections among cytokine network and their role in COPD exacerbations. S. pneumoniae was used to sub-lethally challenge mice chronically exposed to air or cigarette smoke (CS and to stimulate peripheral blood mononuclear cells (PBMC from non-smokers, smokers and COPD patients. The immune response and the cytokine production were evaluated. Delayed clearance of the bacteria and stronger lung inflammation observed in infected CS-exposed mice were associated with an altered production of IL-17 and IL-22 by innate immune cells. This defect was related to a reduced production of IL-1β and IL-23 by antigen presenting cells. Importantly, supplementation with recombinant IL-22 restored bacterial clearance in CS-exposed mice and limited lung alteration. In contrast with non-smokers, blood NK and NKT cells from COPD patients failed to increase IL-17 and IL-22 levels in response to S. pneumoniae, in association with a defect in IL-1β and IL-23 secretion. This study identified IL-17 and IL-22 as susceptibility factors in COPD exacerbation. Therefore targeting such cytokines could represent a potent strategy to control COPD exacerbation.

  5. IL-22 and IDO1 Affect Immunity and Tolerance to Murine and Human Vaginal Candidiasis

    Science.gov (United States)

    De Luca, Antonella; Carvalho, Agostinho; Cunha, Cristina; Iannitti, Rossana G.; Pitzurra, Lucia; Giovannini, Gloria; Mencacci, Antonella; Bartolommei, Lorenzo; Moretti, Silvia; Massi-Benedetti, Cristina; Fuchs, Dietmar; De Bernardis, Flavia; Puccetti, Paolo; Romani, Luigina

    2013-01-01

    The ability to tolerate Candida albicans, a human commensal of the gastrointestinal tract and vagina, implicates that host defense mechanisms of resistance and tolerance cooperate to limit fungal burden and inflammation at the different body sites. We evaluated resistance and tolerance to the fungus in experimental and human vulvovaginal candidiasis (VVC) as well as in recurrent VVC (RVVC). Resistance and tolerance mechanisms were both activated in murine VVC, involving IL-22 and IL-10-producing regulatory T cells, respectively, with a major contribution by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 was responsible for the production of tolerogenic kynurenines, such that replacement therapy with kynurenines restored immunoprotection to VVC. In humans, two functional genetic variants in IL22 and IDO1 genes were found to be associated with heightened resistance to RVVC, and they correlated with increased local expression of IL-22, IDO1 and kynurenines. Thus, IL-22 and IDO1 are crucial in balancing resistance with tolerance to Candida, their deficiencies are risk factors for RVVC, and targeting tolerance via therapeutic kynurenines may benefit patients with RVVC. PMID:23853597

  6. IL-22 is mainly produced by IFNγ-secreting cells but is dispensable for host protection against Mycobacterium tuberculosis infection.

    Directory of Open Access Journals (Sweden)

    Jochen Behrends

    Full Text Available Anti-inflammatory treatment of autoimmune diseases is associated with an increased risk of reactivation tuberculosis (TB. Besides interleukin (IL-17A, IL-22 represents a classical T helper (TH17 cytokine and shares similar pathological effects in inflammatory diseases such as psoriasis or arthritis. Whereas IL-17A supports protective immune responses during mycobacterial infections, the role of IL-22 after infection with Mycobacterium tuberculosis (Mtb is yet poorly characterized. Therefore, we here characterize the cell types producing IL-22 and the protective function of this cytokine during experimental TB in mice. Like IL-17A, IL-22 is expressed early after infection with Mtb in an IL-23-dependent manner. Surprisingly, the majority of IL-22-producing cells are not positive for IL-17A but have rather functional characteristics of interferon-gamma-producing TH1 cells. Although we found minor differences in the number of naive and central memory T cells as well as in the frequency of TH1 and polyfunctional T cells in mice deficient for IL-22, the absence of IL-22 does not affect the outcome of Mtb infection. Our study revealed that although produced by TH1 cells, IL-22 is dispensable for protective immune responses during TB. Therefore, targeting of IL-22 in inflammatory disease may represent a therapeutic approach that does not incur the danger of reactivation TB.

  7. The balance between IL-17 and IL-22 produced by liver-infiltrating T-helper cells critically controls NASH development in mice.

    Science.gov (United States)

    Rolla, Simona; Alchera, Elisa; Imarisio, Chiara; Bardina, Valentina; Valente, Guido; Cappello, Paola; Mombello, Cristina; Follenzi, Antonia; Novelli, Francesco; Carini, Rita

    2016-02-01

    The mechanisms responsible for the evolution of steatosis towards NASH (non-alcoholic steatohepatitis) and fibrosis are not completely defined. In the present study we evaluated the role of CD4(+) T-helper (Th) cells in this process. We analysed the infiltration of different subsets of CD4(+) Th cells in C57BL/6 mice fed on a MCD (methionine choline-deficient) diet, which is a model reproducing all phases of human NASH progression. There was an increase in Th17 cells at the beginning of NASH development and at the NASH-fibrosis transition, whereas levels of Th22 cells peaked between the first and the second expansion of Th17 cells. An increase in the production of IL (interleukin)-6, TNFα (tumour necrosis factor α), TGFβ (transforming growth factor β) and CCL20 (CC chemokine ligand 20) accompanied the changes in Th17/Th22 cells. Livers of IL-17(-/-) mice were protected from NASH development and characterized by an extensive infiltration of Th22 cells. In vitro, IL-17 exacerbated the JNK (c-Jun N-terminal kinase)-dependent mouse hepatocyte lipotoxicity induced by palmitate. IL-22 prevented lipotoxicity through PI3K (phosphoinositide 3-kinase)-mediated inhibition of JNK, but did not play a protective role in the presence of IL-17, which up-regulated the PI3K/Akt inhibitor PTEN (phosphatase and tensin homologue deleted on chromosome 10). Consistently, livers of IL-17(-/-) mice fed on the MCD diet displayed decreased activation of JNK, reduced expression of PTEN and increased phosphorylation of Akt compared with livers of wild-type mice. Hepatic infiltration of Th17 cells is critical for NASH initiation and development of fibrosis in mice, and reflects an infiltration of Th22 cells. Th22 cells are protective in NASH, but only in the absence of IL-17. These data strongly support the potentiality of clinical applications of IL-17 inhibitors that can prevent NASH by both abolishing the lipotoxic action of IL-17 and allowing IL-22-mediated protection. © 2016 Authors

  8. Loss of Dok-1 and Dok-2 in mice causes severe experimental colitis accompanied by reduced expression of IL-17A and IL-22

    International Nuclear Information System (INIS)

    Waseda, Masazumi; Arimura, Sumimasa; Shimura, Eri; Nakae, Susumu; Yamanashi, Yuji

    2016-01-01

    Appropriate immune responses and mucosal barrier functions are required for the maintenance of intestinal homeostasis. Defects in this defense system may lead to inflammatory disorders such as inflammatory bowel disease. Downstream of tyrosine kinases 1 (Dok-1) and its closest homolog, Dok-2, are preferentially expressed in immune cells, and play essential roles in the negative regulation of multiple signaling pathways in both innate and adaptive immunity. However, the function of these proteins in intestinal homeostasis remained unclear. Here we show that Dok-1/-2 double knockout (DKO) mice were highly susceptible to dextran sodium sulfate (DSS)-induced colitis compared with Dok-1 or Dok-2 single KO and wild type (WT) mice. Furthermore, DSS-treated Dok-1/-2 DKO mice exhibited increased colonic tissue damage accompanied by reduced proliferation of the epithelial cells relative to WT controls, suggesting that Dok-1/-2 DKO mice have defects in the repair of intestinal epithelial lesions. In addition, the levels of the Th17 cytokines IL-17A and IL-22, which have protective roles in DSS-induced colitis, were reduced in DSS-treated Dok-1/-2 DKO mice compared with WT mice. Taken together, our results demonstrate that Dok-1 and Dok-2 negatively regulate intestinal inflammation, apparently through the induction of IL-17A and IL-22 expression. - Highlights: • Dok-1 and Dok-2 play a cooperative role in protection against DSS-induced colitis. • Dok-1/-2 double KO (DKO) mice show extensive ulceration of the colon after DSS treatment. • Proliferation of colonic epithelium is inhibited in DSS-treated Dok-1/-2 DKO mice. • Expression of IL-17A and IL-22 is reduced in the colon of DSS-treated Dok-1/-2 DKO mice.

  9. Loss of Dok-1 and Dok-2 in mice causes severe experimental colitis accompanied by reduced expression of IL-17A and IL-22

    Energy Technology Data Exchange (ETDEWEB)

    Waseda, Masazumi; Arimura, Sumimasa [Division of Genetics, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, 108-8639 (Japan); Shimura, Eri [Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, 108-8639 (Japan); Nakae, Susumu [Laboratory of Systems Biology, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, 108-8639 (Japan); Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Saitama, 332-0012 (Japan); Yamanashi, Yuji, E-mail: yyamanas@ims.u-tokyo.ac.jp [Division of Genetics, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, 108-8639 (Japan)

    2016-09-09

    Appropriate immune responses and mucosal barrier functions are required for the maintenance of intestinal homeostasis. Defects in this defense system may lead to inflammatory disorders such as inflammatory bowel disease. Downstream of tyrosine kinases 1 (Dok-1) and its closest homolog, Dok-2, are preferentially expressed in immune cells, and play essential roles in the negative regulation of multiple signaling pathways in both innate and adaptive immunity. However, the function of these proteins in intestinal homeostasis remained unclear. Here we show that Dok-1/-2 double knockout (DKO) mice were highly susceptible to dextran sodium sulfate (DSS)-induced colitis compared with Dok-1 or Dok-2 single KO and wild type (WT) mice. Furthermore, DSS-treated Dok-1/-2 DKO mice exhibited increased colonic tissue damage accompanied by reduced proliferation of the epithelial cells relative to WT controls, suggesting that Dok-1/-2 DKO mice have defects in the repair of intestinal epithelial lesions. In addition, the levels of the Th17 cytokines IL-17A and IL-22, which have protective roles in DSS-induced colitis, were reduced in DSS-treated Dok-1/-2 DKO mice compared with WT mice. Taken together, our results demonstrate that Dok-1 and Dok-2 negatively regulate intestinal inflammation, apparently through the induction of IL-17A and IL-22 expression. - Highlights: • Dok-1 and Dok-2 play a cooperative role in protection against DSS-induced colitis. • Dok-1/-2 double KO (DKO) mice show extensive ulceration of the colon after DSS treatment. • Proliferation of colonic epithelium is inhibited in DSS-treated Dok-1/-2 DKO mice. • Expression of IL-17A and IL-22 is reduced in the colon of DSS-treated Dok-1/-2 DKO mice.

  10. CD4(+) T cells producing interleukin (IL)-17, IL-22 and interferon-? are major effector T cells in nickel allergy

    DEFF Research Database (Denmark)

    Dyring Andersen, Beatrice; Skov, Lone; Løvendorf, Marianne B

    2013-01-01

    the frequencies of CD4(+) , CD8(+) and γδ T cells producing IL-17, IL-22 and interferon (IFN)-γ in the blood and skin from nickel-allergic patients. Patients/materials/methods Blood samples were collected from 14 patients and 17 controls, and analysed by flow cytometry. Biopsies were taken from 5 patients and 6......-allergic patients, there was massive cellular infiltration dominated by CD4(+) T cells producing IL-17, IL-22 and IFN-γ in nickel-challenged skin but not in vehicle-challenged skin. Conclusion CD4(+) T cells producing IL-17, IL-22 and IFN-γ are important effector cells in the eczematous reactions of nickel......Background It has been suggested that interleukin (IL)-17 and IL-22 play important roles in the elicitation of human allergic contact dermatitis; however, the frequencies of T cell subtypes producing IL-17 and IL-22 in human allergic contact dermatitis are unknown. Objectives To determine...

  11. Hes1 promotes the IL-22-mediated antimicrobial response by enhancing STAT3-dependent transcription in human intestinal epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Murano, Tatsuro [Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo (Japan); Okamoto, Ryuichi, E-mail: rokamoto.gast@tmd.ac.jp [Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo (Japan); Department of Advanced GI Therapeutics, Graduate School, Tokyo Medical and Dental University, Tokyo (Japan); Ito, Go; Nakata, Toru; Hibiya, Shuji; Shimizu, Hiromichi; Fujii, Satoru; Kano, Yoshihito; Mizutani, Tomohiro; Yui, Shiro; Akiyama-Morio, Junko; Nemoto, Yasuhiro [Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo (Japan); Tsuchiya, Kiichiro; Nakamura, Tetsuya [Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo (Japan); Department of Advanced GI Therapeutics, Graduate School, Tokyo Medical and Dental University, Tokyo (Japan); Watanabe, Mamoru [Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo (Japan)

    2014-01-17

    Highlights: •Hes1 enhances IL-22-STAT3 signaling in human intestinal epithelial cells. •Hes1 enhances REG family gene induction by IL-22-STAT3 signaling. •Protein level of Hes1 restricts the response to IL-22. •Present regulation of a cytokine signal represents a new mode of Hes1 function. -- Abstract: Notch signaling plays an essential role in the proliferation and differentiation of intestinal epithelial cells (IECs). We have previously shown that Notch signaling is up-regulated in the inflamed mucosa of ulcerative colitis (UC) and thereby plays an indispensable role in tissue regeneration. Here we show that in addition to Notch signaling, STAT3 signaling is highly activated in the inflamed mucosa of UC. Forced expression of the Notch target gene Hes1 dramatically enhanced the IL-22-mediated STAT3-dependent transcription in human IECs. This enhancement of STAT3-dependent transcription was achieved by the extended phosphorylation of STAT3 by Hes1. Microarray analysis revealed that Hes1-mediated enhancement of IL-22-STAT3 signaling significantly increased the induction of genes encoding antimicrobial peptides, such as REG1A, REG3A and REG3G, in human IECs. Conversely, the reduction of Hes1 protein levels with a γ-secretase inhibitor significantly down-regulated the induction of those genes in IECs, resulting in a markedly poor response to IL-22. Our present findings identify a new role for the molecular function of Hes1 in which the protein can interact with cytokine signals and regulate the immune response of IECs.

  12. Cytokines (interleukin-9, IL-17, IL-22, IL-25 and IL-33 and asthma

    Directory of Open Access Journals (Sweden)

    Rahim Farahani

    2014-01-01

    Full Text Available Asthma is a reversible airway obstruction that is characterized by constriction of airway smooth muscle, hyper secretion of mucus, edema and airway hyper responsiveness (AHR, mucus secretion and thickening of the basement membrane underlying the airway epithelium. During the process of airway inflammation, complex interactions of innate and adaptive immune cells as well as structural cells and their cytokines have many important roles. It was believed that airway inflammation is orchestrated by allergen specific T helper (Th 2 cells, which recruit and accumulate in the lungs and produce a range of different effector cytokines. However, more recent studies have revealed the potential collaboration of other helper T cells and their cytokines in this process. Th17 cell may have a role in severe asthma and chronic obstructive pulmonary disease (COPD. Interleukin (IL-9-producing subset called Th9 cell, Th22 cells which primarily secrete IL-22, IL-13 and tumor necrosis factor-α and Th25 cells via producing IL-25 are believed to be important for initiating allergic reactions and developing airway inflammation. Cytokines are important in asthma and play a critical role in orchestrating the allergic inflammatory response, although the precise role of each cytokine remains to be determined. The aim of this review is to summarize the current knowledge about the possible roles of newly identified helper T cells derived cytokines (IL-9, 17, 22, 25 and IL-33 in asthma. The potential therapeutic applications emerging from the roles of these cytokines will be discussed as well.

  13. Identification of cinnabarinic acid as a novel endogenous aryl hydrocarbon receptor ligand that drives IL-22 production.

    Directory of Open Access Journals (Sweden)

    Margaret M Lowe

    Full Text Available The aryl hydrocarbon receptor (AHR binds to environmental toxicants including synthetic halogenated aromatic hydrocarbons and is involved in a diverse array of biological processes. Recently, the AHR was shown to control host immunity by affecting the balance between inflammatory T cells that produce IL-17 (Th17 and IL-22 versus regulatory T cells (Treg involved in tolerance. While environmental AHR ligands can mediate this effect, endogenous ligands are likely to be more relevant in host immune responses. We investigated downstream metabolites of tryptophan as potential AHR ligands because (1 tryptophan metabolites have been implicated in regulating the balance between Th17 and Treg cells and (2 many of the AHR ligands identified thus far are derivatives of tryptophan. We characterized the ability of tryptophan metabolites to bind and activate the AHR and to increase IL-22 production in human T cells. We report that the tryptophan metabolite, cinnabarinic acid (CA, is an AHR ligand that stimulates the differentiation of human and mouse T cells producing IL-22. We compare the IL-22-stimulating activity of CA to that of other tryptophan metabolites and define stimulation conditions that lead to CA production from immune cells. Our findings link tryptophan metabolism to AHR activation and define a novel endogenous AHR agonist with potentially broad biological functions.

  14. Identification of cinnabarinic acid as a novel endogenous aryl hydrocarbon receptor ligand that drives IL-22 production.

    Science.gov (United States)

    Lowe, Margaret M; Mold, Jeff E; Kanwar, Bittoo; Huang, Yong; Louie, Alexander; Pollastri, Michael P; Wang, Cuihua; Patel, Gautam; Franks, Diana G; Schlezinger, Jennifer; Sherr, David H; Silverstone, Allen E; Hahn, Mark E; McCune, Joseph M

    2014-01-01

    The aryl hydrocarbon receptor (AHR) binds to environmental toxicants including synthetic halogenated aromatic hydrocarbons and is involved in a diverse array of biological processes. Recently, the AHR was shown to control host immunity by affecting the balance between inflammatory T cells that produce IL-17 (Th17) and IL-22 versus regulatory T cells (Treg) involved in tolerance. While environmental AHR ligands can mediate this effect, endogenous ligands are likely to be more relevant in host immune responses. We investigated downstream metabolites of tryptophan as potential AHR ligands because (1) tryptophan metabolites have been implicated in regulating the balance between Th17 and Treg cells and (2) many of the AHR ligands identified thus far are derivatives of tryptophan. We characterized the ability of tryptophan metabolites to bind and activate the AHR and to increase IL-22 production in human T cells. We report that the tryptophan metabolite, cinnabarinic acid (CA), is an AHR ligand that stimulates the differentiation of human and mouse T cells producing IL-22. We compare the IL-22-stimulating activity of CA to that of other tryptophan metabolites and define stimulation conditions that lead to CA production from immune cells. Our findings link tryptophan metabolism to AHR activation and define a novel endogenous AHR agonist with potentially broad biological functions.

  15. Interleukin 22 early affects keratinocyte differentiation, but not proliferation, in a three-dimensional model of normal human skin

    Energy Technology Data Exchange (ETDEWEB)

    Donetti, Elena, E-mail: elena.donetti@unimi.it [Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan (Italy); Cornaghi, Laura; Arnaboldi, Francesca; Landoni, Federica [Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan (Italy); Romagnoli, Paolo [Department of Experimental and Clinical Medicine, Università degli Studi di Firenze, 50125 Florence (Italy); Mastroianni, Nicolino [Department of Biomedical Sciences for Health, Università degli Studi di Milano, 20133 Milan (Italy); Pescitelli, Leonardo [Department of Surgery and Translational Medicine, Università degli Studi di Firenze, 50125 Florence (Italy); Baruffaldi Preis, Franz W. [I.R.C.C.S. Istituto Ortopedico Galeazzi, 20161 Milan (Italy); Prignano, Francesca [Department of Surgery and Translational Medicine, Università degli Studi di Firenze, 50125 Florence (Italy)

    2016-07-15

    Interleukin (IL)-22 is a pro-inflammatory cytokine driving the progression of the psoriatic lesion with other cytokines, as Tumor Necrosis Factor (TNF)-alpha and IL-17. Our study was aimed at evaluating the early effect of IL-22 alone or in combination with TNF-alpha and IL-17 by immunofluorescence on i) keratinocyte (KC) proliferation, ii) terminal differentiation biomarkers as keratin (K) 10 and 17 expression, iii) intercellular junctions. Transmission electron microscopy (TEM) analysis was performed. A model of human skin culture reproducing a psoriatic microenvironment was used. Plastic surgery explants were obtained from healthy young women (n=7) after informed consent. Fragments were divided before adding IL-22 or a combination of the three cytokines, and harvested 24 (T24), 48 (T48), and 72 (T72) h later. From T24, in IL-22 samples we detected a progressive decrease in K10 immunostaining in the spinous layer paralleled by K17 induction. By TEM, after IL-22 incubation, keratin aggregates were evident in the perinuclear area. Occludin immunostaining was not homogeneously distributed. Conversely, KC proliferation was not inhibited by IL-22 alone, but only by the combination of cytokines. Our results suggest that IL-22 affects keratinocyte terminal differentiation, whereas, in order to induce a proliferation impairment, a more complex psoriatic-like microenvironment is needed.

  16. Interleukin 22 early affects keratinocyte differentiation, but not proliferation, in a three-dimensional model of normal human skin

    International Nuclear Information System (INIS)

    Donetti, Elena; Cornaghi, Laura; Arnaboldi, Francesca; Landoni, Federica; Romagnoli, Paolo; Mastroianni, Nicolino; Pescitelli, Leonardo; Baruffaldi Preis, Franz W.; Prignano, Francesca

    2016-01-01

    Interleukin (IL)-22 is a pro-inflammatory cytokine driving the progression of the psoriatic lesion with other cytokines, as Tumor Necrosis Factor (TNF)-alpha and IL-17. Our study was aimed at evaluating the early effect of IL-22 alone or in combination with TNF-alpha and IL-17 by immunofluorescence on i) keratinocyte (KC) proliferation, ii) terminal differentiation biomarkers as keratin (K) 10 and 17 expression, iii) intercellular junctions. Transmission electron microscopy (TEM) analysis was performed. A model of human skin culture reproducing a psoriatic microenvironment was used. Plastic surgery explants were obtained from healthy young women (n=7) after informed consent. Fragments were divided before adding IL-22 or a combination of the three cytokines, and harvested 24 (T24), 48 (T48), and 72 (T72) h later. From T24, in IL-22 samples we detected a progressive decrease in K10 immunostaining in the spinous layer paralleled by K17 induction. By TEM, after IL-22 incubation, keratin aggregates were evident in the perinuclear area. Occludin immunostaining was not homogeneously distributed. Conversely, KC proliferation was not inhibited by IL-22 alone, but only by the combination of cytokines. Our results suggest that IL-22 affects keratinocyte terminal differentiation, whereas, in order to induce a proliferation impairment, a more complex psoriatic-like microenvironment is needed.

  17. Card9-dependent IL-1β regulates IL-22 production from group 3 innate lymphoid cells and promotes colitis-associated cancer.

    Science.gov (United States)

    Bergmann, Hanna; Roth, Susanne; Pechloff, Konstanze; Kiss, Elina A; Kuhn, Sabine; Heikenwälder, Mathias; Diefenbach, Andreas; Greten, Florian R; Ruland, Jürgen

    2017-08-01

    Inflammatory bowel diseases (IBD) are key risk factors for the development of colorectal cancer, but the mechanisms that link intestinal inflammation with carcinogenesis are insufficiently understood. Card9 is a myeloid cell-specific signaling protein that regulates inflammatory responses downstream of various pattern recognition receptors and which cooperates with the inflammasomes for IL-1β production. Because polymorphisms in Card9 were recurrently associated with human IBD, we investigated the function of Card9 in a colitis-associated cancer (CAC) model. Card9 -/- mice develop smaller, less proliferative and less dysplastic tumors compared to their littermates and in the regenerating mucosa we detected dramatically impaired IL-1β generation and defective IL-1β controlled IL-22 production from group 3 innate lymphoid cells. Consistent with the key role of immune-derived IL-22 in activating STAT3 signaling during normal and pathological intestinal epithelial cell (IEC) proliferation, Card9 -/- mice also exhibit impaired tumor cell intrinsic STAT3 activation. Our results imply a Card9-controlled, ILC3-mediated mechanism regulating healthy and malignant IEC proliferation and demonstrates a role of Card9-mediated innate immunity in inflammation-associated carcinogenesis. © 2017 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Global gene transcriptome analysis in vaccinated cattle revealed a dominant role of IL-22 for protection against bovine tuberculosis.

    Directory of Open Access Journals (Sweden)

    Sabin Bhuju

    2012-12-01

    Full Text Available Bovine tuberculosis (bTB is a chronic disease of cattle caused by Mycobacterium bovis, a member of the Mycobacterium tuberculosis complex group of bacteria. Vaccination of cattle might offer a long-term solution for controlling the disease and priority has been given to the development of a cattle vaccine against bTB. Identification of biomarkers in tuberculosis research remains elusive and the goal is to identify host correlates of protection. We hypothesized that by studying global gene expression we could identify in vitro predictors of protection that could help to facilitate vaccine development. Calves were vaccinated with BCG or with a heterologous BCG prime adenovirally vectored subunit boosting protocol. Protective efficacy was determined after M. bovis challenge. RNA was prepared from PPD-stimulated PBMC prepared from vaccinated-protected, vaccinated-unprotected and unvaccinated control cattle prior to M. bovis challenge and global gene expression determined by RNA-seq. 668 genes were differentially expressed in vaccinated-protected cattle compared with vaccinated-unprotected and unvaccinated control cattle. Cytokine-cytokine receptor interaction was the most significant pathway related to this dataset with IL-22 expression identified as the dominant surrogate of protection besides INF-γ. Finally, the expression of these candidate genes identified by RNA-seq was evaluated by RT-qPCR in an independent set of PBMC samples from BCG vaccinated and unvaccinated calves. This experiment confirmed the importance of IL-22 as predictor of vaccine efficacy.

  19. Defective IL-17- and IL-22-dependent mucosal host response to Candida albicans determines susceptibility to oral candidiasis in mice expressing the HIV-1 transgene.

    Science.gov (United States)

    Goupil, Mathieu; Cousineau-Côté, Vincent; Aumont, Francine; Sénéchal, Serge; Gaboury, Louis; Hanna, Zaher; Jolicoeur, Paul; de Repentigny, Louis

    2014-10-26

    The tissue-signaling cytokines IL-17 and IL-22 are critical to host defense against oral Candida albicans infection, by their induction of oral antimicrobial peptide expression and recruitment of neutrophils. Mucosal Th17 cells which produce these cytokines are preferentially depleted in HIV-infected patients. Here, we tested the hypothesis that defective IL-17- and IL-22-dependent host responses to C. albicans determine the phenotype of susceptibility to oropharyngeal candidiasis (OPC) in transgenic (Tg) mice expressing HIV-1. Naïve CD4+ T-cells and the differentiated Th1, Th2, Th17, Th1Th17 and Treg lineages were all profoundly depleted in cervical lymph nodes (CLNs) of these Tg mice. However, naive CD4+ cells from Tg mice maintained the capacity to differentiate into these lineages in response to polarizing cytokines in vitro. Expression of Il17, Il22, S100a8 and Ccl20 was enhanced in oral mucosal tissue of non-Tg, but not of Tg mice, after oral infection with C. albicans. Treatment of infected Tg mice with the combination of IL-17 and IL-22, but not IL-17 or Il-22 alone, significantly reduced oral burdens of C. albicans and abundance of Candida hyphae in the epithelium of tongues of infected Tg mice, and restored the ability of the Tg mice to up-regulate expression of S100a8 and Ccl20 in response to C. albicans infection. These findings demonstrate that defective IL-17- and IL-22-dependent induction of innate mucosal immunity to C. albicans is central to the phenotype of susceptibility to OPC in these HIV transgenic mice.

  20. Overrepresentation of IL-17A and IL-22 Producing CD8 T Cells in Lesional Skin Suggests Their Involvement in the Pathogenesis of Psoriasis

    NARCIS (Netherlands)

    Res, P.C.M.; Piskin, G.; de Boer, O.J.; van der Loos, C.M.; Teeling, P.; Bos, J.D.; Teunissen, M.B.M.

    2010-01-01

    Background: Although recent studies indicate a crucial role for IL-17A and IL-22 producing T cells in the pathogenesis of psoriasis, limited information is available on their frequency and heterogeneity and their distribution in skin in situ. Methodology/Principal Findings: By spectral imaging

  1. CD161+CD4+ T cells are enriched in the liver during chronic hepatitis and associated with co-secretion of IL-22 and Interferon-gamma

    Directory of Open Access Journals (Sweden)

    Yu-Hoi eKang

    2012-11-01

    Full Text Available Hepatitis C virus infection is a major cause of chronic liver disease. CD4+ T cells play a key role in disease outcome. However, the critical functions and associated phenotypes of intrahepatic CD4+ T cells are not well defined. We have previously shown that CD8+ T cells expressing the C type lectin CD161 are highly enriched in the human liver, especially during chronic hepatitis. These cells are associated with a type 17 differentiation pattern and express cytokines including IL-17A, IL-22 and IFNγ. We therefore analysed expression of CD161 on CD4+ T cells in blood and liver and addressed the relevant phenotype and functional capacity of these populations. We observed marked enrichment of CD161+CD4+ T cells in the liver during chronic hepatitis such that they are the dominant subtype (mean 55% of CD4+ T cells. IL-22 and IL-17 secreting CD4+ cells were readily found in the livers of HCV+ and NASH donors, although not enriched compared to blood. There was, however, specific enrichment of a novel subset of IL-22/IFN-γ dual secretors (p=0.02 compared to blood, a result reconfirmed with direct ex vivo analyses. These data indicate the dominance of CD161+ expressing lymphocyte populations within the hepatic infiltrate, associated with a distinct cytokine profile. Given their documented roles as antiviral and hepatoprotective cytokines respectively, the impact of co-secretion of IFNγ and IL-22 in the liver may be particularly significant.

  2. Complement component C5a Promotes Expression of IL-22 and IL-17 from Human T cells and its Implication in Age-related Macular Degeneration

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    Klein Michael L

    2011-07-01

    Full Text Available Abstract Background Age related macular degeneration (AMD is the leading cause of irreversible blindness in elderly populations worldwide. Inflammation, among many factors, has been suggested to play an important role in AMD pathogenesis. Recent studies have demonstrated a strong genetic association between AMD and complement factor H (CFH, the down-regulatory factor of complement activation. Elevated levels of complement activating molecules including complement component 5a (C5a have been found in the serum of AMD patients. Our aim is to study whether C5a can impact human T cells and its implication in AMD. Methods Human peripheral blood mononuclear cells (PBMCs were isolated from the blood of exudative form of AMD patients using a Ficoll gradient centrifugation protocol. Intracellular staining and enzyme-linked immunosorbent assays were used to measure protein expression. Apoptotic cells were detected by staining of cells with the annexin-V and TUNEL technology and analyzed by a FACS Caliber flow cytometer. SNP genotyping was analyzed by TaqMan genotyping assay using the Real-time PCR system 7500. Results We show that C5a promotes interleukin (IL-22 and IL-17 expression by human CD4+ T cells. This effect is dependent on B7, IL-1β and IL-6 expression from monocytes. We have also found that C5a could protect human CD4+ cells from undergoing apoptosis. Importantly, consistent with a role of C5a in promoting IL-22 and IL-17 expression, significant elevation in IL-22 and IL-17 levels was found in AMD patients as compared to non-AMD controls. Conclusions Our results support the notion that C5a may be one of the factors contributing to the elevated serum IL-22 and IL-17 levels in AMD patients. The possible involvement of IL-22 and IL-17 in the inflammation that contributes to AMD may herald a new approach to treat AMD.

  3. Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line - Pathways that are shared with and distinct from IL-10

    NARCIS (Netherlands)

    Lejeune, D; Dumoutier, L; Constantinescu, S; Kruijer, W; Schuringa, JJ; Renauld, JC

    2002-01-01

    IL (interleukin)-22 is an IL-10-related cytokine; its main biological activity known thus far is the induction of acute phase reactants in liver and pancreas. IL-22 signals through a receptor that is composed of two chains from the class II cytokine receptor family: IL-22R (also called

  4. Oral Curcumin (Meriva Is Effective as an Adjuvant Treatment and Is Able to Reduce IL-22 Serum Levels in Patients with Psoriasis Vulgaris

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    Emiliano Antiga

    2015-01-01

    Full Text Available Curcumin is a complementary therapy that may be helpful for the treatment of psoriasis due to its anti-inflammatory, antiangiogenic, antioxidant, and antiproliferative effects. In the present study we performed a randomized, double-blind, placebo-controlled clinical trial to assess the effectiveness of a bioavailable oral curcumin in the treatment of psoriasis. Sixty-three patients with mild-to-moderate psoriasis vulgaris (PASI < 10 were randomly divided into two groups treated with topical steroids and Meriva, a commercially available lecithin based delivery system of curcumin, at 2 g per day (arm 1, or with topical steroids alone (arm 2, both for 12 weeks. At the beginning (T0 and at the end of the therapy (T12, clinical assessment and immunoenzymatic analysis of the serum levels of IL-17 and IL-22 were performed. At T12, both groups achieved a significant reduction of PASI values that, however, was higher in patients treated with both topical steroids and oral curcumin than in patients treated only with topical steroids. Moreover, IL-22 serum levels were significantly reduced in patients treated with oral curcumin. In conclusion, curcumin was demonstrated to be effective as an adjuvant therapy for the treatment of psoriasis vulgaris and to significantly reduce serum levels of IL-22.

  5. Interleukin-22 Inhibits Bleomycin-Induced Pulmonary Fibrosis

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    Minrui Liang

    2013-01-01

    Full Text Available Pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Recent insight has suggested that early injury/inflammation of alveolar epithelial cells could lead to dysregulation of tissue repair driven by multiple cytokines. Although dysregulation of interleukin- (IL- 22 is involved in various pulmonary pathophysiological processes, the role of IL-22 in fibrotic lung diseases is still unclear and needs to be further addressed. Here we investigated the effect of IL-22 on alveolar epithelial cells in the bleomycin- (BLM- induced pulmonary fibrosis. BLM-treated mice showed significantly decreased level of IL-22 in the lung. IL-22 produced γδT cells were also decreased significantly both in the tissues of lungs and spleens. Administration of recombinant human IL-22 to alveolar epithelial cell line A549 cells ameliorated epithelial to mesenchymal transition (EMT and partially reversed the impaired cell viability induced by BLM. Furthermore, blockage of IL-22 deteriorated pulmonary fibrosis, with elevated EMT marker (α-smooth muscle actin (α-SMA and overactivated Smad2. Our results indicate that IL-22 may play a protective role in the development of BLM-induced pulmonary fibrosis and may suggest IL-22 as a novel immunotherapy tool in treating pulmonary fibrosis.

  6. ChIP-on-chip analysis identifies IL-22 as direct target gene of ectopically expressed FOXP3 transcription factor in human T cells

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    Jeron Andreas

    2012-12-01

    Full Text Available Abstract Background The transcription factor (TF forkhead box P3 (FOXP3 is constitutively expressed at high levels in naturally occurring CD4+CD25+ regulatory T cells (nTregs. It is not only the most accepted marker for that cell population but is also considered lineage determinative. Chromatin immunoprecipitation (ChIP of TFs in combination with genomic tiling microarray analysis (ChIP-on-chip has been shown to be an appropriate tool for identifying FOXP3 transcription factor binding sites (TFBSs on a genome-wide scale. In combination with microarray expression analysis, the ChIP-on-chip technique allows identification of direct FOXP3 target genes. Results ChIP-on-chip analysis of the human FOXP3 expressed in resting and PMA/ionomycin–stimulated Jurkat T cells revealed several thousand putative FOXP3 binding sites and demonstrated the importance of intronic regions for FOXP3 binding. The analysis of expression data showed that the stimulation-dependent down-regulation of IL-22 was correlated with direct FOXP3 binding in the IL-22 promoter region. This association was confirmed by real-time PCR analysis of ChIP-DNA. The corresponding ChIP-region also contained a matching FOXP3 consensus sequence. Conclusions Knowledge of the general distribution patterns of FOXP3 TFBSs in the human genome under resting and activated conditions will contribute to a better understanding of this TF and its influence on direct target genes, as well as its importance for the phenotype and function of Tregs. Moreover, FOXP3-dependent repression of Th17-related IL-22 may be relevant to an understanding of the phenomenon of Treg/Th17 cell plasticity.

  7. Allergic Rhinitis and Its Relationship with IL-10, IL-17, TGF-β, IFN-γ, IL 22, and IL-35

    Directory of Open Access Journals (Sweden)

    P. Bayrak Degirmenci

    2018-01-01

    Full Text Available Background. We aimed in our study to research the role of new cytokines such as IL-35, IL-22, and IL-17 that may form a target for novel treatment approaches. Methods. IL-10, IL-17, TGF-β, IFN-γ, IL-22, and IL-35 serum levels of allergic rhinitis (AR patients were measured using ELISA method. Allergic sensitization was demonstrated by the skin prick test. Patients only with olive tree sensitivity were evaluated for seasonal AR (SAR. Patients only with mite sensitivity were included in the study for perennial AR (PAR. AR clinic severity was demonstrated by the nasal symptom scores (NSS. Results. In total, 65 AR patients (patient group, having 31 PAR and 34 SAR patients, and 31 healthy individuals (control group participated in the study. Cytokine levels between the patient group and the control group were compared; IL-17 (p=0.038, IL-22 (p=0.001, and TGF-β (p=0.031 were detected as high in the patient group, and IFN-γ (p<0.001 was detected as low in the patient group. When correlation analysis was made between age, gender, prick test result, NSS, AR duration, and cytokine levels in the patient group, a negative correlation was detected only between IFN-γ (p=0.032/r=−0.266 level and NSS. Conclusions. Accompanied by the literature information, these results made us think that T cell subgroups and cytokines have an important role in AR immunopathogenesis. It is thought that future studies to be conducted relating to this subject will form new targets in treatment.

  8. IL-22-producing CD4(+) T cells: Middle-men between the immune system and its environment

    NARCIS (Netherlands)

    Trifari, Sara; Spits, Hergen

    2010-01-01

    CD4(+) Th cell populations such as Th1, Th2, Th17 and regulatory T cells regulate immune responses by inducing (or inhibiting) proliferation, differentiation and activation of other immune cells. Recent findings have expanded the universe of CD4(+) T-cell subsets by identifying a cell population

  9. Human NKp44+IL-22+ cells and LTi-like cells constitute a stable RORC+ lineage distinct from conventional natural killer cells

    NARCIS (Netherlands)

    Crellin, Natasha K.; Trifari, Sara; Kaplan, Charles D.; Cupedo, Tom; Spits, Hergen

    2010-01-01

    Lymphoid tissue inducer (LTi) cells are required for lymph node formation during fetal development, and recent evidence implies a role in mucosal immunity in the adult. LTi cells share some phenotypic features of conventional natural killer (NK; cNK) cells; however, little is known to date about the

  10. Subcutaneous administration of polymerized type I collagen downregulates interleukin (IL)-17A, IL-22 and transforming growth factor-β1 expression, and increases Foxp3-expressing cells in localized scleroderma.

    Science.gov (United States)

    Furuzawa-Carballeda, J; Ortíz-Ávalos, M; Lima, G; Jurado-Santa Cruz, F; Llorente, L

    2012-08-01

    Localized scleroderma (LS) is a disfiguring inflammatory autoimmune disease of the skin and underlying tissue. As in systemic sclerosis, a key feature is the presence of T cells in inflammatory lesions. To evaluate the effect of polymerized type I collagen vs. methylprednisolone (MP) in LS, and to determine the influence of this polymerized collagen (PC) on CD4+ peripheral T cells expressing interleukin (IL)-4, IL-17A, interferon-γ and Forkhead box protein (Foxp)3, and on cells expressing transforming growth factor (TGF)-β1, IL-17A, IL-22 and Foxp3 in the skin. In total, 16 patients with LS were treated for 3 months with monthly subcutaneous intralesional injections of 0.1 mL MP (giving a total dose of 20 mg/mL each month) and 15 patients were treated, with weekly subcutaneous intralesional injections of PC, ranging from 0.2 mL (equivalent to 1.66 mg collagen) for a lesion of 50 mm in size, up to a maximum of 1.0 mL (8.3 mg collagen) for a lesion > 100 mm in size, and followed up for a further 6 months. Skin biopsies were obtained from lesions at baseline (before treatment) and 9 months later (6 months after treatment end). Tissue sections were evaluated by histology and immunohistochemistry (IL-17A, IL-22, TGF-β1 and Foxp3). CD4+ T-cell subsets were determined in peripheral blood by flow cytometry. Abnormal tissue architecture was seen in the biopsies taken from patients treated with MP, whereas the PC treatment restored normal skin architecture. PC downregulated pro-inflammatory/profibrotic cytokine expression in peripheral cells, and upregulated the number of regulatory T cells (Tregs) in skin. PC was safe and well tolerated. PC is not only an antifibrotic/fibrolytic agent but also an immunomodulator biodrug that restores the balance between T helper (Th)1, Th2, Th17 and Tregs, downregulates production of pro-inflammatory or profibrogenic cytokines (IL-17A, IL-22 and TGF-β1), and renews skin architecture, without adverse effects. © The Author(s). CED

  11. Immunomodulatory effects of balneotherapy with hae-un-dae thermal water on imiquimod-induced psoriasis-like murine model.

    Science.gov (United States)

    Lee, Young Bok; Lee, Jun Young; Lee, Hye Jin; Yun, Seong Taek; Lee, Jong Tae; Kim, Hong Jig; Yu, Dong Soo; Woo, So Youn; Kim, Jin-Wou

    2014-04-01

    Balneotherapy, although not a well-established dermatological treatment, is thought to have therapeutic properties for psoriasis and is used as an alternative treatment modality throughout the world. To evaluate the mechanism underlying the therapeutic immunologic effects of thermomineral water. A murine model of imiquimod-induced psoriasis-like skin inflammation was used for evaluating the therapeutic effects of balneotherapy with Hae-Un-Dae hot spring mineral water. The clinical improvements were evaluated by a dermatologist. Lesional cytokines, including interleukin (IL)-17A, IL-23, and IL-22, were quantitatively measured by real-time reverse transcriptase polymerase chain reaction. Serum levels of interferon-γ, IL-4, IL-5, and IL-17A were measured by enzyme-linked immunosorbent assay. T cell proportions in the spleen were evaluated by flow cytometry, and histopathological evaluation of the skin was also performed. The mineral water balneotherapy group showed faster improvement in skin erythema and scales than the distilled water bathing group. A substantial reduction was observed in the lesional mRNA levels of IL-17A and IL-23 in the mineral water group. Serum levels of IL-4 and IL-5 were significantly decreased in the mineral water group but not in the distilled water group. Normalized T cell proportions were observed after bathing. Balneotherapy showed immunomodulatory effects in a psoriasis-like murine model. Balneotherapy suppressed lesional IL-23 and IL-17A, which are important cytokines in the pathogenesis of psoriasis. These results suggest that balneotherapy can be used as an effective and safe treatment for psoriasis.

  12. Multicomponent ensemble models to forecast induced seismicity

    Science.gov (United States)

    Király-Proag, E.; Gischig, V.; Zechar, J. D.; Wiemer, S.

    2018-01-01

    In recent years, human-induced seismicity has become a more and more relevant topic due to its economic and social implications. Several models and approaches have been developed to explain underlying physical processes or forecast induced seismicity. They range from simple statistical models to coupled numerical models incorporating complex physics. We advocate the need for forecast testing as currently the best method for ascertaining if models are capable to reasonably accounting for key physical governing processes—or not. Moreover, operational forecast models are of great interest to help on-site decision-making in projects entailing induced earthquakes. We previously introduced a standardized framework following the guidelines of the Collaboratory for the Study of Earthquake Predictability, the Induced Seismicity Test Bench, to test, validate, and rank induced seismicity models. In this study, we describe how to construct multicomponent ensemble models based on Bayesian weightings that deliver more accurate forecasts than individual models in the case of Basel 2006 and Soultz-sous-Forêts 2004 enhanced geothermal stimulation projects. For this, we examine five calibrated variants of two significantly different model groups: (1) Shapiro and Smoothed Seismicity based on the seismogenic index, simple modified Omori-law-type seismicity decay, and temporally weighted smoothed seismicity; (2) Hydraulics and Seismicity based on numerically modelled pore pressure evolution that triggers seismicity using the Mohr-Coulomb failure criterion. We also demonstrate how the individual and ensemble models would perform as part of an operational Adaptive Traffic Light System. Investigating seismicity forecasts based on a range of potential injection scenarios, we use forecast periods of different durations to compute the occurrence probabilities of seismic events M ≥ 3. We show that in the case of the Basel 2006 geothermal stimulation the models forecast hazardous levels

  13. Induced subgraph searching for geometric model fitting

    Science.gov (United States)

    Xiao, Fan; Xiao, Guobao; Yan, Yan; Wang, Xing; Wang, Hanzi

    2017-11-01

    In this paper, we propose a novel model fitting method based on graphs to fit and segment multiple-structure data. In the graph constructed on data, each model instance is represented as an induced subgraph. Following the idea of pursuing the maximum consensus, the multiple geometric model fitting problem is formulated as searching for a set of induced subgraphs including the maximum union set of vertices. After the generation and refinement of the induced subgraphs that represent the model hypotheses, the searching process is conducted on the "qualified" subgraphs. Multiple model instances can be simultaneously estimated by solving a converted problem. Then, we introduce the energy evaluation function to determine the number of model instances in data. The proposed method is able to effectively estimate the number and the parameters of model instances in data severely corrupted by outliers and noises. Experimental results on synthetic data and real images validate the favorable performance of the proposed method compared with several state-of-the-art fitting methods.

  14. Modelling of settlement induced building damage

    NARCIS (Netherlands)

    Giardina, G.

    2013-01-01

    This thesis focuses on the modelling of settlement induced damage to masonry buildings. In densely populated areas, the need for new space is nowadays producing a rapid increment of underground excavations. Due to the construction of new metro lines, tunnelling activity in urban areas is growing.

  15. Dopamine D2 Receptor Is Involved in Alleviation of Type II Collagen-Induced Arthritis in Mice.

    Science.gov (United States)

    Lu, Jian-Hua; Liu, Yi-Qian; Deng, Qiao-Wen; Peng, Yu-Ping; Qiu, Yi-Hua

    2015-01-01

    Human and murine lymphocytes express dopamine (DA) D2-like receptors including DRD2, DRD3, and DRD4. However, their roles in rheumatoid arthritis (RA) are less clear. Here we showed that lymphocyte DRD2 activation alleviates both imbalance of T-helper (Th)17/T-regulatory (Treg) cells and inflamed symptoms in a mouse arthritis model of RA. Collagen-induced arthritis (CIA) was prepared by intradermal injection of chicken collagen type II (CII) in tail base of DBA/1 mice or Drd2 (-/-) C57BL/6 mice. D2-like receptor agonist quinpirole downregulated expression of proinflammatory Th17-related cytokines interleukin- (IL-) 17 and IL-22 but further upregulated expression of anti-inflammatory Treg-related cytokines transforming growth factor- (TGF-) β and IL-10 in lymphocytes in vitro and in ankle joints in vivo in CIA mice. Quinpirole intraperitoneal administration reduced both clinical arthritis score and serum anti-CII IgG level in CIA mice. However, Drd2 (-/-) CIA mice manifested more severe limb inflammation and higher serum anti-CII IgG level and further upregulated IL-17 and IL-22 expression and downregulated TGF-β and IL-10 expression than wild-type CIA mice. In contrast, Drd1 (-/-) CIA mice did not alter limb inflammation or anti-CII IgG level compared with wild-type CIA mice. These results suggest that DRD2 activation is involved in alleviation of CIA symptoms by amelioration of Th17/Treg imbalance.

  16. Modeling of Corrosion-induced Concrete Damage

    DEFF Research Database (Denmark)

    Thybo, Anna Emilie A.; Michel, Alexander; Stang, Henrik

    2013-01-01

    In the present paper a finite element model is introduced to simulate corrosion-induced damage in concrete. The model takes into account the penetration of corrosion products into the concrete as well as non-uniform formation of corrosion products around the reinforcement. To ac-count for the non...... of corrosion products affects both the time-to cover cracking and the crack width at the concrete surface.......In the present paper a finite element model is introduced to simulate corrosion-induced damage in concrete. The model takes into account the penetration of corrosion products into the concrete as well as non-uniform formation of corrosion products around the reinforcement. To ac-count for the non......-uniform formation of corrosion products at the concrete/reinforcement interface, a deterministic approach is used. The model gives good estimates of both deformations in the con-crete/reinforcement interface and crack width when compared to experimental data. Further, it is shown that non-uniform deposition...

  17. Mefenamic Acid Induced Nephrotoxicity: An Animal Model

    Directory of Open Access Journals (Sweden)

    Muhammad Nazrul Somchit

    2014-12-01

    Full Text Available Purpose: Nonsteroidal anti-inflammatory drugs (NSAIDs are used for the treatment of many joint disorders, inflammation and to control pain. Numerous reports have indicated that NSAIDs are capable of producing nephrotoxicity in human. Therefore, the objective of this study was to evaluate mefenamic acid, a NSAID nephrotoxicity in an animal model. Methods: Mice were dosed intraperitoneally with mefenamic acid either as a single dose (100 or 200 mg/kg in 10% Dimethyl sulfoxide/Palm oil or as single daily doses for 14 days (50 or 100 mg/kg in 10% Dimethyl sulfoxide/Palm oil per day. Venous blood samples from mice during the dosing period were taken prior to and 14 days post-dosing from cardiac puncture into heparinized vials. Plasma blood urea nitrogen (BUN and creatinine activities were measured. Results: Single dose of mefenamic acid induced mild alteration of kidney histology mainly mild glomerular necrosis and tubular atrophy. Interestingly, chronic doses induced a dose dependent glomerular necrosis, massive degeneration, inflammation and tubular atrophy. Plasma blood urea nitrogen was statistically elevated in mice treated with mefenamic acid for 14 days similar to plasma creatinine. Conclusion: Results from this study suggest that mefenamic acid as with other NSAIDs capable of producing nephrotoxicity. Therefore, the study of the exact mechanism of mefenamic acid induced severe nephrotoxicity can be done in this animal model.

  18. A nonlinear model for AC induced corrosion

    Directory of Open Access Journals (Sweden)

    N. Ida

    2012-09-01

    Full Text Available The modeling of corrosion poses particular difficulties. The understanding of corrosion as an electrochemical process has led to simple capacitive-resistive models that take into account the resistance of the electrolytic cell and the capacitive effect of the surface potential at the interface between conductors and the electrolyte. In some models nonlinear conduction effects have been added to account for more complex observed behavior. While these models are sufficient to describe the behavior in systems with cathodic protection, the behavior in the presence of induced AC currents from power lines and from RF sources cannot be accounted for and are insufficient to describe the effects observed in the field. Field observations have shown that a rectifying effect exists that affects the cathodic protection potential and this effect is responsible for corrosion in the presence of AC currents. The rectifying effects of the metal-corrosion interface are totally missing from current models. This work proposes a nonlinear model based on finite element analysis that takes into account the nonlinear behavior of the metal-oxide interface and promises to improve modeling by including the rectification effects at the interface.

  19. Radiation induced peroxidation in model lipid systems

    International Nuclear Information System (INIS)

    Dahlan, K.Z.B.H.M.

    1981-08-01

    In the studies of radiation induced lipid peroxidation, lecithin-liposomes and aqueous micellar solutions of sodium linoleate (or linoleic acid) have been used as models of lipid membrane systems. The liposomes and aqueous linoleate micelles were irradiated in the presence of O 2 and N 2 O/O 2 (80/20 v/v). The peroxidation was initiated using gamma radiation from 60 Co radiation source and was monitored by measuring the increase in absorbance of conjugated diene at 232 nm and by the thiobarbituric acid (TBA) test. The oxidation products were also identified by GLC and GLC-MS analysis. (author)

  20. Modeling aircraft noise induced sleep disturbance

    Science.gov (United States)

    McGuire, Sarah M.

    occurrence of rapid eye movements, sleep spindles, and slow wave sleep. Using these features an approach for classifying sleep stages every one second during the night was developed. From observation of the results of the sleep stage classification, it was determined how to add faster dynamics to the nonlinear dynamic model. Slow and fast REM activity are modeled separately and the activity in the gamma frequency band of the EEG signal is used to model both spontaneous and noise-induced awakenings. The nonlinear model predicts changes in sleep structure similar to those found by other researchers and reported in the sleep literature and similar to those found in obtained survey data. To compare sleep disturbance model predictions, flight operations data from US airports were obtained and sleep disturbance in communities was predicted for different operations scenarios using the modified Markov model, the nonlinear dynamic model, and other aircraft noise awakening models. Similarities and differences in model predictions were evaluated in order to determine if the use of the developed sleep structure model leads to improved predictions of the impact of nighttime noise on communities.

  1. Hierarchical Bayesian Modeling of Fluid-Induced Seismicity

    Science.gov (United States)

    Broccardo, M.; Mignan, A.; Wiemer, S.; Stojadinovic, B.; Giardini, D.

    2017-11-01

    In this study, we present a Bayesian hierarchical framework to model fluid-induced seismicity. The framework is based on a nonhomogeneous Poisson process with a fluid-induced seismicity rate proportional to the rate of injected fluid. The fluid-induced seismicity rate model depends upon a set of physically meaningful parameters and has been validated for six fluid-induced case studies. In line with the vision of hierarchical Bayesian modeling, the rate parameters are considered as random variables. We develop both the Bayesian inference and updating rules, which are used to develop a probabilistic forecasting model. We tested the Basel 2006 fluid-induced seismic case study to prove that the hierarchical Bayesian model offers a suitable framework to coherently encode both epistemic uncertainty and aleatory variability. Moreover, it provides a robust and consistent short-term seismic forecasting model suitable for online risk quantification and mitigation.

  2. Effects of induced stress on seismic forward modelling and inversion

    Science.gov (United States)

    Tromp, Jeroen; Trampert, Jeannot

    2018-05-01

    We demonstrate how effects of induced stress may be incorporated in seismic modelling and inversion. Our approach is motivated by the accommodation of pre-stress in global seismology. Induced stress modifies both the equation of motion and the constitutive relationship. The theory predicts that induced pressure linearly affects the unstressed isotropic moduli with a slope determined by their adiabatic pressure derivatives. The induced deviatoric stress produces anisotropic compressional and shear wave speeds; the latter result in shear wave splitting. For forward modelling purposes, we determine the weak form of the equation of motion under induced stress. In the context of the inverse problem, we determine induced stress sensitivity kernels, which may be used for adjoint tomography. The theory is illustrated by considering 2-D propagation of SH waves and related Fréchet derivatives based on a spectral-element method.

  3. Toward a comprehensive areal model of earthquake-induced landslides

    Science.gov (United States)

    Miles, S.B.; Keefer, D.K.

    2009-01-01

    This paper provides a review of regional-scale modeling of earthquake-induced landslide hazard with respect to the needs for disaster risk reduction and sustainable development. Based on this review, it sets out important research themes and suggests computing with words (CW), a methodology that includes fuzzy logic systems, as a fruitful modeling methodology for addressing many of these research themes. A range of research, reviewed here, has been conducted applying CW to various aspects of earthquake-induced landslide hazard zonation, but none facilitate comprehensive modeling of all types of earthquake-induced landslides. A new comprehensive areal model of earthquake-induced landslides (CAMEL) is introduced here that was developed using fuzzy logic systems. CAMEL provides an integrated framework for modeling all types of earthquake-induced landslides using geographic information systems. CAMEL is designed to facilitate quantitative and qualitative representation of terrain conditions and knowledge about these conditions on the likely areal concentration of each landslide type. CAMEL is highly modifiable and adaptable; new knowledge can be easily added, while existing knowledge can be changed to better match local knowledge and conditions. As such, CAMEL should not be viewed as a complete alternative to other earthquake-induced landslide models. CAMEL provides an open framework for incorporating other models, such as Newmark's displacement method, together with previously incompatible empirical and local knowledge. ?? 2009 ASCE.

  4. A brief overview of models of nucleon-induced reactions

    International Nuclear Information System (INIS)

    Carlson, B.V.

    2003-01-01

    The basic features of low to intermediate energy nucleon-induced reactions are discussed within the contexts of the optical model, the statistical model, preequilibrium and intranuclear cascade models. The calculation of cross sections and other scattering quantities are described. (author)

  5. Literature review on induced exposure models, Task 2 HS-270

    Science.gov (United States)

    1982-02-01

    Sections 1, 2 and 3 of this report describe the development of : induced exposure models, together with d discussion of questions : of validity. These Sections focus on the most important and : relevant results from the literature, while Appendix A c...

  6. Hubble induced mass after inflation in spectator field models

    Energy Technology Data Exchange (ETDEWEB)

    Fujita, Tomohiro [Stanford Institute for Theoretical Physics and Department of Physics, Stanford University, Stanford, CA 94306 (United States); Harigaya, Keisuke, E-mail: tomofuji@stanford.edu, E-mail: keisukeh@icrr.u-tokyo.ac.jp [Department of Physics, University of California, Berkeley, CA 94720 (United States)

    2016-12-01

    Spectator field models such as the curvaton scenario and the modulated reheating are attractive scenarios for the generation of the cosmic curvature perturbation, as the constraints on inflation models are relaxed. In this paper, we discuss the effect of Hubble induced masses on the dynamics of spectator fields after inflation. We pay particular attention to the Hubble induced mass by the kinetic energy of an oscillating inflaton, which is generically unsuppressed but often overlooked. In the curvaton scenario, the Hubble induced mass relaxes the constraint on the property of the inflaton and the curvaton, such as the reheating temperature and the inflation scale. We comment on the implication of our discussion for baryogenesis in the curvaton scenario. In the modulated reheating, the predictions of models e.g. the non-gaussianity can be considerably altered. Furthermore, we propose a new model of the modulated reheating utilizing the Hubble induced mass which realizes a wide range of the local non-gaussianity parameter.

  7. Animal Models of Chemotherapy-induced Mucositis

    DEFF Research Database (Denmark)

    Sangild, Per T; Shen, René Liang; Pontoppidan, Peter Erik Lotko

    2018-01-01

    constitution). Here, we briefly describe CIM pathophysiology, particularly the basic knowledge that has been obtained from CIM animal models. These model studies have indicated potential new preventive and ameliorating interventions, including supplementation with natural bioactive diets (e.g. milk fractions...... easier make clinically-relevant treatment regimens possible. In synergy, animal models improve the basic pathophysiological understanding of CIM and provide new ideas for treatment that are required to make competent decisions in clinical practice....

  8. D-galactose-induced brain ageing model

    DEFF Research Database (Denmark)

    Sadigh-Eteghad, Saeed; Majdi, Alireza; McCann, Sarah K.

    2017-01-01

    Animal models are commonly used in brain ageing research. Amongst these, models where rodents are exposed to d-galactose are held to recapitulate a number of features of ageing including neurobehavioral and neurochemical changes. However, results from animal studies are often inconsistent...

  9. Smeared crack modelling approach for corrosion-induced concrete damage

    DEFF Research Database (Denmark)

    Thybo, Anna Emilie Anusha; Michel, Alexander; Stang, Henrik

    2017-01-01

    In this paper a smeared crack modelling approach is used to simulate corrosion-induced damage in reinforced concrete. The presented modelling approach utilizes a thermal analogy to mimic the expansive nature of solid corrosion products, while taking into account the penetration of corrosion...... products into the surrounding concrete, non-uniform precipitation of corrosion products, and creep. To demonstrate the applicability of the presented modelling approach, numerical predictions in terms of corrosion-induced deformations as well as formation and propagation of micro- and macrocracks were......-induced damage phenomena in reinforced concrete. Moreover, good agreements were also found between experimental and numerical data for corrosion-induced deformations along the circumference of the reinforcement....

  10. Computer modelling of radiation-induced bystander effect

    International Nuclear Information System (INIS)

    Khvostunov, Igor K.; Nikjoo, Hooshang

    2002-01-01

    Radiation-induced genomic instability and bystander effects are now well established consequences of exposure of living cells to ionising radiation. It has been observed that cells not directly hit by radiation tracks may still exhibit radiation effects. We present a quantitative modelling of the radiation-induced bystander effect based on a diffusion model of spreading the bystander signal. The model assumes the bystander factor to be a protein of low molecular weight, given out by the hit cell, diffusing in the medium and reacting with non-hit cells. The model calculations successfully predict the results of cell survival in an irradiated conditioned medium. The model predicts the shape of dose-effect relationship for cell survival and oncogenic transformation induced by broad-beam and micro-beam irradiation by alpha-particles. (author)

  11. Modeling of glutamate-induced dynamical patterns

    DEFF Research Database (Denmark)

    Faurby-Bentzen, Christian Krefeld; Zhabotinsky, A.M.; Laugesen, Jakob Lund

    2009-01-01

    Based on established physiological mechanisms, the paper presents a detailed computer model, which supports the hypothesis that temporal lobe epilepsy may be caused by failure of glutamate reuptake from the extracellular space. The elevated glutamate concentration causes an increased activation...

  12. induced cerebral injury in a rat model

    African Journals Online (AJOL)

    Results: There was a significant decrease in neurological deficit, brain oedema, and volume of ... This is an Open Access article that uses a funding model which does not charge readers or .... Moreover, the percentage of infarct volume was.

  13. An integrated model for radiation induced cancer

    International Nuclear Information System (INIS)

    Hall, E.J.; Varma, M.

    1994-01-01

    Risk estimates for radiation induced cancer are based on epidemiological data, principally the Japanese A bomb survivors. These estimates for radiation are better known than for any other environmental pollutant, but they do not relate directly to exposure to low doses and low dose rate. Recent rapid advances in molecular genetics, coupled with steady gains in cellular biology, radiation physics and chemistry led to the notion that the time may not be far off when it may be possible to arrive at human cancer risk estimates entirely from laboratory data. Whether risk estimates based on laboratory data will ever replace estimates based on epidemiological studies is an open question. What is clear is that laboratory data can supplement the present risk estimates by providing information on the relative effectiveness of high LET radiations, the importance of dose rate and dose protraction, and by identifying subpopulations which are unusually sensitive or resistant to radiation carcinogenesis. (author)

  14. Radiation-induced segregation in model alloys

    Science.gov (United States)

    Ezawa, T.; Wakai, E.; Oshima, R.

    2000-12-01

    The dependence of the size factor of solutes on radiation-induced segregation (RIS) was studied. Ni-Si, Ni-Co, Ni-Cu, Ni-Mn, Ni-Pd, and Ni-Nb binary solid solution alloys were irradiated with electrons in a high voltage electron microscope at the same irradiation conditions. A focused beam and a grain boundary were utilized to generate a flow of point defects to cause RIS. From the concentration profile obtained by an energy dispersive X-ray analysis, the amount of RIS was calculated. The amount of RIS decreased as the size of the solute increased up to about 10%. However, as the size increased further, the amount of RIS increased. This result shows that RIS is not simply determined by the size effect rule.

  15. Drug-induced cholestasis: mechanisms, models, and markers.

    Science.gov (United States)

    Chatterjee, Sagnik; Annaert, Pieter

    2018-04-27

    Drug-induced cholestasis is a risk factor in progression of drug candidates, and poses serious health hazard if not detected before going into human. Intrahepatic accumulation of bile acids (BAs) represents a characteristic phenomenon associated with drug-induced cholestasis. The major challenges in obtaining a complete understanding of drug-induced cholestasis lies in the complexity of BA-mediated toxicity mechanisms and the impact of bile acids at different 'targets' such as transporters, enzymes and nuclear receptors. At the same time, it is not trivial to have a relevant in vitro system that recapitulates these features. In addition, lack of sensitive and early preclinical biomarkers, relevant to the clinical situation, complicates proper detection of drug-induced cholestasis. Significant overlap in biomarker signatures between different mechanisms of drug-induced liver injury (DILI) precludes identification of specific mechanisms. Over the last decade the knowledge gaps in drug-induced cholestasis are closing due to growing mechanistic understanding of BA-mediated toxicity at (patho)physiologically relevant BA concentrations. Significant progress has been made in the mechanistic understanding of drug-induced cholestasis and associated toxicity, biomarkers and susceptibility factors. In addition, novel in vitro models are evolving which provide a holistic understanding of processes underlying drug-induced cholestasis. This review summarizes the challenges and recent understandings about drug-induced cholestasis with a potential path forward. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. Preventing Noise-Induced Extinction in Discrete Population Models

    Directory of Open Access Journals (Sweden)

    Irina Bashkirtseva

    2017-01-01

    Full Text Available A problem of the analysis and prevention of noise-induced extinction in nonlinear population models is considered. For the solution of this problem, we suggest a general approach based on the stochastic sensitivity analysis. To prevent the noise-induced extinction, we construct feedback regulators which provide a low stochastic sensitivity and keep the system close to the safe equilibrium regime. For the demonstration of this approach, we apply our mathematical technique to the conceptual but quite representative Ricker-type models. A variant of the Ricker model with delay is studied along with the classic widely used one-dimensional system.

  17. Dopamine D2 Receptor Is Involved in Alleviation of Type II Collagen-Induced Arthritis in Mice

    Directory of Open Access Journals (Sweden)

    Jian-Hua Lu

    2015-01-01

    Full Text Available Human and murine lymphocytes express dopamine (DA D2-like receptors including DRD2, DRD3, and DRD4. However, their roles in rheumatoid arthritis (RA are less clear. Here we showed that lymphocyte DRD2 activation alleviates both imbalance of T-helper (Th17/T-regulatory (Treg cells and inflamed symptoms in a mouse arthritis model of RA. Collagen-induced arthritis (CIA was prepared by intradermal injection of chicken collagen type II (CII in tail base of DBA/1 mice or Drd2−/− C57BL/6 mice. D2-like receptor agonist quinpirole downregulated expression of proinflammatory Th17-related cytokines interleukin- (IL- 17 and IL-22 but further upregulated expression of anti-inflammatory Treg-related cytokines transforming growth factor- (TGF- β and IL-10 in lymphocytes in vitro and in ankle joints in vivo in CIA mice. Quinpirole intraperitoneal administration reduced both clinical arthritis score and serum anti-CII IgG level in CIA mice. However, Drd2−/− CIA mice manifested more severe limb inflammation and higher serum anti-CII IgG level and further upregulated IL-17 and IL-22 expression and downregulated TGF-β and IL-10 expression than wild-type CIA mice. In contrast, Drd1−/− CIA mice did not alter limb inflammation or anti-CII IgG level compared with wild-type CIA mice. These results suggest that DRD2 activation is involved in alleviation of CIA symptoms by amelioration of Th17/Treg imbalance.

  18. A knowledge-Induced Operator Model

    Directory of Open Access Journals (Sweden)

    M.A. Choudhury

    2007-06-01

    Full Text Available Learning systems are in the forefront of analytical investigation in the sciences. In the social sciences they occupy the study of complexity and strongly interactive world-systems. Sometimes they are diversely referred to as symbiotics and semiotics when studied in conjunction with logical expressions. In the mathematical sciences the methodology underlying learning systems with complex behavior is based on formal logic or systems analysis. In this paper relationally learning systems are shown to transcend the space-time domain of scientific investigation into the knowledge dimension. Such a knowledge domain is explained by pervasive interaction leading to integration and followed by continuous evolution as complementary processes existing between entities and systemic domains in world-systems, thus the abbreviation IIE-processes. This paper establishes a mathematical characterization of the properties of knowledge-induced process-based world-systems in the light of the epistemology of unity of knowledge signified in this paper by extensive complementarities caused by the epistemic and ontological foundation of the text of unity of knowledge, the prime example of which is the realm of the divine laws. The result is formalism in mathematical generalization of the learning phenomenon by means of an operator. This operator summarizes the properties of interaction, integration and evolution (IIE in the continuum domain of knowledge formation signified by universal complementarities across entities, systems and sub-systems in unifying world-systems. The opposite case of ‘de-knowledge’ and its operator is also briefly formalized.

  19. Modeling tsunamis induced by retrogressive submarine landslides

    Science.gov (United States)

    Løvholt, F.; Kim, J.; Harbitz, C. B.

    2015-12-01

    Enormous submarine landslides having volumes up to thousands of km3 and long run-out may cause tsunamis with widespread effects. Clay-rich landslides, such as Trænadjupet and Storegga offshore Norway commonly involve retrogressive mass and momentum release mechanisms that affect the tsunami generation. Therefore, such landslides may involve a large amount of smaller blocks. As a consequence, the failure mechanisms and release rate of the individual blocks are of importance for the tsunami generation. Previous attempts to model the tsunami generation due to retrogressive landslides are few, and limited to idealized conditions. Here, we review the basic effects of retrogression on tsunamigenesis in simple geometries. To this end, two different methods are employed for the landslide motion, a series block with pre-scribed time lags and kinematics, and a dynamic retrogressive model where the inter-block time lag is determined by the model. The effect of parameters such as time lag on wave-height, wave-length, and dispersion are discussed. Finally, we discuss how the retrogressive effects may have influenced the tsunamis due to large landslides such as the Storegga slide. The research leading to these results has received funding from the Research Council of Norway under grant number 231252 (Project TsunamiLand) and the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement 603839 (Project ASTARTE).

  20. Source characterization and dynamic fault modeling of induced seismicity

    Science.gov (United States)

    Lui, S. K. Y.; Young, R. P.

    2017-12-01

    In recent years there are increasing concerns worldwide that industrial activities in the sub-surface can cause or trigger damaging earthquakes. In order to effectively mitigate the damaging effects of induced seismicity, the key is to better understand the source physics of induced earthquakes, which still remain elusive at present. Furthermore, an improved understanding of induced earthquake physics is pivotal to assess large-magnitude earthquake triggering. A better quantification of the possible causes of induced earthquakes can be achieved through numerical simulations. The fault model used in this study is governed by the empirically-derived rate-and-state friction laws, featuring a velocity-weakening (VW) patch embedded into a large velocity-strengthening (VS) region. Outside of that, the fault is slipping at the background loading rate. The model is fully dynamic, with all wave effects resolved, and is able to resolve spontaneous long-term slip history on a fault segment at all stages of seismic cycles. An earlier study using this model has established that aseismic slip plays a major role in the triggering of small repeating earthquakes. This study presents a series of cases with earthquakes occurring on faults with different fault frictional properties and fluid-induced stress perturbations. The effects to both the overall seismicity rate and fault slip behavior are investigated, and the causal relationship between the pre-slip pattern prior to the event and the induced source characteristics is discussed. Based on simulation results, the subsequent step is to select specific cases for laboratory experiments which allow well controlled variables and fault parameters. Ultimately, the aim is to provide better constraints on important parameters for induced earthquakes based on numerical modeling and laboratory data, and hence to contribute to a physics-based induced earthquake hazard assessment.

  1. Hypoxia-induced retinopathy model in adult zebrafish

    DEFF Research Database (Denmark)

    Cao, Ziquan; Jensen, Lasse D.; Rouhi, Pegah

    2010-01-01

    Hypoxia-induced vascular responses, including angiogenesis, vascular remodeling and vascular leakage, significantly contribute to the onset, development and progression of retinopathy. However, until recently there were no appropriate animal disease models recapitulating adult retinopathy available....... In this article, we describe protocols that create hypoxia-induced retinopathy in adult zebrafish. Adult fli1: EGFP zebrafish are placed in hypoxic water for 3-10 d and retinal neovascularization is analyzed using confocal microscopy. It usually takes 11 d to obtain conclusive results using the hypoxia......-induced retinopathy model in adult zebrafish. This model provides a unique opportunity to study kinetically the development of retinopathy in adult animals using noninvasive protocols and to assess therapeutic efficacy of orally active antiangiogenic drugs....

  2. Modeling of environmentally induced transients within satellites

    Science.gov (United States)

    Stevens, N. John; Barbay, Gordon J.; Jones, Michael R.; Viswanathan, R.

    1987-01-01

    A technique is described that allows an estimation of possible spacecraft charging hazards. This technique, called SCREENS (spacecraft response to environments of space), utilizes the NASA charging analyzer program (NASCAP) to estimate the electrical stress locations and the charge stored in the dielectric coatings due to spacecraft encounter with a geomagnetic substorm environment. This information can then be used to determine the response of the spacecraft electrical system to a surface discharge by means of lumped element models. The coupling into the electronics is assumed to be due to magnetic linkage from the transient currents flowing as a result of the discharge transient. The behavior of a spinning spacecraft encountering a severe substorm is predicted using this technique. It is found that systems are potentially vulnerable to upset if transient signals enter through the ground lines.

  3. Shock-induced electrical activity in polymeric solids. A mechanically induced bond scission model

    International Nuclear Information System (INIS)

    Graham, R.A.

    1979-01-01

    When polymeric solids are subjected to high-pressure shock loading, two anomalous electrical phenomena, shock-induced conduction and shock-induced polarization, are observed. The present paper proposes a model of mechanically induced bond scission within the shock front to account for the effects. An experimental study of shock-induced polarization in poly(pyromellitimide) (Vespel SP-1) is reported for shock compressions from 17 to 23% (pressures from 2.5 to 5.4 GPa). Poly(pyromellitimide) is found to be a strong generator of such polarization and the polarization is found to reflect an irreversible or highly hysteretic process. The present measurements are combined with prior measurements to establish a correlation between monomer structure and strength of shock-induced polarization; feeble signals are observed in the simpler monomer repeat units of poly(tetrafluoroethylene) and polyethylene while the strongest signals are observed in more complex monomers of poly(methyl methacrylate) and poly(pyromellitimide). It is also noted that there is an apparent correlation between shock-induced conduction and shock-induced polarization. Such shock-induced electrical activity is also found to be well correlated with the propensity for mechanical bond scission observed in experiments carried out in conventional mechanochemical studies. The bond scission model can account for characteristics observed for electrical activity in shock-loaded polymers and their correlation to monomer structure. Localization of elastic energy within the monomer repeat unit or along the main chain leads to the different propensities for bond scission and resulting shock-induced electrical activity

  4. Mechanistic issues for modeling radiation-induced segregation

    International Nuclear Information System (INIS)

    Simonen, E.P.; Bruemmer, S.M.

    1993-03-01

    Model calculations of radiation-induced chromium depletion and radiation-induced nickel enrichment at grain boundaries are compared to measured depletions and enrichments. The model is calibrated to fit chromium depletion in commercial purity 304 stainless steel irradiated in boiling water reactor (BWR) environments. Predicted chromium depletion profiles and the dose dependence of chromium concentration at grain boundaries are in accord with measured trends. Evaluation of chromium and nickel profiles in three neutron, and two ion, irradiation environments reveal significant inconsistencies between measurements and predictions

  5. 1D models for condensation induced water hammer in pipelines

    International Nuclear Information System (INIS)

    Bloemeling, Frank; Neuhas, Thorsten; Schaffrath, Andreas

    2013-01-01

    Condensation induced water hammer (CIWH) are caused by contact of steam and subcooled water. Thus, modeling the direct contact condensation is a crucial step towards the simulation of condensation induced water hammer with 1D pressure surge codes. Therefore, also the TUeV NORD SysTec GmbH and Co. KG inhouse pressure surge code DYVRO has been equipped with a new contact condensation model. The validation of DYVRO against an experiment dealing with CIWH is presented in this contribution. (orig.)

  6. 1D models for condensation induced water hammer in pipelines

    Energy Technology Data Exchange (ETDEWEB)

    Bloemeling, Frank; Neuhas, Thorsten; Schaffrath, Andreas [TUEV NORD SysTec GmbH und Co. KG, Hamburg (Germany)

    2013-03-15

    Condensation induced water hammer (CIWH) are caused by contact of steam and subcooled water. Thus, modeling the direct contact condensation is a crucial step towards the simulation of condensation induced water hammer with 1D pressure surge codes. Therefore, also the TUeV NORD SysTec GmbH and Co. KG inhouse pressure surge code DYVRO has been equipped with a new contact condensation model. The validation of DYVRO against an experiment dealing with CIWH is presented in this contribution. (orig.)

  7. Atomistic modeling of ion beam induced amorphization in silicon

    International Nuclear Information System (INIS)

    Pelaz, Lourdes; Marques, Luis A.; Lopez, Pedro; Santos, Ivan; Aboy, Maria; Barbolla, Juan

    2005-01-01

    Ion beam induced amorphization in Si has attracted significant interest since the beginning of the use of ion implantation for the fabrication of Si devices. Nowadays, a renewed interest in the modeling of amorphization mechanisms at atomic level has arisen due to the use of preamorphizing implants and high dopant implantation doses for the fabrication of nanometric-scale Si devices. In this work, we briefly describe the existing phenomenological and defect-based amorphization models. We focus on the atomistic model we have developed to describe ion beam induced amorphization in Si. In our model, the building block for the amorphous phase is the bond defect or IV pair, whose stability increases with the number of surrounding IV pairs. This feature explains the regrowth behavior of different damage topologies and the kinetics of the crystalline to amorphous transition. The model provides excellent quantitative agreement with experimental results

  8. Accelerated oxygen-induced retinopathy is a reliable model of ischemia-induced retinal neovascularization.

    Science.gov (United States)

    Villacampa, Pilar; Menger, Katja E; Abelleira, Laura; Ribeiro, Joana; Duran, Yanai; Smith, Alexander J; Ali, Robin R; Luhmann, Ulrich F; Bainbridge, James W B

    2017-01-01

    Retinal ischemia and pathological angiogenesis cause severe impairment of sight. Oxygen-induced retinopathy (OIR) in young mice is widely used as a model to investigate the underlying pathological mechanisms and develop therapeutic interventions. We compared directly the conventional OIR model (exposure to 75% O2 from postnatal day (P) 7 to P12) with an alternative, accelerated version (85% O2 from P8 to P11). We found that accelerated OIR induces similar pre-retinal neovascularization but greater retinal vascular regression that recovers more rapidly. The extent of retinal gliosis is similar but neuroretinal function, as measured by electroretinography, is better maintained in the accelerated model. We found no systemic or maternal morbidity in either model. Accelerated OIR offers a safe, reliable and more rapid alternative model in which pre-retinal neovascularization is similar but retinal vascular regression is greater.

  9. Dietary models for inducing hypercholesterolemia in rats

    Directory of Open Access Journals (Sweden)

    Sheyla Leite Matos

    2005-03-01

    Full Text Available The present work aimed at finding a dietetical model capable of promoting the highest hypercholesterolemia without affecting the development of the rats. Sixty female Fisher rats were divided into five groups. The first one was fed a control diet; the remaining four were fed hypercholesterolemic diets with cholesterol and different contents of soybean oil, starch, casein, micronutrients and fiber and, consequently, different caloric values. After eight weeks animals were evaluated in relation to growth, fecal excretion, liver weight and fat, cholesterol and its fractions, serum biochemical parameters and sistolic pressure and compared with controls. The best result was obtained with the diet containing 25 % soybean oil, 1.0 % cholesterol, 13 % fiber and 4,538.4 Kcal/Kg, since it promoted an increase in LDL-cholesterol, a decrease in the HDL fraction and affected less the hepatic function of the animals.Modelos animais têm sido usados para investigar a relação entre desordens no metabolismo do colesterol e a aterogênese. A estratégia utilizada a fim de induzir hipercolesterolemia (dietas com alto teor de gordura e com colesterol adicionado leva à redução de sua ingestão pelos animais, o que induz desnutrição. O presente trabalho objetivou encontrar um modelo dietético capaz de promover a maior hipercolesterolemia, sem afetar o desenvolvimento dos animais. Sessenta ratas Fisher foram divididas em cinco grupos. O primeiro foi alimentado com uma dieta controle; os quatros restantes receberam dietas hipercolesterolêmicas, com colesterol e diferentes teores de óleo de soja, amido, caseína, micronutrientes e fibra e, conseqüentemente, diferentes valores calóricos. Após oito semanas os animais foram avaliados em relação ao crescimento, excreção fecal, peso e teor de gordura do fígado, colesterol e suas frações, parâmetros bioquímicos séricos e pressão sistólica. Os melhores resultados foram obtidos com a dieta contendo 25

  10. Evaluation of induced seismicity forecast models in the Induced Seismicity Test Bench

    Science.gov (United States)

    Király, Eszter; Gischig, Valentin; Zechar, Jeremy; Doetsch, Joseph; Karvounis, Dimitrios; Wiemer, Stefan

    2016-04-01

    Induced earthquakes often accompany fluid injection, and the seismic hazard they pose threatens various underground engineering projects. Models to monitor and control induced seismic hazard with traffic light systems should be probabilistic, forward-looking, and updated as new data arrive. Here, we propose an Induced Seismicity Test Bench to test and rank such models. We apply the test bench to data from the Basel 2006 and Soultz-sous-Forêts 2004 geothermal stimulation projects, and we assess forecasts from two models that incorporate a different mix of physical understanding and stochastic representation of the induced sequences: Shapiro in Space (SiS) and Hydraulics and Seismics (HySei). SiS is based on three pillars: the seismicity rate is computed with help of the seismogenic index and a simple exponential decay of the seismicity; the magnitude distribution follows the Gutenberg-Richter relation; and seismicity is distributed in space based on smoothing seismicity during the learning period with 3D Gaussian kernels. The HySei model describes seismicity triggered by pressure diffusion with irreversible permeability enhancement. Our results show that neither model is fully superior to the other. HySei forecasts the seismicity rate well, but is only mediocre at forecasting the spatial distribution. On the other hand, SiS forecasts the spatial distribution well but not the seismicity rate. The shut-in phase is a difficult moment for both models in both reservoirs: the models tend to underpredict the seismicity rate around, and shortly after, shut-in. Ensemble models that combine HySei's rate forecast with SiS's spatial forecast outperform each individual model.

  11. Modeling compaction-induced energy dissipation of granular HMX

    Energy Technology Data Exchange (ETDEWEB)

    Gonthier, K.A. [Lamar Univ., Beaumont, TX (US). Dept. of Mechanical Engineering; Menikoff, R.; Son, S.F.; Asay, B.W. [Los Alamos National Lab., NM (US)

    1998-12-31

    A thermodynamically consistent model is developed for the compaction of granular solids. The model is an extension of the single phase limit of two-phase continuum models used to describe Deflagration-to-Detonation Transition (DDT) experiments. The focus is on the energetics and dissipation of the compaction process. Changes in volume fraction are partitioned into reversible and irreversible components. Unlike conventional DDT models, the model is applicable from the quasi-static to dynamic compaction regimes for elastic, plastic, or brittle materials. When applied to the compaction of granular HMX (a brittle material), the model predicts results commensurate with experiments including stress relaxation, hysteresis, and energy dissipation. The model provides a suitable starting point for the development of thermal energy localization sub-scale models based on compaction-induced dissipation.

  12. Scale modeling flow-induced vibrations of reactor components

    International Nuclear Information System (INIS)

    Mulcahy, T.M.

    1982-06-01

    Similitude relationships currently employed in the design of flow-induced vibration scale-model tests of nuclear reactor components are reviewed. Emphasis is given to understanding the origins of the similitude parameters as a basis for discussion of the inevitable distortions which occur in design verification testing of entire reactor systems and in feature testing of individual component designs for the existence of detrimental flow-induced vibration mechanisms. Distortions of similitude parameters made in current test practice are enumerated and selected example tests are described. Also, limitations in the use of specific distortions in model designs are evaluated based on the current understanding of flow-induced vibration mechanisms and structural response

  13. MODELING OF AN AIRPLANE WING MOMENTS INDUCED BY ATMOSPHERIC TURBULENCE

    Directory of Open Access Journals (Sweden)

    Anna Antonova

    2014-07-01

    Full Text Available We have used Diederich’s theory of wingspan average correlation functions to obtain analytical expressions for the local spectral density of aircraft wing moments induced by horizontal and vertical wind gusts. We have assumed that the correlation functions of atmospheric turbulence belong to the Bullen family which includes both partial cases of known Dryden’s model as well as von Karman’s  model.

  14. The valproic acid-induced rodent model of autism.

    Science.gov (United States)

    Nicolini, Chiara; Fahnestock, Margaret

    2018-01-01

    Autism is a lifelong neurodevelopmental disorder characterized by impairments in social communication and interaction and by repetitive patterns of behavior, interests and activities. While autism has a strong genetic component, environmental factors including toxins, pesticides, infection and drugs are known to confer autism susceptibility, likely by inducing epigenetic changes. In particular, exposure to valproic acid (VPA) during pregnancy has been demonstrated to increase the risk of autism in children. Furthermore, rodents prenatally exposed to this drug display behavioral phenotypes characteristics of the human condition. Indeed, in utero exposure of rodents to VPA represents a robust model of autism exhibiting face, construct and predictive validity. This model might better represent the many cases of idiopathic autism which are of environmental/epigenetic origins than do transgenic models carrying mutations in single autism-associated genes. The VPA model provides a valuable tool to investigate the neurobiology underlying autistic behavior and to screen for novel therapeutics. Here we review the VPA-induced rodent model of autism, highlighting its importance and reliability as an environmentally-induced animal model of autism. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Rocking media over ex vivo corneas improves this model and allows the study of the effect of proinflammatory cytokines on wound healing.

    Science.gov (United States)

    Deshpande, Pallavi; Ortega, Ílida; Sefat, Farshid; Sangwan, Virender S; Green, Nicola; Claeyssens, Frederik; MacNeil, Sheila

    2015-02-05

    The aim of this work was to develop an in vitro cornea model to study the effect of proinflammatory cytokines on wound healing. Initial studies investigated how to maintain the ex vivo models for up to 4 weeks without loss of epithelium. To study the effect of cytokines, corneas were cultured with the interleukins IL-17A, IL-22, or a combination of IL-17A and IL-22, or lipopolysaccharide (LPS). The effect of IL-17A on wound healing was then examined. With static culture conditions, organ cultures deteriorated within 2 weeks. With gentle rocking of media over the corneas and carbon dioxide perfusion, the ex vivo models survived for up to 4 weeks without loss of epithelium. The cytokine that caused the most damage to the cornea was IL-17A. Under static conditions, wound healing of the central corneal epithelium occurred within 9 days, but only a single-layered epithelium formed whether the cornea was exposed to IL-17A or not. With rocking of media gently over the corneas, a multilayered epithelium was achieved 9 days after wounding. In the presence of IL-17A, however, there was no wound healing evident. Characterization of the cells showed that wherever epithelium was present, both differentiated cells and highly proliferative cells were present. We propose that introducing rocking to extend the effective working life of this model and the introduction of IL-17A to this model to induce aspects of inflammation extend its usefulness to study the effects of agents that influence corneal regeneration under normal and inflamed conditions. Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

  16. A model of hemorrhagic cystitis induced with acrolein in mice

    Directory of Open Access Journals (Sweden)

    C.K.L.P. Batista

    2006-11-01

    Full Text Available Acrolein is a urinary metabolite of cyclophosphamide and ifosfamide, which has been reported to be the causative agent of hemorrhagic cystitis induced by these compounds. A direct cytotoxic effect of acrolein, however, has not yet been demonstrated. In the present study, the effects of intravesical injection of acrolein and mesna, the classical acrolein chemical inhibitor, were evaluated. Male Swiss mice weighing 25 to 35 g (N = 6 per group received saline or acrolein (25, 75, 225 µg intravesically 3, 6, 12, and 24 h before sacrifice for evaluation of bladder wet weight, macroscopic and histopathological changes by Gray's criteria, and 3 and 24 h for assessment of increase in vascular permeability. In other animals, mesna was administered intravesically (2 mg or systemically (80 mg/kg 1 h before acrolein. Intravesical administration of acrolein induced a dose- and time-dependent increase in vascular permeability and bladder wet weight (within 3 h: 2.2- and 21-fold increases in bladder wet weight and Evans blue dye exuded, respectively, at doses of 75 µg/bladder, as confirmed by Gray's criteria. Pretreatment with mesna (2-mercaptoethanesulfonic acid, which interacts with acrolein resulting in an inactive compound, inhibited all changes induced by acrolein. Our results are the first demonstration that intravesical administration of acrolein induces hemorrhagic cystitis. This model of acrolein-induced hemorrhagic cystitis in mice may be an important tool for the evaluation of the mechanism by which acrolein induces bladder lesion, as well as for investigation of new uroprotective drugs.

  17. Modeling Shear Induced Von Willebrand Factor Binding to Collagen

    Science.gov (United States)

    Dong, Chuqiao; Wei, Wei; Morabito, Michael; Webb, Edmund; Oztekin, Alparslan; Zhang, Xiaohui; Cheng, Xuanhong

    2017-11-01

    Von Willebrand factor (vWF) is a blood glycoprotein that binds with platelets and collagen on injured vessel surfaces to form clots. VWF bioactivity is shear flow induced: at low shear, binding between VWF and other biological entities is suppressed; for high shear rate conditions - as are found near arterial injury sites - VWF elongates, activating its binding with platelets and collagen. Based on parameters derived from single molecule force spectroscopy experiments, we developed a coarse-grain molecular model to simulate bond formation probability as a function of shear rate. By introducing a binding criterion that depends on the conformation of a sub-monomer molecular feature of our model, the model predicts shear-induced binding, even for conditions where binding is highly energetically favorable. We further investigate the influence of various model parameters on the ability to predict shear-induced binding (vWF length, collagen site density and distribution, binding energy landscape, and slip/catch bond length) and demonstrate parameter ranges where the model provides good agreement with existing experimental data. Our results may be important for understanding vWF activity and also for achieving targeted drug therapy via biomimetic synthetic molecules. National Science Foundation (NSF),Division of Mathematical Sciences (DMS).

  18. In silico modeling to predict drug-induced phospholipidosis

    International Nuclear Information System (INIS)

    Choi, Sydney S.; Kim, Jae S.; Valerio, Luis G.; Sadrieh, Nakissa

    2013-01-01

    Drug-induced phospholipidosis (DIPL) is a preclinical finding during pharmaceutical drug development that has implications on the course of drug development and regulatory safety review. A principal characteristic of drugs inducing DIPL is known to be a cationic amphiphilic structure. This provides evidence for a structure-based explanation and opportunity to analyze properties and structures of drugs with the histopathologic findings for DIPL. In previous work from the FDA, in silico quantitative structure–activity relationship (QSAR) modeling using machine learning approaches has shown promise with a large dataset of drugs but included unconfirmed data as well. In this study, we report the construction and validation of a battery of complementary in silico QSAR models using the FDA's updated database on phospholipidosis, new algorithms and predictive technologies, and in particular, we address high performance with a high-confidence dataset. The results of our modeling for DIPL include rigorous external validation tests showing 80–81% concordance. Furthermore, the predictive performance characteristics include models with high sensitivity and specificity, in most cases above ≥ 80% leading to desired high negative and positive predictivity. These models are intended to be utilized for regulatory toxicology applied science needs in screening new drugs for DIPL. - Highlights: • New in silico models for predicting drug-induced phospholipidosis (DIPL) are described. • The training set data in the models is derived from the FDA's phospholipidosis database. • We find excellent predictivity values of the models based on external validation. • The models can support drug screening and regulatory decision-making on DIPL

  19. Modeling neurodegenerative diseases with patient-derived induced pluripotent cells

    DEFF Research Database (Denmark)

    Poon, Anna; Zhang, Yu; Chandrasekaran, Abinaya

    2017-01-01

    patient-specific induced pluripotent stem cells (iPSCs) and isogenic controls generated using CRISPR-Cas9 mediated genome editing. The iPSCs are self-renewable and capable of being differentiated into the cell types affected by the diseases. These in vitro models based on patient-derived iPSCs provide...... the possibilities of generating three-dimensional (3D) models using the iPSCs-derived cells and compare their advantages and disadvantages to conventional two-dimensional (2D) models....

  20. A Drosophila model of high sugar diet-induced cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Jianbo Na

    Full Text Available Diets high in carbohydrates have long been linked to progressive heart dysfunction, yet the mechanisms by which chronic high sugar leads to heart failure remain poorly understood. Here we combine diet, genetics, and physiology to establish an adult Drosophila melanogaster model of chronic high sugar-induced heart disease. We demonstrate deterioration of heart function accompanied by fibrosis-like collagen accumulation, insulin signaling defects, and fat accumulation. The result was a shorter life span that was more severe in the presence of reduced insulin and P38 signaling. We provide evidence of a role for hexosamine flux, a metabolic pathway accessed by glucose. Increased hexosamine flux led to heart function defects and structural damage; conversely, cardiac-specific reduction of pathway activity prevented sugar-induced heart dysfunction. Our data establish Drosophila as a useful system for exploring specific aspects of diet-induced heart dysfunction and emphasize enzymes within the hexosamine biosynthetic pathway as candidate therapeutic targets.

  1. A comparative review of radiation-induced cancer risk models

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Seung Hee; Kim, Ju Youl [FNC Technology Co., Ltd., Yongin (Korea, Republic of); Han, Seok Jung [Risk and Environmental Safety Research Division, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2017-06-15

    With the need for a domestic level 3 probabilistic safety assessment (PSA), it is essential to develop a Korea-specific code. Health effect assessments study radiation-induced impacts; in particular, long-term health effects are evaluated in terms of cancer risk. The objective of this study was to analyze the latest cancer risk models developed by foreign organizations and to compare the methodology of how they were developed. This paper also provides suggestions regarding the development of Korean cancer risk models. A review of cancer risk models was carried out targeting the latest models: the NUREG model (1993), the BEIR VII model (2006), the UNSCEAR model (2006), the ICRP 103 model (2007), and the U.S. EPA model (2011). The methodology of how each model was developed is explained, and the cancer sites, dose and dose rate effectiveness factor (DDREF) and mathematical models are also described in the sections presenting differences among the models. The NUREG model was developed by assuming that the risk was proportional to the risk coefficient and dose, while the BEIR VII, UNSCEAR, ICRP, and U.S. EPA models were derived from epidemiological data, principally from Japanese atomic bomb survivors. The risk coefficient does not consider individual characteristics, as the values were calculated in terms of population-averaged cancer risk per unit dose. However, the models derived by epidemiological data are a function of sex, exposure age, and attained age of the exposed individual. Moreover, the methodologies can be used to apply the latest epidemiological data. Therefore, methodologies using epidemiological data should be considered first for developing a Korean cancer risk model, and the cancer sites and DDREF should also be determined based on Korea-specific studies. This review can be used as a basis for developing a Korean cancer risk model in the future.

  2. An intermittency model for predicting roughness induced transition

    Science.gov (United States)

    Ge, Xuan; Durbin, Paul

    2014-11-01

    An extended model for roughness-induced transition is proposed based on an intermittency transport equation for RANS modeling formulated in local variables. To predict roughness effects in the fully turbulent boundary layer, published boundary conditions for k and ω are used, which depend on the equivalent sand grain roughness height, and account for the effective displacement of wall distance origin. Similarly in our approach, wall distance in the transition model for smooth surfaces is modified by an effective origin, which depends on roughness. Flat plate test cases are computed to show that the proposed model is able to predict the transition onset in agreement with a data correlation of transition location versus roughness height, Reynolds number, and inlet turbulence intensity. Experimental data for a turbine cascade are compared with the predicted results to validate the applicability of the proposed model. Supported by NSF Award Number 1228195.

  3. A model for chemically-induced mechanical loading on MEMS

    DEFF Research Database (Denmark)

    Amiot, Fabien

    2007-01-01

    The development of full displacement field measurements as an alternative to the optical lever technique to measure the mechanical response for microelectro-mechanical systems components in their environment calls for a modeling of chemically-induced mechanical fields (stress, strain, and displac......The development of full displacement field measurements as an alternative to the optical lever technique to measure the mechanical response for microelectro-mechanical systems components in their environment calls for a modeling of chemically-induced mechanical fields (stress, strain...... of the system free energy and its dependence on the surface amount. It is solved in the cantilever case thanks to an asymptotic analysis, and an approached closed-form solution is obtained for the interfacial stress field. Finally, some conclusions regarding the transducer efficiency of cantilevers are drawn...

  4. Test particle modeling of wave-induced energetic electron precipitation

    International Nuclear Information System (INIS)

    Chang, H.C.; Inan, U.S.

    1985-01-01

    A test particle computer model of the precipitation of radiation belt electrons is extended to compute the dynamic energy spectrum of transient electron fluxes induced by short-duration VLF wave packets traveling along the geomagnetic field lines. The model is adapted to estimate the count rate and associated spectrum of precipitated electrons that would be observed by satellite-based particle detectors with given geometric factor and orientation with respect to the magnetic field. A constant-frequency wave pulse and a lightning-induced whistler wave packet are used as examples of the stimulating wave signals. The effects of asymmetry of particle mirror heights in the two hemispheres and the atmospheric backscatter of loss cone particles on the computed precipitated fluxes are discussed

  5. A small nonhuman primate model for filovirus-induced disease.

    Science.gov (United States)

    Carrion, Ricardo; Ro, Youngtae; Hoosien, Kareema; Ticer, Anysha; Brasky, Kathy; de la Garza, Melissa; Mansfield, Keith; Patterson, Jean L

    2011-11-25

    Ebolavirus and Marburgvirus are members of the filovirus family and induce a fatal hemorrhagic disease in humans and nonhuman primates with 90% case fatality. To develop a small nonhuman primate model for filovirus disease, common marmosets (Callithrix jacchus) were intramuscularly inoculated with wild type Marburgvirus Musoke or Ebolavirus Zaire. The infection resulted in a systemic fatal disease with clinical and morphological features closely resembling human infection. Animals experienced weight loss, fever, high virus titers in tissue, thrombocytopenia, neutrophilia, high liver transaminases and phosphatases and disseminated intravascular coagulation. Evidence of a severe disseminated viral infection characterized principally by multifocal to coalescing hepatic necrosis was seen in EBOV animals. MARV-infected animals displayed only moderate fibrin deposition in the spleen. Lymphoid necrosis and lymphocytic depletion observed in spleen. These findings provide support for the use of the common marmoset as a small nonhuman primate model for filovirus induced hemorrhagic fever. Copyright © 2011 Elsevier Inc. All rights reserved.

  6. New model for surface fracture induced by dynamical stress

    OpenAIRE

    Andersen, J. V.; Lewis, L. J.

    1997-01-01

    We introduce a model where an isotropic, dynamically-imposed stress induces fracture in a thin film. Using molecular dynamics simulations, we study how the integrated fragment distribution function depends on the rate of change and magnitude of the imposed stress, as well as on temperature. A mean-field argument shows that the system becomes unstable for a critical value of the stress. We find a striking invariance of the distribution of fragments for fixed ratio of temperature and rate of ch...

  7. Model of Structural Fragmentation Induced by High Pressure Torsion

    Czech Academy of Sciences Publication Activity Database

    Kratochvíl, J.; Kružík, Martin; Sedláček, R.

    2010-01-01

    Roč. 25, č. 1 (2010), s. 88-98 ISSN 1606-5131 Institutional research plan: CEZ:AV0Z10750506 Keywords : High-pressure torsion * intergranular glide * homogeneous deformation mode Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 0.649, year: 2010 http://library.utia.cas.cz/separaty/2010/MTR/kruzik-model of structural fragmentation induced by high pressure torsion.pdf

  8. Establishment of an induced rat model of malignant pleural mesothelioma

    International Nuclear Information System (INIS)

    Han Dan; Wu Beihai; Yang Hongsheng; Song Guangyi

    2004-01-01

    Objective: To establish a convenient and practical malignant pleural mesothelioma (MPM) model induced by crocidolite in Da Yao, which has a high induction rate and can be used for imaging and multiple experimental studies and is similar to human MPM. Methods 40 mg of crocidolite suspension was injected into the right chest cavity in 100 Wistar rats in the test group, while same amount of sterilized saline water was injected in 20 rats in the control group. The animals were observed daily , and weighted once a month. CT scanning was performed regularly. When the rats were dead or dying, they were dissected immediately and pathological changes were recorded after CT examination. The experiment lasted for 2 years. Results: The overall induction rate was 71.6%. The survival time of the first MPM rat was 285 days. The mean living span of rats with MPM was (469 ± 21) days. The pathological features of the induced MPMs were multiple morphologically and there were some CT features in different periods. CT imaging could show some MPM features and find the tumour earlier. Conclusion: The cause, positions, tissues and clinical condition of induced tumors were the same as humans. The model had a higher similarity with human MPM in differentiation degree and histological type, and the model can be used to study the mechanism of MPM, to discuss the measures of prevention, and to guide clinical diagnosis and treatment. Multi-morphology of the history from the induced tumors could make up the shortage, which was the difficulty in getting all periods of tissue samples in clinical research and being used in imaging and many kinds of researches. It was a valuable animal model to study MPM. (authors)

  9. Particle transport model sensitivity on wave-induced processes

    Science.gov (United States)

    Staneva, Joanna; Ricker, Marcel; Krüger, Oliver; Breivik, Oyvind; Stanev, Emil; Schrum, Corinna

    2017-04-01

    Different effects of wind waves on the hydrodynamics in the North Sea are investigated using a coupled wave (WAM) and circulation (NEMO) model system. The terms accounting for the wave-current interaction are: the Stokes-Coriolis force, the sea-state dependent momentum and energy flux. The role of the different Stokes drift parameterizations is investigated using a particle-drift model. Those particles can be considered as simple representations of either oil fractions, or fish larvae. In the ocean circulation models the momentum flux from the atmosphere, which is related to the wind speed, is passed directly to the ocean and this is controlled by the drag coefficient. However, in the real ocean, the waves play also the role of a reservoir for momentum and energy because different amounts of the momentum flux from the atmosphere is taken up by the waves. In the coupled model system the momentum transferred into the ocean model is estimated as the fraction of the total flux that goes directly to the currents plus the momentum lost from wave dissipation. Additionally, we demonstrate that the wave-induced Stokes-Coriolis force leads to a deflection of the current. During the extreme events the Stokes velocity is comparable in magnitude to the current velocity. The resulting wave-induced drift is crucial for the transport of particles in the upper ocean. The performed sensitivity analyses demonstrate that the model skill depends on the chosen processes. The results are validated using surface drifters, ADCP, HF radar data and other in-situ measurements in different regions of the North Sea with a focus on the coastal areas. The using of a coupled model system reveals that the newly introduced wave effects are important for the drift-model performance, especially during extremes. Those effects cannot be neglected by search and rescue, oil-spill, transport of biological material, or larva drift modelling.

  10. Infrared Thermography in Serotonin-Induced Itch Model in Rats

    DEFF Research Database (Denmark)

    Jasemian, Yousef; Gazerani, Parisa; Dagnæs-Hansen, Frederik

    2012-01-01

    The study validated the application of infrared thermography in a serotonin-induced itch model in rats since the only available method in animal models of itch is the count of scratching bouts. Twenty four adult Sprague-Dawley male rats were used in 3 experiments: 1) local vasomotor response...... with no scratching reflex was investigated. Serotonin elicited significant scratching and lowered the local temperature at the site of injection. A negative dose-temperature relationship of serotonin was found by thermography. Vasoregulation at the site of serotonin injection took place in the absence of scratching...

  11. Inflation and reheating in induced-gravity models

    International Nuclear Information System (INIS)

    Barr, S.; Segre, G.

    1990-01-01

    The Planck mass is generated dynamically in induced-gravity models, typically being related to the vacuum expectation value of a scalar field φ, ε 1/2 left-angle φ right-angle=M Pl / √8π , where ε is a dimensionless parameter, typically smaller than one. We discuss in this paper the decay of the φ particle, which is mainly into gravitons, and the consequences this has for models in which the φ field is responsible for inflation. We show in particular that too much energy is stored in φ oscillations and adequate reheating does not occur

  12. Distraction induced enterogenesis: a unique mouse model using polyethylene glycol.

    Science.gov (United States)

    Okawada, Manabu; Maria, Haytham Mustafa; Teitelbaum, Daniel H

    2011-09-01

    Recent studies have demonstrated that the small intestine can be lengthened by applying mechanical forces to the bowel lumen-distraction-induced enterogenesis. However, the mechanisms which account for this growth are unknown, and might be best examined using a mouse model. The purpose of this study is to establish the feasibility of developing distractive-induced small bowel growth in mouse. Twelve-week old C57BL/6J mice had a jejunal segment taken out of continuity, and distended with polyethylene glycol (PEG: 3350 KDa); this group was compared with a control group without stretching. Segment length and diameter were measured intra-operatively and after 5 d. Villus height, crypt depth, and muscle thickness in the isolated segment were assessed. Rate of epithelial cell proliferation (5-bromo-2-deoxyuridine: BrdU incorporation) in crypts were also examined. The mucosal mRNA expression of targeted factors was performed to investigate potential mechanisms which might lead to distraction-induced enterogenesis. At harvest, the PEG-stretched group showed a significant increase in length and diameter versus controls. Villus height, crypt depth, and muscular layer thickness increased in the PEG group. The PEG group also showed significantly increased rates of epithelial cell proliferation versus controls. Real-time PCR showed a trend toward higher β-catenin and c-myc mRNA expression in the PEG-stretched group; however, this difference was not statistically significant. Radial distraction-induced enterogenesis with PEG is a viable method for increasing small intestinal length and diameter. This model may provide a new method for studying the mechanisms leading to distraction-induced enterogenesis. Copyright © 2011 Elsevier Inc. All rights reserved.

  13. Modeling drug- and chemical- induced hepatotoxicity with systems biology approaches

    Directory of Open Access Journals (Sweden)

    Sudin eBhattacharya

    2012-12-01

    Full Text Available We provide an overview of computational systems biology approaches as applied to the study of chemical- and drug-induced toxicity. The concept of ‘toxicity pathways’ is described in the context of the 2007 US National Academies of Science report, Toxicity testing in the 21st Century: A Vision and A Strategy. Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically-based analysis of dose-response behavior and the safety of chemicals and drugs. We focus on toxicity of the liver (hepatotoxicity – a complex phenotypic response with contributions from a number of different cell types and biological processes. We describe three case studies of complementary multi-scale computational modeling approaches to understand perturbation of toxicity pathways in the human liver as a result of exposure to environmental contaminants and specific drugs. One approach involves development of a spatial, multicellular virtual tissue model of the liver lobule that combines molecular circuits in individual hepatocytes with cell-cell interactions and blood-mediated transport of toxicants through hepatic sinusoids, to enable quantitative, mechanistic prediction of hepatic dose-response for activation of the AhR toxicity pathway. Simultaneously, methods are being developing to extract quantitative maps of intracellular signaling and transcriptional regulatory networks perturbed by environmental contaminants, using a combination of gene expression and genome-wide protein-DNA interaction data. A predictive physiological model (DILIsymTM to understand drug-induced liver injury (DILI, the most common adverse event leading to termination of clinical development programs and regulatory actions on drugs, is also described. The model initially focuses on reactive metabolite-induced DILI in response to administration of acetaminophen, and spans multiple biological scales.

  14. Protein engineering of the chemokine CCL20 prevents psoriasiform dermatitis in an IL-23-dependent murine model

    DEFF Research Database (Denmark)

    Getschman, A E; Imai, Y; Larsen, O

    2017-01-01

    signaling. When given in an IL-23-dependent mouse model for psoriasis, CCL20 S64C prevented psoriatic inflammation and the up-regulation of IL-17A and IL-22. Our results validate CCR6 as a tractable therapeutic target for psoriasis and demonstrate the value of CCL20 S64C as a lead compound....

  15. Modeling of hydrogen induced cold cracking in a ferritic steel

    International Nuclear Information System (INIS)

    Chen, Qianqiang

    2015-01-01

    This thesis is aimed at studying the hydrogen induced cold cracking (HICC) in the heated affected zone (HAZ) of weldments and at proposing a criterion to predict this phenomenon. HICC is attributable to three factors: i) a susceptible microstructure; ii) hydrogen concentration; and iii) a critical stress. To this end, first tensile tests on smooth specimens charged with hydrogen were performed to investigate hydrogen embrittlement of martensite. According to these results, a ductile-brittle damage model is proposed in order to establish a HICC criterion. In order to validate this criterion, we performed the modified Tekken tests. The Tekken test was chosen because one can control the welding parameters in order to induce cold cracking. The modified Tekken tests have then been modeled using a fully coupled thermo-metallo-mechanical-diffusion model using the finite element method. This model allows to compute martensite's portion, residual stress level and hydrogen concentration in the HAZ. By applying the HICC criterion to these tests, cold cracking phenomenon has been correctly predicted. (author)

  16. Modelling of helical current filaments induced by LHW on EAST

    Energy Technology Data Exchange (ETDEWEB)

    Rack, Michael; Denner, Peter; Liang, Yunfeng [Institute of Energy and Climate Research - Plasma Physics, Forschungszentrum Juelich GmbH, Association EURATOM-FZJ, Partner in the Trilateral Euregio Cluster, D-52425 Juelich (Germany); Zeng, Long [Institute of Energy and Climate Research - Plasma Physics, Forschungszentrum Juelich GmbH, Association EURATOM-FZJ, Partner in the Trilateral Euregio Cluster, D-52425 Juelich (Germany); Institute of Plasma Physics, Chinese Academy of Sciences, Hefei 230031 (China); Gong, Xianzu; Gan, Kaifu; Wang, Liang; Liu, Fukun; Qian, Jinping; Shen, Biao; Li, Jiangang [Institute of Plasma Physics, Chinese Academy of Sciences, Hefei 230031 (China); Gauthier, Eric [Association EURATOM-CEA, IRFM, F-13108 Saint-Paul-lez-Durance (France); Collaboration: the EAST Team

    2013-07-01

    Helical radiation belts have been observed in the scrape-off layer (SOL) of the plasma during the application of lower hybrid wave (LHW) heating at the superconducting tokamak EAST. Modelled SOL field lines, starting in-front of the LHW antennas, show agreement in position and pitch angle to the experimental observed radiation belts. A splitting of the strike-line can be observed on the outer divertor plates during the application of LHW heating. Agreement in the comparison of the Mirnov coil signals and a modelled electric current flow along these SOL field lines was found. A lower hybrid current drive can induce such an electric current flow near the plasma edge. This electric current flow causes a change of the plasma topology which could result in the splitting of the strike-line as known from the application of resonant magnetic perturbation fields. Comparisons of modelled footprint structures and experimental observed heat load patterns in the divertor region are discussed.

  17. Mathematical modeling of Myosin induced bistability of Lamellipodial fragments.

    Science.gov (United States)

    Hirsch, S; Manhart, A; Schmeiser, C

    2017-01-01

    For various cell types and for lamellipodial fragments on flat surfaces, externally induced and spontaneous transitions between symmetric nonmoving states and polarized migration have been observed. This behavior is indicative of bistability of the cytoskeleton dynamics. In this work, the Filament Based Lamellipodium Model (FBLM), a two-dimensional, anisotropic, two-phase continuum model for the dynamics of the actin filament network in lamellipodia, is extended by a new description of actin-myosin interaction. For appropriately chosen parameter values, the resulting model has bistable dynamics with stable states showing the qualitative features observed in experiments. This is demonstrated by numerical simulations and by an analysis of a strongly simplified version of the FBLM with rigid filaments and planar lamellipodia at the cell front and rear.

  18. FDTD modelling of induced polarization phenomena in transient electromagnetics

    Science.gov (United States)

    Commer, Michael; Petrov, Peter V.; Newman, Gregory A.

    2017-04-01

    The finite-difference time-domain scheme is augmented in order to treat the modelling of transient electromagnetic signals containing induced polarization effects from 3-D distributions of polarizable media. Compared to the non-dispersive problem, the discrete dispersive Maxwell system contains costly convolution operators. Key components to our solution for highly digitized model meshes are Debye decomposition and composite memory variables. We revert to the popular Cole-Cole model of dispersion to describe the frequency-dependent behaviour of electrical conductivity. Its inversely Laplace-transformed Debye decomposition results in a series of time convolutions between electric field and exponential decay functions, with the latter reflecting each Debye constituents' individual relaxation time. These function types in the discrete-time convolution allow for their substitution by memory variables, annihilating the otherwise prohibitive computing demands. Numerical examples demonstrate the efficiency and practicality of our algorithm.

  19. Hypoxia-induced metastasis model in embryonic zebrafish

    DEFF Research Database (Denmark)

    Rouhi, Pegah; Jensen, Lasse D.; Cao, Ziquan

    2010-01-01

    Hypoxia facilitates tumor invasion and metastasis by promoting neovascularization and co-option of tumor cells in the peritumoral vasculature, leading to dissemination of tumor cells into the circulation. However, until recently, animal models and imaging technology did not enable monitoring...... of the early events of tumor cell invasion and dissemination in living animals. We recently developed a zebrafish metastasis model to dissect the detailed events of hypoxia-induced tumor cell invasion and metastasis in association with angiogenesis at the single-cell level. In this model, fluorescent Di......I-labeled human or mouse tumor cells are implanted into the perivitelline cavity of 48-h-old zebrafish embryos, which are subsequently placed in hypoxic water for 3 d. Tumor cell invasion, metastasis and pathological angiogenesis are detected under fluorescent microscopy in the living fish. The average...

  20. Radiatively induced neutrino mass model with flavor dependent gauge symmetry

    Science.gov (United States)

    Lee, SangJong; Nomura, Takaaki; Okada, Hiroshi

    2018-06-01

    We study a radiative seesaw model at one-loop level with a flavor dependent gauge symmetry U(1) μ - τ, in which we consider bosonic dark matter. We also analyze the constraints from lepton flavor violations, muon g - 2, relic density of dark matter, and collider physics, and carry out numerical analysis to search for allowed parameter region which satisfy all the constraints and to investigate some predictions. Furthermore we find that a simple but adhoc hypothesis induces specific two zero texture with inverse mass matrix, which provides us several predictions such as a specific pattern of Dirac CP phase.

  1. Modeling Neuropsychiatric and Neurodegenerative Diseases With Induced Pluripotent Stem Cells.

    Science.gov (United States)

    LaMarca, Elizabeth A; Powell, Samuel K; Akbarian, Schahram; Brennand, Kristen J

    2018-01-01

    Human-induced pluripotent stem cells (hiPSCs) have revolutionized our ability to model neuropsychiatric and neurodegenerative diseases, and recent progress in the field is paving the way for improved therapeutics. In this review, we discuss major advances in generating hiPSC-derived neural cells and cutting-edge techniques that are transforming hiPSC technology, such as three-dimensional "mini-brains" and clustered, regularly interspersed short palindromic repeats (CRISPR)-Cas systems. We examine specific examples of how hiPSC-derived neural cells are being used to uncover the pathophysiology of schizophrenia and Parkinson's disease, and consider the future of this groundbreaking research.

  2. Collagen-Induced Arthritis: A model for Murine Autoimmune Arthritis

    OpenAIRE

    Pietrosimone, K. M.; Jin, M.; Poston, B.; Liu, P.

    2015-01-01

    Collagen-induced arthritis (CIA) is a common autoimmune animal model used to study rheumatoid arthritis (RA). The development of CIA involves infiltration of macrophages and neutrophils into the joint, as well as T and B cell responses to type II collagen. In murine CIA, genetically susceptible mice (DBA/1J) are immunized with a type II bovine collagen emulsion in complete Freund’s adjuvant (CFA), and receive a boost of type II bovine collagen in incomplete Freund’s adjuvant (IFA) 21 days aft...

  3. Conceptual models of microseismicity induced by fluid injection

    Science.gov (United States)

    Baro Urbea, J.; Lord-May, C.; Eaton, D. W. S.; Joern, D.

    2017-12-01

    Variations in the pore pressure due to fluid invasion are accountable for microseismic activity recorded in geothermal systems and during hydraulic fracturing operations. To capture this phenomenon on a conceptual level, invasion percolation models have been suggested to represent the flow network of fluids within a porous media and seismic activity is typically considered to be directly related to the expansion of the percolated area. Although such models reproduce scale-free frequency-magnitude distributions, the associated b-values of the Gutenberg-Richter relation do not align with observed data. Here, we propose an alternative conceptual invasion percolation model that decouples the fluid propagation from the microseismic events. Instead of a uniform pressure, the pressure is modeled to decay along the distance from the injection site. Wet fracture events are simulated with a stochastic spring block model exhibiting stick-slip dynamics as a result of the variations of the pore pressure. We show that the statistics of the stick-slip events are scale-free, but now the b-values depend on the level of heterogeneity in the local static friction coefficients. Thus, this model is able to reproduce the wide spectrum of b-values observed in field catalogs associated with fluid induced microseismicity. Moreover, the spatial distribution of microseismic events is also consistent with observations.

  4. Preprocedural Prediction Model for Contrast-Induced Nephropathy Patients.

    Science.gov (United States)

    Yin, Wen-Jun; Yi, Yi-Hu; Guan, Xiao-Feng; Zhou, Ling-Yun; Wang, Jiang-Lin; Li, Dai-Yang; Zuo, Xiao-Cong

    2017-02-03

    Several models have been developed for prediction of contrast-induced nephropathy (CIN); however, they only contain patients receiving intra-arterial contrast media for coronary angiographic procedures, which represent a small proportion of all contrast procedures. In addition, most of them evaluate radiological interventional procedure-related variables. So it is necessary for us to develop a model for prediction of CIN before radiological procedures among patients administered contrast media. A total of 8800 patients undergoing contrast administration were randomly assigned in a 4:1 ratio to development and validation data sets. CIN was defined as an increase of 25% and/or 0.5 mg/dL in serum creatinine within 72 hours above the baseline value. Preprocedural clinical variables were used to develop the prediction model from the training data set by the machine learning method of random forest, and 5-fold cross-validation was used to evaluate the prediction accuracies of the model. Finally we tested this model in the validation data set. The incidence of CIN was 13.38%. We built a prediction model with 13 preprocedural variables selected from 83 variables. The model obtained an area under the receiver-operating characteristic (ROC) curve (AUC) of 0.907 and gave prediction accuracy of 80.8%, sensitivity of 82.7%, specificity of 78.8%, and Matthews correlation coefficient of 61.5%. For the first time, 3 new factors are included in the model: the decreased sodium concentration, the INR value, and the preprocedural glucose level. The newly established model shows excellent predictive ability of CIN development and thereby provides preventative measures for CIN. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  5. Modeling geomagnetic induced currents in Australian power networks

    Science.gov (United States)

    Marshall, R. A.; Kelly, A.; Van Der Walt, T.; Honecker, A.; Ong, C.; Mikkelsen, D.; Spierings, A.; Ivanovich, G.; Yoshikawa, A.

    2017-07-01

    Geomagnetic induced currents (GICs) have been considered an issue for high-latitude power networks for some decades. More recently, GICs have been observed and studied in power networks located in lower latitude regions. This paper presents the results of a model aimed at predicting and understanding the impact of geomagnetic storms on power networks in Australia, with particular focus on the Queensland and Tasmanian networks. The model incorporates a "geoelectric field" determined using a plane wave magnetic field incident on a uniform conducting Earth, and the network model developed by Lehtinen and Pirjola (1985). Model results for two intense geomagnetic storms of solar cycle 24 are compared with transformer neutral monitors at three locations within the Queensland network and one location within the Tasmanian network. The model is then used to assess the impacts of the superintense geomagnetic storm of 29-31 October 2003 on the flow of GICs within these networks. The model results show good correlation with the observations with coefficients ranging from 0.73 to 0.96 across the observing sites. For Queensland, modeled GIC magnitudes during the superstorm of 29-31 October 2003 exceed 40 A with the larger GICs occurring in the south-east section of the network. Modeled GICs in Tasmania for the same storm do not exceed 30 A. The larger distance spans and general east-west alignment of the southern section of the Queensland network, in conjunction with some relatively low branch resistance values, result in larger modeled GICs despite Queensland being a lower latitude network than Tasmania.

  6. An experimental model of hemolysis-induced acute pancreatitis

    Directory of Open Access Journals (Sweden)

    Saruc M.

    2003-01-01

    Full Text Available The literature indicates that acute pancreatitis is a complication of massive hemolysis with a prevalence of about 20%. We describe an experimental model of hemolysis-induced acute pancreatitis. Hemolytic anemia was induced in rats by a single ip injection of 60 mg/kg of 20 mg/ml acetylphenylhydrazine (APH in 20% (v/v ethanol on the first experimental day (day 0. One hundred and fifty Wistar albino rats weighing 180-200 g were divided into three groups of 50 animals each: groups 1, 2 and 3 were injected ip with APH, 20% ethanol, and physiological saline, respectively. Ten rats from each group were sacrificed on study days 1, 2, 3, 4 and 5. Serum amylase, lipase levels and pancreatic tissue tumor necrosis factor-alpha (TNF-alpha and platelet-activating factor (PAF contents were determined and a histological examination of the pancreas was performed. No hemolysis or pancreatitis was observed in any of the rats in groups 2 and 3. In group 1, massive hemolysis was observed in 35 (70% of 50 rats, moderate hemolysis in seven (14%, and no hemolysis in eight (16%. Thirty-three of 35 (94.2% rats with massive hemolysis had hyperamylasemia, and 29 of these rats (82.8% had histologically proven pancreatitis. The most severe pancreatitis occurred on day 3, as demonstrated by histology. Tissue TNF-alpha and PAF levels were statistically higher in group 1 than in groups 2 and 3. Acute massive hemolysis induced acute pancreatitis, as indicated by histology, in almost 80% of cases. Hemolysis may induce acute pancreatitis by triggering the release of proinflammatory and immunoregulatory cytokines.

  7. A novel model for NSAID induced gastroenteropathy in rats.

    Science.gov (United States)

    Singh, Devendra Pratap; Borse, Swapnil P; Nivsarkar, Manish

    2016-01-01

    Progress in management of Nonsteroidal anti-inflammatory drug (NSAID) induced gastrointestinal toxicity requires the availability of appropriate experimental animal models that are as close to humans as feasible. Our objective was to develop a rat model for NSAID-induced gastroenteropathy and also to simulate the common clinical scenario of co-administration of NSAID and proton pump inhibitor (PPI) to explore if PPI contribute to exacerbation of NSAID-enteropathy. Rats were treated twice daily with pantoprazole sodium (PTZ; 10mg/kg peroral) or vehicle for a total of 10days. In some experiments, Diclofenac sodium (DCF; 9mg/kg) or vehicle was administered orally twice daily for the final 5days of PTZ/vehicle administration. After the last dose on 9th day, rats in all the groups were fasted but water was provided ad libitum. 12h after the last dose on 10th day, rats in all the groups were euthanized and their gastrointestinal tracts were assessed for haemorrhagic lesions, lipid peroxidation, intestinal permeability and gastrointestinal luminal pH alterations. Changes in haemoglobin, haematocrit and serum levels of albumin, total protein, ALT and bilirubin were calculated. The macroscopic and histological evidence suggested that administration of DCF resulted in significant gastroenteropathic damage and co-administration of PTZ resulted in significant exacerbation of NSAID enteropathy, while attenuation of NSAID induced gastropathy was observed. Our results were further supported by the significant decrease in haemoglobin and haematocrit levels and serum levels of albumin and total proteins, an increase in oxidative stress and intestinal permeability with the use of DCF either alone or in combination with PTZ. This model was developed to simulate the human clinical situation during NSAID therapy and indeed the present DCF regimen caused both gastric and small bowel alterations, such as multiple erosive lesions, together with a decrease in haemoglobin, haematocrit

  8. Diagnostics and modeling of high pressure streamer induced discharges

    International Nuclear Information System (INIS)

    Marode, E.; Dessante, P.; Deschamps, N.; Deniset, C.

    2001-01-01

    A great variety of diagnostic has been applied to gain information on basic parameter governing high pressure nonthermal filamentary plasmas (and namely streamer induced filamentary discharges). Apart from electrical diagnostics, gas discharge, in contrast with solid state physics, can greatly benefit from all optical techniques owing to its ''transparent'' state. Emission and absorption spectroscopy, as well as LIF or CARS (talk are given during this meeting on these two techniques) are among such specific possibilities. The figures gained from these diagnostic measurements has generally no meaning by itself. They must be worked out, by means of calibrated former results, and/or by using them as input in high pressure plasma modeling. Mixing experimental and modeling approach is necessary for reaching relevant physical knowledge of the high pressure filamentary discharges processes. It is shown that diffusion, and thermal space and time distribution, must fully be taken into account

  9. Useful models for simulating policies to induce technological change

    International Nuclear Information System (INIS)

    Rivers, Nic; Jaccard, Mark

    2006-01-01

    Conventional top-down and bottom-up energy-economy models have limitations that affect their usefulness to policy-makers. Efforts to develop hybrid models, that incorporate valuable aspects of these two frameworks, may be more useful by representing technologies in the energy-economy explicitly while also representing more realistically the way in which businesses and consumers choose between those technologies. This representation allows for the realistic simulation of a wide range of technology-specific regulations and fiscal incentives alongside economy-wide fiscal incentives and disincentives. These policies can be assessed based on the costs required to reach a goal in the medium term, as well as on the degree to which they induce technological change that affects costs over long time periods

  10. Induced Monoculture in Axelrod Model with Clever Mass Media

    Science.gov (United States)

    Rodríguez, Arezky H.; Del Castillo-Mussot, M.; Vázquez, G. J.

    A new model is proposed, in the context of Axelrod's model for the study of cultural dissemination, to include an external vector field (VF) which describes the effects of mass media on social systems. The VF acts over the whole system and it is characterized by two parameters: a nonnull overlap with each agent in the society and a confidence value of its information. Beyond a threshold value of the confidence, there is induced monocultural globalization of the system lined up with the VF. Below this value, the multicultural states are unstable and certain homogenization of the system is obtained in opposite line up according to that we have called negative publicity effect. Three regimes of behavior for the spread process of the VF information as a function of time are reported.

  11. Computer modeling of flow induced in-reactor vibrations

    International Nuclear Information System (INIS)

    Turula, P.; Mulcahy, T.M.

    1977-01-01

    An assessment of the reliability of finite element method computer models, as applied to the computation of flow induced vibration response of components used in nuclear reactors, is presented. The prototype under consideration was the Fast Flux Test Facility reactor being constructed for US-ERDA. Data were available from an extensive test program which used a scale model simulating the hydraulic and structural characteristics of the prototype components, subjected to scaled prototypic flow conditions as well as to laboratory shaker excitations. Corresponding analytical solutions of the component vibration problems were obtained using the NASTRAN computer code. Modal analyses and response analyses were performed. The effect of the surrounding fluid was accounted for. Several possible forcing function definitions were considered. Results indicate that modal computations agree well with experimental data. Response amplitude comparisons are good only under conditions favorable to a clear definition of the structural and hydraulic properties affecting the component motion. 20 refs

  12. Modelling low velocity impact induced damage in composite laminates

    Science.gov (United States)

    Shi, Yu; Soutis, Constantinos

    2017-12-01

    The paper presents recent progress on modelling low velocity impact induced damage in fibre reinforced composite laminates. It is important to understand the mechanisms of barely visible impact damage (BVID) and how it affects structural performance. To reduce labour intensive testing, the development of finite element (FE) techniques for simulating impact damage becomes essential and recent effort by the composites research community is reviewed in this work. The FE predicted damage initiation and propagation can be validated by Non Destructive Techniques (NDT) that gives confidence to the developed numerical damage models. A reliable damage simulation can assist the design process to optimise laminate configurations, reduce weight and improve performance of components and structures used in aircraft construction.

  13. Concise Review: Cardiac Disease Modeling Using Induced Pluripotent Stem Cells.

    Science.gov (United States)

    Yang, Chunbo; Al-Aama, Jumana; Stojkovic, Miodrag; Keavney, Bernard; Trafford, Andrew; Lako, Majlinda; Armstrong, Lyle

    2015-09-01

    Genetic cardiac diseases are major causes of morbidity and mortality. Although animal models have been created to provide some useful insights into the pathogenesis of genetic cardiac diseases, the significant species differences and the lack of genetic information for complex genetic diseases markedly attenuate the application values of such data. Generation of induced pluripotent stem cells (iPSCs) from patient-specific specimens and subsequent derivation of cardiomyocytes offer novel avenues to study the mechanisms underlying cardiac diseases, to identify new causative genes, and to provide insights into the disease aetiology. In recent years, the list of human iPSC-based models for genetic cardiac diseases has been expanding rapidly, although there are still remaining concerns on the level of functionality of iPSC-derived cardiomyocytes and their ability to be used for modeling complex cardiac diseases in adults. This review focuses on the development of cardiomyocyte induction from pluripotent stem cells, the recent progress in heart disease modeling using iPSC-derived cardiomyocytes, and the challenges associated with understanding complex genetic diseases. To address these issues, we examine the similarity between iPSC-derived cardiomyocytes and their ex vivo counterparts and how this relates to the method used to differentiate the pluripotent stem cells into a cardiomyocyte phenotype. We progress to examine categories of congenital cardiac abnormalities that are suitable for iPSC-based disease modeling. © AlphaMed Press.

  14. Ultraviolet radiation-induced carcinogenesis: mechanisms and experimental models

    International Nuclear Information System (INIS)

    Ramasamy, Karthikeyan; Shanmugam, Mohana; Balupillai, Agilan; Govindhasamy, Kanimozhi; Gunaseelan, Srithar; Muthusamy, Ganesan; Robert, Beualah Mary; Nagarajan, Rajendra Prasad

    2017-01-01

    Ultraviolet radiation (UVR) is a very prominent environmental toxic agent. UVR has been implicated in the initiation and progression of photocarcinogenesis. UVR exposure elicits numerous cellular and molecular events which include the generation of inflammatory mediators, DNA damage, epigenetic modifications, and oxidative damages mediated activation of signaling pathways. UVR-initiated signal transduction pathways are believed to be responsible for tumor promotion effects. UVR-induced carcinogenic mechanism has been well studied using various animal and cellular models. Human skin-derived dermal fibroblasts, epidermal keratinocytes, and melanocytes served as excellent cellular model systems for the understanding of UVR-mediated carcinogenic events. Apart from this, scientists developed reconstituted three-dimensional normal human skin equivalent models for the study of UVR signaling pathways. Moreover, hairless mice such as SKH-1, devoid of Hr gene, served as a valuable model for experimental carcinogenesis. Scientists have also used transgenic mice and dorsal portion shaved Swiss albino mice for UVR carcinogenesis studies. In this review, we have discussed the current progress in the study on ultraviolet B (UVB)-mediated carcinogenesis and outlined appropriate experimental models for both ultraviolet A- and UVB-mediated carcinogenesis. (author)

  15. A canine distemper model of virus-induced anergy.

    Science.gov (United States)

    Mangi, R J; Munyer, T P; Krakowka, S; Jacoby, R O; Kantor, F S

    1976-05-01

    For development of an animal model of virus-induced anergy, the effect of canine distemper virus (CDV) upon cell-mediated immunity in dogs was investigated. First, canine cutaneous reactions and in vitro lymphocyte responses to soluble protein antigens were characterized. Dogs immunized with picryl guinea pig albumin and with keyhole limpet hemocyanin (both in complete Freund's adjuvant) responded reproducibly to intracutaneous challenge with these antigens. Reactivity peaked in 20-40 days (maximal induration, 6-50 mm). Lymphocytes from these animals responded in vitro to stimulation with keyhole limpet hemocyanin or purified protein derivative. This stimulation was antigen-specific and was maximal on day 6 of culture. Infection with CDV depressed cutaneous reactivity and lymphocyte response in vitro to antigens and mitogens. This effect was transient in animals previously vaccinated with attenuated CDV; however, gnotobiotic puppies (susceptible to CDV) had prolonged depression of cell-mediated immunity and lymphopenia. Some of these animals developed neurologic symptoms and died. The findings indicate that CDV infection is a potentially useful model for study of virus-induced depression of T (thymus)-cell responses and support the hypothesis that there is more than one mechanism responsible for this phenomenon.

  16. Asparaginase Potentiates Glucocorticoid-Induced Osteonecrosis in a Mouse Model.

    Directory of Open Access Journals (Sweden)

    Chengcheng Liu

    Full Text Available Osteonecrosis is a common dose-limiting toxicity of glucocorticoids. Data from clinical trials suggest that other medications can increase the risk of glucocorticoid-induced osteonecrosis. Here we utilized a mouse model to study the effect of asparaginase treatment on dexamethasone-induced osteonecrosis. Mice receiving asparaginase along with dexamethasone had a higher rate of osteonecrosis than those receiving only dexamethasone after 6 weeks of treatment (44% vs. 10%, P = 0.006. Similarly, epiphyseal arteriopathy, which we have shown to be an initiating event for osteonecrosis, was observed in 58% of mice receiving asparaginase and dexamethasone compared to 17% of mice receiving dexamethasone only (P = 0.007. As in the clinic, greater exposure to asparaginase was associated with greater plasma exposure to dexamethasone (P = 0.0001. This model also recapitulated other clinical risk factors for osteonecrosis, including age at start of treatment, and association with the systemic exposure to dexamethasone (P = 0.027 and asparaginase (P = 0.036. We conclude that asparaginase can potentiate the osteonecrotic effect of glucocorticoids.

  17. STRESS INDUCED OBESITY: LESSONS FROM RODENT MODELS OF STRESS

    Directory of Open Access Journals (Sweden)

    Zachary Robert Patterson

    2013-07-01

    Full Text Available Stress is defined as the behavioral and physiological responses generated in the face of, or in anticipation of, a perceived threat. The stress response involves activation of the sympathetic nervous system and recruitment of the hypothalamic-pituitary-adrenal (HPA axis. When an organism encounters a stressor (social, physical, etc., these endogenous stress systems are stimulated in order to generate a fight-or-flight response, and manage the stressful situation. As such, an organism is forced to liberate energy resources in attempt to meet the energetic demands posed by the stressor. A change in the energy homeostatic balance is thus required to exploit an appropriate resource and deliver useable energy to the target muscles and tissues involved in the stress response. Acutely, this change in energy homeostasis and the liberation of energy is considered advantageous, as it is required for the survival of the organism. However, when an organism is subjected to a prolonged stressor, as is the case during chronic stress, a continuous irregularity in energy homeostasis is considered detrimental and may lead to the development of metabolic disturbances such as cardiovascular disease, type II diabetes mellitus and obesity. This concept has been studied extensively using animal models, and the neurobiological underpinnings of stress induced metabolic disorders are beginning to surface. However, different animal models of stress continue to produce divergent metabolic phenotypes wherein some animals become anorexic and loose body mass while others increase food intake and body mass and become vulnerable to the development of metabolic disturbances. It remains unclear exactly what factors associated with stress models can be used to predict the metabolic outcome of the organism. This review will explore a variety of rodent stress models and discuss the elements that influence the metabolic outcome in order to further our understanding of stress-induced

  18. Modeling human neurological disorders with induced pluripotent stem cells.

    Science.gov (United States)

    Imaizumi, Yoichi; Okano, Hideyuki

    2014-05-01

    Human induced pluripotent stem (iPS) cells obtained by reprogramming technology are a source of great hope, not only in terms of applications in regenerative medicine, such as cell transplantation therapy, but also for modeling human diseases and new drug development. In particular, the production of iPS cells from the somatic cells of patients with intractable diseases and their subsequent differentiation into cells at affected sites (e.g., neurons, cardiomyocytes, hepatocytes, and myocytes) has permitted the in vitro construction of disease models that contain patient-specific genetic information. For example, disease-specific iPS cells have been established from patients with neuropsychiatric disorders, including schizophrenia and autism, as well as from those with neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. A multi-omics analysis of neural cells originating from patient-derived iPS cells may thus enable investigators to elucidate the pathogenic mechanisms of neurological diseases that have heretofore been unknown. In addition, large-scale screening of chemical libraries with disease-specific iPS cells is currently underway and is expected to lead to new drug discovery. Accordingly, this review outlines the progress made via the use of patient-derived iPS cells toward the modeling of neurological disorders, the testing of existing drugs, and the discovery of new drugs. The production of human induced pluripotent stem (iPS) cells from the patients' somatic cells and their subsequent differentiation into specific cells have permitted the in vitro construction of disease models that contain patient-specific genetic information. Furthermore, innovations of gene-editing technologies on iPS cells are enabling new approaches for illuminating the pathogenic mechanisms of human diseases. In this review article, we outlined the current status of neurological diseases-specific iPS cell research and described recently obtained

  19. Elastase-induced pulmonary emphysema: insights from experimental models

    Directory of Open Access Journals (Sweden)

    Mariana A. Antunes

    2011-12-01

    Full Text Available Several distinct stimuli can be used to reproduce histological and functional features of human emphysema, a leading cause of disability and death. Since cigarette smoke is the main cause of emphysema in humans, experimental researches have attempted to reproduce this situation. However, this is an expensive and cumbersome method of emphysema induction, and simpler, more efficacious alternatives have been sought. Among these approaches, elastolytic enzymes have been widely used to reproduce some characteristics of human cigarette smoke-induced disease, such as: augmentation of airspaces, inflammatory cell influx into the lungs, and systemic inflammation. Nevertheless, the use of elastase-induced emphysema models is still controversial, since the disease pathways involved in elastase induction may differ from those occurring in smoke-induced emphysema. This indicates that the choice of an emphysema model may impact the results of new therapies or drugs being tested. The aim of this review is to compare the mechanisms of disease induction in smoke and elastase emphysema models, to describe the differences among various elastase models, and to establish the advantages and disadvantages of elastase-induced emphysema models. More studies are required to shed light on the mechanisms of elastase-induced emphysema.Diversos estímulos podem ser utilizados para reproduzir características histológicas e funcionais do enfisema humano, uma das principais causas de incapacidade e morte. Uma vez que a fumaça de cigarro é a principal causa de enfisema em humanos, estudos experimentais têm tentado reproduzir esta situação. No entanto, esse é um método dispendioso e complicado para a indução do enfisema e, alternativas mais simples e eficazes, têm sido pesquisadas. Entre essas abordagens, enzimas elastolíticas vêm sendo amplamente utilizadas para reproduzir algumas das características do enfisema humano, tais como: aumento dos espaços a

  20. Revisiting the mouse model of oxygen-induced retinopathy

    Directory of Open Access Journals (Sweden)

    Kim CB

    2016-05-01

    Full Text Available Clifford B Kim,1,2 Patricia A D’Amore,2–4 Kip M Connor1,2 1Angiogenesis Laboratory, Massachusetts Eye and Ear, 2Department of Ophthalmology, Harvard Medical School, 3Schepens Eye Research Institute, Massachusetts Eye and Ear, 4Department of Pathology, Harvard Medical School, Boston, MA, USA Abstract: Abnormal blood vessel growth in the retina is a hallmark of many retinal diseases, such as retinopathy of prematurity (ROP, proliferative diabetic retinopathy, and the wet form of age-related macular degeneration. In particular, ROP has been an important health concern for physicians since the advent of routine supplemental oxygen therapy for premature neonates more than 70 years ago. Since then, researchers have explored several animal models to better understand ROP and retinal vascular development. Of these models, the mouse model of oxygen-induced retinopathy (OIR has become the most widely used, and has played a pivotal role in our understanding of retinal angiogenesis and ocular immunology, as well as in the development of groundbreaking therapeutics such as anti-vascular endothelial growth factor injections for wet age-related macular degeneration. Numerous refinements to the model have been made since its inception in the 1950s, and technological advancements have expanded the use of the model across multiple scientific fields. In this review, we explore the historical developments that have led to the mouse OIR model utilized today, essential concepts of OIR, limitations of the model, and a representative selection of key findings from OIR, with particular emphasis on current research progress. Keywords: ROP, OIR, angiogenesis

  1. Sex and smoking sensitive model of radon induced lung cancer

    International Nuclear Information System (INIS)

    Zhukovsky, M.; Yarmoshenko, I.

    2006-01-01

    Radon and radon progeny inhalation exposure are recognized to cause lung cancer. Only strong evidence of radon exposure health effects was results of epidemiological studies among underground miners. Any single epidemiological study among population failed to find reliable lung cancer risk due to indoor radon exposure. Indoor radon induced lung cancer risk models were developed exclusively basing on extrapolation of miners data. Meta analyses of indoor radon and lung cancer case control studies allowed only little improvements in approaches to radon induced lung cancer risk projections. Valuable data on characteristics of indoor radon health effects could be obtained after systematic analysis of pooled data from single residential radon studies. Two such analyses are recently published. Available new and previous data of epidemiological studies of workers and general population exposed to radon and other sources of ionizing radiation allow filling gaps in knowledge of lung cancer association with indoor radon exposure. The model of lung cancer induced by indoor radon exposure is suggested. The key point of this model is the assumption that excess relative risk depends on both sex and smoking habits of individual. This assumption based on data on occupational exposure by radon and plutonium and also on the data on external radiation exposure in Hiroshima and Nagasaki and the data on external exposure in Mayak nuclear facility. For non-corrected data of pooled European and North American studies the increased sensitivity of females to radon exposure is observed. The mean value of ks for non-corrected data obtained from independent source is in very good agreement with the L.S.S. study and Mayak plutonium workers data. Analysis of corrected data of pooled studies showed little influence of sex on E.R.R. value. The most probable cause of such effect is the change of men/women and smokers/nonsmokers ratios in corrected data sets in North American study. More correct

  2. Sex and smoking sensitive model of radon induced lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zhukovsky, M.; Yarmoshenko, I. [Institute of Industrial Ecology of Ural Branch of Russian Academy of Sciences, Yekaterinburg (Russian Federation)

    2006-07-01

    Radon and radon progeny inhalation exposure are recognized to cause lung cancer. Only strong evidence of radon exposure health effects was results of epidemiological studies among underground miners. Any single epidemiological study among population failed to find reliable lung cancer risk due to indoor radon exposure. Indoor radon induced lung cancer risk models were developed exclusively basing on extrapolation of miners data. Meta analyses of indoor radon and lung cancer case control studies allowed only little improvements in approaches to radon induced lung cancer risk projections. Valuable data on characteristics of indoor radon health effects could be obtained after systematic analysis of pooled data from single residential radon studies. Two such analyses are recently published. Available new and previous data of epidemiological studies of workers and general population exposed to radon and other sources of ionizing radiation allow filling gaps in knowledge of lung cancer association with indoor radon exposure. The model of lung cancer induced by indoor radon exposure is suggested. The key point of this model is the assumption that excess relative risk depends on both sex and smoking habits of individual. This assumption based on data on occupational exposure by radon and plutonium and also on the data on external radiation exposure in Hiroshima and Nagasaki and the data on external exposure in Mayak nuclear facility. For non-corrected data of pooled European and North American studies the increased sensitivity of females to radon exposure is observed. The mean value of ks for non-corrected data obtained from independent source is in very good agreement with the L.S.S. study and Mayak plutonium workers data. Analysis of corrected data of pooled studies showed little influence of sex on E.R.R. value. The most probable cause of such effect is the change of men/women and smokers/nonsmokers ratios in corrected data sets in North American study. More correct

  3. Using Human Induced Pluripotent Stem Cells to Model Skeletal Diseases.

    Science.gov (United States)

    Barruet, Emilie; Hsiao, Edward C

    2016-01-01

    Musculoskeletal disorders affecting the bones and joints are major health problems among children and adults. Major challenges such as the genetic origins or poor diagnostics of severe skeletal disease hinder our understanding of human skeletal diseases. The recent advent of human induced pluripotent stem cells (human iPS cells) provides an unparalleled opportunity to create human-specific models of human skeletal diseases. iPS cells have the ability to self-renew, allowing us to obtain large amounts of starting material, and have the potential to differentiate into any cell types in the body. In addition, they can carry one or more mutations responsible for the disease of interest or be genetically corrected to create isogenic controls. Our work has focused on modeling rare musculoskeletal disorders including fibrodysplasia ossificans progressive (FOP), a congenital disease of increased heterotopic ossification. In this review, we will discuss our experiences and protocols differentiating human iPS cells toward the osteogenic lineage and their application to model skeletal diseases. A number of critical challenges and exciting new approaches are also discussed, which will allow the skeletal biology field to harness the potential of human iPS cells as a critical model system for understanding diseases of abnormal skeletal formation and bone regeneration.

  4. Relaxation model of radiation-induced conductivity in polymers

    Science.gov (United States)

    Zhutayeva, Yu. R.; Khatipov, S. A.

    1999-05-01

    The paper suggests a relaxation model of radiation-induced conductivity (RIC) in polymers. According to the model, the transfer of charges generated in the polymer volume by ionizing radiation takes place with the participation of molecular relaxation processes. The mechanism of electron transport consists in the transfer of the charge directly between traps when they draw close to one another due to the rotation of macromolecule segments. The numerical solutions of the corresponding kinetic equations for different distribution functions Q( τ) of the times of molecular relaxation and for different functions of the probability P( τ, τ') of charge transfer in the `overlapping' regions of the diffusion spheres of the segments are analyzed. The relaxation model provides an explanation of the non-Arrhenius behavior of the RIC temperature dependence, the power dependence of RIC on the dose rate with a power index in the interval 0.5-1.0, the appearance of maxima in the curves of the RIC temporal dependence and their irreversible character in the region of large dose rates (more than 1 Gy/s). The model can be used for interpreting polymer RIC in conditions of kinetic mobility of macromolecules.

  5. Cannabis exacerbates depressive symptoms in rat model induced by reserpine.

    Science.gov (United States)

    Khadrawy, Yasser A; Sawie, Hussein G; Abdel-Salam, Omar M E; Hosny, Eman N

    2017-05-01

    Cannabis sativa is one of the most widely recreational drugs and its use is more prevalent among depressed patients. Some studies reported that Cannabis has antidepressant effects while others showed increased depressive symptoms in Cannabis users. Therefore, the present study aims to investigate the effect of Cannabis extract on the depressive-like rats. Twenty four rats were divided into: control, rat model of depression induced by reserpine and depressive-like rats treated with Cannabis sativa extract (10mg/kg expressed as Δ9-tetrahydrocannabinol). The depressive-like rats showed a severe decrease in motor activity as assessed by open field test (OFT). This was accompanied by a decrease in monoamine levels and a significant increase in acetylcholinesterase activity in the cortex and hippocampus. Na + ,K + -ATPase activity increased in the cortex and decreased in the hippocampus of rat model. In addition, a state of oxidative stress was evident in the two brain regions. This was indicated from the significant increase in the levels of lipid peroxidation and nitric oxide. No signs of improvement were observed in the behavioral and neurochemical analyses in the depressive-like rats treated with Cannabis extract. Furthermore, Cannabis extract exacerbated the lipid peroxidation in the cortex and hippocampus. According to the present findings, it could be concluded that Cannabis sativa aggravates the motor deficits and neurochemical changes induced in the cortex and hippocampus of rat model of depression. Therefore, the obtained results could explain the reported increase in the depressive symptoms and memory impairment among Cannabis users. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Induced pluripotent stem cell-derived neuron as a human model for testing environmentally induced developmental neurotoxicity

    Science.gov (United States)

    Induced pluripotent stem cell-derived neurons as a human model for testing environmentally induced developmental neurotoxicity Ingrid L. Druwe1, Timothy J. Shafer2, Kathleen Wallace2, Pablo Valdivia3 ,and William R. Mundy2. 1University of North Carolina, Curriculum in Toxicology...

  7. Collagen-Induced Arthritis: A model for Murine Autoimmune Arthritis.

    Science.gov (United States)

    Pietrosimone, K M; Jin, M; Poston, B; Liu, P

    2015-10-20

    Collagen-induced arthritis (CIA) is a common autoimmune animal model used to study rheumatoid arthritis (RA). The development of CIA involves infiltration of macrophages and neutrophils into the joint, as well as T and B cell responses to type II collagen. In murine CIA, genetically susceptible mice (DBA/1J) are immunized with a type II bovine collagen emulsion in complete Freund's adjuvant (CFA), and receive a boost of type II bovine collagen in incomplete Freund's adjuvant (IFA) 21 days after the first injection. These mice typically develop disease 26 to 35 days after the initial injection. C57BL/6J mice are resistant to arthritis induced by type II bovine collagen, but can develop arthritis when immunized with type II chicken collagen in CFA, and receive a boost of type II chicken collagen in IFA 21 days after the first injection. The concentration of heat-killed Mycobacterium tuberculosis H37RA (MT) in CFA also differs for each strain. DBA/1J mice develop arthritis with 1 mg/ml MT, while C57BL/6J mice require and 3-4 mg/ml MT in order to develop arthritis. CIA develops slowly in C57BL/6J mice and cases of arthritis are mild when compared to DBA/1J mice. This protocol describes immunization of DBA/1J mice with type II bovine collagen and the immunization of C57BL/6J mice with type II chicken collagen.

  8. Predictive model for convective flows induced by surface reactivity contrast

    Science.gov (United States)

    Davidson, Scott M.; Lammertink, Rob G. H.; Mani, Ali

    2018-05-01

    Concentration gradients in a fluid adjacent to a reactive surface due to contrast in surface reactivity generate convective flows. These flows result from contributions by electro- and diffusio-osmotic phenomena. In this study, we have analyzed reactive patterns that release and consume protons, analogous to bimetallic catalytic conversion of peroxide. Similar systems have typically been studied using either scaling analysis to predict trends or costly numerical simulation. Here, we present a simple analytical model, bridging the gap in quantitative understanding between scaling relations and simulations, to predict the induced potentials and consequent velocities in such systems without the use of any fitting parameters. Our model is tested against direct numerical solutions to the coupled Poisson, Nernst-Planck, and Stokes equations. Predicted slip velocities from the model and simulations agree to within a factor of ≈2 over a multiple order-of-magnitude change in the input parameters. Our analysis can be used to predict enhancement of mass transport and the resulting impact on overall catalytic conversion, and is also applicable to predicting the speed of catalytic nanomotors.

  9. Modeling Neuropsychiatric and Neurodegenerative Diseases With Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Elizabeth A. LaMarca

    2018-04-01

    Full Text Available Human-induced pluripotent stem cells (hiPSCs have revolutionized our ability to model neuropsychiatric and neurodegenerative diseases, and recent progress in the field is paving the way for improved therapeutics. In this review, we discuss major advances in generating hiPSC-derived neural cells and cutting-edge techniques that are transforming hiPSC technology, such as three-dimensional “mini-brains” and clustered, regularly interspersed short palindromic repeats (CRISPR-Cas systems. We examine specific examples of how hiPSC-derived neural cells are being used to uncover the pathophysiology of schizophrenia and Parkinson’s disease, and consider the future of this groundbreaking research.

  10. A minimal model of burst-noise induced bistability.

    Directory of Open Access Journals (Sweden)

    Johannes Falk

    Full Text Available We investigate the influence of intrinsic noise on stable states of a one-dimensional dynamical system that shows in its deterministic version a saddle-node bifurcation between monostable and bistable behaviour. The system is a modified version of the Schlögl model, which is a chemical reaction system with only one type of molecule. The strength of the intrinsic noise is varied without changing the deterministic description by introducing bursts in the autocatalytic production step. We study the transitions between monostable and bistable behavior in this system by evaluating the number of maxima of the stationary probability distribution. We find that changing the size of bursts can destroy and even induce saddle-node bifurcations. This means that a bursty production of molecules can qualitatively change the dynamics of a chemical reaction system even when the deterministic description remains unchanged.

  11. A current induced diffusion model of gas sputtering

    International Nuclear Information System (INIS)

    Hotston, E.S.

    1980-01-01

    A model is proposed to explain the experimental results on deuteron trapping in stainless steel targets at low temperatures carried out at Garching and Culham. The model proposes that the ions are trapped in two kinds of sites: Deep sites with high activation energy and shallow sites of low activation energy. Trapped deuterons reach the surface of the target by being expelled from shallow sites by the action of the ion beam and migrate to nearby sites in a random way, thus moving by a bombardment induced diffusion. Ions diffusing to the target surface and being released are said to be sputtered from the target. It has been necessary to assume numerical values for sizes of some of the processes which occur. With a suitable choice of values the model successfully predicts the numbers of deuterons trapped per unit area of the target, the obserbed density profile of the trapped ions and the threshold at which sputtering starts. The model also successfully describes the replacement of the trapped deuterons by protons, when the deuteron beam is replaced by a proton beam. The collision cross-section for beam ions and ions trapped in shallow sites is too large, 4 x 10 -13 cm 2 , for a binary collision and it is tentatively suggested that the ions in the shallow sites may be in small voids in the target which may be connected with blister formation. Comparison of the present model with one being developed to describe the trapping of deuterons in carbon suggests that it may be possible to describe all gas sputtering experiments in terms of diffusion processes. (orig.)

  12. Ketamine induced renal fibrosis in a ketamine addition rat model

    Directory of Open Access Journals (Sweden)

    Mei-Yu Jang

    2017-09-01

    Conclusion: Ketamine treatment not only induced cystitis-like syndrome, but also renal fibrosis. These renal interstitial fibrosis changes may be induced by the TGF-β pathway. These preliminary results can provide valuable information from a clinical perspective.

  13. Antinociception induced by atorvastatin in different pain models.

    Science.gov (United States)

    Garcia, G G; Miranda, H F; Noriega, V; Sierralta, F; Olavarría, L; Zepeda, R J; Prieto, J C

    2011-11-01

    Atorvastatin is a statin that inhibits the 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase. Several landmark clinical trials have demonstrated the beneficial effects of statin therapy for primary and secondary prevention of cardiovascular disease. It is assumed that the beneficial effects of statin therapy are entirely due to cholesterol reduction. Statins have an additional activity (pleiotropic effect) that has been associated to their anti-inflammatory effects. The aim of the present study was to assess the antinociceptive activity of atorvastatin in five animal pain models. The daily administration of 3-100mg/kg of atorvastatin by oral gavage induced a significant dose-dependent antinociception in the writhing, tail-flick, orofacial formalin and formalin hind paw tests. However, this antinociceptive activity of atorvastatin was detectable only at high concentrations in the hot plate assay. The data obtained in the present study demonstrates the effect of atorvastatin to reduce nociception and inflammation in different animal pain models. Copyright © 2011 Elsevier Inc. All rights reserved.

  14. Cosmology of a holographic induced gravity model with curvature effects

    International Nuclear Information System (INIS)

    Bouhmadi-Lopez, Mariam; Errahmani, Ahmed; Ouali, Taoufiq

    2011-01-01

    We present a holographic model of the Dvali-Gabadadze-Porrati scenario with a Gauss-Bonnet term in the bulk. We concentrate on the solution that generalizes the normal Dvali-Gabadadze-Porrati branch. It is well known that this branch cannot describe the late-time acceleration of the universe even with the inclusion of a Gauss-Bonnet term. Here, we show that this branch in the presence of a Gauss-Bonnet curvature effect and a holographic dark energy with the Hubble scale as the infrared cutoff can describe the late-time acceleration of the universe. It is worthwhile to stress that such an energy density component cannot do the same job on the normal Dvali-Gabadadze-Porrati branch (without Gauss-Bonnet modifications) nor in a standard four-dimensional relativistic model. The acceleration on the brane is also presented as being induced through an effective dark energy which corresponds to a balance between the holographic one and geometrical effects encoded through the Hubble parameter.

  15. Hybrid model of the radiation-induced bystander effect

    International Nuclear Information System (INIS)

    Braga, Viviane V.B.; Faria, Fernando Pereira de; Grynberg, Suely Epsztein

    2013-01-01

    The radiation-induced bystander effect (RIBE) refer to biological alterations in non-irradiated cells that occupy the same medium (culture or tissue) of irradiated cells. The biochemical mechanisms of the RIBE are not completely elucidated. However, several experiments indicate its existence. The objective of this work is to quantify the effect via stochastic and deterministic approaches. The hypotheses of the model are: a) one non-irradiated healthy cell interacts with signals that propagate through the medium. These signals are released by irradiated cells. At the time of interaction cell-signal, the cell can become damaged and signaling or damage and not signaling; b) Both types of damage cells repair with certain rate becoming health cells; c) The diffusion of signals obey the discrete diffusion equation with decay in two dimensions. d) The signal concentration released by irradiated cells depends on the dose in the low dose range (< 0.3 Gy) and saturates for higher dose values. As expected, the temporal analysis of the model as a function of the repair rate shows that the survival fraction decreases as the repair rate is reduced. The analysis of the extent of damage triggered by a signal concentration released by a single irradiated cell at time zero show that the damage grows with the maximum simulation time. The results show good agreement with the experimental data. The stochastic and deterministic methods used are in qualitative agreement, as expected. (author)

  16. Hybrid model of the radiation-induced bystander effect

    Energy Technology Data Exchange (ETDEWEB)

    Braga, Viviane V.B.; Faria, Fernando Pereira de; Grynberg, Suely Epsztein, E-mail: vitoriabraga06@gmail.com, E-mail: fernandopereirabh@gmail.com, E-mail: seg@cdtn.br [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil)

    2013-07-01

    The radiation-induced bystander effect (RIBE) refer to biological alterations in non-irradiated cells that occupy the same medium (culture or tissue) of irradiated cells. The biochemical mechanisms of the RIBE are not completely elucidated. However, several experiments indicate its existence. The objective of this work is to quantify the effect via stochastic and deterministic approaches. The hypotheses of the model are: a) one non-irradiated healthy cell interacts with signals that propagate through the medium. These signals are released by irradiated cells. At the time of interaction cell-signal, the cell can become damaged and signaling or damage and not signaling; b) Both types of damage cells repair with certain rate becoming health cells; c) The diffusion of signals obey the discrete diffusion equation with decay in two dimensions. d) The signal concentration released by irradiated cells depends on the dose in the low dose range (< 0.3 Gy) and saturates for higher dose values. As expected, the temporal analysis of the model as a function of the repair rate shows that the survival fraction decreases as the repair rate is reduced. The analysis of the extent of damage triggered by a signal concentration released by a single irradiated cell at time zero show that the damage grows with the maximum simulation time. The results show good agreement with the experimental data. The stochastic and deterministic methods used are in qualitative agreement, as expected. (author)

  17. Olfactory-Induced Synesthesias: A Review and Model

    Science.gov (United States)

    Stevenson, Richard J.; Tomiczek, Caroline

    2007-01-01

    Recent reviews of synesthesia concentrate upon rare neurodevelopmental examples and exclude common olfactory-induced experiences with which they may profitably be compared. Like the neurodevelopmental synesthesias, odor-induced experiences involve different sensory modalities; are reliable, asymmetric (concurrents cannot induce), and automatic;…

  18. STAT3, a Key Parameter of Cytokine-driven Tissue Protection During Sterile Inflammation – the Case of Experimental Acetaminophen (Paracetamol-induced Liver Damage

    Directory of Open Access Journals (Sweden)

    Heiko eMühl

    2016-05-01

    Full Text Available Acetaminophen (APAP, N-acetyl-p-aminophenol, or paracetamol overdosing is a prevalent cause of acute liver injury. While clinical disease is initiated by overt parenchymal hepatocyte necrosis in response to the analgetic, course of intoxication is substantially influenced by associated activation of innate immunity. This process is supposed to be set in motion by release of danger associated molecular patterns (DAMPs from dying hepatocytes and is accompanied by an inflammatory cytokine response. Murine models of APAP-induced liver injury emphasize the complex role that DAMPs and cytokines play in promoting either hepatic pathogenesis or resolution and recovery from intoxication. Whereas the function of key inflammatory cytokines is controversially discussed, a subclass of specific cytokines capable of efficiently activating the hepatocyte signal transducer and activator of transcription (STAT-3 pathway stands out as being consistently protective in murine models of APAP intoxication. Those include foremost interleukin (IL-6, IL-11, IL-13, and IL-22. Above all, activation of STAT3 under the influence of these cytokines has the capability to drive hepatocyte compensatory proliferation, a key principle of the regenerating liver. Herein, the role of these specific cytokines during experimental APAP-induced liver injury is highlighted and discussed in a broader perspective. In hard-to-treat or at-risk patients standard therapy may fail and APAP intoxication can proceed towards a fatal condition. Focused administration of recombinant STAT3-activating cytokines may evolve as novel therapeutic approach under those ill-fated conditions.

  19. Development of porcine model of chronic tachycardia-induced cardiomyopathy.

    Science.gov (United States)

    Paslawska, Urszula; Gajek, Jacek; Kiczak, Liliana; Noszczyk-Nowak, Agnieszka; Skrzypczak, Piotr; Bania, Jacek; Tomaszek, Alicja; Zacharski, Maciej; Sambor, Izabela; Dziegiel, Piotr; Zysko, Dorota; Banasiak, Waldemar; Jankowska, Ewa A; Ponikowski, Piotr

    2011-11-17

    There are few experimental models of heart failure (HF) in large animals, despite structural and functional similarities to human myocardium. We have developed a porcine model of chronic tachycardia-induced cardiomyopathy. Homogenous siblings of White Large breed swine (n=6) underwent continuous right ventricular (RV) pacing at 170 bpm; 2 subjects served as controls. In the course of RV pacing, animals developed a clinical picture of HF and were presented for euthanasia at subsequent stages: mild, moderate and end-stage HF. Left ventricle (LV) sections were analyzed histologically and relative ANP, BNP, phospholamban and sarcoplasmic reticulum calcium ATPase 2a transcript levels in LV were quantified by real time RT-PCR. In the course of RV pacing, animals demonstrated reduced exercise capacity (time of running until being dyspnoeic: 6.6 ± 0.5 vs. 2.4 ± 1.4 min), LV dilatation (LVEDD: 4.9 ± 0.4 vs. 6.7 ± 0.4 cm), impaired LV systolic function (LVEF: 69 ± 8 vs. 32 ± 7 %), (all baseline vs. before euthanasia, all p<0.001). LV tissues from animals with moderate and end-stage HF demonstrated local foci of interstitial fibrosis, congestion, cardiomyocyte hypertrophy and atrophy, which was not detected in controls and mild HF animals. The up-regulation of ANP and BNP and a reduction in a ratio of sarcoplasmic reticulum calcium ATPase 2a and phospholamban in failing myocardium were observed as compared to controls. In pigs, chronic RV pacing at relatively low rate can be used as an experimental model of HF, as it results in a gradual deterioration of exercise tolerance accompanied by myocardial remodeling confirmed at subcellular level. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  20. Tamoxifen induces regression of estradiol-induced mammary cancer in ACI.COP-Ept2 rat model

    OpenAIRE

    Ruhlen, Rachel L.; Willbrand, Dana M.; Besch-Williford, Cynthia L.; Ma, Lixin; Shull, James D.; Sauter, Edward R.

    2008-01-01

    The ACI rat is a unique model of human breast cancer in that mammary cancers are induced by estrogen without carcinogens, irradiation, xenografts or transgenic manipulations. We sought to characterize mammary cancers in a congenic variant of the ACI rat, the ACI.COP-Ept2. All rats with estradiol implants developed mammary cancers in 5–7 months. Rats bearing estradiol-induced mammary cancers were treated with tamoxifen for three weeks. Tamoxifen reduced tumor mass, measured by magnetic resonan...

  1. Induced polarization of clay-sand mixtures: experiments and modeling

    International Nuclear Information System (INIS)

    Okay, G.; Leroy, P.; Tournassat, C.; Ghorbani, A.; Jougnot, D.; Cosenza, P.; Camerlynck, C.; Cabrera, J.; Florsch, N.; Revil, A.

    2012-01-01

    were performed with a cylindrical four-electrode sample-holder (cylinder made of PVC with 30 cm in length and 19 cm in diameter) associated with a SIP-Fuchs II impedance meter and non-polarizing Cu/CuSO 4 electrodes. These electrodes were installed at 10 cm from the base of the sample holder and regularly spaced (each 90 degree). The results illustrate the strong impact of the Cationic Exchange Capacity (CEC) of the clay minerals upon the complex conductivity. The amplitude of the in-phase conductivity of the kaolinite-clay samples is strongly dependent to saturating fluid salinity for all volumetric clay fractions, whereas the in-phase conductivity of the smectite-clay samples is quite independent on the salinity, except at the low clay content (5% and 1% of clay in volume). This is due to the strong and constant surface conductivity of smectite associated with its very high CEC. The quadrature conductivity increases steadily with the CEC and the clay content. We observe that the dependence on frequency of the quadrature conductivity of sand-kaolinite mixtures is more important than for sand-bentonite mixtures. For both types of clay, the quadrature conductivity seems to be fairly independent on the pore fluid salinity except at very low clay contents (1% in volume of kaolinite-clay). This is due to the constant surface site density of Na counter-ions in the Stern layer of clay materials. At the lowest clay content (1%), the magnitude of the quadrature conductivity increases with the salinity, as expected for silica sands. In this case, the surface site density of Na counter-ions in the Stern layer increases with salinity. The experimental data show good agreement with predicted values given by our Spectral Induced Polarization (SIP) model. This complex conductivity model considers the electrochemical polarization of the Stern layer coating the clay particles and the Maxwell-Wagner polarization. We use the differential effective medium theory to calculate the complex

  2. Acrylamide induces accelerated endothelial aging in a human cell model.

    Science.gov (United States)

    Sellier, Cyril; Boulanger, Eric; Maladry, François; Tessier, Frédéric J; Lorenzi, Rodrigo; Nevière, Rémi; Desreumaux, Pierre; Beuscart, Jean-Baptiste; Puisieux, François; Grossin, Nicolas

    2015-09-01

    Acrylamide (AAM) has been recently discovered in food as a Maillard reaction product. AAM and glycidamide (GA), its metabolite, have been described as probably carcinogenic to humans. It is widely established that senescence and carcinogenicity are closely related. In vitro, endothelial aging is characterized by replicative senescence in which primary cells in culture lose their ability to divide. Our objective was to assess the effects of AAM and GA on human endothelial cell senescence. Human umbilical vein endothelial cells (HUVECs) cultured in vitro were used as model. HUVECs were cultured over 3 months with AAM or GA (1, 10 or 100 μM) until growth arrest. To analyze senescence, β-galactosidase activity and telomere length of HUVECs were measured by cytometry and semi-quantitative PCR, respectively. At all tested concentrations, AAM or GA reduced cell population doubling compared to the control condition (p < 0.001). β-galactosidase activity in endothelial cells was increased when exposed to AAM (≥10 μM) or GA (≥1 μM) (p < 0.05). AAM (≥10 μM) or GA (100 μM) accelerated telomere shortening in HUVECs (p < 0.05). In conclusion, in vitro chronic exposure to AAM or GA at low concentrations induces accelerated senescence. This result suggests that an exposure to AAM might contribute to endothelial aging. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Aspartame induces angiogenesis in vitro and in vivo models.

    Science.gov (United States)

    Yesildal, F; Aydin, F N; Deveci, S; Tekin, S; Aydin, I; Mammadov, R; Fermanli, O; Avcu, F; Acikel, C H; Ozgurtas, T

    2015-03-01

    Angiogenesis is the process of generating new blood vessels from preexisting vessels and is considered essential in many pathological conditions. The purpose of the present study is to evaluate the effect of aspartame on angiogenesis in vivo chick chorioallantoic membrane (CAM) and wound-healing models as well as in vitro 2,3-bis-2H-tetrazolium-5-carboxanilide (XTT) and tube formation assays. In CAM assay, aspartame increased angiogenesis in a concentration-dependent manner. Compared with the control group, aspartame has significantly increased vessel proliferation (p aspartame group had better healing than control group, and this was statistically significant at p aspartame on human umbilical vein endothelial cells on XTT assay in vitro, but it was not statistically significant; and there was no antiangiogenic effect of aspartame on tube formation assay in vitro. These results provide evidence that aspartame induces angiogenesis in vitro and in vivo; so regular use may have undesirable effect on susceptible cases. © The Author(s) 2015.

  4. Monte Carlo modeling of ion beam induced secondary electrons

    Energy Technology Data Exchange (ETDEWEB)

    Huh, U., E-mail: uhuh@vols.utk.edu [Biochemistry & Cellular & Molecular Biology, University of Tennessee, Knoxville, TN 37996-0840 (United States); Cho, W. [Electrical and Computer Engineering, University of Tennessee, Knoxville, TN 37996-2100 (United States); Joy, D.C. [Biochemistry & Cellular & Molecular Biology, University of Tennessee, Knoxville, TN 37996-0840 (United States); Center for Nanophase Materials Science, Oak Ridge National Laboratory, Oak Ridge, TN 37831 (United States)

    2016-09-15

    Ion induced secondary electrons (iSE) can produce high-resolution images ranging from a few eV to 100 keV over a wide range of materials. The interpretation of such images requires knowledge of the secondary electron yields (iSE δ) for each of the elements and materials present and as a function of the incident beam energy. Experimental data for helium ions are currently limited to 40 elements and six compounds while other ions are not well represented. To overcome this limitation, we propose a simple procedure based on the comprehensive work of Berger et al. Here we show that between the energy range of 10–100 keV the Berger et al. data for elements and compounds can be accurately represented by a single universal curve. The agreement between the limited experimental data that is available and the predictive model is good, and has been found to provide reliable yield data for a wide range of elements and compounds. - Highlights: • The Universal ASTAR Yield Curve was derived from data recently published by NIST. • IONiSE incorporated with the Curve will predict iSE yield for elements and compounds. • This approach can also handle other ion beams by changing basic scattering profile.

  5. Development of bubble-induced turbulence model for advanced two-fluid model

    International Nuclear Information System (INIS)

    Hosoi, Hideaki; Yoshida, Hiroyuki

    2011-01-01

    A two-fluid model can simulate two-phase flow by computational cost less than detailed two-phase flow simulation method such as interface tracking method. The two-fluid model is therefore useful for thermal hydraulic analysis in the large-scale domain such as rod bundles. However, since the two-fluid model includes a lot of constitutive equations verified by use of experimental results, it has problems that the result of analyses depends on accuracy of the constitutive equations. To solve these problems, an advanced two-fluid model has been developed by Japan Atomic Energy Agency. In this model, interface tracking method is combined with two-fluid model to accurately predict large interface structure behavior. Liquid clusters and bubbles larger than a computational cell are calculated using the interface tracking method, and those smaller than the cell are simulated by the two-fluid model. The constitutive equations to evaluate the effects of small bubbles or droplets on two-phase flow are also required in the advanced two-fluid model, just as with the conventional two-fluid model. However, the dependency of small bubbles and droplets on two-phase flow characteristics is relatively small, and fewer experimental results are required to verify the characteristics of large interface structures. Turbulent dispersion force model is one of the most important constitutive equations for the advanced two-fluid model. The turbulent dispersion force model has been developed by many researchers for the conventional two-fluid model. However, existing models implicitly include the effects of large bubbles and the deformation of bubbles, and are unfortunately not applicable to the advanced two-fluid model. In the previous study, the authors suggested the turbulent dispersion force model based on the analogy of Brownian motion. And the authors improved the turbulent dispersion force model in consideration of bubble-induced turbulence to improve the analysis results for small

  6. An effective finite element model for the prediction of hydrogen induced cracking in steel pipelines

    KAUST Repository

    Traidia, Abderrazak; Alfano, Marco; Lubineau, Gilles; Duval, Sé bastien; Sherik, Abdelmounam M.

    2012-01-01

    This paper presents a comprehensive finite element model for the numerical simulation of Hydrogen Induced Cracking (HIC) in steel pipelines exposed to sulphurous compounds, such as hydrogen sulphide (H2S). The model is able to mimic the pressure

  7. Geraniin suppresses RANKL-induced osteoclastogenesis in vitro and ameliorates wear particle-induced osteolysis in mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Xiao, Fei; Zhai, Zanjing; Jiang, Chuan; Liu, Xuqiang; Li, Haowei; Qu, Xinhua [Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Ouyang, Zhengxiao [Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Department of Orthopaedics, Hunan Provincial Tumor Hospital and Tumor Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013 (China); Fan, Qiming; Tang, Tingting [Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Qin, An, E-mail: dr.qinan@gmail.com [Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Gu, Dongyun, E-mail: dongyungu@gmail.com [Department of Orthopedics, Shanghai Key Laboratory of Orthopedic Implant, Shanghai Ninth People' s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (China); Engineering Research Center of Digital Medicine and Clinical Translation, Ministry of Education of PR China (China); School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai 200030 (China)

    2015-01-01

    Wear particle-induced osteolysis and subsequent aseptic loosening remains the most common complication that limits the longevity of prostheses. Wear particle-induced osteoclastogenesis is known to be responsible for extensive bone erosion that leads to prosthesis failure. Thus, inhibition of osteoclastic bone resorption may serve as a therapeutic strategy for the treatment of wear particle induced osteolysis. In this study, we demonstrated for the first time that geraniin, an active natural compound derived from Geranium thunbergii, ameliorated particle-induced osteolysis in a Ti particle-induced mouse calvaria model in vivo. We also investigated the mechanism by which geraniin exerts inhibitory effects on osteoclasts. Geraniin inhibited RANKL-induced osteoclastogenesis in a dose-dependent manner, evidenced by reduced osteoclast formation and suppressed osteoclast specific gene expression. Specially, geraniin inhibited actin ring formation and bone resorption in vitro. Further molecular investigation demonstrated geraniin impaired osteoclast differentiation via the inhibition of the RANKL-induced NF-κB and ERK signaling pathways, as well as suppressed the expression of key osteoclast transcriptional factors NFATc1 and c-Fos. Collectively, our data suggested that geraniin exerts inhibitory effects on osteoclast differentiation in vitro and suppresses Ti particle-induced osteolysis in vivo. Geraniin is therefore a potential natural compound for the treatment of wear particle induced osteolysis in prostheses failure. - Highlights: • Geraniin suppresses osteoclasts formation and function in vitro. • Geraniin impairs RANKL-induced nuclear factor-κB and ERK signaling pathway. • Geraniin suppresses osteolysis in vivo. • Geraniin may be used for treating osteoclast related diseases.

  8. A critical discussion of the vacancy diffusion model of ion beam induced epitaxial crystallization

    International Nuclear Information System (INIS)

    Heera, V.

    1989-01-01

    A simple vacancy diffusion model of ion beam induced epitaxial crystallization of silicon including divacancy formation is developed. The model reproduces some of the experimental findings, as e.g. the dose rate dependence of the crystallization rate. However, the measured activation energy of the ion beam induced epitaxial crystallization cannot be accounted for by vacancy diffusion alone. (author)

  9. A Prominent Role of Interleukin-18 in Acetaminophen-Induced Liver Injury Advocates Its Blockage for Therapy of Hepatic Necroinflammation

    Directory of Open Access Journals (Sweden)

    Malte Bachmann

    2018-02-01

    Full Text Available Acetaminophen [paracetamol, N-acetyl-p-aminophenol (APAP]-induced acute liver injury (ALI not only remains a persistent clinical challenge but likewise stands out as well-characterized paradigmatic model of drug-induced liver damage. APAP intoxication associates with robust hepatic necroinflammation the role of which remains elusive with pathogenic but also pro-regenerative/-resolving functions being ascribed to leukocyte activation. Here, we shine a light on and put forward a unique role of the interleukin (IL-1 family member IL-18 in experimental APAP-induced ALI. Indeed, amelioration of disease as previously observed in IL-18-deficient mice was further substantiated herein by application of the IL-18 opponent IL-18-binding protein (IL-18BPd:Fc to wild-type mice. Data altogether emphasize crucial pathological action of this cytokine in APAP toxicity. Adding recombinant IL-22 to IL-18BPd:Fc further enhanced protection from liver injury. In contrast to IL-18, the role of prototypic pro-inflammatory IL-1 and tumor necrosis factor-α is controversially discussed with lack of effects or even protective action being repeatedly reported. A prominent detrimental function for IL-18 in APAP-induced ALI as proposed herein should relate to its pivotal role for hepatic expression of interferon-γ and Fas ligand, both of which aggravate APAP toxicity. As IL-18 serum levels increase in patients after APAP overdosing, targeting IL-18 may evolve as novel therapeutic option in those hard-to-treat patients where standard therapy with N-acetylcysteine is unsuccessful. Being a paradigmatic experimental model of ALI, current knowledge on ill-fated properties of IL-18 in APAP intoxication likewise emphasizes the potential of this cytokine to serve as therapeutic target in other entities of inflammatory liver diseases.

  10. A modified wake oscillator model for predicting vortex induced vibration of heat exchanger tube

    International Nuclear Information System (INIS)

    Feng Zhipeng; Zang Fenggang; Zhang Yixiong; Ye Xianhui

    2014-01-01

    Base on the classical wake oscillator model, a new modified wake oscillator model is proposed, for predicting vortex induced vibration of heat exchanger tube in uniform current. The comparison between the new wake oscillator model and experimental show that the present model can simulate the characteristics of vortex induced vibration of tube. Firstly, the research shows that the coupled fluid-structure dynamical system should be modeled by combined displacement and acceleration mode. Secondly, the empirical parameter in wake oscillator model depends on the material properties of the structure, instead of being a universal constant. Lastly, the results are compared between modified wake oscillator model and fluid-structure interaction numerical model. It shows the present, predicted results are compared to the fluid-structure interaction numerical data. The new modified wake oscillator model can predict the vortex induced heat exchanger tube vibration feasibly. (authors)

  11. Cowhage-induced itch as an experimental model for pruritus. A comparative study with histamine-induced itch.

    Directory of Open Access Journals (Sweden)

    Alexandru D P Papoiu

    2011-03-01

    Full Text Available Histamine is the prototypical pruritogen used in experimental itch induction. However, in most chronic pruritic diseases, itch is not predominantly mediated by histamine. Cowhage-induced itch, on the other hand, seems more characteristic of itch occurring in chronic pruritic diseases.We tested the validity of cowhage as an itch-inducing agent by contrasting it with the classical itch inducer, histamine, in healthy subjects and atopic dermatitis (AD patients. We also investigated whether there was a cumulative effect when both agents were combined.Fifteen healthy individuals and fifteen AD patients were recruited. Experimental itch induction was performed in eczema-free areas on the volar aspects of the forearm, using different itch inducers: histamine, cowhage and their combination thereof. Itch intensity was assessed continuously for 5.5 minutes after stimulus application using a computer-assisted visual analogue scale (COVAS.In both healthy and AD subjects, the mean and peak intensity of itch were higher after the application of cowhage compared to histamine, and were higher after the combined application of cowhage and histamine, compared to histamine alone (p<0.0001 in all cases. Itch intensity ratings were not significantly different between healthy and AD subjects for the same itch inducer used; however AD subjects exhibited a prolonged itch response in comparison to healthy subjects (p<0.001.Cowhage induced a more intense itch sensation compared to histamine. Cowhage was the dominant factor in itch perception when both pathways were stimulated in the same time. Cowhage-induced itch is a suitable model for the study of itch in AD and other chronic pruritic diseases, and it can serve as a new model for testing antipruritic drugs in humans.

  12. Modelling the exposure induced by a criticality excursion in solution

    International Nuclear Information System (INIS)

    Kerouanton, David; Delgovea, Laure; Castaniera, Eric; Raimondia, Nicolas

    2008-01-01

    During a criticality accident, significant exposure is generated by 4 radiation origins: radiation directly induced by fissions (prompt neutrons and gamma), gamma radiations induced by (n, γ) reactions in crossed materials (capture gamma) and gamma radiations emitted by fission products. Due to boiling of the solution, a fraction of fissions products is airborne and is deposited in the ventilation shafts. 5.10 18 fissions are considered in a dissolution tank containing uranyl nitrate by using the deterministic ATTILA radiation transport code. Instantaneous radiations rates are evaluated as a function of the distance and compared with data available in the literature. Dose rates induced behind various shielding materials such as concrete, steel or glass are assessed. In all cases, relative contributions of prompt or capture radiations is detailed. (author)

  13. MODELLING SLOW EXTRACTION INDUCED RADIOACTIVITY IN SPS LSS2

    CERN Document Server

    Araujo Martinez, Aurora Cecilia; CERN. Geneva. TE Department

    2017-01-01

    The Accelerator and Beam Transfer (ABT) group is investigating the impact of recent proposals to extract higher proton intensities to Fixed Target experiments at the SPS. The 400 GeV high-energy proton beam is typically extracted over a few seconds using a resonant slow-extraction technique that induces small but unavoidable beam losses on the extraction equipment in SPS LSS2. In this report, the induced radioactivity for 2016-2017 is used to predict future activation levels and cool-down times, using a past intervention as a reference to predict dose to the personnel carrying-out maintenance of the accelerator.

  14. Medicinal lavender modulates the enteric microbiota to protect against Citrobacter rodentium-induced colitis.

    Science.gov (United States)

    Baker, J; Brown, K; Rajendiran, E; Yip, A; DeCoffe, D; Dai, C; Molcan, E; Chittick, S A; Ghosh, S; Mahmoud, S; Gibson, D L

    2012-10-01

    Inflammatory bowel disease, inclusive of Crohn's disease and ulcerative colitis, consists of immunologically mediated disorders involving the microbiota in the gastrointestinal tract. Lavender oil is a traditional medicine used to relieve many gastrointestinal disorders. The goal of this study was to examine the therapeutic effects of the essential oil obtained from a novel lavender cultivar, Lavandula×intermedia cultivar Okanagan lavender (OLEO), in a mouse model of acute colitis caused by Citrobacter rodentium. In colitic mice, oral gavage with OLEO resulted in less severe disease, including decreased morbidity and mortality, reduced intestinal tissue damage, and decreased infiltration of neutrophils and macrophages, with reduced levels of TNF-α, IFN-γ, IL-22, macrophage inflammatory protein-2α, and inducible nitric oxide synthase expression. This was associated with increased levels of regulatory T cell populations compared with untreated colitic mice. Recently, we demonstrated that the composition of the enteric microbiota affects susceptibility to C. rodentium-induced colitis. Here, we found that oral administration of OLEO induced microbiota enriched with members of the phylum Firmicutes, including segmented filamentous bacteria, which are known to protect against the damaging effects of C. rodentium. Additionally, during infection, OLEO treatment promoted the maintenance of microbiota loads, with specific increases in Firmicutes bacteria and decreases in γ-Proteobacteria. We observed that Firmicutes bacteria were intimately associated with the apical region of the intestinal epithelial cells during infection, suggesting that their protective effect was through contact with the gut wall. Finally, we show that OLEO inhibited C. rodentium growth and adherence to Caco-2 cells, primarily through the activities of 1,8-cineole and borneol. These results indicate that while OLEO promoted Firmicutes populations, it also controlled pathogen load through

  15. Delay induced stability switch, multitype bistability and chaos in an intraguild predation model.

    Science.gov (United States)

    Shu, Hongying; Hu, Xi; Wang, Lin; Watmough, James

    2015-12-01

    In many predator-prey models, delay has a destabilizing effect and induces oscillations; while in many competition models, delay does not induce oscillations. By analyzing a rather simple delayed intraguild predation model, which combines both the predator-prey relation and competition, we show that delay in intraguild predation models promotes very complex dynamics. The delay can induce stability switches exhibiting a destabilizing role as well as a stabilizing role. It is shown that three types of bistability are possible: one stable equilibrium coexists with another stable equilibrium (node-node bistability); one stable equilibrium coexists with a stable periodic solution (node-cycle bistability); one stable periodic solution coexists with another stable periodic solution (cycle-cycle bistability). Numerical simulations suggest that delay can also induce chaos in intraguild predation models.

  16. A pig model of acute Staphylococcus aureus induced pyemia

    DEFF Research Database (Denmark)

    Nielsen, O. L.; Iburg, T.; Aalbæk, B.

    2009-01-01

    Background: Sepsis caused by Staphylococcus aureus constitutes an important cause of morbidity and mortality in humans, and the incidence of this disease-entity is increasing. In this paper we describe the initial microbial dynamics and lesions in pigs experimentally infected with S. aureus....... aureus isolated from man and an extension of the timeframe aiming at inducing sepsis, severe sepsis and septic shock....

  17. Evidence-based quantification of uncertainties induced via simulation-based modeling

    International Nuclear Information System (INIS)

    Riley, Matthew E.

    2015-01-01

    The quantification of uncertainties in simulation-based modeling traditionally focuses upon quantifying uncertainties in the parameters input into the model, referred to as parametric uncertainties. Often neglected in such an approach are the uncertainties induced by the modeling process itself. This deficiency is often due to a lack of information regarding the problem or the models considered, which could theoretically be reduced through the introduction of additional data. Because of the nature of this epistemic uncertainty, traditional probabilistic frameworks utilized for the quantification of uncertainties are not necessarily applicable to quantify the uncertainties induced in the modeling process itself. This work develops and utilizes a methodology – incorporating aspects of Dempster–Shafer Theory and Bayesian model averaging – to quantify uncertainties of all forms for simulation-based modeling problems. The approach expands upon classical parametric uncertainty approaches, allowing for the quantification of modeling-induced uncertainties as well, ultimately providing bounds on classical probability without the loss of epistemic generality. The approach is demonstrated on two different simulation-based modeling problems: the computation of the natural frequency of a simple two degree of freedom non-linear spring mass system and the calculation of the flutter velocity coefficient for the AGARD 445.6 wing given a subset of commercially available modeling choices. - Highlights: • Modeling-induced uncertainties are often mishandled or ignored in the literature. • Modeling-induced uncertainties are epistemic in nature. • Probabilistic representations of modeling-induced uncertainties are restrictive. • Evidence theory and Bayesian model averaging are integrated. • Developed approach is applicable for simulation-based modeling problems

  18. Modeling of plasma plume induced during laser welding

    International Nuclear Information System (INIS)

    Moscicki, T.; Hoffman, J.; Szymanski, Z.

    2005-01-01

    During laser welding, the interaction of intense laser radiation with a work-piece leads to the formation of a long, thin, cylindrical cavity in a metal, called a keyhole. Generation of a keyhole enables the laser beam to penetrate into the work-piece and is essential for deep welding. The keyhole contains ionized metal vapour and is surrounded by molten material called the weld pool. The metal vapour, which flows from the keyhole mixes with the shielding gas flowing from the opposite direction and forms a plasma plume over the keyhole mouth. The plasma plume has considerable influence on the processing conditions. Plasma strongly absorbs laser radiation and significantly changes energy transfer from the laser beam to a material. In this paper the results of theoretical modelling of plasma plume induced during welding with CO 2 laser are presented. The set of equations consists of equation of conservation of mass, energy, momentum and the diffusion equation: ∂ρ/∂t + ∇·(ρ ρ ν =0; ∂(ρE)/∂t + ∇·( ρ ν (ρE + p)) = ∇ (k eff ∇T - Σ j h j ρ J j + (τ eff · ρ ν )) + Σ i κ i I i - R; ∂/∂t(ρ ρ ν ) + ∇· (ρ ρ ν ρ ν ) = - ∇p + ∇(τ) + ρ ρ g + ρ F, where τ is viscous tensor τ = μ[(∇ ρ ν + ∇ ρT ν )-2/3∇· ρ ν I]; ∂/∂t(ρY i ) + ∇·(ρ ρ ν Y i ) = ∇·ρD i,m ∇T i ; where μ ν denotes velocity vector, E - energy, ρ mass density; k - thermal conductivity, T- temperature, κ - absorption coefficient, I i local laser intensity, R - radiation loss function, p - pressure, h j enthalpy, J j - diffusion flux of j component, ν g - gravity, μ F - external force, μ - dynamic viscosity, I - unit tensor, Y i - mass fraction of iron vapor in the gas mixture, D i,m - mass diffusion coefficient. The terms k eff and τ eff contain the turbulent component of the thermal conductivity and the viscosity, respectively. All the material functions are functions of the temperature and mass fraction only. The equations

  19. Allergen immunotherapy induces a suppressive memory response mediated by IL-10 in a mouse asthma model

    NARCIS (Netherlands)

    Vissers, Joost L. M.; van Esch, Betty C. A. M.; Hofman, Gerard A.; Kapsenberg, Martien L.; Weller, Frank R.; van Oosterhout, Antoon J. M.

    2004-01-01

    Background: Human studies have demonstrated that allergen immunotherapy induces memory suppressive responses and IL-10 production by allergen-specific T cells. Previously, we established a mouse model in which allergen immunotherapy was effective in the suppression of allergen-induced asthma

  20. Construction of radiation - induced metastasis model in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jong Kuk; Jang, Su Jin; Kang, Sung Wook; Kim, Jae Sung; Hwang, Sang Gu; Kang, Joo Hyun [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2011-05-15

    In treatment of cancer, distant metastases are important limiting factor because an estimated 50% of all cancer patients will develop metastases, and the metastases are major causing of cancer treatment failure. Recently a few reports indicated {gamma}-radiation induced an increase of invasiveness of several cancer cells. In this study, we had tried to show the possibility that radiation could also induce metastasis in vivo system. To prove our hypothesis, we constructed primary tumor by using C6-TL transfectant cell line expressing HSV1-tk and firefly luciferase (fLuc), and then {gamma}-radiation was treated to xenografts locally. Treatment of {gamma}-radiation to primary C6-TL xenografts of mice reduced size of xenografts and elongated survival of mice than those of mock control mice. But we also show that {gamma}-radiation treatment was followed by the growth of dormant metastases in various organs including lung and intestine after 2-4 weeks of {gamma}-radiation treatment. When bioluminescence imaging indicated growth of tumor in organs in mice, we sacrificed the mice and repeat acquired bioluminescence imaging after repeatedly. These images presented tumor growth locations exactly in organs. Because metastatic tumor candidates have morphology of foci, biopsies were performed for histological analysis or PCR analysis to confirm metastases. In most foci, histological analysis indicated several features of typical cancer tissue and PCR analysis showed present of fLuc gene in metastases. Detection of fLuc gene in metastases indicated these foci were originated from primary C6-TL xenografts, and the results suggest that {gamma}-radiation could promote metastasis in vivo as well as in vitro system. Although we need to understand changes of intracellular signaling or physiological phenomena of the radiation-induced metastasis yet, these results also imply that {gamma}-radiation treatment only to cancer patients need to pay attention carefully, and development of new

  1. Using multistage models to describe radiation-induced leukaemia

    International Nuclear Information System (INIS)

    Little, M.P.; Muirhead, C.R.; Boice, J.D. Jr.; Kleinerman, R.A.

    1995-01-01

    The Armitage-Doll model of carcinogenesis is fitted to data on leukaemia mortality among the Japanese atomic bomb survivors with the DS86 dosimetry and on leukaemia incidence in the International Radiation Study of Cervical Cancer patients. Two different forms of model are fitted: the first postulates up to two radiation-affected stages and the second additionally allows for the presence at birth of a non-trivial population of cells which have already accumulated the first of the mutations leading to malignancy. Among models of the first form, a model with two adjacent radiation-affected stages appears to fit the data better than other models of the first form, including both models with two affected stages in any order and models with only one affected stage. The best fitting model predicts a linear-quadratic dose-response and reductions of relative risk with increasing time after exposure and age at exposure, in agreement with what has previously been observed in the Japanese and cervical cancer data. However, on the whole it does not provide an adequate fit to either dataset. The second form of model appears to provide a rather better fit, but the optimal models have biologically implausible parameters (the number of initiated cells at birth is negative) so that this model must also be regarded as providing an unsatisfactory description of the data. (author)

  2. Friction induced hunting limit cycles : a comparison between the LuGre and switch friction model

    NARCIS (Netherlands)

    Hensen, R.H.A.; Molengraft, van de M.J.G.; Steinbuch, M.

    2003-01-01

    In this paper, friction induced limit cycles are predicted for a simple motion system consisting of a motor-driven inertia subjected to friction and a PID-controlled regulator task. The two friction models used, i.e., (i) the dynamic LuGre friction model and (ii) the static switch friction model,

  3. The demand-induced strain compensation model : renewed theoretical considerations and empirical evidence

    NARCIS (Netherlands)

    de Jonge, J.; Dormann, C.; van den Tooren, M.; Näswall, K.; Hellgren, J.; Sverke, M.

    2008-01-01

    This chapter presents a recently developed theoretical model on jobrelated stress and performance, the so-called Demand-Induced Strain Compensation (DISC) model. The DISC model predicts in general that adverse health effects of high job demands can best be compensated for by matching job resources

  4. Efficient Weibull channel model for salinity induced turbulent underwater wireless optical communications

    KAUST Repository

    Oubei, Hassan M.; Zedini, Emna; Elafandy, Rami T.; Kammoun, Abla; Ng, Tien Khee; Alouini, Mohamed-Slim; Ooi, Boon S.

    2017-01-01

    Recent advances in underwater wireless optical communications necessitate a better understanding of the underwater channel. We propose the Weibull model to characterize the fading of salinity induced turbulent underwater wireless optical channels

  5. Modelling ionising radiation induced defect generation in bipolar oxides with gated diodes

    International Nuclear Information System (INIS)

    Barnaby, H.J.; Cirba, C.; Schrimpf, R.D.; Kosier, St.; Fouillat, P.; Montagner, X.

    1999-01-01

    Radiation-induced oxide defects that degrade electrical characteristics of bipolar junction transistor (BJTs) can be measured with the use of gated diodes. The buildup of defects and their effect on device radiation response are modeled with computer simulation. (authors)

  6. Modeling of fault reactivation and induced seismicity during hydraulic fracturing of shale-gas reservoirs

    Science.gov (United States)

    We have conducted numerical simulation studies to assess the potential for injection-induced fault reactivation and notable seismic events associated with shale-gas hydraulic fracturing operations. The modeling is generally tuned toward conditions usually encountered in the Marce...

  7. Tamoxifen induces regression of estradiol-induced mammary cancer in the ACI.COP-Ept2 rat model.

    Science.gov (United States)

    Ruhlen, Rachel L; Willbrand, Dana M; Besch-Williford, Cynthia L; Ma, Lixin; Shull, James D; Sauter, Edward R

    2009-10-01

    The ACI rat is a unique model of human breast cancer in that mammary cancers are induced by estrogen without carcinogens, irradiation, xenografts or transgenic manipulations. We sought to characterize mammary cancers in a congenic variant of the ACI rat, the ACI.COP-Ept2. All rats with estradiol implants developed mammary cancers in 5-7 months. Rats bearing estradiol-induced mammary cancers were treated with tamoxifen for three weeks. Tamoxifen reduced tumor mass, measured by magnetic resonance imaging, by 89%. Tumors expressed estrogen receptors (ER), progesterone receptor (PR), and Erbb2. ERalpha and PR were overexpressed in tumor compared to adjacent non-tumor mammary gland. Thus, this model is highly relevant to hormone responsive human breast cancers.

  8. Agent Model Development for Assessing Climate-Induced Geopolitical Instability.

    Energy Technology Data Exchange (ETDEWEB)

    Boslough, Mark B.; Backus, George A.

    2005-12-01

    We present the initial stages of development of new agent-based computational methods to generate and test hypotheses about linkages between environmental change and international instability. This report summarizes the first year's effort of an originally proposed three-year Laboratory Directed Research and Development (LDRD) project. The preliminary work focused on a set of simple agent-based models and benefited from lessons learned in previous related projects and case studies of human response to climate change and environmental scarcity. Our approach was to define a qualitative model using extremely simple cellular agent models akin to Lovelock's Daisyworld and Schelling's segregation model. Such models do not require significant computing resources, and users can modify behavior rules to gain insights. One of the difficulties in agent-based modeling is finding the right balance between model simplicity and real-world representation. Our approach was to keep agent behaviors as simple as possible during the development stage (described herein) and to ground them with a realistic geospatial Earth system model in subsequent years. This work is directed toward incorporating projected climate data--including various C02 scenarios from the Intergovernmental Panel on Climate Change (IPCC) Third Assessment Report--and ultimately toward coupling a useful agent-based model to a general circulation model.3

  9. Sensitivity analysis of the noise-induced oscillatory multistability in Higgins model of glycolysis

    Science.gov (United States)

    Ryashko, Lev

    2018-03-01

    A phenomenon of the noise-induced oscillatory multistability in glycolysis is studied. As a basic deterministic skeleton, we consider the two-dimensional Higgins model. The noise-induced generation of mixed-mode stochastic oscillations is studied in various parametric zones. Probabilistic mechanisms of the stochastic excitability of equilibria and noise-induced splitting of randomly forced cycles are analysed by the stochastic sensitivity function technique. A parametric zone of supersensitive Canard-type cycles is localized and studied in detail. It is shown that the generation of mixed-mode stochastic oscillations is accompanied by the noise-induced transitions from order to chaos.

  10. In Vitro Studies and Preliminary Mathematical Model for Jet Fuel and Noise Induced Auditory Impairment

    Science.gov (United States)

    2015-06-01

    of JP-8 and a Fischer- Tropsch synthetic jet fuel following subacute inhalation exposure in rats. Toxicol Sci 116(1): 239-248. Gallinat, J...AFRL-RH-WP-TR-2015-0084 IN VITRO STUDIES AND PRELIMINARY MATHEMATICAL MODEL FOR JET FUEL AND NOISE INDUCED AUDITORY IMPAIRMENT...April 2014 – September 2014 4. TITLE AND SUBTITLE In Vitro Studies and Preliminary Mathematical Model for Jet Fuel and Noise Induced Auditory

  11. Integrated modelling of corrosion-induced deterioration in rein-forced concrete structures

    DEFF Research Database (Denmark)

    Michel, Alexander; Geiker, M.R.; Stang, Henrik

    2013-01-01

    at the reinforcement surface, a FEM based me-chanical model was used to simulate corrosion-induced concrete damage. Both FEM models were fully coupled, i.e. information, such as corrosion current density, dam-age state of concrete cover, etc., were constantly exchanged between the models. To demonstrate the potential......An integrated finite element based modelling approach is presented, which allows for fully coupled simulation of reinforcement corrosion and corrosion-induced concrete damage. While a finite element method (FEM) based corrosion model was used to describe electrochemical processes...... use of the modelling approach, a numerical example is presented which illustrates full coupling of formation of corrosion cells, propagation of corrosion, and subsequent development of corrosion-induced concrete damage....

  12. Flow-induced vibration test of an advanced water reactor model. Pt. 1. Turbulence-induced forcing function

    International Nuclear Information System (INIS)

    Au-Yang, M.K.; Brenneman, B.; Raj, D.

    1995-01-01

    A 1:9 scale model of a proposed advanced water reactor was tested for flow-induced vibration. The main objectives of this test were: (1) to derive an empirical equation for the turbulence forcing function which can be applied to the full-sized prototype; (2) to study the effect of viscosity on the turbulence; (3) to verify the ''superposition'' assumption widely used in dynamic analysis of weakly coupled fluid-shell systems; and (4) to measure the shell responses to verify methods and computer programs used in the flow-induced vibration analysis of the prototype. This paper describes objectives (1), (2), and (3); objective (4) will be discussed in a companion paper.The turbulence-induced fluctuating pressure was measured at 49 locations over the surface of a thick-walled, non-responsive scale model of the reactor vessel/core support cylinders. An empirical equation relating the fluctuating pressure, the frequency, and the distance from the inlet nozzle center line was derived to fit the test data. This equation involves only non-dimensional, fluid mechanical parameters that are postulated to represent the full-sized, geometrically similar prototype. While this postulate cannot be verified until similar measurements are taken on the full-sized unit, a similar approach using a 1:6 scale model of a commercial pressurized water reactor was verified in the mid-1970s by field measurements on the full-sized reactor. (orig.)

  13. Effect of Human Model Height and Sex on Induced Current Dosimetry in Household Induction Heater Users

    Science.gov (United States)

    Tarao, Hiroo; Hayashi, Noriyuki; Isaka, Katsuo

    Induced currents in the high-resolution, anatomical human models are numerically calculated by the impedance method. The human models are supposed to be exposed to highly inhomogeneous 20.9 kHz magnetic fields from a household induction heater (IH). In the case of the adult models, the currents ranging from 5 to 19 mA/m2 are induced for between the shoulder and lower abdomen. Meanwhile, in the case of the child models, the currents ranging from 5 to 21 mA/m2 are induced for between the head and abdomen. In particular, the induced currents near the brain tissue are almost the same as those near the abdomen. When the induced currents in the central nervous system tissues are considered, the induced currents in the child model are 2.1 to 6.9 times as large as those in the adult model under the same B-field exposure environment. These results suggest the importance of further investigation intended for a pregnant female who uses the IH as well as for a child (or the IH users of small standing height).

  14. Noise-and delay-induced phase transitions of the dimer–monomer surface reaction model

    International Nuclear Information System (INIS)

    Zeng Chunhua; Wang Hua

    2012-01-01

    Highlights: ► We study the dimer–monomer surface reaction model. ► We show that noise induces first-order irreversible phase transition (IPT). ► Combination of noise and time-delayed feedback induce first- and second-order IPT. ► First- and second-order IPT is viewed as noise-and delay-induced phase transitions. - Abstract: The effects of noise and time-delayed feedback in the dimer–monomer (DM) surface reaction model are investigated. Applying small delay approximation, we construct a stochastic delayed differential equation and its Fokker–Planck equation to describe the state evolution of the DM reaction model. We show that the noise can only induce first-order irreversible phase transition (IPT) characteristic of the DM model, however the combination of the noise and time-delayed feedback can simultaneously induce first- and second-order IPT characteristics of the DM model. Therefore, it is shown that the well-known first- and second-order IPT characteristics of the DM model may be viewed as noise-and delay-induced phase transitions.

  15. Heater induced quenches in SSC [Superconducting Super Collider] model dipoles

    International Nuclear Information System (INIS)

    Hassenzahl, W.V.

    1986-10-01

    A 1-m long SSC dipole constructed at the Lawrence Berkeley laboratory was subjected to a series of heater induced quenches to determine: axial quench propagation velocities, transverse quench propagation, and conductor temperature rise. Quenches were produced by 3 heaters at different locations in the magnet and at several currents. The results of these studies are described and are compared to previously published theoretical studies of quenches on the SSC dipoles. These results are shown to be in agreement with the calculations of the program ''QUENCH'', which includes an increase of the quench velocity during the first few milliseconds of the quench

  16. Transition polarizability model of induced resonance Raman optical activity

    Czech Academy of Sciences Publication Activity Database

    Yamamoto, S.; Bouř, Petr

    2013-01-01

    Roč. 34, č. 25 (2013), s. 2152-2158 ISSN 0192-8651 R&D Projects: GA ČR GAP208/11/0105; GA ČR GA13-03978S; GA MŠk(CZ) LH11033 Grant - others:AV ČR(CZ) M200551205 Institutional support: RVO:61388963 Keywords : induced resonance Raman optical activity * europium complexes * density functional computations * light scattering Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 3.601, year: 2013

  17. Transmembrane helices can induce domain formation in crowded model membranes

    NARCIS (Netherlands)

    Domanski, Jan; Marrink, Siewert J.; Schäfer, Lars V.

    We studied compositionally heterogeneous multi-component model membranes comprised of saturated lipids, unsaturated lipids, cholesterol, and a-helical TM protein models using coarse-grained molecular dynamics simulations. Reducing the mismatch between the length of the saturated and unsaturated

  18. Model of CSR Induced Bursts in Slicing Experiments

    International Nuclear Information System (INIS)

    Stupakov, G.; Heifets, S.

    2006-01-01

    We suggest a model describing the CSR bursts observed in recent experiments at the Advanced Light Source at the LBL. The model is based on the linear theory of the CSR instability in electron rings. We describe how an initial perturbation of the beam generated by the laser pulse evolves in time when the beam is unstable due to the CSR wakefield

  19. A constraints-induced model of park choice

    NARCIS (Netherlands)

    Stemerding, M.P.; Oppewal, H.; Timmermans, H.J.P.

    1999-01-01

    Conjoint choice models have been used widely in the consumer-choice literature as an approach to measure and predict consumer-choice behavior. These models typically assume that consumer preferences and choice rules are independent from any constraints that might impact the behavior of interest.

  20. Semiclassical calculation for collision induced dissociation. II. Morse oscillator model

    International Nuclear Information System (INIS)

    Rusinek, I.; Roberts, R.E.

    1978-01-01

    A recently developed semiclassical procedure for calculating collision induced dissociation probabilities P/sup diss/ is applied to the collinear collision between a particle and a Morse oscillator diatomic. The particle--diatom interaction is described with a repulsive exponential potential function. P/sup diss/ is reported for a system of three identical particles, as a function of collision energy E/sub t/ and initial vibrational state of the diatomic n 1 . The results are compared with the previously reported values for the collision between a particle and a truncated harmonic oscillator. The two studies show similar features, namely: (a) there is an oscillatory structure in the P/sup diss/ energy profiles, which is directly related to n 1 ; (b) P/sup diss/ becomes noticeable (> or approx. =10 -3 ) for E/sub t/ values appreciably higher than the energetic threshold; (c) vibrational enhancement (inhibition) of collision induced dissociation persists at low (high) energies; and (d) good agreement between the classical and semiclassical results is found above the classical dynamic threshold. Finally, the convergence of P/sup diss/ for increasing box length is shown to be rapid and satisfactory

  1. Numerical Modelling and Prediction of Erosion Induced by Hydrodynamic Cavitation

    Science.gov (United States)

    Peters, A.; Lantermann, U.; el Moctar, O.

    2015-12-01

    The present work aims to predict cavitation erosion using a numerical flow solver together with a new developed erosion model. The erosion model is based on the hypothesis that collapses of single cavitation bubbles near solid boundaries form high velocity microjets, which cause sonic impacts with high pressure amplitudes damaging the surface. The erosion model uses information from a numerical Euler-Euler flow simulation to predict erosion sensitive areas and assess the erosion aggressiveness of the flow. The obtained numerical results were compared to experimental results from tests of an axisymmetric nozzle.

  2. Complex structure-induced deformations of σ-models

    Energy Technology Data Exchange (ETDEWEB)

    Bykov, Dmitri [Max-Planck-Institut für Gravitationsphysik, Albert-Einstein-Institut,Am Mühlenberg 1, D-14476 Potsdam-Golm (Germany); Steklov Mathematical Institute of Russ. Acad. Sci.,Gubkina str. 8, 119991 Moscow (Russian Federation)

    2017-03-24

    We describe a deformation of the principal chiral model (with an even-dimensional target space G) by a B-field proportional to the Kähler form on the target space. The equations of motion of the deformed model admit a zero-curvature representation. As a simplest example, we consider the case of G=S{sup 1}×S{sup 3}. We also apply a variant of the construction to a deformation of the AdS{sub 3}×S{sup 3}×S{sup 1} (super-)σ-model.

  3. Modeling of Plasma-Induced Ignition and Combustion

    National Research Council Canada - National Science Library

    Boyd, Iain D; Keidar, Michael

    2008-01-01

    .... Phenomena that must be considered in an electrothermal chemical gun model include the initial capillary plasma properties, the plasma-air interaction, plasma sheath effects, and the plasma-propellant interaction itself...

  4. Pressure induced valence transitions in the Anderson lattice model

    International Nuclear Information System (INIS)

    Bernhard, B.H.; Coqblin, B.

    2009-01-01

    We apply the equation of motion method to the Anderson lattice model, which describes the physical properties of heavy fermion compounds. In particular, we focus here on the variation of the number of f electrons with pressure, associated to the crossover from the Kondo regime to the intermediate valence regime. We treat here the non-magnetic case and introduce an improved approximation, which consists of an alloy analogy based decoupling for the Anderson lattice model. It is implemented by partial incorporation of the spatial correlations contained in higher-order Green's functions involved in the problem that have been formerly neglected. As it has been verified in the framework of the Hubbard model, the alloy analogy avoids the breakdown of sum rules and is more appropriate to explore the asymmetric case of the periodic Anderson Hamiltonian. The densities of states for a simple cubic lattice are calculated for various values of the model parameters V, t, E f , and U.

  5. Competition-induced criticality in a model of meme popularity.

    Science.gov (United States)

    Gleeson, James P; Ward, Jonathan A; O'Sullivan, Kevin P; Lee, William T

    2014-01-31

    Heavy-tailed distributions of meme popularity occur naturally in a model of meme diffusion on social networks. Competition between multiple memes for the limited resource of user attention is identified as the mechanism that poises the system at criticality. The popularity growth of each meme is described by a critical branching process, and asymptotic analysis predicts power-law distributions of popularity with very heavy tails (exponent α<2, unlike preferential-attachment models), similar to those seen in empirical data.

  6. Competition-Induced Criticality in a Model of Meme Popularity

    Science.gov (United States)

    Gleeson, James P.; Ward, Jonathan A.; O'Sullivan, Kevin P.; Lee, William T.

    2014-01-01

    Heavy-tailed distributions of meme popularity occur naturally in a model of meme diffusion on social networks. Competition between multiple memes for the limited resource of user attention is identified as the mechanism that poises the system at criticality. The popularity growth of each meme is described by a critical branching process, and asymptotic analysis predicts power-law distributions of popularity with very heavy tails (exponent α <2, unlike preferential-attachment models), similar to those seen in empirical data.

  7. Modelling Of Residual Stresses Induced By High Speed Milling Process

    International Nuclear Information System (INIS)

    Desmaison, Olivier; Mocellin, Katia; Jardin, Nicolas

    2011-01-01

    Maintenance processes used in heavy industries often include high speed milling operations. The reliability of the post-process material state has to be studied. Numerical simulation appears to be a very interesting way to supply an efficient residual stresses (RS) distribution prediction.Because the adiabatic shear band and the serrated chip shaping are features of the austenitic stainless steel high speed machining, a 2D high speed orthogonal cutting model is briefly presented. This finite element model, developed on Forge registered software, is based on data taken from Outeiro and al.'s paper [1]. A new behaviour law fully coupling Johnson-Cook's constitutive law and Latham and Cockcroft's damage model is detailed in this paper. It ensures results that fit those found in literature.Then, the numerical tools used on the 2D model are integrated to a 3D high speed milling model. Residual stresses distribution is analysed, on the surface and into the depth of the material. Various revolutions and passes of the two teeth hemispheric mill on the workpiece are simulated. Thus the sensitivity of the residual stresses generation to the cutting conditions can be discussed. In order to validate the 3D model, a comparison of the cutting forces measured by EDF R and D to those given by numerical simulations is achieved.

  8. Modeling photothermal and acoustical induced microbubble generation and growth.

    Science.gov (United States)

    Krasovitski, Boris; Kislev, Hanoch; Kimmel, Eitan

    2007-12-01

    Previous experimental studies showed that powerful heating of nanoparticles by a laser pulse using energy density greater than 100 mJ/cm(2), could induce vaporization and generate microbubbles. When ultrasound is introduced at the same time as the laser pulse, much less laser power is required. For therapeutic applications, generation of microbubbles on demand at target locations, e.g. cells or bacteria can be used to induce hyperthermia or to facilitate drug delivery. The objective of this work is to develop a method capable of predicting photothermal and acoustic parameters in terms of laser power and acoustic pressure amplitude that are needed to produce stable microbubbles; and investigate the influence of bubble coalescence on the thresholds when the microbubbles are generated around nanoparticles that appear in clusters. We develop and solve here a combined problem of momentum, heat and mass transfer which is associated with generation and growth of a microbubble, filled with a mixture of non-vaporized gas (air) and water vapor. The microbubble's size and gas content vary as a result of three mechanisms: gas expansion or compression, evaporation or condensation on the bubble boundary, and diffusion of dissolved air in the surrounding water. The simulations predict that when ultrasound is applied relatively low threshold values of laser and ultrasound power are required to obtain a stable microbubble from a single nanoparticle. Even lower power is required when microbubbles are formed by coalescence around a cluster of 10 nanoparticles. Laser pulse energy density of 21 mJ/cm(2) is predicted for instance together with acoustic pressure of 0.1 MPa for a cluster of 10 or 62 mJ/cm(2) for a single nanoparticle. Those values are well within the safety limits, and as such are most appealing for targeted therapeutic purposes.

  9. An Integrated Biomechanical Model for Microgravity-Induced Visual Impairment

    Science.gov (United States)

    Nelson, Emily S.; Best, Lauren M.; Myers, Jerry G.; Mulugeta, Lealem

    2012-01-01

    When gravitational unloading occurs upon entry to space, astronauts experience a major shift in the distribution of their bodily fluids, with a net headward movement. Measurements have shown that intraocular pressure spikes, and there is a strong suspicion that intracranial pressure also rises. Some astronauts in both short- and long-duration spaceflight develop visual acuity changes, which may or may not reverse upon return to earth gravity. To date, of the 36 U.S. astronauts who have participated in long-duration space missions on the International Space Station, 15 crew members have developed minor to severe visual decrements and anatomical changes. These ophthalmic changes include hyperopic shift, optic nerve distension, optic disc edema, globe flattening, choroidal folds, and elevated cerebrospinal fluid pressure. In order to understand the physical mechanisms behind these phenomena, NASA is developing an integrated model that appropriately captures whole-body fluids transport through lumped-parameter models for the cerebrospinal and cardiovascular systems. This data feeds into a finite element model for the ocular globe and retrobulbar subarachnoid space through time-dependent boundary conditions. Although tissue models and finite element representations of the corneo-scleral shell, retina, choroid and optic nerve head have been integrated to study pathological conditions such as glaucoma, the retrobulbar subarachnoid space behind the eye has received much less attention. This presentation will describe the development and scientific foundation of our holistic model.

  10. Gut Microbial Diversity in Rat Model Induced by Rhubarb

    Science.gov (United States)

    Peng, Ying; Wu, Chunfu; Yang, Jingyu; Li, Xiaobo

    2014-01-01

    Rhubarb is often used to establish chronic diarrhea and spleen (Pi)-deficiency syndrome animal models in China. In this study, we utilized the enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR) method to detect changes in bacterial diversity in feces and the bowel mucosa associated with this model. Total microbial genomic DNA from the small bowel (duodenum, jejunum, and ileum), large bowel (proximal colon, distal colon, and rectum), cecum, and feces of normal and rhubarb-exposed rats were used as templates for the ERIC-PCR analysis. We found that the fecal microbial composition did not correspond to the bowel bacteria mix. More bacterial diversity was observed in the ileum of rhubarb-exposed rats (Panalysis with the SPSS software, the Canonical Discriminant Function Formulae for model rats was established. PMID:25048267

  11. Progress in microscopic direct reaction modeling of nucleon induced reactions

    Energy Technology Data Exchange (ETDEWEB)

    Dupuis, M.; Bauge, E.; Hilaire, S.; Lechaftois, F.; Peru, S.; Pillet, N.; Robin, C. [CEA, DAM, DIF, Arpajon (France)

    2015-12-15

    A microscopic nuclear reaction model is applied to neutron elastic and direct inelastic scatterings, and pre-equilibrium reaction. The JLM folding model is used with nuclear structure information calculated within the quasi-particle random phase approximation implemented with the Gogny D1S interaction. The folding model for direct inelastic scattering is extended to include rearrangement corrections stemming from both isoscalar and isovector density variations occurring during a transition. The quality of the predicted (n,n), (n,n{sup '}), (n,xn) and (n,n{sup '}γ) cross sections, as well as the generality of the present microscopic approach, shows that it is a powerful tool that can help improving nuclear reactions data quality. Short- and long-term perspectives are drawn to extend the present approach to more systems, to include missing reactions mechanisms, and to consistently treat both structure and reaction problems. (orig.)

  12. Neuroprotective and Therapeutic Effect of Caffeine on the Rat Model of Parkinson's Disease Induced by Rotenone.

    Science.gov (United States)

    Khadrawy, Yasser A; Salem, Ahmed M; El-Shamy, Karima A; Ahmed, Emad K; Fadl, Nevein N; Hosny, Eman N

    2017-09-03

    The present study aimed to investigate the protective and therapeutic effects of caffeine on rotenone-induced rat model of Parkinson's disease (PD). Rats were divided into control, PD model induced by rotenone (1.5 mg/kg intraperitoneally (i.p.) for 45 days), protected group injected with caffeine (30 mg/kg, i.p.) and rotenone for 45 days (during the development of PD model), and treated group injected with caffeine (30 mg/kg, i.p.) for 45 days after induction of PD model. The data revealed a state of oxidative and nitrosative stress in the midbrain and the striatum of animal model of PD as indicated from the increased lipid peroxidation and nitric oxide levels and the decreased reduced glutathione level and activities of glutathione-S-transferase and superoxide dismutase. Rotenone induced a decrease in acetylcholinesterase and Na + /K + -ATPase activities and an increase in tumor necrosis factor-α level in the midbrain and the striatum. Protection and treatment with caffeine ameliorated the oxidative stress and the changes in acetylcholinesterase and Na + /K + -ATPase activities induced by rotenone in the midbrain and the striatum. This was associated with improvement in the histopathological changes induced in the two areas of PD model. Caffeine protection and treatment restored the depletion of midbrain and striatal dopamine induced by rotenone and prevented decline in motor activities (assessed by open field test) and muscular strength (assessed by traction and hanging tests) and improved norepinephrine level in the two areas. The present study showed that caffeine offered a significant neuroprotection and treatment against neurochemical, histopathological, and behavioral changes in a rotenone-induced rat model of PD.

  13. An Effective Model of the Retinoic Acid Induced HL-60 Differentiation Program.

    Science.gov (United States)

    Tasseff, Ryan; Jensen, Holly A; Congleton, Johanna; Dai, David; Rogers, Katharine V; Sagar, Adithya; Bunaciu, Rodica P; Yen, Andrew; Varner, Jeffrey D

    2017-10-30

    In this study, we present an effective model All-Trans Retinoic Acid (ATRA)-induced differentiation of HL-60 cells. The model describes reinforcing feedback between an ATRA-inducible signalsome complex involving many proteins including Vav1, a guanine nucleotide exchange factor, and the activation of the mitogen activated protein kinase (MAPK) cascade. We decomposed the effective model into three modules; a signal initiation module that sensed and transformed an ATRA signal into program activation signals; a signal integration module that controlled the expression of upstream transcription factors; and a phenotype module which encoded the expression of functional differentiation markers from the ATRA-inducible transcription factors. We identified an ensemble of effective model parameters using measurements taken from ATRA-induced HL-60 cells. Using these parameters, model analysis predicted that MAPK activation was bistable as a function of ATRA exposure. Conformational experiments supported ATRA-induced bistability. Additionally, the model captured intermediate and phenotypic gene expression data. Knockout analysis suggested Gfi-1 and PPARg were critical to the ATRAinduced differentiation program. These findings, combined with other literature evidence, suggested that reinforcing feedback is central to hyperactive signaling in a diversity of cell fate programs.

  14. A practical MGA-ARIMA model for forecasting real-time dynamic rain-induced attenuation

    Science.gov (United States)

    Gong, Shuhong; Gao, Yifeng; Shi, Houbao; Zhao, Ge

    2013-05-01

    novel and practical modified genetic algorithm (MGA)-autoregressive integrated moving average (ARIMA) model for forecasting real-time dynamic rain-induced attenuation has been established by combining genetic algorithm ideas with the ARIMA model. It is proved that due to the introduction of MGA into the ARIMA(1,1,7) model, the MGA-ARIMA model has the potential to be conveniently applied in every country or area by creating a parameter database used by the ARIMA(1,1,7) model. The parameter database is given in this paper based on attenuation data measured in Xi'an, China. The methods to create the parameter databases in other countries or areas are offered, too. Based on the experimental results, the MGA-ARIMA model has been proved practical for forecasting dynamic rain-induced attenuation in real time. The novel model given in this paper is significant for developing adaptive fade mitigation technologies at millimeter wave bands.

  15. A mouse model of mammary hyperplasia induced by oral hormone ...

    African Journals Online (AJOL)

    Methods and Materials: To address the mechanism, we developed a mouse model of mammary hyperplasia. We gave mice estradiol valerate tablets and progesterone capsules sequentially for one month by intragastric administration. Results: Mice treated by this method had a series of pathological changes which are ...

  16. Modeling of chronic radiation-induced cystitis in mice

    Directory of Open Access Journals (Sweden)

    Bernadette M.M. Zwaans, PhD

    2016-10-01

    Conclusions: We developed an RC model that mimics the human pathology and functional changes. Furthermore, radiation exposure attenuates the urothelial integrity long-term, allowing for potential continuous irritability of the bladder wall from exposure to urine. Future studies will focus on the underlying molecular changes associated with this condition and investigate novel treatment strategies.

  17. Toxin-Induced Experimental Models of Learning and Memory Impairment.

    Science.gov (United States)

    More, Sandeep Vasant; Kumar, Hemant; Cho, Duk-Yeon; Yun, Yo-Sep; Choi, Dong-Kug

    2016-09-01

    Animal models for learning and memory have significantly contributed to novel strategies for drug development and hence are an imperative part in the assessment of therapeutics. Learning and memory involve different stages including acquisition, consolidation, and retrieval and each stage can be characterized using specific toxin. Recent studies have postulated the molecular basis of these processes and have also demonstrated many signaling molecules that are involved in several stages of memory. Most insights into learning and memory impairment and to develop a novel compound stems from the investigations performed in experimental models, especially those produced by neurotoxins models. Several toxins have been utilized based on their mechanism of action for learning and memory impairment such as scopolamine, streptozotocin, quinolinic acid, and domoic acid. Further, some toxins like 6-hydroxy dopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and amyloid-β are known to cause specific learning and memory impairment which imitate the disease pathology of Parkinson's disease dementia and Alzheimer's disease dementia. Apart from these toxins, several other toxins come under a miscellaneous category like an environmental pollutant, snake venoms, botulinum, and lipopolysaccharide. This review will focus on the various classes of neurotoxin models for learning and memory impairment with their specific mechanism of action that could assist the process of drug discovery and development for dementia and cognitive disorders.

  18. Plasticity induced by phase transformation in steel: experiment vs modeling

    International Nuclear Information System (INIS)

    Tahimi, Abdeladhim

    2011-01-01

    The objectives of this work are: (i) understand the mechanisms and phenomena involved in the plasticity of steels in the presence of a diffusive or martensitic phase transformation. (ii) develop tools for predicting TRIP, which are able to correctly reproduce the macroscopic deformation for cases of complex loading and could also provide information about local elasto-visco-plastic interactions between product and parent phases. To this purpose, new experimental tests are conducted on 35NCD16 steel for austenite to martensite transformation and on 100C6 steel for austenite to pearlite transformation. The elasto viscoplastic properties of austenite and pearlite of the 100C6 steel are characterized through tension compression and relaxation tests. The parameters of macro-homogeneous and crystal-based constitutive laws could then be identified such as to analyse different models with respect to the experimental TRIP: the analytical models of Leblond (1989) and Taleb and Sidoroff (2003) but also, above all, different numerical models which can be distinguished by the prevailing assumptions concerning the local kinetics and the constitutive laws. An extension of the single-grain model dedicated to martensitic transformations developed during the thesis of S. Meftah (2007) is proposed. It consists in introducing the polycrystalline character of the austenite through a process of homogenization based on a self-consistent scheme by calculating the properties of an Equivalent Homogeneous Medium environment (EHM). (author)

  19. Model for optical-laser-induced impulse in vacuo

    International Nuclear Information System (INIS)

    Dingus, R.S.; Goldman, S.R.

    1985-01-01

    A simple model, along with its derivation, is presented for calculating the impulse from targets in a vacuum exposed to single-pulse, optical lasers. Figures demonstrate that throughout most of the range of interest, results from the model agree well with experimental data and LASNEX radiation-hydrodynamic computer code calculations. The model assumes isothermal blowoff and thus takes advantage of the insensitivity of impulse to energy distribution within the ablated mass. The density profile in the blowoff is estimated and the Saha equation is used to evaluate the degree of ionization. The laser absorption coefficient and thermal radiation opacity are evaluated as a function of position in the blowoff in order to evaluate the energy reaching the ablation surface. An overall energy balance plus an energy balance at the ablation surface are used to determine the blowoff mass and temperature. The success of the model indicates that the impulse is insensitive to detailed interactions in the vicinity of the ablation surface. 11 refs., 6 figs

  20. Physical model study of neutron noise induced by vibration of reactor internals

    International Nuclear Information System (INIS)

    Liu Jinhui; Gu Fangyu

    1999-01-01

    The author presents a physical model of neutron noise induced by reactor internals vibration in frequency domain. Based on system control theory, the reactor dynamic equations are coupled with random vibration equation, and non-linear terms are also taken into accounted while treating the random vibration. Experiments carried out on a zero-power reactor show that the model can be used to describe dynamic character of neutron noise induced by internals' vibration. The model establishes a method to help to determine internals'vibration features, and to diagnosis anomalies through neutron noise

  1. A Model for Microcontroller Functionality Upset Induced by External Pulsed Electromagnetic Irradiation

    Science.gov (United States)

    2016-11-21

    AFRL-RD-PS- AFRL-RD-PS- TN-2016-0003 TN-2016-0003 A Model for Microcontroller Functionality Upset Induced by External Pulsed Electromagnetic...TYPE Technical Note 3. DATES COVERED (From - To) 22-11-2015 – 21-11-2016 4. TITLE AND SUBTITLE A Model for Microcontroller Functionality Upset Induced by... microcontroller (µC) subjected to external irradiation by a narrowband electromagnetic (EM) pulse. In our model, the state of a µC is completely specified by

  2. Dispersive FDTD analysis of induced electric field in human models due to electrostatic discharge.

    Science.gov (United States)

    Hirata, Akimasa; Nagai, Toshihiro; Koyama, Teruyoshi; Hattori, Junya; Chan, Kwok Hung; Kavet, Robert

    2012-07-07

    Contact currents flow from/into a charged human body when touching a grounded conductive object. An electrostatic discharge (ESD) or spark may occur just before contact or upon release. The current may stimulate muscles and peripheral nerves. In order to clarify the difference in the induced electric field between different sized human models, the in-situ electric fields were computed in anatomically based models of adults and a child for a contact current in a human body following ESD. A dispersive finite-difference time-domain method was used, in which biological tissue is assumed to obey a four-pole Debye model. From our computational results, the first peak of the discharge current was almost identical across adult and child models. The decay of the induced current in the child was also faster due mainly to its smaller body capacitance compared to the adult models. The induced electric fields in the forefingers were comparable across different models. However, the electric field induced in the arm of the child model was found to be greater than that in the adult models primarily because of its smaller cross-sectional area. The tendency for greater doses in the child has also been reported for power frequency sinusoidal contact current exposures as reported by other investigators.

  3. Dispersive FDTD analysis of induced electric field in human models due to electrostatic discharge

    International Nuclear Information System (INIS)

    Hirata, Akimasa; Nagai, Toshihiro; Koyama, Teruyoshi; Hattori, Junya; Chan, Kwok Hung; Kavet, Robert

    2012-01-01

    Contact currents flow from/into a charged human body when touching a grounded conductive object. An electrostatic discharge (ESD) or spark may occur just before contact or upon release. The current may stimulate muscles and peripheral nerves. In order to clarify the difference in the induced electric field between different sized human models, the in-situ electric fields were computed in anatomically based models of adults and a child for a contact current in a human body following ESD. A dispersive finite-difference time-domain method was used, in which biological tissue is assumed to obey a four-pole Debye model. From our computational results, the first peak of the discharge current was almost identical across adult and child models. The decay of the induced current in the child was also faster due mainly to its smaller body capacitance compared to the adult models. The induced electric fields in the forefingers were comparable across different models. However, the electric field induced in the arm of the child model was found to be greater than that in the adult models primarily because of its smaller cross-sectional area. The tendency for greater doses in the child has also been reported for power frequency sinusoidal contact current exposures as reported by other investigators. (paper)

  4. Modeling TSC and LAM Using Patient Derived Induced Pluripotent Stem Cells

    Science.gov (United States)

    2016-10-01

    drug screens . We have now made TSC2 deficient human cells using patient induced pluripotent stem cells (iPSCs...Therapeutics.” Canadian Association of Research in Regenerative Medicine (CARRM), Ottawa, ON, CANADA March 7, 2015 • “ Stem cell approaches to model human... Stem cell approaches to model human development and disease.” Australian Regenerative Medicine Institute, Melbourne, Victoria, AUSTRALIA November

  5. An Energy Balanced Double Oscillator Model for Vortex-Induced Vibrations

    DEFF Research Database (Denmark)

    Krenk, S.; Nielsen, Søren R. K.

    A model consisting of two couple oscillators is developed for the representation of vortex-induced oscillations of structural elements. The mutual forcing terms are different from previous models and based on exact transfer of energy from the fluid to the structural oscillator. This leads...

  6. Efficient Weibull channel model for salinity induced turbulent underwater wireless optical communications

    KAUST Repository

    Oubei, Hassan M.

    2017-12-13

    Recent advances in underwater wireless optical communications necessitate a better understanding of the underwater channel. We propose the Weibull model to characterize the fading of salinity induced turbulent underwater wireless optical channels. The model shows an excellent agreement with the measured data under all channel conditions.

  7. Rat model of cancer-induced bone pain: changes in nonnociceptive sensory neurons in vivo

    Directory of Open Access Journals (Sweden)

    Yong Fang Zhu

    2017-08-01

    Conclusion:. After induction of the CIBP model, Aβ-fiber LTMs at >2 weeks but not <1 week had undergone changes in electrophysiological properties. Importantly, changes observed are consistent with observations in models of peripheral neuropathy. Thus, Aβ-fiber nonnociceptive primary sensory neurons might be involved in the peripheral sensitization and tumor-induced tactile hypersensitivity in CIBP.

  8. Validation of infrared thermography in serotonin-induced itch model in rats

    DEFF Research Database (Denmark)

    Dagnæs-Hansen, Frederik; Jasemian, Yousef; Gazerani, Parisa

    The number of scratching bouts is generally used as a standard method in animal models of itch. The aim of the present study was to validate the application of infrared thermography (IR-Th) in a serotonin-induced itch model in rats. Adult Sprague-Dawley male rats (n = 24) were used in 3 consecuti...

  9. NMR relaxation induced by iron oxide particles: testing theoretical models.

    Science.gov (United States)

    Gossuin, Y; Orlando, T; Basini, M; Henrard, D; Lascialfari, A; Mattea, C; Stapf, S; Vuong, Q L

    2016-04-15

    Superparamagnetic iron oxide particles find their main application as contrast agents for cellular and molecular magnetic resonance imaging. The contrast they bring is due to the shortening of the transverse relaxation time T 2 of water protons. In order to understand their influence on proton relaxation, different theoretical relaxation models have been developed, each of them presenting a certain validity domain, which depends on the particle characteristics and proton dynamics. The validation of these models is crucial since they allow for predicting the ideal particle characteristics for obtaining the best contrast but also because the fitting of T 1 experimental data by the theory constitutes an interesting tool for the characterization of the nanoparticles. In this work, T 2 of suspensions of iron oxide particles in different solvents and at different temperatures, corresponding to different proton diffusion properties, were measured and were compared to the three main theoretical models (the motional averaging regime, the static dephasing regime, and the partial refocusing model) with good qualitative agreement. However, a real quantitative agreement was not observed, probably because of the complexity of these nanoparticulate systems. The Roch theory, developed in the motional averaging regime (MAR), was also successfully used to fit T 1 nuclear magnetic relaxation dispersion (NMRD) profiles, even outside the MAR validity range, and provided a good estimate of the particle size. On the other hand, the simultaneous fitting of T 1 and T 2 NMRD profiles by the theory was impossible, and this occurrence constitutes a clear limitation of the Roch model. Finally, the theory was shown to satisfactorily fit the deuterium T 1 NMRD profile of superparamagnetic particle suspensions in heavy water.

  10. Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Afford New Opportunities in Inherited Cardiovascular Disease Modeling

    Directory of Open Access Journals (Sweden)

    Daniel R. Bayzigitov

    2016-01-01

    Full Text Available Fundamental studies of molecular and cellular mechanisms of cardiovascular disease pathogenesis are required to create more effective and safer methods of their therapy. The studies can be carried out only when model systems that fully recapitulate pathological phenotype seen in patients are used. Application of laboratory animals for cardiovascular disease modeling is limited because of physiological differences with humans. Since discovery of induced pluripotency generating induced pluripotent stem cells has become a breakthrough technology in human disease modeling. In this review, we discuss a progress that has been made in modeling inherited arrhythmias and cardiomyopathies, studying molecular mechanisms of the diseases, and searching for and testing drug compounds using patient-specific induced pluripotent stem cell-derived cardiomyocytes.

  11. Modelling irradiation-induced softening in BCC iron by crystal plasticity approach

    International Nuclear Information System (INIS)

    Xiao, Xiazi; Terentyev, Dmitry; Yu, Long; Song, Dingkun; Bakaev, A.; Duan, Huiling

    2015-01-01

    Crystal plasticity model (CPM) for BCC iron to account for radiation-induced strain softening is proposed. CPM is based on the plastically-driven and thermally-activated removal of dislocation loops. Atomistic simulations are applied to parameterize dislocation-defect interactions. Combining experimental microstructures, defect-hardening/absorption rules from atomistic simulations, and CPM fitted to properties of non-irradiated iron, the model achieves a good agreement with experimental data regarding radiation-induced strain softening and flow stress increase under neutron irradiation. - Highlights: • A stress- and thermal-activated defect absorption model is proposed for the dislocation-loop interaction. • A temperature-dependent plasticity theory is proposed for the irradiation-induced strain softening of irradiated BCC metals. • The numerical results of the model match with the corresponding experimental data.

  12. Modelling irradiation-induced softening in BCC iron by crystal plasticity approach

    Energy Technology Data Exchange (ETDEWEB)

    Xiao, Xiazi [State Key Laboratory for Turbulence and Complex System, Department of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing 100871 (China); CAPT, HEDPS and IFSA Collaborative Innovation Center of MoE, Peking University, Beijing 100871 (China); Terentyev, Dmitry, E-mail: dterenty@SCKCEN.BE [Structural Material Group, Institute of Nuclear Materials Science, SCK-CEN, Mol (Belgium); Yu, Long; Song, Dingkun [State Key Laboratory for Turbulence and Complex System, Department of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing 100871 (China); Bakaev, A. [Structural Material Group, Institute of Nuclear Materials Science, SCK-CEN, Mol (Belgium); Duan, Huiling, E-mail: hlduan@pku.edu.cn [State Key Laboratory for Turbulence and Complex System, Department of Mechanics and Engineering Science, College of Engineering, Peking University, Beijing 100871 (China); CAPT, HEDPS and IFSA Collaborative Innovation Center of MoE, Peking University, Beijing 100871 (China)

    2015-11-15

    Crystal plasticity model (CPM) for BCC iron to account for radiation-induced strain softening is proposed. CPM is based on the plastically-driven and thermally-activated removal of dislocation loops. Atomistic simulations are applied to parameterize dislocation-defect interactions. Combining experimental microstructures, defect-hardening/absorption rules from atomistic simulations, and CPM fitted to properties of non-irradiated iron, the model achieves a good agreement with experimental data regarding radiation-induced strain softening and flow stress increase under neutron irradiation. - Highlights: • A stress- and thermal-activated defect absorption model is proposed for the dislocation-loop interaction. • A temperature-dependent plasticity theory is proposed for the irradiation-induced strain softening of irradiated BCC metals. • The numerical results of the model match with the corresponding experimental data.

  13. Modeling of Mud-Wave Interaction: Mud-Induced Wave Transport & Wave-Induced Mud Transport

    National Research Council Canada - National Science Library

    Winterwerp, Johan C

    2007-01-01

    .... Also a new rheological model has been proposed to describe liquefaction of soft mud by waves, and the subsequent strength recovery after the passage of the waves. A scheme is presented on how to implement these formulations in Delft3D.

  14. Electrical stimulation induces propagated colonic contractions in an experimental model.

    Science.gov (United States)

    Aellen, S; Wiesel, P H; Gardaz, J-P; Schlageter, V; Bertschi, M; Virag, N; Givel, J-C

    2009-02-01

    Direct colonic electrical stimulation may prove to be a treatment option for specific motility disorders such as chronic constipation. The aim of this study was to provoke colonic contractions using electrical stimulation delivered from a battery-operated device. Electrodes were inserted into the caecal seromuscular layer of eight anaesthetized pigs. Contractions were induced by a neurostimulator (Medtronic 3625). Caecal motility was measured simultaneously by video image analysis, manometry and a technique assessing colonic transit. Caecal contractions were generated using 8-10 V amplitude, 1000 micros pulse width, 120 Hz frequency for 10-30 s, with an intensity of 7-15 mA. The maximal contraction strength was observed after 20-25 s. Electrical stimulation was followed by a relaxation phase of 1.5-2 min during which contractions propagated orally and aborally over at least 10 cm. Spontaneous and stimulated caecal motility values were significantly different for both intraluminal pressure (mean(s.d.) 332(124) and 463(187) mmHg respectively; P < 0.001, 42 experiments) and movement of contents (1.6(0.9) and 3.9(2.8) mm; P < 0.001, 40 experiments). Electrical stimulation modulated caecal motility, and provoked localized and propagated colonic contractions.

  15. Statistical modeling of competitive threshold collision-induced dissociation

    Science.gov (United States)

    Rodgers, M. T.; Armentrout, P. B.

    1998-08-01

    Collision-induced dissociation of (R1OH)Li+(R2OH) with xenon is studied using guided ion beam mass spectrometry. R1OH and R2OH include the following molecules: water, methanol, ethanol, 1-propanol, 2-propanol, and 1-butanol. In all cases, the primary products formed correspond to endothermic loss of one of the neutral alcohols, with minor products that include those formed by ligand exchange and loss of both ligands. The cross-section thresholds are interpreted to yield 0 and 298 K bond energies for (R1OH)Li+-R2OH and relative Li+ binding affinities of the R1OH and R2OH ligands after accounting for the effects of multiple ion-molecule collisions, internal energy of the reactant ions, and dissociation lifetimes. We introduce a means to simultaneously analyze the cross sections for these competitive dissociations using statistical theories to predict the energy dependent branching ratio. Thermochemistry in good agreement with previous work is obtained in all cases. In essence, this statistical approach provides a detailed means of correcting for the "competitive shift" inherent in multichannel processes.

  16. Mitomycin C induced alterations in antioxidant enzyme levels in a model insect species, Spodoptera eridania.

    Science.gov (United States)

    Batcabe, J P; MacGill, R S; Zaman, K; Ahmad, S; Pardini, R S

    1994-05-01

    1. An insect species, the southern armyworm Spodoptera eridania, was used as an in vivo model to examine mitomycin C's (MMC) pro-oxidant effect reflected in alterations of antioxidant enzymes. 2. Following a 2-day exposure to 0.01 and 0.05% w/w dietary concentrations, MMC only induced superoxide dismutase activity. All other enzyme activities were not affected, indicating oxidative stress was mild. 3. Following a 5-day exposure to 0.05% w/w dietary MMC, the activities of superoxide dismutase, glutathione-S-transferase and its peroxidase activity and DT-diaphorase were induced. GR activity was not altered. The high constitutive catalase activity was also not affected. These responses of S. eridania's antioxidant enzymes are analogous to those of mammalian systems in alleviating MMC-induced oxidative stress. 4. S. eridania emerges as an appropriate non-mammalian model for initial and cost-effective screening of drug-induced oxidative stress.

  17. Young at Heart: Pioneering Approaches to Model Nonischaemic Cardiomyopathy with Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Aoife Gowran

    2016-01-01

    Full Text Available A mere 9 years have passed since the revolutionary report describing the derivation of induced pluripotent stem cells from human fibroblasts and the first in-patient translational use of cells obtained from these stem cells has already been achieved. From the perspectives of clinicians and researchers alike, the promise of induced pluripotent stem cells is alluring if somewhat beguiling. It is now evident that this technology is nascent and many areas for refinement have been identified and need to be considered before induced pluripotent stem cells can be routinely used to stratify, treat and cure patients, and to faithfully model diseases for drug screening purposes. This review specifically addresses the pioneering approaches to improve induced pluripotent stem cell based models of nonischaemic cardiomyopathy.

  18. Buckling induced by cyclic straining: Analysis of simple models

    International Nuclear Information System (INIS)

    Devos, J.; Gontier, C.; Hoffmann, A.

    1983-01-01

    Progressive buckling of a structure may occur under imposed loads below the critical value in cases where progressive distortion due to cyclic straining is possible. This interaction between ratchetting and buckling is usually not taken into account in design rules, such as the ASME rules. This paper presents the complete analysis of two simple cases and gives rules established on this basis. The first model is a modified version of SHANLEY's two bars; it is submitted to a constant axial compressive force F and a variable thermal stress Q. It simulates a compressed clamped-clamped beam subjected to a variable through-thickness thermal gradient. The second model is a refined version of the first taking into account strain-hardening of the deformable sections. One finds that progressive buckling is possible only if the applied force F is greater than SHANLEY's critical load and tangent moduli of the moment-curvature law, respectively. (orig./GL)

  19. Learning about hydrothermal volcanic activity by modeling induced geophysical changes

    Science.gov (United States)

    Currenti, Gilda M.; Napoli, Rosalba

    2017-05-01

    Motivated by ongoing efforts to understand the nature and the energy potential of geothermal resources, we devise a coupled numerical model (hydrological, thermal, mechanical), which may help in the characterization and monitoring of hydrothermal systems through computational experiments. Hydrothermal areas in volcanic regions arise from a unique combination of geological and hydrological features which regulate the movement of fluids in the vicinity of magmatic sources capable of generating large quantities of steam and hot water. Numerical simulations help in understanding and characterizing rock-fluid interaction processes and the geophysical observations associated with them. Our aim is the quantification of the response of different geophysical observables (i.e. deformation, gravity and magnetic field) to hydrothermal activity on the basis of a sound geological framework (e.g. distribution and pathways of the flows, the presence of fractured zones, caprock). A detailed comprehension and quantification of the evolution and dynamics of the geothermal systems and the definition of their internal state through a geophysical modeling approach are essential to identify the key parameters for which the geothermal system may fulfill the requirements to be exploited as a source of energy. For the sake of illustration only, the numerical computations are focused on a conceptual model of the hydrothermal system of Vulcano Island by simulating a generic 1-year unrest and estimating different geophysical changes. We solved (i) the mass and energy balance equations of flow in porous media for temperature, pressure and density changes, (ii) the elastostatic equation for the deformation field and (iii) the Poisson’s equations for gravity and magnetic potential fields. Under the model assumptions, a generic unrest of 1-year engenders on the ground surface low amplitude changes in the investigated geophysical observables, that are, however, above the accuracies of the modern

  20. Models of Tidally Induced Gas Filaments in the Magellanic Stream

    Science.gov (United States)

    Pardy, Stephen A.; D’Onghia, Elena; Fox, Andrew J.

    2018-04-01

    The Magellanic Stream and Leading Arm of H I that stretches from the Large and Small Magellanic Clouds (LMC and SMC) and over 200° of the Southern sky is thought to be formed from multiple encounters between the LMC and SMC. In this scenario, most of the gas in the Stream and Leading Arm is stripped from the SMC, yet recent observations have shown a bifurcation of the Trailing Arm that reveals LMC origins for some of the gas. Absorption measurements in the Stream also reveal an order of magnitude more gas than in current tidal models. We present hydrodynamical simulations of the multiple encounters between the LMC and SMC at their first pass around the Milky Way, assuming that the Clouds were more extended and gas-rich in the past. Our models create filamentary structures of gas in the Trailing Stream from both the LMC and SMC. While the SMC trailing filament matches the observed Stream location, the LMC filament is offset. In addition, the total observed mass of the Stream in these models is underestimated by a factor of four when the ionized component is accounted for. Our results suggest that there should also be gas stripped from both the LMC and SMC in the Leading Arm, mirroring the bifurcation in the Trailing Stream. This prediction is consistent with recent measurements of spatial variation in chemical abundances in the Leading Arm, which show that gas from multiple sources is present, although its nature is still uncertain.

  1. Continuum model for chiral induced spin selectivity in helical molecules

    Energy Technology Data Exchange (ETDEWEB)

    Medina, Ernesto [Centro de Física, Instituto Venezolano de Investigaciones Científicas, 21827, Caracas 1020 A (Venezuela, Bolivarian Republic of); Groupe de Physique Statistique, Institut Jean Lamour, Université de Lorraine, 54506 Vandoeuvre-les-Nancy Cedex (France); Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287 (United States); González-Arraga, Luis A. [IMDEA Nanoscience, Cantoblanco, 28049 Madrid (Spain); Finkelstein-Shapiro, Daniel; Mujica, Vladimiro [Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287 (United States); Berche, Bertrand [Centro de Física, Instituto Venezolano de Investigaciones Científicas, 21827, Caracas 1020 A (Venezuela, Bolivarian Republic of); Groupe de Physique Statistique, Institut Jean Lamour, Université de Lorraine, 54506 Vandoeuvre-les-Nancy Cedex (France)

    2015-05-21

    A minimal model is exactly solved for electron spin transport on a helix. Electron transport is assumed to be supported by well oriented p{sub z} type orbitals on base molecules forming a staircase of definite chirality. In a tight binding interpretation, the spin-orbit coupling (SOC) opens up an effective π{sub z} − π{sub z} coupling via interbase p{sub x,y} − p{sub z} hopping, introducing spin coupled transport. The resulting continuum model spectrum shows two Kramers doublet transport channels with a gap proportional to the SOC. Each doubly degenerate channel satisfies time reversal symmetry; nevertheless, a bias chooses a transport direction and thus selects for spin orientation. The model predicts (i) which spin orientation is selected depending on chirality and bias, (ii) changes in spin preference as a function of input Fermi level and (iii) back-scattering suppression protected by the SO gap. We compute the spin current with a definite helicity and find it to be proportional to the torsion of the chiral structure and the non-adiabatic Aharonov-Anandan phase. To describe room temperature transport, we assume that the total transmission is the result of a product of coherent steps.

  2. Modeling of excavation induced coupled hydraulic-mechanical processes in claystone

    Energy Technology Data Exchange (ETDEWEB)

    Massmann, Jobst

    2009-07-01

    Concepts for the numerical modeling of excavation induced processes in claystone are investigated. The study has been motivated by the international discussion on the adequacy of claystone as a potential host rock for a final repository of radioactive waste. The processes, which could impact the safety of such a repository, are manifold and strongly interacting. Thus, a multiphysics approach is needed, regarding solid mechanics and fluid mechanics within a geological context. A coupled modeling concept is therefore indispensable. Based on observations and measurements at an argillaceous test site (the underground laboratory Tournemire, operated by the Institute of Radioprotection and Nuclear Safety, France) the modeling concept is developed. Two main processes constitute the basis of the applied model: deformation (linear elasticity considering damage) and fluid flow (unsaturated one-phase flow). Several coupling phenomena are considered: Terzaghi 's effective stress concept, mass conservation of the liquid in a deformable porous media, drying induced shrinkage, and a permeability which depends on deformation and damage. In addition, transversely isotropic material behavior is considered. The numerical simulations are done with the finite element code RockFlow, which is extended to include: an orthotropic non-linear shrinkage model, a continuum damage model, and an orthotropic permeability model. For these new methods the theory and a literature review are presented, followed by applications, which illustrate the capability to model excavation induced processes in principle. In a comprehensive case study, the modeling concept is used to simulate the response of the Tournemire argillite to excavation. The results are compared with observations and measurements of three different excavations (century old tunnel, two galleries excavated in 1996 and 2003). In summary, it can be concluded that the developed model concept provides a prediction of the excavation

  3. Modeling of excavation induced coupled hydraulic-mechanical processes in claystone

    Energy Technology Data Exchange (ETDEWEB)

    Massmann, Jobst

    2009-07-01

    Concepts for the numerical modeling of excavation induced processes in claystone are investigated. The study has been motivated by the international discussion on the adequacy of claystone as a potential host rock for a final repository of radioactive waste. The processes, which could impact the safety of such a repository, are manifold and strongly interacting. Thus, a multiphysics approach is needed, regarding solid mechanics and fluid mechanics within a geological context. A coupled modeling concept is therefore indispensable. Based on observations and measurements at an argillaceous test site (the underground laboratory Tournemire, operated by the Institute of Radioprotection and Nuclear Safety, France) the modeling concept is developed. Two main processes constitute the basis of the applied model: deformation (linear elasticity considering damage) and fluid flow (unsaturated one-phase flow). Several coupling phenomena are considered: Terzaghi 's effective stress concept, mass conservation of the liquid in a deformable porous media, drying induced shrinkage, and a permeability which depends on deformation and damage. In addition, transversely isotropic material behavior is considered. The numerical simulations are done with the finite element code RockFlow, which is extended to include: an orthotropic non-linear shrinkage model, a continuum damage model, and an orthotropic permeability model. For these new methods the theory and a literature review are presented, followed by applications, which illustrate the capability to model excavation induced processes in principle. In a comprehensive case study, the modeling concept is used to simulate the response of the Tournemire argillite to excavation. The results are compared with observations and measurements of three different excavations (century old tunnel, two galleries excavated in 1996 and 2003). In summary, it can be concluded that the developed model concept provides a prediction of the excavation induced

  4. Modeling of excavation induced coupled hydraulic-mechanical processes in claystone

    International Nuclear Information System (INIS)

    Massmann, Jobst

    2009-01-01

    Concepts for the numerical modeling of excavation induced processes in claystone are investigated. The study has been motivated by the international discussion on the adequacy of claystone as a potential host rock for a final repository of radioactive waste. The processes, which could impact the safety of such a repository, are manifold and strongly interacting. Thus, a multiphysics approach is needed, regarding solid mechanics and fluid mechanics within a geological context. A coupled modeling concept is therefore indispensable. Based on observations and measurements at an argillaceous test site (the underground laboratory Tournemire, operated by the Institute of Radioprotection and Nuclear Safety, France) the modeling concept is developed. Two main processes constitute the basis of the applied model: deformation (linear elasticity considering damage) and fluid flow (unsaturated one-phase flow). Several coupling phenomena are considered: Terzaghi 's effective stress concept, mass conservation of the liquid in a deformable porous media, drying induced shrinkage, and a permeability which depends on deformation and damage. In addition, transversely isotropic material behavior is considered. The numerical simulations are done with the finite element code RockFlow, which is extended to include: an orthotropic non-linear shrinkage model, a continuum damage model, and an orthotropic permeability model. For these new methods the theory and a literature review are presented, followed by applications, which illustrate the capability to model excavation induced processes in principle. In a comprehensive case study, the modeling concept is used to simulate the response of the Tournemire argillite to excavation. The results are compared with observations and measurements of three different excavations (century old tunnel, two galleries excavated in 1996 and 2003). In summary, it can be concluded that the developed model concept provides a prediction of the excavation induced

  5. A comparative bear model for immobility-induced osteopenia

    Science.gov (United States)

    Milbury, P. E.; Vaughan, M. R.; Farley, S.; Matula, G. J. Jr; Convertino, V. A.; Matson, W. R.

    1998-01-01

    The National Institutes of Health (NIH) and the National Aeronautics and Space Administration (NASA) are seeking solutions to the human problem of osteopenia, or immobility-induced bone loss. Bears, during winter dormancy, appear uniquely exempted from the debilitating effects of immobility osteopenia. NIH and ESA, Inc. are creating a large database of metabolic information on human ambulatory and bedrest plasma samples for comparison with metabolic data obtained from bear plasma samples collected in different seasons. The database generated from NASA's HR113 human bedrest study showed a clear difference between plasma samples of ambulatory and immobile subjects through cluster analysis using compounds determined by high performance liquid chromatography with coulometric electrochemical array detection (HPLC-EC). We collected plasma samples from black bears (Ursus americanus) across 4 seasons and from 3 areas and subjected them to similar analysis, with particular attention to compounds that changed significantly in the NASA human study. We found seasonal differences in 28 known compounds and 33 unknown compounds. A final database contained 40 known and 120 unknown peaks that were reliably assayed in all bear and human samples; these were the primary data set for interspecies comparison. Six unidentified compounds changed significantly but differentially in wintering bears and immobile humans. The data are discussed in light of current theories regarding dormancy, starvation, and anabolic metabolism. Work is in progress by ESA Laboratories on a larger database to confirm these findings prior to a chemical isolation and identification effort. This research could lead to new pharmaceuticals or dietary interventions for the treatment of immobility osteopenia.

  6. Proteomic profiling of the hypothalamus in a mouse model of cancer-induced anorexia-cachexia

    OpenAIRE

    Ihnatko, Robert; Post, Claes; Blomqvist, Anders

    2013-01-01

    Background: Anorexia-cachexia is a common and severe cancer-related complication but the underlying mechanisms are largely unknown. Here, using a mouse model for tumour-induced anorexia-cachexia, we screened for proteins that are differentially expressed in the hypothalamus, the brain’s metabolic control centre. Methods: The hypothalamus of tumour-bearing mice with implanted methylcholanthrene-induced sarcoma (MCG 101) displaying anorexia and their sham-implanted pair-fed or free-fed litterma...

  7. Numerical simulation of self-induced rainout using a dynamic convective cloud model

    International Nuclear Information System (INIS)

    Molenkamp, C.R.

    1980-03-01

    The hypothesis that self-induced rainout can occur is supported by observations in Hiroshima and Nagasaki, where deposition of weapons debris with precipitation occurred several km downwind of the burst point. This precipitation was initiated either directly by the nuclear weapons or by the ensuing fires. Simulation of the Nagasaki event with a convection cloud precipitation scavenging model, although fraught with many questionable assumptions, agrees surprisingly well with the observations and supports the hypothesis that self-induced rainout can occur

  8. Protein regulation of induced pluripotent stem cells by transplanting in a Huntington's animal model.

    Science.gov (United States)

    Mu, S; Han, L; Zhou, G; Mo, C; Duan, J; He, Z; Wang, Z; Ren, L; Zhang, J

    2016-10-01

    The purpose of this study was to determine the functional recovery and protein regulation by transplanted induced pluripotent stem cells in a rat model of Huntington's disease (HD). In a quinolinic acid-induced rat model of striatal degeneration, induced pluripotent stem cells were transplanted into the ipsilateral lateral ventricle 10 days after the quinolinic acid injection. At 8 weeks after transplantation, fluorodeoxyglucose-PET/CT scan and balance-beam test were performed to evaluate the functional recovery of experimental rats. In addition, immunofluorescence and protein array analysis were used to investigate the regulation of stimulated protein expression in the striatum. At 8 weeks after induced pluripotent stem cell transplantation, motor function was improved in comparison with the quinolinic acid-treated rats. High fluorodeoxyglucose accumulation in the injured striatum was also observed by PET/CT scans. In addition, immunofluorescence analysis demonstrated that implanted cells migrated from the lateral ventricle into the lesioned striatum and differentiated into striatal projection neurons. Array analysis showed a significant upregulation of GFR (Glial cell line-derived neurotrophic factor receptor) alpha-1, Adiponectin/Acrp30, basic-fibroblast growth factors, MIP-1 (Macrophage-inflammatory protein) alpha and leptin, as well as downregulation of cytokine-induced neutrophil chemoattractant-3 in striatum after transplantatation of induced pluripotent stem cells in comparison with the quinolinic acid -treated rats. The findings in this work indicate that transplantation of induced pluripotent stem cells is a promising therapeutic candidate for HD. © 2016 British Neuropathological Society.

  9. New parameterization of external and induced fields in geomagnetic field modeling, and a candidate model for IGRF 2005

    DEFF Research Database (Denmark)

    Olsen, Nils; Sabaka, T.J.; Lowes, F.

    2005-01-01

    When deriving spherical harmonic models of the Earth's magnetic field, low-degree external field contributions are traditionally considered by assuming that their expansion coefficient q(1)(0) varies linearly with the D-st-index, while induced contributions are considered assuming a constant ratio...... Q(1) of induced to external coefficients. A value of Q(1) = 0.27 was found from Magsat data and has been used by several authors when deriving recent field models from Orsted and CHAMP data. We describe a new approach that considers external and induced field based on a separation of D-st = E-st + I......-st into external (E-st) and induced (I-st) parts using a 1D model of mantle conductivity. The temporal behavior of q(1)(0) and of the corresponding induced coefficient are parameterized by E-st and I-st, respectively. In addition, we account for baseline-instabilities of D-st by estimating a value of q(1...

  10. Learning about Hydrothermal Volcanic Activity by Modeling Induced Geophysical Changes

    Directory of Open Access Journals (Sweden)

    Gilda M. Currenti

    2017-05-01

    Full Text Available Motivated by ongoing efforts to understand the nature and the energy potential of geothermal resources, we devise a coupled numerical model (hydrological, thermal, mechanical, which may help in the characterization and monitoring of hydrothermal systems through computational experiments. Hydrothermal areas in volcanic regions arise from a unique combination of geological and hydrological features which regulate the movement of fluids in the vicinity of magmatic sources capable of generating large quantities of steam and hot water. Numerical simulations help in understanding and characterizing rock-fluid interaction processes and the geophysical observations associated with them. Our aim is the quantification of the response of different geophysical observables (i.e., deformation, gravity, and magnetic fields to hydrothermal activity on the basis of a sound geological framework (e.g., distribution and pathways of the flows, the presence of fractured zones, caprock. A detailed comprehension and quantification of the evolution and dynamics of the geothermal systems and the definition of their internal state through a geophysical modeling approach are essential to identify the key parameters for which the geothermal system may fulfill the requirements to be exploited as a source of energy. For the sake of illustration only, the numerical computations are focused on a conceptual model of the hydrothermal system of Vulcano Island by simulating a generic 1-year unrest and estimating different geophysical changes. We solved (i the mass and energy balance equations of flow in porous media for temperature, pressure and density changes, (ii the elastostatic equation for the deformation field and (iii the Poisson's equations for gravity and magnetic potential fields. Under the model assumptions, a generic unrest of 1-year engenders on the ground surface low amplitude changes in the investigated geophysical observables, that, being above the accuracies of

  11. Stepping toward a Macaque Model of HIV-1 Induced AIDS

    Directory of Open Access Journals (Sweden)

    Jason T. Kimata

    2014-09-01

    Full Text Available HIV-1 exhibits a narrow host range, hindering the development of a robust animal model of pathogenesis. Past studies have demonstrated that the restricted host range of HIV-1 may be largely due to the inability of the virus to antagonize and evade effector molecules of the interferon response in other species. They have also guided the engineering of HIV-1 clones that can replicate in CD4 T-cells of Asian macaque species. However, while replication of these viruses in macaque hosts is persistent, it has been limited and without progression to AIDS. In a new study, Hatziioannou et al., demonstrate for the first time that adapted macaque-tropic HIV-1 can persistently replicate at high levels in pigtailed macaques (Macaca nemestrina, but only if CD8 T-cells are depleted at the time of inoculation. The infection causes rapid disease and recapitulates several aspects of AIDS in humans. Additionally, the virus undergoes genetic changes to further escape innate immunity in association with disease progression. Here, the importance of these findings is discussed, as they relate to pathogenesis and model development.

  12. Warning Model for Shallow Landslides Induced by Extreme Rainfall

    Directory of Open Access Journals (Sweden)

    Lien-Kwei Chien

    2015-08-01

    Full Text Available In this study, the geophysical properties of the landslide-prone catchment of the Gaoping River in Taiwan were investigated using zones based on landslide history in conjunction with landslide analysis using a deterministic approach based on the TRIGRS (Transient Rainfall Infiltration and Grid-based Regional Slope-Stability model. Typhoon Morakot in 2009 was selected as a simulation scenario to calibrate the combination of geophysical parameters in each zone before analyzing changes in the factor of safety (FS. Considering the amount of response time required for typhoons, suitable FS thresholds for landslide warnings are proposed for each town in the catchment area. Typhoon Fanapi of 2010 was used as a test scenario to verify the applicability of the FS as well as the efficacy of the cumulative rainfall thresholds derived in this study. Finally, the amount of response time provided by the FS thresholds in cases of yellow and red alerts was determined. All five of the landslide events reported by the Soil and Water Conservation Bureau were listed among the unstable sites identified in the proposed model, thereby demonstrating its effectiveness and accuracy in determining unstable areas and areas that require evacuation. These cumulative rainfall thresholds provide a valuable reference to guide disaster prevention authorities in the issuance of yellow and red alerts with the ability to reduce losses and save lives.

  13. An in vitro model of Mycobacterium leprae induced granuloma formation.

    Science.gov (United States)

    Wang, Hongsheng; Maeda, Yumi; Fukutomi, Yasuo; Makino, Masahiko

    2013-06-20

    Leprosy is a contagious and chronic systemic granulomatous disease caused by Mycobacterium leprae. In the pathogenesis of leprosy, granulomas play a key role, however, the mechanisms of the formation and maintenance of M. leprae granulomas are still not clearly understood. To better understand the molecular physiology of M. leprae granulomas and the interaction between the bacilli and human host cells, we developed an in vitro model of human granulomas, which mimicked the in vivo granulomas of leprosy. Macrophages were differentiated from human monocytes, and infected with M. leprae, and then cultured with autologous human peripheral blood mononuclear cells (PBMCs). Robust granuloma-like aggregates were obtained only when the M. leprae infected macrophages were co-cultured with PBMCs. Histological examination showed M. leprae within the cytoplasmic center of the multinucleated giant cells, and these bacilli were metabolically active. Macrophages of both M1 and M2 types co-existed in the granuloma like aggregates. There was a strong relationship between the formation of granulomas and changes in the expression levels of cell surface antigens on macrophages, cytokine production and the macrophage polarization. The viability of M. leprae isolated from granulomas indicated that the formation of host cell aggregates benefited the host, but the bacilli also remained metabolically active. A simple in vitro model of human M. leprae granulomas was established using human monocyte-derived macrophages and PBMCs. This system may be useful to unravel the mechanisms of disease progression, and subsequently develop methods to control leprosy.

  14. A new model to study sleep deprivation-induced seizure.

    Science.gov (United States)

    Lucey, Brendan P; Leahy, Averi; Rosas, Regine; Shaw, Paul J

    2015-05-01

    A relationship between sleep and seizures is well-described in both humans and rodent animal models; however, the mechanism underlying this relationship is unknown. Using Drosophila melanogaster mutants with seizure phenotypes, we demonstrate that seizure activity can be modified by sleep deprivation. Seizure activity was evaluated in an adult bang-sensitive seizure mutant, stress sensitive B (sesB(9ed4)), and in an adult temperature sensitive seizure mutant seizure (sei(ts1)) under baseline and following 12 h of sleep deprivation. The long-term effect of sleep deprivation on young, immature sesB(9ed4) flies was also assessed. Laboratory. Drosophila melanogaster. Sleep deprivation. Sleep deprivation increased seizure susceptibility in adult sesB(9ed4)/+ and sei(ts1) mutant flies. Sleep deprivation also increased seizure susceptibility when sesB was disrupted using RNAi. The effect of sleep deprivation on seizure activity was reduced when sesB(9ed4)/+ flies were given the anti-seizure drug, valproic acid. In contrast to adult flies, sleep deprivation during early fly development resulted in chronic seizure susceptibility when sesB(9ed4)/+ became adults. These findings show that Drosophila is a model organism for investigating the relationship between sleep and seizure activity. © 2015 Associated Professional Sleep Societies, LLC.

  15. Tobacco experimental model to induce urinary bladder neoplasms

    Directory of Open Access Journals (Sweden)

    José Alexandre Colli Neto

    2014-01-01

    Full Text Available OBJECTIVE: to develop an experimental model of exposure to tobacco burning (cigarette products to assess the effects of its chronic use in relation to cancers of the bladder. METHODS: the animals were chronically exposed to the burning tobacco products in a semi-open chamber to simulate smoking. Thirty young Wistar rats were divided into two groups: one with 20 animals simulating smoking for six months, and ten not exposed control animals for the same period. After exposure by inhalation of cigarette smoke, animals were euthanized and subjected to histopathological study of the bladder wall. RESULTS: no tumor was found but mild and non significant alterations. The studies of hemo-oximetry (carboxyhemoglobin and methemoglobin and the concentration of carbon dioxide (CO2 confirm that the animals were exposed to high concentrations of tobacco smoke and its derivatives. CONCLUSION: no bladder mucosal neoplasia was found in the pathological study of animals. The developed experimental models were highly efficient, practical and easy to use and can be used in other similar studies to determine the harmful effects caused by smoking.

  16. Using delay differential equations to induce alternans in a model of cardiac electrophysiology.

    Science.gov (United States)

    Eastman, Justin; Sass, Julian; Gomes, Johnny M; Dos Santos, Rodrigo Weber; Cherry, Elizabeth M

    2016-09-07

    Cardiac electrical alternans is a period-2 dynamical behavior with alternating long and short action potential durations (APD) that often precedes dangerous arrhythmias associated with cardiac arrest. Despite the importance of alternans, many current ordinary differential equations models of cardiac electrophysiology do not produce alternans, thereby limiting the use of these models for studying the mechanisms that underlie this condition. Because delay differential equations (DDEs) commonly induce complex dynamics in other biological systems, we investigate whether incorporating DDEs can lead to alternans development in cardiac models by studying the Fox et al. canine ventricular action potential model. After suppressing the alternans in the original model, we show that alternans can be obtained by introducing DDEs in the model gating variables, and we quantitatively compare the DDE-induced alternans with the alternans present in the original model. We analyze the behavior of the voltage, currents, and gating variables of the model to study the effects of the delays and to determine how alternans develops in that setting, and we discuss the mathematical and physiological implications of our findings. In future work, we aim to apply our approach to induce alternans in models that do not naturally exhibit such dynamics. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. String and brane models with spontaneously or dynamically induced tension

    International Nuclear Information System (INIS)

    Guendelman, E.I.; Kaganovich, A.; Nissimov, E.; Pacheva, S.

    2002-01-01

    We study in some detail the properties of a previously proposed new class of string and brane models whose world-sheet (world-volume) actions are built with a modified reparametrization-invariant measure of integration and which do not contain any ad hoc dimensionful parameters. The ratio of the new and the standard Riemannian integration measure densities plays the role of a dynamically generated string or brane tension. The latter is identified as (the magnitude of) an effective (non-Abelian) electric field strength on the world-sheet or world-volume obeying the standard Gauss-law constraint. As a result a simple classical mechanism for confinement via modified-measure 'color' strings is proposed where the colorlessness of the 'hadrons' is an automatic consequence of the new string dynamics

  18. Wake-Model Effects on Induced Drag Prediction of Staggered Boxwings

    Directory of Open Access Journals (Sweden)

    Julian Schirra

    2018-01-01

    Full Text Available For staggered boxwings the predictions of induced drag that rely on common potential-flow methods can be of limited accuracy. For example, linear, freestream-fixed wake models cannot resolve effects related to wake deflection and roll-up, which can have significant affects on the induced drag projection of these systems. The present work investigates the principle impact of wake modelling on the accuracy of induced drag prediction of boxwings with stagger. The study compares induced drag predictions of a higher-order potential-flow method that uses fixed and relaxed-wake models, and of an Euler-flow method. Positive-staggered systems at positive angles of attack are found to be particularly prone to higher-order wake effects due to vertical contraction of wakes trajectories, which results in smaller effective height-to-span ratios than compared with negative stagger and thus closer interactions between trailing wakes and lifting surfaces. Therefore, when trying to predict induced drag of positive staggered boxwings, only a potential-flow method with a fully relaxed-wake model will provide the high-degree of accuracy that rivals that of an Euler method while being computationally significantly more efficient.

  19. 3D numerical modeling of coupled phenomena in induced processes of heat treatment with malice

    Directory of Open Access Journals (Sweden)

    Triwong Peeteenut

    2008-01-01

    Full Text Available This paper describes a multi-method Malice package for three dimension coupled phenomena in induced processes of heat treatment by an algorithm weakly coupled with the Migen package integral method defining the electromagnetic model and the Flux-Expert package finite element method defining the thermal model. The integral method is well suited to inductive systems undergoing sinusoidal excitation at midrange or high frequency. The unknowns of both models are current density, scalar potential and temperature. Joule power in the electromagnetic model is generated by Eddy currents. It becomes the heat source in the thermal model.

  20. Estimating radiation-induced cancer risk using MVK two-stage model for carcinogenesis

    International Nuclear Information System (INIS)

    Kai, M.; Kusama, T.; Aoki, Y.

    1993-01-01

    Based on the carcinogenesis model as proposed by Moolgavkar et al., time-dependent relative risk models were derived for projecting the time variation in excess relative risk. If it is assumed that each process is described by time-independent linear dose-response relationship, the time variation in excess relative risk is influenced by the parameter related with the promotion process. The risk model based carcinogenesis theory would play a marked role in estimating radiation-induced cancer risk in constructing a projection model or transfer model

  1. Stochastic resonance induced by novel random transitions of motion of FitzHugh-Nagumo neuron model

    International Nuclear Information System (INIS)

    Zhang Guangjun; Xu Jianxue

    2005-01-01

    In contrast to the previous studies which have dealt with stochastic resonance induced by random transitions of system motion between two coexisting limit cycle attractors in the FitzHugh-Nagumo (FHN) neuron model after Hopf bifurcation and which have dealt with the phenomenon of stochastic resonance induced by external noise when the model with periodic input has only one attractor before Hopf bifurcation, in this paper we have focused our attention on stochastic resonance (SR) induced by a novel transition behavior, the transitions of motion of the model among one attractor on the left side of bifurcation point and two attractors on the right side of bifurcation point under the perturbation of noise. The results of research show: since one bifurcation of transition from one to two limit cycle attractors and the other bifurcation of transition from two to one limit cycle attractors occur in turn besides Hopf bifurcation, the novel transitions of motion of the model occur when bifurcation parameter is perturbed by weak internal noise; the bifurcation point of the model may stochastically slightly shift to the left or right when FHN neuron model is perturbed by external Gaussian distributed white noise, and then the novel transitions of system motion also occur under the perturbation of external noise; the novel transitions could induce SR alone, and when the novel transitions of motion of the model and the traditional transitions between two coexisting limit cycle attractors after bifurcation occur in the same process the SR also may occur with complicated behaviors types; the mechanism of SR induced by external noise when FHN neuron model with periodic input has only one attractor before Hopf bifurcation is related to this kind of novel transition mentioned above

  2. Penguin effects induced by the two-Higgs-doublet model and charmless B-meson decays

    International Nuclear Information System (INIS)

    Davies, A.J.; Joshi, G.C.; Matsuda, M.

    1991-01-01

    Nonstandard physical effects through the penguin diagram induced by the charged Higgs scalar contribution in the two-Higgs-doublet model are analysed. Since non-leptonic B-decay processes to final states consisting of s+s+anti s are induced only through the penguin diagram they are important tests of such contributions. We compare these decays including the non-standard two-Higgs-doublet contribution with the standard model results, which arise from the magnetic gluon transistion term. The charged Higgs contribution can give a sizable enhancement to the branching fraction of B-meson charmless decay. (orig.)

  3. Modeling Restrained Shrinkage Induced Cracking in Concrete Rings Using the Thick Level Set Approach

    Directory of Open Access Journals (Sweden)

    Rebecca Nakhoul

    2018-03-01

    Full Text Available Modeling restrained shrinkage-induced damage and cracking in concrete is addressed herein. The novel Thick Level Set (TLS damage growth and crack propagation model is used and adapted by introducing shrinkage contribution into the formulation. The TLS capacity to predict damage evolution, crack initiation and growth triggered by restrained shrinkage in absence of external loads is evaluated. A study dealing with shrinkage-induced cracking in elliptical concrete rings is presented herein. Key results such as the effect of rings oblateness on stress distribution and critical shrinkage strain needed to initiate damage are highlighted. In addition, crack positions are compared to those observed in experiments and are found satisfactory.

  4. Independencies Induced from a Graphical Markov Model After Marginalization and Conditioning: The R Package ggm

    Directory of Open Access Journals (Sweden)

    Giovanni M. Marchetti

    2006-02-01

    Full Text Available We describe some functions in the R package ggm to derive from a given Markov model, represented by a directed acyclic graph, different types of graphs induced after marginalizing over and conditioning on some of the variables. The package has a few basic functions that find the essential graph, the induced concentration and covariance graphs, and several types of chain graphs implied by the directed acyclic graph (DAG after grouping and reordering the variables. These functions can be useful to explore the impact of latent variables or of selection effects on a chosen data generating model.

  5. Cellular Automata Modelling of Photo-Induced Oxidation Processes in Molecularly Doped Polymers

    Directory of Open Access Journals (Sweden)

    David M. Goldie

    2016-11-01

    Full Text Available The possibility of employing cellular automata (CA to model photo-induced oxidation processes in molecularly doped polymers is explored. It is demonstrated that the oxidation dynamics generated using CA models exhibit stretched-exponential behavior. This dynamical characteristic is in general agreement with an alternative analysis conducted using standard rate equations provided the molecular doping levels are sufficiently low to prohibit the presence of safe-sites which are impenetrable to dissolved oxygen. The CA models therefore offer the advantage of exploring the effect of dopant agglomeration which is difficult to assess from standard rate equation solutions. The influence of UV-induced bleaching or darkening upon the resulting oxidation dynamics may also be easily incorporated into the CA models and these optical effects are investigated for various photo-oxidation product scenarios. Output from the CA models is evaluated for experimental photo-oxidation data obtained from a series of hydrazone-doped polymers.

  6. Exciton model and quantum molecular dynamics in inclusive nucleon-induced reactions

    International Nuclear Information System (INIS)

    Bevilacqua, Riccardo; Pomp, Stephan; Watanabe, Yukinobu

    2011-01-01

    We compared inclusive nucleon-induced reactions with two-component exciton model calculations and Kalbach systematics; these successfully describe the production of protons, whereas fail to reproduce the emission of composite particles, generally overestimating it. We show that the Kalbach phenomenological model needs to be revised for energies above 90 MeV; agreement improves introducing a new energy dependence for direct-like mechanisms described by the Kalbach model. Our revised model calculations suggest multiple preequilibrium emission of light charged particles. We have also compared recent neutron-induced data with quantum molecular dynamics (QMD) calculations complemented by the surface coalescence model (SCM); we observed that the SCM improves the predictive power of QMD. (author)

  7. Radiation-Induced Breast Cancer Incidence and Mortality From Digital Mammography Screening: A Modeling Study.

    Science.gov (United States)

    Miglioretti, Diana L; Lange, Jane; van den Broek, Jeroen J; Lee, Christoph I; van Ravesteyn, Nicolien T; Ritley, Dominique; Kerlikowske, Karla; Fenton, Joshua J; Melnikow, Joy; de Koning, Harry J; Hubbard, Rebecca A

    2016-02-16

    Estimates of risk for radiation-induced breast cancer from mammography screening have not considered variation in dose exposure or diagnostic work-up after abnormal screening results. To estimate distributions of radiation-induced breast cancer incidence and mortality from digital mammography screening while considering exposure from screening and diagnostic mammography and dose variation among women. 2 simulation-modeling approaches. U.S. population. Women aged 40 to 74 years. Annual or biennial digital mammography screening from age 40, 45, or 50 years until age 74 years. Lifetime breast cancer deaths averted (benefits) and radiation-induced breast cancer incidence and mortality (harms) per 100,000 women screened. Annual screening of 100,000 women aged 40 to 74 years was projected to induce 125 breast cancer cases (95% CI, 88 to 178) leading to 16 deaths (CI, 11 to 23), relative to 968 breast cancer deaths averted by early detection from screening. Women exposed at the 95th percentile were projected to develop 246 cases of radiation-induced breast cancer leading to 32 deaths per 100,000 women. Women with large breasts requiring extra views for complete examination (8% of population) were projected to have greater radiation-induced breast cancer risk (266 cancer cases and 35 deaths per 100,000 women) than other women (113 cancer cases and 15 deaths per 100,000 women). Biennial screening starting at age 50 years reduced risk for radiation-induced cancer 5-fold. Life-years lost from radiation-induced breast cancer could not be estimated. Radiation-induced breast cancer incidence and mortality from digital mammography screening are affected by dose variability from screening, resultant diagnostic work-up, initiation age, and screening frequency. Women with large breasts may have a greater risk for radiation-induced breast cancer. Agency for Healthcare Research and Quality, U.S. Preventive Services Task Force, National Cancer Institute.

  8. Modeling Chemotherapy-Induced Hair Loss: From Experimental Propositions toward Clinical Reality.

    Science.gov (United States)

    Botchkarev, Vladimir A; Sharov, Andrey A

    2016-03-01

    Chemotherapy-induced hair loss is one of the most devastating side effects of cancer treatment. To study the effects of chemotherapeutic agents on the hair follicle, a number of experimental models have been proposed. Yoon et al. report that transplantation of human scalp hair follicles onto chemotherapy-treated immunodeficient mice serves as an excellent in vivo model for chemotherapy-induced hair loss. Yoon et al. demonstrate that (i) the response of human hair follicles grafted onto immunodeficient mice to cyclophosphamide resembles the key features of the chemotherapy-induced hair loss seen in patients with cancer and (ii) this human in vivo model for chemotherapy-induced hair loss is closer to clinical reality than to any earlier models. Undoubtedly, this model will serve as a valuable tool for analyses of the mechanisms that underlie this devastating side effect of anti-cancer therapy. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  9. The Model of Optimum Economic Growth with the Induced Scientific-Technological Progress

    Directory of Open Access Journals (Sweden)

    Dilenko Viktor A.

    2017-07-01

    Full Text Available On the basis of the economic dynamics of the Harrod – Domar model, a model of optimum economic growth in line with the induced scientific-technological progress (STP has been built. In order to reflect the induced scientific-technological progress, with this model is proposed to further allocate the income element that is specially used for the investment of innovation activity, implementation of which reduces the capital intensity in development of the discussed economy. For the simplest way of presenting an economic mechanism for the investment of induced STP, analytical solutions of an appropriate task in optimum management have been obtained. Studying these decisions allowed to reveal the characteristics of the impact of parameters of scientific-technological progress and the analyzed economic system on choosing the best trajectory for its evolution. Possible directions for further developing the results presented can be considered the tasks in building and analyzing models of optimum economic growth that implement different investment options for the induced STP, as well as the models in which this investment mechanism is not exogenouslyed, but rather the result of the corresponding economic-mathematical research.

  10. A Prospective Cohort Study on Radiation-induced Hypothyroidism: Development of an NTCP Model

    International Nuclear Information System (INIS)

    Boomsma, Marjolein J.; Bijl, Hendrik P.; Christianen, Miranda E.M.C.; Beetz, Ivo; Chouvalova, Olga; Steenbakkers, Roel J.H.M.; Laan, Bernard F.A.M. van der; Wolffenbuttel, Bruce H.R.; Oosting, Sjoukje F.; Schilstra, Cornelis; Langendijk, Johannes A.

    2012-01-01

    Purpose: To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced hypothyroidism. Methods and Materials: The thyroid-stimulating hormone (TSH) level of 105 patients treated with (chemo-) radiation therapy for head-and-neck cancer was prospectively measured during a median follow-up of 2.5 years. Hypothyroidism was defined as elevated serum TSH with decreased or normal free thyroxin (T4). A multivariate logistic regression model with bootstrapping was used to determine the most important prognostic variables for radiation-induced hypothyroidism. Results: Thirty-five patients (33%) developed primary hypothyroidism within 2 years after radiation therapy. An NTCP model based on 2 variables, including the mean thyroid gland dose and the thyroid gland volume, was most predictive for radiation-induced hypothyroidism. NTCP values increased with higher mean thyroid gland dose (odds ratio [OR]: 1.064/Gy) and decreased with higher thyroid gland volume (OR: 0.826/cm 3 ). Model performance was good with an area under the curve (AUC) of 0.85. Conclusions: This is the first prospective study resulting in an NTCP model for radiation-induced hypothyroidism. The probability of hypothyroidism rises with increasing dose to the thyroid gland, whereas it reduces with increasing thyroid gland volume.

  11. A Prospective Cohort Study on Radiation-induced Hypothyroidism: Development of an NTCP Model

    Energy Technology Data Exchange (ETDEWEB)

    Boomsma, Marjolein J.; Bijl, Hendrik P.; Christianen, Miranda E.M.C.; Beetz, Ivo; Chouvalova, Olga; Steenbakkers, Roel J.H.M. [Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen (Netherlands); Laan, Bernard F.A.M. van der [Department of Otorhinolaryngology/Head and Neck Surgery, University Medical Center Groningen, University of Groningen, Groningen (Netherlands); Wolffenbuttel, Bruce H.R. [Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen (Netherlands); Oosting, Sjoukje F. [Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen (Netherlands); Schilstra, Cornelis [Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen (Netherlands); Langendijk, Johannes A., E-mail: j.a.langendijk@umcg.nl [Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen (Netherlands)

    2012-11-01

    Purpose: To establish a multivariate normal tissue complication probability (NTCP) model for radiation-induced hypothyroidism. Methods and Materials: The thyroid-stimulating hormone (TSH) level of 105 patients treated with (chemo-) radiation therapy for head-and-neck cancer was prospectively measured during a median follow-up of 2.5 years. Hypothyroidism was defined as elevated serum TSH with decreased or normal free thyroxin (T4). A multivariate logistic regression model with bootstrapping was used to determine the most important prognostic variables for radiation-induced hypothyroidism. Results: Thirty-five patients (33%) developed primary hypothyroidism within 2 years after radiation therapy. An NTCP model based on 2 variables, including the mean thyroid gland dose and the thyroid gland volume, was most predictive for radiation-induced hypothyroidism. NTCP values increased with higher mean thyroid gland dose (odds ratio [OR]: 1.064/Gy) and decreased with higher thyroid gland volume (OR: 0.826/cm{sup 3}). Model performance was good with an area under the curve (AUC) of 0.85. Conclusions: This is the first prospective study resulting in an NTCP model for radiation-induced hypothyroidism. The probability of hypothyroidism rises with increasing dose to the thyroid gland, whereas it reduces with increasing thyroid gland volume.

  12. Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

    Science.gov (United States)

    Zhang, Jing; Li, Pei; Guo, Hai-fang; Liu, Li; Liu, Xiao-dong

    2012-01-01

    Aim: To characterize pharmacokinetic-pharmacodynamic modeling of diclofenac in Freund's complete adjuvant (FCA)-induced arthritic rats using prostaglandin E2 (PGE2) as a biomarker. Methods: The pharmacokinetics of diclofenac was investigated using 20-day-old arthritic rats. PGE2 level in the rats was measured using an enzyme immunoassay. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to illustrate the relationship between the plasma concentration of diclofenac and the inhibition of PGE2 production. The inhibition of diclofenac on lipopolysaccharide (LPS)-induced PGE2 production in blood cells was investigated in vitro. Results: Similar pharmacokinetic behavior of diclofenac was found both in normal and FCA-induced arthritic rats. Diclofenac significantly decreased the plasma levels of PGE2 in both normal and arthritic rats. The inhibitory effect on PGE2 levels in the plasma was in proportion to the plasma concentration of diclofenac. No delay in the onset of inhibition was observed, suggesting that the effect compartment was located in the central compartment. An inhibitory effect sigmoid Imax model was selected to characterize the relationship between the plasma concentration of diclofenac and the inhibition of PGE2 production in vivo. The Imax model was also used to illustrate the inhibition of diclofenac on LPS-induced PGE2 production in blood cells in vitro. Conclusion: Arthritis induced by FCA does not alter the pharmacokinetic behaviors of diclofenac in rats, but the pharmacodynamics of diclofenac is slightly affected. A PK-PD model characterizing an inhibitory effect sigmoid Imax can be used to fit the relationship between the plasma PGE2 and diclofenac levels in both normal rats and FCA-induced arthritic rats. PMID:22842736

  13. A mathematical model for leukemogenesis of radiation-induced acute myeloid leukemia in C3H/He mice

    International Nuclear Information System (INIS)

    Kai, M.; Ban, N.

    2002-01-01

    We developed a mathematical model in leukemogenesis of acute myeloid leukemia(AML) in C3H/He mice irradiated. Our previous study indicated that the leukemogenesis of AML was associated with a deletion of chromosome 2 directly induced by acute radiation. We hypothesized that radiation-induced AML needs both inactivation of one allele of a causative gene directly induced by acute radiation and another mutational event at the other allele. We analyzed data using a two-stage stochastic model for carcinogenesis. Model fitting was based on the maximum likelihood method. Our model analysis suggested that a single exposure might induce the long-lasting delayed cell death of radiation-induced initiated cells, and that the incidence of AML may be determined through both radiation-induced initiation and persistent increase of delayed cell death of the initiated cell induced by radiation

  14. Radiation-induced mammary carcinogenesis in rodent models. What's different from chemical carcinogenesis?

    International Nuclear Information System (INIS)

    Imaoka, Tatsuhiko; Nishimura, Mayumi; Iizuka, Daisuke; Daino, Kazuhiro; Takabatake, Takashi; Okamoto, Mieko; Kakinuma, Shizuko; Shimada, Yoshiya

    2009-01-01

    Ionizing radiation is one of a few well-characterized etiologic factors of human breast cancer. Laboratory rodents serve as useful experimental models for investigating dose responses and mechanisms of cancer development. Using these models, a lot of information has been accumulated about mammary gland cancer, which can be induced by both chemical carcinogens and radiation. In this review, we first list some experimental rodent models of breast cancer induction. We then focus on several topics that are important in understanding the mechanisms and risk modification of breast cancer development, and compare radiation and chemical carcinogenesis models. We will focus on the pathology and natural history of cancer development in these models, genetic changes observed in induced cancers, indirect effects of carcinogens, and finally risk modification by reproductive factors and age at exposure to the carcinogens. In addition, we summarize the knowledge available on mammary stem/progenitor cells as a potential target of carcinogens. Comparison of chemical and radiation carcinogenesis models on these topics indicates certain similarities, but it also indicates clear differences in several important aspects, such as genetic alterations of induced cancers and modification of susceptibility by age and reproductive factors. Identification of the target cell type and relevant translational research for human risk management may be among the important issues that are addressed by radiation carcinogenesis models. (author)

  15. A phase field model for segregation and precipitation induced by irradiation in alloys

    Science.gov (United States)

    Badillo, A.; Bellon, P.; Averback, R. S.

    2015-04-01

    A phase field model is introduced to model the evolution of multicomponent alloys under irradiation, including radiation-induced segregation and precipitation. The thermodynamic and kinetic components of this model are derived using a mean-field model. The mobility coefficient and the contribution of chemical heterogeneity to free energy are rescaled by the cell size used in the phase field model, yielding microstructural evolutions that are independent of the cell size. A new treatment is proposed for point defect clusters, using a mixed discrete-continuous approach to capture the stochastic character of defect cluster production in displacement cascades, while retaining the efficient modeling of the fate of these clusters using diffusion equations. The model is tested on unary and binary alloy systems using two-dimensional simulations. In a unary system, the evolution of point defects under irradiation is studied in the presence of defect clusters, either pre-existing ones or those created by irradiation, and compared with rate theory calculations. Binary alloys with zero and positive heats of mixing are then studied to investigate the effect of point defect clustering on radiation-induced segregation and precipitation in undersaturated solid solutions. Lastly, irradiation conditions and alloy parameters leading to irradiation-induced homogeneous precipitation are investigated. The results are discussed in the context of experimental results reported for Ni-Si and Al-Zn undersaturated solid solutions subjected to irradiation.

  16. A phase field model for segregation and precipitation induced by irradiation in alloys

    International Nuclear Information System (INIS)

    Badillo, A; Bellon, P; Averback, R S

    2015-01-01

    A phase field model is introduced to model the evolution of multicomponent alloys under irradiation, including radiation-induced segregation and precipitation. The thermodynamic and kinetic components of this model are derived using a mean-field model. The mobility coefficient and the contribution of chemical heterogeneity to free energy are rescaled by the cell size used in the phase field model, yielding microstructural evolutions that are independent of the cell size. A new treatment is proposed for point defect clusters, using a mixed discrete-continuous approach to capture the stochastic character of defect cluster production in displacement cascades, while retaining the efficient modeling of the fate of these clusters using diffusion equations. The model is tested on unary and binary alloy systems using two-dimensional simulations. In a unary system, the evolution of point defects under irradiation is studied in the presence of defect clusters, either pre-existing ones or those created by irradiation, and compared with rate theory calculations. Binary alloys with zero and positive heats of mixing are then studied to investigate the effect of point defect clustering on radiation-induced segregation and precipitation in undersaturated solid solutions. Lastly, irradiation conditions and alloy parameters leading to irradiation-induced homogeneous precipitation are investigated. The results are discussed in the context of experimental results reported for Ni–Si and Al–Zn undersaturated solid solutions subjected to irradiation. (paper)

  17. Th17 cell-mediated neuroinflammation is involved in neurodegeneration of aβ1-42-induced Alzheimer's disease model rats.

    Directory of Open Access Journals (Sweden)

    Jun Zhang

    Full Text Available Neuroinflammation, especially innate immunocyte-mediated neuroinflammation, has been reported to participate in pathogenesis of Alzheimer's disease (AD. However, the involvement of adaptive immune cells, such as CD4(+ T lymphocytes, in pathogenesis of AD is not well clarified. Herein, we focus on T helper 17 (Th17 cells, a subpopulation of CD4(+ T cells with high proinflammation, and show the implication of the cells in neurodegeneration of AD. Amyloid β1-42 (Aβ1-42 was bilaterally injected into hippocampus of rats to induce AD. On days 7 and 14 following the Aβ1-42 administration, escape latency of the rats in Morris water maze was increased, expression of amyloid precursor protein was upregulated, but expression of protein phosphatase 2A was downregulated in the hippocampus, and Nissl stain showed neuronal loss and gliosis in CA1 region. Infusion of FITC-linked albumin in blood circulation and combination with immunostaining of hippocampal sections for RORγ, a specific transcriptional factor of Th17 cells, demonstrated blood-brain barrier (BBB disruption and Th17 cells' infiltration into brain parenchyma of AD rats. Expression of Th17 proinflammatory cytokines, interleukin (IL-17 and IL-22, was increased in the hippocampus, and concentrations of the two cytokines were elevated in both the cerebrospinal fluid and the serum in AD occurrence and development. Compared with intact or saline-treated control rats, AD animals indicated an upregulated expression of Fas and FasL in the hippocampus. Further, the immunofluorescent histochemistry on AD hippocampal sections with NeuN, RORγ, Fas and FasL displayed that Fas was principally expressed by neurons and FasL was predominantly expressed by Th17 cells, and that neuronal apoptosis shown by TUNEL and NeuN double-labeled cells increased. These results suggest that Th17 cells, which were infiltrated into AD brain parenchyma, participate in neuroinflammation and neurodegeneration of AD by release of

  18. Optimization of an Image-Guided Laser-Induced Choroidal Neovascularization Model in Mice.

    Directory of Open Access Journals (Sweden)

    Yan Gong

    Full Text Available The mouse model of laser-induced choroidal neovascularization (CNV has been used in studies of the exudative form of age-related macular degeneration using both the conventional slit lamp and a new image-guided laser system. A standardized protocol is needed for consistent results using this model, which has been lacking. We optimized details of laser-induced CNV using the image-guided laser photocoagulation system. Four lesions with similar size were consistently applied per eye at approximately double the disc diameter away from the optic nerve, using different laser power levels, and mice of various ages and genders. After 7 days, the mice were sacrificed and retinal pigment epithelium/choroid/sclera was flat-mounted, stained with Isolectin B4, and imaged. Quantification of the area of the laser-induced lesions was performed using an established and constant threshold. Exclusion criteria are described that were necessary for reliable data analysis of the laser-induced CNV lesions. The CNV lesion area was proportional to the laser power levels. Mice at 12-16 weeks of age developed more severe CNV than those at 6-8 weeks of age, and the gender difference was only significant in mice at 12-16 weeks of age, but not in those at 6-8 weeks of age. Dietary intake of omega-3 long-chain polyunsaturated fatty acid reduced laser-induced CNV in mice. Taken together, laser-induced CNV lesions can be easily and consistently applied using the image-guided laser platform. Mice at 6-8 weeks of age are ideal for the laser-induced CNV model.

  19. Softened food reduces weight loss in the streptozotocin-induced male mouse model of diabetic nephropathy

    DEFF Research Database (Denmark)

    Nørgaard, Sisse A; Sand, Fredrik W; Sørensen, Dorte B

    2018-01-01

    The streptozotocin (STZ)-induced diabetic mouse is a widely used model of diabetes and diabetic nephropathy (DN). However, it is a well-known issue that this model is challenged by high weight loss, which despite supportive measures often results in high euthanization rates. To overcome...... these issues, we hypothesized that supplementing STZ-induced diabetic mice with water-softened chow in addition to normal chow would reduce weight loss, lower the need for supportive treatment, and reduce the number of mice reaching the humane endpoint of 20% weight loss. In a 15 week STZ-induced DN study we...... demonstrated that diabetic male mice receiving softened chow had reduced acute weight loss following STZ treatment ( p = 0.045) and additionally fewer mice were euthanized due to weight loss. By supplementing the diabetic mice with softened chow, no mice reached 20% weight loss whereas 37.5% of the mice...

  20. Charge collection efficiency degradation induced by MeV ions in semiconductor devices: Model and experiment

    Energy Technology Data Exchange (ETDEWEB)

    Vittone, E., E-mail: ettore.vittone@unito.it [Department of Physics, NIS Research Centre and CNISM, University of Torino, via P. Giuria 1, 10125 Torino (Italy); Pastuovic, Z. [Centre for Accelerator Science (ANSTO), Locked bag 2001, Kirrawee DC, NSW 2234 (Australia); Breese, M.B.H. [Centre for Ion Beam Applications (CIBA), Department of Physics, National University of Singapore, Singapore 117542 (Singapore); Garcia Lopez, J. [Centro Nacional de Aceleradores (CNA), Sevilla University, J. Andalucia, CSIC, Av. Thomas A. Edison 7, 41092 Sevilla (Spain); Jaksic, M. [Department for Experimental Physics, Ruder Boškovic Institute (RBI), P.O. Box 180, 10002 Zagreb (Croatia); Raisanen, J. [Department of Physics, University of Helsinki, Helsinki 00014 (Finland); Siegele, R. [Centre for Accelerator Science (ANSTO), Locked bag 2001, Kirrawee DC, NSW 2234 (Australia); Simon, A. [International Atomic Energy Agency (IAEA), Vienna International Centre, P.O. Box 100, 1400 Vienna (Austria); Institute of Nuclear Research of the Hungarian Academy of Sciences (ATOMKI), Debrecen (Hungary); Vizkelethy, G. [Sandia National Laboratories (SNL), PO Box 5800, Albuquerque, NM (United States)

    2016-04-01

    Highlights: • We study the electronic degradation of semiconductors induced by ion irradiation. • The experimental protocol is based on MeV ion microbeam irradiation. • The radiation induced damage is measured by IBIC. • The general model fits the experimental data in the low level damage regime. • Key parameters relevant to the intrinsic radiation hardness are extracted. - Abstract: This paper investigates both theoretically and experimentally the charge collection efficiency (CCE) degradation in silicon diodes induced by energetic ions. Ion Beam Induced Charge (IBIC) measurements carried out on n- and p-type silicon diodes which were previously irradiated with MeV He ions show evidence that the CCE degradation does not only depend on the mass, energy and fluence of the damaging ion, but also depends on the ion probe species and on the polarization state of the device. A general one-dimensional model is derived, which accounts for the ion-induced defect distribution, the ionization profile of the probing ion and the charge induction mechanism. Using the ionizing and non-ionizing energy loss profiles resulting from simulations based on the binary collision approximation and on the electrostatic/transport parameters of the diode under study as input, the model is able to accurately reproduce the experimental CCE degradation curves without introducing any phenomenological additional term or formula. Although limited to low level of damage, the model is quite general, including the displacement damage approach as a special case and can be applied to any semiconductor device. It provides a method to measure the capture coefficients of the radiation induced recombination centres. They can be considered indexes, which can contribute to assessing the relative radiation hardness of semiconductor materials.

  1. Proces-based modeling of the overflow induced growth of erosional channels

    NARCIS (Netherlands)

    Tuan, T.Q.; Stive, M.J.F.; Verhagen, H.J.; Visser, P.J.

    2008-01-01

    A new process-based approach is introduced for a more efficient computation of the overflow-induced growth of an erosional channel in a noncohesive homogeneous narrow landmass such as the breach growth in a sand-dike. The approach is easy to incorporate in a 1D/2DV morphodynamic model to compute the

  2. Pathophysiological Responses in Rat and Mouse Models of Radiation-Induced Brain Injury.

    Science.gov (United States)

    Yang, Lianhong; Yang, Jianhua; Li, Guoqian; Li, Yi; Wu, Rong; Cheng, Jinping; Tang, Yamei

    2017-03-01

    The brain is the major dose-limiting organ in patients undergoing radiotherapy for assorted conditions. Radiation-induced brain injury is common and mainly occurs in patients receiving radiotherapy for malignant head and neck tumors, arteriovenous malformations, or lung cancer-derived brain metastases. Nevertheless, the underlying mechanisms of radiation-induced brain injury are largely unknown. Although many treatment strategies are employed for affected individuals, the effects remain suboptimal. Accordingly, animal models are extremely important for elucidating pathogenic radiation-associated mechanisms and for developing more efficacious therapies. So far, models employing various animal species with different radiation dosages and fractions have been introduced to investigate the prevention, mechanisms, early detection, and management of radiation-induced brain injury. However, these models all have limitations, and none are widely accepted. This review summarizes the animal models currently set forth for studies of radiation-induced brain injury, especially rat and mouse, as well as radiation dosages, dose fractionation, and secondary pathophysiological responses.

  3. Using Rouse-Fowler model to describe radiation-induced electrical conductivity of nanocomposite materials

    Science.gov (United States)

    Dyuryagina, N. S.; Yalovets, A. P.

    2017-05-01

    Using the Rouse-Fowler (RF) model this work studies the radiation-induced electrical conductivity of a polymer nanocomposite material with spherical nanoparticles against the intensity and exposure time of gamma-ray, concentration and size of nanoparticles. The research has found the energy distribution of localized statesinduced by nanoparticles. The studies were conducted on polymethylmethacrylate (PMMA) with CdS nanoparticles.

  4. Exact solution in the cosmological chaotic inflation model with induced gravity

    International Nuclear Information System (INIS)

    Wang Wenfu

    2004-01-01

    We present a new, exact solution in the cosmological chaotic inflation model with induced gravity. The spectral index of the scalar density fluctuations, n s , is computed, and is consistent with the analyses of BOOMERANG data. The effective cosmological constant Λ eff tends to zero when inflation ends

  5. Gamma ray induced sensitization in CaSO4:Dy and competing trap model

    International Nuclear Information System (INIS)

    Nagpal, J.S.; Kher, R.K.; Gangadharan, P.

    1979-01-01

    Gamma ray induced sensitization in CaSO 4 :Dy has been compared (by measurement of TL glow curves) for different temperatures during irradiation (25 0 , 120 0 and 250 0 C). Enhanced sensitization at elevated temperatures seems to support the competing trap model for supralinearity and sensitization in CaSO 4 :Dy. (author)

  6. Oxidative stress in a rat model of cotton smoke inhalation-induced ...

    African Journals Online (AJOL)

    Background: Smoke inhalation injury refers to airway and lung parenchyma injury and general chemical damage caused by inhaling toxic gases and substances. The aim of this study was to explore the oxidative stress mechanism of cotton smoke inhalation-induced pulmonary injury in a rat model. Materials and Methods: ...

  7. A continuum model for flow induced by metachronal coordination between beating cilia

    NARCIS (Netherlands)

    Hussong, J.; Breugem, W.P.; Westerweel, J.

    2011-01-01

    In this numerical study we investigate the flow induced by metachronal coordination between beating cilia arranged in a densely packed layer by means of a continuum model. The continuum approach allows us to treat the problem as two-dimensional as well as stationary, in a reference frame moving with

  8. Numerical modeling of large field-induced strains in ferroelastic bodies: a continuum approach

    International Nuclear Information System (INIS)

    Raikher, Yu L; Stolbov, O V

    2008-01-01

    A consistent continuum model of a soft magnetic elastomer (SME) is presented and developed for the case of finite strain. The numeric algorithm enabling one to find the field-induced shape changes of an SME body is described. The reliability of the method is illustrated by several examples revealing specifics of the magnetostriction effect in SME samples of various geometries

  9. Evaluating of the Anticonvulsant Gabapentin against Nerve Agent-Induced Seizures in a Guinea Pig Model

    Science.gov (United States)

    2010-07-01

    treating neuropathic pain. This study evaluated whether gabapentin could terminate or moderate nerve agent-induced seizures using a validated guinea ... pig model. Male Hartley guinea pigs were surgically prepared to record electroencephalographic (EEG) activity. After a week recovery, animals were

  10. Towards a 3D modelling of the microwave photo-induced load in CPW technology

    Science.gov (United States)

    Gary, Rene; Arnould, Jean-Daniel; Vilcot, Anne

    2005-09-01

    The optical control study works on both the optical and the microwave behaviours of the plasma photo-induced in the semiconductor enlightened by a laser beam. The presented study is based on the necessity to be able to foresee the microwave response of CPW microwave devices versus different optical powers and different kinds of optical fibers, single-mode or multimode. The optical part has been achieved analytically by solving the diffusion equation of photo-induced carriers using the Hankel transform in 3-Dimensions. The added value of this technique is its precision and fastness. For the electromagnetic part we have chosen to use CST Microwave Studio software, which solves numerically Maxwell's equations with a Finite Integration Technique (FIT). For this aim we have had to model the photo-induced load using the locally changed conductivity directly depending of the excess carriers distribution. In the final paper, the first part will deal with the analytical computation of the photo-induced excess carrier in silicon substrate using the Hankel transform under permanent enlightening. Then the explanation of the model will be based on the need of a 3-Dimension model that may be described in an electromagnetic software. Finally simulation results of simple CPW devices as stub will be compared to measurements. In conclusion, we will show that the model is suitable for designing more complex devices and that it can be simplified in case of low precision needs.

  11. The rotationally induced quadrupole pair field in the particle-rotor model

    International Nuclear Information System (INIS)

    Almberger, J.

    1980-04-01

    A formalism is developed which makes it possible to consider the influence of the rotationally induced quadrupole pair field and corresponding quasi-particle residual interactions within the particle-rotor model. The Y 21 pair field renormalizes both the Coriolis and the recoil interactions. (Auth.)

  12. Penguin effects induced by the two-Higgs-doublet model and charmless B-meson decays

    International Nuclear Information System (INIS)

    Davies, A.J.; Joshi, G.C.; Matsuda, M.

    1991-03-01

    Nonstandard physical effects through the penguin diagram induced by the charged Higgs scalar contribution in the two-Higgs-doublet model are analysed. The non-leptonic β-decay processes including the non-standard two-Higgs-doublet contribution are compared with the standard model results, which arise from the magnetic gluon transition term. The charged Higgs contribution gives a sizable enhancement to the branching fractions of β-meson charmless decay. 13 refs., 4 figs

  13. An inducible model of abacterial prostatitis induces antigen specific inflammatory and proliferative changes in the murine prostate

    Science.gov (United States)

    Haverkamp, Jessica M.; Charbonneau, Bridget; Meyerholz, David K.; Cohen, Michael B.; Snyder, Paul W.; Svensson, Robert U.; Henry, Michael D.; Wang, Hsing- Hui

    2011-01-01

    Background Prostatitis is a poorly understood disease and increasing evidence suggests inflammation is involved in other prostatic diseases, including prostate cancer. Methods The ability of pre-activated CD8 T cells to induce prostatitis was examined by adoptive transfer into POET-3 mice or POET-3/Luc/Pten−/+ mice. Characterization of the inflammatory response was determined by examining leukocyte infiltration by histological analysis, flow cytometry and by evaluating cytokine and chemokine levels in prostate tissue. The impact of inflammation on the prostate was evaluated by monitoring epithelial cell proliferation over time. Results Initiation of inflammation by ovalbumin specific CD8+ T cells (OT-I cells) resulted in development of acute prostatitis in the anterior, dorsolateral and anterior prostate of POET-3 and POET-3/Luc/Pten−/+ mice. Acute prostatitis was characterized by recruitment of adoptively transferred OT-I cells and importantly, autologous CD4+ and CD8+ T cells, myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg). In concert with leukocyte infiltration elevated levels of pro-inflammatory cytokines and chemokines were observed. Inflammation also resulted in marked epithelial cell proliferation that was sustained up to 80 days post adoptive-transfer of OT-I cells. Conclusions The POET-3 model represents a novel mouse model to study both acute and chronic prostate inflammation in an antigen-specific system. Further, the POET-3 mouse model can be crossed with other genetic models of disease such as the C57/Luc/Pten−/− model of prostate cancer, allowing the impact of prostatitis on other prostatic diseases to be evaluated. PMID:21656824

  14. A statistical model describing combined irreversible electroporation and electroporation-induced blood-brain barrier disruption.

    Science.gov (United States)

    Sharabi, Shirley; Kos, Bor; Last, David; Guez, David; Daniels, Dianne; Harnof, Sagi; Mardor, Yael; Miklavcic, Damijan

    2016-03-01

    Electroporation-based therapies such as electrochemotherapy (ECT) and irreversible electroporation (IRE) are emerging as promising tools for treatment of tumors. When applied to the brain, electroporation can also induce transient blood-brain-barrier (BBB) disruption in volumes extending beyond IRE, thus enabling efficient drug penetration. The main objective of this study was to develop a statistical model predicting cell death and BBB disruption induced by electroporation. This model can be used for individual treatment planning. Cell death and BBB disruption models were developed based on the Peleg-Fermi model in combination with numerical models of the electric field. The model calculates the electric field thresholds for cell kill and BBB disruption and describes the dependence on the number of treatment pulses. The model was validated using in vivo experimental data consisting of rats brains MRIs post electroporation treatments. Linear regression analysis confirmed that the model described the IRE and BBB disruption volumes as a function of treatment pulses number (r(2) = 0.79; p disruption, the ratio increased with the number of pulses. BBB disruption radii were on average 67% ± 11% larger than IRE volumes. The statistical model can be used to describe the dependence of treatment-effects on the number of pulses independent of the experimental setup.

  15. Dietary Compound Kaempferol Inhibits Airway Thickening Induced by Allergic Reaction in a Bovine Serum Albumin-Induced Model of Asthma.

    Science.gov (United States)

    Shin, Daekeun; Park, Sin-Hye; Choi, Yean-Jung; Kim, Yun-Ho; Antika, Lucia Dwi; Habibah, Nurina Umy; Kang, Min-Kyung; Kang, Young-Hee

    2015-12-16

    Asthma is characterized by aberrant airways including epithelial thickening, goblet cell hyperplasia, and smooth muscle hypertrophy within the airway wall. The current study examined whether kaempferol inhibited mast cell degranulation and prostaglandin (PG) release leading to the development of aberrant airways, using an in vitro model of dinitrophenylated bovine serum albumin (DNP-BSA)-sensitized rat basophilic leukemia (RBL-2H3) mast cells and an in vivo model of BSA-challenged asthmatic mice. Nontoxic kaempferol at 10-20 μM suppressed β-hexosaminidase release and cyclooxygenase 2 (COX2)-mediated production of prostaglandin D2 (PGD2) and prostaglandin F2α (PGF2α) in sensitized mast cells. Oral administration of ≤20 mg/kg kaempferol blocked bovine serum albumin (BSA) inhalation-induced epithelial cell excrescence and smooth muscle hypertrophy by attenuating the induction of COX2 and the formation of PGD2 and PGF2α, together with reducing the anti-α-smooth muscle actin (α-SMA) expression in mouse airways. Kaempferol deterred the antigen-induced mast cell activation of cytosolic phospholipase A2 (cPLA2) responsive to protein kinase Cμ (PKCμ) and extracellular signal-regulated kinase (ERK). Furthermore, the antigen-challenged activation of Syk-phospholipase Cγ (PLCγ) pathway was dampened in kaempferol-supplemented mast cells. These results demonstrated that kaempferol inhibited airway wall thickening through disturbing Syk-PLCγ signaling and PKCμ-ERK-cPLA2-COX2 signaling in antigen-exposed mast cells. Thus, kaempferol may be a potent anti-allergic compound targeting allergic asthma typical of airway hyperplasia and hypertrophy.

  16. Modelling of Vortex-Induced Loading on a Single-Blade Installation Setup

    DEFF Research Database (Denmark)

    Skrzypinski, Witold Robert; Gaunaa, Mac; Heinz, Joachim Christian

    2016-01-01

    the same procedure. The reference time series were significantly different, depending on the inflow angle. This made the modelling of all the time series with a single and relatively simple engineering model challenging. In order to find model parameters, optimizations were carried out, based on the root-mean-square......Vortex-induced integral loading fluctuations on a single suspended blade at various inflow angles were modeled in the presents work by means of stochastic modelling methods. The reference time series were obtained by 3D DES CFD computations carried out on the DTU 10MW reference wind turbine blade...... varied depending on the inflow angle. None the less, the modelled and reference time series showed a satisfactory general agreement in terms of their visual and frequency characteristics. This indicated that the proposed method is suitable to model loading fluctuations on suspended blades....

  17. Comparison of Cole-Cole and Constant Phase Angle modeling in time-domain induced polarization

    DEFF Research Database (Denmark)

    Lajaunie, Myriam; Maurya, Pradip Kumar; Fiandaca, Gianluca

    The Cole-Cole model and the constant phase angle (CPA) model are two prevailing phenomenological descriptions of the induced polarization (IP), used for both frequency domain (FD) and time domain (TD) modeling. The former one is a 4-parameter description, while the latest one involves only two......, forward modeling of quadrupolar sequences on 1D and 2D heterogeneous CPA models shows that the CPA decays differ among each other only by a multiplication factor. Consequently, the inspection of field data in log-log plots gives insight on the modeling needed for fitting them: the CPA inversion cannot...... is reflected in TDIP data, and therefore, at identifying (1) if and when it is possible to distinguish, in time domain, between a Cole-Cole description and a CPA one, and (2) if features of time domain data exist in order to know, from a simple data inspection, which model will be the most adapted to the data...

  18. Establishment of a Radiation-Induced Fibrosis Model in BALB/c Mice

    Energy Technology Data Exchange (ETDEWEB)

    Ryu, Seung Hee; Lee, Sang Wook; Moon, Soo Young; Oh, Jeong Yoon; Yang, Youn Joo; Park, Jin Hong [Dept. of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2010-11-15

    Although radiation-induced fibrosis is one of the common sequelae occurring after irradiation of skin and soft tissues, the treatment methods are not well standardized. This study aimed to establish the skin fibrosis mouse model by fractionated radiation for the further mechanism studies or testing the efficacy of therapeutic candidates. The right hind limbs of BALB/c mice received two fractions of 20 Gy using a therapeutic linear accelerator. Early skin damages were scored and tissue fibrosis was assessed by the measurement of a leg extension. Morphological changes were assessed by H and E staining and by Masson's Trichrome staining. TGF-{beta}1 expression from soft tissues was also detected by immunohistochemistry and PCR. Two fractions of 20 Gy irradiation were demonstrated as being enough to induce early skin damage effects such as erythema, mild skin dryness, dry and wet desquamation within several weeks of radiation. After 13 weeks of irradiation, the average radiation-induced leg contraction was 11.1 {+-} 6.2 mm. Morphologic changes in irradiated skin biopsies exhibited disorganized collagen and extracellular matrix fibers, as well as the accumulation of myofibroblasts compared to the non-irradiated skin. Moreover, TGF-{beta}1 expression in tissue was increased by radiation. These results show that two fractions of 20 Gy irradiation can induce skin fibrosis in BALB/c mice accompanied by other common characteristics of skin damages. This animal model can be a useful tool for studying skin fibrosis induced by radiation.

  19. Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Kanae Iijima-Ando

    2009-12-01

    Full Text Available The amyloid-beta 42 (Abeta42 is thought to play a central role in the pathogenesis of Alzheimer's disease (AD. However, the molecular mechanisms by which Abeta42 induces neuronal dysfunction and degeneration remain elusive. Mitochondrial dysfunctions are implicated in AD brains. Whether mitochondrial dysfunctions are merely a consequence of AD pathology, or are early seminal events in AD pathogenesis remains to be determined. Here, we show that Abeta42 induces mitochondrial mislocalization, which contributes to Abeta42-induced neuronal dysfunction in a transgenic Drosophila model. In the Abeta42 fly brain, mitochondria were reduced in axons and dendrites, and accumulated in the somata without severe mitochondrial damage or neurodegeneration. In contrast, organization of microtubule or global axonal transport was not significantly altered at this stage. Abeta42-induced behavioral defects were exacerbated by genetic reductions in mitochondrial transport, and were modulated by cAMP levels and PKA activity. Levels of putative PKA substrate phosphoproteins were reduced in the Abeta42 fly brains. Importantly, perturbations in mitochondrial transport in neurons were sufficient to disrupt PKA signaling and induce late-onset behavioral deficits, suggesting a mechanism whereby mitochondrial mislocalization contributes to Abeta42-induced neuronal dysfunction. These results demonstrate that mislocalization of mitochondria underlies the pathogenic effects of Abeta42 in vivo.

  20. Effects of Streptococcus thermophilus TH-4 in a rat model of doxorubicin-induced mucositis.

    Science.gov (United States)

    Wang, Hanru; Brook, Caitlin L; Whittaker, Alexandra L; Lawrence, Andrew; Yazbeck, Roger; Howarth, Gordon S

    2013-08-01

    Mucositis is a debilitating intestinal side effect of chemotherapeutic regimens. Probiotics have been considered a possible preventative treatment for mucositis. Streptococcus thermophilus TH-4 (TH-4), a newly identified probiotic, has been shown to partially alleviate mucositis induced by administration of the antimetabolite chemotherapy drug, methotrexate in rats; likely mediated through a mechanism of folate production. However, its effects against other classes of chemotherapy drug have yet to be determined. The authors investigated the effects of TH-4 in a rat model of mucositis induced by the anthracycline chemotherapy drug, doxorubicin. Gastrointestinal damage was induced in female Dark Agouti rats (148.3 ± 1.5 g) by intraperitoneal injection of doxorubicin (20 mg/kg). Animals recieved a daily oral gavage of TH-4 at 10(9) cfu/ml or skim milk (vehicle) from days 0 to 8. At day 6, rats were injected with either saline or doxorubicin. At kill, small intestinal tissues were collected for determination of sucrase and myeloperoxidase (MPO) activities and histological assessment. Body weight was significantly decreased by doxorubicin compared with normal controls (p TH-4 partially prevented the loss of body weight induced by doxorubicin (2.3% compared with 4%), but provided no further therapeutic benefit. The minimal amelioration of doxorubicin-induced mucositis by TH-4 further supports folate production as a likely mechanism of TH-4 action against methotrexate-induced mucositis. Further studies into TH-4 are required to confirm its applicability to other conventional chemotherapy regimens.

  1. Hepatocyte-based in vitro model for assessment of drug-induced cholestasis

    International Nuclear Information System (INIS)

    Chatterjee, Sagnik; Richert, Lysiane; Augustijns, Patrick; Annaert, Pieter

    2014-01-01

    Early detection of drug-induced cholestasis remains a challenge during drug development. We have developed and validated a biorelevant sandwich-cultured hepatocytes- (SCH) based model that can identify compounds causing cholestasis by altering bile acid disposition. Human and rat SCH were exposed (24–48 h) to known cholestatic and/or hepatotoxic compounds, in the presence or in the absence of a concentrated mixture of bile acids (BAs). Urea assay was used to assess (compromised) hepatocyte functionality at the end of the incubations. The cholestatic potential of the compounds was expressed by calculating a drug-induced cholestasis index (DICI), reflecting the relative residual urea formation by hepatocytes co-incubated with BAs and test compound as compared to hepatocytes treated with test compound alone. Compounds with clinical reports of cholestasis, including cyclosporin A, troglitazone, chlorpromazine, bosentan, ticlopidine, ritonavir, and midecamycin showed enhanced toxicity in the presence of BAs (DICI ≤ 0.8) for at least one of the tested concentrations. In contrast, the in vitro toxicity of compounds causing hepatotoxicity by other mechanisms (including diclofenac, valproic acid, amiodarone and acetaminophen), remained unchanged in the presence of BAs. A safety margin (SM) for drug-induced cholestasis was calculated as the ratio of lowest in vitro concentration for which was DICI ≤ 0.8, to the reported mean peak therapeutic plasma concentration. SM values obtained in human SCH correlated well with reported % incidence of clinical drug-induced cholestasis, while no correlation was observed in rat SCH. This in vitro model enables early identification of drug candidates causing cholestasis by disturbed BA handling. - Highlights: • Novel in vitro assay to detect drug-induced cholestasis • Rat and human sandwich-cultured hepatocytes (SCH) as in vitro models • Cholestatic compounds sensitize SCH to toxic effects of accumulating bile acids • Drug-induced

  2. Hepatocyte-based in vitro model for assessment of drug-induced cholestasis

    Energy Technology Data Exchange (ETDEWEB)

    Chatterjee, Sagnik, E-mail: Sagnik.Chatterjee@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Richert, Lysiane, E-mail: l.richert@kaly-cell.com [KaLy-Cell, 20A rue du Général Leclerc, 67115 Plobsheim (France); Augustijns, Patrick, E-mail: Patrick.Augustijns@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Annaert, Pieter, E-mail: Pieter.Annaert@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium)

    2014-01-01

    Early detection of drug-induced cholestasis remains a challenge during drug development. We have developed and validated a biorelevant sandwich-cultured hepatocytes- (SCH) based model that can identify compounds causing cholestasis by altering bile acid disposition. Human and rat SCH were exposed (24–48 h) to known cholestatic and/or hepatotoxic compounds, in the presence or in the absence of a concentrated mixture of bile acids (BAs). Urea assay was used to assess (compromised) hepatocyte functionality at the end of the incubations. The cholestatic potential of the compounds was expressed by calculating a drug-induced cholestasis index (DICI), reflecting the relative residual urea formation by hepatocytes co-incubated with BAs and test compound as compared to hepatocytes treated with test compound alone. Compounds with clinical reports of cholestasis, including cyclosporin A, troglitazone, chlorpromazine, bosentan, ticlopidine, ritonavir, and midecamycin showed enhanced toxicity in the presence of BAs (DICI ≤ 0.8) for at least one of the tested concentrations. In contrast, the in vitro toxicity of compounds causing hepatotoxicity by other mechanisms (including diclofenac, valproic acid, amiodarone and acetaminophen), remained unchanged in the presence of BAs. A safety margin (SM) for drug-induced cholestasis was calculated as the ratio of lowest in vitro concentration for which was DICI ≤ 0.8, to the reported mean peak therapeutic plasma concentration. SM values obtained in human SCH correlated well with reported % incidence of clinical drug-induced cholestasis, while no correlation was observed in rat SCH. This in vitro model enables early identification of drug candidates causing cholestasis by disturbed BA handling. - Highlights: • Novel in vitro assay to detect drug-induced cholestasis • Rat and human sandwich-cultured hepatocytes (SCH) as in vitro models • Cholestatic compounds sensitize SCH to toxic effects of accumulating bile acids • Drug-induced

  3. An Overview of GIS-Based Modeling and Assessment of Mining-Induced Hazards: Soil, Water, and Forest

    OpenAIRE

    Suh, Jangwon; Kim, Sung-Min; Yi, Huiuk; Choi, Yosoon

    2017-01-01

    In this study, current geographic information system (GIS)-based methods and their application for the modeling and assessment of mining-induced hazards were reviewed. Various types of mining-induced hazard, including soil contamination, soil erosion, water pollution, and deforestation were considered in the discussion of the strength and role of GIS as a viable problem-solving tool in relation to mining-induced hazards. The various types of mining-induced hazard were classified into two or t...

  4. Cartilage regeneration by chondrogenic induced adult stem cells in osteoarthritic sheep model.

    Science.gov (United States)

    Ude, Chinedu C; Sulaiman, Shamsul B; Min-Hwei, Ng; Hui-Cheng, Chen; Ahmad, Johan; Yahaya, Norhamdan M; Saim, Aminuddin B; Idrus, Ruszymah B H

    2014-01-01

    In this study, Adipose stem cells (ADSC) and bone marrow stem cells (BMSC), multipotent adult cells with the potentials for cartilage regenerations were induced to chondrogenic lineage and used for cartilage regenerations in surgically induced osteoarthritis in sheep model. Osteoarthritis was induced at the right knee of sheep by complete resection of the anterior cruciate ligament and medial meniscus following a 3-weeks exercise regimen. Stem cells from experimental sheep were culture expanded and induced to chondrogenic lineage. Test sheep received a single dose of 2 × 10(7) autologous PKH26-labelled, chondrogenically induced ADSCs or BMSCs as 5 mls injection, while controls received 5 mls culture medium. The proliferation rate of ADSCs 34.4 ± 1.6 hr was significantly higher than that of the BMSCs 48.8 ± 5.3 hr (P = 0.008). Chondrogenic induced BMSCs had significantly higher expressions of chondrogenic specific genes (Collagen II, SOX9 and Aggrecan) compared to chondrogenic ADSCs (P = 0.031, 0.010 and 0.013). Grossly, the treated knee joints showed regenerated de novo cartilages within 6 weeks post-treatment. On the International Cartilage Repair Society grade scores, chondrogenically induced ADSCs and BMSCs groups had significantly lower scores than controls (P = 0.0001 and 0.0001). Fluorescence of the tracking dye (PKH26) in the injected cells showed that they had populated the damaged area of cartilage. Histological staining revealed loosely packed matrixes of de novo cartilages and immunostaining demonstrated the presence of cartilage specific proteins, Collagen II and SOX9. Autologous chondrogenically induced ADSCs and BMSCs could be promising cell sources for cartilage regeneration in osteoarthritis.

  5. Cartilage regeneration by chondrogenic induced adult stem cells in osteoarthritic sheep model.

    Directory of Open Access Journals (Sweden)

    Chinedu C Ude

    Full Text Available OBJECTIVES: In this study, Adipose stem cells (ADSC and bone marrow stem cells (BMSC, multipotent adult cells with the potentials for cartilage regenerations were induced to chondrogenic lineage and used for cartilage regenerations in surgically induced osteoarthritis in sheep model. METHODS: Osteoarthritis was induced at the right knee of sheep by complete resection of the anterior cruciate ligament and medial meniscus following a 3-weeks exercise regimen. Stem cells from experimental sheep were culture expanded and induced to chondrogenic lineage. Test sheep received a single dose of 2 × 10(7 autologous PKH26-labelled, chondrogenically induced ADSCs or BMSCs as 5 mls injection, while controls received 5 mls culture medium. RESULTS: The proliferation rate of ADSCs 34.4 ± 1.6 hr was significantly higher than that of the BMSCs 48.8 ± 5.3 hr (P = 0.008. Chondrogenic induced BMSCs had significantly higher expressions of chondrogenic specific genes (Collagen II, SOX9 and Aggrecan compared to chondrogenic ADSCs (P = 0.031, 0.010 and 0.013. Grossly, the treated knee joints showed regenerated de novo cartilages within 6 weeks post-treatment. On the International Cartilage Repair Society grade scores, chondrogenically induced ADSCs and BMSCs groups had significantly lower scores than controls (P = 0.0001 and 0.0001. Fluorescence of the tracking dye (PKH26 in the injected cells showed that they had populated the damaged area of cartilage. Histological staining revealed loosely packed matrixes of de novo cartilages and immunostaining demonstrated the presence of cartilage specific proteins, Collagen II and SOX9. CONCLUSION: Autologous chondrogenically induced ADSCs and BMSCs could be promising cell sources for cartilage regeneration in osteoarthritis.

  6. Improving predictive power of physically based rainfall-induced shallow landslide models: a probabilistic approach

    Directory of Open Access Journals (Sweden)

    S. Raia

    2014-03-01

    Full Text Available Distributed models to forecast the spatial and temporal occurrence of rainfall-induced shallow landslides are based on deterministic laws. These models extend spatially the static stability models adopted in geotechnical engineering, and adopt an infinite-slope geometry to balance the resisting and the driving forces acting on the sliding mass. An infiltration model is used to determine how rainfall changes pore-water conditions, modulating the local stability/instability conditions. A problem with the operation of the existing models lays in the difficulty in obtaining accurate values for the several variables that describe the material properties of the slopes. The problem is particularly severe when the models are applied over large areas, for which sufficient information on the geotechnical and hydrological conditions of the slopes is not generally available. To help solve the problem, we propose a probabilistic Monte Carlo approach to the distributed modeling of rainfall-induced shallow landslides. For this purpose, we have modified the transient rainfall infiltration and grid-based regional slope-stability analysis (TRIGRS code. The new code (TRIGRS-P adopts a probabilistic approach to compute, on a cell-by-cell basis, transient pore-pressure changes and related changes in the factor of safety due to rainfall infiltration. Infiltration is modeled using analytical solutions of partial differential equations describing one-dimensional vertical flow in isotropic, homogeneous materials. Both saturated and unsaturated soil conditions can be considered. TRIGRS-P copes with the natural variability inherent to the mechanical and hydrological properties of the slope materials by allowing values of the TRIGRS model input parameters to be sampled randomly from a given probability distribution. The range of variation and the mean value of the parameters can be determined by the usual methods used for preparing the TRIGRS input parameters. The outputs

  7. Improving predictive power of physically based rainfall-induced shallow landslide models: a probablistic approach

    Science.gov (United States)

    Raia, S.; Alvioli, M.; Rossi, M.; Baum, R.L.; Godt, J.W.; Guzzetti, F.

    2013-01-01

    Distributed models to forecast the spatial and temporal occurrence of rainfall-induced shallow landslides are deterministic. These models extend spatially the static stability models adopted in geotechnical engineering and adopt an infinite-slope geometry to balance the resisting and the driving forces acting on the sliding mass. An infiltration model is used to determine how rainfall changes pore-water conditions, modulating the local stability/instability conditions. A problem with the existing models is the difficulty in obtaining accurate values for the several variables that describe the material properties of the slopes. The problem is particularly severe when the models are applied over large areas, for which sufficient information on the geotechnical and hydrological conditions of the slopes is not generally available. To help solve the problem, we propose a probabilistic Monte Carlo approach to the distributed modeling of shallow rainfall-induced landslides. For the purpose, we have modified the Transient Rainfall Infiltration and Grid-Based Regional Slope-Stability Analysis (TRIGRS) code. The new code (TRIGRS-P) adopts a stochastic approach to compute, on a cell-by-cell basis, transient pore-pressure changes and related changes in the factor of safety due to rainfall infiltration. Infiltration is modeled using analytical solutions of partial differential equations describing one-dimensional vertical flow in isotropic, homogeneous materials. Both saturated and unsaturated soil conditions can be considered. TRIGRS-P copes with the natural variability inherent to the mechanical and hydrological properties of the slope materials by allowing values of the TRIGRS model input parameters to be sampled randomly from a given probability distribution. The range of variation and the mean value of the parameters can be determined by the usual methods used for preparing the TRIGRS input parameters. The outputs of several model runs obtained varying the input parameters

  8. Protein Kinase B (Akt) Promotes Pathological Angiogenesis in Murine Model of Oxygen-Induced Retinopathy

    International Nuclear Information System (INIS)

    Wang, Peng; Tian, Xiao-Feng; Rong, Jun-Bo; Liu, Dan; Yi, Guo-Guo; Tan, Qian

    2011-01-01

    Akt, or protein kinase B, is an important signaling molecule that modulates many cellular processes such as cell growth, survival, and metabolism. However, the vivo roles and effectors of Akt in retinal angiogenesis are not explicitly clear. We therefore detected the expression of Akt using Western blotting or RT-PCR technologies in an animal model of oxygen-induced retinopathy, and investigated the effects of recombinant Akt on inhibiting vessels loss and Akt inhibitor on suppressing experimental retinal neovascularization in this model. We showed that in the hyperoxic phase of oxygen-induced retinopathy, the expression of Akt was greatly suppressed. In the hypoxic phase, the expression of Akt was increased dramatically. No significant differences were found in normoxic groups. Compared with control groups, administration of the recombinant Akt in the first phase of retinopathy markedly reduced capillary-free areas, while the administration of the Akt inhibitor in the second phase of retinopathy significantly decreased retinal neovascularization but capillary-free areas. These results indicate that Akt play a critical role in the pathological process (vessels loss and neovascularization) of mouse model of oxygen-induced retinopathy, which may provide a valubale therapeutic tool for ischemic-induced retinal diseases

  9. THMC Modeling of EGS Reservoirs -- Continuum through Discontinuum Representations. Capturing Reservoir Stimulation, Evolution and Induced Seismicity

    Energy Technology Data Exchange (ETDEWEB)

    Elsworth, Derek [Pennsylvania State Univ., State College, PA (United States); Izadi, Ghazal [Pennsylvania State Univ., State College, PA (United States); Gan, Quan [Pennsylvania State Univ., State College, PA (United States); Fang, Yi [Pennsylvania State Univ., State College, PA (United States); Taron, Josh [US Geological Survey, Menlo Park, CA (United States); Sonnenthal, Eric [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2015-07-28

    This work has investigated the roles of effective stress induced by changes in fluid pressure, temperature and chemistry in contributing to the evolution of permeability and induced seismicity in geothermal reservoirs. This work has developed continuum models [1] to represent the progress or seismicity during both stimulation [2] and production [3]. These methods have been used to resolve anomalous observations of induced seismicity at the Newberry Volcano demonstration project [4] through the application of modeling and experimentation. Later work then focuses on the occurrence of late stage seismicity induced by thermal stresses [5] including the codifying of the timing and severity of such responses [6]. Furthermore, mechanistic linkages between observed seismicity and the evolution of permeability have been developed using data from the Newberry project [7] and benchmarked against field injection experiments. Finally, discontinuum models [8] incorporating the roles of discrete fracture networks have been applied to represent stimulation and then thermal recovery for new arrangements of geothermal wells incorporating the development of flow manifolds [9] in order to increase thermal output and longevity in EGS systems.

  10. Evaluation of Lercanidipine in Paclitaxel-Induced Neuropathic Pain Model in Rat: A Preliminary Study

    OpenAIRE

    Saha, Lekha; Hota, Debasish; Chakrabarti, Amitava

    2012-01-01

    Objective. To demonstrate the antinociceptive effect of lercanidipine in paclitaxel-induced neuropathy model in rat. Materials and Methods. A total of 30 rats were divided into five groups of six rats in each group as follows: Gr I: 0.9% NaCl, Gr II: paclitaxel + 0.9% NaCl, Gr III: paclitaxel + lercanidipine 0.5 μg/kg, Gr IV: paclitaxel + lercanidipine 1 μg/kg, and Gr V: paclitaxel + lercanidipine 2.5 μg/kg. Paclitaxel-induced neuropathic pain in rat was produced by single intraperitoneal (i....

  11. Model for Stress-induced Protein Degradation in Lemna minor1

    Science.gov (United States)

    Cooke, Robert J.; Roberts, Keith; Davies, David D.

    1980-01-01

    Transfer of Lemna minor fronds to adverse or stress conditions produces a large increase in the rate of protein degradation. Cycloheximide partially inhibits stress-induced protein degradation and also partially inhibits the protein degradation which occurs in the absence of stress. The increased protein degradation does not appear to be due to an increase in activity of soluble proteolytic enzymes. Biochemical evidence indicates that stress, perhaps acting via hormones, affects the permeability of certain membranes, particularly the tonoplast. A general model for stress-induced protein degradation is presented in which changes in membrane properties allow vacuolar proteolytic enzymes increased access to cytoplasmic proteins. PMID:16661588

  12. An affine microsphere approach to modeling strain-induced crystallization in rubbery polymers

    Science.gov (United States)

    Nateghi, A.; Dal, H.; Keip, M.-A.; Miehe, C.

    2018-01-01

    Upon stretching a natural rubber sample, polymer chains orient themselves in the direction of the applied load and form crystalline regions. When the sample is retracted, the original amorphous state of the network is restored. Due to crystallization, properties of rubber change considerably. The reinforcing effect of the crystallites stiffens the rubber and increases the crack growth resistance. It is of great importance to understand the mechanism leading to strain-induced crystallization. However, limited theoretical work has been done on the investigation of the associated kinetics. A key characteristic observed in the stress-strain diagram of crystallizing rubber is the hysteresis, which is entirely attributed to strain-induced crystallization. In this work, we propose a micromechanically motivated material model for strain-induced crystallization in rubbers. Our point of departure is constructing a micromechanical model for a single crystallizing polymer chain. Subsequently, a thermodynamically consistent evolution law describing the kinetics of crystallization on the chain level is proposed. This chain model is then incorporated into the affine microsphere model. Finally, the model is numerically implemented and its performance is compared to experimental data.

  13. The potential of induced pluripotent stem cells in models of neurological disorders: implications on future therapy.

    Science.gov (United States)

    Crook, Jeremy Micah; Wallace, Gordon; Tomaskovic-Crook, Eva

    2015-03-01

    There is an urgent need for new and advanced approaches to modeling the pathological mechanisms of complex human neurological disorders. This is underscored by the decline in pharmaceutical research and development efficiency resulting in a relative decrease in new drug launches in the last several decades. Induced pluripotent stem cells represent a new tool to overcome many of the shortcomings of conventional methods, enabling live human neural cell modeling of complex conditions relating to aberrant neurodevelopment, such as schizophrenia, epilepsy and autism as well as age-associated neurodegeneration. This review considers the current status of induced pluripotent stem cell-based modeling of neurological disorders, canvassing proven and putative advantages, current constraints, and future prospects of next-generation culture systems for biomedical research and translation.

  14. Hormone-induced rat model of polycystic ovary syndrome: A systematic review.

    Science.gov (United States)

    Noroozzadeh, Mahsa; Behboudi-Gandevani, Samira; Zadeh-Vakili, Azita; Ramezani Tehrani, Fahimeh

    2017-12-15

    Despite polycystic ovary syndrome (PCOS) being one of the most common endocrine disorders affecting reproductive-aged women, the etiopathogenesis and mechanisms of this syndrome remain unclear. Considering the ethical limitations in human studies, animal models that reflect many features of PCOS are crucial resources to investigate this syndrome. We aimed to introduce the most suitable rat model of PCOS that closely mimics the endocrine, ovarian and metabolic disturbances of human PCOS phenotype, while maintaining normal reproductive system morphology in adulthood, in order to further more detailed investigations about PCOS. We searched Pubmed, Science direct, and Web of science between 1990 and 2016, for relevant English manuscripts, using keywords including the "Polycystic Ovary Syndrome AND Rat Model" to generate a subset of citations relevant to our research. Included were those articles that compared at least both ovarian histology or estrous cycle and reproductive hormonal profiles in hormone-induced rat model of PCOS and controls. Differences in the findings between hormone-induced PCOS rats appear to be a result of the degree of transplacental transfer of the steroid administered into the fetus, dose and type of hormone, route of administration and timing and duration of exposure. We conclude that prenatal hormone-induced rat model with a lower dose and shorter time of exposure during the critical period of fetal development that exhibits endocrine, ovarian and metabolic disturbances similar to PCOS in women, while maintaining normal reproductive system morphology in adulthood is more suitable than postnatal hormone-induced rat model to facilitate studies regarding PCOS. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Predicting climate-induced range shifts: model differences and model reliability.

    Science.gov (United States)

    Joshua J. Lawler; Denis White; Ronald P. Neilson; Andrew R. Blaustein

    2006-01-01

    Predicted changes in the global climate are likely to cause large shifts in the geographic ranges of many plant and animal species. To date, predictions of future range shifts have relied on a variety of modeling approaches with different levels of model accuracy. Using a common data set, we investigated the potential implications of alternative modeling approaches for...

  16. Simple statistical channel model for weak temperature-induced turbulence in underwater wireless optical communication systems

    KAUST Repository

    Oubei, Hassan M.

    2017-06-16

    In this Letter, we use laser beam intensity fluctuation measurements to model and describe the statistical properties of weak temperature-induced turbulence in underwater wireless optical communication (UWOC) channels. UWOC channels with temperature gradients are modeled by the generalized gamma distribution (GGD) with an excellent goodness of fit to the measured data under all channel conditions. Meanwhile, thermally uniform channels are perfectly described by the simple gamma distribution which is a special case of GGD. To the best of our knowledge, this is the first model that comprehensively describes both thermally uniform and gradient-based UWOC channels.

  17. Model calculations of excitation functions of neutron-induced reactions on Rh

    International Nuclear Information System (INIS)

    Strohmaier, Brigitte

    1995-01-01

    Cross sections of neutron-induced reactions on 103 Rh have been calculated by means of the statistical model and the coupled-channels optical model for incident-neutron energies up to 30 MeV. The incentive for this study was a new measurement of the 103 Rh(n, n') 103m Rh cross section which will - together with the present calculations -enter into a dosimetry-reaction evaluation. The validation of the model parameters relied on nuclear-structure data as far as possible. (author)

  18. Pharmacokinetic/Pharmacodynamic Relationship of Gabapentin in a CFA-induced Inflammatory Hyperalgesia Rat Model

    DEFF Research Database (Denmark)

    Larsen, Malte Selch; Keizer, Ron; Munro, Gordon

    2016-01-01

    PURPOSE: Gabapentin displays non-linear drug disposition, which complicates dosing for optimal therapeutic effect. Thus, the current study was performed to elucidate the pharmacokinetic/pharmacodynamic (PKPD) relationship of gabapentin's effect on mechanical hypersensitivity in a rat model of CFA......-induced inflammatory hyperalgesia. METHODS: A semi-mechanistic population-based PKPD model was developed using nonlinear mixed-effects modelling, based on gabapentin plasma and brain extracellular fluid (ECF) time-concentration data and measurements of CFA-evoked mechanical hyperalgesia following administration...

  19. Modeling of radiation-induced charge trapping in MOS devices under ionizing irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Petukhov, M. A., E-mail: m.a.petukhov@gmail.com; Ryazanov, A. I. [National Research Center Kurchatov Institute (Russian Federation)

    2016-12-15

    The numerical model of the radiation-induced charge trapping process in the oxide layer of a MOS device under ionizing irradiation is developed; the model includes carrier transport, hole capture by traps in different states, recombination of free electrons and trapped holes, kinetics of hydrogen ions which can be accumulated in the material during transistor manufacture, and accumulation and charging of interface states. Modeling of n-channel MOSFET behavior under 1 MeV photon irradiation is performed. The obtained dose dependences of the threshold voltage shift and its contributions from trapped holes and interface states are in good agreement with experimental data.

  20. Chronic treatment with antipsychotics in rats as a model for antipsychotic-induced weight gain in human

    DEFF Research Database (Denmark)

    Pouzet, B; Mow, T; Kreilgaard, Mads

    2003-01-01

    compounds in an animal model of weight gain. With the aim of evaluating whether the rat can be used as a model for antipsychotic-induced weight gain, we have investigated the effect of chronic treatment (3 weeks) with one antipsychotic drug inducing weight gain in clinic (olanzapine) and one antipsychotic...

  1. Investigation of nucleon-induced reactions in the Fermi energy domain within the microscopic DYWAN model

    Energy Technology Data Exchange (ETDEWEB)

    Sebille, F.; Bonilla, C. [SUBATECH, Universite de Nantes, CNRS/IN2P3, 44 - Nantes (France); Blideanu, V.; Lecolley, J.F. [Laboratoire de Physique Corpusculaire, ENSICAEN, Universite de Caen, IN2P3-CNRS, 14 - Caen (France)

    2004-06-01

    A microscopic investigation of nucleon-induced reactions is addressed within the DYWAN model, which is based on the projection methods of out of equilibrium statistical physics and on the mathematical theory of wavelets. Due to a strongly compressed representation of the fermionic wave-functions, the numerical simulations of the nucleon transport in target are therefore able to preserve the quantum nature of the colliding system, as well as a least biased many-body information needed to keep track of the cluster formation. A special attention is devoted to the fingerprints of the phase space topology induced by the fluctuations of the self-consistent mean-field. Comparisons be ween theoretical results and experimental data point out that ETDHF type approaches are well suited to describe reaction mechanisms in the Fermi energy domain. The observed sensitivity to physical effects shows that the nucleon-induced reactions provide a valuable probe of the nuclear interaction in this range of energy. (authors)

  2. Knockdown of the placental growth factor gene inhibits laser induced choroidal neovascularization in a murine model.

    Science.gov (United States)

    Nourinia, Ramin; Soheili, Zahra-Soheila; Ahmadieh, Hamid; Akrami, Hassan; Rezaei Kanavi, Mozhgan; Samiei, Shahram

    2013-01-01

    To evaluate the effect of placental growth factor (PlGF) gene knockdown in a murine model of laser-induced choroidal neovascularization. Choroidal neovascularization was induced in the left eyes of 11 mice by infrared laser. Small interfering RNA (siRNA, 20 picomoles/10 μl) corresponding to PlGF mRNA was administered intravitreally by Hamilton syringe in all subjects. One month later, fluorescein angiography and histolologic examination were performed. No leakage was apparent in the 11 eyes treated with siRNA cognate to PlGF. The results of histological evaluation were consistent with angiographic findings showing absence of choroidal neovascularization. Knockdown of the PlGF gene can inhibit the growth of laser-induced choroidal neovascularization in mice.

  3. Knockdown of the Placental Growth Factor Gene Inhibits Laser Induced Choroidal Neovascularization in a Murine Model

    Directory of Open Access Journals (Sweden)

    Ramin Nourinia

    2013-01-01

    Full Text Available Purpose: To evaluate the effect of placental growth factor (PlGF gene knockdown in a murine model of laser-induced choroidal neovascularization. Methods: Choroidal neovascularization was induced in the left eyes of 11 mice by infrared laser. Small interfering RNA (siRNA, 20 picomoles/10 μl corresponding to PlGF mRNA was administered intravitreally by Hamilton syringe in all subjects. One month later, fluorescein angiography and histolologic examination were performed. Results: No leakage was apparent in the 11 eyes treated with siRNA cognate to PlGF. The results of histological evaluation were consistent with angiographic findings showing absence of choroidal neovascularization. Conclusion: Knockdown of the PlGF gene can inhibit the growth of laser-induced choroidal neovascularization in mice.

  4. A mouse model of mitochondrial complex III dysfunction induced by myxothiazol

    Energy Technology Data Exchange (ETDEWEB)

    Davoudi, Mina [Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185 (Sweden); Kallijärvi, Jukka; Marjavaara, Sanna [Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, 00014 (Finland); Kotarsky, Heike; Hansson, Eva [Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185 (Sweden); Levéen, Per [Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185 (Sweden); Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, 00014 (Finland); Fellman, Vineta, E-mail: Vineta.Fellman@med.lu.se [Pediatrics, Department of Clinical Sciences, Lund, Lund University, Lund 22185 (Sweden); Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, 00014 (Finland); Children’s Hospital, Helsinki University Hospital, University of Helsinki, Helsinki 00029 (Finland)

    2014-04-18

    Highlights: • Reversible chemical inhibition of complex III in wild type mouse. • Myxothiazol causes decreased complex III activity in mouse liver. • The model is useful for therapeutic trials to improve mitochondrial function. - Abstract: Myxothiazol is a respiratory chain complex III (CIII) inhibitor that binds to the ubiquinol oxidation site Qo of CIII. It blocks electron transfer from ubiquinol to cytochrome b and thus inhibits CIII activity. It has been utilized as a tool in studies of respiratory chain function in in vitro and cell culture models. We developed a mouse model of biochemically induced and reversible CIII inhibition using myxothiazol. We administered myxothiazol intraperitoneally at a dose of 0.56 mg/kg to C57Bl/J6 mice every 24 h and assessed CIII activity, histology, lipid content, supercomplex formation, and gene expression in the livers of the mice. A reversible CIII activity decrease to 50% of control value occurred at 2 h post-injection. At 74 h only minor histological changes in the liver were found, supercomplex formation was preserved and no significant changes in the expression of genes indicating hepatotoxicity or inflammation were found. Thus, myxothiazol-induced CIII inhibition can be induced in mice for four days in a row without overt hepatotoxicity or lethality. This model could be utilized in further studies of respiratory chain function and pharmacological approaches to mitochondrial hepatopathies.

  5. A new model for the spectral induced polarization signature of bacterial growth in porous media

    Science.gov (United States)

    Zhang, C.; Revil, A.; Atekwana, E. A.; Jardani, A.; Smith, S.

    2012-12-01

    Recent biogeophysics studies demonstrated the sensitivity of complex conductivity to bacterial growth and microbial mediated mineral transformations in porous media. Frequency-domain induced polarization is a minimally invasive manner to measure the complex conductivity of a material over a broad range of frequencies. The real component of complex conductivity is associated with electromigration of the charge carriers, and the imaginary component represents reversible energy storage of charge carriers at polarization length scales. Quantitative relationship between frequency-domain induced polarization responses and bacterial growth and decay in porous media is analyzed in this study using a new developed model. We focus on the direct contribution of bacteria themselves to the complex conductivity in porous media in the absence of biomineralization. At low frequencies, the induced polarization of bacteria (α-polarization) is related to the properties of the electrical double layer surrounding the membrane surface of bacteria. Surface conductivity and α-polarization are due to the Stern layer of the counterions occurring in a brush of polymers coating the surface of the bacteria, and can be related to the cation exchange capacity of the bacteria. From the modeling results, at low frequencies (model with reactive transport modeling in which the evolution of bacterial populations are usually described by Monod kinetics, we show that the changes in imaginary conductivity with time can be used to determine bacterial growth kinetics parameters such as the growth and endogenous decay coefficient.

  6. Oligonol improves memory and cognition under an amyloid β(25-35)-induced Alzheimer's mouse model.

    Science.gov (United States)

    Choi, Yoon Young; Maeda, Takahiro; Fujii, Hajime; Yokozawa, Takako; Kim, Hyun Young; Cho, Eun Ju; Shibamoto, Takayuki

    2014-07-01

    Alzheimer's disease is an age-dependent progressive neurodegenerative disorder that results in impairments of memory and cognitive function. It is hypothesized that oligonol has ameliorative effects on memory impairment and reduced cognitive functions in mice with Alzheimer's disease induced by amyloid β(25-35) (Aβ(25-35)) injection. The protective effect of an oligonol against Aβ(25-35)-induced memory impairment was investigated in an in vivo Alzheimer's mouse model. The aggregation of Aβ25-35 was induced by incubation at 37°C for 3 days before injection into mice brains (5 nmol/mouse), and then oligonol was orally administered at 100 and 200 mg/kg of body weight for 2 weeks. Memory and cognition were observed in T-maze, object recognition, and Morris water maze tests. The group injected with Aβ(25-35) showed impairments in both recognition and memory. However, novel object recognition and new route awareness abilities were dose dependently improved by the oral administration of oligonol. In addition, the results of the Morris water maze test indicated that oligonol exerted protective activity against cognitive impairment induced by Aβ(25-35). Furthermore, nitric oxide formation and lipid peroxidation were significantly elevated by Aβ(25-35), whereas oligonol treatment significantly decreased nitric oxide formation and lipid peroxidation in the brain, liver, and kidneys. The present results suggest that oligonol improves Aβ(25-35)-induced memory deficit and cognition impairment. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. High-fat diet induces significant metabolic disorders in a mouse model of polycystic ovary syndrome.

    Science.gov (United States)

    Lai, Hao; Jia, Xiao; Yu, Qiuxiao; Zhang, Chenglu; Qiao, Jie; Guan, Youfei; Kang, Jihong

    2014-11-01

    Polycystic ovary syndrome (PCOS) is the most common female endocrinopathy associated with both reproductive and metabolic disorders. Dehydroepiandrosterone (DHEA) is currently used to induce a PCOS mouse model. High-fat diet (HFD) has been shown to cause obesity and infertility in female mice. The possible effect of an HFD on the phenotype of DHEA-induced PCOS mice is unknown. The aim of the present study was to investigate both reproductive and metabolic features of DHEA-induced PCOS mice fed a normal chow or a 60% HFD. Prepubertal C57BL/6 mice (age 25 days) on the normal chow or an HFD were injected (s.c.) daily with the vehicle sesame oil or DHEA for 20 consecutive days. At the end of the experiment, both reproductive and metabolic characteristics were assessed. Our data show that an HFD did not affect the reproductive phenotype of DHEA-treated mice. The treatment of HFD, however, caused significant metabolic alterations in DHEA-treated mice, including obesity, glucose intolerance, dyslipidemia, and pronounced liver steatosis. These findings suggest that HFD induces distinct metabolic features in DHEA-induced PCOS mice. The combined DHEA and HFD treatment may thus serve as a means of studying the mechanisms involved in metabolic derangements of this syndrome, particularly in the high prevalence of hepatic steatosis in women with PCOS. © 2014 by the Society for the Study of Reproduction, Inc.

  8. Modelling the ethanol-induced sleeping time in mice through a zero inflated model

    OpenAIRE

    FOGAP, Njinju Tongwa

    2007-01-01

    In the analysis of data in statistics, it is imperative to select most suitable models. Wrong choice of model selection leads to bias parameter estimates and standard errors. In the ethanol anesthesia data set used in this thesis, we observe more than expected zero counts, usually termed zero-inflation. Traditional application of Poisson and negative binomial distributions for model fitting may not be adequate due to the presence of excess zeros. This zero-inflation comes from two sources;...

  9. The common parasite Toxoplasma gondii induces prostatic inflammation and microglandular hyperplasia in a mouse model.

    Science.gov (United States)

    Colinot, Darrelle L; Garbuz, Tamila; Bosland, Maarten C; Wang, Liang; Rice, Susan E; Sullivan, William J; Arrizabalaga, Gustavo; Jerde, Travis J

    2017-07-01

    Inflammation is the most prevalent and widespread histological finding in the human prostate, and associates with the development and progression of benign prostatic hyperplasia and prostate cancer. Several factors have been hypothesized to cause inflammation, yet the role each may play in the etiology of prostatic inflammation remains unclear. This study examined the possibility that the common protozoan parasite Toxoplasma gondii induces prostatic inflammation and reactive hyperplasia in a mouse model. Male mice were infected systemically with T. gondii parasites and prostatic inflammation was scored based on severity and focality of infiltrating leukocytes and epithelial hyperplasia. We characterized inflammatory cells with flow cytometry and the resulting epithelial proliferation with bromodeoxyuridine (BrdU) incorporation. We found that T. gondii infects the mouse prostate within the first 14 days of infection and can establish parasite cysts that persist for at least 60 days. T. gondii infection induces a substantial and chronic inflammatory reaction in the mouse prostate characterized by monocytic and lymphocytic inflammatory infiltrate. T. gondii-induced inflammation results in reactive hyperplasia, involving basal and luminal epithelial proliferation, and the exhibition of proliferative inflammatory microglandular hyperplasia in inflamed mouse prostates. This study identifies the common parasite T. gondii as a new trigger of prostatic inflammation, which we used to develop a novel mouse model of prostatic inflammation. This is the first report that T. gondii chronically encysts and induces chronic inflammation within the prostate of any species. Furthermore, T. gondii-induced prostatic inflammation persists and progresses without genetic manipulation in mice, offering a powerful new mouse model for the study of chronic prostatic inflammation and microglandular hyperplasia. © 2017 Wiley Periodicals, Inc.

  10. Swept-sine noise-induced damage as a hearing loss model for preclinical assays

    Directory of Open Access Journals (Sweden)

    Lorena eSanz

    2015-02-01

    Full Text Available Mouse models are key tools for studying cochlear alterations in noise-induced hearing loss and for evaluating new therapies. Stimuli used to induce deafness in mice are usually white and octave band noises that include very low frequencies, considering the large mouse auditory range. We designed different sound stimuli, enriched in frequencies up to 20 kHz (violet noises to examine their impact on hearing thresholds and cochlear cytoarchitecture after short exposure. In addition, we developed a cytocochleogram to quantitatively assess the ensuing structural degeneration and its functional correlation. Finally, we used this mouse model and cochleogram procedure to evaluate the potential therapeutic effect of transforming growth factor β1 inhibitors P17 and P144 on noise-induced hearing loss. CBA mice were exposed to violet swept-sine noise with different frequency ranges (2-20 or 9-13 kHz and levels (105 or 120 dB SPL for 30 minutes. Mice were evaluated by auditory brainstem response and otoacoustic emission tests prior to and 2, 14 and 28 days after noise exposure. Cochlear pathology was assessed with gross histology; hair cell number was estimated by a stereological counting method. Our results indicate that functional and morphological changes induced by violet swept-sine noise depend on the sound level and frequency composition. Partial hearing recovery followed the exposure to 105 dB SPL, whereas permanent cochlear damage resulted from the exposure to 120 dB SPL. Exposure to 9-13 kHz noise caused an auditory threshold shift in those frequencies that correlated with hair cell loss in the corresponding areas of the cochlea that were spotted on the cytocochleogram. In summary, we present mouse models of noise-induced hearing loss, which depending on the sound properties of the noise, cause different degrees of cochlear damage, and could therefore be used to study molecules which are potential players in hearing loss protection and repair.

  11. CCL20, (gamma)(delta) T cells, and IL-22 in corneal epithelial healing

    Science.gov (United States)

    After corneal epithelial abrasion, leukocytes and platelets rapidly enter the corneal stroma, and CCR6 (+) IL-17(+) gamma delta T cells migrate into the epithelium. Gamma delta T-cell-deficient (TCRd(-/-)) mice have significantly reduced inflammation and epithelial wound healing. Epithelial CCL20 mR...

  12. Three-Dimensional Culture Model of Skeletal Muscle Tissue with Atrophy Induced by Dexamethasone.

    Science.gov (United States)

    Shimizu, Kazunori; Genma, Riho; Gotou, Yuuki; Nagasaka, Sumire; Honda, Hiroyuki

    2017-06-15

    Drug screening systems for muscle atrophy based on the contractile force of cultured skeletal muscle tissues are required for the development of preventive or therapeutic drugs for atrophy. This study aims to develop a muscle atrophy model by inducing atrophy in normal muscle tissues constructed on microdevices capable of measuring the contractile force and to verify if this model is suitable for drug screening using the contractile force as an index. Tissue engineered skeletal muscles containing striated myotubes were prepared on the microdevices for the study. The addition of 100 µM dexamethasone (Dex), which is used as a muscle atrophy inducer, for 24 h reduced the contractile force significantly. An increase in the expression of Atrogin-1 and MuRF-1 in the tissues treated with Dex was established. A decrease in the number of striated myotubes was also observed in the tissues treated with Dex. Treatment with 8 ng/mL Insulin-like Growth Factor (IGF-I) for 24 h significantly increased the contractile force of the Dex-induced atrophic tissues. The same treatment, though, had no impact on the force of the normal tissues. Thus, it is envisaged that the atrophic skeletal muscle tissues induced by Dex can be used for drug screening against atrophy.

  13. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

    Energy Technology Data Exchange (ETDEWEB)

    Yannam, Govardhana Rao [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Han, Bing [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi' an Jiaotong University, Xi' an, Shaanxi (China); Setoyama, Kentaro [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamamoto, Toshiyuki [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Ito, Ryotaro; Brooks, Jenna M. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Guzman-Lepe, Jorge [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Galambos, Csaba [Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Fong, Jason V. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Deutsch, Melvin; Quader, Mubina A. [Department of Radiation Oncology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamanouchi, Kosho [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York (United States); Kabarriti, Rafi; Mehta, Keyur [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Soto-Gutierrez, Alejandro [Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); and others

    2014-02-01

    Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.

  14. Expression of MDM2 in an acute lymphocytic leukemia mice model induced by γ-radiation

    International Nuclear Information System (INIS)

    Huang Yuecheng; Cai Jianming; Han Ling; Gao Fu; Cui Jianguo; Gao Jianguo

    2004-01-01

    Objective: To investigate the role of the MDM 2 in the process of carcinogenesis induced by γ-rays and its molecular mechanisms. Methods: Animal model of radiation-induced leukemia was established by γ-irradiation. According to the histological and morphological results, mice tissues were divided into three groups: cancerization group, incancerization group and control group. Expression of MDM 2 protein and mRNA in thymus/bone marrow was detected with Western blot and in situ hybridization (ISH), respectively. The authors also examined the protein phosphorylation level of MDM 2 protein by immunoprecipitation (IP). PCR-SSCP was performed to detect gene mutation. Results: A mice leukemia model was successfully established as verified by pathological findings and confirmed by transplantation test in nude mice. The protein expression in thymus/bone marrow in irradiation groups was significantly higher than that in controls (P 2 was found to be hyper-phosphorylated in the cancerization group as compared with other groups. No gene mutation was detected by SSCP/silver-staining assay in the tumor samples. Conclusion: MDM 2 may be involved in the development and progression of leukemia induced by γ-irradiation. The over-expression but not gene mutation may be responsible for malignant transformation induced by radiation. Phosphorylation is at least partly attributed to activation of MDM 2

  15. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

    International Nuclear Information System (INIS)

    Yannam, Govardhana Rao; Han, Bing; Setoyama, Kentaro; Yamamoto, Toshiyuki; Ito, Ryotaro; Brooks, Jenna M.; Guzman-Lepe, Jorge; Galambos, Csaba; Fong, Jason V.; Deutsch, Melvin; Quader, Mubina A.; Yamanouchi, Kosho; Kabarriti, Rafi; Mehta, Keyur; Soto-Gutierrez, Alejandro

    2014-01-01

    Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury

  16. The plant decapeptide OSIP108 prevents copper-induced toxicity in various models for Wilson disease

    Energy Technology Data Exchange (ETDEWEB)

    Spincemaille, Pieter [Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, 3001 Heverlee (Belgium); Pham, Duc-Hung [Laboratory for Molecular Biodiscovery, KU Leuven, Campus Gasthuisberg, Herestraat 49, O and N2, 3000 Leuven (Belgium); Chandhok, Gursimran [Clinic for Transplantation Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, Building A14, D-48149 Münster (Germany); Verbeek, Jef [Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven (Belgium); Zibert, Andree [Clinic for Transplantation Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, Building A14, D-48149 Münster (Germany); Libbrecht, Louis [Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven (Belgium); Department of Pathology, University Hospital Ghent, De Pintelaan 185, 9000 Ghent (Belgium); Schmidt, Hartmut [Clinic for Transplantation Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, Building A14, D-48149 Münster (Germany); Esguerra, Camila V.; Witte, Peter A.M. de [Laboratory for Molecular Biodiscovery, KU Leuven, Campus Gasthuisberg, Herestraat 49, O and N2, 3000 Leuven (Belgium); Cammue, Bruno P.A., E-mail: bruno.cammue@biw.kuleuven.be [Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, 3001 Heverlee (Belgium); Department of Plant Systems Biology, VIB, Technologiepark 927, 9052 Ghent (Belgium); Cassiman, David [Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven (Belgium); Thevissen, Karin [Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, 3001 Heverlee (Belgium)

    2014-10-15

    Background: Wilson disease (WD) is caused by accumulation of excess copper (Cu) due to a mutation in the gene encoding the liver Cu transporter ATP7B, and is characterized by acute liver failure or cirrhosis and neuronal cell death. We investigated the effect of OSIP108, a plant derived decapeptide that prevents Cu-induced apoptosis in yeast and human cells, on Cu-induced toxicity in various mammalian in vitro models relevant for WD and in a Cu-toxicity zebrafish larvae model applicable to WD. Methods: The effect of OSIP108 was evaluated on viability of various cell lines in the presence of excess Cu, on liver morphology of a Cu-treated zebrafish larvae strain that expresses a fluorescent reporter in hepatocytes, and on oxidative stress levels in wild type AB zebrafish larvae. Results: OSIP108 increased not only viability of Cu-treated CHO cells transgenically expressing ATP7B and the common WD-causing mutant ATP7B{sup H1069Q}, but also viability of Cu-treated human glioblastoma U87 cells. Aberrancies in liver morphology of Cu-treated zebrafish larvae were observed, which were further confirmed as Cu-induced hepatotoxicity by liver histology. Injections of OSIP108 into Cu-treated zebrafish larvae significantly increased the amount of larvae with normal liver morphology and decreased Cu-induced production of reactive oxygen species. Conclusions: OSIP108 prevents Cu-induced toxicity in in vitro models and in a Cu-toxicity zebrafish larvae model applicable to WD. General significance: All the above data indicate the potential of OSIP108 as a drug lead for further development as a novel WD treatment. - Highlights: • Wilson disease (WD) is characterized by accumulation of toxic copper (Cu). • OSIP108 increases viability of Cu-treated cellular models applicable to WD. • OSIP108 injections preserve liver morphology of Cu-treated zebrafish larvae. • OSIP108 injections into zebrafish larvae abrogates Cu-induced oxidative stress.

  17. Diet-induced metabolic hamster model of nonalcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    Bhathena J

    2011-06-01

    Full Text Available Jasmine Bhathena, Arun Kulamarva, Christopher Martoni, Aleksandra Malgorzata Urbanska, Meenakshi Malhotra, Arghya Paul, Satya PrakashBiomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Artificial Cells and Organs Research Centre, Faculty of Medicine, McGill University, Montreal, Québec, CanadaBackground: Obesity, hypercholesterolemia, elevated triglycerides, and type 2 diabetes are major risk factors for metabolic syndrome. Hamsters, unlike rats or mice, respond well to diet-induced obesity, increase body mass and adiposity on group housing, and increase food intake due to social confrontation-induced stress. They have a cardiovascular and hepatic system similar to that of humans, and can thus be a useful model for human pathophysiology.Methods: Experiments were planned to develop a diet-induced Bio F1B Golden Syrian hamster model of dyslipidemia and associated nonalcoholic fatty liver disease in the metabolic syndrome. Hamsters were fed a normal control diet, a high-fat/high-cholesterol diet, a high-fat/high-cholesterol/methionine-deficient/choline-devoid diet, and a high-fat/high-cholesterol/choline-deficient diet. Serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, atherogenic index, and body weight were quantified biweekly. Fat deposition in the liver was observed and assessed following lipid staining with hematoxylin and eosin and with oil red O.Results: In this study, we established a diet-induced Bio F1B Golden Syrian hamster model for studying dyslipidemia and associated nonalcoholic fatty liver disease in the metabolic syndrome. Hyperlipidemia and elevated serum glucose concentrations were induced using this diet. Atherogenic index was elevated, increasing the risk for a cardiovascular event. Histological analysis of liver specimens at the end of four weeks showed increased fat deposition in the liver of animals fed

  18. Well-posed Euler model of shock-induced two-phase flow in bubbly liquid

    Science.gov (United States)

    Tukhvatullina, R. R.; Frolov, S. M.

    2018-03-01

    A well-posed mathematical model of non-isothermal two-phase two-velocity flow of bubbly liquid is proposed. The model is based on the two-phase Euler equations with the introduction of an additional pressure at the gas bubble surface, which ensures the well-posedness of the Cauchy problem for a system of governing equations with homogeneous initial conditions, and the Rayleigh-Plesset equation for radial pulsations of gas bubbles. The applicability conditions of the model are formulated. The model is validated by comparing one-dimensional calculations of shock wave propagation in liquids with gas bubbles with a gas volume fraction of 0.005-0.3 with experimental data. The model is shown to provide satisfactory results for the shock propagation velocity, pressure profiles, and the shock-induced motion of the bubbly liquid column.

  19. Adequacy of relative and absolute risk models for lifetime risk estimate of radiation-induced cancer

    International Nuclear Information System (INIS)

    McBride, M.; Coldman, A.J.

    1988-03-01

    This report examines the applicability of the relative (multiplicative) and absolute (additive) models in predicting lifetime risk of radiation-induced cancer. A review of the epidemiologic literature, and a discussion of the mathematical models of carcinogenesis and their relationship to these models of lifetime risk, are included. Based on the available data, the relative risk model for the estimation of lifetime risk is preferred for non-sex-specific epithelial tumours. However, because of lack of knowledge concerning other determinants of radiation risk and of background incidence rates, considerable uncertainty in modelling lifetime risk still exists. Therefore, it is essential that follow-up of exposed cohorts be continued so that population-based estimates of lifetime risk are available

  20. NEESROCK: A Physical and Numerical Modeling Investigation of Seismically Induced Rock-Slope Failure

    Science.gov (United States)

    Applegate, K. N.; Wartman, J.; Keefer, D. K.; Maclaughlin, M.; Adams, S.; Arnold, L.; Gibson, M.; Smith, S.

    2013-12-01

    Worldwide, seismically induced rock-slope failures have been responsible for approximately 30% of the most significant landslide catastrophes of the past century. They are among the most common, dangerous, and still today, least understood of all seismic hazards. Seismically Induced Rock-Slope Failure: Mechanisms and Prediction (NEESROCK) is a major research initiative that fully integrates physical modeling (geotechnical centrifuge) and advanced numerical simulations (discrete element modeling) to investigate the fundamental mechanisms governing the stability of rock slopes during earthquakes. The research is part of the National Science Foundation-supported Network for Earthquake Engineering Simulation Research (NEES) program. With its focus on fractures and rock materials, the project represents a significant departure from the traditional use of the geotechnical centrifuge for studying soil, and pushes the boundaries of physical modeling in new directions. In addition to advancing the fundamental understanding of the rock-slope failure process under seismic conditions, the project is developing improved rock-slope failure assessment guidelines, analysis procedures, and predictive tools. Here, we provide an overview of the project, present experimental and numerical modeling results, discuss special considerations for the use of synthetic rock materials in physical modeling, and address the suitability of discrete element modeling for simulating the dynamic rock-slope failure process.

  1. Carbon accounting and economic model uncertainty of emissions from biofuels-induced land use change.

    Science.gov (United States)

    Plevin, Richard J; Beckman, Jayson; Golub, Alla A; Witcover, Julie; O'Hare, Michael

    2015-03-03

    Few of the numerous published studies of the emissions from biofuels-induced "indirect" land use change (ILUC) attempt to propagate and quantify uncertainty, and those that have done so have restricted their analysis to a portion of the modeling systems used. In this study, we pair a global, computable general equilibrium model with a model of greenhouse gas emissions from land-use change to quantify the parametric uncertainty in the paired modeling system's estimates of greenhouse gas emissions from ILUC induced by expanded production of three biofuels. We find that for the three fuel systems examined--US corn ethanol, Brazilian sugar cane ethanol, and US soybean biodiesel--95% of the results occurred within ±20 g CO2e MJ(-1) of the mean (coefficient of variation of 20-45%), with economic model parameters related to crop yield and the productivity of newly converted cropland (from forestry and pasture) contributing most of the variance in estimated ILUC emissions intensity. Although the experiments performed here allow us to characterize parametric uncertainty, changes to the model structure have the potential to shift the mean by tens of grams of CO2e per megajoule and further broaden distributions for ILUC emission intensities.

  2. Analytical Model of Underground Train Induced Vibrations on Nearby Building Structures in Cameroon: Assessment and Prediction

    Directory of Open Access Journals (Sweden)

    Lezin Seba MINSILI

    2013-11-01

    Full Text Available The purpose of this research paper was to assess and predict the effect of vibrations induced by an underground railway on nearby-existing buildings prior to the construction of projected new railway lines of the National Railway Master Plan of Cameroon and after upgrading of the railway conceded to CAMRAIL linking the two most densely populated cities of Cameroon: Douala and Yaoundé. With the source-transmitter-receiver mathematical model as the train-soil-structure interaction model, taking into account sub-model parameters such as type of the train-railway system, typical geotechnical conditions of the ground and the sensitivity of the nearby buildings, the analysis is carried out over the entire system using the dynamic finite element method in the time domain. This subdivision of the model is a powerful tool that allows to consider different alternatives of sub-models with different characteristics, and thus to determine any critical excessive vibration impact. Based on semi-empirical analytical results obtained from presented models, the present work assesses and predicts characteristics of traffic-induced vibrations as a function of time duration, intensity and vehicle speed, as well as their influence on buildings at different levels.

  3. Tadpole-induced electroweak symmetry breaking and pNGB Higgs models

    Energy Technology Data Exchange (ETDEWEB)

    Harnik, Roni; Howe, Kiel; Kearney, John [Theoretical Physics Department, Fermi National Accelerator Laboratory, Batavia, IL 60510 (United States)

    2017-03-22

    We investigate induced electroweak symmetry breaking (EWSB) in models in which the Higgs is a pseudo-Nambu-Goldstone boson (pNGB). In pNGB Higgs models, Higgs properties and precision electroweak measurements imply a hierarchy between the EWSB and global symmetry-breaking scales, v{sub H}≪f{sub H}. When the pNGB potential is generated radiatively, this hierarchy requires fine-tuning to a degree of at least ∼v{sub H}{sup 2}/f{sub H}{sup 2}. We show that if Higgs EWSB is induced by a tadpole arising from an auxiliary sector at scale f{sub Σ}≪v{sub H}, this tuning is significantly ameliorated or can even be removed. We present explicit examples both in Composite Higgs models based on SO(5)/SO(4) and in Twin Higgs models. For the Twin case, the result is a fully natural model with f{sub H}∼1 TeV and the lightest colored top partners at 2 TeV. These models also have an appealing mechanism to generate the scales of the auxiliary sector and Higgs EWSB directly from the scale f{sub H}, with a natural hierarchy f{sub Σ}≪v{sub H}≪f{sub H}∼TeV. The framework predicts modified Higgs coupling as well as new Higgs and vector states at LHC13.

  4. Mathematical models of blast induced TBI: current status, challenges and prospects

    Directory of Open Access Journals (Sweden)

    Raj K Gupta

    2013-05-01

    Full Text Available Blast induced traumatic brain injury (TBI has become a signature wound of recent military activities and is the leading cause of death and long-term disability among U.S. soldiers. The current limited understanding of brain injury mechanisms impedes the development of protection, diagnostic and treatment strategies. We believe mathematical models of blast wave brain injury biomechanics and neurobiology, complemented with in vitro and in vivo experimental studies, will enable a better understanding of injury mechanisms and accelerate the development of both protective and treatment strategies. The goal of this paper is to review the current state of the art in mathematical and computational modeling of blast induced TBI, identify research gaps and recommend future developments. A brief overview of blast wave physics, injury biomechanics and the neurobiology of brain injury is used as a foundation for a more detailed discussion of multiscale mathematical models of primary biomechanics and secondary injury and repair mechanisms. The paper also presents a discussion of model development strategies, experimental approaches to generate benchmark data for model validation and potential applications of the model for prevention and protection against blast wave TBI.

  5. Validation of infrared thermography in serotonin-induced itch model in rats

    DEFF Research Database (Denmark)

    Dagnæs-Hansen, Frederik; Jasemian, Yousef; Gazerani, Parisa

    The number of scratching bouts is generally used as a standard method in animal models of itch. The aim of the present study was to validate the application of infrared thermography (IR-Th) in a serotonin-induced itch model in rats. Adult Sprague-Dawley male rats (n = 24) were used in 3 consecutive...... experiments. The first experiment evaluated vasomotor response (IR-Th) and scratching behavior (number of bouts) induced by intradermal serotonin (10 μl, 2%). Isotonic saline (control: 10 μl, 0.9%) and Methysergide (antagonist: 10 μl, 0.047 mg/ml) were used. The second experiment evaluated the dose......-response effect of intradermal serotonin (1%, 2% and 4%) on local temperature. The third experiment evaluated the anesthetized rats to test the local vasomotor responses in absent of scratching. Serotonin elicited significant scratching and lowered the local temperature at the site of injection. A dose...

  6. Numerical investigation on effects of induced jet on boundary layer and turbulent models around airfoils

    Energy Technology Data Exchange (ETDEWEB)

    Shojaeefard, M.H.; Pirnia, A.; Fallahian, M.A. [Iran University of Science and Technology, School of Mechanical Engineering, Tehran (Iran, Islamic Republic of); Tahani, M. [Iran University of Science and Technology, School of Mechanical Engineering, Tehran (Iran, Islamic Republic of); University of Tehran, Faculty of New Science and Technology, Tehran (Iran, Islamic Republic of)

    2012-06-15

    In this study the effects of induced jet at trailing edge of a two dimensional airfoil on its boundary layer shape, separation over surface and turbulent parameters behind trailing edge are numerically investigated and compared against a previous experimental data. After proving independency of results from mesh size and obtaining the required mesh size, different turbulent models are examined and RNG k-epsilon model is chosen because of good agreement with experimental data in velocity and turbulent intensity variations. A comparison between ordinary and jet induced cases, regarding numerical data, is made. The results showed that because of low number of measurement points in experimental study, turbulent intensity extremes are not captured. While in numerical study, these values and their positions are well calculated and exact variation of turbulent intensity is acquired. Also a study in effect of jet at high angles of attack is done and the results showed the ability of jet in controlling separation and reducing wake region. (orig.)

  7. Anisotropic Constitutive Model of Strain-induced Phenomena in Stainless Steels at Cryogenic Temperatures

    CERN Document Server

    Garion, C

    2004-01-01

    A majority of the thin-walled components subjected to intensive plastic straining at cryogenic temperatures are made of stainless steels. The examples of such components can be found in the interconnections of particle accelerators, containing the superconducting magnets, where the thermal contraction is absorbed by thin-walled, axisymetric shells called bellows expansion joints. The stainless steels show three main phenomena induced by plastic strains at cryogenic temperatures: serrated (discontinuous) yielding, gamma->alpha' phase transformation and anisotropic ductile damage. In the present paper, a coupled constitutive model of gamma->alpha' phase transformation and orthotropic ductile damage is presented. A kinetic law of phase transformation, and a kinetic law of evolution of orthotropic damage are presented. The model is extended to anisotropic plasticity comprising a constant anisotropy (texture effect), which can be classically taken into account by the Hill yield surface, and plastic strain induced ...

  8. Modeling of Low Frequency MHD Induced Beam Ion Transport In NSTX

    International Nuclear Information System (INIS)

    Gorelenkov, N.N.; Medley, S.S.

    2004-01-01

    Beam ion transport in the presence of low frequency MHD activity in National Spherical Tokamak Experiment (NSTX) plasma is modeled numerically and analyzed theoretically in order to understand basic underlying physical mechanisms responsible for the observed fast ion redistribution and losses. Numerical modeling of the beam ions flux into the NPA in NSTX shows that after the onset of low frequency MHD activity high energy part of beam ion distribution, E b > 40keV, is redistributed radially due to stochastic diffusion. Such diffusion is caused by high order harmonics of the transit frequency resonance overlap in the phase space. Large drift orbit radial width induces such high order resonances. Characteristic confinement time is deduced from the measured NPA energy spectrum and is typically ∼ 4msec. Considered MHD activity may induce losses on the order of 10% at the internal magnetic field perturbation (delta)B/B = Ο (10 -3 ), which is comparable to the prompt orbit losses

  9. Thermodynamic modeling of transcription: sensitivity analysis differentiates biological mechanism from mathematical model-induced effects.

    Science.gov (United States)

    Dresch, Jacqueline M; Liu, Xiaozhou; Arnosti, David N; Ay, Ahmet

    2010-10-24

    Quantitative models of gene expression generate parameter values that can shed light on biological features such as transcription factor activity, cooperativity, and local effects of repressors. An important element in such investigations is sensitivity analysis, which determines how strongly a model's output reacts to variations in parameter values. Parameters of low sensitivity may not be accurately estimated, leading to unwarranted conclusions. Low sensitivity may reflect the nature of the biological data, or it may be a result of the model structure. Here, we focus on the analysis of thermodynamic models, which have been used extensively to analyze gene transcription. Extracted parameter values have been interpreted biologically, but until now little attention has been given to parameter sensitivity in this context. We apply local and global sensitivity analyses to two recent transcriptional models to determine the sensitivity of individual parameters. We show that in one case, values for repressor efficiencies are very sensitive, while values for protein cooperativities are not, and provide insights on why these differential sensitivities stem from both biological effects and the structure of the applied models. In a second case, we demonstrate that parameters that were thought to prove the system's dependence on activator-activator cooperativity are relatively insensitive. We show that there are numerous parameter sets that do not satisfy the relationships proferred as the optimal solutions, indicating that structural differences between the two types of transcriptional enhancers analyzed may not be as simple as altered activator cooperativity. Our results emphasize the need for sensitivity analysis to examine model construction and forms of biological data used for modeling transcriptional processes, in order to determine the significance of estimated parameter values for thermodynamic models. Knowledge of parameter sensitivities can provide the necessary

  10. Cyr61/CCN1 induces CCL20 production by keratinocyte via activating p38 and JNK/AP-1 pathway in psoriasis.

    Science.gov (United States)

    Li, Huidan; Li, Haichuan; Huo, Rongfen; Wu, Pinru; Shen, Zhengyu; Xu, Hui; Shen, Baihua; Li, Ningli

    2017-10-01

    Psoriasis is a common chronic skin disease characterized by epidermal hyperplasia and inflammation. Cysteine-rich angiogenic inducer 61 (Cyr61/CCN1) has recently been implicated in psoriasis pathogenesis by promoting keratinocyte activation. However, the mechanisms by which CCN1 enhances cutaneous inflammation are not fully understood. In this study, we investigated the role of CCN1 on the expression of CCL20 in human keratinocyte. By double-label immunofluorescence staining, we first identified that the expression of CCN1 colocalized well with CCL20 production in the epidermis of psoriasis skin lesion. Furthermore, in vivo, blocking or knockdown CCN1 expression ameliorated skin inflammation and reduced the expression of CCL20 in both imiquimod and IL-23-induced psoriasis-like mouse models, which indicated that CCN1 might be involved in the regulation of CCL20 production in psoriasis. Next, in vitro, we stimulated primary normal human epidermal keratinocyte (NHEK) with exogenous protein CCN1 and found that CCN1 directly upregulated CCL20 production independent of TNF-α, IL-22 and IL-17 pathway. Lastly, the signaling pathway study showed that CCN1 enhanced the binding of AP-1 to the CCL20 promoter via crosstalk with p38 and JNK. Our study demonstrates that CCN1 stimulates CCL20 production in vitro and in vivo, and thus supports the notion that overexpressed CCN1 in hyperproliferating keratinocyte is functionally involved in the recruitment of inflammatory cells to skin lesions affected by psoriasis. Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

  11. The effect of montelukast in a model of gouty arthritis induced by sodium monourate crystals

    OpenAIRE

    Ponce, Loida; Arjona, Marjorie; Blanco, Gustavo; Alvarez, Stuart; Arcila, Eduardo; Ortega, Arnaldo; Nuñez, Dubelis; Verzura, Julie; Tovar, Robert; Bethencourt, Sarah; Riera, Ricardo; Mora-Orta, Sioly; Corado, José

    2011-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDS) are the first line of therapy in acute gouty arthritis. NSAIDs inhibit the cyclooxygenase pathway, but not the lipooxygenase activity and can have many adverse effects and thus have a limited effect on the control of inflammation in this disease. In this work we studied the effect of montelukast on the cellular inflammatory infiltrate in a model of murine arthritis induced by sodium monourate crystals (SMU), using a subcutaneous air cavity (air p...

  12. Nephroprotective effect of Corn Silk extract on oxalic acid-induced nephrocalcinosis in rabbit model

    OpenAIRE

    Faruk Hassan Al-Jawad; Rafi Abdul Majeed Al-Razzuqi; Zainab Awaen Al-Ebady; Thulfuqar Abdul Majeed Al-Razzuqi

    2012-01-01

    ABSTRACT Background : Nephrocalcinosis is a state of deposition of calcium phosphate or oxalate in the renal parenchyma. It may occur in patients with renal tubular acidosis, vitamin D intoxication, and hyperparathyroidism. Corn silk was used in traditional Chinese medicine to relieve renal pains. Aim: To evaluate the effect of Corn silk aqueous extract in reducing calcium deposits from renal parenchyma in oxalic acid-induced nephrocalcinosis model. Materials and methods: Fourteen healthy...

  13. Long-term characterization of the diet-induced obese and diet-resistant rat model

    DEFF Research Database (Denmark)

    Madsen, Andreas Nygaard; Hansen, Gitte; Paulsen, Sarah Juel

    2010-01-01

    , namely the selectively bred diet-induced obese (DIO) and diet-resistant (DR) rat strains. We show that they constitute useful models of the human obesity syndrome. DIO and DR rats were fed either a high-energy (HE) or a standard chow (Chow) diet from weaning to 9 months of age. Metabolic characterization......, the results underscore the effectiveness of GLP-1 mimetics both as anti-diabetes and anti-obesity agents....

  14. Simple quantal model for collision-induced dissociation: An Airy basis calculation

    International Nuclear Information System (INIS)

    Hunt, P.M.; Sridharan, S.

    1982-01-01

    New matrix elements for the Airy continuum basis are employed to find quantum mechanical dissociation probabilities for the the forced Morse oscillator. The calculations performed illustrate the ease with which the continuously infinite Airy basis can be manipulated, and they illustrate the transition from vibrational enhancement to vibrational inhibition of diatomic breakup. The forced Morse oscillator model thus reproduces the behavior of more complicated collinear collision-induced dissociation systems

  15. Noise-Induced Transition in a Voltage-Controlled Oscillator Neuron Model

    International Nuclear Information System (INIS)

    Xie Huizhang; Liu Xuemei; Li Zhibing; Ai Baoquan; Liu Lianggang

    2008-01-01

    In the presence of Gaussian white noise, we study the properties of voltage-controlled oscillator neuron model and discuss the effects of the additive and multiplicative noise. It is found that the additive noise can accelerate and counterwork the firing of neuron, which depends on the value of central frequency of neuron itself, while multiplicative noise can induce the continuous change or mutation of membrane potential

  16. Collective properties of injection-induced earthquake sequences: 1. Model description and directivity bias

    Science.gov (United States)

    Dempsey, David; Suckale, Jenny

    2016-05-01

    Induced seismicity is of increasing concern for oil and gas, geothermal, and carbon sequestration operations, with several M > 5 events triggered in recent years. Modeling plays an important role in understanding the causes of this seismicity and in constraining seismic hazard. Here we study the collective properties of induced earthquake sequences and the physics underpinning them. In this first paper of a two-part series, we focus on the directivity ratio, which quantifies whether fault rupture is dominated by one (unilateral) or two (bilateral) propagating fronts. In a second paper, we focus on the spatiotemporal and magnitude-frequency distributions of induced seismicity. We develop a model that couples a fracture mechanics description of 1-D fault rupture with fractal stress heterogeneity and the evolving pore pressure distribution around an injection well that triggers earthquakes. The extent of fault rupture is calculated from the equations of motion for two tips of an expanding crack centered at the earthquake hypocenter. Under tectonic loading conditions, our model exhibits a preference for unilateral rupture and a normal distribution of hypocenter locations, two features that are consistent with seismological observations. On the other hand, catalogs of induced events when injection occurs directly onto a fault exhibit a bias toward ruptures that propagate toward the injection well. This bias is due to relatively favorable conditions for rupture that exist within the high-pressure plume. The strength of the directivity bias depends on a number of factors including the style of pressure buildup, the proximity of the fault to failure and event magnitude. For injection off a fault that triggers earthquakes, the modeled directivity bias is small and may be too weak for practical detection. For two hypothetical injection scenarios, we estimate the number of earthquake observations required to detect directivity bias.

  17. Formation region and amplitude of colour superconductivity in an instanton-induced model

    CERN Document Server

    Liao Jin Feng

    2002-01-01

    Colour superconductivity is investigated in the frame of a two flavour instanton-induced model. The ratio of diquark to quark-antiquark coupling constants is restricted to be c/(N sub c -1) with 1 <=c <=2.87 and controls the formation region and amplitude of colour superconductivity. While the finite current quark mass changes the chiral transition significantly, it does not considerably change the colour superconductivity

  18. Solute induced relaxation in glassy polymers: Experimental measurements and nonequilibrium thermodynamic model

    International Nuclear Information System (INIS)

    Minelli, Matteo; Doghieri, Ferruccio

    2014-01-01

    Data for kinetics of mass uptake from vapor sorption experiments in thin glassy polymer samples are here interpreted in terms of relaxation times for volume dilation. To this result, both models from non-equilibrium thermodynamics and from mechanics of volume relaxation contribute. Different kind of sorption experiments have been considered in order to facilitate the direct comparison between kinetics of solute induced volume dilation and corresponding data from process driven by pressure or temperature jumps

  19. Abnormal muscle afferent function in a model of Taxol chemotherapy-induced painful neuropathy

    OpenAIRE

    Chen, Xiaojie; Green, Paul G.; Levine, Jon D.

    2011-01-01

    Despite muscle pain being a well-described symptom in patients with diverse forms of peripheral neuropathy, the role of neuropathic mechanisms in muscle pain have received remarkably little attention. We have recently demonstrated in a well-established model of chemotherapy-induced painful neuropathy (CIPN) that the anti-tumor drug paclitaxel (Taxol) produces mechanical hyperalgesia in skeletal muscle, of similar time course to and with shared mechanism with cutaneous symptoms. In the present...

  20. A two stream radiative transfer model for scaling solar induced fluorescence from leaf to canopy

    Science.gov (United States)

    Quaife, T. L.

    2017-12-01

    Solar induced fluorescence (SIF) is becoming widely used as a proxy for gross primary productivity (GPP), in particular with the advent of its measurement by Earth Observation satellites such as OCO and GOSAT. A major attraction of SIF is that it is independent of the assumptions embedded in light use efficiency based GPP products derived from satellite missions such as MODIS. The assumptions in such products are likely not compatible with any given land surface model and hence comparing the two is problematic. On the other hand to compare land surface model predictions of GPP to satellite based SIF data requires either (a) translation of SIF into estimates of GPP, or (b) direct predictions of SIF from the land surface model itself. The former typically relies on empirical relationships, whereas the latter can make direct use of our physiological understanding of the link between photosynthesis and fluorescence at the leaf scale and is therefore preferable. Here I derive a two stream model for fluorescence that is capable of translating between leaf scale models of SIF and the canopy leaving radiance taking into account all levels of photon scattering. Other such models have been developed previously but the model described here is physically consistent with the Sellers' two stream radiative transfer scheme which is widely used in modern land surface models. Consequently any model that already employs the Sellers's scheme can use the new model without requiring modification. This includes, for example, JULES, the land surface model of the new UK Earth System Model (UKESM) and CLM, the US Community Land Model (part of the NCAR Earth System Model). The new canopy SIF model is extremely computationally efficient and can be applied to vertically inhomogeneous canopies.

  1. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments.

    Science.gov (United States)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk. Copyright © 2016 The Committee on Space Research (COSPAR). Published by Elsevier Ltd. All rights reserved.

  2. Lessons learned using different mouse models during space radiation-induced lung tumorigenesis experiments

    Science.gov (United States)

    Wang, Jian; Zhang, Xiangming; Wang, Ping; Wang, Xiang; Farris, Alton B.; Wang, Ya

    2016-06-01

    Unlike terrestrial ionizing radiation, space radiation, especially galactic cosmic rays (GCR), contains high energy charged (HZE) particles with high linear energy transfer (LET). Due to a lack of epidemiologic data for high-LET radiation exposure, it is highly uncertain how high the carcinogenesis risk is for astronauts following exposure to space radiation during space missions. Therefore, using mouse models is necessary to evaluate the risk of space radiation-induced tumorigenesis; however, which mouse model is better for these studies remains uncertain. Since lung tumorigenesis is the leading cause of cancer death among both men and women, and low-LET radiation exposure increases human lung carcinogenesis, evaluating space radiation-induced lung tumorigenesis is critical to enable safe Mars missions. Here, by comparing lung tumorigenesis obtained from different mouse strains, as well as miR-21 in lung tissue/tumors and serum, we believe that wild type mice with a low spontaneous tumorigenesis background are ideal for evaluating the risk of space radiation-induced lung tumorigenesis, and circulating miR-21 from such mice model might be used as a biomarker for predicting the risk.

  3. A human model of dietary saturated fatty acid induced insulin resistance.

    Science.gov (United States)

    Koska, Juraj; Ozias, Marlies K; Deer, James; Kurtz, Julie; Salbe, Arline D; Harman, S Mitchell; Reaven, Peter D

    2016-11-01

    Increased consumption of high-fat diets is associated with the development of insulin resistance and type 2 diabetes. Current models to study the mechanisms of high-fat diet-induced IR in humans are limited by their long duration or low efficacy. In the present study we developed and characterized an acute dietary model of saturated fatty acid-enriched diet induced insulin resistance. High caloric diets enriched with saturated fatty acids (SFA) or carbohydrates (CARB) were evaluated in subjects with normal and impaired glucose tolerance (NGT or IGT). Both diets were compared to a standard eucaloric American Heart Association (AHA) control diet in a series of crossover studies. Whole body insulin resistance was estimated as steady state plasma glucose (SSPG) concentrations during the last 30min of a 3-h insulin suppression test. SSPG was increased after a 24-h SFA diet (by 83±74% vs. control, n=38) in the entire cohort, which was comprised of participants with NGT (92±82%, n=22) or IGT (65±55%, n=16) (all pinsulin resistance in both NGT and IGT subjects. Insulin resistance persisted overnight after the last SFA meal and was attenuated by one day of a healthy diet. This model offers opportunities for identifying early mechanisms and potential treatments of dietary saturated fat induced insulin resistance. Published by Elsevier Inc.

  4. Disease modeling and phenotypic drug screening for diabetic cardiomyopathy using human induced pluripotent stem cells.

    Science.gov (United States)

    Drawnel, Faye M; Boccardo, Stefano; Prummer, Michael; Delobel, Frédéric; Graff, Alexandra; Weber, Michael; Gérard, Régine; Badi, Laura; Kam-Thong, Tony; Bu, Lei; Jiang, Xin; Hoflack, Jean-Christophe; Kiialainen, Anna; Jeworutzki, Elena; Aoyama, Natsuyo; Carlson, Coby; Burcin, Mark; Gromo, Gianni; Boehringer, Markus; Stahlberg, Henning; Hall, Benjamin J; Magnone, Maria Chiara; Kolaja, Kyle; Chien, Kenneth R; Bailly, Jacques; Iacone, Roberto

    2014-11-06

    Diabetic cardiomyopathy is a complication of type 2 diabetes, with known contributions of lifestyle and genetics. We develop environmentally and genetically driven in vitro models of the condition using human-induced-pluripotent-stem-cell-derived cardiomyocytes. First, we mimic diabetic clinical chemistry to induce a phenotypic surrogate of diabetic cardiomyopathy, observing structural and functional disarray. Next, we consider genetic effects by deriving cardiomyocytes from two diabetic patients with variable disease progression. The cardiomyopathic phenotype is recapitulated in the patient-specific cells basally, with a severity dependent on their original clinical status. These models are incorporated into successive levels of a screening platform, identifying drugs that preserve cardiomyocyte phenotype in vitro during diabetic stress. In this work, we present a patient-specific induced pluripotent stem cell (iPSC) model of a complex metabolic condition, showing the power of this technique for discovery and testing of therapeutic strategies for a disease with ever-increasing clinical significance. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Residual stress behaviors induced by laser peening along the edge of curved models

    International Nuclear Information System (INIS)

    Im, Jong Bin; Grandhi, Ramana V.; Ro, Young Hee

    2012-01-01

    Laser peening (LP) induces high magnitude compressive residual stresses in a small region of a component. The compressive residual stresses cause plastic deformation that is resistant to fatigue fracture. Fatigue cracks are generally nucleated at critical areas, and LP is applied for those regions so as to delay the crack initiation. Many critical regions are located on the edge of the curved portion of structures because of stress concentration effects. Several investigations that are available for straight components may not give meaningful guidelines for peening curved components. Therefore, in this paper, we investigate residual stress behaviors induced by LP along the edge of curved models. Three curved models that have different curvatures are investigated for peening performance. Two types of peening configurations, which are simultaneous corner shot and sequential corner shots, are considered in order to obtain compressive residual stresses along an edge. LP simulations of multiple shots are performed to identify overlapping effects on the edge portion of a curved model. In addition, the uncertainty calculation of residual stress induced by LP considering laser pulse duration is performed

  6. Kainic Acid-Induced Excitotoxicity Experimental Model: Protective Merits of Natural Products and Plant Extracts

    Directory of Open Access Journals (Sweden)

    Nur Shafika Mohd Sairazi

    2015-01-01

    Full Text Available Excitotoxicity is well recognized as a major pathological process of neuronal death in neurodegenerative diseases involving the central nervous system (CNS. In the animal models of neurodegeneration, excitotoxicity is commonly induced experimentally by chemical convulsants, particularly kainic acid (KA. KA-induced excitotoxicity in rodent models has been shown to result in seizures, behavioral changes, oxidative stress, glial activation, inflammatory mediator production, endoplasmic reticulum stress, mitochondrial dysfunction, and selective neurodegeneration in the brain upon KA administration. Recently, there is an emerging trend to search for natural sources to combat against excitotoxicity-associated neurodegenerative diseases. Natural products and plant extracts had attracted a considerable amount of attention because of their reported beneficial effects on the CNS, particularly their neuroprotective effect against excitotoxicity. They provide significant reduction and/or protection against the development and progression of acute and chronic neurodegeneration. This indicates that natural products and plants extracts may be useful in protecting against excitotoxicity-associated neurodegeneration. Thus, targeting of multiple pathways simultaneously may be the strategy to maximize the neuroprotection effect. This review summarizes the mechanisms involved in KA-induced excitotoxicity and attempts to collate the various researches related to the protective effect of natural products and plant extracts in the KA model of neurodegeneration.

  7. Helicobacter pylori-induced gastric pathology: insights from in vivo and ex vivo models

    Directory of Open Access Journals (Sweden)

    Michael D. Burkitt

    2017-02-01

    Full Text Available Gastric colonization with Helicobacter pylori induces diverse human pathological conditions, including superficial gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue (MALT lymphoma, and gastric adenocarcinoma and its precursors. The treatment of these conditions often relies on the eradication of H. pylori, an intervention that is increasingly difficult to achieve and that does not prevent disease progression in some contexts. There is, therefore, a pressing need to develop new experimental models of H. pylori-associated gastric pathology to support novel drug development in this field. Here, we review the current status of in vivo and ex vivo models of gastric H. pylori colonization, and of Helicobacter-induced gastric pathology, focusing on models of gastric pathology induced by H. pylori, Helicobacter felis and Helicobacter suis in rodents and large animals. We also discuss the more recent development of gastric organoid cultures from murine and human gastric tissue, as well as from human pluripotent stem cells, and the outcomes of H. pylori infection in these systems.

  8. Developing better mouse models to study cisplatin-induced kidney injury.

    Science.gov (United States)

    Sharp, Cierra N; Siskind, Leah J

    2017-10-01

    Cisplatin is a potent chemotherapeutic used for the treatment of many types of cancer. However, its dose-limiting side effect is nephrotoxicity leading to acute kidney injury (AKI). Patients who develop AKI have an increased risk of mortality and are more likely to develop chronic kidney disease (CKD). Unfortunately, there are no therapeutic interventions for the treatment of AKI. It has been suggested that the lack of therapies is due in part to the fact that the established mouse model used to study cisplatin-induced AKI does not recapitulate the cisplatin dosing regimen patients receive. In recent years, work has been done to develop more clinically relevant models of cisplatin-induced kidney injury, with much work focusing on incorporation of multiple low doses of cisplatin administered over a period of weeks. These models can be used to recapitulate the development of CKD after AKI and, by doing so, increase the likelihood of identifying novel therapeutic targets for the treatment of cisplatin-induced kidney injury. Copyright © 2017 the American Physiological Society.

  9. Modelling of liquid sodium induced crack propagation in T91 martensitic steel: Competition with ductile fracture

    Energy Technology Data Exchange (ETDEWEB)

    Hemery, Samuel [Institut PPRIME, CNRS, Université de Poitiers, ISAE ENSMA, UPR 3346, Téléport 2, 1 Avenue Clément Ader, BP 40109, 86961 Futuroscope Chasseneuil Cedex (France); Berdin, Clotilde, E-mail: clotilde.berdin@u-psud.fr [Univ Paris-Sud, SP2M-ICMMO, CNRS UMR 8182, F-91405 Orsay Cedex (France); Auger, Thierry; Bourhi, Mariem [Ecole Centrale-Supelec, MSSMat CNRS UMR 8579, F-92295 Chatenay Malabry Cedex (France)

    2016-12-01

    Liquid metal embrittlement (LME) of T91 steel is numerically modeled by the finite element method to analyse experimental results in an axisymmetric notched geometry. The behavior of the material is identified from tensile tests then a crack with a constant crack velocity is introduced using the node release technique in order to simulate the brittle crack induced by LME. A good agreement between the simulated and the experimental macroscopic behavior is found: this suggests that the assumption of a constant crack velocity is correct. Mechanical fields during the embrittlement process are then extracted from the results of the finite element model. An analysis of the crack initiation and propagation stages: the ductile fracture probably breaks off the LME induced brittle fracture. - Highlights: • T91 martensitic steel is embrittled by liquid sodium depending on the loading rate at 573 K. • The mechanical behavior is modeled by a von Mises elastic-plastic law. • The LME induced crack propagates at a constant velocity. • The mechanical state at the crack tip does not explain a brittle crack arrest. • The occurrence of the ductile fracture breaks off the brittle fracture.

  10. Disease Modeling and Phenotypic Drug Screening for Diabetic Cardiomyopathy using Human Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Faye M. Drawnel

    2014-11-01

    Full Text Available Diabetic cardiomyopathy is a complication of type 2 diabetes, with known contributions of lifestyle and genetics. We develop environmentally and genetically driven in vitro models of the condition using human-induced-pluripotent-stem-cell-derived cardiomyocytes. First, we mimic diabetic clinical chemistry to induce a phenotypic surrogate of diabetic cardiomyopathy, observing structural and functional disarray. Next, we consider genetic effects by deriving cardiomyocytes from two diabetic patients with variable disease progression. The cardiomyopathic phenotype is recapitulated in the patient-specific cells basally, with a severity dependent on their original clinical status. These models are incorporated into successive levels of a screening platform, identifying drugs that preserve cardiomyocyte phenotype in vitro during diabetic stress. In this work, we present a patient-specific induced pluripotent stem cell (iPSC model of a complex metabolic condition, showing the power of this technique for discovery and testing of therapeutic strategies for a disease with ever-increasing clinical significance.

  11. Modelling chelate-Induced phytoextraction: functional models predicting bioavailability of metals in soil, metal uptake and shoot biomass

    Directory of Open Access Journals (Sweden)

    Pasqualina Sacco

    Full Text Available Chelate-induced phytoextraction of heavy metals from contaminated soils requires special care to determine, a priori, the best method of chelate application, in terms of both dose and timing. In fact, the chelate dose must assure the bioavailability of the metal to the plant without increasing leaching risk and giving toxic effects. Three mathematical models are here proposed for usefully interpreting the processes taking place: a increased soil bioavailability of metals by chelants; b metal uptake by plants; c variation in plant biomass. The models are implemented and validated using data from pot and lysimeter trials. Both the chelate dose and the time elapsed since its application affected metal bioavailability and plant response. Contrariwise, the distribution strategy (single vs. split application seems to produce significant differences both in plant growth and metal uptake, but not in soil metal bioavailability. The proposed models may help to understand and predict the chelate dose – effect relationship with less experimental work.

  12. Modelling chelate-Induced phytoextraction: functional models predicting bioavailability of metals in soil, metal uptake and shoot biomass

    Directory of Open Access Journals (Sweden)

    Pasqualina Sacco

    2006-06-01

    Full Text Available Chelate-induced phytoextraction of heavy metals from contaminated soils requires special care to determine, a priori, the best method of chelate application, in terms of both dose and timing. In fact, the chelate dose must assure the bioavailability of the metal to the plant without increasing leaching risk and giving toxic effects. Three mathematical models are here proposed for usefully interpreting the processes taking place: a increased soil bioavailability of metals by chelants; b metal uptake by plants; c variation in plant biomass. The models are implemented and validated using data from pot and lysimeter trials. Both the chelate dose and the time elapsed since its application affected metal bioavailability and plant response. Contrariwise, the distribution strategy (single vs. split application seems to produce significant differences both in plant growth and metal uptake, but not in soil metal bioavailability. The proposed models may help to understand and predict the chelate dose – effect relationship with less experimental work.

  13. Computational fluid-dynamic model of laser-induced breakdown in air

    International Nuclear Information System (INIS)

    Dors, Ivan G.; Parigger, Christian G.

    2003-01-01

    Temperature and pressure profiles are computed by the use of a two-dimensional, axially symmetric, time-accurate computational fluid-dynamic model for nominal 10-ns optical breakdown laser pulses. The computational model includes a kinetics mechanism that implements plasma equilibrium kinetics in ionized regions and nonequilibrium, multistep, finite-rate reactions in nonionized regions. Fluid-physics phenomena following laser-induced breakdown are recorded with high-speed shadowgraph techniques. The predicted fluid phenomena are shown by direct comparison with experimental records to agree with the flow patterns that are characteristic of laser spark decay

  14. Microdose Induced Drain Leakage Effects in Power Trench MOSFETs: Experiment and Modeling

    Science.gov (United States)

    Zebrev, Gennady I.; Vatuev, Alexander S.; Useinov, Rustem G.; Emeliyanov, Vladimir V.; Anashin, Vasily S.; Gorbunov, Maxim S.; Turin, Valentin O.; Yesenkov, Kirill A.

    2014-08-01

    We study experimentally and theoretically the micro-dose induced drain-source leakage current in the trench power MOSFETs under irradiation with high-LET heavy ions. We found experimentally that cumulative increase of leakage current occurs by means of stochastic spikes corresponding to a strike of single heavy ion into the MOSFET gate oxide. We simulate this effect with the proposed analytic model allowing to describe (including Monte Carlo methods) both the deterministic (cumulative dose) and stochastic (single event) aspects of the problem. Based on this model the survival probability assessment in space heavy ion environment with high LETs was proposed.

  15. Computational models to determine fluiddynamical transients due to condensation induced water hammer (CIWH)

    International Nuclear Information System (INIS)

    Swidersky, Harald; Schaffrath, Andreas; Dudlik, Andreas

    2012-01-01

    Condensation induced water hammer ('condensation hammer', CIWH) represent a dangerous phenomenon in pipings, which can endanger the pipe integrity. If they cannot be excluded, they have to be taken into account for the integrity proof of components and pipe structures. Up to now, there exists no substantiated model, which sufficiently determines loads due to CIWH. Within the framework of the research alliance CIWA, a tool for estimating the potential and the amount of pressure loads will be developed based on theoretical work and supported by experimental results. This first study discusses used computational models, results of experimental observations and gives an outlook onto future techniques. (orig.)

  16. Computational models to determine fluid dynamical transients due to condensation induced water hammer (CIWH)

    International Nuclear Information System (INIS)

    Swidersky, H.; Schaffrath, A.; Dudlik, A.

    2011-01-01

    Condensation induced water hammer (CIWH) represent a dangerous phenomenon in pipings, which can endanger the pipe integrity. If they cannot be excluded, they have to be taken into account for the integrity proof of components and pipe structures. Up to now, there exists no substantiated model, which sufficiently determines loads due to CIWH. Within the framework of the research alliance CIWA, a tool for estimating the potential and the amount of pressure loads will be developed based on theoretical work and supported by experimental results. This first study discusses used computational models, compares their results against experimental observations and gives an outlook onto future techniques. (author)

  17. Mathematical model for cross-flow-induced vibrations of tube rows

    International Nuclear Information System (INIS)

    Chen, S.S.

    1976-09-01

    A mathematical model for flow-induced vibrations in heat exchanger tube banks is presented which includes the effects of vortex shedding, fluidelastic coupling, drag force, and fluid inertia coupling. Once the fluid forces are known, the model can predict the details of complex tube-fluid interactions: (1) natural frequencies and mode shapes of coupled vibrations; (2) critical flow velocities; (3) responses to vortex shedding, drag force, and other types of excitations; and (4) the dominant excitation mechanism at a given flow velocity. The analytical results are in good agreement with the published experimental results

  18. EG-VEGF Maintenance Over Early Gestation to Develop a Pregnancy-Induced Hypertensive Animal Model.

    Science.gov (United States)

    Reynaud, Déborah; Sergent, Frédéric; Abi Nahed, Roland; Brouillet, Sophie; Benharouga, Mohamed; Alfaidy, Nadia

    2018-01-01

    During the last decade, multiple animal models have been developed to mimic hallmarks of pregnancy-induced hypertension (PIH) diseases, which include gestational hypertension, preeclampsia (PE), or eclampsia. Converging in vitro, ex vivo, and clinical studies from our group strongly suggested the potential involvement of the new angiogenic factor EG-VEGF (endocrine gland-derived-VEGF) in the development of PIH. Here, we described the protocol that served to demonstrate that maintenance of EG-VEGF production over 11.5 days post coitus (dpc) in the gravid mice caused the development of PIH. The developed model exhibited most hallmarks of preeclampsia.

  19. DART model for irradiation-induced swelling of dispersion fuel elements including aluminum-fuel interaction

    International Nuclear Information System (INIS)

    Rest, J.; Hofman, G.L.

    1997-01-01

    The Dispersion Analysis Research Tool (DART) contains models for fission-gas-induced fuel swelling, interaction of fuel with the matrix aluminum, for the resultant reaction-product swelling, and for the calculation of the stress gradient within the fuel particle. The effects of an aluminide shell on fuel particle swelling are evaluated. Validation of the model is demonstrated by a comparison of DART calculations of fuel swelling of U 3 SiAl-Al and U 3 Si 2 -Al for various dispersion fuel element designs with the data

  20. Kinetic model for electric-field induced point defect redistribution near semiconductor surfaces

    Science.gov (United States)

    Gorai, Prashun; Seebauer, Edmund G.

    2014-07-01

    The spatial distribution of point defects near semiconductor surfaces affects the efficiency of devices. Near-surface band bending generates electric fields that influence the spatial redistribution of charged mobile defects that exchange infrequently with the lattice, as recently demonstrated for pile-up of isotopic oxygen near rutile TiO2 (110). The present work derives a mathematical model to describe such redistribution and establishes its temporal dependence on defect injection rate and band bending. The model shows that band bending of only a few meV induces significant redistribution, and that the direction of the electric field governs formation of either a valley or a pile-up.

  1. Kinetic model for electric-field induced point defect redistribution near semiconductor surfaces

    International Nuclear Information System (INIS)

    Gorai, Prashun; Seebauer, Edmund G.

    2014-01-01

    The spatial distribution of point defects near semiconductor surfaces affects the efficiency of devices. Near-surface band bending generates electric fields that influence the spatial redistribution of charged mobile defects that exchange infrequently with the lattice, as recently demonstrated for pile-up of isotopic oxygen near rutile TiO 2 (110). The present work derives a mathematical model to describe such redistribution and establishes its temporal dependence on defect injection rate and band bending. The model shows that band bending of only a few meV induces significant redistribution, and that the direction of the electric field governs formation of either a valley or a pile-up.

  2. The gut microbiota influence behavior in the subchronic PCP induced animal model of schizophrenia

    DEFF Research Database (Denmark)

    Jørgensen, Bettina Merete Pyndt; Redrobe, Paul; Brønnum Pedersen, Tina

    The gut microbiota has major impact on the individual. Here we show that the gut microbiota influence behavior in the subchronic PCP induced animal model of schizophrenia. The gut microbiota were changed in the group treated subchronic with PCP, and restoration coincided with normalisation...... of memory performance in lister hooded rats. Furthermore the individual gut microbiota correlated to the individual behavior abserved in the tests conducted. In conclusion results show an influence of the gut microbiota on behavior in this model, and therefore it might be relavant to include the information...

  3. Effect of sex in the MRMT-1 model of cancer-induced bone pain

    DEFF Research Database (Denmark)

    Falk, Sarah; Al-Dihaissy, Tamara; Mezzanotte, Laura

    2015-01-01

    An overwhelming amount of evidence demonstrates sex-induced variation in pain processing, and has thus increased the focus on sex as an essential parameter for optimization of in vivo models in pain research. Mammary cancer cells are often used to model metastatic bone pain in vivo......, and are commonly used in both males and females. Here we demonstrate that compared to male rats, female rats have an increased capacity for recovery following inoculation of MRMT-1 mammary cells, thus potentially causing a sex-dependent bias in interpretation of the data....

  4. A 3-dimensional in vitro model of epithelioid granulomas induced by high aspect ratio nanomaterials

    Directory of Open Access Journals (Sweden)

    Hurt Robert H

    2011-05-01

    Full Text Available Abstract Background The most common causes of granulomatous inflammation are persistent pathogens and poorly-degradable irritating materials. A characteristic pathological reaction to intratracheal instillation, pharyngeal aspiration, or inhalation of carbon nanotubes is formation of epithelioid granulomas accompanied by interstitial fibrosis in the lungs. In the mesothelium, a similar response is induced by high aspect ratio nanomaterials, including asbestos fibers, following intraperitoneal injection. This asbestos-like behaviour of some engineered nanomaterials is a concern for their potential adverse health effects in the lungs and mesothelium. We hypothesize that high aspect ratio nanomaterials will induce epithelioid granulomas in nonadherent macrophages in 3D cultures. Results Carbon black particles (Printex 90 and crocidolite asbestos fibers were used as well-characterized reference materials and compared with three commercial samples of multiwalled carbon nanotubes (MWCNTs. Doses were identified in 2D and 3D cultures in order to minimize acute toxicity and to reflect realistic occupational exposures in humans and in previous inhalation studies in rodents. Under serum-free conditions, exposure of nonadherent primary murine bone marrow-derived macrophages to 0.5 μg/ml (0.38 μg/cm2 of crocidolite asbestos fibers or MWCNTs, but not carbon black, induced macrophage differentiation into epithelioid cells and formation of stable aggregates with the characteristic morphology of granulomas. Formation of multinucleated giant cells was also induced by asbestos fibers or MWCNTs in this 3D in vitro model. After 7-14 days, macrophages exposed to high aspect ratio nanomaterials co-expressed proinflammatory (M1 as well as profibrotic (M2 phenotypic markers. Conclusions Induction of epithelioid granulomas appears to correlate with high aspect ratio and complex 3D structure of carbon nanotubes, not with their iron content or surface area. This model

  5. Faslodex inhibits estradiol-induced extracellular matrix dynamics and lung metastasis in a model of lymphangioleiomyomatosis.

    Science.gov (United States)

    Li, Chenggang; Zhou, Xiaobo; Sun, Yang; Zhang, Erik; Mancini, John D; Parkhitko, Andrey; Morrison, Tasha A; Silverman, Edwin K; Henske, Elizabeth P; Yu, Jane J

    2013-07-01

    Lymphangioleiomyomatosis (LAM) is a destructive lung disease primarily affecting women. Genetic studies indicate that LAM cells carry inactivating tuberous sclerosis complex (TSC)-2 mutations, and metastasize to the lung. We previously discovered that estradiol increases the metastasis of TSC2-deficient cells in mice carrying xenograft tumors. Here, we investigate the molecular basis underlying the estradiol-induced lung metastasis of TSC2-deficient cells, and test the efficacy of Faslodex (an estrogen receptor antagonist) in a preclinical model of LAM. We used a xenograft tumor model in which estradiol induces the lung metastasis of TSC2-deficient cells. We analyzed the impact of Faslodex on tumor size, the extracellular matrix organization, the expression of matrix metalloproteinase (MMP)-2, and lung metastasis. We also examined the effects of estradiol and Faslodex on MMP2 expression and activity in tuberin-deficient cells in vitro. Estradiol resulted in a marked reduction of Type IV collagen deposition in xenograft tumors, associated with 2-fold greater MMP2 concentrations compared with placebo-treated mice. Faslodex normalized the Type IV collagen changes in xenograft tumors, enhanced the survival of the mice, and completely blocked lung metastases. In vitro, estradiol enhanced MMP2 transcripts, protein accumulation, and activity. These estradiol-induced changes in MMP2 were blocked by Faslodex. In TSC2-deficient cells, estradiol increased MMP2 concentrations in vitro and in vivo, and induced extracellular matrix remodeling. Faslodex inhibits the estradiol-induced lung metastasis of TSC2-deficient cells. Targeting estrogen receptors with Faslodex may be of efficacy in the treatment of LAM.

  6. Inhibition of STAT3 activity delays obesity-induced thyroid carcinogenesis in a mouse model

    Science.gov (United States)

    Park, Jeong Won; Han, Cho Rong; Zhao, Li; Willingham, Mark C.; Cheng, Sheue-yann

    2015-01-01

    Compelling epidemiologic studies indicate that obesity is a risk factor for many human cancers, including thyroid cancer. In recent decades, the incidence of thyroid cancer has dramatically increased along with a marked rise in obesity prevalence. We previously demonstrated that a high fat diet (HFD) effectively induced the obese phenotype in a mouse model of thyroid cancer (ThrbPV/PVPten+/− mice). Moreover, HFD activates the STAT3 signal pathway to promote more aggressive tumor phenotypes. The aim of the present study was to evaluate the effect of S3I-201, a specific inhibitor of STAT3 activity, on HFD-induced aggressive cancer progression in the mouse model of thyroid cancer. Wild type and ThrbPV/PVPten+/− mice were treated with HFD together with S3I-201 or vehicle-only as controls. We assessed the effects of S3I-201 on HFD-induced thyroid cancer progression, the leptin-JAK2-STAT3 signaling pathway, and key regulators of epithelial-mesenchymal transition. S3I-201 effectively inhibited HFD-induced aberrant activation of STAT3 and its downstream targets to markedly inhibit thyroid tumor growth and to prolong survival. Decreased protein levels of cyclins D1 and B1, cyclin dependent kinase (CDK) 4, CDK 6, and phosphorylated retinoblastoma protein led to the inhibition of tumor cell proliferation in S3I-201-treated ThrbPV/PVPten+/− mice. Reduced occurrence of vascular invasion and blocking of anaplasia and lung metastasis in thyroid tumors of S3I-201-treated ThrbPV/PVPten+/− mice were mediated via decreased expression of vimentin and matrix metalloproteinases, two key effectors of epithelial-mesenchymal transition. The present findings suggest that inhibition of the STAT3 activity would be a novel treatment strategy for obesity-induced thyroid cancer. PMID:26552408

  7. Faslodex Inhibits Estradiol-Induced Extracellular Matrix Dynamics and Lung Metastasis in a Model of Lymphangioleiomyomatosis

    Science.gov (United States)

    Li, Chenggang; Zhou, Xiaobo; Sun, Yang; Zhang, Erik; Mancini, John D.; Parkhitko, Andrey; Morrison, Tasha A.; Silverman, Edwin K.; Henske, Elizabeth P.

    2013-01-01

    Lymphangioleiomyomatosis (LAM) is a destructive lung disease primarily affecting women. Genetic studies indicate that LAM cells carry inactivating tuberous sclerosis complex (TSC)–2 mutations, and metastasize to the lung. We previously discovered that estradiol increases the metastasis of TSC2-deficient cells in mice carrying xenograft tumors. Here, we investigate the molecular basis underlying the estradiol-induced lung metastasis of TSC2-deficient cells, and test the efficacy of Faslodex (an estrogen receptor antagonist) in a preclinical model of LAM. We used a xenograft tumor model in which estradiol induces the lung metastasis of TSC2-deficient cells. We analyzed the impact of Faslodex on tumor size, the extracellular matrix organization, the expression of matrix metalloproteinase (MMP)–2, and lung metastasis. We also examined the effects of estradiol and Faslodex on MMP2 expression and activity in tuberin-deficient cells in vitro. Estradiol resulted in a marked reduction of Type IV collagen deposition in xenograft tumors, associated with 2-fold greater MMP2 concentrations compared with placebo-treated mice. Faslodex normalized the Type IV collagen changes in xenograft tumors, enhanced the survival of the mice, and completely blocked lung metastases. In vitro, estradiol enhanced MMP2 transcripts, protein accumulation, and activity. These estradiol-induced changes in MMP2 were blocked by Faslodex. In TSC2-deficient cells, estradiol increased MMP2 concentrations in vitro and in vivo, and induced extracellular matrix remodeling. Faslodex inhibits the estradiol-induced lung metastasis of TSC2-deficient cells. Targeting estrogen receptors with Faslodex may be of efficacy in the treatment of LAM. PMID:23526212

  8. Nicotine Prevents and Reverses Paclitaxel-Induced Mechanical Allodynia in a Mouse Model of CIPN.

    Science.gov (United States)

    Kyte, S Lauren; Toma, Wisam; Bagdas, Deniz; Meade, Julie A; Schurman, Lesley D; Lichtman, Aron H; Chen, Zhi-Jian; Del Fabbro, Egidio; Fang, Xianjun; Bigbee, John W; Damaj, M Imad; Gewirtz, David A

    2018-01-01

    Chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration, continues to be a dose-limiting and debilitating side effect during and/or after cancer chemotherapy. Paclitaxel, a taxane commonly used to treat breast, lung, and ovarian cancers, causes CIPN in 59-78% of cancer patients. Novel interventions are needed due to the current lack of effective CIPN treatments. Our studies were designed to investigate whether nicotine can prevent and/or reverse paclitaxel-induced peripheral neuropathy in a mouse model of CIPN, while ensuring that nicotine will not stimulate lung tumor cell proliferation or interfere with the antitumor properties of paclitaxel. Male C57BL/6J mice received paclitaxel every other day for a total of four injections (8 mg/kg, i.p.). Acute (0.3-0.9 mg/kg, i.p.) and chronic (24 mg/kg per day, s.c.) administration of nicotine respectively reversed and prevented paclitaxel-induced mechanical allodynia. Blockade of the antinociceptive effect of nicotine with mecamylamine and methyllycaconitine suggests that the reversal of paclitaxel-induced mechanical allodynia is primarily mediated by the α 7 nicotinic acetylcholine receptor subtype. Chronic nicotine treatment also prevented paclitaxel-induced intraepidermal nerve fiber loss. Notably, nicotine neither promoted proliferation of A549 and H460 non-small cell lung cancer cells nor interfered with paclitaxel-induced antitumor effects, including apoptosis. Most importantly, chronic nicotine administration did not enhance Lewis lung carcinoma tumor growth in C57BL/6J mice. These data suggest that the nicotinic acetylcholine receptor-mediated pathways may be promising drug targets for the prevention and treatment of CIPN. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  9. Modeling quiescent phase transport of air bubbles induced by breaking waves

    Science.gov (United States)

    Shi, Fengyan; Kirby, James T.; Ma, Gangfeng

    Simultaneous modeling of both the acoustic phase and quiescent phase of breaking wave-induced air bubbles involves a large range of length scales from microns to meters and time scales from milliseconds to seconds, and thus is computational unaffordable in a surfzone-scale computational domain. In this study, we use an air bubble entrainment formula in a two-fluid model to predict air bubble evolution in the quiescent phase in a breaking wave event. The breaking wave-induced air bubble entrainment is formulated by connecting the shear production at the air-water interface and the bubble number intensity with a certain bubble size spectra observed in laboratory experiments. A two-fluid model is developed based on the partial differential equations of the gas-liquid mixture phase and the continuum bubble phase, which has multiple size bubble groups representing a polydisperse bubble population. An enhanced 2-DV VOF (Volume of Fluid) model with a k - ɛ turbulence closure is used to model the mixture phase. The bubble phase is governed by the advection-diffusion equations of the gas molar concentration and bubble intensity for groups of bubbles with different sizes. The model is used to simulate air bubble plumes measured in laboratory experiments. Numerical results indicate that, with an appropriate parameter in the air entrainment formula, the model is able to predict the main features of bubbly flows as evidenced by reasonable agreement with measured void fraction. Bubbles larger than an intermediate radius of O(1 mm) make a major contribution to void fraction in the near-crest region. Smaller bubbles tend to penetrate deeper and stay longer in the water column, resulting in significant contribution to the cross-sectional area of the bubble cloud. An underprediction of void fraction is found at the beginning of wave breaking when large air pockets take place. The core region of high void fraction predicted by the model is dislocated due to use of the shear

  10. Evaluation of performance of distributed delay model for chemotherapy-induced myelosuppression.

    Science.gov (United States)

    Krzyzanski, Wojciech; Hu, Shuhua; Dunlavey, Michael

    2018-04-01

    The distributed delay model has been introduced that replaces the transit compartments in the classic model of chemotherapy-induced myelosuppression with a convolution integral. The maturation of granulocyte precursors in the bone marrow is described by the gamma probability density function with the shape parameter (ν). If ν is a positive integer, the distributed delay model coincides with the classic model with ν transit compartments. The purpose of this work was to evaluate performance of the distributed delay model with particular focus on model deterministic identifiability in the presence of the shape parameter. The classic model served as a reference for comparison. Previously published white blood cell (WBC) count data in rats receiving bolus doses of 5-fluorouracil were fitted by both models. The negative two log-likelihood objective function (-2LL) and running times were used as major markers of performance. Local sensitivity analysis was done to evaluate the impact of ν on the pharmacodynamics response WBC. The ν estimate was 1.46 with 16.1% CV% compared to ν = 3 for the classic model. The difference of 6.78 in - 2LL between classic model and the distributed delay model implied that the latter performed significantly better than former according to the log-likelihood ratio test (P = 0.009), although the overall performance was modestly better. The running times were 1 s and 66.2 min, respectively. The long running time of the distributed delay model was attributed to computationally intensive evaluation of the convolution integral. The sensitivity analysis revealed that ν strongly influences the WBC response by controlling cell proliferation and elimination of WBCs from the circulation. In conclusion, the distributed delay model was deterministically identifiable from typical cytotoxic data. Its performance was modestly better than the classic model with significantly longer running time.

  11. Low-dose ionizing radiation alleviates Aβ42-induced defective phenotypes in Drosophila Alzheimer's disease models

    International Nuclear Information System (INIS)

    Hwang, SooJin; Jeong, Hae Min; Nam, Seon Young

    2017-01-01

    Alzheimer's disease (AD) is the most common neurodegenerative disease that is characterized by amyloid plaques, progressive neuronal loss, and gradual deterioration of memory. Amyloid imaging using positron emission tomography (PET) radiotracers have been developed and approved for clinical use in the evaluation of suspected neurodegenerative disease, including AD. Particularly, previous studies involving low-dose ionizing radiation on Aβ 42-treated mouse hippocampal neurons have suggested a potential role for low-dose ionizing radiation in the treatment of AD. However, associated in vivo studies involving the therapy effects of low-dose ionizing radiation on AD are still insufficient. As a powerful cell biological system, Drosophila AD models have been generated and established a useful model organism for study on the etiology of human AD. In this study, we investigated the hormesis effects of low-dose ionizing radiation on Drosophila AD models. Our results suggest that low-dose ionizing radiation have the beneficial effects on not only the Aβ42-induced developmental defective phenotypes but also motor defects in Drosophila AD models. These results might be due to a regulation of apoptosis, and provide insight into the hormesis effects of low-dose ionizing radiation. Our results suggest that low-dose ionizing radiation have the beneficial effects on not only the Aβ42-induced developmental defective phenotypes but also motor defects in Drosophila AD models. These results might be due to a regulation of apoptosis, and provide insight into the hormesis effects of low-dose ionizing radiation.

  12. Membrane-elasticity model of Coatless vesicle budding induced by ESCRT complexes.

    Directory of Open Access Journals (Sweden)

    Bartosz Różycki

    Full Text Available The formation of vesicles is essential for many biological processes, in particular for the trafficking of membrane proteins within cells. The Endosomal Sorting Complex Required for Transport (ESCRT directs membrane budding away from the cytosol. Unlike other vesicle formation pathways, the ESCRT-mediated budding occurs without a protein coat. Here, we propose a minimal model of ESCRT-induced vesicle budding. Our model is based on recent experimental observations from direct fluorescence microscopy imaging that show ESCRT proteins colocalized only in the neck region of membrane buds. The model, cast in the framework of membrane elasticity theory, reproduces the experimentally observed vesicle morphologies with physically meaningful parameters. In this parameter range, the minimum energy configurations of the membrane are coatless buds with ESCRTs localized in the bud neck, consistent with experiment. The minimum energy configurations agree with those seen in the fluorescence images, with respect to both bud shapes and ESCRT protein localization. On the basis of our model, we identify distinct mechanistic pathways for the ESCRT-mediated budding process. The bud size is determined by membrane material parameters, explaining the narrow yet different bud size distributions in vitro and in vivo. Our membrane elasticity model thus sheds light on the energetics and possible mechanisms of ESCRT-induced membrane budding.

  13. Forecasting Induced Seismicity Using Saltwater Disposal Data and a Hydromechanical Earthquake Nucleation Model

    Science.gov (United States)

    Norbeck, J. H.; Rubinstein, J. L.

    2017-12-01

    The earthquake activity in Oklahoma and Kansas that began in 2008 reflects the most widespread instance of induced seismicity observed to date. In this work, we demonstrate that the basement fault stressing conditions that drive seismicity rate evolution are related directly to the operational history of 958 saltwater disposal wells completed in the Arbuckle aquifer. We developed a fluid pressurization model based on the assumption that pressure changes are dominated by reservoir compressibility effects. Using injection well data, we established a detailed description of the temporal and spatial variability in stressing conditions over the 21.5-year period from January 1995 through June 2017. With this stressing history, we applied a numerical model based on rate-and-state friction theory to generate seismicity rate forecasts across a broad range of spatial scales. The model replicated the onset of seismicity, the timing of the peak seismicity rate, and the reduction in seismicity following decreased disposal activity. The behavior of the induced earthquake sequence was consistent with the prediction from rate-and-state theory that the system evolves toward a steady seismicity rate depending on the ratio between the current and background stressing rates. Seismicity rate transients occurred over characteristic timescales inversely proportional to stressing rate. We found that our hydromechanical earthquake rate model outperformed observational and empirical forecast models for one-year forecast durations over the period 2008 through 2016.

  14. Orofacial neuropathic pain mouse model induced by Trigeminal Inflammatory Compression (TIC of the infraorbital nerve

    Directory of Open Access Journals (Sweden)

    Ma Fei

    2012-12-01

    Full Text Available Abstract Background Trigeminal neuropathic pain attacks can be excruciating for patients, even after being lightly touched. Although there are rodent trigeminal nerve research models to study orofacial pain, few models have been applied to studies in mice. A mouse trigeminal inflammatory compression (TIC model is introduced here which successfully and reliably promotes vibrissal whisker pad hypersensitivity. Results The chronic orofacial neuropathic pain model is induced after surgical placement of chromic gut suture in the infraorbital nerve fissure in the maxillary bone. Slight compression and chemical effects of the chromic gut suture on the portion of the infraorbital nerve contacted cause mild nerve trauma. Nerve edema is observed in the contacting infraorbital nerve bundle as well as macrophage infiltration in the trigeminal ganglia. Centrally in the spinal trigeminal nucleus, increased immunoreactivity for an activated microglial marker is evident (OX42, postoperative day 70. Mechanical thresholds of the affected whisker pad are significantly decreased on day 3 after chromic gut suture placement, persisting at least 10 weeks. The mechanical allodynia is reversed by suppression of microglial activation. Cold allodynia was detected at 4 weeks. Conclusions A simple, effective, and reproducible chronic mouse model mimicking clinical orofacial neuropathic pain (Type 2 is induced by placing chromic gut suture between the infraorbital nerve and the maxillary bone. The method produces mild inflammatory compression with significant continuous mechanical allodynia persisting at least 10 weeks and cold allodynia measureable at 4 weeks.

  15. Volcano and ship tracks indicate excessive aerosol-induced cloud water increases in a climate model.

    Science.gov (United States)

    Toll, Velle; Christensen, Matthew; Gassó, Santiago; Bellouin, Nicolas

    2017-12-28

    Aerosol-cloud interaction is the most uncertain mechanism of anthropogenic radiative forcing of Earth's climate, and aerosol-induced cloud water changes are particularly poorly constrained in climate models. By combining satellite retrievals of volcano and ship tracks in stratocumulus clouds, we compile a unique observational dataset and confirm that liquid water path (LWP) responses to aerosols are bidirectional, and on average the increases in LWP are closely compensated by the decreases. Moreover, the meteorological parameters controlling the LWP responses are strikingly similar between the volcano and ship tracks. In stark contrast to observations, there are substantial unidirectional increases in LWP in the Hadley Centre climate model, because the model accounts only for the decreased precipitation efficiency and not for the enhanced entrainment drying. If the LWP increases in the model were compensated by the decreases as the observations suggest, its indirect aerosol radiative forcing in stratocumulus regions would decrease by 45%.

  16. Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond.

    Science.gov (United States)

    Liu, Chun; Oikonomopoulos, Angelos; Sayed, Nazish; Wu, Joseph C

    2018-03-08

    The advent of human induced pluripotent stem cells (iPSCs) presents unprecedented opportunities to model human diseases. Differentiated cells derived from iPSCs in two-dimensional (2D) monolayers have proven to be a relatively simple tool for exploring disease pathogenesis and underlying mechanisms. In this Spotlight article, we discuss the progress and limitations of the current 2D iPSC disease-modeling platform, as well as recent advancements in the development of human iPSC models that mimic in vivo tissues and organs at the three-dimensional (3D) level. Recent bioengineering approaches have begun to combine different 3D organoid types into a single '4D multi-organ system'. We summarize the advantages of this approach and speculate on the future role of 4D multi-organ systems in human disease modeling. © 2018. Published by The Company of Biologists Ltd.

  17. FFTF scale-model characterization of flow-induced vibrational response of reactor internals

    International Nuclear Information System (INIS)

    Ryan, J.A.; Julyk, L.J.

    1977-01-01

    As an integral part of the Fast Test Reactor Vibration Program for Reactor Internals, the flow-induced vibrational characteristics of scaled Fast Test Reactor core internal and peripheral components were assessed under scaled and simulated prototype flow conditions in the Hydraulic Core Mockup. The Hydraulic Core Mockup, a 0.285 geometric scale model, was designed to model the vibrational and hydraulic characteristics of the Fast Test Reactor. Model component vibrational characteristics were measured and determined over a range of 36 percent to 111 percent of the scaled prototype design flow. Selected model and prototype components were shaker tested to establish modal characteristics. The dynamic response of the Hydraulic Core Mockup components exhibited no anomalous flow-rate dependent or modal characteristics, and prototype response predictions were adjudged acceptable

  18. Phenomenological model for non-equilibrium deuteron emission in nucleon induced reactions

    International Nuclear Information System (INIS)

    Broeders, C.H.M.; Konobeyev, A.Yu.

    2005-01-01

    A new approach is proposed for the calculation of non-equilibrium deuteron energy distributions in nuclear reactions induced by nucleons of intermediate energies. It combines the model of the nucleon pick-up, the coalescence and the deuteron knock-out. Emission and absorption rates for excited particles are described by the pre-equilibrium hybrid model. The model of Sato, Iwamoto, Harada is used to describe the nucleon pick-up and the coalescence of nucleons from the exciton configurations starting from (2p, 1h). The model of deuteron knock-out is formulated taking into account the Pauli principle for the nucleon-deuteron interaction inside a nucleus. The contribution of the direct nucleon pick-up is described phenomenologically. The multiple pre-equilibrium emission of particles is taken into account. The calculated deuteron energy distributions are compared with experimental data from 12 C to 209 Bi. (orig.)

  19. FFTF scale-model characterization of flow induced vibrational response of reactor internals

    Energy Technology Data Exchange (ETDEWEB)

    Ryan, J A; Julyk, L J [Hanford Engineering Development Laboratory, Richland, WA (United States)

    1977-12-01

    As an integral part of the Fast Test Reactor Vibration Program for Reactor Internals, the flow-induced vibrational characteristics of scaled Fast Test Reactor core internal and peripheral components were assessed under scaled and simulated prototype flow conditions in the Hydraulic Core Mockup. The Hydraulic Core Mockup, a 0.285 geometric scale model, was designed to model the vibrational and hydraulic characteristics of the Fast Test Reactor. Model component vibrational characteristics were measured and determined over a range of 36% to 111% of the scaled prototype design flow. Selected model and prototype components were shaker tested to establish modal characteristics. The dynamic response of the Hydraulic Core Mockup components exhibited no anomalous flow-rate dependent or modal characteristics, and prototype response predictions were adjudged acceptable. (author)

  20. FFTF scale-model characterization of flow induced vibrational response of reactor internals

    International Nuclear Information System (INIS)

    Ryan, J.A.; Julyk, L.J.

    1977-01-01

    As an integral part of the Fast Test Reactor Vibration Program for Reactor Internals, the flow-induced vibrational characteristics of scaled Fast Test Reactor core internal and peripheral components were assessed under scaled and simulated prototype flow conditions in the Hydraulic Core Mockup. The Hydraulic Core Mockup, a 0.285 geometric scale model, was designed to model the vibrational and hydraulic characteristics of the Fast Test Reactor. Model component vibrational characteristics were measured and determined over a range of 36% to 111% of the scaled prototype design flow. Selected model and prototype components were shaker tested to establish modal characteristics. The dynamic response of the Hydraulic Core Mockup components exhibited no anomalous flow-rate dependent or modal characteristics, and prototype response predictions were adjudged acceptable. (author)

  1. Softened food reduces weight loss in the streptozotocin-induced male mouse model of diabetic nephropathy.

    Science.gov (United States)

    Nørgaard, Sisse A; Sand, Fredrik W; Sørensen, Dorte B; Abelson, Klas Sp; Søndergaard, Henrik

    2018-01-01

    The streptozotocin (STZ)-induced diabetic mouse is a widely used model of diabetes and diabetic nephropathy (DN). However, it is a well-known issue that this model is challenged by high weight loss, which despite supportive measures often results in high euthanization rates. To overcome these issues, we hypothesized that supplementing STZ-induced diabetic mice with water-softened chow in addition to normal chow would reduce weight loss, lower the need for supportive treatment, and reduce the number of mice reaching the humane endpoint of 20% weight loss. In a 15 week STZ-induced DN study we demonstrated that diabetic male mice receiving softened chow had reduced acute weight loss following STZ treatment ( p = 0.045) and additionally fewer mice were euthanized due to weight loss. By supplementing the diabetic mice with softened chow, no mice reached 20% weight loss whereas 37.5% of the mice without this supplement reached this humane endpoint ( p = 0.0027). Excretion of corticosterone metabolites in faeces was reduced in diabetic mice on softened chow ( p = 0.0007), suggesting lower levels of general stress. Finally, it was demonstrated that the water-softened chow supplement did not significantly affect the induction of key disease parameters, i.e. %HbA1C and albuminuria nor result in abnormal teeth wear. In conclusion, supplementation of softened food is refining the STZ-induced diabetic mouse model significantly by reducing stress, weight loss and the number of animals sacrificed due to humane endpoints, while maintaining the key phenotypes of diabetes and nephropathy.

  2. Cryptosporidium parvum-induced ileo-caecal adenocarcinoma and Wnt signaling in a mouse model

    Directory of Open Access Journals (Sweden)

    Sadia Benamrouz

    2014-06-01

    Full Text Available Cryptosporidium species are apicomplexan protozoans that are found worldwide. These parasites constitute a large risk to human and animal health. They cause self-limited diarrhea in immunocompetent hosts and a life-threatening disease in immunocompromised hosts. Interestingly, Cryptosporidium parvum has been related to digestive carcinogenesis in humans. Consistent with a potential tumorigenic role of this parasite, in an original reproducible animal model of chronic cryptosporidiosis based on dexamethasone-treated or untreated adult SCID mice, we formerly reported that C. parvum (strains of animal and human origin is able to induce digestive adenocarcinoma even in infections induced with very low inoculum. The aim of this study was to further characterize this animal model and to explore metabolic pathways potentially involved in the development of C. parvum-induced ileo-caecal oncogenesis. We searched for alterations in genes or proteins commonly involved in cell cycle, differentiation or cell migration, such as β-catenin, Apc, E-cadherin, Kras and p53. After infection of animals with C. parvum we demonstrated immunohistochemical abnormal localization of Wnt signaling pathway components and p53. Mutations in the selected loci of studied genes were not found after high-throughput sequencing. Furthermore, alterations in the ultrastructure of adherens junctions of the ileo-caecal neoplastic epithelia of C. parvum-infected mice were recorded using transmission electron microscopy. In conclusion, we found for the first time that the Wnt signaling pathway, and particularly the cytoskeleton network, seems to be pivotal for the development of the C. parvum-induced neoplastic process and cell migration of transformed cells. Furthermore, this model is a valuable tool in understanding the host-pathogen interactions associated with the intricate infection process of this parasite, which is able to modulate host cytoskeleton activities and several host

  3. Immunotherapy for choroidal neovascularization in a laser-induced mouse model simulating exudative (wet) macular degeneration

    Science.gov (United States)

    Bora, Puran S.; Hu, Zhiwei; Tezel, Tongalp H.; Sohn, Jeong-Hyeon; Kang, Shin Goo; Cruz, Jose M. C.; Bora, Nalini S.; Garen, Alan; Kaplan, Henry J.

    2003-03-01

    Age-related macular degeneration (AMD) is the leading cause of blindness after age 55 in the industrialized world. Severe loss of central vision frequently occurs with the exudative (wet) form of AMD, as a result of the formation of a pathological choroidal neovasculature (CNV) that damages the macular region of the retina. We tested the effect of an immunotherapy procedure, which had been shown to destroy the pathological neovasculature in solid tumors, on the formation of laser-induced CNV in a mouse model simulating exudative AMD in humans. The procedure involves administering an Icon molecule that binds with high affinity and specificity to tissue factor (TF), resulting in the activation of a potent cytolytic immune response against cells expressing TF. The Icon binds selectively to TF on the vascular endothelium of a CNV in the mouse and pig models and also on the CNV of patients with exudative AMD. Here we show that the Icon dramatically reduces the frequency of CNV formation in the mouse model. After laser treatment to induce CNV formation, the mice were injected either with an adenoviral vector encoding the Icon, resulting in synthesis of the Icon by vector-infected mouse cells, or with the Icon protein. The route of injection was i.v. or intraocular. The efficacy of the Icon in preventing formation of laser-induced CNV depends on binding selectively to the CNV. Because the Icon binds selectively to the CNV in exudative AMD as well as to laser-induced CNV, the Icon might also be efficacious for treating patients with exudative AMD.

  4. Modeling neutrino-induced charged pion production on water at T2K kinematics

    Science.gov (United States)

    Nikolakopoulos, A.; González-Jiménez, R.; Niewczas, K.; Sobczyk, J.; Jachowicz, N.

    2018-05-01

    Pion production is a significant component of the signal in accelerator-based neutrino experiments. Over the last years, the MiniBooNE, T2K, and MINERvA collaborations have reported a substantial amount of data on (anti)neutrino-induced pion production on the nucleus. However, a comprehensive and consistent description of the whole data set is still missing. We aim at improving the current understanding of neutrino-induced pion production on the nucleus. To this end, the comparison of experimental data with theoretical predictions, preferably based on microscopic models, is essential to disentangle the different reaction mechanisms involved in the process. To describe single-pion production, we use a hybrid model that combines low- and a high-energy approaches. The low-energy model contains resonances and background terms. At high invariant masses, a high-energy model based on a Regge approach is employed. The model is implemented in the nucleus using the relativistic plane wave impulse approximation (RPWIA). We present a comparison of the hybrid-RPWIA and low-energy model with the recent neutrino-induced charged-current 1 π+ -production cross section on water reported by T2K. In order to judge the impact of final-state interactions (FSI), we confront our results with those of the nuwro Monte Carlo generator. The hybrid-RPWIA model and nuwro results compare favorably to the data, albeit that FSI are not included in the former. The need of a high-energy model at T2K kinematics is made clear. These results complement our previous work [Phys. Rev. D 97, 013004 (2018), 10.1103/PhysRevD.97.013004], in which we compared the models to the MINERvA and MiniBooNE 1 π+ data. The hybrid-RPWIA model tends to overpredict both the T2K and MINERvA data in kinematic regions where the largest suppression due to FSI is expected and agrees remarkably well with the data in other kinematic regions. On the contrary, the MiniBooNE data are underpredicted over the whole kinematic range.

  5. Predicting musically induced emotions from physiological inputs: linear and neural network models.

    Science.gov (United States)

    Russo, Frank A; Vempala, Naresh N; Sandstrom, Gillian M

    2013-01-01

    Listening to music often leads to physiological responses. Do these physiological responses contain sufficient information to infer emotion induced in the listener? The current study explores this question by attempting to predict judgments of "felt" emotion from physiological responses alone using linear and neural network models. We measured five channels of peripheral physiology from 20 participants-heart rate (HR), respiration, galvanic skin response, and activity in corrugator supercilii and zygomaticus major facial muscles. Using valence and arousal (VA) dimensions, participants rated their felt emotion after listening to each of 12 classical music excerpts. After extracting features from the five channels, we examined their correlation with VA ratings, and then performed multiple linear regression to see if a linear relationship between the physiological responses could account for the ratings. Although linear models predicted a significant amount of variance in arousal ratings, they were unable to do so with valence ratings. We then used a neural network to provide a non-linear account of the ratings. The network was trained on the mean ratings of eight of the 12 excerpts and tested on the remainder. Performance of the neural network confirms that physiological responses alone can be used to predict musically induced emotion. The non-linear model derived from the neural network was more accurate than linear models derived from multiple linear regression, particularly along the valence dimension. A secondary analysis allowed us to quantify the relative contributions of inputs to the non-linear model. The study represents a novel approach to understanding the complex relationship between physiological responses and musically induced emotion.

  6. Predicting musically induced emotions from physiological inputs: Linear and neural network models

    Directory of Open Access Journals (Sweden)

    Frank A. Russo

    2013-08-01

    Full Text Available Listening to music often leads to physiological responses. Do these physiological responses contain sufficient information to infer emotion induced in the listener? The current study explores this question by attempting to predict judgments of 'felt' emotion from physiological responses alone using linear and neural network models. We measured five channels of peripheral physiology from 20 participants – heart rate, respiration, galvanic skin response, and activity in corrugator supercilii and zygomaticus major facial muscles. Using valence and arousal (VA dimensions, participants rated their felt emotion after listening to each of 12 classical music excerpts. After extracting features from the five channels, we examined their correlation with VA ratings, and then performed multiple linear regression to see if a linear relationship between the physiological responses could account for the ratings. Although linear models predicted a significant amount of variance in arousal ratings, they were unable to do so with valence ratings. We then used a neural network to provide a nonlinear account of the ratings. The network was trained on the mean ratings of eight of the 12 excerpts and tested on the remainder. Performance of the neural network confirms that physiological responses alone can be used to predict musically induced emotion. The nonlinear model derived from the neural network was more accurate than linear models derived from multiple linear regression, particularly along the valence dimension. A secondary analysis allowed us to quantify the relative contributions of inputs to the nonlinear model. The study represents a novel approach to understanding the complex relationship between physiological responses and musically induced emotion.

  7. Statistical Analysis and ETAS Modeling of Seismicity Induced by Production of Geothermal Energy from Hydrothermal Systems

    Science.gov (United States)

    Dinske, C.; Langenbruch, C.; Shapiro, S. A.

    2017-12-01

    We investigate seismicity related to hydrothermal systems in Germany and Italy, focussing on temporal changes of seismicity rates. Our analysis was motivated by numerical simulations The modeling of stress changes caused by the injection and production of fluid revealed that seismicity rates decrease on a long-term perspective which is not observed in the considered case studies. We analyze the waiting time distributions of the seismic events in both time domain (inter event times) and fluid volume domain (inter event volume). We find clear indications that the observed seismicity comprises two components: (1) seismicity that is directly triggered by production and re-injection of fluid, i.e. induced events, and (2) seismicity that is triggered by earthquake interactions, i.e. aftershock triggering. In order to better constrain our numerical simulations using the observed induced seismicity we apply catalog declustering to seperate the two components. We use the magnitude-dependent space-time windowing approach introduced by Gardner and Knopoff (1974) and test several published algorithms to calculate the space-time windows. After declustering, we conclude that the different hydrothermal reservoirs show a comparable seismic response to the circulation of fluid and additional triggering by earthquake interactions. The declustered catalogs contain approximately 50 per cent of the number of events in the original catalogs. We then perform ETAS (Epidemic Type Aftershock; Ogata, 1986, 1988) modeling for two reasons. First, we want to know whether the different reservoirs are also comparable regarding earthquake interaction patterns. Second, if we identify systematic patterns, ETAS modeling can contribute to forecast seismicity during production of geothermal energy. We find that stationary ETAS models cannot accurately capture real seismicity rate changes. One reason for this finding is given by the rate of observed induced events which is not constant over time. Hence

  8. Radiation-Induced Leukemia at Doses Relevant to Radiation Therapy: Modeling Mechanisms and Estimating Risks

    Science.gov (United States)

    Shuryak, Igor; Sachs, Rainer K.; Hlatky, Lynn; Mark P. Little; Hahnfeldt, Philip; Brenner, David J.

    2006-01-01

    Because many cancer patients are diagnosed earlier and live longer than in the past, second cancers induced by radiation therapy have become a clinically significant issue. An earlier biologically based model that was designed to estimate risks of high-dose radiation induced solid cancers included initiation of stem cells to a premalignant state, inactivation of stem cells at high radiation doses, and proliferation of stem cells during cellular repopulation after inactivation. This earlier model predicted the risks of solid tumors induced by radiation therapy but overestimated the corresponding leukemia risks. Methods: To extend the model to radiation-induced leukemias, we analyzed in addition to cellular initiation, inactivation, and proliferation a repopulation mechanism specific to the hematopoietic system: long-range migration through the blood stream of hematopoietic stem cells (HSCs) from distant locations. Parameters for the model were derived from HSC biologic data in the literature and from leukemia risks among atomic bomb survivors v^ ho were subjected to much lower radiation doses. Results: Proliferating HSCs that migrate from sites distant from the high-dose region include few preleukemic HSCs, thus decreasing the high-dose leukemia risk. The extended model for leukemia provides risk estimates that are consistent with epidemiologic data for leukemia risk associated with radiation therapy over a wide dose range. For example, when applied to an earlier case-control study of 110000 women undergoing radiotherapy for uterine cancer, the model predicted an excess relative risk (ERR) of 1.9 for leukemia among women who received a large inhomogeneous fractionated external beam dose to the bone marrow (mean = 14.9 Gy), consistent with the measured ERR (2.0, 95% confidence interval [CI] = 0.2 to 6.4; from 3.6 cases expected and 11 cases observed). As a corresponding example for brachytherapy, the predicted ERR of 0.80 among women who received an inhomogeneous low

  9. Development of a flood-induced health risk prediction model for Africa

    Science.gov (United States)

    Lee, D.; Block, P. J.

    2017-12-01

    Globally, many floods occur in developing or tropical regions where the impact on public health is substantial, including death and injury, drinking water, endemic disease, and so on. Although these flood impacts on public health have been investigated, integrated management of floods and flood-induced health risks is technically and institutionally limited. Specifically, while the use of climatic and hydrologic forecasts for disaster management has been highlighted, analogous predictions for forecasting the magnitude and impact of health risks are lacking, as is the infrastructure for health early warning systems, particularly in developing countries. In this study, we develop flood-induced health risk prediction model for African regions using season-ahead flood predictions with climate drivers and a variety of physical and socio-economic information, such as local hazard, exposure, resilience, and health vulnerability indicators. Skillful prediction of flood and flood-induced health risks can contribute to practical pre- and post-disaster responses in both local- and global-scales, and may eventually be integrated into multi-hazard early warning systems for informed advanced planning and management. This is especially attractive for areas with limited observations and/or little capacity to develop flood-induced health risk warning systems.

  10. Effect of curcumin in mice model of vincristine-induced neuropathy.

    Science.gov (United States)

    Babu, Anand; Prasanth, K G; Balaji, Bhaskar

    2015-06-01

    Curcumin exhibits a wide spectrum of biological activities which include neuroprotective, antinociceptive, anti-inflammatory, and antioxidant activity. The present study evaluates the effect of curcumin in vincristine-induced neuropathy in a mice model. Vincristine sulfate (0.1 mg/kg, i.p. for 10 consecutive days) was administered to mice to induce neuropathy. Pain behavior was assessed at different days, i.e., 0, 7, 10, and 14 d. Sciatic nerve total calcium, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), nitric oxide (NO), and lipid peroxidation (LPO) were also estimated after the 14th day of study. Pregabalin (10 mg/kg, p.o.) and curcumin (15, 30, and 60 mg/kg, p.o.) were administered for 14 consecutive days. Curcumin at 60 mg/kg significantly attenuated the vincristine-induced neuropathic pain manifestations in terms of thermal hyperalgesia (p Curcumin at 30 and 60 mg/kg exhibited significant changes (p Curcumin at 30 and 60 mg/kg dose levels significantly attenuated vincristine-induced neuropathy which may be due to its multiple actions including antinociceptive, calcium inhibitory, and antioxidant effect.

  11. A new synthetic granular calcium phosphate compound induces new bone in a sinus lift rabbit model.

    Science.gov (United States)

    Trbakovic, Amela; Hedenqvist, Patricia; Mellgren, Torbjörn; Ley, Cecilia; Hilborn, Jöns; Ossipov, Dmitri; Ekman, Stina; Johansson, Carina B; Jensen-Waern, Marianne; Thor, Andreas

    2018-03-01

    The aim of this study was to investigate if a synthetic granular calcium phosphate compound (CPC) and a composite bisphosphonate-linked hyaluronic acid-calcium phosphate hydrogel (HABP·CaP) induced similar or more amount of bone as bovine mineral in a modified sinus lift rabbit model. Eighteen adult male New Zeeland White rabbits, received randomly one of the two test materials on a random side of the face, and bovine mineral as control on the contralateral side. In a sinus lift, the sinus mucosa was elevated and a titanium mini-implant was placed in the alveolar bone. Augmentation material (CPC, HABP·CaP or bovine bone) was applied in the space around the implant. The rabbits were euthanized three months after surgery and qualitative and histomorphometric evaluation were conducted. Histomorphometric evaluation included three different regions of interest (ROIs) and the bone to implant contact on each installed implant. Qualitative assessment (p = <.05), histomorphometric evaluations (p = < .01), and implant incorporation (p = <.05) showed that CPC and bovine mineral induced similar amount of bone and more than the HABP·CaP hydrogel. CPC induced similar amount of bone as bovine mineral and both materials induced more bone than HABP·CaP hydrogel. The CPC is suggested as a synthetic alternative for augmentations in the maxillofacial area. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Identification of Novel Targets for Lung Cancer Therapy Using an Induced Pluripotent Stem Cell Model.

    Science.gov (United States)

    Shukla, Vivek; Rao, Mahadev; Zhang, Hongen; Beers, Jeanette; Wangsa, Darawalee; Wangsa, Danny; Buishand, Floryne O; Wang, Yonghong; Yu, Zhiya; Stevenson, Holly; Reardon, Emily; McLoughlin, Kaitlin C; Kaufman, Andrew; Payabyab, Eden; Hong, Julie A; Zhang, Mary; Davis, Sean R; Edelman, Daniel C; Chen, Guokai; Miettinen, Markku; Restifo, Nicholas; Ried, Thomas; Meltzer, Paul S; Schrump, David S

    2018-04-01

    small cell lung cancer lines and specimens. Overexpression of the additional sex combs like-3 gene correlated with increased genomic copy number in small cell lung cancer lines. Knock-down of the additional sex combs like-3 gene inhibited proliferation, clonogenicity, and teratoma formation by lung induced pluripotent stem cells and significantly diminished in vitro clonogenicity and growth of small cell lung cancer cells in vivo. Collectively, these studies highlight the potential utility of this lung induced pluripotent stem cell model for elucidating epigenetic mechanisms contributing to pulmonary carcinogenesis and suggest that additional sex combs like-3 is a novel target for small cell lung cancer therapy.

  13. An Overview of GIS-Based Modeling and Assessment of Mining-Induced Hazards: Soil, Water, and Forest.

    Science.gov (United States)

    Suh, Jangwon; Kim, Sung-Min; Yi, Huiuk; Choi, Yosoon

    2017-11-27

    In this study, current geographic information system (GIS)-based methods and their application for the modeling and assessment of mining-induced hazards were reviewed. Various types of mining-induced hazard, including soil contamination, soil erosion, water pollution, and deforestation were considered in the discussion of the strength and role of GIS as a viable problem-solving tool in relation to mining-induced hazards. The various types of mining-induced hazard were classified into two or three subtopics according to the steps involved in the reclamation procedure, or elements of the hazard of interest. Because GIS is appropriated for the handling of geospatial data in relation to mining-induced hazards, the application and feasibility of exploiting GIS-based modeling and assessment of mining-induced hazards within the mining industry could be expanded further.

  14. An Overview of GIS-Based Modeling and Assessment of Mining-Induced Hazards: Soil, Water, and Forest

    Science.gov (United States)

    Kim, Sung-Min; Yi, Huiuk; Choi, Yosoon

    2017-01-01

    In this study, current geographic information system (GIS)-based methods and their application for the modeling and assessment of mining-induced hazards were reviewed. Various types of mining-induced hazard, including soil contamination, soil erosion, water pollution, and deforestation were considered in the discussion of the strength and role of GIS as a viable problem-solving tool in relation to mining-induced hazards. The various types of mining-induced hazard were classified into two or three subtopics according to the steps involved in the reclamation procedure, or elements of the hazard of interest. Because GIS is appropriated for the handling of geospatial data in relation to mining-induced hazards, the application and feasibility of exploiting GIS-based modeling and assessment of mining-induced hazards within the mining industry could be expanded further. PMID:29186922

  15. An Overview of GIS-Based Modeling and Assessment of Mining-Induced Hazards: Soil, Water, and Forest

    Directory of Open Access Journals (Sweden)

    Jangwon Suh

    2017-11-01

    Full Text Available In this study, current geographic information system (GIS-based methods and their application for the modeling and assessment of mining-induced hazards were reviewed. Various types of mining-induced hazard, including soil contamination, soil erosion, water pollution, and deforestation were considered in the discussion of the strength and role of GIS as a viable problem-solving tool in relation to mining-induced hazards. The various types of mining-induced hazard were classified into two or three subtopics according to the steps involved in the reclamation procedure, or elements of the hazard of interest. Because GIS is appropriated for the handling of geospatial data in relation to mining-induced hazards, the application and feasibility of exploiting GIS-based modeling and assessment of mining-induced hazards within the mining industry could be expanded further.

  16. Good Models Gone Bad: Quantifying and Predicting Parameter-Induced Climate Model Simulation Failures

    Science.gov (United States)

    Lucas, D. D.; Klein, R.; Tannahill, J.; Brandon, S.; Covey, C. C.; Domyancic, D.; Ivanova, D. P.

    2012-12-01

    Simulations using IPCC-class climate models are subject to fail or crash for a variety of reasons. Statistical analysis of the failures can yield useful insights to better understand and improve the models. During the course of uncertainty quantification (UQ) ensemble simulations to assess the effects of ocean model parameter uncertainties on climate simulations, we experienced a series of simulation failures of the Parallel Ocean Program (POP2). About 8.5% of our POP2 runs failed for numerical reasons at certain combinations of parameter values. We apply support vector machine (SVM) classification from the fields of pattern recognition and machine learning to quantify and predict the probability of failure as a function of the values of 18 POP2 parameters. The SVM classifiers readily predict POP2 failures in an independent validation ensemble, and are subsequently used to determine the causes of the failures via a global sensitivity analysis. Four parameters related to ocean mixing and viscosity are identified as the major sources of POP2 failures. Our method can be used to improve the robustness of complex scientific models to parameter perturbations and to better steer UQ ensembles. This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344 and was funded by the Uncertainty Quantification Strategic Initiative Laboratory Directed Research and Development Project at LLNL under project tracking code 10-SI-013 (UCRL LLNL-ABS-569112).

  17. Modeling fructose-load-induced hepatic de-novo lipogenesis by model simplification

    Directory of Open Access Journals (Sweden)

    Richard J Allen

    2017-03-01

    Full Text Available Hepatic de-novo lipogenesis is a metabolic process implemented in the pathogenesis of type 2 diabetes. Clinically, the rate of this process can be ascertained by use of labeled acetate and stimulation by fructose administration. A systems pharmacology model of this process is desirable because it facilitates the description, analysis, and prediction of this experiment. Due to the multiple enzymes involved in de-novo lipogenesis, and the limited data, it is desirable to use single functional expressions to encapsulate the flux between multiple enzymes. To accomplish this we developed a novel simplification technique which uses the available information about the properties of the individual enzymes to bound the parameters of a single governing ‘transfer function’. This method should be applicable to any model with linear chains of enzymes that are well stimulated. We validated this approach with computational simulations and analytical justification in a limiting case. Using this technique we generated a simple model of hepatic de-novo lipogenesis in these experimental conditions that matched prior data. This model can be used to assess pharmacological intervention at specific points on this pathway. We have demonstrated this with prospective simulation of acetyl-CoA carboxylase inhibition. This simplification technique suggests how the constituent properties of an enzymatic chain of reactions gives rise to the sensitivity (to substrate of the pathway as a whole.

  18. Modeling fructose-load-induced hepatic de-novo lipogenesis by model simplification.

    Science.gov (United States)

    Allen, Richard J; Musante, Cynthia J

    2017-01-01

    Hepatic de-novo lipogenesis is a metabolic process implemented in the pathogenesis of type 2 diabetes. Clinically, the rate of this process can be ascertained by use of labeled acetate and stimulation by fructose administration. A systems pharmacology model of this process is desirable because it facilitates the description, analysis, and prediction of this experiment. Due to the multiple enzymes involved in de-novo lipogenesis, and the limited data, it is desirable to use single functional expressions to encapsulate the flux between multiple enzymes. To accomplish this we developed a novel simplification technique which uses the available information about the properties of the individual enzymes to bound the parameters of a single governing 'transfer function'. This method should be applicable to any model with linear chains of enzymes that are well stimulated. We validated this approach with computational simulations and analytical justification in a limiting case. Using this technique we generated a simple model of hepatic de-novo lipogenesis in these experimental conditions that matched prior data. This model can be used to assess pharmacological intervention at specific points on this pathway. We have demonstrated this with prospective simulation of acetyl-CoA carboxylase inhibition. This simplification technique suggests how the constituent properties of an enzymatic chain of reactions gives rise to the sensitivity (to substrate) of the pathway as a whole.

  19. Review of analytical models to stream depletion induced by pumping: Guide to model selection

    Science.gov (United States)

    Huang, Ching-Sheng; Yang, Tao; Yeh, Hund-Der

    2018-06-01

    Stream depletion due to groundwater extraction by wells may cause impact on aquatic ecosystem in streams, conflict over water rights, and contamination of water from irrigation wells near polluted streams. A variety of studies have been devoted to addressing the issue of stream depletion, but a fundamental framework for analytical modeling developed from aquifer viewpoint has not yet been found. This review shows key differences in existing models regarding the stream depletion problem and provides some guidelines for choosing a proper analytical model in solving the problem of concern. We introduce commonly used models composed of flow equations, boundary conditions, well representations and stream treatments for confined, unconfined, and leaky aquifers. They are briefly evaluated and classified according to six categories of aquifer type, flow dimension, aquifer domain, stream representation, stream channel geometry, and well type. Finally, we recommend promising analytical approaches that can solve stream depletion problem in reality with aquifer heterogeneity and irregular geometry of stream channel. Several unsolved stream depletion problems are also recommended.

  20. Disease-induced mortality in density-dependent discrete-time S-I-S epidemic models.

    Science.gov (United States)

    Franke, John E; Yakubu, Abdul-Aziz

    2008-12-01

    The dynamics of simple discrete-time epidemic models without disease-induced mortality are typically characterized by global transcritical bifurcation. We prove that in corresponding models with disease-induced mortality a tiny number of infectious individuals can drive an otherwise persistent population to extinction. Our model with disease-induced mortality supports multiple attractors. In addition, we use a Ricker recruitment function in an SIS model and obtained a three component discrete Hopf (Neimark-Sacker) cycle attractor coexisting with a fixed point attractor. The basin boundaries of the coexisting attractors are fractal in nature, and the example exhibits sensitive dependence of the long-term disease dynamics on initial conditions. Furthermore, we show that in contrast to corresponding models without disease-induced mortality, the disease-free state dynamics do not drive the disease dynamics.

  1. Modeling neurodegenerative diseases with patient-derived induced pluripotent cells: Possibilities and challenges.

    Science.gov (United States)

    Poon, Anna; Zhang, Yu; Chandrasekaran, Abinaya; Phanthong, Phetcharat; Schmid, Benjamin; Nielsen, Troels T; Freude, Kristine K

    2017-10-25

    The rising prevalence of progressive neurodegenerative diseases coupled with increasing longevity poses an economic burden at individual and societal levels. There is currently no effective cure for the majority of neurodegenerative diseases and disease-affected tissues from patients have been difficult to obtain for research and drug discovery in pre-clinical settings. While the use of animal models has contributed invaluable mechanistic insights and potential therapeutic targets, the translational value of animal models could be further enhanced when combined with in vitro models derived from patient-specific induced pluripotent stem cells (iPSCs) and isogenic controls generated using CRISPR-Cas9 mediated genome editing. The iPSCs are self-renewable and capable of being differentiated into the cell types affected by the diseases. These in vitro models based on patient-derived iPSCs provide the opportunity to model disease development, uncover novel mechanisms and test potential therapeutics. Here we review findings from iPSC-based modeling of selected neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia and spinocerebellar ataxia. Furthermore, we discuss the possibilities of generating three-dimensional (3D) models using the iPSCs-derived cells and compare their advantages and disadvantages to conventional two-dimensional (2D) models. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Considerations for the optimization of induced white matter injury preclinical models

    Directory of Open Access Journals (Sweden)

    Abdullah Shafique Ahmad

    2015-08-01

    Full Text Available The white matter injury in relation to acute neurologic conditions, especially stroke, has remained obscure until recently. Current advances in the imaging technologies in the field of stroke have confirmed that white matter injury plays an important role in the prognosis of stroke and suggest that white matter protection is essential for functional recovery and post-stroke rehabilitation. However, due to the lack of a reproducible animal model of white matter injury, the pathophysiology and mechanisms of this injury are not well studied. Moreover, producing selective white matter injury in animals, especially in rodents, has proven to be challenging. Problems associated with inducing selective white matter ischemic injury in the rodent derive from differences in the architecture of the brain, most particularly the ratio of white matter to gray matter in rodents compared to humans, the agents used to induce the injury, and the location of the injury. Aging, gender differences, and comorbidities further add to this complexity. This review provides a brief account of the techniques commonly used to induce general white matter injury in animal models (stroke and non-stroke related and highlights relevance, optimization issues, and translational potentials associated with this particular form of injury.

  3. Bilirubin treatment suppresses pulmonary inflammation in a rat model of smoke-induced emphysema.

    Science.gov (United States)

    Wei, Jingjing; Zhao, Hui; Fan, Guoquan; Li, Jianqiang

    2015-09-18

    Cigarette smoking is a significant risk factor for emphysema, which is characterized by airway inflammation and oxidative damage. To assess the capacity of bilirubin to protect against smoke-induced emphysema. Smoking status and bilirubin levels were recorded in 58 patients with chronic obstructive pulmonary diseases (COPD) and 71 non-COPD participants. The impact of smoking on serum bilirubin levels and exogenous bilirubin (20 mg/kg/day) on pulmonary injury was assessed in a rat model of smoking-induced emphysema. At sacrifice lung histology, airway leukocyte accumulation and cytokine and chemokine levels in serum, bronchoalveolar lavage fluid (BALF) and lung were analyzed. Oxidative lipid damage and anti-oxidative components was assessed by measuring malondialdehyde, superoxide dismutase (SOD) activity and glutathione. Total serum bilirubin levels were lower in smokers with or without COPD than non-smoking patients without COPD (P pulmonary injury by suppressing inflammatory cell recruitment and pro-inflammatory cytokine secretion, increasing anti-inflammatory cytokine levels, and anti-oxidant SOD activity in a rat model of smoke-induced emphysema. Copyright © 2015. Published by Elsevier Inc.

  4. Average spectral power changes at the hippocampal electroencephalogram in schizophrenia model induced by ketamine.

    Science.gov (United States)

    Sampaio, Luis Rafael L; Borges, Lucas T N; Silva, Joyse M F; de Andrade, Francisca Roselin O; Barbosa, Talita M; Oliveira, Tatiana Q; Macedo, Danielle; Lima, Ricardo F; Dantas, Leonardo P; Patrocinio, Manoel Cláudio A; do Vale, Otoni C; Vasconcelos, Silvânia M M

    2018-02-01

    The use of ketamine (Ket) as a pharmacological model of schizophrenia is an important tool for understanding the main mechanisms of glutamatergic regulated neural oscillations. Thus, the aim of the current study was to evaluate Ket-induced changes in the average spectral power using the hippocampal quantitative electroencephalography (QEEG). To this end, male Wistar rats were submitted to a stereotactic surgery for the implantation of an electrode in the right hippocampus. After three days, the animals were divided into four groups that were treated for 10 consecutive days with Ket (10, 50, or 100 mg/kg). Brainwaves were captured on the 1st or 10th day, respectively, to acute or repeated treatments. The administration of Ket (10, 50, or 100 mg/kg), compared with controls, induced changes in the hippocampal average spectral power of delta, theta, alpha, gamma low or high waves, after acute or repeated treatments. Therefore, based on the alterations in the average spectral power of hippocampal waves induced by Ket, our findings might provide a basis for the use of hippocampal QEEG in animal models of schizophrenia. © 2017 Société Française de Pharmacologie et de Thérapeutique.

  5. Inhibitory effect of kefiran on ovalbumin-induced lung inflammation in a murine model of asthma.

    Science.gov (United States)

    Kwon, Ok-Kyoung; Ahn, Kyung-Seop; Lee, Mee-Young; Kim, So-Young; Park, Bo-Young; Kim, Mi-Kyoung; Lee, In-Young; Oh, Sei-Ryang; Lee, Hyeong-Kyu

    2008-12-01

    Kefiran is a major component of kefir which is a microbial symbiont mixture that produces jelly-like grains. This study aimed to evaluate the therapeutic availability of kefiran on the ovalbumin-induced asthma mouse model in which airway inflammation and airway hyper-responsiveness were found in the lung. BALB/c mice sensitized and challenged to ovalbumin were treated intra-gastrically with kefiran 1 hour before the ovalbumin challenge. Kefiran significantly suppressed ovalbumin-induced airway hyper-responsiveness (AHR) to inhaled methacholine. Administration of kefiran significantly inhibited the release of both eosinophils and other inflammatory cells into bronchoalveolar lavage (BAL) fluid and lung tissue which was measured by Diff-Quik. Interleukin-4 (IL-4) and interleukin-5 (IL-5) were also reduced to normal levels after administration of kefiran in BAL fluid. Histological studies demonstrate that kefiran substantially inhibited ovalbumin-induced eosinophilia in lung tissue by H&E staining and goblet cell hyperplasia in the airway by PAS staining. Taken above data, kefiran may be useful for the treatment of inflammation of lung tissue and airway hyper-responsiveness in a murine model and may have therapeutic potential for the treatment of allergic bronchial asthma.

  6. Induced Hypothermia Does Not Harm Hemodynamics after Polytrauma: A Porcine Model

    Science.gov (United States)

    Mommsen, Philipp; Pfeifer, Roman; Mohr, Juliane; Ruchholtz, Steffen; Flohé, Sascha; Fröhlich, Matthias; Keibl, Claudia; Seekamp, Andreas; Witte, Ingo

    2015-01-01

    Background. The deterioration of hemodynamics instantly endangers the patients' life after polytrauma. As accidental hypothermia frequently occurs in polytrauma, therapeutic hypothermia still displays an ambivalent role as the impact on the cardiopulmonary function is not yet fully understood. Methods. We have previously established a porcine polytrauma model including blunt chest trauma, penetrating abdominal trauma, and hemorrhagic shock. Therapeutic hypothermia (34°C) was induced for 3 hours. We documented cardiovascular parameters and basic respiratory parameters. Pigs were euthanized after 15.5 hours. Results. Our polytrauma porcine model displayed sufficient trauma impact. Resuscitation showed adequate restoration of hemodynamics. Induced hypothermia had neither harmful nor major positive effects on the animals' hemodynamics. Though heart rate significantly decreased and mixed venous oxygen saturation significantly increased during therapeutic hypothermia. Mean arterial blood pressure, central venous pressure, pulmonary arterial pressure, and wedge pressure showed no significant differences comparing normothermic trauma and hypothermic trauma pigs during hypothermia. Conclusions. Induced hypothermia after polytrauma is feasible. No major harmful effects on hemodynamics were observed. Therapeutic hypothermia revealed hints for tissue protective impact. But the chosen length for therapeutic hypothermia was too short. Nevertheless, therapeutic hypothermia might be a useful tool for intensive care after polytrauma. Future studies should extend therapeutic hypothermia. PMID:26170533

  7. Induced Hypothermia Does Not Harm Hemodynamics after Polytrauma: A Porcine Model

    Directory of Open Access Journals (Sweden)

    Matthias Weuster

    2015-01-01

    Full Text Available Background. The deterioration of hemodynamics instantly endangers the patients’ life after polytrauma. As accidental hypothermia frequently occurs in polytrauma, therapeutic hypothermia still displays an ambivalent role as the impact on the cardiopulmonary function is not yet fully understood. Methods. We have previously established a porcine polytrauma model including blunt chest trauma, penetrating abdominal trauma, and hemorrhagic shock. Therapeutic hypothermia (34°C was induced for 3 hours. We documented cardiovascular parameters and basic respiratory parameters. Pigs were euthanized after 15.5 hours. Results. Our polytrauma porcine model displayed sufficient trauma impact. Resuscitation showed adequate restoration of hemodynamics. Induced hypothermia had neither harmful nor major positive effects on the animals’ hemodynamics. Though heart rate significantly decreased and mixed venous oxygen saturation significantly increased during therapeutic hypothermia. Mean arterial blood pressure, central venous pressure, pulmonary arterial pressure, and wedge pressure showed no significant differences comparing normothermic trauma and hypothermic trauma pigs during hypothermia. Conclusions. Induced hypothermia after polytrauma is feasible. No major harmful effects on hemodynamics were observed. Therapeutic hypothermia revealed hints for tissue protective impact. But the chosen length for therapeutic hypothermia was too short. Nevertheless, therapeutic hypothermia might be a useful tool for intensive care after polytrauma. Future studies should extend therapeutic hypothermia.

  8. Induced Pluripotent Stem Cell Models of Progranulin-Deficient Frontotemporal Dementia Uncover Specific Reversible Neuronal Defects

    Directory of Open Access Journals (Sweden)

    Sandra Almeida

    2012-10-01

    Full Text Available The pathogenic mechanisms of frontotemporal dementia (FTD remain poorly understood. Here we generated multiple induced pluripotent stem cell lines from a control subject, a patient with sporadic FTD, and an FTD patient with a novel heterozygous GRN mutation (progranulin [PGRN] S116X. In neurons and microglia differentiated from PGRN S116X induced pluripotent stem cells, the levels of intracellular and secreted PGRN were reduced, establishing patient-specific cellular models of PGRN haploinsufficiency. Through a systematic screen of inducers of cellular stress, we found that PGRN S116X neurons, but not sporadic FTD neurons, exhibited increased sensitivity to staurosporine and other kinase inhibitors. Moreover, the serine/threonine kinase S6K2, a component of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways, was specifically downregulated in PGRN S116X neurons. Both increased sensitivity to kinase inhibitors and reduced S6K2 were rescued by PGRN expression. Our findings identify cell-autonomous, reversible defects in patient neurons with PGRN deficiency, and provide a compelling model for studying PGRN-dependent pathogenic mechanisms and testing potential therapies.

  9. Temperature-induced changes in lecithin model membranes detected by novel covalent spin-labelled phospholipids.

    Science.gov (United States)

    Stuhne-Sekalec, L; Stanacev, N Z

    1977-02-01

    Several spin-labelled phospholipids carrying covalently bound 5-doxylstearic acid (2-(3-carboxydecyl)-2-hexyl-4,4-dimethyl-3-oxazolidinoxyl) were intercalated in liposomes of saturated and unsaturated lecithins. Temperature-induced changes of these liposomes, detected by the spin-labelled phospholipids, were found to be in agreement with the previously described transitions of hydrocarbon chains of host lecithins detected by different probes and different techniques, establishing that spin-labelled phosopholipids are sensitive probes for the detection of temperature-induced changes in lecithin model membranes. In addition to the detection of already-known transitions in lecithin liposomes, the coexistence of two distinctly different enviroments was observed above the characteristic transition temperature. This phenomenon was tentatively attributed to the influence of the lecithin polar group on the fluidity of fatty acyl chains near the polar group. Combined with other results from the literature, the coexistence of two environments could be associated with the coexistence of two conformational isomers of lecithin, differing in the orientation of the polar head group with respect to the plane of bilayer. These findings have been discussed in view of the present state of knowledge regarding temperature-induced changes in model membranes.

  10. Computational model of dose response for low-LET-induced complex chromosomal aberrations

    International Nuclear Information System (INIS)

    Eidelman, Y.A.; Andreev, S.G.

    2015-01-01

    Experiments with full-colour mFISH chromosome painting have revealed high yield of radiation-induced complex chromosomal aberrations (CAs). The ratio of complex to simple aberrations is dependent on cell type and linear energy transfer. Theoretical analysis has demonstrated that the mechanism of CA formation as a result of interaction between lesions at a surface of chromosome territories does not explain high complexes-to-simples ratio in human lymphocytes. The possible origin of high yields of γ-induced complex CAs was investigated in the present work by computer simulation. CAs were studied on the basis of chromosome structure and dynamics modelling and the hypothesis of CA formation on nuclear centres. The spatial organisation of all chromosomes in a human interphase nucleus was predicted by simulation of mitosis-to-interphase chromosome structure transition. Two scenarios of CA formation were analysed, 'static' (existing in a nucleus prior to irradiation) centres and 'dynamic' (formed in response to irradiation) centres. The modelling results reveal that under certain conditions, both scenarios explain quantitatively the dose-response relationships for both simple and complex γ-induced inter-chromosomal exchanges observed by mFISH chromosome painting in the first post-irradiation mitosis in human lymphocytes. (authors)

  11. Amniotic membrane extract ameliorates benzalkonium chloride-induced dry eye in a murine model.

    Science.gov (United States)

    Xiao, Xinye; Luo, Pingping; Zhao, Hui; Chen, Jingyao; He, Hui; Xu, Yuxue; Lin, Zhirong; Zhou, Yueping; Xu, Jianjiang; Liu, Zuguo

    2013-10-01

    Human amniotic membrane (AM) is avascular but contains various beneficial bioactive factors, its extract (AE) is also effective in treating many ocular surface disorders. In this study, we for the first time evaluated the therapeutic effects of AE on dry eye induced by benzalkonium chloride in a BALB/c mouse model. Topical application of AE (1.5 and 3 μg/eye/day) resulted in significantly longer tear break-up time on Day 3 and 6, lower fluorescein staining scores on Day 3, and lower inflammatory index on Day 6. AE reduced corneal epithelial K10 expression, inflammatory infiltration, and levels of TNF-α, IL-1β and IL-6 in BAC treated mice than that in the control mice. Moreover, decreased TUNEL positive cells in cornea and increased goblet cells in conjunctiva were also observed in AE treated corneas. Finally, AE induced more Ki-67 positive cells in corneal epithelium of dry eye mouse. Taken together, our data provide further support for BAC induced dry eye model as a valuable for dry eye study and suggest a great potential for AE as a therapeutic agent in the clinical treatment of dry eye. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Pharmacological evaluation of NSAID-induced gastropathy as a "Translatable" model of referred visceral hypersensitivity.

    Science.gov (United States)

    Hummel, Michele; Knappenberger, Terri; Reilly, Meghan; Whiteside, Garth T

    2017-09-07

    To evaluate whether non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity. Gastric ulcer pain was induced by the oral administration of indomethacin to male, CD1 mice ( n = 10/group) and then assessed by measuring referred abdominal hypersensitivity to tactile application. A diverse range of pharmacological mechanisms contributing to the pain were subsequently investigated. These mechanisms included: transient receptor potential (TRP), sodium and acid-sensing ion channels (ASICs) as well as opioid receptors and guanylate cyclase C (GC-C). Results showed that two opioids and a GC-C agonist, morphine, asimadoline and linaclotide, respectively, the TRP antagonists, AMG9810 and HC-030031 and the sodium channel blocker, carbamazepine, elicited a dose- and/or time-dependent attenuation of referred visceral hypersensitivity, while the ASIC blocker, amiloride, was ineffective at all doses tested. Together, these findings implicate opioid receptors, GC-C, and sodium and TRP channel activation as possible mechanisms associated with visceral hypersensitivity. More importantly, these findings also validate NSAID-induced gastropathy as a sensitive and clinically predictive mouse model suitable for assessing novel molecules with potential pain-attenuating properties.

  13. [Assessment of anti-tremorogenic drugs--nicotine-induced tail-tremor model].

    Science.gov (United States)

    Suemaru, K; Kawasaki, H; Gomita, Y

    1997-06-01

    The repeated administration of nicotine at small doses, which do not produce whole body tremor or convulsion, causes tremor only in the tail (tail-tremor) of rats. The tremor is accompanied by locomotor hyperactivity without rigidity and immobility of the whole body, suggesting that the nicotine-induced tail-tremor model is useful for studying the mechanism underlying tremor associated with movement. The tail-tremor induced by nicotine was suppressed by mecamylamine, a nicotinic antagonist, but not by atropine or scopolamine, muscalinic antagonists. Moreover, the tail-tremor was suppressed by the beta-blockers propranolol and pindolol, as well as the benzodiazepines diazepam and clonazepam. Tremor at rest is observed only in Parkinson's disease, which is improved with anti-muscalinic drugs. Essential tremor is one of the typical tremors connected with movement (postural and kinetic tremor) and is improved with beta-blocker. These findings and results suggest that nicotine-induced tail-tremor is useful for the study of essential tremor in animal models.

  14. Lessons from Mouse Models of High-Fat Diet-Induced NAFLD

    Directory of Open Access Journals (Sweden)

    Yasuo Terauchi

    2013-10-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD encompasses a clinicopathologic spectrum of diseases ranging from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH, the more aggressive form of fatty liver disease that may progress to cirrhosis and cirrhosis-related complications, including hepatocellular carcinoma. The prevalence of NAFLD, including NASH, is also increasing in parallel with the growing epidemics of obesity and diabetes. However, the causal relationships between obesity and/or diabetes and NASH or liver tumorigenesis have not yet been clearly elucidated. Animal models of NAFLD/NASH provide crucial information, not only for elucidating the pathogenesis of NAFLD/NASH, but also for examining therapeutic effects of various agents. A high-fat diet is widely used to produce hepatic steatosis and NASH in experimental animals. Several studies, including our own, have shown that long-term high-fat diet loading, which can induce obesity and insulin resistance, can also induce NASH and liver tumorigenesis in C57BL/6J mice. In this article, we discuss the pathophysiology of and treatment strategies for NAFLD and subsequent NAFLD-related complications such as NASH and liver tumorigenesis, mainly based on lessons learned from mouse models of high-fat diet-induced NAFLD/NASH.

  15. Aseismic and seismic slip induced by fluid injection from poroelastic and rate-state friction modeling

    Science.gov (United States)

    Liu, Y.; Deng, K.; Harrington, R. M.; Clerc, F.

    2016-12-01

    Solid matrix stress change and pore pressure diffusion caused by fluid injection has been postulated as key factors for inducing earthquakes and aseismic slip on pre-existing faults. In this study, we have developed a numerical model that simulates aseismic and seismic slip in a rate-and-state friction framework with poroelastic stress perturbations from multi-stage hydraulic fracturing scenarios. We apply the physics-based model to the 2013-2015 earthquake sequences near Fox Creek, Alberta, Canada, where three magnitude 4.5 earthquakes were potentially induced by nearby hydraulic fracturing activity. In particular, we use the relocated December 2013 seismicity sequence to approximate the fault orientation, and find the seismicity migration spatiotemporally correlate with the positive Coulomb stress changes calculated from the poroelastic model. When the poroelastic stress changes are introduced to the rate-state friction model, we find that slip on the fault evolves from aseismic to seismic in a manner similar to the onset of seismicity. For a 15-stage hydraulic fracturing that lasted for 10 days, modeled fault slip rate starts to accelerate after 3 days of fracking, and rapidly develops into a seismic event, which also temporally coincides with the onset of induced seismicity. The poroelastic stress perturbation and consequently fault slip rate continue to evolve and remain high for several weeks after hydraulic fracturing has stopped, which may explain the continued seismicity after shut-in. In a comparison numerical experiment, fault slip rate quickly decreases to the interseismic level when stress perturbations are instantaneously returned to zero at shut-in. Furthermore, when stress perturbations are removed just a few hours after the fault slip rate starts to accelerate (that is, hydraulic fracturing is shut down prematurely), only aseismic slip is observed in the model. Our preliminary results thus suggest the design of fracturing duration and flow

  16. Development of an equine groove model to induce metacarpophalangeal osteoarthritis: a pilot study on 6 horses.

    Science.gov (United States)

    Maninchedda, Ugo; Lepage, Olivier M; Gangl, Monika; Hilairet, Sandrine; Remandet, Bernard; Meot, Francoise; Penarier, Geraldine; Segard, Emilie; Cortez, Pierre; Jorgensen, Christian; Steinberg, Régis

    2015-01-01

    The aim of this work was to develop an equine metacarpophalangeal joint model that induces osteoarthritis that is not primarily mediated by instability or inflammation. The study involved six Standardbred horses. Standardized cartilage surface damage or "grooves" were created arthroscopically on the distal dorsal aspect of the lateral and medial metacarpal condyles of a randomly chosen limb. The contralateral limb was sham operated. After 2 weeks of stall rest, horses were trotted 30 minutes every other day for 8 weeks, then evaluated for lameness and radiographed. Synovial fluid was analyzed for cytology and biomarkers. At 10 weeks post-surgery, horses were euthanized for macroscopic and histologic joint evaluation. Arthroscopic grooving allowed precise and identical damage to the cartilage of all animals. Under the controlled exercise regime, this osteoarthritis groove model displayed significant radiographic, macroscopic, and microscopic degenerative and reactive changes. Histology demonstrated consistent surgically induced grooves limited to non-calcified cartilage and accompanied by secondary adjacent cartilage lesions, chondrocyte necrosis, chondrocyte clusters, cartilage matrix softening, fissuring, mild subchondral bone inflammation, edema, and osteoblastic margination. Synovial fluid biochemistry and cytology demonstrated significantly elevated total protein without an increase in prostaglandin E2, neutrophils, or chondrocytes. This equine metacarpophalangeal groove model demonstrated that standardized non-calcified cartilage damage accompanied by exercise triggered altered osteochondral morphology and cartilage degeneration with minimal or inefficient repair and little inflammatory response. This model, if validated, would allow for assessment of disease processes and the effects of therapy.

  17. Modelling geomagnetically induced currents in midlatitude Central Europe using a thin-sheet approach

    Science.gov (United States)

    Bailey, Rachel L.; Halbedl, Thomas S.; Schattauer, Ingrid; Römer, Alexander; Achleitner, Georg; Beggan, Ciaran D.; Wesztergom, Viktor; Egli, Ramon; Leonhardt, Roman

    2017-06-01

    Geomagnetically induced currents (GICs) in power systems, which can lead to transformer damage over the short and the long term, are a result of space weather events and geomagnetic variations. For a long time, only high-latitude areas were considered to be at risk from these currents, but recent studies show that considerable GICs also appear in midlatitude and equatorial countries. In this paper, we present initial results from a GIC model using a thin-sheet approach with detailed surface and subsurface conductivity models to compute the induced geoelectric field. The results are compared to measurements of direct currents in a transformer neutral and show very good agreement for short-period variations such as geomagnetic storms. Long-period signals such as quiet-day diurnal variations are not represented accurately, and we examine the cause of this misfit. The modelling of GICs from regionally varying geoelectric fields is discussed and shown to be an important factor contributing to overall model accuracy. We demonstrate that the Austrian power grid is susceptible to large GICs in the range of tens of amperes, particularly from strong geomagnetic variations in the east-west direction.

  18. Development of an equine groove model to induce metacarpophalangeal osteoarthritis: a pilot study on 6 horses.

    Directory of Open Access Journals (Sweden)

    Ugo Maninchedda

    Full Text Available The aim of this work was to develop an equine metacarpophalangeal joint model that induces osteoarthritis that is not primarily mediated by instability or inflammation. The study involved six Standardbred horses. Standardized cartilage surface damage or "grooves" were created arthroscopically on the distal dorsal aspect of the lateral and medial metacarpal condyles of a randomly chosen limb. The contralateral limb was sham operated. After 2 weeks of stall rest, horses were trotted 30 minutes every other day for 8 weeks, then evaluated for lameness and radiographed. Synovial fluid was analyzed for cytology and biomarkers. At 10 weeks post-surgery, horses were euthanized for macroscopic and histologic joint evaluation. Arthroscopic grooving allowed precise and identical damage to the cartilage of all animals. Under the controlled exercise regime, this osteoarthritis groove model displayed significant radiographic, macroscopic, and microscopic degenerative and reactive changes. Histology demonstrated consistent surgically induced grooves limited to non-calcified cartilage and accompanied by secondary adjacent cartilage lesions, chondrocyte necrosis, chondrocyte clusters, cartilage matrix softening, fissuring, mild subchondral bone inflammation, edema, and osteoblastic margination. Synovial fluid biochemistry and cytology demonstrated significantly elevated total protein without an increase in prostaglandin E2, neutrophils, or chondrocytes. This equine metacarpophalangeal groove model demonstrated that standardized non-calcified cartilage damage accompanied by exercise triggered altered osteochondral morphology and cartilage degeneration with minimal or inefficient repair and little inflammatory response. This model, if validated, would allow for assessment of disease processes and the effects of therapy.

  19. Simple wealth distribution model causing inequality-induced crisis without external shocks

    Science.gov (United States)

    Benisty, Henri

    2017-05-01

    We address the issue of the dynamics of wealth accumulation and economic crisis triggered by extreme inequality, attempting to stick to most possibly intrinsic assumptions. Our general framework is that of pure or modified multiplicative processes, basically geometric Brownian motions. In contrast with the usual approach of injecting into such stochastic agent models either specific, idiosyncratic internal nonlinear interaction patterns or macroscopic disruptive features, we propose a dynamic inequality model where the attainment of a sizable fraction of the total wealth by very few agents induces a crisis regime with strong intermittency, the explicit coupling between the richest and the rest being a mere normalization mechanism, hence with minimal extrinsic assumptions. The model thus harnesses the recognized lack of ergodicity of geometric Brownian motions. It also provides a statistical intuition to the consequences of Thomas Piketty's recent "r >g " (return rate > growth rate) paradigmatic analysis of very-long-term wealth trends. We suggest that the "water-divide" of wealth flow may define effective classes, making an objective entry point to calibrate the model. Consistently, we check that a tax mechanism associated to a few percent relative bias on elementary daily transactions is able to slow or stop the build-up of large wealth. When extreme fluctuations are tamed down to a stationary regime with sizable but steadier inequalities, it should still offer opportunities to study the dynamics of crisis and the inner effective classes induced through external or internal factors.

  20. Spectroscopic evaluation of painted layer structural changes induced by gamma radiation in experimental models

    International Nuclear Information System (INIS)

    Manea, Mihaela M.; Moise, Ioan V.; Virgolici, Marian; Negut, Constantin D.; Barbu, Olimpia-Hinamatsuri; Cutrubinis, Mihalis; Fugaru, Viorel; Stanculescu, Ioana R.; Ponta, Corneliu C.

    2012-01-01

    The degradation of cultural heritage objects by insects and microorganisms is an important issue for conservators, art specialists and humankind in general. Gamma irradiation is an efficient method of polychrome wooden artifacts disinfestation. Color changes and other modifications in the physical chemical properties of materials induced by gamma irradiation are feared by cultural heritage responsible committees and they have to be evaluated objectively and precisely. In this paper FTIR and FT-Raman spectroscopy methods were used to investigate the structural changes in some experimental models of tempera paint layers on wood following 11 kGy gamma irradiation at two dose rates. Radiation chemistry depends on the particular pigment, matrix formed by protein, resin (in case of varnished samples) and water presence. For the majority of painted layer in experimental models very small spectral variations were observed. Small changes in the FTIR spectra were observed for the raw sienna experimental model: for the higher dose rate the egg yolk protein oxidation peaks and the CH stretching bands due to lipids degradation products increased. - Highlights: ► Experimental models of tempera paint layers on wood were γ-irradiated at two dose rates. ► Changes induced by γ-irradiation were evaluated by vibrational spectroscopy. ► Minor spectral variations of painted layer were observed. ► Raw sienna FTIR spectra showed little changes of egg yolk and lipids at higher dose rate. ► Gamma irradiation is recommended for disinfection of painted wooden artifacts.

  1. Centrifuge model tests of rainfall-induced slope failures for the investigation of the initiation conditions

    Science.gov (United States)

    Matziaris, Vasileios; Marshall, Alec; Yu, Hai-Sui

    2015-04-01

    Rainfall-induced landslides are very common natural disasters which cause damage to properties and infrastructure and may result in the loss of human lives. These phenomena often take place in unsaturated soil slopes and are triggered by the saturation of the soil profile, due to rain infiltration, which leads to a loss of shear strength. The aim of this study is to determine rainfall thresholds for the initiation of landslides under different initial conditions. Model tests of rainfall-induced landslides are conducted in the Nottingham Centre for Geomechanics 50g-T geotechnical centrifuge. Initially unsaturated plane-strain slope models made with fine silica sand are prepared at varying densities at 1g and accommodated within a climatic chamber which provides controlled environmental conditions. During the centrifuge flight at 60g, rainfall events of varying intensity and duration are applied to the slope models causing the initiation of slope failure. The impact of soil state properties and rainfall characteristics on the landslide initiation process are discussed. The variation of pore water pressures within the slope before, during and after simulated rainfall events is recorded using miniature pore pressure transducers buried in the soil model. Slope deformation is determined by using a high-speed camera and digital image analysis techniques.

  2. 3-D Forward modeling of Induced Polarization Effects of Transient Electromagnetic Method

    Science.gov (United States)

    Wu, Y.; Ji, Y.; Guan, S.; Li, D.; Wang, A.

    2017-12-01

    In transient electromagnetic (TEM) detection, Induced polarization (IP) effects are so important that they cannot be ignored. The authors simulate the three-dimensional (3-D) induced polarization effects in time-domain directly by applying the finite-difference time-domain method (FDTD) based on Cole-Cole model. Due to the frequency dispersion characteristics of the electrical conductivity, the computations of convolution in the generalized Ohm's law of fractional order system makes the forward modeling particularly complicated. Firstly, we propose a method to approximate the fractional order function of Cole-Cole model using a lower order rational transfer function based on error minimum theory in the frequency domain. In this section, two auxiliary variables are introduced to transform nonlinear least square fitting problem of the fractional order system into a linear programming problem, thus avoiding having to solve a system of equations and nonlinear problems. Secondly, the time-domain expression of Cole-Cole model is obtained by using Inverse Laplace transform. Then, for the calculation of Ohm's law, we propose an e-index auxiliary equation of conductivity to transform the convolution to non-convolution integral; in this section, the trapezoid rule is applied to compute the integral. We then substitute the recursion equation into Maxwell's equations to derive the iterative equations of electromagnetic field using the FDTD method. Finally, we finish the stimulation of 3-D model and evaluate polarization parameters. The results are compared with those obtained from the digital filtering solution of the analytical equation in the homogeneous half space, as well as with the 3-D model results from the auxiliary ordinary differential equation method (ADE). Good agreements are obtained across the three methods. In terms of the 3-D model, the proposed method has higher efficiency and lower memory requirements as execution times and memory usage were reduced by 20

  3. Effects of wave-induced forcing on a circulation model of the North Sea

    Science.gov (United States)

    Staneva, Joanna; Alari, Victor; Breivik, Øyvind; Bidlot, Jean-Raymond; Mogensen, Kristian

    2017-04-01

    The effect of wind waves on water level and currents during two storms in the North Sea is investigated using a high-resolution NEMO model forced with fluxes and fields from a high-resolution wave model. The additional terms accounting for wave-current interaction that are considered in this study are the Stokes-Coriolis force and the sea-state dependent energy and momentum fluxes. The individual and collective role of these processes is quantified and the results are compared with a control run without wave effects as well as against current and water level measurements from coastal stations. We find a better agreement with observations when the circulation model is forced by sea-state dependent fluxes, especially in extreme events. The two extreme events, the storm Christian (25-27 October 2013), and about a month later, the storm Xaver (5-7 December 2013), induce different wave and surge conditions over the North Sea. Including the wave effects in the circulation model for the storm Xaver raises the modelled surge by more than 40 cm compared with the control run in the German Bight area. For the storm Christian, a difference of 20-30 cm in the surge level between the wave-forced and the stand-alone ocean model is found over the whole southern part of the North Sea. Moreover, the modelled vertical velocity profile fits the observations very well when the wave forcing is accounted for. The contribution of wave-induced forcing has been quantified indicating that this represents an important mechanism for improving water level and current predictions.

  4. Honokiol inhibits pathological retinal neovascularization in oxygen-induced retinopathy mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Vavilala, Divya Teja [Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, MO (United States); O’Bryhim, Bliss E. [Department of Ophthalmology, University of Kansas Medical Center, Kansas City, KS (United States); Ponnaluri, V.K. Chaithanya [Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, MO (United States); White, R. Sid; Radel, Jeff [Department of Ophthalmology, University of Kansas Medical Center, Kansas City, KS (United States); Symons, R.C. Andrew [Department of Ophthalmology, University of Kansas Medical Center, Kansas City, KS (United States); Ophthalmology Department, Royal Melbourne Hospital, University of Melbourne, Victoria (Australia); Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Victoria (Australia); Mukherji, Mridul, E-mail: mukherjim@umkc.edu [Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, MO (United States)

    2013-09-06

    Highlights: •Aberrant activation of HIF pathway is the underlying cause of ischemic neovascularization. •Honokiol has better therapeutic index as a HIF inhibitor than digoxin and doxorubicin. •Daily IP injection of honokiol in OIR mouse model reduced retinal neovascularization. •Honokiol also prevents vaso-obliteration, the characteristic feature of the OIR model. •Honokiol enhanced physiological revascularization of the retinal vascular plexuses. -- Abstract: Aberrant activation of the hypoxia inducible factor (HIF) pathway is the underlying cause of retinal neovascularization, one of the most common causes of blindness worldwide. The HIF pathway also plays critical roles during tumor angiogenesis and cancer stem cell transformation. We have recently shown that honokiol is a potent inhibitor of the HIF pathway in a number of cancer and retinal pigment epithelial cell lines. Here we evaluate the safety and efficacy of honokiol, digoxin, and doxorubicin, three recently identified HIF inhibitors from natural sources. Our studies show that honokiol has a better safety to efficacy profile as a HIF inhibitor than digoxin and doxorubicin. Further, we show for the first time that daily intraperitoneal injection of honokiol starting at postnatal day (P) 12 in an oxygen-induced retinopathy (OIR) mouse model significantly reduced retinal neovascularization at P17. Administration of honokiol also prevents the oxygen-induced central retinal vaso-obliteration, characteristic feature of the OIR model. Additionally, honokiol enhanced physiological revascularization of the retinal vascular plexuses. Since honokiol suppresses multiple pathways activated by HIF, in addition to the VEGF signaling, it may provide advantages over current treatments utilizing specific VEGF antagonists for ocular neovascular diseases and cancers.

  5. WARBURG EFFECT AND TRANSLOCATION-INDUCED GENOMIC INSTABILITY: TWO YEAST MODELS FOR CANCER CELLS

    Directory of Open Access Journals (Sweden)

    Valentina eTosato

    2013-01-01

    Full Text Available Yeast has been established as an efficient model system to study biological principles underpinning human health. In this review we focus on yeast models covering two aspects of cancer formation and progression i the activity of pyruvate kinase (PK, which recapitulates metabolic features of cancer cells, including the Warburg effect, and ii Bridge-Induced chromosome Translocation (BIT mimicking genome instability in cancer. Saccharomyces cerevisiae is an excellent model to study cancer cell metabolism, as exponentially growing yeast cells exhibit many metabolic similarities with rapidly proliferating cancer cells. The metabolic reconfiguration includes an increase in glucose uptake and fermentation, at the expense of respiration and oxidative phosphorylation (the Warburg effect, and involves a broad reconfiguration of nucleotide and amino acid metabolism. Both in yeast and humans, the regulation of this process seems to have a central player, pyruvate kinase, which is up-regulated in cancer, and to occur mostly on a post-transcriptional and posttranslational basis. Furthermore, BIT allows to generate selectable translocation-derived recombinants (translocants, between any two desired chromosomal locations, in wild-type yeast strains transformed with a linear DNA cassette carrying a selectable marker flanked by two DNA sequences homologous to different chromosomes. Using the Bridge-Induced Translocation system, targeted non-reciprocal translocations in mitosis are easily inducible. An extensive collection of different yeast translocants exhibiting genome instability and aberrant phenotypes similar to cancer cells has been produced and subjected to analysis. In this review, we hence provide an overview upon two yeast cancer models, and extrapolate general principles for mimicking human disease mechanisms in yeast.

  6. Radiation-induced relief of pain in an animal model with bone invasion from cancer

    International Nuclear Information System (INIS)

    Seong, J.; Kim, J.; Kim, K.H.; Kim, U.J.; Lee, B.W.

    2003-01-01

    In clinic, local radiation is effective for relief of pain from cancer invasion into the bones. This effect is usually observed before the regression of tumor occurs, which implies radiation-induced pain relief by mechanisms other than tumor irradication. In this study, possible mechanisms were explored in animal model system. To establish an animal model, syngeneic hepatocarcinoma, HCa-I was transplanted on femoral periosteum of C3H/HeJ male mice and bone-invasive tumor growth was identified through the histological analysis. Development of tumor-induced pain was assessed by von Frey filament test, acetone test, and radiant heat test. Animals were also irradiated for their tumors. Any change in pain was analyzed by above tests for the quantitative change and by immunohistochemical stain for the expression of molecules such as c-fos, substance P, and calcitonin gene-related peptide (CGRP) in lumbar spinal cord. Cancer invasion into the bone was started from 7th day after transplantation and became evident at day 14. Objective increase of pain in the ipsilateral thigh was observed at day 14 on von Frey filament test and acetone test, while there was no remarkable regression of the tumors. In this model system, local radiation of tumor resulted in decrease in objective pain on von Frey filament test and acetone test. In the immunohistochemical stain for lumbar spinal cord, the expression of substance P and CGRP but not c-fos increased in tumor-bearing animal compared to the control. The expression of these molecules decreased in animals given local radiation. In summary, an animal model system was established for objective pain from cancer invasion into the bones. Local radiation of tumor induced objective pain relief and this effect seems to be mediated not by tumor regression but through altered production of pain-related molecules

  7. Radiation-induced relief of pain in an animal model with bone invasion from cancer

    Energy Technology Data Exchange (ETDEWEB)

    Seong, J; Kim, J; Kim, K H; Kim, U J; Lee, B W [Yonsei University Medical College, (Korea, Republic of)

    2003-07-01

    In clinic, local radiation is effective for relief of pain from cancer invasion into the bones. This effect is usually observed before the regression of tumor occurs, which implies radiation-induced pain relief by mechanisms other than tumor irradication. In this study, possible mechanisms were explored in animal model system. To establish an animal model, syngeneic hepatocarcinoma, HCa-I was transplanted on femoral periosteum of C3H/HeJ male mice and bone-invasive tumor growth was identified through the histological analysis. Development of tumor-induced pain was assessed by von Frey filament test, acetone test, and radiant heat test. Animals were also irradiated for their tumors. Any change in pain was analyzed by above tests for the quantitative change and by immunohistochemical stain for the expression of molecules such as c-fos, substance P, and calcitonin gene-related peptide (CGRP) in lumbar spinal cord. Cancer invasion into the bone was started from 7th day after transplantation and became evident at day 14. Objective increase of pain in the ipsilateral thigh was observed at day 14 on von Frey filament test and acetone test, while there was no remarkable regression of the tumors. In this model system, local radiation of tumor resulted in decrease in objective pain on von Frey filament test and acetone test. In the immunohistochemical stain for lumbar spinal cord, the expression of substance P and CGRP but not c-fos increased in tumor-bearing animal compared to the control. The expression of these molecules decreased in animals given local radiation. In summary, an animal model system was established for objective pain from cancer invasion into the bones. Local radiation of tumor induced objective pain relief and this effect seems to be mediated not by tumor regression but through altered production of pain-related molecules.

  8. A Constitutive Model for Flow-Induced Anisotropic Behavior of Viscoelastic Complex Fluids

    International Nuclear Information System (INIS)

    Zhu, H.; De Kee, D.

    2008-01-01

    Flow-induced structural anisotropy could result when a complex fluid system is removed from equilibrium by means of hydrodynamic forces. In this paper, a general theory is developed to model flow induced anisotropic behavior of complex viscoelastic systems, e.g. polymer solutions/melts and suspensions. The rheological properties are characterized by viscosity and relaxation time tensors. We consider a second-rank tensor as a measure of the microstructure. We consider the effect of the flow on the structural changes: i.e. the evolution of the microstructure tensor is governed by a relaxation-type differential equation. We also propose that the viscosity and the relaxation time tensors depend on the second-rank microstructure tensor. That is as the microstructure tensor changes with the applied rate of deformation, the viscosity and relaxation time tensors evolve accordingly. As an example we consider elongational flow of two complex fluids

  9. Stochastic fluctuation induced the competition between extinction and recurrence in a model of tumor growth

    International Nuclear Information System (INIS)

    Li, Dongxi; Xu, Wei; Sun, Chunyan; Wang, Liang

    2012-01-01

    We investigate the phenomenon that stochastic fluctuation induced the competition between tumor extinction and recurrence in the model of tumor growth derived from the catalytic Michaelis–Menten reaction. We analyze the probability transitions between the extinction state and the state of the stable tumor by the Mean First Extinction Time (MFET) and Mean First Return Time (MFRT). It is found that the positional fluctuations hinder the transition, but the environmental fluctuations, to a certain level, facilitate the tumor extinction. The observed behavior could be used as prior information for the treatment of cancer. -- Highlights: ► Stochastic fluctuation induced the competition between extinction and recurrence. ► The probability transitions are investigated. ► The positional fluctuations hinder the transition. ► The environmental fluctuations, to a certain level, facilitate the tumor extinction. ► The observed behavior can be used as prior information for the treatment of cancer.

  10. Current densities in a pregnant woman model induced by simultaneous ELF electric and magnetic field exposure

    International Nuclear Information System (INIS)

    Cech, R; Leitgeb, N; Pediaditis, M

    2008-01-01

    The pregnant woman model SILVY was studied to ascertain to what extent the electric current densities induced by 50 Hz homogeneous electric and magnetic fields increase in the case of simultaneous exposure. By vectorial addition of the electric current densities, it could be shown that under worst case conditions the basic restrictions recommended by ICNIRP (International Commission on Non-Ionizing Radiation Protection) guidelines are exceeded within the central nervous system (CNS) of the mother, whereas in sole field exposure they are not. However, within the foetus the induced current densities do not comply with basic restrictions, either from single reference-level electric fields or from simultaneous exposure to electric and magnetic fields. Basic limits were considerably exceeded

  11. Annealing of radiation-induced defects in silicon in a simplified phenomenological model

    International Nuclear Information System (INIS)

    Lazanu, S.; Lazanu, I.

    2001-01-01

    The concentration of primary radiation-induced defects has been previously estimated considering both the explicit mechanisms of the primary interaction between the incoming particle and the nuclei of the semiconductor lattice, and the recoil energy partition between ionisation and displacements, in the frame of the Lindhard theory. The primary displacement defects are vacancies and interstitials that are essentially unstable in silicon. They interact via migration, recombination, annihilation or produce other defects. In the present work, the time evolution of the concentration of defects induced by pions in medium and high resistivity silicon for detectors is modelled, after irradiation. In some approximations, the differential equations representing the time evolution processes could be decoupled. The theoretical equations so obtained are solved analytically in some particular cases, with one free parameter, for a wide range of particle fluences and/or for a wide energy range of incident particles, for different temperatures; the corresponding stationary solutions are also presented

  12. Scintigraphic and Endoscopic Evaluation of Radiation-induced Acute Gastrointestinal Syndrome in Micro-pig Model

    International Nuclear Information System (INIS)

    Lee, Seung-Sook; Kim, Kyung-Min; Kim, Jin; Jang, Won-Suk; Lee, Jung-Eun; Kim, Noo-Ri; Lee, Sun-Joo; Kim, Mi-Sook; Ji, Young-Hoon; Cheon, Gi-Jeong; Lim, Sang-Moo

    2007-01-01

    Micro-pig model can be served as a proper substitute for humans in studying acute radiation syndrome following radiation-exposure accidents, especially showing similar clinico-pathologic response of hematopoietic and gastrointestinal (GI) syndrome to human. Among acute GI syndrome induced by radiation, GI motility disturbance has not been studied, however, it would be important in a viewpoint of affecting infectious progression from GI tract. Here, we employed scintigraphy of GI transit time and sequential endoscopic examination and tissue sampling in micropigs followed by abdominal radiation exposure. The specific aims of this study are to evaluate objective evidence of GI motility disturbance by scintigraphic evaluation and to find corresponding clinicoapthologic changes in radiation-induced acute GI syndrome

  13. Antioxidative role of ocular melanin pigment in the model of lens induced uveitis.

    Science.gov (United States)

    Bilgihan, A; Bilgihan, M K; Akata, R F; Aricioğlu, A; Hasanreisoğlu, B

    1995-12-01

    Ocular melanin pigment has antioxidant effect against excess of dispersed light. To investigate whether it has a similar effect in ocular inflammations, we used albino and pigmented guinea pigs and measured retinal glutathione peroxidase activities and lipid peroxide levels (expressed as thiobarbituric acid reactive substances) in a model of lens induced uveitis. Although the increase in the levels of the retinal lipid peroxides were higher in the albino group (204%, p < 0.05), the decrease in the activities of glutathione peroxidase were higher in pigmented guinea pigs (26%, p < 0.005). The results of the study suggest that pigmentless animals are more sensitive to the ocular inflammations, and ocular melanin pigment may act as an endojen antioxidant in lens induced uveitis.

  14. Constitutive Model Of Graded Micro-Structure Obtained Via Strain Induced Phase Transformation

    CERN Document Server

    Ortwein, Rafał

    The literature review has been divided into three main sub-chapters. The first one is concentrated on the general information about stainless steels and their applications. It is important to perform a general overview and get an idea where the results of the present thesis could be applied. Description of all the brands of stainless steels, their microstructures and properties are important, as similar characteristics can be found in the newly created functionally graded structures. The second sub-chapter is an overview of the most important constitutive models and the experimental results for materials that undergo plastic strain induced phase transformation. Finally, the last one is devoted to functionally graded microstructures obtained via strain induced martensitic transformation – the subject of particular importance for the present thesis. As a general note, the literature review is organized mainly in a chronological order. In some cases similar publications or publications of the same Authors were...

  15. Physicians' perception of demand-induced supply in the information age: a latent class model analysis.

    Science.gov (United States)

    Shih, Ya-Chen Tina; Tai-Seale, Ming

    2012-03-01

    This paper introduces a concept called 'demand-induced supply' that reflects the excess supply of services due to an increase in demand initiated by patients. We examine its association with the proportion of information-savvy patients in physicians' practice. Using data from a national representative physician survey, we apply latent class models to analyze this association. Our analyses categorize physicians into three 'types' according to the frequency with which they provided additional medical services at their patients' requests: frequent, occasional, and rare. The proportion of information-savvy patients is significantly and positively correlated with demand-induced supply for the frequent or occasional type, but not among physicians in the rare type. Efforts to contain healthcare costs through utilization control need to recognize the pattern of responses from physicians who treat an increasing number of information-savvy patients. Copyright © 2011 John Wiley & Sons, Ltd.

  16. Development and validation of a dynamic outcome prediction model for paracetamol-induced acute liver failure

    DEFF Research Database (Denmark)

    Bernal, William; Wang, Yanzhong; Maggs, James

    2016-01-01

    : The models developed here show very good discrimination and calibration, confirmed in independent datasets, and suggest that many patients undergoing transplantation based on existing criteria might have survived with medical management alone. The role and indications for emergency liver transplantation......BACKGROUND: Early, accurate prediction of survival is central to management of patients with paracetamol-induced acute liver failure to identify those needing emergency liver transplantation. Current prognostic tools are confounded by recent improvements in outcome independent of emergency liver...... transplantation, and constrained by static binary outcome prediction. We aimed to develop a simple prognostic tool to reflect current outcomes and generate a dynamic updated estimation of risk of death. METHODS: Patients with paracetamol-induced acute liver failure managed at intensive care units in the UK...

  17. Mobile interstitial model and mobile electron model of mechano-induced luminescence in coloured alkali halide crystals

    International Nuclear Information System (INIS)

    Chandra, B.P.; Singh, Seema; Ojha, Bharti; Shrivastava, R.G.

    1996-01-01

    A theoretical study is made on the mobile interstitial and mobile electron models of mechano-induced luminescence in coloured alkali halide crystals. Equations derived indicate that the mechanoluminescence intensity should depend on several factors like strain rate, applied stress, temperature, density of F-centres and volume of crystal. The equations also involve the efficiency and decay time of mechanoluminescence. Results of mobile interstitial and mobile electron models are compared with the experimental observations, which indicated that the latter is more suitable as compared to the former. From the temperature dependence of ML, the energy gaps between the dislocation band and ground state of F-centre is calculated which are 0.08, 0.072 and 0.09 eV for KCl, KBr and NaCl crystals, respectively. The theory predicts that the decay of ML intensity is related to the process of stress relaxation in crystals. (author). 33 refs., 5 figs., 1 tab

  18. Chronic ultraviolet exposure-induced p53 gene alterations in sencar mouse skin carcinogenesis model

    International Nuclear Information System (INIS)

    Tong, Ying; Smith, M.A.; Tucker, S.B.

    1997-01-01

    Alterations of the tumor suppressor gene p53 have been found in ultraviolet radiation (UVR) related human skin cancers and in UVR-induced murine skin tumors. However, links between p53 gene alterations and the stages of carcinogenesis induced by UVR have not been clearly defined. We established a chronic UVR exposure-induced Sencar mouse skin carcinogenesis model to determine the frequency of p53 gene alterations in different stages of carcinogenesis, including UV-exposed skin, papillomas, squamous-cell carcinomas (SCCs), and malignant spindle-cell tumors (SCTs). A high incidence of SCCs and SCTs were found in this model. Positive p53 nuclear staining was found in 10137 (27%) of SCCs and 12124 (50%) of SCTs, but was not detected in normal skin or papillomas. DNA was isolated from 40 paraffin-embedded normal skin, UV-exposed skin, and tumor sections. The p53 gene (exons 5 and 6) was amplified from the sections by using nested polymerase chain reaction (PCR). Subsequent single-strand conformation polymorphism (SSCP) assay and sequencing analysis revealed one point mutation in exon 6 (coden 193, C → A transition) from a UV-exposed skin sample, and seven point mutations in exon 5 (codens 146, 158, 150, 165, and 161, three C → T, two C → A, one C → G, and one A → T transition, respectively) from four SCTs, two SCCs and one UV-exposed skin sample. These experimental results demonstrate that alterations in the p53 gene are frequent events in chronic UV exposure-induced SCCs and later stage SCTs in Sencar mouse skin. 40 refs., 5 figs., 1 tab

  19. Chemotherapy-Induced Apoptosis in a Transgenic Model of Neuroblastoma Proceeds Through p53 Induction

    Directory of Open Access Journals (Sweden)

    Louis Chesler

    2008-11-01

    Full Text Available Chemoresistance in neuroblastoma is a significant issue complicating treatment of this common pediatric solid tumor. MYCN-amplified neuroblastomas are infrequently mutated at p53 and are chemosensitive at diagnosis but acquire p53 mutations and chemoresistance with relapse. Paradoxically, Myc-driven transformation is thought to require apoptotic blockade. We used the TH-MYCN transgenic murine model to examine the role of p53-driven apoptosis on neuroblastoma tumorigenesis and the response to chemotherapy. Tumors formed with high penetrance and low latency in p53-haploinsufficient TH-MYCN mice. Cyclophosphamide (CPM induced a complete remission in p53 wild type TH-MYCN tumors, mirroring the sensitivity of childhood neuroblastoma to this agent. Treated tumors showed a prominent proliferation block, induction of p53 protein, and massive apoptosis proceeding through induction of the Bcl-2 homology domain-3-only proteins PUMA and Bim, leading to the activation of Bax and cleavage of caspase-3 and -9. Apoptosis induced by CPM was reduced in p53-haploinsufficient tumors. Treatment of MYCN-expressing human neuroblastoma cell lines with CPM induced apoptosis that was suppressible by siRNA to p53. Taken together, the results indicate that the p53 pathway plays a significant role in opposing MYCN-driven oncogenesis in a mouse model of neuroblastoma and that basal inactivation of the pathway is achieved in progressing tumors. This, in part, explains the striking sensitivity of such tumors to chemotoxic agents that induce p53-dependent apoptosis and is consistent with clinical observations that therapy-associated mutations in p53 are a likely contributor to the biology of tumors at relapse and secondarily mediate resistance to therapy.

  20. Toward development of an in vitro model of methamphetamine-induced dopamine nerve terminal toxicity.

    Science.gov (United States)

    Kim, S; Westphalen, R; Callahan, B; Hatzidimitriou, G; Yuan, J; Ricaurte, G A

    2000-05-01

    To develop an in vitro model of methamphetamine (METH)-induced dopamine (DA) neurotoxicity, striatal synaptosomes were incubated at 37 degrees C with METH for different periods of time (10-80 min), washed once, then tested for DA transporter function at 37 degrees C. METH produced time- and dose-dependent reductions in the V(max) of DA uptake, without producing any change in K(m). Incubation of synaptosomes with the DA neurotoxins 1-methyl-4-phenyl-pyridinium ion, 6-hydroxydopamine, and amphetamine under similar conditions produced comparable effects. In contrast, incubation with fenfluramine, a serotonin neurotoxin, did not. METH-induced decreases in DA uptake were selective, insofar as striatal glutamate uptake was unaffected. Various DA transporter blockers (cocaine, methylphenidate, and bupropion) afforded complete protection against METH-induced decreases in DA uptake, without producing any effect themselves. METH's effects were also temperature dependent, with greater decreases in DA uptake occurring at higher temperatures. Tests for residual drug revealed small amounts (0.1-0.2 microM) of remaining METH, but kinetic studies indicated that decreases in DA uptake were not likely to be due to METH acting as a competitive inhibitor of DA uptake. Decreases in the V(max) of DA uptake were not accompanied by decreases in B(max) of [(3)H]WIN 35,428 binding, possibly because there is no mechanism for removing damaged DA nerve endings from the in vitro preparation Collectively, these results give good support to the development of a valid in vitro model that may prove helpful for elucidating the mechanisms underlying METH-induced DA neurotoxicity.

  1. Agmatine Improves Cognitive Dysfunction and Prevents Cell Death in a Streptozotocin-Induced Alzheimer Rat Model

    Science.gov (United States)

    Song, Juhyun; Hur, Bo Eun; Bokara, Kiran Kumar; Yang, Wonsuk; Cho, Hyun Jin; Park, Kyung Ah; Lee, Won Taek; Lee, Kyoung Min

    2014-01-01

    Purpose Alzheimer's disease (AD) results in memory impairment and neuronal cell death in the brain. Previous studies demonstrated that intracerebroventricular administration of streptozotocin (STZ) induces pathological and behavioral alterations similar to those observed in AD. Agmatine (Agm) has been shown to exert neuroprotective effects in central nervous system disorders. In this study, we investigated whether Agm treatment could attenuate apoptosis and improve cognitive decline in a STZ-induced Alzheimer rat model. Materials and Methods We studied the effect of Agm on AD pathology using a STZ-induced Alzheimer rat model. For each experiment, rats were given anesthesia (chloral hydrate 300 mg/kg, ip), followed by a single injection of STZ (1.5 mg/kg) bilaterally into each lateral ventricle (5 µL/ventricle). Rats were injected with Agm (100 mg/kg) daily up to two weeks from the surgery day. Results Agm suppressed the accumulation of amyloid beta and enhanced insulin signal transduction in STZ-induced Alzheimer rats [experimetal control (EC) group]. Upon evaluation of cognitive function by Morris water maze testing, significant improvement of learning and memory dysfunction in the STZ-Agm group was observed compared with the EC group. Western blot results revealed significant attenuation of the protein expressions of cleaved caspase-3 and Bax, as well as increases in the protein expressions of Bcl2, PI3K, Nrf2, and γ-glutamyl cysteine synthetase, in the STZ-Agm group. Conclusion Our results showed that Agm is involved in the activation of antioxidant signaling pathways and activation of insulin signal transduction. Accordingly, Agm may be a promising therapeutic agent for improving cognitive decline and attenuating apoptosis in AD. PMID:24719136

  2. Therapeutic effects of topical doxycycline in a benzalkonium chloride-induced mouse dry eye model.

    Science.gov (United States)

    Zhang, Zhen; Yang, Wen-Zhao; Zhu, Zhen-Zhen; Hu, Qian-Qian; Chen, Yan-Feng; He, Hui; Chen, Yong-Xiong; Liu, Zu-Guo

    2014-05-06

    We investigated the therapeutic effects and underlying mechanisms of topical doxycycline in a benzalkonium chloride (BAC)-induced mouse dry eye model. Eye drops containing 0.025%, 0.1% doxycycline or solvent were administered to a BAC-induced dry eye model four times daily. The clinical evaluations, including tear break-up time (BUT), fluorescein staining, inflammatory index, and tear volume, were performed on days 0, 1, 4, 7, and 10. Global specimens were collected on day 10 and processed for immunofluorescent staining, TUNEL, and periodic acid-Schiff assay. The levels of inflammatory mediators in the corneas were determined by real-time PCR. The total and phosphorylated nuclear factor-κB (NF-κB) were detected by Western blot. Both 0.025% and 0.1% doxycycline treatments resulted in increased BUT, lower fluorescein staining scores, and inflammatory index on days 4, 7, and 10, while no significant change in tear volume was observed. The 0.1% doxycycline-treated group showed more improvements in decreasing fluorescein staining scores, increasing Ki-67-positive cells, and decreasing TUNEL- and keratin-10-positive cells than other groups. The mucin-filled goblet cells in conjunctivas were increased, and the expression of CD11b and levels of matrix metalloproteinase-9, IL-1β, IL-6, TNF-α, macrophage inflammatory protein-2, and cytokine-induced neutrophil chemoattractant in corneas were decreased in both doxycycline-treated groups. In addition, doxycycline significantly reduced the phosphorylation of NF-κB activated in the BAC-treated corneas. Topical doxycycline showed clinical improvements and alleviated ocular surface inflammation on BAC-induced mouse dry eye, suggesting a potential as an anti-inflammatory agent in the clinical treatment of dry eye.

  3. Ranitidine reduced levodopa-induced dyskinesia in a rat model of Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Cui G

    2013-12-01

    Full Text Available Guiyun Cui,1,* Xinxin Yang,1,* Xiaoying Wang,2,* Zunsheng Zhang,1 Xuanye Yue,1 Hongjuan Shi,1 Xia Shen11Department of Neurology, 2Department of Ultrasound, the Affiliated Hospital of Xuzhou Medical College, Jiangsu, People’s Republic of China *These authors contributed equally to this workBackground: Chronic administration of levodopa in Parkinson’s disease leads to debilitating involuntary movements, termed levodopa-induced dyskinesia (LID. The pathogenesis of LID is poorly understood. Previous research has shown that histamine H2 receptors are highly expressed in the input (striatum and output (globus pallidus, substantia nigra regions of the basal ganglia, particularly in the GABAergic striatopallidal and striatonigral pathways. Therefore, a histamine H2 receptor antagonist could be used to reduce LID. In the present work, we investigated whether ranitidine has the potential to diminish LID in rats with dyskinesia and explored the underlying mechanisms involved.Methods: A rat model of PD was induced by 6-hydroxydopamine. Valid PD rats were then treated with levodopa (25 mg/kg, intraperitoneally and benserazide (12.5 mg/kg, intraperitoneally for 21 days to induce a rat model of LID. The acute and chronic effects of administration of ranitidine at different doses (5 mg/kg, 10 mg/kg, and 20 mg/kg on abnormal involuntary movements, levodopa-induced rotations, and the forelimb adjusting steps test were investigated in LID rats. The chronic effect of ranitidine (10 mg/kg on the expression of Arc and proenkephalin was also evaluated.Results: Levodopa elicited increased dyskinesia in PD rats. Acute ranitidine treatment had no effect on LID, but chronic ranitidine administration (10 mg/kg, 20 mg/kg reduced LID in rats with dyskinesia. Importantly, levodopa-induced rotations were not affected by chronic treatment with ranitidine. In addition, chronic ranitidine (10 mg/kg, 20 mg/kg significantly improved stepping of the lesioned forepaw. Real

  4. Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease.

    Science.gov (United States)

    Peng, Ruoqi; Sridhar, Sriram; Tyagi, Gaurav; Phillips, Jonathan E; Garrido, Rosario; Harris, Paul; Burns, Lisa; Renteria, Lorena; Woods, John; Chen, Leena; Allard, John; Ravindran, Palanikumar; Bitter, Hans; Liang, Zhenmin; Hogaboam, Cory M; Kitson, Chris; Budd, David C; Fine, Jay S; Bauer, Carla M T; Stevenson, Christopher S

    2013-01-01

    The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF), has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFβ was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease.

  5. Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease.

    Directory of Open Access Journals (Sweden)

    Ruoqi Peng

    Full Text Available The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF, has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFβ was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease.

  6. Fission gas induced deformation model for FRAP-T6 and NSRR irradiated fuel test simulations

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, Takehiko; Sasajima, Hideo; Fuketa, Toyoshi [Japan Atomic Energy Research Inst., Tokai, Ibaraki (Japan). Tokai Research Establishment; Hosoyamada, Ryuji; Mori, Yukihide

    1996-11-01

    Pulse irradiation tests of irradiated fuels under simulated reactivity initiated accidents (RIAs) have been carried out at the Nuclear Safety Research Reactor (NSRR). Larger cladding diameter increase was observed in the irradiated fuel tests than in the previous fresh fuel tests. A fission gas induced cladding deformation model was developed and installed in a fuel behavior analysis code, FRAP-T6. The irradiated fuel tests were analyzed with the model in combination with modified material properties and fuel cracking models. In Test JM-4, where the cladding temperature rose to higher temperatures and grain boundary separation by the pulse irradiation was significant, the fission gas model described the cladding deformation reasonably well. The fuel had relatively flat radial power distribution and the grain boundary gas from the whole radius was calculated to contribute to the deformation. On the other hand, the power density in the irradiated LWR fuel rods in the pulse irradiation tests was remarkably higher at the fuel periphery than the center. A fuel thermal expansion model, GAPCON, which took account of the effect of fuel cracking by the temperature profile, was found to reproduce well the LWR fuel behavior with the fission gas deformation model. This report present details of the models and their NSRR test simulations. (author)

  7. The selection pressures induced non-smooth infectious disease model and bifurcation analysis

    International Nuclear Information System (INIS)

    Qin, Wenjie; Tang, Sanyi

    2014-01-01

    Highlights: • A non-smooth infectious disease model to describe selection pressure is developed. • The effect of selection pressure on infectious disease transmission is addressed. • The key factors which are related to the threshold value are determined. • The stabilities and bifurcations of model have been revealed in more detail. • Strategies for the prevention of emerging infectious disease are proposed. - Abstract: Mathematical models can assist in the design strategies to control emerging infectious disease. This paper deduces a non-smooth infectious disease model induced by selection pressures. Analysis of this model reveals rich dynamics including local, global stability of equilibria and local sliding bifurcations. Model solutions ultimately stabilize at either one real equilibrium or the pseudo-equilibrium on the switching surface of the present model, depending on the threshold value determined by some related parameters. Our main results show that reducing the threshold value to a appropriate level could contribute to the efficacy on prevention and treatment of emerging infectious disease, which indicates that the selection pressures can be beneficial to prevent the emerging infectious disease under medical resource limitation

  8. [Induced thymus aging: radiation model and application perspective for low intensive laser radiation].

    Science.gov (United States)

    Sevost'ianova, N N; Trofimov, A V; Lin'kova, N S; Poliakova, V O; Kvetnoĭ, I M

    2010-01-01

    The influence of gamma-radiation on morphofunctional state of thymus is rather like as natural thymus aging. However gamma-radiation model of thymus aging widely used to investigate geroprotectors has many shortcomings and limitations. Gamma-radiation can induce irreversible changes in thymus very often. These changes are more intensive in comparison with changes, which can be observed at natural thymus aging. Low intensive laser radiation can not destroy structure of thymus and its effects are rather like as natural thymus aging in comparison with gamma-radiation effects. There are many parameters of low intensive laser radiation, which can be changed to improve morphofunctional thymus characteristics in aging model. Using low intensive laser radiation in thymus aging model can be very perspective for investigations of aging immune system.

  9. A macroscopic model to simulate the mechanically induced martensitic transformation in metastable austenitic stainless steels

    International Nuclear Information System (INIS)

    Perdahcıoğlu, E.S.; Geijselaers, H.J.M.

    2012-01-01

    Mechanically induced martensitic transformation and the associated transformation plasticity phenomena in austenitic stainless steels are studied. The mechanisms responsible for the transformation are investigated and put into perspective based on experimental evidence. The stress and strain partitioning into the austenite and martensite phases are formulated using a mean-field homogenization approach. At this intermediate length-scale the average stress in the austenite phase is computed and utilized to compute the mechanical driving force resolved in the material. The amount of transformation and the transformation plasticity is derived as a function of the driving force. The mechanical response of the material is obtained by combining the homogenization and the transformation models. The model is verified by mechanical tests under biaxial loading conditions during which different transformation rates are observed. As a final verification of the model, a bending test is used which manifests the stress-state dependency of the transformation.

  10. Mathematical modeling of calcium waves induced by mechanical stimulation in keratinocytes.

    Directory of Open Access Journals (Sweden)

    Yasuaki Kobayashi

    Full Text Available Recent studies have shown that the behavior of calcium in the epidermis is closely related to the conditions of the skin, especially the differentiation of the epidermal keratinocytes and the permeability barrier function, and therefore a correct understanding of the calcium dynamics is important in explaining epidermal homeostasis. Here we report on experimental observations of in vitro calcium waves in keratinocytes induced by mechanical stimulation, and present a mathematical model that can describe the experimentally observed wave behavior that includes finite-range wave propagation and a ring-shaped pattern. A mechanism of the ring formation hypothesized by our model may be related to similar calcium propagation patterns observed during the wound healing process in the epidermis. We discuss a possible extension of our model that may serve as a tool for investigating the mechanisms of various skin diseases.

  11. LHC signals of radiatively-induced neutrino masses and implications for the Zee-Babu model

    Science.gov (United States)

    Alcaide, Julien; Chala, Mikael; Santamaria, Arcadi

    2018-04-01

    Contrary to the see-saw models, extended Higgs sectors leading to radiatively-induced neutrino masses do require the extra particles to be at the TeV scale. However, these new states have often exotic decays, to which experimental LHC searches performed so far, focused on scalars decaying into pairs of same-sign leptons, are not sensitive. In this paper we show that their experimental signatures can start to be tested with current LHC data if dedicated multi-region analyses correlating different observables are used. We also provide high-accuracy estimations of the complicated Standard Model backgrounds involved. For the case of the Zee-Babu model, we show that regions not yet constrained by neutrino data and low-energy experiments can be already probed, while most of the parameter space could be excluded at the 95% C.L. in a high-luminosity phase of the LHC.

  12. A Simulation Study of the Radiation-Induced Bystander Effect: Modeling with Stochastically Defined Signal Reemission

    Directory of Open Access Journals (Sweden)

    Kohei Sasaki

    2012-01-01

    Full Text Available The radiation-induced bystander effect (RIBE has been experimentally observed for different types of radiation, cell types, and cell culture conditions. However, the behavior of signal transmission between unirradiated and irradiated cells is not well known. In this study, we have developed a new model for RIBE based on the diffusion of soluble factors in cell cultures using a Monte Carlo technique. The model involves the signal emission probability from bystander cells following Poisson statistics. Simulations with this model show that the spatial configuration of the bystander cells agrees well with that of corresponding experiments, where the optimal emission probability is estimated through a large number of simulation runs. It was suggested that the most likely probability falls within 0.63–0.92 for mean number of the emission signals ranging from 1.0 to 2.5.

  13. Modeling induced polarization effects in helicopter time domain electromagnetic data: Synthetic case studies

    DEFF Research Database (Denmark)

    Viezzoli, Andrea; Kaminskiy, Vladislav; Fiandaca, Gianluca

    2017-01-01

    constrained multiparametric inversion was evaluated, including recovery of chargeability distributions from shallow and deep targets based on analysis of induced polarization (IP) effects, simulated in airborne TDEM data. Different scenarios were studied, including chargeable targets associated...... processing and the effect of constraints, and a priori information. We have used a 1D layered earth model approximation and lateral constraints. Synthetic simulations were performed for several models and the corresponding Cole-Cole parameters. The possibility to recover these models by means of laterally...... the airborne electromagnetic is most sensitive (e.g., approximately 1 ms), it is possible to recover deep chargeable targets (to depths more than 130 m) in association with high electrical conductivity and in resistive environments. Furthermore, it was found that the recovery of a deep conductor, masked...

  14. Modelling and Analysis of the Feeding Regimen Induced Entrainment of Hepatocyte Circadian Oscillators Using Petri Nets

    Science.gov (United States)

    Tareen, Samar Hayat Khan; Ahmad, Jamil

    2015-01-01

    Circadian rhythms are certain periodic behaviours exhibited by living organism at different levels, including cellular and system-wide scales. Recent studies have found that the circadian rhythms of several peripheral organs in mammals, such as the liver, are able to entrain their clocks to received signals independent of other system level clocks, in particular when responding to signals generated during feeding. These studies have found SIRT1, PARP1, and HSF1 proteins to be the major influencers of the core CLOCKBMAL1:PER-CRY circadian clock. These entities, along with abstracted feeding induced signals were modelled collectively in this study using Petri Nets. The properties of the model show that the circadian system itself is strongly robust, and is able to continually evolve. The modelled feeding regimens suggest that the usual 3 meals/day and 2 meals/day feeding regimens are beneficial with any more or less meals/day negatively affecting the system. PMID:25789928

  15. Incorporating excitation-induced dephasing into the Maxwell-Bloch numerical modeling of photon echoes

    International Nuclear Information System (INIS)

    Burr, G.W.; Harris, Todd L.; Babbitt, Wm. Randall; Jefferson, C. Michael

    2004-01-01

    We describe the incorporation of excitation-induced dephasing (EID) into the Maxwell-Bloch numerical simulation of photon echoes. At each time step of the usual numerical integration, stochastic frequency jumps of ions--caused by excitation of neighboring ions--is modeled by convolving each Bloch vector with the Bloch vectors of nearby frequency detunings. The width of this convolution kernel follows the instantaneous change in overall population, integrated over the simulated bandwidth. This approach is validated by extensive comparison against published and original experimental results. The enhanced numerical model is then used to investigate the accuracy of experiments designed to extrapolate to the intrinsic dephasing time T 2 from data taken in the presence of EID. Such a modeling capability offers improved understanding of experimental results, and should allow quantitative analysis of engineering tradeoffs in realistic optical coherent transient applications

  16. Novel, high incidence exercise-induced muscle bleeding model in hemophilia B mice

    DEFF Research Database (Denmark)

    Tranholm, M.; Kristensen, Annemarie Thuri; Broberg, M. L.

    2015-01-01

    INTRODUCTION: Muscle hematomas are the second most common complication of hemophilia and insufficient treatment may result in serious and even life-threatening complications. Hemophilic dogs and rats do experience spontaneous muscle bleeding, but currently, no experimental animal model is available...... specifically investigating spontaneous muscle bleeds in a hemophilic setting. AIM: The objective of this study was to develop a model of spontaneous muscle bleeds in hemophilia B mice. We hypothesized that treadmill exercise would induce muscle bleeds in hemophilia B mice but not in normal non-hemophilic mice...... and that treatment with recombinant factor IX (rFIX) before treadmill exercise could prevent the occurrence of pathology. METHODS: A total of 203 mice (123 F9-KO and 80 C57BL/6NTac) were included in three separate studies: (i) the model implementation study investigating the bleeding pattern in hemophilia B mice...

  17. Cardiovascular Disease Modeling Using Patient-Specific Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Atsushi Tanaka

    2015-08-01

    Full Text Available The generation of induced pluripotent stem cells (iPSCs has opened up a new scientific frontier in medicine. This technology has made it possible to obtain pluripotent stem cells from individuals with genetic disorders. Because iPSCs carry the identical genetic anomalies related to those disorders, iPSCs are an ideal platform for medical research. The pathophysiological cellular phenotypes of genetically heritable heart diseases such as arrhythmias and cardiomyopathies, have been modeled on cell culture dishes using disease-specific iPSC-derived cardiomyocytes. These model systems can potentially provide new insights into disease mechanisms and drug discoveries. This review focuses on recent progress in cardiovascular disease modeling using iPSCs, and discusses problems and future perspectives concerning their use.

  18. Modelling and analysis of the feeding regimen induced entrainment of hepatocyte circadian oscillators using petri nets.

    Directory of Open Access Journals (Sweden)

    Samar Hayat Khan Tareen

    Full Text Available Circadian rhythms are certain periodic behaviours exhibited by living organism at different levels, including cellular and system-wide scales. Recent studies have found that the circadian rhythms of several peripheral organs in mammals, such as the liver, are able to entrain their clocks to received signals independent of other system level clocks, in particular when responding to signals generated during feeding. These studies have found SIRT1, PARP1, and HSF1 proteins to be the major influencers of the core CLOCKBMAL1:PER-CRY circadian clock. These entities, along with abstracted feeding induced signals were modelled collectively in this study using Petri Nets. The properties of the model show that the circadian system itself is strongly robust, and is able to continually evolve. The modelled feeding regimens suggest that the usual 3 meals/day and 2 meals/day feeding regimens are beneficial with any more or less meals/day negatively affecting the system.

  19. Comparison of two mathematical models for describing heat-induced cell killing

    International Nuclear Information System (INIS)

    Roti Roti, J.L.; Henle, K.J.

    1980-01-01

    A computer-based minimization algorithm is utilized to obtain the optimum fits of two models to hyperthermic cell killing data. The models chosen are the multitarget, single-hit equation, which is in general use, and the linear-quadratic equation, which has been applied to cell killing by ionizing irradiation but not to heat-induced cell killing. The linear-quadratic equation fits hyperthermic cell killing data as well as the multitarget, single-hit equation. Both parameters of the linear-quadratic equation obey the Arrhenius law, whereas only one of the two parameters of the multitarget, single-hit equation obeys the Arrhenius law. Thus the linear-quadratic function can completely define cell killing as a function of both time and temperature. In addition, the linear-quadratic model will provide a simplified approach to the study of the synergism between heat and X irradiation

  20. Animal models of surgically manipulated flow velocities to study shear stress-induced atherosclerosis.

    Science.gov (United States)

    Winkel, Leah C; Hoogendoorn, Ayla; Xing, Ruoyu; Wentzel, Jolanda J; Van der Heiden, Kim

    2015-07-01

    Atherosclerosis is a chronic inflammatory disease of the arterial tree that develops at predisposed sites, coinciding with locations that are exposed to low or oscillating shear stress. Manipulating flow velocity, and concomitantly shear stress, has proven adequate to promote endothelial activation and subsequent plaque formation in animals. In this article, we will give an overview of the animal models that have been designed to study the causal relationship between shear stress and atherosclerosis by surgically manipulating blood flow velocity profiles. These surgically manipulated models include arteriovenous fistulas, vascular grafts, arterial ligation, and perivascular devices. We review these models of manipulated blood flow velocity from an engineering and biological perspective, focusing on the shear stress profiles they induce and the vascular pathology that is observed. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.